Tanezumab in Osteoarthritis of the Knee

Study Overview
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Brief Summary
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Test the efficacy and safety of 3 doses in Osteoarthritis of the knee in patients.

Official Title
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A PHASE 3 RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED MULTICENTER STUDY OF THE ANALGESIC EFFICACY AND SAFETY OF TANEZUMAB IN PATIENTS WITH OSTEOARTHRITIS OF THE KNEE

Conditions
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Arthritis, Osteoarthritis

Intervention / Treatment
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* Biological: tanezumab
* Biological: tanezumab
* Biological: tanezumab
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Osteoarthritis of the knee according to ACR criteria with a Kellgren-Lawrence x-ray grade of 2. Unwilling or unable to take non-opiate pain medications, for whom non-opiate pain medications have not provided adequate pain relief or are candidates for knee injections arthroplasty or replace surgery. Pain level and function levels as required by the protocol at Screening and Baseline. Willing to discontinue pain medications (acetaminophen will be permitted up to a certain level) before and during the study. Must agree to the contraceptive requirements of the protocol if applicable. Must agree to the treatment plan, scheduled visits, and procedures of the protocol. Exclusion Criteria: Pregnancy or intent to become pregnant during the study BMI greater than 39 other severe pain, significant cardiac, neurological or psychological conditions, or above the protocol limits for laboratory and blood pressure results

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tanezumab 10 mg<br> | Biological: tanezumab<br>* IV tanezumab 10 mg at 1 dose every 8 weeks<br>|
| Experimental: Tanezumab 5 mg<br> | Biological: tanezumab<br>* IV tanezumab 5 mg at 1 dose every 8 weeks<br>|
| Experimental: Tanezumab 2.5 mg<br> | Biological: tanezumab<br>* IV tanezumab 2.5 mg at 1 dose every 8 weeks<br>|
| Placebo Comparator: Placebo<br> | Biological: Placebo<br>* IV placebo to match tanezumab at 1 dose every 8 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Subscale at Week 16: Baseline Observation Carried Forward (BOCF) | WOMAC: Self-administered, disease-specific questionnaire which assesses clinically important, participant-relevant symptoms for pain, stiffness and physical function in participants with osteoarthritis (OA). WOMAC pain subscale is a 5-item questionnaire used to assess the amount of pain experienced due to osteoarthritis in index knee during past 48 hours. It is calculated as mean of the scores from 5 individual questions, each scored on a numerical rating scale (NRS) of 0 (no pain) to 10 (extreme pain), where higher scores indicate higher pain. Total score range for WOMAC pain subscale score is 0 (no pain) to 10 (extreme pain), where higher scores indicate higher pain. | Baseline (Day 1), Week 16 | 
| Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Physical Function Subscale at Week 16: Baseline Observation Carried Forward (BOCF) | WOMAC: Self-administered, disease-specific questionnaire which assesses clinically important, participant-relevant symptoms for pain, stiffness and physical function in participants with OA. WOMAC physical function is a 17-item questionnaire used to assess the degree of difficulty experienced due to osteoarthritis in index knee during past 48 hours. It is calculated as mean of the scores from 17 individual questions, each scored on a NRS of 0 (no difficulty) to 10 (extreme difficulty), where higher scores indicate 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. Physical function refers to participant's ability to move around and perform usual activities of daily living. | Baseline, Week 16 | 
