Analgesic Efficacy And Safety of Tanezumab Added On To Diclofenac SR In Patients With Osteoarthritis Of The Knee Or Hip

Study Overview
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Brief Summary
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The purpose of this study is to investigate the analgesic efficacy and safety of tanezumab added on to diclofenac SR in patients with osteoarthritis of the knee or hip currently experiencing partial benefit from, and are tolerating, diclofenac 150 mg/day therapy.

Detailed Description
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This study was terminated on 16 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, CONTROLLED, MULTI CENTER STUDY OF THE ANALGESIC EFFICACY AND SAFETY OF TANEZUMAB ADDED ON TO DICLOFENAC SR IN PATIENTS WITH OSTEOARTHRITIS OF THE KNEE OR HIP

Conditions
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Osteoarthritis

Intervention / Treatment
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* Biological: tanezumab
* Drug: diclofenac
* Biological: tanezumab
* Drug: diclofenac
* Biological: tanezumab
* Drug: diclofenac
* Drug: diclofenac
* Other: IV placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Osteoarthritis of the knee or hip according to ACR criteria with Kellgren-Lawrence X-ray grade equal to, or greater than, 2. Patients must be experiencing some benefit from their current stable dose regimen of oral diclofenac 150 mg/day and be tolerating their diclofenac regimen. Pain and function levels as required by the protocol at Screening and Baseline. Willing to discontinue all non-study pain medications throughout the study except as permitted per protocol. Willing and able to comply with lifestyle guidelines, scheduled visits, treatment plan, laboratory tests and other study procedures. Exclusion Criteria: Pregnant women. BMI greater than 39. History of other disease that may involve index knee or hip including inflammatory joint diseases, chrystalline disease (gout or pseudogout), endocrinopathies, metabolic joint diseases, lupus erythematosus, rheumatoid arthritis (RA), joint infections, neuropathic disorders, avascular necrosis, Paget's disease or tumors. Fibromyalgia, regional pain caused by lumbar or cervical compression with radiculopathy or other moderate to severe pain that may confound assessments or self-evaluation of the pain associated with OA. Signs and symptoms of clinically significant cardiac disease within 6 months prior to screening. Diagnosis or TIA within 6 months prior to screening or diagnosis of stroke with residual deficits that would preclude completion of required study activities. History, diagnosis , signs or symptoms of clinically significant neurological and/or psychiatric disease/disorder. At Screening: uncontrolled hypertension, hemoglobin A1c greater than or equal to 10%, ALT or AST greater than or equal to 3X upper limit of normal, creatinine exceeding 150 micro-mol/L in men or 133 micro-mol/L in women. Patients on warfarin or other coumadin anticoagulant therapy and/or lithium therapy within 30 days prior to Screening. Known hypersensitivity to NSAIDs (eg, diclofenac), cyclooxygenase inhibitors or paracetamol (acetaminophen).

