Flare Prevention Study of Canakinumab in Patients With Active Systemic Juvenile Idiopathic Arthritis (SJIA) (β-SPECIFIC 2)

A Randomized, Double-blind, Placebo Controlled, Withdrawal Study of Flare Prevention of Canakinumab (ACZ885) in Patients With Systemic Juvenile Idiopathic Arthritis (SJIA) and Active Systemic Manifestations

This two-part study assessed the sustained efficacy of canakinumab in the double-blind Part II and the ability to taper steroids in the open label Part I.

Study Overview

• Status: Completed
• Conditions: Systemic Juvenile Idiopathic Arthritis With Active Flare
• Intervention / Treatment: Drug: canakinumab; Drug: placebo

• Study Type: Interventional
• Enrollment (Actual): 177
• 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 Janiero, Brazil
    • Novartis Investigative Site
  • Sao Paulo, Brazil
    • Novartis Investigative Site
• Canada
  • 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
• France
  • Le Kremlin Bicetre, France
    • Novartis Investigative Site
  • Lyon, France
    • Novartis Investigative Site
  • Paris, France
    • Novartis Investigative Site
  • Strasbourg, France
    • Novartis Investigative Site
• Germany
  • Bad Bamstedt, Germany
    • Novartis Investigative Site
  • Berlin, Germany
    • Novartis Investigative Site
  • Bremen, Germany
    • Novartis Investigative Site
  • Freiburg, Germany
    • Novartis Investigative Site
  • Geissen, Germany
    • Novartis Investigative Site
  • Hamburg, Germany
    • Novartis Investigative Site
  • Muenster, Germany
    • Novartis Investigative Site
  • Saint Augustin, Germany
    • Novartis Investigative Site
  • Stuttgart, Germany
    • 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
  • Johannesburg, South Africa
    • Novartis Investigative Site
  • 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 States
  • Arkansas
    • Little Rock, Arkansas, United States, 72202
      • Arkansas Children's Hospital Research Inst
  • 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
      • New England Medical Center - Department 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
    • Cincinnati, Ohio, United States, 45229
      • Children's Hospital/Neurology
  • 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:

• Confirmed diagnosis of systemic juvenile idiopathic arthritis as per International League Against Rheumatism (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 for at least 3 days with accompanying symptoms

• Active disease at the time of enrollment defined as follows:

  • At least 2 joints with active arthritis (using American College of rheumatology) ACR definition of active joint)
  • Documented spiking, intermittent fever (body temperature > 38oC) for at least 1 day during the screening period within 1 week before first study drug dose
  • C-reactive protein > 30 mg/L (normal range < 10 mg/L)

• No concomitant use of second line agents such as disease-modifying and/ or immunosuppressive drugs will be allowed with the exception of:

  • Stable dose of methotrexate for at least 8 weeks prior to the screening visit, and/or folic/folinic acid per standard medical practice
  • Stable dose of no more than one non-steroidal anti-inflammatory drug for at least 2 weeks prior to the screening visit
  • Stable dose of steroid treatment < or = to 1.0 mg/kg/day in 1-2 doses per day of oral prednisone or equivalent

Exclusion criteria:

• Diagnosis of active macrophage-activation syndrome (MAS) within the last 6 months
• Risk factors for tuberculosis
• Patients with active or recurrent bacterial, fungal or viral infection at the time of enrollment, including patients with evidence of HIV infection, Hepatitis B and Hepatitis C infection

