Study to Evaluate the Effects of Fasinumab on Peripheral Nerve Function in Patients With Pain Due to Osteoarthritis of the Hip or Knee

Study Overview
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Brief Summary
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The primary objective of the study is to evaluate the effect of fasinumab compared to placebo on peripheral nerves in participants with pain due to Osteoarthritis (OA) of the hip or knee. The secondary objectives of the study are to: Evaluate the efficacy of fasinumab compared to placebo in participants with pain due to OA of the hip or knee Evaluate the safety and tolerability of fasinumab compared to placebo in participants with pain due to OA of the hip or knee Characterize the concentrations of fasinumab in serum in participants with pain due to OA of the hip or knee Evaluate the immunogenicity of fasinumab in participants with pain due to OA of the hip or knee.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Evaluate the Effects of Fasinumab on Peripheral Nerve Function in Patients With Pain Due to Osteoarthritis of the Hip or Knee

Conditions
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Osteoarthritis, Knee, Osteoarthritis, Hip

Intervention / Treatment
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* Drug: Fasinumab
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: A clinical diagnosis of 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 Moderate-to-severe pain in the index joint defined as a WOMAC average pain subscale score of ≥4 at both the screening and randomization visits Willing to discontinue current pain medications and to adhere to study requirements for rescue treatments A history of regular use of analgesic medications for OA pain (defined as an average of 4 days per week over the 4 weeks prior to the screening visit), including oral nonsteroidal anti-inflammatory drugs (NSAIDs), selective cyclooxygenase 2 inhibitors, opioids, paracetamol/acetaminophen, or combinations thereof Consent to allow all radiographs and medical/surgical/hospitalization records of care received elsewhere prior to and during the study period to be shared with the investigator Key Exclusion Criteria: History or presence at the screening visit of non-OA inflammatory joint disease (eg, rheumatoid arthritis, lupus erythematosus, psoriatic arthritis, pseudo-gout, gout, spondyloarthropathy, polymyalgia rheumatica, joint infections within the past 5 years), Paget's disease of the spine, pelvis or femur, neuropathic disorders, multiple sclerosis, fibromyalgia, tumors or infections of the spinal cord, or renal osteodystrophy History or presence on imaging of arthropathy (osteonecrosis, subchondral insufficiency fracture, rapidly progressive OA type 1 or type 2), stress fracture, recent stress fracture, neuropathic joint arthropathy, hip dislocation (prosthetic hip dislocation is eligible), knee dislocation (patella dislocation is eligible), congenital hip dysplasia with degenerative joint disease, extensive subchondral cysts, evidence of bone fragmentation or collapse, or primary metastatic tumor with the exception of chondromas or pathologic fractures during the screening period Trauma to the index joint within 3 months prior to the screening visit History or presence of signs or symptoms of compression neuropathy, including carpal tunnel syndrome or sciatica Participant is not a candidate for Magnetic Resonance Imaging (MRI) Poorly controlled diabetes Known history of human immunodeficiency virus (HIV) infection Known history of ocular herpes simplex virus, herpes simplex virus pneumonia, or herpes simplex virus encephalitis History of poorly controlled hypertension Known history of infection with hepatitis B or C virus Note: Other protocol defined Inclusion/Exclusion apply

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fasinumab<br> | Drug: Fasinumab<br>* Subcutaneous (SC) every four weeks (Q4W)<br>* Other names: REGN475;|
| Placebo Comparator: Placebo<br> | Other: Placebo<br>* Subcutaneous (SC) every four weeks (Q4W)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Peroneal Motor Nerve Conduction Velocity at Week 16 | Peroneal motor nerve conduction velocity was evaluated by electrical stimulation of the nerve and recorded the compound muscle action potential from surface electrodes overlying a muscle supplied by the nerve. Change from baseline in peroneal motor nerve conduction velocity at Week 16 was reported. | Baseline, Week 16 | 
| Change From Baseline in Peroneal Motor Nerve Action Potential Amplitude at Week 16 | Peroneal motor nerve action potential amplitude was evaluated at ankle by electrical stimulation of the nerve and recorded the compound muscle action potential from surface electrodes overlying a muscle supplied by the nerve. Change from baseline in peroneal motor nerve action potential amplitude at Week 16 was reported. | Baseline, Week 16 | 
| Change From Baseline in Sural Sensory Nerve Conduction Velocity at Week 16 | Sural sensory nerve conduction velocity was evaluated by electrically stimulating sensory fibers and recorded the nerve action potential at a point further along that nerve. Change from baseline in sural sensory nerve conduction velocity at Week 16 was reported. | Baseline, Week 16 | 
| Change From Baseline in Sural Sensory Nerve Action Potential Amplitude at Week 16 | Sural sensory nerve action potential amplitude was evaluated by electrically stimulating sensory fibers and recorded the nerve action potential at a point further along that nerve. Change from baseline in sural sensory nerve action potential amplitude at Week 16 was reported. | Baseline, Week 16 | 
| Change From Baseline in Ulnar Sensory Nerve Conduction Velocity at Week 16 | Ulnar sensory nerve conduction velocity was evaluated by electrically stimulating sensory fibers and recorded the nerve action potential at a point further along that nerve. Change from baseline in ulnar sensory nerve conduction velocity at Week 16 was reported. | Baseline, Week 16 | 
| Change From Baseline in Ulnar Sensory Nerve Action Potential Amplitude at Week 16 | Ulnar sensory nerve action potential amplitude was evaluated by electrically stimulating sensory fibers and recorded the nerve action potential at a point further along that nerve. Change from baseline ulnar sensory nerve action potential amplitude at Week 16 was reported. | Baseline, Week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Subscale Score at Week 16 | 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. Total score range for WOMAC pain subscale score is 0 to 10, where higher scores indicate higher pain. A negative change from baseline indicated improvement. Change from baseline in WOMAC Pain subscale score at Week 16 was reported. | Baseline, Week 16 | 
| Change From Baseline in WOMAC Physical Function Subscale Score at Week 16 | Physical function referred to subject'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 (no difficulty) to 10 (extreme difficulty), where higher scores indicated worse function. Total score range for WOMAC physical function subscale score is 0 (no difficulty) to 10 (extreme difficulty), where higher scores indicate worse function. A negative change from baseline indicated improvement. Change from baseline in WOMAC physical function subscale score at Week 16 was reported. | Baseline, Week 16 | 
| 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. 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. TEAE was defined as an AE with an onset that occurs after receiving study drug. Any TEAE included participants with both serious and non-serious TEAEs. Number of participants with TEAEs were reported. | Baseline up to Week 16 | 
| Number of 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. Number of confirmed AA events from baseline up to follow-up (Week 36) were reported. | Baseline up to follow-up (Week 36) | 
| Number of AA Events Meeting Destructive Arthropathy (DA) Criteria | AAs were evaluated to determine if they met 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. Number of confirmed AA events meeting DA criteria from baseline up to follow-up (Week 36) were reported. | Baseline up to follow-up (Week 36) | 
| Number of 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. Number of SNS dysfunction events from baseline up to follow-up (Week 36) were reported. | Baseline up to follow-up (Week 36) | 
| Number of Peripheral Sensory Adverse Events (AEs) That Require a Neurology Consultation | Any peripheral sensory AE (for example [e.g.], paraesthesia and hypoaesthesia) that required a neurology consultation. Number of peripheral sensory adverse events from baseline up to follow-up (Week 36) were reported. | Baseline up to follow-up (Week 36) | 
| Number of All-Cause Joint Replacement (JR) Surgery Events | All joint replacement surgery events regardless of cause. | Baseline up to follow-up (Week 36) | 
| Number of Joint Replacement (JR) Surgery Events Reported at Telephone Survey After Last Dose of Study Drug | An end of study phone contact was conducted approximately 52 weeks following the last dose of study drug (Week 64) to evaluate the number of participants who had undergone or were scheduled for JR surgery. | Baseline up to EOS (Week 64) | 
| Serum Concentration of Functional Fasinumab | Serum concentrations of functional Fasinumab were reported. | Baseline, Week 1, 2, 4, 8, 12, 16 and 36 | 
| Number of Participants With At-least One Positive Anti-Drug Antibody (ADA) | Samples for ADA evaluation were collected at baseline and at subsequent study visits. ADA variables included ADA status (+/-) and titer as follows: Total participants negative in ADA assay at all time points analyzed. Pre-existing immunoreactivity- positive response at baseline with all post-dose results negative/positive response at baseline with all post-dose responses less than 9-fold over baseline titer levels. Treatment emergent - post-dose positive result when baseline results were negative. Persistent - A positive result detected in at least/ more 2 consecutive post baseline samples separated by at least a 16-week post baseline period, with no negative results in-between. Indeterminate - A positive result at the last collection time point analyzed only. Transient - Not persistent or indeterminate regardless of any missing samples. Treatment boosted- positive response in ADA assay post first dose that is greater than/equal 9-fold over baseline level when baseline is positive. | Baseline up to follow-up period (Week 36) |