Efficacy and Safety of a Subcutaneous Tanezumab Titration Dosing Regimen in Subjects With Moderate to Severe Osteoarthritis of the Hip or Knee

Study Overview
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Brief Summary
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The primary purpose of this study is to evaluate the efficacy of a titration arm of tanezumab in which treatment is started at a lower dose (2.5 mg) and increased to a higher dose (5 mg) at Week 8, compared to giving 2 doses of tanezumab 2.5 mg or 2 doses of placebo. The study also evaluates the safety of the treatment regimens.

Official Title
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A PHASE 3 RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, MULTICENTER STUDY OF THE ANALGESIC EFFICACY AND SAFETY OF A DOSE TITRATION REGIMEN FOR THE SUBCUTANEOUS ADMINISTRATION OF TANEZUMAB IN SUBJECTS WITH OSTEOARTHRITIS OF THE HIP OR KNEE

Conditions
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Osteoarthritis, Knee, Osteoarthritis, Hip

Intervention / Treatment
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* Other: Placebo
* Biological: Tanezumab 2.5 mg
* Biological: Tanezumab 2.5mg/5mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of Osteoarthritis of the knee or hip confirmed by X-ray Documented history that subject tried the following medications and had insufficient pain relief or is cannot take or tolerate them: acetaminophen, NSAIDs and either tramadol or opioids Meet the protocol requirements for pain at screening and pain, physical function and patient global assessment of osteoarthritis at baseline Willing to discontinue all pain medications except study medication and rescue medication during the course of the study and use those as directed per protocol Women able to have children must agree to use 2 forms of contraception during the study Exclusion Criteria: Body Mass Index (BMI) greater than 39 History of diseases other than osteoarthritis in a shoulder, hip or knee (example, rheumatoid arthritis, gout, joint infections, osteonecrosis) Patients with x-ray showing joint conditions such as osteonecrosis (dead bone) or certain types of fractures Patients who have had significant trauma or surgery to a knee, hip or shoulder within the previous year Planned surgical procedure during the study Patients who are largely or wholly incapacitated (example bedridden or confined to a wheelchair, permitting little or no self-care) Patients who would be unwilling or unable to undergo joint replacement surgery if one eventually became necessary Patients with significant conditions other than osteoarthritis that could interfere with assessment of pain in the joints (example fibromyalgia, lupus erythematosus) Patients with significant heart, neurological or psychiatric diseases Patients who had cancer other than certain skin cancers within the past 5 years Patients with alcohol, analgesic (pain medications) or drug abuse within the past 2 years Women who are pregnant, breast-feeding or intending to become pregnant or breast-feed during the course of the study.

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 |
| --- | --- |
| Placebo Comparator: Placebo<br>placebo administered subcutaneously at day 0 and week 8 | Other: Placebo<br>* Patient receives one dose of placebo to match tanezumab subcutaneously on Day 1 and one dose of placebo to match tanezumab subcutaneously at Week 8.<br>|
| Experimental: Tanezumab 2.5 mg<br>tanezumab 2.5 mg administered subcutaneously at day 0 and week 8 | Biological: Tanezumab 2.5 mg<br>* Patient receives one dose of tanezumab 2.5 mg subcutaneously on Day 1 and one dose of tanezumab 2.5 mg subcutaneously at Week 8.<br>|
| Experimental: Tanezumab 2.5mg/5mg<br>tanezumab 2.5 mg administered subcutaneously at day 0 and tanezumab 5 mg administered subcutaneously at week 8 | Biological: Tanezumab 2.5mg/5mg<br>* Patient receives one dose of tanezumab 2.5 mg subcutaneously on Day 1 and one dose of tanezumab 5 mg subcutaneously at Week 8.<br>* Other names: Titration Arm;|

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 | WOMAC: self-administered, disease-specific questionnaire which assesses clinically important, participant-relevant symptoms for pain, stiffness and physical function in participants with osteoarthritis. The WOMAC pain subscale is a 5-item questionnaire used to assess the amount of pain experienced due to osteoarthritis of index joint (knee or hip) during past 48 hours. It was calculated as the mean of scores from 5 individual questions scored on a numerical rating scale (NRS) of 0 (no pain) to 10 (extreme pain), where higher scores indicated higher pain. | Baseline, Week 16 | 
| Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Physical Function Subscale 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. Physical function refers to participant's ability to move around and perform usual activities of daily living. The WOMAC physical function subscale is 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 (minimum difficulty) to 10 (extreme difficulty), where higher scores indicated extreme difficulty/worse physical function. | Baseline, Week 16 | 
| Change From Baseline in Patient's Global Assessment (PGA) of Osteoarthritis at Week 16 | PGA of osteoarthritis was assessed by asking a question from participants: Considering all the ways your osteoarthritis in your knee or hip (index joint) 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 Weeks 2, 4, 8 and 12 | WOMAC: self-administered, disease-specific questionnaire which assesses clinically important, participant-relevant symptoms for pain, stiffness and physical function in participants with osteoarthritis. The WOMAC pain subscale is a 5-item questionnaire used to assess the amount of pain experienced due to osteoarthritis of index joint (knee or hip) during past 48 hours. It was calculated as the mean of scores from 5 individual questions scored on NRS of 0 (no pain) to 10 (extreme pain), where higher scores indicated higher pain. | Baseline, Weeks 2, 4, 8 and 12 | 
| Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Subscale at Week 24 | WOMAC: self-administered, disease-specific questionnaire which assesses clinically important, participant-relevant symptoms for pain, stiffness and physical function in participants with osteoarthritis. The WOMAC pain subscale is a 5-item questionnaire used to assess the amount of pain experienced due to osteoarthritis of index joint (knee or hip) during past 48 hours. It was calculated as the mean of scores from 5 individual questions scored on NRS of 0 (no pain) to 10 (extreme pain), where higher scores indicated higher pain. | Baseline, Week 24 | 
| Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Physical Function Subscale at Weeks 2, 4, 8 and 12 | WOMAC: self-administered, disease-specific questionnaire which assesses clinically important, participant-relevant symptoms for pain, stiffness and physical function in participants with osteoarthritis. Physical function refers to participant's ability to move around and perform usual activities of daily living. The WOMAC physical function subscale is 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 (minimum difficulty) to 10 (extreme difficulty), where higher scores indicated extreme difficulty/worse physical function. | Baseline, Weeks 2, 4, 8 and 12 | 
| Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Physical Function Subscale at Week 24 | WOMAC: self-administered, disease-specific questionnaire which assesses clinically important, participant-relevant symptoms for pain, stiffness and physical function in participants with osteoarthritis. Physical function refers to participant's ability to move around and perform usual activities of daily living. The WOMAC physical function subscale is 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 (minimum difficulty) to 10 (extreme difficulty), where higher scores indicated maximum difficulty/worse physical function. | Baseline, Week 24 | 
| Change From Baseline in Patient's Global Assessment (PGA) of Osteoarthritis at Weeks 2, 4, 8 and 12 | PGA of osteoarthritis was assessed by asking a question from participants: Considering all the ways your osteoarthritis in your knee or hip (index joint) 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). | Baseline, Weeks 2, 4, 8 and 12 | 
| Change From Baseline in Patient's Global Assessment (PGA) of Osteoarthritis at Week 24 | PGA of osteoarthritis was assessed by asking a question from participants: Considering all the ways your osteoarthritis in your knee or hip (index joint) 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 worse condition. | Baseline, Week 24 | 
| Percentage of Participants Meeting Outcomes Measures in Arthritis Clinical Trials-Osteoarthritis Research Society International (OMERACT-OARSI) Responder Index | Participants were considered as OMERACT-OARSI responders: if the change (improvement) from baseline to week of interest was greater than or equal to (>=) 50 percent and greater or equal to (>=) 2 units in either WOMAC pain subscale or physical function subscale score; if change (improvement) from baseline to week of interest was >=20 percent and >=1 unit in at least 2 of the following: 1) WOMAC pain subscale score, 2) WOMAC physical function subscale score, 3) PGA of osteoarthritis. WOMAC pain subscale assess amount of pain experienced (score: 0 [no pain] to 10 [extreme pain], higher score = more pain), WOMAC physical function subscale assess degree of difficulty experienced (score: 0 [minimum difficulty] to 10 [extreme difficulty], higher score = worse physical function) and PGA of osteoarthritis (score: 1 [very good] to 5 [very poor], higher score = worse condition). Missing data was imputed using mixed baseline/last observation carried forward (BOCF/LOCF). | Weeks 2, 4, 8, 12, 16 and 24 | 
