Osteoarthritis, Hip, Osteoarthritis, Knee
Conditions
Brief summary
The primary objective of the study is to evaluate the efficacy of fasinumab compared to placebo, when administered for up to 24 weeks in patients with pain due to osteoarthritis (OA) of the knee or hip. The secondary objectives of the study are: * To evaluate the efficacy of fasinumab compared to non-steroidal anti-inflammatory drugs (NSAID)s, when administered for up to 24 weeks in patients with pain due to OA of the knee or hip * To assess the safety and tolerability of fasinumab compared to placebo and compared to NSAIDs, when administered for up to 24 weeks in patients with pain due to OA of the knee or hip
Interventions
DRUGFasinumab
Solution for injection in pre-filled syringe
OTHERDiclofenac
NSAID active comparator (capsule)
OTHERCelecoxib
NSAID active comparator (capsule)
DRUGMatching placebo
Fasinumab-matching placebo (solution for injection in pre-filled syringe); NSAID-matching placebo (capsule)
Sponsors
Teva Pharmaceutical Industries, Ltd.
Regeneron Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria (additional criteria may apply at screening): 1. A clinical diagnosis of osteoarthritis (OA) of the knee or hip based on the American College of Rheumatology criteria with radiologic evidence of OA (K-L score ≥2 for the index joint) at the screening visit. 2. Willing to discontinue current pain medications and to adhere to study requirements for rescue treatments (acetaminophen/paracetamol to be taken as needed with a maximum daily dose of 2500 mg \[countries where 500 mg strength tablets/capsules are available\] or 2600 mg \[countries where 325 mg strength tablets/capsules are available\]) 3. A history of at least 12 weeks of inadequate pain relief or intolerance to analgesics used for pain due to OA of the knee or hip 4. Currently using a stable dose of NSAID 5. Willing to discontinue glucosamine sulfate and chondroitin sulfate treatments during the 24 weeks of treatment Key
Exclusion criteria
(additional criteria may apply at screening): 1. Non-compliance with the numeric rating scale (NRS) recording during the pre-randomization period 2. History or presence at the screening visit of non-OA inflammatory joint disease, Paget's disease of the spine, pelvis or femur, neuropathic disorders, multiple sclerosis, fibromyalgia, tumors or infections of the spinal cord, or renal osteodystrophy 3. History or presence on imaging of arthropathy, hip or knee dislocation, extensive subchondral cysts, evidence of severe structural damage, bone collapse, or primary metastatic tumor with the exception of chondromas or pathologic fractures 4. Trauma to the index joint within 3 months prior to the screening visit 5. Signs or symptoms of carpal tunnel syndrome within 6 months of screening 6. Patient is not a candidate for magnetic resonance imaging (MRI) 7. Is scheduled for a JR surgery to be performed during the study period or who would be unwilling or unable to undergo JR surgery if needed 8. History or presence at the screening visit of autonomic or diabetic neuropathy, or other peripheral neuropathy, including reflex sympathetic dystrophy 9. Evidence of autonomic neuropathy as defined in the schedule of assessments (SoAs) 10. History or diagnosis of chronic autonomic failure syndrome including pure autonomic failure, multiple system atrophy 11. Use of systemic corticosteroids within 30 days prior to the screening visit. Intra-articular corticosteroids in the index joint within 12 weeks prior to the screening visit, or to any other joint within 30 days prior to the screening visit 12. Exposure to an anti-NGF antibody prior to the screening visit or known sensitivity or intolerance to anti-NGF antibodies 13. Women of childbearing potential who are unwilling to practice highly effective contraception prior to the start of the first treatment, during the study, and for at least 20 weeks after the last dose
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Subscale Scores up to Week 24 in Participants Treated With Fasinumab Compared to Placebo | Baseline up to Week 24 | WOMAC pain subscale was a 5-item questionnaire used to assess the amount of pain experienced due to osteoarthritis in the index joint (knee or hip) in past 48 hours. It was calculated as the mean of the scores from the 5 individual questions scored on a numerical rating scale (NRS) of 0 (no pain) to 10 (higher pain), where higher scores indicated higher pain. |
| Change From Baseline in WOMAC Physical Function Subscale Scores up to Week 24 in Participants Treated With Fasinumab Compared to Placebo | Baseline up to Week 24 | Physical function referred to participant's ability to move around and perform usual activities of daily living. The WOMAC physical function subscale was a 17-item questionnaire used to assess the degree of difficulty experienced due to osteoarthritis in index joint (knee or hip) during past 48 hours. It was calculated as mean of the scores from 17 individual questions scored on a NRS of 0 (minimum difficulty) to 10 (maximum difficulty), where higher scores indicated maximum difficulty. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in WOMAC Pain Subscale Scores up to Week 24 in Participants Treated With Fasinumab Compared to Participants Treated With NSAIDs | Baseline up to Week 24 | WOMAC pain subscale is a 5-item questionnaire used to assess the amount of pain experienced due to osteoarthritis in the index joint (knee or hip) in the past 48 hours. It is calculated as the mean of the scores from the 5 individual questions scored on a NRS of 0 (no pain) to 10 (higher pain), where higher scores indicated higher pain. |
| Change From Baseline in WOMAC Physical Function Subscale Scores up to Week 24 in Participants Treated With Fasinumab Compared to Participants Treated With NSAIDs | Baseline up to Week 24 | Physical function referred to participant's ability to move around and perform usual activities of daily living. The WOMAC physical function subscale was a 17-item questionnaire used to assess the degree of difficulty experienced due to osteoarthritis in index joint (knee or hip) during past 48 hours. It was calculated as mean of the scores from 17 individual questions scored on a NRS of 0 (minimum difficulty) to 10 (maximum difficulty), where higher scores indicated maximum difficulty. |
