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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)

Primary Purpose

Hemophilia A With Inhibitors

Status
Completed
Phase
Phase 4
Locations
International
Study Type
Interventional
Intervention
rFVIIIFc
Sponsored by
Bioverativ, a Sanofi company
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hemophilia A With Inhibitors

Eligibility Criteria

undefined - undefined (Child, Adult, Older Adult)MaleDoes not accept healthy volunteers

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

Sites / Locations

  • Center for Inherited Blood Disorders
  • University of Colorado Hemophilia & Thrombosis Center
  • Children's National Medical Center
  • Rush University Medical Center
  • Indiana Hemophilia and Thrombosis Center
  • University of Iowa Children's Hospital
  • Childrens Hospital of Michigan
  • Dayton Children's Hospital
  • El Paso Children's Hospital
  • Cook Children's Medical Center
  • Gulf States Hemophilia and Thrombophilia Center
  • Blood Center of Southeast Wisconsin
  • Cliniques Universitaires Saint-Luc
  • UZ Leuven
  • UMHAT "Sv. Georgi", EAD
  • UMHAT 'Tsaritsa Yoanna - ISUL', EAD
  • Children's & Women's Health Centre of British Columbia
  • McMaster Children's Hospital
  • The Hospital for Sick Children
  • Hôpital de la Timone
  • CHU Besançon - Hôpital Jean Minjoz
  • CHU de Toulouse - Hôpital Purpan
  • Hemostase Clinique - Institut Cœur-Poumons (4eme étage aile est)
  • Hôpital Necker - Enfants Malades
  • Universitaetsklinikum Bonn AoeR
  • Fondazione IRCCS CA' Granda Ospedale Maggiore Policlinico
  • Azienda Ospedaliera Pediatrica Santobono Pausillipon
  • Ospedale San Bortolo di Vicenza
  • Nagoya University Hospital
  • St. Marianna University School of Medicine Hospital
  • Nara Medical University Hospital
  • Hospital Universitari Vall d'Hebron
  • Hospital Universitario La Paz
  • Hospital Universitari i Politecnic La Fe
  • St Thomas' Hospital
  • John Radcliffe Hospital
  • Royal Hospital for Children

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Recombinant coagulation factor VIII Fc (rFVIIIFc)

Arm Description

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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
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.
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.
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.
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.
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.
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.
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.
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.
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.

Full Information

First Posted
March 10, 2017
Last Updated
March 21, 2022
Sponsor
Bioverativ, a Sanofi company
Collaborators
Swedish Orphan Biovitrum
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1. Study Identification

Unique Protocol Identification Number
NCT03093480
Brief Title
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)
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
March 2022
Overall Recruitment Status
Completed
Study Start Date
December 8, 2017 (Actual)
Primary Completion Date
May 4, 2020 (Actual)
Study Completion Date
February 16, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Bioverativ, a Sanofi company
Collaborators
Swedish Orphan Biovitrum

4. Oversight

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
Data Monitoring Committee
No

5. Study Description

Brief Summary
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hemophilia A With Inhibitors

