BMJ · Confidential: For Review Only Trial to Re-evaluate Ultrasound in the Treatment of Tibial Fractures (TRUST): A Randomized Clinical Trial Journal: BMJ Manuscript ID BMJ.2016.032767

Confidential: For Review O

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Trial to Re-evaluate Ultrasound in the Treatment of Tibial

Fractures (TRUST): A Randomized Clinical Trial

Journal: BMJ

Manuscript ID BMJ.2016.032767.R1

Article Type: Research

BMJ Journal: BMJ

Date Submitted by the Author: 30-Jun-2016

Complete List of Authors: Busse, Jason; McMaster University, Anesthesia Bhandari, Mohit; Mcmaster University, Surgery Einhorn, Thomas; New York University Langone Medical Center Schemitsch, Emil; University of Western Ontario, Department of Surgery Heckman, James; Dartmouth-Hitchcock Medical Center

Tornetta III, Paul; New York University Langone Medical Center Leung, Kwok-Sui; The Chinese University of Hong Kong, Department of Orthopaedics and Traumatology; Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Translational Medicine Research & Development Center Heels-Ansdell, Diane; McMaster University, Clinical Epidemiology and Biostatistics Makosso-Kallyth, Sun ; McMaster University Della Rocca, Gregory; University of Missouri Health Care Jones, Clifford; Banner University Guyatt, Gordon; McMaster University,

Keywords: Ultrasound, Fracture Healing, Randomized controlled trial

https://mc.manuscriptcentral.com/bmj

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TRUST Supplementary Appendix

TRUST Committees........................................................................................................ 2

TRUST Study Investigators............................................................................................ 3-6

Figure S1: Sensitivity analysis of SF-36 PCS scores using

a non-linear model to impute missing data ………………………….…… 7

Table S1: Patients affected by early trial stoppage ………………….......................... 8

Table S2: SF-36 PCS scores at each follow-up for LIPUS and sham therapy ……… 9

Table S3: HUI-III scores at each follow-up for LIPUS and sham therapy ………….. 10

Table S4: Radiographic healing at each follow-up for LIPUS and sham therapy …… 11

Table S5: Return to work at each follow-up for LIPUS and sham therapy ………….. 12

Table S6: Return to household activities at each follow-up for LIPUS and sham therapy. 13

Table S7: Return to full weight-bearing at each follow-up for LIPUS and sham therapy. 14

Table S8: Return to ≥80% pre-injury function at each follow-up for LIPUS and sham

therapy ……………………………………………………………………….. 15

Table S9: Return to leisure activities at each follow-up for LIPUS and sham therapy … 16

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TRUST Committees

Study Trial Co-Principal Investigators: Jason W. Busse, Mohit Bhandari; Steering

Committee: Mohit Bhandari (Chair), Jason W. Busse, Thomas A. Einhorn, James D. Heckman,

Kwok-Sui Leung, Emil H. Schemitsch, Paul Tornetta III, Stephen D. Walter, Gordon H. Guyatt;

Writing Committee: Jason W. Busse (Chair), Mohit Bhandari (Associate Chair), Thomas A.

Einhorn, Emil Schemitsch, James D. Heckman, Paul Tornetta III, Kwok-Sui Leung, Diane-

Heels-Ansdell, Gregory J. Della Rocca, Clifford B. Jones, Sun M. Kallyth, Gordon H. Guyatt;

Central Adjudication Committee: Mohit Bhandari (Chair), Emil H. Schemitsch, David

Sanders, Yves Laflamme; TRUST Methods Centre Staff: McMaster University, Hamilton,

Ontario: Sheila Sprague, Paula McKay, Kim Madden, Nicole Simunovic, Diane Heels-Ansdell,

Lisa Buckingham, Helena Viveiros, Qi Zhou, Marilyn Swinton.; TRUST Data Safety and

Monitoring Board Members: George A. Tomlinson (Chair), Mark Munro, Rob GHH Nelissen.

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TRUST Study Investigators: Greenville Health System – Kyle J. Jeray, J. Scott Broderick,

Stephanie L. Tanner, Becky Snider.

Orthopaedics of Indianapolis – Dean Maar, Renn Crichlow, Greg Reveal, David Kaehr, Joseph

Baele, Kevin Douglas Scheid, David Brokaw, Tim Weber, Brad Jelen, Matt Edison, Anna Clark

Temple University Hospital – Saqib Rehman, Alyssa A. Schaffer, Asif M. Ilyas, J. Milo

Sewards, Joanne M. Donnelly.

QEII Health Sciences Centre – Chad Coles, Michael Dunbar, David Alexander, David Amirault,

Catherine Coady, Mark Glazebrook, Michael Gross, David Johnston, Ross Leighton, William

Oxner, Gerald Reardon, William Stanish, Glen Richardson, Michael Biddulph, Kelly Trask,

Gwen Dobbin, Shelley MacDonald.

Duke University Medical Center – Steven Olson, Robert Zura, Rachel Reilly, Maria Manson.

University of California, San Francisco/San Francisco General Hospital – Theodore Miclau,

Saam Morshed, Amir Matityahu, Utku Kandemir, Tigist Belaye, Jonathan Kwong.

Vancouver General Hospital – Peter O’Brien, Piotr Blachut, Pierre Guy, Henry Broekhuyse,

Kelly A Lefaivre, Raman Johal, Irene Leung.

Orthopaedic Speciality Associates – Cory A. Collinge, Keith Watson, Derek Dombroski, Tara

Craig.

West Virginia University – David Hubbard, Michelle A Bramer, John France, E. Barry

McDonough, George K. Bal, John P. Lubicky, Brock Lindsey, Robert Santrock, Scott Daffner,

Sheila Rye, Christina Carey, Stacy Skidmore, Nina Clovis.

Rothman Institute – Javad Parvizi, Matt Austin, John A. Abraham, Charlie Getz, James Purtill,

Steven Raikin, Tiffany Morrison, Bora Og.

Emory University – Thomas Moore, George Wright, Allen McDonald, Maria Davila, Lauren

Rabach, Whitney Barnes.

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Cooper University Hospital – Kenneth Graf, Robert Ostrum, David Fuller, Robert Marburger

University of Missouri Health Care - Gregory J. Della Rocca, Brett D. Crist, Yvonne M. Murtha,

David A. Volgas, James P. Stannard, Toni K. Kliewer, Sharon L. Jarrett, Kelly A. Moore,

Kathleen Markley, Angela Ballew, Abigail K. Stidham.

Foothills Medical Centre – Paul Duffy, Robert Korley, Shannon Puloski, Richard Buckley, Kelly

Johnston, Kimberly Carcary, Ross McKercher.

University of Kentucky – Jeffrey Selby, Mauro Giordani, Eric Moghadamian, Daniel D. Primm,

Raymond D. Wright Jr, Brandon Bruce, Justin Perry, Amy Trivette, Regina Mosley, Melinda M.

Dowden-Kruger, Dorothy Ross.

Insall Scott Kelly Institute – Craig S. Radnay, Timothy Reish, Michael Kang, William Long,

Michael Nett, Priya Chadha, Elizabeth H. Jett, Jesie Paniagua.

Florida Orthopaedic Institute – H. Claude Sagi, Anthony Infante, David T. Watson, Daniel

Chan, George Haidukewych, Anjan Shah, Barbara Steverson, Veronica Colon.

Eastern Maine Medical Center – David Carmack, Rajendra Tripathi, F. Parke Oldenburg, Denise

Michaud, Teresa White.

University of South Alabama – Jorge Alonso, Kelley Prutzman.

University of British Columbia/Royal Columbian Hospital/Fraser Health Authority – Trevor

Stone, Kelly Apostle, Dory Boyer, Farhad Moola, Bertrand Perey, Darius Viskontas, H. Michael

Lemke, Robert McCormack, Mauri Zomar, Karyn Moon, Raely Moon, Amber Oatt.

Shrock Orthopaedic Research – Kevin Shrock, Matthew Wells, Natalie Shrock

Denver Health – David Hak, Philip F Stahel, Mark Hammerberg, Cyril Mauffrey, Corey

Henderson, Erin Ross, Douglas Gibula, Hannah Gissel.

University of Virginia – David B. Weiss, David Kahler, Jacquelyn Sedlock, Vasantha Reddi,

Veronica C. Lester-Ballard, Wendy M. Novicoff.

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Pensacola Research Consultants Inc – Eugene Jean Dabezies, Kurt Morrison, Kirby Turnage,

Robert Lurate, Gary Crawley, Donna Lawson, Iris McCants, Anna Brunson, Mary Whitaker,

Stefanie White, Michael Ellis.

Sunnybrook Health Sciences Centre – Hans Kreder, Terry S. Axelrod, Joel A. Finkelstein,

Patrick D.G. Henry, Richard Jenkinson, John J. Murnaghan, Diane Nam, Markku Nousiainen,

Sebastian Rodriguez-Elizalde, Veronica M.R. Wadey, Robin Richards, David Stephen and

Albert Yee, Katrine Milner, Monica Kunz, Melanie MacNevin, Ayushi Dhingra.

London Health Sciences Centre – Abdel-Rahman Lawendy, David Sanders, Christina Tieszer.

Texas Orthopedic Specialists – O. David Taunton Jr., Jason Ahuero, Amber Morgan.

University of Kansas Medical Center – Archie Heddings, John Sojka, Michael Tilley, Sharon

Bradshaw.

Orthopaedic Associates of Michigan – Clifford B. Jones, James R. Ringler, Terrence J. Endres,

Debra L. Sietsema, Jane E. Walker, Susan M. Engerman.

Lahey Hospital and Medical Center – Andrew Marcantonio, Michael S. Kain, John Garfi.

Texas Orthopedics, Sports & Rehabilitation Associates – Christopher M. Danney, Marc DeHart,

Scott Smith, Barbara Bergin, Joel Hurt, Tyler Miller, Todd Curry, Karl Adcock.

Marshall University – Franklin D. Shuler, Amber Simmons.

Southlake Regional Health Centre – Christopher Lindsay, Cleo Rogakou, Pat Gamble, Debbie

Nemtean.

KSF Orthopaedic Center– John P. Seaberg, Derrick Clay, Cameron Wood, Todd Curry, Tyler

Miller

Clinical Research Niagara, Inc. – David Martin, John Song, Robert Josefchak, Paul Robert,

Avril McKenna-Norton, Marnie-Lynn Sennett, Olwen McKenna.

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York Hospital/WellSpan Health – Thomas DiPasquale, Mark Richardson, Paul Muccino,

Adrienne Brandon.

Mission Hospital – H. Michael Frisch, C. Michael LeCroy, Susan Sutherland, Rachel Alosky,

Leslie Elliott, Lynne Hampton, Tracy Nanney, Claudine Cuento, Stephanie Shepard.

Louisiana State University – Melissa Gorman, Peter Krause, Ronald Rooney, Jennifer Perilloux.

Inova Fairfax Hospital – Robert A. Hymes, Cary Schwartzbach, A. Stephen Malekzadeh, Jeff E.

Schulman, Daniel Dziadosz, Laura Thurston, Jihui Li.

Texas Sports Medicine Institute – Michael C. Maier, Tyler Miller, Todd Curry.

Anthony G. Sanzone, MD, Inc – Anthony Sanzone, Kaelin Schickedanz.

Orthopaedic Associates of South Broward, P.A – Steven D. Steinlauf, Richard E. Strain, Daniel

Chan, Warren Grossman, Judy Magnum.

University Orthopaedics Center – Bradley A. Barter, Douglas Roeshot, Thomas Ellis, Edwin

Rogusky, Paula Sensiba, Andrew Marcus, Kenneth Cherry, Sue Jepson, Jennifer Gramley.

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Figure S1: Sensitivity analysis of SF-36 PCS scores using a non-linear model to impute

missing data

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Table S1: Patients affected by early trial stoppage

Follow-up visit

No. of patients

affected by early

stoppage by

study visit

Cumulative no. of

patients affected

by early stoppage

6 week visit 3 3

12 week visit 3 6

18 week visit 3 9

26 week visit 32 41

38 week visit 30 71

52 week visit 2 73

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Table S2: SF-36 PCS scores for LIPUS and sham therapy

Follow-up Visit

Active Sham

N Mean (SD) N Mean (SD)

6 weeks 237 31.8 (8.4) 238 32.0 (7.6)

12 weeks 227 39.4 (8.9) 215 38.6 (9.0)

18 weeks 212 43.5 (9.9) 193 43.6 (9.4)

26 weeks 193 46.6 (9.2) 182 46.3 (8.9)

38 weeks 160 48.4 (8.7) 145 48.4 (8.8)

52 weeks 153 51.0 (7.9) 148 49.3 (8.8)

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Table S3: HUI-III scores at each follow-up for LIPUS and sham therapy

Follow-up Visit

Active Sham

N Mean (SD) N Mean (SD)

6 weeks 237 0.515 (0.253) 238 0.509 (0.255)

12 weeks 227 0.667 (0.240) 215 0.659 (0.244)

18 weeks 212 0.761 (0.225) 193 0.756 (0.239)

26 weeks 194 0.812 (0.201) 182 0.812 (0.212)

38 weeks 160 0.838 (0.194) 144 0.834 (0.192)

52 weeks 153 0.853 (0.190) 149 0.846 (0.192)

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Table S4: Radiographic healing at each follow-up for LIPUS and sham therapy *

Achieved Radiographic Healing, n (%)

Follow-up Visit Active Sham Total

6 weeks 1/238 (0.4) 0/240 (0.0) 1/478 (0.2)

12 weeks 54/225 (24.0) 49/218 (22.5) 103/443 (23.3)

18 weeks 142/214 (66.4) 125/201 (62.2) 267/415 (64.3)

26 weeks 189/213 (88.7) 167/197 (84.8) 356/410 (86.8)

38 weeks 200/205 (97.6) 188/194 (96.9) 388/399 (97.2)

52 weeks 206/209 (98.6) 194/195 (99.5) 400/404 (99.0)

* We included patients affected by early trial stoppage if they achieved radiographic healing

before the trial was terminated

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Table S5: Return to work without limitations at each follow-up for LIPUS and sham

therapy (368 patients were employed prior to their injury) *

Reported Return to Work Without Limitations, n (%)

Active Sham Total

Follow-up Visit

6 weeks 7/171 (4.1) 8/170 (4.7) 15/341 (4.4)

12 weeks 31/166 (18.7) 27/153 (17.6) 58/319 (18.2)

18 weeks 60/160 (37.5) 64/147 (43.5) 124/307 (40.4)

26 weeks 90/153 (58.8) 85/146 (58.2) 175/299 (58.5)

38 weeks 114/149 (76.5) 104/134 (77.6) 218/283 (77.0)

52 weeks 126/149 (84.6) 110/138 (79.7) 236/287 (82.2)

* We included patients affected by early trial stoppage if they reported return to work without

limitations before the trial was terminated

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Table S6: Return to household activities without limitations at each follow-up for LIPUS

and sham therapy *

Reported Return to Household Activities Without Limitations, n (%)

Active Sham Total

Follow-up Visit

6 weeks 6/237 (2.5) 3/238 (1.3) 9/475 (1.9)

12 weeks 32/227 (14.1) 28/215 (13.0) 60/442 (13.6)

18 weeks 68/217 (31.3) 69/196 (35.2) 137/413 (33.2)

26 weeks 102/202 (50.5) 102/193 (52.8) 204/395 (51.6)

38 weeks 128/189 (67.7) 130/171 (76.0) 258/360 (71.7)

52 weeks 157/190 (82.6) 147/185 (79.5) 304/375 (81.1)

* We included patients affected by early trial stoppage if they reported return to household

activities without limitations before the trial was terminated

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Table S7: Return to full weight-bearing at each follow-up for LIPUS and sham therapy *

Achieved Full Weight-Bearing, n (%)

Active Sham Total

Follow-up Visit

6 weeks 82/238 (34.4) 92/240 (38.3) 174/478 (36.4)

12 weeks 188/234 (80.3) 194/229 (84.7) 382/463 (82.5)

18 weeks 224/232 (96.6) 221/226 (97.8) 445/458 (97.2)

26 weeks 233/234 (99.6) 225/227 (99.1) 458/461 (99.3)

38 weeks 234/235 (99.6) 227/227 (100.0) 461/462 (99.8)

52 weeks 234/235 (99.6) 227/227 (100.0) 461/462 (99.8)

* We included patients affected by early trial stoppage if they achieved full weight-bearing


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Table S8: Return to ≥80% pre-injury function at each follow-up for LIPUS and sham

therapy *

Reported ≥80% Pre-injury Function, n (%)

Active Sham Total

Follow-up Visit

6 weeks 40/237 (16.9) 48/238 (20.2) 88/475 (18.5)

12 weeks 100/230 (43.5) 97/221 (43.9) 197/451 (43.7)

18 weeks 156/221 (70.6) 148/208 (71.2) 304/429 (70.9)

26 weeks 181/221 (81.9) 176/209 (84.2) 357/430 (83.0)

38 weeks 197/216 (91.2) 188/204 (92.2) 385/420 (91.7)

52 weeks 206/216 (95.4) 196/209 (93.8) 402/425 (94.6)

* We included patients affected by early trial stoppage if they reported ≥80% pre-injury function


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Table S9: Return to leisure activities without limitations at each follow-up for LIPUS and

sham therapy *

Reported Return to Leisure Activities Without Limitations, n (%)

Active Sham Total

Follow-up Visit

6 weeks 3/237 (1.3) 1/238 (0.4) 4/475 (0.8)

12 weeks 16/226 (7.1) 6/214 (2.8) 22/440 (5.0)

18 weeks 30/214 (14.0) 26/193 (13.5) 56/407 (13.8)

26 weeks 58/199 (29.1) 51/184 (27.7) 109/383 (28.5)

38 weeks 82/174 (47.1) 72/153 (47.1) 154/327 (47.1)

52 weeks 99/175 (56.6) 95/166 (57.2) 194/341 (56.9)

* We included patients affected by early trial stoppage if they reported returning to leisure

activities without limitations before the trial was terminated

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This supplement contains the following items:

1. Original protocol, final protocol, summary of changes.

2. Statistical analysis plan, summary of changes

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Original Protocol, submitted to the Canadian Institutes for Health Research (CIHR)

in September 2006

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nly1. THE NEED FOR A TRIAL

1.1 What is the problem to be addressed? While results of a number of small randomized trials have suggested that therapeutic ultrasound may improve fracture healing, their findings are not definitive, and the therapy remains controversial. We therefore propose a study of 500 patients (450 patients + 50 patients from our Pilot Study) to determine the effect of low-intensity, pulsed ultrasound on functional outcomes following operatively treated tibial shaft fractures in skeletally mature adults at least 18 years of age. This study has the potential to resolve the role of therapeutic ultrasound in healing of the most common long bone fracture, the tibia, an issue that has remained unresolved for over five decades. If therapeutic ultrasound does significantly reduce time spent disabled following tibia fracture the socioeconomic benefits would prove substantial. 1.2 What are the principal research questions to be addressed? The primary objective of the multicentre, randomized controlled trial is:

1. To evaluate the impact of low-intensity, pulsed ultrasound, applied to operatively treated tibial shaft fractures, on functional status as measured by the Physical Summary score of the SF-36.

Secondary objectives of the trial are to assess the impact of therapeutic ultrasound versus placebo on:

1. Functional status as measured by the Health Utilities Index (HUI) Mark II/III. 2. Time to radiographic healing of tibial fractures. 3. Rates of malunion and non-union of tibial fractures. 4. Rates of secondary procedures (operative and non-operative).

1.3 Why is a trial needed now? 1.3.1 Incidence and Burden of Fractures on the Health Care System Of all long-bone fractures, those of the tibia are the most common.1 The National Center for Health Statistics reports an annual incidence of 492 000 fractures of the tibia and fibula per year in the United States.2 Patients with tibial fractures remain in hospital for a total of 569 000 hospital days and incur 825 000 total physician visits per year in the United States.2

Tibial fractures take time to heal – typically, three to six months are required before patients are experiencing minimal pain and have returned to their pre-injury functional status. Since most tibial fractures occur in young people, this disability is associated with substantial loss in productivity. Moreover, tibial fractures are prone to complications.3-6 The lack of a circumferential soft tissue envelope around the bone makes the ends of the bones in tibial fractures more likely to fail to unite (nonunions), a complication that approximately 50 000 North Americans suffer each year.7 Non-unions require surgery to promote fracture healing, associated with its own complications,8,9. Optimal management strategies to best reduce fracture healing time, and minimize complications, remain controversial.

1

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nly1.3.2 Clinical Course of Tibial Shaft Fractures Surgeons currently manage most tibial shaft fractures operatively 10 and radiologic fracture healing has constituted the primary basis for determining outcome following management. Oni and colleagues prospectively followed a cohort of 100 patients with closed tibial shaft fractures.11 They defined healing as callus bridging across the fracture site and reported that 81% of fractures were healed by 20 weeks (5 months), and 96% were healed by 30 weeks (7.5 months). Littenberg and colleagues reported on a pooled analysis of studies examining tibial shaft fractures.12 The authors found that the median time to union (n=1435 patients) was 14.7 weeks (range 12-18 weeks), and the median nonunion rate (n=999 patients) was 1.1% (range 0-13%).12 These results show that tibial fracture healing is a prolonged process. The longer the time to heal, the greater the cost of treatment. Based on results of one trial that found therapeutic ultrasound reduces time to tibia fracture healing by an average of 37 days (placebo = 98 ± 5 days vs. ultrasound = 61 ± 3 days), 13 Heckman and Sarasohn-Khan 1 calculated savings of over $15,000 (US) per tibial fracture managed concurrently with low intensity, pulsed ultrsound. This cost analysis model considered both direct and indirect costs, with substantial savings attributed to earlier return to work. 1.3.3 The Use of Low Intensity Ultrasound to Promote Fracture Healing Historically, on the basis of early animal studies that found therapeutic ultrasound delayed healing and damaged healing bone,14,15 (and despite some contradictory findings 16,17), authorities have considered fracture sites an absolute contraindication to therapeutic ultrasound. More recent work, however, has shown that the intensity of therapeutic ultrasound determines its effect on healing bone. The high intensity (1.0 W/cm2) continuous wave ultrasound applied in earlier animal studies is harmful, 18,19 whereas low intensity pulsed ultrasound (30 mW/cm2) appears to accelerate healing.20,21 Positive findings (i.e. decreased time to fracture healing vs. controls) in animal trials 22,23 and uncontrolled human trials 24,25 have provided further support for the inference that low intensity ultrasound may be beneficial. Mechanisms of beneficial effects may include positive impact on signal transduction (second-messenger activity of chondroblasts and osteoblasts), gene expression, blood flow, tissue modeling and remodeling, and the mechanical attributes of the callus. 14,19 18,20,22

We conducted a survey of orthopaedic surgeons and senior physiotherapy students (77% response rate) and found that beliefs on the role of therapeutic ultrasound in fracture healing remain very divergent, with approximately a quarter of respondents making use of this modality.26 We also surveyed 450 members of the Canadian Orthopedic Trauma Association (60% response rate) and found that 45% of surgeons reported use of bone stimulators for fracture healing, evenly split between low intensity pulsed ultrasound and electrical stimulation.10 Until a large trial is undertaken the utility of therapeutic ultrasound in assisting fracture healing will remain uncertain.27,28

1.4 Give references to any relevant systematic review(s) and discuss the need for your trial in the light of the(se) review(s). 1.4.1 Systematic Review of Therapeutic Ultrasound and Fracture Healing To assess the strongest evidence available, we conducted a systematic review and meta-analysis of relevant randomized controlled trials to determine if low intensity, pulsed ultrasound affects the time to fracture healing.

