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

A Phase 1b, Randomized, Double-Blind, Placebo-Controlled, Multi-Center, Single Ascending Dose 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

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.

Study Overview

• Status: Completed
• Conditions: Pulmonary Embolism; Thrombotic Disease
• Intervention / Treatment: Drug: DS-1040b; Drug: Enoxaparin; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 134
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Austria
  • Graz, Austria, 8036
    • Medical University Graz
  • Innsbruck, Austria, 6020
    • Medical University Innsbruck
  • Vienna, Austria, 1090
    • Medical University of Vienna
• Belgium
  • Bruxelles, Belgium, 1200
    • Cliniques Universitaires Saint-Luc
  • Bruxelles, Belgium, 1070
    • Université libre de Bruxelles (ULB) - Hôpital Erasme
  • Leuven, Belgium, 3000
    • University Hospital Leuven
• France
  • Brest, France, 29609
    • CHU de Brest - Hôpital de la Cavale Blanche
  • Clermont-Ferrand, France, 63000
    • CHU Gabriel Montpied Clermont-Ferrand
  • La Tronche, France, 38700
    • CHU de GRENOBLE
  • Paris, France, 75017
    • Hôpital Européen Georges Pompidou
  • Saint-étienne, France, 42055
    • CHU St Etienne - Hôpital Nord
  • Strasbourg, France, 67091
    • Hopital Civil de strasbourg
• Germany
  • Dresden, Germany, 01307
    • Universitaetsklinikum Dresden
  • Dresden, Germany, 01067
    • Staedtisches Klinikum Dresden-Friedrichstadt
  • Greifswald, Germany, 17475
    • Universitaetsmedizin Greifswald
  • Magdeburg, Germany, 39120
    • Universitätsklinikum Magdeburg
  • München, Germany, 81675
    • Klinikum rechts der Isar, Technische Universität München
• Italy
  • Ancona, Italy, 60126
    • AOU Ospedali Riuniti di Ancona
  • Perugia, Italy, 06129
    • Universit degli Studi di Perugia - Azienda Ospedaliera di Perugia
  • Rozzano, Italy, 20089
    • Humanitas Research Hospital
  • Varese, Italy, 21100
    • Ospedale di Circolo
• Netherlands
  • Alkmaar, Netherlands, 1815 JD
    • Noordwest Ziekenhuisgroep
  • Amsterdam, Netherlands, 1105 AZ
    • Academisch Medisch Centrum
  • Dordrecht, Netherlands, 3318 AT
    • Albert Schweitzer Hospital
  • Leiden, Netherlands, 2333 ZA
    • Leiden University Medical Center - Leids Universitair Medisch Centrum (LUMC)
  • The Hague, Netherlands, 2545 AA
    • HagaZiekenhuis
  • Utrecht, Netherlands, 3584 CX
    • UMC Utrecht
• Spain
  • Girona, Spain, 17007
    • Hospital Universitario
  • Madrid, Spain, 28034
    • Hospital Universitario Ramón y Cajal
  • Madrid, Spain, 28040
    • Hospital Clinico San Carlos
  • Sevilla, Spain, 41014
    • Hospital Virgen del Rocío
• United States
  • Alabama
    • Mobile, Alabama, United States, 36608
      • Pulmonary Associates of Mobile
  • California
    • Beverly Hills, California, United States, 90211
      • Cedars-Sinai Medical Center
    • San Diego, California, United States, 92103
      • University of California, San Diego (UCSD) Medical Center
  • Florida
    • Sarasota, Florida, United States, 34239
      • Intercoastal Medical Group
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern Memorial Hospital
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic - Rochester
  • Montana
    • Butte, Montana, United States, 59701
      • Mercury Street Medical
  • New York
    • Bronx, New York, United States, 10461
      • Jacobi Medical Center
    • New York, New York, United States, 10016
      • NYU Radiology Associate
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center (DUMC)
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • The Cleveland Clinic Foundation
  • Pennsylvania
    • Camp Hill, Pennsylvania, United States, 17011
      • Capital Area Research
    • Philadelphia, Pennsylvania, United States, 19140
      • Temple University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: DS-1040b; Single, continuous intravenous infusion over 12 to 24 hours (depending on cohort); Drug: Enoxaparin; Subcutaneous injection 1 mg/kg twice daily
Placebo Comparator: 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.	Drug: Enoxaparin; Subcutaneous injection 1 mg/kg twice daily; Drug: Placebo; Single, continuous intravenous infusion of 0.9% sodium chloride over 12 to 24 hours

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	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.	Baseline up to Day 30 post infusion, up to approximately 3 years 2 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	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.	Baseline to 12-72 hours post start of infusion, up to approximately 3 years 2 months
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	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.	Baseline to 12-72 hours post start of infusion, up to approximately 3 years 2 months
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	Plasma concentrations at each time point and PK parameter Cmax of DS 1040b was calculated using non-compartmental analysis.	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
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	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.	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
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	Plasma concentrations at each time point and PK parameter Terminal Half-life of DS-1040b was calculated using non-compartmental analysis.	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

Collaborators and Investigators

• Sponsor: Daiichi Sankyo, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): June 23, 2016
• Primary Completion (Actual): August 5, 2019
• Study Completion (Actual): August 5, 2019

Study Registration Dates

• First Submitted: September 30, 2016
• First Submitted That Met QC Criteria: September 30, 2016
• First Posted (Estimate): October 4, 2016

Study Record Updates

• Last Update Posted (Actual): April 19, 2023
• Last Update Submitted That Met QC Criteria: April 18, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: Pulmonary embolism (PE); Venous thromboembolism (VTE); Acute Submassive Pulmonary Embolism
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Embolism and Thrombosis; Embolism; Pulmonary Embolism; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Anticoagulants; Enoxaparin
• Other Study ID Numbers: DS1040-B-U107; 2015-005211-32 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified individual participant data (IPD) and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/
• IPD Sharing Time Frame: Studies for which the medicine and indication have received European Union (EU) and United States (US), and/or Japan (JP) marketing approval on or after 01 January 2014 or by the US or EU or JP Health Authorities when regulatory submissions in all regions are not planned and after the primary study results have been accepted for publication.
• IPD Sharing Access Criteria: Formal request from qualified scientific and medical researchers on IPD and clinical study documents from clinical trials supporting products submitted and licensed in the United States, the European Union and/or Japan from 01 January 2014 and beyond for the purpose of conducting legitimate research. This must be consistent with the principle of safeguarding study participants' privacy and consistent with provision of informed consent.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR