A Long Term Study of the Safety of Tanezumab When Administered By Subcutaneous Injections

Study Overview
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Brief Summary
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This study will investigate the safety of three fixed dose levels of tanezumab (2.5 mg, 5 mg, and 10 mg) administered at an 8-week interval by subcutaneous injection multiple (7) times during the study treatment period.

Detailed Description
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Safety study of tanezumab in relief of osteoarthritis pain This study was terminated on 6 December 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 MULTICENTRE, RANDOMIZED, DOUBLE-BLIND,LONG TERM STUDY OF THE SAFETY OF SUBCUTANEOUS ADMINISTRATION OF TANEZUMAB IN PATIENTS WITH OSTEOARTHRITIS OF THE KNEE OR HIP

Conditions
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Osteoarthritis, Knee, Osteoarthritis, Hip

Intervention / Treatment
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* Drug: Tanezumab 2.5 mg
* Drug: Tanezumab 5 mg
* Drug: Tanezumab 10 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Osteoarthritis of the knee or hip based on American College of Rheumatology criteria with a radiographic (X ray) confirmation (a Kellgren Lawrence x-ray grade of ≥2); Exclusion Criteria: Body mass index (BMI) of >39 kg/m2; Pregnancy or intent to become pregnant Planned surgical procedure during the duration of the study History of clinically significant cardiovascular, central nervous system or psychiatric disease Previous exposure to exogenous NGF or to an anti NGF antibody; Use of biologics other than study medication, Live or live-attenuated intranasal vaccines (eg, Flumist), are allowable exceptions

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: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tanezumab 2.5 mg<br> | Drug: Tanezumab 2.5 mg<br>* Tanezumab 2.5 mg administered by subcutaneous injection every 8 weeks for a total of 7 injections administered over approximately 1 year<br>* Other names: Biological;|
| Experimental: Tanezumab 5 mg<br> | Drug: Tanezumab 5 mg<br>* Tanezumab 5 mg administered by subcutaneous injection every 8 weeks for a total of 7 injections administered over approximately 1 year<br>* Other names: Biological;|
| Experimental: Tanezumab 10 mg<br> | Drug: Tanezumab 10 mg<br>* Tanezumab 10 mg administered by subcutaneous injection every 8 weeks for a total of 7 injections administered over approximately 1 year<br>* Other names: Biological;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Emergent Adverse Events (AEs) or 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 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. | Baseline up to 112 days after last dose of study medication (up to 345 days) | 
| Number of Participants With Laboratory Abnormalities | Laboratory analysis included blood chemistry, hematology, urinalysis and pregnancy test. | Baseline to Week 50 | 
| Number of Participants With Abnormal Electrocardiogram (ECG) Findings | All standard intervals (PR, QRS, QT, QT interval corrected for heart rate using Fridericia's formula [QTcF], QT interval corrected for heart rate using Bazett's formula [QTcB], RR intervals and heart rate) were analyzed. Participants with abnormal ECG findings reported as adverse events were presented. | Baseline up to Week 50 | 
| Change From Baseline in Neuropathy Impairment Score (NIS) at Week 2 | NIS: 74-item, assess cranial nerves, muscle weakness, reflexes, sensation; scored separately for left, right limbs (37 items for each). Cranial nerves included 5 items (3rd nerve, 6th nerve, facial weakness, palate weakness, tongue weakness), muscle weakness included 19 items (respiratory,neck flexion, shoulder abduction, elbow flexion, brachioradialis,elbow extension, wrist flexion,wrist extension,finger flexion,finger spread,thumb abduction,hip flexion,hip extension,knee flexion,knee extension,ankle dorsiflexors,ankle plantar flexors,toe extensors,toe flexors), each item scored on scale 0=normal to 4=paralysis, higher score=greater weakness. Reflexes included 5 items (quadriceps femoris, triceps surae, biceps brachii, triceps brachii, brachioradialis), sensation included 4 items each for great toe and index finger (touch pressure, pin prick, vibration, joint position), each item scored as 0=normal, 1=decreased, 2=absent. Total NIS score range 0-244, higher score=greater impairment. | Baseline, Week 2 | 
