The Natural History of Knee Osteoarthritis: India-based Knee Osteoarthritis Evaluation (iKare): A Study Protocol

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Journal of Long-Term Effects of Medical Implants, 23(2–3): 93–104 (2013)

The Natural History of Knee Osteoarthritis: India-based Knee Osteoarthritis

Evaluation (iKare): A Study Protocol

Alexa Gilbert,1 Chuan Silvia Li,1 Parag Sancheti,2 Beate Hanson,3 Mandeep S. Dhillon,4,5 Rajeev Naik,6,7 Nishith V. Shah,8 Vijay D. Shetty,9 Gurava Reddy,10 Jairam Jagiasi,11 Anil Kumar Reddy,10 Utsav Ganguly,10

Neelam Jhangiani,2 & Mohit Bhandari12

1Global Research Solutions, Inc., Burlington, Ontario, Canada; 2Sancheti Institute for Orthopaedics & Rehabilitation, Shivajinagar, Pune, Maharashtra, India; 3AO-Clinical

Investigation, Switzerland; 4Department of Physical Medicine & Rehabilitation, Post Graduate Institute of Medical Education and Research, Chandigarh, India; 5Department of

Orthopaedics, Post Graduate Institute of Medical Education and Research, Chandigarh, India; 6Department of Orthopaedics, Dr. B.R. Ambedkar Medical College, Bangalore, India;

7Tamil Nadu Dr. M.G.R. Medical University, Tamil Nadu, India; 8Arthroscopy Sports Medicine, Aash Arthroscopy Centre, Opp. Jalaram Temple, Paldi, Ahmedabad, India; 9Hiranandani

Orthopaedic Medical Education, Dr. L.H. Hiranandani Hospital Hiranandani Gardens, Powai, Mumbai, India; 10Sunshine Hospitals, Secunderabad, India; 11B.Y.L. Nair Hospital &

T.N. Medical College, Bombay Central, Mumbai, India; and 12Division of Orthopaedic Surgery, Centre for Evidence-Based Orthopaedics, McMaster University, Hamilton, Ontario, Canada

*Address all correspondence to: Chuan Silvia Li, Global Research Solutions, Inc., 3228 South Service Road, Suite 206, Burlington, ON, Canada, L7N 3H8; E-mail: [email protected].

ABSTRACTMethodology: Multi-center, cross-sectional, observational study.Study Center(s): Multiple centers in India.Number of Participants: 1,000. Primary Research Objective: To characterize patients and treatment utilized for orthopedic patients presenting to both private and public hospital centers in India with knee pain and symptoms sugges-tive of knee arthritis. Inclusion Criteria: All patients 18 years of age or older who present to a recruiting hospital for treat-ment of knee pain will be eligible for participation. The subjects must be able to understand and complete the questionnaire. Exclusion Criteria: Patients with total knee replacement, open wound or evidence of recent surgery, or with a current or a history of tumor and/or fracture in the tibial plateau, femoral condyle or patella, in the affected knee are not eligible. Study Outcomes: This study aims to characterize the following: general demographics of patients presenting with knee pain, severity of knee symptoms at time of presentation, severity of knee pathology at time of presentation, factors associated with the decision to seek medical care, previ-ous treatments and health care contacts, planned treatment, and gaps in treatment perceived by the patient and treating surgeons.

KEY WORDS: knee, osteoarthritis, observational study, India

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abilities. Pharmacological interventions, consisting largely of analgesics and anti-inflam-matory agents such as acetaminophen or cyclo- oxygenase inhibitors (COX), are available, but their effect is transient and partial and they are often associated with residual side effects.1 Natural supplements such as glucosamine and chondroitin sulfates are also widely used for pain management in OA patients.12 Although the long-term use of these products seems to be safe, their efficacy remains controversial and unproven.13–15 Beyond pharmaceutical and nutraceutical interventions, more invasive approaches, such as intra-articular injections of corticosteroid or hyaluronic acid (HA), are commonly used. These viscosupplementation treatments are designed to improve the visco-elasticity of the synovial fluid,13 thus improving joint lubrication and easing stress on the articu-lar surfaces. Their overall efficacy, however, is still being debated.1 In most patients, a combi-nation of these treatment modalities, plus active treatments such as physical therapy, exercise, orthotics or manual therapy aimed at improving strength and mobility, constitute the treatment approach. Treatment selection depends largely on the severity of the condition, presence of comorbidities, access to the healthcare system, and cost.2 For patients who do not respond favorably to these treatment options, surgical replacement of the knee joint remains a last resort. While invasive and significant, knee replacement surgery is nonetheless effective at relieving pain and improving function in case of severe OA.3

