STUDY REFERENCE MANUAL - Home | · PDF fileChapter 9: Unscheduled Visits and Visit Windows ..... 36 9.1 Unscheduled Visits ... Chapter 10: Study Medications ... METS Study Reference

STUDY REFERENCE MANUAL

Version 2.1

March 26, 2009

METS Study Reference Manual

March 26, 2009 2 Version 2.1

Table of Contents

Chapter 1: General Study Information ...................................................................................... 7

1.1 Welcome ....................................................................................................................................... 7

1.2 Study Contact Information ............................................................................................................. 8

1.3 Site Roster .................................................................................................................................. 10

1.4 Getting Help ................................................................................................................................ 10

1.5 Important Websites ..................................................................................................................... 10

1.5.1 STN Website ........................................................................................................................ 10

1.5.2 Blackboard............................................................................................................................ 11

1.5.3 Clinicaltrials.gov .................................................................................................................... 11

1.5.4 Data Management System (DMS) ........................................................................................ 11

Chapter 2: Study Start-Up and Activation .............................................................................. 12

2.1 Start-up Requirements ................................................................................................................ 12

2.2 Where to Send Study Documents ............................................................................................... 12

2.3 Study Supplies ............................................................................................................................ 12

Chapter 3: Overview of Study Design ..................................................................................... 14

3.1 Schedule of Events ..................................................................................................................... 17

Chapter 4: Eligibility and Recruitment .................................................................................... 18

4.1 Inclusion and Exclusion Criteria Considerations ......................................................................... 18

4.2 Recruitment ................................................................................................................................. 18

4.2.1 Prescreening ........................................................................................................................ 18

4.2.2 Lab Prescreening ................................................................................................................. 18

4.3 Recruitment Material ................................................................................................................... 19

4.3.1 Developing Your Own Recruitment Materials ....................................................................... 19

4.4 Recruitment Ideas ....................................................................................................................... 19

4.5 Recruitment Questions or Ideas? ................................................................................................ 19

Chapter 5: General Visit Procedures ...................................................................................... 20

5.1 Assigning Patient IDs .................................................................................................................. 20

5.2 Fasting Laboratory Visits ............................................................................................................. 20

5.3 Study Blinding ............................................................................................................................. 20

5.4 Staff Codes ................................................................................................................................. 20

Chapter 6: Informed Consent and Screening (Visit 1) .......................................................... 21

6.1 Informed Consent ........................................................................................................................ 21



6.2 Visit 1 Procedures ....................................................................................................................... 21

6.3 Screen Failures ........................................................................................................................... 22

6.4 Re-Screening Policy .................................................................................................................... 23

Chapter 7: Baseline (Visit 2) and Randomization .................................................................. 24

7.1 Baseline Visit 2 Procedures ........................................................................................................ 24

7.2 Introduction to Randomization .................................................................................................... 25

7.2.1 Getting Help with Randomization ......................................................................................... 25

7.3 Study Medication Dispensing and Dosing and Adherence Form (SMF) ..................................... 25

7.3.1 Drug Accountability Log ........................................................................................................ 25

Chapter 8: Post- Baseline Visit Procedures and Schedules ................................................ 27



8.3 Telephone Procedures for Week 3 ............................................................................................. 28







8.10 Visit 8 Procedures ..................................................................................................................... 32

8.11 Telephone Procedures for Week 11 ......................................................................................... 33

8.12 Visit 9 Procedures ..................................................................................................................... 33


8.14 Visit 10 Procedures ................................................................................................................... 34


8.16 Visit 11 (or Discontinuation Visit) Procedures ........................................................................... 35

Chapter 9: Unscheduled Visits and Visit Windows ............................................................... 36

9.1 Unscheduled Visits ...................................................................................................................... 36

9.2 Visit Windows .............................................................................................................................. 37

9.2.1 Baseline Visit: ....................................................................................................................... 37

9.2.2 Weekly Visits (Visit 3 and 4): ................................................................................................ 37

9.2.3 Bi-Weekly Visits (Visits 5-11): ............................................................................................... 37

9.2.4 Out of Window Visits ............................................................................................................ 37

9.2.5 Early Visits ............................................................................................................................ 37



9.2.6 Late Visits ............................................................................................................................. 38

9.2.7 Very Late Visits..................................................................................................................... 38

Chapter 10: Study Medications ............................................................................................... 39

10.1 Dosing and Titration of Study Medication ................................................................................. 39

10.2 Study Medication Guidelines ..................................................................................................... 39

10.3 Product Description ................................................................................................................... 39

10.4 Acknowledge Receipt of Shipment ........................................................................................... 39

10.5 Packaging and Labeling ............................................................................................................ 39

10.6 Drug Accountability Log ............................................................................................................ 39

10.7 Study Medication Expiration Notices ......................................................................................... 39

10.7.1 Returning Expired and Used Study Medication .................................................................. 39

10.8 Emergency Unblinding .............................................................................................................. 40

Chapter 11: Study Discontinuation ......................................................................................... 41

11.1 Discontinuation from the Study ................................................................................................. 41

11.2 Study Procedures for Early Study Discontinuation ................................................................... 41

Chapter 12: Medical Management and Patient Safety ........................................................... 42

12.1 Contacting the Project Medical Officer ...................................................................................... 42

12.2 Laboratory Results and Abnormalities ...................................................................................... 42

12.3 Patient Noncompliance with Study Procedures ........................................................................ 42

12.3.1 Non-fasting ......................................................................................................................... 42

12.3.2 Medication Non-Compliance .............................................................................................. 42

12.3.3 Behavioral Treatment Intervention Non-Compliance .......................................................... 42

12.4 Patient Safety and Adverse Event Management ...................................................................... 42

12.4.1 Clinical Adverse Event (AE) ............................................................................................... 42

12.4.2 Serious Adverse Events (SAE) ........................................................................................... 43

12.4.3 Timeframe for Reporting SAEs ........................................................................................... 43

12.4.4 SAE Initial Report ............................................................................................................... 43

12.4.5 SAE Follow-up Information ................................................................................................. 44

12.4.6 SAES and IRBs .................................................................................................................. 44

12.4.7 Immediately Reportable SAEs ............................................................................................ 44

Chapter 13: New Staff ............................................................................................................... 45

13.1 New Staff Training ..................................................................................................................... 45

13.2 Site Number/Patient Number Assignment ................................................................................ 45

13.3 Staff Codes ............................................................................................................................... 45



Chapter 14: Study Websites-STN Website and Blackboard ................................................. 46

14.1 Study Website-CSCC STN Website ......................................................................................... 46

14.2 Study Website-BLACKBOARD ................................................................................................. 48

Chapter 15: Laboratory Procedures ....................................................................................... 51

15.1 Laboratory Procedures .............................................................................................................. 51

15.2 Shipments to the Core Lab ....................................................................................................... 51

15.3 Clinical Trials Materials for Laboratory ...................................................................................... 51

Chapter 16: Supplies and Re-Supply Requests ..................................................................... 52

16.1 Source Documents .................................................................................................................... 52

16.1.1 Source Documentation ....................................................................................................... 52

16.1.2 Source Documents – Initial Supply ..................................................................................... 52

16.1.3 Source Document Re-Supply ............................................................................................. 52

16.1.4 Obtaining Source Documents on Short Notice ................................................................... 52

16.1.5 Questions about Source Documents .................................................................................. 52

16.2 Re-Supply Requests ................................................................................................................. 52

Chapter 17: Regulatory Documents and Monitoring Guidelines ......................................... 54

17.1 Regulatory Documentation Requirements ................................................................................ 54

17.1.1 Protocol and Amendments ................................................................................................. 54

17.1.2 IRB Approvals and Correspondence .................................................................................. 54

17.1.2.1 Protocol ........................................................................................................................ 54

17.1.2.2 Informed Consent ........................................................................................................ 54

17.1.2.3 Recruitment Materials .................................................................................................. 54

17.1.2.4 Adverse Events/Serious Adverse Event Reports ......................................................... 54

17.1.2.5 HIPAA .......................................................................................................................... 54

17.1.3 List of Signatures ................................................................................................................ 55

17.1.4 FDA Form 1572 .................................................................................................................. 55

17.1.5 Proof of Human Subjects Training for all Study Staff ......................................................... 55

17.1.6 Drug Supply Documentation ............................................................................................... 55

17.1.7 Supplies Confirmation Sheet .............................................................................................. 55

17.1.8 Correspondence ................................................................................................................. 56

17.1.9 Subject Identification List .................................................................................................... 56

17.1.10 Miscellaneous Documents & Study Manuals ................................................................... 56

17.1.11 Updating Regulatory Documents ...................................................................................... 56

17.1.12 Suggested Regulatory Documents to Have on File .......................................................... 56



17.1.12.1 Study Medication Package Inserts ............................................................................. 56

17.1.12.2 IRB Roster or IRB assurance number ....................................................................... 56

17.1.12.3 Curriculum Vitae of the Principal Investigator ............................................................ 57

17.1.12.4 Laboratory Certification, Lab Director’s CV, Lab normal ranges ................................ 57

These documents are provided on CSCC STN website http://www.cscc.unc.edu/stn/ ................. 57

17.2 Monitoring Plan and Guidelines ................................................................................................ 57

17.3 Investigator’s Responsibilities (Good Clinical Practice) ............................................................ 57

Appendix 1: Instrument Instructions

Instructions for Measuring Waist and Hip Circumference

Instructions for Measuring Height

Instructions for Use of Pedometer

Appendix 2: Laboratory Manual

Appendix 2A-Supply Reorder From

Appendix 2B-METS Patient ID Barcode Labels

Appendix 2C-BSF

Appendix 2D-Collection & Processing

Appendix 2E-Packaging Specimens for Shipment

Appendix 3: Data Completion Guide

Appendix 4: Instructions for Completing Source Documents (Forms and QxQs)

Appendix 5: Data Management Manual

Appendix 6: Quick Reference Guide



Chapter 1: General Study Information

1.1 Welcome On behalf of the National Institute of Mental Health (NIMH), the Schizophrenia Trials Network (STN), the University of North Carolina (UNC), and Columbia University, we welcome you to Metformin in the Treatment of Antipsychotic-Induced Weight Gain in Schizophrenia (METS) pilot study.

The Schizophrenia Trials Network is collaborating with the UNC Collaborative Studies Coordinating Center (CSCC) and Columbia University to manage the study. The NIMH will provide oversight. The University of Minnesota Laboratory will serve as a Core Laboratory. All study medication will be provided from Aptuit, Inc.

A study monitor will visit your site during the course of the study. Please regard this manual and your assigned monitor as resources throughout the course of this project.

Information about how to get help is contained in the General Assistance section of this Study Reference Manual.

Before beginning the study, please read this manual and accompanying appendices.

The Instrument Instructions (Appendix 1) outline how to measure waist and height as well as how to use the pedometer for the Behavioral Treatment.

The Laboratory Manual (Appendix 2) outlines in detail how to process and package samples.

The Data Completion Guidelines (Appendix 3) provide general instructions on how to complete case report forms.

The Instructions for Completing Case Report Forms (Appendix 4) provide question-by-question instructions for completing all forms.