2

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nly We searched five electronic databases (MEDLINE, EMBASE, The Cochrane Collection, HealthStar, and CINAHL) for trials on ultrasound and fracture healing, in any language, published from 1966 to December 2000. Hand searching of selected journals from 1996 to December 2000, and contact with content experts, facilitated a comprehensive identification of all relevant studies. Trials selected for review met the following criteria: inclusion of skeletally mature patients of either gender with one or more fractures; random allocation of treatments; blinding of both the patient and the assessor(s) of fracture healing; administration of low intensity, pulsed ultrasound to at least one of the treatment groups; assessment of time to fracture healing as determined radiographically by bridging of three or four cortices. Two reviewers independently applied selection criteria to blinded articles, and scored selected articles for methodological quality. Internal validity of each trial was assessed using a 5-point scale that evaluates the quality of trial methodology on the basis of description and appropriateness of randomization and blinding of both patients and clinicians, and assessment of study withdrawals. The search identified 138 potentially eligible studies (Figure 1), of which 6 met our eligibility criteria (Table 1).13,29-33 Four trials found ultrasound reduced time to fracture healing as indicated by plain films, 13,29,32,33 and two reported equivocal results, 30,31. One trial was a re-analysis of previously reported data 29 and two trials, which reported on fractures that had prior operative treatment with an intramedullary nail, appeared to report on a shared data set 30,31. On the basis that ultrasound may have qualitatively different effects on conservatively and surgically managed fractures, we excluded these studies from the pooled analysis. Three trials (158 fractures) proved sufficiently homogeneous for pooling.13,32,33

When pooled, the results from the three studies demonstrated that use of low intensity ultrasound led to significantly shorter time to fracture healing when compared with placebo (weighted mean effect size = 64 days; 95% confidence interval = 10.1 to 118 days).34 Even the pooled analysis included far too few fractures to make inferences concerning rates of delayed union (malunion or non-union). The re-analysis of trials by Cook and colleagues 29 examining the impact of therapeutic ultrasound on tibial and radial shaft fractures (n=111) found that treatment with therapeutic ultrasound resulted in a trend towards a reduced incidence of tibial delayed unions, although this difference did not reach significance except for a subgroup of patients that were either smoking at the time of the study or had been a smoker within the last 10 years (p=0.02).

We recently updated our systematic review to locate any RCTs published from January 2001 to June 2006 that explored the effect of low intensity pulsed ultrasound on tibial shaft fractures managed operatively. We located one trial 35 that randomized 30 operatively managed tibial fractures to either low intensity pulsed ultrasound or a sham device, and found that actively treated fractures healed in an average of 11.5 weeks (±3) versus 20 weeks (±4.4) in the control group (p<0.05). In conclusion, we found evidence from small randomized trials that low intensity ultrasound might significantly reduce the time to fracture healing in non-operatively treated fractures. 34 Of the two small RCTs that address the effect of low-intensity, pulsed ultrasound on healing in operatively managed tibial fractures one suggested a benefit for the procedure,35 the other a trend in favor of control30. No trials have explored the effect of low-intensity, pulsed ultrasound on functional recovery from tibial fractures. Uncertainty about the utilityof ultrasound in tibial fractures remains, and a further large trial is necessary. The reasons follow:

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nly1. Despite the widespread use of low intensity pulsed ultrasound as an adjunct to fracture care,27

there are currently only 2 small trials that explore the effect of low intensity pulsed ultrasound on operatively managed tibia fracture healing,30,35 and these trialsprovide divergent results.

2. Previous trials have focused upon radiographic assessment of fracture healing with little

attention to outcomes of primary importance to patients such as functional status and health-related quality of life.36

3. As indicated by our recent survey, opinions on the role of therapeutic ultrasound in fracture

healing among orthopaedic surgeons and physiotherapists remain divergent.26 We found that 24% of respondents have used therapeutic ultrasound for the promotion of fracture healing, while 76% have “never” done so. Many physiotherapists (21% in our survey) believe therapeutic ultrasound is contraindicated as an adjunct to promote fracture healing, and many orthopaedic surgeons (32.0%) considered that evidence was too limited to make use of this modality.26

1.4.2 Why A Large Randomized Trial is Feasible We have recently completed a large, multi-center, randomized clinical trial of reamed versus non-reamed intramedullary nails in the management of patients with tibial shaft fractures (the eponym for which is SPRINT). This trial involved 23 trauma centers across North America and one site in the Netherlands, and we sucessfully recruited 1339 patients over a period of approximately 5 years. Ten of the trauma centers that have agreed to recruit patients for TRUST were participants in SPRINT (Hamilton Health Sciences-General Site, St. Joseph's Healthcare, Hamilton General Hospital, St. Michael’s Hospital, Sunnybrook Hospital, London Health Sciences Center, New West Orthopaedic & Sport Medicine Centre, University of Buffalo, Wakeforest School of Medicine, North Carolina, and the Greeenville Hospital System, Greenville, South Carolina). These centers’ record of recruitment and excellent adherence to protocol in SPRINT suggests they will be able to recruit patients, adhere to study protocols, follow patients, and provide high quality data for the new trial. Our recent Pilot Study further confirms the feasibility of a large randomized trial (see Summary of Progress). 1.5 How will the results of this trial be used? The results of the trial will guide practice, and will potentially reduce delay in return to function in tibial fracture patients, as well as reduce cost to the health care system. 1.6 Describe any risks to the safety of participants involved in this trial? No complications have been reported in any of the previous trials that have applied low intensity, pulsed ultrasound to fresh fractures. 13,29-33,35 Our Data Safety Monitoring Board (DSMB) will, at regular intervals, review safety data. 2.0 THE PROPOSED STUDY 2.1 What is the proposed trial design? We propose a study of 500 patients (450 patients + 50 patients from our Pilot Study) with operatively treated tibial shaft fractures. Patients will be randomized to active or sham ultrasound

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nlyunits, stratified by fracture type (open or closed) and centre using permuted blocks for centre, and assessed for differences in functional outcomes at 3, 6, 9 and 12 months, and for radiographic fracture healing. Surgeons, patients, outcome assessors and data analysts will be blind to treatment allocation. 2.2 What are the planned trial interventions? 2.2.1 Reduction and Immobilization of Tibial Fractures Surgeons will treat tibial shaft fractures amenable to surgery according to a standardized approach. Briefly, this approach entails: [1] operative management with intramedullary nailing or plating, [2] patients will weight-bear as tolerated as per surgeons discretion, [3] all patients will receive peri-operative antibiotics. By 6 weeks time we will expect all patients to have begun weight-bearing, barring complications. See Appendix A for details on surgical management. Patients will return weekly for the first month, every other week for the second month, monthly until 6 months, and then at 9 and 12 months. Surgeons will recommend weight bearing, as clinically indicated.

2

2.2.2 Low Intensity Pulsed UltrasoundIn order to ensure a standardized signal, each patient will use a newly calibrated Sonic Accelerated Fracture Healing System (SAFHS 2A – Figure 2) manufactured by Smith & Nephew (Memphis, TN). Smith & Nephew have donated all ultrasound units required for this trial. Neither the patient nor the clinician will be able to adjust the ultrasound signal.

To ensure reliable positioning of the SAFHS 2A unit during treatment, the surgeon will insert a retaining and alignment fixture made of molded plastic into a window centered over the anteromedial surface of the cast at the site of the tibial fracture. This fixture will hold the treatment head module in place during the daily 20-minute treatment period, thus ensuring that the patient can effectively administer the treatment. After removal of the felt plug and following the application of a small amount of ultrasonic coupling gel (approximately 5 milliliters) to the surface of the ultrasound head, the patient will position the treatment head module in the window. The main operating unit emits a warning signal if there is not proper coupling to the skin. In addition, the main operating unit contains an integral timer that monitors treatment times and automatically turns the unit off after twenty minutes. A visual and audible signal serves to alert the patient that treatment is complete. The active and placebo devices are identical in every way save the administration of ultrasound, in that they have the same visual, tactile, and auditory signals. 2.3 What are the proposed practical arrangements for allocating participants to trial groups? Visually identical active and sham ultrasound units will be labeled with a unit number at the methods center, and shipped to the participating centers. After patients have provided informed consent, and as close in time to surgery as possible, the patients will be randomized to receive either an active or a placebo-treatment ultrasound device (Figure 2). The research coordinator or resident/fellow will call a 24-hour telephone computer randomization service (toll free number) at the Methods Centre at McMaster University or access an internet-based randomization service and provide information documenting eligibility, unique hospital site code and patient hospital identification number; they will then be provided with a unit number corresponding to either an active or a placebo-treatment ultrasound device. This procedure guarantees concealed

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nlyrandomization. Since patients could have fractures in one or both tibia, we will allocate patients rather than fracture to intervention or control. We will stratify patients according to centre and according to whether they have sustained a closed or open fracture of the tibia. We will randomize in blocks; clinical centres will be unaware of the block size. 2.4 What are the proposed methods for protecting against other sources of bias? The patients (who will be applying their own ultrasound or sham-ultrasound therapy), clinicians, outcome assessors, data analysts, and the site investigator will be unaware of the treatment assignments. This code will be broken only after all radiographic evaluations and reviews and data analysis are complete. Surgical co-intervention, such as a general, neurosurgical or orthopaedic procedure, is likely to confound outcomes. Our standardization of management protocols should limit co-intervention, and we will document the use of drugs that effect the bone, and major additional procedures that patients undergo. 2.5 What are the planned inclusion/exclusion criteria? Eligible patients will include those with radiographically verified tibial fractures presenting to one of twenty-five participating centres. Site investigators/research co-ordinators will enroll patients with the following characteristics: [1] Men or women age over 18 years; [2] Fracture of the tibial shaft with complete anterioposterior and lateral radiographs; [3] Open or closed tibial shaft fracture (Tscherne Grade 0-3, or Gustillo Grade I-IIIb) amenable to operative treatment by intramedullary nail fixation or plating,37,38 as determined by the attending surgeon; [4] Provision of informed consent by the patient; [5] Consent takes place within 14 days of surgical fixation. Patients will be excluded if: [1] Circumferential, open wound that precludes placement of ultrasound at fracture site; [2] General wound care the precludes ultrasound-skin contact (e.g. bandaging); [3] Fracture associated with a nerve or vascular injury requiring repair (Gustilo Grade IIIc injuries); [4] Pathologic fractures (defined as chronic infection, chronic osteomyelitis, etc.); [5] Bilateral fractures; [6] A concomitant lower limb injury which, in the opinion of the attending surgeon, is likely to impair function for over 6-months; [7] Tibial fractures that extend into the joint and require reduction; [8] Multiple traumas that are likely to compromise the patient’s mobilization for as long as or longer than the patient’s tibial fracture; [9] Surgical delay of > 2 weeks from time of injury for closed fractures; [10] Surgical delay of 12 hours from time of injury for open fractures; [11] They state that they cannot comply with the study protocol; [12] There are likely to be problems, in the judgment of the Investigator or Research Coordinator, with maintaining follow-up (such as no fixed address, plans to move out of town in the next year, or those with language difficulties that would impede the valid completion of questionnaires); [13] Already making use of therapeutic ultrasound at the fracture site; [14] Participation in a competing study. 2.5.1 Eligibility Review and Central Adjudication Committee We will register all patients who meet the eligibility criteria and document reasons for failure to randomize. A Central Adjudication Committee (CAC), blinded to allocation, will review the initial radiographs and eligibility forms from all randomized patients to ensure that they met eligibility criteria. Patients will only be ruled ineligible if the grounds for ineligibility were known at the time of randomization. The CAC will include the Study Biostatistician (SW), the

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nlyNominated Principal Investigator (GHG), Co-Principal investigator (MB), the Co-Investigator (JWB), and two additional orthopaedic surgeons with expertise in fracture care (EHS, DS). 2.6 What is the proposed duration of treatment period? Treatment with either the active or placebo ultrasound unit will begin within seven days after the fracture and consist of one twenty-minute period per fracture each day. Treatment will continue for thirty weeks as per protocol or until the site investigator concludes that the fracture is healed sufficiently to discontinue therapy (see RUST protocol for assessment of fracture healing – Table 2). All patients will return for follow-up radiographs as per standard care: weekly for the first month, bi-weekly for the second month, monthly until the 6 month period, and then the 9 and 12 month period after the fracture. Anteroposterior and lateral radiographs will be standardized whenever possible, with use of the same x-ray machine at each site and the same exposure settings. 2.7 What is the proposed frequency and duration of follow-up? Patients will be assessed by the blinded research coordinator at discharge, at 3, 6, 9 months, and at 1 year (Figure 3). 2.8 What are the proposed primary and secondary outcome measures? 2.8.1 Primary Outcome Measures for the Trial In section 1.4.2, we have described the primary outcome measure for the proposed trial is Return of Function as measured by the Physical Summary Score of the SF-36 39-41 . The primary outcome measure will be assessed by self-administered questionnaires which the Research Coordinator will supervise at discharge, at 3, 6, 9 months, and at 1 year following surgery. The Research Coordinator is available to answer questions, review questionnaires, and point out missing answers or apparently bizarre answers that suggest misunderstanding, and try to ensure accurate answers. All Research Coordinators will undergo training in the optimal supervision of the SF-36 with one individual at the McMaster Methods Centre with extensive experience and formal training with this instrument. 2.8.2 Secondary Outcome Measures for the Trial – Functional Status We will document when previously working patients return to work, when patients report they return to normal function, and when they achieve a pre-specified level of activity that they consider an acceptable outcome. We will also administer the HUI (the Health Utilities Index Mark II/III) as additional measures of patient function. The HUI is a validated generic utility measure will be administered along with the SF-36 42-44. 2.8.3 Secondary Outcome Measures for the Trial – Radiological We will determine time (in days) to a healed fracture, as judged on radiography as bridging of four cortices. On each radiographic evaluation at each time-point (Figure 3) four cortices (two on the anteroposterior radiograph and two on the lateral radiograph) will be evaluated for cortical bridging. We will also record rates of malunion and non-union of tibial fractures, and rates of secondary procedures.

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nly2.9 How will the outcome measures be measured at follow-up? The CAC will independently adjudicate fracture healing, and rates of malunion and non-union and all secondary procedures from radiographs and clinical notes. The CAC will be blinded to treatment allocation. We have previously evaluated the reliability of surgeons’ assessment of fracture healing utilizing cortices bridged by fracture callus (Table 3).45 Good reliability was achieved utilizing this method (weighted Kappa = 0.75, 95%CI 0.61-0.89). Additionally, fracture healing will be assessed utilizing a radiographic scoring method based upon the assessment of cortical bridging that has shown excellent reliability among residents, community surgeons and traumatologists (Table 3). 2.10 Will health services research issues be measured at follow up? An responsive, valid, appropriate instrument to measure the key potential effect of ultrasound, more rapid return to optimal function, is available. The SF-36 is a widely accepted, well-validated functional status measure that was developed from the Medical Outcomes Study. It is a self-administered, 36-item questionnaire that measures health-related quality of life in eight domains:1) physical functioning, by measuring the ability to perform a variety of daily activities and tasks that require physical effort (10 items); 2) role limitations due to physical problems (4 items); 3) role limitations due to emotional problems (3 items); 4) vitality, measuring perceived level of energy and fatigue (4 items); 5) freedom from bodily pain (2 items); 6)social functioning (2 items); 7) mental health, by measuring both negative and positive emotional states (5 items); and 8)general health perceptions (6 items). Both physical and mental summary scores can be obtained. Each domain is scored separately from 0 (lowest level) to 100 (highest level). The instrument has demonstrated good construct validity, high internal consistency, and high test- retest reliability. In a previous study, we have shown that the SF-36 Physical Summary Score is responsive to improvement in functional recovery in patients with ankle fractures over the period of one year (Table 4).36

Including an economic analysis in the current proposal will substantially increase the resources requirements. To ensure the future feasibility of an economic analysis, we are currently collecting patient utilities utilizing the HUI-markII/III42-44 and developing a proposal for additional funds to conduct a full economic analysis. 2.11 What are the proposed practical arrangements for allocating patients to trials groups? (See Section 2.3) 2.12 What is the proposed sample size? 2.12.1 Sample Size for the Trial Our choice of sample size is based upon the primary outcome, patient-important gains in functional status as measured by the Physical Summary score of the SF-36. All statistical hypotheses will be two-sided. The alpha level for comparisons of the main outcome measurement will be 0.05 for the primary and 0.01 for the secondary outcomes. The trial will be designed to have a statistical power of 80% for the primary comparison. The smallest important difference in the SF-36 is not well-established, and investigators have provided different estimates; however, a 3 to 5 point change in score on a 0 to 100 scale is often cited as a clinically meaningful threshold in evaluating patient changes, based on the work by Stewart and colleagues.46 More recent work by other authors have suggested that the smallest important difference is larger than 3 to 5 points,47-50 and a recent systematic review suggested

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nlyfound that the threshold of discrimination for changes in the SF-36 are approximately half a standard deviation 51. Normative data from the Oxford Healthy Lifestyle Survey III reported standard deviations of Role Physical, Physical Functioning, and Summary Physical scores for the SF-36 ranging from 6.7 to 28.9, depending on age and occupational category.52 Based on our previous study of Health Related Quality of Life in patients with distal tibial fractures, we anticipate a standard deviation of approximately 12 to 14 for Summary Physical scores.36 Considering these findings (Table 5) a study of 500 patients, 250 per arm, will be adequate to identify a patient-important difference in absolute SF-36 scores across a plausible range in the magnitude of the standard deviation. For our sample size calculations, we have used low estimates of the minimal important difference, 3 to 5, which makes our calculation conservative. 2.13 What is the planned recruitment rate? During the past 6 months we have enrolled 30 eligible patients for our TRUST pilot study with the assistance of 4 Canadian centres (see Progress Summary), which equates to a recruitment rate of 1.25 patients/month/centre. Our decision to expand our eligibility criteria for the definitive trial provides us with good assurances that we can expect to increase this rate to at least 1.5 patients/centre/month. At this rate we will require the participation of 25 centres to meet our recruitment target in 12 months. 2.14 Are there likely to be any problems with compliance? All previous randomized trials of therapeutic ultrasound treatment of fractures have reported full compliance;13,29-33 Use of the SAFHS 2A device is to be measured by both a timer inside the main operating unit and a patient-maintained daily treatment log. Research coordinators will review patient’s treatment journals and access the timer at follow-up visits to monitor compliance during the trial. Data from our Pilot Study has found that this strategy leads to excellent compliance (96%). 2.15 What is the likely rate of loss to follow-up? All previous randomized trials on treatment of fractures with therapeutic ultrasound have reported very high rates of follow-up.13,28-32 In the current trial, we will implement the following measures to enhance the likelihood of complete follow-up: [1] We will exclude individuals who are likely to present problems in with follow-up (see exclusion criteria); [2] At the time of randomization, as well as their own address and phone number, each patient will provide the name and address of their primary care physician, and the name, address and phone number of three people at different addresses with whom the patient does not live who are likely to be aware of the patient’s whereabouts. The research coordinator will confirm that these numbers are accurate prior to the patient’s discharge from hospital; [3] Participants will receive information on expectations for personal benefit from study participation, and motivation for adherence with follow up visits and research protocols in the form of a patient information booklet and a toll free telephone number for advice or questions regarding follow up visits; [4] Patients will receive reminders for upcoming clinic visits from local study personnel; [5] Follow up schedules will coincide with normal fracture clinic visits; [6] Study personnel will contact patients no less frequently than once every three months to maintain contact and obtain information about any planned change in residence. Using these strategies, we obtained 97% follow up for our Pilot Study.

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nly2.16 How many centres will be involved? Our trial is designed to recruit patients from 25 centres. The centres participating in Canada are: 1) Sunnybrook & Women’s College Health Sciences Centre, Toronto, Ontario; 2) St. Michael’s Hospital, Toronto, Ontario; 3) Hamilton Health Sciences Centre, Hamilton, Ontario; 4) St. Joseph's Healthcare, Hamilton, Ontario; 5) Hamilton General Hospital, Hamilton, Ontario; 6) London Health Sciences Centre, London, Ontario; 7) New West Orthopaedic & Sport Medicine Centre, New Westminster, British Columbia; 8) Queen Elizabeth II Health Sciences Centre, Nova Scotia; 9) Ottawa Hospital, Ottawa, Ontario; 10) Durham Sports Specialists, Durham, Ontario; 11) University of Alberta Hospital, Edmonton, Alberta

The centres participating in the US are: 1) Wakeforest School of Medicine, North Carolina; 2) University if Michigan, Ann Arbor, Michigan; 3) University of Pittsburg, Pittsburg, Pennsylvania; 4) Greenville Hospital System, Greenville, South Carolina; 5) UC Davis School of Medicine, Sacramento, CA; 6) Carolina Medical Centres, Charlotte, NC; 7) Erie County Medical Centre, Buffalo, NY; 8) Orthopedic Trauma Associates of North Texas, Dallas, TX: 9) University of California, San Francisco, CA; 10) University of Indiana, Bloomington, IN; 11) Harborview Medical Centre, Seattle, WA.

International participating centres are: 1) Assistance Publique Hopitaux de Paris, Paris, France; 2) Spaarne Hospital, Hoofddorp, the Netherlands; 3) Maatschap Orthopaedie en Traumatologie; Eindhoven, the Netherlands. 2.17 Give details of the planned analyses.2.17.1 Data Analyses for the Trial All analyses will be performed with the SPSS Advanced Statistics software package (version 14.0, SPSS Inc., Chicago, Illinois, USA). A statistician who is unaware of treatment group allocation status will perform all statistical analyses. The primary analysis will use generalized linear models to compare SF-36 Physical Summary scores over time considering factors of time, treatment and the interaction between time and treatment. All patients entered into the trial and randomized will be included in the analysis, regardless of compliance with treatment, or any other deviation from protocol.

For the secondary analysis, all of the patients who were randomized into each study group will be analyzed for the time to radiographic healing, again following the intention-to-treat principle. Each fracture will be considered healed only at the time of a scheduled follow-up visit and no interim visit will be used to assign a healing time. The number of days to the last completed follow-up examination will be used for the time to healing for the fractures that have not reached a healed status by the last follow-up visit.

We will evaluate time to fracture healing, time to return to functional status and return to normal activities, as compared between ultrasound and control groups, using Kaplan-Meier survival analysis (Cox proportional hazards model), as well as the comparison of two independent proportions. Specifically, the proportion of patients with healed fractures, reporting return to functional status and return to normal activities and work in the ultrasound group will be compared to the proportion of patients reporting return to functional status and return to normal activities and work in the placebo group at 3 months, 6 months, and 9 months follow up. In addition to functional status, we will compared the occurrence of secondary outcomes including malunion and nonunion with Pearson’s chi-square test. 2.17.2 Completeness of Data Collection

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nlyEach centre will receive a monthly study status report, showing the number of: 1) patients entered into the trial; 2) completed follow ups; 3) outstanding data clarification requests and overdue assessments. Centres will be identified by number to preserve their anonymity but each centre will be able to compare their performance with that of all other centres. The Principal Investigator will keep a close watch on centre performance and contact centres by phone, when necessary, to discuss any problems that may arise. 2.18 What is the proposed frequency of anaysis? The proposed frequency of analyses is detailed in Figure 3. 2.19 Are there any planned subgroup analyses? We plan to compare the effects of low intensity pulsed ultrasound versus sham in patients with closed and open tibial shaft fractures. Preliminary analysis of our Pilot Study data suggests that 30% of our sample size will include patients with open fractures. Thus, we anticipate 150 patients (75 per treatment arm) with open fractures at the conclusion of our trial. 2.20 Has a Pilot Study been Carried out Using this Design? We have previously been funded by CIHR to perform a pilot study of 50 patients utilizing the current protocol (see Progress Summary). The objectives of our pilot study were to confirm out ability to recruitment adequately, determine the degree to which site investigators can adhere to trial protocol, confirm or refute our anticipated ability to achieve close to 100% follow-up, confirm or refute our ability to blind all relevant parties to treatment allocation (i.e. active vs. placebo), and provide an estimate of the degree to which patients are compliant with treatment. Our recruitment rate for our Pilot Study was 1.25 patients/centre/month which will allow for the required recruitment rate required for our definitive trial (with 25 centres), investigators at all 4 centres were able to adhere to trial protocol, our follow-up was 97% (one patient was lost at 6 months), patients were not able to guess their allocation, and compliance with treatment was 96%. 2.21 What is the estimated cost and duration of the trial? Phase I: Preparation (3 months): Participating centres will begin to screen patients and complete data forms to sort out any initial difficulties or queries regarding the recruitment protocol. Phase II: Patient Recruitment (12 months): Centres will recruit patients as defined by the study protocol. Having proceeded with earlier screening will minimize the early lag phase in recruitment seen in many trials. Phase III: Patient Follow up (12 months): Follow up visits at 2 weeks, 3 months, 6 and 9, and 12 months will occur by which time we expect that virtually all fractures will have healed. Previous randomized trials have reported closed tibial fractures to heal at a mean 3.9 months (St. Dev. 2.8-6.3). Phase IV: Trial Close Out and Data Analysis: (6 months). Any missing data will be obtained, recent clinical events will be confirmed, the results will be analyzed and prepared for publication.