Patients who are non-responsive to conser-vative care but are not eligible for, or unwilling to undergo, surgery are said to fall in a “treat-ment gap” where they experience extended periods of debilitating pain, reduced quality of life, and a significant financial burden.16 Disease management of patients in this “treat-ment gap” is uncertain. We recently conducted a worldwide study to understand orthopedic surgeons’ views, preferences, and awareness of

I. INTRODUCTION

Osteoarthritis (OA) is one of the most common forms of musculoskeletal disease worldwide.1 The World Health Organization (WHO) esti-mates that 10% of the world’s population over 60 years old suffers from symptomatic OA.2 OA is a chronic condition typically defined as the degeneration of the articular cartilage, compromising a patient’s functional status as it results in joint pain and stiffness.2 OA is often referred to as “wear and tear” arthritis, resulting from accumulated minor trauma to the joints.2 Because the degenerative effects of OA are not reversible, its prevalence tends to increase indefinitely with age.3 Risk factors include, but are not limited to, age, gender, obesity, geo-graphic factors, genetics and race, previous trauma, and diet.2 Additionally, while it may affect any joint in the body, OA is more preva-lent in selected joints such as the hand, spine, knee, foot and hip, as opposed to the joints of the ankle, wrist, elbow, and shoulder.3,4

Osteoarthritis is generally diagnosed using a combination of both radiographic and clinical criteria.2,5 The most widely used criteria for a clinical diagnosis of OA was developed by the American College of Rheumatology (ACR), which base diagnosis on a history of joint pain, especially following periods of inactivity, such as sleeping, for most days in the month prior to diagnosis.6,7 Radiographic evidence is also used to diagnose degenerative changes associ-ated with OA; however, radiographic evidence of OA does not always coordinate directly with functional disability.8,9 OA is generally graded using the Kellgren–Lawrence Empire Rheumatism Council system, which grades the severity of OA on a scale of 0 to 4 at various sites, comparing joint sites with a radiographic atlas (see Appendix A).10,11

OA is a progressive, irreversible disease for which there is no cure. Treatment gener-ally consists of symptom management, with a hope of improving the patient’s functional

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95India-based Knee Osteoarthritis Evaluation (iKare): A Study Protocol

both private and public hospitals in India. Approximately 1,000 patients suffering from knee pain will be enrolled.

1. Questionnaire Development

The questionnaire was developed using the available literature and key informants and includes questions that will address each of the objectives listed in section 2.0. Specifically, the questions regard disease severity and treatment history/plan, patient socioeconomics, patient demographics, and patient knowledge of OA (Appendix B).

To help ensure a high response and comple-tion rate, several factors were incorporated into the questionnaire design: (1) clearly defining the purpose and objectives of the questionnaire, (2) providing the questionnaire with an appro-priate and accurate title, and (3) making the questionnaire as brief and simple as possible. Each question is short, simple, unambiguous, and unidimensional.

The questionnaire has been reviewed by a group of content experts to test for validity prior to the beginning of the study. Ten Indian orthopedic surgeons reviewed the questionnaire and identified any questions that they believed cause a problem for the patient, the attending physician, and/or the research coordinator. By pre-testing the questionnaire with this subset of orthopedic surgeons, we have ensured that all questions are worded adequately and are cultur-ally relevant and appropriate. All suggestions were recorded, and the questionnaire was modi-fied accordingly.

Once the study begins, one research associate from Global Research Solutions, Inc. (GRS) will review the first 50 completed questionnaires to assess whether a pattern of incomplete responses is occurring. If the researcher from GRS iden-tifies any issues with comprehension, layout, method of delivery, and cultural or personal bar-riers to the questionnaire’s proper completion, the questionnaire may be modified further.

the “treatment gap” and various conservative and surgical treatments for early to mid-stage knee osteoarthritis. The results indicated that more than two of three surgeons (68.4%) per-ceived that a treatment gap for early knee OA exists.17

Very little is known about the treatment gap for patients living in India with early knee arthritis. This study aims to attempt to answer some of the questions surrounding this cohort of patients and to determine the influence that various socio-economic factors may have on treatment-seeking behavior.