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: Tanezumab 10 mg + diclofenac<br>IV tanezumab 10 mg every 8 weeks (through Week 16) and oral diclofenac SR 75 mg BID (through Week 32) | Biological: tanezumab<br>* IV tanezumab 10 mg every 8 weeks (through Week 16)<br>Drug: diclofenac<br>* Oral diclofenac SR 75 mg BID for 32 weeks<br>|
| Experimental: Tanezumab 5 mg + diclofenac<br>IV tanezumab 5 mg every 8 weeks (through Week 16) and oral diclofenac SR 75 mg BID (through Week 32) | Biological: tanezumab<br>* IV tanezumab 5 mg every 8 weeks (through Week 16)<br>Drug: diclofenac<br>* Oral diclofenac SR 75 mg BID for 32 weeks<br>|
| Experimental: Tanezumab 2.5 mg + diclofenac<br>IV tanezumab 2.5 mg every 8 weeks (through Week 16) and oral diclofenac SR 75 mg BID (through Week 32) | Biological: tanezumab<br>* IV tanezumab 2.5 mg every 8 weeks (through Week 16)<br>Drug: diclofenac<br>* Oral diclofenac SR 75 mg BID for 32 weeks<br>|
| Placebo Comparator: IV placebo + diclofenac<br>IV placebo to match tanezumab every 8 weeks (through Week 16) and oral diclofenac SR 75 mg BID (through Week 32) | Drug: diclofenac<br>* Oral diclofenac SR 75 mg BID for 32 weeks<br>Other: IV placebo<br>* IV placebo to match tanezumab every 8 weeks (through Week 16)<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 | 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 or hip 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 16 | 
| Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Physical Function Subscale Score at Week 16 | 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 or hip 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 Score at Week 16 | Participants answered: Considering all the ways your osteoarthritis in your index joint (knee/hip) affects you, how are you doing today? Participants responded by using 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 are intolerable and inability to carry out all normal activities). Higher score indicated worst condition. | Baseline, Week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Subscale Score at Weeks 2, 4, 8, 12 and 24 | 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 or hip 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, Weeks 2, 4, 8, 12, and 24 | 
| Change From Baseline in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Physical Function Subscale Score at Weeks 2, 4, 8, 12, and 24 | 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 or hip 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, Weeks 2, 4, 8, 12, and 24 | 
| Change From Baseline in Patient Global Assessment (PGA) of Osteoarthritis Score at Weeks 2, 4, 8, 12, and 24 | Participants answered: Considering all the ways your osteoarthritis in your index joint (knee/hip) affects you, how are you doing today? Participants responded by using 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 are intolerable and inability to carry out all normal activities). Higher score indicated worst condition. | Baseline, Weeks 2, 4, 8, 12, and 24 | 
| Percentage of Participants With Outcome Measures in Rheumatology - Osteoarthritis Research Society International (OMERACT-OARSI) Response; LOCF | OMERACT-OARSI responder: participant has >=50 percent (%) change and >=2 absolute change from Baseline in either WOMAC pain or physical function subscale scores or at least 2 of the following being true: >=20% change and >=1 absolute change from Baseline in WOMAC pain subscale; >=20% change and >=1 absolute change from Baseline in the WOMAC physical function subscale; >=20% change and >=1 absolute change from Baseline in PGA of osteoarthritis. WOMAC pain and physical function score: 0 to 10 with higher score = worse response. PGA score: 1 = very good and 5 = very poor. | Weeks 2, 4, 8, 12, 16, and 24 | 
| Percentage of Participants With Cumulative Reduction From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Subscale Score at Week 16 and 24 | 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 or hip 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. Greater percentage reduction indicates greater improvement. Percentage of participants with cumulative reduction (as percent) (greater than 0%; >= 10, 20, 30, 40, 50, 60, 70, 80 and 90%; = 100 %) in WOMAC pain subscale from Baseline to Weeks 16 and 24 were reported. | Baseline, Week 16 and 24 | 
| 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; LOCF | 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 or hip 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. Greater percentage reduction indicates greater improvement. Percentage of participants with reduction in WOMAC pain intensity of at least (>=) 30%, 50%, 70% and 90% at Weeks 2, 4, 8, 12, 16, 24 and 32 compared to baseline were classified as responders to WOMAC pain subscale and are reported here. | Baseline, Weeks 2, 4, 8, 12, 16, and 24 | 
| Percentage of Participants With Improvement of at Least 2 Points in Patient Global Assessment (PGA) of Osteoarthritis; LOCF | Participants answered: Considering all the ways your osteoarthritis in your index joint (knee/hip) affects you, how are you doing today? Participants responded by using 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 are intolerable and inability to carry out all normal activities). Higher score indicated worst condition. A decrease of at least 2 points on the 5-point scale relative to baseline value indicated improvement. | Weeks 2, 4, 8, 12, 16, and 24 | 
| Percentage of Participants With Improvement of at Least 2 Points in Patient Global Assessment (PGA) of Osteoarthritis; Baseline Observation Carried Forward (BOCF) | Participants answered: Considering all the ways your osteoarthritis in your index joint (knee/hip) affects you, how are you doing today? Participants responded by using 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 are intolerable and inability to carry out all normal activities). Higher score indicated worst condition. A decrease of at least 2 points on the 5-point scale relative to baseline value indicates improvement. | Weeks 2, 4, 8, 12, 16, and 24 | 
