Study to Assess the Safety, Pharmacokinetics/Dynamics of DS-1040b in Subjects With Acute Submassive Pulmonary Embolism
- Conditions
- Pulmonary EmbolismThrombotic Disease
- Interventions
- 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
- 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.
- 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)
Albert Schweitzer Hospital
🇳🇱Dordrecht, Netherlands
University of California, San Diego (UCSD) Medical Center
🇺🇸San Diego, California, United States
Duke University Medical Center (DUMC)
🇺🇸Durham, North Carolina, United States
Jacobi Medical Center
🇺🇸Bronx, New York, United States
Temple University Hospital
🇺🇸Philadelphia, Pennsylvania, United States
Cliniques Universitaires Saint-Luc
🇧🇪Bruxelles, Belgium
Northwestern Memorial Hospital
🇺🇸Chicago, Illinois, United States
Mercury Street Medical
🇺🇸Butte, Montana, United States
Medical University Graz
🇦🇹Graz, Austria
Universitatsklinikum Magdeburg
🇩🇪Magdeburg, Germany
Capital Area Research
🇺🇸Camp Hill, Pennsylvania, United States
Hopital Europeen Georges Pompidou
🇫🇷Paris, France
The Cleveland Clinic Foundation
🇺🇸Cleveland, Ohio, United States
Universite Libre de Bruxelles (ULB) - Hopital Erasme
🇧🇪Bruxelles, Belgium
CHU St Etienne - Hopital Nord
🇫🇷Saint-étienne, France
Intercoastal Medical Group
🇺🇸Sarasota, Florida, United States
CHU de Grenoble
🇫🇷La Tronche, France
Medical University of Vienna
🇦🇹Vienna, Austria
Klinikum rechts der Isar, Technische Universität München
🇩🇪München, Germany
Hospital Clinico San Carlos
🇪🇸Madrid, Spain
UMC Utrecht
🇳🇱Utrecht, Netherlands
Humanitas Research Hospital
🇮🇹Rozzano, Italy
Hospital Virgen del RocÃo
🇪🇸Sevilla, Spain
Hospital Universitario Ramon y Cajal
🇪🇸Madrid, Spain
Universit degli Studi di Perugia - Azienda Ospedaliera di Perugia
🇮🇹Perugia, Italy
Massachusetts General Hospital
🇺🇸Boston, Massachusetts, United States
Pulmonary Associates of Mobile
🇺🇸Mobile, Alabama, United States
Cedars-Sinai Medical Center
🇺🇸Beverly Hills, California, United States
Mayo Clinic - Rochester
🇺🇸Rochester, Minnesota, United States
University of Kentucky Medical Center
🇺🇸Lexington, Kentucky, United States
NYU Radiology Associate
🇺🇸New York, New York, United States
Medical University Innsbruck
🇦🇹Innsbruck, Austria
CHU Gabriel Montpied Clermont-Ferrand
🇫🇷Clermont-Ferrand, France
University Hospital Leuven
🇧🇪Leuven, Belgium
CHU de Brest - Hopital de la Cavale Blanche
🇫🇷Brest, France
Hopital Civil de Strasbourg
🇫🇷Strasbourg, France
Universitaetsklinikum Dresden
🇩🇪Dresden, Germany
Staedtisches Klinikum Dresden-Friedrichstadt
🇩🇪Dresden, Germany
Universitaetsmedizin Greifswald
🇩🇪Greifswald, Germany
HagaZiekenhuis
🇳🇱The Hague, Netherlands
AOU Ospedali Riuniti di Ancona
🇮🇹Ancona, Italy
Ospedale di Circolo
🇮🇹Varese, Italy
Noordwest Ziekenhuisgroep
🇳🇱Alkmaar, Netherlands
Academisch Medisch Centrum
🇳🇱Amsterdam, Netherlands
Leiden University Medical Center - Leids Universitair Medisch Centrum (LUMC)
🇳🇱Leiden, Netherlands
Hospital Universitario
🇪🇸Girona, Spain