Intra-articular Polyacrylamide Hydrogel in Knee Osteoarthritis

Study Overview
=================
Brief Summary
-----------------
The aim of this double-blinded controlled study is to assess clinical efficacy and safety of intra-articular polyacrylamide hydrogel with ions of silver in comparison with placebo (0.9% sodium chloride solution) in Kellgren Lawrence radiological grade II-III knee osteoarthritis

Detailed Description
-----------------
Polyacrylamide hydrogel (hereinafter - PAHG) is intended for a symptomatic effect leading to the decrease of joint pain intensity and improvement of functional joint characteristics. Therefore PAHG is intended for symptom-modifying therapy of joint osteoarthritis (hereinafter - OA). The aim of this study is to estimate efficacy and safety of intra-articular injections of PAHG in comparison with saline solution. Men and women above 50 years with verified knee osteoarthritis in accordance with the ACR criteria will be randomized 2 groups depends on treatment (PAHG or saline solution). Each patient will receive to the target knee joint 4.0 ml for one injection either PAHG or placebo with one-week interval between injections. Course - 2 injections. To avoid the joint overfilling with the dense, slowly resorbing material, with a good clinical result, the course of injections will be stopped. Primary and secondary efficacy endpoints, and safety parameters will be assessed on visits on Week 6, 13 and 25.

Official Title
-----------------
Multicenter Double-blind Randomized Comparative Placebo-controlled Study of Efficacy and Safety of Intra-articular Polyacrylamide Hydrogel With Silver Ions (NOLTREX™) in Knee Osteoarthritis

Conditions
-----------------
Osteoarthritis

Intervention / Treatment
-----------------
* Device: hydrous biopolymer with silver ions Argiform
* Device: saline solution


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Verified knee osteoarthritis in accordance with the ACR (knee pain combined with one of the following signs: age above 50 years, knee crepitus or morning joint stiffness lasting for less than 30 minutes combined with radiologic signs of knee osteoarthritis); Kellgren Lawrence radiological grade II-III knee osteoarthritis with the predominant involvement of the medial tibiofemoral region of the knee joint; Joint space width (JSW) of the target knee joint at least 2.5 mm. Exclusion Criteria: History of any injury or surgical intervention on the target knee joint (except for diagnostic arthroscopy made not longer than 60 days at the study entry); Severe degenerative changes in the target knee joint determined as the joint space narrowing less than 2 mm; Varus or valgus deformation of the target knee joint; Instability of the target knee joint; Active inflammation of the target knee joint (edema, hyperemia, present effusion) at the study entry; Microcrystalline arthropathies; Systemic inflammatory disease (rheumatoid arthritis, systemic lupus erythematosus, etc.); Seronegative spondyloarthritis and reactive arthritis; Inflammatory diseases of the skin and soft tissues in the proposed injection site for the test MD or placebo in the target joint; History of venous thrombosis and thromboembolia; Coagulogram abnormalities (APTT, prothrombin time, prothrombin index, fibrinogen); Inflammatory changes in the complete blood count (leukocytosis, increase of erythrocyte sedimentation rate [ESR]); Platelet count abnormality (in accordance with the reference ranges of the local laboratory; Increase of rheumatoid factor level; Increase of uric acid level > 360 μmol/l; Diabetes mellitus; Hemophilia and other hemorrhagic diatheses, as well administration of anticoagulants and disaggregants; Positive results of HIV, HBs-Ag, anti-HCV, RW tests; Intra-articular injection to the target knee joint: Noltrex - within 24 months prior patient's inclusion to the study; hyaluronates - within 6 months prior patient's inclusion to the study; glucocorticosteroids - within 1 month prior the study inclusion; non-steroidal anti-inflammatory drugs (NSAID) - within 3 weeks prior patient's inclusion to the study. Oral administration of non-steroidal anti-inflammatory drugs (NSAID) within 2 weeks prior the study inclusion; Necessity of systemic glucocorticosteroids in any dosage form; Paracetamol administration within 48 hours prior the study inclusion; Pregnancy and lactation; Hypersensitivity to components of the test MD or placebo; Severe liver disorder determined as the increase of one of the values: ALT, AST, ALP, total bilirubin, GGTP more than 3 times the upper limit of normal; Renal diseases with the glomerular filtration rate estimated per Cockraft-Gault formula less than 60 ml/min/1.73 m2 (III-V stage chronic renal disease [CRD]); Clinically manifest hip osteoarthritis; History of knee and coxofemoral endoprosthesis; Acute infectious diseases or infectious aggravations of chronic diseases (respiratory infections) within one month prior the study inclusion; Severe decompensated chronic or acute diseases and other conditions which, by the opinion of the study physician, may preclude the patient's participation in the study or affect the study results.

Ages Eligible for Study
-----------------
Minimum Age: 50 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: multicenter double-blind randomized comparative placebo-controlled
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NOLTREX™, II-III grade OA<br>72 patients with II-III grade of gonarthrosis will randomised to receive PAHG | Device: hydrous biopolymer with silver ions Argiform<br>* 4.0 ml for one injection with one-week interval between injections. Course - 2 injections.<br>* Other names: Synovial fluid endoprosthesis NOLTREX™;|
| Placebo Comparator: Placebo, II-III grade ОА<br>72 patients with II-III grade of gonarthrosis will randomised to receive saline solution | Device: saline solution<br>* 4.0 ml for one injection with one-week interval between injections. Course - 2 injections.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of the total WOMAC score (WOMAC-T) | Estimated per the corresponding subscales and total arthritis index score developed by WOMAC | at Week 25 in comparison with baseline at Week 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The total score | Change of the total score of WOMAC scale (WOMAC-T) | at Week 13 in comparison with baseline at Week 1 | 
| The pain | Change of the pain subscale score (WOMAC-A) | at Week 6, Week 13 and Week 25 and in comparison with baseline at Week 1 | 
| The rigidity and functionality | Change of rigidity (WOMAC-B) and functionality (WOMAC-C) subscale scores | at Week 6, Week 13 and Week 25 and in comparison with baseline at Week 1 | 
| Patient's assessment of the treatment efficacy | per scale from 1 - evident aggravation to 6 - significant improvement | Week 6, Week 13 and Week 25 | 
| Investigator's assessment of the treatment efficacy | per scale from 1 - evident aggravation to 6 - significant improvement | Week 6, Week 13 and Week 25 | 
| Assessment of the total number of paracetamol tablets taken | the need in paracetamol intake to relieve the knee pain during administration of intra-articular MD NOLTREX™ in comparison with placebo | Week 6, Week 13 and Week 25 | 
| Patient withdrawal rates due to safety | Proportion of patient who left the study due to: Need in paracetamol intake due to knee osteoarthritis 4 days a week and more during 2 successive weeks; The investigator makes the decision that a patient should discontinue the study in the best interests of the patient; Individual intolerability or contraindications to the test MD, placebo or paracetamol; AE/SAE which requires examination and/or treatment affecting significantly the study procedures (in particular, in particular, development of active arthritis or hemarthrosis of the target knee joint). | Week 25 | 
| Patient withdrawal rates due to poor patient's treatment compliance | Proportion of patient who left the study due to: Informed consent withdrawal (patient's unwillingness to continue the study); Major deviation from the study protocol. | Week 25 | 
| Intensity of pain in the target knee joint (100-mm VAS) | Assessment of pain intensity in the target knee joint per mm visual analogous scale (100-mm VAS) | Week 1, Week 2 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
intra-articular, polyacrylamide hydrogel