E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Ischemic Stroke or Transient Ischemic Attack (TIA) |
|
E.1.1.1 | Medical condition in easily understood language |
Study for the Prevention of a New Stroke or New Covert stroke in
Patients Receiving Aspirin and Clopidogrel Following Acute Ischemic
Stroke or mini stroke (TIA) |
|
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 | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10044390 |
E.1.2 | Term | Transient ischaemic attack |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 22.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10061256 |
E.1.2 | Term | Ischaemic stroke |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
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 estimate the dose-response relationship of BMS-986177, by identifying a MED(a) and ED90(b), in participants with ischemic stroke or TIA treated with aspirin + clopidgrel. |
|
E.2.2 | Secondary objectives of the trial |
To assess the rate of major bleeding after treatment with BMS-986177 relative to placebo
To assess the rate of all bleeding after treatment with BMS-986177 relative to placebo
To compare the rate of the composite of new ischemic stroke and new covert brain infarction detected by MRI at 90 days on treatment with BMS-986177 compared to placebo
To assess the effect of BMS-986177 on characteristics of brain lesions on Day 90 MRI
To compare the rate of the composite of new ischemic stroke, myocardial infarction (MI) and all-cause mortality during treatment with BMS-986177 vs. placebo
To assess stroke severity, neurological, and cognitive function following BMS-986177 treatment vs. placebo
To assess the safety and tolerability of BMS-986177
To assess the pharmacokinetics (PK) of BMS-986177 and potential effects of covariates on exposure
To assess the dose-response of BMS-986177 on pharmacodynamic (PD) biomarkers |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1) Type of Participant and Target Disease Characteristics
a) Ischemic stroke: a neurological deficit attributable to a non-lacunar, acute brain infarction
detected by neuroimaging (CT or MRI) and relevant to the clinical symptoms
AND
National Institutes of Health Stroke Score (NIHSS) ≤5 at time of randomization
AND
Evidence of relevant intracranial or cervical arterial atherosclerotic plaque, ulceration or
thrombus in a feeding artery documented by imaging (either Doppler ultrasound or CTA
or MRA or catheter angiography)
Notes: Atherosclerotic plaque does not need to be severe or stenotic, but must be visible
Participants with complete occlusion of a cervical carotid or intracranial artery should be
excluded.
AND
Modified Rankin Score (mRS) ≤3 before the index event (pre-morbid)
b) TIA: acute onset neurological deficit attributable to focal ischemia of the brain by history
or examination, with complete resolution of the deficit and no brain infarction on
neuroimaging (CT or MRI)
AND
ABCD2 SCORE ≥6 or motor symptoms
AND
Evidence of relevant intracranial or cervical arterial atherosclerotic plaque, ulceration or
thrombus in a feeding artery documented by imaging (either Doppler ultrasound or CTA
or MRA or catheter angiography)
Notes: Atherosclerotic plaque does not need to be severe or stenotic, but must be visible
Participants with complete occlusion of a cervical carotid or intracranial artery should be
excluded.
AND
Modified Rankin Score (mRS) ≤3 before the index event (pre-morbid)
2) The participant must be able to be evaluated by study-specific MRI within 48 hours of index
event and prior to randomization. Therefore, participants must have a body habitus suitable for
MRI and cannot have any contraindications to the performance of the MRI (e.g., weight limit,
MRI-incompatible implanted devices, infusion pump that cannot be discontinued temporarily
for the scan).
3) All participants must be suitable for treatment with clopidogrel for 21 days and uncoated
aspirin 100 mg daily for at least 90 days |
|
E.4 | Principal exclusion criteria |
1) Predicted inability to swallow study medication
2) Women who are pregnant or breastfeeding
3) Any condition that, in the opinion of the Investigator, contraindicates anticoagulant therapy or would have an unacceptable risk of bleeding such as a large infarct volume (per Investigator discretion) or uncontrolled hypertension.
4) Hemorrhage, tumor, arteritis, large vessel dissection, arteriovenous malformation (AVM), or other pathology that could account for index symptoms must be excluded by CT or MRI interpreted locally.
5) Symptomatic carotid stenosis for which endarterectomy or stenting is planned within 90 days.
6) Use of thrombolytic therapy or mechanical thrombectomy for treatment of index event
7) Any condition for which chronic anticoagulation is indicated and expected to be initiated (e.g. NVAF, DVT, PE)
8) Requirement for continued use of dual antiplatelet therapy (DAPT) for more than 21 days or non-aspirin antiplatelet therapy or anticoagulant for another medical condition (e.g. prophylaxis for venous thromboembolism).