II. STUDY DESIGN

A. Objectives

The objective of this cross-sectional study is to examine and describe the challenges that patients experience when undergoing treatment for knee OA in India. The data collected will allow us to formulate a better description and understanding of the “treatment gap” that patients with early knee OA are experiencing in India. We will char-acterize patients and the treatments utilized for orthopedic patients presenting to both private and public hospital centers in India with knee pain and symptoms suggestive of knee arthri-tis. Specifically, we will describe the following aspects of this prospective study: (1) general demographics of patients presenting with knee pain; (2) severity of knee symptoms at time of presentation; (3) severity of knee pathology at time of presentation; (4) factors associated with decision to seek medical care; (5) previous treat-ments and health care contacts; (6) planned treatment; and (7) gaps in treatment perceived by the patient and treating surgeons.

B. Study Design

The iKare study is a multicenter, cross-sec-tional observational study which will include

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C. Data Collection

After the approval of the Research Ethics Board is received, participating facilities will be pro-vided with the appropriate training on survey completion, and the use of the online database (electronic data capture, i.e., the EDC system). As such, all participating clinical sites will be required to have access to a computer and Internet connection. At each site, research coor-dinators and investigators (if applicable) will be assigned a username and password by GRS to access the online EDC system. After the first login, the user will be prompted to change his or her password to guarantee the confidentiality and integrity of the submitted data.

The questionnaires will be administered on site to both patient and attending physician by the site research coordinator or designee, who will then enter the responses into the EDC system. Paper copies of the survey will not be forwarded to GRS. Survey administration will continue until 1,000 completed surveys have been obtained.

D. Population

A patient population will be drawn from both public and private hospitals in India to recruit patients that are representative of the coun-try socioeconomically and demographically. Between 5 and 10 sites will be selected to par-ticipate in the study.

E. Inclusion and Exclusion Criteria

The study has minimal exclusion criteria by design. The inclusion and exclusion are listed below.

1. Inclusion Criteria

• Subject is at least 18 years old.• Subject has knee pain.

• Subject is able to understand and complete the questionnaire.

• Subject agrees to participate in the study.

2. Exclusion Criteria

• A history of total knee replacement in the affected knee

• An open wound or evidence of recent surgery in the affected knee

• A current or history of tumour in the affected knee or proximal skeletal structure

• A current or history of fracture in the tibial plateau, femoral condyle, or patella

F. Statistical Analysis

Data will be analyzed using SPSS Version 21.0 (SPSS, Chicago, IL). Descriptive statistics using continuous variables will be presented as means with standard deviations, and categori-cal variables will be presented as proportions to summarize the following items:

• The demographic characteristics of enrolled patients

• Severity of knee symptoms and pathology at time of presentation

• Previous treatments and healthcare contacts• Planned treatment

The influence of the demographic charac-teristics on the decision to seek medical care will be analyzed using logistic regression. A chi-squared analysis will be used to compare medical seeking behavior between the private and public sector.

G. Ethics and Confidentiality

This study will be conducted according to inter-national standards of Good Clinical Practice, applicable government regulations, and applicable institutional research policies and procedures as relevant to observational studies.



This protocol and any amendments will be submitted to a properly constituted independent Research Ethics Board, in agreement with local legal prescriptions, for formal approval of the study to be conducted at each clinical site. The decision of the Research Ethics Board concerning the conduct of the study will be made in writing to the investigator, and a copy of this decision will be provided to GRS before the study begins.

Because this is an observational study that is not dictating the treatment used for each patient or approaching patients for follow-up data, we will not seek informed consent from participants. The inclusion criteria stipulate that the subject agrees to participate but we will not be collecting a formal signed Informed Consent Form (ICF) as no foreseeable harm to the sub-ject is expected to result from this study; this study was granted a waiver of informed consent form. This will allow us to capture data from all patients that present to participating hospi-tals with knee pain and will enable us to make stronger conclusions in presenting our results on the epidemiology of OA and the manage-ment methods used. Each site will maintain a master sheet with identifying information during the enrollment period to ensure that mul-tiple entries into the database are not made for the same patient. However, all of the data sub-mitted to GRS will be identified by a numeric identification number (starting at 0001).

