A Study of the Efficacy and Safety of EUFLEXXA™ for Treatment of Painful Osteoarthritis of the Knee

Study Overview
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Brief Summary
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This multicenter, randomized, double-blind study will be performed in approximately 600 subjects with chronic idiopathic osteoarthritis (OA) of the knee. An open-label safety extension will follow.

Official Title
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A Double-Blind, Randomized, Placebo-Controlled Study of the Efficacy and Safety of EUFLEXXA™ for Treatment of Painful Osteoarthritis of the Knee, With an Open-Label Safety Extension

Conditions
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Osteoarthritis, Knee

Intervention / Treatment
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* Device: EUFLEXXA™
* Device: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Chronic OA of target knee confirmed by ACR Criteria Pain due to OA in target knee present for at least 6 months: • Moderate to severe pain score of 41 mm to 90 mm recorded on a 100 mm VAS immediately following a 50-foot walk A bilateral standing AP X-ray confirming OA of the target knee-obtained within a 6-month period prior to the Screening Visit-and a grade of 2 or 3 according to the Kellgren and Lawrence Grading Scale Ability and willingness to use only acetaminophen as the analgesic (rescue) study medication The acetaminophen dose must not exceed 4 grams/day (4000 mg) If subject has known chronic liver disease, the maximum dose of acetaminophen must not exceed 2 grams/day (2000 mg) The subject must be willing and able to discontinue acetaminophen at least 24 hours prior to all study-specific visits The study specific acetaminophen provided will only be used for knee pain. Ability to perform procedures required of the pain index evaluations (unassisted walking 50 feet on a flat surface and going up and down stairs). Willingness and ability to complete efficacy and safety questionnaires and ability to read and understand study instructions Signed study-specific Subject Informed Consent Form Exclusion Criteria: Any major injury (including sports injuries) to the target knee within the 12 months prior to the Screening Visit Any surgery to the target knee within the 12 months prior to the Screening Visit, or surgery to the contralateral knee or other weight-bearing joint if it will interfere with knee assessments Prior articular procedures, such as transplants or ligament reconstruction to the target knee Inflammatory arthropathies such as rheumatoid arthritis, lupus arthropathy, or psoriatic arthritis Gout or calcium pyrophosphate (pseudogout) diseases that have flared within the previous 6 months prior to the Screening Visit X-ray findings of acute fractures, severe loss of bone density, avascular necrosis, and/or severe bone or joint deformity in the target knee Osteonecrosis of either knee Fibromyalgia, pes anserine bursitis, lumbar radiculopathy, and/or neurogenic or vascular claudication Significant anterior knee pain due to diagnosed isolated patella-femoral syndrome or chondromalacia in the target knee Significant target knee joint infection or skin disorder/infection within the previous 6 months prior to study enrollment Symptomatic OA of the hips, spine, or ankle, if it would interfere with the evaluation of the target knee Known hypersensitivity to acetaminophen, EUFLEXXA™, or Phosphate buffered saline solution Women of childbearing potential who are pregnant, nursing, or planning to become pregnant, and those who do not agree to remain on an acceptable method of birth control throughout the entire study period Recurrent medical history of severe allergic or immune-mediated reactions or other immune disorders Vascular insufficiency of lower limbs or peripheral neuropathy severe enough to interfere with the study evaluation Current treatment or treatment within the previous 2 years prior to the Screening Visit for any malignancy unless specific written permission is provided by the Sponsor (excluding basal cell or squamous cell carcinoma of the skin) Active liver disease based on liver profile of AST, ALT, and conjugated bilirubin >2 times the upper limit of normal Renal insufficiency based on serum creatinine >2.0 mg/dL Any clinically significant laboratory value based on clinical history that the Investigator feels may affect the study evaluation Any intercurrent chronic disease or condition that may interfere with the completion of the 6-month (or 12-month) follow-up of the study, such as liver disease, severe coronary disease, drug abuse, disordered mental state, or other clinically significant condition Current alcoholism, and/or any known current addiction to pain medications Any clinically significant finding that would place the patient at health risk, impact the study, or affect the completion of the study Any psychiatric illness that would prevent comprehension of the details and nature of the study Participation in any experimental drug or device study within the 6 months prior to the Screening Visit