| Change From Baseline in Average Pain Score in the Index Knee or Hip at Weeks 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, and 24 | Participants were asked to assess index joint (knee/hip) pain during the past 24 hours on an 0-10 point integer scale ranging from 0 (no pain) to 10 (worst possible pain). Baseline score was calculated as the mean of the scores in the index joint over the 3 days days in the initial pain assessment period and a weekly mean was calculated using the daily pain scores in the index joint within each study week. The change from Baseline was calculated using the difference between each post-baseline weekly mean and the baseline mean score, where negative change indicated an improvement. | Baseline, Weeks 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, and 24 | 
| Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Stiffness Subscale Score at Weeks 2, 4, 8, 12, 16, and 24 | 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 or hip 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/hip. Negative change indicated an improvement. | Baseline, Weeks 2, 4, 8, 12, 16, and 24 | 
| Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Average Score at Weeks 2, 4, 8, 12, 16, and 24 | WOMAC Index: 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 the hip and/or knee. WOMAC average score is the mean of the WOMAC pain, physical function and stiffness subscale scores and ranges from 0 to 10, with higher score indicating worse response. Greater reduction in WOMAC average score indicated greater improvement. | Baseline, Weeks 2, 4, 8, 12, 16, and 24 | 
| Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Subscale Item: Pain When Walking on a Flat Surface at Weeks 2, 4, 8, 12, 16, and 24 | Participants answered the question: How much pain have you had when walking on a flat surface? Participants responded by using an 11-point scale where 0 = no pain and 10 = extreme pain. Where 0 is the best response and negative change indicated an improvement. | Baseline, Week 2, 4, 8, 12, 16, 24 | 
| Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Subscale Item: Pain When Going Up or Downstairs at Weeks 2, 4, 8, 12, 16, and 24 | Participants answered the question: How much pain have you had when going up or down the stairs? Participants responded by using an 11-point scale, where 0 = no pain and 10 = extreme pain. Where 0 is the best response and negative change indicated an improvement. | Baseline, Weeks 2, 4, 8, 12, 16, and 24 | 
| Change From Baseline in 36-Item Short-Form Health Survey Version 2 (SF-36v2) Domain Scores at Week 12 and 24 | SF-36v2 was a standardized survey evaluating 8 aspects of functional health and well-being: physical and social functioning, physical and role limitations due to emotional problems, bodily pain, general health, vitality, and mental health. The total score and the score for a section was an average of the individual question scores, which were scaled 0-100. Higher scores reflected better participant status and positive change indicated an improvement. | Baseline, Week 12, and 24 | 
| Change From Baseline in 36-Item Short-Form Health Survey Version 2 (SF-36v2) Physical and Mental Component Scores at Week 12 and 24 | SF-36v2: standardized survey evaluating 8 aspects of functional health and wellbeing (physical and social functioning, role limitations due to physical and emotional problems, bodily pain, general health, vitality, mental health). Total score for each aspect were scaled 0-100. Higher scores reflect better participant status and positive change indicated an improvement. 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 and 24 | 
| Change From Baseline in European Quality of Life - 5 Dimension (EQ-5D) Index Score at Week 24 | EQ-5D was a standardized, participant-administered measure of health outcome. It provides a descriptive profile for 5 dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression), using 3 levels (no, moderate, or extreme dysfunction) and a single index value characterizing current health status using a visual analog scale with score ranging from 0 (worst) to 100 (best). EQ-5D summary index was obtained with a formula that weights each level of the dimensions. The index-based score was interpreted along a continuum of 0 (death) to 1 (perfect health). Negative change from baseline represented worsening. | Baseline, Week 24 | 
| Number of Participants With Change From Baseline in European Quality of Life - 5 Dimension (EQ-5D) Individual Health State Profile at Week 24 | EQ-5D was a standardized, participant-administered measure of health outcome. It provides a descriptive profile for 5 dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression), using 3 levels (no, moderate, or extreme dysfunction) and a single index value characterizing current health status using a visual analog scale with score ranging from 0 (worst) to 100 (best). Baseline EQ-5D individual health state profile was determined as number of participants no dysfunction, moderate or some dysfunction and extreme dysfunction and change from baseline in EQ-5D individual health state profile was determined as number of participants improved, no change or worsened. | Baseline, Week 24 | 
| Number of Participants Who Discontinued Due to Lack of Efficacy | Number of participants who discontinued due to lack of efficacy were reported. | Baseline up to end of study (Week 32) | 
| Time to Discontinuation (TTD) 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 and 24 | 
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to 112 days after last dose that were absent before treatment or that worsened relative to pretreatment state. AEs included SAEs as well as non-serious AEs which occurred during the trial. | Baseline up to 112 days after last intravenous dose (up to Week 32) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Arthritis monoclonal antibody nerve growth factor (NGF) anti-NGF tanezumab PF-04383119 RN-624 OA