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nly 3.0 TRIAL MANAGEMENT3.1 What are the arrangements for day to day management of the trial? All patients presenting to participating surgeons with a diagnosed tibial fracture amenable to operative management will be documented. Such patients will be classified as 1) excluded (if they subsequently do not meet the eligibility criteria, 2) missed (due to error) or 3) eligible and randomized. If the participating surgeon identifies the eligible patient who consents to randomization, the surgeon or delegate will call the automated computer randomization line which randomizes the patient to receive an active or sham ultrasound unit. Standardized forms will be used at each investigational centre for documentation of initial patient and fracture-related information. Research personnel at participating centers will fax these data collection forms directly into the DataFax Management System at the Methods Centre. Upon receipt of the data, the staff at the Methods Centre will make a visual check of each “scanned” form. They will note missing data, implausible data, and inconsistencies. Methods Centre staff will contact by phone Research Coordinators from each clinical centre regarding omission, implausible data and other inconsistencies. Each center will receive faxed copies of these phone edits that will also be kept at the Methods Centre. Once problems have been resolved and data forms are deemed complete and accurate, the data are entered into the DataFax System. The system will include built-in range and logic checks. When logic errors have been corrected, the information will be entered into the master file containing data suitable for analysis. 3.2 What will be the role of each applicant, associate and collaborator proposed? Our confidence in the feasibility of the proposed study rests largely with our success in the conduct of previous multi-centre RCTs with surgeons including a recently competed randomized trial involving patients with tibial shaft fractures. Dr. Guyat, the nominated Principal investigator, has extensive experience in the design, conduct and analysis of multi-centre trials, including SPRINT. SPRINT is jointly funded by the Canadian Institute of Health Research and National Institutes of Health and is the largest multi-center initiative in fracture care and considered a benchmark trial due to the rigor in its methodology and conduct. Dr. Guyatt oversees a clinical trial methods centre at McMaster University, and has co-ordinated 27 randomized trials, of which 11 have been multi-centre studies. Dr. Guyatt has also made important contributions to clinical trials methodology, particularly in the area of quality of life measurement. Dr. Bhandari, the co-principal investigator, is an orthopaedic surgeon with a Masters Degree in Health Research Methodology who acted as the project officer in the SPRINT trial of tibial shaft fractures. He currently holds Canada Research Chair in Musculoskeletal Trauma at McMaster University. Dr. Busse is a chiropractor who is currently pursuing his PhD in Clinical Epidemiology at McMaster University, funded by a Canadian Institute of Health Research Training Fellowship, and has, under Dr. Guyatt’s supervision, taken the lead role in development of this protocol. Drs. Mandel, Stephen, Schemitsch, and Sanders are orthopaedic surgeons who have led and participated in several national orthopaedic clinical trials. As per Figure 4, Gordon Guyatt will be responsible for overall completion of successful study, coordination of research activities, and data presentation in peer reviewed journals and conferences. Mohit Bhandari will supervise trial methodology and data interpretation. Jason

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nlyBusse will be responsible for day to day operation of trial, training and supervision of staff, assist with preparation of trial documents, including manual of operations and weekly trial update newsletter. Emil H. Schemitsch and David Sanders will participate in an adjudication committee of the trial, and provide clinical expertise in research in orthopaedic trauma. The study will involve an independent Data Safety Monitoring Board, which will be comprised of a statistician (to be named), an epidemiologist (to be named), and three orthopaedic surgeons (to be named). 3.3 Describe the trial steering committee and if relevant the data and safety monitoring committee (See Figure 4) The steering committee members are: Dr. Gordon Guyatt (chair), Dr. Mohit Bhandari, Dr. Jason Busse, Dr. Emil H. Schemitsch and Dr. Stephen Walter. The TRUST Data Safety and Monitoring Board (DSMB) will be comprised of an experienced independent biostatistician, a clinical epidemiologist, and 3 orthopedic surgeons, who are arms-length from the Steering Committee. The DSMB will have terms of reference for the roles and responsibilities of members, and reporting relationships. The primary roles of the DSMB will be ongoing independent review of: 1) regular study reports; 2) procedures such as randomization and protocol adherence; 3) indicators of trial management (e.g. enrolment, consent); 4) efficacy and safety reports including serious adverse events; and 5) interim and final analyses.

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nlyREFERENCES 1. Heckman JD, Sarasohn-Kahn J. The economics of treating fracture healing. Bull Hosp Jt Dis.

1997; 56: 63-72. 2. Russell TA: Fractures of the tibial diaphysis. In Levine AM (ed) Orthopaedic Knowledge

Update Trauma. Rosemont IL, American Academy of Orthopaedic Surgeons, 171-9, 1996 3. Turen CH, Burgess AR, Vanco B. Skeletal stabilization of tibial fractures associated with acute

compartment syndrome. Clin Orthop. 1995; 315:163-9. 4. Watson JT, Anders M, Moed B. Management strategies for bone loss in tibial fractures Clin

Orthop. 1995; 315: 138-53. 5. Burgess AR, Poka A, et al. Pedestrian tibial injuries. J Trauma. 1987; 27: 596-601. 6. Blick SS, Brumback RJ, Poka A, et al. Compartment syndrome in open tibial fractures. J Bone

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nly16. De Nunno R. L’azione degli ultrasuoni sulla formazione del callo osseo (ricerche

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vitro by therapeutic ultrasound. Ultrasound Med Biol. 1997; 23: 1251-1258. 19. Tsai C-L, Chang WH, Liu T-K. Preliminary studies of duration and intensity of ultrasonic

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147. 21. Pilla AA, Figueiredo M, Nasser PR, Mont M, Khan S, Kaufman JJ, Siffert RS. Non-invasive

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nly30. Emami A, Petrén-Mallmin M, Larsson S. No effect of low-intensity ultrasound on healing

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intrameduallary fixed tibial fractures. Clin Orthop Rel Res. 1999; 368: 220-229. 32. Heckman JD, Ryaby JP, McCabe J, Frey JJ, Kilcoyne RF. Acceleration of tibial fracture-

healing by non-invasive, low-intensity pulsed ultrasound. J Bone Joint Surg [Am]. 1994; 76-A: 26-34.

33. Mayr E, Rudzki M-M, Rudzki M, Borchardt B, Haüsser H, Rüter. Beschleunigt niedrig

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Ultrasound Therapy on Time to Fracture Healing: a Meta-Analysis. Canadian Medical Association Journal. 2002; 166: 437-441

35. Leung KS, Lee WS, Tsui HF, Liu PP, Cheung WH. Complex tibial fracture outcomes

following treatment with low-intensity pulsed ultrasound. Ultrasound Med Biol. 2004; 30: 389-95.

36. Bhandari M, Sprague S, Busse JW, Hanson B, Dawe D, Moro JK, Guyatt GH. Health-

Related Quality of Life following Operative Treatment of Unstable Ankle Fractures: A Prospective Observational Study. Accepted for publication in J Orthop Trauma.

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twenty-five open fractures of long bones: retrospective and prospective analyses. J Bone Joint Surg [Am]. 1976; 58: 453-8.

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fractures treated with functional bracing. Clin Orthop. 1995; 315: 8-25.

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Tests of data quality, scaling assumptions, and reliability across diverse patient groups. Med Care. 1994; 32:40-66.

41. Greenwood DC, Muir KR, Doherty M et al. Conservatively managed tibial shaft fractures in

Nottingham UK: are pain, osteoarthritis, and disability long-term complications? Greenwood DC, Muir KR, Doherty M et al. J Epidemiol Community Health. 1997; 51: 701-4.

42. Trudel JG, Rivard M, Dobkin PL et al. Psychometric properties of the health utilities index

mark 2 system in paediatric oncology patients. Qual Life Res. 1998: 7: 421-32.

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the 1991 cycle 6 Canadian general social survey health questionnaire. Qual Life Res. 1995; 4: 249-57.

44. Torrence GW, Feeny D, Furlong WJ et al. Multiattribute utility function for a comprehensive

health status classification system. health utilities index mark 2. Med Care. 1996; 34: 702-22. 45. Whelan DB, Bhandari M, McKee MD, Guyatt GH, Kreder HJ, Stephen D, Schemitsch EH.

Interobserver and intraobserver variation in the assessment of the healing of tibial fractures after intramedullary fixation. J Bone Joint Surg [Br]. 2002; 84: 15-8.

46. Stewart AL, Greenfield S, Hays RD, Wells K, Rogers WH, Berry SD, McGlynn EA, Ware JE

Jr. Functional status and well-being of patients with chronic conditions. Results from the Medical Outcomes Study. JAMA. 1989; 262: 907-13.

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49. Wyrwich KW, Fihn SD, Tierney WM, Kroenke K, Babu AN, Wolinsky FD. Clinically

important changes in health-related quality of life for patients with chronic obstructive pulmonary disease: an expert consensus panel report. J Gen Intern Med. 2003; 18: 196-202.

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important changes in generic and disease-specific health-related quality of life questionnaires in clinical trials of rheumatoid arthritis. Arthritis Rheum. 2000; 43: 1478-87.

51. Norman GR, Sloan JA, Wyrwich KW. Interpretation of changes in health-related quality of

life: the remarkable universality of half a standard deviation. Med Care. 2003; 41: 582-92. 52. Jenkinson C, Stewart-Brown S, Petersen S, Paice C. Assessment of the SF-36 version 2 in the

United Kingdom. J Epidemiol Community Health. 1999; 53: 46-50. Available at: http://www.hsru.ox.ac.uk/sf36v2.htm

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nly

Heckm

an et al

1994

Kristiansen et al

1997

Mayr et al

2000

Emam

i et al

1999

Emam

i et al

1999

Basso et al

1998

Reference and

Publication

Tibial Shaft

Distal

Radius

Scaphoid

Tibial Shaft

Tibial Shaft

Distal

Radius

Location of

Fracture

33

30

15

15

15

19

Treatm

ent

Group

34

31

15

15

17

19

Control

Group

Sample Size

(# of fractures)

Active: 36±2

Placebo: 31±2

Active: 54±3

Placebo: 58±2

Total: 37±14

Active: 40±16

Placebo: 37±13

Active: 40±16

Placebo: 34±15

Active: 57 **

Placebo: 63 **

Mean age *

(years)

54:13

10:51

25:5

Gender not

Reported

24:8

16:22

Proportion

(male:fem

ale)

3 (Grade I)

0

N/A

4 (Grade I)

0

Open

Fracture

grade

64

61

N/A

Not R

eported

28

38

Closed

114±7.5***

61±3***

43±11***

155±22

155±22

Treatm

ent G

roup

182±15.8

***

98±5***

62±19***

129±12

125±11

Not R

eported

Control

Group

Tim

e to Heal (days)

Table 1 – Identified T

rials Investigating Ultrasound and Fracture H

ealing

* V

alues provided ± standard deviation.

** Values w

ere reported as the median. R

anges were not provided.

*** Treatment effect betw

een groups was significant.

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nly Table 2 - Radiographic Union Scale for Tibial Fractures (RUST)

Inter and Intra-observer ICC values for the RUST

Reviewers Inter-observer ICC (95% CI)

Intra-observer ICC (95% CI)

Traumatologists 0.86 (0.76 - 0.92)

0.89 (0.80 - 0.95)

Community surgeons 0.83 (0.72 - 0.91)

0.85 (0.72 - 0.92)

Residents 0.81 (0.66 - 0.89)

0.83 (0.68 - 0.90)

Overall 0.86 (0.79 - 0.91)

0.88 (0.80 - 0.96)

Legend: The RUST assigns a score to a given set of AP and lateral radiographs based on the assessment of healing at each of the four cortices visible on these projections (i.e. medial and lateral cortices on the AP x-ray, anterior and posterior cortices on the lateral x-ray). Each cortex receives score of one point if it is deemed to have a fracture line with no callus, two points if there is callus present but a fracture line is still visible, and three points if there is bridging callus with no evidence of a fracture line. The individual cortical scores are added to give a total for the set of films with four being the minimum, indicating the fracture is definitely not healed and twelve the maximum score, indicating the fracture is definitely healed

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nlyTable 3 - Agreement Among Surgeons in the Assessment of Fracture Healing

Parameter

Overall weighted Kappa

95% CI

General impression 0.67 0.59-0.75

Cortices bridged by callus 0.75 0.61-0.89

Cortices with fracture line 0.70 0.56-0.84

Extent of callus 0.57 0.43-0.71

Methods: Anteroposterior and lateral x-rays of the tibia from 30 patients treated with an intramedullary nail were identified from a trauma database at St. Michael’s Hospital. These x-rays represented a wide spectrum in the progression of healing (not healed to completed healed). These x-rays were typical of those which we expect surgeons in the trial to be able to evaluate at follow up ( 6 months). Four orthopaedic surgeons from 2 centres in Toronto (Sunnybrook Health Sciences Centre, St. Michael’s Hospital) were asked to independently review 30 x-rays of tibial fractures treated with intramedullary nails. For each x-ray surgeons described their impression of the fracture as: definitely healed, probably healed, indeterminate, probably not healed and definitely not healed.

Results: Agreement in responses were analyzed by a quadratically weighted kappa statistic. The overall agreement among surgeons was good (kappa=0.67). 45

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nlyTable 4 - Change in SF-36 Subscores Over Time Domain Post-Op 3 mon 6 mon 12 mon 24 mon US Norm Pvalue# (Age Matched) Physical Function 13.3 32.5 61.0 66.0 67.5** 89.3 P<0.01 Bodily Pain 30.0 47.7 60.54 68.7 75.3** 80.2 N.S. Social Function 33.3 51.1 75.5 76.5 78.3** 85.1 N.S. Role-Physical 15.0 28.5 55.2 66.0 68.5** 89.2 P<0.01 Role-Emotional 66.7 89.9 88.9 81.3 89.4** 88.6 N.S Vitality 35.0 48.9 54.5 60.0 62.7** 60.6 N.S General Health 68.5 71.4 66.5 63.8 65.3 70.2 N.S Mental Health 72.1 69.2 70.0 76.0 77.3* 74.2 N.S #P value comparing US Norm to 24 month follow up SF-36 subscores. Significant change in score over time- *p<0.05,**p<0.01 (ANOVA) Methods: We conducted a two year prospective observational cohort study to evaluate health-related quality of life in thirty patients with unstable ankle fractures who were otherwise healthy. Only patients from two university-affiliated hospitals suffering unstable Type B Weber ankle (tibia/fibula) injury patterns requiring surgery were eligible. Patients completed the short-form 36 (SF-36) questionnaire and a visual analogue pain scale at discharge, and 3, 6, 12 and 24 months post-operation. 36

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nly

Table 5 - Sample Size per Arm (80% Study Power, Alpha=0.05)

Difference in SF-36 scores, between treatment and control groups

Legend: Table 6 shows the number of patients required per arm across a range of plausible standard deviations and absolute differences of SF-36 scores between treatment and control groups. Shaded areas represent conditions for which our trial is adequately powered to detect clinically important differences.

3-point 4-point 5-point 24 1005 566 362 20 698

393 252 16 447 252 161 12 252 142 91 8 112 63 41

Standard Deviation

4 28 16 11

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nlyFigure 1 – Meta-Analysis Search Strategy 1. Literature Search of Electronic Databases:

Medline Embase CINAHL HealthSTAR Cochrane Collection

67 42 2 37 10

158 articles

2. Hand Searching: (Clinical Orthopaedics and Related Research, Physiotherapy, Journal of

Bone and Joint Surgery: American and British Volumes, Physical Therapy, Archives of Physical

Medicine and Rehabilitation, and The Journal of Orthopaedic Trauma) from 1996 to December

2000

0 additional articles 3. Screening of the 158 Identified Articles:

Random Allocation of Treatments (119) Inclusion of Skeletally Mature Patients of Either Gender with One or More Fractures (29) Blinding of both the Patient and the Assessor(s) of Fracture Healing (11) Administration of Therapeutic Ultrasound to at least one of the Treatment Groups (7) Assessment of Time to Fracture Healing as Determined Radiographically (6)

Total of 6 Articles Selected for Review

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nlyFigure 2 - The EXOGEN Sonic Accelerated Fracture Healing System (SAFHS)

EXOGEN 2000+ SYSTEM

COMPONENTS a. The Main Operating Unit (MOU) b. The Transducer c. Target Ring Locator d. Retaining and Alignment Fixture (RAF)- In-Cast & On-Cast Application e. Red Plastic Cap f. Felt and Foam Pads g. RAF/Snap-on Cap/ Strap Assembly h. Foam Pads i. Coupling Gel

Technical Specifications of the EXOGEN SAFHS Ultrasound Signal

Ultrasound frequency………………. .1.5 ± 5% megahertz (MHz) Modulating signal burst width……… 200 ± 10% microseconds (uS) Repetition rate.……………………… 1.0 ± 10% kilohertz (kHz) Effective radiating area ……………. 3.88±1% square centimeters (cm2) Temporal average power ………….. 117 ± 30% milliwatt (mW) Temporal maximum power ………… 625 ± 30% milliwatt (mW) Peak power ………………………….. 1.25 ± 30% watts (W) Spatial avg.-temporal avg. (SATA)….. 30 ± 30% mW/cm2 Spatial avg.-temporal maximum (SATM) 161 ± 30% mW/cm2 Beam non-uniformity ratio (BNR) …... 4.0 maximum

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nlyFigure 3 - Recruitment and Follow-up Schedule Data Collected Identification of Patients Direct referral-within centre, or between centres Assessment of Patient Eligibility Study explanation History-review eligibility criteria, Eligibility Form and other relevant medical conditions Physical Examination Baseline Data Form Radiographs Informed Consent, if eligible Informed Consent All eligible Patients who consent to the trial Randomization 24 HOUR TOLL FREE NUMBER Eligibility criteria reviewed again Key patient information recorded Entry Form at at methods centre Methods Centre Randomization issued to patient Intervention Either Ultrasound or Sham Treatment Unit will be assigned

Follow Up Schedule*

Discharge Assessment of outcome events Follow Up Form, SF-36,

HUI, x-ray 2 Week post-discharge Assessment of outcome events x-ray 6 Week Post-Surgery Assessment of outcome events Follow up Form, x-ray 3 Month Assessment of outcome events Follow up Form , SF-36,

HUI, x-ray 6 Month Assessment of outcome events Follow up Form, SF-36,



HUI, x-ray * x-rays will also be obtained at week 1, 3, 4, 8 and at month 4 and 5

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nlyFigure 4 - Trial Organization

STEERING COMMITTEE Overall Responsibility of the Trial

Gordon H. Guyatt (Chair)

Jason Busse Mohit Bhandari

Emil H. Schemitsch Stephen Walter (Statistician)

CENTRAL (OUTCOMES) SAFETY AND EFFICACY ADJUDICATION COMMITTEE MONITORING COMMITTEE Review and Classification of all clinical events Review of adverse events, early termination

of study based on benefit/harm Gordon Guyatt Jason Busse Chair (to be named) Mohit Bhandari Statistician (to be named) Stephen Walter (Statistician) Epidemiologist (to be named) Dave Sanders 3 Orthopaedic Surgeons (to be named) Emil H. Schemitsch

METHODS AND CO-ORDINATING CENTRE

Data management, Daily conduct of trial

Gordon Guyatt Jason Busse

Mohit Bhandari Stephen Walter (Statistician)

Study Coordinator and Support Staff

PARTICIPATING CENTRES Recruitment and follow up

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nlyAppendix A – Details of Surgical Management

Reamed Nail Insertion Reaming is conducted over the guide wire with cannulated power reamers. The operating surgeon chooses the reamer. To avoid inconsistencies in the degree of reaming, surgeons adhere to the following protocol 1) Surgeons ream the intramedullary canal until the first detection of “cortical chatter” (ie the reamer just begins to contact the cortical bone of the tibia) 2) The size of the nail (diameter) corresponds to the point of “cortical chatter” (if chatter occurs with a 11mm reamer, then the nail size is 11mm 3). Following the appearance of “cortical chatter”, surgeons ream 1-1.5 mm larger than the chosen nail's diameter to facilitate its insertion. The chosen nail, which is as long as possible without distracting the fracture by impinging on dense distal metaphyseal bone or protruding above the cortex at the insertion site, is inserted with the appropriate instruments. Distraction of a tibial shaft fracture interferes with healing, so surgeons employ all strategies for achieving cortical contact (up to 10 mm shortening acceptable to achieve contact of fracture ends). The choice of intramedullary nail (ie Company) and material (titanium or stainless steel) is at the discretion of the operating surgeon. Non-Reamed Nail Insertion Surgeons insert non-reamed nails across the fracture site with great attention to the prevention of over-distraction. The goal is to achieve cortical contact of the fracture ends. An upper diameter limit of 10 mm is employed for non-reamed nails. In principle, however, the nail should be at least 2 mm less than the diameter at the isthmus of the tibia on anteroposterior and lateral radiographs. Tibial Plating Plates may be inserted with open or percutaneous methods. If present, nondisplaced intra-articular fracture lines may be used with reduction clamps, provisionally stabilized with k-wires, and repaired with 2 –3 screws. Once provisional fracture reduction is accomplished, a plate of correct length is selected. The specific design of plate used is left to the discretion of the surgeon, but the plate must have angular stable (locking) screws in its upper end. The plate should be long enough to extend at least 4 screw holes beyond the most distal extent of the fracture although longer plates are encouraged. Through the chosen incision the proximal origins of the anterior tibial musculature is released from the tibia, and a blunt elevator is used to separate the muscle from the lateral face of the tibia distally. The plate is affixed to insertion jig (if one exists) and inserted in a sub-muscular fashion. The fracture should be provisionally reduced during this step. With use of fluoroscopy and, at the surgeon’s discretion, a small distal incision is used to center the distal tip of the plate on the bone. Correct cranial – caudal position of the plate on the tibia is assured, and the plate is provisionally fixed to the tibia at both ends. Final reduction of the fracture must be done at this point. If necessary, non-locking reduction screws or temporary pins can be used to “pull” the plate to the bone or to correct minor deviations in alignment. Once this is done, multiple locking screws are inserted into the proximal tibia and locking or non-locking screws into the tibial shaft. Not all of the distal screw holes should be used; every other screw hole filled is the desired configuration of diaphyseal screws.

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nlyInterlocking Screws All fractures are interlocked, both proximally and distally. Surgeons use at least one proximal locking screw and one distal locking screw. The number of screws, one, two or three is left to the discretion of the surgeon. Peri-operative Treatment Common to Both Groups To ensure similar peri-operative regimens, participating centres standardize key aspects of pre- and post-operative care. In Closed Fractures: 1) Pre-operative antibiotic administration is continued for 24 hours post-operatively (specific antibiotic regimens at the discretion of the operating surgeon: gram positive coverage), 2) With intramedullary nailing cortical contact of the fracture ends guides weight bearing. If cortical contact is achieved, patients are allowed to weight bear as tolerated. However, when cortical contact is not achieved, patients are allowed to partially weight bear on the affected limb until a definitive procedure to achieve contact is performed. Patients managed with tibial plating begin weight bearing at approximately 6 weeks, 3) Dynamization, a technique in which the interlocking screws are removed distally to allow compression at the fracture site, is allowed prior to 6 months only if the fracture is distracted following nail insertion. In Open Fractures: 1) Pre-operative intravenous antibiotic administration include a cephalosporin and an aminoglycoside which are continued for 72 hours post-operatively (specific antibiotics used at the discretion of the attending surgeon. The recommended guidelines will include: ancef I.V. for Grade I-II injuries, ancef I.V. and gentamycin I.V. for Grade III injuries, and ancef I.V., gentamycin I.V. and penicillin for gross contaminated injuries), 2) Copious irrigation and debridement of soft tissues and contaminated bone repeated as necessary, 3) Delayed wound closure, split thickness skin grafting, or muscle flaps (for grade IIIB only) should occur by 7 days following the initial surgery, 4) Weigthbearing and dynamization per closed fractures.