| Change From Baseline in Patient Global Assessment (PGA) of Osteoarthritis at Week 16: Baseline Observation Carried Forward (BOCF) | Participants answered: Considering all the ways your osteoarthritis in your knee affects you, how are you doing today?. Participants responded on a scale ranging from 1-5, where 1= very good (no symptom 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 and inability to carry out all normal activities). Higher scores indicated worsening of condition. | 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 at Week 2, 4, 8, 12, 24: Baseline Observation Carried Forward (BOCF) | WOMAC: Self-administered, disease-specific questionnaire which assesses clinically important, participant-relevant symptoms for pain, stiffness and physical function in participants with OA. WOMAC pain subscale is a 5-item questionnaire used to assess the amount of pain experienced due to osteoarthritis in index knee during past 48 hours. It is calculated as mean of the scores from 5 individual questions, each scored on a numerical rating scale (NRS) of 0 (no pain) to 10 (extreme pain), where higher scores indicate higher pain. Total score range for WOMAC pain subscale score is 0 (no pain) to 10 (extreme pain), where higher scores indicate higher pain. | Baseline, Week 2, 4, 8, 12, 24 | 
| Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Subscale at Week 2, 4, 8, 12, 16, 24: Last Observation Carried Forward (LOCF) | WOMAC: Self-administered, disease-specific questionnaire which assesses clinically important, participant-relevant symptoms for pain, stiffness and physical function in participants with OA. WOMAC pain subscale is a 5-item questionnaire used to assess the amount of pain experienced due to osteoarthritis in index knee during past 48 hours. It is calculated as mean of the scores from 5 individual questions, each scored on a numerical rating scale (NRS) of 0 (no pain) to 10 (extreme pain), where higher scores indicate higher pain. Total score range for WOMAC pain subscale score is 0 (no pain) to 10 (extreme pain), where higher scores indicate higher pain. | Baseline, Week 2, 4, 8, 12, 16, 24 | 
| Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Physical Function Subscale at Week 2, 4, 8, 12, 24: Baseline Observation Carried Forward (BOCF) | WOMAC: Self-administered, disease-specific questionnaire which assesses clinically important, participant-relevant symptoms for pain, stiffness and physical function in participants with OA. WOMAC physical function is a 17-item questionnaire used to assess the degree of difficulty experienced due to osteoarthritis in index joint during past 48 hours. It is calculated as mean of the scores from 17 individual questions, each scored on a NRS of 0 (no difficulty) to 10 (extreme difficulty), where higher scores indicate 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. Physical function refers to participant's ability to move around and perform usual activities of daily living | Baseline, Week 2, 4, 8, 12, 24 | 
| Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Physical Function Subscale at Week 2, 4, 8, 12, 16, 24: Last Observation Carried Forward (LOCF) | WOMAC: Self-administered, disease-specific questionnaire which assesses clinically important, participant-relevant symptoms for pain, stiffness and physical function in participants with OA. WOMAC physical function is a 17-item questionnaire used to assess the degree of difficulty experienced due to osteoarthritis in index joint during past 48 hours. It is calculated as mean of the scores from 17 individual questions, each scored on a NRS of 0 (no difficulty) to 10 (extreme difficulty), where higher scores indicate 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. Physical function refers to participant's ability to move around and perform usual activities of daily living | Baseline, Week 2, 4, 8, 12, 16, 24 | 
| Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Stiffness Subscales at Week 2, 4, 8, 12, 16, 24: Baseline Observation Carried Forward (BOCF) | WOMAC: Self-administered, disease-specific questionnaire which assesses clinically important, participant-relevant symptoms for pain, stiffness and physical function in participants with OA. WOMAC stiffness subscale is a 2-item questionnaire used to assess the amount of stiffness experienced due to osteoarthritis in index knee during past 48 hours. It is calculated as mean of the scores from 2 individual questions scored on NRS of (no stiffness) to 10 (extreme stiffness), with higher scores indicate higher stiffness. Total score range for WOMAC stiffness subscale score is (no stiffness) to 10 (extreme stiffness), where higher scores indicate higher stiffness. Stiffness is defined as a sensation of decreased ease in movement of knee. | Baseline, Week 2, 4, 8, 12, 16, 24 | 
| Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Stiffness Subscale at Week 2, 4, 8, 12, 16, 24: Last Observation Carried Forward (LOCF) | WOMAC: Self-administered, disease-specific questionnaire which assesses clinically important, participant-relevant symptoms for pain, stiffness and physical function in participants with OA. WOMAC stiffness subscale is a 2-item questionnaire used to assess the amount of stiffness experienced due to osteoarthritis in index knee during past 48 hours. It is calculated as mean of the scores from 2 individual questions scored on NRS of (no stiffness) to 10 (extreme stiffness), with higher scores indicate higher stiffness. Total score range for WOMAC stiffness subscale score is (no stiffness) to 10 (extreme stiffness), where higher scores indicate higher stiffness. Stiffness is defined as a sensation of decreased ease in movement of knee. | Baseline, Week 2, 4, 8, 12, 16, 24 | 
| Change From Baseline in Patient Global Assessment (PGA) of Osteoarthritis at Week 2, 4, 8, 12, 24: Baseline Observation Carried Forward (BOCF) | Participants answered: Considering all the ways your osteoarthritis in your knee affects you, how are you doing today. Participants responded on a scale ranging from 1-5, where 1= very good (no symptom 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 and inability to carry out all normal activities). Higher scores indicated worsening of condition. | Baseline, Week 2, 4, 8, 12, 24 | 
| Change From Baseline in Patient Global Assessment (PGA) of Osteoarthritis at Week 2, 4, 8, 12, 16, 24: Last Observation Carried Forward (LOCF) | Participants answered: Considering all the ways your osteoarthritis in your knee affects you, how are you doing today. Participants responded on a scale ranging from 1-5, where 1= very good (no symptom 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 and inability to carry out all normal activities). Higher scores indicated worsening of condition. | Baseline, Week 2, 4, 8, 12, 16, 24 | 
| Percentage of Participants With Outcome Measures in Rheumatology-Osteoarthritis Research Society International (OMERACT-OARSI) Response: Baseline Observation Carried Forward (BOCF) | OMERACT-OARSI response: greater than or equal to (>=) 50 percent (%) improvement from baseline and absolute change from baseline of >=2 units at Week of interest in WOMAC pain or physical function subscale, or at least 2 of the following 3 being true: >=20% improvement from baseline and absolute change from baseline of >=1 unit at Week of interest in 1) WOMAC pain subscale, 2) WOMAC physical function subscale, 3) PGA of osteoarthritis (score: 1-5, higher score=more affected). WOMAC pain, physical function subscales assess amount of pain/difficulty experienced (score: 0-10, higher score=higher pain/difficulty). | Week 2, 4, 8, 12, 16, 24 | 
| Percentage of Participants With Outcome Measures in Rheumatology-Osteoarthritis Research Society International (OMERACT-OARSI) Response: Last Observation Carried Forward (LOCF) | OMERACT-OARSI response: >= 50% improvement from baseline and absolute change from baseline of >=2 units at Week of interest in WOMAC pain or physical function subscale, or at least 2 of the following 3 being true: >=20% improvement from baseline and absolute change from baseline of >=1 unit at Week of interest in 1) WOMAC pain subscale, 2) WOMAC physical function subscale, 3) PGA of osteoarthritis (score: 1-5, higher score=more affected). WOMAC pain, physical function subscales assess amount of pain/difficulty experienced (score: 0-10, higher score=higher pain/difficulty). | Week 2, 4, 8, 12, 16, 24 | 
| Percentage of Participants With at Least 30% and 50% Reduction From Baseline in Western Ontario and McMaster Osteoarthritis Index (WOMAC) Pain Subscale Score: Baseline Observation Carried Forward (BOCF) | WOMAC: Self-administered, disease-specific questionnaire which assesses clinically important, participant-relevant symptoms for pain, stiffness and physical function in participants with OA. WOMAC pain subscale is a 5-item questionnaire used to assess the amount of pain experienced due to osteoarthritis in index knee during past 48 hours. It is calculated as mean of the scores from 5 individual questions, each scored on a numerical rating scale (NRS) of 0 (no pain) to 10 (extreme pain), where higher scores indicate higher pain. Total score range for WOMAC pain subscale score is 0 (no pain) to 10 (extreme pain), where higher scores indicate higher pain. | Baseline, Week 2, 4, 8, 12, 16, 24 | 
