Pulmonary Embolism, Thrombotic Disease
Conditions
Keywords
Venous thromboembolism (VTE), Pulmonary embolism (PE), Acute Submassive Pulmonary Embolism
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.
Interventions
DRUGDS-1040b
Single, continuous intravenous infusion over 12 to 24 hours (depending on cohort)
DRUGPlacebo
Single, continuous intravenous infusion of 0.9% sodium chloride over 12 to 24 hours
DRUGEnoxaparin
Subcutaneous injection 1 mg/kg twice daily
Sponsors
Daiichi Sankyo
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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 (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 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. |
| 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. |
Countries
Austria, Belgium, France, Germany, Italy, Netherlands, Spain, United States
Participant flow
Recruitment details
A total of 134 participants who met all inclusion and no exclusion criteria were enrolled in the study at 47 clinic sites (15 in the United States and 32 in Europe). Of the 134 participants randomized to treatment, 125 received treatment.
Pre-assignment details
This study enrolled up to 5 sequential, ascending-dose, continuous infusion cohorts (starting DS1040b dose 20 mg). In Cohorts 1 and 2, eligible participants were randomized in a 2:1 ratio to either DS-1040b or placebo. Starting with Cohort 3, the ratio changed to 3:1. All participants received standard of care enoxaparin during study drug infusion.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1: DS-1040b 20 mg Participants who received an intravenous infusion of 20 mg DS-1040b in addition to standard of care anticoagulation therapy. | 12 |
| Cohort 2: DS-1040b 40 mg Participants who received an intravenous infusion of 40 mg DS-1040b in addition to standard of care anticoagulation therapy. | 16 |
| Cohort 3: DS-1040b 60 mg Participants who received an intravenous infusion of 60 mg DS-1040b in addition to standard of care anticoagulation therapy. | 20 |
| Cohort 4: DS-1040b 80 mg Participants who received an intravenous infusion of 80 mg DS-1040b in addition to standard of care anticoagulation therapy. | 22 |
| Cohort 5: DS-1040b 40 mg Participants who received an intravenous infusion of 40 mg DS-1040b in addition to standard of care anticoagulation therapy. | 17 |
| Placebo Participants who received an intravenous infusion of placebo in addition to standard of care anticoagulation therapy. | 38 |
| Total | 125 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Randomized, but not dosed | 0 | 0 | 3 | 1 | 5 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Cohort 2: DS-1040b 40 mg | Cohort 3: DS-1040b 60 mg | Cohort 4: DS-1040b 80 mg | Cohort 1: DS-1040b 20 mg | Cohort 5: DS-1040b 40 mg | Placebo | Total |
|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 9 Participants | 8 Participants | 7 Participants | 4 Participants | 3 Participants | 15 Participants | 46 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants | 12 Participants | 15 Participants | 8 Participants | 14 Participants | 23 Participants | 79 Participants |
| Age, Continuous | 62.1 years STANDARD_DEVIATION 10.9 | 55.1 years STANDARD_DEVIATION 17.5 | 55.0 years STANDARD_DEVIATION 13.5 | 56.1 years STANDARD_DEVIATION 16.3 | 56.5 years STANDARD_DEVIATION 9.8 | 58.3 years STANDARD_DEVIATION 10.7 | 57.2 years STANDARD_DEVIATION 13 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 3 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 15 Participants | 19 Participants | 22 Participants | 12 Participants | 16 Participants | 34 Participants | 118 Participants |
| Sex: Female, Male Female | 8 Participants | 4 Participants | 7 Participants | 4 Participants | 5 Participants | 12 Participants | 40 Participants |
| Sex: Female, Male Male | 8 Participants | 16 Participants | 15 Participants | 8 Participants | 12 Participants | 26 Participants | 85 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 16 | 0 / 20 | 0 / 22 | 0 / 17 | 0 / 38 |
| other Total, other adverse events | 8 / 12 | 6 / 16 | 13 / 20 | 10 / 22 | 8 / 17 | 25 / 38 |
| serious Total, serious adverse events | 3 / 12 | 0 / 16 | 2 / 20 | 1 / 22 | 3 / 17 | 5 / 38 |
Outcome results
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.
