SAFE Study: Safety of aPCC Following Emicizumab Prophylaxis

Study Overview
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Brief Summary
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The purpose of the aPCC-emicizumab safety study is to prospectively investigate the safety and hemostatic efficacy of a personalized dose of aPCC in children and adults with hemophilia A and inhibitors on emicizumab prophylaxis during acute bleeding events or prior to procedures.

Detailed Description
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The previous standard of care for high titer antibody eradication in hemophilia A (HA) included a labor-intensive, immune tolerance induction (ITI) regimen administered with concomitant bypassing agent (BPA) prophylaxis, either daily recombinant activated factor VII (rFVIIa) or at least 3 non-consecutive days of activated prothrombin complex concentrate (aPCC) given intravenously (IV) each week. The purpose of the aPCC-emicizumab safety study is to prospectively investigate the safety and hemostatic efficacy of a personalized dose of aPCC in children and adults with hemophilia A and inhibitors on emicizumab prophylaxis during acute bleeding events or prior to procedures.

Official Title
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aPCC and Emicizumab Safety Study in Congenital Hemophilia A Patients With Inhibitors (SAFE Study: Safety of aPCC Following Emicizumab Prophylaxis)

Conditions
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Hemophilia A

Intervention / Treatment
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* Drug: aPCC-emicizumab
* Drug: FEIBA
* Drug: rFVIIa


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Moderately severe hemophilia A, defined as FVIII level <0.02 IU/mL in the central laboratory prior to development of an inhibitor Age ≥6 years of age at time of informed consent Documented on 2 occasions a high titer inhibitor (>5 BU/mL) with a 72-hour washout within 2 years of enrollment Parent/guardian (caregiver henceforth) or patient has provided written informed consent Adequate hematologic function (Hgb >8 g/dL and platelet count >100,000 µL) Adequate hepatic function (total bilirubin ≤1.5 x ULN and both AST/ALT ≤3x ULN at screening (excluding known Gilbert's) Adequate renal function (≤2.5 x ULN and CrCl ≥30 mL/min) Exclusion Criteria: Inherited or acquired bleeding disorder other than hemophilia A excluding low VWF (>30% VWF:RCo or VWF:GP1bm) Previous or current treatment for thromboembolic disease or signs of thromboembolic disease (excluding previous resolved line associated thrombosis) Conditions that may increase risk of bleeding or thrombosis History of clinically significant hypersensitivity associated with monoclonal antibody therapies or components of the emicizumab injection Known HIV infection with CD4 count <200 cells/µL within 24 weeks prior to screening. Testing not required if <35 years of age. Use of systemic immunomodulators at enrollment or planned use during the study Participants who are at high risk for TMA (for example, have a previous medical/family history of TMA), in the investigator's judgment Concurrent disease, treatment, or abnormality in clinical laboratory tests that could interfere with the conduct of the study, may pose additional risk, or would, in the opinion of the investigator, preclude the participant's safe participation in and completion of the study Every effort will be made to include participants that are considering minor and major procedures over the next 2 years to capture this important data with the goal of 10 procedures.

Ages Eligible for Study
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Minimum Age: 6 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental treatment<br>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. | Drug: aPCC-emicizumab<br>* 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.<br>* Other names: ACE910, Hemlibra and RO5534262;Drug: FEIBA<br>* FEIBA is an Anti-Inhibitor Coagulant Complex indicated for use in hemophilia patients with inhibitors for: control and prevention of bleeding episodes, perioperative management, routine prophylaxis to prevent or reduce the frequency of bleeding episodes. If there is less than a good' response in bleed event at 48 hours or less than moderate for surgical event control, the local PI can consider the use of thrombin generation guided rFVIIa with a max dose of no more than 90 µg/kg/dose every 8 hours for 72 hours, with wean to occur for no more than 7 total days.<br>* Other names: Anti-Inhibitor Coagulant Complex;Drug: rFVIIa<br>* rFVIIa is a coagulation factor VIIa concentrate indicated for the treatment and control of bleeding episodes occurring in adults and adolescents with hemophilia with inhibitors.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of serious adverse events | Number of serious adverse events will be recorded | up to 2 years | 
| Number of serious bleeding episodes | Number of serious bleeding episodes will be recorded | up to 2 years | 
| Number of episodes of thrombotic events including thrombotic microangiopathy (TMA) | Number of episodes of thrombotic events including thrombotic microangiopathy (TMA) will be recorded | up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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 will be recorded. | up to 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hemostatic efficacy, safety, prothrombin complex concentrate