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nly

Final Protocol submitted by the Industry Sponsor to the Federal Drug

Administration (FDA) in April 2009

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nly

TRial to evaluate UltraSound in the Treatment of tibial Fractures (TRUST)

Clinical Protocol

April 17, 2009 CONFIDENTIAL Page 1 of 47

Protocol Number EX-TIB-0907

Protocol Version Protocol Effective Date

Version 5 April 17, 2009

Lead Principal Investigator Mohit Bhandari, MD, MSc, FRCSC Assistant Professor Department of Clinical Epidemiology & Biostatistics Department of Surgery McMaster University

Coordinating Center CLARITY Methods Center McMaster University 293 Wellington St. North, Suite 110 Hamilton, ON L8L 8E7

This document contains confidential information belonging to McMaster University. Except as may be otherwise agreed to in writing, by accepting or reviewing these materials, you agree to hold such information in confidence and not to disclose it to others (except where required by applicable law), nor use it for unauthorized purposes.

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nly


Clinical Protocol


Table of Contents 1. TRIAL CONTACT INFORMATION....................................................................................................................5

2. DEFINITION OF ABBREVIATIONS ...................................................................................................................6

3. INTRODUCTION.............................................................................................................................................7 3.1 BACKGROUND INFORMATION................................................................................................................................... 7 3.2 DEVICE DESCRIPTION.............................................................................................................................................. 7 3.3 TRIAL RATIONALE ................................................................................................................................................... 8 3.4 TRIAL OBJECTIVES AND ENDPOINTS ......................................................................................................................... .9 3.5 TRIAL DESIGN OVERVIEW........................................................................................................................................ .9 3.6 TRIAL SCOPE AND DURATION .................................................................................................................................13

4. TRIAL METHODOLOGY ............................................................................................................................... .14 4.1 LOW INTENSITY PULSED ULTRASOUND .....................................................................................................................14 4.2 SUBJECT INCLUSION CRITERIA .................................................................................................................................15 4.3 SUBJECT EXCLUSION CRITERIA ................................................................................................................................15 4.4 INFORMED CONSENT .............................................................................................................................................16 4.5 PACKAGING, BLINDING AND LABELING OF SUPPLIES..................................................................................................16 4.6 UNBLINDING.........................................................................................................................................................16 4.7 DEVICE ACCOUNTABILITY/ DISPOSITION.................................................................................................................. .17 4.8 RANDOMIZATION................................................................................................................................................. .17 4.9 CLINICAL ASSESSMENTS ........................................................................................................................................18

5. TRIAL PROCEDURES ....................................................................................................................................23 5.1 SCHEDULE OF EVENTS ..........................................................................................................................................23 5.2 SUBJECT SCREENING .......................................................................................................................................... .25 5.3 ENROLLMENT...................................................................................................................................................... .25 5.4 FOLLOW-UP ASSESSMENTS- 6 WEEKS THROUGH 52 WEEKS .................................................................................... .25 5.5 SUBJECT EARLY WITHDRAW AND LOST TO FOLLOW UP.............................................................................................. .27 5.6 SUBJECT TRIAL COMPLETION ................................................................................................................................ .27 5.7 SUBJECT DEATH................................................................................................................................................ ...27

6. ADVERSE EVENTS ASSESSMENT................................................................................................................ .27 6.1 ADVERSE EVENT - DEFINITIONS ............................................................................................................................. .27 6.2 RELATIONSHIP TO EXOGEN 4000+ TREATMENT .................................................................................................... .28 6.3 UNANTICIPATED ADVERSE DEVICE EFFECT (UADE) REPORTING .................................................................................. .28 6.4 DATA SAFETY MONITORING BOARD (DSMB) ...........................................................................................................29

7. STATISTICS..................................................................................................................................................29 7.1 HISTORICAL DATA AND SAMPLE SIZE ESTIMATION ...................................................................................................29 7.2 ANALYSIS POPULATION ........................................................................................................................................30 7.3 PRIMARY EFFECTIVENESS ANALYSES ........................................................................................................................31 7.4 SECONDARY EFFECTIVENESS ANALYSES ...................................................................................................................31 7.4.1 RETURN TO WORK...........................................................................................................................................31 7.4.2 RETURN TO PRE-INJURY LEVEL OF FUNCTION .......................................................................................................31 7.4.3 LEVEL OF ACTIVITY ..........................................................................................................................................32 7.4.4 HEALTH UTILITIES INDEX (HUI) MARK II/III.........................................................................................................32

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7.5 PRIMARY SAFETY ANALYSES ...................................................................................................................................32 7.6 SECONDARY SAFETY ANALYSES ..............................................................................................................................32 7.7 DESCRIPTIVE AND SUMMARY STATISTICS.................................................................................................................32 7.8 MISSING DATA....................................................................................................................................................32 7.9 POOLING OF DATA ACROSS STUDY SITES .................................................................................................................32

8. INTERIM ANALYSIS AND EARLY STOPPING RULES......................................................................................32

9. TRIAL MONITORING....................................................................................................................................33 9.1 PERIODIC MONITORING VISITS ............................................................................................................................... .33 9.2 CLOSE-OUT VISIT ................................................................................................................................................ .33

10. ADMINISTRATION PROCEDURES ................................................................................................................34 10.1 INVESTIGATIONAL SITES ....................................................................................................................................... .34 10.2 INVESTIGATOR TRAINING...................................................................................................................................... .34 10.3 DATA REQUIREMENTS & HANDLING ...................................................................................................................... .34 10.4 CASE REPORT FORMS .......................................................................................................................................... .34 10.5 SOURCE DOCUMENTATION .................................................................................................................................. .34 10.6 PROTOCOL DEVIATIONS ....................................................................................................................................... .35 10.7 PROTOCOL AMENDMENTS ....................................................................................................................................35 10.8 DOCUMENT RETENTION AND AVAILABILITY ..............................................................................................................35 10.9 REGULATORY/ETHICAL OBLIGATIONS......................................................................................................................36 10.10 INSTITUTIONAL REVIEW BOARD/RESEARCH ETHICS BOARD .........................................................................................36 10.11 OTHER INSTITUTIONS............................................................................................................................................36 10.12 RECORDS AND REPORTS ....................................................................................................................................... 37

10.12.1 Investigator Records.............................................................................................................................. 37 10.12.2 Investigator Reports .............................................................................................................................. 37 10.12.3 Sponsor Records ...................................................................................................................................38

10.13 DATA QUALITY ASSURANCE ..................................................................................................................................38 10.14 FINANCIAL DISCLOSURE ........................................................................................................................................38 10.15 INVESTIGATOR RESPONSIBILITIES ............................................................................................................................39 10.16 CONFIDENTIALITY .................................................................................................................................................39

11 RISK/BENEFIT ANALYSIS .............................................................................................................................39 11.1 KNOWN AND ANTICIPATED RISKS .......................................................................................................................... .39 11.2 METHODS TO MINIMIZE RISK.................................................................................................................................40 11.3 POTENTIAL BENEFITS.............................................................................................................................................40

12. INVESTIGATOR STATEMENT AND SIGNATURE............................................................................................ 41

13. REFERENCES................................................................................................................................................42

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Figures

Figure 1: Subject Enrollment Scheme through 26-Week Follow-up...................................................................................11

Figure 2: Subject Enrollment Scheme following 26-Week Follow-up............................................................................... 12

Figure 3: EXOGEN 4000+ Bone Healing SYSTEM.............................................................................................................. 14

Figure 4: Schedule of Events ............................................................................................................................................. 24

Figure 5: Trial Organization................................................................................................................................................ 46

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1. Trial Contact Information

Lead Principal Investigator Mohit Bhandari, MD, MSc, FRCSC Associate Professor Department of Clinical Epidemiology & Biostatistics Department of Surgery McMaster University Tel: 905.527.4322. Ext 44490 Fax: 905.523.8781 Email: [email protected]

Senior Study Coordinator McMaster University

Sheila Sprague, MSc CLARITY Research Group McMaster University 293 Wellington St. North, Suite 110 Hamilton, Ontario, Canada L8L 8E7 Tel: 905.527.4322. Ext 44490 Fax: 905.523.8781

Email: [email protected]

Study Coordinator McMaster University

Paula McKay, BSc CLARITY Research Group McMaster University 293 Wellington St. North, Suite 110 Hamilton, Ontario, Canada L8L 8E7 Tel: 905.527.4322. Ext 44131 Fax: 905.523.8781 Email: [email protected]

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2. Definitions of Abbreviations

AE - Adverse Event CAC - Central Adjudication Committee CFR - Code of Federal Regulations CRF - Case Report Form CRO - Contract Research Organization DCF - Data Clarification Form DSMB Data Safety Monitoring Board FDA - Food and Drug Administration GCP - Good Clinical Practice HUI - Health Utilities Index ICF - Informed Consent Form IRB - Institutional Review Board REB - Research Ethics Board SF-36 - Short Form-36 UADE - Unanticipated Adverse Device Effect

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3. Introduction

3.1 Background Information Of all long-bone fractures, those of the tibia are the most common.1 The National Center for Health Statistics reports an annual incidence of 492 000 fractures of the tibia and fibula per year in the United States.2 Patients with tibial fractures remain in hospital for a total of 569 000 hospital days and incur 825 000 total physician visits per year in the United States. 2

Traumatic fractures of the lower extremities are one group of injuries that often require prolonged rehabilitation or multiple operative procedures to achieve maximal functional recovery. Tibial fractures take time to heal – typically, three to six months are required before patients are experiencing minimal pain and have returned to their pre-injury functional status. Since most tibial fractures occur in young people, this disability is associated with substantial loss in productivity. Moreover, tibial fractures are prone to complications.3,4,5,6 The lack of a circumferential soft tissue envelope around the bone makes the ends of the bones in tibial fractures more likely to fail to unite (nonunions), a complication that approximately 50 000 North Americans suffer each year.7 Nonunions require surgery to promote fracture healing, associated with its own complications.8,9 Optimal management strategies that minimize both fracture healing time and complication rates remain controversial.

3.2 Device Description The Pre-Market Approval (PMA) application (P900009) for the Sonic Accelerated Fracture

Healing System (SAFHS) device was approved for commercial marketing by the FDA on October 5, 1994 with indications for the acceleration of the time to a healed fracture for fresh, closed, posteriorly displaced distal radius (Colles’) fractures and fresh, closed or Grade I open tibial diaphysis fractures in skeletally mature individuals when these fractures are orthopaedically managed by closed reduction and cast immobilization. Additionally, on February 22, 2000, in Supplement S006 of the same PMA application, FDA granted expansion of the labeling to include the treatment of established non-unions.

The EXOGEN 4000+ Bone Healing System provides a non-invasive therapy for the healing of nonunions and the acceleration of fresh fracture healing that the patient administers, once daily, for 20 minutes. The device transmits a low intensity ultrasound signal (30 mW/cm2) to the fracture site through coupling gel. This is comparable to diagnostic ultrasound levels used in sonogram (fetal monitoring) procedures. Due to the very low intensity of the ultrasound no sensation is felt by the patient during treatment. The EXOGEN 4000+ Bone Healing System consists of one main operating unit and a transducer permanently connected by a coiled electrical cable. The investigational and control devices, and their packaging, will be labeled with “Caution – Investigational device: Limited by U.S. law to investigational use” and tracked by a unique lot number.

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3.3 Trial Rationale Historically, on the basis of early animal studies that found therapeutic ultrasound delayed healing and damaged healing bone,10,11 (and despite some contradictory findings 12,13), authorities considered fracture sites an absolute contraindication to therapeutic ultrasound. More recent work, however, has shown that the intensity of therapeutic ultrasound determines its effect on healing bone. The high intensity (1.0 W/cm2) continuous wave ultrasound applied in earlier animal studies is harmful,14,15 whereas low intensity pulsed ultrasound (30 mW/cm2) appears to accelerate healing.16,17 Positive findings (i.e. decreased time to fracture healing vs. controls) in animal trials 18,19 and uncontrolled human trials 20,21 have provided further support for the inference that low intensity ultrasound may be beneficial. Mechanisms of effects may include positive impact on signal transduction (second-messenger activity of chondroblasts and osteoblasts), gene expression, blood flow, tissue modeling and remodeling, and the mechanical attributes of the callus.14,15,16,22,23 Based on results of one randomized controlled trial that found therapeutic ultrasound reduces time to tibial fracture healing by an average of 37 days (placebo = 98 ± 5 days vs. ultrasound = 61 ± 3 days)24, Heckman and Sarasohn-Khan 1 calculated savings of over $15,000 (US) per tibial fracture managed concurrently with low intensity, pulsed ultrasound. This cost analysis model considered both direct and indirect costs, with substantial savings attributed to earlier return to work. However, while results of a number of small randomized trials have suggested that therapeutic ultrasound may improve fracture healing, our meta-analysis has found that their findings are not definitive and the therapy remains controversial.25

The CLARITY Research Group at McMaster University recently conducted a survey of orthopaedic surgeons and senior physiotherapy students (n=77; 77% response rate) and found that beliefs on the role of therapeutic ultrasound in fracture healing remain very divergent, with approximately a quarter of respondents making use of this modality.26 The group also surveyed 450 members of the Canadian Orthopaedic Association (60% response rate) and found that 45% of surgeons reported use of bone stimulators for fracture healing in at least some cases, evenly split between low intensity pulsed ultrasound and electrical stimulation.27 Until a large trial is undertaken, the utility of therapeutic ultrasound in assisting fracture healing will remain uncertain.28,29 A trial of 500 skeletally mature adults at least 18 years of age is proposed to determine the effect of low-intensity, pulsed ultrasound on functional and clinical outcomes in tibial fractures treated with intramedullary nailing. This study has the potential to resolve the role of therapeutic ultrasound in healing of the most common long bone fracture, the tibia, an issue that has remained unresolved for over five decades. If therapeutic ultrasound does significantly reduce time spent disabled following tibial fracture, the socioeconomic benefits will prove substantial.

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3.4 Trial Objectives and End Points The primary objectives of this randomized, placebo-treatment controlled, clinical trial are to evaluate the impact of low-intensity, pulsed ultrasound, applied to tibial fractures treated with intramedullary nailing on:

1. Functional status as measured by the Physical Component Summary score of the Short Form-36 (SF-36).

2. Time to radiographic healing of tibial fractures.

The primary safety objectives of this trial are to demonstrate safety by showing that the number and proportion of subjects with device related adverse events and unplanned secondary procedures related to bone healing and infection are clinically equivalent between treatment groups.

Secondary objectives of the trial are to assess the impact of low-intensity, pulsed ultrasound versus placebo-treatment on:

1. Functional status as measured by the Health Utilities Index (HUI) Mark II/III.

2. Rates of nonunion of tibial fractures.

End Points

The primary effectiveness endpoints for this trial are the Physical Component Summary (PCS) score of the SF-36 and the time to radiographic fracture healing. Success of the TRUST study will be evaluated in terms of the statistical and clinical significance of both an objective radiographic success criterion as well as in terms of group comparisons of physical health related quality of life during the follow-up period. Care must be taken when defining the relative roles of these endpoints for defining overall study success. Therefore, a separate Statistical Analysis Plan will be developed that summarizes precisely how these endpoints are used to establish evidence in support of investigation device efficacy while at the same time appropriately controlling inflation in the study-wide type 1 rate (i.e., the chance of a false positive finding).

The primary safety endpoints for this trial are the number and proportion of subjects with device related adverse events and unplanned secondary procedures related to bone healing and infection.

The secondary endpoints include additional functional outcomes and rates of non-unions. The endpoints are further defined in Section 4.9, Clinical Assessments.

3.5 Trial Design Overview

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This multi-center study is a prospective, blinded, randomized placebo-treatment controlled trial comparing the safety and effectiveness of the use of low intensity pulsed ultrasound in the treatment of tibial fractures treated with intramedullary nailing. Blinding will involve subjects, surgeons, data assessors, data analysts, and all clinical investigators until the data analysis is complete.

Enrollment for this study will be conducted at up to 40 orthopaedic surgeon sites across the United States and Canada. A total of 500 subjects with operatively treated fractures of the tibia will be enrolled; 450 plus an additional 50 subjects to allow for approximately 10% loss to follow-up. Visually identical active and inactivated (sham) EXOGEN 4000+ ultrasound device units with a unit number will be labeled and shipped from the manufacturer, Smith & Nephew, to the CLARITY Methods Center. Randomization will be in blocks; clinical centers will be unaware of the block size. The CLARITY Methods Center will ship the labeled units to clinical study sites. After subjects have provided informed consent, local study personnel will provide each subject with the next sequential study device as recorded on the randomization list provided by McMaster. Stratification will occur by subject according to center and according to whether the subject has sustained a closed or open fracture of the tibia. Subjects will self-administer treatment with their study device once daily, for 20 minutes. Treatment will continue until the Central Adjudication Committee (CAC) has determined that the fracture demonstrates radiographic evidence of bridging at all 4 cortices, or until the 52-week follow-up visit, which ever occurs first. Subjects will be assessed at enrollment and will return for follow-up assessments at 6, 12, 18, 26, 38, and 52 weeks post-enrollment. Schematics of the study design follow on the next pages. Subjects who do not show documented bridging of 4 cortices at the 26 week follow-up visit will be required to return for a follow-up visit at 32 weeks. Subjects who do not show documented bridging of 4 cortices at the 38 week follow-up visit will be required to return for a follow-up visit at 44 weeks.

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Figure 1 Subject Enrollment Scheme through 269Week Follow9up

NO

Subjects Randomized to Study Device or Placebo-Treatment Device

6-Week Follow-up Visit SF-36, HUI, X-Rays, Record AEs and Meds

Initial screening of all tibial fracture subjects

All criteria met and consent

documented?

Do Not Enroll - Record reason for exclusion on

screening form.

YES

YES

Baseline H&P, SF-36, HUI, X-Rays Record Medications

Subject successfully uses

device? NO

Train subject on use of Exogen 4000 study device

12-Week Follow-up Visit SF-36, HUI, X-Rays*, Record AEs and Meds

18-Week Follow-up Visit SF-36, HUI, X-Rays*, Record AEs and Meds

26-Week Follow-up Visits SF-36, HUI, X-Rays*, Record AEs and Meds

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Figure 2 Subject Enrollment Scheme Following 269Week Follow9up

*No further x9rays will be acquired after a patient has demonstrated bridging at all 4 cortices

Documented bridging of 4

cortices?

YES

NO

26-Week Follow-up Visits SF-36, HUI, X-Rays*, Record AEs and Meds

32-Week Follow-up Visit SF-36, HUI, X-Rays,

Record AEs


cortices?

YES

52-Week Follow-up Visits SF-36, HUI, Record AEs

44-Week Follow-up Visit SF-36, HUI, X-Rays,

Record AEs and Meds

38-Week Follow-up Visit SF-36, HUI, X-Rays, Record

AEs

38-Week Follow-up Visits SF-36, HUI, Record AEs

NO


cortices?

YES

NO

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3.6 Trial Scope and Duration A total of 500 subjects will be enrolled at up to 40 U.S and Canadian sites. Enrollment is anticipated to take 24 months. The duration of participation in the study for each subject will be approximately 12 months. It is possible that the FDA will require a subjects progress be followed for a period of two years. It is expected that it will take approximately 36 months from the start of enrollment to complete the trial. The EXOGEN 4000+ ultrasound device is adjunct therapy to standard care. Subjects will continue use of the EXOGEN 4000+ device for 12 months following enrollment or until the fracture shows radiographic evidence of bridging at all 4 cortices, whichever occurs first.

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4. Trial Methodology 4.1 Low Intensity Pulsed Ultrasound In order to ensure a standardized signal, each subject will use an EXOGEN 4000+ device (Figure 3) manufactured by Smith & Nephew. Smith & Nephew will provide all ultrasound units required for this trial. Neither the subject nor the clinical investigator will be able to adjust the ultrasound signal.

Figure 3 EXOGEN 4000+ Bone Healing SYSTEM

At enrollment, the site Research Coordinator, or designee, will provide subjects with instructions for use of the EXOGEN 4000+ device, and with a booklet containing detailed instructions. In brief, after the application of a small amount of ultrasonic coupling gel (approximately 5 milliliters) to the surface of the ultrasound head, the subject will position the treatment head module over the fracture site and turn on the EXOGEN 4000+ device. The main operating unit contains a timer that monitors treatment times and automatically turns the unit off after 20 minutes. A visual and audible signal serves to alert the subject that treatment is complete. The active and placebo-treatment devices are identical in every way with the

EXOGEN 4000+ SYSTEM COMPONENTS a. The Main Operating Unit (MOU) b. The Transducer c. Target Ring Locator g. RAF/Snap-on Cap/ Strap Assembly i. Coupling Gel

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exception of the administration of ultrasound, in that they have the same visual, tactile, and auditory signals.

Using X-ray the clinician marks the skin with a skin marking pen, which becomes the locator for the patient when applying the EXOGEN 4000+ device. In the presence of an open wound or broken skin the physician should mark the skin medial or lateral to the area to be treated. On follow-up visits the clinician may re-mark the site if necessary.

4.2 Subject Inclusion Criteria A subject must meet all of the following criteria to be eligible for trial participation.

• Males and females age 18 years or older • Have an open (Gustillo Grade I-IIIb) or closed (Tscherne Grade 0-3) tibial fracture,

amenable to intramedullary nail fixation in the opinion of the attending surgeon • For open fractures, debridement must have taken place within 24-hours of

presentation to the trauma center or emergency department • Provide written informed consent for trial participation and initiate treatment with the

device within 14 days of definitive treatment with intramedullary nail of the tibia fracture

• Be willing and able to comply with the study protocol including return for all follow-up evaluations

4.3 Subject Exclusion Criteria Subjects will be excluded from trial participation if any of the following exist:

• Circumferential, open wound that precludes placement of ultrasound at the fracture site

• General wound care that precludes ultrasound-skin contact (e.g. coverage of a wound that cannot be modified to allow for skin contact)

• Tibial fracture associated with a vascular injury requiring repair (Gustillo Grade IIIc injuries)

• Pilon fractures

• Tibial fractures that extend into the joint and require intra articular reduction • Pathologic fractures (defined as chronic infection, chronic osteomyelitis, etc.)

• Bilateral tibial fractures

• Concomitant injury which, in the opinion of the attending surgeon, is likely to impair function for as long as or longer than the subject’s tibial fracture

• Segmental fractures

• Spiral fractures that extend greater than 3 inches in length

• Use of an external fixation device or plate as definitive treatment • Surgical delay of definitive treatment > 2 weeks from time of tibial injury

• Tibial fractures that show less than 25% cortical contact and > 1cm gap following intramedullary nail fixation

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• There are likely to be problems, in the judgment of the Investigator or Research Coordinator, with maintaining follow-up (such as no fixed address, plans to move out of town in the next year, etc.)

• Subject is already making use of therapeutic ultrasound at the fracture site

• Subject is participating in another research study

• Subject is implanted with bone morphogenic protein(s) or other osteobiologic at the site of the tibial fracture, or use of osteobiologics is planned

• Subject is using electrical stimulation at the site of the tibial fracture

• Cognitive impairment or language difficulties that would impede the valid completion of questionnaires

• Women who are pregnant or nursing or plan to become pregnant during their treatment period

• Subject is a prisoner or is at high risk of incarceration during the follow-up period

• Subjects with active implantable devices, such as cardiac pacemakers

• Subject states they cannot comply with the study protocol

4.4 Informed Consent Each subject must sign and date the current Institutional Review Board (IRB) or Research Ethics Board (REB) approved version of the Informed Consent Form (ICF) prior to enrollment. A subject will be provided ample time and opportunity to inquire about the details of the trial and decide whether to participate before informed consent is obtained. Coercion or undue influencing of a subject for participation will be strictly avoided; a subject’s legal rights will not be waived. An ICF will be given to each prospective subject that includes an explanation of the trial and its duration, expected benefits and risks and inconveniences, and explanation of alternative treatments, medical record access and subject anonymity. The ICF is written in non-technical language. Informed consent shall be documented by the subject’s dated signature and the dated signature of the research personnel obtaining consent. The Investigator may delegate this responsibility to one or more staff members, and must document this on a Delegation of Authority Form.

4.5 Packaging, Blinding and Labeling of Supplies Smith & Nephew will manufacture and supply the investigational and sham control devices. The devices will be labeled according to U.S. requirements and the randomization plan established by the CLARITY Methods Center at McMaster University. The investigational device (EXOGEN 4000+) used in this trial is identical to the approved and commercially marketed EXOGEN Class III medical device. The investigational device and the control will be labeled as required by 21 CFR Part 812.5:

“Caution – Investigational device: Limited by U.S. law to investigational use” At the trial’s conclusion, all used and surplus devices will be returned to the sponsor.

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4.6 Unblinding Investigators, subjects, outcome assessors and data analysts will be blind to treatment allocation. The active and placebo-treatment devices cannot be distinguished by the subject or Investigator as the signal provides no audible or physical sensation. All information regarding device randomization will be kept confidential and secure until blinded adjudication and data analyses are complete. In the event of a medical emergency that directly affects the health status of the subject, it may become necessary to unblind allocation status to determine the specific treatment the subject has received while enrolled in the study. A medical emergency is defined as an event which necessitates immediate attention regarding the treatment of a subject. The Site Investigator is required to contact the CLARITY Methods Center and provide details of the medical emergency as soon as possible after the event. At no time will the subject’s health be compromised or medical treatment delayed. If a subject’s treatment allocation is unblinded the subject will, if feasible, continue in the study and follow the designated follow-up schedule as per protocol. The Site Investigator will document the details of the medical emergency as required and report the reason for unblinding in the subject’s medical record and on the appropriate forms to CLARITY Methods Center.

4.7 Device Accountability/ Disposition The CLARITY Methods Center at McMaster University is responsible for traceability of all investigational devices under this trial. The CLARITY Methods Center will provide each investigational site with sets of boxes containing active or inactive EXOGEN 4000+ devices labeled with sequential numbers. Access to EXOGEN 4000+ investigational devices will be limited to trial personnel. Investigational sites will use the Disposition Log to track the devices. Site Investigators are responsible for proper storage of the received sets of trial device and for maintaining the Disposition Log at their investigational site. All used and surplus investigational devices will be returned to CLARITY Methods Center for reconciliation and then returned to Smith & Nephew for final disposition. The CRO Clinical Project Manager (or designee) will review location of the device storage and completion of the investigational site’s Disposition Log at site monitoring visits

4.8 Randomization Randomization and initial treatment with the study device will occur as soon as possible following the definitive treatment with an intramedullary nail and documentation that the subject has provided written informed consent. Per inclusion criteria, subjects will not be randomized if consent has not been obtained within 14 days of intramedullary nailing of the

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tibial fracture. The Research Coordinator will use a randomization list provided by the CLARITY Methods Center at McMaster University to assign subjects a unit number corresponding to either an active or a placebo-treatment ultrasound device. Subjects will be stratified according to investigational site, and according to whether they have sustained a closed or open fracture of the tibia. Randomization will take place in blocks; sites will be unaware of the block size. The CLARITY Methods Center will prepare separate stratified randomization schedules for each investigational site. A subject may agree to participate and sign the ICF, but ultimately not receive the active or placebo-treatment device following randomization. Reasons for this might include a change in medical condition or subject withdrawal of consent. If this occurs, the investigational site will not assign the randomized treatment assigned to that subject to another subject. The unused study device will be returned to CLARITY Methods Center.

4.9 Clinical Assessments Primary Outcome Measures for the Trial The two primary effectiveness outcome measures for this trial are: 1) the Physical Component Summary Score of the SF-36. 35,36,37 and 2) the time to radiographic fracture healing. 1) Physical Component Summary Score of the SF-36 The SF-36 is a widely accepted, well-validated functional status measure that was developed from the Medical Outcomes Study.30,31,32 It is a self-administered, 36-item questionnaire that measures health-related quality of life in eight domains:1) physical functioning, by measuring the ability to perform a variety of daily activities and tasks that require physical effort (10 items); 2) role limitations due to physical problems (4 items); 3) role limitations due to emotional problems (3 items); 4) vitality, measuring perceived level of energy and fatigue (4 items); 5) freedom from bodily pain (2 items); 6) social functioning (2 items); 7) mental health, by measuring both negative and positive emotional states (5 items); and 8) general health perceptions (6 items). Each domain is scored separately from 0 (lowest level) to 100 (highest level). Both physical and mental summary scores can be obtained by summarizing the domains. The physical component summary score (PCS) is composed of the following domains: physical functioning, bodily pain, role-physical, and general health. The SF-36 has demonstrated good construct validity, high internal consistency, and high test-retest reliability. In a previous study, the CLARITY Research Group has shown that 3 of 4 domains comprising the SF-36 Physical Component Summary Score are responsive to improvement in functional recovery in subjects with ankle fractures over the period of one year (Table 1).33

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Table 1 9 Change in SF936 Subscores Over Time

Methods: Clarity Research Group conducted a two year prospective observational cohort study to evaluate health-related quality of life in thirty patients with unstable ankle fractures who were otherwise healthy. Only patients from two university-affiliated hospitals suffering unstable Type B Weber ankle (tibia/fibula) injury patterns requiring surgery were eligible. Patients completed the short-form 36 (SF-36) questionnaire and a visual analogue pain scale at discharge, and 3, 6, 12 and 24 months post-operation. 33

2) Time to Radiographic Fracture Healing Radiographic fracture healing will be defined as bridging of 3 cortices using the Radiographic Union Scale for Tibial Fractures (RUST) system. The RUST system assigns a score to a given set of AP and lateral radiographs based on the assessment of healing at each of the four cortices visible on these projections (i.e. medial and lateral cortices on the AP x-ray, anterior and posterior cortices on the lateral x-ray). Each cortex receives a score of one point if it is deemed to have a fracture line with no callus, two points if there is callus present but a fracture line is still visible, and three points if there is bridging callus with no evidence of a fracture line. The individual cortical scores are added to give a total for the set of films with four being the minimum, indicating the fracture is definitely not healed and twelve the maximum score, indicating the fracture is definitely healed.

Domain Post-op 3 mon 6 mon 12 mon 24 mon AMERICAN Norm

(Age Matched)

P-value1

Physical Function 13.3 32.5 61.0 66.0 67.5** 89.3 P<0.01

Bodily Pain 30.0 47.7 60.54 68.7 75.3** 80.2 N.S.

Social Function 33.3 51.1 75.5 76.5 78.3** 85.1 N.S.

Role-Physical 15.0 28.5 55.2 66.0 68.5** 89.2 P<0.01

Role-Emotional 66.7 89.9 88.9 81.3 89.4** 88.6 N.S.

Vitality 35.0 48.9 54.5 60.0 62.7** 60.6 N.S.

General Health 68.5 71.4 66.5 63.8 65.3 70.2 N.S.

Mental Health 72.1 69.2 70.0 76.0 77.3* 74.2 N.S.

N.S. = Non Significant 1 P-value comparing AMERICAN Norm to 24 month follow-up SF-36 subscores. Significant change in score over time- *p<0.05,**p<0.01 (ANOVA)

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Anteroposterior and lateral view x-rays will be evaluated to assess the number of bridged cortices. A cortex will be judged bridged when it achieves a minimum RUST score of 2 or 3. Although deemed radiographically healed when 3 cortices are bridged, subject will continue to undergo radiographic evaluation until all 4 cortices are bridged. Anteroposterior and lateral radiographs will be standardized whenever possible, with use of the same x-ray machine at each site and the same exposure settings. The RUST scoring system is a radiographic method based upon the assessment of cortical bridging that has shown excellent reliability among residents, community surgeons and traumatologists (Table 2).

Table 2 9 Radiographic Union Scale for Tibial Fractures (RUST)

Inter and Intra9observer ICC values for the RUST

Reviewers Inter9observer ICC

(95% CI) Intra9observer ICC

(95% CI)

Traumatologists 0.86

(0.76 - 0.92) 0.89

(0.80 - 0.95)

Community surgeons 0.83

(0.72 - 0.91) 0.85

(0.72 - 0.92)

Residents 0.81

(0.66 - 0.89) 0.83

(0.68 - 0.90)

Overall 0.86

(0.79 - 0.91) 0.88

(0.80 - 0.96)

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The CLARITY Research Group has previously evaluated the reliability of surgeons’ assessment of fracture healing utilizing cortices bridged by fracture callus (Table 3).37

Table 3 9 Agreement Among Surgeons in the Assessment of Fracture Healing

Parameter

Overall weighted Kappa

95% CI

General impression 0.67 0.59-0.75

Cortices bridged by callus 0.75 0.61-0.89

Cortices with fracture line 0.70 0.56-0.84

Extent of callus 0.57 0.43-0.71

Methods: Anteroposterior and lateral x-rays of the tibia from 30 patients treated with an intramedullary nail were identified from a trauma database at St. Michael’s Hospital, Toronto, Ontario, Canada. These x-rays represented a wide spectrum in the progression of healing (not healed to completed healed). These x-rays were typical of those which surgeons are expected to be able to evaluate at follow up (6 months). Four orthopaedic surgeons from 2 centers in Toronto (Sunnybrook Health Sciences Center, St. Michael’s Hospital) were asked to independently review 30 x-rays of tibial fractures treated with intramedullary nails. For each x-ray surgeons described their impression of the fracture as: definitely healed, probably healed, indeterminate, probably not healed and definitely not healed.

Results: Agreement in responses was analyzed by a quadratically weighted kappa statistic. The overall agreement among surgeons was good (kappa=0.67). 37 Good reliability was achieved utilizing this method (weighted Kappa = 0.75, 95%CI 0.61-0.89).

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Primary Safety Outcome Measures for the Trial

The primary safety outcome measures of this trial are to demonstrate safety by showing that the number and proportion of subjects with device related adverse events and unplanned secondary procedures related to bone healing and infection are clinically equivalent between treatment groups.

Reports of secondary procedures and adverse events will be summarized. Secondary procedures that will be classified as study events include: 1) bone grafts, implant exchange or implant removal for nonunion or malunion; 2) dynamization; 3) removal of locking screw(s) due to hardware breakage or loosening of screws; and 4) re-operation to treat infection. Failure of screw-bone mechanical constructs (i.e., broken or bent screws) that dynamize a fracture will also be considered study events. The following secondary procedures will not be considered study events: 1) re-operations planned at the time of initial surgery; 2) removal of proximal or distal locking screws that do not dynamize the fracture; 3) soft tissue coverage in the absence of infection; 4) in open fractures copious irrigation and debridement of soft tissues and contaminated bone may be repeated as necessary following the initial surgery; 5) treatment of wound or tissue necrosis in the absence of infection; and 6) re-operations to correct an unacceptable degree of mal-alignment following the initial surgery. A re-operation to correct zero percent cortical contact will not be classified as a study event. Once a procedure has been performed and cortical contact achieved, however, subsequent procedures required to maintain cortical contact may be identified as study event. Secondary Outcome Measures for the Trial – Functional Status Other functional status measurements will be reported as secondary outcome measurements. The investigational sites will document when previously working subjects return to work, when subjects report they return to pre-injury function, and when they achieve a pre-specified level of activity that they consider an acceptable outcome. Subjects will complete the Health Utilities Index Mark II/III (HUI) as an additional measure of function at each study visit. The HUI is a validated generic utility measure that will be administered along with the SF-36.34, 35, 36 Baseline quality-of-life data will be collected retrospectively on the SF-36 during completion of enrollment data collection forms.

Secondary Outcome Measures for the Trial – Rates of Non9union

Rates of non-union will be recorded from reports of secondary procedures and adverse events. Adjudication of Outcomes and Events Three voting surgeon members of the CAC will adjudicate time to fracture healing, non-union, secondary procedures, fracture-related adverse events, and infections treated non-surgically.

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The members of the CAC are not participating as investigators in the trial.

There will be two independent reviews of radiographs by voting members of the Central Adjudication Committee (CAC). None of the members of the CAC are participating as investigators in this trial.

The first independent review is the rapid adjudication process which occurs when the investigator determines the presence of bridging callus at all 4 cortices (a RUST score of at least 2 out of 3 at all four cortices) based on the current visit’s x-rays. One of the three voting members of the CAC will review only the x-rays from the current follow-up visit to determine the number of cortices bridged.

If the CAC member agrees with the investigator’s assessment, the investigator will be notified to instruct the subject to discontinue use of the study device and to follow the subject according to the schedule for subjects who are radiographically healed.

If the CAC member disagrees with the investigator’s assessment, the investigator will be notified to follow the subject according to the schedule for subjects who are not radiographically healed. The subject will continue use of the study device.

The second independent review of radiographs is the final adjudication process which occurs after subjects have completed all follow-up visits. Three voting members of the CAC will review all x-rays for each subject and determine the number of cortices bridged at each visit.

The x-rays will be blinded as to treatment group and treating investigator; however, the x-rays will be evaluated sequentially by follow-up visit as this represents the standard practice of medicine. Any bias introduced by sequential review of the x-rays should impact the active and sham treatment groups similarly due to the randomization and concealment of allocation status.

The reviewers will evaluate the x-rays independently and then reach consensus on the number of cortices bridged at each follow-up interval. Determination from the final adjudication process will be used in the primary effectiveness analysis...

5. Trial Procedures

5.1 Schedule of Events The schedule of observations and assessments to take place during the study is outlined in Figure 4. The remainder of this section describes the events and assessments that are to take place at each study time point. Note that adverse events (AEs) are monitored and recorded from the time of the first treatment through the last follow-up visit.

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Figure 4 Schedule of Events

Event Window

Enroll

6 weeks

+ or –

14 days

12 Weeks

+ or –

14 days

18 Weeks

+ or –

14 days

26 Weeks

+ or –

14 days

32+ Weeks

+ or –

14 days

38 Weeks

+ or –

14 days

44+ Weeks

+ or –

14 days

52 Weeks

+ or –

14 days

Inclusion/Exclusion x

Informed consent x

Randomization x

Enrollment Package Forms:

o Baseline Characteristics

o Fracture Characteristics

o Surgical Report

x

X-rays and Radiograph Form*

x x x x x x x x x

Return to Function Form x x x x x x x x x

Follow-Up Assessment Form

x x x x x x x x x

SF 36 x x x x x x x x x

HUI (Health Utilities Index) x x x x x x x x x

Medications Form* x x x x x x x x x

Adverse Event Assessment**

x x x x x x x x

Study Completion*** x

+ Subjects who do not have bridging of all 4 cortices at the 26 week follow up and/or the 38 week follow up will be required to return at 32 weeks and 44 weeks for follow up.

*The Medications Form, X-rays, and Radiographic Form will no longer be required once the CAC confirms that the subject’s fracture shows radiographic evidence of bridging at all 4 cortices. Subjects who do not demonstrate bridging at all 4 cortices will continue to return for follow-up assessment, x-rays and study questionnaires until this criterion is met or until their 52-week follow up.

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** See Section 6 for a detailed description of Adverse Event Assessment procedures.

*** Completions, voluntary withdrawal, lost to follow-up and study termination will be recorded on the Study Completion form as they occur.

5.2 Subject Screening Investigational sites will utilize a Subject Screening Log to collect information on all subjects considered for the trial, regardless of whether the selection criteria are met. The screening log is to be completed throughout the duration of trial recruitment. 5.3 Enrollment For this trial, subjects are considered enrolled once they have been assigned to one of the two treatment groups. The following baseline data must be collected prior to the first treatment with the study device:

• Written Informed Consent • Baseline Characteristics • Pregnancy test, if applicable • Medication Assessment • Baseline Radiographs • Baseline SF-36 • Baseline HUI • Return to Functioning Questionnaire

Instructions on use of the EXOGEN 4000+ ultrasound device will be provided to enrolled subjects. The first treatment must begin not later than 14 days after definitive operative treatment with intramedullary nailing. The responsible study personnel at the study center will review the study requirements with the subject to help ensure compliance with the treatment and follow-up schedule. 5.4 Follow9up Assessments – 6 Weeks through 52 Weeks Following the enrollment visit, all subjects will return to the study center for follow-up evaluation at 6, 12, 18, 26, 38 and 52 weeks. During these visits, subjects will complete questionnaires and be assessed for adverse events. Subject will also have a follow-up assessment, and radiographic evaluation until all 4 cortices are bridged. If all 4 cortices are not bridged at 26 weeks, subjects will return for up to 2 additional visits (32 and 44 weeks) for follow-up assessment, to complete questionnaires and undergo radiographic evaluation. All subjects will return at 38 and 52 weeks for physical examination and to complete study questionnaires, and an adverse event assessment, and those without 4 bridged cortices will undergo a follow-up assessment and radiographic evaluation..

The investigator will interpret the radiographs using the RUST scoring system (see Section_4.9, Secondary Outcome Measures for the Trial – Radiological) to determine the

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number of cortices bridged. Once the investigator determines that 4 cortices are bridged, the CAC will review the radiographs to confirm the number of bridged cortices. Once the CAC confirms that all 4 cortices are bridged, no further radiographs will be required.

Subjects with fewer than 4 bridged cortices at 26 weeks will be asked to return to undergo radiographic evaluation and complete study questionnaires at the following intervals until all cortices are bridged:

� 32 weeks � 38 weeks (a regular follow-up visit where all patients complete study questionnaires); � 44 weeks � 52 weeks (the final follow-up visit where all patients complete study questionnaires)

Once all 4 cortices are bridged, the subject will only be required to return to the study center for their remaining scheduled visits (6, 12, 18, 26, 38 & 52 weeks) to complete study questionnaires and be assessed for adverse events.

Data will be recorded on the CRF according to the schedule noted in Figure 4. All adverse events and complications, device related or not, will be recorded and reported appropriately. Patient compliance with EXOGEN 4000+ ultrasound treatment will be checked using the Patient Compliance Monitor function of the device at each office visit until the CAC has determined that the fracture has healed.

The Exogen 4000 contains an internal patient use timer, which monitors and records the daily use of the device. When the device turns ON it initially performs a self-test after which it displays the total number of FULL treatments completed, then the number of PARTIAL treatments. If the device is removed prior to the daily treatment completion, the unit will shut off and the abbreviated treatment time will be recorded. At each follow-up visit the Investigator will be able to determine if a patient has used the device as instructed by checking the device compliance monitor.

The following information and assessments will be collected for all subjects:

• SF-36 • HUI • Return to Functioning Questionnaire • Follow-up Assessment Form (until fracture has healed) • Adverse Event assessment • Medications Form (until fracture has healed) • Radiographs and Radiograph Form (until fracture has healed)

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Self-administered questionnaires will be used for each follow up visit. If a patient fails to return to the office for a follow-up visit, they will be mailed the self-administered version of the questionnaires if time permits completion of the questionnaires within the study visit window. Telephone-administered questionnaires will only be used as a last resort.

5.5 Subject Early Withdrawal and Lost to follow up A subject can elect to withdraw from this trial at any time. A withdrawn subject’s ongoing follow-up treatment will not be compromised in any way subsequent to withdrawal. If a subject elects to withdraw prior to completing the trial, the site Research Coordinator will make an effort to collect final data and information regarding the reason for withdrawal, and will record the subjects’ withdrawal on the Study Completion form.

5.6 Subject Trial Completion The 52-week follow-up visit will serve as the final study visit. If the subject’s fracture is still not healed, he or she will discontinue treatment with the study device at this time, and will return the device to the local study personnel.

5.7 Subject Death If a subject death occurs during the clinical investigation the local study personnel are to notify the reviewing IRB/REB and the CLARITY Methods Center immediately. The CLARITY Methods Center will notify both Smith and Nephew and the CRO immediately. Smith and Nephew will be responsible for notifying the appropriate regulatory authorities. Local study personnel will complete both an Adverse Event form and a Study Completion form for any subject death, device related or not.

6. Adverse Event Assessment

6.1 Adverse Event – Definitions Adverse events will be assessed starting immediately after the first treatment is administered and at each follow-up visit. The Site Investigator will report all directly observed adverse events and all adverse events reported by subjects. All adverse events that occur in trial subjects will be reported, whether or not the event is considered device related. All Adverse Events (AEs) will be documented on the Adverse Event form. The definition of an AE is as follows:

Adverse Event: Any undesirable experience (associated with signs, symptoms, illnesses, or other medical events) observed in or reported by a subject, whether or not associated with the investigational product(s) or related procedures. AEs include the following:

• All suspected device-related adverse reactions

• All reactions from medication overdose, abuse, withdrawal, sensitivity, or toxicity

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• Apparently unrelated illnesses, including the worsening of a preexisting illness

• Injury or accidents. If a medical condition is known to have caused the injury or accident (e.g. a hip fracture secondary to dizziness), the medical condition (dizziness) and the diagnosis (hip fracture) should be reported as 2 separate adverse events.

• Clinically significant abnormalities in physiological testing or physical examination findings that require clinical intervention or further investigation beyond ordering a repeat (confirmatory) test.

The following definitions will be used in the classification of AEs:

Unanticipated Adverse Device Effect (UADE): Any adverse effect on health or safety or any life-threatening problem or death potentially caused by, or associated with, the EXOGEN 4000+ device, if that effect, problem or death was not previously identified in nature, severity, or degree of incidence in the protocol or application (including a supplementary plan or application), or any other unanticipated serious problem associated with the EXOGEN 4000+ device that related to the rights, safety, or welfare of subjects [21 CRF 812.3 (s)].

6.2 Relationship to EXOGEN 4000+Treatment: The Investigator is also required to comment on the likely relationship to treatment with the EXOGEN 4000+ ultrasound device. The following definitions will be used for that determination:

Definite 9 The AE follows a clear temporal sequence from administration of the study device; the AE follows a known or expected response pattern to the study device and the AE could not be reasonably explained by the known characteristics of the subject's clinical state. Probable 9 The AE follows a reasonable temporal sequence from administration of the study device; the AE follows a known or expected response pattern to the study device. Possible - The AE follows a reasonable temporal sequence from administration of the study device; the AE follows a known or expected response pattern to the study device, but could readily have been produced by a number of other factors. None – An AE for which sufficient information exists to indicate that the etiology is unrelated to the study device; the AE does not follow a reasonable temporal sequence following administration of the study device; the AE is readily explained by the subject’s clinical state or other therapies.

6.3 Unanticipated Adverse Device Effect (UADE) Reporting: As required in 21 CFR 812.150, if the AE involves an “unanticipated adverse device effect” a detailed report must be submitted to the FDA and to the reviewing IRB/REB no later than 10 working days after the Site Investigator or Research Coordinator first learns of the AE. The Site Investigator is required to notify the CLARITY Methods Center within two working days of learning of the UADE. The CLARITY Methods Center will notify both the Sponsor and the CRO.

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Smith & Nephew, Inc. will be responsible for reporting UADEs to the appropriate regulatory authorities.

