Study of the Effect of Chondroitin Sulfate on Structural Changes in Knee Osteoarthritis Patients Assessed by MRI

Study Overview
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Brief Summary
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The main purpose of this study is to compare the cartilage volume loss at the Baseline visit and after 24 months of treatment in patients treated with CHONDROITIN SULPHATE (CONDROSAN) 1200 mg daily vs. patients treated with CELECOXIB 200 mg daily.

Detailed Description
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To compare long term disease modifiying and symptomatic effects at the Baseline visit and after 24 months of treatment in patients treated with CHONDROITIN SULPHATE 1200 mg daily vs. patients treated with CELECOXIB 200 mg daily.

Official Title
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Twenty-four Month Exploratory Study of the Effect of Chondroitin Sulphate on Structural Changes in Knee Osteoarthritis Patients as Assessed by MRI

Conditions
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Knee Osteoarthritis

Intervention / Treatment
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* Drug: Chondroitin sulfate
* Drug: Celecoxib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Individuals of either sex, aged 40 years and more Subjects presenting primary OA of the knee according to ACR criteria with signs of synovitis (warmth, swelling or effusion OA of radiological stages 2 and 3 according to Kellgren-Lawrence; Minimum joint space width ≥2 mm in the medial femorotibial compartment on standing knee X-ray VAS of pain while walking ≥ 40 mm Exclusion Criteria: Known allergy to CHONDROITIN SULPHATE, hypersensitivity to CELECOXIB, demonstrated allergic-type reactions to sulphonamides, experienced asthma, urticaria or allergic-type reactions after taking sulphonamides, aspirin (acetyl salicylic acid [ASA]), lactose or NSAIDs Active malignancy of any type or history of a malignancy within the last five years other than basal cell carcinoma Increased risk for prostate cancer, with prostate cancer, or with a history of prostate cancer within the last five years Subjects with other bone and articular diseases (antecedents and/or current signs) such as chondrocalcinosis, Paget's disease of the ipsilateral limb to the target knee, rheumatoid arthritis, aseptic osteonecrosis, gout, septic arthritis, ochronosis, acromegaly, haemochromatosis, Wilson's disease, osteochondromatosis seronegative spondylo-arthropathy, mixed connective tissue disease, collagen vascular disease, psoriasis, inflammatory bowel disease Isolated knee lateral compartment OA defined by joint space loss in the lateral compartment only Class IV functional capacity using the American Rheumatism Association criteria Have had surgery in any lower limb or arthroscopy, aspiration or lavage in any lower limb joint within 180 days of the Baseline Visit History of heart attack or stroke, or experienced serious chest pain related to heart disease, or who have had serious diseases of the heart such as congestive heart failure High risk of CV events, according to the AHA assessment of CV risk tables History of recurrent UGI ulceration or active inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis), a significant coagulation defect, or any other condition, which in the investigator's opinion might preclude the chronic use of CELECOXIB. Subjects may, at the Investigator's discretion, take a PPI or antacids daily as required Have been diagnosed as having or have been treated for oesophageal, gastric, pyloric channel, or duodenal ulceration within 30 days prior to receiving the first dose of study medication Subjects using corticosteroids (oral, injectable; exception of intraarticular/soft tissue injection at the exclusion of the target knee), indomethacin, tramadol, codeine, empracet, therapeutic dose of glucosamine or CHONDROITIN SULPHATE during the 12 weeks preceding inclusion Using hyaluronic acid (intra-articular target knee) during the 26 weeks preceding inclusion Using Natural Health Products (e.g. capsaicin, boswellia, willow bark), and creams and analgesic gels (e.g. camphor and alcohol based gels) during one week preceding baseline; Using Natural Health Products susceptible to increase the risk of bleeding (e.g. garlic, dong quai, etc.) during one week preceding baseline; Receiving radioactive synovectomy (target knee) during the 12 weeks preceding inclusion; Subjects who are receiving NSAID and do not want to stop during the study If treatment of osteoporosis (biphosphonates, SERMS, THS) is necessary, it will have to be continued, unmodified, for the entire duration of the study Have used medications with MMP-inhibitory properties (e.g. tetracycline or structurally related compounds) within 28 days prior to the Baseline Visit Are taking lithium carbonate, phenytoin or anticoagulants (with the exception of ASA up to a maximum daily dose of 325 mg) Have received chondrocyte transplants in any lower extremity joint Use oral or topical COXIBs, calcitonin or immunosuppressive drugs

