Single-dose Study to Assess Efficacy of Canakinumab (ACZ885) in Patients With Active Juvenile Idiopathic Arthritis (SJIA) (β-SPECIFIC 1)

A Randomized, Double-blind, Placebo Controlled, Single-dose Study to Assess the Initial Efficacy of Canakinumab (ACZ885) With Respect to the Adapted ACR Pediatric 30 Criteria in Patients With Systemic Juvenile Idiopathic Arthritis (SJIA) and Active Systemic Manifestations

This study assessed the initial efficacy and safety of canakinumab over a 4 week period in patients with systemic juvenile idiopathic arthritis (SJIA) having a flare. Response to treatment will be according to the adapted American College of Rheumatology(ACR)Pediatric 30 criteria at Day 15.

Study Overview

• Status: Terminated
• Conditions: Systemic Juvenile Idiopathic Arthritis
• Intervention / Treatment: Drug: Canakinumab; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 84
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina
    • Novartis Investigative Site
  • Capital Federal, Argentina
    • Novartis Investigative Site
  • La Plata, Argentina
    • Novartis Investigative Site
• Belgium
  • Bruxelles, Belgium
    • Novartis Investigative Site
  • Gent, Belgium
    • Novartis Investigative Site
  • Laeken, Belgium
    • Novartis Investigative Site
  • Leuven, Belgium
    • Novartis Investigative Site
• Brazil
  • Curitiba, Brazil
    • Novartis Investigative Site
  • Porto Alegre, Brazil
    • Novartis Investigative Site
  • Rio de Janeiro, Brazil
    • Novartis Investigative Site
  • Sao Paulo, Brazil
    • Novartis Investigative Site
• Canada
  • Calgary, Canada
    • Novartis Investigative Site
  • British Columbia
    • Vancouver, British Columbia, Canada
      • Novartis Investigative Site
  • Nova Scotia
    • Halifax, Nova Scotia, Canada
      • Novartis Investigative Site
  • Ontario
    • Toronto, Ontario, Canada
      • Novartis Investigative Site
  • Quebec
    • Montreal, Quebec, Canada
      • Novartis Investigative Site
• Denmark
  • Arhus N, Denmark
    • Novartis Investigative Site
• France
  • Le Kremlin Bicetre, France
    • Novartis Investigative Site
  • Lyon, France
    • Novartis Investigative Site
  • Paris, France
    • Novartis Investigative Site
  • Strassbourg, France
    • Novartis Investigative Site
• Germany
  • Bad Bamstedt, Germany
    • Novartis Investigative Site
  • Berlin, Germany
    • Novartis Investigative Site
  • Bremen, Germany
    • Novartis Investigative Site
  • Dresden, Germany
    • Novartis Investigative Site
  • Freiburg, Germany
    • Novartis Investigative Site
  • Garmisch-Partenkirch, Germany
    • Novartis Investigative Site
  • Geissen, Germany
    • Novartis Investigative Site
  • Hamburg, Germany
    • Novartis Investigative Site
  • Hannover, Germany
    • Novartis Investigative Site
  • Krefeld, Germany
    • Novartis Investigative Site
  • Mainz, Germany
    • Novartis Investigative Site
  • Muenster, Germany
    • Novartis Investigative Site
  • Saint Augustin, Germany
    • Novartis Investigative Site
  • Stuttgart, Germany
    • Novartis Investigative Site
  • Tubingen, Germany
    • Novartis Investigative Site
• Greece
  • Thessaloniki, Greece
    • Novartis Investigative Site
• Hungary
  • Budapest, Hungary
    • Novartis Investigative Site
• Israel
  • Haifa, Israel
    • Novartis Investigative Site
  • Kfar Saba, Israel
    • Novartis Investigative Site
  • Petach-Tikva, Israel
    • Novartis Investigative Site
  • Ramat Gan, Israel
