A PHASE 3 RANDOMIZED, DOUBLE-BLIND, ACTIVE-CONTROLLED, MULTICENTER STUDY OF THE LONG-TERM SAFETY AND EFFICACY OF SUBCUTANEOUS ADMINISTRATION OF TANEZUMAB IN SUBJECTS WITH OSTEOARTHRITIS OF THE HIP OR KNEE
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- Pfizer
- 入组人数
- 3,021
- 试验地点
- 485
- 主要终点
- Percentage of Participants With Adjudicated Primary Composite Joint Safety Outcome
研究概览
简要总结
The purpose of this study is to compare the long-term joint safety and efficacy (pain relief) of the investigational study drug, tanezumab compared to non-steroidal anti inflammatory drugs (NSAIDs) in subjects with osteoarthritis of the hips or knees.
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
- •A diagnosis of osteoarthritis of the index hip or knee based on American College of Rheumatology criteria with Kellgren Lawrence X ray Grade of 2 as diagnosed by the Central Reader
- •Currently receiving a stable dose regimen of oral NSAID (naproxen, celecoxib, diclofenac, aceclofenac, loxoprofen, ibuprofen, meloxicam, nabumetone, sulindac or ketoprofen) as described in the protocol along with a history of insufficient pain relief from, inability to tolerate or contraindication to taking acetaminophen and, tramadol or opioid treatments. Subjects must also maintain a stabilized, protocol specified NSAID dose regimen for at least the final 2 or 3 weeks of the Screening period
- •WOMAC Pain subscale score of at least 5 in the index knee or hip at Screening
- •Be willing to discontinue all non study pain medications for osteoarthritis and not use prohibited pain medications throughout the duration of the study
- •Female subjects of childbearing potential must agree to comply with protocol specified contraceptive requirements
排除标准
- •Subjects exceeding protocol defined BMI or body weight limits
- •History of other diseases specified in the protocol (eg, inflammatory joint diseases, crystalline diseases such as gout or pseudogout) that may involve the index joint and that could interfere with efficacy assessments
- •Radiographic evidence of protocol specified bone or joint conditions in any screening radiograph as determined by the central radiology reviewer
- •A history of osteonecrosis or osteoporotic fracture
- •History of significant trauma or surgery to a knee, hip or shoulder within the previous year
- •Planned surgical procedure during the duration of the study
- •Presence of conditions (eg, fibromyaliga, radiculopathy) associated with moderate to severe pain that may confound assessments or self evaluation of osteoarthritis pain
- •Signs or symptoms of carpal tunnel syndrome in the 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
- •Contraindications to magnetic resonance imaging
- •History of intolerance or hypersensitivity to the oral NSAID (naproxen, celecoxib or diclofenac) the subject could be randomized to receive or any of its excipients or existence of a medical condition or use of concomitant medication for which the use of this NSAID is contraindicated
- •History of intolerance or hypersensitivity to acetaminophen or any of its excipients or existence of a medical condition or use of concomitant medication for which the use of acetaminophen is contraindicated
- •Use of prohibited medications without the appropriate washout period prior to Screening or Initial Pain Assessment Period
- •History of cancer within 5 years of Screening, except for cutaneous basal cell or squamous cell cancer resolved by excision
- •Subjects with signs and symptoms of clinically significant cardiac disease as described in the protocol
- •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, diagnosis, or signs and symptoms of clinically significant neurological disease such as but not limited to peripheral or autonomic neuropathy
- •History, diagnosis, signs or symptoms of any clinically significant psychiatric disorder
- •History of known alcohol, analgesic or drug abuse within 2 years of Screening
- •Previous exposure to exogenous NGF or to an anti-NGF antibody
- •History of allergic or anaphylactic reaction to a therapeutic or diagnostic monoclonal antibody or IgG fusion protein
- •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
- •Screening AST, ALT, serum creatinine or HbA1c values that exceed protocol defined limits
- •Presence of drugs of abuse in screening urine toxicology panel
- •Positive hepatitis B, hepatitis C or HIV test results indicative of current infection
- •Participation in other investigational drug studies within protocol defined time limits
- •Pregnant, breastfeeding or female subjects of childbearing potential who are unwilling or unable to follow protocol required contraceptive requirements