The Data Management Manual (Appendix 5) provides instructions on accessing the Data Management System.

The Quick Reference Guides (Appendix 6) offer helpful tools for recruitment, lab procedures, data management, and study medications.

We will provide one copy of the complete Study Reference Manual for use at your site.

Please note that the study reference manual may be amended during the course of the study. Current versions will be posted on CSCC’s STN website http://www.cscc.unc.edu/stn/ and study coordinators will be notified via email of any modifications.

Thank you for your participation in the METS study.



1.2 Study Contact Information Principal Investigator and Project Medical Officer

L. Fredrik Jarskog, MD Columbia University, NYSPI Phone: 212-543-6711 Cell: 646-321-8564 Fax: 877-285-7846 [email protected]

Back-up Project Medical Officer Lauren Golden, MD

Columbia University Phone:212-851-5494 Beeper:917-247-1006 Fax: 212-851-5493 [email protected]

Safety Officer (Serious Adverse Events) Scott Stroup, MD, MPH

University of North Carolina at Chapel Hill Phone: 919-843-7366 Beeper:919-216-2887 Fax: 877-285-7846 [email protected]

Study Manager Marlene Carlson, MPH

Columbia University, NYSPI Phone: 212-543-5678 Cell: 914-882-8369 Fax: 877-285-7846 [email protected]

Project Coordinators Stephanie Brazis, BA

Columbia University, NYSPI Phone: 212-543-6066 Fax: 877-285-7846 [email protected] Graham Tugetman, BA Columbia University, NYSPI Phone: 212-543-5358 Fax: 877-285-7846 [email protected]

Data Management Project Manager Dawn Stewart

University of North Carolina Phone:919-962-3029 Fax:919-962-3265 [email protected]



Study Monitor Jan Smith, RN, BSN, MPH University of North Carolina Phone: 919-966-7588 [email protected] Dianne Mattingly, RN University of North Carolina Phone: 919-962-3085 [email protected]

Data Coordinator Lauren Eakin, BA University of North Carolina Phone: 919-966-6094 [email protected]

Schizophrenia Trials Network (STN) Administrative Director

General Questions Payment Questions

Ingrid Rojas, MPM University of North Carolina Phone: 919-843-7365 Fax: 877-285-7846 [email protected]

Schizophrenia Trials Network Project Assistant

Janice Linn University of North Carolina Phone: 919-843-7366 Fax: 877-285-7846 [email protected]

Schizophrenia Trials Network Clinical and Functional Outcomes Assessment Unit

Training Issues

Jennifer Nieri, MSW University of North Carolina Phone: 919-966-8341 Fax: 919-966-5628 [email protected]

Schizophrenia Trials Network Clinical and Functional Outcomes Assessment Unit

Diana Perkins, MD, MPH University of North Carolina Phone: 919-966-3813 Fax: 919-966-5628 [email protected]

Biostatistician Robert Hamer, PhD

University of North Carolina Phone: 919-843 5508 Fax: 919-966-5811 [email protected]



Contract Specialist

Dana Gatz University of North Carolina Phone: 919-843-0833 Fax: 919-843-2399 [email protected]

1.3 Site Roster A list of sites, including contact information is listed on the STN website. Please visit http://www.cscc.unc.edu/stn/. Please check the website for accuracy and provide Marlene Carlson at [email protected] with updates as necessary.

1.4 Getting Help For General Study Questions: Please call Marlene Carlson at 212-543-5678 (Mondays – Fridays), at 914-882-8369 (evenings and weekends), or email [email protected]. If Marlene is not available, please call Stephanie Brazis at 212-543-6066 (Mondays-Fridays), at 585-368-8229 (evenings and weekends), or email at [email protected] or Graham Tugetman at 212-543-5358 or email at [email protected]. A “Frequently Asked Questions” section is available on the CSCC’s STN website http://www.cscc.unc.edu/stn/ for commonly asked questions. We ask that you become familiar with these questions and procedures in the event that your site is presented with a similar situation. For Data Management Issues: Our toll-free ‘help line’ number is 1-866-659-3064, Monday - Friday. If someone is not available to answer your call, please leave a voicemail and a CSCC staff member will respond to your call within 24 hours. Calls concerning patient randomization that require immediate attention can be directed to the Marlene Carlson (212-543-5678) if CSCC is unavailable.

For Clinical Questions Clinical questions should come from the study physician and should be directed to: Project Medical Officer Back-up Project Medical Officer L. Fredrik Jarskog Lauren Golden, MD Phone: 212-543-6711 Phone: 212-851-5494 Cell: 646- 321-8564 Beeper: 917-247-1006

1.5 Important Websites

1.5.1 STN Website

http://www.cscc.unc.edu/stn/

The STN website contains documents, policies, manuals, call summaries, and other important study information. All information pertaining to this study can be found under “METS”. Each site will be give a site specific username and password for the STN website from the CSCC. Site coordinators can distribute the username and password to new staff at their site. Please see Section 14.1 for further instructions on accessing the website.



1.5.2 Blackboard http://blackboard.unc.edu

Blackboard contains the rater training materials for the METS study. All information pertaining to this study can be found under “STN Training.” To be issued a username and password for Blackboard, submit a Blackboard Username and Password request form or submit an email to Janice Linn at [email protected] containing your name, study site and email address.

1.5.3 Clinicaltrials.gov http://www.clinicaltrials.gov

The National Institutes of Health (NIH) website provides patients, family members, health care professionals, and members of the public information on clinical trials sponsored primarily by the National Institute of Health and other Federal agencies

1.5.4 Data Management System (DMS) The METS Data Management System (DMS) is located at https://dms.cscc.unc.edu/mets

For any questions regarding the METS DMS please call 1-866-659-3064. You must have Internet Explorer, as well as two sets of user names and passwords to access the DMS.

IMPORTANT: All data recorded on the source documents must be entered in the Data Management System within 48 hours of the corresponding visit.

Please see Appendix 3, the Data Completion Guide, for general instructions on how to complete source documents, and Appendix 5, the Data Management Manual, for instructions on how to operate the Data Management System.



Chapter 2: Study Start-Up and Activation

2.1 Start-up Requirements Sites must satisfy the following requirements to be activated. When a site is activated, study supplies as well as a letter of activation will be sent and the site may begin screening patients.

IRB approval of study protocol (dated September 5, 2008), informed consent, and HIPAA form

Completed 1572 (original on file at UNC)

CV of Principal Investigator on file at UNC

Conflict of Interest Form signed by Principal Investigator

Fully executed contract or contract amendment

Training Requirements

o One STN Certified SCID rater

o STN Certified rater(s) for CGI

o Study physician (s) has viewed Reason for Treatment Discontinuation on Blackboard and completed RTD Vignettes

o One trained and certified staff member on DMS system

o Attended METS training calls scheduled on December 16, 2008 and January 6, 2009 or viewed recordings on the internet.

2.2 Where to Send Study Documents Please send original 1572 to:

Attn: Janice Linn Dept. of Psychiatry, UNC-CH CB# 7160, 7023 Neurosciences Hospital 101 Manning Drive Chapel Hill, NC 27599-7160 Office: 919-843-7366 Fax: 1-877-285-7846

Please fax copies of IRB approval documentation, COI, and CV for Principal Investigator to 1-877-285-7846.

2.3 Study Supplies Upon completion of the start-up activities listed above, the site will be activated. Sites will be notified via email from Columbia with a Site Activation Notification. The notification will include further details and a checklist of study supplies.

Sites will be provided with specimen collection kits and instructions for clinical laboratory specimen collection, study documents (source documents, behavioral treatment manual, drug logs, etc) and study medication. In addition, sites will be provided with pedometers, digital scales, and behavioral treatment handbooks for enrolled participants.

*Sites participating in the CAMP study should already have a Gulick II tape measure for measuring waist and hip as well as a stadiometer for measuring height. If a new Gulick II or stadiometer is needed, please contact the Study Manager.



Item Source Supplies

Study Medication Aptuit Please see page 40 for details

Laboratory Kits University of Minnesota Fairview Laboratories

See Lab manual- Appendix 2

NOTE: It is the site’s responsibility to maintain lab kit supply.

Source Documents

Patient Labels

Screen Fail Binder

CSCC

CSCC

CSCC

Initial shipment will contain enough supplies to screen 12 patients and randomize 8 patients

Initial shipment will contain enough for 18 patients

Initial shipment will consist of 1 binder for screen failures

Behavioral Treatment Handbook

CSCC Initial shipment will consist of 8 patient handbooks and 1 manual

Digital Scales for participants

Amazon.com Initial shipment will consist of 5 scales

Pedometers CSCC Initial shipment will consist of 8 pedometers

DMS Password CSCC Trained staff person will receive a phone call with their username and password

Staff codes CSCC Study coordinator will receive an email with staff codes

**Please see Chapter 16 for information on requesting more supplies.

If any of the above study supplies are not received within 10 business days of site activation please contact the Study Manager. The study supply checklist, sent upon site activation, must be faxed to 1-877-285-7846 upon receipt of all study supplies.



Chapter 3: Overview of Study Design

Title of Study: Metformin in the Treatment of Medication-Induced Weight Gain in Schizophrenia: Pilot Study

Estimated Number of Study Centers and Countries/Regions: 15/USA Study Phase: Phase IV-Pilot Research Hypothesis: This study will compare the effects of the two study conditions on body weight in patients as well as to assess the effect of metformin on waist-hip ratio, fasting lipid levels (i.e., total cholesterol, HDL, LDL, triglycerides), fasting glucose, fasting insulin and HgA1C. Primary Objectives:

1. To assess the mean difference in body weight between patients assigned to metformin compared to patients assigned to placebo at the last observation. Only patients who have at least one post-baseline measurement of weight will be evaluable for this aim.

2. To assess the effect of metformin on waist-hip ratio, fasting lipid levels (i.e., total cholesterol, HDL, LDL, triglycerides), fasting glucose, fasting insulin and HgA1c.

Study Design: Double-blind, multi-site, randomized placebo-controlled trial Duration of Study: 16 weeks Number of Subjects per Group: A total of 80 subjects, 18-65 years of age, will be randomly assigned to receive metformin (N = 40) or placebo (N = 40). All patients will receive a behavioral therapy intervention focused on diet and exercise. Study Population: Patients with a DSM-IV-TR diagnosis of schizophrenia or schizoaffective disorder, have a BMI 27, and are currently treated with one or a combination of two medications (typical or atypical antipsychotics) AND on that drug regimen for at least two months prior to study entry (with stable dosages for at least 1 month).

Treatments: Starting dose for metformin will be 500 mg bid and this will be titrated up weekly by 500 mg up to a final dose of 1000 mg bid, as tolerated.



Inclusion Criteria 1. Outpatients with a diagnosis of schizophrenia or schizoaffective disorder as defined

by DSM-IV-TR criteria and confirmed by the Structured Clinical Interview for DSM-IV (SCID).

2. Duration of illness must be greater than one year, as defined by having initiated antipsychotic treatment at least 1 year prior to study enrollment.

3. Patients must be 18-65 years of age.

4. Patients must demonstrate adequate decisional capacity to make a choice about participating in this research study and must provide informed consent to participate.

