A PHASE 3 RANDOMIZED, DOUBLE-BLIND, ACTIVE-CONTROLLED, MULTICENTER STUDY OF THE LONG-TERM SAFETY AND EFFICACY OF SUBCUTANEOUS ADMINISTRATION OF TANEZUMAB IN JAPANESE ADULT SUBJECTS WITH CHRONIC LOW BACK PAIN
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- Pfizer
- 入组人数
- 277
- 试验地点
- 55
- 主要终点
- Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
研究概览
简要总结
This study will investigate the long-term safety and efficacy of a fixed dose of tanezumab 5 mg and 10 mg administered subcutaneously (SC) seven times at 8 week intervals. The primary objective of this study is to evaluate the long term safety of tanezumab 5 mg and 10 mg administrated SC every 8 weeks (7 administrations). In addition, the study will evaluate the long term analgesic efficacy of tanezumab 5 mg and 10 mg SC administered every 8 weeks (7 administrations).
详细描述
This is a randomized, double-blind, active-controlled, multicenter, parallel-group Phase 3 study of the safety and efficacy of tanezumab when administered by SC injection for up to 56 weeks in subjects with chronic low back pain. Subjects will be randomized to 1 of 3 treatment groups in a 1:1:1 ratio. Treatment groups will include: 1) Placebo SC matching tanezumab administered at an 8-week interval (total of 7 times) plus celecoxib 100 mg twice a day (BID) to be administered orally for 56 weeks; 2) Tanezumab 5 mg SC administered at an 8-week interval (total of 7 times) plus placebo matching celecoxib to be administered orally BID for 56 weeks; 3) Tanezumab 10 mg SC administered at an 8-week interval (total of 7 times) plus placebo matching celecoxib to be administered orally BID for 56 weeks. The study is designed with a total duration (post-randomization) of up to 80 weeks and will consist of three periods: Screening (up to 37 days; includes a Washout Period and an Initial Pain Assessment Period [IPAP]), a Double-blind Treatment Period (56 weeks) and a Follow-up Period (24 weeks). The Screening Period (beginning up to 37 days prior to Randomization) includes a Washout Period (lasting 2 to 32 days), if required, and an IPAP (the 5 days prior to Randomization/Baseline). Prior to entering the study, subjects must be experiencing some benefit (eg, analgesic effect) from their current stable dose regimen of oral NSAID (celecoxib, loxoprofen or meloxicam) treatment, be tolerating their NSAID regimen, be taking this medication regularly (defined as an average of at least 5 days per week) during the 30 day period prior to the Screening Visit.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Duration of chronic low back pain for ≥3 months, and treatment with agents for low back pain for ≥3 months.
- •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, classified as Category 1 or 2 according to the classification of the Quebec Task Force in Spinal Disorders.
- •Subjects must be experiencing some benefits from their current stable dose regimen of oral NSAID (celecoxib, loxoprofen or meloxicam) treatment as described in the protocol, be tolerating their NSAID regimen, be taking this medication regularly during the 30 day period prior to the Screening visit and must have had some improvement in low back pain, but still require additional pain relief at Screening.
- •Subjects must maintain a stabilized, protocol specified NSAID dose regimen for at least the final 2 or 3 weeks of the Screening period.
- •Low Back Pain Intensity (LBPI) score of ≥5 at Screening.
- •Subjects must be willing to discontinue all pain medications for chronic low back pain except rescue medication and investigational product and not use prohibited pain medications throughout the duration of the study.
- •Female subjects of childbearing potential and at risk for pregnancy must agree to comply with protocol specified contraceptive requirements.
排除标准
- •Subjects exceeding protocol defined BMI limits.
- •Diagnosis of osteoarthritis of the knee or hip as defined by the ACR combined clinical and radiographic criteria.
- •Subjects who have Kellgren Lawrence Grade > or =2 radiographic evidence of hip or Grade > or =3 radiographic evidence of knee osteoarthritis will be excluded.
- •Subjects who have Kellgren Lawrence Grade < or =2 radiographic evidence of knee osteoarthritis but who do not meet ACR criteria and do not have pain associated with their knee osteoarthritis will be allowed.