| Percentage of Participants Achieving Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Subscale Reduction >= 30 Percent (%), >=50%, >=70% and >=90% Response | Percentage of participants with reduction in WOMAC pain intensity of at least (>=) 30%, 50%, 70% and 90% at Weeks 2, 4, 8, 12, 16 and 24 compared to baseline were classified as responders to WOMAC pain subscale and are reported here. WOMAC: self-administered, disease-specific questionnaire which assesses clinically important, participant-relevant symptoms for pain, stiffness and physical function in participants with osteoarthritis. The WOMAC pain subscale is a 5-item questionnaire used to assess the amount of pain experienced due to osteoarthritis of index joint (knee or hip) during past 48 hours. It was calculated as the mean of scores from 5 individual questions scored on a numerical rating scale (NRS) of 0 (no pain) to 10 (extreme pain), where higher scores indicated higher pain. Missing data was imputed using mixed BOCF/LOCF. | Week 2, 4, 8, 12, 16 and 24 | 
| Percentage of Participants With Cumulative Percent Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Subscale 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. The WOMAC pain subscale is a 5-item questionnaire used to assess the amount of pain experienced due to osteoarthritis of index joint during past 48 hours. It was calculated as the mean of scores from 5 individual questions scored on a NRS of 0 (no pain) to 10 (extreme pain), where higher scores indicated higher pain. Total score range for WOMAC pain subscale score was 0 (no pain) to 10 (extreme pain), where higher scores indicated higher pain. 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 Week 16 were reported, participants (%) are reported more than once in categories specified. Missing data was imputed using mixed BOCF/LOCF. | Baseline to Week 16 | 
| Percentage of Participants Achieving Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Physical Function Subscale Reduction >= 30 Percent (%), >=50%, >=70% and >=90% Response | Percentage of participants with reduction in WOMAC physical function of at least (>=) 30%, 50%, 70% and 90% at weeks 2, 4, 8, 12, 16 and 24 compared to baseline were classified as responders to WOMAC physical function subscale. WOMAC: self-administered, disease-specific questionnaire which assesses clinically important, participant-relevant symptoms for pain, stiffness and physical function in participants with osteoarthritis. Physical function refers to participant's ability to move around and perform usual activities of daily living. WOMAC physical function subscale: 17-item questionnaire used to assess the degree of difficulty experienced due to osteoarthritis in index joint (knee or hip) during past 48 hours,calculated as mean of the scores from 17 individual questions scored on a NRS of 0 (minimum difficulty) to 10 (extreme difficulty), where higher scores indicated extreme difficulty/worse physical function. Missing data was imputed using mixed BOCF/LOCF. | Weeks 2, 4, 8, 12, 16 and 24 | 
| Percentage of Participants With Cumulative Percent Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Physical Function Subscale 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. Physical function: participant's ability to move around and perform usual activities of daily living. WOMAC physical function subscale: 17-item questionnaire used to assess the degree of difficulty experienced due to osteoarthritis in index joint (knee or hip) during past 48 hours, calculated as mean of the scores from 17 individual questions scored on a NRS of 0 (minimum difficulty) to 10 (extreme difficulty),higher scores indicate extreme difficulty/worse physical function. Percentage of participants with cumulative reduction (as percent) (greater than 0 %; >= 10 %, 20 %, 30 %, 40 %, 50 %, 60 %, 70 %, 80 % and 90%; = 100 %) in WOMAC physical function subscale from Baseline to Week 16 were reported. Missing data was imputed using mixed BOCF/LOCF. | Baseline to Week 16 | 