    • Novartis Investigative Site
  • Rehovot, Israel
    • Novartis Investigative Site
• Italy
  • Bologna, Italy
    • Novartis Investigative Site
  • Firenze, Italy
    • Novartis Investigative Site
  • Genova, Italy
    • Novartis Investigative Site
  • Milano, Italy
    • Novartis Investigative Site
  • Napoli, Italy
    • Novartis Investigative Site
  • Padova, Italy
    • Novartis Investigative Site
  • Rome, Italy
    • Novartis Investigative Site
  • Scafati, Italy
    • Novartis Investigative Site
  • Torino, Italy
    • Novartis Investigative Site
• Netherlands
  • Utrecht, Netherlands
    • Novartis Investigative Site
• Norway
  • Oslo, Norway
    • Novartis Investigative Site
• Peru
  • Lima, Peru
    • Novartis Investigative Site
• Poland
  • Warszawa, Poland
    • Novartis Investigative Site
• South Africa
  • Pretoria, South Africa
    • Novartis Investigative Site
  • Durban
    • Berea, Durban, South Africa
      • Novartis Investigative Site
    • Mayville, Durban, South Africa
      • Novartis Investigative Site
• Spain
  • Barcelona, Spain
    • Novartis Investigative Site
  • Madrid, Spain
    • Novartis Investigative Site
  • Valencia, Spain
    • Novartis Investigative Site
• Sweden
  • Stockholm, Sweden
    • Novartis Investigative Site
• Switzerland
  • Bern, Switzerland
    • Novartis Investigative Site
  • Lausanne, Switzerland
    • Novartis Investigative Site
  • Zurich, Switzerland
    • Novartis Investigative Site
• Turkey
  • Ankara, Turkey
    • Novartis Investigative Site
  • Istanbul, Turkey
    • Novartis Investigative Site
  • Izmir, Turkey
    • Novartis Investigative Site
• United Kingdom
  • Birmingham, United Kingdom
    • Novartis Investigative Site
  • Liverpool, United Kingdom
    • Novartis Investigative Site
  • London, United Kingdom
    • Novartis Investigative Site
  • Manchester, United Kingdom
    • Novartis Investigative Site
  • New Castle Upon Tyne, United Kingdom
    • Novartis Investigative Site
  • Norwich, United Kingdom
    • Novartis Investigative Site
  • Oxford, United Kingdom
    • Novartis Investigative Site
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama at Birmingham
  • Arkansas
    • Little Rock, Arkansas, United States, 72202
      • Arkansas Children's Hospital Research Inst
  • California
    • Los Angeles, California, United States, 90027
      • Children's Hospital Los Angeles
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Children's National Medical Center
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University Of Chicago Medical Center
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • University of Louisville
  • Massachusetts
    • Boston, Massachusetts, United States, 02111
      • Tufts Medical Center
    • Boston, Massachusetts, United States, 02111
      • Tufts New England Medical Center-Dept. of Allergy
  • New Jersey
    • Livingston, New Jersey, United States, 07039
      • St. Barnabas Ambulatory Care Center
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Children's Hospital Medical Center
    • Cinncinati, Ohio, United States, 45229
      • Children's Hospital/Neurology
    • Columbus, Ohio, United States, 43205
      • Nationwide Children's Hospital
  • Oregon
    • Portland, Oregon, United States, 97227
      • Legacy Emanuel Hospital
    • Portland, Oregon, United States, 97232
      • Legacy Emanual Research
  • Texas
    • Austin, Texas, United States, 78723
      • Specially For Children