| Change From Baseline in PGA Score up to Week 24 in Participants Treated With Fasinumab Compared to Participants Treated With NSAIDs | Baseline up to Week 24 | The PGA was a patient-rated assessment of current disease state on a 5-point Likert scale where 1 = very good (asymptomatic and no limitation of normal activities), 2 = good (mild symptoms and no limitation of normal activities), 3 = fair (moderate symptoms and limitation of some normal activities), 4 = poor (Severe symptoms and inability to carry out most normal activities) and, 5 =very poor (Very severe symptoms which were intolerable and inability to carry out all normal activities). Higher score indicated severe condition. |
| Change From Baseline in Weekly Average Walking Index Joint Pain Score up to Week 24 by Using the Numeric Rating Scale (NRS) Pain Scale | Baseline up to Week 24 | Participants reported weekly average walking index joint pain based on NRS. The NRS was nationally recognized numeric scale from 0 to 10, where 0 would demonstrate no pain, 1 to 3 would demonstrate mild pain, 4 to 6 would be moderate pain, 7 to 9 would be severe pain and 10 would be the worst pain possible. Higher score indicated greater pain. |
| Number of Participants With Adjudicated Arthropathy (AA) Events | Baseline up to follow-up period (Week 44) | AA was a composite term that encompasses the following conditions: Rapidly progressive Osteoarthritis (OA) type 1 and 2, Subchondral insufficiency fractures, and Primary Osteonecrosis confirmed by an arthropathy adjudication committee. AAs were also evaluated to determine if they met Destructive Arthropathy criteria. |
| Number of Participants With AA Events Meeting Destructive Arthropathy (DA) Criteria | Baseline up to follow-up period (Week 44) | DA is a unique clinical form of rapidly destructive arthropathy over and above that seen in the normal progression of OA. DA criteria can be associated with Rapidly Progressive OA type 2, Subchondral Insufficiency fracture, and Primary Osteonecrosis confirmed by an arthropathy adjudication committee. |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Baseline up to follow-up period (Week 44) | An adverse event (AE) was defined as any untoward medical occurrence in a participant administered a study drug which may or may not have a causal relationship with the study drug. TEAE was defined as an AE with an onset that occurs after receiving study drug. A serious adverse event (SAE) was defined as any untoward medical occurrence that resulted in any of the following outcomes: death, life-threatening, required initial or prolonged in-patient hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect, or considered as medically important event. Any TEAE included participants with both serious and non-serious TEAEs. |
| Percentage of Participants With Greater Than or Equal to (≥) 30 Percent (%) Reduction From Baseline up to Week 24 in WOMAC Pain Subscale Score in Participants Treated With Fasinumab Compared to Placebo | Baseline up to Week 24 | WOMAC pain subscale was a 5-item questionnaire used to assess the amount of pain experienced due to osteoarthritis in the index knee during past 48 hours. It was calculated as mean of the scores from 5 individual questions scored on a NRS of 0 (minimum pain) to 10 (maximum pain), where higher scores indicate more pain. |
| Number of Participants With At-least One Peripheral Sensory Adverse Events (AEs) | Baseline up to Week 44 | Any participants with a peripheral sensory event that persisted for 2 months was referred for a neurology or other specialty consultation and reported as an Adverse Events of Special Interest (AESI). |
| Number of Participants Who Underwent a Joint Replacements (JR) Surgery From Baseline up to Week 24 | Baseline up to Week 24 | Number of participants who underwent a JR surgery from baseline up to Week 24 were reported. |
| Number of Participants Who Underwent a Joint Replacements (JR) Surgery From Baseline up to Week 44 | Baseline up to Week 44 | Number of participants who underwent a JR surgery from baseline up to follow-up period (Week 44) were reported. |
| Number of Participants With Joint Replacement (JR) Surgery Reported at End of Study (EOS) (Week 72) | At Week 72 | An EOS phone contact was conducted at Week 72 following the last dose of study drug (Week 24) to evaluate the number of participants who had undergone or were scheduled for JR surgery. |
| Serum Concentrations of Functional Fasinumab | At Weeks 0, 4, 8, 16, 24 and 44 | — |
| Number of Participants With At-least One Positive Anti-Drug Antibody (ADA) Development | Baseline up to Week 44 | Immunogenicity was characterized by ADA responses & titers. Responses categories: Pre-existing immunoreactivity - ADA positive response at baseline with all post first dose negative results or positive response at baseline with all post first dose ADA responses \< 9-fold over baseline titer levels; Treatment-boosted response - positive response in the assay post first dose, \>= 9-fold over baseline titer levels, when baseline results are positive; Treatment-emergent response - ADA positive response post first dose when baseline results = negative or missing. |
| Number of Participants With Sympathetic Nervous System (SNS) Dysfunction Events | Baseline up to follow-up period (Week 44) | Potential events of SNS dysfunction were monitored throughout the study through physical examination, AE reporting, assessment of orthostatic hypotension, and the Survey of Autonomic Symptoms. Sympathetic nervous system dysfunction was diagnosed after consultation with an appropriate specialist, such as a neurologist and/or cardiologist. |
| Change From Baseline in Patient Global Assessment (PGA) Score up to Week 24 in Participants Treated With Fasinumab Compared to Placebo | Baseline up to Week 24 | The PGA was a patient-rated assessment of current disease state on a 5-point Likert scale where 1 = very good (asymptomatic and no limitation of normal activities), 2 = good (mild symptoms and no limitation of normal activities), 3 = fair (moderate symptoms and limitation of some normal activities), 4 = poor (Severe symptoms and inability to carry out most normal activities) and, 5 =very poor (Very severe symptoms which were intolerable and inability to carry out all normal activities). Higher score indicated severe condition. |
Countries
United States
Participant flow
Recruitment details
A total of 4531 participants were screened in this study. Out of which, 1650 participants were randomized to 1 of the following arms: Fasinumab (1 milligram \[mg\]), non-steroidal anti-inflammatory drug (NSAIDs), matched placebo, Fasinumab 3 and 6 mg. Screen failure was mostly due to inclusion criteria not met/exclusion criteria met. Eligible participants were randomized to receive placebo matched to Fasinumab/NSAIDs, NSAIDs (Diclofenac and Celecoxib) and Fasinumab 1 mg.