6.4 Data Safety Monitoring Board (DSMB) The Data Safety Monitoring Board (DSMB) will be an independent group who are not participating in the study and have no affiliation with the Study Investigators or the manufacturer Smith & Nephew, Inc. The proposed DSMB will consist of two orthopaedic surgeons and one biostatistician. DSMB responsibilities, membership, and procedures will be documented in a committee charter. 7. Statistics All analyses will be performed with the SAS® software package (SAS Institute Inc., Cary, NC, USA). A statistician who is unaware of treatment group allocation status will perform all statistical analyses. 7.1 Historical Data and Sample Size Estimation The choice of sample size for this study is based upon the primary outcome, patient-important gains in functional status as measured by the Physical Component Summary score of the SF-36. All statistical hypotheses will be two-sided. The alpha level for comparisons will be 0.05 for the primary and secondary outcomes. The trial is designed to have a statistical power of 80% for the primary comparison. The smallest important difference in the SF-36 is not well-established, and investigators have provided different estimates; however, a 3 to 5 point change in score on a 0 to 100 scale is often cited as a clinically meaningful threshold in evaluating patient changes, based on the work by Stewart and colleagues.38 More recent work by other authors have suggested that the smallest important difference is larger than 3 to 5 points,39,40 ,41,42 and a recent systematic review found that the threshold of discrimination for changes in the SF-36 is approximately half a standard deviation43. Normative data from the Oxford Healthy Lifestyle Survey III reported standard deviations of Summary Physical scores for the SF-36 ranging from 6.7 to 28.9, depending on age and occupational category.44, 45 Based on a previous CLARITY Research Group study of Health Related Quality of Life in patients with distal tibial fractures, the investigators anticipate a standard deviation of approximately 12 to 14 for Summary Physical scores.33 Considering these findings a study of 450 subjects, 225 per arm, will be adequate to identify a subject-important difference in absolute SF-36 Physical Component Summary scores across a plausible range in the magnitude of the standard deviation (Table 4). Sample size calculations for this trial are based on low estimates of the minimal important difference, 3 to 5, which makes the calculation conservative. Assuming a 10% loss to follow-up, the study will recruit and enroll an additional 50 subjects in order to have 450 subjects for the analysis population)

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Table 4 9 Sample Size per Arm (80% Study Power, Alpha=0.05)

Difference in SF-36 scores, between treatment and control groups

Legend: Table 4 shows the number of patients required per arm across a range of plausible standard deviations and absolute differences of SF-36 scores between treatment and control groups. Shaded areas represent conditions for which the trial is adequately powered to detect clinically important differences. The CLARITY Group at McMaster recently coordinated and submitted for publication, a large, multi-center, randomized clinical trial of reamed versus non-reamed intramedullary nails in the management of patients with tibial shaft fractures (the eponym for which is SPRINT). This study successfully recruited 1339 patients with open (Gustillo Grade I-IIIb) and closed (Tscherne Grade 0-3) tibial fractures. We found that at 3-months post operation 80% of fractures did not demonstrate radiographic healing, 47% at 6-months, and 13% at 12 months. Table 5 shows the study power for a sample size of 450 patients (225 per group) and demonstrates that given the chosen sample size of 225 per group, they will have a high likelihood of detecting moderate treatment effects across the plausible range of radiographic healing rates.

Table 5: Estimate of Study Power for N=225 Per Group

Relative Risk Reduction

25% 30% 35% 40%

Absolute Percent of 40% 0.61 0.77 0.89 0.96

3-point 4-point 5-point 6-point

24 1005 566 362 252

20 698 393 252 175

16 447 252 161 112

12 252 142 91 63

8 112 63 41 28

Standard Deviation

4 28 16 11 7

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45% 0.68 0.84 0.93 0.98

50% 0.76 0.90 0.97 0.99

55% 0.83 0.94 0.99 0.99

Unhealed Fractures in the Control Group at 6 Months

60% 0.89 0.97 0.99 0.99

Legend: Table shows the power of a proposed study to detect the indicated relative risk reduction, for a given control group percentage of unhealed fractures at 6-months, assuming an alpha error of 5% for a two tailed test, and providing for a sample size of 450 patients (225 per group)

7.2 Analysis Population All subjects entered into the trial and randomized will be included in the analysis, regardless of compliance with treatment, or any other deviation from protocol (Intent-to-Treat population). A per-protocol analysis population will be performed following review of the ultrasound device Patient Compliance Monitor, which records information on treatment compliance. Treatments of at least 18 minutes duration will be counted as full treatments. Distributions of compliance rates of both treatment and control groups will be compared to ensure they are similar. This study will compare the effects of low intensity pulsed ultrasound versus placebo-treatment in subjects with closed and open tibial shaft fractures. Preliminary analysis of the Pilot Study data suggests that 30% of the sample size will include subjects with open fractures. Thus, it is anticipated that this study will include 150 subjects with open fractures (75 per treatment arm). We are including only fractures of the tibia in the proposed trial. Random allocation of patients will be stratified by whether their fracture is open or closed, and we are excluding Gustillo Grade IIIc injuries. Stratified randomization with permuted blocks will ensure that treatment and control groups have equal representation of eligible closed (Tscherne Grade 0-3) and open (Gustillo Grade I-IIIb) tibial fractures. If ultrasound improves function and time to fracture healing, we anticipate that it will do so across the range of tibial fracture severity and location. However, we are collecting detailed data on fracture characteristics and will include the fracture type as an independent variable in our analyses using generalized linear models. Evidence based on validated models suggests that fitted regression models are reliable when the limiting sample size is 10 to 20

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for each predictor considered. 46 Our trial is sufficiently powered to accommodate our planned independent variables. 7.3 Primary Effectiveness Analyses The primary effectiveness analysis for return to function will use linear models to compare SF-36 Physical Component Summary scores over time considering factors of time, treatment and the interaction between time and treatment. We will capture the following variables for inclusion in our linear models: age, gender, smoking status, trial site, fracture type (open or closed), fracture location (metaphyseal or diaphyseal), and fracture grade. All subjects entered into the trial and randomized will be included in the analysis, regardless of compliance with treatment, or any other deviation from protocol. SF-36 Physical Component Summary scores will be examined in order to acquire an estimate of a value that corresponds to functional recovery (i.e. return to work and/or return to pre-injury activities of daily living). Success of the SF-36 PCS endpoint will be dependent on demonstrating a statistically significant improvement in subjects assigned to the active Exogen treatment group compared to those assigned to sham group. The primary effectiveness analysis for time to radiographic fracture healing will be based on the Central Adjudication Committee (CAC) final adjudication review of x-rays and determination of fracture healing. To assess radiographic healing all of the subjects that were randomized into each study group will be analyzed for the time to radiographic healing in an intention-to treat analysis and will be defined as bridging of 3 cortices using the RUST system. Bridging is defined by a RUST score of at least 2 out of 3. Each fracture will be considered healed only at the time of a scheduled follow-up visit and no interim visit will be used to assign a healing time. Those patients that are not healed will be censored at the end of their follow-up.

Success of the time to radiographic healing endpoint will be dependent on demonstrating a statistically significant improvement in subjects assigned to the active Exogen treatment group compared to those assigned to sham group.

Details of the analysis are documented in a comprehensive statistical analysis plan (SAP) that will be finalized prior to unblinding of the study results.

We will perform the following subgroup analyses: (1) open vs. closed fractures, (2) analysis by fracture grade of severity, and (3) fracture location (metaphyseal vs. diaphyseal).

For any subjects that experience a non-union or fracture-related adverse event, or undergo an unplanned secondary procedure related to bone healing or infection, clinical sites also will be required to submit any additional x-rays, in-hospital notes, and clinic notes related to the event or secondary procedure.

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7.4 Secondary Effectiveness Analyses 7.4.1 Return to Work Time to return to work, as compared between ultrasound and control groups, will be evaluated using Kaplan-Meier survival analysis, as well as the comparison of two independent proportions. Specifically, the proportion of subjects who were working before their injury reporting return to work in the ultrasound group will be compared to the proportion of subjects who were working before their injury reporting return to work in the placebo-treatment group at 6-week, 12-week, 18-week, 26-week, 38-week and 52-week follow-up. 7.4.2 Return to Pre9Injury Level of Function Time to return to pre-injury level of function, as compared between ultrasound and control groups, will be evaluated using Kaplan-Meier survival analysis, as well as the comparison of two independent proportions. Specifically, the proportion of subjects reporting return to pre-injury level of function in the ultrasound group will be compared to the proportion of subjects reporting return to pre-injury level of function in the placebo-treatment group at 6-week, 12-week, 18-week, 26-week, 38-week and 52-week follow-up. 7.4.3 Level of Activity Time to return to normal activities, as compared between ultrasound and control groups, will be evaluated using Kaplan-Meier survival analysis, as well as the comparison of two independent proportions. Specifically, the proportion of subjects reporting return to normal activities in the ultrasound group will be compared to the proportion of subjects reporting return to normal activities in the placebo-treatment group at 6-week, 12-week, 18-week, 26-week, 38-week and 52-week follow-up. 7.4.4 Health Utilities Index (HUI) Mark II/III Linear models will be constructed to compare HUI scores between ultrasound and placebo-treatment groups over time considering factors of time, treatment and the interaction between time and treatment. 7.5 Primary Safety Analyses The proportion of device related adverse events and unplanned secondary procedures related to bone healing and infection will be compared between ultrasound and control groups with Pearson’s chi-square test, and association with independent variables will be explored with logistic regression. 7.4 Secondary Safety Analyses The occurrence of secondary outcomes including nonunion will be compared between ultrasound and control groups with Pearson’s chi-square test, and association with independent variables will be explored with logistic regression.

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7.7 Descriptive and Summary Statistics Detailed demographic data on recruited subjects, including their injuries and co-morbidities, and treatment will be collected and reported. 7.8 Missing Data The linear models will adjust for missing data. 7.9 Pooling of Data across Study Sites It is expected that data will be poolable across study sites since all sites and investigators will follow a common protocol with identical inclusion/exclusion criteria (same population), treatment, and outcome assessment. Any difference in data across study sites will be accounted for by including a factor for treatment by site interaction in the primary analysis model. 8. Interim Analysis and Early Stopping Rules Interim analyses will be performed when approximately 300 subjects (150 per treatment group) have completed the trial, including those subjects lost to follow-up. The data analyst will present the results of these analyses, including confidence intervals, to an independent DSMB. The DSMB will be charged with considering all of the available data, and will then advise the Steering Committee on whether the trial should be continued or stopped. If the DSMB thinks that early stopping may be appropriate, they have the option of performing another analysis of the data after the next 50 patients have completed the trial. Details of the interim analysis and early stopping rules are documented in a comprehensive statistical analysis plan (SAP). No one other than DSMB members will be aware of the data on which the DSMB makes its decision, and no one involved in the study will be aware of the content of their deliberations. 9. Trial Monitoring Monitoring of the clinical trial will be a continuous, interactive process overseen by the CRO Clinical Project Manager to ensure that high-quality data are obtained. The trial will be conducted in compliance with the protocol, applicable laws, regulations, and Good Clinical Practice (GCP). Appropriately trained personnel designated by CRO Clinical Project Manager will monitor all subjects at investigative sites. Monitoring will be conducted according to the 21 CFR 812; 21 CFR 50 and by the CRO’s Standard Operating Procedures (SOPs) or TRUST trial-specific SOPs and under the guidelines specified in the Monitoring Plan. It is important that the Investigator and the relevant study personnel are available during the monitoring visits and possible audits and that sufficient time is devoted to the process.

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9.1 Periodic Monitoring Visits Monitoring visits during the trial are necessary to assess the Investigator’s adherence to the protocol, agreement, and regulation. Monitoring will occur at a mutually agreeable time between investigative sites, the CRO, and the CLARITY Methods Center. The study may also be subject to an inspection by appropriate regulatory authorities. It is important that the Investigator and the relevant study personnel are available during the monitoring visits and possible audits and that sufficient time is devoted to the process. 9.2 Close9Out Visit This visit will be conducted through the CLARITY Methods Center and the CRO with each investigative site to review and audit charts, to ensure that all study events have been captured. Any ongoing responsibilities will be discussed with the Investigator. This communication will be documented. 10. Administration Procedures 10.1 Investigational Sites This trial is designed to recruit subjects from up to 40 investigational sites. We will combine sites that enroll less than 10 patients to give more power to a test for differences

between sites, as long as this results in combining less than 25% of all enrolled

patients. The CLARITY Methods Center may recruit an additional 15 orthopaedic surgeon sites to serve as replacements for sites that have consistent quality problems with study data or do not meet minimal recruitment expectations (no subjects enrolled over a 4-month consecutive period). Replacement of an investigational site will be at the discretion of the Principal Investigator. The CLARITY Methods Center will coordinate communication with investigative sites (Figure 5).

10.2 Investigator Training Site Investigators and/or Research Coordinators from each recruiting site will be trained in the use of the EXOGEN 4000+ device, as well as in the administration of the SF-36, HUI, and the completion of all CRFs/worksheets. 10.3 Data Requirements & Handling At enrollment, a subject will be assigned a unique Subject ID to provide an additional safeguard for confidentiality. The Subject ID will be used on all data collection forms. Subject IDs will be assigned consecutively at each site.

10.4 Case Report Forms This trial will utilize a web-based remote data collection system with a site choosing to do their own data entry from worksheets or completing paper CRFs and submitting them to the

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CRO for data entry. The decision for which method to use is left to the site. Training for both methods will be provided to the sites. Sites using the web-based system can make data corrections at any time. If the form to be changed has already been electronically signed by the Investigator, a reason for the change must be provided. The form status will then change, requiring the Investigator to resign the form. For sites using paper CRFs, 3-ring binders will be provided to the sites at their site initiation. Additional binders and CRFs can be requested through the CLARITY Methods Center. The only identifiers on the CRFs will be subject ID and subject initials. Appropriate copies of the CRFs will be sent to the CRO for data entry and they will be filed in the subject binder. 10.5 Source Documentation Regulations require that Investigators maintain information in the trial subject’s medical records that corroborate data collected on the CRF. In order to comply with these regulatory requirements, the following information will be maintained and made available as required for monitors and/or regulatory inspectors.

• Medical history/ physical condition of the trial subject before involvement in the trial sufficient to verify eligibility according to protocol entry criteria

• Informed Consent • Dated and signed documentation from each trial subject visit with reference to

the CRFs/worksheets

• AEs reporting and follow-up of the AEs (event description, onset date, duration, relationship to device , outcome and treatment for AE)

• Trial subject’s condition upon completion of or withdrawal from the trial

10.6 Protocol Deviations Deviations from the Protocol by the Investigator are not allowed except in cases of medical emergency. Investigational sites will report protocol deviations to their reviewing IRB/REB per local standard practice. All deviations will be reported to CLARITY Methods Center on a Protocol Deviation form.

Documentation of deviations identified by the Investigational site, the CRO monitor, or CLARITY Methods Center will be recorded in the monitoring reports for the purpose of tracking compliance in accordance with the protocol and GCP guidelines. The CRO monitor or CLARITY Methods Center will initiate corrective actions consistent with the protocol guidelines based on individual deviations or trends, as appropriate.

The following is a list of potential events considered to be protocol deviations. This list is not exhaustive:

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• Missed visit • Eligibility criteria not met

• Trial procedures not followed

• Subject signed ICF after trial activities started

10.7 Protocol Amendments Changes to the protocol may occur during the course of the trial. Upon approval from the FDA, of the amended protocol, the CLARITY Methods Center will send the amended protocol to each site for IRB/REB approval. It is the Site Investigator’s responsibility to obtain approval from the reviewing IRB/REB.

10.8 Document Retention and Availability All essential trial documents will be retained in a readily-accessible location for 2 years after the FDA approval of the investigational product or discontinuation of the IDE, or longer if required by local regulatory requirements. Records are subject to inspection by the CLARITY Methods Center, the CRO, Smith & Nephew, the FDA and other regulatory agencies as applicable.

The Investigator is responsible for the retention of the following records:

• IRB/REB approval documents, including approved ICF

• All correspondence pertaining to the investigation (including IRB/REB and sponsor)

• Device administration and use recorded on the Device Disposition Log

• Subject’s case medical history

• Signed/dated ICF for each subject • Protocol deviations, documentation showing the dates and reasons for each

• Investigational Plan

• Case Report Forms and applicable source documentation • Records of AEs

• Financial Disclosure Forms

• Site Personnel Signature Log • Monitoring Site Visit Log

The Site Investigator is required to notify CLARITY Methods Center prior to destroying/deleting any investigational records and allow CLARITY Methods Center (or Sponsor) the option to transfer records to its own facility.

If a Site Investigator relocates, retires, or for any reason withdraws during the course of the study, the CLARITY Methods Center will be notified immediately and the respective study records will be transferred to another Site Investigator.

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10.9 Regulatory/Ethical Obligations As the device manufacturer, Smith & Nephew has the overall responsibility for the ethical conduct of the trial, including assurance that the trial meets the regulatory requirements of the FDA. This trial will also be performed in accordance with good clinical practice guidelines (GCP), the Declaration of Helsinki, and applicable local regulatory requirements and laws.

10.10 Institutional Review Board/Research Ethics Board The trial will be conducted in compliance with this protocol, and according to 21 CFR Parts 50, 54, 56 and 812. The final protocol for this clinical trial will be submitted to the reviewing IRB/REBs.

It is the responsibility of the Investigator at each site to obtain and retain the following:

• IRB/REB written approval for the site to participate in the trial

• IRB/REB written approval of the site’s ICF

• Review and approval of all amended protocols • A copy of the IRB/REB membership roster or, alternatively, its general assurance

number or letter of assurance

• All other IRB/REB correspondence

10.11 Other Institutions No other institutions will be utilized in this trial.

10.12 Records and Reports

10.12.1 Investigator Records

The Site Investigator is responsible for the retention of the following records:

• IRB/REB approval documents, including approved ICF • All correspondence pertaining to the investigation (including IRB/REB and

sponsor)

• Investigational plan • Financial disclosure forms

• Signed protocol/amendments

• Signed agreements • Investigator CVs

• Device shipping records

• Device administration and use, recorded on the Device Disposition log • Subject screening records

• Subject identification code list

• Subject’s case medical history • Signed/dated ICF for each subject

• CRFs/worksheets and applicable source documentation

• Records of AEs

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• Site personnel signature log • Monitoring site visit log

• Site training records

10.12.2 Investigator Reports

Site Investigators are responsible for the preparation and submission of the following reports:

• Unanticipated adverse device effects within 10 days of learning of the UADE to the CLARITY Methods Center

• Withdrawal of IRB approval to the CLARITY Methods Center

• Progress reports on the investigation no less often than yearly to the reviewing IRB/REB and CLARITY Methods Center

• Deviations from the investigational plan to the CLARITY Methods Center

• Informed consent violations within 5 working days after the use occurs to the IRB/REB and CLARITY Methods Center

• Final report within 3 months after termination or completion of the study to the IRB/REB and CLARITY Methods Center

The Investigator is responsible to forward to the CLARITY Methods Center any action that is taken by the IRB/REB with respect to the trial. The Investigator must also follow the requirements of their IRB/REB.

10.12.3 Sponsor Records

The CLARITY Methods Center will maintain the following records:

• All correspondence that pertains to the trial (involving sites, sponsor, CRO, regulatory authorities)

• Signed Investigator Agreements

• Signed protocol/amendments • Signed IRB/REB trial approval letters

• Documentation of Regulatory Approval

• Copy of the approved Permission for Access to and Use of Health Information )if applicable) and ICF

• Investigator CVs

• Device shipping records

• Master randomization list • Trial monitoring reports

• Device disposition logs

• Records of AEs

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10.13 Data Quality Assurance Continuous monitoring of trial data by the CRO and the CLARITY Methods Center will ensure that data quality is closely scrutinized. Standardized CRFs or worksheets will be used at each investigational center for documentation of subject and fracture-related information, and assessment results. For sites choosing to use paper CRFs, completed CRFs will be sent to the CRO for data processing. Following data entry, edit checks will be applied to identify missing or inconsistent data. The CRO will issue Data Clarification Forms (DCFs) to the sites and work with the sites to clarify the errant data. For sites choosing to use the web-based database, entry will occur by site research personnel and edit checks will be applied to identify missing or inconsistent data at time of form submission. The site will be responsible to review the queries and update incorrect data or provide comments to the query which will help the monitor or data reviewer determine query resolution.

10.14 Financial Disclosure In compliance with the requirements of 21 CFR Part 54, the CLARITY Methods Center will obtain the necessary financial information from the clinical Investigator in order to certify to the absence of certain financial interests or to disclose those financial interests at the time of a premarketing submission to the FDA. 10.15 Investigator Responsibilities The Site Investigator will be responsible for ensuring that this trial is conducted according to protocol, GCP guidelines, and FDA’s IDE regulations. The Site Investigator will be responsible for obtaining and maintaining IRB/REB approval. In addition, the Site Investigator is responsible for protecting the rights, safety and welfare of the subjects and for obtaining informed consent from each subject prior to initiating and study treatment.

10.16 Confidentiality All information generated during this clinical trial is considered highly confidential and must not be disclosed by any method to persons not directly involved with the trial without prior written consent from the CLARITY Methods Center and Smith & Nephew, Inc. All subjects’ health information will be kept confidential in accordance with all applicable laws and regulations. The CRO, FDA, Smith & Nephew representatives and local regulatory authorities will be allowed full access to review, audit and to copy subject records as required with personal identifiers removed.

11. Risk/Benefit Analysis 11.1 Known and Anticipated Risks Risks which may be associated with the use of the EXOGEN 4000+ ultrasound device and the use of ultrasound therapy for bone stimulation include:

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• Mild skin irritations due to the coupling gel that often resolve by changing the type of gel used.

• Mild skin irritations due to the device strap which is tightened to hold the study device in place over the fracture site, although a foam pad is included with the device to provide a padded surface when a cast is not used.

• Pain during treatment has been reported in a very small number of subjects Although low-intensity pulsed ultrasound is non-invasive and widely used in the treatment of fractures, the safety and effectiveness of the device has not been established under the following conditions:

• Individuals lacking skeletal maturity

• Individuals with active, implantable devices, such as cardiac pacemakers, operation may be adversely affected by close exposure to the EXOGEN 4000+ ultrasound device

• Pregnant or nursing women • Use of the ultrasound device for more than one daily 20-minute treatment period

• Simultaneous use of the ultrasound device and cellular phones which may cause interference to the EXOGEN 4000+ device ultrasound signal

• Pathological fractures due to bone pathology or malignancy • Individuals with thrombophlebitis, vascular insufficiency, abnormal skin sensitivity,

sensory paralysis, alcoholism and or/nutritional deficiency

• Individuals receiving steroid, anti-coagulant, prescription non-steroidal anti-inflammatory, calcium channel blocker and or diphosphonate therapy

11.2 Methods to Minimize Risk The following methods will be employed to minimize the subject’s risk:

• Subjects who are under the age of 18 will be exclude

• Subjects with pacemakers or other electronic implants will be excluded

• Pregnant or nursing females will be excluded • Subjects with pathological fractures will be excluded

• Subjects will be instructed not to use a cellular phone while applying the device

• Subjects will be instructed to: (1) always apply the gel before applying the ultrasound, (2) not apply the gel or ultrasound directly to an open wound, and (3) only use the ultrasound device for one 20-minute treatment per day.

11.3 Potential Benefits Possible benefits may include a significantly shorter time to fracture healing. This study may also help other individuals with tibial fractures in the future if this study treatment becomes a standard therapy.

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12. Investigator Statement and Signature I agree that I have read the accompanying protocol. I agree to conduct this study according to the approved protocol, and all applicable regulatory regulations, and any conditions of approval imposed by the governing IRB/REB or regulatory agency. I agree that I am responsible for protecting the rights, safety and welfare of the subjects under my care in this clinical study. I will ensure that the governing IRB/EC complies with 21CFR Part 56 and all regulatory requirements, and will be responsible for the initial and any continuing review and approval of this study. I understand that I am responsible for the control of all investigational devices in accordance with 21 CFR 812.110, and I will only permit the investigational device to be used only in subjects under my supervision. I agree to ensure that all associates, colleagues, and employees assisting in the conduct of this study are informed regarding their obligations in meeting the commitments of the study.

Investigator Name:________________________________________________________________

Investigator Signature:_______________________________________Date___________________

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9. Geerts, W.H.; Code, K.I.; Jay, R.M.; et al. A prospective study of venous thromboembolism after major trauma. New Engl J Med. 1994; 333: 1601–1606.

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sperimentali). Ann Italiani di Chir. 1952; 29: 211-220.

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ultrasonic treatments on fracture repair. Chinese J Physiol. 1992; 35: 21-26.