- •Subjects with symptoms and radiologic findings consistent with osteoarthritis in the shoulder.
- •History of lumbosacral radiculopathy within the past 2 years, history of spinal stenosis associated with neurological impairment, or history of neurogenic claudication.
- •Back pain due to recent major trauma within 6 months prior to Screening.
- •Surgical intervention during the past 6 months for the treatment of low back pain.
- •Planned surgical procedure during the duration of the study.
- •History or radiographic evidence of other diseases that could confound efficacy or safety assessments (eg, rheumatoid arthritis).
- •History or radiographic evidence of orthopedic conditions that may increase the risk of, or confound assessment of joint safety conditions during the study.
- •History of osteonecrosis or osteoporotic fracture.
- •History of significant trauma or surgery to a knee, hip, or shoulder within the previous year.
- •Signs or symptoms of carpal tunnel syndrome in the one year prior to Screening.
- •Considered unfit for surgery based upon American Society of Anesthesiologists physical classification system for surgery grading, or subjects who would not be willing to undergo joint replacement surgery if required.
- •History of intolerance or hypersensitivity to celecoxib/acetaminophen or any of its excipients or existence of a medical condition or use of concomitant medication for which the use of celecoxib/acetaminophen is contraindicated.
- •Use of prohibited medications or prohibited non-pharmacological treatments without the appropriate washout period (if applicable) prior to Screening or IPAP.
- •History of known alcohol, analgesic or narcotic abuse within 2 years of Screening.
- •Presence of drugs of abuse or illegal drugs 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.
- •Signs and symptoms of clinically significant cardiac disease.
- •Poorly controlled hypertension as defined in the protocol or taking an antihypertensive that has not been stable for at least 1 month prior to Screening.
- •Evidence of protocol defined orthostatic hypotension at Screening.
- •Disqualifying score on the Survey of Autonomic Symptoms questionnaire at Screening.
- •Diagnosis of a transient ischemic attack in the 6 months prior to Screening, diagnosis of stroke with residual deficits that would preclude completion of required study activities.
- •History of cancer within 5 years prior to Screening, except for cutaneous basal cell or squamous cell cancer resolved by excision.
- •Expected to undergo a therapeutic procedure or to use any analgesic other than those specified in the protocol throughout the pre-treatment and treatment periods that is likely to confound assessment of analgesic efficacy or safety.
- •Previous exposure to exogenous NGF or to an anti-NGF antibody.
- •Screening AST, ALT, serum creatinine or HbA1c values that exceed protocol defined limits.
- •Positive Hepatitis B, Hepatitis C, or HIV tests at screening indicative of current infection.
- •History, diagnosis, or signs and symptoms of clinically significant neurological disease or clinically significant psychiatric disorder.
- •Pregnant, breastfeeding or female subjects of childbearing potential who are unwilling or unable to follow protocol required contraceptive requirements.
- •Participation in other investigational drug studies within protocol defined time limits.
- •Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that in the judgment of the investigator, would make the subject inappropriate for entry into this study.
研究组 & 干预措施
Celecoxib
Subcutaneous injection of placebo for tanezumab every 8 weeks plus oral celecoxib 100 mg twice daily for 56 weeks
干预措施: Celecoxib (Drug)
Celecoxib
Subcutaneous injection of placebo for tanezumab every 8 weeks plus oral celecoxib 100 mg twice daily for 56 weeks
干预措施: Placebo for tanezumab (Biological)
Tanezumab 5 mg
Subcutaneous injection of tanezumab 5 mg every 8 weeks plus oral placebo for celecoxib twice daily for 56 weeks
干预措施: Tanezumab 5 mg (Biological)
Tanezumab 5 mg
Subcutaneous injection of tanezumab 5 mg every 8 weeks plus oral placebo for celecoxib twice daily for 56 weeks
干预措施: Placebo for celecoxib (Drug)
Tanezumab 10 mg
Subcutaneous injection of tanezumab 10 mg every 8 weeks plus oral placebo for celecoxib twice daily for 56 weeks
干预措施: Tanezumab 10 mg (Biological)
Tanezumab 10 mg
Subcutaneous injection of tanezumab 10 mg every 8 weeks plus oral placebo for celecoxib twice daily for 56 weeks
干预措施: Placebo for celecoxib (Drug)
结局指标
主要结局
Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
时间窗: Baseline (Day 1) up to 24 weeks after last dose of study drug (up to Week 80)
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 24 weeks after last dose of study drug (up to Week 80) that were absent before treatment or that worsened relative to pretreatment state. AEs included both serious and non-serious AEs.
Number of Participants With Treatment-Emergent Treatment Related Adverse Events (AEs) and Serious Adverse Events (SAEs)
时间窗: Baseline up to 24 weeks after last dose of study drug (up to Week 80)
Treatment-related AE was any untoward medical occurrence attributed to study drug in 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 24 weeks after last dose of study drug (up to Week 80). Relatedness to study drug was assessed by the investigator. AEs included both serious and non-serious AEs.
Number of Participants With Clinically Significant Laboratory Test Abnormalities
时间窗: Baseline up to Week 80
Abnormality criteria included: hemoglobin (HGB); hematocrit; erythrocytes \< 0.8\*lower limit of normal (LLN); erythrocyte mean corpuscular volume/HGB/ HGB concentration, erythrocytes distribution width \<0.9\*LLN, \>1.1\*upper limit of normal (ULN); platelets \<0.5\*LLN,\>1.75\* 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; total bilirubin\>1.5\*ULN; aspartate aminotransferase (AT), alanine AT, gamma glutamyl transferase, lactate dehydrogenase, 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; HGB A1C \>1.3\*ULN; creatine kinase \>2.0\*ULN; nitrite \>=1. Investigator judged clinical significance of laboratory test abnormalities.
Number of Participants With Clinically Significant Vital Signs Abnormalities
时间窗: Baseline up to Week 80
Vital signs included systolic blood pressure, diastolic blood pressure and pulse rate. Investigator judged clinical significance of vital signs' abnormalities.
Observation Time-Adjusted Event Rate for Total Joint Replacement (TJR) Event
时间窗: Baseline (Day 1) up to Week 80
Observation time was defined as the start day of first SC study medication until either the (i) date of completion of or withdrawal from study, if a participant had no TJR, or (ii) date of TJR (earliest TJR within each participant in the case of multiple TJRs). Event rate = number of events per 1000 participant-years at risk.
Change From Screening in Mean Total Symptom Impact Score as Per Survey of Autonomic Symptoms (SAS) at Week 56
时间窗: Screening, Week 56
SAS is a participant rated 12 items questionnaire for males and 11 items questionnaire for females. SAS measures autonomic symptoms of neuropathy and their impact on participants' well-being, during the past 6 months. Each item was related to a symptom/health problem. At scheduled time points, participants were asked to answer "Yes" or "No" for each of symptoms/health problems experienced during past 6 months. If a participant answered "Yes" for a symptom, then impact of that symptom was rated on a 5 point scale, ranged from 1 (least sever impact) to 5 (most severe impact), where higher scores signified more severe impact of symptoms. The total symptom impact score was calculated as the sum of impact of all symptoms. Overall possible range for the total symptom impact score was 0 (no impact) to 60 (extreme impact) for males and 0 (no impact) to 55 (extreme impact) for females, higher scores indicated more severe impact of symptoms on participants' well-being.
Change From Screening in Mean Total Symptom Impact Scores as Per Survey of Autonomic Symptoms (SAS) at Week 80
时间窗: Screening, Week 80
SAS is a participant rated 12 items questionnaire for males and 11 items questionnaire for females. SAS measures autonomic symptoms of neuropathy and their impact on participants' well-being, during the past 6 months. Each item was related to a symptom/health problem. At scheduled time points, participants were asked to answer "Yes" or "No" for each of symptoms/health problems experienced during past 6 months. If a participant answered "Yes" for a symptom, then impact of that symptom was rated on a 5 point scale, ranged from 1 (least sever impact) to 5 (most severe impact), where higher scores signified more severe impact of symptoms. The total symptom impact score was calculated as the sum of impact of all symptoms. Overall possible range for the total symptom impact score was 0 (no impact) to 60 (extreme impact) for males and 0 (no impact) to 55 (extreme impact) for females, higher scores indicated more severe impact of symptoms on participants' well-being.
Percentage of Participants With Individual Adjudicated Joint Safety Outcome/Event
时间窗: Baseline up to Week 80
Percentage of participants with individual joint safety adjudication outcomes: rapidly progressive osteoarthritis (OA) type-1 only, rapidly progressive OA type-2 only, primary osteonecrosis, pathological fracture and subchondral insufficiency fracture is reported. Rapidly progressive (RP) OA type 1 events were those that the adjudication committee considered to have significant loss of joint space width \>= 2 millimeter within approximately 1 year without gross structural failure. RP OA type 2 events were those considered to have destruction of bone including limited or total collapse of at least 1 subchondral surface that is not normally present in conventional end-stage osteoarthritis. Subchondral insufficiency fractures are a type of stress fractures which occur below the cartilage on the weight bearing surface of a bone.
Change From Baseline in Neuropathy Impairment Score (NIS) at Week 64
时间窗: Baseline, Week 64
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.
Change From Baseline in Neuropathy Impairment Score (NIS) at Week 80
时间窗: Baseline, Week 80
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.
Change From Baseline in Neuropathy Impairment Score (NIS) at Week 2
时间窗: Baseline, Week 2
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.
Change From Baseline in Neuropathy Impairment Score (NIS) at Week 4
时间窗: Baseline, Week 4
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.
Change From Baseline in Neuropathy Impairment Score (NIS) at Week 8
时间窗: Baseline, Week 8
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.
Change From Screening in Mean Total Symptom Impact Score as Per Survey of Autonomic Symptoms (SAS) at Early Termination Follow-up Visit 1
时间窗: Screening, Early Termination Follow-up Visit 1 (at 8 weeks after last dose of tanezumab or placebo matched to tanezumab)
SAS: participant rated 12 items questionnaire for males; 11 items questionnaire for females. SAS measures autonomic symptoms of neuropathy and their impact on participants' well-being, during past 6 months. Each item was related to a symptom/health problem. At scheduled time points, participants answered "Yes" or "No" for each of symptoms/health problems experienced during past 6 months. If participant answered "Yes" for a symptom, then impact of that symptom was rated on 5 point scale (1 \[least sever impact\] to 5 \[most severe impact\]); higher scores = more severe impact of symptoms. Total impact score = sum of impact of all symptoms; range for males =0 (no impact) to 60 (extreme impact); females =0 (no impact) to 55 (extreme impact); higher scores = more severe impact of symptoms on participants' well-being. Participants discontinuing from study treatment before Week 56, had early termination follow-up visit 1 at 8 weeks after last dose of tanezumab or placebo matched to tanezumab.
Number of Participants With Clinically Significant Electrocardiogram (ECG) Assessments
时间窗: Baseline up to Week 16
Electrocardiogram assessment included PR, QRS, QT, QT interval corrected using Fridericia's formula (QTcF), QT interval corrected using Bazett's formula (QTcB), RR intervals, and heart rate. Investigator judged clinical significance of electrocardiogram assessment.
Change From Baseline in Neuropathy Impairment Score (NIS) at Week 16
时间窗: Baseline, Week 16
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.
Change From Baseline in Neuropathy Impairment Score (NIS) at Week 24
时间窗: Baseline, Week 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.
Change From Baseline in Neuropathy Impairment Score (NIS) at Week 32
时间窗: Baseline, Week 32
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.
Largest Change From Baseline in Neuropathy Impairment Score (NIS) to Any Post-baseline Visit
时间窗: Baseline to any post-baseline visit (until Week 80)
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. Largest change from baseline here means worst post- baseline change value (among all change from baseline values).
Number of Participants With Anti Tanezumab Antibodies From Baseline up to Week 80
时间窗: Baseline up to Week 80
Human serum samples were analyzed for the presence or absence of anti-tanezumab antibodies by using a validated analytical method. Number of participants with presence of anti-tanezumab antibodies are reported.
