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

NCT00889863 | Completed Phase 3 Results

• 2 other identifiers: CACZ885G2301EudraCT: 2008-005479-82
• Study Type: interventional
• Target: 177
• Locations: 19 countries
• Sites: 73

Brief Summary

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.

Conditions

Systemic Juvenile Idiopathic Arthritis With Active Flare

Keywords

Flare; arthritis; IL-1beta antagonist; systemic juvenile idiopathic arthritis; Juvenile rheumatoid

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (11)

• 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

  Baseline, 32 Weeks

• Part I: Time to First Minimum American College of Rheumatology (ACR50) and Normal C-Reactive Protein

  Baseline, Week 32

• Part I: Time to First Minimum American College of Rheumatology (ACR70) and Normal C-Reactive Protein

  Baseline, Week 32

Study Arms (2)

Canakinumab

EXPERIMENTAL

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

Placebo

PLACEBO COMPARATOR

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

Interventions

canakinumab DRUG

Canakinumab 4 mg/kg dose subcutaneous injection supplied as 6 mL glass vials each containing 150 mg canakinumab as a lyophilized cake.

Canakinumab

placebo DRUG

Placebo powder matching canakinumab supplied as 6 mL glass vials containing a lyophilized cake for subcutaneous injection every 4 weeks in Part II.

Placebo

Eligibility Criteria

• Age: 2 Years - 19 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead
• Pediatric Rheumatology International Trials Organization: collaborator

Study Sites (73)

Arkansas Children's Hospital Research Inst

Little Rock, Arkansas, 72202, United States

Location

Children's National Medical Center

Washington D.C., District of Columbia, 20010, United States

Location

University of Chicago Medical Center

Chicago, Illinois, 60637, United States

Location

University of Louisville

Louisville, Kentucky, 40202, United States

Location

New England Medical Center - Department of Allergy

Boston, Massachusetts, 02111, United States

Location

Tufts Medical Center

Boston, Massachusetts, 02111, United States

Location

St Barnabas Ambulatory Care Center

Livingston, New Jersey, 07039, United States

Location

Children's Hospital Medical Center

Cincinnati, Ohio, 45229, United States

Location

Children's Hospital/Neurology

Cincinnati, Ohio, 45229, United States

Location

Legacy Emanuel Hospital

Portland, Oregon, 97227, United States

Location

Legacy Emanual Research

Portland, Oregon, 97232, United States

Location

Specially For Children

Austin, Texas, 78723, United States

Location

Novartis Investigative Site

Buenos Aires, Argentina

Location

Novartis Investigative Site

Capital Federal, Argentina

Location

Novartis Investigative Site

La Plata, Argentina

Location

Novartis Investigative site

Brussels, Belgium

Location

Novartis Investigative site

Ghent, Belgium

Location

Novartis Investigative Site

Laken, Belgium

Location

Novartis Investigative site

Leuven, Belgium

Location

Novartis Investigative Site

Curitiba, Brazil

Location

Novartis Investigative site

Porto Alegre, Brazil

Location

Novartis Investigative site

Rio de Janiero, Brazil

Location

Novartis Investigative site

São Paulo, Brazil

Location

Novartis Investigative site

Vancouver, British Columbia, Canada

Location

Novartis Investigative site

Halifax, Nova Scotia, Canada

Location

Novartis Investigative site

Toronto, Ontario, Canada

Location

Novartis Investigative site

Montreal, Quebec, Canada

Location

Novartis Investigative Site

Le Kremlin-Bicêtre, France

Location

Novartis Investigative Site

Lyon, France

Location

Novartis Investigative Site

Paris, France

Location

Novartis Investigative Site

Strasbourg, France

Location

Novartis Investigative Site

Bad Bamstedt, Germany

Location

Novartis Investigative site

Berlin, Germany

Location

Novartis Investigative Site

Bremen, Germany

Location

Novartis Investigative Site

Freiburg im Breisgau, Germany

Location

Novartis Investigative Site

Geißen, Germany

Location

Novartis Investigative Site

Hamburg, Germany

Location

Novartis Investigative Site

Münster, Germany

Location

Novartis Investigative Site

Saint Augustin, Germany

Location

Novartis Investigative Site

Stuttgart, Germany

Location

Novartis Investigative Site

Budapest, Hungary

Location

Novartis Investigative Site

Haifa, Israel

Location

Novartis Investigative Site

Kfar Saba, Israel

Location

Novartis Investigative Site

Petah Tikva, Israel

Location

Novartis Investigative Site

Ramat Gan, Israel

Location

Novartis Investigative Site

Rehovot, Israel

Location

Novartis Investigative Site

Bologna, Italy

Location

Novartis Investigative Site

Florence, Italy

Location

Novartis Investigative Site

Genova, Italy

Location

Novartis Investigative site

Milan, Italy

Location

Novartis Investigative site

Napoli, Italy

Location

Novartis Investigative site

Padua, Italy

Location

Novartis Investigative site

Rome, Italy

Location

Novartis Investigative site

Scafati, Italy

Location

Novartis Investigative site

Torino, Italy

Location

Novartis Investigative site

Utrecht, Netherlands

Location

Novartis Investigative Site

Oslo, Norway

Location

Novartis Investigative Site

Lima, Peru

Location

Novartis Investigative site

Warsaw, Poland

Location

Novartis Investigative site

Berea, Durban, South Africa

Location

Novartis Investigative site

Mayville, Durban, South Africa

Location

Novartis Investigative site

Johannesburg, South Africa

Location

Novartis Investigative site

Pretoria, South Africa

Location

Novartis Investigative site

Barcelona, Spain

Location

Novartis Investigative site

Madrid, Spain

Location

Novartis Investigative site

Valencia, Spain

Location

Novartis Investigative site

Stockholm, Sweden

Location

Novartis Investigative Site

Bern, Switzerland

Location

Novartis Investigative site

Lausanne, Switzerland

Location

Novartis Investigative site

Zurich, Switzerland

Location

Novartis Investigative site

Ankara, Turkey (Türkiye)

Location

Novartis Investigative Site

Istanbul, Turkey (Türkiye)

Location

Novartis Investigative Site

Izmir, Turkey (Türkiye)

Location

Related Publications (4)

• 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.

  PMID: 30269054 DERIVED

• 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.

  PMID: 28115015 DERIVED

• 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.

  PMID: 26314396 DERIVED

• 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.

  PMID: 23252526 DERIVED

Related Links

• Related Info
• Related Info

MeSH Terms

Conditions

Arthritis; Arthritis, Juvenile

Interventions

canakinumab

Condition Hierarchy (Ancestors)

Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

862-778-8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 21, 2009
• First Posted: April 29, 2009
• Study Start: July 1, 2009
• Primary Completion: September 1, 2011
• Study Completion: September 1, 2011
• Last Updated: October 16, 2012
• Results First Posted: October 16, 2012

Record last verified: 2012-09

Locations

US (12); BE (4); DE (9); ZA (4); CA (4); BR (4); HU (1); IL (5); NL (1); ES (3); TU (3); NO (1); CH (3); FR (4); AR (3); SE (1); PE (1); PL (1); IT (9)