A Study Of Tanezumab as Add-On Therapy to Opioid Medication In Patients With Pain Due To Cancer That Has Spread To Bone

Study Overview
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Brief Summary
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The purpose of this study is to investigate the safety and efficacy of tanezumab in combination with opioids in treating pain due to cancer that has spread to bone.

Official Title
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PHASE II RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED MULTICENTER EFFICACY AND SAFETY STUDY OF TANEZUMAB AS ADD-ON THERAPY TO OPIOID MEDICATION IN PATIENTS WITH PAIN DUE TO BONE METASTASES

Conditions
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Neoplasm Metastasis, Palliative Care

Intervention / Treatment
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* Drug: Tanezumab 10 mg IV
* Drug: IV Placebo for tanezumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Prostate cancer, breast cancer, renal cell carcinoma or multiple myeloma that has spread to bone, causing moderate to severe bone pain. Requires daily opioid medication Exclusion Criteria: Patients who do not have bone pain caused by cancer are not eligible for the study. Patients who started chemotherapy less than 4 weeks ago, or who completed radiotherapy less than 4 weeks ago, are not eligible. Known history or evidence of osteoarthritis. History of significant trauma to a major joint within 1 year prior to Screening. Known history of rheumatoid arthritis.

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 IV + opioids<br> | Drug: Tanezumab 10 mg IV<br>* Single IV infusion of 10 mg tanezumab on Day 1. Maintained on baseline opioid regimen.<br>|
| Placebo Comparator: Placebo + opioids<br>Single IV infusion of placebo for tanezumab on Day 1. Maintained on baseline opioid regimen. | Drug: IV Placebo for tanezumab<br>* Single IV infusion of placebo for tanezumab on Day 1. Maintained on baseline opioid regimen.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Daily Average Pain Intensity Numeric Rating Scale (NRS) Score at Week 6 | Daily average pain was assessed on an 11-point NRS over the past 24 hours (before each specified visit), where a score of 0 indicated no pain and a score of 10 indicated pain as bad as you can imagine. Lower the score, lesser the pain intensity. | Baseline, Week 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Daily Average Pain Intensity Numeric Rating Scale (NRS) Score at Weeks 1, 2, 4, 8, 12 and 16 | Daily average pain was assessed on an 11-point NRS over the past 24 hours (before each specified visit), where a score of 0 indicated no pain and a score of 10 indicated pain as bad as you can imagine. Lower the score, lesser pain intensity. | Baseline, Weeks 1, 2, 4, 8, 12, 16 | 
| Change From Baseline in Daily Worst Pain Intensity Numeric Rating Scale (NRS) Score at Week 1, 2, 4, 6, 8, 12 and 16: Baseline Observation Carried Forward (BOCF) | The worst pain was assessed an 11-point NRS over the past 24 hours where a score of 0 indicated no pain and a score of 10 indicated pain as bad as you can imagine. Lower the score, lesser pain intensity. | Baseline, Week 1, 2, 4, 6, 8, 12, 16 | 
| Change From Baseline in Daily Worst Pain Intensity Numeric Rating Scale (NRS) Score at Week 1, 2, 4, 6, 8, 12 and 16: Last Observation Carried Forward (LOCF) | The worst pain was assessed on 11-point NRS over the past 24 hours where a score of 0 indicated no pain and a score of 10 indicated pain as bad as you can imagine. The lower the value the lesser pain intensity. | Baseline, Week 1, 2, 4, 6, 8, 12, 16 | 
| Change From Baseline in Brief Pain Inventory-Short Form (BPI-sf) Average Pain Scores at Week 1, 2, 4, 6, 8, 12 and 16: BOCF | BPI-sf: self-administered questionnaire developed to assess severity, impact of pain on daily functions, consisted of 5 questions. Questions 1-4 measured magnitude of pain at its worst, least, average, right now. BPI-sf average pain measured the severity of pain based on the average pain experienced over the past 24-hours and ranged from 0 (No Pain) to10 (Pain as bad as you can imagine), lower scores indicates lesser pain intensity. Question 5: 7 item subsets that measured level of interference of pain on daily functions on 11-point NRS at 0 (Does not interfere) to 10 (Completely interferes). | Baseline, Week 1, 2, 4, 6, 8, 12, 16 | 
| Change From Baseline in Brief Pain Inventory-Short Form (BPI-sf) Average Pain Scores at Week 1, 2, 4, 6, 8, 12 and 16: LOCF | BPI-sf: self-administered questionnaire developed to assess severity, impact of pain on daily functions, consisted of 5 questions. Questions 1-4 measured magnitude of pain at its worst, least, average, right now. BPI-sf average pain measured the severity of pain based on the average pain experienced over the past 24-hours and ranged from 0 (No Pain) to 10 (Pain as bad as you can imagine), lower score indicates lesser pain intensity. Question 5: 7 item subsets that measured level of interference of pain on daily functions on 11-point numeric rating scale at 0 (Does not interfere) to 10 (Completely interferes). | Baseline, Week 1, 2, 4, 6, 8, 12, 16 | 
| Change From Baseline in Brief Pain Inventory-Short Form (BPI-sf) Worst Pain Scores at Week 1, 2, 4, 6, 8, 12 and 16: BOCF | BPI-sf: self-administered questionnaire developed to assess severity, impact of pain on daily functions, consisted of 5 questions. Questions 1-4 measured magnitude of pain at its worst, least, average, right now. BPI-sf worst pain measured the severity of pain based on the worst pain experienced over the past 24-hours and ranged from 0 (No Pain) to 10 (Pain as bad as you can imagine), lower scores =lesser pain intensity. Question 5: 7 item subsets that measured level of interference of pain on daily functions on 11-point numeric rating scale at 0 (Does not interfere) to 10 (Completely interferes). | Baseline, Week 1, 2, 4, 6, 8, 12, 16 | 
| Change From Baseline in Brief Pain Inventory-Short Form (BPI-sf) Worst Pain Scores Weeks 1, 2, 4, 6, 8, 12 and 16: LOCF | BPI-sf: self-administered questionnaire developed to assess severity, impact of pain on daily functions, consisted of 5 questions. Questions 1-4 measured magnitude of pain at its worst, least, average, right now. BPI-sf worst pain measured the severity of pain based on the worst pain experienced over the past 24-hours and ranged from 0 (No Pain) to 10 (Pain as bad as you can imagine), lower scores=lesser pain intensity. Question 5: 7 item subsets that measured level of interference of pain on daily functions on11-point numeric rating scale at 0 (Does not interfere) to 10 (Completely interferes). | Baseline, Week 1, 2, 4, 6, 8, 12, 16 | 
| Percentage of Participants Achieving Greater Than or Equal to (>=) 30 Percent (%), >=50%, >=70% and >=90% Reduction in Daily Average Pain Intensity Numeric Rating Scale (NRS) Score: BOCF | Percentage of participant with response as defined by a >=30%, >=50%, >=70%, and >=90%, reduction in the daily average pain intensity NRS score from baseline, that was maintained for a minimum of 3 consecutive days following this original study day (reduction in pain was maintained for a minimum duration of 4 consecutive days). Daily average pain was assessed on 11-point NRS over the past 24 hours where a score of 0 indicated no pain and a score of 10 indicated pain as bad as you can imagine. Lower scores indicate less pain intensity. | Week 1, 2, 4, 6, 8, 12, 16 | 
| Percentage of Participants Achieving Greater Than or Equal to (>=) 30 Percent (%), >=50%, >=70% and >=90% Reduction in Daily Average Pain Intensity Numeric Rating Scale (NRS) Score: LOCF | Percentage of participant with response as defined by a >=30%, >=50%, >=70%, and >=90%, reduction in the daily average pain intensity NRS score from baseline, that was maintained for a minimum of 3 consecutive days following this original study day (reduction in pain was maintained for a minimum duration of 4 consecutive days). Daily average pain was assessed on 11-point NRS over the past 24 hours where a score of 0 indicated no pain and a score of 10 indicated pain as bad as you can imagine. Lower scores indicate less pain intensity | Week 1, 2, 4, 6, 8, 12, 16 | 
| Average Daily Opioid Consumption | The average daily opioid consumption was calculated as the daily sum of total opioid dosage in milligrams. Opioid consumption on each day was converted to the morphine equivalent dosage (MED). Results were summarized for opioid dose adjust period, baseline assessment period and post-baseline period. | Opioid Dose Adjust Period (Day-30 to Day-4), Baseline Assessment period (Day-3 to Day-1), Post Baseline Period (Day 1 to Week 16) | 
| Number of Doses of Rescue Medication Required Per Week | Participants received immediate release (IR) opioid as rescue medication as needed for breakthrough pain from Day 1-113 at the dose determined during the pre-treatment phase, provided the average total daily dose of opioids between study visits does not exceed the baseline total daily opioid dose by more than 10%. | Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 | 