- •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
NSAID
Subcutaneous injection of placebo for tanezumab every 8 weeks plus oral NSAID (naproxen 500 mg, celecoxib 100 mg or diclofenac 75 mg) twice daily for 56 weeks
干预措施: NSAID (Drug)
Tanezumab 2.5 mg
Subcutaneous injection of tanezumab 2.5 mg every 8 weeks plus oral placebo for NSAID (naproxen, celecoxib or diclofenac ER) twice daily for 56 weeks
干预措施: Tanezumab 2.5 mg (Biological)
Tanezumab 5 mg
Subcutaneous injection of tanezumab 5 mg every 8 weeks plus oral placebo for NSAID (naproxen, celecoxib or diclofenac) twice daily for 56 weeks
干预措施: Tanezumab 5 mg (Biological)
结局指标
主要结局
Percentage of Participants With Adjudicated Primary Composite Joint Safety Outcome
时间窗: Baseline up to Week 80
Any participant with incidence of an adjudicated outcome of primary osteonecrosis, rapidly progressive osteoarthritis (OA) type 1 or type 2, subchondral insufficiency fracture, or pathological fracture. Rapidly progressive OA type 1 events were those that the Adjudication Committee considered to have significant loss of joint space width (JSW) (greater than or equal to \[\>=\] 2 millimeters \[mm\]) within approximately 1 year without gross structural failure. Rapidly progressive OA type 2 events were those considered to have abnormal loss/destruction of bone including limited or total collapse of at least one subchondral surface (e.g., medial femoral condyle) that is not normally present in conventional end-stage OA.
Observation Time-Adjusted Event Rate of Participants With Adjudicated Primary Composite Joint Safety Outcome
时间窗: Baseline 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 did not have the event, or (ii) date of the event (earliest event within each participant in the case of multiple events). Primary joint safety outcome included participants with adjudicated outcome of primary osteonecrosis, rapidly progressive OA type 1 or type 2, subchondral insufficiency fracture, or pathological fracture. Event rate was calculated as the number of events per 1000 participant-years at risk.
Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Subscale at Week 16
时间窗: Baseline, Week 16
WOMAC: Self-administered, disease-specific questionnaire which assesses clinically important, participant-relevant symptoms for pain, stiffness and physical function in participants with OA. The WOMAC pain subscale is a 5-item questionnaire used to assess the amount of pain experienced due to OA of index joint (knee or hip) during past 48 hours. It was calculated as the mean of scores from 5 individual questions, which may not be a whole (integer) number, scored on a numerical rating scale (NRS). Scores for each question and WOMAC Pain subscale score on NRS ranged from 0 (no pain) to 10 (extreme pain), where higher scores indicated higher pain.
Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Physical Function Subscale at Week 16
时间窗: Baseline, Week 16
WOMAC: Self-administered, disease-specific questionnaire which assesses clinically important, participant-relevant symptoms for pain, stiffness and physical function in participants with OA. Physical function refers to participant's ability to move around and perform usual activities of daily living. The WOMAC physical function subscale is a 17-item questionnaire used to assess the degree of difficulty experienced due to OA in index joint (knee or hip) during past 48 hours. It was calculated as mean of the scores from 17 individual questions, which may not be a whole (integer) number, scored on a NRS. Scores for each question and WOMAC physical function subscale score on NRS ranged from 0 (no difficulty) to 10 (extreme difficulty), where higher scores indicated extreme difficulty/worse physical function.
Change From Baseline in Patient's Global Assessment (PGA) of Osteoarthritis at Week 16
时间窗: Baseline, Week 16
PGA of OA was assessed by asking a question from participants: "Considering all the ways your OA in your knee or hip (index joint) affects you, how are you doing today?" Participants responded on a scale ranging from 1-5, using Interactive Response Technology (IRT), where 1=very good (no symptom and no limitation of normal activities), 2= good (mild symptoms and no limitation of normal activities), 3= fair (moderate symptoms and limitation of some normal activities), 4= poor (severe symptoms and inability to carry out most normal activities), and 5= very poor (very severe symptoms and inability to carry out all normal activities). Higher scores indicated worsening of condition.