| Percentage of Participants Achieving Improvement of >=2 Points in Patient's Global Assessment (PGA) of Osteoarthritis | PGA of osteoarthritis was assessed by asking a question from participants: Considering all the ways your osteoarthritis in your knee or hip 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 worse condition. Percentage of participants with improvement of at least 2 points from Baseline in PGA of osteoarthritis were reported. Missing data was imputed using mixed BOCF/LOCF. | Weeks 2, 4, 8, 12, 16 and 24 | 
| Change From Baseline for Average Pain Score in the Index Joint at Weeks 1, 2, 3, 4, 6, 8, 10, 12 and 16 | Participants assessed their average pain in the index hip/knee in the past 24 hours using a scale ranging from 0 (no pain) to 10 (worst possible pain). Higher scores indicated higher pain. Data represents averages of the values reported during the 4-week interval up to and including the given week. Change from baseline was calculated using the difference between each post-baseline weekly mean and the baseline mean score. | Baseline, Weeks 1, 2, 3, 4, 6, 8, 10, 12 and 16 | 
| Change From Baseline for Average Pain Score in the Index Joint at Weeks 20 and 24 | Participants assessed their average pain in the index hip/knee in the past 24 hours using a scale ranging from 0 (no pain) to 10 (worst possible pain) weekly beginning at Week 16. Higher scores indicated higher pain. Data represents averages of the values reported during the 4-week interval up to and including the given week. Change from baseline was calculated using the difference between each post-baseline weekly mean and the baseline mean score. | Baseline, Weeks 20 and 24 | 
| Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Stiffness Subscale at Weeks 2, 4, 8, 12 and 16 | WOMAC: self-administered, disease-specific questionnaire which assesses clinically important, participant relevant symptoms for pain, stiffness and physical function in participants with osteoarthritis. Stiffness was defined as a sensation of decreased ease of movement in the index joint (knee or hip).The WOMAC stiffness subscale was a 2-item questionnaire used to assess the amount of stiffness experienced due to osteoarthritis in the index joint (knee or hip) during the past 48 hours. It was calculated as mean of the scores from 2 individual questions scored on NRS of 0 (no stiffness) to 10 (extreme stiffness), where higher scores indicated higher stiffness. | Baseline, Weeks 2, 4, 8, 12 and 16 | 
| Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Stiffness Subscale at Week 24 | WOMAC: self-administered, disease-specific questionnaire which assesses clinically important, participant relevant symptoms for pain, stiffness and physical function in participants with osteoarthritis. Stiffness was defined as a sensation of decreased ease of movement in the index joint (knee or hip).The WOMAC stiffness subscale was a 2-item questionnaire used to assess the amount of stiffness experienced due to osteoarthritis in the index joint (knee or hip) during the past 48 hours. It was calculated as mean of the scores from 2 individual questions scored on NRS of 0 (no stiffness) to 10 (extreme stiffness), where higher scores indicated higher stiffness. | Baseline, Week 24 | 
| Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Average Score at Weeks 2, 4, 8, 12 and 16 | WOMAC: self-administered, disease-specific questionnaire which assesses clinically important, participant-relevant symptoms for pain, stiffness and physical function in participants with osteoarthritis of index joint (knee or hip). WOMAC pain subscale assess amount of pain experienced (score: 0 [no pain] to 10 [extreme pain], higher score = more pain), WOMAC physical function subscale assess degree of difficulty experienced (score: 0 [minimum difficulty] to 10 [extreme difficulty], higher score = worse physical function) and WOMAC stiffness subscale assess the amount of stiffness experienced (score: 0 [no stiffness] to 10 [extreme stiffness], higher score = higher stiffness). WOMAC average score was the mean of WOMAC pain, physical function and stiffness subscale scores and ranges from 0 to 10, where higher scores indicated worse response. | Baseline, Weeks 2, 4, 8, 12 and 16 | 
| Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Average Score at Week 24 | WOMAC: self-administered, disease-specific questionnaire which assesses clinically important, participant-relevant symptoms for pain, stiffness and physical function in participants with osteoarthritis of index joint (knee or hip). WOMAC pain subscale assess amount of pain experienced (score: 0 [no pain] to 10 [extreme pain], higher score = more pain), WOMAC physical function subscale assess degree of difficulty experienced (score: 0 [minimum difficulty] to 10 [extreme difficulty], higher score = worse physical function) and WOMAC stiffness subscale assess the amount of stiffness experienced (score: 0 [no stiffness] to 10 [extreme stiffness], higher score = higher stiffness). WOMAC average score was the mean of WOMAC pain, physical function and stiffness subscale scores and ranges from 0 to 10, where higher scores indicated worse response. | Baseline, Week 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 and 16 | WOMAC: self-administered, disease-specific questionnaire which assesses clinically important, participant-relevant symptoms for pain, stiffness and physical function in participants with osteoarthritis in index joint (knee or hip). Participants answered a question: How much pain have you had when walking on a flat surface?. Participants responded about the amount of pain they experienced when walking on a flat surface by using a NRS of 0 (no pain) to 10 (extreme pain), where higher scores indicated higher pain. | Baseline, Weeks 2, 4, 8, 12 and 16 | 
| Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Subscale Item (Pain When Walking on a Flat Surface) at Week 24 | WOMAC: self-administered, disease-specific questionnaire which assesses clinically important, participant-relevant symptoms for pain, stiffness and physical function in participants with osteoarthritis in index joint (knee or hip). Participants answered a question: How much pain have you had when walking on a flat surface?. Participants responded about the amount of pain they experienced when walking on a flat surface by using a NRS of 0 (no pain) to 10 (extreme pain), where higher scores indicated higher pain. | Baseline, Week 24 | 
| Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Subscale (Pain When Going up or Down Stairs) at Weeks 2, 4, 8, 12 and 16 | WOMAC: self-administered, disease-specific questionnaire which assesses clinically important, participant-relevant symptoms for pain, stiffness and physical function in participants with osteoarthritis in index joint (knee or hip). Participants answered a question: How much pain have you had when going up or down the stairs? Participants responded about the amount of pain they experienced when going up or down stairs by using a NRS of 0 (no pain) to 10 (extreme pain), where higher scores indicated higher pain. | Baseline, Weeks 2, 4, 8, 12 and 16 | 
| Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Subscale (Pain When Going up or Down Stairs) at Week 24 | WOMAC: self-administered, disease-specific questionnaire which assesses clinically important, participant-relevant symptoms for pain, stiffness and physical function in participants with osteoarthritis in index joint (knee or hip). Participants answered a question: How much pain have you had when going up or down the stairs? Participants responded about the amount of pain they experienced when going up or down stairs by using a NRS of 0 (no pain) to 10 (extreme pain), where higher scores indicated higher pain. | Baseline, Week 24 | 
| Work Productivity and Activity Impairment Questionnaire for Osteoarthritis (WPAI:OA) Scores at Baseline | WPAI is 6-question participant rated questionnaire to determine the impact of osteoarthritis on absenteeism, presenteeism, work productivity, and daily activity impairment for a period of 7 days prior to a visit. It yields 4 sub-scores: work time missed (absenteeism), impairment while working (presenteeism), overall work impairment (work productivity) and activity impairment (daily activity impairment). These sub-scores are expressed as an impairment percentage (range from 0 to 100), with higher numbers indicating greater impairment and less productivity. | Baseline | 
| Change From Baseline in Work Productivity and Activity Impairment Questionnaire for Osteoarthritis (WPAI:OA) Scores at Week 16 | WPAI is 6-question participant rated questionnaire to determine the impact of osteoarthritis on absenteeism, presenteeism, work productivity, and daily activity impairment for a period of 7 days prior to a visit. It yields 4 sub-scores: work time missed (absenteeism), impairment while working (presenteeism), overall work impairment (work productivity) and activity impairment (daily activity impairment). These sub-scores are expressed as an impairment percentage (range from 0 to 100), with higher numbers indicating greater impairment and less productivity. | Baseline and Week 16 | 
