A Study of the Efficacy of Canakinumab in Prevention of Acute Flares in Chronic Gout Patients Initiating Allopurinol Therapy (Core Study) and a Long-term Study of the Efficacy and Safety of Canakinumab in Patients With Gout (Extension Study)

Study Overview
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Brief Summary
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The 24-week, dose-ranging, multi-center, double-blind, double-dummy, active-controlled core study investigated the prophylactic effect of canakinumab on the signs and symptoms of acute flares in chronic gout patients initiating allopurinol therapy. The core study was followed by a 24-week open-label, multicenter extension study to assess the safety, tolerability, and efficacy of canakinumab in patients with gout who were given canakinumab at the time of gout flare.

Official Title
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A 24-week, Dose-ranging, Multicenter, Double-blind, Double-dummy, Active-controlled Core Study to Evaluate Canakinumab for Prophylaxis of Signs and Symptoms of Acute Flares in Chronic Gout Patients Initiating Allopurinol Therapy and a 24-week Open-label, Multicenter Extension Study to Assess Safety, Tolerability and Efficacy of Canakinumab in Patients With Gout Who Are Given Canakinumab at the Time of Gout Flare

Conditions
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Gout

Intervention / Treatment
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* Drug: Canakinumab
* Drug: Colchicine
* Drug: Allopurinol
* Drug: Placebo Matching Canakinumab
* Drug: Placebo Matching Colchicine


Participation Criteria
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Eligibility Criteria
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Core study Inclusion Criteria: Signed written informed consent before any study procedure is performed. History of at least 2 gout flares in the year prior to Screening (Visit 1, based on patient history), thus, candidates for initiating uric acid lowering therapy. Confirmed diagnosis of gout meeting the American College of Rheumatology (ACR) 1977 preliminary criteria for the classification of arthritis of primary gout. Body Mass Index (BMI) ≤ 40 kg/m^2. Willingness to initiate allopurinol therapy as urate lowering agent for their gout therapy or having initiated allopurinol therapy within ≤ 1 month before Screening (Visit 1) or willing to re-initiate allopurinol therapy if this was stopped > 2 months before Screening (Visit 1) for reasons different to toxicity/ intolerance or lack of efficacy. Exclusion Criteria: Acute gout flare within 2 weeks of Screening (Visit 1) and during the Screening period. History of allergy or contraindication to colchicine or allopurinol. History of intolerance to allopurinol or to oral colchicine in appropriate dose for prophylactic use. History of bone marrow suppression. Absolute or relative contraindication to both naproxen and oral prednisolone/ prednisone. Extension study Inclusion criteria: Patients who completed the core study. A patient is defined as completing the core study if he/she completed the study up to and including the last visit (Visit 9). Patients who have signed a written informed consent before any trial procedure is performed. Exclusion Criteria: Patients for whom continuation in the extension study is not considered appropriate by the treating physician. 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). Other protocol-defined inclusion/exclusion criteria applied to the study.