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 19 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Confirmed diagnosis of systemic juvenile idiopathic arthritis as per ILAR definition that must have occurred at least 2 months prior to enrollment with onset of disease < 16 years of age:

   • Arthritis in one or more joints with or preceded by fever of at least 2 weeks duration that is documented to be daily/quotidian for at least 3 days and accompanied by one or more of the following:
   • evanescent nonfixed erythematous rash,
   • generalized lymph node enlargement,
   • hepatomegaly and/ or splenomegaly,
   • serositis
2. Parent's or legal guardian's written informed consent and child's assent, if appropriate, or patient's informed consent for ≥ 18 years of age
3. Male and female patients aged ≥ 2 to < 20 years of age

4. Active disease at the time of enrollment defined as follows:

   • At least 2 joints with active arthritis
   • Documented spiking, intermittent fever (body temperature > 38°C) for at least 1 day during the screening period within 1 week before first canakinumab/placebo dose
   • C-reactive protein (CRP) > 30 mg/L (normal range < 10 mg/L)
5. Naïve to canakinumab
6. Other protocol defined inclusion criteria may apply

Exclusion Criteria:

Patients who fulfilled one or more of the following criteria were not eligible for inclusion in this study:

1. Pregnant or nursing (lactating) female patients
2. Female patients having reached sexual maturity unless their career, lifestyle, or sexual orientation precluded intercourse with a male partner and/or they were using an acceptable method of contraception
3. History of hypersensitivity to study drug or to biologics.
4. Diagnosis of active macrophage-activation syndrome (MAS) (Ravelli, Magni-Manzoni and Pistorio 2005) within the last 6 months
5. With active or recurrent bacterial, fungal or viral infection, including patients with evidence of human immunodeficiency virus (HIV) infection, hepatitis B or hepatitis C infection
6. Other protocol defined exclusion criteria may apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Canakinumab; Patients received a single dose of subcutaneous(sc) injection of canakinumab (4 mg/kg) on Day 1. Maximal total single dose of canakinumab allowed was 300 mg. Any patient who required a dose greater than 150 mg (patients>37.5 kg) received two sc injections.	Drug: Canakinumab; Canakinumab was supplied in individual 6 mL glass vials each containing 150 mg canakinumab powder as a lyophilized cake. Each reconstituted vial provided 150mg of canakinumab per 1 mL.; Other Names: ACZ885
Placebo Comparator: Placebo; Patients received a single dose matching placebo of canakinumab on day 1.	Drug: Placebo; Placebo was provided in individual 6 mL glass vials each containing 150 mg placebo powder matching canakinumab as a lyophilized cake. Each reconstitued vial provided 150mg of placebo per 1 mL.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Patients Who Meet the Adapted American College of Rheumatology (ACR) Pediatric 30 Criteria	Adapted ACR Pediatric 30 criteria determined responders (improved from baseline of at least 30% in at least 3 response variables 1-6 and no intermittent fever in preceding week [variable 7], with no more than one variable 1-6 worsening > 30% ) 1. Physician's Global Assessment of disease activity: 0-100 mm VAS 2.Parent/Patient's Global Assessment of Patient's overall wellbeing: 0-100mmVAS in Child Health Assessment Questionnaire (CHAQ) 3. Functional ability: CHAQ 4.Number of joints with active arthritis 5. Number of joints with limited of motion 6. Laboratory measure of inflammation CRP (mg/L)	Baseline, Day 15, Day 29

