A Study to Evaluate Efficacy of rFVIIIFc for Immune Tolerance Induction (ITI) in Severe Hemophilia A Participants With Inhibitors Undergoing the First ITI Treatment (verITI-8 Study)

A Non-controlled, Open-Label, Multicenter, Study of Efficacy of rFVIIIFc for Immune Tolerance Induction (ITI) in Severe Hemophilia A Subjects With Inhibitors Undergoing the First ITI Treatment

The primary purpose of this study was to describe the time to tolerization (i.e., ITI success) with rFVIIIFc in participants within a maximum of 48 weeks (12 months) of ITI treatment.

Study Overview

• Status: Completed
• Conditions: Hemophilia A With Inhibitors
• Intervention / Treatment: Biological: rFVIIIFc

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 4

Contacts and Locations

Study Locations

• Belgium
  • Bruxelles, Belgium, 1200
    • Cliniques Universitaires Saint-Luc
  • Leuven, Belgium, 3000
    • UZ Leuven
• Bulgaria
  • Plovdiv, Bulgaria, 4000
    • UMHAT "Sv. Georgi", EAD
  • Sofia, Bulgaria, 1527
    • UMHAT 'Tsaritsa Yoanna - ISUL', EAD
• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V6H 3N1
      • Children's & Women's Health Centre of British Columbia
  • Ontario
    • Hamilton, Ontario, Canada, L8N 3Z5
      • McMaster Children's Hospital
    • Toronto, Ontario, Canada, M5G 1X8
      • The Hospital for Sick Children
• France
  • Paris, France, 75015
    • Hopital Necker - Enfants Malades
  • Bouches-Du-Rhône
    • Marseille, Bouches-Du-Rhône, France, 13385
      • hopital de la Timone
  • Doubs
    • Besançon, Doubs, France, 25030
      • CHU Besançon - Hôpital Jean Minjoz
  • Haute Garonne
    • Toulouse, Haute Garonne, France, 31059
      • CHU de Toulouse - Hôpital Purpan
  • Nord
    • Lille, Nord, France, 59037
      • Hemostase Clinique - Institut Cœur-Poumons (4eme étage aile est)
• Germany
  • North Rhine-Westphalia
    • Bonn, North Rhine-Westphalia, Germany, 53127
      • Universitaetsklinikum Bonn AoeR
• Italy
  • Milano, Italy, 20122
    • Fondazione Irccs Ca' Granda Ospedale Maggiore Policlinico
  • Napoli, Italy, 80122
    • Azienda Ospedaliera Pediatrica Santobono Pausillipon
  • Vicenza, Italy, 36100
    • Ospedale San Bortolo di Vicenza
• Japan
  • Aichi-Ken
    • Nagoya-shi, Aichi-Ken, Japan, 466-8550
      • Nagoya University Hospital
  • Kanagawa-Ken
    • Kawasaki, Kanagawa-Ken, Japan, 216-8511
      • St. Marianna University School of Medicine Hospital
  • Nara-Ken
    • Kashihara-Shi, Nara-Ken, Japan, 634-8521
      • Nara Medical University Hospital
• Spain
  • Barcelona, Spain, 8035
    • Hospital Universitari Vall d'Hebron
  • Madrid, Spain, 28046
    • Hospital Universitario La Paz
  • Valencia, Spain, 46026
    • Hospital Universitari i Politecnic La Fe
• United Kingdom
  • Greater London
    • London, Greater London, United Kingdom, SE1 7EH
      • St Thomas' Hospital
  • Oxfordshire
    • Oxford, Oxfordshire, United Kingdom, OX3 9DU
      • John Radcliffe Hospital
  • Strathclyde
    • Glasgow, Strathclyde, United Kingdom, G514TF
      • Royal Hospital For Children
• United States
  • California
    • Orange, California, United States, 92868
      • Center for Inherited Blood Disorders
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Hemophilia & Thrombosis Center
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Children's National Medical Center
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
  • Indiana
    • Indianapolis, Indiana, United States, 46260
      • Indiana Hemophilia and Thrombosis Center
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Children's Hospital
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Childrens Hospital of Michigan
  • Ohio
    • Dayton, Ohio, United States, 45404
      • Dayton Children's Hospital
  • Texas
    • El Paso, Texas, United States, 79905
      • El Paso Children's Hospital
    • Fort Worth, Texas, United States, 76104
      • Cook Children's Medical Center
    • Houston, Texas, United States, 77030
      • Gulf States Hemophilia and Thrombophilia Center
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Blood Center of Southeast Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Ability of the participant or his legally authorized representative (e.g., parent or legal guardian) to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information in accordance with national and local participant privacy regulations
• Male participants of any age diagnosed with severe hemophilia A (as confirmed from the medical record)
• Currently diagnosed with high titer inhibitors (historical peak greater than or equal to (>=) 5 Bethesda units per milliliter (BU/mL), according to medical records)
• Previously treated with any plasma-derived or recombinant conventional or Extended Half-Life FVIII

