A Phase 3 Placebo-controlled Study of Milvexian after an Acute Ischemic Stroke or High-Risk Transient Ischemic Attack

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Janssen - Cilag International

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

Trial duration

4 Aug 2023 → ongoing

Decision date (initial)

2023-07-04

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Prophylaxis, Others, Pharmacoeconomic, Therapy, Pharmacodynamic, Pharmacokinetic, Efficacy, Safety

To evaluate if milvexian reduces the risk of ischemic stroke, compared with placebo

Secondary objectives 3

1. To evaluate if milvexian reduces the risk of CVD, MI, or ischemic stroke, compared with placebo
2. To evaluate if milvexian reduces the risk of ischemic stroke in the first 90 days compared with placebo
3. To evaluate if milvexian reduces the risk of MAVE (ie, the composite of CVD, MI, ischemic stroke, MALE [ie, major (nontraumatic) vascular limb amputation, or acute limb ischemia], symptomatic PE or DVT) compared with placebo

Conditions and MedDRA coding

Acute Ischemic Stroke and High-Risk Transient Ischemic Attack

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

Yes

IPD plan description

The data sharing policy of the Janssen Pharmaceutical Companies of Johnson & Johnson is available at www.janssen.com/clinical-trials/transparency. As noted on this site, requests for access to the study data can be submitted through Yale Open Data Access (YODA) Project site at yoda.yale.edu

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 5

1. Age ≥40 years of age
2. Ischemic Stroke: a neurological deficit attributable to an acute brain infarction and NIHSS score ≤ 7 and at least 1 of the following: Persistent signs or symptoms of the ischemic event at the time of randomization, OR Acute, ischemic brain lesion determined by standard-of-care neuroimaging OR Participant underwent thrombolysis or thrombectomy OR TIA: acute onset neurological deficit attributable to focal ischemia of the brain by history or examination, with complete symptom resolution of the deficit and no brain infarction on neuroimaging (eg, CT scan or MRI, performed as part of standard medical practice), and ABCD2 Score ≥6
3. Participants will be randomized as soon as possible after determining eligibility and within 48 hours of onset of event. In participants in whom a stroke was evident on awakening from sleep, within 48 hours from the time at which the participants’ condition was last reported to be normal. Participants who received thrombolysis and/or mechanical thrombectomy with or without stenting can be randomized but only after 24 hours have elapsed after the end of this treatment and not more than 48 hours after the onset of the index event, and provided that post-treatment neuroimaging excludes cerebral bleeding and have postthrombolytic therapy/post-thrombectomy INR ≤ 1.5 and aPTT ≤ 1.4 times the ULN prior to study randomization. Cerebrovascular vessel stenting is allowed as clinically indicated. If these procedures are done pre-randomization, then randomization should occur at least 24 hours after the end of the procedure and not more than 48 hours after the onset of the index event.
4. Current or planned antiplatelet treatment per international and/or local guidelines. If ASA is used, it will be limited to low dose (75 to 100 mg/day). Loading dose of antiplatelet agents (including ASA) are allowed per standard-of-care
5. A female participant must be a. Not of childbearing potential or b. Of childbearing potential and practicing a highly effective method of contraception (failure rate of <1% per year when used consistently and correctly) and agrees to remain on a highly effective method until 4 days (5 half lives) after last dose of study intervention –the end of relevant exposure. The investigator must evaluate the potential for contraceptive method failure (eg, noncompliance, recently initiated) in relationship to the first dose of study intervention.

Exclusion criteria 9

1. Current intracranial hemorrhage (hemorrhage into the brain, subarachnoid hemorrhage, intraventricular hemorrhage, subdural hematoma or epidural hematoma); except CMB and minor hemorrhagic transformation of infarct manifesting as scattered petechiae (Hemorrhagic Infarction Type 1 [HI1] according to Heidelberg classification).
2. Prior history of intracranial hemorrhage except subarachnoid hemorrhage > 1 year prior with adequate treatment.
3. The index stroke or TIA is considered to have a cardio-embolic etiology based on local standard-of-care investigations and for which guidelines recommend anticoagulation.
4. The index stroke or TIA considered to have an other known cause, not related to athero-thrombotic sources (TOAST Other Determined Etiology) based on local standard-of-care investigations. Examples of such etiologies include intracranial tumor, arteritis, arterial dissection, vasospasm or AVM.
5. Pre-event disability with mRS score of 3 or higher.
6. Any condition that requires chronic anticoagulation at the discretion of the investigator and/or local guidelines. Note: Participants with an indication for chronic antiplatelet therapy after placement of a bio-prosthetic nonmechanical valve (eg, transcatheter aortic valve replacement [TAVR]) do not satisfy this exclusion criterion and are eligible for study participation
7. Conditions with an increased risk of bleeding, including: Clinically significant bleeding within the previous 3 months Known bleeding diathesis Known aPTT prolongation > 1.4 times the ULN or known congenital FXI deficiency Spinal cord hemorrhage Retinal hemorrhage
8. eGFR <15 mL/min/1.73 m2 at screening
9. Any of the following laboratory results, based on local laboratory, outside of the ranges specified below prior to randomization: ALT ˃ 3X ULN Platelet count <75,000 mm3 Total bilirubin ≥ 1.5x ULN unless an alternative causative factor such as Gilbert’s syndrome is identified Hemoglobin <8.0 g/dL

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Time to first occurrence of ischemic stroke

Secondary endpoints 3

1. Time to first occurrence of any component of the composite of CVD, MI, or ischemic stroke
2. Time to first occurrence of ischemic stroke in the first 90 days
3. Time to first occurrence of any component of MAVE (ie, composite of CVD, MI, ischemic stroke, MALE, symptomatic PE or DVT)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Auxiliary 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Janssen - Cilag International

Sponsor organisation

Janssen - Cilag International

Address

Turnhoutseweg 30

City

Beerse

Postcode

2340

Country

Belgium

Scientific contact point

Organisation

Janssen - Cilag International

Contact name

CTIS Point of Contact

Public contact point

Organisation

Janssen - Cilag International

Contact name

CTIS Point of Contact

Third parties 11

Locations

22 EU/EEA countries · 256 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 478 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

62 submissions — initial application plus substantial / non-substantial modifications