rFVIIa for Hemorrhagic Stroke

(FASTEST Trial)

Recruiting at 91 trial locations

Overseen By James Grotta, MD

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Joseph Broderick, MD

Must not be taking: Anticoagulants, Pro-coagulants, Heparin, others

Disqualifiers: Coma, Disability, Thrombosis, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 6

Duration: Immediate (within 2 hours of stroke onset)

860 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

Do I need to stop my current medications to join the trial?

The trial requires that you have not used oral anticoagulants, pro-coagulant drugs, or low-molecular weight heparin within certain time frames before enrollment. If you are taking these medications, you may need to stop them to participate.

What data supports the effectiveness of the drug rFVIIa for hemorrhagic stroke?

Recombinant activated factor VII (rFVIIa) has been used successfully to manage uncontrolled bleeding in various conditions, including trauma and congenital bleeding disorders. It works by helping blood to clot at the site of injury, which can reduce the need for blood transfusions and improve outcomes in severe bleeding situations. ^{1 2 3 4 5}

Is recombinant activated factor VII (rFVIIa) generally safe for humans?

Recombinant activated factor VII (rFVIIa), also known as NovoSeven, has been used safely in various conditions, including congenital bleeding disorders and major hemorrhages in trauma patients. Safety data from clinical trials, such as the CONTROL trial, support its use, although it was initially developed for hemophiliacs with specific antibodies. ^{3 4 6 7 8}

How is the drug rFVIIa unique for treating hemorrhagic stroke?

rFVIIa is unique because it acts quickly to stop bleeding at the site of injury without affecting the entire body's blood clotting system, making it potentially effective for hemorrhagic stroke. It is also used in patients with bleeding disorders like hemophilia and has shown promise in treating various types of severe bleeding, including those in the brain. ^{5 9 10 11 12}

Research Team

Joseph Broderick, MD

Principal Investigator

University of Cincinnati

Eligibility Criteria

This trial is for adults aged 18-80 who've had a spontaneous hemorrhagic stroke and can start treatment within 2 hours of onset. It's not for those with certain pre-existing conditions, drug dependencies, recent participation in other trials, or women who are pregnant/lactating. Patients must be able to follow the trial protocol.

Inclusion Criteria

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)

I have had a stroke caused by bleeding in my brain.

I can take the study medication within 2 hours of my stroke or when I was last well.

Exclusion Criteria

I am not allergic or sensitive to the study medication.

My bleeding is in the brainstem or cerebellum.

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

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive rFVIIa or placebo as an IV injection within 120 minutes of stroke onset

Immediate (within 2 hours of stroke onset)

1 visit (in-person)

Initial Follow-up

Participants are monitored for growth of ICH with CT scans at baseline and 24 hours

24 hours

2 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness with remote assessments at 30 and 90 days

90 days

2 visits (remote)

Long-term Follow-up

Participants' outcomes are assessed at 180 days using the Modified Rankin Scale

180 days

1 visit (remote)

Treatment Details

Interventions

• Placebo
• Recombinant Activated Factor VII (rFVIIa)

Trial Overview The FASTEST Trial is testing if Recombinant Activated Factor VII (rFVIIa), given quickly after a hemorrhagic stroke starts, can improve recovery at six months compared to standard care. Half will get rFVIIa and half a placebo to see which works better.

Participant Groups

Group I: Recombinant Activated Factor VII (rFVIIa) Active Control 1 Intervention

rFVIIa given as IV injection over 2 minutes within 120 minutes of stroke onset

Group II: Placebo Placebo Group 1 Intervention

Matching placebo given as IV injection over 2 minutes within 120 minutes of stroke onset

Recombinant Activated Factor VII (rFVIIa) is already approved in European Union, United States for the following indications:

Approved in European Union as NovoSeven for:

• Hemophilia A and B with inhibitors
• Acquired hemophilia
• Congenital factor VII deficiency
• Glanzmann thrombasthenia

Approved in United States as NovoSeven RT for:

• Hemophilia A and B with inhibitors
• Acquired hemophilia
• Congenital factor VII deficiency
• Glanzmann thrombasthenia

Approved in United States as Sevenfact for:

• Hemophilia A and B with inhibitors
• Acquired hemophilia
• Congenital factor VII deficiency

Approved in European Union as Cevenfacta for:

• Hemophilia A and B with inhibitors
• Acquired hemophilia
• Congenital factor VII deficiency

Who Is Running the Clinical Trial?