Time frame: Baseline up to Day 30 post infusion, up to approximately 3 years 2 months
Population: Adjudicated bleeding events were assessed in the Safety Analysis Set.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1: DS-1040b 20 mg | 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 | Bleeding with Hb drop ≥2g/dL, transfusion ≥2 units | 0 Participants |
| Cohort 1: DS-1040b 20 mg | 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 | Major bleeding event | 0 Participants |
| Cohort 1: DS-1040b 20 mg | 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 | Non-major clinically relevant bleeding event | 0 Participants |
| Cohort 1: DS-1040b 20 mg | 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 | At least 1 bleeding event | 4 Participants |
| Cohort 1: DS-1040b 20 mg | 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 | Minor or nuisance bleeding event | 3 Participants |
| Cohort 1: DS-1040b 20 mg | 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 | Fatal bleeding event | 0 Participants |
| Cohort 2: DS-1040b 40 mg | 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 | At least 1 bleeding event | 3 Participants |
| Cohort 2: DS-1040b 40 mg | 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 | Fatal bleeding event | 0 Participants |
| Cohort 2: DS-1040b 40 mg | 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 | Minor or nuisance bleeding event | 2 Participants |
| Cohort 2: DS-1040b 40 mg | 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 | Non-major clinically relevant bleeding event | 0 Participants |
| Cohort 2: DS-1040b 40 mg | 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 | Major bleeding event | 0 Participants |
| Cohort 2: DS-1040b 40 mg | 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 | Bleeding with Hb drop ≥2g/dL, transfusion ≥2 units | 0 Participants |
| Cohort 3: DS-1040b 60 mg | 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 | Minor or nuisance bleeding event | 3 Participants |
| Cohort 3: DS-1040b 60 mg | 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 | Major bleeding event | 0 Participants |
| Cohort 3: DS-1040b 60 mg | 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 | Fatal bleeding event | 0 Participants |
| Cohort 3: DS-1040b 60 mg | 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 | Non-major clinically relevant bleeding event | 0 Participants |
| Cohort 3: DS-1040b 60 mg | 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 | At least 1 bleeding event | 3 Participants |
| Cohort 3: DS-1040b 60 mg | 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 | Bleeding with Hb drop ≥2g/dL, transfusion ≥2 units | 0 Participants |
| Cohort 4: DS-1040b 80 mg | 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 | At least 1 bleeding event | 4 Participants |
| Cohort 4: DS-1040b 80 mg | 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 | Major bleeding event | 1 Participants |
| Cohort 4: DS-1040b 80 mg | 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 | Non-major clinically relevant bleeding event | 2 Participants |
| Cohort 4: DS-1040b 80 mg | 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 | Minor or nuisance bleeding event | 2 Participants |
| Cohort 4: DS-1040b 80 mg | 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 | Fatal bleeding event | 0 Participants |
| Cohort 4: DS-1040b 80 mg | 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 | Bleeding with Hb drop ≥2g/dL, transfusion ≥2 units | 1 Participants |
| Cohort 5: DS-1040b 40 mg | 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 | At least 1 bleeding event | 1 Participants |
| Cohort 5: DS-1040b 40 mg | 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 | Major bleeding event | 0 Participants |
| Cohort 5: DS-1040b 40 mg | 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 | Non-major clinically relevant bleeding event | 1 Participants |
| Cohort 5: DS-1040b 40 mg | 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 | Minor or nuisance bleeding event | 0 Participants |
| Cohort 5: DS-1040b 40 mg | 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 | Fatal bleeding event | 0 Participants |
| Cohort 5: DS-1040b 40 mg | 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 | Bleeding with Hb drop ≥2g/dL, transfusion ≥2 units | 0 Participants |
| Placebo | 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 | Minor or nuisance bleeding event | 6 Participants |
| Placebo | 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 | Non-major clinically relevant bleeding event | 1 Participants |
| Placebo | 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 | Major bleeding event | 0 Participants |
| Placebo | 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 | At least 1 bleeding event | 10 Participants |
| Placebo | 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 | Bleeding with Hb drop ≥2g/dL, transfusion ≥2 units | 0 Participants |
| Placebo | 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 | Fatal bleeding event | 0 Participants |
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.
Time frame: Baseline to 12-72 hours post start of infusion, up to approximately 3 years 2 months
Population: Changes in total thrombus volume were assessed in the Efficacy Analysis Set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: DS-1040b 20 mg | 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 | -23.78 percent change | Standard Deviation 24.49 |
| Cohort 2: DS-1040b 40 mg | 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 | -38.67 percent change | Standard Deviation 17.34 |
| Cohort 3: DS-1040b 60 mg | 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 | -33.50 percent change | Standard Deviation 17.41 |
| Cohort 4: DS-1040b 80 mg | 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 | -37.36 percent change | Standard Deviation 26.9 |
| Cohort 5: DS-1040b 40 mg | 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 | -32.33 percent change | Standard Deviation 19.03 |
| Placebo | 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 | -31.35 percent change | Standard Deviation 17.74 |
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.
