A Randomized, Double Blind, Placebo and Naproxen Controlled, Multi-center, Study to Determine the Safety, Tolerability, Pharmacokinetics and Effect on Pain of a Single Intra-articular Administration of Canakinumab in Patients With Osteoarthritis in the Knee
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 169
- 试验地点
- 9
- 主要终点
- Part A: Number of Participants With Intolerance Events
研究概览
简要总结
The purpose of this study was to determine whether, in patients with mild to moderate knee osteoarthritis, canakinumab is safe and tolerable when injected intra-articularly.
详细描述
This is a randomized, double-blind, parallel group, placebo controlled 18 weeks study, consisting of two parts:
- Part A: an ascending single dose part in which the safety and tolerability of up to 4 different canakinumab doses are studied (starting dose 150 mg, maximum dose 600 mg).
- Part B: a double-dummy, active-controlled, parallel design part in which the pain reduction of the canakinumab dose selected from part A is studied in comparison to Placebo and Naproxen.
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
- Triple (Participant, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 40 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Written informed consent must be obtained before any assessment is performed.
- •Male and female patients aged 40 - 80 years (inclusive).
- •Diagnosis of knee osteoarthritis
- •Radiographic evidence of tibiofemoral compartment osteoarthritis
- •Pain in the knee during the last 24 hours.The patients should also have had pain in the affected knee on most days over the last month.
- •Patients who are willing to discontinue all non-steroidal anti-inflammatory drugs (NSAIDs) or other analgesic medication taken for any condition, including their knee pain,
- •Patients who are on stable dose of opioids for at least 1 month before screening can continue to take their opioid at this stable dose throughout the study.
- •Patients must also be willing to abstain from any intra-articular or peri-articular injections to the knee or surgery during the treatment period
- •Patients who, if they are currently taking aspirin (325 mg/day or less; as anti-coagulants), are willing to remain on a stable dose one month prior to screening and throughout the study
排除标准
- •Subjects with known hypersensitivity to any biological or investigational drugs.
- •Patients with contraindications to knee injections
- •Patients with joint effusion
- •Patients should not have rheumatoid arthritis or any connective tissue like disease
- •Secondary osteoarthritis with history and/or any evidence of the following diseases: septic arthritis, inflammatory joint disease, gout, Paget's disease of the bone, articular fracture, major dysplasias or congenital abnormality, ochronosis, acromegaly, hemochromatosis, Wilson's disease, primary osteochondromatosis, juvenile chronic arthritis with continued activity in adulthood, heritable disorders (e.g. hypermobility). Patients with secondary osteoarthritis following menisectomy or injuries of a collateral or cruciate ligament are not excluded.
- •Presence or history of underlying metabolic, endocrine, hematologic, pulmonary, cardiac, blood, renal, hepatic, infectious, psychiatric or gastrointestinal conditions
- •Evidence of tuberculosis (TB)
- •One of the risk factors for TB such as:
- •Substance abuse (e.g. injection or non-injection)
- •Health-care workers with unprotected exposure to patients who are at high risk of TB
- •Patients with TB disease before the identification and correct airborne precautions of the patient
- •close contact (i.e. share the same air space in a household or other enclosed environment for a prolonged period (days or weeks, not minutes or hours)) with a person with active pulmonary TB disease.
- •Significant medical problems, including but not limited to the following: uncontrolled hypertension,congestive heart failure, uncontrolled diabetes type I and II
- •Subjects with evidence of hepatic or blood coagulation disorders (i.e. hemophilia, etc), anemia, idiopathic thrombocytopenic purpura, or gastrointestinal disorder: severe hepatic disease, history of alcohol and drug abuse; disease of gall bladder and pancreas; active peptic ulceration, gastrointestinal bleeding or history of severe gastro-esophageal reflux disease or severe hiatus hernia; inflammatory bowel disease.
- •Use of any therapeutic protein drug (e.g. anti-tumor necrosis factor alpha (TNFα) antibody)
- •Presence of severe renal function impairment. History of renal trauma, glomerulonephritis, patients with one kidney, or renal failure requiring regular dialysis treatment.
