Comparative Study of Safety and Efficacy of Two Hyaluronic Acids for the Treatment of Knee Osteoarthritis Pain

Study Overview
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Brief Summary
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The purpose of this study is to determine the comparative safety and efficacy of intra-articular injection of hyaluronic acid, obtained from two different sources, in the treatment of osteoarthritic pain of the knee.

Detailed Description
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This is a multicenter, randomized, double blind, parallel-controlled clinical trial using a non-inferiority comparison to evaluate the efficacy and safety of an intra-articular injection of Durolane® vs Artz® in the treatment of knee osteoarthritis. Subjects will be randomized 1:1 to receive either Durolane or Artz. All subjects will be followed up for 26 weeks from the initial treatment.The screening period is expected to be up to 2 weeks in duration before the baseline visit. Each subject will provide a written informed consent and undergo a qualifying screening. Assessment at screening will include postero-anterior view of standing weight-bearing semi-flexed radiographs of the study knee. The osteoarthritis changes of the study knee will be graded 0,1,2,3 or 4 according to the Kellgren-Lawrence radiographic scoring criteria. Radiographic assessment will be made by an assigned and well trained investigator at each study center. The study knee and contralateral knee will use the Likert WOMAC 5-point scoring for pain assessment. Physical examination of the knees and vital signs will be performed (this examination will be repeated at end).

Official Title
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A Multicenter, Randomized, Double-blind, Parallel, Active-controlled Clinical Trial With Non-inferiority Comparison to Evaluate Efficacy and Safety of Intra-articular Injection of DUROLANE® vs. ARTZ® in Treatment of Knee Osteoarthritis

Conditions
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Knee Osteoarthritis

Intervention / Treatment
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* Device: ARTZ
* Device: DUROLANE


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject (female or male) 40-80 years of age, inclusive Documented diagnosis of mild to moderate osteoarthritis of the study knee that fulfil the ACR(American College of Rheumatology) criteria Radiographic evidence of osteoarthritis in the study knee (Kellgren Lawrence radiographic score is 2 or 3) Exclusion Criteria: Clinically apparent tense effusion of the study knee on examination determined by either a positive bulge sign or positive ballottement of the patella Kellgren-Lawrence radiographic score 0, 1 or 4 in the study knee Symptomatic osteoarthritis of the contralateral knee or of either hip that is not responsive to acetaminophen/paracetamol and/or requires any protocol prohibited therapies

