Study to Assess the Safety, Pharmacokinetics/Dynamics of DS-1040b in Subjects With Acute Submassive Pulmonary Embolism

Phase 1

Completed

Conditions: Pulmonary Embolism
Thrombotic Disease

Interventions: Drug: DS-1040b
Drug: Placebo
Drug: Enoxaparin

Registration Number: NCT02923115

Lead Sponsor: Daiichi Sankyo

Brief Summary: This is a Phase 1b, double-blind (participants and Investigators), placebo-controlled, randomized, single-ascending dose, multi-center study to assess the safety, efficacy, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of DS-1040b in participants with acute submassive pulmonary embolism.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 134

Inclusion Criteria

Male or female subjects, age 18 to 75 years admitted to hospital with a clinical diagnosis of acute pulmonary embolism (PE) categorized as low risk or intermediate-risk or submassive PE and for whom catheter-based therapy is not planned;
Subjects must have a computed tomography angiography (CTA) scan confirming the PE diagnosis and with at least one measurable index lesion in a segmental or larger pulmonary artery prior to randomization;
Subjects should be in otherwise satisfactory health in the opinion of the Investigator;
Subjects must be able to provide written informed consent.

Exclusion Criteria

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;
Subjects for whom use of a thrombolytic, either systemic or via catheter, is planned;
Subjects with PE lesions only in the sub-segmental or smaller arteries;
Subjects receiving any vitamin K antagonists (VKAs) prior to randomization or receiving more than 36 hours treatment with low molecular weight (LMW) Heparin in therapeutic doses prior to randomization;
Subjects who had a prior intracranial hemorrhage, known arteriovenous malformation or aneurysm, head trauma, or evidence of active bleeding;
Subjects who within 48 hours of randomization have used an anti-Factor IIa agent such as dabigatran or an anti-FXa agent such as rivaroxaban, apixaban, or edoxaban;
Subjects who within 21 days prior to randomization have had gastrointestinal or genitourinary bleeding;
Subjects who within 14 days prior to randomization have had major surgery or a lumbar puncture (or epidural steroid injection);
Subjects with diagnosed active liver disease or with elevation of liver enzymes/bilirubin.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
DS-1040b	DS-1040b	Participants who are randomized to receive DS-1040b as a single, continuous intravenous infusion (initial loading dose 3-6 mg). All participants will also receive standard of care anticoagulation enoxaparin therapy during the study drug infusion.
DS-1040b	Enoxaparin	Participants who are randomized to receive DS-1040b as a single, continuous intravenous infusion (initial loading dose 3-6 mg). All participants will also receive standard of care anticoagulation enoxaparin therapy during the study drug infusion.
Placebo	Placebo	Participants who are randomized to receive placebo as a single, continuous intravenous infusion. All participants will also receive standard of care anticoagulation enoxaparin therapy during the study drug infusion.
Placebo	Enoxaparin	Participants who are randomized to receive placebo as a single, continuous intravenous infusion. All participants will also receive standard of care anticoagulation enoxaparin therapy during the study drug infusion.

Primary Outcome Measures

Name	Time	Method
Number of Participants Experiencing Adjudicated Clinically Relevant Bleeding Events Following Intravenous Infusion of DS-1040b or Placebo in Addition to Standard of Care Anti-coagulation Therapy in Participants With Acute Submassive Pulmonary Embolism	Baseline up to Day 30 post infusion, up to approximately 3 years 2 months	Clinically relevant bleeding was defined as major or clinically relevant non-major (CRNM) bleeding adjudicated by the Clinical Events Committee (CEC) based on International Society of Thrombosis and Haemostasis (ISTH) definitions and the CEC charter.

Secondary Outcome Measures

Name	Time	Method
Participants Achieving Reductions in Total Thrombus Volume at 12-72 Hours Post Infusion of DS-1040b Compared to Placebo When Added to Standard of Care Anticoagulation Therapy in Participants With Acute Submassive Pulmonary Embolism	Baseline to 12-72 hours post start of infusion, up to approximately 3 years 2 months	Change in total pulmonary thrombus burden (total thrombus volume) was assessed by computed tomography pulmonary angiography (CTPA). All CTPA scans were evaluated by a central imaging laboratory in a blinded manner by radiologists.
Pharmacokinetic Parameter Area Under the Concentration Versus Time Curve (0 to Last) Following Intravenous Infusion of DS-1040b In Addition to Standard of Care Anti-coagulation Therapy in Participants With Acute Submassive Pulmonary Embolism	Cohort 1: 0 up to 72 h post infusion; Cohorts 2 and 3: 0 up to 96 h post infusion; Cohort 4 and 5: 0 up to 120 h post infusion	Plasma concentrations at each time point and PK parameter of Area Under the Concentration Versus Time Curve (0 to last) of DS-1040b was calculated using non-compartmental analysis.
Mean Percent Change From Baseline in Total Thrombus Volume at 12-72 Hours Post Start of Infusion of DS-1040b Compared to Placebo When Added to Standard of Care Anticoagulation Therapy in Participants With Acute Submassive Pulmonary Embolism	Baseline to 12-72 hours post start of infusion, up to approximately 3 years 2 months	The change from baseline in total thrombus volume was assessed by computed tomography angiography in segmental or larger pulmonary arteries following intravenous infusion of DS-1040b or placebo in addition to standard of care anti-coagulation therapy.
Pharmacokinetic (PK) Parameter Maximum Concentration (CMax) Following Intravenous Infusion of DS-1040b in Addition to Standard of Care Anti-coagulation Therapy in Participants With Acute Submassive Pulmonary Embolism	Cohort 1: 0 up to 72 h post infusion; Cohorts 2 and 3: 0 up to 96 h post infusion; Cohort 4 and 5: 0 up to 120 h post infusion	Plasma concentrations at each time point and PK parameter Cmax of DS 1040b was calculated using non-compartmental analysis.
Pharmacokinetic Parameter Terminal Half-life Following Intravenous Infusion of DS-1040b Combined With Standard of Care Anti-coagulation Therapy in Participants With Acute Submassive Pulmonary Embolism	Cohort 1: 0 up to 72 h post infusion; Cohorts 2 and 3: 0 up to 96 h post infusion; Cohort 4 and 5: 0 up to 120 h post infusion	Plasma concentrations at each time point and PK parameter Terminal Half-life of DS-1040b was calculated using non-compartmental analysis.

Trial Locations

Locations (46): Pulmonary Associates of Mobile
🇺🇸
Mobile, Alabama, United States
Cedars-Sinai Medical Center
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Beverly Hills, California, United States
University of California, San Diego (UCSD) Medical Center
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San Diego, California, United States
Intercoastal Medical Group
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Sarasota, Florida, United States
Northwestern Memorial Hospital
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Chicago, Illinois, United States
University of Kentucky Medical Center
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Lexington, Kentucky, United States
Massachusetts General Hospital
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Boston, Massachusetts, United States
Mayo Clinic - Rochester
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Rochester, Minnesota, United States
Mercury Street Medical
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Butte, Montana, United States
Jacobi Medical Center
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Bronx, New York, United States
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Pulmonary Associates of Mobile
🇺🇸Mobile, Alabama, United States