Pre-assignment details
In May 2018, the sponsor implemented an urgent safety measure to stop dosing for participants randomized to Fasinumab (6 mg and 3 mg), to prevent further randomization to these regimens across the Fasinumab program based on review of unblinded data in an ongoing study R475-PN-1523 (NCT02683239). Participants from Fasinumab 3 mg and 6 mg group were moved directly into the 20-week follow-up period.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants who received subcutaneous (SC) injection of placebo matched to Fasinumab every 4 weeks (Q4W) or every 8 weeks (Q8W) alternatively or oral placebo matched to NSAID twice daily (BID) up to 24 weeks. | 308 |
| NSAIDs Participants received oral capsule of Diclofenac at a dose of 75 mg BID or oral capsule of Celecoxib at a dose of 200 mg once daily (QD) up to 24 weeks. | 612 |
| Fasinumab 1 mg Participants received SC injection of Fasinumab at a dose of 1 mg Q4W up to 24 weeks and NSAID-matching placebo oral, BID | 612 |
| Fasinumab 3 mg Participants received SC injection of Fasinumab at a dose of 3 mg Q4W up to 24 weeks and NSAID-matching placebo oral, BID | 59 |
| Fasinumab 6 mg Participants received SC injection of Fasinumab at a dose of 6 mg Q8W up to 24 weeks, alternating with Q8W placebo injections. Participants received placebo injections at the Q4W study visits where study drug was not administered and NSAID-matching placebo oral, BID | 59 |
| Total | 1,650 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 4 | 20 | 17 | 1 | 0 |
| Overall Study | Death | 1 | 2 | 0 | 0 | 0 |
| Overall Study | Lack of Efficacy | 17 | 16 | 20 | 0 | 0 |
| Overall Study | Lost to Follow-up | 8 | 24 | 35 | 4 | 0 |
| Overall Study | Other | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Physician Decision | 6 | 10 | 6 | 9 | 10 |
| Overall Study | Protocol Violation | 8 | 10 | 5 | 0 | 2 |
| Overall Study | Withdrawal by Subject | 26 | 58 | 66 | 3 | 5 |
Baseline characteristics
| Characteristic | Placebo | Total | Fasinumab 6 mg | Fasinumab 3 mg | Fasinumab 1 mg | NSAIDs |
|---|---|---|---|---|---|---|
| Age, Continuous | 62.0 Years STANDARD_DEVIATION 9.3 | 62.2 Years STANDARD_DEVIATION 9.28 | 61.5 Years STANDARD_DEVIATION 9.55 | 62.8 Years STANDARD_DEVIATION 9.38 | 62.1 Years STANDARD_DEVIATION 9.13 | 62.3 Years STANDARD_DEVIATION 9.41 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 20 Participants | 110 Participants | 10 Participants | 5 Participants | 31 Participants | 44 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 285 Participants | 1537 Participants | 49 Participants | 54 Participants | 581 Participants | 568 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 3 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 33 Participants | 155 Participants | 3 Participants | 8 Participants | 54 Participants | 57 Participants |
| Race (NIH/OMB) Black or African American | 60 Participants | 354 Participants | 16 Participants | 12 Participants | 132 Participants | 134 Participants |
| Race (NIH/OMB) More than one race | 11 Participants | 53 Participants | 0 Participants | 0 Participants | 18 Participants | 24 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 202 Participants | 1082 Participants | 40 Participants | 39 Participants | 405 Participants | 396 Participants |
| Sex: Female, Male Female | 222 Participants | 1146 Participants | 34 Participants | 36 Participants | 436 Participants | 418 Participants |
| Sex: Female, Male Male | 86 Participants | 504 Participants | 25 Participants | 23 Participants | 176 Participants | 194 Participants |
| Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Subscale Score | 6.42 Score on a scale STANDARD_DEVIATION 1.394 | 6.42 Score on a scale STANDARD_DEVIATION 1.344 | 6.54 Score on a scale STANDARD_DEVIATION 1.279 | 6.43 Score on a scale STANDARD_DEVIATION 1.401 | 6.46 Score on a scale STANDARD_DEVIATION 1.321 | 6.38 Score on a scale STANDARD_DEVIATION 1.344 |
| WOMAC Physical Function Subscale Scores | 6.40 Score on a scale STANDARD_DEVIATION 1.495 | 6.37 Score on a scale STANDARD_DEVIATION 1.445 | 6.34 Score on a scale STANDARD_DEVIATION 1.392 | 6.50 Score on a scale STANDARD_DEVIATION 1.35 | 6.39 Score on a scale STANDARD_DEVIATION 1.462 | 6.32 Score on a scale STANDARD_DEVIATION 1.418 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 309 | 3 / 609 | 1 / 609 | 0 / 58 | 0 / 59 |
| other Total, other adverse events | 121 / 309 | 263 / 609 | 261 / 609 | 17 / 58 | 15 / 59 |
| serious Total, serious adverse events | 20 / 309 | 45 / 609 | 35 / 609 | 5 / 58 | 2 / 59 |
Outcome results
Primary
Change From Baseline in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Subscale Scores up to Week 24 in Participants Treated With Fasinumab Compared to Placebo
WOMAC pain subscale was a 5-item questionnaire used to assess the amount of pain experienced due to osteoarthritis in the index joint (knee or hip) in past 48 hours. It was calculated as the mean of the scores from the 5 individual questions scored on a numerical rating scale (NRS) of 0 (no pain) to 10 (higher pain), where higher scores indicated higher pain.