Exclusion Criteria:

• Other coagulation disorder(s) in addition to hemophilia A
• Previous immune tolerance induction (ITI)
• History of hypersensitivity or anaphylaxis associated with any factor VIII (FVIII) administration
• Planned major surgery scheduled during the study unless deferred until after study completion (minor surgery such as tooth extraction or insertion/replacement of central venous access device is allowed)
• Abnormal renal function (serum creatinine >1.5 milligram per deciliter (mg/dL) or 2 × upper limit of normal (ULN) for participant age based on local laboratory range) as assessed by local laboratory
• Serum alanine aminotransferase or aspartate aminotransferase > 5 × upper limit of normal (ULN) as assessed by local laboratory

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: Recombinant coagulation factor VIII Fc (rFVIIIFc); Participants were to receive rFVIIIFc at a dose of 200 international units (IU)/kilogram (kg) as once daily injections or divided on several injections per day at the discretion of the Investigator, starting at baseline visit up to maximum of 48 Weeks in ITI Period. Participants who met the criteria for immune tolerance induction (ITI) success entered the tapering period and received rFVIIIFc at a dose adjusted according to Investigator judgment based on the FVIII activity levels and with the aim of tapering the rFVIIIFc dose to reach a prophylactic dosing regimen within 16 weeks (4 months). Follow-Up was for 32 weeks under an adjusted prophylactic regimen according to Investigator judgment.

Biological: rFVIIIFc; rFVIIIFc 200 IU/kg/day in ITI Period, 50 or 100 IU/kg (adjusted according to Investigator judgement) in tapering Period, and prophylactic regimen in Follow-Up period as powder for injection administered intravenously.; Other Names: Fc fusion protein; ELOCTATE/ELOCTA; BIIB031; efmoroctocog alfa; antihemophilic factor [recombinant]

