Efficacy And Safety Study Of Tanezumab Subcutaneous Administration In Osteoarthritis - A Subcutaneous/Intravenous Bridging Study

Study Overview
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Brief Summary
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This is an efficacy and safety study of 3 doses (2.5 mg, 5 mg and 10mg) of tanezumab administered subcutaneously versus placebo. This study will also compare a subcutaneous (SC) administration of 10 mg of tanezumab) with an intravenous (IV) administration of 10 mg of tanezumab. Each person will receive an IV infusion and a SC infusion. The study will last 16 weeks for those who wish to enter a 64-week extension study or 24 weeks for those who do not.

Detailed Description
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This study was terminated on 08 Nov 2010 following a US FDA clinical hold for tanezumab osteoarthritis clinical studies which halted dosing and enrollment of patients on 23 June 2010 for potential safety issues.

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

Conditions
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Osteoarthritis, Arthritis, Pain

Intervention / Treatment
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* Biological: Placebo IV
* Biological: Placebo SC
* Biological: Tanezumab SC
* Biological: Placebo IV
* Biological: Tanezumab SC
* Biological: Placebo IV
* Biological: Tanezumab SC
* Biological: Placebo IV
* Biological: Tanezumab IV
* Biological: Placebo SC


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of osteoarthritis (OA) of the knee according to American College of Rheumatology (ACR) criteria with a Kellgren- Lawrence score of greater than or equal to 2 18 years of age or greater Two methods of birth control one of which must be barrier if of childbearing potential Willing to discontinue pain medication except as permitted per protocol Exclusion Criteria: Pregnancy or wishing to be pregnant during the course of the study, lactating women Body Mass Index (BMI) greater than 39 Clinically significant cardiac, neurological, psychiatric conditions and other conditions that are excluded by the protocol. Previous exposure to a Nerve Growth Factor (NGF) antibody

