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

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

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 Overview

• Status: Recruiting
• Conditions: Hemophilia A
• Intervention / Treatment: Drug: aPCC-emicizumab; Drug: FEIBA; Drug: rFVIIa

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 Type: Interventional
• Enrollment (Estimated): 20
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Robert Sidonio, MD; Phone Number: 404-785-1637; Email: robert.sidonio.jr@emory.edu

Study Locations

• United States
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Recruiting
      • Emory University Hospital
    • Atlanta, Georgia, United States, 30322
      • Recruiting
      • Children's Healthcare of Atlanta
      • Contact: Robert Sidonio, MD; Phone Number: 404-785-1637; Email: robert.sidonio.jr@emory.edu

Participation Criteria

Eligibility Criteria

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

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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 Names: 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 Names: 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Emory University
• Collaborators: Takeda Pharmaceuticals North America, Inc.
• Investigators: Principal Investigator: Robert Sidonio, MD, Emory University

Study record dates

Study Major Dates

• Study Start (Estimated): May 1, 2024
• Primary Completion (Estimated): September 1, 2025
• Study Completion (Estimated): September 1, 2025

Study Registration Dates

• First Submitted: September 21, 2020
• First Submitted That Met QC Criteria: September 21, 2020
• First Posted (Actual): September 24, 2020

Study Record Updates

• Last Update Posted (Actual): March 28, 2024
• Last Update Submitted That Met QC Criteria: March 27, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: safety; hemostatic efficacy; prothrombin complex concentrate
• Additional Relevant MeSH Terms: Hematologic Diseases; Blood Coagulation Disorders, Inherited; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Blood Coagulation Disorders; Hemophilia A; Anti-inhibitor coagulant complex; Coagulants
• Other Study ID Numbers: STUDY00000804

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All of the individual participant data collected during the trial, after de-identification, will be available
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• 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