Osteoarthritis
Conditions
Brief summary
Primary Objective: -To evaluate the efficacy of a single 6-milliliter (mL) intra-articular (IA) injection of Hylan G-F 20 measured by Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Numerical Rating Scale (NRS) 3.1 A1 score, in comparison to an IA placebo injection over 26 weeks, in Chinese participants with symptomatic Osteoarthritis (OA) of the knee. Secondary Objectives: * To evaluate the efficacy of a single 6-mL IA injection of Hylan G-F 20 measured by 7-day average score of WOMAC A1 pain sub-score in comparison to an IA placebo injection over 26 weeks. * To evaluate the efficacy of a single 6-mL IA injection of Hylan G-F 20 measured by WOMAC A, patient global assessment (PTGA) and clinical observer global assessment (COGA) in comparison to an IA placebo injection over 26 weeks. * To evaluate the response rate of a single 6-mL IA injection of Hylan G-F 20 in comparison to an IA placebo injection over 26 weeks. Response was defined as WOMAC A1 greater than or equal to (\>=) 2-point improvement from baseline on NRS. * To evaluate the safety of a single 6-mL IA injection of Hylan G-F 20, in comparison to an IA placebo injection over 26 weeks.
Detailed description
The duration of the study was 29 weeks at maximum. The screening and wash-out period lasted for up to 14 days, depending on the half-life of the medications followed by an 8-day baseline period including the treatment day. Overall, there were up to 21 days between signing informed consent (at screening visit) and the randomization (Day 1). Treatment was administered on Day 1, and follow-up period was 26 weeks.
Interventions
DEVICEHylan G-F 20 (GZ402662/SAR402662)
Pharmaceutical form: Solution for injection Route of administration: Intra articular
DRUGPlacebo
Pharmaceutical form: Solution for injection Route of administration: Intra articular
Sponsors
Genzyme, a Sanofi Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
: * Symptomatic OA of the target knee joint with WOMAC A1 NRS score of \>=4.0 and less than or equal to (\<=) 8.0 as recorded in the baseline period. * Confirmed by standard X-rays performed within 3 months prior to screening visit: modified Kellgren-Lawrence Numerical Grading System of Grade I-III in the target knee joint. * According to the American College of Rheumatology (ACR) Criteria. * With failure to respond adequately to conservative non-pharmacologic therapy and/or simple analgesics, such as acetaminophen. * Participant was willing and was able to provide signed informed consent prior to any study related procedures being performed.
Exclusion criteria
* The score of contralateral knee pain (if present) \>3.0 NRS at screening visit. * Ipsilateral hip OA. * Participant with systemic corticosteroids within 12 weeks prior to screening visit. * Participant with injection of IA corticosteroids in the target knee joint within 26 weeks prior to screening visit. * Concurrent chronic pain conditions with pain score \>3.0 NRS at screening, or peripheral or central neuropathy that may affect sensation of the target knee area, including but not limited to back pain, hip pain, disc herniation, sciatica, diabetic neuropathy, post-stroke pain or fibromyalgia. The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) A1 Pain (Walking Pain) Subscale Score Over 26 Weeks | From Baseline up to Week 26 | The WOMAC Numerical Rating Scale (NRS) version 3.1 questionnaire was a self-administered, health status measure questionnaire of 24 questions comprising 3 subscales (joint pain, stiffness and physical function) for participants with Osteoarthritis (OA) of the knee. WOMAC A1 pain subscale (measure of pain during walking on a flat surface) was measured on 11-point (NRS) ranging from 0 (none) to 10 (extreme), where lower score represented no pain and higher score represented extreme pain. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in WOMAC A Score Over 26 Weeks | From Baseline up to Week 26 | The WOMAC NRS version 3.1 questionnaire was a self-administered, health status measure questionnaire of 24 questions comprising 3 subscales (joint pain, stiffness and physical function) for participants with OA of the knee. WOMAC A (5 items: measure of pain while walking, using stairs, at night while in bed, sitting or lying, and standing); each item was measured on 11-point (NRS) ranging from 0 (none) to 10 (extreme), where lower score represented no pain and higher score represented extreme pain. Total WOMAC A score was the sum of 5 item scores and ranges from 0 (none) to 50 (extreme); where lower score represented no pain and higher score represented extreme pain. |
| Change From Baseline in Patient Global Self-Assessment (PTGA) Score of Osteoarthritis Over 26 Weeks | From Baseline up to Week 26 | PTGA (self-assessment of target knee OA condition) was measured using an 11-point NRS ranging from 0 (best possible) to 10 (worst possible), where lower score represented best possible condition and higher score represented worst possible condition. |