| European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Dimensions Score | EQ-5D-5L is a standardized participant completed questionnaire that measures health-related quality of life and translates that score into an index value or utility score. EQ-5D-5L consists of two components: a health state profile and an optional visual analogue scale (VAS). EQ-5D health state profile is comprised of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: 1=no problems, 2=slight problems, 3=moderate problems, 4=severe problems, and 5=extreme problems. The health utility score for a patient with no problems in all 5 items is 1 for all countries (except for Zimbabwe where it is 0.9), and is reduced where a patient reports greater levels of problems across the five dimensions. | Baseline, Weeks 8 and 16 | 
| European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Overall Health Utility Score/Index Value | EQ-5D-5L: standardized participant completed questionnaire that measures health-related quality of life and translates that score into an index value or utility score. EQ-5D-5L consists of two components: a health state profile and an optional VAS. EQ-5D health state profile comprises of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: 1=no problems, 2=slight problems, 3=moderate problems, 4=severe problems, and 5=extreme problems. Responses from the five domains were used to calculate a single utility index (the Overall health utility score) where values are <=1. The Overall health utility score for a patient with no problems in all 5 items is 1 for all countries (except for Zimbabwe where it is 0.9), and is reduced where a patient reports greater levels of problems across the five dimensions. | Baseline, Weeks 8 and 16 | 
| Health Care Resource Utilization (HCRU): Number of Visits of Services Directly Related to Osteoarthritis | Osteoarthritis HCRU assessed healthcare usage during last 3 months (for Baseline and Week 40) and past 8 weeks (for Week 24). Visits of services directly related to osteoarthritis evaluated were: visits to primary care physician, neurologist, rheumatologist, physician assistant or nurse practitioner, pain specialist, orthopedist, physical therapist, chiropractor, alternative medicine or therapy, podiatrist, nutritionist/dietitian, radiologist, home healthcare services and other practitioner. | Baseline, Weeks 24 and 40 | 
| Health Care Resource Utilization (HCRU): Number of Participants Who Visited the Emergency Room Due to Osteoarthritis | Osteoarthritis HCRU assessed healthcare usage during last 3 months (for Baseline and Week 40) and past 8 weeks (for Week 24). Domain evaluated was number of participants who visited the emergency room due to osteoarthritis (OA). | Baseline, Weeks 24 and 40 | 
| Health Care Resource Utilization (HCRU): Number of Visits to the Emergency Room Due to Osteoarthritis | Osteoarthritis HCRU assessed healthcare usage during last 3 months (for Baseline and Week 40) and past 8 weeks (for Week 24). Domain evaluated was number of visits to the emergency room due to OA. | Baseline, Weeks 24 and 40 | 
| Health Care Resource Utilization (HCRU): Number of Participants Hospitalized Due to Osteoarthritis | Osteoarthritis HCRU assessed healthcare usage during last 3 months (for Baseline and Week 40) and past 8 weeks (for Week 24). Domain evaluated was number of participants who were hospitalized due to OA. | Baseline, Weeks 24 and 40 | 
| Health Care Resource Utilization (HCRU): Number of Nights Stayed in the Hospital Due to Osteoarthritis | Osteoarthritis HCRU assessed healthcare usage during last 3 months (for Baseline and Week 40) and past 8 weeks (for Week 24). Domain evaluated was number of nights stayed in the hospital due to OA. | Baseline, Weeks 24 and 40 | 
| Health Care Resource Utilization (HCRU): Number of Participants Who Used Any Aids/Devices for Doing Things | Osteoarthritis HCRU assessed healthcare usage during last 3 months (for Baseline and Week 40) and past 8 weeks (for Week 24). Domain evaluated was number of participants who used any aids/devices for doing things. Aids such as walking aid, wheelchair, device or utensil for dress/bathe/eat and any other aids/devices. | Baseline, Weeks 24 and 40 | 
| Health Care Resource Utilization (HCRU): Number of Participants Who Quit Job Due to Osteoarthritis | Osteoarthritis HCRU assessed healthcare usage (during 3 months prior to baseline) at baseline, Week 24 and Week 40. Domain evaluated was number of participants who quit job due to OA. | Baseline, Weeks 24 and 40 | 
| Health Care Resource Utilization (HCRU): Duration Since Quitting Job Due to Osteoarthritis | Osteoarthritis HCRU assessed healthcare usage (during 3 months prior to baseline) at baseline, Week 24 and Week 40. Domain evaluated was duration since quitting job due to OA. | Baseline, Weeks 24 and 40 | 