| Change From Baseline in Neuropathy Impairment Score (NIS) at Week 4 | NIS: 74-item, assess cranial nerves, muscle weakness, reflexes, sensation; scored separately for left, right limbs (37 items for each). Cranial nerves included 5 items (3rd nerve, 6th nerve, facial weakness, palate weakness, tongue weakness), muscle weakness included 19 items (respiratory,neck flexion, shoulder abduction, elbow flexion, brachioradialis,elbow extension, wrist flexion,wrist extension,finger flexion,finger spread,thumb abduction,hip flexion,hip extension,knee flexion,knee extension,ankle dorsiflexors,ankle plantar flexors,toe extensors,toe flexors), each item scored on scale 0=normal to 4=paralysis, higher score=greater weakness. Reflexes included 5 items (quadriceps femoris, triceps surae, biceps brachii, triceps brachii, brachioradialis), sensation included 4 items each for great toe and index finger (touch pressure, pin prick, vibration, joint position), each item scored as 0=normal, 1=decreased, 2=absent. Total NIS score range 0-244, higher score=greater impairment. | Baseline, Week 4 | 
| Change From Baseline in Neuropathy Impairment Score (NIS) at Week 8 | NIS: 74-item, assess cranial nerves, muscle weakness, reflexes, sensation; scored separately for left, right limbs (37 items for each). Cranial nerves included 5 items (3rd nerve, 6th nerve, facial weakness, palate weakness, tongue weakness), muscle weakness included 19 items (respiratory,neck flexion, shoulder abduction, elbow flexion, brachioradialis,elbow extension, wrist flexion,wrist extension,finger flexion,finger spread,thumb abduction,hip flexion,hip extension,knee flexion,knee extension,ankle dorsiflexors,ankle plantar flexors,toe extensors,toe flexors), each item scored on scale 0=normal to 4=paralysis, higher score=greater weakness. Reflexes included 5 items (quadriceps femoris, triceps surae, biceps brachii, triceps brachii, brachioradialis), sensation included 4 items each for great toe and index finger (touch pressure, pin prick, vibration, joint position), each item scored as 0=normal, 1=decreased, 2=absent. Total NIS score range 0-244, higher score=greater impairment. | Baseline, Week 8 | 
| Change From Baseline in Neuropathy Impairment Score (NIS) at Week 16 | NIS: 74-item, assess cranial nerves, muscle weakness, reflexes, sensation; scored separately for left, right limbs (37 items for each). Cranial nerves included 5 items (3rd nerve, 6th nerve, facial weakness, palate weakness, tongue weakness), muscle weakness included 19 items (respiratory,neck flexion, shoulder abduction, elbow flexion, brachioradialis,elbow extension, wrist flexion,wrist extension,finger flexion,finger spread,thumb abduction,hip flexion,hip extension,knee flexion,knee extension,ankle dorsiflexors,ankle plantar flexors,toe extensors,toe flexors), each item scored on scale 0=normal to 4=paralysis, higher score=greater weakness. Reflexes included 5 items (quadriceps femoris, triceps surae, biceps brachii, triceps brachii, brachioradialis), sensation included 4 items each for great toe and index finger (touch pressure, pin prick, vibration, joint position), each item scored as 0=normal, 1=decreased, 2=absent. Total NIS score range 0-244, higher score=greater impairment. | Baseline, Week 16 | 
| Change From Baseline in Neuropathy Impairment Score (NIS) at Week 24 | NIS: 74-item, assess cranial nerves, muscle weakness, reflexes, sensation; scored separately for left, right limbs (37 items for each). Cranial nerves included 5 items (3rd nerve, 6th nerve, facial weakness, palate weakness, tongue weakness), muscle weakness included 19 items (respiratory,neck flexion, shoulder abduction, elbow flexion, brachioradialis,elbow extension, wrist flexion,wrist extension,finger flexion,finger spread,thumb abduction,hip flexion,hip extension,knee flexion,knee extension,ankle dorsiflexors,ankle plantar flexors,toe extensors,toe flexors), each item scored on scale 0=normal to 4=paralysis, higher score=greater weakness. Reflexes included 5 items (quadriceps femoris, triceps surae, biceps brachii, triceps brachii, brachioradialis), sensation included 4 items each for great toe and index finger (touch pressure, pin prick, vibration, joint position), each item scored as 0=normal, 1=decreased, 2=absent. Total NIS score range 0-244, higher score=greater impairment. | Baseline, Week 24 | 