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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Accepts Healthy Volunteers

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: EUFLEXXA™ Double-blind<br>Each subject received 3 single-dose injections of EUFLEXXA™ into the target knee; one injection per week at weeks 0, 1 and 2. Patients were followed for 26 weeks following the first injection. | Device: EUFLEXXA™<br>* EUFLEXXA™ is supplied in a single-dose syringe containing 20 mg/2 ml of 1% sodium hyaluronate (molecular weight 2.4-3.6 MD); sodium chloride, 17 mg; disodium hydrogen phosphate dodecahydrate, 1.12 mg; sodium dihydrogen phosphate dihydrate, 0.1 mg; enough water for injection to make 2.0 ml. EUFLEXXA™ is supplied in 2.25 ml nominal volume, disposable prefilled glass syringes containing 2 mL of EUFLEXXA™. Only the contents of the syringe are sterile. EUFLEXXA™ is nonpyrogenic. See package insert for further details.<br>|
| Placebo Comparator: Placebo Double-blind<br>Each subject received 3 single-dose injections of placebo into the target knee; one injection per week at weeks 0, 1 and 2. Patients were followed for 26 weeks following the first injection. | Device: placebo<br>* Placebo is supplied in a disposable prefilled glass syringe. Each single-dose syringe will contain 2 mL of phosphate buffered saline. Only the contents of the syringe are sterile.<br>|
| Experimental: EUFLEXXA™ Open Label<br>All patients who participated in the 26 week double-blind study (including participants randomized to the placebo treatment group) and elected to participate in the open label extension, received three injections of EUFLEXXA™ in the target knee. Injections were given once a week on weeks 26, 27 and 28. | Device: EUFLEXXA™<br>* EUFLEXXA™ is supplied in a single-dose syringe containing 20 mg/2 ml of 1% sodium hyaluronate (molecular weight 2.4-3.6 MD); sodium chloride, 17 mg; disodium hydrogen phosphate dodecahydrate, 1.12 mg; sodium dihydrogen phosphate dihydrate, 0.1 mg; enough water for injection to make 2.0 ml. EUFLEXXA™ is supplied in 2.25 ml nominal volume, disposable prefilled glass syringes containing 2 mL of EUFLEXXA™. Only the contents of the syringe are sterile. EUFLEXXA™ is nonpyrogenic. See package insert for further details.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Observed Pain Scores on 50-foot Walk Test During the Double-blind Study | The level of pain is estimated by the participant following a walk of 50 feet in length which is observed by the investigator. Pain estimates were evaluated on a 100 millimeter visual analog scale. A score of 0 millimeters means there was no pain observed; a score of 100 millimeters means extreme pain was observed. | Weeks 0, 26 | 
| Percent Change From Baseline in Observed Pain Scores on 50-foot Walk Test During the Double-blind Study | The percent difference in participant pain recorded by the participant during a walk of 50 feet in length between the baseline (week 0) and week 26 scores. Scores are measured on a visual analog scale of 100 millimeters; a score of 0 millimeters meaning no pain was observed; a score of 100 millimeters meaning extreme pain was observed. | Weeks 0 and 26 | 
| Shifts From Extension Study Baseline (Week 26) in Range of Motion Findings at Week 52 | Number of participants in various categories of target knee joint examination findings from baseline (week 26 pre-injection) to week 52. Range of motion indicates the flexibility of the knee, and is measured by the number of degrees between when the knee is hyper-extended and when the knee is flexed. | weeks 26 and 52 | 
| Shifts From Extension Study Baseline (Week 26) in Ratings of Knee Tenderness at Week 52 | Number of participants in various categories of target knee joint examination findings from baseline (week 26 pre-injection) to week 52. Tenderness of the knee was subjectively rated by participants as none, mild, moderate or severe. | weeks 26 and 52 | 
