| 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 in participants with ischemic stroke or TIA treated with aspirin and clopidogrel |
|
| 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) Signed Written Informed Consent
a) Participants ≥40 years of age (or legally acceptable representatives, as per country guidelines) from whom a signed and dated written consent for participation has been obtained.
2) 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) ≤7 at time of randomization.
AND
thrombus in a feeding artery documented by imaging (either Doppler ultrasound or CTA or MRA or catheter angiography).
Note: 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 that is proximal to the index lesion 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 ≥63 or presence of 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).
Note: 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 that is proximal to the index lesion should be excluded.
AND
Modified Rankin Score (mRS) ≤3 before the index event (pre-morbid).
3) Two MRI scans are required for participation in this study (see Section 9.2.12). Therefore, participants must have a body habitus suitable for MRI and cannot have any contraindications to the performance of the MRI (see Section 7.7.2.1).
4) No contraindication to clopidogrel or aspirin and suitable for treatment with aspirin 100 mg per day for at least 90 days.
5) Age and Reproductive Status
a) Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study treatment.
b) Women of childbearing potential (WOCBP) must agree to follow instructions for method(s) of contraception for the duration of treatment with BMS-986177 plus 5 halflives of study treatment plus 30 days (duration of ovulatory cycle) for a total of 34 days
post-treatment completion.
c) Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception (Appendix 4) for the duration of treatment with study treatment turnover) for a total of 94 days post-treatment completion. In addition, male participants
must be willing to refrain from sperm donation during this time.
d) Azoospermic males are exempt from contraceptive requirements. WOCBP who are continuously not heterosexually active, or are not of childbearing potential, are also exempt from contraceptive requirements, and still must undergo pregnancy testing as described in this section.
e) Investigators shall counsel WOCBP, and male participants who are sexually active with WOCBP, on the importance of pregnancy prevention and the implications of an unexpected pregnancy. Investigators shall advise on the use of highly effective methods of
contraception, (see Appendix 4). Highly effective methods of contraception have a failure rate of <1% when used consistently and correctly.
6) Enrollment of subjects who have received thrombolytic therapy or mechanical thrombectomy (without stenting) for the treatment of the index event is permitted if all of the following conditions are met:
• At least 24 hours have elapsed between end of IV thrombolytic use/thrombectomy and first dose of study medication.
• Neuroimaging (either clinical imaging or study MRI) after IV thrombolytic therapy/ post-thrombectomy excludes any hemorrhagic transformation.
• NIHSS ≤ 7 at time of randomization.
• Post-thrombolytic therapy/post-thrombectomy INR ≤ 1.5, aPTT ≤1.4 prior to study treatment administration.
• No contraindications have been identified that in the opinion of the investigator would
preclude start of study medication (e.g. large infarct volume, procedure-related bleeding).
• All other study criteria are met.
In addition, we recommend following local practice and considering fibrinogen > 150 mg/dL before initiation of study treatment. |
|
| E.4 | Principal exclusion criteria |
1) Medical Conditions
a) Predicted inability to swallow study medication.
b) Women who are pregnant or breastfeeding.
c) 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.
d) 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.
e) Symptomatic carotid stenosis or intracranial artery stenosis for which endarterectomy or angioplasty is planned within 90 days.
f) Not applicable per global protocol amendment 06.
g) Any condition for which chronic anticoagulation is indicated and expected to be initiated (eg, NVAF, DVT, PE).
h) Requirement for continued use of dual anti-platelet therapy (DAPT) for more than 21 days
or non-aspirin antiplatelet therapy or anticoagulant for another medical condition (eg, 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 participant 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/dipyridamole-containing treatment.
i) 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 hemosiderosis, or non-hemorrhagic subcortical mineralization on T2* weighted MRI.
j) History of clinically meaningful hepatic disease and/or clinically significant abnormal liver function.
k) Intracranial tumor (except meningioma, which is permitted) or aneurysm >5 mm (except treated aneurysm without history of intracranial bleed, which is permitted) or
AVM.
l) History of end -stage renal disease (ESRD) with eGFR <15 mL/min/1.73 m2, or requiring dialysis.
2) Prior/Concomitant Therapy
a) Any investigational drug or placebo exposure within 4 weeks of study drug administration.
b) Any prior exposure to BMS-986177.
c) 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 UFH or LMWH for DVT prophylaxis prior to enrollment can be randomized. The use of anticoagulants for post-stroke DVT
prophylaxis after randomization is prohibited. For post-stroke DVT prophylaxis, nonpharmacological prophylaxis (ie, intermittent pneumatic compression) is recommended.
d) Planned concomitant use of omeprazole or esomeprazole after randomization for the duration of clopidogrel treatment (eg, H2 blockers [except cimetidine] and other PPIs are allowed).
e) Anticipated concomitant chronic (>14 days) use of systemic nonsteroidal antiinflammatory drugs (NSAIDs). NSAID (including COX-2 inhibitors) use prior to
randomization is allowed.
f) Use of combined P-gp and strong CYP3A4 inhibitors or combined P-gp and strong CYP3A4 inducers in the 7 days prior to randomization or the need for ongoing treatment with concomitant oral or intravenous therapy with combined P-gp and strong CYP3A4 inhibitors or combined P-gp and strong CYP3A4/P-gp inducers during the study. A list of combined P-gp and strong CYP3A4 inhibitors is attached as Appendix 11. A list of combined P-gp and strong CYP3A4 inducers is attached as Appendix 12.
g)Inability to comply with restrictions and prohibited treatments as listed in Section 7.7.1. |
|
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 196 |
| 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 |
| Brazil |
| Canada |
| Chile |
| Israel |
| Japan |
| Korea, Republic of |
| Mexico |
| United States |
| Austria |
| Finland |
| France |
| Poland |
| Sweden |
| Spain |
| Switzerland |
| Czechia |
| Germany |
| Greece |
| Italy |
| Belgium |
| Denmark |
| Hungary |
| Norway |
| Russian Federation |
| United Kingdom |
|
| 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 | 3 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 2 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 2 |
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