What side effects are associated with this type of intervention?

Common treatments for Hemophilia A, such as Activated Prothrombin Complex Concentrate (aPCC), recombinant factor VIIa, and emicizumab, have several known side effects. aPCC can lead to thromboembolic events, especially when used in combination with emicizumab. Recombinant factor VIIa may cause thrombotic complications and hypersensitivity reactions. Emicizumab, while effective in reducing bleeding episodes, can also result in thrombotic microangiopathy and injection site reactions. Monitoring and individualized dosing are essential to mitigate these risks.

What prior FDA approvals exist?

The FDA has approved several treatments for Hemophilia A that provide clotting factors to help control bleeding. Notable approvals include recombinant factor VIII products such as rFVIII-Fc (Eloctate), which is a fusion protein designed to extend the half-life of factor VIII, and PEGylated factor VIII, which is covalently fused to polyethylene glycol to prolong its activity. Additionally, activated prothrombin complex concentrates (aPCC) like FEIBA have been used to manage bleeding in patients with inhibitors. These treatments aim to replace the missing or deficient clotting factors, thereby improving hemostasis in individuals with Hemophilia A.

What other types of research exist?

Promising novel alternatives to aPCC for Hemophilia A patients include Emicizumab, a bispecific monoclonal antibody that bridges activated factor IX and factor X to restore the function of missing activated factor VIII, and gene therapy approaches such as Valoctocogene Roxaparvovec, which aims to provide a long-term solution by introducing a functional copy of the factor VIII gene. Both have shown significant efficacy and safety in clinical trials and are expected to be key treatments by 2024.

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Coagulation Factor Replacement Therapy

aPCC-Emicizumab Safety for Hemophilia A (SAFE Trial)

Phase 3

Recruiting

Led By Robert Sidonio, MD

Research Sponsored by Emory University

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Age ≥6 years of age at time of informed consent

Adequate hematologic function (Hgb >8 g/dL and platelet count >100,000 µL)

Must not have

Use of systemic immunomodulators at enrollment or planned use during the study

Inherited or acquired bleeding disorder other than hemophilia A excluding low VWF (>30% VWF:RCo or VWF:GP1bm)

Timeline

Screening 3 weeks

Treatment Varies

Follow Up up to 2 years

Awards & highlights

No Placebo-Only Group

Pivotal Trial

Summary

This trial uses a special blood-clotting medicine along with emicizumab to help control bleeding in children and adults with hemophilia A who have inhibitors. The treatment works by helping the blood to clot better. Emicizumab is approved for regular use in patients with severe hemophilia A with and without inhibitors.

Who is the study for?

The SAFE Study is for children and adults over 6 years old with severe hemophilia A and inhibitors, who have not responded to standard treatments. Participants must have good blood, liver, and kidney function but cannot join if they have other bleeding disorders, high risk of clotting or bleeding conditions, HIV with low CD4 counts, a history of thromboembolic disease or significant reactions to monoclonal antibody therapies.

What is being tested?

This study tests the safety and effectiveness of personalized doses of aPCC in combination with emicizumab during acute bleeding events or before procedures in those on emicizumab prophylaxis. It aims to understand how well this treatment works for people with hemophilia A who also have inhibitors.

What are the potential side effects?

Potential side effects may include allergic reactions related to monoclonal antibodies or components in the injection. There's also a concern about increased risks of clotting (thrombosis) due to the nature of these medications.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I am 6 years old or older.

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My blood counts are within the required range.

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My liver tests are within the required range.

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My kidney function is within the required range.

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My hemophilia A is moderately severe with very low FVIII levels.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I am not using and do not plan to use immune system medications during the study.

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I have a bleeding disorder that is not hemophilia A.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ up to 2 years

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~up to 2 years

This trial's timeline: 3 weeks for screening, Varies for treatment, and up to 2 years for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Number of episodes of thrombotic events including thrombotic microangiopathy (TMA)

Number of serious adverse events

Number of serious bleeding episodes

Secondary study objectives

Number of infusions of aPCC required to achieve hemostatic efficacy for treatment of an acute bleeding episode, or prevention of bleeding with emergent and non-emergent procedures

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Pivotal Trial

The final step before approval, pivotal trials feature drugs that have already shown basic safety & efficacy.

Trial Design

1Treatment groups

Experimental Treatment

Group I: Experimental treatmentExperimental Treatment3 Interventions

Personalized dose of aPCC-emicizumab will be administered to participants. The max dose allowed for aPCC will be 25 U/kg/dose every 8 hours, for no more than 72 hours without further discussion with the PI. If there is less than a "good' response in bleed event response efficacy as stated above at 48 hours or less than "moderate" for surgical event control, the local PI can consider the use of thrombin generation guided rFVIIa with max dose no more than 90 µg/kg/dose every 8 hours for 72 hours, with wean to occur for no more than 7 total days without further discussion with the PI.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

FEIBA

2016

Completed Phase 3

~60

rFVIIa

2005

Completed Phase 4

~230

0 / 7Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Hemophilia A treatments primarily aim to replace the deficient factor VIII or bypass its need to control bleeding. Activated Prothrombin Complex Concentrate (aPCC) is a key treatment that provides a mix of clotting factors, including activated factors VII, IX, and X, which facilitate clot formation and control bleeding. This is crucial for patients with inhibitors against factor VIII, as aPCC can bypass the inhibited pathway, ensuring effective hemostasis and reducing bleeding episodes.

In vitro evaluation of factor VIII--bypassing activity of activated prothrombin complex concentrate, prothrombin complex concentrate, and factor VIIa in the plasma of patients with factor VIII inhibitors: thrombin generation test in the presence of collagen-activated platelets.Recombinant Factor VIIa concentrate versus plasma derived concentrates for the treatment of acute bleeding episodes in people with haemophilia and inhibitors.