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Patients Achieving the Adapted ACR Pediatric 50 Criteria	Adapted ACR Pediatric 50 criteria determined responders (improved from baseline of at least 50% in at least 3 response variables 1-6 and no intermittent fever in preceding week [variable 7], with no more than one variable 1-6 worsening > 30%) 1. Physician's Global Assessment of disease activity: 0-100 mm VAS 2. Parent/Patient's Global Assessment of Patient's overall wellbeing: 0-100mmVAS in Child Health Assessment Questionnaire (CHAQ) 3. Functional ability: CHAQ 4. Number of joints with active arthritis 5. Number of joints with limited of motion 6. Laboratory measure of inflammation CRP (mg/L)	Baseline, Day 15, Day 29
Percentage of Patients Achieving the Adapted ACR Pediatric 70	Adapted ACR Pediatric 70 criteria determined responders (improved from baseline of at least 70% in at least 3 response variables 1-6 and no intermittent fever in preceding week [variable 7], with no more than one variable 1-6 worsening > 30% ) 1. Physician's Global Assessment of disease activity: 0-100 mm VAS 2. Parent/Patient's Global Assessment of Patient's overall wellbeing: 0-100mmVAS in Child Health Assessment Questionnaire (CHAQ) 3. Functional ability: CHAQ 4. Number of joints with active arthritis 5. Number of joints with limited of motion 6. Laboratory measure of inflammation CRP(mg/L)	Baseline, Day 15, Day 29
Percentage of Patients Achieving the Adapted ACR Pediatric 90	Adapted ACR Pediatric 90 criteria determined responders (improved from baseline of at least 90% in at least 3 response variables 1-6 and no intermittent fever in preceding week [variable 7], with no more than one variable 1-6 worsening > 30% ) 1. Physician's Global Assessment of disease activity: 0-100 mm VAS 2. Parent/Patient's Global Assessment of Patient's overall wellbeing: 0-100mmVAS in Child Health Assessment Questionnaire (CHAQ) 3. Functional ability: CHAQ 4. Number of joints with active arthritis 5. Number of joints with limited of motion 6. Laboratory measure of inflammation CRP(mg/L)	Baseline, Day 15, Day 29
Percentage of Patients Achieving the Adapted ACR Pediatric 100	Adapted ACR Pediatric 100 criteria determined responders (ie improved from baseline of at least 100% in at least 3 response variables 1-6 and no intermittent fever in preceding week [variable 7], with no more than one variable 1-6 worsening > 30% ) 1. Physician's Global Assessment of disease activity: 0-100 mm VAS 2. Parent/Patient's Global Assessment of Patient's overall wellbeing: 0-100mmVAS in Child Health Assessment Questionnaire (CHAQ) 3. Functional ability: CHAQ 4. Number of joints with active arthritis 5. Number of joints with limited of motion 6. Laboratory measure of inflammation	baseline, Day 15, Day 29
Change in Patient's Pain Intensity as Assessed on a 100-mm Visual Analog Scale (VAS)as Part of the Childhood Health Assessment Questionnaire(CHAQ)	CHAQ assessed physical ability and functional status of patients as well as quality of life. The disability dimension consisted of 20 multiple choice items about difficulty in doing eight common activities of daily living; dressing and grooming, arising, eating, walking, reaching, personal hygiene, gripping and activities. Four response categories range from 'without any difficulty' (0) to 'unable to do' (3). The parent's or patient's pain assessment was on VAS that was part of CHAQ. The VAS scale ranges from no pain (0 mm) to very severe pain (100 mm). Negative change indicates improvement.	Baseline, Day 15
Change in Patient's Pain Intensity as Assessed on a 100-mm Visual Analog Scale (VAS) as Part of CHAQ	CHAQ, assessed physical ability and functional status of patients as well as quality of life. The disability dimension consisted of 20 multiple choice items about difficulty in doing eight common activities of daily living; dressing and grooming, arising, eating, walking, reaching, personal hygiene, gripping and activities. Four response categories range from 'without any difficulty'(0) to 'unable to do' (3). The parent's or patient's pain assessment was on VAS that was part of CHAQ. The VAS scale ranges from no pain (0 mm) to very severe pain (100 mm). Negative change indicates improvement.	Baseline, Day 29
Percentage of Patients Who Had Body Temperature ≤ 38°C	Body temperature was derived from vital signs evaluation. No conversion of body temperature was performed, no matter how it was measured.	Day 3
Change in Health-related Quality of Life (HRQoL)Over Time by Use of the Child Health Questionnaire - Parent Form (CHQ-PF50)	CHQ-PF50 measures HRQoL in children 5-18 years old from parent's perspective. Questionnaire completed by parent without input from patient. Total score ranges from 0-100. Increases in scores represent improved well-being in subjects as assessed by their parents. Mixed linear model on change from baseline in CHQ-PF50 score with treatment group, stratification factors, day of assessment and interaction between group and day as covariates. Covariance analysis used a repeated measures approach, so all timepoints over time were taken into account.	Over 4 week study period (Baseline, Day 15, Day 29)
Change in Disability Score Over Time by Use of the CHAQ	The disability dimension of CHAQ consisted of 20 multiple choice items about difficulty in doing eight common activities of daily living; dressing and grooming, arising, eating, walking, reaching, personal hygiene, gripping and activities. Four response categories range from 'without any difficulty'(0) to 'unable to do' (3). Mixed linear model on change from baseline in CHAQ score included treatment group, stratification factors, day of assessment and interaction between group and day as covariates. Negative change indicates improvement.	At 4 week study period