Note: Treatment with clopidogrel, aspirin, dipyridamole or another P2Y12 inhibitor prior to enrollment is allowed. Treatment with aspirin at a different dose before enrollment is also allowed. All participants must transition to the protocol-defined treatments and doses at randomization. No clopidogrel loading dose is needed for participants who received a clopidogrel loading dose prior to randomization. Participants who report taking chronic clopidogrel also require a 300-mg clopidogrel loading dose unless the Investigator can verify that the patient has taken the daily dose for at least the preceding 3 days. Participants who have received dipyridamole or another P2Y12 inhibitor must receive the
clopidogrel loading dose after discontinuing the non-clopidogrel P2Y12 inhibitor or dipyridamole/dipyridamolecontaining treatment.
9) History of hemorrhage into the brain, subarachnoid hemorrhage, subdural hematoma or spinal cord hemorrhage except cerebral microbleeds (CMB) and minor hemorrhagic transformation of prior infarct manifesting as scattered petechiae (Hemorrhagic Infarction Type 1 [HI1] according to Heidelberg classification).
Note: CMBs are defined as rounded foci of <10 mm in size that appear hypointense and distinct from vascular flow voids, leptomeningeal hemasiderosis, or nonhemorrhagic
subcortical mineralization on T2* weighted MRI.
10) History of clinically meaningful hepatic disease and or clinically significant abnormal liver function.
11) Participants with pre-treatment elevation of ALT or AST >3x ULN
12) Intracranial tumor (except meningioma, which is permitted) or aneurysm >5 mm or AVM
13) History of end-stage renal disease (ESRD) with eGFR <15 mL/min/1.73m2, or requiring dialysis
14) Planned use of anticoagulants including warfarin or other vitamin K antagonists, oral thrombin and Factor Xa inhibitors, bivalirudin, hirudin, argatroban, unfractionated
and low molecular weight heparins, with the exception of heparin or low molecular weight heparin (LMWH) used to maintain patency of indwelling catheters.
Note: Participants who received 1 or 2 doses of UFH or LMWH for DVT prophylaxis prior to randomization can be enrolled. The use of anticoagulants for post-stroke
DVT prophylaxis is prohibited. For post-stroke DVT prophylaxis, non-pharmacological prophylaxis (i.e. intermittent pneumatic compression) is recommended.
15) Anticipated concomitant chronic (>14 days) use of nonsteroidal anti-inflammatory drugs (NSAIDs). NSAID (including COX-2 inhibitors) use prior to randomization is allowed.
16) CYP3A4 and/or p-glycoprotein strong inhibitors/inducers within 7 days of randomization
17) Concomitant use of omeprazole or esomeprazole after randomization for the duration of clopidogrel treatment (eg, H2 blockers (except cimetidine) and other PPIs are allowed)
18) Screening 12-lead ECG with atrial fibrillation, atrial flutter, complete or Mobitz 2 seconddegree heart block |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Composite of new ischemic stroke during the treatment period and new covert brain infarction (FLAIR + DWI) detected by MRI at Day 90 (MRI assessed by central review) |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
Event rate based on bleeding according to Bleeding Academic Research Consortium (BARC) Type 3 and 5
Event rate based on BARC, ISTH and PLATO-defined criteria
Rate of the composite of new ischemic stroke during the treatment period and new covert brain infarction (FLAIR + DWI) detected by MRI at 90 days
Location, number, and volume of new FLAIR + DWI lesions
Event rates for new ischemic, non-fatal stroke, non-fatal MI and all-cause death during the treatment period
National Institutes of Health Stroke Scale (NIHSS) Modified Rankin Scale (mRS), Montreal Cognitive Assessment (MoCA), and Digit Symbol Substitution Test (subtest of WAIS-IV) at baseline, on days 21 and 90, and at the time of a new stroke event.
Adverse events, vital signs, physical exams,electrocardiogram (ECG) and clinical laboratory results
Estimated clearance (CL) and volume of distribution (Vd) and effect of body weight, age, gender, race, renal function, liver function, concomitant medications
% change from baseline in aPTT and Factor XI clotting activity during treatment |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
During the treatment period (90 days)
MRI at 90 days
During the treatment period (90 days)
NIHSS, mRS, MoCA and DSST are to be assessed at baseline, Day 21 and 90 and at the time of new stroke
|
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | Yes |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
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 | 6 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 184 |
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 |
Argentina |
Australia |
Austria |
Belgium |
Brazil |
Canada |
Chile |
China |
Czech Republic |
Denmark |
Finland |
France |
Germany |
Greece |
Hungary |
Israel |
Italy |
Japan |
Korea, Republic of |
Norway |
Poland |
Russian Federation |
Spain |
Sweden |
Switzerland |
United Kingdom |
United States |
|
E.8.7 | Trial has a data monitoring committee | Yes |
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
|
End-of-study is defined as the date the last participant completes the Day 97 discharge visit. Study completion is defined as the final date on which data for the primary endpoint was, or is expected to be, collected, if this is not the same as the end-of-study definition. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 2 |
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 | 2 |