| Percentage of Participants With at Least 30 Percent (%) and 50% Reduction From Baseline in Western Ontario and McMaster Osteoarthritis Index (WOMAC) Pain Subscale Score: Last Observation Carried Forward (LOCF) | WOMAC: Self-administered, disease-specific questionnaire which assesses clinically important, participant-relevant symptoms for pain, stiffness and physical function in participants with OA. WOMAC pain subscale is a 5-item questionnaire used to assess the amount of pain experienced due to osteoarthritis in index knee during past 48 hours. It is calculated as mean of the scores from 5 individual questions, each scored on a numerical rating scale (NRS) of 0 (no pain) to 10 (extreme pain), where higher scores indicate higher pain. Total score range for WOMAC pain subscale score is 0 (no pain) to 10 (extreme pain), where higher scores indicate higher pain. | Baseline, Week 2, 4, 8, 12, 16, 24 | 
| Percentage of Participants With at Least 2 Points Improvement From Baseline in Patient Global Assessment (PGA) of Osteoarthritis: Baseline Observation Carried Forward (BOCF) | Participants answered: Considering all the ways your osteoarthritis in your knee affects you, how are you doing today. Participants responded on a scale ranging from 1-5, where 1= very good (no symptom 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 and inability to carry out all normal activities). Higher scores indicated worsening of condition. | Baseline, Week 2, 4, 8, 12, 16, 24 | 
| Percentage of Participants With at Least 2 Points Improvement From Baseline in Patient Global Assessment (PGA) of Osteoarthritis: Last Observation Carried Forward (LOCF) | Participants answered: Considering all the ways your osteoarthritis in your knee affects you, how are you doing today. Participants responded on a scale ranging from 1-5, where 1= very good (no symptom 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 and inability to carry out all normal activities). Higher scores indicated worsening of condition. | Baseline, Week 2, 4, 8, 12, 16, 24 | 
| Percentage of Participants With Cumulative Reduction From Baseline to Week 16 in Western Ontario and McMaster Osteoarthritis Index (WOMAC) Pain Subscale Score: Baseline Observation Carried Forward (BOCF) | WOMAC: Self-administered, disease-specific questionnaire which assesses clinically important, participant-relevant symptoms for pain, stiffness and physical function in participants with OA. WOMAC pain subscale is a 5-item questionnaire used to assess the amount of pain experienced due to osteoarthritis in index knee during past 48 hours. It is calculated as mean of the scores from 5 individual questions, each scored on a numerical rating scale (NRS) of 0 (no pain) to 10 (extreme pain), where higher scores indicate higher pain. Total score range for WOMAC pain subscale score is 0 (no pain) to 10 (extreme pain), where higher scores indicate higher pain. Participants with specified reduction (as percent) from baseline up to Week 16 are reported. | Baseline up to Week 16 | 
| Percentage of Participants With Cumulative Reduction From Baseline to Week 16 in Western Ontario and McMaster Osteoarthritis Index (WOMAC) Pain Subscale Score: Last Observation Carried Forward (LOCF) | WOMAC: Self-administered, disease-specific questionnaire which assesses clinically important, participant-relevant symptoms for pain, stiffness and physical function in participants with OA. WOMAC pain subscale is a 5-item questionnaire used to assess the amount of pain experienced due to osteoarthritis in index knee during past 48 hours. It is calculated as mean of the scores from 5 individual questions, each scored on a numerical rating scale (NRS) of 0 (no pain) to 10 (extreme pain), where higher scores indicate higher pain. Total score range for WOMAC pain subscale score is 0 (no pain) to 10 (extreme pain), where higher scores indicate higher pain. Total score range for WOMAC pain subscale score is 0 to 10, where higher scores indicate higher pain. Participants with specified reduction (as percent) from baseline up to Week 16 are reported. | Baseline up to Week 16 | 
