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    Summary
    EudraCT Number:2013-000965-34
    Sponsor's Protocol Code Number:E5501-G000-310
    National Competent Authority:Portugal - INFARMED
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2014-03-20
    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 ConcernedPortugal - INFARMED
    A.2EudraCT number2013-000965-34
    A.3Full title of the trial
    A Randomized, Global, Double-blind, Placebo-controlled, Parallel-group
    Study to Evaluate the Efficacy and Safety of Once-daily Oral
    Avatrombopag for the Treatment of Adults with Thrombocytopenia
    Associated with Liver Disease Prior to an Elective Procedure
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to investigate the effectiveness of avatrombopag in increasing the amount of platelets (a type of cell found in the blood) in patients with chronic liver disease who need to have a planned procedure but have thrombocytopenia (low platelet counts) related to the chronic liver disease.
    A.3.2Name or abbreviated title of the trial where available
    Adapt I
    A.4.1Sponsor's protocol code numberE5501-G000-310
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01972529
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation PlanP/309/2011
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorEisai Limited
    B.1.3.4CountryUnited Kingdom
    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 supportEisai Incorporation
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationEisai Limited
    B.5.2Functional name of contact pointMedical Information
    B.5.3 Address:
    B.5.3.1Street AddressEuropean Knowledge Centre, Mosquito Way
    B.5.3.2Town/ cityHatfield, Hertfordshire
    B.5.3.3Post codeAL10 9SN
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+4408456761400
    B.5.5Fax number+4408456761401
    B.5.6E-mailLmedInfo@eisai.net
    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 nameAvatrombopag
    D.3.2Product code E5501
    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 INNAvatrombopag maleate
    D.3.9.1CAS number 1254322-84-3
    D.3.9.2Current sponsor codeE5501
    D.3.9.3Other descriptive nameAKR-501, YM-477
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Thrombocytopenia in Patients with Chronic Liver Disease
    E.1.1.1Medical condition in easily understood language
    Low platelet counts in patients with chronic liver disease
    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 18.1
    E.1.2Level HLGT
    E.1.2Classification code 10035534
    E.1.2Term Platelet disorders
    E.1.2System Organ Class 10005329 - Blood and lymphatic system disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.1
    E.1.2Level PT
    E.1.2Classification code 10043554
    E.1.2Term Thrombocytopenia
    E.1.2System Organ Class 10005329 - Blood and lymphatic system disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.1
    E.1.2Level SOC
    E.1.2Classification code 10005329
    E.1.2Term Blood and lymphatic system disorders
    E.1.2System Organ Class 10005329 - Blood and lymphatic system disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.1
    E.1.2Level LLT
    E.1.2Classification code 10039884
    E.1.2Term Secondary thrombocytopenia
    E.1.2System Organ Class 10005329 - Blood and lymphatic system disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of the study is to confirm that avatrombopag (60 mg avatrombopag for subjects with platelet count <40 × 109/L and 40 mg avatrombopag for subjects with platelet count from 40 to <50 × 109/L) is superior to placebo in removing the need for platelet transfusions or any rescue procedure for bleeding after randomization and up to 7 days following an elective procedure in subjects with chronic liver disease who have thrombocytopenia.
    E.2.2Secondary objectives of the trial
    To confirm that avatrombopag is superior to placebo in achieving a platelet count of ≥50 x 109/L on Procedure Day in the proposed target population

    To confirm that avatrombopag is superior to placebo in elevating platelet counts from baseline on Procedure Day in the proposed target population

    To evaluate whether the observed incidence of bleeding in subjects treated with avatrombopag is noninferior to placebo in those subjects expected to receive a platelet transfusion prior to their procedure