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invasive low-intensity pulsed ultrasound intensity on accelerated bone repair in a rabbit model. Trans Orthop Res Soc. 1991; 37: 452.

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Biol. 1983; 2 (Suppl): s61-s66.

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20. Xavier CAM, Duarte LR. Estimulacão ultra-sonica de calo osseo: aplicacão clinica.

Revista Brasileira de Ortopedia. 1983; 18: 73-80.

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Joint Surg [Am]. 1957; 39-A: 394-402.

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radial fractures with the use of specific, low-intensity ultrasound. J Bone Joint Surg [Am]. 1997; 79-A: 961-973.

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ultrasound therapy on time to fracture healing: a meta-analysis. CMAJ. 2002 Feb 19; 166(4):437-41.

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Tibial Shaft Fractures: A Survey of 450 Canadian Orthopedic Trauma Surgeons. Acta Orthop, 2008;79(5): 689-94

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fractures in Nottingham UK: are pain, osteoarthritis, and disability long-term complications? Greenwood DC, Muir KR, Doherty M et al. J Epidemiol Community Health. 1997; 51: 701-4.

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Health-Related Quality of Life following Operative Treatment of Unstable Ankle Fractures: A Prospective Observational Study. J Orthop Trauma. 2004; 18: 338-45.

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Schemitsch EH. Interobserver and intraobserver variation in the assessment of the healing of tibial fractures after intramedullary fixation. J Bone Joint Surg [Br]. 2002; 84: 15-8.

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EA, Ware JE Jr. Functional status and well-being of patients with chronic conditions. Results from the Medical Outcomes Study. JAMA. 1989; 262: 907-13. 39. wich KW, Nelson HS, Tierney WM, Babu AN, Kroenke K, Wolinsky FD. Clinically important differences in health-related quality of life for patients with asthma: an expert consensus panel report. Ann Allergy Asthma Immunol. 2003; 91: 148-53.

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Figure 5 Trial Organization

STEERING COMMITTEE

Overall clinical responsibility for the trial

Mohit Bhandari Thomas Einhorn Gordon Guyatt

James Heckman Kwok Sui Leung Emil Schemitsch

Paul Tornetta Stephen Walter

ALQUEST INC.

Data management, monitoring

Debra Jovanovich, Project Manager Christine Tjossem, Project Manager

Study Support Staff

CENTRAL (OUTCOMES) ADJUDICATION COMMITTEE

Review and classification of all clinical events

Members: Mohit Bhandari Gordon Guyatt Dave Sanders

Emil Schemitsch Stephen Walter

SAFETY AND EFFICACY MONITORING COMMITTEE

Review of adverse events, early termination of study based on

benefit/harm

Members: TBD

CLARITY METHODS CENTER

Communication with sites, randomization, data analysis

Mohit Bhandari Gordon Guyatt Paula McKay

Sheila Sprague Stephen Walter (Statistician)

Study Support Staff

PARTICIPATING CENTERS

Subject recruitment and follow-up

SMITH & NEPHEW Regulatory responsibility for the trial

Sponsor

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1. The initial follow-up times were at enrollment, 12 weeks, 24 weeks, 36

weeks, and 52 weeks post-enrollment.

The amended follow-up times were at enrollment and at 6, 12, 18, 26, 38,

and 52 weeks post-enrollment. Further, participants who did not show

radiographic bridging of all 4 cortices at the 26 week follow up and/or the

38 week follow up were required to return at 32 weeks and 44 weeks for

follow-up.

** This amendment was made to meet the Industry sponsor's desire to

have more follow-up assessments in order to capture any difference in time

to radiographic healing between treatment and control groups.

2. The initial primary outcome was functional recovery, as measured by short-

form-36 (SF-36) physical component summary scores.

The amended co-primary outcome was SF-36 physical component summary

scores and radiographic healing.

** This amendment was a compromise with the FDA's request to have

radiographic healing as a single primary outcome (the industry sponsor was

also supportive of radiographic healing as a single primary outcome

measure)

Here is the exact request from the FDA:

“If the device is intended to accelerate healing, it appears that the incidence

of healing and time to healing would be more appropriate primary

endpoints than SF-36 scores. Time to complete healing is also easier to

interpret than the relationship between time and SF-36 score, and if there is

a lower incidence of healing in the treatment group than in the placebo,

then showing a small improvement in SF-36 score might not be enough to

justify treatment. Please justify your primary endpoint or revise it to time to

complete healing.”

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nlyAnd this was our reply:

“If radiographic healing is accelerated by low-intensity pulsed ultrasound,

but return to function is neither more rapid not complete and other

procedures are not decreased (in other words, there is no benefit on any

patient-important outcome) allocating limited health care resources to the

intervention will be in the interest of neither the patient nor society. Thus,

considering this study positive on the basis of radiographic healing alone

may be misleading.

On the other hand, the outcome postulated by the reviewers, benefit

in SF-36 with the intervention but slower healing, is completely inconsistent

with the putative biological effect of the intervention. Such an outcome

would raise serious questions about the validity of the trial, and would

permit only the weakest of inferences.

Therefore, in response to the reviewer’s concerns, we would propose

two primary outcomes: (1) time to radiographic healing of tibial fractures,

and (2) functional status as measured by the Physical Component Summary

score of the Short Form-36. Success of the TRUST study will be dependent,

therefore, on demonstrating a statistically and clinically significant

improvement in both primary endpoints.”

3. The initial definition of radiographic healing was radiographic bridging at 4-

cortices.

The amended definition of radiographic healing was radiographic bridging

at 3-cortices.

** This amendment was a response to the industry sponsor's concern that

some patients may be told by their surgeon to discontinue use of low

intensity pulsed ultrasound (LIPUS) before the central adjudication

committee (CAC) agreed that radiographic healing had occurred. As such,

we advised all site investigators that patients were to administer LIPUS until

radiographic healing had occurred at all 4-cortices, and we instructed our

CAC to consider radiographic healing as bridging of 3-cortices.

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4. The initial protocol declared that only an intention-to-treat analysis would

be conducted.

The final FDA protocol declared that a per-protocol analysis would also be

conducted.

** This amendment was written in by the industry sponsor; however, we

believe that any analysis restricted to compliant patients would present a

real risk to the prognostic balance achieved by randomization, and the

results would be very vulnerable to bias. We have, therefore, avoided any

such analysis.

5. The Industry Sponsor included the following statement in the final protocol

they submitted to the FDA: "Details of the analysis are documented in a

comprehensive statistical analysis plan (SAP) that will be finalized prior to

unblinding of the study results."

**We have not seen this SAP, and our analyses were conducted in

accordance with the original analysis plan that we submitted to CIHR and

the more detailed SAP that our team developed.

6. The initial protocol declared only a single subgroup analysis would be

conducted based on open vs. closed fractures.

The Industry Sponsor amended our subgroup statement in the final

protocol they submitted to the FDA as follows: "We will perform the

following subgroup analyses: (1) open vs. closed fractures, (2) analysis by

fracture grade of severity, and (3) fracture location (metaphyseal vs.

diaphyseal)."

** We did perform adjusted analyses that added the following independent

variables to our models: age, gender, smoking status, fracture gap, fracture

pattern, and fracture grade, but we restricted our subgroup analysis to only

the 1 comparison that we originally planned (open vs. closed fractures).

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7. The final protocol stated that we would conduct one interim analyses when

300 participants (150 per treatment group) had completed the trial. The

data analyst would then present the results of these analyses, including

confidence intervals, to an independent DSMB. The DSMB was to be

charged with considering all of the available data, and advise the Steering

Committee on whether the trial should be continued or stopped.

** Shortly after the industry sponsor (Smith & Nephew) was acquired by

Bioventus, the new majority owner conducted an unplanned interim

analysis of 237 TRUST patients with 1-year follow-up in November 2012.

They then advised their intent to discontinue funding for the trial early due

to futility. We continued to collect data from the 501 enrolled patients as

long as possible.

8. The initial protocol listed Jason Busse as a member of the Steering

Committee, the CAC, and the Methods Centre.

The final FDA protocol had Jason Busse removed from the Trial

Organization chart.

** Jason Busse was the co-PI of the TRUST trial and served on the Steering

Committee and was acknowledged as such on the CIHR grant and funding

decision. The sponsor submitted the FDA protocol acknowledging only co-

PI, Mohit Bhandari as lead. The omission was an unfortunate one but did

not reflect Dr. Busse’s ongoing roles or leadership in the trial.

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Statistical analysis plan

We only had 1 detailed Statistical Analysis Plan, which was finalized on Feb. 13, 2014 - after the TRUST protocol was finalized, and before any data were analysed

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- 2 -

Feb. 13, 2014

TRUST Definitive Trial – Analysis Plan for the Main Manuscript Randomized treatment: Active vs Sham low intensity pulsed ultrasound in patients with operatively managed tibial fractures. SF-36 PCS measured at 6, 12, 18, 26, 38, and 52 weeks is our original primary outcome. Radiographic healing is now a co-primary outcome following discussion with the FDA. Primary Analysis Our primary analysis is a repeated measures analysis of SF-36 PCS over time. This will be a multi-level model with 3 levels: centre, patient, visit. Outcome:

PCS at follow-up visits Independent variables: Randomized treatment Time (categorical) Open vs closed fracture (randomization was stratified on open/closed) Time by treatment interaction Open/closed fracture by time interaction There may be many centres with very few patients, therefore we are concerned about how this will affect the model. If including site causes the model to become unstable, we will combine all sites that enrolled less than 10 patients, as long as this results in aggregating no more than 25% of all enrolled patients. Subgroup Analyses

a) Open vs Closed Fractures: Our primary analysis plus an interaction term for treatment by open vs closed fracture.

Adjusted analysis Our primary analysis plus the following baseline factors entered as independent variables: Age Gender Current smoker Fracture gap Fracture pattern Fracture grade HUI Mark 3 We will repeat all of the above analyses with HUI Mark 3 (HUI3) as the outcome. Time to Radiographic Healing

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A Cox Proportional Hazards regression model. Outcome: Time to radiographic healing Independent variable: Randomized treatment Stratification variables: Open vs closed fracture Clinical site There may be many centres with very few patients, therefore we are concerned about how this will affect the model. If including site causes the model to become unstable, we will combine all sites that enrolled less than 10 patients, as long as this results in aggregating no more than 25% of all enrolled patients. Subgroup Analyses for Radiographic Healing

a) Open vs Closed Fractures: The Cox regression model plus a main effect for open vs closed fracture, and an interaction term for treatment by open/closed fracture. We will not stratify this analysis by open/closed fracture.

Adjusted analysis for Radiographic Healing The Cox regression model plus the following baseline factors entered as independent variables: Age Gender Current smoker Fracture gap Fracture pattern Fracture grade Patient Characteristics We will report patient demographics and fracture characteristics by randomized treatment group.

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Changes to the SAP ** In response to feedback from a Steering Committee member (and before the data were analysed) we replaced “fracture location” with “fracture pattern”, and added “fracture gap” as independent factors in our adjusted analyses. ** Our SAP did not specify a sensitivity analysis to explore for the effect of missing data on our results (although we had discussed that we would conduct a sensitivity analysis). After we understood the distribution of the SF-36 physical component summary score data, we decided to conduct a sensitivity analysis using non-linear multiple imputation (fully conditional specification approach) to address missing observations.

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Trial to Re-evaluate Ultrasound in the Treatment of Tibial Fractures

(TRUST): A Randomized Clinical Trial

Running Head: Ultrasound for Fracture Healing

The TRUST Investigators

The writing group [Jason W. Busse (chair), associate professor,1,2,3 Mohit Bhandari (associate

chair), professor,1,4 Thomas A. Einhorn, professor,5 Emil Schemitsch, professor,6 James D.

Heckman, clinical professor,7 Paul Tornetta III, professor,5 Kwok-Sui Leung, professor,8 Diane

Heels-Ansdell, clinical epidemiologist,1 Sun Makosso-Kallyth, clinical epidemiologist,2 Gregory

J. Della Rocca, associate professor,9 Clifford B. Jones, clinical professor,10 Gordon H. Guyatt,

distinguished professor,1,11] assumes responsibility for the overall content and integrity of the

manuscript.

1. Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton,

ON, L8S 4K1, Canada

2. Department of Anesthesia, McMaster University, Hamilton, ON L8S 4K1, Canada

3. The Michael G. DeGroote Institute for Pain Research and Care, McMaster University,

Hamilton, ON L8S 4K1, Canada

4. Department of Surgery, McMaster University, Hamilton, ON L8S 4L8, Canada

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5. Department of Orthopedic Surgery, New York University Langone Medical Center, New

York, NY 10016, United States

6. Department of Surgery, University of Western Ontario, London, ON N6A 4V2, Canada

7. Department of Orthopedic Surgery, Dartmouth-Hitchcock Medical Center, Lebanon, NH

03766, United States

8. Department of Orthopaedics & Traumatology, the Chinese University of Hong Kong,

Shatin, Hong Kong

9. Department of Orthopaedic Surgery, University of Missouri, Columbia, MO 65212, United

States

10. The Center for Orthopaedic Research and Education, CORE, Banner University, Phoenix,

AZ, 85023, United States

11. Department of Medicine, McMaster University, Hamilton, ON L8S 4K1, Canada

Corresponding Author: Jason W. Busse at 1200 Main St. West, HSC-2U1, Department of

Anesthesia, McMaster University, Hamilton, ON, L8S 4K1, Canada ([email protected]).

Word Count of Manuscript Text: 3,679

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Abstract

Objective: To determine, in patients with operatively managed tibial fractures, whether low

intensity pulsed ultrasound (LIPUS), compared with sham therapy, accelerates functional

recovery and radiographic healing.

Design: A concealed, randomized, blinded, sham-controlled clinical trial with a parallel group

design of 501 patients, enrolled between October 2008 and September 2012, and followed for 1-

year.

Setting: 43 North American academic trauma centers.

Participants: Skeletally mature men or women with an open or closed tibial fracture amenable

to intramedullary nail fixation were eligible for this trial. We excluded pilon fractures, tibial shaft

fractures that extended into the joint and required reduction, pathological fractures, bilateral

tibial fractures, segmental fractures, spiral fractures >3 inches in length, concomitant injuries

which were likely to impair function for at least as long as the patient’s tibial fracture, and tibial

fractures that showed < 25% cortical contact and >1cm gap following surgical fixation. 3105

consecutive patients who underwent intramedullary nailing for tibial fracture were assessed, 599

were eligible and 501 provided informed consent and were enrolled in our trial.

Interventions: Patients were allocated centrally to self-administer daily LIPUS (n=250) or a

sham device (n=251) until their tibial fracture demonstrated radiographic healing, or until 1-year

after intramedullary fixation.

Main Outcome Measures: Primary outcomes were short form-36 physical component summary

(SF-36 PCS) scores and radiographic healing within 1-year of fixation. Secondary outcomes

were return to work, return to household activities, return to ≥80% pre-injury function, return to

leisure activities, time to full weight-bearing, and Health Utilities Index-III scores.

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Results: We acquired SF-36 PCS data from 481 of 501 (96%) patients, from whom we had

2,303 of 2,886 (80%) observations, and radiographic healing data from 482 of 501 (96%)

patients, of whom 82 were censored. Results showed no impact on SF-36 PCS scores between

LIPUS and control groups (mean difference 0.55, 95% confidence interval [CI], -0.75 to 1.84;

p=0.30 for the interaction between time and treatment; minimal important difference is 3 to 5

points) or in other functional measures. We also found no difference in time to radiographic

healing (hazard ratio [HR], 1.07, 95%CI, 0.86 to 1.34).

Patient compliance was moderate - 73% of our patients administered ≥50% of all

recommended treatments; however, the study devices are administered by patients in an out-

patient setting and likely reflects patient utilization in routine clinical settings.

Conclusions: Post-operative use of LIPUS following tibial fracture fixation does not accelerate

radiographic healing and fails to improve functional recovery.

Study Registration: ClinicalTrialGov Identifier: NCT00667849

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Print Abstract

Study Question

Does low intensity pulsed ultrasound (LIPUS) accelerate functional recovery and radiographic

healing among patients with operatively managed tibial fractures?

Methods

We carried out a concealed, randomized, blinded, sham-controlled clinical trial with a parallel

group design at 43 North American academic trauma centers. Between October 2008 and

September 2012, 501 patients who underwent intramedullary nailing for tibial fracture were

randomized 1:1 to self-administer LIPUS (n=250) or a sham device (n=251) until their tibial

fracture demonstrated radiographic healing, or until 1-year after intramedullary fixation. Primary

outcomes were short form-36 physical component summary (SF-36 PCS) scores and

radiographic healing within 1-year of fixation. Secondary outcomes were return to work, return

to household activities, return to ≥80% pre-injury function, return to leisure activities, time to

full weight-bearing, and Health Utilities Index-III scores.

Study Answer and Limitations

We acquired SF-36 PCS data from 481 of 501 (96%) patients, from whom we had 2,303 of 2,886

(80%) observations, and radiographic healing data from 482 of 501 (96%) patients, of whom 82

were censored. Results showed no impact on SF-36 PCS scores between LIPUS and control

groups (mean difference 0.55, 95% confidence interval [CI], -0.75 to 1.84; p=0.30 for the

interaction between time and treatment; minimal important difference is 3 to 5 points) or in other

functional measures. We also found no difference in time to radiographic healing (hazard ratio

[HR], 1.07, 95%CI, 0.86 to 1.34).

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The primary limitation of our trial is failure to obtain 100% follow-up for our outcomes;

however, multiple imputation led to similar estimates of treatment effects, providing reassurance

that loss to follow-up was unlikely to have biased our results. Patient compliance was moderate -

73% of our patients administered ≥50% of all recommended treatments; however, the study

devices are administered by patients in an out-patient setting and likely reflects patient utilization

in routine clinical settings.

What this Study Adds

Post-operative use of LIPUS following tibial fracture fixation does not accelerate radiographic

healing and fails to improve functional recovery.

Funding, Competing Interests, Data Sharing

This study was an investigator-initiated trial, supported by grants from the Canadian Institutes of

Health Research (CIHR) # [MCT 67815, Co-PIs: G.H. Guyatt, M. Bhandari], and an industry

grant from Smith & Nephew. Potential competing interests have been reported and are available

on thebmj.com. Patient level data are available from the corresponding author; patient consent to

share data was not obtained but the data are anonymised and risk of identification is low.

Study Registration

ClinicalTrialGov Identifier: NCT00667849

Key Words: Ultrasound; Fracture healing; Randomized controlled trial

Suggestion for an accompanying figure: Figure 3: SF-36 PCS scores over time

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Introduction

Tibial shaft fractures, the most common long-bone fracture,1 are typically managed with

intramedullary nailing.2 Operatively managed tibial fractures generally require three to six

months before patients return to their pre-injury functional status. Moreover, the limited soft

tissue envelope surrounding the bone predisposes tibial fractures to nonunion.3 Low-intensity

pulsed ultrasound (LIPUS) is commonly used in North America after fracture surgery to

accelerate fracture healing and avert nonunions.2,4 Although randomized trials have suggested

that LIPUS improves radiographic healing, inferences are limited because of small sample size,

risk of bias, and inconsistent results.5 Moreover, radiographic fracture healing represents a

surrogate outcome that may not translate into accelerated functional recovery.6

Global revenues for bone stimulators were approximately $400m (US) in 2004;7

however, widespread use does not assure effectiveness. Unnecessary interventions are estimated

to account for 10-30% of spending on healthcare in the US, or $250bn-$800bn (£154bn-£490bn;

€190bn-€610bn) annually.8 Reasons for unnecessary treatment include knowledge gaps, biased

research, profit seeking, patient demand, and rapid uptake of unproved technology.9 Interest in

curtailing unnecessary treatment is growing. For instance, the American Board of Internal

Medicine launched its Choosing Wisely campaign in December 2011, and the BMJ’s “Too Much

Medicine” initiative highlights the waste of resources on unnecessary care 10,11.

In order to resolve the uncertainty regarding the role of LIPUS in operatively managed

patients with tibial fractures, we conducted a multicentre, sham-controlled, randomized

controlled trial that prioritized functional recovery. The design of our trial was informed by a

pilot study 12 and a survey of 450 orthopedic trauma surgeons 2 that found surgeons were

managing almost all tibial fractures operatively, and using intramedullary nailing in >80% of

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fractures. Of the respondents, 45% used bone stimulators - evenly split between LIPUS and

electrical stimulation. Our null hypothesis was that there would be no difference in functional

recovery or radiographic healing following surgical repair of a traumatic tibial fracture with

intramedullary nailing whether managed with adjunctive LIPUS or a sham device.

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Methods

Trial Design

This multicenter, randomized, blinded, parallel-group clinical trial was conducted at 43 North

American university-affiliated academic trauma centres between October 2008 and September

2012. There were no shared patients between the TRUST pilot study 12 and the TRUST

definitive trial.

Patient Selection

Skeletally mature men or women with an open (Gustilo Type I-IIIB) or closed (Tscherne Grade

0-3) tibial fracture amenable to intramedullary nail fixation who provided written informed

consent within 14 days of intramedullary nailing, and were willing and able to comply with the

study protocol, were eligible for this trial.

We excluded patients in whom wound care precluded ultrasound-skin contact, pilon

fractures, tibial shaft fractures that extended into the knee or ankle joint and required reduction,

pathological fractures, bilateral tibial fractures, segmental fractures, spiral fractures >3 inches in

length, concomitant injuries which, in the opinion of the attending surgeon, were likely to impair

function for at least as long as the patient’s tibial fracture, and tibial fractures that showed less

than 25% cortical contact and >1cm gap following intramedullary nail fixation. We also

excluded patients if there were likely to be problems with maintaining follow-up (such as no

fixed address), patients with cognitive impairment or language difficulties that would impede the

valid completion of questionnaires, women who were pregnant or nursing or planned to become

pregnant during their treatment period, or patients implanted with osteobiologics at the site of

their tibial fracture, or with active implanted devices such as cardiac pacemakers.

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Randomization and masking

The manufacturer labeled and shipped visually identical active and inactivated (sham) EXOGEN

4000+ ultrasound device units (Figure 1) to investigational sites according to a computer

generated randomization plan created by the McMaster University Methods Center.

Randomization was stratified by center and severity of soft-tissue injury (open or closed) with

randomly varied block sizes ranging from 2 to 4. After fracture fixation with an intramedullary

nail, participating investigators randomized patients, in a 1:1 ratio, to LIPUS or a deactivated

LIPUS device (identical in appearance and apparent function) by accessing a 24-hour toll-free

remote telephone randomization system that ensured concealment. Patients, surgeons and other

clinicians, data collectors, outcome adjudicators, data analysts, and the industry sponsor were

blind to treatment allocation until the data analysis was complete.

Peri-operative care

Trauma fellowship-trained orthopaedic surgeons administered standardized pre- and post-

operative care. The type of intramedullary nailing (reamed or unreamed), and the number of

interlocking screws used, were at the discretion of the attending surgeon. For closed fractures,

the protocol specified preoperative antibiotic administration be continued for 24 hours

postoperatively, and for open fractures, antibiotic administration (which included a

cephalosporin, and an aminoglycoside - if indicated for grades IIIA-IIIB fractures) continued for

72 hours postoperatively. Irrigation and debridement of soft tissues and contaminated bone was

repeated as necessary and delayed wound closure, split thickness skin grafting, or muscle flaps

(for grade IIIB only) occurred only after the initial surgery. For both open and closed fractures

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cortical contact of the fracture ends guided weight bearing. If cortical contact was achieved,

patients were instructed to weight bear as tolerated. Otherwise, patients were instructed to

partially weight bear on the affected limb until performance of a definitive procedure to achieve

contact.

Interventions

Each patient received a LIPUS device containing a timer that monitored treatment times and

automatically turned the unit off after 20 minutes, verbal instructions in its use, and a booklet

containing detailed instructions. The device transmits a low intensity ultrasound signal (30

mW/cm2) to the fracture site through coupling gel. This is similar to diagnostic ultrasound levels

used in sonogram (fetal monitoring) procedures. Due to the very low intensity of the ultrasound,

patients feel no sensation during treatment. The active and placebo-treatment devices had the

same visual, tactile, and auditory signals and were therefore indistinguishable. Patients self-

administered treatment once daily for 20-minutes until their surgeon determined that their

fracture demonstrated radiographic evidence of bridging at all 4 cortices, or until the 52-week

follow-up visit, whichever occurred first.

