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    Summary
    EudraCT Number:2014-002500-24
    Sponsor's Protocol Code Number:AOSD.2014.001
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2014-10-08
    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 ConcernedGermany - BfArM
    A.2EudraCT number2014-002500-24
    A.3Full title of the trial
    Open-label, multicenter, dose-escalating phase II study to investigate the safety, tolerability, and early signs of efficacy of subcutaneous administrations of Tadekinig alfa (IL-18BP) in patients with Adult -onset Still’s Disease (AoSD) during 12 weeks
    N/A
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    THERAPEUTIC USE OF TADEKINIG ALFA IN ADULT-ONSET STILL’S DISEASE
    N/A
    A.3.2Name or abbreviated title of the trial where available
    THERAPEUTIC USE OF TADEKINIG ALFA IN ADULT-ONSET STILL’S DISEASE
    N/A
    A.4.1Sponsor's protocol code numberAOSD.2014.001
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorAB2 Bio Ltd.
    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 supportAB2 Bio Ltd.
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAB2 Bio Ltd.
    B.5.2Functional name of contact pointEduardo Schiffrin, Medical Director
    B.5.3 Address:
    B.5.3.1Street AddressEPFL Innovation Park, Building B, 4th floor
    B.5.3.2Town/ cityLausanne
    B.5.3.3Post codeCH-1015
    B.5.3.4CountrySwitzerland
    B.5.4Telephone number+4121693 82 83
    B.5.5Fax number+4121693 82 81
    B.5.6E-maileduardo.schiffrin@ab2bio.com
    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.3.1Product nameTadekinig alfa
    D.3.2Product code IL-18 BP
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    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 INNTadekinig alfa
    D.3.9.1CAS number 220712-29-8
    D.3.9.2Current sponsor codeIL-18 BP
    D.3.9.3Other descriptive nameN/A
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number80
    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
    Adult -onset Still’s Disease (AoSD)
    E.1.1.1Medical condition in easily understood language
    Adult -onset Still’s Disease (AoSD)
    E.1.1.2Therapeutic area Diseases [C] - Immune System Diseases [C20]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.1
    E.1.2Level PT
    E.1.2Classification code 10064056
    E.1.2Term Still's disease adult onset
    E.1.2System Organ Class 10028395 - Musculoskeletal and connective tissue disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess the safe use of Tadekinig alfa in AoSD patients
    E.2.2Secondary objectives of the trial
    To assess clinical efficacy
    To assess laboratory/biological evidence of efficacy
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    CHARACTERIZATION OF THE PHARMACOKINETIC (PK) AND PHARMACODYNAMIC (PD) PROFILE OF TADEKINIG ALFA AFTER REPEATED S.C. INJECTIONS
    (version: AoSD Phase II Study Protocol 3.0, 28 AUG 2015)

    The objective is to determine the PK/PD profile of Tadekinig alfa.
    E.3Principal inclusion criteria
    Patients aged 18 years and older, diagnosed as AoSD based on the presence of the Yamaguchi criteria with active disease, irrespective of the continuation of the permitted treatment mentioned below

    Patients with active disease will be considered if they exhibit at least two of the Yamaguchi’s major criteria at the screening visit plus at least either fever or elevation of markers of inflammation (CRP ≥ 10 mg/L).

    Patients that have been exposed to NSAIDS, Prednisone (at least 5 mg/day) for ≥ 1 month) and/or synthetic sDMARDs (methotrexate at a dose of at least 10mg/week) for ≥ 3 months without response to treatment or with incomplete response to treatment

    Women of childbearing potential with negative pregnancy test at screening, V3, V4, V5 and V6 and that agree to follow highly effective birth control recommendations during the study and until 1 month after the end of the treatment. Birth control methods that are considered as highly effective are either: combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation, progestogen-only hormonal contraception associated with inhibition of ovulation, intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized partner or sexual abstinence.
    In each case of delayed menstrual period (over one month between menstruations, confirmation of absence of pregnancy is strongly recommended. This recommendation also applies to women of child bearing potential with infrequent or irregular menstrual cycles.
    As regards the duration of contraception after the study, taking into account the median half-life of Tadekinig alfa of almost 40h, 5 half-lives represent duration of 200 hours. In order to be on the safe side, a post-study contraception duration of 4 weeks is recommended

    Patients can maintain treatment with stable doses of Non-Steroidal anti-inflammatory Drugs (NSAIDs), Prednisone (stable dose of Prednisone (of at least 5 mg/day), and sDMARDs during Tadekinig alfa treatment (methotrexate at a dose of at least 10mg/week). Specifically baseline levels of prednisone treatment can be maintained or tapered (due to patient improvement), any requirement for prednisone increase during treatment will be considered a treatment failure.