Joseph Broderick, MD

Lead Sponsor

Trials

1

Recruited

860+

National Institute of Neurological Disorders and Stroke (NINDS)

Collaborator

Trials

1,403

Recruited

655,000+

Novo Nordisk A/S

Industry Sponsor

Trials

1,578

Recruited

3,813,000+

Lars Fruergaard Jørgensen

Novo Nordisk A/S

Chief Executive Officer since 2017

MSc in Finance and Business Administration, Aarhus School of Business, Aarhus University, Denmark

Martin Holst Lange

Novo Nordisk A/S

Chief Medical Officer since 2021

MD from University of Copenhagen

Findings from Research

Recombinant activated factor VII (rFVIIa) is an effective hemostatic agent primarily used to treat bleeding in hemophilic patients with inhibitors, demonstrating its efficacy in managing severe bleeding episodes.

In addition to its established use in hemophilia, rFVIIa is increasingly being applied to treat uncontrolled bleeding in various congenital and acquired hemostatic disorders, indicating its expanding role in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recombinant factor VIIa: a review on its clinical use. Franchini, M.[2018]

Recombinant activated factor VII (rFVIIa) is effective in treating bleeding episodes in patients with antibodies against coagulation factors VIII and IX, demonstrating its established role in managing specific bleeding disorders.

Recent applications of rFVIIa have expanded to include the management of uncontrolled bleeding in various congenital and acquired haemostatic abnormalities, indicating its potential versatility in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recombinant factor VIIa. An update on its clinical use. Franchini, M., Zaffanello, M., Veneri, D.[2005]

In a study of 59 patients receiving off-label recombinant activated factor VII (rFVIIa) in major teaching hospitals in Paris, 82% of prescriptions were found to be adequate or acceptable according to established guidelines.

The use of rFVIIa was particularly appropriate in multiple trauma cases, with 100% of prescriptions meeting the necessary criteria, and 83% in obstetrical cases, indicating a high level of adherence to recommended practices.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Off-label use of recombinant factor VII (rFVIIa) in teaching hospitals in Paris in 2010]. Bardon, J., Fink, J., de Montblanc, J., et al.[2016]

Recombinant activated factor VII (rFVIIa) is used to treat hemophilic patients with inhibitors against coagulation factors, but the evidence supporting its efficacy is weak due to limited sample sizes and study variability across eight randomized controlled trials involving 256 patients.

The authors recommend that rFVIIa treatment should be tailored to the individual's thrombin generation ability rather than solely relying on weight, suggesting that tests like thromboelastography could enhance treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evidence supporting the use of recombinant activated factor VII in congenital bleeding disorders. Johansson, PI., Ostrowski, SR.[2021]

Recombinant activated Factor VII (rFVIIa) is effective in managing severe bleeding in hemophilia patients with inhibitors and shows promise as an adjuvant therapy for critical bleeding from trauma, demonstrating rapid and significant hemostasis.

The use of rFVIIa can reduce the need for blood transfusions and improve clinical outcomes in patients experiencing massive blood loss, highlighting its potential as a powerful treatment option in emergency situations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The emerging role of recombinant activated Factor VII (rFVIIa) in the treatment of blunt traumatic haemorrhage. Rizoli, SB., Chughtai, T.[2019]

Recombinant activated coagulation factor VII (rFVIIa) is highly effective in treating bleeding episodes in pediatric patients with congenital hemophilia with inhibitors, achieving effectiveness in 95.4% of cases across various age groups.

The treatment is considered safe, with adverse reactions similar to those seen in adults, and only one confirmed thrombotic event related to rFVIIa, indicating a favorable safety profile for pediatric use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of recombinant factor VIIa by pediatric age cohort: reassessment of compassionate use and trial data supporting US label. Croteau, SE., Nakar, C., Neufeld, EJ., et al.[2018]

In a large phase III study involving 560 actively hemorrhaging trauma patients, recombinant activated factor VII (rFVIIa) did not increase the overall risk of adverse events or mortality compared to placebo, indicating its safety in this critical setting.

While there was a slight imbalance in reported myocardial infarctions in the rFVIIa group, the use of rFVIIa was associated with a significantly lower rate of acute respiratory distress syndrome compared to the placebo group (3.0% vs. 7.2%), suggesting potential benefits in respiratory outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recombinant activated factor VII safety in trauma patients: results from the CONTROL trial. Dutton, RP., Parr, M., Tortella, BJ., et al.[2020]

In a study of 32 patients undergoing vascular surgery, the use of recombinant activated factor VII (rFVIIa) effectively controlled severe bleeding in 29 patients, demonstrating its potential as a haemostatic agent when conventional methods fail.