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: ARTZ sodium hyaluronate<br>The comparator product, ARTZ, is manufactured by Seikagaku Corporation, Japan. Subjects randomized to the ARTZ group were administered five weekly intra-articular injections (2.5 ml, NASHA 25 mg). ARTZ is a sterile, viscoelastic nonpyrogenic solution of purified, high molecular weight (620,000-1,170,000 daltons) sodium hyaluronate having a pH of 6.8-7.8. The sodium hyaluronate is extracted from chicken combs. | Device: ARTZ<br>* Hyaluronic acid (five 2.5 mL injections)<br>|
| Active Comparator: DUROLANE hyaluronic acid<br>The investigational product was provided in pre-filled syringes containing stabilized non-animal hyaluronic acid (20 mg/mL). Only one injection was given for those subjects randomized to the DUROLANE group, followed by 4 sham injections. DUROLANE is free from products of animal origin and is manufactured by Q-Med AB Corporation.The sham injection procedure was same as the active injection, except that they were subcutaneous and an empty syringe was used. | Device: DUROLANE<br>* Hyaluronic acid stabilized (one 3.0 mL injection + four weekly 0 mL sham injections)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| WOMAC (Western Ontario and McMaster Osteoarthritis Index) Pain Subscale Change From Baseline | Pain assessment is made of 5 items; each has 5 possible values 0=none, 1=mild, 2=moderate, 3=severe, 4=extreme. The items are summed for a total range of 0 to 20. Therefore, the pain change from baseline range is -20 to 20. A negative change is a reduction in pain from the baseline pain score. A mixed-effect repeated measures regression model was used to estimate a least square mean for the entire Measured Time Frame. Change from baseline was the dependent variable. Subject baseline score was a fixed effect covariate. Enrollment site, treatment, visit, and treatment by visit interaction were fixed class effects. Subject was a random effect. A least square mean single point estimate and 95%CI was calculated for the entire Measured Time Frame using all data collected at each time point within the Measured Time Frame. | over 18 weeks (week timepoints 6, 10, 14, and 18) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| WOMAC (Western Ontario and McMaster Osteoarthritis Index) Pain Subscale Change From Baseline | Pain assessment is made of 5 items; each has 5 possible values 0=none, 1=mild, 2=moderate, 3=severe, 4=extreme. The items are summed for a total range of 0 to 20. Therefore, the pain change from baseline range is -20 to 20. A negative change is a reduction in pain from the baseline pain score. A mixed-effect repeated measures regression model was used to estimate a least square mean for the entire Measured Time Frame. Change from baseline was the dependent variable. Subject baseline score was a fixed effect covariate. Enrollment site, treatment, visit, and treatment by visit interaction were fixed class effects. Subject was a random effect. A least square mean single point estimate and 95%CI was calculated for the entire Measured Time Frame using all data collected at each time point within the Measured Time Frame. | over 26 weeks (week 6, 10, 14, 18, and 26) | 
| WOMAC (Western Ontario and McMaster Osteoarthritis Index) Physical Function Subscale Change From Baseline | Physical Function assessment is made of 17 items; each has 5 possible values 0=none, 1=mild, 3=moderate, 4=extreme. The items are summed for a total range of 0 to 68. Therefore, the physical function change from baseline range is -68 to 68. A negative change is an improvement in physical function from the baseline physical function score. A mixed-effect repeated measures regression model was used to estimate a least square mean for the entire Measured Time Frame. Change from baseline was the dependent variable. Subject baseline score was a fixed effect covariate. Enrollment site, treatment, visit, and treatment by visit interaction were fixed class effects. Subject was a random effect. A least square mean single point estimate and 95%CI was calculated for the entire Measured Time Frame using all data collected at each time point within the Measured Time Frame. | over 18 weeks (week timepoints 6, 10, 14, and 18) | 
| WOMAC (Western Ontario and McMaster Osteoarthritis Index) Physical Function Subscale Change From Baseline | Physical Function assessment is made of 17 items; each has 5 possible values 0=none, 1=mild, 3=moderate, 4=extreme. The items are summed for a total range of 0 to 68. Therefore, the physical function change from baseline range is -68 to 68. A negative change is an improvement in physical function from the baseline physical function score. A mixed-effect repeated measures regression model was used to estimate a least square mean for the entire Measured Time Frame. Change from baseline was the dependent variable. Subject baseline score was a fixed effect covariate. Enrollment site, treatment, visit, and treatment by visit interaction were fixed class effects. Subject was a random effect. A least square mean single point estimate and 95%CI was calculated for the entire Measured Time Frame using all data collected at each time point within the Measured Time Frame. | over 26 weeks (week timepoints 6, 10, 14, 18, and 26) | 
| Subject Global Assessment Change From Baseline | Subject global assessment is one question Considering all the ways your knee osteoarthritis affects you, how are you doing today?. It has 11 values 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 labeled only at the extremes; 0 = very bad and 10 = very good. The change from baseline range is -10 to 10. A positive change is an improvement from the baseline subject global assessment score. A mixed-effect repeated measures regression model was used to estimate a least square mean for the entire Measured Time Frame. Change from baseline was the dependent variable. Subject baseline score was a fixed effect covariate. Enrollment site, treatment, visit, and treatment by visit interaction were fixed class effects. Subject was a random effect. A least square mean single point estimate and 95%CI was calculated for the entire Measured Time Frame using all data collected at each time point within the Measured Time Frame. | over 18 weeks (week timepoints 6, 10, 14, and 18) | 
| Subject Global Assessment Change From Baseline | Subject global assessment is one question Considering all the ways your knee osteoarthritis affects you, how are you doing today?. It has 11 values 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 labeled only at the extremes; 0 = very bad and 10 = very good. The change from baseline range is -10 to 10. A positive change is an improvement from the baseline subject global assessment score. A mixed-effect repeated measures regression model was used to estimate a least square mean for the entire Measured Time Frame. Change from baseline was the dependent variable. Subject baseline score was a fixed effect covariate. Enrollment site, treatment, visit, and treatment by visit interaction were fixed class effects. Subject was a random effect. A least square mean single point estimate and 95%CI was calculated for the entire Measured Time Frame using all data collected at each time point within the Measured Time Frame. | over 26 weeks (week timepoints 6, 10, 14, 18, and 26) | 
| WOMAC (Western Ontario and McMaster Osteoarthritis Index) Knee Stiffness Subscale Change From Baseline | Knee stiffness assessment is made of 2 items; each has 5 possible values 0=none, 1=mild, 2=moderate, 3=severe, 4=extreme. The items are summed for a total range of 0 to 8. Therefore, the knee stiffness change from baseline range is -8 to 8. A negative change is a reduction in knee stiffness from the baseline knee stiffness score. A mixed-effect repeated measures regression model was used to estimate a least square mean for the entire Measured Time Frame. Change from baseline was the dependent variable. Subject baseline score was a fixed effect covariate. Enrollment site, treatment, visit, and treatment by visit interaction were fixed class effects. Subject was a random effect. A least square mean single point estimate and 95%CI was calculated for the entire Measured Time Frame using all data collected at each time point within the Measured Time Frame. | over 18 weeks (week timepoints 6, 10, 14, and 18) | 
| WOMAC (Western Ontario and McMaster Osteoarthritis Index) Knee Stiffness Subscale Change From Baseline | Knee stiffness assessment is made of 2 items; each has 5 possible values 0=none, 1=mild, 2=moderate, 3=severe, 4=extreme. The items are summed for a total range of 0 to 8. Therefore, the knee stiffness change from baseline range is -8 to 8. A negative change is a reduction in knee stiffness from the baseline knee stiffness score. A mixed-effect repeated measures regression model was used to estimate a least square mean for the entire Measured Time Frame. Change from baseline was the dependent variable. Subject baseline score was a fixed effect covariate. Enrollment site, treatment, visit, and treatment by visit interaction were fixed class effects. Subject was a random effect. A least square mean single point estimate and 95%CI was calculated for the entire Measured Time Frame using all data collected at each time point within the Measured Time Frame. | over 26 weeks (week timepoints 6, 10, 14, 18, and 26) |