| Change From Baseline in Average Pain Score in the Index Knee at Week 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24: Baseline Observation Carried Forward (BOCF) | Participants assessed daily average knee pain during the past 24 hours on an 11-point NRS ranging from 0 (no pain) to 10 (worst pain). Baseline score was calculated as the mean of the scores over the 3 days and a weekly mean was calculated using the daily pain scores within each study week. The change from Baseline was calculated using difference between each post-baseline weekly mean and the Baseline mean score. | Baseline, Week 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24 | 
| Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Average Score at Week 2, 4, 8, 12, 16, 24: Baseline Observation Carried Forward (BOCF) | WOMAC: self-administered, disease-specific 24-item questionnaire which assesses clinically important, participant-relevant symptoms for pain (5 items), stiffness (2 items) and physical function (17 items) in participants with osteoarthritis of knee. WOMAC average score is the mean of WOMAC pain, physical function and stiffness subscale scores and ranges from 0 to 10, where higher score indicates worse response. | Baseline, Week 2, 4, 8, 12, 16, 24 | 
| Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Subscale Item at Week 2, 4, 8, 12, 16, 24: Baseline Observation Carried Forward (BOCF) | Participants answered, Question (Q)1: How much pain have you had when walking on a flat surface? and Q2: How much pain have you had when going up or down the stairs?. Participants responded by using a NRS of 0 to 10, where 0 = no pain and 10 = extreme pain. | Baseline, Week 2, 4, 8, 12, 16, 24 | 
| Change From Baseline in 36-Item Short-Form Health Survey Version 2 (SF-36v2) Domain Scores at Week 12, 24: Baseline Observation Carried Forward (BOCF) | SF-36v2: standardized survey evaluating 8 domains of functional health and wellbeing (physical and social functioning, physical and emotional role limitations, bodily pain, general health, vitality, mental health). Total score for each domain were scaled 0 (poor health) to 100 (best health), higher scores indicating good health condition. | Baseline, Week 12, 24 | 
| Change From Baseline in 36-Item Short-Form Health Survey Version 2 (SF-36v2) Physical and Mental Component Scores at Week 12, 24: Baseline Observation Carried Forward (BOCF) | SF-36v2: standardized survey evaluating 8 domains of functional health and wellbeing (physical and social functioning, physical and emotional role limitations, bodily pain, general health, vitality, mental health). Total score for each domain were scaled 0 (poor health) to 100 (best health), higher scores indicating good health condition. For obtaining physical and mental component scores, z-score for each scale = (observed score - mean score for general 1990 United States [US] population)/corresponding standard deviation. The 2 component scores were obtained by multiplying each aspect z-score by physical or mental factor score coefficient (1990 general US population) and summing the eight products. Component scores indicated how many standard deviations higher (in case of positive z-score [better functioning])/lower (in case of negative z-score [worse functioning]) participant's value was relative to the mean of the reference population. | Baseline, Week 12, 24 | 
| Time to Discontinuation Due to Lack of Efficacy | Median time to discontinuation due to lack of efficacy was estimated using Kaplan-Meier method. | Baseline up to Week 16 | 
| Percentage of Participants Who Used Rescue Medications | In case of inadequate pain relief for osteoarthritis, acetaminophen up to 4000 mg per day up to 3 days per week could be taken as rescue medication. | Week 2, 4, 8, 12, 16, 24 | 
| Duration of Rescue Medication Use | In case of inadequate pain relief for osteoarthritis, acetaminophen up to 4000 mg per day up to 3 days per week could be taken as rescue medication. | Week 2, 4, 8, 12, 16, 24 | 
| Amount of Rescue Medication Taken | In case of inadequate pain relief for osteoarthritis, acetaminophen up to 4000 mg per day up to 3 days per week could be taken as rescue medication. | Week 2, 4, 8, 12, 16, 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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monoclonal antibody, RN624, PF-04383119, nerve growth factor, anti-nerve growth factor, OA, pain