Osteoarthritis
Conditions
Brief summary
The study is a prospective, multi-center, randomized, three-arm, parallel group, clinical study to evaluate the superiority of 3 weekly intra-articular (IA) doses of 2 mL of Investigational hyaluronate as compared to placebo injected into the target knee for the treatment of pain in subjects with Osteoarthritis (OA).The safety and effectiveness of the investigational product will also be compared with Euflexxa.
Detailed description
The primary objective is to evaluate the safety and effectiveness of 3 weekly IA doses of 2 mL of hyaluronate viscosupplement as compared to placebo injected into the target knee for the treatment of pain in subjects with OA As secondary objectives, the study will evaluate the safety and effectiveness of 3 weekly IA doses of 2 mL of Viscosupplement as compared to Euflexxa injected into the target knee for the treatment of pain in subjects with OA. In addition, to assess the effect of Viscosupplement on pain, stiffness, and physical function of the target knee, as well as functional health and general well-being
Interventions
DEVICEHyaluronate Injectable Viscosupplement
Test product of a 1% sodium hyaluronate for injection
DEVICEEuflexxa IA injection
Brand product of a 1% sodium hyaluronate for injection
DEVICEPlacebo
0.9% sodium chloride, sterile
Sponsors
Actavis Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Chronic OA of target knee confirmed by American College of Rheumatology Criteria * Pain due to OA in target knee that had been present for at least 6 months, with a moderate to severe pain score of \>50 mm recorded on a 100 mm Visual Analogue Scale (VAS) following a 50-foot walk * Subject agrees to discontinue all pain medications for at least 7 days prior to start of study * A bilateral standing anteroposterior x-ray confirming Grade 2 or 3 OA of the target knee * Body mass index ≤40kg/m2 * Able and willing to use only acetaminophen as the analgesic (rescue) study medication under the following conditions: * acetaminophen dose is not to exceed 4 grams (4000mg)/day * if the subject has known chronic liver disease, the maximum dose of acetaminophen is not to exceed 2 grams (2000 mg)/day * subject must be able and willing to discontinue acetaminophen at least 24 hours prior to all study-specific visits * Ability to perform procedures required of the pain index evaluations (unassisted walking for a distance of 50 feet on a flat surface and going up and down stairs) * Agrees to use a highly effective contraception * Able and willing to complete effectiveness and safety questionnaires and able to read and understand study instructions
Exclusion criteria
* Any major injury to the target knee within the 12 months prior to the Screening and Enrollment Visit * Any surgery to the target knee within the 12 months prior to the Screening and Enrollment Visit, * Articular procedures such as transplants or ligament reconstruction to the target knee within 12 months prior to Screening and Enrollment Visit * Inflammatory arthropathies such as rheumatoid arthritis, lupus arthropathy, or psoriatic arthritis * Gout or calcium pyrophosphate diseases of the target knee that have flared within the 6 months prior to the Screening and Enrollment 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 * Clinical signs and symptoms of active knee infection or crystal disease of the target 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 6 months prior to study enrollment * Symptomatic OA of the hips, spine, or ankle, that interferes with the evaluation of the target knee * Known hypersensitivity to acetaminophen or any of the study medications or their components * Women of childbearing potential who are pregnant, nursing, or planning to become pregnant * History of recurrent 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 * Intra-arterial corticosteroid (investigational or marketed) in any joint within 3 months of Screening and Enrollment Visit * Current treatment, or treatment within the 2 years prior to the Screening and Enrollment Visit, for any malignancy * Active liver disease based on liver profile of aspartate aminotransferase, alanine aminotransferase, and conjugated bilirubin \>2 times the upper limit of normal * Renal insufficiency based on serum creatinine \>2.0mg/dL * Any intercurrent chronic disease or condition that might interfere with the completion of the study * Current alcoholism and/or any known current addiction to pain medications * Participation in any experimental device study within 6 months prior to the Screening and Enrollment Visit, or participation in an experimental drug study within 1 month prior to the Screening and Enrollment Visit.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the WOMAC Pain Score in the Target Knee at Week 26 [Western Ontario and McMaster Universities Arthritis Index (WOMAC®)] | Baseline and 26 weeks | The primary effectiveness endpoint was the change from Baseline in the Western Ontario and McMaster Universities Arthritis Index (WOMAC®) pain score in the target knee at Week 26.The validated WOMAC was used to assess pain, stiffness, and physical function of the target knee.The range of pain score was 0 to 500 mm with higher scores for worse pain. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Pain Over Time From Baseline to Week 1, Week 6, Week 12 and Week 26 | 26 weeks | The change from Baseline in the WOMAC pain score over time (baseline to Week 1, Week 6, Week 12 and Week 26) using Western Ontario and McMaster Universities Arthritis Index (WOMAC®)\].The validated WOMAC was used to assess pain, stiffness, and physical function of the target knee.The range of pain score was 0 to 500 mm with higher scores for worse pain. |
| Change in Stiffness of the Knee After 26 Weeks as Measured by the WOMAC Pain Score in the Target Knee at Week 26 [Western Ontario and McMaster Universities Arthritis Index (WOMAC®)] | 26 weeks | The change from baseline in the stiffness in the target knee at Week 26. The validated WOMAC was used to assess pain, stiffness, and physical function of the target knee.The range of stiffness score was 0 to 100 mm with higher scores for worse stiffness. |
Countries
United States
Participant flow
Recruitment details
The populations for this study included the Safety Population, the modified Intent-to-Treat (mITT) population, and the Per-Protocol (PP) Population.