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 |
| --- | --- |
| Placebo Comparator: Placebo<br> | Biological: Placebo IV<br>* 1 ml of placebo administered SC and IV once every 8 weeks.<br>Biological: Placebo SC<br>* 1 ml of placebo administered SC and IV once every 8 weeks.<br>|
| Experimental: 2.5 mg tanezumab SC and placebo IV<br> | Biological: Tanezumab SC<br>* 1 ml tanezumab injection SC administered every 8 weeks<br>Biological: Placebo IV<br>* 1 ml placebo administered IV every 8 weeks<br>|
| Experimental: 5 mg tanezumab SC and placebo IV<br> | Biological: Tanezumab SC<br>* 1 ml tanezumab injection SC administered every 8 weeks<br>Biological: Placebo IV<br>* 1ml placebo administered IV every 8 weeks<br>|
| Experimental: 10 mg tanezumab SC and placebo IV<br> | Biological: Tanezumab SC<br>* 1 ml tanezumab injection SC administered every 8 weeks<br>Biological: Placebo IV<br>* 1ml placebo administered IV every 8 weeks<br>|
| Experimental: 10 mg tanezumab IV<br> | Biological: Tanezumab IV<br>* 1 ml tanezumab injection IV administered every 8 weeks<br>Biological: Placebo SC<br>* 1ml placebo administered SC 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 Score at Week 16 | The WOMAC pain subscale is a 5-item questionnaire used to assess the amount of pain experienced due to osteoarthritis in the index knee in the past 48 hours. It is calculated as the mean of the scores from the 5 individual questions scored on a numerical rating scale (NRS) of 0 to 10, where higher scores indicate higher pain. Total score range for WOMAC pain subscale score is 0 to 10, where higher scores indicate higher pain. | Baseline, Week 16 | 
| Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Physical Function Subscale Score at Week 16 | The WOMAC physical function subscale is a 17-item questionnaire used to assess the degree of difficulty experienced due to osteoarthritis in the index joint in the past 48 hours. It is calculated as the mean of the scores from the 17 individual questions scored on a NRS of 0 to 10, where higher scores indicate worse function. Total score range for WOMAC physical function subscale score is 0 to 10, where higher scores indicate worse function. | Baseline, Week 16 | 
| Change From Baseline in Patient's Global Assessment (PGA) of Osteoarthritis Score at Week 16 | Participants answered the question: Considering all the ways your osteoarthritis in your knee affects you, how are you doing today? Participants responded by using a 5-point 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 are intolerable and inability to carry out all normal activities). Higher score indicated severe 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 Weeks 1, 2, 4, 8, and 12 | The WOMAC pain subscale is a 5-item questionnaire used to assess the amount of pain experienced due to osteoarthritis in the index knee in the past 48 hours. It is calculated as the mean of the scores from the 5 individual questions scored on a numerical rating scale (NRS) of 0 to 10, where higher scores indicate higher pain. Total score range for WOMAC pain subscale score is 0 to 10, where higher scores indicate higher pain. | Baseline, Weeks 1, 2, 4, 8, and 12 | 
| Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Physical Function Subscale at Weeks 1, 2, 4, 8, and 12 | The WOMAC physical function subscale is a 17-item questionnaire used to assess the degree of difficulty experienced due to osteoarthritis in the index joint in the past 48 hours. It is calculated as the mean of the scores from the 17 individual questions scored on a NRS of 0 to 10, where higher scores indicate worse function. Total score range for WOMAC physical function subscale score is 0 to 10, where higher scores indicate worse function. | Baseline, Weeks 1, 2, 4, 8, and 12 | 
| Change From Baseline in Patient Global Assessment (PGA) of Osteoarthritis at Weeks 1, 2, 4, 8, and 12 | Participants answered the question: Considering all the ways your osteoarthritis in your knee affects you, how are you doing today? Participants responded by using a 5-point 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 are intolerable and inability to carry out all normal activities). Higher score indicated severe condition. | Baseline, Weeks 1, 2, 4, 8, and 12 | 
| Percentage of Participants With Outcome Measures in Rheumatology - Osteoarthritis Research Society International (OMERACT-OARSI) Response | The OMERACT-OARSI responder index is based on 3 parameters. 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 range: 1-5, higher score=more affected). WOMAC pain, physical function subscales assess amount of pain/difficulty experienced (score range: 0-10, higher score=higher pain/difficulty). | Weeks 1, 2, 4, 8, 12, and 16 | 
| Percentage of Participants With at Least 30%, 50%, 70% and 90% Reduction From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Subscale Score | The WOMAC pain subscale is a 5-item questionnaire used to assess the amount of pain experienced due to osteoarthritis in the index knee in the past 48 hours. It is calculated as the mean of the scores from the 5 individual questions scored on a numerical rating scale (NRS) of 0 to 10, where higher scores indicate higher pain. Total score range for WOMAC pain subscale score is 0 to 10, where higher scores indicate higher pain. | Weeks 1, 2, 4, 8, 12, and 16 | 