次要结局
- Percentage of Participants With Adjudicated Secondary Composite Joint Safety Outcome(Baseline up to Week 80)
- Observation Time-Adjusted Event Rate of Participants With Adjudicated Secondary Composite Joint Safety Outcome(Baseline up to Week 80)
- Percentage of Participants With Individual Adjudicated Joint Safety Outcome(Baseline up to Week 80)
- Observation Time-Adjusted Event Rate of Participants With Individual Adjudicated Joint Safety Outcome(Baseline up to Week 80)
- Percentage of Participants With Total Joint Replacement or Adjudicated Primary Composite Joint Safety Outcome(Baseline up to Week 80)
- Observation Time-Adjusted Event Rate of Participants With Total Joint Replacement or Adjudicated Primary Composite Joint Safety Outcome(Baseline up to Week 80)
- Change From Baseline in Medial or Lateral Joint Space Width of the Index Knee (Kellgren-Lawrence Grade 2 or 3) at Weeks 56 and 80(Baseline, Weeks 56 and 80)
- Change From Baseline in Joint Space Width of the Index Hip (Kellgren-Lawrence Grade 2 or 3) at Weeks 56 and 80(Baseline, Weeks 56 and 80)
- Number of Participants With Progression of Osteoarthritis in the Index Knee (Kellgren-Lawrence Grade 2 or 3) According to Bland and Altman Method at Weeks 56 and 80(Weeks 56 and 80)
- Number of Participants With Progression of Osteoarthritis in the Index Hip (Kellgren-Lawrence Grade 2 or 3) According to Bland and Altman Method at Weeks 56 and 80(Weeks 56 and 80)
- Change From Baseline in WOMAC Pain Subscale at Weeks 2, 4, 8, 24, 32, 40, 48 and 56(Baseline, Weeks 2, 4, 8, 24, 32, 40, 48 and 56)
- Change From Baseline in WOMAC Pain Subscale at Week 64(Baseline, Week 64)
- Change From Baseline in WOMAC Physical Function Subscale at Weeks 2, 4, 8, 24, 32, 40, 48 and 56(Baseline, Weeks 2, 4, 8, 24, 32, 40, 48 and 56)
- Change From Baseline in WOMAC Physical Function Subscale at Week 64(Baseline, Week 64)
- Change From Baseline in Patient's Global Assessment (PGA) of Osteoarthritis at Weeks 2, 4, 8, 24, 32, 40, 48 and 56(Baseline, Weeks 2, 4, 8, 24, 32, 40, 48 and 56)
- Change From Baseline in Patient's Global Assessment (PGA) of Osteoarthritis at Week 64(Baseline, Week 64)
- Percentage of Participants Meeting Outcome Measures in Arthritis Clinical Trials-Osteoarthritis Research Society International (OMERACT-OARSI) Responder Index at Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56 and 64(Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56 and 64)
- Percentage of Participants Achieving Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Subscale Reduction >=30 Percent (%), >=50%, >=70% and >=90% Response at Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56 and 64(Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56 and 64)
- Percentage of Participants With Cumulative Percent Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Subscale at Weeks 16, 24 and 56(Baseline, Weeks 16, 24 and 56)
- Percentage of Participants Achieving Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Physical Function Subscale Reduction of >=30%, >=50%, >=70% and >=90% Response at Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56 and 64(Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56 and 64)
- Percentage of Participants With Cumulative Percent Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Physical Function Subscale at Weeks 16, 24 and 56(Baseline, Weeks 16, 24 and 56)
- Percentage of Participants Achieving Improvement of >=2 Points in Patient's Global Assessment (PGA) of Osteoarthritis at Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56 and 64(Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56 and 64)
- Change From Baseline in Average Pain Score in the Index Joint at Weeks 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 32, 40, 48 and 56(Baseline, Weeks 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 32, 40, 48 and 56)