| Change From Baseline in 7-day Average WOMAC A1 Pain (Walking Pain) Subscale Score Over 26 Weeks | From Baseline up to Week 26 | The WOMAC NRS version 3.1 questionnaire was a self-administered, health status measure questionnaire of 24 questions comprising 3 subscales (joint pain, stiffness and physical function) for participants with OA of the knee. WOMAC A1 pain subscale (measure of pain during walking on a flat surface) was measured on 11-point (NRS) ranging from 0 (none) to 10 (extreme), where lower score represented no pain and higher score represented extreme pain. For 7-day average WOMAC A1, the baseline value was defined as the average of the WOMAC A1 scores recorded 7 days prior to the first investigational medicinal product (IMP) administration (WOMAC A1 score recorded on Day 1 included). The 7-day average WOMAC A1 was set as missing if 3 or more of the 7 WOMAC A1 scores were missing. |
| Percentage of Positive WOMAC A1 Responder Over 26 Weeks | Week 4, Week 8, Week 12, Week 16, Week 20 and Week 26 | WOMAC A1 responder were defined as \>=2-point improvement from baseline in the WOMAC A1 NRS. The WOMAC NRS version 3.1 questionnaire was a self-administered, health status measure questionnaire of 24 questions comprising 3 subscales (joint pain, stiffness and physical function) for participants with OA of the knee. WOMAC A1 pain subscale (measure of pain during walking on a flat surface) was measured on 11-point (NRS) ranging from 0 (none) to 10 (extreme), where lower score represented no pain and higher score represented extreme pain. |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) | From Baseline up to Week 26 | Adverse Event (AE) was defined as any untoward medical occurrence in a participant who received study drug and did not necessarily had a causal relationship with the treatment. TEAEs were defined as AEs that developed, worsened (according to the Investigator opinion), or became serious during the on-treatment period (time from the injection of IMP up to Week 26 follow-up visit). |
| Change From Baseline in Clinical Observer Global Assessment (COGA) Score of Osteoarthritis Over 26 Weeks | From Baseline up to Week 26 | COGA was used by the physicians to perform a global assessment of the participant's target knee OA condition. The response was captured using the 11-point NRS pain intensity rating scale ranging from 0 (best possible) to 10 (worst possible) at the specified time points, where lower score represented best possible condition and higher score represented worst possible condition. |
Countries
China
Participant flow
Recruitment details
The study was conducted at 21 sites in China from 21 August 2017 to 28 January 2019. A total of 524 participants were screened, of which, 84 participants were screen failures. Screen failures were mainly due to inclusion criteria not met.
Pre-assignment details
A total of 440 participants were enrolled and randomized in the study. Assignment to arms was done centrally using an interactive voice response system/interactive web response system (IVRS/IWRS) in 1:1 ratio (Placebo: Hylan G-F 20).
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received a single IA injection of phosphate buffered saline on Day 1 and were observed for 26 weeks. | 220 |
| Hylan G-F 20 Participants received a single IA injection of 6 mL Hylan G-F 20 (Synvisc-One) on Day 1 and were observed for 26 weeks. | 220 |
| Total | 440 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Poor compliance to protocol | 0 | 1 |
| Overall Study | Randomized but not treated | 0 | 2 |
| Overall Study | Withdraw before treatment | 1 | 5 |
Baseline characteristics
| Characteristic | Hylan G-F 20 | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 61.5 years STANDARD_DEVIATION 7.9 | 61.5 years STANDARD_DEVIATION 7.9 | 61.6 years STANDARD_DEVIATION 7.8 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 220 Participants | 440 Participants | 220 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 170 Participants | 342 Participants | 172 Participants |
| Sex: Female, Male Male | 50 Participants | 98 Participants | 48 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 220 | 0 / 218 |
| other Total, other adverse events | 66 / 220 | 75 / 218 |
| serious Total, serious adverse events | 10 / 220 | 14 / 218 |
Outcome results
Primary
Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) A1 Pain (Walking Pain) Subscale Score Over 26 Weeks
The WOMAC Numerical Rating Scale (NRS) version 3.1 questionnaire was a self-administered, health status measure questionnaire of 24 questions comprising 3 subscales (joint pain, stiffness and physical function) for participants with Osteoarthritis (OA) of the knee. WOMAC A1 pain subscale (measure of pain during walking on a flat surface) was measured on 11-point (NRS) ranging from 0 (none) to 10 (extreme), where lower score represented no pain and higher score represented extreme pain.