Time frame: Baseline up to Week 24
Population: This outcome measure examined only placebo vs. fasinumab 1mg arms. Here, Number of Subjects Analysed signifies those subjects who were evaluable for this endpoint. Modified full analysis set (mFAS) includes all randomized participants in FAS but excludes participants from 4 sites for which there were potential concerns regarding data quality, identified prior to database lock.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Subscale Scores up to Week 24 in Participants Treated With Fasinumab Compared to Placebo | FAS | -2.21 Score on a Scale | Standard Error 0.165 |
| Placebo | Change From Baseline in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Subscale Scores up to Week 24 in Participants Treated With Fasinumab Compared to Placebo | mFAS | -2.01 Score on a Scale | Standard Error 0.182 |
| Fasinumab 1 mg | Change From Baseline in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Subscale Scores up to Week 24 in Participants Treated With Fasinumab Compared to Placebo | FAS | -2.84 Score on a Scale | Standard Error 0.127 |
| Fasinumab 1 mg | Change From Baseline in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Subscale Scores up to Week 24 in Participants Treated With Fasinumab Compared to Placebo | mFAS | -2.78 Score on a Scale | Standard Error 0.141 |
Comparison: Analyses were based on a multiple imputation approach using a Mixed-Effect Model With Repeated Measure (MMRM) model with baseline randomization strata, baseline, treatment, visit and treatment by-visit interaction.p-value: =0.000395% CI: [-0.971, -0.286]MMRM
Comparison: (mFAS)~Analyses were based on a multiple imputation approach using a MMRM model with baseline, randomization strata, baseline, treatment, visit and treatment by-visit interactionp-value: >0.000195% CI: [-1.154, -0.383]MMRM
Primary
Change From Baseline in WOMAC Physical Function Subscale Scores up to Week 24 in Participants Treated With Fasinumab Compared to Placebo
Physical function referred to participant's ability to move around and perform usual activities of daily living. The WOMAC physical function subscale was a 17-item questionnaire used to assess the degree of difficulty experienced due to osteoarthritis in index joint (knee or hip) during past 48 hours. It was calculated as mean of the scores from 17 individual questions scored on a NRS of 0 (minimum difficulty) to 10 (maximum difficulty), where higher scores indicated maximum difficulty.
Time frame: Baseline up to Week 24
Population: This outcome measure examined only placebo vs. fasinumab 1mg arms. Here, Number of Participants Analyzed signifies those participants who were evaluable for this endpoint. The modified full analysis set (mFAS) includes all randomized participants in the FAS but excludes participants from four sites for which there were potential concerns regarding data quality, identified prior to database lock.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in WOMAC Physical Function Subscale Scores up to Week 24 in Participants Treated With Fasinumab Compared to Placebo | FAS | -2.02 Score on a Scale | Standard Error 0.164 |
| Placebo | Change From Baseline in WOMAC Physical Function Subscale Scores up to Week 24 in Participants Treated With Fasinumab Compared to Placebo | mFAS | -1.80 Score on a Scale | Standard Error 0.18 |
| Fasinumab 1 mg | Change From Baseline in WOMAC Physical Function Subscale Scores up to Week 24 in Participants Treated With Fasinumab Compared to Placebo | FAS | -2.65 Score on a Scale | Standard Error 0.125 |
| Fasinumab 1 mg | Change From Baseline in WOMAC Physical Function Subscale Scores up to Week 24 in Participants Treated With Fasinumab Compared to Placebo | mFAS | -2.62 Score on a Scale | Standard Error 0.138 |
Comparison: Analyses were based on a multiple imputation approach using a Mixed-Effect Model With Repeated Measure (MMRM) model with baseline randomization strata, baseline, treatment, visit and treatment by-visit interaction.p-value: =0.000395% CI: [-0.981, -0.29]MMRM
Comparison: (mFAS)~Analyses were based on a multiple imputation approach using an Mixed-Effect Model With Repeated Measure (MMRM) model with baseline randomization strata, baseline, treatment, visit and treatment by-visit interaction.p-value: <0.000195% CI: [-1.198, -0.443]MMRM
Secondary
Change From Baseline in Patient Global Assessment (PGA) Score up to Week 24 in Participants Treated With Fasinumab Compared to Placebo
The PGA was a patient-rated assessment of current disease state on a 5-point Likert scale where 1 = very good (asymptomatic and no limitation of normal activities), 2 = good (mild symptoms and no limitation of normal activities), 3 = fair (moderate symptoms and limitation of some normal activities), 4 = poor (Severe symptoms and inability to carry out most normal activities) and, 5 =very poor (Very severe symptoms which were intolerable and inability to carry out all normal activities). Higher score indicated severe condition.