Participants by arm
| Arm | Count |
|---|---|
| Generic Hyaluronate Injectable, 1% Patients were administered intra-articular (IA) injection of 2 mL to the knee once weekly for 3 weeks. | 200 |
| Euflexxa Injection 1% Patients received intra-articular (IA) injection of 2 mL to the knee once weekly for 3 weeks. | 200 |
| Vehicle Solution Patients received intra-articular (IA) injection of 2mL to the knee once weekly for 3 weeks. | 199 |
| Total | 599 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 5 | 0 | 1 |
| Overall Study | Lost to Follow-up | 4 | 5 | 3 |
| Overall Study | Other | 3 | 3 | 2 |
| Overall Study | Physician Decision | 0 | 1 | 0 |
| Overall Study | Protocol Violation | 1 | 1 | 2 |
| Overall Study | Withdrawal by Subject | 9 | 6 | 10 |
Baseline characteristics
| Characteristic | Generic Hyaluronate Injectable, 1% | Euflexxa Injection 1% | Vehicle Solution | Total |
|---|---|---|---|---|
| Age, Continuous | 63.2 years STANDARD_DEVIATION 9.45 | 63.3 years STANDARD_DEVIATION 9.36 | 62.0 years STANDARD_DEVIATION 10.04 | 62.8 years STANDARD_DEVIATION 9.62 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 70 Participants | 54 Participants | 54 Participants | 178 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 130 Participants | 146 Participants | 145 Participants | 421 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 2 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) Asian | 13 Participants | 10 Participants | 8 Participants | 31 Participants |
| Race (NIH/OMB) Black or African American | 20 Participants | 27 Participants | 31 Participants | 78 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 163 Participants | 161 Participants | 160 Participants | 484 Participants |
| Sex: Female, Male Female | 79 Participants | 83 Participants | 89 Participants | 251 Participants |
| Sex: Female, Male Male | 121 Participants | 117 Participants | 110 Participants | 348 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 199 | 0 / 199 | 0 / 197 |
| other Total, other adverse events | 76 / 199 | 82 / 199 | 76 / 197 |
| serious Total, serious adverse events | 5 / 199 | 2 / 199 | 3 / 197 |
Outcome results
Primary
Change From Baseline in the WOMAC Pain Score in the Target Knee at Week 26 [Western Ontario and McMaster Universities Arthritis Index (WOMAC®)]
The primary effectiveness endpoint was the change from Baseline in the Western Ontario and McMaster Universities Arthritis Index (WOMAC®) pain score in the target knee at Week 26.The validated WOMAC was used to assess pain, stiffness, and physical function of the target knee.The range of pain score was 0 to 500 mm with higher scores for worse pain.
Time frame: Baseline and 26 weeks
Population: Intention-To-Treat (ITT) Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Generic Hyaluronate Injectable, 1% | Change From Baseline in the WOMAC Pain Score in the Target Knee at Week 26 [Western Ontario and McMaster Universities Arthritis Index (WOMAC®)] | -51.43 Percentage of change from baseline | Standard Deviation 41.012 |
| Euflexxa Injection 1% | Change From Baseline in the WOMAC Pain Score in the Target Knee at Week 26 [Western Ontario and McMaster Universities Arthritis Index (WOMAC®)] | -54.49 Percentage of change from baseline | Standard Deviation 37.042 |
| Vehicle Solution | Change From Baseline in the WOMAC Pain Score in the Target Knee at Week 26 [Western Ontario and McMaster Universities Arthritis Index (WOMAC®)] | -36.86 Percentage of change from baseline | Standard Deviation 52.826 |
95% CI: [10.25, 62.11]
Secondary
Change in Pain Over Time From Baseline to Week 1, Week 6, Week 12 and Week 26
The change from Baseline in the WOMAC pain score over time (baseline to Week 1, Week 6, Week 12 and Week 26) using Western Ontario and McMaster Universities Arthritis Index (WOMAC®)\].The validated WOMAC was used to assess pain, stiffness, and physical function of the target knee.The range of pain score was 0 to 500 mm with higher scores for worse pain.
