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    Summary
    EudraCT Number:2015-005211-32
    Sponsor's Protocol Code Number:DS1040-B-U107
    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:2016-10-04
    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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2015-005211-32
    A.3Full title of the trial
    A Phase 1b, Randomized, Double-Blind, Placebo-Controlled, Multi-Center, Single Ascending Dose Study to Assess the Safety, Efficacy, Pharmacokinetics, and Pharmacodynamics of DS-1040b when Added to Standard of Care Anticoagulation Therapy in Subjects with Acute Submassive Pulmonary Embolism
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study to Assess the Safety, Pharmacokinetics, and Pharmacodynamics of DS-1040b when added to standard of care anticoagulation therapy in Subjects With Acute Submassive Pulmonary Embolism
    A.4.1Sponsor's protocol code numberDS1040-B-U107
    A.5.4Other Identifiers
    Name:INDNumber:128380
    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 Development Ltd
    B.5.2Functional name of contact pointClinical Trial Information
    B.5.3 Address:
    B.5.3.1Street Address399 Thornall Street
    B.5.3.2Town/ cityEdison
    B.5.3.3Post codeNJ 08837
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1732590 5000
    B.5.5Fax number+1732906 5690
    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 nameDS-1040b
    D.3.2Product code DS-1040b
    D.3.4Pharmaceutical form 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 INNDS-1040B
    D.3.9.2Current sponsor codeDS-1040B
    D.3.9.3Other descriptive nameDS-1040B
    D.3.9.4EV Substance CodeSUB128772
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    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 placeboSolution 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
    DS-1040b is an inhibitor of the activated form of thrombin-activatable fibrinolysis inhibitor (TAFIa) intended to be used for the treatment of thrombotic diseases including Pulmonary Embolism (PE)
    E.1.1.1Medical condition in easily understood language
    Blockage in the pulmonary artery, the blood vessel that carries blood from the heart to the lungs
    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
    The primary objective of the study is to assess the safety and tolerability of ascending doses of DS-1040b given as a single intravenous (IV) infusion over 12, 24, 48 and 72 hours (h), respectively, when added to standard of care (SOC) anticoagulation therapy compared to placebo by evaluating the rate of clinically relevant bleeding ie, major or clinically relevant non-major [CRNM] bleeding (adjudicated by the Clinical Events Committee [CEC] based on the International Society of Thrombosis and Haemostasis [ISTH] definitions).
    E.2.2Secondary objectives of the trial
    1. Relative reduction in total thrombus volume from baseline to ≤ 12h from end of DS-1040b infusion, assessed by CTA in segmental/larger pulmonary arteries;
    2. Proportion of subjects who achieve a ≥ 20% greater relative reduction in total thrombus volume assessed by CTA in segmental/larger pulmonary arteries, from baseline to ≤ 12h from end of DS-1040b infusion and compared to placebo;
    3. Proportion of subjects who achieve a ≥ 50% greater relative reduction in total thrombus volume assessed by CTA in segmental/larger pulmonary arteries, from baseline to ≤ 12h from end of DS-1040b infusion compared to placebo;
    4. Recurrence of VTE up to hospital discharge and up to Day 30 Visit after dosing;
    5. Adjudicated death, major cardiovascular events, hemodynamic decompensation, treatment escalation up to hospital discharge and up to D30 Visit after dosing;
    6. Overall safety evaluation;
    7. Pharmacokinetics of DS-1040b;
    8. Assess the PD effect of DS-1040b on biomarkers, in subjects with PE.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or female subjects, age 18 to 75 years and body weight between 50 and 130 kg, inclusive;
    2. Subjects admitted to the hospital with a clinical diagnosis of acute PE with an onset of symptoms in the 5 days prior to diagnosis categorized as low risk or intermediate-risk or submassive PE and for whom catheter-based therapy is not planned;
    a. Subjects must have a CTA scan confirming the PE diagnosis and with at least one measurable index lesion in a segmental or larger pulmonary artery prior to randomization;
    b. Subjects should be in otherwise satisfactory health in the opinion of the Investigator;
    c. Subjects may have concurrent DVT and have an inferior vena cava (IVC) filter placed prior to randomization;
    d. Subjects may already be on SOC low molecular weight LMW heparin at the time of randomization but for no longer than 36 hours.
    3. Able to provide written informed consent.
    E.4Principal exclusion criteria
    1. Subjects with acute PE categorized as high-risk or massive, or who are hemodynamically unstable, evidenced by a heart rate > 120 /min and a systolic blood pressure (SBP) of < 90 mmHg for more than 15 consecutive minutes or a drop in SBP of > 40 mmHg since presentation;
    2. Subjects for whom use of a thrombolytic, either systemic or via catheter, is planned;
    3. Subjects with PE lesions only in the sub-segmental or smaller arteries, which due to limitations of the imaging method may not be consistently identified and measured;
    4. Subjects unable or unwilling to take the required SOC anticoagulation therapy;
    5. Subjects receiving more than 36 hours of SOC anticoagulants for treatment of the index PE event prior to randomization. Study drug infusion will ideally begin within 6hr after randomization
    6. Subjects who had prior intracranial hemorrhage, known arteriovenous malformation or aneurysm, or evidence of active bleeding;
    7. Subjects with bleeding diathesis, a platelet count < 100,000, international normalized ratio (INR) > 1.7, or clinically significant elevated activated partial thromboplastin time (aPTT) that is not explained by use of LMW heparin;
    8. Subjects with active endocarditis;
    9. Subjects with < 6 month history of acute coronary syndrome (ACS) whether or not they have undergone percutaneous coronary intervention (PCI);
    10. Subjects who require ongoing dual antiplatelet therapy or treatment with aspirin alone in a dosage of more than 100 mg/per day;
    11. Chronic treatment with non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs) including both cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) inhibitors for ≥ 4 days/week anticipated to continue during the study;
    12. Subjects with uncontrolled hypertension at randomization, evidenced by systolic blood pressure > 180 mm Hg or diastolic blood pressure>120 mmHg, or who require parenteral medication to maintain blood pressure below these limits;
    13. Subjects who within 3 months prior to randomization have had intracranial surgery, clinically significant head trauma (in the opinion of the Principal Investigator), a stroke, or have received thrombolytic treatment;
    14. Subjects with ECG evidence of 2nd degree or higher atrioventricular (AV) block or with QTcB or QTcF >450 ms;
    15. Subjects who within 21 days prior to randomization have had gastrointestinal or genitourinary bleeding;
    16. Subjects who within 14 days prior to randomization have had major surgery or a lumbar puncture (or epidural steroid injection);
    17. Subjects with hemoglobin < 10 g/dL;
    18. Subjects with an estimated creatinine clearance < 60 mL/min;
    19. Subjects with diagnosed active liver disease or with elevation of liver enzymes/bilirubin:
    a. Alanine transaminase (ALT) or aspartate transaminase (AST) ≥ 2 times upper limit of normal (ULN)
    b. Total bilirubin (TBL) ≥ 1.5 times ULN (except due to confirmed Gilbert’s syndrome)
    20. Subjects with known history of testing positive for Hepatitis B antigen or Hepatitis C antibody before randomization;
    21. Subjects with known history of testing positive for the human immunodeficiency virus (HIV);
    22. Subjects with active cancer, defined as recurrent, regionally advanced, metastatic disease, or a hematologic malignancy not in complete remission and subjects with malignancy diagnosed within 2 years prior to randomization, except for adequately treated non-melanoma skin cancer or other non-invasive or in-situ neoplasm;
    23. Subjects currently receiving chemotherapy or radiation therapy or having received any treatment for cancer during the 12 months prior to randomization, or expected to initiate such therapy during study participation;
    24. Subjects with NYHA Class III or IV congestive heart failure;
    25. Subjects with chronic obstructive pulmonary disease;
    26. Female subjects of child bearing potential with a positive pregnancy test, lactating women or women unwilling to use highly effective methods of birth control. Highly effective methods of birth control include combination hormonal therapy (estrogen and progesterone), 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.
