Targeted Dose Finding of Canakinumab (ACZ885) for Management of Acute Flare in Refractory or Contraindicated Gout Patients

Study Overview
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Brief Summary
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This 8-week study is designed to determine the target dose of canakinumab (ACZ885) for the management of acute flare in gout patients who are contraindicated to Non-Steroidal anti-inflammatory drugs and/or colchicine. The efficacy of ACZ885 will be compared to the corticosteroid triamcinolone acetonide.

Official Title
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An Adaptive Dose-ranging, Multi-center, Single-blind, Double-dummy, Active-controlled Trial to Determine the Target Dose of Canakinumab (ACZ885) in the Treatment of Acute Flares in Gout Patients Who Are Refractory or Contraindicated to NSAIDs and/or Colchicine

Conditions
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Acute Gout

Intervention / Treatment
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* Drug: Canakinumab
* Drug: Canakinumab
* Drug: Canakinumab
* Drug: Canakinumab
* Drug: Canakinumab
* Drug: Triamcinolone acetonide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: History of at least 1 gout flare prior to the Screening Visit Meeting the American College of Rheumatology (ACR) 1977 preliminary criteria for the classification of acute arthritis of primary gout. Presence of acute gout flare for no longer than 5 days. Baseline pain intensity > or = to 50 mm on the 0-100 mm VAS. Contraindicated for, intolerant or unresponsive to NSAIDs, colchicine or both. Exclusion Criteria: Rheumatoid arthritis, evidence/suspicion of infectious/septic arthritis, or other acute inflammatory arthritis. Presence of severe renal function impairment Contraindication to intramuscular injection Known presence or suspicion of active or recurrent bacterial, fungal or viral infection at the time of enrollment Evidence of active pulmonary disease Live vaccinations within 3 months prior to the start of the study Use of forbidden therapy Other protocol-defined inclusion/exclusion criteria applied

