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    Summary
    EudraCT Number:2017-000552-25
    Sponsor's Protocol Code Number:DS9231-A-U201
    National Competent Authority:Hungary - National Institute of Pharmacy
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2017-05-31
    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 ConcernedHungary - National Institute of Pharmacy
    A.2EudraCT number2017-000552-25
    A.3Full title of the trial
    Evaluation of Safety and Thrombolytic Effect of Ascending Doses of DS-9231 (TS23) in Subjects with Intermediate-Risk (sub-massive) Acute Pulmonary Embolism (PE)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study to evaluate the safety and thrombolytic effect of increasing doses of DS9231 in sujbects with severe pulmonary embolism
    A.4.1Sponsor's protocol code numberDS9231-A-U201
    A.5.4Other Identifiers
    Name:INDNumber:118619
    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 SponsorDaiichi Sankyo Inc.
    B.1.3.4CountryUnited States
    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 supportDaiichi Sankyo Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationDaiichi Sankyo Inc.
    B.5.2Functional name of contact pointClinical Trial Information
    B.5.3 Address:
    B.5.3.1Street Address211 Mt Airy Road
    B.5.3.2Town/ cityBasking Ridge
    B.5.3.3Post code NJ 07920
    B.5.3.4CountryUnited States
    B.5.4Telephone number+19089926400
    B.5.5Fax number+17329066652
    B.5.6E-maileu_cta@dsi.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 nameDS9231
    D.3.2Product code DS9231
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNDS9231
    D.3.9.2Current sponsor codeDS9231
    D.3.9.3Other descriptive nameDS-9231 (TS23)
    D.3.9.4EV Substance CodeSUB186762
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboConcentrate for solution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    DS9231, also known as TS23, is an inhibitor of alpha2-antiplasmin, incrasing plasmin acitivy and enhances fibrinolysis (thrombolysis) and intended to be used for the treatment of patients with Intermediate-Risk (Sub-Massive) Acute Pulmonary Embolism (PE).
    E.1.1.1Medical condition in easily understood language
    Blood clot in the lung(s).
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level HLT
    E.1.2Classification code 10037379
    E.1.2Term Pulmonary embolism and thrombosis
    E.1.2System Organ Class 100000004866
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10037377
    E.1.2Term Pulmonary embolism
    E.1.2System Organ Class 10038738 - Respiratory, thoracic and mediastinal disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    1. To compare the incidence of adjudicated major or clinically relevant non-major (CRNM) bleeding events
    2. To compare the change from baseline (% reduction) in total thrombus volume, assessed by computed tomography pulmonary angiography (CTPA) scan,
    3. To compare the % of subjects with various gradations of decrease in total thrombus volume (no decrease, ≥20% decrease, ≥30% decrease, ≥50% decrease or 100% resolution)
    E.2.2Secondary objectives of the trial
    1. To compare the change from baseline (% reduction) in total thrombus volume (by CTPA scan)
    2. compare the % of subjects with various gradations of decrease in total thrombus volume (no decrease, ≥20% decrease, ≥30% decrease, ≥50% decrease or 100% resolution)
    3. compare the change from baseline in right ventricular-to-left ventricular (RV/LV) diameter ratio (by CTPA) scan
    4. compare the incidence of major or clinically relevant non-major (CRNM) bleeding events (adjudicated by clinical events committee [CEC])
    5. compare the rate of PE related deaths
    6. compare the rate of all-cause deaths with ascending doses of DS-9231
    7. compare the % of subjects with clinical deterioration requiring additional rescue therapies.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or female subjects, age >18 years;
    2. PE involving a segmental or more proximal pulmonary artery confirmed by CTPA scan and with an onset of symptoms not more than 5 days prior to diagnosis;
    3. Subject is hemodynamically stable with a systolic blood pressure (SBP) >90 mm Hg
    4. Subject has evidence of RV dysfunction (at least one of the following):
    • Right ventricular-to-left ventricular (RV/LV) diameter ratio > 0.9 on CTPA scan (measuring the minor axis of the right and left ventricle in the transverse plane),
    • or myocardial injury as evidenced by an elevated cardiac Troponin T or Troponin I (using the test of the local laboratory of Clinical Chemistry at the participating site). An abnormal value is that above the 99th percentile of the healthy population as a cutoff using an assay with acceptable precision. The 99th percentile cutoff point for cardiac Troponin T (cTnT) is well-known at 0.01 ng/mL as only one cTnT assay exists. In contrast, several different assays are commercially available for cardiac Troponin I (cTnI), so the 99th percentile cut point varies based on the assay being used. Please refer to Appendix 17.3 as guideline for acceptable abnormal Troponin I values.
    • or RV/LV ratio > 0.9 on echocardiogram (apical or subcostal 4 - chamber view echocardiogram). A trained cardiac sonographer may not be available during non-business hours (for emergency admissions); however, if feasible, obtain echocardiogram prior to the initiation of study drug administration.
    Eligible subjects, who qualify and have executed informed consent, will be randomized as early as possible and every effort will be made to administer the study medication (DS-9231 versus placebo) as soon as possible within the first 6 hours after the randomization
    E.4Principal exclusion criteria
    1. Subjects for whom thrombolytic therapy or thrombectomy is planned; or subjects with history of administration of thrombolytic agents within the previous 4 days;
    2. Subjects receiving ≥ 48 hours of therapeutic doses of heparin or LMWH or other anticoagulant therapy immediately prior to randomization;
    3. Subjects with contraindications to SOC therapies such as unfractionated heparin or LMWH or oral anticoagulant, or any of the excipients (including study drug excipients);
    4. Subjects who are considered at very high risk of bleeding:
    a. Known coagulation disorder with history of pathologic bleeding tendencies
    b. Subjects with prior intracranial hemorrhage, known arteriovenous malformation or aneurysm of the
    brain, or evidence of active bleeding;
    c. Subjects with a history of major surgery, clinically significant head trauma (in the opinion of the
    Principal Investigator), or stroke in the past 3 months prior to randomization;
    d. Subjects with uncontrolled hypertension defined as SBP ≥180 mm Hg and/or diastolic BP
    (DBP) ≥110 mm Hg at randomization
    e. Subjects requiring concomitant dual antiplatelet therapy
    5. Subjects with Creatinine Clearance (CrCL) < 30 mL/min or serum creatinine ≥ 2.5 mg/dL;
    6. Subjects with hemoglobin < 8.0 g/dL;
    7. Subjects with a platelet count < 100,000/µL;
    8. Subjects with acute or persistent hepatitis or diagnosed active liver disease or with elevation of liver enzymes: Alanine transaminase (ALT) or aspartate transaminase (AST) ≥ 3 x upper limit of normal (ULN);
    9. Subjects with known history of testing positive for Hepatitis B antigen or Hepatitis C antibody;
    10. Subjects with known history of testing positive for the human immunodeficiency virus (HIV);
    11. Subjects with life-expectancy < 6 months;
    12. Female subjects of child bearing potential with a positive pregnancy test or who are lactating, or unwilling to use highly effective methods of contraception. Highly effective methods of birth control include combination hormonal therapy (estrogen and progresterone), contraceptives administered orally, intravaginally or transdermally, progesterone-only contraceptives administered orally, by injection or implantation, use of an intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, partner vasectomy or sexual abstinence;
    13. Subjects currently participating in another investigational study or who have participated in an investigational drug study within 30 days (or longer depending on the half-life of the investigational drug; should allow at least five half-life of the investigational drug) prior to randomization.
    E.5 End points
    E.5.1Primary end point(s)
    Primary efficacy endpoints:
    • % reduction in total thrombus volume at 48-96 hours after completion of study drug administration, as assessed by CTPA scan.
    • % of subjects with various gradations of decrease in total thrombus volume (no decrease, ≥20% decrease, ≥30% decrease, ≥50% decrease or 100% resolution) at 48-96 hours after the completion of study drug administration