5. BMI 27

6. Currently treated with one or a combination of two antipsychotic medications (typical or atypical antipsychotics) AND on that drug regimen for at least two months prior to study entry (with stable dosages for at least 1 month).

7. If the patient is taking antidepressants, mood stabilizers, and/or anxiolytics, the dose must be stable for at least 1 month prior to study entry.

8. Women who can become pregnant must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 4 weeks after the study in such a manner that the risk of pregnancy is minimized. Acceptable methods include oral, injectable or implanted contraceptives, intrauterine devices or barrier methods such as condoms, diaphragm and spermicides. Women who can become pregnant must have a negative serum pregnancy test at the Screening Visit.

Exclusion Criteria

1. Inpatient status

2. Clinical Global Impression Severity (CGI-S) score >6

3. Current treatment with more than 2 antipsychotic medications

4. Fasting glucose > 125

5. Diagnosis of diabetes mellitus or treatment with insulin or oral hypoglycemics

6. Previous or current treatment with metformin

7. Diagnosis of congestive heart failure

8. Renal impairment (serum creatinine > 1.5 in males; > 1.4 in females) or creatinine estimated glomerular filtration rate (GFR) outside of normal limits.

9. Hepatic disease (AST, ALT or GGT > 1.5 times upper limit of normal (ULN), total bilirubin > 1.2 times ULN)

10. Metabolic acidosis (serum CO2 < lower limit of normal)

11. Known hypersensitivity to metformin

12. Women who are pregnant or breastfeeding

13. Recent (in the past 30 days) or scheduled radiological studies involving iodinated contrast material

14. Alcohol abuse/dependence as determined by SCID within the past month

15. Other serious and unstable medical condition in the judgment of the investigator



16. DSM-IV-TR diagnosis of mental retardation, delirium or dementia

17. Any medication used for weight loss must have been discontinued four weeks prior to study entry.

18. Concurrent treatment with the following drugs that are known to increase metformin blood levels should be discussed with the Project Medical Officer: furosemide, nifedipine, and cationic drugs including cimetidine, amiloride, digoxin, morphine, procainamide, quinidine, ranitidine, triamterene, trimethoprim, and vancomycin.

Criteria for Evaluation: The primary outcome measure is the mean difference in body weight between patients assigned to metformin compared to patients assigned to placebo at the last observation. Only patients who have at least one post-baseline measurement of weight will be evaluable for this primary outcome. The secondary outcome measure is the effect of metformin on waist-hip ratio, fasting lipid levels (i.e., total cholesterol, HDL, LDL, triglycerides), fasting glucose, fasting insulin and HgA1c. Other Outcomes: Frequency and Severity of Adverse Events/Side Effects

Clinical Global Impressions-Severity Scale (CGI-S)

Statistical Methods: The primary outcome is endpoint body weight. In addition to descriptive statistics and graphics, an analysis of covariance (ANCOVA) with endpoint body weight as the dependent variable, treatment group as the predictor, and baseline weight as the covariate. Additional sensitivity analyses will use fasting glucose, LDL cholesterol and “higher (i.e. clozapine, olanzapine, quetiapine, risperidone) versus lower (i.e. first generation antipsychotics, aripiprazole, ziprasidone) liability for weight gain” concomitant antipsychotic use as covariates in order to assess their impact on weight in this study.



3.1 Schedule of Events

V1 V2 V3 V4 V5 V6 V7* V8 V9 V10 V11/DC Schedule of Events

Assessments SCR BASE WK

1 WK

2 WK

4 WK

6 WK

8 WK10

WK12

WK14

WK16

1-Study Coordinator/Clinician

Demographics DEM 1 2-STN Certified Rater

Vital Signs VSS 1 1 1 1 1 1 1 1 1 1 1 3-Study Physician

SCID/Psychiatric History SCD

2

4- Clinician or Study Physician

Med History & Physical Exam MHX

3 CAN be completed at unscheduled visits

Inclusion/Exclusion Criteria IEC

3 Possible, but not expected

Study Medication Dispensing and/or Adherence

SMF 1 1 1 1 1 1 1 1 1 1

Clinical Global Impressions - S CGI 2 2 2 2 2 2

Substance Use Scale DUS 4 4 4 4 4

Alcohol Use Questionnaire AUQ 4 4 4 4 4 4 4 4 4 4

Other Medications Record OMR 3 3 3 3 3 3 3 3 3 3

Lipid Lowering Agent LLA 3 3 3 3 3 3 3 3 3 3

Randomization Form RDM 3

Adverse Events/Side Effects AES 4 4 4 4 4 4 4 4 4 4

Behavioral Treatment Counseling and Adherence Record

BTA 1 1 1 1 1 1 1 1 1

Global Behavioral Treatment Adherence

GBT 1

Reason for Assigned Treatment Discontinuation.

RTD 3

Unscheduled Visit Form UVF 1 1 1 1 1 1 1 1 1 1 1

Serious Adverse Events SAE 3 3 3 3 3 3 3 3 3 3 3

LABS

Biospecimen Shipping Form BSF 1 1 1 1 1

Pregnancy Screen (serum) X X

Chemistry, CBC X X

TSH X

Lactate X X X X X

LFT X X X X X

Urine Drug Screen X

Fasting Plasma Glucose X X X

Fasting Insulin X X X

Fasting Lipid Profile X X X

HgbA1C X X X



Chapter 4: Eligibility and Recruitment

4.1 Inclusion and Exclusion Criteria Considerations Eligible patients will be outpatients with schizophrenia or schizoaffective disorder who have a BMI 27 and are currently being treated with one or a combination of two antipsychotic medications (typical or atypical antipsychotics) for at least 2 months prior to study entry. The dose(s) of the antipsychotic medication(s) must have been unchanged for the month prior to study entry.

A complete list of inclusion and exclusion criteria can be found on pages 15 and 16 of this Study Reference Manual.

Some additional clarifications:

Patients currently receiving treatment with more than 2 antipsychotic medications must be excluded.

Concomitant medications (antidepressants, mood stabilizers, anxiolytics) are allowed if at stable dose for at least 1 month prior to study entry. The addition of these medications during the study must be discussed with the Project Medical Officer.

Treatment with insulin or any oral antihyperglycemic or hypoglycemic agent is not permitted. Cimetidine and other cationic drugs (including amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, or vancomycin) are permitted only with the permission of the Project Medical Officer. Furosemide and nifedipine are also permitted only with the permission of the Project Medical Officer.

Patients should not undergo any elective medical procedure without prior consultation with the Investigator. An elective procedure (minor surgery, dental surgery, orthopedic surgery, etc.) that might require hospitalization or anesthesia should be deferred until after the study whenever clinically appropriate.

Patients with active alcohol abuse or dependence (within the month prior to screening) are NOT eligible for the study because alcohol use increases the risk of developing lactic acidosis while taking metformin. Patients with other substance abuse or dependence diagnoses ARE eligible for the study.

Please contact the Project Medical Officer, Fred Jarskog, (phone: 212-543-6711 cell: 646-321-8564) if you have additional questions. If the PMO is not available, please contact the Back-up PMO, Lauren Golden (phone: 212-851-5494, beeper: 917-247-1006).

4.2 Recruitment

4.2.1 Prescreening Prescreening should eliminate any obviously ineligible patients. This can be accomplished by reviewing the patient’s medical records, speaking to the patient’s treating clinicians, and interviewing the patient (if the patient assents). This should be done prior to beginning screening to determine the likelihood of eligibility. Site staff should bring up the topic of research participation with the patient, and the patient should express an initial openness to this possibility, prior to beginning screening.

4.2.2 Lab Prescreening In many cases lab data from clinical care will inform site personnel regarding an individual’s likely eligibility. However, no labs can be conducted by the METS central lab or paid for by the study unless informed consent to participate in the study has been obtained.



4.3 Recruitment Material Template recruitment materials are located on CSCC’s STN website under METS, http://www.cscc.unc.edu/stn/. You will need to obtain approval from your own IRB if you would like to use these materials. Please note that UNC will not pay for printing of your customized IRB approved documents.

Documentation of IRB approval for these materials must be faxed to 1-877-285-7846 upon receipt.

4.3.1 Developing Your Own Recruitment Materials All forms of recruitment materials (flyers, radio scripts, newspaper ads, etc.) developed by your site must be faxed to 1-877-285-7846 for review prior to submitting to your IRB.

Documentation of IRB approval for these materials must be faxed to 1-877-285-7846 upon receipt.

4.4 Recruitment Ideas Place an ad in your local NAMI newsletter and ask to speak at one of their meetings.

Establish a rapport with you local Mental Health Center. Several of our sites visit the Mental Health Centers everyday to encourage referrals.

Hang fliers or place brochures at rest homes and assisted living facilities. The patients in these facilities may be more likely to qualify for our study because their health issues may not be adequately addressed by their current care providers.

Show our Behavioral Treatment Handbook to clinicians and prospective patients so they can better understand this benefit of the study.

Screen outpatient clinics to find potential patients (most sites will need permission from their IRBs to review patients’ medical records).

Make presentations at Grand Rounds, Team Meetings, or on hospital units.

Advertise on Craig’s List

4.5 Recruitment Questions or Ideas? If you have any recruitment questions, or have a recruitment idea that’s been successful at your site, please e-mail Marlene Carlson at [email protected].



Chapter 5: General Visit Procedures

5.1 Assigning Patient IDs Each site will be provided with two sets of labels.

A. The first set of labels (the larger 1” x 2 5/8” AVERY Address Labels) has 9 unique IDs per page with one ID per row. These labels are used to assign an ID to all SCREENED patients. The first column has the patient ID and a blank space in which to record the patient’s name, this label remains on the label sheet. The second column repeats the patient ID, the third is space available for comments if needed. If the patient is eligible and randomized after the baseline visit, peel off the ID label in the second column and affix it to the spine of the patient’s binder. The ID labels which remain in the second column serve as a record of which patients were screened but not randomized. These label listings which contain patient IDs and names of participants should be kept in a secure location.

B. The second set of labels (the smaller ½” x 1 ¾” AVERY Return Address Labels) has 80 labels per page, all of the same ID, and these will be used for:

1. Visit 1 (screening) forms for all screened patients.

2. Visit 2 (baseline) forms for eligible patients who return for the baseline visit.

3. Visit 3 – 11, SAE and Unscheduled Visit forms for the randomized patients.

Each site will be supplied with enough labels for 18 participants. If more labels are needed, please request them from the Data Management Project Manager.

5.2 Fasting Laboratory Visits Patients must be fasting (at least 8 hours without caloric intake) for the Screening Visit and Visits 7 and 11 or discontinuation visit. Fasting laboratory tests are required for patients to be randomized to study treatment. Study sites should call participants the day before study visits to remind them of the appointment and the need to fast. If a patient comes in for a visit in which fasting labs are to be drawn and is NOT fasting, lab tests should not be conducted at this visit and should be rescheduled for another day (preferably within 1-2 days, but always within the visit window).

NOTE: Fasting is not required for laboratory tests for Visits 5 and 9.

