Knee Osteoarthritis
Conditions
Brief summary
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
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).
Interventions
DEVICEARTZ
Hyaluronic acid (five 2.5 mL injections)
DEVICEDUROLANE
Hyaluronic acid stabilized (one 3.0 mL injection + four weekly 0 mL sham injections)
Sponsors
Smith & Nephew, Inc.
Bioventus LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Investigational product was masked from study staff and participants with the exception of the unblinded treating investigator conducting the intra-articular injections.
Eligibility
Sex/Gender
ALL
Age
40 Years to 80 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| WOMAC (Western Ontario and McMaster Osteoarthritis Index) Pain Subscale Change From Baseline | over 18 weeks (week timepoints 6, 10, 14, and 18) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| WOMAC (Western Ontario and McMaster Osteoarthritis Index) Pain Subscale Change From Baseline | over 26 weeks (week 6, 10, 14, 18, and 26) | 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. |
| WOMAC (Western Ontario and McMaster Osteoarthritis Index) Physical Function Subscale Change From Baseline | over 18 weeks (week timepoints 6, 10, 14, and 18) | 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. |
| Subject Global Assessment Change From Baseline | over 18 weeks (week timepoints 6, 10, 14, and 18) | 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. |
| WOMAC (Western Ontario and McMaster Osteoarthritis Index) Knee Stiffness Subscale Change From Baseline | over 18 weeks (week timepoints 6, 10, 14, and 18) | 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. |
Countries
China
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| ARTZ ARTZ: Hyaluronic acid (five 2.5 mL injections) | 174 |
| DUROLANE DUROLANE: Hyaluronic acid stabilized (one 3.0 mL injection + four weekly 0 mL sham injections) | 175 |
| Total | 349 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 1 |
| Overall Study | Lack of Efficacy | 1 | 0 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Other: family objection | 0 | 1 |
| Overall Study | Other: inconvenience | 1 | 0 |
| Overall Study | Protocol Violation | 4 | 2 |
| Overall Study | Withdrawal by Subject | 1 | 4 |
Baseline characteristics
| Characteristic | ARTZ | DUROLANE | Total |
|---|---|---|---|
| Age, Continuous | 60.6 years STANDARD_DEVIATION 8.16 | 60.3 years STANDARD_DEVIATION 8.11 | 60.4 years STANDARD_DEVIATION 8.13 |
| Race/Ethnicity, Customized Nationality: Han | 173 participants | 168 participants | 341 participants |
| Race/Ethnicity, Customized Nationality: Other | 1 participants | 7 participants | 8 participants |
| Region of Enrollment China | 174 participants | 175 participants | 349 participants |
| Sex: Female, Male Female | 139 Participants | 132 Participants | 271 Participants |
| Sex: Female, Male Male | 35 Participants | 43 Participants | 78 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 37 / 174 | 39 / 175 |
| serious Total, serious adverse events | 6 / 174 | 3 / 175 |
Outcome results
Primary
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.
Time frame: over 18 weeks (week timepoints 6, 10, 14, and 18)
Population: per protocol: all subjects randomized and treated with no important protocol deviation(s), which were established at a blinded data review meeting. An important deviation is any deviation that has the potential to bias the primary outcome.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| ARTZ | WOMAC (Western Ontario and McMaster Osteoarthritis Index) Pain Subscale Change From Baseline | -5.87 units on a scale |
| DUROLANE | WOMAC (Western Ontario and McMaster Osteoarthritis Index) Pain Subscale Change From Baseline | -5.97 units on a scale |
Comparison: Primary Hypothesis:~Ho: μDUR\[18\] - μArtz\[18\] ≥ +1.6 units Ha: μDUR\[18\] - μArtz\[18\] \< +1.6 units~Power Calculations:~Assume the over 18 weeks difference is 0mm, SD 20mm (5 on the Likert scale), 90% power, 2-sided test alpha 5%, and a 8mm non-inferiority margin (1.6 on the Likert scale), the sample size required is 132 subjects per group adjusted to 175 to hold power constant due to loss to follow-up and dropout.95% CI: [-0.58, 0.39]
Secondary
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.
Time frame: over 18 weeks (week timepoints 6, 10, 14, and 18)
Population: per protocol: all subjects randomized and treated with no important protocol deviation(s), which were established at a blinded data review meeting. An important deviation is any deviation that has the potential to bias the primary outcome.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| ARTZ | Subject Global Assessment Change From Baseline | 2.55 units on a scale |
| DUROLANE | Subject Global Assessment Change From Baseline | 2.70 units on a scale |
Comparison: Ho: μDUR\[18\] - μArtz\[18\] ≤ -0.8 units Ha: μDUR\[18\] - μArtz\[18\] \> -0.8 units95% CI: [-0.15, 0.45]
Secondary
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.