Time frame: Baseline to 12-72 hours post start of infusion, up to approximately 3 years 2 months
Population: Reductions in total thrombus volume were assessed in the Efficacy Analysis Set.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1: DS-1040b 20 mg | 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 | No change or increase | 2 Participants |
| Cohort 1: DS-1040b 20 mg | 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 | Missing data | 1 Participants |
| Cohort 1: DS-1040b 20 mg | 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 | <20% reduction | 2 Participants |
| Cohort 1: DS-1040b 20 mg | 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 | ≥20% reduction | 7 Participants |
| Cohort 2: DS-1040b 40 mg | 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 | ≥20% reduction | 12 Participants |
| Cohort 2: DS-1040b 40 mg | 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 | Missing data | 0 Participants |
| Cohort 2: DS-1040b 40 mg | 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 | No change or increase | 0 Participants |
| Cohort 2: DS-1040b 40 mg | 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 | <20% reduction | 3 Participants |
| Cohort 3: DS-1040b 60 mg | 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 | <20% reduction | 3 Participants |
| Cohort 3: DS-1040b 60 mg | 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 | Missing data | 0 Participants |
| Cohort 3: DS-1040b 60 mg | 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 | ≥20% reduction | 16 Participants |
| Cohort 3: DS-1040b 60 mg | 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 | No change or increase | 1 Participants |
| Cohort 4: DS-1040b 80 mg | 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 | No change or increase | 0 Participants |
| Cohort 4: DS-1040b 80 mg | 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 | <20% reduction | 5 Participants |
| Cohort 4: DS-1040b 80 mg | 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 | Missing data | 0 Participants |
| Cohort 4: DS-1040b 80 mg | 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 | ≥20% reduction | 17 Participants |
| Cohort 5: DS-1040b 40 mg | 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 | Missing data | 1 Participants |
| Cohort 5: DS-1040b 40 mg | 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 | <20% reduction | 3 Participants |
| Cohort 5: DS-1040b 40 mg | 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 | ≥20% reduction | 12 Participants |
| Cohort 5: DS-1040b 40 mg | 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 | No change or increase | 1 Participants |
| Placebo | 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 | <20% reduction | 5 Participants |
| Placebo | 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 | Missing data | 2 Participants |
| Placebo | 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 | No change or increase | 3 Participants |
| Placebo | 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 | ≥20% reduction | 28 Participants |
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.
Time frame: 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
Population: Pharmacokinetic parameters were assessed in the Pharmacokinetic Analysis Set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: DS-1040b 20 mg | 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 | 5532.92 ng*h/mL | Standard Deviation 4090.34 |
| Cohort 2: DS-1040b 40 mg | 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 | 7819.53 ng*h/mL | Standard Deviation 2870.13 |
| Cohort 3: DS-1040b 60 mg | 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 | 13403.15 ng*h/mL | Standard Deviation 8047.13 |
| Cohort 4: DS-1040b 80 mg | 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 | 17147.27 ng*h/mL | Standard Deviation 15024.61 |
| Cohort 5: DS-1040b 40 mg | 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 | 8014.73 ng*h/mL | Standard Deviation 2870.19 |
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.
Time frame: 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
Population: Terminal half-life was assessed in patients with available data in the Pharmacokinetic Analysis Set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: DS-1040b 20 mg | 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 | 22.81 hours | Standard Deviation 3.13 |
| Cohort 2: DS-1040b 40 mg | 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 | 28.44 hours | Standard Deviation 5.75 |
| Cohort 3: DS-1040b 60 mg | 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 | 29.06 hours | Standard Deviation 7.6 |
| Cohort 4: DS-1040b 80 mg | 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 | 36.39 hours | Standard Deviation 2.07 |
| Cohort 5: DS-1040b 40 mg | 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 | 30.06 hours | Standard Deviation 3.45 |
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.
Time frame: 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
Population: Pharmacokinetic parameters were assessed in the Pharmacokinetic Analysis Set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: DS-1040b 20 mg | 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 | 970.09 ng/mL | Standard Deviation 1373.43 |
| Cohort 2: DS-1040b 40 mg | 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 | 421.73 ng/mL | Standard Deviation 515.57 |
| Cohort 3: DS-1040b 60 mg | 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 | 608.84 ng/mL | Standard Deviation 562.94 |
| Cohort 4: DS-1040b 80 mg | 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 | 1006.41 ng/mL | Standard Deviation 1883.49 |
| Cohort 5: DS-1040b 40 mg | 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 | 526.12 ng/mL | Standard Deviation 535.03 |