DS-1040b is an inhibitor of the activated form of thrombin-activatable fibrinolysis inhibitor (TAFIa) intended to be used for the treatment of thrombotic diseases including acute ischemic stroke (AIS).
Conditions
Interventions
Product Name: DS-1040b
Product Code: DS-1040b
Pharmaceutical Form: Solution for infusion
INN or Proposed INN: DS-1040B
Current Sponsor code: DS-1040B
Other descriptive name: DS-1040B
Concentration uni
Sponsors
Daiichi Sankyo, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Subjects have a clinical diagnosis of acute ischemic stroke (including lacunar stroke) supported by computed topography or magnetic resonance imaging to rule out alternative cause for presenting symptoms. 2. Men and women 18 years of age and older. 3. Subjects have stroke symptoms onset within 4.5 to 12 hours before initiation of study drug administration. For subjects with a wake-up stroke, symptoms onset time refers to the last time the subject was known to be well. 4. Subjects have a NIHSS score of >2 (Cohort 1-5). 4a. NIHSS score = 5 (Cohort 6). 5. In Cohort 6, subjects who have been treated or are anticipated to be treated with IAT for index stroke, at the time of randomization, can be enrolled in the IAT subgroup. 6. Subjects (or their legally authorized representative-where applicable and based on country-specific practice), must give written informed consent to participate in the study prior to participating in any study-related procedures. A separate written informed consent is required for collecting a blood sample for genotyping. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 20 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 76
Exclusion criteria
Exclusion criteria: 1. Cohort 1-5: Subjects have been treated or are anticipated to be treated with tissue plasminogen activator and / or endovascular thrombectomy during current stroke. Eligible subjects declining these treatments can be enrolled to this study. 1a. Cohort 6: subjects have been treated and/or are anticipated to be treated with tPA during current stroke. Eligible subjects declining tPA treatment can be enrolled to this study. Subjects have been treated or anticipated to be treated with IAT can be enrolled. 2. Subjects have evidence of intracranial hemorrhage on non-contrast computed tomography (CT) (or magnetic resonance [MR]) 3. Subjects have symptoms of subarachnoid hemorrhage, even with normal CT. 4. Subjects have an Alberta Stroke Program Early CT Score (ASPECTS) 1.7. 10. Subjects have used unfractionated heparin within 24 hours prior to treatment and have an elevated partial thromboplastin time. 11. Subjects have used a nonvitamin K antagonist oral anticoagulant such as dabigatran, rivaroxaban, apixaban, or other factor Xa inhibitors within 24 hours prior to treatment. 12. Subjects have used fondaparinux or low molecular weight heparin at an anticoagulation dose within 24 hours prior to treatment. 13. Subjects with anticipated use of an anticoagulation dose of heparin, or fondaparinux or low molecular weight heparin, or nonvitamin K antagonist oral anticoagulant such as dabigatran, rivaroxaban, apixaban, or other factor Xa inhibitors within 48 hours after completion of study drug treatment. Low dose heparin or low molecular weight heparin at a preventive dose are allowed from 24 hours after treatment completion and after confirmation of no intracranial bleeding on the 24 hours repeat brain imaging. In Cohort 6, heparin treatment associated with IAT is allowed. 14. Subjects have blood pressure > 185/110 mmHg, or require aggressive medication to maintain blood pressure below this limit (routine medical treatment is allowed to lower the blood pressure below this limit). 15. Subjects have had intracranial surgery, clinically significant head trauma (in the opinion of Principal Investigator), Alteplase treatment, or a previous stroke within 1 months. 16. Subjects have had major surgery within 14 days. 17. Subjects have had gastrointestinal or genitourinary bleeding in the last 21 days. 18. Subjects have had a lumbar puncture (or epidural steroid injection) within 14 days. 19. Subjects have a preexisting disability classified by mRS > 2. 20. Subjects have an estimated glomerular filtration rate (using Modification of Diet in Renal Disease equation) < 60 mL/min/1.73 m2. 21. Subjects have baseline haemoglobin < 10.5 g/dL. 22. Subjects have a positive pregnancy test. Serum or urine pregnancy tests will be performed (according to site-specific practice) in women of childbearing potential (childbearing potential is assumed in women up to 55 years of age). 23. Subject is currently participating in another investigational study or has participated in an investigational drug study within 30 days or 5 half lives of that investigational drug prior to administration of the study drug. 24. Subject is an employee
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To assess the safety and tolerability of DS-1040b (IV infusion over 6 hours) in subjects with AIS within 4.5 to 12 hours after stroke symptom onset;Secondary Objective: • To assess the plasma and urinary PK of DS-1040b in subjects with AIS. • To assess the effect of DS-1040b on fibrinolysis biomarkers in subjects with AIS. • To assess the effect of DS-1040b on recanalization at 24 hours in subjects with AIS and a visible occlusion demonstrated on brain imaging at predose. • To assess the effect of DS-1040b on neurological outcome by using the National Institute of Health Stroke Scale (NIHSS) and functional outcome by using the modified Rankin Scale (mRS) in subjects with AIS. ;Primary end point(s): • Safety parameters: Safety parameters will include adverse events occurrence, physical examination findings, vital sign measurements, standard clinical laboratory parameters (including serum chemistry, hematology, urinalysis, and coagulation parameters), and electrocardiogram (ECG) parameters. Other safety parameters will include bleeding events and neurologic function. Bleeding events will be assessed and categorized as sICH, any intracranial hemorrhage (ICH), or non-ICH major bleeding. Neurologic function will be measured using the NIHSS. ;Timepoint(s) of evaluation of this end point: Day 1, day 2, day 3, day 4, day 5 and at follow up (day 30 and day 90). | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): • Pharmacokinetic parameters: Standard noncompartmental PK parameters will be assessed. Plasma samples for PK assessments will be taken at multiple timepoints in the study. Additionally, a PK sample may also be obtained outside of the specified timepoints during the study if deemed clinically necessary. Urine PK samples will also be collected and evaluated in the study. • Pharmacodynamic parameters: Pharmacodynamic analysis for TAFIa antigen and clot lysis along with D-dimer and total TAFIa activity will be performed. Remaining blood samples will be used for post-hoc TAFIa inhibition-related coagulation biomarker assessments. Recanalization will be assessed during the study. • Other parameters: An assessment of functional outcome using the mRS will be performed during the study. Exploratory Parameter: For subjects treated with IAT, the retrieved clots will be collected (when possible) for exploratory histopathology assessment on clot formation and dissolution, and analyses on thrombosis and thrombolysis related biomarkers. A blood sample from the location proximal to the thrombus will be collected via the thrombectomy catheter (when possible) for exploratory biomarker evaluation (TAFI and/or TAFIa levels).;Timepoint(s) of evaluation of this end point: PK: Day 1, day 2, day 3, day 4 and day 5 PD: Day 1, day 2 and day 3 | — |
Countries
Czech Republic, France, Germany, Italy, Slovakia, Spain, United Kingdom, United States
Contacts
Public ContactClinical Trial Information Contact
Daiichi Sankyo, Inc.
Outcome results
None listed