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Tolerization With rFVIIIFc	Time required for participants to achieve immune tolerance induction (ITI) success where ITI success is defined as achieving all 3 of the following criteria: confirmed negative titers consisting of 2 consecutive negative inhibitor assessments within 2 weeks (less than [<] 0.6 Bethesda units/milliliter [mL] by the Nijmegen-modified Bethesda assay); incremental recovery (IR) greater than or equal to (>=) 66 percent (%) of the expected IR in 2 consecutive assessments; half-life (t½) >= 7 hours.	Up to 48 Weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Immune Tolerance Induction (ITI) Success	Number of participants who achieve ITI success where ITI success is defined as achieving all 3 of the following criteria: confirmed negative titers consisting of 2 consecutive negative inhibitor assessments within 2 weeks (<0.6 Bethesda units/mL by the Nijmegen-modified Bethesda assay); incremental recovery (IR) >= 66% of the expected IR at 2 consecutive assessments; half-life (t½) >=7 hours.	Up to 48 Weeks
Number of Participants Who Experienced Relapse	Number of Participants with ITI success who reaches the criteria for relapse (defined as confirmed positive inhibitor titer >= 0.6 BU/mL or abnormal recovery after tolerance is achieved, and t½ less than [<] 7 hours) evaluated during the Tapering or Follow-Up Periods	Up to 48 weeks (16 weeks Tapering period and 32 weeks follow-up period)
Annualized Bleeding Rates During ITI Period	A bleeding episode started from the first sign of a bleed and ended no more than 72 hours after the last treatment for the bleed, within which any symptoms of bleeding at the same location or injections less than or equal to 72 hours apart were considered the same bleeding episode. Annualized bleeding rate for a patient during the ITI period is defined as the number of bleeding episodes divided by the length of the ITI period in days* 365.25.	Up to 48 weeks
Annualized Bleeding Rates After ITI Period	A bleeding episode started from the first sign of a bleed and ended no more than 72 hours after the last treatment for the bleed, within which any symptoms of bleeding at the same location or injections less than or equal to 72 hours apart were considered the same bleeding episode. Annualized bleeding rate for a patient after the ITT period (for tapering and follow-up period) is defined as the number of bleeding episodes divided by the length of the period after the ITI period in days* 365.25.	Up to 48 weeks (16 weeks Tapering period and 32 weeks follow-up period)
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (TESAEs) as a Measure of Safety and Tolerability	An AE is any untoward medical occurrence that does not necessarily have a causal relationship with this treatment. An SAE is any untoward medical occurrence that at any dose: results in death; in the view of the Investigator, places the participant at immediate risk of death (a life-threatening event); requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; results in a congenital anomaly/birth defect; any other medically important event that, in the opinion of the Investigator, may jeopardize the participant or may require intervention to prevent one of the other outcomes listed in the definition.	Up to 2 Years
Average Number of Days Missed From Work or School Per Month During ITI Period	Average number of days missed from school or work per month for a period (counting in non-missing diary days) is defined as number of the missing school/work days in the period divided by number of days with data entry in the period. Number of days per month missed from school or work is reported for those who attend school or have a job.	Up to 48 weeks
Average Number of Days Missed From Work or School Per Month After ITI Period	Average number of days missed from school or work per month for a period (counting in non-missing diary days) is defined as number of the missing school/work days in the period divided by number of days with data entry in the period. Number of days per month missed from school or work is reported for those who attend school or have a job.	Up to 48 weeks (16 weeks Tapering period & 32 weeks Follow-up period)
Annualized Number of Hospitalization Days During ITI Period	Annualized number of hospitalization days during a period for a patient is defined as the number of hospitalization days divided by the length of the period in days * 365.25.	Up to 48 weeks
Annualized Number of Hospitalization Days After ITI Period	Annualized number of hospitalization days during a period for a patient is defined as the number of hospitalization days divided by the length of the period in days * 365.25.	Up to 48 weeks (16 weeks Tapering period & 32 weeks Follow-up period)
Adherence to Treatment Regimen Overall Study Period	Adherence to treatment is based on prescribed daily dose for the overall study period which is defined as the percentage of administered doses versus the prescribed doses to a patient for the entire study duration.	Up to 2 Years
Annualized rFVIIIFc Consumption for Overall Study Period	Annualized rFVIIIFc consumption for a treatment period is the total nominal rFVIIIFc (IU/kg) / length of period in days * 365.25.	Up to 2 Years

Collaborators and Investigators

• Sponsor: Bioverativ, a Sanofi company
• Collaborators: Swedish Orphan Biovitrum

Study record dates

Study Major Dates

• Study Start (Actual): December 8, 2017
• Primary Completion (Actual): May 4, 2020
• Study Completion (Actual): February 16, 2021

Study Registration Dates

• First Submitted: March 10, 2017
• First Submitted That Met QC Criteria: March 22, 2017
• First Posted (Actual): March 28, 2017

Study Record Updates

• Last Update Posted (Actual): March 28, 2022
• Last Update Submitted That Met QC Criteria: March 21, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Hematologic Diseases; Blood Coagulation Disorders, Inherited; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Blood Coagulation Disorders; Hemophilia A; Coagulants; Factor VIII
• Other Study ID Numbers: LPS16473; 2017-000373-36 (EudraCT Number); 997HA402 (Other Identifier: Bioverativ Therapeutics Inc.)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org

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