- Change From Baseline in Average Pain Score in the Index Joint at Week 64(Baseline, Week 64)
- Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Stiffness Subscale at Weeks 2, 4, 8, 16, 24, 32, 40, 48 and 56(Baseline, Weeks 2, 4, 8, 16, 24, 32, 40, 48 and 56)
- Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Stiffness Subscale at Week 64(Baseline, Week 64)
- Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Average Score at Weeks 2, 4, 8, 16, 24, 32, 40, 48 and 56(Baseline, Weeks 2, 4, 8, 16, 24, 32, 40, 48 and 56)
- Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Average Score at Week 64(Baseline, Week 64)
- Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Subscale Item: Pain When Walking on a Flat Surface at Weeks 2, 4, 8, 16, 24, 32, 40, 48 and 56(Baseline, Weeks 2, 4, 8, 16, 24, 32, 40, 48 and 56)
- Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Subscale Item: Pain When Walking on a Flat Surface at Week 64(Baseline, Week 64)
- Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Subscale Item: Pain When Going Up or Down Stairs at Weeks 2, 4, 8, 16, 24, 32, 40, 48 and 56(Baseline, Weeks 2, 4, 8, 16, 24, 32, 40, 48 and 56)
- Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Subscale Item: Pain When Going Up or Down Stairs at Week 64(Baseline, Week 64)
- Change From Baseline in Work Productivity and Activity Impairment Questionnaire for Osteoarthritis (WPAI:OA) Scores at Weeks 16, 24 and 56(Weeks 16, 24 and 56)
- Change From Baseline in Work Productivity and Activity Impairment Questionnaire for Osteoarthritis (WPAI:OA) Scores at Week 64(Baseline, Week 64)
- Number of Participants With Responses to European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L): Mobility Domain(Baseline, Weeks 8, 16, 24, 40, 56 and 64)
- Number of Participants With Responses to European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L): Self-Care Domain(Baseline, Weeks 8, 16, 24, 40, 56 and 64)
- Number of Participants With Responses to European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L): Usual Activities Domain(Baseline, Weeks 8, 16, 24, 40, 56 and 64)
- Number of Participants With Responses to European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L): Pain/Discomfort Domain(Baseline, Weeks 8, 16, 24, 40, 56 and 64)
- Number of Participants With Responses to European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L): Anxiety/ Depression Domain(Baseline, Weeks 8, 16, 24, 40, 56 and 64)
- European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Overall Health Utility Score/Index Value(Baseline, Weeks 8, 16, 24, 40, 56 and 64)
- Treatment Satisfaction Questionnaire Medicine Version II (TSQM v.II) Score With Effectiveness, Side Effects, Convenience, and Overall Satisfaction Responses(Weeks 16 and 56)
- Patient-Reported Treatment Impact Assessment- Modified (mPRTI) Score at Weeks 16 and 56: Participant Global Preference Assessment- What is The Current or Most Recent Treatment You Were Receiving for Osteoarthritis Pain Before Enrolling?(Weeks 16 and 56)
- Patient Reported Treatment Impact Assessment-Modified (mPRTI) Score at Weeks 16 and 56: Participant Global Preference Assessment- Overall, do You Prefer the Drug That You Received in This Study to Previous Treatment?(Weeks 16 and 56)
- Patient Reported Treatment Impact Assessment-Modified (mPRTI) Score at Weeks 16 and 56: Participant Willingness to Use Drug Again Assessment- Willing to Use the Same Drug That You Have Received in This Study for Your Osteoarthritis Pain?(Weeks 16 and 56)
- Number of Participants Who Withdrew 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, 16, 24, 32, 40, 48 and 56(Weeks 2, 4, 8, 16, 24, 32, 40, 48 and 56)