Despite its effectiveness, the use of rFVIIa is recommended cautiously due to the lack of randomized controlled trials confirming its safety and efficacy in vascular patients, along with its high cost of approximately $4080 for a 4.8 mg dose.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Recombinant activated factor VII in the treatment of intractable non-surgical bleeding following major vascular procedures]. Koncar, IB., Savić, N., Davidović, LB., et al.[2019]

In a retrospective analysis of 5 very low birth weight preterm infants with disseminated intravascular coagulation (DIC) and severe gastrointestinal bleeding, recombinant activated Factor VII (rFVIIa) was effective in stopping intestinal hemorrhage in 3 out of the 5 cases.

While rFVIIa showed promise as a rescue therapy for hemorrhagic shock, it was ineffective in patients with severe acidosis, hypothermia, and thrombopenia, highlighting the need for careful patient selection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recombinant activated Factor VII as a hemostatic agent in very low birth weight preterms with gastrointestinal hemorrhage and disseminated intravascular coagulation. Fischer, D., Schloesser, R., Buxmann, H., et al.[2011]

Recombinant-activated factor VII (rFVIIa) is effective in managing bleeding in hemophiliacs with inhibitors and shows promise as a hemostatic agent in nonhemophilic patients, acting quickly and with minimal complications.

Ongoing clinical trials aim to evaluate the safety and efficacy of rFVIIa for reversing coagulopathy in various conditions, including trauma and CNS hemorrhage, which could expand its use beyond hemophilia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The emerging role of recombinant-activated factor VII in neurocritical care. Fewel, ME., Park, P.[2018]

Recombinant activated factor VII (rFVIIa) was successfully used in a Jehovah's Witness patient who was anticoagulated with warfarin and had an acute subdural hematoma, demonstrating its potential efficacy in managing bleeding in patients with coagulation abnormalities.

The use of rFVIIa allowed for the surgical evacuation of the hematoma without excessive blood loss, leading to a good recovery for the patient, highlighting its safety and effectiveness in critical situations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recombinant activated factor VII for a warfarinised Jehovah's Witness with an acute subdural haematoma. Goldberg, R., Drummond, KJ.[2013]

In a study of 46 patients with intracerebral hemorrhage treated with recombinant-activated factor VII (rFVIIa), no significant difference in treatment outcomes was observed based on the timing of treatment (within 3 hours vs. 3 to 4 hours after symptom onset).

The study found that rFVIIa treatment did not significantly reduce ICH growth or improve outcomes compared to a control group, and thrombotic adverse events occurred in 11.1% of treated patients, suggesting the need for further criteria to identify which patients may benefit from this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of activated factor VII for intracerebral hemorrhage beyond 3 hours versus within 3 hours. Hallevi, H., Gonzales, NR., Barreto, AD., et al.[2019]

References

1. Japan pubmed.ncbi.nlm.nih.gov

Recombinant factor VIIa: a review on its clinical use. [2018]

2. Germany pubmed.ncbi.nlm.nih.gov

Recombinant factor VIIa. An update on its clinical use. [2005]

3. France pubmed.ncbi.nlm.nih.gov

[Off-label use of recombinant factor VII (rFVIIa) in teaching hospitals in Paris in 2010]. [2016]

4. New Zealand pubmed.ncbi.nlm.nih.gov

Evidence supporting the use of recombinant activated factor VII in congenital bleeding disorders. [2021]

5. England pubmed.ncbi.nlm.nih.gov

The emerging role of recombinant activated Factor VII (rFVIIa) in the treatment of blunt traumatic haemorrhage. [2019]

6. United States pubmed.ncbi.nlm.nih.gov

Safety and efficacy of recombinant factor VIIa by pediatric age cohort: reassessment of compassionate use and trial data supporting US label. [2018]

7. United States pubmed.ncbi.nlm.nih.gov

Recombinant activated factor VII safety in trauma patients: results from the CONTROL trial. [2020]

8. Serbia pubmed.ncbi.nlm.nih.gov

[Recombinant activated factor VII in the treatment of intractable non-surgical bleeding following major vascular procedures]. [2019]

9. United States pubmed.ncbi.nlm.nih.gov

Recombinant activated Factor VII as a hemostatic agent in very low birth weight preterms with gastrointestinal hemorrhage and disseminated intravascular coagulation. [2011]

10. United States pubmed.ncbi.nlm.nih.gov

The emerging role of recombinant-activated factor VII in neurocritical care. [2018]

11. Scotland pubmed.ncbi.nlm.nih.gov

Recombinant activated factor VII for a warfarinised Jehovah's Witness with an acute subdural haematoma. [2013]

12. United States pubmed.ncbi.nlm.nih.gov

The effect of activated factor VII for intracerebral hemorrhage beyond 3 hours versus within 3 hours. [2019]