REFERENCES

1. Wieland HA, Michaelis M, Kirschbaum BJ, Rudolphi KA. Osteoarthritis—an untreat-able disease? Nat Rev Drug Discov. 2005 Apr;4(4):331–44.

2. Das SK, Farooqi A. Osteoarthritis. Best Pract Res Clin Rheumatol. 2008 Aug;22(4):657–75.

3. Symmons D, Mathers C, Pfleger B. Global bur-den of osteoarthritis in the year 2000. Geneva: World Health Organization; 2003.

4. Buckwalter JA, Saltzman C, Brown T. The impact of osteoarthritis: implications for

research. Clin Orthop Relat Res. 2004 Oct(427 Suppl):S6–15.

5. Raju PK, Kini SG, Verma A. Wear patterns of tibiofemoral articulation in osteoarthritic knees: analysis and review of literature. Arch Orthop Trauma Surg. 2012 Sep;132(9):1267–71.

6. Altman R, Alarcon G, Appelrouth D, Bloch D, Borenstein D, Brandt K, Brown C, Cooke TD, Daniel W, Feldman D. The American College of Rheumatology criteria for the classifica-tion and reporting of osteoarthritis of the hip. Arthritis Rheum. 1991 May;34(5):505–14.

7. Altman R, Alarcon G, Appelrouth D, Bloch D, Borenstein D, Brandt K, Brown C, Cooke TD, Daniel W, Gray R. The American College of Rheumatology criteria for the classifica-tion and reporting of osteoarthritis of the hand. Arthritis Rheum. 1990 Nov;33(11):1601–10.

8. Issa SN, Sharma L. Epidemiology of osteoar-thritis: an update. Curr Rheumatol Rep. 2006 Feb;8(1):7–15.

9. Sowers M. Epidemiology of risk factors for osteoarthritis: systemic factors. Curr Opin Rheumatol. 2001 Sep;13(5):447–51.

10. Arden N, Nevitt MC. Osteoarthritis: epidemi-ology. Best Pract Res Clin Rheumatol. 2006 Feb;20(1):3–25.

11. Kellgren JH, Lawrence JS. Radiological assessment of osteoarthrosis. Ann Rheum Dis. 1957 Dec;16(4):494–502.

12. Jordan KM, Arden NK, Doherty M, Bannwarth B, Bijlsma JW, Dieppe P, Gunther K, Hauselmann H, Herrero-Beaumont G, Kaklamanis P, Lohmander S, Leeb B, Lequesne M, Mazieres B, Martin-Mola E, Pavelka K, Pendleton A, Punzi L, Serni U, Swoboda B, Verbruggen G, Zimmerman-Gorska I, Dougados M. EULAR Recommendations 2003: an evidence-based approach to the management of knee osteoarthritis: Report of a Task Force of the Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT). Ann Rheum Dis. [Review]. 2003 Dec;62(12):1145–55.

13. McAlindon TE, LaValley MP, Gulin JP, Felson DT. Glucosamine and chondroitin for treat-ment of osteoarthritis: a systematic quality assessment and meta-analysis. JAMA. 2000

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Mar 15;283(11):1469–75.14. Zerkak D, Dougados M. The use of

glucosamine therapy in osteoarthritis. Curr Pain Headache Rep. 2004 Dec;8(6):507–11.

15. Chard J, Dieppe P. Glucosamine for osteoar-thritis: magic, hype, or confusion? It’s prob-ably safe-but there’s no good evidence that it works. BMJ. 2001 Jun 16;322(7300):1439–40.

16. London NJ, Miller LE, Block JE. Clinical and economic consequences of the treatment gap in knee osteoarthritis management. Med Hypotheses. [Research Support, Non-U.S. Gov’t]. 2011 Jun;76(6):887–92.

17. Li CS, Karlsson J, Winemaker M, Sancheti P, Bhandari M. Orthopaedic surgeons feel that there is a treatment gap in management of early OA—International survey. 2013.

