Clinical trial NCT03496883: Recombinant Factor VIIa (rFVIIa) for Hemorrhagic Stroke Trial
Official title: Recombinant Factor VIIa (rFVIIa) for Acute Hemorrhagic Stroke Administered at Earliest Time (FASTEST) Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Intracerebral Hemorrhage
Lead sponsor: University of Cincinnati
Sponsor class: OTHER
Collaborators: name: Novo Nordisk A/S
name: National Institute of Neurological Disorders and Stroke (NINDS)
First posted: 2018-04-12
Enrollment: 860
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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. 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 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.

Eligibility criteria: 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
4. 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:

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

Primary outcomes:
measure: Modified Rankin Scale (mRS)
timeFrame: 180 days
Secondary outcomes:
measure: mRS
timeFrame: 180 days
measure: mRS
timeFrame: 180 days
measure: EQ-5D
timeFrame: 180 days
measure: Change in the volume of ICH and ICH+IVH
timeFrame: Between baseline CT and 24-hour CT
measure: mRS
timeFrame: 90 days
measure: EQ-5D
timeFrame: 90 days
measure: mRS
timeFrame: 180 days
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama Hospital
state: Alabama
city: Phoenix
country: United States
facility: St. Joseph's Hospital and Medical Center
state: Arizona
city: Baldwin Park
country: United States
facility: Kaiser Permanente Baldwin Park Medical Center
state: California
city: Burlingame
country: United States
facility: Mills Peninsula Medical Center
state: California
city: Downey
country: United States
facility: Kaiser Permanente Downey Medical Center
state: California
city: Fontana
country: United States
facility: Kaiser Permanente Fontana Medical Center
state: California
city: Harbor City
country: United States
facility: Kaiser Permanente South Bay Medical Center
state: California
city: La Jolla
country: United States
facility: UCSD Health La Jolla
state: California
city: Los Angeles
country: United States
facility: Kaiser Permanente Los Angeles Medical Center
state: California
city: Los Angeles
country: United States
facility: Kaiser Permanente West Los Angeles Medical Center
state: California
city: Los Angeles
country: United States
facility: Ronald Reagan UCLA Medical Center
state: California
city: Orange
country: United States
facility: UC Irvine Medical Center,
state: California
city: Riverside
country: United States
facility: Kaiser Permanente Riverside Medical Center
state: California
city: Sacramento
country: United States
facility: UC Davis Medical Center
state: California
city: San Diego
country: United States
facility: UCSD Medical Center - Hillcrest Hospital
state: California
city: San Francisco
country: United States
facility: San Francisco General Hospital
state: California
city: Gainesville
country: United States
facility: UF Health Shands Hospital
state: Florida
city: Jacksonville
country: United States
facility: Mayo Clinic
state: Florida
city: Atlanta
country: United States
facility: Grady Memorial Hospital
state: Georgia
city: Marietta
country: United States
facility: WellStar Kennestone Hospital
state: Georgia
city: Honolulu
country: United States
facility: The Queen's Medical Center
state: Hawaii
city: Chicago
country: United States
facility: Northwestern Memorial Hospital
state: Illinois
city: Chicago
country: United States
facility: University of Chicago Medical Center
state: Illinois
city: Winfield
country: United States
facility: Central DuPage Hospital
state: Illinois
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Worcester
country: United States
facility: UMass Memorial Medical Center
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Hospital
state: Michigan
city: Burnsville
country: United States
facility: M Health Fairview Ridges Hospital,
state: Minnesota
city: Edina
country: United States
facility: M Health Fairview Southdale Hospital
state: Minnesota
city: Maplewood
country: United States
facility: M Health Fairview St. John's Hospital
state: Minnesota
city: Minneapolis
country: United States
facility: M Health Fairview University of Minnesota Medical Center Hospital,
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic Saint Marys Campus
state: Minnesota
city: St. Louis
country: United States
facility: Barnes Jewish Hospital
state: Missouri
city: Manhasset
country: United States
facility: North Shore University Hospital
state: New York
city: New York
country: United States
facility: Mount Sinai West
state: New York
city: New York
country: United States
facility: The Mount Sinai Hospital
state: New York
city: Stony Brook
country: United States
facility: Stony Brook University Hospital
state: New York