| Number of Participants Who Withdrew Due to Lack of Efficacy | Number of participants who withdrew from treatment due to lack of efficacy have been reported here. | Baseline up to Week 16 | 
| Time to Discontinuation Due to Lack of Efficacy | Time to discontinuation due to lack of efficacy was defined as the time interval from the date of first study drug administration up to the date of discontinuation of participant from treatment due to lack of efficacy. | Baseline up to Week 16 | 
| Number of Participants Who Took Rescue Medication During Weeks 2, 4, 8, 12 and 16 | In case of inadequate pain relief, acetaminophen up to 3000 mg per day up to 3 days in a week could be taken as rescue medication between day 1 and week 16. Number of participants with any use of rescue medication during the particular study week were summarized. | Week 2, 4, 8, 12 and 16 | 
| Number of Participants Who Took Rescue Medication During Week 24 | In case of inadequate pain relief, after Week 16, acetaminophen up to 3000 mg per day up to 7 days in a week could be taken as rescue medication and use was reported weekly via diary. Number of participants with any use of rescue medication during the 4 weeks up to the particular study week were summarized. | Week 24 | 
| Number of Days of Rescue Medication Use at Week 2, 4, 8, 12 and 16 | In case of inadequate pain relief during the treatment period, acetaminophen up to 3000 mg per day up to 3 days in a week could be taken as rescue medication. Number of days the participants used the rescue medication during the particular study weeks were summarized. | Week 2, 4, 8, 12, 16 | 
| Number of Days of Rescue Medication Use at Week 24 | In case of inadequate pain relief, after Week 16, acetaminophen up to 3000 mg per day up to 7 days in a week could be taken as rescue medication and use was reported weekly via diary. Number of days per week the participants used the rescue medication during the 4 weeks up to the particular study week were summarized. | Week 24 | 
| Amount of Rescue Medication Taken at Weeks 2, 4, 8, 12 and 16 | In case of inadequate pain relief , acetaminophen up to 3000 mg per day up to 3 days in a week could be taken as rescue medication. The total dosage of acetaminophen in milligrams used during the specified week were summarized. | Week 2, 4, 8, 12, 16 | 
| Number of Participants With Treatment-Emergent 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. 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 were events between first dose of study drug and up to Week 40 that were absent before treatment or that worsened relative to pretreatment state. AEs included both serious and non-serious AEs. | Baseline up to Week 40 | 
| Number of Participants With Treatment-Emergent Treatment-Related Adverse Events (AEs) and Serious Adverse Events (SAEs) | Treatment-related AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. 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 were events between first dose of study drug and up to Week 40 that were absent before treatment or that worsened relative to pre-treatment state. Relatedness to study drug was assessed by the investigator. | Baseline up to Week 40 | 
| Number of Participants With Laboratory Test Abnormalities With Regard to Normal Baseline | Primary Abnormality criteria: hemoglobin; hematocrit; RBC count [less than{<}0.8* lower limit of normal[LLN]; Ery. mean corpuscular volume/ hemoglobin/ HGB concentration, erythrocytes distribution width <0.9*LLN, >1.1*ULN; platelets <0.5*LLN,>1.75*upper limit of normal (ULN); white blood cell count<0.6*LLN, >1.5*ULN; Lymphocytes,Leukocytes,Neutrophils <0.8*LLN, >1.2*ULN; Basophils, Eosinophils, Monocytes >1.2*ULN; Prothrombin time/Intl. normalized ratio >1.1*ULN; total bilirubin>1.5*ULN; aspartate aminotransferase, alanine aminotransferase, gamma GT,LDH, alkaline phosphatase >3.0*ULN; total protein; albumin<0.8*LLN, >1.2*ULN; blood urea nitrogen, creatinine, Cholesterol, triglycerides >1.3*ULN; Urate >1.2*ULN; sodium <0.95*LLN,>1.05*ULN; potassium, chloride, calcium, magnesium, bicarbonate <0.9*LLN, >1.1*ULN; phosphate <0.8*LLN, >1.2*ULN; glucose <0.6*LLN, >1.5*ULN;Hemoglobin A1C >1.3*ULN; creatine kinase >2.0*ULN, specific gravity <1.003, >1.030; pH<4.5, >8; Urine Leukocytes >=20. | Baseline up to Week 40 | 