| Change From Baseline in Neuropathy Impairment Score (NIS) at Week 32 | NIS: 74-item, assess cranial nerves, muscle weakness, reflexes, sensation; scored separately for left, right limbs (37 items for each). Cranial nerves included 5 items (3rd nerve, 6th nerve, facial weakness, palate weakness, tongue weakness), muscle weakness included 19 items (respiratory,neck flexion, shoulder abduction, elbow flexion, brachioradialis,elbow extension, wrist flexion,wrist extension,finger flexion,finger spread,thumb abduction,hip flexion,hip extension,knee flexion,knee extension,ankle dorsiflexors,ankle plantar flexors,toe extensors,toe flexors), each item scored on scale 0=normal to 4=paralysis, higher score=greater weakness. Reflexes included 5 items (quadriceps femoris, triceps surae, biceps brachii, triceps brachii, brachioradialis), sensation included 4 items each for great toe and index finger (touch pressure, pin prick, vibration, joint position), each item scored as 0=normal, 1=decreased, 2=absent. Total NIS score range 0-244, higher score=greater impairment. | Baseline, Week 32 | 
| Change From Baseline in Neuropathy Impairment Score (NIS) at Week 40 | NIS: 74-item, assess cranial nerves, muscle weakness, reflexes, sensation; scored separately for left, right limbs (37 items for each). Cranial nerves included 5 items (3rd nerve, 6th nerve, facial weakness, palate weakness, tongue weakness), muscle weakness included 19 items (respiratory,neck flexion, shoulder abduction, elbow flexion, brachioradialis,elbow extension, wrist flexion,wrist extension,finger flexion,finger spread,thumb abduction,hip flexion,hip extension,knee flexion,knee extension,ankle dorsiflexors,ankle plantar flexors,toe extensors,toe flexors), each item scored on scale 0=normal to 4=paralysis, higher score=greater weakness. Reflexes included 5 items (quadriceps femoris, triceps surae, biceps brachii, triceps brachii, brachioradialis), sensation included 4 items each for great toe and index finger (touch pressure, pin prick, vibration, joint position), each item scored as 0=normal, 1=decreased, 2=absent. Total NIS score range 0-244, higher score=greater impairment. | Baseline, Week 40 | 
| Change From Baseline in Neuropathy Impairment Score (NIS) at Week 48 | NIS: 74-item, assess cranial nerves, muscle weakness, reflexes, sensation; scored separately for left, right limbs (37 items for each). Cranial nerves included 5 items (3rd nerve, 6th nerve, facial weakness, palate weakness, tongue weakness), muscle weakness included 19 items (respiratory,neck flexion, shoulder abduction, elbow flexion, brachioradialis,elbow extension, wrist flexion,wrist extension,finger flexion,finger spread,thumb abduction,hip flexion,hip extension,knee flexion,knee extension,ankle dorsiflexors,ankle plantar flexors,toe extensors,toe flexors), each item scored on scale 0=normal to 4=paralysis, higher score=greater weakness. Reflexes included 5 items (quadriceps femoris, triceps surae, biceps brachii, triceps brachii, brachioradialis), sensation included 4 items each for great toe and index finger (touch pressure, pin prick, vibration, joint position), each item scored as 0=normal, 1=decreased, 2=absent. Total NIS score range 0-244, higher score=greater impairment. | Baseline, Week 48 | 
| Number of Participants With Clinically Significant Change From Baseline in Physical Findings | Physical examination included examination of abdomen, ears, extremities, eyes, head, heart, lungs, lymph nodes, neck, nose, skin, throat, thyroid, muscoskeletal, neurological and peripheral vascular system. | Baseline to Week 50 | 
| Number of Participants With Anti-Drug Antibody (ADA) at Day 1 | Human serum ADA samples were analyzed for the presence or absence of anti-tanezumab antibodies by using the semi-quantitative enzyme-linked immunosorbent assay (ELISA). | Day 1 | 
| Number of Participants With Anti-Drug Antibody (ADA) at Week 8 | Human serum ADA samples were analyzed for the presence or absence of anti-tanezumab antibodies by using the semi-quantitative ELISA. | Week 8 | 
| Number of Participants With Anti-Drug Antibody (ADA) at Week 24 | Human serum ADA samples were analyzed for the presence or absence of anti-tanezumab antibodies by using the semi-quantitative ELISA. | Week 24 | 
| Number of Participants With Anti-Drug Antibody (ADA) at Week 50 | Human serum ADA samples were analyzed for the presence or absence of anti-tanezumab antibodies by using the semi-quantitative ELISA. | Week 50 | 
| Number of Participants With Vital Sign Abnormalities | Examination of vital signs included body temperature, systolic blood pressure, diastolic blood pressure, pulse rate and respiratory rate. Participants with abnormal vital sign findings reported as adverse events were presented. | Baseline up to Week 50 | 
| Number of Participants With Injection-Site Reactions at Day 1 | Assessment of the injection-site reactions were based on presence of erythema (redness), induration (swelling), ecchymosis (bruising), pruritus (itching) and pain that occurred after the injection had been administered (not related to pain of needle insertion). | Day 1 | 
