Efficacy and Safety of MT-5547 in Patients With Osteoarthritis Accompanied by Moderate to Severe Pain

Study Overview
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Brief Summary
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The objective of this study is to verify the superiority of 16 weeks of MT-5547 treatment to placebo, as evidenced by the WOMAC pain score (the efficacy outcome measure), in patients with osteoarthritis of the knee or hip. Additional objectives of the study are to investigate the efficacy, safety, and pharmacokinetics of MT-5547 in long-term use.

Detailed Description
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The blind will be maintained, including for the study sponsor, until the key code is opened after the data have been fixed for all subjects in Week 24. In addition, in order to eliminate any bias that could affect the study assessments, to the extent possible, the blind will be maintained with respect to the study site and the subject even after the opening of the study sponsor key code.

Official Title
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A Phase 2/3 (Placebo-Controlled, Double-Blind, Comparative) Study on MT-5547 in Patients With Osteoarthritis Accompanied by Moderate to Severe Pain

Conditions
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Osteoarthritis, Knee / Osteoarthritis, Hip

Intervention / Treatment
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* Drug: MT-5547
* Drug: MT-5547-matching placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Additional screening criteria check may apply for qualification: Male and female Japanese patients, 40 years to 85 years at the time written informed consent is obtained. Patients who have been diagnosed with osteoarthritis (OA) of the knee or hip based on the American College of Rheumatology (ACR) criteria. Patients with an evaluated joint (knee or hip) with a K-L (Kellgren-Lawrence) score of ≥2 based on the X-ray test performed. Moderate to severe pain in the evaluated joint, defined as a WOMAC pain score of ≥4 (mean of the 5 items), on the WOMAC assessments. Patients who satisfy both 1) and 2) below. Inadequate OA pain relief from at least 1 oral NSAID. Intolerance to or inadequate OA pain relief from at least 1 opioid (including combination drugs), or unwillingness to take opioid therapy. Patients who agree to not change their current lifestyle (daily living activities and exercise) throughout the study. Patients who are able to complete post-operative follow-up for any joint replacement surgery that is performed during the study. Body mass index at screening ≤39. Patient who are able to understand and answer endpoint questions used in the study. Exclusion Criteria: Additional screening criteria check may apply for qualification: Presence of symptoms of carpal tunnel syndrome within 6 months before screening. Patients who cannot undergo MRI. Trauma to the index joint within 3 months prior to screening. Presence or history of inflammatory joint diseases other than OA, Paget's disease of the spine, pelvis or femur, multiple sclerosis, fibromyalgia, vertebral tumors or infections, or renal osteodystrophy. Presence or history, confirmed by imaging, of arthropathy, neuropathic joint arthropathy, hip dislocation, knee dislocation, extensive subchondral cyst, marked bone destruction or bone loss, or pathologic fractures. Autonomic neuropathy diagnosed in the assessment of autonomic nerve symptoms performed at screening, or baseline. Presence or history of orthostatic hypotension at the orthostatic hypotension assessments performed at screening, prerandomization, or baseline. Presence or history of autonomic neuropathy, diabetic neuropathy, or other peripheral neuropathy such as reflex sympathetic dystrophy at screening. Presence or history of chronic familial dysautonomia. Intolerance to naproxen. Systemic (excluding topical, intranasal, ophthalmic, and inhaled formulations) corticosteroids within 4 weeks prior to screening. Intra-articular corticosteroids in the evaluated joint within 12 weeks prior to screening, or in any other joint within 4 weeks prior to screening. Received an intra-articular injection of hyaluronic acid in any joint within the period specified for each medicine prior to screening. Resting heart rate of <50 bpm or >100 bpm at screening, or baseline. Presence or history of 2nd or 3rd degree heart block, 1st degree heart block with abnormal QRS, or bifascicular block by ECG assessment at screening. Non-compliance with the Numerical rating scale (NRS) recording (average pain on walking in the evaluated joint over 1 day) during the pre-treatment observation period. Women who are pregnant, breast-feeding, or may be pregnant. Use of an anti-Nerve growth factor (anti-NGF) antibody in the past, or apparent hypersensitivity or intolerance to anti-NGF antibodies.