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Canakinumab 10 mg<br>Canakinumab 10 mg subcutaneous (s.c) once. The s.c. injection could be administered into the arm or thigh. Randomized patients received one s.c. injection of canakinumab and placebo matching triamcinolone acetonide (0.9% sodium chloride) intramuscularly (i.m.) once, on Day 1. The i.m. injection was recommended to be administered deeply into the gluteal muscle. | Drug: Canakinumab<br>* Randomized patients received one s.c. injection of canakinumab and placebo matching triamcinolone acetonide (0.9% sodium chloride) intramuscularly (i.m.) once, on Day 1. The i.m. injection was recommended to be administered deeply into the gluteal muscle.<br>|
| Experimental: Canakinumab 25 mg<br>Canakinumab 25 mg subcutaneous (s.c) once. The s.c. injection could be administered into the arm or thigh. Randomized patients received one s.c. injection of canakinumab and placebo matching triamcinolone acetonide (0.9% sodium chloride) intramuscularly (i.m.) once, on Day 1. The i.m. injection was recommended to be administered deeply into the gluteal muscle. | Drug: Canakinumab<br>* Randomized patients received one s.c. injection of canakinumab and placebo matching triamcinolone acetonide (0.9% sodium chloride) intramuscularly (i.m.) once, on Day 1.<br>|
| Experimental: Canakinumab 50 mg<br>Canakinumab 50 mg subcutaneous (s.c) once. The s.c. injection could be administered into the arm or thigh. Randomized patients received one s.c. injection of canakinumab and placebo matching triamcinolone acetonide (0.9% sodium chloride) intramuscularly (i.m.) once, on Day 1. The i.m. injection was recommended to be administered deeply into the gluteal muscle. | Drug: Canakinumab<br>* Randomized patients received one s.c. injection of canakinumab and placebo matching triamcinolone acetonide (0.9% sodium chloride) intramuscularly (i.m.) once, on Day 1.<br>|
| Experimental: Canakinumab 90 mg<br>Canakinumab 90 mg subcutaneous (s.c) once. The s.c. injection could be administered into the arm or thigh. Randomized patients received one s.c. injection of canakinumab and placebo matching triamcinolone acetonide (0.9% sodium chloride) intramuscularly (i.m.) once, on Day 1. The i.m. injection was recommended to be administered deeply into the gluteal muscle. | Drug: Canakinumab<br>* Randomized patients received one s.c. injection of canakinumab and placebo matching triamcinolone acetonide (0.9% sodium chloride) intramuscularly (i.m.) once, on Day 1.<br>|
| Experimental: Canakinumab 150 mg<br>Canakinumab 150 mg subcutaneous (s.c) once. The s.c. injection could be administered into the arm or thigh. Randomized patients received one s.c. injection of canakinumab and placebo matching triamcinolone acetonide (0.9% sodium chloride) intramuscularly (i.m.) once, on Day 1. The i.m. injection was recommended to be administered deeply into the gluteal muscle. | Drug: Canakinumab<br>* Randomized patients received one s.c. injection of canakinumab and placebo matching triamcinolone acetonide (0.9% sodium chloride) intramuscularly (i.m.) once, on Day 1.<br>|
| Active Comparator: Triamcinolone acetonide 40 mg<br>Triamcinolone acetonide 40 mg intramuscularly (i.m) once. The i.m. injection was recommended to be administered deeply into the gluteal muscle. Randomized patients received triamcinolone acetonide 40 mg i.m. once and placebo matching canakinumab s.c. once, on Day 1. | Drug: Triamcinolone acetonide<br>* Randomized patients received triamcinolone acetonide 40 mg i.m. once and placebo matching canakinumab s.c. once, on Day 1.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Dose of Canakinumab for Treatment of Acute Flares in Gout Patients That Leads to the Same Efficacy as Triamcinolone Acetonide With Respect to Pain Intensity on a 0-100 mm Visual Analog Scale (VAS) | Mean target dose at 24, 48 and 72 hours. Four models: Emax, Logistic, Linear in log-dose, Linear were selected to describe the potential dose-response curve and hence estimate the target dose of canakinumab using baseline Visual Analog Scale (VAS) and Body Mass Index (BMI) as covariates. Target dose was defined as the dose for which the efficacy is equivalent to the efficacy of triamcinolone acetonide 40 mg and was identified by assessing the dose response relationship with regards to the pain intensity in the target joint measured on a 0- 100 mm VAS (0= no pain and 100= unbearable pain). | at 24,48 and 72 hours post-baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Change in Pain Intensity in the Target Joint Following Canakinumab Administration Compared to Triamcinolone Acetonide | The change in pain intensity from baseline to 72 hours and 7 days post dose as measured on a 0-100 mm Visual Analog Scale(VAS): 0= no pain and 100= severe pain. Analysis of Covariance (ANCOVA) with treatment group, VAS at baseline and Body mass Index (BMI) at baseline as covariates. Change from baseline = (post-baseline measurement - baseline). | Baseline,at 72 hrs post-dose and 7 days post-dose | 
| Percentage of Participants With an Excellent or Good Response With Regards to the Patient's Global Assessment of Response to Treatment | Participants scored their global assessment of response to treatment using a 5-point Likert scale: Excellent, Good, Acceptable, Slight and Poor. | at 72 hours post-baseline | 
| The Time to 50% Reduction of Baseline Pain Intensity in the Target Joint | The median time in days to at least 50% reduction in Pain intensity from baseline as measured by Visual Analog Scale (VAS) for each treatment group. Participants scored their pain intensity in the target joint on a 0-100 mm VAS, ranging from no pain (0) to unbearable pain (100). | Baseline, within 7 days after randomization | 
| High Sensitivity C-reactive Protein (hsCRP) at 72 Hours, 7days, 4 Weeks and 8 Weeks Post Dose for Each Treatment Group | High sensitivity C-reactive protein (hsCRP) was determined in serum at all visits (Visits 1-5) in order to identify the presence of inflammation, to determine its severity, and to monitor response to treatment. ANCOVA with treatment group, protein level at baseline and BMI at baseline as covariates. | at 72 hours and 7 days, 4 and 8 weeks post-dose | 
| Serum Amyloid Protein (SAA) Levels at 72 Hours, 7days, 4 Weeks and 8 Weeks Post Dose for Each Treatment Group | Serum amyloid A (SAA) were determined in serum at all visits (Visits 1-5) in order to identify the presence of inflammation, to determine its severity, and to monitor response to treatment. ANCOVA with treatment group, protein level at baseline and BMI at baseline as covariates. | at 72 hours and 7 days, 4 and 8 weeks post-dose | 
| Amount of Rescue Medication Taken for Each Treatment Group | Participants who had difficulty in tolerating their pain after the 6-hour post-dose pain assessments and during the first 7 study days were allowed to take a maximum of 30 mg prednisolone (or equivalent dose of prednisone [30 mg]) orally once a day for a maximum of 5 days. In addition, participants could use 500 mg acetaminophen (paracetamol) and/or 30 mg codeine as needed during the first 7 study days. A maximum of 1 g/dose or 3 g/day of acetaminophen and 30 mg/dose or 180 mg/day of codeine was allowed during the first 7 days of the study. | 7 days after study drug administration | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute flares, Gout, Anti-interleukin-1β monoclonal antibody, Colchicine, Triamcinolone acetonide