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Chondroitin sulfate (Condrosan)<br>CHONDROITIN SULPHATE Group: 1200 mg (three capsules of 400 mg each) taken once a day in the morning | Drug: Chondroitin sulfate<br>* Chondroitin sulphate 1200 mg/day, 24 months treatment period<br>* Other names: Condrosan;|
| Active Comparator: Celecoxib<br>CELECOXIB Group: 200 mg (one capsule of 200 mg CELECOXIB + two placebo capsules) taken in the morning | Drug: Celecoxib<br>* Celecoxib 200 mg/day, 24 months treatment period<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cartilage Volume Loss of the Lateral Compartment | To compare the cartilage volume loss of the lateral compartment (femoral condyle and tibial plateau) at the Baseline visit and after 12 and 24 months of treatment either with CHONDROITIN SULPHATE (CONDROSAN) 1200 mg daily or with CELECOXIB 200 mg daily. | 12 months (Day 364) and 24 months (Day 728) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cartilage Volume Loss of the Global Knee | To compare the cartilage volume loss of the global knee at the Baseline visit and after 12 and 24 months. | 12 months (Day 364) and 24 months (Day 728) | 
| Cartilage Volume in the Medial Compartment | To compare the cartilage volume loss of the medial compartment at the Baseline visit and after 12 and 24 months. | 12 months (Day 364) and 24 months (Day 728) | 
| Synovial Membrane Thickness | To compare the severity of synovitis score (Thickness of the Synovial Membrane in mm) in Global Knee , at the baseline visit and the follow-up visits in subjects treated either with CHONDROITIN SULPHATE (CONDROSAN) or CELECOXIB. The severity of synovitis was evaluated through four regions of interest (ROIs) in the images of the axial T1-weighted acquisition complemented with the use of the images of the axial T2-weighted acquisition. The thickness of the synovial membrane was evaluated in the global knee and each of the ROIs and results were expressed in millimetres. The four ROIs were the proximal lateral, distal lateral, proximal medial and distal medial. | Baseline, 12 months (Day 364) and 24 months (Day 728) | 
| Bone Marrow Lesions Score | To compare the bone marrow lesions (BMLs) score in the global knee and the different sub regions at the baseline visit and the follow-up visits in subjects treated either with CHONDROITIN SULPHATE (CONDROSAN) or CELECOXIB. The BMLs were assessed in the global knee and the different sub region of the knee (medial trochlea, plateau of the medial femoro-tibial joint, femur of the medial femoro-tibial joint, medial posterior condyle, lateral trochlea, plateau of the lateral femoro-tibial joint, femur of the lateral femoro-tibial joint, lateral posterior femur). The BMLs score was defined as a grade (between 0 and 3) in each knee sub region and summed to derive a global knee score ranging between 0 (absent) and 30 (present). Specifically, each grade was scored as follows: Grade 0 = Absence of lesion in the sub region Grade 1 = less than 25% of the surface Grade 2 = 25-50% of the surface Grade 3 = more than 50% of the surface | Baseline, 12 months (Day 364) and 24 months (Day 728) | 
| Synovial Fluid Volume | To compare the synovial fluid volume of the global knee at the Baseline visit and after 24 months. | Baseline, 12 months (Day 364) and 24 months (Day 728) | 
| Percentage of Participants With the Presence of Extrusion in the Meniscus | The presence of a meniscal extrusion was assessed in each of sub regions. The absence of a severe extrusion in all the sub regions was considered as an absence (score=0) of a severe extrusion in the meniscus. The presence of a severe extrusion in at least one region of the meniscus was sufficient to consider the presence (score=1) of a severe extrusion in the meniscus. | Baseline, 12 months (Day 364) and 24 months (Day 728) | 