Other protocol inclusion/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; In Part I participants received open label 4 mg/kg canakinumab subcutaneous injection every 4 weeks for up to 32 weeks. For the first 8 weeks Part Ia (4 weeks) and Ib (4 weeks) patients maintained a stable oral steroid dose (prednisone or equivalent) followed by Ic an up to 20 week steroid tapering period and then Id a 4 week stable steroid dose period. Participants were then randomized to receive either 4 mg/kg canakinumab subcutaneous injection or placebo comparator in Part II and remained on the stable oral steroid dose for 24 weeks. At 24 weeks in Part II participants with a >0.2 mg/kg and ≤ 0.5 mg/kg and no flare could restart steroid tapering. If the steroid dose was ≤ 0.2 mg/kg participants continued to maintain their current dose for the remainder of Part II.	Drug: canakinumab; Canakinumab 4 mg/kg dose subcutaneous injection supplied as 6 mL glass vials each containing 150 mg canakinumab as a lyophilized cake.
Placebo Comparator: Placebo; Participants in Part II received placebo matching canakinumab subcutaneous injection every 4 weeks. At 24 weeks in Part II participants with a >0.2 mg/kg and ≤0.5 mg/kg and no flare could restart steroid tapering. If the steroid dose was ≤0.2 mg/kg participants continued to maintain their current dose for the remainder of Part II.	Drug: placebo; Placebo powder matching canakinumab supplied as 6 mL glass vials containing a lyophilized cake for subcutaneous injection every 4 weeks in Part II.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part I: Percentage of Patients Who Were on Steroids at Entry Into Part I and Who Were Able to Taper Steroid as Per Protocol in at Least 25% of the Patients Who Entered the Study Taking a Steroid	Ability to taper oral steroids: if dose reduced from start of Part I to end of Part Ic from > 0.8 mg/kg/day to ≤ 0.5 mg/kg/day, or from ≥ 0.5 mg/kg/day and ≤ 0.8 mg/kg/day by at least 0.3 mg/kg, or from any initial dose to ≤ 0.2 mg/kg/day, while maintaining a minimum adapted ACR 30 pediatric criterion. Patients on oral steroids at study entry who did not enter Part 1c are considered steroid tapering failures.	32 Weeks
Part II: Survival Estimate of Time to Flare	Kaplan Meier estimate of the probability to experience a flare. Flare was defined as at least 1 of the following.; Reappearance of fever (>38°C, lasting for at least 2 consecutive days) not due to infections; Flare according to the JIA pediatric criteria for flare (all criteria must have been met):; ≥ 30% worsening in at least 3 of the first 6 response variables; ≥ 30% improvement in not more than 1 of the first 6 response variables Patients who discontinued the study while in Part II were counted as flared unless they discontinued because of inactive disease for at least 24 weeks in Part II.	Part II was event driven. The study was stopped when the required number of 37 flares had occurred (88 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part I: Percentage of Patients on Steroids at Study Start Who Reached a Steroid Dose ≤0.2 mg/kg at End of Part Ic		28 Weeks
Part I: Percentage of Participants on Steroids at the Start of 1c Who Were Able to Taper Steroids by the End of Part 1c		Start of Part Ic (After Week 8) to End of Part Ic (Week 28)
Part I: Percentage of Participants With Minimum American College of Rheumatology (ACR) 30/50/70/90/100 at the End of Part I	Adapted ACR Pediatric 30/50/70/90/100 criteria are defined as meeting all of the following: improvement from baseline of ≥ 30%, ≥ 50%, ≥ 70%, ≥ 90%, or 100%, in at least 3 of the first 6 response variablesPhysician's global assessment of disease activityCHAQ-patient's overall well-beingCHAQ-Functional ability# of joints with active arthritis# of joints with limitation of motionC-Reactive Protein.; no intermittent fever in the preceding week; no more than one of the first 6 response variables worsening by more than 30%	Baseline, 32 Weeks
Part I: Time to First Minimum American College of Rheumatology (ACR50) and Normal C-Reactive Protein	Duration in days in the study to the first minimum adapted ACR Pediatric 50 criteria and a normal (<10mg/L) C-Reactive Protein	Baseline, Week 32
Part I: Time to First Minimum American College of Rheumatology (ACR70) and Normal C-Reactive Protein	Duration in days in the study to the first minimum adapted ACR Pediatric 70 criteria and a normal (<10mg/L) C-Reactive Protein	Baseline, Week 32
Part I: Percentage of Participants With Body Temperature ≤ 38 Degrees Celsius at Day 3 in Part 1a		Day 3
