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    Summary
    EudraCT Number:2008-005479-82
    Sponsor's Protocol Code Number:CACZ885G2301
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2009-03-19
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedFrance - ANSM
    A.2EudraCT number2008-005479-82
    A.3Full title of the trial
    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
    A.4.1Sponsor's protocol code numberCACZ885G2301
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorNovartis Pharma Services AG
    B.1.3.4CountrySwitzerland
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/08/527
    D.3 Description of the IMP
    D.3.1Product nameCanakinumab
    D.3.2Product code ACZ885
    D.3.4Pharmaceutical form Powder for solution for injection
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCanakinumab
    D.3.9.2Current sponsor codeACZ885
    D.3.9.3Other descriptive nameRecombinant human monoclonal antibody to human IL-1Beta of the IgG1/K class
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number150
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Information not present in EudraCT
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Information not present in EudraCT
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product Yes
    D.3.11.13.1Other medicinal product typeRecombinant human monoclonal antibody
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboPowder for solution for injection
    D.8.4Route of administration of the placeboSubcutaneous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Active systemic manifestations of Systemic Juvenile Idiopathic Arthritis (SJIA)
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level LLT
    E.1.2Classification code 10059176
    E.1.2Term Juvenile idiopathic arthritis
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Part II: to demonstrate that the time to flare in Part II is higher with canakinumab than with placebo.
    Part I: to assess if canakinumab allows tapering of steroids as per protocol in at least 25% of the patients.
    E.2.2Secondary objectives of the trial
    Part II:
    • To evaluate the maintenance of efficacy (length of time that patients continuously maintain or improve their adapted ACR Pediatric 30/ 50/ 70/ 90/ 100 criteria reached at entry into Part II) of canakinumab as compared to placebo
    Part I:
    • To evaluate number of patients who have reached a steroid dose ≤ 0.2 mg/kg at end of Part Ic
    • To evaluate the level of steroid tapering achieved at the end of Part Ic
    • To evaluate the efficacy (percentage of patients who meet the adapted ACR Pediatric 30/ 50/ 70/ 90/ 100 criteria) of canakinumab in Part I
    • To evaluate the efficacy of canakinumab to show clinical signs of response (percentage of patients who have body temperature ≤ 38°C) at Day 3 in Part Ia
    • To evaluate time to adapted ACR Pediatric 50 criteria and no fever and normal C-Reactive Protein (CRP <10 mg/L) during Part I
    see other objectives in protocol pages 24-25
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. 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 before any study related activity is performed.
    2. Male and female patients aged ≥ 2 to < 20 years at the time of the screening visit
    3. Confirmed diagnosis of SJIA as per ILAR definition that must have occurred at least 2 months prior to enrollment with an 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
    4. Active disease at the time of enrollment defined as follows:
    • At least 2 joints with active arthritis (using ACR definition of active joint)
    • Documented spiking, intermittent fever (body temperature > 38°C) for at least 3 days during the screening period (minimum duration of screening 3 days) before first canakinumab/placebo dose
    • C-reactive protein (CRP) > 30 mg/L (normal range < 10 mg/L)
    5. Patient’s willingness to discontinue anakinra, rilonacept, toclizumab or other experimental drug under close monitoring (Please refer to Exclusion criteria #15 for washout period.)
    6. 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 (maximum of 20 mg/ m2/ week) for at least 8 weeks prior to the screening visit, and folic/folinic acid supplementation (according to standard medical practice of the center)
    • Stable dose of no more than one non-steroidal anti-inflammatory drug (NSAID) for at least 2 weeks prior to the screening visit
    • Stable dose of steroid treatment ≤ 1.0 mg/kg/day (maximum 60 mg/day for children over 60 kg) in 1-2 doses of oral prednisone (or equivalent) for at least 3 days prior to baseline (Day 1)
    7. Negative Purified Protein Derivative (PPD) test (< 5 mm induration) at screening or within 1 month prior to the screening visit, according to the national guidelines. Patients with a positive PPD test (≥ 5 mm induration) at screening may be enrolled only if they have either a negative chest x-ray or a negative QuantiFERON test (QFT-TB G In-Tube).
    E.4Principal exclusion criteria
    1. Pregnant or nursing (lactating) female patients, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (> 5 mIU/ mL) at screening visit
    2. Female patients having reached sexual maturity, i.e. being physiologically capable of becoming pregnant UNLESS they are:
    • female patients whose career, lifestyle, or sexual orientation precludes intercourse with a male partner
    • using an acceptable method of contraception with a failure rate (Pearl Index (PI)) < 1. Reliable contraception should be maintained throughout the study and for 2 months after study drug discontinuation.