Number of Participants With Abnormal Physical Examination Findings
时间窗: At Screening
Physical examination included assessment of general appearance, skin, head, neck, eyes, ears, nose, throat, abdomen, lungs, heart, thyroid, and extremities. Investigator judged abnormality in physical examinations. Only those rows have been reported which had at least 1 participant with abnormality data in any of the reporting arms.
Change From Screening in Mean Total Symptom Impact Scores as Per Survey of Autonomic Symptoms (SAS) at Early Termination Follow-up Visit 3
时间窗: Screening, Early Termination Follow-up Visit 3 (at 24 weeks after last dose of tanezumab or placebo matched to tanezumab)
SAS: participant rated 12 items questionnaire for males; 11 items questionnaire for females. SAS measures autonomic symptoms of neuropathy and their impact on participants' well-being, during past 6 months. Each item was related to a symptom/health problem. At scheduled time points, participants answered "Yes" or "No" for each of symptoms/health problems experienced during past 6 months. If participant answered "Yes" for a symptom, then impact of that symptom was rated on 5 point scale (1 \[least sever impact\] to 5 \[most severe impact\]); higher scores = more severe impact of symptoms. Total impact score = sum of impact of all symptoms; range for males =0 (no impact) to 60 (extreme impact); females =0 (no impact) to 55 (extreme impact); higher scores = more severe impact of symptoms on participants' well-being. Participants discontinuing from study treatment before Week 56, had early termination follow-up visit 3 at 24 weeks after last dose of tanezumab or placebo matched to tanezumab.
Observation Time-Adjusted Event Rate for an Individual Adjudicated Joint Safety Outcome/Event
时间窗: Baseline (Day 1) up to Week 80
Individual adjudicated joint safety outcomes/event: rapidly progressive OA (type-1,type-2), primary osteonecrosis, pathological fracture and subchondral insufficiency fracture. Observation time was defined as the start day of first SC study medication until either the (i) date of completion of or withdrawal from study, if a participant did not have the event, or (ii) date of the event (earliest event within each participant in the case of multiple events). Event rate for any individual adjudicated joint safety outcome/event = the number of events per 1000 participant-years at risk.
Percentage of Participants With At Least 1 Total Joint Replacement
时间窗: Baseline (Day 1) up to Week 80
Percentage of participants with at least 1 total knee, total hip or total shoulder joint replacement were reported.
Change From Baseline in Neuropathy Impairment Score (NIS) at Week 40
时间窗: Baseline, Week 40
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.
Change From Baseline in Neuropathy Impairment Score (NIS) at Week 48
时间窗: Baseline, Week 48
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.
Change From Baseline in Neuropathy Impairment Score (NIS) at Week 56
时间窗: Baseline, Week 56
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.
Number of Participants With Confirmed Orthostatic Hypotension From Baseline up to Week 80
时间窗: Baseline up to Week 80
Orthostatic hypotension was defined as postural change (supine to standing) that met the following criteria: for systolic blood pressure (BP) less than or equal to (\<=) 150 millimeter of mercury (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 greater than (\>) 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.
Change From Screening in Mean Total Symptom Impact Score as Per Survey of Autonomic Symptoms (SAS) at Week 24
时间窗: Screening (up to 37 days before Day 1), Week 24
SAS is a participant rated 12 items questionnaire for males and 11 items questionnaire for females. SAS measures autonomic symptoms of neuropathy and their impact on participants' well-being, during the past 6 months. Each item was related to a symptom/health problem. At scheduled time points, participants were asked to answer "Yes" or "No" for each of symptoms/health problems experienced during past 6 months. If a participant answered "Yes" for a symptom, then impact of that symptom was rated on a 5 point scale, ranged from 1 (least sever impact) to 5 (most severe impact), where higher scores signified more severe impact of symptoms. The total symptom impact score was calculated as the sum of impact of all symptoms. Overall possible range for the total symptom impact score was 0 (no impact) to 60 (extreme impact) for males and 0 (no impact) to 55 (extreme impact) for females, higher scores indicated more severe impact of symptoms on participants' well-being.