    Ability to understand and willingness to sign a written informed consent

    Previous treatments with biologicals are allowed if the following wash-out periods are respected: one week for anakinra, two weeks for etanercept, and 6 weeks for adalimumab, certolizumab, golimumab, tocilizumab, abatacept and 8 weeks for infliximab. Previous rituximab administration will require 6 months of washout and normal B-cell counts and previous treatment with canakinumab will require 6 months of washout.
    E.4Principal exclusion criteria
    Patients with a first episode of AoSD with less than one month of therapy with Prednisone or sDMARDs

    Patients with active or chronic infections (i.e. Tuberculosis (TB), HIV, HBV & HCV)

    Patients suffering from inherited immunodeficiency diseases

    Patients suffering from immune-mediated inflammatory diseases, including autoimmune diseases such as RA, SLE, etc., or spondylarthropathies, or inflammatory bowel disease.

    Patients with white blood cell counts below 2’500 cells/mm3

    Patients with Neutrophils below 1’000 cells/mm3

    Concomitantly treated with biologicals

    Women of childbearing potential who are unwilling to use highly effective birth control methods (see definition in Inclusion criteria above) up to 1 month after the end of her participation in the study.

    Inability to understand and unwilling to sign a written informed consent

    Active Macrophage Activation Syndrome (MAS)

    Any acute or chronic life-threatening disease: such as cancer, and irreversible organ failures of heart, liver, lung and kidney (creatinine not higher than 1.5 X upper limit of normal)

    Patients having received adalimumab, certolizumab, golimumab, tocilizumab and abatacept within 6 weeks, infliximab within 8 weeks, canakinumab within 6 months, etanercept within 2 weeks, or anakinra 1 week prior to the start of Tadekinig alfa will not be enrolled into the study. Patients that have received rituximab within 6 months and/or have persistent low B-cell counts will not be eligible for enrolment.

    Subject who cannot be expected to comply with the study procedures

    Currently participating or having participated in another clinical trial during the last 4 weeks prior to the beginning of this study.

    Patients with no social security coverage

    Patients with a history of severe hypersensitivity reactions
    E.5 End points
    E.5.1Primary end point(s)
    SAFETY AND TOLERABILITY END POINTS :

    Reports of adverse events: The incidence, nature and severity of AEs will be reported. Reports will be produced according to the MedDRA highest hierarchy / System Organ Class), Common Terminology Criteria for Adverse Events (CTCAE), (MedDRA Lowest Level Term), and grade of severity.

    Abnormal physical examination: body temperature, heart rate, arterial blood pressure, lymph node enlargement, and abdominal palpation with specific examination of liver and spleen, presence of skin rash.

    Electrocardiogram change since baseline (ECG): A 12-lead ECG will be performed. ECG registers will collect all observed abnormalities. Clinically significant abnormalities occurring during the study execution will be reported as AEs.

    Abnormal laboratory results: The Common Terminology Criteria for Adverse Events (CTCAE, version 4.0) will be followed where SAEs are categories 3 and 4. Category 5 is death. For example:
    - SAE hemoglobin: < 8-6.5 g/dl. (Grade 3) and <6.5 g/dl (Grade 4).
    - SAE neutrophils: < 1-0.5 x 109/L (grade 3) and < 0.5 x 109/L (Grade 4).
    - SAE Platelets <50-25 x 109/L (grade 3) and <25 x 109/L (grade 4).
    - Increase of alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase: > 5.0-20.0 x ULN; >5 x ULN for > 2 weeks (Grade 3) and > 20.0 x ULN (Grade 4).
    - SAE kidney injury: Creatinine > 3 x baseline or > 4.0 mg/dl (grade 3), need of dialysis (grade 4).

    All clinically significant abnormal laboratory results or assessments (the above mentioned parameters and all other laboratory parameters considered clinically significant by the Investigator) must be followed until they resolve (return to normal or baseline values) or stabilise, or until they are judged by the Investigator to be no longer clinically significant.

