E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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). |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10055221 |
E.1.2 | Term | Ischemic stroke |
E.1.2 | System Organ Class | 100000004852 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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 |
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E.2.2 | Secondary objectives of the trial |
1. To assess plasma and urinary pharmacokinetics (PK) of DS-1040b in subjects with AIS.
2. To assess the effect of DS-1040b on fibrinolysis biomarkers in subjects with AIS.
3. 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.
4. 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. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Subjects have a clinical diagnosis of acute ischemic stroke (including lacunar stroke) supported by computed topography or magnetic resonance imaging.
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 .
5. 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. |
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E.4 | Principal exclusion criteria |
1.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.
2. Subjects have evidence of intracranial hemorrhage on noncontrast 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) < 6.
5. Subjects have prior non-traumatic intracranial haemorrhage(excluding microhemorrahages observed in imaging).
6. Subjects have known arteriovenous malformation or aneurysm.
7. Subjects have evidence of active bleeding.
8. Subjects have platelet count < 100,000.
9. Subjects have INR>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 of randomization. Low dose heparin or low molecular weight heparin at a preventive dose are allowed from 24 hours after treatment start and after no intracranial bleeding has been confirmed on 24 hours repeat brain imaging.
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 month.
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 hemoglobin<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 or an immediate family member of an employee of the Sponsor, the CRO (INC Research), or the Site.
25. Any other reason, in the opinion of the Investigator, which precludes subject participation in the study. |
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E.5 End points |
E.5.1 | 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. |
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E.5.1.1 | 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). |
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E.5.2 | 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. |
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E.5.2.1 | 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 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 10 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Canada |
Czech Republic |
France |
Germany |
Italy |
Korea, Republic of |
Slovakia |
Spain |
Taiwan |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |