A Study of Tanezumab in Adults With Chronic Low Back Pain

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy and safety of multiple doses of tanezumab administered every 8 weeks in treating chronic low back pain. Tanezumab is a monoclonal antibody directed against human nerve growth factor.

Official Title
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A RANDOMIZED, DOUBLE-BLIND, MULTI-DOSE, ACTIVE- AND PLACEBO-CONTROLLED, MULTI-CENTER, PARALLEL GROUP STUDY OF THE ANALGESIC EFFECTS OF TANEZUMAB IN ADULT PATIENTS WITH CHRONIC LOW BACK PAIN

Conditions
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Low Back Pain

Intervention / Treatment
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* Biological: Tanezumab 20 mg IV
* Drug: Placebo for naproxen
* Biological: Tanezumab 10 mg IV
* Drug: Placebo for naproxen
* Biological: Tanezumab 5 mg IV
* Drug: Placebo for naproxen
* Biological: Placebo for tanezumab
* Drug: Naproxen
* Biological: Placebo for tanezumab
* Drug: Placebo for naproxen


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Present with duration of low back pain of ≥3 months requiring regular use of analgesic medication (>4 days per week for the past month). Analgesic medication may consist of NSAIDs, selective COX-2 inhibitors, immediate release opioids, or combinations, with certain protocol-defined limitations. Primary location of low back pain must be between the 12th thoracic vertebra and the lower gluteal folds, with or without radiation into the posterior thigh Must meet criteria for pain severity and global assessment of low back pain at Screening and Baseline visits Female patients of child-bearing potential (and male patients with female partners who are of child-bearing potential) must use 2 methods of contraception throughout the study Patients must be willing to discontinue all pain medications for chronic low back pain except rescue medication and not use prohibited pain medications throughout the duration of the study Exclusion Criteria: History of lumbosacral radiculopathy within the past 2 years. Back pain due to visceral disorder (eg, endometriosis). Back pain due to major trauma or osteoporotic compression fracture in the past 6 months. History of rheumatoid arthritis, seronegative spondyloarthropathy, Paget's disease of spine, pelvis or femur; fibromyalgia; tumors or infections of the spinal cord. Surgical intervention during the past 6 months for the treatment of low back pain or plans for surgical intervention during the course of the study. Current or pending worker's compensation, litigation, disability, or any other monetary settlement regarding his/her CLBP or any other pain condition, or any closed claim within the past 5 years. Use of any analgesic or muscle relaxant within 48 hours prior to the five days before Baseline Patients receiving only acetaminophen, gabapentin or pregabalin to manage their chronic low back pain. Patients taking >325 mg/day of aspirin. Use of any antidepressants with the exception of stable treatment with selective serotonin reuptake inhibitors (SSRIs). Use of any sedatives/hypnotics, anxiolytics, tranquilizers, or benzodiazepines unless daily dose has been stable and will remain unchanged throughout the study period. Systemic corticosteroid therapy within 30 days (inhaled and topical corticosteroids are permitted). Local or epidural injection of corticosteroids, as well as injections of corticosteroids in the back within 3 months. Botulinum toxin (Botox®) injection for chronic low back pain within 4 months. Requirement for new, concomitant physiotherapy including, but not limited to, transdermal electroneural stimulation (TENS), massage or spinal manipulation for the duration of the study period. Active or suspected esophageal, gastric, pyloric channel, or duodenal ulceration within 3 months, or any history of gastrointestinal bleeding. Current use of lithium or anticoagulant agents. Known hypersensitivity or intolerance to NSAIDs; history of asthma, urticaria, or allergic type reactions after taking aspirin or NSAIDs. Inflammatory bowel disease, a chronic or acute renal or hepatic disorder, a significant coagulation defect, or other condition that might preclude the use of an NSAID. History of intolerance to acetaminophen or paracetamol or any of its excipients. History of known alcohol, analgesic or narcotic abuse within 2 years. Presence of drugs of abuse (including prescription medications without a valid prescription), other illegal drugs or marijuana in the urine toxicology screen obtained at Screening. History of allergic or anaphylactic reaction to a therapeutic or diagnostic monoclonal antibody or IgG fusion protein. Use of biologics other than study medication, including any live vaccines, within 3 months, or use during the study (intranasal Flumist® vaccine is an exception). Signs and symptoms of clinically significant cardiac disease. Diagnosis of a transient ischemic attack within the 6 months, or residual deficits from stroke that would preclude completion of required study activities. History of cancer within 5 years. Use of any investigational medication within 30 days (3 months for investigational biologics). Expected to undergo a therapeutic procedure or to use any analgesic other than those specified in the protocol throughout the study period. Previous exposure to exogenous NGF or to an anti NGF antibody. Screening laboratory results and blood pressure within specified limits. Positive Hepatitis B, Hepatitis C, or human immunodeficiency virus (HIV) tests at screening. History, diagnosis, or signs and symptoms of clinically significant neurological disease. History, diagnosis, signs or symptoms of any clinically significant psychiatric disorder. Hospital admission for depression or suicide attempt within 5 years or active, severe major depression at Screening. Likelihood of being non compliant with study procedures.

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tanezumab 20 mg IV<br> | Biological: Tanezumab 20 mg IV<br>* 2 IV administrations of tanezumab 20 mg at an 8 week interval<br>Drug: Placebo for naproxen<br>* Oral placebo for naproxen twice a day for 16 weeks<br>|
| Experimental: Tanezumab 10 mg IV<br> | Biological: Tanezumab 10 mg IV<br>* 2 IV administrations of tanezumab 10 mg at an 8 week interval<br>Drug: Placebo for naproxen<br>* Oral placebo for naproxen twice a day for 16 weeks<br>|
| Experimental: Tanezumab 5 mg IV<br> | Biological: Tanezumab 5 mg IV<br>* 2 IV administrations of tanezumab 5 mg at an 8 week interval<br>Drug: Placebo for naproxen<br>* Oral placebo for naproxen twice a day for 16 weeks<br>|
| Active Comparator: Naproxen<br> | Biological: Placebo for tanezumab<br>* 2 IV administrations of placebo for tanezumab at an 8 week interval<br>Drug: Naproxen<br>* Oral naproxen 500 mg twice a day for 16 weeks<br>|
| Placebo Comparator: Placebo<br> | Biological: Placebo for tanezumab<br>* 2 IV administrations of placebo for tanezumab at an 8 week interval<br>Drug: Placebo for naproxen<br>* Oral placebo for naproxen twice a day for 16 weeks<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 Low Back Pain Intensity (LBPI) Score at Week 16: Baseline Observation Carried Forward (BOCF) | Daily average back pain was assessed on an 11-point numeric rating scale (NRS) captured through an interactive voice response system (IVRS). The participant described the chronic low back pain (CLBP) during the past 24 hours on a scale ranging from 0 (no pain) to 10 (worst possible pain). Baseline value was calculated as mean of the scores over 5 days prior to randomization (initial pain assessment period). Post-baseline value was calculated as mean of the scores over the 7-day period prior to and including the post-baseline visit. Overall possible score range for daily average LBPI at specified visit was 0= no pain to 10= worst possible pain, where higher scores indicated higher pain intensity. | Baseline, Week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Roland-Morris Disability Questionnaire (RMDQ) Total Score at Week 2, 4, 8, 12 and 16: Baseline Observation Carried Forward (BOCF) | RMDQ: back-specific, participant administered questionnaire that assesses how well participants with low back pain were able to function with regard to daily activities. The questionnaire consists of 24 statements and the participant is instructed to put a mark next to each appropriate statement if it describes his/her functional ability on the day of assessment. The number of statements marked are added up by the clinician. Total RMDQ score is calculated as the sum of number of statements marked. Total possible RMDQ score: 0 (best functioning) to 24 (worst functioning), with higher scores indicated greater disability. | Baseline, Week 2, 4, 8, 12, 16 | 
| Change From Baseline in Patient's Global Assessment (PGA) of Low Back Pain Score at Week 2, 4, 8, 12 and 16: Baseline Observation Carried Forward (BOCF) | Participants answered: Considering all ways your low back pain affects you, how are you doing today? Participants rated their condition using scale assessing symptoms and limitations to carry out normal daily activities. Score range:1 to 5. 1: Very Good (No symptoms and limitations); 2: Good (Mild symptoms and no limitations); 3: Fair (Moderate symptoms and some limitations); 4: Poor (Severe symptoms and inability to carry out most activities); 5: Very Poor (Very severe, intolerable symptoms and inability to carry all activities). | Baseline, Week 2, 4, 8, 12, 16 | 
| Change From Baseline in Daily Average Low Back Pain Intensity (LBPI) Score at Week 2, 4, 8 and 12: Baseline Observation Carried Forward (BOCF) | Daily average back pain was assessed on an 11-point numeric rating scale (NRS) captured through an interactive voice response system (IVRS). The participant described the chronic low back pain (CLBP) during the past 24 hours on a scale ranging from 0 (no pain) to 10 (worst possible pain). Baseline value was calculated as mean of the scores over 5 days prior to randomization (initial pain assessment period). Post-baseline value was calculated as mean of the scores over the 7-day period prior to and including the post-baseline visit. | Baseline, Week 2, 4, 8, 12 | 
| Number of Participants With Cumulative Reduction From Baseline at Week 16 in Daily Average Low Back Pain Intensity (LBPI) Score : Baseline Observation Carried Forward (BOCF) | Daily average back pain was assessed on an 11-point numeric rating scale (NRS) captured through an interactive voice response system (IVRS). The participant described the chronic low back pain (CLBP) during the past 24 hours on a scale ranging from 0 (no pain) to 10 (worst possible pain). Baseline value was calculated as mean of the scores over 5 days prior to randomization (initial pain assessment period). Post-baseline value was calculated as mean of the scores over the 7-day period prior to and including the post-baseline visit. Participants with specified reduction (as percent) from baseline at Week 16 are reported. | Baseline, Week 16 | 
| Percentage of Participants With at Least 30 Percent (%) and 50% Reduction From Baseline in Daily Average Low Back Pain Intensity (LBPI) Score at Week 2, 4, 8, 12 and 16: Baseline Observation Carried Forward (BOCF) | Daily average back pain was assessed on an 11-point numeric rating scale (NRS) captured through an interactive voice response system (IVRS). The participant described the chronic low back pain (CLBP) during the past 24 hours on a scale ranging from 0 (no pain) to 10 (worst possible pain). Baseline value was calculated as mean of the scores over 5 days prior to randomization (initial pain assessment period). Post-baseline value was calculated as mean of the scores over the 7-day period prior to and including the post-baseline visit. | Baseline, Week 2, 4, 8, 12, 16 | 
| Change From Baseline in Brief Pain Inventory-short Form (BPI-sf) Score for Worst and Average Pain at Week 2, 4, 8, 12, 16: Baseline Observation Carried Forward (BOCF) | BPI-sf: self-report questionnaire rated on an 11-point scale, consists of 5 questions to assess severity and impact of pain on daily functions. Question 1-4 (Q1-Q4) measure severity of pain (worst, least, average, right now), each question ranging between 0 (no pain) to 10 (pain as bad as you can imagine). Question 5 (Q5) consists of 7 items which measure level of interference of pain on daily functions (general activity, mood, walking ability, normal work, relations with other people, sleep, and enjoyment of life), each item ranging from 0 (does not interfere) to 10 (completely interferes). Results are reported for worst and average pain, each with a score range: 0 (no pain) and 10 (pain as bad as you can imagine), higher scores indicated worse pain. | Baseline, Week 2, 4, 8, 12, 16 | 
| Change From Baseline in Brief Pain Inventory-short Form (BPI-sf) Score for Pain Interference Index, Pain Interference Score for General Activity, Walking Ability, Sleep and Normal Work at Week 2, 4, 8, 12 and 16: BOCF | BPI-sf: self-report questionnaire rated on an 11-point scale, consists of 5 questions to assess severity and impact of pain on daily functions. Question 1-4 (Q1-Q4) measure severity of pain (worst, least, average, right now), each question ranging between 0 (no pain) to 10 (pain as bad as you can imagine). Question 5 (Q5) consists of 7 items which measure pain interference (PI) on daily functions (general activity, mood, walking ability, normal work, relations with other people, sleep, and enjoyment of life), each item ranging from 0 (does not interfere) to 10 (completely interferes); higher score = greater impairment. The 7 items in Q5 averaged to obtain pain interference index (function composite score), range: 0 (no interference) to 10 (complete interference); higher score = greater impairment. | Baseline, Week 2, 4, 8, 12, 16 | 
| 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 16 | 
