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    Summary
    EudraCT Number:2014-000363-40
    Sponsor's Protocol Code Number:8409032
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2015-09-01
    Trial 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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2014-000363-40
    A.3Full title of the trial
    A prospective Randomized multicenter study comparing horse Antithymocyte globuline (hATG) + Cyclosporine A (CsA) with or without Eltrombopag as front-line therapy for severe aplastic anemia patients.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A trial in which will be studied if the addition of a medicine that is used for improving platelet counts (eltrombopag) to the regular treatment for aplastic anemia (hATG + CsA) also improves the numbers of other cell lines and therefore the overall bone marrow function.
    A.3.2Name or abbreviated title of the trial where available
    RACE
    A.4.1Sponsor's protocol code number8409032
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02099747
    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 SponsorEuropean Society for Blood and Marrow Transplantation
    B.1.3.4CountryNetherlands
    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 supportNovartis
    B.4.2CountryUnited Kingdom
    B.4.1Name of organisation providing supportPfizer
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationEBMT
    B.5.2Functional name of contact pointMarleen Van Os
    B.5.3 Address:
    B.5.3.1Street AddressRijnsburgerweg 10
    B.5.3.2Town/ cityLeiden
    B.5.3.3Post code2333 AA
    B.5.3.4CountryNetherlands
    B.5.4Telephone number+31715261998
    B.5.5Fax number+31715266185
    B.5.6E-mailRACEtrial@lumc.nl
    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 REVOLADE
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Europharm Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNELTROMBOPAG
    D.3.9.1CAS number 496775-61-2
    D.3.9.4EV Substance CodeSUB30140
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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 No
    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
    Idiopathic (Severe) Aplastic Anemia, a bone marrow failure syndrome which results in the normal hematopoietic tissue completely missing from the bone marrow, accounting for the subsequent pancytopenia.
    E.1.1.1Medical condition in easily understood language
    Severe aplastic anemia is an hematological disease of the bone marrow resulting in pancytopenia, a medical condition where there is a reduction in numbers of red-, white blood cells and platelets.
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level PT
    E.1.2Classification code 10002967
    E.1.2Term Aplastic anaemia
    E.1.2System Organ Class 10005329 - Blood and lymphatic system 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 investigate whether Eltrombopag added to standard immunosuppressive treatment increases the rate of early (at three months) complete response in untreated AA patient.
    E.2.2Secondary objectives of the trial
    To investigate the impact of Eltrombopag added to standard treatment on all heamatology outcome measures, Quality of Life and safety/tolerability in untreated AA patients.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Diagnosis of severe or very severe aplastic anemia, defined by
    • At least two of the following:
    – Absolute neutrophil counts <0.5 x 10(9)/L (severe) or
    <0.2 x 10(9)/L (very severe)
    – Platelet counts <20 x 10(9)/L
    – Reticulocyte counts <60 x 10(9)/L
    • Hypocellular bone marrow (<30% cellularity), without evidences of fibrosis or malignant cells
    2.Age ≥ 15 years;
    3.Written informed consent
    E.4Principal exclusion criteria
    1.Prior immunosuppressive therapy with ATG (horse of rabbit) or any other lymphocyte depleting agent (i.e., alemtuzumab)

    2.Eligibility to a sibling allogeneic stem cell transplantation

    3.Evidence of a myelodysplastic syndrome, defined by the presence of myelodysplastic features, excess of blasts or karyotypic abnormalities typical of MDS (according to revised WHO 2008
    criteria) , as well as other primitive marrow disease. Patients with diagnosis of AA with cytogenetic abnormalities which are recurrent in MDS (according to revised WHO 2008 criteria) should be included in this category, and are not eligible for the study; patients with del(20q), +8 and –Y are not included in this category, and thus are eligible for this study. The list of karyotypic abnormalities which qualifies for the diagnosis of MDS are listed in the Appendix 1.

    4.History or clinical suspect of constitutional aplastic anemia (i.e. Fanconi Anemia with positive DEB/MMC test or Dyskeratosis Congenita)

    5.History of malignant tumors with active disease within 5 years from enrollment and/or previous chemo-rediotherapy

    6.Previous history of stem cell transplantation

    7.Treatment with cyclosporin:
    • <4 weeks of cyclosporin A treatment before enrollment.
    • Wash out period of 2 weeks before enrollment.

    8.CMV viremia, as defined by positive PCR or pp65 test

    9.WHO performance status ≥3

    10.Pregnant or breast feeding patients

    11.Patients with hepatic, renal or cardiac failure, or any other life-
    threatening concurrent disease

    12.Patients with HIV infection

    13.Patients without social health care assistance

    14.Participation in another clinical trial within 1 month before the start of this trial

    15.Subjects with known hypersensitivity to any of the component medications
    E.5 End points
    E.5.1Primary end point(s)
    Rate of Complete response (defined as Hb >10 g/dL, ANC > 1,000/μL and Plt >100,000 μL) at 3 months since start of treatment in untreated severe AA patients.
    E.5.1.1Timepoint(s) of evaluation of this end point
    For the main endpoint a valid response has to be measured between month 3 plus or minus 10 days; in case of more than one measurement available in this time period, the best response will be taken.
    E.5.2Secondary end point(s)
    1.Time to first hematological response (complete or partial) described by a cumulative incidence curve (see paragraph 9.6)

    2.Time to best hematological response, described by a cumulative incidence curve (see paragraph 9.6)

    3.Time to complete response (see paragraph 9.6)

    4.Rates of hematological response (overall, complete, partial) at 6, 12, 18 and 24 months

    5.Overall survival (OS) probability; OS is defined as time from treatment starting (day 1) to death, or last follow-up for patients alive

    6.Event-free survival (EFS) probability; EFS is defined as time from treatment starting to either relapse, death, treatment failure or clonal evolution (whichever occurs first), or last follow-up for patients alive in response

    7.Cumulative incidence of relapse, from first hematological response (complete or partial) (see paragraph 9.6)

    8.Cumulative incidence of clonal evolution (as defined below, see 9.5): AML, MDS or karyotypic abnormalities (see paragraph 9.6)

    9.Cumulative incidence of PNH population occurrence and clinical hemolytic PNH occurrence (see paragraph 9.6)

    10.Cumulative incidence of discontinuation of immunosuppressive therapy

    11.Rate of CsA-independent hematological response at 24 months

    12.Need for transfusions (packed red cell units and platelet units) and number of transfusions required from treatment.

    13.Need for any supportive care, including hospitalization

    14.Quality of life (as assessed by the validated EORTC QLQ-C30 questionnaire)(changes over time and differences between treatment arms)

    15.Safety and tolerability of the investigational treatment, including SAE
    E.5.2.1Timepoint(s) of evaluation of this end point
    3, 6, 12, 18 and 24 months
    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 No
    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) 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 No
    E.8.1.5Parallel group Yes
    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) Yes
    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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA37
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months0
    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 Yes
    F.1.1Number of subjects for this age range: 15
    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) Yes
    F.1.1.6.1Number of subjects for this age range: 15
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 160
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 25
    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 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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    This trial includes minors (15-18 years of age) because a peak in AA occurence has been observed around this age. For these patients, the signature of a legal representative is required.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state48
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 200
    F.4.2.2In the whole clinical trial 200
    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)
    Standard treatment
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2015-09-01
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-01-07
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2021-04-12
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