- •Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive pregnancy test (serum or urine).
- •Subjects with known contra-indications to naproxen (e.g. heart or circulation problems, history of ulcer disease etc.), analgesics, antipyretics, or NSAIDs.
- •Disease of the spine or other lower extremity joints which may interfere with the assessment of the target joint.
- •Surgery on the knee within the last year. Observational arthroscopy, arthroscopic surgery or lavage of the knee within the last 6 months.
- •Use of assistive devices other than a cane (walking stick) or knee brace.
- •Subjects who have experienced, any time in the past, asthma, acute rhinitis, nasal polyps, angioneurotic edema, urticaria or other allergic-type reaction after taking acetylsalicylic acid (ASA)/ aspirin or NSAIDs.
- •Any history of prior peptic ulcer disease or prior NSAID gastrointestinal complications for the past 5 years.
- •Other protocol defined inclusion/exclusion criteria may apply.
研究组 & 干预措施
Part A: Canakinumab
In this ascending dose part, participants received a single intra-articular injection of canakinumab. The beginning dose was 150 mg, escalating to the 300 mg dose and then to 600 mg.
干预措施: Canakinumab (Biological)
Part A: Placebo
Participants received a single intra-articular injection of canakinumab-matching placebo.
干预措施: Placebo to canakinumab (Drug)
Part B: Canakinumab
Participants received a single intra-articular injection of canakinumab on Day 1 and naproxen matching placebo tablets orally twice daily for 12 weeks.
干预措施: Canakinumab (Biological)
Part B: Canakinumab
Participants received a single intra-articular injection of canakinumab on Day 1 and naproxen matching placebo tablets orally twice daily for 12 weeks.
干预措施: Placebo to Naproxen (Drug)
Part B: Placebo
Participants received a single intra-articular injection of canakinumab matching placebo on Day 1 and naproxen matching placebo tablets orally twice daily for 12 weeks.
干预措施: Placebo to canakinumab (Drug)
Part B: Placebo
Participants received a single intra-articular injection of canakinumab matching placebo on Day 1 and naproxen matching placebo tablets orally twice daily for 12 weeks.
干预措施: Placebo to Naproxen (Drug)
Part B: Naproxen
Participants received a single intra-articular injection of canakinumab matching placebo on Day 1 and naproxen 500mg tablets orally twice daily for 12 weeks.
干预措施: Placebo to canakinumab (Drug)
Part B: Naproxen
Participants received a single intra-articular injection of canakinumab matching placebo on Day 1 and naproxen 500mg tablets orally twice daily for 12 weeks.
干预措施: Naproxen (Drug)
结局指标
主要结局
Part A: Number of Participants With Intolerance Events
时间窗: Baseline to Day 3
An intolerance event is defined as an acute inflammatory reaction, characterized by a 30 mm increase in pain (on a 100 mm visual analog scale (VAS) and associated with a new or worsened synovial fluid effusion within 3 days following the intra-articular (i.a.) injection. If baseline VAS pain score is ≥ 70 mm, an intolerance event is defined as an increase in pain by 20 mm on a 100 mm VAS associated with new or worsened synovial fluid effusion within 3 days following the i.a. injection. If baseline VAS pain score is ≥ 80 mm, an intolerance event is defined as an increase in pain by 10 mm on a 100 mm VAS associated with new or worsened synovial fluid effusion within 3 days following the i.a. injection. If baseline pain score is ≥ 90 mm, an intolerance event is defined as the patients experiencing an unspecified increase in pain on a 100 mm VAS associated with new or worsened synovial fluid effusion within 3 days following the i.a. injection.
Part B: Change From Baseline to Day 4 in Pain Using 100 mm Visual Analog Scale (VAS)
时间窗: Baseline and Day 4
After walking for 20 meters, participants were asked to assess the pain in their affected knee on a 100 mm linear visual analog scale ranging from no pain (0 mm) to unbearable pain (100 mm). A negative change from Baseline score indicates improvement. Results are from a Bayesian analysis of covariance (ANCOVA) model, fitting baseline pain VAS score as a covariate, time by treatment as fixed effects, region and subject as random effects.