Time frame: 26 weeks
Population: Intention-To-Treat (ITT) Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Generic Hyaluronate Injectable, 1% | Change in Pain Over Time From Baseline to Week 1, Week 6, Week 12 and Week 26 | Week 1 | -14.10 percentage of change from baseline | Standard Deviation 30.568 |
| Generic Hyaluronate Injectable, 1% | Change in Pain Over Time From Baseline to Week 1, Week 6, Week 12 and Week 26 | Week 6 | -46.28 percentage of change from baseline | Standard Deviation 41.042 |
| Generic Hyaluronate Injectable, 1% | Change in Pain Over Time From Baseline to Week 1, Week 6, Week 12 and Week 26 | Week 12 | -51.96 percentage of change from baseline | Standard Deviation 40.894 |
| Generic Hyaluronate Injectable, 1% | Change in Pain Over Time From Baseline to Week 1, Week 6, Week 12 and Week 26 | Week 26 | -51.43 percentage of change from baseline | Standard Deviation 41.012 |
| Euflexxa Injection 1% | Change in Pain Over Time From Baseline to Week 1, Week 6, Week 12 and Week 26 | Week 26 | -54.49 percentage of change from baseline | Standard Deviation 37.042 |
| Euflexxa Injection 1% | Change in Pain Over Time From Baseline to Week 1, Week 6, Week 12 and Week 26 | Week 1 | -15.13 percentage of change from baseline | Standard Deviation 27.341 |
| Euflexxa Injection 1% | Change in Pain Over Time From Baseline to Week 1, Week 6, Week 12 and Week 26 | Week 12 | -52.47 percentage of change from baseline | Standard Deviation 35.749 |
| Euflexxa Injection 1% | Change in Pain Over Time From Baseline to Week 1, Week 6, Week 12 and Week 26 | Week 6 | -49.91 percentage of change from baseline | Standard Deviation 35.543 |
| Vehicle Solution | Change in Pain Over Time From Baseline to Week 1, Week 6, Week 12 and Week 26 | Week 26 | -36.86 percentage of change from baseline | Standard Deviation 52.826 |
| Vehicle Solution | Change in Pain Over Time From Baseline to Week 1, Week 6, Week 12 and Week 26 | Week 6 | -33.96 percentage of change from baseline | Standard Deviation 68.782 |
| Vehicle Solution | Change in Pain Over Time From Baseline to Week 1, Week 6, Week 12 and Week 26 | Week 12 | -39.16 percentage of change from baseline | Standard Deviation 58.08 |
| Vehicle Solution | Change in Pain Over Time From Baseline to Week 1, Week 6, Week 12 and Week 26 | Week 1 | -15.08 percentage of change from baseline | Standard Deviation 32.68 |
95% CI: [10.25, 62.11]
Secondary
Change in Stiffness of the Knee After 26 Weeks as Measured by the WOMAC Pain Score in the Target Knee at Week 26 [Western Ontario and McMaster Universities Arthritis Index (WOMAC®)]
The change from baseline in the stiffness in the target knee at Week 26. The validated WOMAC was used to assess pain, stiffness, and physical function of the target knee.The range of stiffness score was 0 to 100 mm with higher scores for worse stiffness.
Time frame: 26 weeks
Population: Intention-To-Treat (ITT) Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Generic Hyaluronate Injectable, 1% | Change in Stiffness of the Knee After 26 Weeks as Measured by the WOMAC Pain Score in the Target Knee at Week 26 [Western Ontario and McMaster Universities Arthritis Index (WOMAC®)] | -47.37 percentage of change from baseline | Standard Deviation 45.275 |
| Euflexxa Injection 1% | Change in Stiffness of the Knee After 26 Weeks as Measured by the WOMAC Pain Score in the Target Knee at Week 26 [Western Ontario and McMaster Universities Arthritis Index (WOMAC®)] | -47.25 percentage of change from baseline | Standard Deviation 63.02 |
| Vehicle Solution | Change in Stiffness of the Knee After 26 Weeks as Measured by the WOMAC Pain Score in the Target Knee at Week 26 [Western Ontario and McMaster Universities Arthritis Index (WOMAC®)] | -35.77 percentage of change from baseline | Standard Deviation 63.103 |
95% CI: [-13.61, 8.49]