Ages Eligible for Study
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Minimum Age: 18 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Core study: Canakinumab 25 mg<br>Canakinumab 25 mg subcutaneously (sc) once at Day 1, placebo sc at Days 29, 57, and 85 plus daily placebo capsules for 16 weeks. Allopurinol treatment was initiated at the latest at baseline (Visit 2) according to the patient's renal function / estimated creatinine clearance at screening (Visit 1). Allopurinol was administered orally to all randomized patients once daily (100 mg-300 mg) for 24 weeks. | Drug: Canakinumab<br>* Canakinumab was supplied in glass vials as a lyophilized powder.<br>Drug: Allopurinol<br>* 100-300 mg orally once daily for 24 weeks.<br>Drug: Placebo Matching Canakinumab<br>* Subcutaneous injection.<br>Drug: Placebo Matching Colchicine<br>* Capsule orally once daily for 16 weeks.<br>|
| Experimental: Core study: Canakinumab 50 mg<br>Canakinumab 50 mg sc once at Day 1, placebo sc at Days 29, 57, and 85 plus daily placebo capsules for 16 weeks. Allopurinol treatment was initiated at the latest at baseline (Visit 2) according to the patient's renal function / estimated creatinine clearance at screening (Visit 1). Allopurinol was administered orally to all randomized patients once daily (100 mg-300 mg) for 24 weeks. | Drug: Canakinumab<br>* Canakinumab was supplied in glass vials as a lyophilized powder.<br>Drug: Allopurinol<br>* 100-300 mg orally once daily for 24 weeks.<br>Drug: Placebo Matching Canakinumab<br>* Subcutaneous injection.<br>Drug: Placebo Matching Colchicine<br>* Capsule orally once daily for 16 weeks.<br>|
| Experimental: Core study: Canakinumab 100 mg<br>Canakinumab 100 mg sc once at Day 1, placebo sc at Days 29, 57, and 85 plus daily placebo capsules for 16 weeks. Allopurinol treatment was initiated at the latest at baseline (Visit 2) according to the patient's renal function / estimated creatinine clearance at screening (Visit 1). Allopurinol was administered orally to all randomized patients once daily (100 mg-300 mg) for 24 weeks. | Drug: Canakinumab<br>* Canakinumab was supplied in glass vials as a lyophilized powder.<br>Drug: Allopurinol<br>* 100-300 mg orally once daily for 24 weeks.<br>Drug: Placebo Matching Canakinumab<br>* Subcutaneous injection.<br>Drug: Placebo Matching Colchicine<br>* Capsule orally once daily for 16 weeks.<br>|
| Experimental: Core study: Canakinumab 200 mg<br>Canakinumab 100 mg sc once at Day 1, placebo sc at Days 29, 57, and 85 plus daily placebo capsules for 16 weeks. Allopurinol treatment was initiated at the latest at baseline (Visit 2) according to the patient's renal function / estimated creatinine clearance at screening (Visit 1). Allopurinol was administered orally to all randomized patients once daily (100 mg-300 mg) for 24 weeks. | Drug: Canakinumab<br>* Canakinumab was supplied in glass vials as a lyophilized powder.<br>Drug: Allopurinol<br>* 100-300 mg orally once daily for 24 weeks.<br>Drug: Placebo Matching Canakinumab<br>* Subcutaneous injection.<br>Drug: Placebo Matching Colchicine<br>* Capsule orally once daily for 16 weeks.<br>|
| Experimental: Core study: Canakinumab 300 mg<br>Canakinumab 300 mg sc once at Day 1, placebo sc at Days 29, 57, and 85 plus daily placebo capsules for 16 weeks. Allopurinol treatment was initiated at the latest at baseline (Visit 2) according to the patient's renal function / estimated creatinine clearance at screening (Visit 1). Allopurinol was administered orally to all randomized patients once daily (100 mg-300 mg) for 24 weeks. | Drug: Canakinumab<br>* Canakinumab was supplied in glass vials as a lyophilized powder.<br>Drug: Allopurinol<br>* 100-300 mg orally once daily for 24 weeks.<br>Drug: Placebo Matching Canakinumab<br>* Subcutaneous injection.<br>Drug: Placebo Matching Colchicine<br>* Capsule orally once daily for 16 weeks.<br>|
| Experimental: Core study: Canakinumab q4wk<br>Canakinumab 50 mg sc at Days 1, and 29 followed by canakinumab 25 mg sc on Days 57, and 85 plus daily placebo capsules for 16 weeks, repeated every 4 week (q4wk). Allopurinol treatment was initiated at the latest at baseline (Visit 2) according to the patient's renal function / estimated creatinine clearance at screening (Visit 1). Allopurinol was administered orally to all randomized patients once daily (100 mg-300 mg) for 24 weeks. | Drug: Canakinumab<br>* Canakinumab was supplied in glass vials as a lyophilized powder.<br>Drug: Allopurinol<br>* 100-300 mg orally once daily for 24 weeks.<br>Drug: Placebo Matching Colchicine<br>* Capsule orally once daily for 16 weeks.<br>|
| Active Comparator: Core study: Colchicine 0.5 mg<br>Colchicine 0.5 mg capsule orally once daily throughout the whole treatment phase of 16 weeks plus placebo matching canakinumab s.c. at Days 1, 29, 57, and 85. Allopurinol treatment was initiated at the latest at baseline (Visit 2) according to the patient's renal function / estimated creatinine clearance at screening (Visit 1). Allopurinol was administered orally to all randomized patients once daily (100 mg-300 mg) for 24 weeks. | Drug: Colchicine<br>* 0.5 mg capsule orally once daily for 16 weeks.<br>Drug: Allopurinol<br>* 100-300 mg orally once daily for 24 weeks.<br>Drug: Placebo Matching Canakinumab<br>* Subcutaneous injection.<br>|
| Experimental: Extension study: Group A<br>Participants who were randomized to canakinumab in the core study and were treated with canakinumab for at least 1 flare in the extension study. | Drug: Canakinumab<br>* Canakinumab was supplied in glass vials as a lyophilized powder.<br>|
| Experimental: Extension study: Group B<br>Patients who were randomized to canakinumab in the core study but did not receive treatment with canakinumab in the extension study. | Drug: Canakinumab<br>* Canakinumab was supplied in glass vials as a lyophilized powder.<br>|