Time frame: Baseline up to Week 24
Population: This outcome measure examined only placebo vs. fasinumab 1mg arms. Here, Number of Participants Analyzed signifies those participants who were evaluable for this endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Patient Global Assessment (PGA) Score up to Week 24 in Participants Treated With Fasinumab Compared to Placebo | -0.66 Score on a Scale | Standard Error 0.063 |
| Fasinumab 1 mg | Change From Baseline in Patient Global Assessment (PGA) Score up to Week 24 in Participants Treated With Fasinumab Compared to Placebo | -0.81 Score on a Scale | Standard Error 0.047 |
Comparison: A hierarchical testing procedure was used to control type I error and handle multiple secondary endpoint analyses. Testing was then performed sequentially in the order the endpoints are reported. The hierarchical testing sequence continued only when the previous endpoint was statistically significant at 0.05 level. Analyses are based on a multiple imputation approach using Mixed-Effect Model With Repeated Measure (MMRM) model.p-value: =0.036595% CI: [-0.28, -0.009]MMRM
Secondary
Change From Baseline in PGA Score up to Week 24 in Participants Treated With Fasinumab Compared to Participants Treated With NSAIDs
The PGA was a patient-rated assessment of current disease state on a 5-point Likert scale where 1 = very good (asymptomatic and no limitation of normal activities), 2 = good (mild symptoms and no limitation of normal activities), 3 = fair (moderate symptoms and limitation of some normal activities), 4 = poor (Severe symptoms and inability to carry out most normal activities) and, 5 =very poor (Very severe symptoms which were intolerable and inability to carry out all normal activities). Higher score indicated severe condition.
Time frame: Baseline up to Week 24
Population: This outcome measure examined only NSAIDs vs. fasinumab 1mg arms. Here, Number of Participants Analyzed signifies those participants who were evaluable for this endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in PGA Score up to Week 24 in Participants Treated With Fasinumab Compared to Participants Treated With NSAIDs | -0.75 Score on a Scale | Standard Error 0.048 |
| Fasinumab 1 mg | Change From Baseline in PGA Score up to Week 24 in Participants Treated With Fasinumab Compared to Participants Treated With NSAIDs | -0.81 Score on a Scale | Standard Error 0.047 |
Secondary
Change From Baseline in Weekly Average Walking Index Joint Pain Score up to Week 24 by Using the Numeric Rating Scale (NRS) Pain Scale
Participants reported weekly average walking index joint pain based on NRS. The NRS was nationally recognized numeric scale from 0 to 10, where 0 would demonstrate no pain, 1 to 3 would demonstrate mild pain, 4 to 6 would be moderate pain, 7 to 9 would be severe pain and 10 would be the worst pain possible. Higher score indicated greater pain.
Time frame: Baseline up to Week 24
Population: This outcome measure examined only placebo, NSAIDs vs. fasinumab 1mg arms. Here, Number of Participants Analyzed signifies those participants who were evaluable for this endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Weekly Average Walking Index Joint Pain Score up to Week 24 by Using the Numeric Rating Scale (NRS) Pain Scale | -1.85 Score on a Scale | Standard Error 0.13 |
| Fasinumab 1 mg | Change From Baseline in Weekly Average Walking Index Joint Pain Score up to Week 24 by Using the Numeric Rating Scale (NRS) Pain Scale | -2.13 Score on a Scale | Standard Error 0.101 |
| Fasinumab 1 mg | Change From Baseline in Weekly Average Walking Index Joint Pain Score up to Week 24 by Using the Numeric Rating Scale (NRS) Pain Scale | -2.51 Score on a Scale | Standard Error 0.1 |
Secondary
Change From Baseline in WOMAC Pain Subscale Scores up to Week 24 in Participants Treated With Fasinumab Compared to Participants Treated With NSAIDs
WOMAC pain subscale is a 5-item questionnaire used to assess the amount of pain experienced due to osteoarthritis in the index joint (knee or hip) in the past 48 hours. It is calculated as the mean of the scores from the 5 individual questions scored on a NRS of 0 (no pain) to 10 (higher pain), where higher scores indicated higher pain.