    27. Subjects currently participating in another investigational study or who have participated in an investigational drug study within 30 days or prior to randomization;
    28. Subjects unlikely to comply with the protocol (eg, uncooperative attitude, inability to return for subsequent visits, and/or otherwise considered by the investigator to be unlikely to complete the study);
    29. Subjects with any condition (including laboratory abnormalities) that, in the opinion of the Investigator, would potentially place the subject at increased risk of harm through participation in this study.
    E.5 End points
    E.5.1Primary end point(s)
    Efficacy:
    1. Relative reduction (% reduction) in total thrombus volume from baseline to ≤ 12h from end of DS-1040b infusion assessed by CTA) in segmental or larger pulmonary arteries;
    2. Proportion of subjects who achieve a ≥ 20% greater relative reduction in total thrombus volume assessed by CTA in segmental or larger pulmonary arteries, from baseline to ≤ 12h from end of DS-1040b infusion;
    3. Proportion of subjects who achieve a ≥ 50% greater relative reduction in total thrombus volume assessed by CTA in segmental or larger pulmonary arteries, from baseline to ≤ 12h from end of DS-1040b infusion.
    Safety:
    1. Clinically relevant bleeding (adjudicated major or CRNM bleeding);
    2. Serious adverse events and TEAEs.
    E.5.1.1Timepoint(s) of evaluation of this end point
    All Efficacy: Baseline to ≤ 12h from end of infusion
    All Safety: Continuous through the study
    E.5.2Secondary end point(s)
    Efficacy:
    1. Recurrence of VTE (Composite of recurrent symptomatic PE, new or recurrent symptomatic DVT, VTE-related death; as well as the individual components) up to hospital discharge and up to Day 30 Visit;
    2. Death, hemodynamic decompensation, or treatment escalation (defined as catecholamine infusion, secondary thrombolysis, endotracheal intubation, cardiopulmonary resuscitation, or emergency surgical embolectomy or thrombus fragmentation by catheter) up to hospital discharge and up to Day 30 post randomization;
    3. MACE (defined as a composite of cardiovascular death, or non-fatal myocardial infarction, stroke, or SEE) up to hospital discharge and up to Day 30 Visit.
    PK/PD:
    1. Plasma concentrations of DS-1040a:
    2. Pharmacodynamic endpoints including:
    a. total TAFIa activity;
    b. D-dimer;
    c. TAFI antigen;
    E.5.2.1Timepoint(s) of evaluation of this end point
    All Efficacy: Up to hospital discharge and up to Day 30 Visit
    PK/PD:
    1. - Area under concentration-versus-time curve, from time 0 to the last quantifiable concentration sampling point (AUClast) and from time 0 extrapolated to infinity (AUC0-inf), if data allows
    - Maximum (peak) observed plasma concentration (Cmax);
    - Time of maximum observed concentration (Tmax);
    - Immediately prior to the end of continuous infusion;
    - Elimination half-life (T1/2), if data allows
    - Total clearance (CL), if data allows
    2. The following for a,b&c:
    All cohorts (C): Baseline (predose), 0.5 (end of loading infusion) plus:
    C1: 6, 12 (end of maintenance infusion - EoMI), 18, 24 & 48 hrs
    C2&3: 24 (EoMI), 36, 48 & 72 hrs
    C4&5: 48 (EoMI), 60, 72 & 96 hrs
    C6: 72 (EoMI), 84, 96 & 120 hrs
    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 No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    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 No
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Single Ascending dose
    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 trial6
    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 concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA35
    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
    Austria
    Belgium
    France
    Germany
    Italy
    Netherlands
    Spain
    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 months0
    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 months7
    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: 75
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 75
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    The ICF should be signed & personally dated by a legally acceptable representative who is an individual / other body authorized under applicable law to consent, on behalf of a prospective subject, to the subject’s participation in the clinical study.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state12
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 85
    F.4.2.2In the whole clinical trial 116
    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)
    A Day 30 long-term follow-up visit will take place in an outpatient setting. Following the end of the enoxaparin/study drug administration period, subjects will be switched to the anticoagulant treatment of choice at the investigator’s discretion consistent with local practice and current treatment guidelines
    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 Decision2016-10-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-03-08
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-08-05
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