| Experimental: Extension study: Group C<br>Patients who were randomized to colchicine in the core study and were treated with canakinumab for at least 1 flare in the extension study. | Drug: Canakinumab<br>* Canakinumab was supplied in glass vials as a lyophilized powder.<br>Drug: Colchicine<br>* 0.5 mg capsule orally once daily for 16 weeks.<br>|
| Experimental: Extension study: Group D<br>Patients who were randomized to colchicine in the core study but did not receive treatment with canakinumab in the extension study. | Drug: Colchicine<br>* 0.5 mg capsule orally once daily for 16 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Core Study: Mean Number of Gout Flares Per Participant | A gout flare was defined as an increase in participant-reported gout pain in the most affected joint during a gout attack. | Baseline of the core study to Week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Core Study: Mean Number of Gout Flares for the Repeat Dose Regimen of Canakinumab as Compared to the Single Doses of Canakinumab |  | up to 16 weeks after randomization | 
| Core Study: Percentage of Participants With at Least 1 Gout Flare Within 16 Weeks After Randomization | The percentage of participants experiencing at least 1 gout flare within 16 weeks after randomization. A gout flare was defined as an increase in participant-reported gout pain in the most affected joint during a gout attack. | Baseline of the core study to Week 16 | 
| Core Study: Percentage of Participants With Gout Flare at Different Time Points | A gout flare was defined as an increase in participant-reported gout pain in the most affected joint during a gout attack. | Days 2, 4, 6, and Weeks 2, 4, 6, 10, and 16 of the core study | 
| Core Study: Participant's Assessment of Gout Pain on a 0-100 mm Visual Analog Scale up to Day 7 of All Gout Flares | Participants rated the intensity of pain in the most affected joint on a 0-100 mm visual analog scale, which ranged from no pain (left end, 0) to unbearable pain (right end, 100). Participants assessed pain intensity on the day of onset of the gout flare and in the morning of the 6 following days. | Baseline of the core study to Week 16 | 
| Core Study: Participant's Assessment of Gout Pain on a 5-point Likert Scale up to Day 7 of All Gout Flares | Participants assessed the intensity of pain in the most affected joint on a 5-point Likert scale, which ranged from 1 to 5 (1=None, 2=Mild, 3=Moderate, 4=Severe, 5=Extreme). Participants assessed pain intensity on the day of onset of the gout flare and in the morning of the 6 following days. | Baseline of the core study to Week 16 | 
| Core Study: Physician's Global Assessment of Response to Therapy on a 5-point Likert Scale | The study physician made a global assessment of the participant's response to treatment on a 5-point Likert scale (Very good, Good, Fair, Poor, Very poor) at Days 15, 29, 57, 85, 113, and 141. The category 'Not assessed' includes missing data and 'not done'. The number of participants in each of the 5 categories of the Likert scale are reported. | Days 15, 29, 57, 85, 113, and 141 of the core study | 
| Extension Study: Participant's Assessment of Gout Pain on a 100 mm Visual Analog Scale During the First Flare | Participant's rated the intensity of pain in the most affected joint during the first flare on a 0-100 mm visual analog scale, which ranged from no pain (left end, 0) to unbearable pain (right end, 100). Assessments were made pre-dose and 24 hours, 3 days, 4 days, and an average of 5-7 days post-dose | Baseline of the extension study until 7 days after the onset of the first gout flare (up to 24 weeks) | 
| Extension Study: Participant's Global Assessment of Response to Treatment on a 5-point Likert Scale | Study participants made a global assessment of their response to treatment on a 5-point Likert scale (Excellent, Good, Acceptable, Slight, Poor) at the control visit 7±2 days following each of their first 3 flares. The number of participants in each of the 5 categories of the Likert scale are reported. | Baseline of the extension study until the end of the study (up to 24 weeks) | 
| Extension Study: Physician's Global Assessment of Response to Treatment on a 5-point Likert Scale | The study physician made a global assessment of the participant's response to treatment on a 5-point Likert scale (Very good, Good, Fair, Poor, Very poor) at the control visit 7±2 days following each of the first 3 flares. The category 'Not assessed' includes missing data and 'not done'. The number of participants in each of the 5 categories of the Likert scale are reported. | Baseline of the extension study until the end of the study (up to 24 weeks) | 
| Extension Study: Physician's Assessment of Tenderness, Swelling, and Erythema in the Most Affected Joint During the First Flare | Tenderness was rated on a 0-3 point scale: 0=no pain, 1=patient states that there is pain, 2=patient states there is pain and winces, and 3=patient states there is pain, winces and withdraws on palpation or passive movement of the most affected joint. Swelling was rated on a 0-3 point scale: 0=no swelling, 1=palpable, 2=visible, and 3=bulging beyond the joint margins. Erythema was rated as present, absent, or not assessable. Assessments were performed at the flare and control visits. | Baseline of the extension study until the end of the study (up to 24 weeks) | 
| Extension Study: Amount of Rescue Medication Taken | The amount of naproxen and prednisolone taken after receiving treatment for each of the first 3 flares was recorded. | Baseline of the extension study until the end of the study (up to 24 weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gout, Chronic gout, Gouty arthritis, Gout flares