Time frame: Baseline up to Week 24
Population: This outcome measure examined only NSAIDs vs. fasinumab 1mg arms. Here, Number of Participants Analyzed signifies those participants who were evaluable for this endpoint. The modified full analysis set (mFAS) includes all randomized participants in the FAS but excludes participants from four sites for which there were potential concerns regarding data quality, identified prior to database lock.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in WOMAC Pain Subscale Scores up to Week 24 in Participants Treated With Fasinumab Compared to Participants Treated With NSAIDs | FAS | -2.60 Score on a Scale | Standard Error 0.128 |
| Placebo | Change From Baseline in WOMAC Pain Subscale Scores up to Week 24 in Participants Treated With Fasinumab Compared to Participants Treated With NSAIDs | mFAS | -2.48 Score on a Scale | Standard Error 0.14 |
| Fasinumab 1 mg | Change From Baseline in WOMAC Pain Subscale Scores up to Week 24 in Participants Treated With Fasinumab Compared to Participants Treated With NSAIDs | FAS | -2.84 Score on a Scale | Standard Error 0.127 |
| Fasinumab 1 mg | Change From Baseline in WOMAC Pain Subscale Scores up to Week 24 in Participants Treated With Fasinumab Compared to Participants Treated With NSAIDs | mFAS | -2.78 Score on a Scale | Standard Error 0.141 |
Secondary
Change From Baseline in WOMAC Physical Function Subscale Scores up to Week 24 in Participants Treated With Fasinumab Compared to Participants Treated With NSAIDs
Physical function referred to participant's ability to move around and perform usual activities of daily living. The WOMAC physical function subscale was a 17-item questionnaire used to assess the degree of difficulty experienced due to osteoarthritis in index joint (knee or hip) during past 48 hours. It was calculated as mean of the scores from 17 individual questions scored on a NRS of 0 (minimum difficulty) to 10 (maximum difficulty), where higher scores indicated maximum difficulty.
Time frame: Baseline up to Week 24
Population: This outcome measure examined only NSAIDs vs. fasinumab 1mg arms. Here, Number of Subjects Analysed signifies those subjects who were evaluable for this endpoint. The modified full analysis set (mFAS) includes all randomized participants in the FAS but excludes participants from four sites for which there were potential concerns regarding data quality, identified prior to database lock.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in WOMAC Physical Function Subscale Scores up to Week 24 in Participants Treated With Fasinumab Compared to Participants Treated With NSAIDs | FAS | -2.33 Score on a Scale | Standard Error 0.127 |
| Placebo | Change From Baseline in WOMAC Physical Function Subscale Scores up to Week 24 in Participants Treated With Fasinumab Compared to Participants Treated With NSAIDs | mFAS | -2.26 Score on a Scale | Standard Error 0.14 |
| Fasinumab 1 mg | Change From Baseline in WOMAC Physical Function Subscale Scores up to Week 24 in Participants Treated With Fasinumab Compared to Participants Treated With NSAIDs | FAS | -2.65 Score on a Scale | Standard Error 0.125 |
| Fasinumab 1 mg | Change From Baseline in WOMAC Physical Function Subscale Scores up to Week 24 in Participants Treated With Fasinumab Compared to Participants Treated With NSAIDs | mFAS | -2.62 Score on a Scale | Standard Error 0.138 |
Secondary
Number of Participants Who Underwent a Joint Replacements (JR) Surgery From Baseline up to Week 24
Number of participants who underwent a JR surgery from baseline up to Week 24 were reported.
Time frame: Baseline up to Week 24
Population: This outcome measure examined only placebo, NSAIDs vs. fasinumab 1mg arms. SAF included all randomized participants from the FAS who received any study drug. It is based on the actual treatment received.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants Who Underwent a Joint Replacements (JR) Surgery From Baseline up to Week 24 | 2 Participants |
| Fasinumab 1 mg | Number of Participants Who Underwent a Joint Replacements (JR) Surgery From Baseline up to Week 24 | 7 Participants |
| Fasinumab 1 mg | Number of Participants Who Underwent a Joint Replacements (JR) Surgery From Baseline up to Week 24 | 3 Participants |
Secondary
Number of Participants Who Underwent a Joint Replacements (JR) Surgery From Baseline up to Week 44
Number of participants who underwent a JR surgery from baseline up to follow-up period (Week 44) were reported.
Time frame: Baseline up to Week 44
Population: This outcome measure examined only placebo, NSAIDs vs. fasinumab 1mg arms. SAF included all randomized participants from the FAS who received any study drug. It is based on the actual treatment received.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants Who Underwent a Joint Replacements (JR) Surgery From Baseline up to Week 44 | 6 Participants |
| Fasinumab 1 mg | Number of Participants Who Underwent a Joint Replacements (JR) Surgery From Baseline up to Week 44 | 13 Participants |
| Fasinumab 1 mg | Number of Participants Who Underwent a Joint Replacements (JR) Surgery From Baseline up to Week 44 | 10 Participants |
Secondary
Number of Participants With AA Events Meeting Destructive Arthropathy (DA) Criteria
DA is a unique clinical form of rapidly destructive arthropathy over and above that seen in the normal progression of OA. DA criteria can be associated with Rapidly Progressive OA type 2, Subchondral Insufficiency fracture, and Primary Osteonecrosis confirmed by an arthropathy adjudication committee.