次要结局
- Change From Baseline in Brief Pain Inventory-short Form (BPI-sf) Scores for Pain Interference Index at Weeks 2, 4, 8, 16, 24, 40, 56, and 64(Baseline, Weeks 2, 4, 8, 16, 24, 40, 56 and 64)
- Percentage of Participants With >=30 Percent (%), >=50%, >=70% and >=90% Reduction From Baseline in Weekly Average Low Back Pain Intensity (LBPI) Score at Weeks 16, 24, 40 and 56(Baseline, Weeks 16, 24, 40 and 56)
- Change From Baseline in Roland-Morris Disability Questionnaire (RMDQ) Total Scores at Weeks 2, 4, 8, 16, 24, 32, 40, 48, and 56: Multiple Imputation(Baseline, Weeks 2, 4, 8, 16, 24, 32, 40, 48 and 56)
- Change From Baseline in Roland-Morris Disability Questionnaire (RMDQ) Total Score at Week 64: Observed Data(Baseline, Week 64)
- Change From Baseline in the Patient's Global Assessment (PGA) of Low Back Pain at Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56 and 64(Baseline, Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56 and 64)
- Change From Baseline in Brief Pain Inventory-short Form (BPI-sf) Scores for Average Pain at Weeks 2, 4, 8, 16, 24, 40, 56, and 64(Baseline, Weeks 2, 4, 8, 16, 24, 40, 56 and 64)
- Change From Baseline in Average Low Back Pain Intensity (LBPI) at Weeks 2, 4, 8, 12, 16, 24, 32, 40, 48, and 56: Multiple Imputation(Baseline, Weeks 2, 4, 8, 12, 16, 24, 32, 40, 48 and 56)
- Change From Baseline in Average Low Back Pain Intensity (LBPI) at Week 64: Observed Data(Baseline, Week 64)
- Percentage of Participants With Cumulative Percent Change From Baseline in Average Low Back Pain Intensity (LBPI) Score at Weeks 16, 24 and 56(Baseline, Weeks 16, 24 and 56)
- Change From Baseline in Brief Pain Inventory-short Form (BPI-sf) Scores for Worst Pain at Weeks 2, 4, 8, 16, 24, 40, 56, and 64(Baseline, Weeks 2, 4, 8, 16, 24, 40, 56 and 64)
- Change From Baseline in Work Productivity and Activity Impairment Questionnaire: Low Back Pain (WPAI:LBP)- Percent Work Time Missed Due to Chronic Low Back Pain at Weeks 16, 56 and 64(Baseline, Weeks 16, 56 and 64)
- Change From Baseline in Work Productivity and Activity Impairment Questionnaire: Low Back Pain (WPAI:LBP)- Percent Activity Impairment Due to Chronic Low Back Pain at Weeks 16, 56 and 64(Baseline, Weeks 16, 56 and 64)
- Change From Baseline in Brief Pain Inventory-short Form (BPI-sf) Scores for Pain Interference With General Activity at Weeks 2, 4, 8, 16, 24, 40, 56, and 64(Baseline, Weeks 2, 4, 8, 16, 24, 40, 56 and 64)
- Change From Baseline in Brief Pain Inventory-short Form (BPI-sf) Scores for Pain Interference With Walking Ability at Weeks 2, 4, 8, 16, 24, 40, 56, and 64(Baseline, Weeks 2, 4, 8, 16, 24, 40, 56 and 64)
- Change From Baseline in Brief Pain Inventory-short Form (BPI-sf) Scores for Pain Interference With Sleep at Weeks 2, 4, 8, 16, 24, 40, 56, and 64(Baseline, Weeks 2, 4, 8, 16, 24, 40, 56 and 64)
- Percentage of Participants With Chronic Low Back Pain Responders Index at Weeks 16, 24, 40 and 56(Weeks 16, 24, 40 and 56)
- European Quality of Life-5 Dimension-5 Levels (EQ-5D-5L): Overall Health Utility Score/ Index Value(Baseline, Weeks 16 and 56)
- Change From Baseline in Brief Pain Inventory-short Form (BPI-sf) Scores for Pain Interference With Normal Work at Weeks 2, 4, 8, 16, 24, 40, 56 and 64(Baseline, Weeks 2, 4, 8, 16, 24, 40, 56 and 64)
- Percentage of Participants Achieving Change of >=2 Points From Baseline in Patient's Global Assessment (PGA) of Low Back Pain at Weeks 16, 24, 40 and 56(Baseline, Weeks 16, 24, 40 and 56)
- Change From Baseline in in Work Productivity and Activity Impairment Questionnaire: Low Back Pain (WPAI:LBP)- Percent Impairment While Working Due to Chronic Low Back Pain at Weeks 16, 56 and 64(Baseline, Weeks 16, 56 and 64)
- Change From Baseline in Work Productivity and Activity Impairment Questionnaire: Low Back Pain (WPAI:LBP)- Percent Overall Work Impairment Due to Chronic Low Back Pain at Weeks 16, 56 and 64(Baseline, Weeks 16, 56 and 64)
- European Quality of Life-5 Dimension-5 Levels (EQ-5D-5L): Dimensions Scores at Baseline, Weeks 16 and 56(Baseline, Weeks 16 and 56)
- Number of Participants Who Discontinued Due to Lack of Efficacy(Baseline up to Week 56)
- Time to Discontinuation Due to Lack of Efficacy(Baseline up to Week 56)
- Number of Participants Who Took Rescue Medication During Weeks 2, 4, 8, 12, 16, 24, 32, 40, 48, 56 and 64: Observed Data(Weeks 2, 4, 8, 12, 16, 24, 32, 40, 48, 56 and 64)
- Number of Participants Who Took Rescue Medication During Weeks 2, 4, 8, 12, 16, 24, 32, 40, 48 and 56: Last Observation Carried Forward (LOCF)(Weeks 2, 4, 8, 12, 16, 24, 32, 40, 48 and 56)
- Number of Days of Rescue Medication Use During Weeks 2, 4, 8, 12, 16, 24, 32, 40, 48, 56 and 64: Observed Data(Weeks 2, 4, 8, 12, 16, 24, 32, 40, 48, 56 and 64)
- Number of Days of Rescue Medication Use During Weeks 2, 4, 8, 12, 16, 24, 32, 40, 48 and 56: LOCF(Weeks 2, 4, 8, 12, 16, 24, 32, 40, 48 and 56)
- Health Care Resource Utilization (HCRU): Number of Participants Visited to the Emergency Room Due to Low Back Pain(Baseline, Weeks 64 and 80)
- Health Care Resource Utilization (HCRU): Number of Participants Hospitalized Due to Low Back Pain(Baseline, Weeks 64 and 80)
- Health Care Resource Utilization (HCRU): Number of Participants Who Quit Job Due to Low Back Pain(Baseline, Weeks 64 and 80)
- Health Care Resource Utilization (HCRU): Duration Since Quitting Job Due to Low Back Pain(Baseline, Weeks 64 and 80)
- Treatment Satisfaction Questionnaire for Medication Version II (TSQM v II) Scores at Weeks 16 and 56(Weeks 16 and 56)
- Amount of Rescue Medication Used in Weeks 2, 4, 8, 12, and 16: Observed Data(Weeks 2, 4, 8, 12 and 16)
- Amount of Rescue Medication Used in Weeks 2, 4, 8, 12, and 16: LOCF(Weeks 2, 4, 8, 12 and 16)
- Health Care Resource Utilization (HCRU): Number of Visits of Services Received Directly Related to Low Back Pain(Baseline, Weeks 64 and 80)
- Health Care Resource Utilization (HCRU): Number of Nights Stayed in the Hospital Due to Low Back Pain(Baseline, Weeks 64 and 80)
- Number of Participants Responding to Patient Reported Treatment Impact Assessment-Modified (mPRTI) at Weeks 16 and 56 for Preference of Study Drug Versus Prior Treatment(Weeks 16 and 56)
- Health Care Resource Utilization (HCRU): Number of Participants Who Used Any Aids/Devices for Doing Things(Baseline, Weeks 64 and 80)
- Number of Participants Responding to Patient Reported Treatment Impact Assessment-Modified (mPRTI) at Weeks 16 and 56 for Willingness to Use Study Drug Again(Weeks 16 and 56)