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

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

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.

Study Overview

• Status: Completed
• Conditions: Acute Gout
• Intervention / Treatment: Drug: Canakinumab; Drug: Canakinumab; Drug: Triamcinolone acetonide

• Study Type: Interventional
• Enrollment (Actual): 200
• Phase: Phase 2

Contacts and Locations

Study Locations

• Argentina
  • Rosario, Argentina
    • Novartis Investigative Site
• Belgium
  • Gozée, Belgium
    • Novartis Investigative Site
• Canada
  • Moncton, Canada
    • Novartis Investigative Site
  • Mount Pearl, Canada
    • Novartis Investigative Site
  • St. John's, Canada
    • Novartis Investigative Site
• France
  • Paris cedex 10, France
    • Novartis Investigative Site
• Germany
  • Bad Nauheim, Germany
    • Novartis Investigative Site
  • Bautzen, Germany
    • Novartis Investigative Site
  • Berlin, Germany
    • Novartis Investigative Site
  • Chemnitz, Germany
    • Novartis Investigative Site
  • Dachau, Germany
    • Novartis Investigative Site
  • Dresden, Germany
    • Novartis Investigative Site
  • Frankfurt, Germany
    • Novartis Investigative Site
  • Georgensgmuend, Germany
    • Novartis Investigative Site
  • Hamburg, Germany
    • Novartis Investigative Site
  • Leipzig, Germany
    • Novartis Investigative Site
  • Loehne, Germany
    • Novartis Investigative Site
  • Magdeburg, Germany
    • Novartis Investigative Site
  • Messkirch, Germany
    • Novartis Investigative Site
  • Munich, Germany
    • Novartis Investigative Site
  • Schwabach, Germany
    • Novartis Investigative Site
  • Zerbst, Germany
    • Novartis Investigative Site
• Poland
  • Poznan, Poland
    • Novartis Investigative Site
  • Szczecin, Poland
    • Novartis Investigative Site
  • Wroclaw, Poland
    • Novartis Investigative Site
• Russian Federation
  • Chelyabinsk, Russian Federation
    • Novartis Investigative Site
  • Moscow, Russian Federation
    • Novartis Investigative Site
  • St. Petersburg, Russian Federation
    • Novartis Investigative Site
  • Tyumen, Russian Federation
    • Novartis Investigative Site
  • Yaroslavl, Russian Federation
    • Novartis Investigative Site
  • Yekaterinburg, Russian Federation
    • Novartis Investigative Site
• Switzerland
  • Baden, Switzerland
    • Novartis Investigative Site
  • Basel, Switzerland
    • Novartis Investigative Site
  • Bern, Switzerland
    • Novartis Investigative Site
  • Lausanne, Switzerland
    • Novartis Investigative Site
• Turkey
  • Adana, Turkey
    • Novartis Investigative Site
  • Ankara, Turkey
    • Novartis Investigative Site
  • Antalya, Turkey
    • Novartis Investigative Site
  • Aydin, Turkey
    • Novartis Investigative Site
  • Gaziantep, Turkey
    • Novartis Investigative Site
  • Istanbul, Turkey
    • Novartis Investigative Site
  • Izmir, Turkey
    • Novartis Investigative Site
  • Manisa, Turkey
    • Novartis Investigative Site
  • Sihhiye/Ankara, Turkey
    • Novartis Investigative Site
• United Kingdom
  • Antrim, United Kingdom
    • Novartis Investigative Site
  • Coventry, United Kingdom
    • Novartis Investigative Site
  • Lancashire, United Kingdom
    • Novartis Investigative Site
  • Wellingborough, United Kingdom
    • Novartis Investigative Site
• United States
  • Alabama
    • Anniston, Alabama, United States, 36207-5710
      • Pinnacle Research Group, LLC
    • Birmingham, Alabama, United States, 35294
      • University of Alabama at Birmingham
  • California
    • Buena Park, California, United States, 90620
      • Associated Pharmaceutical Research
    • Oakland, California, United States, 94609
      • Northern California Institute for Bone Health
    • San Diego, California, United States, 92108
      • San Diego Arthritis & Osteoporosis Medical Clinic
    • West Covina, California, United States, 91790
      • Center for Clinical Trials of San Gabriel
  • Florida
    • Tampa, Florida, United States, 33614
      • Tampa Medical Group, P.A.
    • Zephyrhills, Florida, United States, 33542
      • Florida Medical Clinic, PA
  • Georgia
    • Rome, Georgia, United States, 30165
      • Harbin Clinic
  • Idaho
    • Boise, Idaho, United States, 83702
      • Intermountain Orthopedics
    • Boise, Idaho, United States, 83704
      • Northwest Clinical Trials
  • Illinois
    • Springfield, Illinois, United States, 62704
      • The Arthritis Center
  • Kansas
    • Topeka, Kansas, United States, 66606
      • Cotton O'Neil Clinic
  • Louisiana
    • Monroe, Louisiana, United States, 71203
      • Arthritis and Diabetes Clinic
  • Missouri
    • St. Louis, Missouri, United States, 63141
      • Arthritis Consultants, Inc.
  • Montana
    • Billings, Montana, United States, 59101
      • Billings Clinic Research Center
    • Missoula, Montana, United States, 59804
      • Montana Medical Research
  • Nebraska
    • Omaha, Nebraska, United States, 68134
      • Heartland Clinical Research, Inc.
  • New Mexico
    • Albuquerque, New Mexico, United States, 87106
      • New Mexico Clinical Research & Osteoporosis Center, Inc.
  • New York
    • Binghamton, New York, United States, 13905
      • Regional Clinical Research Rheumatology Assoc.
  • Pennsylvania
    • Duncansville, Pennsylvania, United States, 16635
      • Altoona Center for Clinical Research
  • South Carolina
    • Varnville, South Carolina, United States, 29944
      • Community Research Partners, Inc.
  • Tennessee
    • Hendersonville, Tennessee, United States, 37075
      • Comprehensive Rheumatology
    • Johnson City, Tennessee, United States, 37601
      • MultiSpecialty Clinical Research
    • Milan, Tennessee, United States, 38358
      • Integrity Clinical Research, LLC
  • Texas
    • Mesquite, Texas, United States, 75150
      • Southwest Rheumatology
  • Virginia
    • Newport News, Virginia, United States, 23606
      • Health Research of Hampton Roads