| Visual Analog Scale (VAS) | Visual Analogue Scale: 0 No Pain 10 Maximum Pain Huskisson's VAS measures global pain intensity. Patients were asked to quantify their disease status on a 10 cm VAS as follows: Please indicate the severity of knee pain experienced during the last 48 hours by marking a (I) through the line. Left hand marker represents No pain and right hand marker represents The worst pain imaginable. | Baseline, 12 months (Day 364) and 24 months (Day 728) | 
| WOMAC Pain Subscale | Western Ontario & McMaster Universities Osteoarthritis Index (WOMAC) Pain subscale Score Range: 0 (no pain) - 50 (maximum pain) The study was designed such that the outcome of primary interest is knee pain related to OA. The measure selected to best evaluate this is an improvement in the WOMAC pain subscales. This subscale consists of 5 items which assesses the pain during walking, using stairs, in bed, sitting or lying, and standing.Each item is a 10 cm VAS with 0 and 10 cm representing no pain and extreme pain respectively. | Baseline, 12 months (Day 364) and 24 months (Day 728) | 
| WOMAC Stiffness Subscale | Western Ontario & McMaster Universities Osteoarthritis Index, from 0 No Stiffness to 20 Maximum Stiffness WOMAC stiffness subscale was used to measure the stiffness of the knee with pain. Two items are used to assess stiffness grade: after first waking and later in the day.Each item is a 10 cm VAS with 0 and 10 cm representing no difficulty and extreme difficulty respectively. | Baseline, 12 months (Day 364) and 24 months (Day 728) | 
| WOMAC Function Subscale | Western Ontario & McMaster Universities Osteoarthritis Index, from 0 No Function to 170 Maximum Function WOMAC functional limitation subscale was used to measure the functionality of the knee with pain. Seventeen items are used to assess functionality of the knee: tair use, rising from sitting, standing, bending, walking, getting in / out of a car, shopping, putting on / taking off socks, rising from bed, lying in bed, getting in / out of bath, sitting, getting on / off toilet, heavy household duties, light household duties. Each item is a 10 cm VAS with 0 and 10 cm representing no difficulty and extreme difficulty respectively. | Baseline, 12 months (Day 364) and 24 months (Day 728) | 
| Short Form (SF-36) Health Survey | The SF-36 is composed of 35 items measuring: 8 health concepts (or dimensions), [(Physical Functioning (PF), Role Physical (RP), Bodily Pain (BP), General Health (GH), Vitality (VT), Social Functioning (SF), Role Emotional (RE) and Mental Health (MH)] and 1 reported health transition item. The 8 health concepts are summarized in 1 physical (PCS) and 1 mental (MCS) component summary measures. PCS is represented by physical function, role limitations-physical, pain, and general health perception. MCS is represented by vitality, social function, role limitations-emotional, and mental health. Subscale items are summed and scaled from 0-100 to give subscale scores; 0= worst health related quality of life (HRQL), 100=best HRQL. PCS and MCS summary scores are constructed as T-scores (mean =50, standard deviation=10) with no minimum or maximum score; higher scores indicate better health status. | Baseline, 12 months (Day 364) and 24 months (Day 728) | 
| Percentage of Participants With Presence of Joint Swelling and Effusion | Study knees were evaluated at each visit for the presence or absence of swelling and effusion. | Baseline, 12 months (Day 364) and 24 months (Day 728) | 
| Use of Acetaminophen | Consumption of Acetaminophen: At each post-baseline visit, the investigator had to assess the consumption of acetaminophen, rescue analgesic authorised throughout the study, by reporting the number of caplets dispensed/retrieved since the previous visit. Daily consumption of acetaminophen was calculated as an average. | 3 months (Day 91), 6 momnths (Day 182), 12 months (Day 364), 18 monts (Day 546) and 24 months (Day 728) |