| Number of Participants With Laboratory Test Abnormalities With Regard to Abnormal Baseline | Primary Abnormality criteria: hemoglobin; hematocrit; RBC count < 0.8*LLN; Ery. mean corpuscular volume/ hemoglobin/ HGB concentration, erythrocytes distribution width <0.9*LLN, >1.1*ULN; platelets <0.5*LLN,>1.75*upper limit of normal (ULN); white blood cell count<0.6*LLN, >1.5*ULN; Lymphocytes, Leukocytes, Neutrophils <0.8*LLN, >1.2*ULN; Basophils, Eosinophils, Monocytes >1.2*ULN; Prothrombin time/Intl. normalized ratio >1.1*ULN; total bilirubin>1.5*ULN; aspartate aminotransferase, alanine aminotransferase, gamma GT,LDH, alkaline phosphatase >3.0*ULN; total protein; albumin<0.8*LLN, >1.2*ULN; blood urea nitrogen, creatinine, Cholesterol, triglycerides >1.3*ULN; Urate >1.2*ULN; sodium <0.95*LLN,>1.05*ULN; potassium, chloride, calcium, magnesium, bicarbonate <0.9*LLN, >1.1*ULN; phosphate <0.8*LLN, >1.2*ULN; glucose <0.6*LLN, >1.5*ULN; Hemoglobin A1C >1.3*ULN; creatine kinase >2.0*ULN; Urine erythrocytes >=20. | Baseline up to Week 40 | 
| Change From Baseline in Blood Pressure (BP) at Weeks 2, 4, 8, 12, 16, 24, 40 | Measurement of BP included sitting systolic (SBP) and diastolic BP (DBP). | Baseline, Weeks 2, 4, 8, 12, 16, 24, 40 | 
| Change From Baseline in Heart Rate at Weeks 2, 4, 8, 12,16, 24, 40 | Heart rate was measured at sitting position. | Baseline, Weeks 2, 4, 8, 12, 16, 24 and 40 | 
| Change From Baseline in Electrocardiogram (ECG) Parameters at Weeks 16 and 40 | A 12-lead ECG was recorded after participants had rested for at least 5 minutes in the supine position in a quiet environment. All standard intervals (PR, QRS, QT, QTcF, QTcB, QTcF, RR intervals) were collected. | Baseline, Weeks 16, 40 | 
| Change From Baseline in Heart Rate (as Assessed by ECG) at Weeks 16 and 40 |  | Baseline, Weeks 16 and 40 | 
| Percentage of Participants With Adjudicated Joint Safety Outcomes | Incidence of participants with any of the joint safety adjudication outcomes of primary osteonecrosis, rapidly progressive osteoarthritis (OA) (type 1 and type 2), subchondral insufficiency fracture (or SPONK), or pathological fracture. | Baseline up to Week 40 | 
| Percentage of Participants With Total Joint Replacements | Percentage of participants who underwent total knee, hip or shoulder joint replacement surgery. | Baseline up to Week 40 | 
| Change From Baseline in Neuropathy Impairment Score (NIS) at Weeks 2, 4, 8,12,16, 24 and 40 | NIS is a standardized instrument used to evaluate participant for signs of peripheral neuropathy. NIS is the sum of scores of 37 items, from both the left and right side, where 24 items scored from 0 (normal) to 4 (paralysis), higher score indicated higher abnormality/impairment and 13 items scored from 0 (normal), 1 (decreased) and 2 (absent), higher score indicated higher impairment. NIS possible overall score ranged from 0 (no impairment) to 244 (maximum impairment), higher scores indicated increased impairment. | Baseline, Weeks 2, 4, 8,12,16, 24 and 40 | 
| Number of Participants With Confirmed Orthostatic Hypotension | Orthostatic hypotension was defined as postural change (supine to standing) that met the following criteria: For systolic BP <=150 mmHg (mean supine): Reduction in systolic BP>=20 mmHg or reduction in diastolic BP>=10 mmHg at the 1 and/or 3 minute standing BP measurements. For systolic BP >150 mmHg (mean supine): Reduction in systolic BP>=30 mmHg or reduction in diastolic BP>=15 mmHg at the 1 and/or 3 minute standing BP measurements. If the 1 minute or 3 minute standing BP in a sequence met the orthostatic hypotension criteria, then that sequence was considered positive. If 2 of 2 or 2 of 3 sequences were positive, then orthostatic hypotension was considered confirmed. | Baseline up to Week 40 | 
| Change From Baseline in Survey of Autonomic Symptom (SAS) Scores at Weeks 24 and 40 | The SAS is a 12 item (11 for females) questionnaire, from which the total number of symptoms (0-12 for males and 0-11 for females) is calculated. Each positive symptom is rated from 1 (not at all) to 5 (a lot). The total impact score was the sum of all symptom rating scores, with 0 assigned where the participant did not have the particular symptom. The range for the total impact score is 0-60 for males and 0-55 for females, higher scores indicating higher impact. | Baseline, Weeks 24 and 40 | 
| Number of Participants With Anti-Tanezumab Antibodies | Human serum ADA samples were analyzed for the presence or absence of anti-tanezumab antibodies by using a semi quantitative enzyme linked immunosorbent assay (ELISA). Participants listed as having anti-tanezumab antibodies had ADA titer level >=3.32. Less than 3.32 was considered below the limit of quantitation. | Baseline, Weeks 8,16, 24 and 40 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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osteoarthritis of the knee, osteoarthritis of the hip, nerve growth factor inhibitor, tanezumab