| Shifts From Extension Study Baseline (Week 26) in Ratings of Knee Local Warmth at Week 52 | Number of participants in various categories of target knee joint examination findings from baseline (week 26 pre-injection) to week 52. Local warmth of the target knee was recorded as Yes (warmth present) or No (knee was not warmer than expected). | weeks 26 and 52 | 
| Shifts From Extension Study Baseline (Week 26) in Ratings of Knee Redness at Week 52 | Number of participants in various categories of target knee joint examination findings from baseline (week 26 pre-injection) to week 52. Redness of the knee was subjectively rated as Yes (knee was red) and No (knee was not red). | weeks 26 and 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Screening in Observed Pain Scores on 50-foot Walk Test During the Double-blind Study | The percent difference in participant pain recorded by the participant during a walk of 50 feet in length between the screening (week -1) and week 26 scores. Scores are measured on a visual analog scale of 100 millimeters; a score of 0 millimeters means there was no pain observed; a score of 100 millimeters means extreme pain was observed. | weeks -1 and 26 | 
| Percent Change From Baseline in Observed Pain Scores on 50-foot Walk Test During the Double-blind Study for a Subpopulation of Participants With More Severe Knee Pain | Percent difference in participant pain during a walk of 50 feet in length between the mean screening (week -1) and baseline(week 0) scores, and week 26 scores. Scores are recorded by participants and measured on a visual analog scale of 100 millimeters, with 0 millimeters meaning there was no pain observed; 100 millimeters meaning extreme pain was observed. | weeks -1, 0, and 26 | 
| Number of Observed Osteoarthritis Research Society International (OARSI30) Responders Using the 50-Foot Walk Test at Week 12 | Responders are identified based on a calculation of three scales: 50-foot walk test for pain, function and global assessment scales. Each of the individual scales was completed by the participant. A participant was a responder (answer: YES) if there was high improvement in pain or function (>=50 percent and absolute change of >=20 millimeters), or improvement in at least two of three categories: Pain and/or Function and/or Patient Global Assessment scales of >=20 percent and absolute change >=10 millimeter. | Week 12 | 
| Number of Observed Osteoarthritis Research Society International (OARSI30) Responders Using the 50-Foot Walk Test at Week 26 | Responders are identified based on a calculation of three scales: 50-foot walk test for pain, function and global assessment scales. Each of the individual scales was completed by the participant. A participant was a responder (answer: YES) if there was high improvement in pain or function (>=50 percent and absolute change of >=20 millimeters), or improvement in at least two of three categories: Pain and/or Function and/or Patient Global Assessment scales of >=20 percent and absolute change >=10 millimeter. | Week 26 | 
| Number of Observed Osteoarthritis Research Society International (OARSI30) Responders Using the Western Ontario McMaster University Osteoarthritis Index (WOMAC A) Pain Scale at Week 12 | Responders are identified based on a calculation of three scales: WOMAC (A) pain, function and global assessment scales. Each of the individual scales was completed by the participant. A participant was a responder (answer: YES) if there was high improvement in pain or function (>=50 percent and absolute change of >=20 millimeters), or improvement in at least two of three categories: Pain and/or Function and/or Patient Global Assessment scales of >=20 percent and absolute change >=10 millimeter. | Week 12 | 
| Number of Observed Osteoarthritis Research Society International (OARSI30) Responders Using the Western Ontario McMaster University Osteoarthritis Index (WOMAC A) Pain Scale at Week 26 | Responders are identified based on a calculation of three scales: WOMAC (A) pain, function and global assessment scales. Each of the individual scales was completed by the participant. A participant was a responder (answer: YES) if there was high improvement in pain or function (>=50 percent and absolute change of >=20 millimeters), or improvement in at least two of three categories: Pain and/or Function and/or Patient Global Assessment scales of >=20 percent and absolute change >=10 millimeter. | week 26 | 
| Change From Baseline in Patient Global Assessment of Knee Pain at Week 26 | Participant assessment of knee pain evaluated on a 100 millimeter visual analog scale. A score of 0 millimeters means there was no pain; a score of 100 millimeters means extreme pain. | Weeks 0 and 26 | 
