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    Summary
    EudraCT Number:2013-000300-42
    Sponsor's Protocol Code Number:03AR0298
    Clinical Trial Type:Outside EU/EEA
    Date on which this record was first entered in the EudraCT database:2013-01-18
    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
    H.4 THIRD COUNTRY IN WHICH THE TRIAL WAS FIRST AUTHORISED
    Expand All   Collapse All
    A. Protocol Information
    A.2EudraCT number2013-000300-42
    A.3Full title of the trial
    A long-term outcome study with the IL-1 receptor antagonist Anakinra/Kineret® in patients with Neonatal onset multisystem inflammatory disease (Nomid/Cinca syndrome)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A long-term study with the IL-1 receptor blocker anakinra/kineret® in patients with neonatal onset multisystem inflammatory disease (NOMID/CINCA syndrome)
    A.4.1Sponsor's protocol code number03AR0298
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT00069329
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/066/2012
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorNational Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportNational Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNational Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
    B.5.2Functional name of contact pointNIH Clinical Center
    B.5.3 Address:
    B.5.3.1Street Address9000 Rockville Pike
    B.5.3.2Town/ cityBethesda, Maryland
    B.5.3.3Post code20892
    B.5.3.4CountryUnited States
    B.5.4Telephone number0018004111222TTY8
    B.5.6E-mailprpl@mail.cc.nih.gov
    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 Yes
    D.2.1.1.1Trade name Kineret
    D.2.1.1.2Name of the Marketing Authorisation holderSwedish Orphan Biovitrum
    D.2.1.2Country which granted the Marketing AuthorisationUnited States
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Solution for injection in pre-filled syringe
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    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) No
    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 No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    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 Yes
    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 No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    neonatal onset multisystem inflammatory disease (NOMID/CINCA)
    E.1.1.1Medical condition in easily understood language
    neonatal onset multisystem inflammatory disease (NOMID), also known as chronic infantile neurological, cutaneous and arthropathy (CINCA) syndrome.
    E.1.1.2Therapeutic area Diseases [C] - Immune System Diseases [C20]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    •Assess the change in the disease diary score after 3-6 months of open-label administration of anakinra/Kineret.
    •Assess the change in serum amyloid A (SAA) levels before and after 3-6 months of drug treatment.
    •Assess the change in SAA levels after drug withdrawal of up to 7 days.
    E.2.2Secondary objectives of the trial
    •Resolution or improvement in central nervous system (CNS) disease activity: intracranial pressure, pleiocytosis, number and intensity of recurrent headaches, vomiting, seizures and eye disease: uveitis, papilledema; skin disease: extent and intensity of rash; joint disease: joint count
    •Resolution, improvement or stabilization of hearing impairment: audiogram evaluation
    •Improvement and/or resolution of fever
    •Change in bone mineral density; magnetic resonance imaging (MRI)
    •Difference in total amount of steroids, nonsteroidal anti-inflammatory drugs (NSAIDs), and/or disease-modifying anti-rheumatic drugs (DMARDs) used
    •Change in aerobic endurance
    •Change in questionnaire score (Childhood Health Assessment Questionnaire [CHAQ], Pediatric Quality of Life [PedsQL], psycho-social evaluation)
    •Assessment of long-term improvement in disease diary score
    •Pharmacokinetic profiling
    •Evaluation of safety
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    No age limitation (valid from July 2007)
    2. Patients fulfilled at least 2 of the following 3 clinical manifestations:
    •Typical NOMID rash
    •CNS involvement (papilledema, cerebrospinal fluid (CSF) pleiocytosis, sensorineural hearing loss)
    •Typical arthropathic changes on radiographs (epiphyseal and/or patellar overgrowth)
    3. Onset of manifestations of NOMID/CINCA at ≤6 months of age
    4. Stable dose of steroids, NSAIDs, DMARDs for 4 weeks prior to enrolment visit
    5. Washout period for biologics: 6 half-lives before Kineret administration for all drugs with anti-TNF properties. For etanercept (6 half-lives=24 days), this calculated to drug discontinuation 3 days before enrolment into the observation period, infliximab and adalimumab (6 half-lives=48 days) drug were to be discontinued 27 days before the observation period, and thalidomide (6 half lives=3 days) were to be discontinued 3 days prior to Kineret administration
    6. Patient’s or legal guardian’s ability and willingness to give informed consent
    7. Females of childbearing potential (young women who have had at least one menstrual period regardless of age) had to have a negative urine pregnancy test at baseline prior to performance of any radiologic procedure or administration of study medication. Women of childbearing age and men able to father a child, who were sexually active, were asked to use a form of effective birth control, including abstinence
    8. Negative purified protein derivative (PPD) test using 5 T.U. intradermal testing per CDC guidelines with exception of inclusion criteria no. 9 below
    9. Patients with latent tuberculosis (TB) (positive PPD test) had to have adequate therapy for TB initiated prior to first dose of study medication as recommended in published guidelines.
    E.4Principal exclusion criteria
    Having received live virus vaccine during 3 months prior to baseline visit (first visit to NIH)
    2. Active infections or a history of pulmonary TB infection with or without documented adequate therapy, patients with current active TB, or recent close exposure to an individual with active TB
    3. Positive testing for HIV, Hepatitis B or C known or documented at screening, enrolment or baseline visit
    4. A history of, or concomitant diagnosis of, congestive heart failure.
    5. A history of malignancy
    6. Prior use of anti-CD4 antibody
    7. Known hypersensitivity to E. coli derived products or any components of Kineret
    8. Presence of any other rheumatic disease or major chronic infectious/ inflammatory/ immunologic disease (e.g. inflammatory bowel disease, psoriatic arthritis, spondyloarthropathy, SLE in addition to NOMID/CINCA)
    9. Presence of the following at enrolment visit: ALT or AST >2.0 x upper limit of normal (ULN) of the local laboratories values, creatinine >1.5 x ULN, WBC <3.6 x 109/L; platelet count <150,000 mm3
    10. Enrolment in any other investigational clinical study or receiving an investigational agent, or had not yet completed at least 4 weeks since ending another investigational device or drug trial
    11. Existing concern about compliance with the protocol procedures by patient and/or parent/s and legally acceptable representative/s
    12. Lactating females or pregnant females
    13. Patients with asthma were only included after evaluation by a pulmonary and infectious disease consultation
    14. The use of other anti-IL-1 inhibiting agents or the initiation of a longer acting IL-1 inhibiting agent while on study led to non-enrolment or termination respectively.
    E.5 End points
    E.5.1Primary end point(s)
    Change in DSSS (fever, rash, joint pain, vomiting, and headache) from baseline to Month 3-6.

