Recombinant Factor VIIa (rFVIIa) for Hemorrhagic Stroke Trial

Study Overview
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Brief Summary
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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 180 days as measured by the Modified Rankin Score (mRS) and decrease ongoing bleeding as compared to standard therapy.

Detailed Description
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The investigators will perform 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) (IVH score ≤ 7), age ≥ 18 and ≤ 80, Glasgow Coma Scale of ≥ 8, and treated within 120 minutes from stroke onset. To minimize time-to-treatment, the study will use 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 860 participants over 3½ years is planned. Countries participating in the trial include the United States, Canada, Japan, Germany, Spain, and the United Kingdom. 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 180 days, but participants will be followed by remote assessment at 30 days and 90 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.

Official Title
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Recombinant Factor VIIa (rFVIIa) for Acute Hemorrhagic Stroke Administered at Earliest Time (FASTEST) Trial

Conditions
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Intracerebral Hemorrhage

Intervention / Treatment
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* Biological: Recombinant Activated Factor VII (rFVIIa)
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients aged 18-80 years, inclusive Patients with spontaneous ICH Able to treat with study medication (rFVIIa/placebo) within 120 minutes of stroke onset or last known well Efforts to obtain informed consent per EFIC guidelines (U.S.) or adherence to country-specific emergency research informed consent regulations (Canada, Germany, Spain, U.K., Japan) Exclusion Criteria: Score of 3 to 7 on the Glasgow Coma Scale 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.) ICH volume < 2 cc or ≥ 60 cc Blood filling 2/3 or more of one lateral ventricle of the brain, OR, blood filling at least 1/3 of both lateral ventricles. Pre-existing disability (mRS > 2) Symptomatic thrombotic or vaso-occlusive disease in past 90 days (e.g., cerebral infarction, myocardial infarction, pulmonary embolus, deep vein thrombosis, or unstable angina) Clinical or EKG evidence of ST elevation consistent with acute myocardial ischemia Brainstem location of hemorrhage (patients with cerebellar hemorrhage may be enrolled) Refusal to participate in study by patient, legal representative, or family member Known or suspected thrombocytopenia (unless current platelet count documented above 50,000/μL) Unfractionated heparin use with abnormal PTT Pro-coagulant drugs within 24 hours prior to patient enrollment into the FASTEST trial (example, tranexamic acid or aminocaproic acid) Low-molecular weight heparin use within the previous 24 hours Recent (within 90 days) carotid endarterectomy or coronary or cerebrovascular angioplasty or stenting Advanced or terminal illness or any other condition the investigator feels would pose a significant hazard to the patient if rFVIIa were administered 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 Planned withdrawal of care or comfort care measures Patient known or suspected of not being able to comply with trial protocol (e.g., due to alcoholism, drug dependency, or psychological disorder) Known or suspected allergy to trial medication(s), excipients, or related products Contraindications to study medication Previous participation in this trial (previously randomized) Females of childbearing potential who are known to be pregnant or within 12 weeks post-partum and/or lactating at time of enrollment

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Recombinant Activated Factor VII (rFVIIa)<br>rFVIIa given as IV injection over 2 minutes within 120 minutes of stroke onset | Biological: Recombinant Activated Factor VII (rFVIIa)<br>* Participants will be randomized in a double-blinded fashion to rFVIIa 80 µg/kg dose (maximum 10 mg dose) or matching 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.<br>* Other names: NiaStase;|
| Placebo Comparator: Placebo<br>Matching placebo given as IV injection over 2 minutes within 120 minutes of stroke onset | Biological: Placebo<br>* Participants will be randomized in a double-blinded fashion to rFVIIa 80 µg/kg dose (maximum 10 mg dose) or matching 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Modified Rankin Scale (mRS) | Ordinal distribution with the following steps: 0-2, 3, 4-6 | 180 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| mRS | Utility-weighted | 180 days | 
| mRS | Score of 0-2 | 180 days | 
| EQ-5D | Quality of life scale | 180 days | 
| Change in the volume of ICH and ICH+IVH | As measured by non-contrast CT of the head | Between baseline CT and 24-hour CT | 
| mRS | Ordinal distribution | 90 days | 
| EQ-5D | Quality of life scale | 90 days | 
| mRS | Ordinal distribution | 180 days |