    To evaluate the safety of avatrombopag in the proposed target population
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Subjects ≥18 years of age at Screening with chronic liver disease
    2. Subjects who have a mean baseline platelet count of <50 × 109/L. Platelet counts must be measured on 2 separate occasions, during the Screening Period and at Baseline, and must be performed at least one day apart with neither platelet count >60 × 109/L. The mean of these 2 platelet counts (mean baseline platelet count) will be used for entry criteria and for assignment to the low or high baseline platelet count cohort.
    3. Subjects scheduled to undergo a permitted elective procedure and who, in the opinion of the investigator, will otherwise require a platelet transfusion to address a risk of bleeding associated with the procedure unless there is a clinically significant change in platelet count from
    baseline
    4. Model For End-stage Liver Disease (MELD) score ≤24 at Screening
    5. If taking inhibitors of P glycoprotein (P-gp), except for verapamil, dose must be stable for 7 days prior to Screening (see Appendix 2 for the list of P-gp Inhibitors)
    6. Provide written informed consent
    7. Willing and able to comply with all aspects of the protocol
    E.4Principal exclusion criteria
    1. Any history of arterial or venous thrombosis, including partial or complete thrombosis
    2. Evidence of thrombosis (partial or complete) in the main portal vein, portal vein branches, or any part of the splenic mesenteric system at Screening
    3. Portal vein blood flow velocity rate <10 cm/second at Screening
    4. Hepatic encephalopathy that cannot be effectively treated
    5. Subjects with HCC and Barcelona Clinic Liver Cancer (BCLC) staging classification C or D
    6. Platelet transfusion or receipt of blood products containing platelets within 7 days of Screening. However packed red blood cells are permitted
    7. Heparin, warfarin, nonsteroidal anti-inflammatory drugs (NSAID), aspirin, verapamil, and antiplatelet therapy with ticlopidine or glycoprotein IIb/IIIa antagonists (eg, tirofiban) within 7 days of Screening
    8. Use of erythropoietin stimulating agents within 7 days of Screening
    9. Interferon (IFN) use within 14 days of Screening
    10. Estrogen-containing hormonal contraceptive or hormone replacement therapy use within 30 days of Screening
    11. Active infection requiring systemic antibiotic therapy within 7 days of Screening. However, prophylactic use of antibiotics is permitted.
    12. Alcohol abuse, alcohol dependence syndrome, drug abuse, or drug dependence within 6 months of the study start (unless participating in a controlled rehabilitation program) or acute alcoholic hepatitis (chronic alcoholic hepatitis is allowed) within 6 months of the study start
    13. Elective procedure performed prior to Visit 4 (Procedure Day)
    14. Known to be human immunodeficiency virus (HIV) positive
    15. Any clinically significant acute or active bleeding(gastrointestinal, central nervous system, etc.)
    16. Known history of any primary hematologic disorder (eg, ITP, myelodysplastic syndrome, etc.)
    17. Known medical history of genetic prothrombotic syndromes (eg, Factor V Leiden; prothrombin G20210A; ATIII deficiency etc.) (revised per Amendment 01)
    18. Subjects with a history of significant cardiovascular disease (eg, congestive heart failure New York Heart Association Grade III/IV, arrhythmia known to increase the risk of thromboembolic events [eg, atrial fibrillation], coronary artery stent placement, angioplasty, and coronary artery bypass graft [CABG])
    19. Females of childbearing potential who have had unprotected sexual intercourse within 30 days before study entry and who do not agree to use a highly effective method of contraception (eg, total abstinence, an intrauterine device, a double-barrier method[such as condom plus diaphragm with spermicide], a progesterone-only contraceptive implant/injection, or have a vasectomized partner with confirmed azoospermia) throughout the entire study period and for 30 days after study drug discontinuation. If currently abstinent, the subject must agree to use a double-barrier method as described above if she becomes sexually active during the study period or for 30 days after study drug discontinuation. All females will be considered to be of childbearing potential unless they are postmenopausal (at least 12 months consecutive amenorrhea in the appropriate age group and without other known or suspected cause) or have been sterilized surgically (ie, bilateral tubal ligation, hysterectomy, or bilateral oophorectomy) at least 1 month before dosing.
    20. Females who are lactating or pregnant at Screening or Baseline (as documented by a positive serum beta-human chorionic gonadotropin [β-hCG]test with a minimum sensitivity 25 IU/L or equivalent units of β-hCG). A separate baseline ssessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of study drug.
    21. Post liver transplant subjects
    22. Any subject who has previously received avatrombopag
    23. Hypersensitivity to avatrombopag maleate or any of its excipients
    24. Hemoglobin levels ≤8.0 or ≥18.0 g/dL for men and >15 for women
    at Screening, with hematocrit ≥54% for men and ≥45% for women
    27. Current malignancy including solid tumors and hematologic
    malignancies (except HCC)
    28. Any history of or concomitant
    28. Any history of or concomitant medical condition that, in the opinion of the investigator(s), would compromise the subject’s ability to safely complete the study
    29. Currently enrolled in another clinical trial or used any investigational drug or device within 30 days of Screening
    E.5 End points
    E.5.1Primary end point(s)
    Proportion of subjects who do not require a platelet transfusion or any rescue procedure for bleeding after randomization and up to 7 days following an elective procedure
    E.5.1.1Timepoint(s) of evaluation of this end point
    Between randomisation and 7 days post procedure.
    E.5.2Secondary end point(s)
    Proportion of subjects who achieve platelet counts of ≥50 × 109/L on Procedure Day (ie, prior to receiving a platelet transfusion or undergoing the elective procedure)

    Change from baseline in platelet count on Procedure Day (ie, prior to receiving a platelet transfusion or undergoing the elective procedure)

    Proportion of subjects with a WHO bleeding score ≥2 after randomization and up to 7 days following an elective procedure
    E.5.2.1Timepoint(s) of evaluation of this end point
    On procedure day and between randomisation and 7 days post procedure
    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 No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic Yes
    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 No
    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 No
    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.8.2.4Number 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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA30
    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
    Argentina
    Australia
    Austria
    Belgium
    Brazil
    Bulgaria
    Canada
    Chile
    China
    France
    Germany
    Hungary
    Italy
    Korea, Republic of
    Mexico
    Poland
    Portugal
    South Africa
    Spain
    Taiwan
    United Kingdom
    United States
    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
    Clinical data base lock is the definition of the end of the trial as provided in the protocol. For the patients the end of the trial is the LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months36
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial months36
    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: 285
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 15
    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 state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 114
    F.4.2.2In the whole clinical trial 300
    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 of care
    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 Decision2014-03-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-08-22
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-01-26
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