| Change From Baseline in Opioid-Related Symptom Distress Scale (OR-SDS) at Weeks 2, 4, 6, 12, and 16 | OR-SDS: participant-rated levels of frequency (F), severity (S), degree of bother (DoB) for 10 symptoms: fatigue, drowsiness, concentration, confusion, nausea, dizziness, constipation, itching, difficulty with urination, retching/vomiting. For each symptom levels of F, S and DoB scored as: frequency (0 to 4:'did not have' to 'almost constantly'), severity (0 to 4:'did not have' to 'very severe'), degree of bother (0 to 5:'did not have' to 'very much'). Mean of F, S and DoB was calculated for each symptom to derive composite scores/multi-domain average (MDA) scores which ranges from 0 to 4.33. Higher MDA=worse symptom. Composite scores for frequency (FCS), severity (SCS), degree of bother, and MDA were calculated as mean of these scores across 10 symptoms and had same ranges as individual scores frequency (0 to 4:'did not have' to 'almost constantly'), severity (0 to 4:'did not have' to 'very severe'), degree of bother (0 to 5:'did not have' to 'very much'); higher scores=more distress | Baseline, Week 2, 4, 6, 12, 16 | 
| Change From Baseline in Brief Pain Inventory (BPI) Pain Interference With Function Composite Score and Individual Pain Interference Item Scores of General Activity, Walking Ability and Normal Work at Weeks 1, 2, 4, 6, 8, 12, and 16: BOCF | Participant-rated 11 point Likert rating scale ranging from 0 (does not interfere) to 10 (completely interferes) assessed interference of pain in functional activities (general activity, walking ability, and normal work) in past 24 hours. Measures were scored by individual item as well as function composite score (calculated by taking mean of individual interference scores), both (individual scores and composite scores) ranging from 0 to 10 with lower scores being indicative of less pain interference. | Baseline, Week 1, 2, 4, 6, 8, 12, 16 | 
| Change From Baseline in Brief Pain Inventory (BPI) Pain Interference With Function Composite Score and Individual Pain Interference Item Scores at Weeks 1, 2, 4, 6, 8, 12, and 16: LOCF | Participant-rated 11 point Likert rating scale ranging from 0 (does not interfere) to 10 (completely interferes) assessed interference of pain in functional activities (general activity, walking ability, and normal work) in past 24 hours. Measures were scored by individual item as well as function composite score (calculated by taking mean of individual interference scores), both (individual items and composite scores) ranging from 0 to 10 with lower scores being indicative of less pain interference. | Baseline, Week 1, 2, 4, 6, 8, 12, 16 | 
| Patient's Global Evaluation of Study Medication | The Patient's Global Evaluation of Study Medication (PGESM) was a single item that assessed the participant's perception of his/her response to the study medication. It was a self-administered question that utilizes a 4-point Likert scale from 1=Poor to 4=Excellent, where higher score represented better outcome. | Week 1, 2, 4, 6, 8, 12, 16 | 
| Change From Baseline in Patient's Global Assessment of Disease (Cancer Pain) Activity at Weeks 1, 2, 4, 6, 8, 12, and 16: BOCF | The Patient's Global Assessment of Cancer Pain was a global evaluation that utilized a 5-point Likert scale with a score of 1 being the best (Very Good) and a score of 5 being the worst (Very Poor), where higher score represented more pain. | Baseline, Week 1, 2, 4, 6, 8, 12, 16 | 
| Change From Baseline in Patient's Global Assessment of Disease (Cancer Pain) Activity at Weeks 1, 2, 4, 6, 8, 12, and 16: LOCF | The Patient's Global Assessment of Cancer Pain was a global evaluation that utilized a 5-point Likert scale with a score of 1 being the best (Very Good) and a score of 5 being the worst (Very Poor), where higher score represented more pain. | Baseline, Week 1, 2, 4, 6, 8, 12, 16 | 
| Percentage of Participants Achieving Improvement of >=2 Points in Patient's Global Assessment Of Disease (Cancer Pain) Activity: BOCF | The Patient's Global Assessment of Cancer Pain was a global evaluation that utilized a 5-point Likert scale with a score of 1 being the best (Very Good) and a score of 5 being the worst (Very Poor), where higher score represented more pain. | Week 1, 2, 4, 6, 8, 12, 16 | 
| Percentage of Participants Achieving Improvement Of >=2 Points in Patient's Global Assessment Of Disease (Cancer Pain) Activity: LOCF | The Patient's Global Assessment of Cancer Pain was a global evaluation that utilized a 5-point Likert scale with a score of 1 being the best (Very Good) and a score of 5 being the worst (Very Poor), where higher score represented more pain. | Week 1, 2, 4, 6, 8, 12, 16 | 
| 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. An SAE was an AE resulting in any of 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 113 days that were absent before treatment or that worsened relative to pretreatment state. | Baseline up to 113 days | 