| Number of Participants With Cumulative Reduction From Baseline in Western Ontario and McMaster Universities Osteoarthritis (WOMAC) Pain Subscale Score at Weeks 1, 2, 4, 8, 12, and 16 | The WOMAC pain subscale is a 5-item questionnaire used to assess the amount of pain experienced due to osteoarthritis in the index knee 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 to 10, 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 at Week 16 are reported. | Weeks 1, 2, 4, 8, 12, 16 | 
| Number of Participants With Improvement of at Least 2 Points in Patient's Global Assessment (PGA) of Osteoarthritis | Participants answered the question: Considering all the ways your osteoarthritis in your knee affects you, how are you doing today? Participants responded by using a 5-point 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 are intolerable and inability to carry out all normal activities). Higher score indicated severe condition. Improvement signifies a decrease of at least 2 points on the 5-point scale relative to baseline value. | Weeks 1, 2, 4, 8, 12, and 16 | 
| Change From Baseline in Average Pain Score in the Index Knee at Weeks 1, 2, 4, 8, 12 and 16 | Participants assessed average osteoarthritis pain in their knee in the past 24 hours on an 11-point NRS ranging from 0 (no pain) to 10 (worst pain). Higher score indicated greater pain. Baseline score was calculated as the mean of the scores over the 3 days in the initial pain assessment period and a weekly mean was calculated using the daily pain scores within each study week. | Baseline, Weeks 1, 2, 4, 8, 12, and 16 | 
| Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Stiffness Subscale Score at Weeks 1, 2, 4, 8, 12, and 16 | The WOMAC stiffness subscale is a 2-item questionnaire used to assess the amount of stiffness experienced in the index joint in the past 48 hours. It is calculated as the mean of the scores from the 2 individual questions scored on NRS of 0 to 10, with higher scores indicating more stiffness. Total score range for WOMAC stiffness subscale score is 0 to 10, where higher scores indicate more stiffness. Stiffness is defined as a sensation of decreased ease in movement of the knee. | Baseline, Weeks 1, 2, 4, 8, 12, and 16 | 
| Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Average Score at Weeks 1, 2, 4, 8, 12, and 16 | 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. WOMAC pain, physical function and stiffness subscale and average score ranges from 0 to 10, where higher score indicates worse response. | Baseline, Weeks 1, 2, 4, 8, 12, and 16 | 
| Change From Baseline For Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Subscale Item: Pain When Walking on a Flat Surface at Weeks 1, 2, 4, 8, 12, and 16 | Participants answered: How much pain have you had when walking on a flat surface? Participants responded by using a NRS of 0 to 10, where 0 = no pain and 10 = extreme pain. Higher score indicated greater pain. | Baseline, Weeks 1, 2, 4, 8, 12, and 16 | 
| Change From Baseline For Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Subscale Item: Pain When Going Up or Down Stairs at Weeks 1, 2, 4, 8, 12, and 16 | Participants answered: How much pain have you had when going up or down stairs? Participants responded by using a NRS of 0 to 10, where 0 = no pain and 10 = extreme pain. Higher score indicated greater pain. | Baseline, Weeks 1, 2, 4, 8, 12, and 16 | 
| Change From Baseline in 36-Item Short-Form Health Survey Version 2 (SF-36v2) Domain Scores at Week 16 | SF-36v2 is a standardized self-administered survey evaluating 8 aspects/domains of functional health and well-being: physical and social functioning, physical and emotional role limitations, bodily pain, general health, vitality, mental health. The total score for each domain is scaled 0-100 (100 = highest level of functioning). | Baseline, Week 16 | 
| Change From Baseline in 36-Item Short-Form Health Survey Version 2 (SF-36v2) Physical and Mental Component Scores at Week 16 | SF-36v2: standardized self-administered survey evaluating 8 aspects 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 aspect were scaled 0-100 (100=highest level of functioning). 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 16 | 
| Time to Discontinuation Due to Lack of Efficacy | Median time to discontinuation due to lack of efficacy for participants who discontinued due to lack of efficacy was reported. | Baseline up to Week 24 | 
| Percentage of Participants Who Used Rescue Medication | In case of inadequate pain relief for osteoarthritis, acetaminophen up to 3000 mg per day up to 3 days per week could be taken as rescue medication. Incidence of rescue medication use is calculated as any use of rescue medication during the study week in question. | Weeks 1, 2, 4, 8, 12, and 16 | 
| Duration of Rescue Medication Use | In case of inadequate pain relief for osteoarthritis, acetaminophen up to 3000 mg per day up to 3 days per week could be taken as rescue medication. Duration of rescue medication use is calculated as the number of study days per week when any rescue medication was taken. | Weeks 1, 2, 4, 8, 12, and 16 | 
| Amount of Rescue Medication Taken | In case of inadequate pain relief for osteoarthritis, acetaminophen up to 3000 mg per day up to 3 days per week could be taken as rescue medication. The amount of rescue medication taken is the total dose (in mg) of acetaminophen rescue medication over the study week in question. | Weeks 1, 2, 4, 8, 12, and 16 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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safety, efficacy, parallel group, double-blind, multicenter, injection, infusion, osteoarthritis, bridging, subcutaneous, intravenous, tanezumab