| Number of Participants With Injection-Site Reactions at Week 2 | Assessment of the injection-site reactions were based on presence of erythema (redness), induration (swelling), ecchymosis (bruising), pruritus (itching) and pain that occurred after the injection had been administered (not related to pain of needle insertion). | Week 2 | 
| Number of Participants With Injection-Site Reactions at Week 4 | Assessment of the injection-site reactions were based on presence of erythema (redness), induration (swelling), ecchymosis (bruising), pruritus (itching) and pain that occurred after the injection had been administered (not related to pain of needle insertion). | Week 4 | 
| Number of Participants With Injection-Site Reactions at Week 8 | Assessment of the injection-site reactions were based on presence of erythema (redness), induration (swelling), ecchymosis (bruising), pruritus (itching) and pain that occurred after the injection had been administered (not related to pain of needle insertion). | Week 8 | 
| Number of Participants With Injection-Site Reactions at Week 16 | Assessment of the injection-site reactions were based on presence of erythema (redness), induration (swelling), ecchymosis (bruising), pruritus (itching) and pain that occurred after the injection had been administered (not related to pain of needle insertion). | Week 16 | 
| Number of Participants With Injection-Site Reactions at Week 24 | Assessment of the injection-site reactions were based on presence of erythema (redness), induration (swelling), ecchymosis (bruising), pruritus (itching) and pain that occurred after the injection had been administered (not related to pain of needle insertion). | Week 24 | 
| Number of Participants With Injection-Site Reactions at Week 32 | Assessment of the injection-site reactions were based on presence of erythema (redness), induration (swelling), ecchymosis (bruising), pruritus (itching) and pain that occurred after the injection had been administered (not related to pain of needle insertion). | Week 32 | 
| Number of Participants With Injection-Site Reactions at Week 40 | Assessment of the injection-site reactions were based on presence of erythema (redness), induration (swelling), ecchymosis (bruising), pruritus (itching) and pain that occurred after the injection had been administered (not related to pain of needle insertion). | Week 40 | 

Secondary 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 2, 4, 8, 16, 24, 32, 40, 48 and 56 | WOMAC pain subscale is a 5-item questionnaire used to assess the amount of pain experienced due to osteoarthritis in index knee or index hip during past 48 hours. It was calculated as mean of the scores from the 5 individual questions scored on a numerical rating scale (NRS) of 0 to 10, where higher scores indicated higher pain. Total score range for WOMAC pain subscale score was 0 to 10, where higher scores indicated higher pain. | Baseline, Week 2, 4, 8, 16, 24, 32, 40, 48, 56 | 
| Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Physical Function Subscale Score at Week 2, 4, 8, 16, 24, 32, 40, 48 and 56 | WOMAC physical function subscale is a 17-item questionnaire used to assess the degree of difficulty experienced due to osteoarthritis in index joint and index hip during past 48 hours. It was calculated as mean of the scores from 17 individual questions scored on NRS of 0 to 10, with higher scores indicated worse function. Total score range for WOMAC physical function subscale score was 0 to 10, where higher scores indicated worse function. | Baseline, Week 2, 4, 8, 16, 24, 32, 40, 48, 56 | 
| Change From Baseline in Patient Global Assessment (PGA) of Osteoarthritis at Week 2, 4, 8,16, 24, 32, 40, 48 and 56 | Participants answered: Considering all the ways your osteoarthritis in your knee (or hip) affects you, how are you doing today? Participants responded by using a 5-point scale where 1 = very good (no symptom and limitation of normal activities) and 5 = very poor (very severe symptoms and inability to carry out normal activities). | Baseline, Week 2, 4, 8, 16, 24, 32, 40, 48, 56 | 
| Percentage of Participants With Outcome Measures in Rheumatology - Osteoarthritis Research Society International (OMERACT-OARSI) Response | OMERACT-OARSI response: greater than or equal to (>=) 50 percent (%) improvement from baseline and absolute change from baseline of >=2 units 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 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, 16, 24, 32, 40, 48, 56 | 