Time frame: over 26 weeks (week timepoints 6, 10, 14, 18, and 26)
Population: per protocol: all subjects randomized and treated with no important protocol deviation(s), which were established at a blinded data review meeting. An important deviation is any deviation that has the potential to bias the primary outcome.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| ARTZ | Subject Global Assessment Change From Baseline | 2.67 units on a scale |
| DUROLANE | Subject Global Assessment Change From Baseline | 2.81 units on a scale |
Comparison: Ho: μDUR\[18\] - μArtz\[18\] ≤ -0.8 units Ha: μDUR\[18\] - μArtz\[18\] \> -0.8 units95% CI: [-0.16, 0.43]
Secondary
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.
Time frame: over 26 weeks (week timepoints 6, 10, 14, 18, and 26)
Population: per protocol: all subjects randomized and treated with no important protocol deviation(s), which were established at a blinded data review meeting. An important deviation is any deviation that has the potential to bias the primary outcome.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| ARTZ | WOMAC (Western Ontario and McMaster Osteoarthritis Index) Knee Stiffness Subscale Change From Baseline | -1.80 units on a scale |
| DUROLANE | WOMAC (Western Ontario and McMaster Osteoarthritis Index) Knee Stiffness Subscale Change From Baseline | -1.95 units on a scale |
Comparison: Ho: μDUR\[26\] - μArtz\[26\] ≥ +0.64 units Ha: μDUR\[26\] - μArtz\[26\] \< +0.64 units95% CI: [-0.33, 0.03]
Secondary
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.
Time frame: over 18 weeks (week timepoints 6, 10, 14, and 18)
Population: per protocol: all subjects randomized and treated with no important protocol deviation(s), which were established at a blinded data review meeting. An important deviation is any deviation that has the potential to bias the primary outcome.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| ARTZ | WOMAC (Western Ontario and McMaster Osteoarthritis Index) Knee Stiffness Subscale Change From Baseline | -1.73 units on a scale |
| DUROLANE | WOMAC (Western Ontario and McMaster Osteoarthritis Index) Knee Stiffness Subscale Change From Baseline | -1.87 units on a scale |
Comparison: Ho: μDUR\[18\] - μArtz\[18\] ≥ +0.64 units Ha: μDUR\[18\] - μArtz\[18\] \< +0.64 units95% CI: [-0.33, 0.05]
Secondary
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.
Time frame: over 26 weeks (week 6, 10, 14, 18, and 26)
Population: per protocol: all subjects randomized and treated with no important protocol deviation(s), which were established at a blinded data review meeting. An important deviation is any deviation that has the potential to bias the primary outcome.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| ARTZ | WOMAC (Western Ontario and McMaster Osteoarthritis Index) Pain Subscale Change From Baseline | -6.05 units on a scale |
| DUROLANE | WOMAC (Western Ontario and McMaster Osteoarthritis Index) Pain Subscale Change From Baseline | -6.15 units on a scale |
Comparison: Ho: μDUR\[26\] - μArtz\[26\] ≥ +1.6 units Ha: μDUR\[26\] - μArtz\[26\] \< +1.6 units95% CI: [-0.56, 0.37]
Secondary
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.
Time frame: over 26 weeks (week timepoints 6, 10, 14, 18, and 26)
Population: per protocol: all subjects randomized and treated with no important protocol deviation(s), which were established at a blinded data review meeting. An important deviation is any deviation that has the potential to bias the primary outcome.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| ARTZ | WOMAC (Western Ontario and McMaster Osteoarthritis Index) Physical Function Subscale Change From Baseline | -12.58 units on a scale |
| DUROLANE | WOMAC (Western Ontario and McMaster Osteoarthritis Index) Physical Function Subscale Change From Baseline | -13.16 units on a scale |
Comparison: Ho: μDUR\[26\] - μArtz\[26\] ≥ +5.44 units Ha: μDUR\[26\] - μArtz\[26\] \< +5.44 units95% CI: [-1.69, 0.53]
Secondary
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.
Time frame: over 18 weeks (week timepoints 6, 10, 14, and 18)
Population: per protocol: all subjects randomized and treated with no important protocol deviation(s), which were established at a blinded data review meeting. An important deviation is any deviation that has the potential to bias the primary outcome.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| ARTZ | WOMAC (Western Ontario and McMaster Osteoarthritis Index) Physical Function Subscale Change From Baseline | -12.10 units on a scale |
| DUROLANE | WOMAC (Western Ontario and McMaster Osteoarthritis Index) Physical Function Subscale Change From Baseline | -12.75 units on a scale |
Comparison: Ho: μDUR\[18\] - μArtz\[18\] ≥ +5.44 units Ha: μDUR\[18\] - μArtz\[18\] \< +5.44 units95% CI: [-1.81, 0.51]