Part B: Change From Baseline to Week 4 in Western Ontario and McMaster Osteoarthritis Index (WOMAC) Pain Subscale
时间窗: Baseline and Week 4
The Western Ontario and McMaster osteoarthritis Index (WOMAC) pain subscale asks patients to rate pain in the index knee joint in the last 48 hours doing different activities on a scale from none (0) to extreme pain (4). The answers are summed and the total pain subscale score ranges from 0 to 20, where higher scores indicate more pain. A negative change from Baseline score indicates improvement. Results are from a Bayesian ANCOVA model, fitting baseline WOMAC pain score as a covariate, time by treatment as fixed effects, region and patient as random effects.
次要结局
- Part B: Change From Baseline in Pain Using 100 mm Visual Analog Scale (VAS)(Baseline and Weeks 4, 8 and 12)
- Part B: Percentage of Responders in the Pain 100 mm Visual Analog Scale (VAS)(Baseline, Day 4, Weeks 1, 2, 4, 8 and 12)
- Part B: Physician's Global Assessment of Response to Treatment at Week 2(Week 2)
- Part B: Physician's Global Assessment of Response to Treatment at Week 4(Week 4)
- Part B: Change From Baseline in WOMAC Pain, Stiffness and Physical Function Subscales(Baseline and Weeks 4, 8 and 12)
- Part B: Proportion of Participants Who Used Rescue Analgesic During Study(Day 4, Weeks 1, 2, 4, 8 and 12)
- Part B: Physician's Global Assessment of Response to Treatment at Week 12(Week 12)
- Patient's Global Assessment of Response to Treatment at Week 4(Week 4)
- Patient's Global Assessment of Response to Treatment on Day 4(Day 4)
- Patient's Global Assessment of Response to Treatment at Week 2(Week 2)
- Patient's Global Assessment of Response to Treatment at Week 8(Week 8)
- Patient's Global Assessment of Response to Treatment at Week 12(Week 12)
- Part B: Physician's Global Assessment of Response to Treatment at Day 4(Day 4)
- Part B: Physician's Global Assessment of Response to Treatment at Week 8(Week 8)
- Maximum Observed Plasma Concentration of Canakinumab (Cmax)(Day 1, pre-dose and 1, 3, 6 and 8 hours post-dose (Part A only), Day 2, 4, 8, 15, 29, 57, 85 and 126.)
- Time to Reach the Maximum Observed Plasma Concentration of Canakinumab (Tmax)(Day 1, pre-dose and 1, 3, 6 and 8 hours post-dose (Part A only), Day 2, 4, 8, 15, 29, 57, 85 and 126.)
- Area Under the Concentration Time Curve up to the Last Measurable Concentration (AUClast)(Day 1, pre-dose and 1, 3, 6 and 8 hours post-dose (Part A only), Day 2, 4, 8, 15, 29, 57, 85 and 126.)
- Area Under the Concentration Time Curve From Time Zero to Infinity AUC(0-inf)(Day 1, pre-dose and 1, 3, 6 and 8 hours post-dose (Part A only), Day 2, 4, 8, 15, 29, 57, 85 and 126.)
- Terminal Phase Half-life (t1/2) of Canakinumab(Day 1, pre-dose and 1, 3, 6 and 8 hours post-dose (Part A only), Day 2, 4, 8, 15, 29, 57, 85 and 126.)
- Apparent Clearance of Canakinumab From Plasma (CL/F)(Day 1, pre-dose and 1, 3, 6 and 8 hours post-dose (Part A only), Day 2, 4, 8, 15, 29, 57, 85 and 126.)
- Apparent Volume of Distribution During Terminal Phase (Vz/F)(Day 1, pre-dose and 1, 3, 6 and 8 hours post-dose (Part A only), Day 2, 4, 8, 15, 29, 57, 85 and 126.)