| Change From Baseline in the Number of Tablets of Rescue Medication Used at Week 26. | The change in the number of tablets of 500 milligram acetaminophen used in a week as rescue medication is compared at weeks 0 and weeks 26. | Weeks 0 and 26 | 
| Mean Change From Baseline in Short Form 36 Questionnaire (SF-36) Physical Function (PF) Score at Week 26 | The SF-36 questionnaire yields a score for each domain of health. All domains are scored on a scale from 0 (negative health) to 100 (positive health), with 100 representing the best possible health state. This table summarizes the change from baseline in participants' physical function. The questionnaire is completed by participants. | Weeks 0, 26 | 
| Mean Change From Baseline in Short Form 36 Questionnaire (SF-36) Bodily Pain(BP) Score at Week 26 | The SF-36 questionnaire yields a score for each domain of health. All domains are scored on a scale from 0 (negative health) to 100 (positive health), with 100 representing the best possible health state. This table summarizes the change from baseline in participants' bodily pain scores. The questionnaire is completed by participants. | weeks 0 and 26 | 
| Mean Change From Baseline in Short Form 36 Questionnaire (SF-36) General Health(GH) Score at Week 26 | The SF-36 questionnaire yields a score for each domain of health. All domains are scored on a scale from 0 (negative health) to 100 (positive health), with 100 representing the best possible health state. This table summarizes the change from baseline in participants' general health scores. The questionnaire is completed by participants. | weeks 0 and 26 | 
| Mean Change From Baseline in Short Form 36 Questionnaire (SF-36) Physical Component Summary (PCS) Score at Week 26 | The SF-36 questionnaire yields a score for each domain of health. All domains are scored on a scale from 0 (negative health) to 100 (positive health), with 100 representing the best possible health state. The questionnaire is completed by participants. This table summarizes the change from baseline in participants' physical health. | Weeks 0, 26 | 
| Number of Participants With 20 Millimeter or Greater Improvement in Pain Scores on the 50-foot Walk Test | Yes represents the number of participants whose pain during a walk of 50 feet in length was improved at week 26 over baseline by at least 20 millimeters. Pain was evaluated on a 100 millimeter visual analog scale by participants. A score of 0 millimeters means there was no pain observed; a score of 100 millimeters means extreme pain was observed. | Weeks 0 and 26 | 
| Observed Pain Scores on the 50-foot Walk Test During the Extension Study | Participant pain during a walk of 50 feet in length was evaluated by participants on a 100 millimeter visual analog scale. A score of 0 millimeters means there was no pain observed; a score of 100 millimeters means extreme pain was observed. | Baseline (week 26), week 52 | 
| Mean Change From Baseline in Observed Pain Scores on 50-foot Walk Test During the Extension Study | The mean difference in participant pain as measured by participants during a walk of 50 feet in length between the baseline (week 26 pre-dose) and week 52 scores. Scores are measured on a visual analog scale of 100 millimeters, with a score of 0 millimeters meaning there was no pain observed; a score of 100 millimeters meaning extreme pain was observed. | Extension baseline (week 26), week 52 | 
| Number of Observed Osteoarthritis Research Society International (OARSI30) Responders Using the 50-Foot Walk Test at Week 52 | Responders are identified based on a calculation of three scales: 50-foot walk test for pain, function and global assessment scales. Each of the individual scales was completed by the participant. A participant was a responder (answer:YES) if there was high improvement in pain or function (>=50 percent and absolute change of >=20 millimeters), or improvement in at least two of three categories: Pain and/or Function and/or Patient Global Assessment scales of >=20 percent and absolute change >=10 millimeter. | Week 52 (Extension Study) | 
| Change From Baseline (Extension Study Week 26) in Use of Rescue Medication at Week 52. | The change in the number of tablets of study-specific acetaminophen taken per week as a rescue medication from knee pain. | Extension baseline (week 26 pre-dose), week 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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osteoarthritis, knee