Part II: Survival Analysis of Time to a Worsening in American College of Rheumatology (ACR) Response	Kaplan Meier estimate of the time in days to the probability of worsening of the ACR response. ACR response is determined by the following items: Physician's global assessment of disease activity; CHAQ-patient's overall wellbeing; CHAQ-Functional ability; Number of joints with active arthritis; Number of joints with limitation of motion; C-Reactive Protein.; No intermittent fever in the preceding week	Part II was event driven. The study was stopped when the required number of 37 flares had occurred (88 weeks)
Part I: Change in Disability Over Time in the Child Health Assessment Questionnaire-Disability Index (CHAQ-DI) From Baseline to End of Part I	The childhood health assessment questionnaire, CHAQ was used to assess physical ability and functional status of patients as well as quality of life. The disability dimension consists of 20 multiple choice items concerning difficulty in performing eight common activities of daily living; dressing and grooming, arising, eating, walking, reaching, personal hygiene, gripping and other "activities". Parents choose from four response categories, ranging from 0(without any difficulty) to 3(unable to do). A negative change indicates improvement.	Baseline, End of Part I (Week 32)
Part II: Change in Disability Over Time by the Child Health Assessment Questionnaire-Disability Index (CHAQ-DI)	CHAQ-DI assessed physical ability and functional status of patients and quality of life. 20 multiple choice items concerning difficulty in performing 8 common activities of daily living; dressing and grooming, arising, eating, walking, reaching, personal hygiene, gripping and other "activities". Parents choose from 4 response categories, ranging from 0(without any difficulty) to 3(unable to do). Repeated measures Analysis of Covariance with treatment group, visit day, prednisone (or equivalent) dose and adapted ACR 70 response reached at the end of Part Id as covariates.	Start of Part II (Week 32), End of Part II ( total duration-88 weeks)
Part I: Change in Health Related Quality of Life Over Time by Child Health Questionnaire (CHQ-PF50)	The CHQ-PF50© is an instrument used to measure Health Related Quality of Life in children 5-18 from the parent's perspective. The questionnaire measures the following concepts: Physical functioning, Role/social emotional, Role/social behavior, Role/social physical, Bodily pain, General behavior, Mental health, Self-esteem, General health perception, Change in health, Parental impact - emotional, Parental impact - time, Family activities, and Family cohesion. Summaries are provided for Physical Health and Psychosocial Health. Scores range from 0-100. Increase in score represents improvement.	Baseline, End of Part I ( Week 32)
Part II: Change in Health Related Quality of Life Over Time by Child Health Questionnaire (CHQ-PF50)	CHQ-PF50 measures Physical functioning, Role/social emotional, behavior and physical, Bodily pain, General behavior, Mental health, Self-esteem, General health perception, Change in health, Parental impact-emotional, Parental impact-time, Family activities and cohesion. Summaries are provided for Physical Health and Psychosocial Health. An increase in score indicates improvement. Repeated measures Analysis of Covariance change from start of Part II with treatment group, visit day, prednisone(or equivalent) dose and adapted ACR70 Pediatric response reached at the end of Part Id as covariates.	Start Part II (Week 32), End Part II (total duration - 88 Weeks)

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Collaborators: Pediatric Rheumatology International Trials Organization

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.
• 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.
• 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.

Helpful Links

• Related Info
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Study record dates

Study Major Dates

• Study Start: July 1, 2009
• Primary Completion (Actual): September 1, 2011
• Study Completion (Actual): September 1, 2011

Study Registration Dates

• First Submitted: April 21, 2009
• First Submitted That Met QC Criteria: April 28, 2009
• First Posted (Estimate): April 29, 2009

Study Record Updates

• Last Update Posted (Estimate): October 16, 2012
• Last Update Submitted That Met QC Criteria: September 13, 2012
• Last Verified: September 1, 2012

More Information

Terms related to this study

• Keywords: arthritis; Flare; IL-1beta antagonist; systemic juvenile idiopathic arthritis; Juvenile rheumatoid
• 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: CACZ885G2301; EudraCT: 2008-005479-82