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Canakinumab 10 mg; 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; 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; 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.
EXPERIMENTAL: Canakinumab 25 mg; 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; 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; 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.
EXPERIMENTAL: Canakinumab 50 mg; 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; 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; 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.
EXPERIMENTAL: Canakinumab 90 mg; 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; 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; 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.
EXPERIMENTAL: Canakinumab 150 mg; 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; 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; 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.
ACTIVE_COMPARATOR: Triamcinolone acetonide 40 mg; 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; Randomized patients received triamcinolone acetonide 40 mg i.m. once and placebo matching canakinumab s.c. once, on Day 1.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Novartis

Publications and helpful links

General Publications

• Chakraborty A, Van LM, Skerjanec A, Floch D, Klein UR, Krammer G, Sunkara G, Howard D. Pharmacokinetic and pharmacodynamic properties of canakinumab in patients with gouty arthritis. J Clin Pharmacol. 2013 Dec;53(12):1240-51. doi: 10.1002/jcph.162. Epub 2013 Sep 30.
• Schlesinger N, De Meulemeester M, Pikhlak A, Yucel AE, Richard D, Murphy V, Arulmani U, Sallstig P, So A. Canakinumab relieves symptoms of acute flares and improves health-related quality of life in patients with difficult-to-treat Gouty Arthritis by suppressing inflammation: results of a randomized, dose-ranging study. Arthritis Res Ther. 2011 Mar 25;13(2):R53. doi: 10.1186/ar3297.
• So A, De Meulemeester M, Pikhlak A, Yucel AE, Richard D, Murphy V, Arulmani U, Sallstig P, Schlesinger N. Canakinumab for the treatment of acute flares in difficult-to-treat gouty arthritis: Results of a multicenter, phase II, dose-ranging study. Arthritis Rheum. 2010 Oct;62(10):3064-76. doi: 10.1002/art.27600.

Study record dates

Study Major Dates

• Study Start: November 1, 2008
• Primary Completion (ACTUAL): August 1, 2009
• Study Completion (ACTUAL): August 1, 2009

Study Registration Dates

• First Submitted: November 25, 2008
• First Submitted That Met QC Criteria: November 25, 2008
• First Posted (ESTIMATE): November 26, 2008

Study Record Updates

• Last Update Posted (ESTIMATE): April 10, 2012
• Last Update Submitted That Met QC Criteria: April 9, 2012
• Last Verified: April 1, 2012

More Information

Terms related to this study

• Keywords: Gout; Colchicine; Anti-interleukin-1β monoclonal antibody; Triamcinolone acetonide; Acute flares
• Additional Relevant MeSH Terms: Metabolic Diseases; Genetic Diseases, Inborn; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Arthritis; Metabolism, Inborn Errors; Crystal Arthropathies; Purine-Pyrimidine Metabolism, Inborn Errors; Gout; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Anti-Inflammatory Agents; Immunosuppressive Agents; Immunologic Factors; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Triamcinolone; Antibodies, Monoclonal; Triamcinolone Acetonide; Triamcinolone hexacetonide; Triamcinolone diacetate
• Other Study ID Numbers: CACZ885H2255; EudraCT 2008-004666-61