Recombinant Factor VIIa (rFVIIa) for Hemorrhagic Stroke Trial - Part 2

Recombinant Factor VIIa (rFVIIa) for Acute Hemorrhagic Stroke Administered at Earliest Time (FASTEST) Trial - Part 2

The objective of the rFVIIa for Acute Hemorrhagic Stroke Administered at Earliest Time (FASTEST) Trial is to establish the first treatment for acute spontaneous intracerebral hemorrhage (ICH) within a time window and subgroup of patients that is most likely to benefit. The central hypothesis is that rFVIIa, administered within 120 minutes from stroke onset with an identified subgroup of patients most likely to benefit, will improve outcomes at 90 days as measured by the Modified Rankin Score (mRS) and decrease ongoing bleeding as compared to standard therapy. FASTEST Part 2 is an extension of the FASTEST Trial where the subgroups include those treated within 2 hours with a positive spot sign on a baseline CT angiogram or patients treated within 90 minutes of stroke onset, with or without a positive spot sign.

FASTEST Part 2 is a global, Phase III, randomized, double-blind controlled trial of rFVIIa plus best standard therapy vs. placebo and best standard therapy alone. The investigators will include participants with a volume of ICH ≥ 2 and < 60 cc, no more than a small volume of intraventricular hemorrhage (IVH) (less than 2/3 of one lateral ventricle and less than 1/3 in both lateral ventricles), age ≥ 18 and ≤ 80, Glasgow Coma Scale of ≥ 8, and with a positive spot sign on a baseline CTA treated within 120 minutes from stroke onset or patients treated within 90 minutes of stroke onset, with or without a positive spot sign. This is based upon data from FASTEST Part 1 from the overall FASTEST Trial where the greatest potential for benefit was demonstrated. To minimize time-to-treatment, the study uses emergency research informed consent procedures (including exception from informed consent (EFIC) in the United States) and mobile stroke units (MSUs), with a goal of ½ of participants treated within 90 minutes, as accomplished in the NINDS t-PA trials. The FASTEST Trial will include approximately 100 hospital sites and at least 15 MSUs in the NINDS-funded StrokeNet and key global institutions with large volumes of ICH patients and the ability to treat them within 120 minutes of stroke onset.

Recruitment of a maximum of 350 participants over approximately 3½ years is planned. Countries participating in the trial include the United States, Canada, Japan, Germany, Spain, Finland, the United Kingdom, and Australia. Involving other countries may be possible in the future depending upon recruitment needs.

Participants will be randomized in a double-blinded fashion to rFVIIa 80 µg/kg dose (maximum 10 mg dose) or placebo. Participants in both arms will receive best standard therapy as per published AHA Guidelines for ICH, including a target systolic blood pressure of 140 mm Hg. The primary outcome (ordinal mRS with the following categories: 0-2, 3, and 4-6) will be determined at 90 days, but participants will be followed by remote assessment at 30 days and 180 days. To measure growth of ICH, all participants will have a standard of care baseline non-contrast CT of the head and a repeat scan at 24 hours. Centralized volumetric measurements of ICH, IVH, and edema will be performed for both time points.

Novo Nordisk A/S will manufacture and supply rFVIIa as a research medication for use in the FASTEST Trial. Novo Nordisk A/S will also manufacture and supply matching placebo that is identical to rFVIIa in appearance and administration.

Inclusion Criteria:

1. Patients aged 18-80 years, inclusive
2. Patients with spontaneous ICH
3. Able to treat with study medication (rFVIIa/placebo) within 120 minutes of stroke onset or last known well with a positive spot sign on pretreatment CT angiography or treatment within 90 minutes with or without spot sign.
4. Efforts to obtain informed consent per EFIC guidelines (U.S.) or adherence to country-specific emergency research informed consent regulations (Canada, Germany, Spain, Finland, U.K., Japan, Australia)

Exclusion Criteria:

1. Score of 3 to 7 on the Glasgow Coma Scale
2. Secondary ICH related to known causes (e.g., trauma, aneurysm, arteriovenous malformation (AVM), oral anticoagulant use (vitamin K antagonists or novel oral anticoagulants) within the past 7 days, coagulopathy, etc.)
3. ICH volume < 2 cc or ≥ 60 cc
4. Blood filling 2/3 or more of one lateral ventricle of the brain, OR, blood filling at least 1/3 of both lateral ventricles.
5. Pre-existing disability (mRS > 2)
6. Symptomatic thrombotic or vaso-occlusive disease in past 90 days (e.g., cerebral infarction, myocardial infarction, pulmonary embolus, deep vein thrombosis, or unstable angina)
7. Clinical or EKG evidence of ST elevation consistent with acute myocardial ischemia
8. Brainstem location of hemorrhage (patients with cerebellar hemorrhage may be enrolled)
9. Refusal to participate in study by patient, legal representative, or family member
10. Known or suspected thrombocytopenia (unless current platelet count documented above 50,000/μL)
11. Unfractionated heparin use with abnormal PTT
12. Pro-coagulant drugs within 24 hours prior to patient enrollment into the FASTEST trial (example, tranexamic acid or aminocaproic acid)
13. Low-molecular weight heparin use within the previous 24 hours
14. Recent (within 90 days) carotid endarterectomy or coronary or cerebrovascular angioplasty or stenting
15. Advanced or terminal illness or any other condition the investigator feels would pose a significant hazard to the patient if rFVIIa were administered
16. Recent (within 30 days) participation in any investigational drug or device trial or earlier participation in any investigational drug or device trial for which the duration of effect is expected to persist until to the time of FASTEST enrollment
17. Planned withdrawal of care or comfort care measures
18. Patient known or suspected of not being able to comply with trial protocol (e.g., due to alcoholism, drug dependency, or psychological disorder)
19. Known or suspected allergy to trial medication(s), excipients, or related products
20. Contraindications to study medication
21. Previous participation in this trial (previously randomized)
22. Females of childbearing potential who are known to be pregnant or within 12 weeks post-partum and/or lactating at time of enrollment -