- Number of Participants Who Took Rescue Medication During Week 64(Week 64)
- Number of Days of Rescue Medication Used During Weeks 2, 4, 8, 16, 24, 32, 40, 48 and 56(Weeks 2, 4, 8, 16, 24, 32, 40, 48 and 56)
- Number of Days of Rescue Medication Used During Week 64(Week 64)
- Amount of Rescue Medication Used During Weeks 2, 4, 8 and 16(Weeks 2, 4, 8 and 16)
- Health Care Resource Utilization (HCRU): Number of Visits of Services Directly Related to Osteoarthritis(Baseline, Weeks 64 and 80)
- Health Care Resource Utilization (HCRU): Number of Participants Who Visited the Emergency Room Due to Osteoarthritis(Baseline, Weeks 64 and 80)
- Health Care Resource Utilization (HCRU): Number of Visits to the Emergency Room Due to Osteoarthritis(Baseline, Weeks 64 and 80)
- Health Care Resource Utilization (HCRU): Number of Participants Hospitalized Due to Osteoarthritis(Baseline, Weeks 64 and 80)
- Health Care Resource Utilization (HCRU): Number of Nights Stayed in the Hospital Due to Osteoarthritis(Baseline, Weeks 64 and 80)
- Health Care Resource Utilization (HCRU): Number of Participants Who Used Any Aids/Devices for Doing Things Due to Osteoarthritis(Baseline, Weeks 64 and 80)
- Health Care Resource Utilization (HCRU): Number of Participants Who Quit Job Due to Osteoarthritis(Baseline, Weeks 64 and 80)
- Health Care Resource Utilization (HCRU): Duration Since Quitting Job Due to Osteoarthritis(Baseline, Weeks 64 and 80)
- Number of Participants With Categorical Change From Baseline in Lower Extremity Activity Scale (LEAS) at Weeks 4, 8, 16, 24, 56 and 80(Baseline, Weeks 4, 8, 16, 24, 56 and 80)
- Change From Baseline in Average Daily Minutes of Physical Activity at Weeks 16 and 56(Baseline, Weeks 16 and 56)
- Change From Baseline in Average Daily Physical Activity Counts at Weeks 16 and 56(Baseline, Weeks 16 and 56)
- Change From Baseline in Average Daily Minutes of Moderate to Vigorous Physical Activity at Weeks 16 and 56(Baseline, Weeks 16 and 56)
- Change From Baseline in Average Daily Minutes of Bouted (Sustained) Moderate to Vigorous Physical Activity at Weeks 16 and 56(Baseline, Weeks 16 and 56)
- Change From Baseline in Average Daily Step Count at Weeks 16 and 56(Baseline, Weeks 16 and 56)
- Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)(Baseline up to Week 80)
- Number of Participants With Treatment-Related Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)(Baseline up to Week 80)
- Number of Participants With Laboratory Test Abnormalities With Regard to Normal Baseline(Baseline up to Week 80)
- Number of Participants With Laboratory Test Abnormalities With Regard to Abnormal Baseline(Baseline up to Week 80)
- Change From Baseline in Blood Pressure (BP) at Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56, 64 and 80(Baseline, Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56, 64 and 80)
- Change From Baseline in Heart Rate at Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56, 64 and 80(Baseline, Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56, 64 and 80)
- Change From Baseline in Electrocardiogram (ECG) Parameters at Weeks 56 and 80(Baseline, Weeks 56 and 80)
- Change From Baseline in Heart Rate (as Assessed by ECG) at Weeks 56 and 80(Baseline, Weeks 56 and 80)
- Number of Participants With Confirmed Orthostatic Hypotension(Baseline, Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56, 64 and 80)
- Change From Baseline in Survey of Autonomic Symptom (SAS) Scores at Weeks 24, 56 and 80(Baseline, Weeks 24, 56 and 80)
- Change From Baseline in Neuropathy Impairment Score (NIS) at Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56, 64 and 80(Baseline, Weeks 2, 4, 8, 16, 24, 32, 40, 48, 56, 64 and 80)
- Number of Participants With Anti-Tanezumab Antibodies(Baseline, Weeks 8, 16, 32, 48, 56, 64 and 80)