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    Summary
    EudraCT Number:2004-002980-26
    Sponsor's Protocol Code Number:CACZ885A2102
    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:2007-03-29
    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 number2004-002980-26
    A.3Full title of the trial
    An open-label, phase II dose titration study of ACZ885 (human anti-IL-1beta monoclonal antibody) to assess the clinical efficacy, safety, pharmacokinetics and pharmacodynamics in patients with NALP3 mutations
    A.3.2Name or abbreviated title of the trial where available
    A2102
    A.4.1Sponsor's protocol code numberCACZ885A2102
    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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.2Product code ACZ885
    D.3.4Pharmaceutical form Powder and solvent 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.3.9.2Current sponsor codeACZ885
    D.3.9.3Other descriptive nameACZ885 drug substance
    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 typerecombinanat human monoclonal antibody
    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
    Muckle-Wells Syndrome: rare hereditary, autosomal dominant, systemic inflammatory disease, characterized by recurrent episodes of fever, arthralgia, myalgia, urticarial rash, and conjunctivitis. Laboratory findings show an elevation of acute phase proteins such as CRP and SAA, a high ESR, together with leukocytosis, and hypergammaglobulinemia. Severe long term complications include progressive sensorineural deafness, and systemic AA amyloidosis.
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level LLT
    E.1.2Classification code 10064573
    E.1.2Term Neonatal-onset multisystemic inflammatory disease
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level LLT
    E.1.2Classification code 10064570
    E.1.2Term Familial cold autoinflammatory syndrome
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine the efficacy of ACZ885 administered as intravenous infusion (original protocol) and subcutaneous injection (current amendment) to improve the clinical status of patients with NALP3 (CIAS1, PYPAF1) mutations.
    E.2.2Secondary objectives of the trial
    • To assess the safety, tolerability and immunogenicity of ACZ885 administered as intravenous infusion and subcutaneous injection in patients with NALP3 (CIAS1, PYPAF1) mutations.

    • To evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of ACZ885 administered as intravenous infusion and subcutaneous injection in patients with NALP3 (CIAS1, PYPAF1) mutations.

    • To assess PK/PD relationships in order to derive a dose and dosing regimen for phase III.

    • To conduct exploratory genomic studies to identify gene expression patterns of blood that are associated with treatment response to ACZ885, or that possibly correlate with the severity or progression of autoinflammatory diseases.

    • To assess the efficacy of ACZ885 to modify disease progression with regards to deafness, kidney function, neurological and ophthalmological symptoms.

    • To assess the efficacy of ACZ885 to modify health-related quality of life.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male and female patients aged 4 to 75 years (inclusive) at the time of the screening visit, having passed screening examinations. (only adults patients ≥18 years for French center)

    2. Female subjects of child-bearing potential may participate if they have a negative pregnancy test at screening and prior to dosing, and are willing to use, if adequate for age, an effective method of contraception (e.g. birth control pills, abstinence, double-barrier contraception, etc.) during the study (from the date of screening) and for at least 3 months following the last dose.

    3. Molecular diagnosis of NALP3 mutations and clinical picture resembling MWS/ FCAS/ NOMID requiring medical intervention being either untreated or insufficiently treated.

    4. Molecular diagnosis of NALP3 mutations and documented history of a clinical picture resembling MWS/FCAS/NOMID. Patients under anakinra therapy or any other IL-1 blocking therapy being in complete remission and willing to discontinue anakinra/IL-1 blocking therapy until a clinical picture of the disease (relapse) becomes evident.

    5. Patients with a very severe phenotype requiring stable doses of oral prednisone (≤ 0.4 mg/kg/day or ≤ 20 mg/day, whichever is lower) for at least one week prior to the screening visit. Steroid therapy may be tapered during treatment with ACZ885 at the discretion of the investigator.

    6. Body weight < 100 kg.

    7. Able to communicate well with the investigator and comply with the requirements of the study.

    8. Smokers may participate in the study.

    9. Negative tuberculin skin test reaction (PPD 5 tuberculin units or as according to local standard practice) (< 5 mm induration) at 48 to 72 hours after administration at the screening visit or within 2 months prior to the screening visit, according to national guidelines. Patients who have a positive PPD skin test with a documentation of BCG vaccination, who are at low environmental risk for tuberculosis (TB) infection or reactivation, and have a negative chest X-ray can be included. A positive PPD sample will be defined using the MMWR 2000 guidance, summarized as criteria for tuberculin positivity by risk group.
    E.4Principal exclusion criteria
    1. Participation in any clinical investigation within 4 weeks prior to dosing or longer if required by local regulation with the exception of trials with anakinra.

    2. Antiinflammatory therapy with colchicine, chlorambucil, dapsone, azathioprine, mycophenolate mofetil, within 3 weeks prior to dosing. In case patients have been treated with therapeutic antibodies (e.g. anti-TNF-alpha antibodies), discontinuation of this therapy is required at least 60 days before dosing.

    3. Donation or loss of 400 mL or more of blood within 8 weeks prior to dosing.

    4. A past medical history of clinically significant ECG abnormalities or a family history of a prolonged QT-interval syndrome.

    5. History of immunocompromise, including a positive HIV (ELISA and Western blot) test result.

    6. A positive Hepatitis B surface antigen (HBsAg) or Hepatitis C test result.

    7. History of drug or alcohol abuse within the 12 months prior to dosing.

    8. Active medical condition such as infection, poorly controlled diabetes etc.

    9. History of tuberculosis.

    10. No live vaccination within 3 months prior to the start of the trial, during the trial and up to 3 months following the last dose.
    E.5 End points
    E.5.1Primary end point(s)
    See E.2.1
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic Yes
    E.6.13Others Information not present in EudraCT
    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) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    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 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 concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA4
    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 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
    LPLV

    End of study will be defined once relapse occurs after the last dose and all patients with Muckle-Wells syndrome will be transitioned to the Phase III protocol or have discontinued the study. Patients with a diagnosis of NOMID or FCAS syndrome may stay in this study until an extension phase.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months
    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 months3
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    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) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.3Elderly (>=65 years) Yes
    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 No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state3
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 32
    F.4.2.2In the whole clinical trial 34
    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)
    Responding patients will be rolled over to a phase III protocol.
    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 Decision2007-05-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2007-06-07
    P. End of Trial
    P.End of Trial StatusCompleted
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