Time frame: From Baseline up to Week 26
Population: Analysis was performed on modified Intent-To-Treat (mITT) population which included all randomized and treated participants. Participants were analyzed in the treatment group to which they were randomized.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) A1 Pain (Walking Pain) Subscale Score Over 26 Weeks | -2.271 score on a scale | Standard Error 0.11 |
| Hylan G-F 20 | Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) A1 Pain (Walking Pain) Subscale Score Over 26 Weeks | -2.146 score on a scale | Standard Error 0.108 |
Comparison: Least-square (LS) means, standard errors (SE) were analyzed from repeated measures analysis of covariance (ANCOVA). The model included treatment groups (Hylan G-F 20 and placebo), site, visit and visit by treatment interaction, as well as the baseline WOMAC A1 score as a covariate).p-value: 0.36195% CI: [-0.144, 0.395]ANCOVA
Secondary
Change From Baseline in 7-day Average WOMAC A1 Pain (Walking Pain) Subscale Score Over 26 Weeks
The WOMAC NRS version 3.1 questionnaire was a self-administered, health status measure questionnaire of 24 questions comprising 3 subscales (joint pain, stiffness and physical function) for participants with OA of the knee. WOMAC A1 pain subscale (measure of pain during walking on a flat surface) was measured on 11-point (NRS) ranging from 0 (none) to 10 (extreme), where lower score represented no pain and higher score represented extreme pain. For 7-day average WOMAC A1, the baseline value was defined as the average of the WOMAC A1 scores recorded 7 days prior to the first investigational medicinal product (IMP) administration (WOMAC A1 score recorded on Day 1 included). The 7-day average WOMAC A1 was set as missing if 3 or more of the 7 WOMAC A1 scores were missing.
Time frame: From Baseline up to Week 26
Population: Analysis was performed on mITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in 7-day Average WOMAC A1 Pain (Walking Pain) Subscale Score Over 26 Weeks | -2.275 score on a scale | Standard Error 0.108 |
| Hylan G-F 20 | Change From Baseline in 7-day Average WOMAC A1 Pain (Walking Pain) Subscale Score Over 26 Weeks | -2.176 score on a scale | Standard Error 0.106 |
Secondary
Change From Baseline in Clinical Observer Global Assessment (COGA) Score of Osteoarthritis Over 26 Weeks
COGA was used by the physicians to perform a global assessment of the participant's target knee OA condition. The response was captured using the 11-point NRS pain intensity rating scale ranging from 0 (best possible) to 10 (worst possible) at the specified time points, where lower score represented best possible condition and higher score represented worst possible condition.
Time frame: From Baseline up to Week 26
Population: Analysis was performed on mITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Clinical Observer Global Assessment (COGA) Score of Osteoarthritis Over 26 Weeks | -2.145 score on a scale | Standard Error 0.095 |
| Hylan G-F 20 | Change From Baseline in Clinical Observer Global Assessment (COGA) Score of Osteoarthritis Over 26 Weeks | -2.225 score on a scale | Standard Error 0.094 |
Secondary
Change From Baseline in Patient Global Self-Assessment (PTGA) Score of Osteoarthritis Over 26 Weeks
PTGA (self-assessment of target knee OA condition) was measured using an 11-point NRS ranging from 0 (best possible) to 10 (worst possible), where lower score represented best possible condition and higher score represented worst possible condition.