Time frame: Baseline up to follow-up period (Week 44)
Population: This outcome measure examined only placebo, NSAIDs vs. fasinumab 1mg arms. SAF included all randomized participants from the FAS who received any study drug. It was based on the actual treatment received. Here, Number of Participants Analyzed signifies those participants who had positive AA.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With AA Events Meeting Destructive Arthropathy (DA) Criteria | 0 Participants |
| Fasinumab 1 mg | Number of Participants With AA Events Meeting Destructive Arthropathy (DA) Criteria | 0 Participants |
| Fasinumab 1 mg | Number of Participants With AA Events Meeting Destructive Arthropathy (DA) Criteria | 2 Participants |
Secondary
Number of Participants With Adjudicated Arthropathy (AA) Events
AA was a composite term that encompasses the following conditions: Rapidly progressive Osteoarthritis (OA) type 1 and 2, Subchondral insufficiency fractures, and Primary Osteonecrosis confirmed by an arthropathy adjudication committee. AAs were also evaluated to determine if they met Destructive Arthropathy criteria.
Time frame: Baseline up to follow-up period (Week 44)
Population: This outcome measure examined only placebo, NSAIDs vs. fasinumab 1mg arms. Safety Analysis set (SAF) included all randomized participants from the FAS who received any study drug. It was based on the actual treatment received.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With Adjudicated Arthropathy (AA) Events | 5 Participants |
| Fasinumab 1 mg | Number of Participants With Adjudicated Arthropathy (AA) Events | 9 Participants |
| Fasinumab 1 mg | Number of Participants With Adjudicated Arthropathy (AA) Events | 34 Participants |
Secondary
Number of Participants With At-least One Peripheral Sensory Adverse Events (AEs)
Any participants with a peripheral sensory event that persisted for 2 months was referred for a neurology or other specialty consultation and reported as an Adverse Events of Special Interest (AESI).
Time frame: Baseline up to Week 44
Population: This outcome measure examined only placebo, NSAIDs vs. fasinumab 1mg arms. SAF included all randomized participants from the FAS who received any study drug. It is based on the actual treatment received
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With At-least One Peripheral Sensory Adverse Events (AEs) | 8 Participants |
| Fasinumab 1 mg | Number of Participants With At-least One Peripheral Sensory Adverse Events (AEs) | 24 Participants |
| Fasinumab 1 mg | Number of Participants With At-least One Peripheral Sensory Adverse Events (AEs) | 31 Participants |
Secondary
Number of Participants With At-least One Positive Anti-Drug Antibody (ADA) Development
Immunogenicity was characterized by ADA responses & titers. Responses categories: Pre-existing immunoreactivity - ADA positive response at baseline with all post first dose negative results or positive response at baseline with all post first dose ADA responses \< 9-fold over baseline titer levels; Treatment-boosted response - positive response in the assay post first dose, \>= 9-fold over baseline titer levels, when baseline results are positive; Treatment-emergent response - ADA positive response post first dose when baseline results = negative or missing.
Time frame: Baseline up to Week 44
Population: This outcome measure examined only placebo, NSAIDs vs. fasinumab 1mg arms. The ADA analysis set included all participants who received any study drug and had at least 1 non-missing ADA result following the first dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With At-least One Positive Anti-Drug Antibody (ADA) Development | Treated-Boosted Response | 0 Participants |
| Placebo | Number of Participants With At-least One Positive Anti-Drug Antibody (ADA) Development | Pre-Existing Immunoreactivity | 10 Participants |
| Placebo | Number of Participants With At-least One Positive Anti-Drug Antibody (ADA) Development | Treatment-Emergent Response | 3 Participants |
| Fasinumab 1 mg | Number of Participants With At-least One Positive Anti-Drug Antibody (ADA) Development | Treated-Boosted Response | 0 Participants |
| Fasinumab 1 mg | Number of Participants With At-least One Positive Anti-Drug Antibody (ADA) Development | Pre-Existing Immunoreactivity | 9 Participants |
| Fasinumab 1 mg | Number of Participants With At-least One Positive Anti-Drug Antibody (ADA) Development | Treatment-Emergent Response | 1 Participants |
| Fasinumab 1 mg | Number of Participants With At-least One Positive Anti-Drug Antibody (ADA) Development | Pre-Existing Immunoreactivity | 15 Participants |
| Fasinumab 1 mg | Number of Participants With At-least One Positive Anti-Drug Antibody (ADA) Development | Treatment-Emergent Response | 4 Participants |
| Fasinumab 1 mg | Number of Participants With At-least One Positive Anti-Drug Antibody (ADA) Development | Treated-Boosted Response | 0 Participants |
Secondary
Number of Participants With Joint Replacement (JR) Surgery Reported at End of Study (EOS) (Week 72)
An EOS phone contact was conducted at Week 72 following the last dose of study drug (Week 24) to evaluate the number of participants who had undergone or were scheduled for JR surgery.