city: Winston-Salem
country: United States
facility: Wake Forest Baptist Medical Center
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati Medical Center
state: Ohio
city: Columbus
country: United States
facility: OSU Wexner Medical Center
state: Ohio
city: Columbus
country: United States
facility: Riverside Methodist Hospital
state: Ohio
city: Toledo
country: United States
facility: Toledo Hospital
state: Ohio
city: Tulsa
country: United States
facility: St. John Medical Center
state: Oklahoma
city: Portland
country: United States
facility: Providence St. Vincent Medical Center
state: Oregon
city: Philadelphia
country: United States
facility: Temple University Hospital
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina University Hospital
state: South Carolina
city: Greenville
country: United States
facility: Prisma Health Greenville Memorial Hospital
state: South Carolina
city: Houston
country: United States
facility: Memorial Hermann Memorial City Medical Center
state: Texas
city: Houston
country: United States
facility: Memorial Hermann-Texas Medical Center
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah Healthcare
state: Utah
city: Richmond
country: United States
facility: VCU Medical Center
state: Virginia
city: Calgary
country: Canada
facility: University of Calgary - Foothills Medical Centre
state: Alberta
city: Edmonton
country: Canada
facility: University of Alberta Hospital
state: Alberta
city: Vancouver
country: Canada
facility: Vancouver General Hospital
state: British Columbia
city: Hamilton
country: Canada
facility: Hamilton General Hospital
state: Ontario
city: Ottawa
country: Canada
facility: Ottawa Hospital Research Institute
state: Ontario
city: Toronto
country: Canada
facility: Sunnybrook Health Sciences Center
state: Ontario
city: Toronto
country: Canada
facility: St. Michaels Hospital
state: Ontario
city: Montreal
country: Canada
facility: University of Montreal Hospital
state: Quebec
city: Heidelberg
country: Germany
facility: University Hospital Heidelberg
state: Baden-Württemberg
city: Frankfurt
country: Germany
facility: Clinic Frankfurt Hoechst
state: Hessen
city: Augsburg
country: Germany
facility: University Hospital Augsburg
city: Berlin
country: Germany
facility: Charite University Medicine Berlin
city: Tuebingen
country: Germany
facility: University Hospital Tuebingen
city: Suita
country: Japan
facility: National Cerebral and Cardiovascular Center
state: Osaka
city: Fukuoka
country: Japan
facility: Kyushu Medical Center
city: Gifu
country: Japan
facility: Gifu University Hospital
city: Kagoshima
country: Japan
facility: Kagoshima City Hospital
city: Kobe
country: Japan
facility: Kobe City Medical Center General Hospital
city: Kyoto
country: Japan
facility: Japanese Red Cross Kyoto Daini Hospital
city: Morioka
country: Japan
facility: Iwate Prefectural Central Hospital
city: Niigata
country: Japan
facility: Niigata City General Hospital
city: Osaka
country: Japan
facility: KMU University Hospital
city: Osaka
country: Japan
facility: NHO Osaka National Hospital
city: Sapporo
country: Japan
facility: Nakamura Memorial Hospital
city: Shimotsuke
country: Japan
facility: Jichi Medical University Hospital
city: Tokyo
country: Japan
facility: Kyorin University Hospital
city: Tokyo
country: Japan
facility: Toranomon Hospital
city: Badalona
country: Spain
facility: Hospital Universitari Germans Trias i Pujol
state: Barcelona
city: Horta
country: Spain
facility: Vall d'Hebron University Hospital (VHUH)
state: Barcelona
city: L'Hospitalet de Llobregat
country: Spain
facility: Bellvitge University Hospital,
state: Barcelona
city: Barcelona
country: Spain
facility: Santa Creu and Sant Pau Hospital
state: Catalonia
city: Girona
country: Spain
facility: Girona University Hospital
state: Catalonia
city: Lleida
country: Spain
facility: Arnau de Vilanova University Hospital
state: Catalonia
city: Oxford
country: United Kingdom
facility: John Radcliffe Hospital
state: Oxfordshire
city: Stoke-on-Trent
country: United Kingdom
facility: Royal Stoke University Hospital
state: Staffordshire
city: Newcastle upon Tyne
country: United Kingdom
facility: Royal Victoria Infirmary
city: Nottingham
country: United Kingdom
facility: Queens Medical Centre
Study officials:
affiliation: University of Cincinnati
name: Joseph Broderick, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Naidech AM, Grotta J, Elm J, Janis S, Dowlatshahi D, Toyoda K, Steiner T, Mayer SA, Khanolkar P, Denlinger J, Audebert HJ, Molina C, Khatri P, Sprigg N, Vagal A, Broderick JP. Recombinant factor VIIa for hemorrhagic stroke treatment at earliest possible time (FASTEST): Protocol for a phase III, double-blind, randomized, placebo-controlled trial. Int J Stroke. 2022 Aug;17(7):806-809. doi: 10.1177/17474930211042700. Epub 2021 Sep 5.