    Immunogenicity evaluation: Generation of anti recombinant human interleukin 18 Binding protein (anti-rhIL-18BP) antibodies

    Serum Protein electrophoresis

    Local tolerability at the injection site evaluated by a standardized assessment during the visits (see appendix 6 of the study protocol) and captured in the patient diary in a daily basis
    E.5.1.1Timepoint(s) of evaluation of this end point
    SAFETY ASSESSMENT BY DSMB (LABORATORY AND CLINICAL SAE ASSESSMENT)

    The DSMB will perform safety assessment on clinical and laboratory endpoints at week 3 of the first 5 patients for the three dose cohorts.

    The DSMB may also be requested to perform a safety evaluation in case a patient is not showing any signs of efficacy at 3 weeks (to 80mg or 160mg) prior to the 5 enrolment of that dose.
    E.5.2Secondary end point(s)
    EFFICACY END POINTS :

    1) EARLY SIGNS OF EFFICACY AT 3 WEEKS

    1.1 Clinical

    - Body temperature (normal rage is between 36.3 and 37.4°C measured in the armpit) (measured after discontinuation of NSAID treatment for 24h). Armpit daily temperature readings will be performed by the patient at 10.00 am and 6.00 pm. A patient diary will be used for the daily body temperature records performed by the patient at home
    - Skin rash (if present at screening). The physician will assess evaluation of skin rash as changes from baseline (unchanged, slightly decreased, markedly decreased, resolved). In the patient diary a daily self-assessment of the presence/absence and extension of the skin rash will be recorded.
    - Joint assessment (44 joint assessment for synovitis and tenderness)
    - Patient global assessment of disease activity
    - Physician global assessment of disease activity
    - Pain assessment on VAS
    - Fatigue assessment on VAS
    - Daily dose of prednisone or NSAIDs: % of initial daily dose to identify tapering down or discontinuation of Prednisone, and maintenance or discontinuation of NSAIDS (DMARDs should be maintained stable / No tapering allowed)
    - Health assessment questionnaire (HAQ-DI)
    - Quality of life on SF-36v2®

    1.2) Laboratory:
    - Serum CRP
    - Serum amyloid (SAA) and Serum S100A8/A9, S100A12 (analysis for these biomarkers will be performed according to clinical outcomes)
    - Ferritin and glycosylated ferritin
    - Leukocyte counts (< 10 x 109 granulocytes/liter)
    - Serum levels of total IL-18, free IL-18, IL-18BP, IL-1Ra, IL-6, TNF-α

    1.3) Composite Indices:
    - American College of Rheumatology (ACR) responses, i.e., change from baseline (ACR20, ACR50, ACR70)
    - Simplified Disease Activity Index (SDAI). The SDAI is the numerical sum of five outcome parameters: tender and swollen joint count (based on a 28-joint assessment), patient and physician global assessment of disease activity visual analogue scale (VAS) 0–10 cm and level of C-reactive protein (mg/dl, normal <1 mg/dl)

    THERAPEUTIC RESPONSE : a patient will be considered as responder if at 3 weeks there is
    (1)a normalization of body temperature (measured 24 h after NSAIDs discontinuation) recorded during the visit 3 by the site nurse or physician and
    (2)decrease of ≥ 50% of the baseline levels of CRP or within the reference values.
    In patients with normal body temperature at baseline, a decrease of ≥ 50% of the baseline levels of CRP or within the reference values will be considered as a positive response.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Assessment of early signs of efficacy at 3 weeks
    Assessment of efficacy at 12 weeks

    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 Yes
    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) No
    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 Yes
    E.8.1.7.1Other trial design description
    multicenter, dose-escalating
    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.8.2.4Number of treatment arms in the trial2
    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 concerned10
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA17
    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 No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    France
    Germany
    Switzerland
    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
    End of Trial = Last Visit Last Subject (LVLS)
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months5
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months5
    E.8.9.2In all countries concerned by the trial days0
    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.1.2.1Number of subjects for this age range: 18
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 2
    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 state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 19
    F.4.2.2In the whole clinical trial 20
    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

    All subjects who end their participation in the trial will continue to be monitored by their respective physicians, using standard medical care. No special procedures or extra medical care is needed after the trial that would not be otherwise used in patients who have not participated in the trial.
    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 Decision2015-02-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-11-24
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2016-07-28
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