Time frame: At Week 72
Population: This outcome measure examined only placebo, NSAIDs vs. fasinumab 1mg arms. SAF included all randomized participants from the FAS who received any study drug. It is based on the actual treatment received.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With Joint Replacement (JR) Surgery Reported at End of Study (EOS) (Week 72) | 11 Participants |
| Fasinumab 1 mg | Number of Participants With Joint Replacement (JR) Surgery Reported at End of Study (EOS) (Week 72) | 29 Participants |
| Fasinumab 1 mg | Number of Participants With Joint Replacement (JR) Surgery Reported at End of Study (EOS) (Week 72) | 21 Participants |
Secondary
Number of Participants With Sympathetic Nervous System (SNS) Dysfunction Events
Potential events of SNS dysfunction were monitored throughout the study through physical examination, AE reporting, assessment of orthostatic hypotension, and the Survey of Autonomic Symptoms. Sympathetic nervous system dysfunction was diagnosed after consultation with an appropriate specialist, such as a neurologist and/or cardiologist.
Time frame: Baseline up to follow-up period (Week 44)
Population: This outcome measure examined only placebo, NSAIDs vs. fasinumab 1mg arms. SAF included all randomized participants from the FAS who received any study drug. It was based on the actual treatment received.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With Sympathetic Nervous System (SNS) Dysfunction Events | 0 Participants |
| Fasinumab 1 mg | Number of Participants With Sympathetic Nervous System (SNS) Dysfunction Events | 0 Participants |
| Fasinumab 1 mg | Number of Participants With Sympathetic Nervous System (SNS) Dysfunction Events | 0 Participants |
Secondary
Number of Participants With Treatment Emergent Adverse Events (TEAEs)
An adverse event (AE) was defined as any untoward medical occurrence in a participant administered a study drug which may or may not have a causal relationship with the study drug. TEAE was defined as an AE with an onset that occurs after receiving study drug. A serious adverse event (SAE) was defined as any untoward medical occurrence that resulted in any of the following outcomes: death, life-threatening, required initial or prolonged in-patient hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect, or considered as medically important event. Any TEAE included participants with both serious and non-serious TEAEs.
Time frame: Baseline up to follow-up period (Week 44)
Population: This outcome measure examined only placebo, NSAIDs vs. fasinumab 1mg arms. SAF included all randomized participants from the FAS who received any study drug. It was based on the actual treatment received.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 186 Participants |
| Fasinumab 1 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 406 Participants |
| Fasinumab 1 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 403 Participants |
Secondary
Percentage of Participants With Greater Than or Equal to (≥) 30 Percent (%) Reduction From Baseline up to Week 24 in WOMAC Pain Subscale Score in Participants Treated With Fasinumab Compared to Placebo
WOMAC pain subscale was a 5-item questionnaire used to assess the amount of pain experienced due to osteoarthritis in the index knee during past 48 hours. It was calculated as mean of the scores from 5 individual questions scored on a NRS of 0 (minimum pain) to 10 (maximum pain), where higher scores indicate more pain.
Time frame: Baseline up to Week 24
Population: The FAS included all randomized participants excluding participants affected by the urgent safety measure and was based on the treatment allocated (as randomized). As pre-specified in the protocol, efficacy data from participants randomized to Fasinumab 1 mg Q4W and placebo was only included in the analysis for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Greater Than or Equal to (≥) 30 Percent (%) Reduction From Baseline up to Week 24 in WOMAC Pain Subscale Score in Participants Treated With Fasinumab Compared to Placebo | 48.7 Percentage of Participants |
| Fasinumab 1 mg | Percentage of Participants With Greater Than or Equal to (≥) 30 Percent (%) Reduction From Baseline up to Week 24 in WOMAC Pain Subscale Score in Participants Treated With Fasinumab Compared to Placebo | 59.8 Percentage of Participants |
Comparison: A hierarchical testing procedure was used to control type I error and handle multiple secondary endpoint analyses. Testing was then performed sequentially in the order the endpoints are reported. The hierarchical testing sequence continued only when the previous endpoint was statistically significant at 0.05 level. Analyses are based on Cochran-Mantel-Haenszel model.p-value: =0.001395% CI: [1.195, 2.092]Cochran-Mantel-Haenszel
Secondary
Serum Concentrations of Functional Fasinumab
Time frame: At Weeks 0, 4, 8, 16, 24 and 44
Population: Pharmacokinetic (PK) analysis set included all treated participants who received any study drug and who had at least 1 non-missing drug concentration result following the first study dose. Here, Overall Number of Participants Analyzed = participants who were evaluable for this outcome measure and Number Analyzed = participants who were evaluable at specified time points. Data was planned to be collected and analyzed for Fasinumab 1 mg Q4W arm only.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Serum Concentrations of Functional Fasinumab | Week 0 | 0.000155 Milligrams per Liter (mg/L) | Standard Deviation 0.002 |
| Placebo | Serum Concentrations of Functional Fasinumab | Week 4 | 0.0469 Milligrams per Liter (mg/L) | Standard Deviation 0.0179 |
| Placebo | Serum Concentrations of Functional Fasinumab | Week 8 | 0.0644 Milligrams per Liter (mg/L) | Standard Deviation 0.0275 |
| Placebo | Serum Concentrations of Functional Fasinumab | Week 16 | 0.0738 Milligrams per Liter (mg/L) | Standard Deviation 0.038 |
| Placebo | Serum Concentrations of Functional Fasinumab | Week 24 | 0.0713 Milligrams per Liter (mg/L) | Standard Deviation 0.0379 |
| Placebo | Serum Concentrations of Functional Fasinumab | Week 44 | 0.000349 Milligrams per Liter (mg/L) | Standard Deviation 0.00476 |