| Number of Participants With Chronic Low Back Pain (CLBP) Responder Index: Baseline Observation Carried Forward (BOCF) | Chronic Low Back Pain (CLBP) Responder Index: A response was defined as reduction of at least 30% in mean daily average LBPI from baseline to a specified week, decrease of at least 30% in PGA of low back pain from baseline to the specified week and no worsening (increase) in RMDQ total score from baseline to the specified week. Participants who were responders were reported. | Week 2, 4, 8, 12, 16 | 
| Change From Baseline in Work Productivity and Activity Impairment: Specific Health Problem (WPAI:SHP) at Week 8 and 16 | WPAI:SHP is a self-administered questionnaire that measures the effect of general health and symptom severity on work productivity and regular activities. Four scores are derived as percent: activity impairment (AI), impairment while working (IW), overall work impairment (OWI), work time missed (WTM). Each of 4 scores expressed as impairment percentages with a total possible score range of 0 to 100, high percentage= more impairment, less productivity. | Baseline, Week 8, 16 | 
| Percentage of Participants Who Used Rescue Medications | In case of inadequate pain relief for CLBP or for non-CLBP related pain, acetaminophen up to 3000 mg per day up to 3 days per week could be taken as rescue medication. | Week 2, 4, 8, 12, 16 | 
| Duration of Rescue Medication Use | In case of inadequate pain relief for CLBP or for non-CLBP related pain, acetaminophen up to 3000 mg per day up to 3 days per week could be taken as rescue medication. | Week 2, 4, 8, 12, 16 | 
| Amount of Rescue Medication Taken | In case of inadequate pain relief for CLBP or for non-CLBP related pain, acetaminophen up to 3000 mg per day up to 3 days per week could be taken as rescue medication. | Week 2, 4, 8, 12, 16 | 
| Change From Baseline Neuropathy Impairment Score (NIS) at Week 8, 16 and 24 | NIS is a standardized instrument used to evaluate signs of peripheral neuropathy in participants. NIS is the sum of scores of 37 items, from both the left and right side of following 4 domains: cranial nerves (5 items), muscle weakness (19 items), reflexes (5 items) and sensation (8 items). Each of 24 items related to cranial nerves and muscle weakness, scored from 0 (normal) to 4 (paralysis); higher scores indicated higher abnormality/impairment. Each of 13 items related to reflexes and sensation, scored as 0 (normal), 1 (decreased) and 2 (absent); higher scores indicated lesser reflexes and sensation. For NIS possible overall score (combined of both left and right sides of each domain), ranged from 0 (no impairment) to 244 (maximum impairment), higher scores indicated increased/more neuropathic deficits. | Baseline, Week 8, 16, 24 | 
| Number of Participants Who Developed Anti-Tanezumab Antibodies | Human serum anti-drug antibody (ADA) samples were analyzed for the presence or absence of anti-tanezumab antibodies by using the semi-quantitative enzyme-linked immunosorbent assay (ELISA). Same participant may have positive ADA result at more than 1 time point. | Baseline (Day 1), Week 8, 16, 24 | 
| Plasma Concentration of Tanezumab | Analysis was done by setting concentration values below the lower limit of quantification (LLOQ) to zero. | Baseline (pre-dose and 1 hour [hr] post-dose); Any time point at Week 4 Visit; Week 8 (pre-dose and 1 hr post-dose); Any time point at Week 16 Visit, at Week 24 Visit | 
| Total Nerve Growth Factor (NGF) Concentration |  | Baseline (pre-dose and 1 hour [hr] post-dose); Any time point at Week 4 Visit; Week 8 (pre-dose and 1 hr post-dose); Any time point at Week 16 Visit, at Week 24 Visit | 
| 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 Week 24 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 Week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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randomized controlled trial, monoclonal antibody, nerve growth factor, naproxen