    Primary safety endpoints:
    • Adjudicated major or clinically relevant non-major bleeding events occurring within the first 7 days after completion of study drug administration
    E.5.1.1Timepoint(s) of evaluation of this end point
    Efficacy: 48-96 hours after completion of study drug administration
    Safety: Within the first 7 days after completion of study drug administration
    E.5.2Secondary end point(s)
    Seconday efficacy enpoints:
    1. % reduction in total thrombus volume, as assessed by CTPA scan.
    2. % of subjects with various gradations of decrease in total thrombus volume (no decrease, ≥20% decrease, ≥30% decrease, ≥50% decrease or 100% resolution) .
    3. % change from baseline in RV/LV diameter ratio (by CTPA scan).
    4. PE related deaths .
    5. % of subjects with clinical deterioration requiring additional rescue therapy for PE
    6. % of subjects with recurrent, objectively documented VTE.
    7. Quality of life

    Seconday safety endpoints:
    a. Adjudicated major or clinically relevant non-major bleeding events
    b. All-cause deaths
    c. Re-hospitalizations for any reason
    d. Non-bleeding AEs
    e. Anti-drug antibodies (ADA)
    E.5.2.1Timepoint(s) of evaluation of this end point
    Efficacy:
    1, 2 and 3: at Day 30 after completion of study drug administration
    4: within the first 7 days, 8-30 days, and overall 1-30 days after completion of study drug administration
    5, 6: within the first 7 days, 8-30 days, and overall 1-30 days after completion of study drug administration
    7: at baseline and Day 30

    Safety:
    a. within 8-30 days and overall 1-30 days after completion of study drug administration
    b, c and d: within the first 7 days, 8-30 days and overall 1-30 days after completion of study drug administration
    e: baseline, Day7, and at Day 30 follow-up visit
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis Yes
    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 Yes
    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 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 Yes
    E.8.1.7.1Other trial design description
    Ascending doses
    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 concerned9
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA20
    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
    Canada
    Czech Republic
    Denmark
    Hungary
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months1
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months1
    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: 52
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 52
    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 Yes
    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 state14
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 42
    F.4.2.2In the whole clinical trial 104
    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- expected normal treatment of that condition.
    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 Decision2017-08-07
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-07-31
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    The status of studies in GB is no longer updated from 1.1.2021
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