Time frame: From Baseline up to Week 26
Population: Analysis was performed on mITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Patient Global Self-Assessment (PTGA) Score of Osteoarthritis Over 26 Weeks | -2.138 score on a scale | Standard Error 0.104 |
| Hylan G-F 20 | Change From Baseline in Patient Global Self-Assessment (PTGA) Score of Osteoarthritis Over 26 Weeks | -2.144 score on a scale | Standard Error 0.102 |
Secondary
Change From Baseline in WOMAC A Score Over 26 Weeks
The WOMAC NRS version 3.1 questionnaire was a self-administered, health status measure questionnaire of 24 questions comprising 3 subscales (joint pain, stiffness and physical function) for participants with OA of the knee. WOMAC A (5 items: measure of pain while walking, using stairs, at night while in bed, sitting or lying, and standing); each item was measured on 11-point (NRS) ranging from 0 (none) to 10 (extreme), where lower score represented no pain and higher score represented extreme pain. Total WOMAC A score was the sum of 5 item scores and ranges from 0 (none) to 50 (extreme); where lower score represented no pain and higher score represented extreme pain.
Time frame: From Baseline up to Week 26
Population: Analysis was performed on mITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in WOMAC A Score Over 26 Weeks | -8.747 score on a scale | Standard Error 0.491 |
| Hylan G-F 20 | Change From Baseline in WOMAC A Score Over 26 Weeks | -8.621 score on a scale | Standard Error 0.486 |
Secondary
Number of Participants With Treatment Emergent Adverse Events (TEAEs)
Adverse Event (AE) was defined as any untoward medical occurrence in a participant who received study drug and did not necessarily had a causal relationship with the treatment. TEAEs were defined as AEs that developed, worsened (according to the Investigator opinion), or became serious during the on-treatment period (time from the injection of IMP up to Week 26 follow-up visit).
Time frame: From Baseline up to Week 26
Population: Analysis was performed on safety population which included randomized participants who received at least 1 injection or part of an injection of Hylan G-F 20 or placebo.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 142 Participants |
| Hylan G-F 20 | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 134 Participants |
Secondary
Percentage of Positive WOMAC A1 Responder Over 26 Weeks
WOMAC A1 responder were defined as \>=2-point improvement from baseline in the WOMAC A1 NRS. The WOMAC NRS version 3.1 questionnaire was a self-administered, health status measure questionnaire of 24 questions comprising 3 subscales (joint pain, stiffness and physical function) for participants with OA of the knee. WOMAC A1 pain subscale (measure of pain during walking on a flat surface) was measured on 11-point (NRS) ranging from 0 (none) to 10 (extreme), where lower score represented no pain and higher score represented extreme pain.
Time frame: Week 4, Week 8, Week 12, Week 16, Week 20 and Week 26
Population: Analysis was performed on mITT population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Percentage of Positive WOMAC A1 Responder Over 26 Weeks | Week 4 | 58.6 percentage of participants |
| Placebo | Percentage of Positive WOMAC A1 Responder Over 26 Weeks | Week 8 | 65.0 percentage of participants |
| Placebo | Percentage of Positive WOMAC A1 Responder Over 26 Weeks | Week 12 | 66.4 percentage of participants |
| Placebo | Percentage of Positive WOMAC A1 Responder Over 26 Weeks | Week 16 | 69.1 percentage of participants |
| Placebo | Percentage of Positive WOMAC A1 Responder Over 26 Weeks | Week 20 | 65.0 percentage of participants |
| Placebo | Percentage of Positive WOMAC A1 Responder Over 26 Weeks | Week 26 | 68.2 percentage of participants |
| Hylan G-F 20 | Percentage of Positive WOMAC A1 Responder Over 26 Weeks | Week 20 | 66.5 percentage of participants |
| Hylan G-F 20 | Percentage of Positive WOMAC A1 Responder Over 26 Weeks | Week 4 | 53.2 percentage of participants |
| Hylan G-F 20 | Percentage of Positive WOMAC A1 Responder Over 26 Weeks | Week 16 | 63.3 percentage of participants |
| Hylan G-F 20 | Percentage of Positive WOMAC A1 Responder Over 26 Weeks | Week 8 | 62.4 percentage of participants |
| Hylan G-F 20 | Percentage of Positive WOMAC A1 Responder Over 26 Weeks | Week 26 | 67.0 percentage of participants |
| Hylan G-F 20 | Percentage of Positive WOMAC A1 Responder Over 26 Weeks | Week 12 | 62.8 percentage of participants |