5.3 Study Blinding

Study medication will be overencapsulated so that study assignment will not be known to patient or clinicians. Study treatments are blinded to the patient and all study personnel.

5.4 Staff Codes Once a site is activated, each staff member will receive a 3 digit staff code. The CSCC assigns a code to every person who attends central training or who is trained by a certified staff person as being certified to fill out data collection forms. Each source document requests the staff code of the person completing the form. Each person who completes source documents must enter his/her code number in the boxes provided.

To request a staff code for new personnel, please email the CSCC Data Management Project Coordinator with the person’s name, phone number, email, and specific study role.



Chapter 6: Informed Consent and Screening (Visit 1)

6.1 Informed Consent The social contract for participation is established when the informed consent document is read by the participant and discussed in detail with the staff person conducting the interview. It is important for the staff person to acknowledge the full range of potential risks, costs, and discomforts associated with the experimental design, as well as anticipated benefits of participation. Prospective participants should be given ample opportunity to ask questions and to get answers. Being “fully informed” means that the participant has had an opportunity to discuss concerns about any of the assessment, treatment, or follow-up procedures, and has had an opportunity to consider alternatives to participation in the study.

Information should only be collected for the study after valid informed consent is obtained. This requires that patients should adequately understand the study and the nature of research participation and choose to participate voluntarily. Informed consent is documented by obtaining patient’s signature on the site-specific consent form. Each site must comply with local IRB stipulations and federal OHSR guidelines for clinical research with human participants.

Participants should be given a copy of the signed informed consent and the original should be kept on file at the site. In order to maintain confidentiality, we recommend keeping signed informed consents in a secure location. The patient ID should not be recorded on the informed consent form.

6.2 Visit 1 Procedures

Table 1 Visit Procedures for Screening Visit

Visit Week Assessment Estimated

Time Personnel Completing Assessment

Consent Day 1

Consent 30 min Clinician

Visit 1/Screen Day 2 *** Patient must fast for lab work this week ***

Total Time Consent (If not done beforehand) 30 min Clinician

Up to 3 hrs Demographics (DEM) 5 min Study Personnel/Clinician

Metabolic Weight/ Blood Pressure (VSS)

5 min Trained Personnel

Height and BMI (VSS) 5 min Trained Personnel

Waist & Hip Circumference (VSS) 5 min Trained Personnel

Fasting Lab Work (blood and urine) (BSF)

20 min Lab/ Trained Personnel

Provide a snack/ or meal

Med History & Physical Exam (MHX) 30 min Physician

SCID (SCD) 30 min STN Certified Rater

CGI-S (CGI) 5 min STN Certified Rater

START Inclusion/Exclusion Criteria form (IEC)

5 min Clinician

Payment/ Schedule Next Visit 5 min Study Personnel



Reminders: Before any assessments are completed, patient must provide written informed consent.

Vital signs should be taken before labs are drawn. Please refer to Appendix 1 for instructions

on measuring waist, hip, and height.

Patient must be fasting for blood draw. Please refer to Appendix 2 for instructions on drawing, processing, and shipping blood. Specimens must be shipped on the same day as collection and processing.

Please make sure to use the preprinted air bill for the METS study. You must have dry ice on-site in order to ship your specimens.

Please email Maren Nowicki ([email protected]), Naomi Thompson

([email protected]), and Mike Emerson ([email protected]) at the core lab on the day of shipment with the following information: FedEx Tracking Number (top right hand corner of the pre-printed airbills, site name or number, and visit number. If you do not have access to email at the time of shipment, you may fax the BSF to the core lab with a cover letter including the above information.

The SCID and CGI must be completed by an STN certified rater.

Visit 2 should be scheduled for 3-14 days after the screening visit. However, you should not move onto Visit 2 until the IEC shows that the patient is eligible.

You should complete as much as possible of the IEC on the day of the screening visit. However, you will not be able to determine eligibility based on lab values until you receive the lab results from the Core Lab (usually within 2-3 business days of the lab receiving the specimens). Data should be entered into the DMS within 2 business days of when it is collected.

6.3 Screen Failures No data needs to be captured on patients who are obviously diagnostically ineligible (e.g., they have bipolar disorder rather than schizophrenia), who refuse to be interviewed, or who are not open to the possibility of research participation.

The screening period includes all time between the time the consent form is signed until the baseline visit is complete and the patient is randomized to a treatment condition. Some people will withdraw consent before randomization and some will be determined ineligible due to information gathered during the screening process. Individuals who consent to participate in the METS study but who are not randomized will be considered “screen failures”.

The demographic (DEM), vital sign screening (VSS), and Inclusion Exclusion (IEC) forms should be completed for all patients who consent to participate in METS.

All data collected must be entered into the DMS even if the patient is a screen failure.

Paper source documents for patients who screen fail should be removed from the patient binders and filed under the patient ID in a separate “Screen Fail” binder to be maintained by the study coordinator. UNC still recommends that consents, payment records, and any other documentation that links the patient ID with the patient name (identifying information) should be kept in a separate locked file or cabinet.



6.4 Re-Screening Policy If a patient does not meet the eligibility criteria due to one or more criteria that might be subject to change, the study physician may decide to screen the patient again. The same patient ID should be used for all re-screenings. Please request additional patient ID labels from the Core Laboratory following the procedures in Appendix 2: Laboratory Manual before re-screening the patient. There are two procedures to follow, depending on the number of days between initial screening and re-screening.

For re-screening up to and including 28 days after the initial screening:

BMI (from the VSS form), Clinical Global Impression-S (CGI), and Inclusion Exclusion form (IEC) must be re-assessed on Visit 1 Seq 001 paper forms and then updated in the DMS accordingly. The Visit Date on the VSS and IEC forms is the date of the re-screening visit. If blood is drawn again for re-assessment of eligibility, a new Biospecimen Shipping Form (BSF) is completed for Visit 1 SEQ 002. The demographics (DEM), psychiatric evaluation (SCD) and Medical History (MHX) need not be re-assessed.

For re-screening 28 days after the initial screening:

All screening forms must be completed again. In other words, an entirely new set of Visit 1 forms must be filled out for the Vital Signs (VSS), psychiatric diagnosis (SCD), medical history (MHX), demographics (DEM), Clinical Global Impressions-S (CGI), Biospecimen Shipping Form (BSF) and Inclusion/Exclusion Criteria (IEC). The Visit Date on all of these forms is the date of the re-screening visit. All forms except BSF are recorded as Visit 01 Seq 001 and are updated in DMS. The BSF is completed for Visit 01 Seq 002.

For all re-screens

Regardless of the time lag between initial screening and re-screening, after the re-screening information has been reassessed and keyed into the DMS, a new Visit 1 Inclusion/Exclusion Criteria (IEC) form must be completed, using the date of the re-screening as the Visit Date. Re-assess all of the un-shaded items on the IEC and note any changes on the new form. If blood was drawn at re-screening, ensure that the new lab results have been reviewed to determine eligibility.

Please follow the procedures in the Data Completion Guide in Appendix 3 for specific instructions on how to complete the re-screening information on paper and how to key the information into the DMS. (NOTE: Although new paper forms are completed at re-screening visits, all re-screening source documents except the BSF should be “updated” in SEQ 001 format, instead of creating new SEQ 001 form in the DMS). A new BSF form is completed for the re-screening at Visit 01 Seq 002 and is keyed into DMS as a new form.

In the event that a patient requires a third screening visit, follow the same procedure, depending on the time lag between the initial screening and the third screening visit.



Chapter 7: Baseline (Visit 2) and Randomization

7.1 Baseline Visit 2 Procedures The Baseline visit is typically scheduled 3 – 14 days following the screening visit. This visit should occur only after the site has received a fax with the laboratory values. Lab values are typically faxed to the site 1-3 days after the lab receives the samples.

All screening forms (DEM, MHX, SCD, VSS, BSF, CGI, and IEC) from the Screening visit (Visit 1) must be entered into the DMS before the Baseline Visit.

Complete the Visit Procedures described below. Please see Appendix 4 – Instructions for Completing Source Documents for more detailed instructions.

Table 2 Visit Procedures for Baseline Visit



Visit 2 Baseline

1 hr 20 min Other Medications Record (OMR) 10 min Physician

Lipid Lowering Agent (LLA) 5 min Physician

Metabolic Weight/ Blood Pressure (VSF) 5 min Trained Personnel

Waist measurement (VSF) 5 min Trained Personnel

Review Inclusion/ Exclusion Criteria (IEC) 5 min Physician

Randomization Form (RDM) 5 min Physician

Adverse Events/Side Effects (AES) 10 min Clinician

Substance Use Scale (DUS) 5 min Clinician

Alcohol Use Questionnaire (AUQ) 5 min Clinician

CGI-S (CGI) 5 min STN Certified Rater

Study Medication Dispensing Dosing and Adherence (SMF) 10 min Study Personnel


Reminders:

The study physician must complete and sign the RDM form after reviewing the IEC from Visit 1.

The Other Medications Record (OMR) and Lipid-Lowering Agent Form (LLA) should be completed by the study physician prior to randomization in order to ensure continued eligibility.

Once the OMR, LLA, and RDM forms have been completed by the study physician, we

recommend that the site immediately randomizes the patient in the DMS. That way, if there are problems with randomization, you can get help from the coordinating center.

Once randomized, it is the entry into the DMS that provides the bottle number for study drug

dispensing to the patient. See Section 7.2.1 for help with randomization and Section 7.3 for help with study drug dispensing.

The Drug Accountability Log should be updated with dispensation of study medication



Study Personnel should pay patient and schedule Visit 3 for 1 week after Visit 2. Please refer to Section 9.2 for more instructions on visit windows. Data should be entered into the DMS within 2 business days of when it is collected.

7.2 Introduction to Randomization Please note that all of the Screening Visit forms must be entered into the DMS prior to the Baseline Visit.

To facilitate randomization on the day of the baseline visit, we recommend completing the OMR and LLA forms as soon as possible to gather information needed to determine eligibility. The IEC should be reviewed and updated in the DMS if needed. Then the RDM form can be completed and entered into the DMS to randomize the patient.

Please refer to Appendix 4 – Instructions for Completing Source Documents for further instructions on the RDM form.

The Randomization form (RDM) must be completed by the study physician.

The DMS will randomize participants when the patient is eligible, the Randomization Form (RDM) is entered into the DMS, and randomization is requested. NOTE: Once randomized, it is the entry of the SMF form into the DMS that provides the bottle number for study drug dispensing to the patient. See Section 7.2.1 for help with randomization and Section 7.3 for help with study drug dispensing.

7.2.1 Getting Help with Randomization Randomization and bottle number assignments in METS is web-based and fully automated. The DMS will determine a patient’s eligibility after the Screening visit from the IEC form, and then confirm eligibility one week later at the Baseline visit upon entry of the RDM form. Once randomized, data entry of the SMF form provides the site with the bottle number for study drug dispensing. If you are experiencing difficulty either randomizing a participant in the DMS, or obtaining a study bottle number, please contact the DMS helpline at 1-866-659-3064, emergency telephone randomizations and bottle number assignment procedures are available. You will need to have all of the screening forms, the lab values, the RMD form, and the SMF form available for emergency telephone randomizations.

