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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Osteoarthritis

Intervention / Treatment
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* Biological: Canakinumab
* Drug: Placebo to canakinumab
* Drug: Naproxen
* Drug: Placebo to Naproxen


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 Exclusion Criteria: 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.

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 80 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: Part A: Canakinumab<br>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. | Biological: Canakinumab<br>* Intra-articular injection<br>* Other names: ACZ885;|
| Placebo Comparator: Part A: Placebo<br>Participants received a single intra-articular injection of canakinumab-matching placebo. | Drug: Placebo to canakinumab<br>* Intra-articular injection<br>|
| Experimental: Part B: Canakinumab<br>Participants received a single intra-articular injection of canakinumab on Day 1 and naproxen matching placebo tablets orally twice daily for 12 weeks. | Biological: Canakinumab<br>* Intra-articular injection<br>* Other names: ACZ885;Drug: Placebo to Naproxen<br>* Tablets for oral administration<br>|
| Placebo Comparator: Part B: Placebo<br>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. | Drug: Placebo to canakinumab<br>* Intra-articular injection<br>Drug: Placebo to Naproxen<br>* Tablets for oral administration<br>|
| Active Comparator: Part B: Naproxen<br>Participants received a single intra-articular injection of canakinumab matching placebo on Day 1 and naproxen 500mg tablets orally twice daily for 12 weeks. | Drug: Placebo to canakinumab<br>* Intra-articular injection<br>Drug: Naproxen<br>* Tablets for oral administration<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Number of Participants With Intolerance Events | 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. | Baseline to Day 3 | 
| Part B: Change From Baseline to Day 4 in Pain Using 100 mm Visual Analog Scale (VAS) | 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. | Baseline and Day 4 | 
| Part B: Change From Baseline to Week 4 in Western Ontario and McMaster Osteoarthritis Index (WOMAC) Pain Subscale | 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. | Baseline and Week 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part B: Change From Baseline in Pain Using 100 mm Visual Analog Scale (VAS) | 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). Results are from a Bayesian ANCOVA model, fitting baseline pain VAS score as a covariate, time by treatment as fixed effects, region and patient as random effects. | Baseline and Weeks 4, 8 and 12 | 
| Part B: Percentage of Responders in the Pain 100 mm Visual Analog Scale (VAS) | A responder is defined as a participant with a 50% or greater reduction from baseline on the VAS scale for pain assessment. 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). | Baseline, Day 4, Weeks 1, 2, 4, 8 and 12 | 
| Part B: Change From Baseline in WOMAC Pain, Stiffness and Physical Function Subscales | The WOMAC consists of 3 subscales: The Pain subscale asks patients to rate pain in the index knee joint in the last 48 hours during walking, using stairs, in bed, sitting or lying, and standing on a scale from none (0) to extreme pain (4). The answers are summed and the total pain subscale score ranges from 0-20. The Stiffness subscale assesses stiffness in the index knee joint during the last 48 hours doing different activities on a scale from none (0) to extreme stiffness (4). The total stiffness subscale score ranges from 0-8. The Physical Function subscale assesses difficulty performing daily physical activities during the last 48 hours on a scale from none (0) to extreme difficulty (4). The total physical function subscale score ranges from 0-68. Higher scores indicate more pain/stiffness/difficulty. Results are from a Bayesian ANCOVA model, with baseline WOMAC score as a covariate, time by treatment as fixed effects, region and patient as random effects. | Baseline and Weeks 4, 8 and 12 | 
| Part B: Proportion of Participants Who Used Rescue Analgesic During Study | Participants were permitted to take oral rescue medication (Acetaminophen ≤ 4 gram/day) up until 24 hours of a scheduled assessment visit during the 12-week treatment period. The estimates shown are the Kaplan-Meier estimates of the proportion of participants that took rescue medication. | Day 4, Weeks 1, 2, 4, 8 and 12 | 
| Patient's Global Assessment of Response to Treatment on Day 4 | Participants made a global assessment of their response to treatment using a 5-point Likert scale: Excellent, Good, Acceptable, Poor, Very Poor. | Day 4 | 
| Patient's Global Assessment of Response to Treatment at Week 2 | Participants made a global assessment of their response to treatment using a 5-point Likert scale: Excellent, Good, Acceptable, Poor, Very Poor. | Week 2 | 
| Patient's Global Assessment of Response to Treatment at Week 4 | Participants made a global assessment of their response to treatment using a 5-point Likert scale: Excellent, Good, Acceptable, Poor, Very Poor. | Week 4 | 
| Patient's Global Assessment of Response to Treatment at Week 8 | Participants made a global assessment of their response to treatment using a 5-point Likert scale: Excellent, Good, Acceptable, Poor, Very Poor. | Week 8 | 
| Patient's Global Assessment of Response to Treatment at Week 12 | Participants made a global assessment of their response to treatment using a 5-point Likert scale: Excellent, Good, Acceptable, Poor, Very Poor. | Week 12 | 
| Part B: Physician's Global Assessment of Response to Treatment at Day 4 | The study physician made a global assessment of response to treatment using a 5-point Likert scale: Excellent, Good, Acceptable, Poor, Very Poor. | Day 4 | 
| Part B: Physician's Global Assessment of Response to Treatment at Week 2 | The study physician made a global assessment of response to treatment using a 5-point Likert scale: Excellent, Good, Acceptable, Poor, Very Poor. | Week 2 | 
| Part B: Physician's Global Assessment of Response to Treatment at Week 4 | The study physician made a global assessment of response to treatment using a 5-point Likert scale: Excellent, Good, Acceptable, Poor, Very Poor. | Week 4 | 
| Part B: Physician's Global Assessment of Response to Treatment at Week 8 | The study physician made a global assessment of response to treatment using a 5-point Likert scale: Excellent, Good, Acceptable, Poor, Very Poor. | Week 8 | 
| Part B: Physician's Global Assessment of Response to Treatment at Week 12 | The study physician made a global assessment of response to treatment using a 5-point Likert scale: Excellent, Good, Acceptable, Poor, Very Poor. | Week 12 | 
| 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 | The time it takes for the concentration level of canakinumab to fall to 50% of the original value. | 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. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Knee OA, Osteo arthritis, pain control, intra- articular injections