| Number of Participants With Physical Examination Abnormalities | Physical examinations included general appearance (skin, neck, eyes, ears, nose, throat), cardiovascular system (including rhythm and presence of other cardiac abnormalities, such as gallops, murmurs, and cardiomegaly), respiratory system, gastrointestinal system, genitourinary system, musculoskeletal system, and any additional assessments necessary to establish baseline status or evaluate symptoms or adverse experiences. Abnormalities in physical examination was based on investigator's discretion. | Baseline up to Week 16 or Early Termination (up to 113 days) | 
| Number of Participants With Abnormal Neurological Examination | Neurological examinations assessed strength of groups of muscles of the head and neck, upper limbs and lower limbs, deep tendon reflexes and sensation (tactile, vibration, joint position sense and pin prick) of index finger and great toes in order to complete the neuropathy impairment score (NIS). 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) for muscle strength, higher score indicated higher abnormality/impairment, and 13 items scored from 0 (normal), 1 (decreased) and 2 (absent) for sensation, higher score indicated higher impairment. NIS possible overall score ranged from 0 (no impairment) to 244 (maximum impairment), higher scores indicated increased impairment. | Week 2, 4, 6, 12, 16, Early Termination (up to 113 days) | 
| Vital Sign Examination: Body Temperature |  | Baseline (Day 1 0H), Week 2, 4, 6, 12, 16, Early Termination (up to 113 days) | 
| Vital Sign Examination: Blood Pressure (BP) | Systolic BP: the measurement of the pressure when the heart is contracted (systole). The systolic pressure indicates the maximum amount of work/force the heart has to perform with each stroke in order to move blood through the arteries. Diastolic BP: the pressure in the large arteries during the relaxation of the left ventricle. The diastolic pressure indicates the amount of pressure the heart must overcome in order to generate the next beat. | Baseline (Day 1 0H), Week 2, 4, 6, 12, 16, Early Termination (up to 113 days) | 
| Vital Sign Examination: Respiratory Rate | Respiration rate measured as number of breaths taken per minute. | Baseline (Day 1, 0H), Week 2, 4, 6, 12, 16, Early Termination (up to 113 days) | 
| Vital Sign Examination: Heart Rate | Heart rate is the number of heart beats per minute. | Baseline (Day 1, 0H), Week 2, 4, 6, 12, 16, and Early Termination (up to 113 days) | 
| Body Weight of Participants |  | Baseline, Week 6, 16 and Early Termination (up to 113 days) | 
| Number of Participants With Abnormal Laboratory Examination | Criteria for laboratory tests abnormalities included: hemoglobin, hematocrit (<0.8*lower limit of normal [LLN]); red blood cell count (<0.8*LLN); platelets (<0.5*LLN or >1.75* upper limit of normal [ULN]); leucocytes (<0.6*LLN or >1.5*ULN); lymphocytes, total neutrophils (<0.8*LLN or >1.2*ULN); basophils, eosinophils, monocytes (>1.2*ULN); total bilirubin (>1.5* ULN); aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase (>3*ULN); creatinine, blood urea nitrogen (>1.3*ULN); glucose (<0.6*LLN or >1.5*ULN); uric acid (>1.2*ULN); sodium (<0.95*LLN or 1.05*ULN); potassium, calcium, chloride, bicarbonate (<0.9*LLN or 1.1*ULN); albumin, total protein (<0.8*LLN or 1.2*ULN); urine analysis. Total number of participants without regards to baseline abnormality was summarized. | Baseline up to Week 16, Early Termination (up to 113 days) | 
| Number of Participants With Anti-drug Antibodies | Human serum samples were analyzed using electrochemiluminescent (ECL) immunoassay for the presence of anti-tanezumab antibodies. Same participant may have positive (titer value >=4.32) anti-tanezumab antibodies result at more than 1 time point. | Baseline (Day 1), Week 4, 6, 12, 16 | 
| Electrocardiogram Examination | ECG intervals included: RR (the time interval between consecutive heart beats), PR (time between the onset of atrial depolarization and the onset of ventricular depolarization), QRS (represented ventricular depolarization) and QT (time corresponding to the beginning of depolarization to repolarization of the ventricles), QTcF (QT interval corrected using Fridericia's formula [FF]), QTcB interval (QT interval corrected using Bazett's formula [BF]). | Baseline (Pre-dose and 1 hour Post-dose), Week 4, 16, Early Termination (up to 113 days) | 
| Electrocardiogram Examination: Heart Rate | Standard 12-lead ECG performed after participant had rested quietly for at least 10 minutes in a supine position was measured. The time interval between consecutive heart beats [RR interval] (in beats per minute [bpm]) was used to calculate heart rate. | Baseline (Pre-dose and 1 hour Post-dose), Week 4, 16, Early Termination (up to 113 days) |