7.3 Study Medication Dispensing and Dosing and Adherence Form (SMF) Study medication will be dispensed weekly at Visits 2 and 3 and will be dispensed bi-weekly at Visits 4-11.

Once the SMF form is completed and entered into the DMS, the DMS system will provided the appropriate bottle number needed to dispense study drug. A new study medication bottle(s) should be dispensed at each visit. If you are experiencing difficulty in the DMS please contact the DMS helpline at 1-866-659-3064, emergency telephone procedures for drug bottle number assignment is available.

The patient should be instructed to bring their pill bottles with them to each post-baseline visit to be referenced when completing the Study Medication Dispensing Dosing and Adherence Form (SMF). See Appendix 4 - Instructions for Completing Source Documents for more information.

7.3.1 Drug Accountability Log A running record of all bottles dispensed during the study should be tracked on the Drug Accountability Log. (Note: If a pharmacy dispenses medication for your site, you will not need to keep this log as long as the pharmacy is recording similar information.)

The Drug Accountability Log can be downloaded from CSCC’s STN website, http://www.cscc.unc.edu/stn/. This log should be kept in a binder or folder at the site.



When dispensing a bottle, record each bottle dispensed, date dispensed, patient initials, affix a patient ID label, and attach the tear-off portion of the label from the bottle onto the log. The person dispensing the medication should initial the log. When the patient returns the bottle, record the date returned and the number of pills returned. The person recording this information should initial the line. Please use one line for each bottle dispensed.



Chapter 8: Post- Baseline Visit Procedures and Schedules

Data must be entered into the DMS system no later than 48 hours after it is collected.

Please note: If the patient is discontinuing the assigned study medication prematurely then the discontinuation visit (Visit 11, which includes the Reason for Treatment Discontinuation form) must be completed.

8.1 Visit 3 Procedures Visit Procedures for Visit 3 (Week 1)



Visit 3 Week 1

1 hr 25 min Metabolic Weight/ Blood Pressure (VSF) 5 min Trained Personnel

Waist Measurement (VSF) 5 min Trained Personnel

Other Medications Record (OMR) 10 min Physician


Adverse Events/ Side Effects Form (AES) 10 min Clinician


Behavior Treatment Intervention (Self-Monitoring & Burning Calories)) & Adherence (BTA) 30 min Clinician



Reminders:

Patients should be given a scale, pedometer, and behavioral treatment handbook at this visit. The clinician should begin the behavioral treatment with the participant.

Data entry of the SMF form will provide the bottle number needed for study drug dispensing.

Visit 4 should be scheduled for 1 week after Visit 3. Data should be entered into the DMS within 2 business days of when it is collected.






Visit 4 Week 2







Behavior Treatment Intervention (Self-Monitoring & Burning Calories) & Adherence (BTA) 30 min Clinician



Reminders:


Visit 5 should be scheduled for 2 weeks after Visit 4. Data should be entered into the DMS within 2 business days of when it is collected.

8.3 Telephone Procedures for Week 3



Phone Contact Week 3

Behavioral Treatment Phone reinforcement 15 min Clinician






Visit 5 Week 4 **Patient DOES NOT need to fast

for lab work this week

2 hr Metabolic Weight/ Blood Pressure (VSF)



Lab Work (Blood) (BSF) 30 min Lab/ Trained Personnel






CGI-S 5 min STN Certified Rater

Behavior Treatment Intervention (Controlling Urges) & Adherence (BTA) 30 min Clinician



Reminders:

A STN certified rater must complete the CGI-S (CGI).

Data entry of the SMF form will provide the bottle number needed for study drug dispensing. Specimens must be shipped on the same day as collection and processing. Please make

sure to use the preprinted air bill for the METS study.

You must have dry ice on-site in order to ship your specimens.

Please email Maren Nowicki ([email protected]), Naomi Thompson ([email protected]), and Mike Emerson ([email protected]) at the core lab on the day of shipment with the following information: FedEx Tracking Number (top right hand corner of the pre-printed airbills), site name or number, and visit number. If you do not have access to email at the time of shipment, you may fax the BSF to the core lab with a cover letter including the above information.

Visit 6 should be scheduled for 2 weeks after Visit 5 Data should be entered into the DMS within 2 business days of when it is collected.







Visit 6 Week 6







Behavior Treatment Intervention (Burning Calories by Using Energy) & Adherence (BTA) 30 min Clinician



Reminders:


Visit 7 should be scheduled for 2 weeks after Visit 6.

Patients should be reminded to fast for Visit 7. Data should be entered into the DMS within 2 business days of when it is collected.


Time Personnel Completing

Assessment

Phone Contact Week 5 Behavioral Treatment-Phone Reinforcement 15 min Clinician







Visit 7 Week 8 *** Patient must fast for lab work this week ***

2 hr 5 min Metabolic Weight/ Blood Pressure 5 min Trained Personnel

Waist Measurement 5 min Trained Personnel

Fasting Lab Work (Blood & Urine)/ BSF 30 min Lab/ Trained Personnel

Provide a snack/ or meal



Adverse Event/ Side Effects (AES) 10 min Clinician



CGI-S (CGI) 5 min Clinician

Behavior Treatment Intervention (Decreasing Food Cues) & Adherence (BTA) 30 min Clinician



Reminders:



Please note: A serum pregnancy test will done at this visit.

Specimens must be shipped on the same day as collection and processing. Please make sure to use the preprinted air bill for the METS study.




Assessment




Please email Maren Nowicki ([email protected]), Naomi Thompson ([email protected]), and Mike Emerson ([email protected]) at the core lab on the day of shipment with the following information: FedEx Tracking Number (top right hand corner of the pre-printed airbills), site name or number, and visit number. If you do not have access to email at the time of shipment, you may fax the BSF to the core lab with a cover letter including the above information.






Visit 8 Week 10





Adverse Events/ Side Effects Form (AES)

10 min Clinician


Behavior Treatment Intervention (Developing Good Eating Habits) & Adherence (BTA)

30 min Clinician



Reminders:





Assessment







Assessment





Visit 5 Week 4 Lab work DOES NOT need to be

fasting

2 hr Metabolic Weight/ Blood Pressure (VSF)



Lab Work (Blood) (BSF) 30 min Lab/ Trained Personnel







Behavior Treatment Intervention (Self-control of Overeating) & Adherence (BTA) 30 min Clinician



Reminders:






([email protected]), and Mike Emerson ([email protected]) at the core lab on the day of shipment with the following information: FedEx Tracking Number (top right hand corner of the pre-printed airbills), site name or number, and visit number. If you do not have access to email at the time of shipment, you may fax the BSF to the core lab with a cover letter including the above information.







Assessment

Phone Contact Week 13 Behavioral Treatment-Phone reinforcement 15 min Clinician




Visit 8 Week 10





Adverse Events/ Side Effects Form (AES)

10 min Clinician


Behavior Treatment Intervention (Changing Snack Habits) & Adherence (BTA)

30 min Clinician



Reminders:






Phone Contact Week 15

Behavioral Treatment- Phone reinforcement 15 min Clinician



8.16 Visit 11 (or Discontinuation Visit) Procedures Visit Procedures for Visit 11 (Week 16) or Discontinuation Visit



Visit 11 or D/C Visit

Week 16 *** Patient must fast for lab work this week ***

2 hr 25 min Waist & Hip Circumference (VSF) 5 min Trained Personnel

Metabolic Weight/ Blood Pressure (VSF) 5 min Trained Personnel

Fasting Lab Work (Blood & Urine)/ (BSF) 30 min Lab/ Trained Personnel

Provide snack or meal



Adverse Event/ Side Effects (AES) 10 min Clinician




Behavior Treatment Intervention (Self-Control of Overeating) & Adherence (BTA) 30 min Clinician

Global Behavioral Treatment Adherence Form (GBT) 10 min Clinician

Reason for Assigned Treatment Discontinuation (RTD) 10 min Physician


Payment 5 min Study Personnel

Patient has completed study

Reminders:

The events of this visit are completed at week 16 for all participants (except for the Reason for Treatment Discontinuation form and the Global Behavioral Treatment Adherence Form if it they have been completed earlier). If the patient discontinues from the study prior to Visit 11, this entire visit (including the Reason for Treatment Discontinuation form and Global Behavioral Treatment Adherence Form) should be completed at the time the patient discontinues from the study. For more information about early discontinuation, see Section 11.2.





([email protected]), and Mike Emerson ([email protected]) at the core lab on the day of shipment with the following information: FedEx Tracking Number (top right hand corner of the pre-printed airbills), site name or number, and visit number. If you do not have access to email at the time of shipment, you may fax the BSF to the core lab with a cover letter including the above information.



Chapter 9: Unscheduled Visits and Visit Windows

9.1 Unscheduled Visits We anticipate sites may see patients for many reasons between study visits. These visits do not require completion of an unscheduled visit in the Data Management System unless the unscheduled visit was done for one of the following reasons:

Assessment of possible change in psychiatric symptoms Assessment of possible change in drug tolerability, adverse event Assessment of possible change in medical status Assessment of need for medication changes or adjustment

Forms available for unscheduled visits include:

CGI-S (CGI) Side Effect/Adverse Event Form (AES) Vital signs (VSF) Alcohol Use Questionnaire (AUS) Laboratory tests (BSF) Study Medication Dispensing Dosing and Adherence Form (SMF) Other Medication Record (OMR).

Unscheduled visit source documents need to be completed for only those assessments completed. For example, if labs were not completed as part of the unscheduled visit, you do not need to complete the lab source document. If labs are drawn at an unscheduled visit, please specify the specific lab tests requested in the “Comments” section of the lab source document. A study visit must be associated with the Unscheduled Visit. In general, unscheduled visits are assigned the visit number of the previous scheduled visit. For example, if a patient completes Visit 3, and then presents two days after Visit 3, the Unscheduled Visit is assigned Visit 3. Re-supplying the current study medication is allowed at unscheduled visits. The re-supply of medication should be documented on the Study Medication Dispensing Dosing and Adherence form (SMF), as well as the Drug Accountability Log. Data entry of the SMF form will provide the bottle number needed for study drug dispensing. If labs are drawn at an unscheduled visit, only draw the test appropriate for the unscheduled visit. Complete the BSF with the previous visit’s visit number (Seq 002 if labs were drawn at the previous visit) and the current date. Specify lab tests requested in the “Comments” section of the BSF and note that it is an unscheduled visit.



9.2 Visit Windows

9.2.1 Baseline Visit: The Baseline Visit should be completed no fewer than 3 days after the screening visit (or before the screening labs are available), and no more than 14 days after the screening labs are collected. Please follow the table below when scheduling Baseline Visits:

If you cannot follow this window for any reason, please contact Marlene Carlson, Study Manager, at [email protected] or 212-543-5678 prior to scheduling.

9.2.2 Weekly Visits (Visit 3 and 4): Weekly visits (Visits 3 and 4) are scheduled at 7 days from the previous visit. The visit window allows for scheduling 2 days before and 3 days after the intended date. If unable to schedule within the visit window, then skip to the next weekly visit but cover all Behavioral Treatment material at the next visit.

