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

Pulmonary Embolism Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02923115
• Other study ID #: DS1040-B-U107
• Secondary ID: 2015-005211-32
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: June 23, 2016
• Est. completion date: August 5, 2019

Study information

• Verified date: April 2023
• Source: Daiichi Sankyo, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 134
• Est. completion date: August 5, 2019
• Est. primary completion date: August 5, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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.

Related Conditions & MeSH terms

• Embolism
• Pulmonary Embolism
• Thrombotic Disease

Intervention

Drug:
• DS-1040b
Single, continuous intravenous infusion over 12 to 24 hours (depending on cohort)
• Placebo
Single, continuous intravenous infusion of 0.9% sodium chloride over 12 to 24 hours
• Enoxaparin
Subcutaneous injection 1 mg/kg twice daily

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Daiichi Sankyo, Inc.

Countries where clinical trial is conducted

United States,  Austria,  Belgium,  France,  Germany,  Italy,  Netherlands,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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