APPENDIX B: QUESTIONNAIRE

Inclusion Criteria1. Is the patient 18 years or older? □ Yes □ No2. Does the patient suffer from knee pain? □ Yes □ No3. Does the patient have the ability to understand and complete the

questionnaire?□ Yes □ No

4. Does the subject agree to participate in the study? □ Yes □ NoIf “No” to any of the above questions, the patient is NOT eligible for the study.

Exclusion Criteria1. In the affected knee, has the patient undergone a total knee replacement

to address his/her knee osteoarthritis?□ Yes □ No

2. In the affected knee, does the patient current have or have a history of:a) Tibial plateau, femoral condyle or patellar fracture? □ Yes □ No

b) Tumour affecting the tibia, fibula, femur or patella? □ Yes □ Noc) An open wound or indications of recent surgery? □ Yes □ No

If “Yes” to any of the above questions, the patient is NOT eligible for the study.

TABLE 1: The Kellgren–Lawrence grading system of osteoarthritis11

Grade Definition0 No radiological changes1 Doubtful narrowing of the joint space and possible osteophytic lipping2 Definite osteophytes and possible narrowing of the joint space3 Moderate multiple osteophytes, definite narrowing of the joint space, some sclerosis, and

possible deformity of the bone contour4 Large osteophytes, marked narrowing of the joint space, severe sclerosis, and definite deformity

of the bone contour

APPENDIX A: GRADING SYSTEM



Section 1: Demographic Data(To be completed by the patient and research coordinator.)

1. Age:______________ (years)

2. Gender (check one): □ Male □ Female

3. Height (cm): ______________

4. Weight (kg): ______________

5. What is your primary language? (Check one.)

□ English □ Hindi □ Marathi □ Malayalam

□ Punjabi □ Tamil □ Other:_______________________

6. Do you currently live in a rural (country) or urban (city setting)? (Check one.)

□ Rural (country) □ Urban (city)

7. What is your highest level of education completed? (Check one.)

□ No education

□ Primary school (1st to 4th Std)

□ Secondary school (5th to 10th Std)

□ Junior college (FYJC and SYJC)

□ Degree college - university (FY, SY, TY)

8. What is your current annual household income (Indian Rupees)? (Check one.)

□ <50,000 □ Unknown

□ 50,001–100,000 □ Patient refuses to answer

□ 100,001–300,000

□ 300,001–500,000

□ >500,001

9. Do you have health insurance? (Check one.)

□ No

□ Yes What type of health insurance does the patient have?□ Government health insurance

□ Private health insurance

10. What is your current smoking status? (Check one.)

□ Current smoker □ Ex-smoker □ Never smoked □ Unknown

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Section 2: Functional Limitations Associated with Knee Arthritis(To be completed by patient)

Questions about your knee pain

12. How long have you had pain in your knee(s)? (Check one.)

□ <1 year ago

□ 1–5 years ago

□ 6–10 years ago

□ >11 years ago

□ Unsure

13. In which knee is your pain? (Check one.)

□ Right knee

□ Left knee

□ Both knees

14. Have you been told that you have arthritis in your knee(s)? (Check one.)

□ Yes □ No (If No, please skip to Question 18.)

15. How was your knee arthritis diagnosed? (Check all that apply.)

□ X-ray

□ Other imaging (MRI, CT scan, etc)

□ Physical examination or assessment

□ I haven’t had any tests to diagnose my arthritis

11. Do you have any of the following conditions or illnesses (check all that apply)?

□ Heart disease □ Hypertension

□ Lung disease □ Diabetes

□ Kidney disease □ Osteoporosis

□ Liver disease □ Coagulopathy

□ Neurological disease □ Cancer

□ Gastrointestinal disease □ Other:_______________________________

□ Infection (e.g., tuberculosis) □ None



16. Who diagnosed your knee arthritis? (Check all at that apply.)

□ Family doctor

□ Orthopaedic surgeon

□ Rheumatologist

□ Nurse

□ Pharmacist

□ Social worker

□ Other:_____________________________________________________________________

17. How long ago were you diagnosed with knee arthritis? (Check one.)

□ <1 year ago

□ 1–5 years ago

□ 6–10 years ago

□ >11 years ago

□ Unsure

Questions about how your knee pain affects your life

18. Which one of the following best represents the affect that your knee pain has had on your daily life over the past 6 months? Please indicate the degree to which you agree with the following statements.

a. Do you have knee pain when sitting?

□ Yes □ Nob. Do you have knee pain when lying down?

□ Yes □ Noc. Do you have knee pain when standing?

□ Yes □ Nod. Do you have knee pain when walking short distances?

□ Yes □ Noe. Do you have knee pain when walking long distances?

□ Yes □ Nof. Do you have trouble sleeping at night because of pain in your knee?

□ Yes □ Nog. Do you have knee pain when rising from a seated to a standing position?

□ Yes □ No

h. Do you avoid using the stairs due to knee pain?

□ Yes □ No

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i. Do you have knee stiffness when you wake in the morning?

□ Yes □ No

j. Does your knee pain limit your daily activities?

□ Yes □ No

19. If any, which ambulatory aid(s) do you currently use? (Check all that apply.)

□ None

□ Cane

□ Crutches

□ Wheelchair

□ Other:__________________

Section 3: Management to Date(To be completed by patient)

20. Have you taken any of the following medication to treat your knee osteoarthritis? (Check all that apply.)

□ None □ COX-2 inhibitors

□ Acetaminophen □ Cortisone injections

□ Ibuprofen □ Topical agents

□ Aspirin □ Other medication:________________________________________

□ Other NSAIDs

21. Do you take any of the following supplements to treat your knee osteoarthritis? (Check all that apply.)

□ Glucosamine □ Methylsulfonylmethane (MSM)

□ Chondroitin □ Other vitamin/mineral supplement: _______

22. Do you use any of the following non-pharmacological treatments for your knee osteoarthritis? (Check all that apply.)

□ None □ Splints, supports, or other devices

□ Heat or ice □ Relaxation techniques

□ Exercise □ Arthroscopy

□ Physiotherapy □ Other: _________________________________________________

□ Diet



Section 4: Severity of Disease(To be completed by attending physician or surgeon.)

23. On examination, does this patient demonstrate any visible knee deformity or effusion? (Check one.)

□ Varus

□ Recurvatum

□ Knee effusion

□ No visible deformity

24. What investigations did you perform during this visit? (Check all that apply.)

□ Physical examination

□ Plain x-rays (anterior posterior, lateral)

□ CT scan

□ MRI

□ Other:__________________

25. Does this patient have osteoarthritis in any other joints? (Check all that apply.)

□ Hands □ Feet

□ Lower back □ Other:___________________________________________________

□ Hip □ No

□ Neck

26. Does this patient have unilateral or bilateral knee osteoarthritis?

□ Unilateral □ Left knee □ Right Knee

□ Bilateral

□ None Questionnaire is complete.

27. Using the Kellgren and Lawrence grading system outlined below, what stage in the onset of osteoarthritis would you classify the patient’s condition?

Grade Definition

□ 0 No radiological changes.

□ 1 Doubtful narrowing of the joint space and possible osteophytic lipping.

□ 2 Definite osteophytes and possible narrowing of the joint space.

□ 3 Moderate multiple osteophytes, definite narrowing of the joint space, some sclerosis, and possible deformity of the bone contour.

□ 4 Large osteophytes, marked narrowing of the joint space, severe sclerosis, and definite deformity of the bone contour.

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Section 5: Recommended Treatment(To be completed by attending physician or surgeon.)

29. What is your recommended treatment for this patient? (Check all that apply.)

□ None □ Oral medication □ Knee injection/viscosupplementation

□ Surgery: □ Knee arthroplasty

□ High tibial osteotomy (HTO)

□ Unicompartmental knee replacement

□ Total knee arthroplasty (TKA)

□ Other:__________________________________________________

□ Other:______________________________________________________________________

30. If you did not recommend arthroplasty, what was the key deciding factor?

□ Patient age

□ Knee osteoarthritis too mild

□ Patient lacks resources to pay for total joint replacement

□ Other:______________________________________________________________________

31. Would you consider the KineSpring System as a potential for this patient?

□ Yes □ No Please specify why:______________________

28. How would you classify the severity of the patient’s knee osteoarthritis? (Check one.)

□ Mild □ Moderate □ Severe

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The Natural History of Knee Osteoarthritis: India-based Knee Osteoarthritis Evaluation (iKare): A Study Protocol