Outcome Measures

We assessed outcomes at discharge and at follow-up visits at 6, 12, 18, 26, 38, and 52 weeks

post-operatively. We submitted our trial protocol to the US Food and Drug Administration

(FDA) for approval with a primary outcome of return to function (short form-36 physical

component summary scores [SF-36 PCS] scores); however, the FDA requested we change our

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primary outcome to radiographic healing. After discussion, the FDA agreed to accept a co-

primary outcome of SF-36 PCS scores and time to radiographic healing, with the understanding

that, in independent analyses, both endpoints had to show a clinically important treatment effect

for the trial to be considered positive. The SF-36 has demonstrated construct validity, test-retest

reliability, and acceptable responsiveness in orthopaedic populations; evidence suggests patients

experience a difference of 3 to 5 points or more as important.13-16 Our survey of orthopedic

trauma surgeons found that 80% of respondents felt a reduction in healing time of 6 weeks or

more, attributed to a bone stimulator, would be important to patients.2 The primary safety

outcome was the difference between treatment groups in the proportion of patients with device-

related adverse events and unplanned secondary procedures related to bone healing and

infection.

A central adjudication committee (CAC), comprised of 3 orthopedic trauma surgeons,

blind to device allocation, independently adjudicated time to radiographic healing (bridging of 3

cortices), nonunion, secondary procedures, and fracture-related adverse events. Radiographic

nonunion was defined as failure of the fracture to progress further towards radiographic healing

for at least eight consecutive weeks, after a minimum of six months (26 weeks) following initial

intramedullary nailing. Any disagreements were resolved through discussion.

Study centers sent digital photographs of anteroposterior and lateral radiographs to the

Methods Center. The CAC assessed radiographic healing using the Radiographic Union Scale

for Tibial Fractures (RUST) system, which assigns a score to anteroposterior and lateral

radiographs based on the assessment of healing at each of the four cortices visible on these

projections.17 Each cortex receives a score of one point if it is deemed to have a fracture line with

no callus, two points if there is callus present but a fracture line is still visible, and three points if

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there is bridging callus with no evidence of a fracture line. The individual cortical scores were

added to give a total for each set of films with four being the minimum, indicating the fracture is

definitely not healed, and twelve the maximum score, indicating the fracture is fully healed. A

cortex was judged as bridged when it achieved a RUST score of 2 or 3. Although deemed

radiographically healed when, in the opinion of the CAC, 3 cortices were bridged, in order to

guard against missing data due to misclassification by site investigators, patients continued to

undergo radiographic evaluation until the site investigator determined that all 4 cortices were

bridged. Anteroposterior and lateral radiographs were standardized whenever possible, with use

of the same x-ray machine at each site and the same exposure settings.

Secondary outcomes were return to work without limitations among those who were

employed before their injury; return to household activities without limitations; return to ≥80%

pre-injury function; return to leisure activities without limitations; time to full weight-bearing;

and the Health Utilities Index-III (HUI-III) which is a validated generic utility measure -

evidence suggests patients experience a difference of ≥0.03 points as important 18. We evaluated

self-reported function by having participants indicate at each follow-up visit, on a scale from 0%

to 100%, what their overall level of functioning was with 0% representing no ability to function

and 100% representing their pre-injury level of functioning.

Sample Size

The smallest important difference for the SF-36 PCS score is not well-established, and

investigators have provided different estimates; however, a 3 to 5 point change in score on a 0 to

100 scale is often cited as a minimally important difference, based on the work by Stewart and

colleagues.19 Based on our previous study of health related quality of life in patients with distal

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tibial fractures,15 and the TRUST pilot study,12 we anticipated a standard deviation of ≤ 12 for

SF-36 PCS scores. Considering these findings, we estimated that 250 patients per group would

be required to have a power of 80% (alpha = 0.05, two-tail) to identify a difference in absolute

SF-36 PCS scores of 3 points between treatment and control groups. Our power calculation was

based on detecting an average difference between the groups, rather than the test of the

interaction term planned in the analysis, and was therefore conservative. Our sample size

calculation is based on SF-36 PCS scores as our co-primary outcome measure, radiographic

healing, is a surrogate for functional recovery.

Interim analysis and guidelines for study discontinuation

We planned an interim analysis when 300 patients had completed the trial with review by a data

monitoring committee using the O'Brien-Fleming stopping rule.20 However, the industry sponsor

conducted an unplanned interim analysis of blinded data from 237 TRUST patients with 1-year

follow-up in November 2012 (groups were analyzed as ‘group A’ and ‘group B’). Based on the

finding of no difference in treatment effect between groups and thus a conclusion of futility, the

sponsor discontinued the study in March 2013. We continued to collect data from patients up to

March 2013. All patients, clinicians, investigators, and the data analysts remained blinded to

allocation until analysis of all data was completed.

Statistical Analyses

All patients enrolled were analyzed according to the group they were randomized, regardless of

compliance with treatment or any other deviation from protocol (intention-to-treat principle). All

patients without full follow-up, regardless of reason, were censored at their last follow-up. Data

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analyses were conducted using SAS version 9.4 (SAS Institute) with a threshold p ≤ 0.05. We

calculated compliance with treatment by dividing the number of days that patients administered

≥18 minutes of LIPUS/day from the day they received their study device to when they achieved

radiographic healing or their 52-week follow-up, by the total number of days over this time

period.

Primary analyses considered only available data without imputation for missing data. We

used multi-level linear models to examine SF-36 PCS and HUI-III scores over time including

time, treatment, the interaction between time and treatment, severity of soft tissue injury (open

versus closed), and the interaction between severity and time as independent variables in the

model. The multi-level model, which allows for the clustering of repeated measures within

patient and the clustering of patients within treatment site, included 3 levels: site, patient, and

follow-up visit. We also performed adjusted analyses that added the following independent

variables to our models: age, gender, smoking status, fracture gap, fracture pattern, and fracture

grade, but not severity or its interaction with time because open vs. closed is part of the fracture

grade variable. We conducted a sensitivity analysis for SF-36 PCS scores using non-linear

multiple imputation (fully conditional specification approach) to address missing

observations.21,22

We evaluated time to radiographic healing, time to full weight-bearing, time to return to

work without restrictions, time to return to household duties without restrictions, time to return to

≥80% of pre-injury level of function, and time to return to leisure activities without restrictions,

as compared between LIPUS and control groups, using Cox proportional hazards models

stratified by severity of soft tissue injury and clinical site. For time to radiographic healing, we

also performed an adjusted Cox proportional hazards model including age, gender, smoking

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status, fracture gap, fracture pattern, and fracture grade as covariates. This model was not

stratified by severity of soft tissue injury, because open/closed is included in the fracture grade

variable. The date on which patients received their study device was used as the starting point for

all time-to-event analyses. In our analyses of binary endpoints, because they would be missing

completely at random (uninformed censoring), we included patients who died or who did not

continue to one year because of early stopping of the trial. Data from patients lost to follow-up

were also included up to the point of loss (informed censoring).

We compared the proportion of device related adverse events, deaths, unplanned

secondary procedures related to bone healing and infection, and the occurrence of nonunion

between ultrasound and control groups with Pearson’s chi-square test or Fisher's Exact test.

Subgroup and sensitivity analyses

We planned one a priori subgroup analysis based on open versus closed fractures, with the

anticipation that open fractures would show larger treatment effects.

Patient involvement

No patients were involved in setting the research question or the outcome measures, but we did

prioritize patient-important outcomes (functional recovery) in the design of our trial. We also

responded to patient feedback regarding excessive questionnaire burden in the TRUST pilot

study.12 We conducted an analysis using data from another tibial fracture trial that revealed the

Short Musculoskeletal Function Assessment (SMFA) dysfunction index offered no important

advantages over the SF-36 PCS score,16 and we therefore omitted the SMFA as an outcome

measure for the TRUST definitive trial. We informed the burden of daily administration of

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LIPUS on patients by exploring compliance. No patients were asked to advise on interpretation

or writing up of results. There are no plans to disseminate the results of the research to study

participants or the relevant patient community.

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Results

Participants

Of 3,105 patients screened, 501 met eligibility criteria, provided informed consent and were

randomized (Figure 2). Most exclusions of potentially eligible patients occurred because

fractures were not amenable to an intramedullary nail, patients were <18 years of age, stated they

could not comply with the study protocol, or because of concomitant injury that was likely to

impair function for longer than their tibial fracture.

Patients were predominantly males who had been injured in a fall, resulting in a closed

tibial fracture, and 368 (74%) were employed prior to their injury; patient characteristics were

similar in intervention and control groups (Table 1). As a result of the industry sponsor’s

decision to stop the study early in March 2013, 73 patients were followed for fewer than 12

months (see Table S1 for further details). Patient compliance data was available for 424 patients

(62 did not return their study device, and 15 devices failed to record compliance) and revealed

that 189 (45%) demonstrated ≥75% compliance, and 119 (28%) demonstrated ≥50% but <75%

compliance. There was no difference in compliance between treatment groups.

We acquired SF-36 PCS data from 481 of 501 (96%) patients, from whom we had 2,303

of 2,886 (80%) observations. We included radiographic healing data for 482 of 501 (96%) of

patients in our analysis, of whom 82 were censored. We acquired HUI-III data from 481 of 501

(96%) of patients for whom we had 2,304 of 2,886 (80%) observations. Our rate of follow-up for

secondary functional outcomes was 83% (406 of 490) for return to ≥80% pre-injury function,

78% (269 of 347) for return to work without limitations, 73% (343 of 473) for return to

household activities without limitations, 91% (451 of 497) for return to full weight-bearing, and

70% (321 of 457) for return to leisure activities without limitations. The rate of follow-up for

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secondary functional outcomes considered all enrolled patients minus those affected by early

trial stoppage that had not yet experienced the event of interest.

Effectiveness

Results differed little between primary analyses, adjusted analyses, and analyses using

imputation (Figure S1); we report here the unadjusted analyses. Our repeated measures analyses

found no significant interaction for treatment by time (p=0.30 for SF-36 PCS [Figure 3]; p=0.94

for HUI-III). Treatment failed to influence SF-36 PCS scores (mean difference 0.55, 95%

confidence interval [CI], -0.75 to 1.84; p=0.41) (Table S2), or HUI-III scores (mean difference

0.01, 95%CI, -0.02 to 0.05; p=0.44 for treatment) (Table S3). Time to radiographic healing also

proved very similar between groups (hazard ratio [HR], 1.07; 95%CI, 0.86 to 1.34; p=0.55;

Figure 4) (Table S4).

We found no differences in time to return to work without limitations (HR, 1.11; 95%CI,

0.82 to 1.50; p=0.51) (Table S5), time to return household activities without limitations (HR,

0.94; 95%CI, 0.73 to 1.22; p=0.65) (Table S6), time to full weight-bearing (HR, 0.87; 95%CI,

0.70 to 1.08; p=0.21) (Table S7), time to return to ≥80% pre-injury function (HR, 1.00; 95%CI,

0.80 to 1.25; p=0.97) (Table S8), or time to return to leisure activities without limitations (HR,

1.06; 95%CI, 0.77 to 1.46; p=0.72) (Table S9). Subgroup analyses suggested no difference in

treatment effect for open versus closed fractures for SF-36 PCS scores (interaction p=0.59),

HUI-III scores (interaction p=0.64), or radiographic healing (interaction p=0.65).

Safety

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No site investigators reported adverse events associated with the study treatment. There was one

death among patients randomized to LIPUS and two among patients randomized to sham therapy

(p=0.62). Risk of unplanned secondary procedures related to bone healing (11/250 vs. 9/251;

p=0.66) or infection (2/250 vs. 3/251; p=1.00), and risk of nonunion (9/250 vs. 5/251; p=0.28

were similar between LIPUS and control groups.

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Discussion

Principal findings

In this randomized controlled clinical trial of patients undergoing surgery for fresh tibial fracture,

the addition of LIPUS did not improve functional recovery or accelerate radiographic healing.

Strengths and limitations

Strengths of this randomized trial include our pragmatic design;23 a sample size sufficient to

generate narrow confidence intervals; multiple participating surgeons and centers, enhancing

generalizability; strategies to reduce bias that included central randomization to ensure

concealment, blinding of patients, clinicians, data collectors, outcome assessors, and data

analysts, and independent, blinded adjudication of eligibility and outcomes; and completion of

≥80% of all follow-up visits for our primary outcomes.

The primary limitation of our trial is failure to obtain 100% follow-up for our primary

outcomes, and larger loss to follow-up for some secondary outcomes; however, multiple

imputation led to similar estimates of treatment effects, providing reassurance that loss to follow-

up was unlikely to have biased our results.

Patient compliance was moderate and is a possible explanation for differences in results

between TRUST and prior studies. Two prior trials of LIPUS for fracture healing ensured close

to perfect compliance by having investigators administer LIPUS to hospitalized patients 24 or to

officers stationed at a Naval Academy that were required to report for daily treatment 25. The

former found no effect on time to when the callus was considered strong enough for safe removal

of the fixator following high tibial osteotomy (0.8 weeks earlier; 95%CI, 2.3 weeks earlier to

0.71 weeks later; p=0.31),24 and the latter found no effect on time to return to active duty

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following tibial stress fracture (0.4 days earlier; 95%CI, 14.1 days earlier to 13.3 days later;

p=0.96) 25.

In the outpatient setting in which LIPUS is used, patients self-administer the device.

Patient compliance with treatments is, in general, limited;26 this is particularly true of treatments

that involve the level of inconvenience or burden associated with LIPUS (e.g. the American

College of Chest Physicians Evidence-Based Clinical Practice Guidelines, 9th ed., noted that

compliance is the greatest challenge associated with use of outpatient limb compression devices

in orthopedic surgical patients27). Thus, the compliance found in our trial - 73% of our patients

administered ≥50% of all recommended treatments - likely reflects patient utilization in real

clinical settings. The level of compliance we observed is high enough that, if effects on time to

radiographic healing seen in prior studies were present in our patients, we would have seen a

substantial (albeit possibly attenuated) impact of device use.

Implications

The FDA approved LIPUS for fracture healing in 1994 on the basis of small trials at high risk of

bias which showed that LIPUS accelerated radiographic healing.28 Many medical devices are,

however, approved for sale without randomized trial evidence of patient-important benefit.29 A

study published in 2016 found that of 99 medical devices recently approved by the FDA, 43

devices were cleared or approved before a clinical study was published.30 Further, as is the case

with LIPUS,31-33 device inventors or industry employees are often investigators on clinical trials

that are used to gain regulatory approval.34 Our experience suggests the high desirability of

demanding evidence from randomized trials conducted by investigators other than those who

will gain financially from clinical use of the device before approval by regulatory agencies.

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Conclusions

Among patients undergoing intramedullary nailing for a tibial shaft fracture the addition of

LIPUS does not improve functional recovery or accelerate radiographic healing.

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What is already known on this topic

• Low intensity pulsed ultrasound (LIPUS) is commonly used to promote fracture healing

• The effectiveness of LIPUS remains uncertain due to limitations of prior trials, including

a focus on radiographic fracture healing which is a surrogate for functional recovery

What this study adds

• Adding LIPUS to usual care for fracture patients failed to accelerate radiographic healing

or improve function

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Contributors: JWB, MB, TAE, ES, JDH, PT III, K-SL, and GHG conceived and designed the

study. JWB, MB and GHG acquired the funding. Data collection was monitored by Alquest

(contract research organization). JWB, DH-A, SM-K, and GHG developed the statistical analysis

plan, conducted the analysis and interpreted the data. JWB, DH-A and SM-K had full access to

all of the data in the study, and take responsibility for the integrity of the data and the accuracy of

the data analysis. JWB drafted the manuscript, which was revised by the other authors (MB,

TAE, ES, JDH, PT III, K-SL, GHG, GJDR and CBJ). All authors read and approved the final

manuscript. JWB is the guarantor.

Funding: This study was an investigator-initiated trial, supported by grants from the Canadian

Institutes of Health Research (CIHR) # [MCT 67815, Co-PIs: G.H. Guyatt, M. Bhandari], and an

industry grant from Smith & Nephew. The Canadian Institutes of Health Research (CIHR) had

no role in the design and conduct of the study; collection, management, analysis and

interpretation of the data; preparation, review or approval of the manuscript; or decision to

submit the manuscript for publication. Smith & Nephew personnel reviewed initial drafts of the

trial protocol and raised many issues about alternative approaches to study design. Issues

regarding the protocol were resolved through negotiation between Smith & Nephew and the trial

Steering Committee. Final decisions regarding the protocol and issues that arise during the

conduct of the trial were the purview of the trial Steering Committee. The investigators had full

access to all trial data. Smith & Nephew had no role the initial preparation of the current study

manuscript, but had the right to review the manuscript and make non-binding comments and

suggestions.

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Competing Interests: All authors have completed the ICMJE uniform disclosure form at

www.icmje.org/coi_disclosure.pdf and declare: Drs. Einhorn, Schemitsch and Bhandari have

received consulting fees from Smith & Nephew, the manufacturer of the study device. Dr.

Tornetta receives royalties from Smith & Nephew. Dr. Della Rocca is a paid consultant for

Bioventus LLC, which is 51% owned by Essex Woodlands and 49% by Smith & Nephew. Dr.

Mohit Bhandari is supported, in part, by a Canada Research Chair, McMaster University. No

other disclosures were reported.

Exclusive Licence: The Corresponding Author has the right to grant on behalf of all authors and

does grant on behalf of all authors, a worldwide licence

(http://www.bmj.com/sites/default/files/BMJ%20Author%20Licence%20March%202013.doc) to

the Publishers and its licensees in perpetuity, in all forms, formats and media (whether known

now or created in the future), to i) publish, reproduce, distribute, display and store the

Contribution, ii) translate the Contribution into other languages, create adaptations, reprints,

include within collections and create summaries, extracts and/or, abstracts of the Contribution

and convert or allow conversion into any format including without limitation audio, iii) create

any other derivative work(s) based in whole or part on the on the Contribution, iv) to exploit all

subsidiary rights to exploit all subsidiary rights that currently exist or as may exist in the future

in the Contribution, v) the inclusion of electronic links from the Contribution to third party

material where-ever it may be located; and, vi) licence any third party to do any or all of the

above. All research articles will be made available on an Open Access basis. The terms of such

Open Access shall be governed by a Creative Commons licence—details as to which Creative

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Commons licence will apply to the research article are set out in our worldwide licence referred

to above.

Ethical approval: The McMaster University Research Ethics Board (REB#08-171) and local

boards at each participating site approved the study protocol.

Data sharing: Full dataset and statistical code is available from the corresponding author.

Patient consent was not obtained for data sharing, but the data are anonymised and risk of

identification is low.

Transparency: The lead author (the manuscript’s guarantor) affirms that the manuscript is an

honest, accurate, and transparent account of the study being reported; that no important aspects

of the study have been omitted; and that any discrepancies from the study as planned have been

explained.

This is an Open Access article distributed in accordance with the Creative Commons

Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix,

adapt, build upon this work non-commercially, and license their derivative works on different

terms, provided the original work is properly cited and the use is non-commercial. See:

http://creativecommons.org/licenses/by-nc/4.0/.

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Table 1: Patient Characteristics

LIPUS (n=250) Sham (n=251) Total (n=501)

Age, mean (SD) 37.1 (13.2) 39.1 (14.6) 38.1 (13.9)

Sex, n (%):

Females 81 (32.4) 75 (29.9) 156 (31.1)

Males 169 (67.6) 176 (70.1) 345 (68.9)

Employed prior to their

injury, n (%)

184 (73.6)

184 (73.3)

368 (73.5)

Mechanism of injury, n (%):

Motor vehicle accident 25 (10.0) 14 (5.6) 39 (7.8)

Motor vehicle accident (pedestrian)

28 (11.2) 30 (12.0) 58 (11.6)

Motorcycle accident 25 (10.0) 35 (13.9) 60 (12.0)

Crush injury 7 (2.8) 5 (2.0) 12 (2.4)

Fall 84 (33.6) 87 (34.7) 171 (34.1)

Twist 25 (10.0) 20 (8.0) 45 (9.0)

Direct trauma (penetrating) 0 (0.0) 4 (1.6) 4 (0.8)

Direct trauma (blunt) 43 (17.2) 33 (13.1) 76 (15.2)

Other 13 (5.2) 23 (9.2) 36 (7.2)

Current Smoker 79 (31.6) 86 (34.3) 165 (32.9)

Diabetes*, n (%): 11 (4.4) 19 (7.6) 30 (6.0)

Insulin dependent 7 (2.8) 8 (3.2) 15 (3.0)

Non-insulin dependent 4 (1.6) 11 (4.4) 15 (3.0)

Fracture Type, n (%):

Open 58 (23.2) 56 (22.3) 114 (22.8)

Closed 192 (76.8) 195 (77.7) 387 (77.2)

Gustilo classification for

open fractures, n (% of all

patients):

I 26 (10.4) 25 (10.0) 51 (10.2)

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35

II 15 (6.0) 19 (7.6) 34 (6.8)

IIIA 15 (6.0) 11 (4.4) 26 (5.2)

IIIB 2 (0.8) 1 (0.4) 3 (0.6)

Tscherne classification for

closed fractures, n (% of all

patients):

0 64 (25.6) 62 (24.7) 126 (25.1)

1 110 (44.0) 110 (43.8) 220 (43.9)

2 16 (6.4) 20 (8.0) 36 (7.2)

3 2 (0.8) 3 (1.2) 5 (1.0)

Type of fracture*, n (%):

Comminuted 57 (22.8) 67 (26.7) 124 (24.8)

Transverse 64 (25.6) 55 (21.9) 119 (23.8)

Oblique 77 (30.8) 77 (30.7) 154 (30.7)

Segmental 6 (2.4) 2 (0.8) 8 (1.6)

Spiral 82 (32.8) 95 (37.8) 177 (35.3)

Type of fixation**, n (%):

Nail with prior reaming 249 (100.0) 249 (99.2) 498 (99.6)

Nail without prior reaming 0 (0.0) 2 (0.8) 2 (0.4)

Adjudicated post-operative

fracture gap†, n (%)

10 (4.1) 5 (2.0) 15 (3.0)

* Not mutually exclusive categories; ** n=500 (249 and 251); † n=494 (245 and 249)

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nlyFigure 1: Exogen 4000+ Low-Intensity Pulsed Ultrasound Bone Healing System

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Figure 2: Patient Recruitment and Follow-up Schedule

* 1 patient died and 1 patient provided no post-discharge data due to early trial termination

3105 Assessed for Eligibility

2604 Excluded: 2506 Did not meet eligibility criteria 98 Patients refused to participate

250 Assigned to Treatment (Active LIPUS)

251 Assigned to Control (Sham LIPUS)

241 included in intention-to-treat analysis of SF-36 PCS

scores

240 included in intention-to-treat analysis of SF-36 PCS

scores

501 Randomized

10 patients provided no post-discharge data 41 patients were lost before 6-months 11 patients were lost after 6-months 26 withdrew consent 28 lost contact 8 other withdrawal

10 patients provided no post-discharge data* 28 patients were lost before 6-months 19 patients were lost after 6-months

19 withdrew consent 26 lost contact 10 other withdrawal

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nlyFigure 3: SF-36 PCS scores over time

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Figure 4: Kaplan Meier time to event curve of radiographic fracture healing

Days from First Device Use

Pro

port

ion N

ot

Heale

d

0 100 200 300 400

0.0

0.2

0.4

0.6

0.8

1.0

ActiveSham

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Documents

BMJ · Confidential: For Review Only Trial to Re-evaluate Ultrasound in the Treatment of Tibial Fractures (TRUST): A Randomized Clinical Trial Journal: BMJ Manuscript ID BMJ.2016.032767