9.2.3 Bi-Weekly Visits (Visits 5-11): Bi-weekly visits (Visits 5-11) are scheduled 14 days from the previous visit (based on the randomization date). The visit window allows for scheduling 3 days before and 4 days after the intended date.

9.2.4 Out of Window Visits There will be times when it is impossible to keep a patient on schedule. The patient may miss an appointment for a number of reasons including holidays, conflicts with scheduling, and illness. When this happens please follow these guidelines (for early, late, and very late visits) to get the patient back on schedule. If you know a patient’s next visit will be out of the window, the SMF allows you to dispense a 2nd bottle of study drug if necessary. Always work to get the patient back on track based on the randomization date (e.g., Visit 6—week 6 should occur 6 weeks after the date of randomization, Visit 11—week 16 should occur 16 weeks after randomization).

9.2.5 Early Visits An early visit is a visit attended 4-7 days before the target date.

If a patient comes in early for a visit, the visit should be categorized as the next scheduled visit number. For example, if a patient comes in 6 days early for Visit 7 (8 days rather than 14 days after Visit 6), the visit should be categorized as Visit 7, and Visit 8 will be scheduled 20 days later to get the patient back on track. Be sure enough medication is dispensed to cover this interval or be certain to have the patient come in between visits to re-supply study medication.

Screening Day First Possible Baseline Day

Monday Thursday

Tuesday Friday

Wednesday Monday

Thursday Tuesday

Friday Wednesday



9.2.6 Late Visits A late visit is a visit attended 5-7 days after the target date.

If a patient is late for the visit, simply complete the visit that the patient is late for and code the late visit as the scheduled visit number. The instructions for completing source documents are the same for late visits as they are for regularly scheduled visits. For example, if a patient comes in 5 days late for visit 10, the visit should be classed as Visit 10, and Visit 11 will be scheduled 9 days later to get the patient back on track.

9.2.7 Very Late Visits A very late visit is a visit attended more than 1 week after the scheduled visit date. In this case, the missed visit will be skipped and the visit number will be the next in sequence. If you know a patient’s next visit will be out of the window, the SMF allows you to dispense a 2nd bottle of study drug if necessary.

For example, if a patient is more than 1 week late for Visit 8, Visit 9 should be completed and Visit 8 should be skipped. All assessments for Visit 8 should be saved as “Permanently Missing” in the Data Management System (DMS). This visit would still be off schedule as it is one week early for Visit 9, so Visit 10 should be scheduled 3 weeks later to get the patient back on track.

Please note that once a patient is randomized in the DMS, a Follow-up Visit Schedule Report will become available in the DMS for that patient. The report will generate all future visit dates and windows for that patient. Please refer to this report as a guide when scheduling that patient for the remainder of the study (To access the report, log-in to the DMS and click on the “Reports” tab).

Request the Follow-up Visit Schedule Report and once it generates, right click anywhere on the screen to print the report).

Table 3 Visit Windows for Visits 1-11

Visit Week SCHEDULED VISIT

Complete previous visit forms, and schedule next visit within ___ days since previous visit.

VISIT WINDOW Visit can be completed up to ______ days prior to scheduled date, and up to ______ days after scheduled date.

EARLY VISIT

Visit is early ______ days before scheduled date.

LATE VISIT

Visit is late after ______ days since scheduled date.

VERY LATE VISIT

After _____ days, the Visit is Considered “Permanently Missing” in the DMS, and Visit is Skipped.

V1 SC NA NA NA NA NA

V2 BS 3-14 days

3-14 days from screening visit

NA NA NA

V3 1 1 week (7 days) 2 and 3 NA NA 4 +

V4 2 1 week (7 days) 2 and 3 NA NA 4 +

V5 4 2 week (14 days) 3 and 4 4-7 5-7 8 +

V6 6 2 week (14 days) 3 and 4 4-7 5-7 8+

V7 8 2 weeks (14 days) 3 and 4 4-7 5-7 8+

V8 10 2 weeks (14 days) 3 and 4 4-7 5-7 8+

V9 12 2 weeks (14 days) 3 and 4 4-7 5-7 8+

V10 14 2 weeks (14 days) 3 and 4 4-7 5-7 8+

V11 16 2 weeks (14 days) 3 and 4 4-7 5-7 8+



Chapter 10: Study Medications

10.1 Dosing and Titration of Study Medication Starting dose of metformin will be 500mg bid and this will titrated up weekly by 500mg up to a final dose of 1000mg bid, as tolerated.

All patients will have weekly visits during the first two weeks to attend behavioral intervention sessions and for study medication management.

Patients should be instructed that metformin is best tolerated with meals.

10.2 Study Medication Guidelines Keeping in mind that the well-being of study participants is paramount, the assigned study medication should be discontinued only when clearly clinically indicated.

10.3 Product Description Drug Product Strength Bottle Quantity Metformin Placebo

500 mg 74 74

The initial shipment of study medication will be shipped to sites upon site activation. The initial shipment will include 40 bottles, each identified by a Bottle Number on the label. The CSCC will monitor the use of bottles, and the site will be notified if and when additional bottles are being ordered and shipped. In addition, the site should contact [email protected] if there are any concerns regarding the need for additional bottles.

10.4 Acknowledge Receipt of Shipment Please email [email protected] to acknowledge receipt of study medication. If you receive damaged bottles, please include that in your email.

10.5 Packaging and Labeling Study medication will be supplied in white bottles with unique bottle numbers on the labels.

10.6 Drug Accountability Log The Drug Accountability Log documents the number of study medication capsules dispensed and returned at each visit. This log should be completed at each study visit at which a medication is either dispensed or returned. Please see Section 7.3.1 Drug Accountability Log for further instructions

10.7 Study Medication Expiration Notices Study medication expiration dates are located on the bottles.

10.7.1 Returning Expired and Used Study Medication Expired and used study medication does not need to be returned. Each site is responsible for destroying study medication as per their institution’s regulations. If unable to properly destroy study medication, it can be returned to Aptuit. For more information, please contact the CSCC.



10.8 Emergency Unblinding Patients should be provided with emergency contact information for their research site. In case of hospitalization that absolutely requires revealing the treatment assignment in order to treat the patient, this can be accomplished doing the following:

1. Using the study medication bottle. The label can be swabbed with alcohol to reveal the treatment assignment.

2. Using the tear off label from the study medication bottle: Sites can reveal the treatment assignment using alcohol swab from the tear-off label adhered to the medication dispensing log.

3. Calling the CSCC toll-free ‘help line’ number 866-659-3064 during business hours with the patient ID.

4. If none of the above methods produce results, the site can contact Diane Catellier, the Data Management Investigator at the CSCC, at 919-740-3110 (cell number) after hours or on the weekends with the patient ID.

All incidents of emergency unblinding must be reported to the Data Management Project Manager at the CSCC.



Chapter 11: Study Discontinuation

11.1 Discontinuation from the Study Patients should be discontinued and study medication MUST be stopped for the following reasons:

Withdrawal of informed consent (patient’s decision to withdraw for any reason) or if patient loses the ability to provide continued informed consent in the study

Any clinical adverse event, clinical rating, laboratory abnormality or intercurrent illness which, in the opinion of the investigator, indicates that continued treatment with study therapy is not in the best interest of the patient

Pregnancy

Termination of the study

Patient no long meets inclusion or exclusion criteria, with exception of BMI criterion

Subjects who discontinue the assigned study treatment will continue to attend study visits and participate in all assessments until week 16 unless consent is withdrawn, the study is terminated, or the investigator stops their participation.

11.2 Study Procedures for Early Study Discontinuation All Visit 11 Forms should be completed when a patient discontinues the study (including the RTD and GBT forms).

Visit Number: The visit number of the discontinuation visit should correspond to the scheduled visit number when the discontinuation occurs. All source documents, including the BSF, should reflect this visit number. Visit number can be any visit from 1 to 11 and is recorded as the visit at which the study physician determines the patient discontinued study medication. If a patient is discontinued prior to Visit 11, please record the corresponding visit number, instead of visit “11,” on the source documents and in the DMS.

If the discontinuation visit occurs between two scheduled visits, the visit number should correspond with the next scheduled visit. For example, if the patient discontinues 1 week after Visit 7, the discontinuation visit number is Visit 8.

PLEASE NOTE: Study medication can be stopped without a taper. In a diabetic population, the main risk of stopping metformin would be hyperglycemia, but since the study subjects do not have diabetes, an extended taper is not indicated.

When completing the BSF for early treatment discontinuation visits, the visit number should be the visit that corresponds with the scheduled visit number at the time of discontinuation; however, you must mark Early Discontinuation Visit in the Shipping Contents by Visit table. You must also record “This is an early treatment discontinuation visit at Visit [insert visit number]. Run all tests that correspond to Visit 11,” in the Comments section of the BSF.



Chapter 12: Medical Management and Patient Safety

12.1 Contacting the Project Medical Officer Study physicians should contact the Project Medical Officer, Dr. Fred Jarskog for medical management issues

Fred Jarskog, MD Project Medical Officer Phone: 212-543-6711 Cell: 646-321-8564 [email protected]

12.2 Laboratory Results and Abnormalities All laboratory results will be faxed to the site. The study physician should review the results and make appropriate clinical decisions. It should be noted that the study physician reviewed these results (e.g., sign and date, initial and date, clinical note written by study coordinator, etc) on all the lab results received via email at each site.

The project medical officer (Dr. Jarskog) is available to discuss clinical decision making with regard to lab results and abnormalities.

12.3 Patient Noncompliance with Study Procedures

12.3.1 Non-fasting Patients must be fasting for the Screening Visit as well as Visits 7 and 11 (or discontinuation visit). If a patient is not fasting, please reschedule the blood draw within 1-2 days and always within the visit window.

12.3.2 Medication Non-Compliance All patients should be encouraged to take medications as prescribed. Patients will be asked about his/her medication adherence at each appointment. Study personnel will count and record the number of pills in the patient’s study medication bottles and provide immediate feedback, reinforcing the behaviors of patients who appear to be taking medications as prescribed and problem-solving with those who appear not to be. Clinicians will review with patients the use of pill-minder boxes, as needed.

12.3.3 Behavioral Treatment Intervention Non-Compliance The Behavioral Treatment is a critical component of the study protocol. All patients at all sites should receive the intervention as specified in the manual. Non-compliance with the Behavioral Treatment Intervention should be documented on the Behavioral Treatment Adherence form.

12.4 Patient Safety and Adverse Event Management

12.4.1 Clinical Adverse Event (AE) An Adverse Event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. For this study, clinically significant abnormal laboratory findings must be reported as AEs (Adverse Events). Abnormal findings judged non-clinically significant need not be considered adverse events.



Adverse events should be captured since the last AE assessment was done.

12.4.2 Serious Adverse Events (SAE) A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose:

Results in death Is life-threatening Requires inpatient hospitalization* or prolongation of existing hospitalization Results in persistent or significant disability/incapacity Is a congenital anomaly/birth defect Is medically significant (per Investigator’s judgment) Overdose (per investigator’s judgment)

*hospitalization is defined as more than 24 hours in a crisis, psychiatric, or medical unit.