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 85 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: MT-5547 dosing regimen 1<br>MT-5547 Subcutaneous (SC) dosing regimen 1. Naproxen-matching placebo oral after Week 16. | Drug: MT-5547<br>* Solution for injection in pre-filled syringe<br>* Other names: Fasinumab;|
| Experimental: MT-5547 dosing regimen 2<br>MT-5547 SC dosing regimen 2. Naproxen-matching placebo oral after Week 16. | Drug: MT-5547<br>* Solution for injection in pre-filled syringe<br>* Other names: Fasinumab;Drug: MT-5547-matching placebo<br>* Solution for injection in pre-filled syringe<br>|
| Placebo Comparator: MT-5547-matching placebo<br>MT-5547-matching placebo SC dosing. Naproxen oral after Week 16. | Drug: MT-5547-matching placebo<br>* Solution for injection in pre-filled syringe<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| WOMAC Pain Score (Change From Baseline at Week 16) | The WOMAC is a scale that is used to assess the activities of daily living in osteoarthritis, the WOMAC pain subscale score was defined as the average of 5 items (during walking, using stairs, in bed, sitting or lying, and standing). The participants assessed the past 48 hours on an 11-point numeric rating scale, from 0 (no pain) to 10 (worst pain imaginable), where higher scores indicated worse pain. | Baseline to Week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| WOMAC Physical Function Score (Change From Baseline at Week 16) | The WOMAC physical function subscale score was defined as the average of 17 items(the level of difficulty of activities of daily living: stair use, rising from sitting, standing, bending, walking, getting in and out of a car, shopping, putting on and taking off socks, rising from bed, lying in bed, getting in and out of the bath, sitting, getting on and off the toilet, heavy household duties, light household duties). The participants assessed the past 48 hours on an 11-point numeric rating scale, from 0 (no difficulty) to 10(extremely difficult), where higher scores indicated worse function limitation. | Baseline to Week 16 | 
| WOMAC Pain Score (Change From Baseline at Each Assessment Time Point) | The WOMAC is a scale that is used to assess the activities of daily living in osteoarthritis, the WOMAC pain subscale score was defined as the average of 5 items (during walking, using stairs, in bed, sitting or lying, and standing). The participants assessed the past 48 hours on an 11-point numeric rating scale, from 0 (no pain) to 10 (worst pain imaginable), where higher scores indicated worse pain. | Baseline to Week 68 | 
| WOMAC Physical Function Score (Change From Baseline at Each Assessment Time Point) | The WOMAC physical function subscale score was defined as the average of 17 items(the level of difficulty of activities of daily living: stair use, rising from sitting, standing, bending, walking, getting in and out of a car, shopping, putting on and taking off socks, rising from bed, lying in bed, getting in and out of the bath, sitting, getting on and off the toilet, heavy household duties, light household duties). The participants assessed the past 48 hours on an 11-point numeric rating scale, from 0 (no difficulty) to 10(extremely difficult), where higher scores indicated worse function limitation. | Baseline to Week 68 | 
| WOMAC Stiffness Score (Change From Baseline at Each Assessment Time Point) | The WOMAC stiffness subscale score was defined as the average of 2 items(after first waking and later in the day). The participants assessed the past 48 hours on an 11-point numeric rating scale, from 0 (no stiffness) to 10(extremely stiffness), where higher scores indicated worse stiffness. | Baseline to Week 68 | 
| WOMAC Total Score (Change From Baseline at Each Assessment Time Point) | The WOMAC total subscale score was defined as the average of 24 items(5 pain subscale items, 17 physical functioning subscale items, and 2 stiffness subscale items). The participants assessed the past 48 hours on an 11-point numeric rating scale, from 0 (no stiffness) to 10(extremely stiffness), where smaller values being better. | Baseline to Week 68 | 
| Patient Global Assessment (PGA) (Change From Baseline at Each Assessment Time Point) | Patient Global Assessment(PGA) was a measure whereby the participant assessed global improvement in OA using the 5-level scale(1=very well; 2=well; 3=fair; 4=poor; and 5=very poor). | Baseline to Week 68 | 
| Number of Participants With Adverse Events and Adverse Drug Reactions |  | Baseline to Week 68 (Treatment period=48 weeks, Post-treatment Observation Period=20weeks) | 
| Number of Participants With a Joint Replacement Procedure is Scheduled | All the Joint Replacement surgeries that were performed within 20 weeks from the day after the end date of the treatment period were reported and tabulated in this study in order to assess the outcome of joint damage regardless of the presence or absence of related adjudicated arthropathy. The subjects who were going to undergo JR surgery were to be withdrawn from study treatment. | Baseline to Week 68 |