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). MedDRA version: 20.0 Level: HLT Classification code 10037379 Term: Pulmonary embolism and thrombosis System Organ Class: 100000004866 MedDRA version: 20.0 Level: PT Classification code 10037377 Term: Pulmonary embolism System Organ Class: 100
Conditions
Interventions
Product Name: DS9231
Product Code: DS9231
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: DS9231
Current Sponsor code: DS9231
Other descriptive name: DS-9231 (TS23)
Con
Sponsors
Daiichi Sankyo Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
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 Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 52 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 52
Exclusion criteria
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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 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) ;Secondary Objective: 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. ;Primary 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 ;Timepoint(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 | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary 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) ;Timepoint(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 | — |
Countries
Canada, Czech Republic, Denmark, Hungary, United States
Contacts
Public ContactClinical Trial Information
Daiichi Sankyo Inc.
Outcome results
None listed