Evaluation of the Evolution of Biological and Imaging Markers of Bone and Cartilage Degradation in Patients With Knee Osteoarthritis Receiving Intra-articular Injections of a Hyaluronan Derivative HYMOVIS®

Study Overview
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Brief Summary
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This pilot study MOKHA is aimed to evaluate the beneficial effect of HYMOVIS® on cartilage of patients suffering of knee osteoarthritis as revealed by using scientifically sound, objective measurements of biological and MRI-based imaging markers.

Detailed Description
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This study is a post-marketing, open-label, prospective and multicentric pilot study in 50 patients suffering from knee OA. Investigators will be rheumatologists or articular disease specialists from public or academic hospitals located in Belgium and France. In each investigating center, the same injector will perform all the VS.

Official Title
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Evaluation of the Evolution of Biological and Imaging Markers of Bone and Cartilage Degradation in Patients With Knee Osteoarthritis Receiving Intra-articular Injections of a Hyaluronan Derivative HYMOVIS®

Conditions
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Knee Osteoarthritis

Intervention / Treatment
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* Device: HYMOVIS


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female between the age of 40 and 80 with BMI ≤ 40 Monolateral (unless contralateral knee is grade I and asymptomatic) femorotibial knee OA associated or not with femoropatellar knee OA Responding to clinical and radiological criteria of the American College of Rheumatology (ACR) (Appendix 1) Symptomatic for more than 6 months in the most painful knee Radiological Kellgren & Lawrence (K&L) II or III in radiographs from less than 12 months (Appendix 2) Mean knee pain score at rest over the last 24 hours evaluated on VAS (0-100) ≥ 40 (Appendix 3) with a washout period for Paracetamol and oral NSAIDs depending on the half-life of the drug (Appendix 4). The most painful knee is considered. Able to follow the instructions of the study Having signed an ICF Exclusion Criteria: Related to the OA pathology Bilateral (except asymptomatic and grade I) OA of the knee Radiological K&L grade I or IV (Appendix 2) Chondromatosis or villonodular synovitis of the knee Recent trauma (< 1 month) of the knee responsible of the symptomatic knee Acute inflammatory OA (KOFUS (Knee Osteoarthritis Flare Up Scale) score ≥ 7, Appendix 5) Articular disease resulting from articular dysplasia, aseptic osteonecrosis, acromegaly, Paget's disease, hemophilia, hemochromatosis…. Inflammatory disease i.e. rheumatoid arthritis, gout, infectious arthritis, acute calcium pyrophosphate arthritis Pathologies interfering with the evaluation of OA (radiculalgia in the lower limbs, arteritis…..) Presence of another joint (other than the target knee) affected by OA (confirmed in radiographs and symptomatic) Related to treatments Corticosteroids injection in the target knee in the last month before first injection Hyaluronan injection in the target knee in the last 6 months before first injection Arthroscopy and surgery in the target knee in the last 6 months before first injection Oral corticotherapy ≥ 5mg/day (in Prednisone equivalent) in the last 3 months before first injection OA treatments based on curcuma extract (e.g. FLEXOFYTOL) in the last 3 months before first injection Change in the dosage of SYSAD i.e. chondroitin, glucosamine, diacerein or avocado-soy unsaponifiables in the last 3 months before first injection Paracetamol and oral NSAIDs before inclusion and follow-up visits (washout period depending on the half-life of the drug, Appendix 4). Osteoporosis-related treatments based on strontium ranelate, selective estrogen-receptor modulator (SERM) and parathormone (PTH) in the last 12 months before first injection An anticipated need for any forbidden OA treatments during the trial Contraindications to HYMOVIS®: hypersensitivity to the product components and infections or skin diseases in the area of the injection site. Non-pharmacologic therapy (including physical therapy) for the lower extremities initiated in the month before first injection Anticoagulant (coumarinic compound) and heparin Related to associated diseases Severe diseases (liver or renal failure, lung/heart disease, tumor, HIV….) Allergy or contra-indication to hyaluronan Severe alteration of mobility enabling functional evaluation High risk of hemorrhage and risk of infection at the site of injection Anticipated need for any surgical or other invasive procedure during the trial including prosthesis in the target knee Related to patients Participation to a therapeutic clinical trial in the last 3 months before first injection Under guardianship or judicial protection Pregnancy, breastfeeding, planned conception, premenopausal women without contraception, tubal ligation or hysterectomy Related to MRI counter-indication Patient with a pacemaker, an implantable defibrillator, neurosurgical clips, a neurostimulator, cochlear implant, a stent from less than 3 weeks, an insulin pump Patient with a ferromagnetic splinter in the body, or having wire sutures Serious mobility problem (Parkinson, tremors), Claustrophobia

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 80 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HYMOVIS Arm<br>A treatment cycle consists of two injections administered at one week interval. For the purpose of this study, two treatment cycles of two injections of HYMOVIS® at baseline and 6 months will be performed per patient at V1 (Day 0), V2 (Day 7), V5 (Day 180) and V6 (Day 187). | Device: HYMOVIS<br>* HYMOVIS is a clear hydrogel obtained by hydration of the HA-based derivative named HYADD4p5. The conjugate compound is constituted by a partial hexadecylamide of hyaluronic acid, which is produced by a fermentation process.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assess the variation of type II collagen-specific biomarkers (Coll2-1, Coll2-1NO2 & CTX-II) after HYMOVIS® treatment versus baseline | Measure of the level of Coll2-1, Coll2-1NO2 and CTX-II biomarkers in biological fluids. | Variation of levels of biomarkers from baseline (V1) trough 1 year follow up (V8) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Variation in biomarkers related to cartilage homeostasis (synthesis/degradation balance) after HYMOVIS® treatment vs. baseline | Level of Agrec, COMP, PIIANP, MMP-3 -MPO and IL-6 biomarkers. | ariation of levels of biomarkers from baseline (V1) trough 1 year follow up (V8) | 
| Variation in MRI markers after HYMOVIS® treatment vs. baseline | Semi-quantitative WORMS - T2 relaxation time (T2 mapping) - Cartilage parameters (volume, thickness, curvature) | trough 1 year follow up | 
| Variation in pain and function | Pain and function evaluated with KOOS index - VAS for the mean knee pain over the last 24 hours at rest and while walking pain - VAS for global assessment of disease activity (by patient and by investigator) | trough 1 year follow up | 
| Responder to treatment | Responder rate to treatment (OARSI OMERACT criteria) | trough 1 year follow up | 
| Tolerance and satisfaction | Adverse events and drop-off - Patient satisfaction scale | trough 1 year follow up | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hyaluronic acid, MRI, Biomarkers, Cartilage, pain