12.4.3 Timeframe for Reporting SAEs SAEs must be reported to UNC from the time of informed consent through 30 days after leaving the study. SAEs must also be reported to your IRB. SAEs must be reported in the DMS within 24 hours of occurrence or 24 hours after site becomes aware of occurrence.

12.4.4 SAE Initial Report Sites will be provided with a paper source document, Serious Adverse Event Report (SAE) to gather information and then enter the data into the Data Management System (DMS). Alternatively, information can be entered directly into the DMS.

An SAE is not considered reported until entered into DMS.

Print the electronic screen from the DMS, and have the responsible study physician sign this report. Make sure to include contact information for the PMO to contact the physician who signed the report. Fax the signed form to 888-215-5738. Please call 919-843-7366 to confirm receipt. The signed form is a key source document and should be filed in the source document binder.

To report an SAE:

1. Complete the Serious Adverse Event Report form (SAE) following the “Instructions for Completing the Serious Adverse Event Report” in Appendix 4 of this Study Reference Manual.

2. Key the SAE form into the DMS. For the initial report, use SEQ 101. For any later updates to the form regarding this specific event, use SEQ 102, 103 and so on.

3. Print the form directly from the DMS by clicking your cursor anywhere on the screen and selecting “yes” when asked if you want to print the screen.

4. Have the PI or a Study Physician sign the form.

5. Fax the signed form to 888-215-5738. Please call 919-843-7366 to confirm receipt.

6. Update the SAE as needed with additional sequence numbers in the DMS.

Once the SAE is entered in the DMS the study Safety Officer is immediately alerted by email. Site will be contacted by the Safety Officer by email or by phone. If there is additional information that needs to be provided to the Safety Officer, it can be emailed to him. Please do not include any identifiers (names, initials, DOB) in the email. The Safety Officer will write a narrative for the event and email it to the reporting study physician for review.



In the initial report, please provide rich, focused clinical detail regarding the signs, symptoms and lab values supporting the initial diagnosis. List all medications the patient was taking when the SAE occurred. Make an initial judgment as to relatedness and unexpectedness. Please refer to Appendix 4 of this manual for more detailed instruction on completing the SAE form and required information.

Report SAE to your local IRB.

12.4.5 SAE Follow-up Information Provide additional clinical details through DMS as these become available, using the

appropriate SEQ numbers for each follow-up entry. Describe treatments undertaken and the results of these. Adjust judgments as needed regarding diagnosis, relatedness and unexpectedness. The Safety Officer will contact the study physician to fill in additional detail.

12.4.6 SAES and IRBs All SAEs at a given site (including unrelated and/or unexpected SAEs, such as an inpatient hospitalization for detoxification resulting from a long-standing, concurrent substance use disorder), must be reported to that site’s IRB and UNC. UNC will notify the NIMH Data Safety & Monitoring Board (DSMB) about all SAEs.

12.4.7 Immediately Reportable SAEs All SAEs judged by site clinicians to be related to the study drug, not anticipated, will be immediately reviewed by the Safety Officer). If the Safety Officer and the site clinician concur with the related and unexpected judgments, UNC will rapidly forward the SAE reports to the FDA, to all METS site PIs for reporting to all METS site IRBs, and to the Schizophrenia Trials Network DSMB. SAE Clarifications

Death should always be considered an SAE.

Anticipatedness: If an event is listed on the package insert for metformin, an SAE should be considered anticipated. It is unanticipated if the event is not listed in the package insert for metformin.

Relatedness: An SAE should not be considered “related” simply because the event occurred during the course of the study. There should be a specific reason that the event is considered to be related to the study drug.

Hospitalization: If a patient is hospitalized due to an exacerbation of his or her illness, there is a clear place to mark this on the SAE form. All new-onset seizures or malignancies should be considered SAEs. “Life threatening,” “prolong,” “important medical event,” and “overdose,” all offer some room for clinical judgment as to definition and as to whether a given event represents a reportable SAE. For example, if a patient forgets to take his medication on Monday and takes his medication for both Monday & Tuesday on Tuesday, this probably does not need to be reported. However, if a patient ingests a month’s supply of study drug in a suicide attempt this certainly should be reported. The outcomes of serious overdoses are what guide treatment for future, similar events.

Pregnancy requires administrative discontinuation from the METS study.

All pregnancies that occur while a woman is taking a METS study drug should be followed to completion and the outcome reported. Only then can any risk of congenital anomaly or birth defect be determined. If a patient becomes pregnant during the study, please contact the Project Medical Officer immediately.



Chapter 13: New Staff

13.1 New Staff Training When a new staff member is added to your site please review the “To-Do” List below.

Notify CSCC by contacting the Data Management Project Coordinator. Include phone number, email address, study role and responsibilities. The CSCC will notify the Study Coordinator with the new person’s staff code.

Sign the site signature log and fax to 1-877-285-7846 Complete NIH human subject training (provided by your institution or by going to

http://cme.cancer.gov/clinicaltrials/learning/humanparticipant-protections.asp ) Access the Blackboard training website. If DMS training is needed, please contact the data management center at 1-866-659-3064 and

refer to “Training” on the STN website. The site-specific utility coordinator for the DMS will need to grant the new staff member access, as well as assign he/or she a DMS Username and Password (once granted access, he/or she must change his/or her password). To access this feature in the DMS, select “Utilities,” in the site directory. For more instruction on granting DMS access, and changing passwords, see chapter 7 of this reference manual. (Please Note: staff members who leave the research team will have their DMS account including his/or her username and password, permanently terminated. If at any point he/or she returns as a study staff members, he/or she will need to be granted new DMS access).

Complete appropriate Rater certifications (CGI raters must complete the CGI certification. Study physicians must complete the RTD training. SCID raters must complete the SCID certification). All trainings are available on Blackboard.

Inform Marlene Carlson at [email protected] if you want new staff added to the SC, PI, or study physicians email lists.

13.2 Site Number/Patient Number Assignment Study sites will be assigned a 2-digit site ID. Patient IDs will consist of 8 characters. The first character is always the letter ‘C’. The next two digits are the site ID. The next four digits are the unique patient ID, and the final digit is a check digit (for QC purposes in the DMS).

13.3 Staff Codes All members of your site study staff will receive a 3 digit staff code. This information will be provided to the study coordinator who will be responsible for informing site staff members. The study staff codes will be recorded at the end of each source document to document who completed the form.



Chapter 14: Study Websites-STN Website and Blackboard

14.1 Study Website-CSCC STN Website http://www.cscc.unc.edu/stn/.

The STN website contains documents, policies, manuals, call summaries, and other important study information. Study coordinators are expected familiarize themselves with the function of the website, and to check the website on a regular basis and communicate any new information to the appropriate staff at their site.

The URL of the STN website is http://www.cscc.unc.edu/stn/, and can be accessed by clicking the “Access the secure website” button.

A username and password is required to access the secure website (see photo below). The CSCC will have provided the site specific username and passwords to every Study coordinator, who should then distribute to their sites staff.

Click here to enter secure site.



The first page will be a ‘News Page’ and will contain information on teleconferences, training and other general communication. To access a specific STN study, click on the study name in the header of the page. All information pertaining to this study can be found under “METS”.

Enter Username and Password

Select the METS study here



Once in METS, the website’s functionality is defined by the header bar of buttons. The example below shows the drop down window under the button “Study Documents”.

The website also manages the study Directory. Each site’s study coordinator should occasionally check to make sure this information is current, if not, please send updated information to the CSCC at [email protected].

14.2 Study Website-BLACKBOARD All revlevant study training information can be found on the STN intranet Site in Blackboard. A username and password is required to access the website. A username and password can be obtained by completing the Blackboard Username and Password Request Form and emailing it to [email protected].

The URL is http://blackboard.unc.edu. Internet Explorer 6.0 and 7.0 are the preferred browsers.

.



Click LOGIN

Enter Username in ONYEN field:

Enter Password in PASSWORD field



Click STN Intranet for Sites

Click on STN Training



Chapter 15: Laboratory Procedures

15.1 Laboratory Procedures The Core Laboratory for the METS study is located at the University of Minnesota Medical Center-Fairview in Minneapolis.

Biochemistry Core Laboratory contact numbers: Telephone: 612-273-3645 (lab)

FAX: 612-273-3489

15.2 Shipments to the Core Lab

IMPORTANT: To enable the Core Lab to account for shipment receipt the following day, please email the FedEx Tracking Number, site name or number, Visit Number, and Patient ID on the day of shipment to:

Maren Nowicki ([email protected]) and Naomi Thompson ([email protected]) and Mike Emerson ([email protected])

NOTE: Please make sure to use the preprinted airbill for METS study. This is a different FedEx account than the CAMP study. The Fed Ex account number for the METS study is: 2315-6354-7. REMINDER: Lab specimens must be shipped the same day as collection. You must have dry ice to ship your specimens.

15.3 Clinical Trials Materials for Laboratory The laboratory will provide the following supplies to sites:

Visit-specific kits, which include all materials necessary for collection of blood and urine samples. **It is very important to use the kit that corresponds to the patient’s visit**

Master shippers will be provided to ship ambient samples to University of Minnesota Laboratory.

A supply of pre-addressed courier shipping documents will be provided. NOTE : It is the site’s responsibility to maintain lab kit supply. Allow at least two weeks for receipt of supplies from the core lab.

Please see Appendix 2 Laboratory Manual for more detailed information.



Chapter 16: Supplies and Re-Supply Requests

16.1 Source Documents

16.1.1 Source Documentation A source document is a record that validates information recorded in the Data Management System. The FDA requires that in addition to the protocol and related documentation (CRF), the investigator must maintain records, separate and apart from the study case report forms, for all study patients.

The following are also considered source documentation for the study:

• Patient medical records and chart

• Patient progress notes during the study

• Documentation of all contacts with UNC and Columbia regarding study patient issues

Data recorded in the Data Management System are subject to verification and will be monitored by UNC for legibility, completeness, accuracy and verification with respect to the source records.

16.1.2 Source Documents – Initial Supply Source document templates will be provided by CSCC for all assessments in the study upon site activation. Sites must follow the detailed Instructions for Completing Source Documents, Appendix 4, when completing any METS source document. It is suggested that sites keep a paper copy of these instructions on-hand at the site in order to ensure proper completion of these forms.

All sites are sent the following initial set of source documents:

8 Source Document binders (containing Visits 2-11) 12 shrink wrapped Screening Visit (Visit 1) packets 8 Behavioral Treatment Handbooks Screen Fail Binder

*Sites who are participating in the CAMP study should already have a Gulick II tape measure for measuring waist and hip as well as a stadiometer for measuring height. If a new Gulick II or stadiometer is needed, please contact the Study Manager.

16.1.3 Source Document Re-Supply Additional patient binders may be requested by emailing CSCC. Please allow a one week notice for each request. To obtain copies of only a few source documents please obtain and print them according to the Obtaining Source Documents on Short Notice procedures.

