SAFE Study: Safety of aPCC Following Emicizumab Prophylaxis (SAFE)

• ClinicalTrials.gov Identifier: NCT04563520
• Recruitment Status: Not yet recruiting
• First Posted: September 24, 2020
• Last Update Posted: January 6, 2023
• Sponsor: Emory University
• Collaborator: Takeda Pharmaceuticals North America, Inc.
• Information provided by (Responsible Party): Robert Sidonio, Emory University

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Hemophilia A	Drug: aPCC-emicizumab; Drug: FEIBA; Drug: rFVIIa	Phase 3

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 20 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: aPCC and Emicizumab Safety Study in Congenital Hemophilia A Patients With Inhibitors (SAFE Study: Safety of aPCC Following Emicizumab Prophylaxis)
• Estimated Study Start Date: March 2023
• Estimated Primary Completion Date: September 2023
• Estimated Study Completion Date: September 2023

Arms and Interventions

Arm

Intervention/treatment

Experimental: Experimental treatment; 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; 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.; Other Name: ACE910, Hemlibra and RO5534262; Drug: FEIBA; 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.; Other Name: Anti-Inhibitor Coagulant Complex; Drug: rFVIIa; 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.

Outcome Measures

Primary Outcome Measures :

1. Number of serious adverse events [ Time Frame: up to 2 years ]
   Number of serious adverse events will be recorded
2. Number of serious bleeding episodes [ Time Frame: up to 2 years ]
   Number of serious bleeding episodes will be recorded
3. Number of episodes of thrombotic events including thrombotic microangiopathy (TMA) [ Time Frame: up to 2 years ]
   Number of episodes of thrombotic events including thrombotic microangiopathy (TMA) will be recorded

Secondary Outcome Measures :

1. 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 [ Time Frame: up to 2 years ]
   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.

Eligibility Criteria

• Ages Eligible for Study: 6 Years and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Contacts

Contact: Robert Sidonio, MD; 404-785-1637; robert.sidonio.jr@emory.edu

Locations

United States, Georgia

Children's Healthcare of Atlanta

Atlanta, Georgia, United States, 30322

Contact: Robert Sidonio, MD 404-785-1637 robert.sidonio.jr@emory.edu

Emory University Hospital

Atlanta, Georgia, United States, 30322

Sponsors and Collaborators

Emory University

Takeda Pharmaceuticals North America, Inc.

Investigators

• Principal Investigator: Robert Sidonio, MD; Emory University

More Information

• Responsible Party: Robert Sidonio, Principal Investigator, Emory University
• ClinicalTrials.gov Identifier: NCT04563520
• Other Study ID Numbers: STUDY00000804
• First Posted: September 24, 2020
• Last Update Posted: January 6, 2023
• Last Verified: January 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: All of the individual participant data collected during the trial, after de-identification, will be available
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF)

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by Robert Sidonio, Emory University:

hemostatic efficacy; safety; prothrombin complex concentrate

Additional relevant MeSH terms:

Hemophilia A; Blood Coagulation Disorders, Inherited; Blood Coagulation Disorders; Hematologic Diseases; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Coagulants; Anti-inhibitor coagulant complex