| Percentage of Participants With At Least 30 Percent (%), 50%, 70% and 90% Reduction in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Subscale Score | Percentage of participants with at least 30%, 50%, 70% and 90% reduction from baseline in WOMAC pain subscale score are reported. WOMAC pain subscale is a 5-item questionnaire used to assess the amount of pain experienced due to osteoarthritis in index knee or index hip during past 48 hours. It was calculated as mean of the scores from the 5 individual questions scored on a 0 to 10 NRS, where higher scores indicated higher pain. Total score range for WOMAC pain subscale score is 0 to 10, where higher scores indicated higher pain. | Week 2, 4, 8, 16, 24, 32, 40, 48, 56 | 
| Percentage of Participants With Cumulative Reduction From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Subscale Score | WOMAC pain subscale is a 5-item questionnaire used to assess the amount of pain experienced due to osteoarthritis in index knee or index hip during past 48 hours. It is calculated as mean of the scores from 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. Participants with specified reduction (as percent) from baseline at Week 16 are reported. | Week 2, 4, 8, 16, 24, 32, 40, 48, 56 | 
| Percentage of Participants With Improvement of At Least 2 Points in Patient Global Assessment (PGA) of Osteoarthritis | Participants answered: Considering all the ways your osteoarthritis in your knee (or hip) affects you, how are you doing today? Participants responded by using a 5-point scale where 1 = very good and 5 = very poor. Improvement signifies a decrease of at least 2 points on the 5-point scale relative to baseline value. | Week 2, 4, 8, 16, 24, 32, 40, 48, 56 | 
| Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Stiffness Subscale Score at Week 2, 4, 8, 16, 24, 32, 40, 48 and 56 | WOMAC stiffness subscale is a 2-item questionnaire used to assess the amount of stiffness experienced due to osteoarthritis in index knee or index hip during past 48 hours. It is calculated as mean of the scores from 2 individual questions scored on NRS of 0 to 10, with higher scores indicate higher stiffness. Total score range for WOMAC stiffness subscale score is 0 to 10, where higher scores indicate higher stiffness. Stiffness is defined as a sensation of decreased ease in movement of knee or hip. | Baseline, Week 2, 4, 8, 16, 24, 32, 40, 48, 56 | 
| Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Average Score at Week 2, 4, 8, 16, 24, 32, 40, 48 and 56 | 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 or hip. Each item was scored on a 0 to 10 NRS scale, where higher scores indicated higher pain/stiffness or worse function. WOMAC average score was the mean of WOMAC pain, physical function and stiffness subscale scores and ranged from 0 to 10, where higher score indicated worse response. | Baseline, Week 2, 4, 8, 16, 24, 32, 40, 48, 56 | 
| Change From Baseline in WOMAC Pain Subscale Item: Pain When Walking on a Flat Surface at Week 2, 4, 8, 16, 24, 32, 40, 48 and 56 | 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. | Baseline, Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56 | 
| Change From Baseline in WOMAC Pain Subscale Item: Pain When Going Up or Down Stairs at Week 2, 4, 8, 16, 24, 32, 40, 48 and 56 | Participants answered: 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, Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56 | 
| 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 50 | 
| Number of Participants Who Discontinued Due to Lack of Efficacy |  | Baseline up to Week 50 | 
| Percentage of Participants Who Used Concomitant Analgesic Medication | United States Food and Drug Administration (FDA) approved analgesics were permitted as concomitant medications to relieve the pain of osteoarthritis. These medications included opioids, topical analgesics, non-steroidal anti-inflammatory drugs (NSAIDs), capsaicin products and viscosupplementation (example, hyaluronan) and were prescribed at the discretion of the Investigator. | Week 2, 4, 8, 16, 24, 32, 40, 48, 56, 64 | 
| Days Per Week of Concomitant Analgesic Medication Usage | United States FDA-approved analgesics were permitted as concomitant medications to relieve the pain of OA. These medications included opioids, topical analgesics, NSAIDs, capsaicin products and viscosupplementation (example, hyaluronan) and were prescribed at the discretion of the Investigator. | Week 2, 4, 8, 16, 24, 32, 40, 48, 56, 64 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Double-blind safety