16.1.4 Obtaining Source Documents on Short Notice Electronic copies of the source documents are kept on the CSCC STN website http://www.cscc.unc.edu/stn/

16.1.5 Questions about Source Documents If you have any questions or concerns please call the CSCC helpline.

16.2 Re-Supply Requests Throughout the course of the study, re-supply requests may be made for the following items:



Source documents: An initial shipment will be sent to sites that will supply enough patient binders to randomize 8 patients. If additional binders are needed, please Dawn Stewart at [email protected] with the number of binder sets being requested. Please allow for 2 to 5 days for shipment.

Lab Supplies: After the initial shipment of supplies is received, fax a METS Laboratory Supply Reorder form (Appendix A) to the Core Lab (612-273-3489) in order to obtain more supplies. Please allow 7-10 days for shipment.

o Lab kits: It is the site’s responsibility to monitor their lab kit supply and order additional kits as needed. Do not order more kits than you reasonably expect to use within a few months. Once kits reach the field center, the site coordinator is responsible for monitoring the expiration dates that appear on the blood collection tubes. Expiration dates will differ depending on tube type. NOTE: A blood collection tube expires on the last day of the month printed on the label.

o Patient ID labels o Shipment Materials

Medication: Regular medication re-supply is based on the Study Medication Dispensing Dosing and Adherence form (SMF). Therefore, it is very important to complete and enter the SMF accurately and promptly. In the event that more medication is needed on an urgent basis, please email Dawn Stewart at [email protected]. Please allow 4 days for shipment.



Chapter 17: Regulatory Documents and Monitoring Guidelines

17.1 Regulatory Documentation Requirements The following documents must be maintained, and updated as necessary, during the METS trial. All versions of these documents must be present at your site. A UNC Monitor will review these materials during site monitoring visits.

17.1.1 Protocol and Amendments The original protocol, as well as any revisions or amendments, must be maintained.

17.1.2 IRB Approvals and Correspondence Note: Copies of all IRB approvals and renewal documents should be faxed to 1-877-285-7846.

17.1.2.1 Protocol

A copy of the original submission sent to the IRB. A copy of each subsequent report to the IRB to support continuation of the study, modification

of the study (amendments), and final report to the IRB. The original IRB approval letter for the protocol and approvals of subsequent protocol

revisions and periodic reviews. If a protocol amendment was not submitted to the IRB there should be a note-to-file explaining

the reason it was not submitted. A copy of this note-to-file should be faxed to 1-877-285-7846.

17.1.2.2 Informed Consent

The original IRB approval letter for the informed consent. A copy of the consent form approved by the IRB and any subsequent revisions, as used in the

study. Copies of correspondence with UNC concerning consent form content.

17.1.2.3 Recruitment Materials

Copies of any recruitment materials used in the study. Please note: You must send recruitment materials to UNC for review & approval before they are submitted to your IRB.

A copy of IRB approval documentation for recruitment materials.

17.1.2.4 Adverse Events/Serious Adverse Event Reports

A copy of all serious adverse event reports for patients at your site, including documentation that these events have been submitted to the IRB and UNC.

A copy of all immediately reportable to the FDA SAEs that have occurred in the METS Trial, including documentation that these alert letters have been sent to your IRB.

17.1.2.5 HIPAA

All sites must be compliant with the Health Insurance Portability and Accountability Act (HIPAA).

Sites must have a HIPAA Authorization Document or a consent form that includes the authorization language, which gives permission to disclose or use personal health information for purposes other than treatment.

If a separate HIPAA Authorization Document will be used (rather than incorporating the authorization language into the main consent) then the site will have to determine if IRB approval is required.

Copies of IRB approval documentation should be forwarded to UNC.



17.1.3 List of Signatures Sites must maintain a Signature Log of Study Personnel. This form can be downloaded from CSCC STN website http://www.cscc.unc.edu/stn/

All study personnel must sign the signature log regardless of role. If someone leaves the study team, a stop date should be provided noting the date of

termination. The staff member should not be lined through or deleted from the signature log. Any added study personnel should sign as they join the project. Copies of new versions

should be faxed to1-877-285-7846. For sites utilizing a pharmacy to distribute study medication to patients, it is suggested that the

pharmacy director/overseer’s name be included on the List of Signatures of Study Personnel for the site.

If the pharmacy has multiple personnel distributing study medication to patients, then a supplemental list must be provided that lists all pharmacy staff that dispense medication to METS patients.

A copy of this log must be faxed to 1-877-285-7846 each time someone joins or leaves the study team.

17.1.4 FDA Form 1572 All versions of the FDA Form 1572 must be maintained in the Regulatory Binder. All staff working on the study should be listed in section six of the 1572. Section three should list the name and complete street address for any additional sites where

the study will be conducted and/or drug will be stored. UNC must maintain the original versions of this document. All versions must be sent to UNC.

See section 2.2 for where to send study documents.

17.1.5 Proof of Human Subjects Training for all Study Staff All principal investigators and key personnel are required to undergo training in the protection of human subjects in research. Please complete the training required by your institution and keep records of completing such training on file for all study personnel. If your institution does not offer training in human subjects research, you may complete the training offered by the NIH at http://cme.cancer.gov/clinicaltrials/learning/humanparticipant-protections.asp.

17.1.6 Drug Supply Documentation The shipping invoices that accompany study medication should be maintained at your site. Discrepancies between information on this form and the amount of medication received should be brought to the attention of UNC immediately by emailing [email protected]

Drug accountability logs must be maintained for study medication (Please see Section 7.3.1). Copies of the drug accountability logs will be retrieved by UNC during the close-out visit.

17.1.7 Supplies Confirmation Sheet This checklist was sent to your site upon activation. Your signed copy verifies receiving shipment of the following supplies:

Study medication Source Documents Laboratory collection and shipment supplies Digital Scales Pedometers User names & passwords for DMS



Upon receipt of supplies, a copy of the completed checklist should be faxed to1-877-285-7846.

17.1.8 Correspondence All correspondence between the sites, UNC, and Columbia should be filed in the regulatory

binder. Electronic correspondence between the sites, UNC, and Columbia can be printed and filed in

the regulatory binder or can be filed electronically in a METS specific folder.

17.1.9 Subject Identification List This log contains contact information (i.e. name, telephone number, address) for all patients

that have been randomized. This log should not be sent to UNC This log should be stored in a secure, locked location.

17.1.10 Miscellaneous Documents & Study Manuals Any study-related documents (i.e. lab reports, DMS queries) and study related manuals (study reference manual, Data Completion Guidelines, Laboratory Manual), should be maintained at your site.

17.1.11 Updating Regulatory Documents Your UNC monitor will review the contents of your regulatory files during monitoring visits, and will notify you of any omissions or out of date documents.

Throughout the course of this study, there may be a need to update your regulatory documents. Updates may include the following: IRB renewals, correspondence, revised consents, protocol amendments, updates to the list of signatures, etc.

Copies of updated informed consents and IRB approvals for protocol amendments MUST be sent to UNC. Please fax documents to 1-877-285-7846).

17.1.12 Suggested Regulatory Documents to Have on File The following documents are suggestions of documents to have on file in the regulatory binder but are not required for the study. Please check with your institution and IRB for a list of the documents they require your site to maintain.

17.1.12.1 Study Medication Package Inserts

A package insert was provided for metformin in a regulatory packet sent to all sites in the beginning of the study. A package insert was provided in lieu of an Investigational Drug Brochure, because metformin is a FDA approved compound. A copy of the package insert must be included in the initial submission to the IRB. Updated copies of the package insert must also be submitted to the IRB and maintained at the site.

A current copy of the package insert can be found on the STN website.

17.1.12.2 IRB Roster or IRB assurance number

The roster should contain the IRB’s name, address, or MPA number. If no roster is available, a DHHS number assigned to the IRB must be provided.

If any study personnel are members of the IRB, documentation must be provided from the IRB indicating that he/she was not involved in the voting or approval process for this study.

The site must show proof of Institutional Assurances of Protection for Human Subjects via a SPA, MPA, or FWA number.



17.1.12.3 Curriculum Vitae of the Principal Investigator

The CV must contain the following elements: Education and degree Current Medical License Number and State(s) of Licensure Site affiliation: All site names and addresses from Section 3 of the 1572 must be included. Principal Investigator Signature and Date within the last 2 years. Copies of medical licenses are not required (as long as the medical license number is listed on

the CV; if the medical license number is not listed on the CV a copy of the medical license must be present & must be current within 2 years).

A copy of the most recent CV for the PI’s must be forwarded to UNC at the beginning of the study. Please see Section 2.2 for where to send study documents.

17.1.12.4 Laboratory Certification, Lab Director’s CV, Lab normal ranges

These documents are provided on CSCC STN website http://www.cscc.unc.edu/stn/

17.2 Monitoring Plan and Guidelines The Webinar Training and Orientation (Fall 2008) serves as the Site Initiation visit for this study. If a site cannot attend the training and orientation sessions, then additional training will be arranged by UNC. The first interim monitoring visit will be conducted based on the site’s patient enrollment and performance. The duration of these visits will range from one to two days. At the close-out visit, the UNC monitor will resolve outstanding queries, perform final study drug accountability, ensure proper disposition of study supplies, and review record retention and responsibilities with the site personnel.

During each interim monitoring visit, UNC monitors will verify adherence to the protocol and check the maintenance of the regulatory file (including verification of compliance with informed consent procedures and GCP regulations). There will be an ongoing review of data via the Data Management System. This data review will include sending queries regarding procedural, clinical, and protocol issues. Queries will be issued and resolved continuously online and via email. Sites should respond to these queries within 72 hours of receipt.

Please note the Data Completion Guidelines are contained in a separate manual as an appendix to this manual.

17.3 Investigator’s Responsibilities (Good Clinical Practice) Good Clinical Practice (GCP) guidelines are note regulations or legal requirements but represent a standard of practice acceptable to the FDA. Adherence to GCP guidelines assures sponsors that no adverse action will be taken by the FDA.

Conduct the study in strict adherence to the protocol. Obtain Institutional Review Board (IRB) approval to conduct the clinical trial. Provide UNC with written documentation that the study protocol, any protocol changes, and

the informed consent form have received approval from your IRB. Report to the IRB as required. The IRB must assume continued responsibility for the study

and review the research on at least an annual basis (renewal schedule provided by your IRB). Adhere to Regulatory Document Requirements presented in this manual. Store the study medication in a secure and locked area with limited access. The storage and

custody of the study medication are the responsibility of the investigator. Supervise the use of study medication as outlined in the protocol. The study medication may

only be dispensed by staff working under the supervision of the investigator for use in the study.



Maintain adequate records of the receipt and disposition of all study medication, to include dates, quantities and use by study patients.

Inform each patient of the risks and benefits of participating in the study and obtain a properly signed and dated informed consent form previously approved by your IRB.

Ensure there are procedures for contacting study patients who do not return for scheduled visits. If a patient is lost of follow-up, the site should document two phone calls made to the patient and should send the patient a certified letter requesting a follow-up appointment.

Document all Adverse Events in the DMS and source documents; report all Serious Adverse Events immediately to UNC via the Data Management System (DMS) and document thoroughly.

Report all Serious Adverse Events to the IRB as required by your IRB guidelines. Document and maintain accurate source documents and enter the data in the DMS for all

study patients. Storage and custody of all study-related records are the responsibility of the investigator.