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Collaborators: International Maternal Pediatric Adolescent AIDS Clinical Trials Group; Southwest Pediatric Nephrology Study Group

Publications and helpful links

General Publications

• Ruperto N, Brunner HI, Quartier P, Constantin T, Wulffraat NM, Horneff G, Kasapcopur O, Schneider R, Anton J, Barash J, Berner R, Corona F, Cuttica R, Fouillet-Desjonqueres M, Fischbach M, Foster HE, Foell D, Radominski SC, Ramanan AV, Trauzeddel R, Unsal E, Levy J, Vritzali E, Martini A, Lovell DJ; Paediatric Rheumatology International Trials Organisation (PRINTO) and the Pediatric Rheumatology Collaborative Study Group (PRCSG). Canakinumab in patients with systemic juvenile idiopathic arthritis and active systemic features: results from the 5-year long-term extension of the phase III pivotal trials. Ann Rheum Dis. 2018 Dec;77(12):1710-1719. doi: 10.1136/annrheumdis-2018-213150. Epub 2018 Sep 29.
• Brachat AH, Grom AA, Wulffraat N, Brunner HI, Quartier P, Brik R, McCann L, Ozdogan H, Rutkowska-Sak L, Schneider R, Gerloni V, Harel L, Terreri M, Houghton K, Joos R, Kingsbury D, Lopez-Benitez JM, Bek S, Schumacher M, Valentin MA, Gram H, Abrams K, Martini A, Lovell DJ, Nirmala NR, Ruperto N; Pediatric Rheumatology International Trials Organization (PRINTO) and the Pediatric Rheumatology Collaborative Study Group (PRCSG). Early changes in gene expression and inflammatory proteins in systemic juvenile idiopathic arthritis patients on canakinumab therapy. Arthritis Res Ther. 2017 Jan 23;19(1):13. doi: 10.1186/s13075-016-1212-x.
• Ruperto N, Brunner HI, Quartier P, Constantin T, Wulffraat N, Horneff G, Brik R, McCann L, Kasapcopur O, Rutkowska-Sak L, Schneider R, Berkun Y, Calvo I, Erguven M, Goffin L, Hofer M, Kallinich T, Oliveira SK, Uziel Y, Viola S, Nistala K, Wouters C, Cimaz R, Ferrandiz MA, Flato B, Gamir ML, Kone-Paut I, Grom A, Magnusson B, Ozen S, Sztajnbok F, Lheritier K, Abrams K, Kim D, Martini A, Lovell DJ; PRINTO; PRCSG. Two randomized trials of canakinumab in systemic juvenile idiopathic arthritis. N Engl J Med. 2012 Dec 20;367(25):2396-406. doi: 10.1056/NEJMoa1205099.
• Grom AA, Ilowite NT, Pascual V, Brunner HI, Martini A, Lovell D, Ruperto N; Paediatric Rheumatology International Trials Organisation and the Pediatric Rheumatology Collaborative Study Group; Leon K, Lheritier K, Abrams K. Rate and Clinical Presentation of Macrophage Activation Syndrome in Patients With Systemic Juvenile Idiopathic Arthritis Treated With Canakinumab. Arthritis Rheumatol. 2016 Jan;68(1):218-28. doi: 10.1002/art.39407.

Helpful Links

• Related Info
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Study record dates

Study Major Dates

• Study Start: July 1, 2009
• Primary Completion (Actual): December 1, 2010
• Study Completion (Actual): January 1, 2011

Study Registration Dates

• First Submitted: April 22, 2009
• First Submitted That Met QC Criteria: April 22, 2009
• First Posted (Estimate): April 23, 2009

Study Record Updates

• Last Update Posted (Actual): March 29, 2017
• Last Update Submitted That Met QC Criteria: February 28, 2017
• Last Verified: February 1, 2017

More Information

Terms related to this study

• Keywords: arthritis; Flare; IL-1beta antagonist; systemic juvenile idiopathic arthritis; Juvenile Rheumatoid; Systemic juvenile idiopathic arthritis with active flare
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Arthritis, Juvenile
• Other Study ID Numbers: CACZ885G2305; EudraCT: 2008-005476-27