    3. History of hypersensitivity to study drug or to biologics
    4. Biologic features of MAS [such as hemorrhages, central nervous system dysfunction, hepatomegaly, plasma fibrinogen level < 2.5 g/L, cytopenia, hypertriglyceridemia, decreased platelet count, increased aspartate transaminase, hyperferritinemia (Ravelli, Magni-Manzoni and Pistorio 2005)] at screening or a history of recurrent pericarditis, myocarditis, serositis and/ or biologic features of MAS over the last 6 months
    5. With active or recurrent bacterial, fungal or viral infection at the time of enrollment, including patients with evidence of Human Immunodeficiency Virus (HIV) infection, Hepatitis B and Hepatitis C infection
    6. Any of the risk factors for tuberculosis (TB) such as:
    • History of any of the following: residence in a congregate setting (e.g. jail or prison, homeless shelter, or chronic care facility), substance abuse (e.g. injection or noninjection); health-care workers with unprotected exposure to patients who are at high risk of TB or patients with TB disease before the identification and correct airborne precautions of the patient, or
    • Close contact (i.e. share the same air space in a household or other enclosed environment for a prolonged period (days or weeks, not minutes or hours)) with a person with active pulmonary TB disease within the last year
    7. With underlying metabolic, renal, hepatic, infectious or gastrointestinal conditions which in the opinion of the investigator immunocompromises the patient and/ or places the patient at unacceptable risk for participation in an immunomodulatory therapy. In particular, clinical evidence or history of multiple sclerosis or other demyelinating diseases, or Felty’s syndrome.
    8. With significant medical conditions, which in the opinion of the Investigator will exclude the patient from the study (can be discussed on a case by case basis with Novartis)
    9. History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases
    10. History of autonomic dysfunction (e.g. history of fainting, orthostatic hypotension, sinus arrhythmia)
    11. Uncontrolled hypertension
    12. Long QT syndrome or QTc (calculated using Bazett’s formula) > 450 msec for males and > 470 msec for females at screening or baseline
    13. Clinical evidence of liver disease or liver injury as indicated by abnormal liver function tests at screening such as AST, ALT, GGT, alkaline phosphatase, or serum bilirubin (must not exceed twice the upper limit value of the normal range for age)
    14. Presence of moderate to severe impaired renal function as indicated by clinically significantly abnormal creatinine (≥ 1.5 x upper normal limit (ULN)) or urea values or abnormal urinary constituents (e.g., albuminuria) at screening. Evidence of urinary obstruction or difficulty in voiding at screening.
    15. Use of the following therapies:
    • Anakinra within 24 hours prior to Baseline visit
    • Rilonacept within 1 week prior to Baseline visit
    • Toclizumab within 3 weeks prior to Baseline visit
    • Etanercept within 4 weeks prior to Baseline visit
    • Adalimumab within 8 weeks prior to the Baseline visit
    • Infliximab within 12 weeks prior to the Baseline visit
    • Rituximab within 26 weeks prior to the Baseline visit
    • Leflunomide within 4 weeks prior to the Baseline visit. Documentation of a completion of a full cholestyramine elimination treatment after most recent leflunomide use will be required.
    • Thalidomide within 4 weeks prior to the Baseline visit
    • Cyclosporine within 4 weeks prior to the Baseline visit
    • Intravenous immunoglobulin (i.v. Ig) within 8 weeks prior to the Baseline visit
    • 6-Merceptopurine, azathioprine, cyclophosphamide, or chlorambucil within 12 weeks prior to the Baseline visit
    • Dapsone, mycophenolate mofetil within 3 weeks prior to the Baseline visit
    • Growth hormone within 4 weeks prior to the Baseline visit
    • Corticosteroids (oral prednisone (or equivalent)) > 1.0 mg/kg/day (or greater than the maximum of 60 mg/day for children over 60 kg) within 3 days prior to the Baseline visit
    [...]
    E.5 End points
    E.5.1Primary end point(s)
    Part II: Time to flare in Part II
    Part I: the proportion of patients who were on steroids at entry into Part I and who were able to taper steroid as per protocol
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    tolerability and immunogenicity
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans Information not present in EudraCT
    E.7.1.2Bioequivalence study Information not present in EudraCT
    E.7.1.3Other Information not present in EudraCT
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    withdrawal study
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA34
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months1
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months1
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) Yes
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.2Adults (18-64 years) Yes
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Children < 18 years will sign if possible an informed consent form as well as their parents (or legal guardian)
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state12
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 62
    F.4.2.2In the whole clinical trial 214
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2009-04-17
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2009-05-07
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2011-09-12
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