    Change in SAA levels from baseline to Month 3-6.

    Change in SAA levels from Month 3 (before withdrawal) to end of withdrawal.

    Deaths, premature discontinuations, adverse events, serious adverse events, clinical safety laboratory variables and vital signs up to Month 60.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Baseline to Month 3-6.

    Month 3 to end of withdrawal.

    Up to Month 60.
    E.5.2Secondary end point(s)
    Change from baseline to up to Month 60 in intracranial opening pressure, pleiocytosis measured as change from baseline to up to Month 60 in CSF WBC adjusted cellularity.
    Data related to headaches, vomiting and seizures are included in endpoints for diary data.
    Presence of uveitis up to Month 60, change from baseline to up to Month 60 in papilledema score in best and worst eye.
    Change from baseline to up to Month 60 in ePTA score in best and worst ear based on both air and bone conduction.
    Change from baseline to up to Month 60 in body surface area of rash and VAS measuring intensity of rash.
    Change from baseline to up to Month 60 in the total number of swollen joints, joints with loss of motion, joints with pain on motion, tender joints and joints with warmth.
    Data related to fever are included in endpoints for diary data (see above).
    Change from baseline to up to Month 60 in bone mineral density in L1-L4, L2-L4, femoral neck, Ward's Triangle, total hip area, and radius.
    Interpretation (normal/abnormal) of brain MRI up to Month 60: ventriculomegaly.
    Data based on joint MRI was not analyzed because data was available for only 8 patients.
    Use of steroids and DMARDS at each visit up to Month 60 and prednisone-equivalent steroid dose based on diary data.
    Dose of DMARDs and NSAIDs based on diary data was not analyzed due to incomplete recording of the data
    Change from baseline to up to Month 60 in total distance of 9 minute walk test.
    Change from baseline to up to Month 60 in CHAQ (overalls score, overall pain rating, overall global evaluation, subcategories for dressing and grooming, arising, eating, walking, hygiene, reach, grip and activities), PedsQL child report (individual questions and sum scores), PedsQL parent proxy-report(individual questions and sum scores) and IQ assessment.
    Kineret concentrations and PK parameters (after first dose, Month 3, Month 36-42) and CSF and serum exposure (pre-dose, Month 3).
    E.5.2.1Timepoint(s) of evaluation of this end point
    Baseline to Month 60.
    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 No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.3 Will this trial be conducted at a single site globally? Yes
    E.8.4 Will this trial be conducted at multiple sites globally? No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.2Trial being conducted completely outside of the EEA Yes
    E.8.6.3Specify the countries outside of the EEA in which trial sites are planned
    United States
    E.8.7Trial has a data monitoring committee No
    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
    Long-term outcome study
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.2In all countries concerned by the trial years10
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 36
    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) Yes
    F.1.1.4.1Number of subjects for this age range: 13
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 18
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 5
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 7
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.2 For a multinational trial
    F.4.2.2In the whole clinical trial 50
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
    G.4.3.4Network Country United States
    H.4 Third Country in which the Trial was first authorised
    H.4.1Third Country in which the trial was first authorised: United States
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