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
16 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Recombinant coagulation factor VIII Fc (rFVIIIFc)
Arm Type
Experimental
Arm Description
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.
Intervention Type
Biological
Intervention Name(s)
rFVIIIFc
Other Intervention Name(s)
ELOCTATE/ELOCTA; BIIB031; efmoroctocog alfa; antihemophilic factor [recombinant], Fc fusion protein
Intervention Description
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.
Primary Outcome Measure Information:
Title
Time to Tolerization With rFVIIIFc
Description
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.
Time Frame
Up to 48 Weeks
Secondary Outcome Measure Information:
Title
Number of Participants With Immune Tolerance Induction (ITI) Success
Description
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.
Time Frame
Up to 48 Weeks
Title
Number of Participants Who Experienced Relapse
Description
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
Time Frame
Up to 48 weeks (16 weeks Tapering period and 32 weeks follow-up period)
Title
Annualized Bleeding Rates During ITI Period
Description
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.
Time Frame
Up to 48 weeks
Title
Annualized Bleeding Rates After ITI Period
Description
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.
Time Frame
Up to 48 weeks (16 weeks Tapering period and 32 weeks follow-up period)
Title
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (TESAEs) as a Measure of Safety and Tolerability
Description
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.
Time Frame
Up to 2 Years
Title
Average Number of Days Missed From Work or School Per Month During ITI Period
Description
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.
Time Frame
Up to 48 weeks
Title
Average Number of Days Missed From Work or School Per Month After ITI Period
Description
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.
Time Frame
Up to 48 weeks (16 weeks Tapering period & 32 weeks Follow-up period)
Title
Annualized Number of Hospitalization Days During ITI Period
Description
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.
Time Frame
Up to 48 weeks
Title
Annualized Number of Hospitalization Days After ITI Period
Description
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.
Time Frame
Up to 48 weeks (16 weeks Tapering period & 32 weeks Follow-up period)
Title
Adherence to Treatment Regimen Overall Study Period
Description
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.
Time Frame
Up to 2 Years
Title
Annualized rFVIIIFc Consumption for Overall Study Period
Description
Annualized rFVIIIFc consumption for a treatment period is the total nominal rFVIIIFc (IU/kg) / length of period in days * 365.25.
Time Frame
Up to 2 Years

10. Eligibility

Sex
Male
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Clinical Sciences & Operations
Organizational Affiliation
Sanofi
Official's Role
Study Director
Facility Information:
Facility Name
Center for Inherited Blood Disorders
City
Orange
State/Province
California
ZIP/Postal Code
92868
Country
United States
Facility Name
University of Colorado Hemophilia & Thrombosis Center
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
Facility Name
Children's National Medical Center
City
Washington
State/Province
District of Columbia
ZIP/Postal Code
20010
Country
United States
Facility Name
Rush University Medical Center
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60612
Country
United States
Facility Name
Indiana Hemophilia and Thrombosis Center
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
46260
Country
United States
Facility Name
University of Iowa Children's Hospital
City
Iowa City
State/Province
Iowa
ZIP/Postal Code
52242
Country
United States
Facility Name
Childrens Hospital of Michigan
City
Detroit
State/Province
Michigan
ZIP/Postal Code
48201
Country
United States
Facility Name
Dayton Children's Hospital
City
Dayton
State/Province
Ohio
ZIP/Postal Code
45404
Country
United States
Facility Name
El Paso Children's Hospital
City
El Paso
State/Province
Texas
ZIP/Postal Code
79905
Country
United States
Facility Name
Cook Children's Medical Center
City
Fort Worth
State/Province
Texas
ZIP/Postal Code
76104
Country
United States
Facility Name
Gulf States Hemophilia and Thrombophilia Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
Blood Center of Southeast Wisconsin
City
Milwaukee
State/Province
Wisconsin
ZIP/Postal Code
53226
Country
United States
Facility Name
Cliniques Universitaires Saint-Luc
City
Bruxelles
ZIP/Postal Code
1200
Country
Belgium
Facility Name
UZ Leuven
City
Leuven
ZIP/Postal Code
3000
Country
Belgium
Facility Name
UMHAT "Sv. Georgi", EAD
City
Plovdiv
ZIP/Postal Code
4000
Country
Bulgaria
Facility Name
UMHAT 'Tsaritsa Yoanna - ISUL', EAD
City
Sofia
ZIP/Postal Code
1527
Country
Bulgaria
Facility Name
Children's & Women's Health Centre of British Columbia
City
Vancouver
State/Province
British Columbia
ZIP/Postal Code
V6H 3N1
Country
Canada
Facility Name
McMaster Children's Hospital
City
Hamilton
State/Province
Ontario
ZIP/Postal Code
L8N 3Z5
Country
Canada
Facility Name
The Hospital for Sick Children
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 1X8
Country
Canada
Facility Name
Hôpital de la Timone
City
Marseille
State/Province
Bouches-Du-Rhône
ZIP/Postal Code
13385
Country
France
Facility Name
CHU Besançon - Hôpital Jean Minjoz
City
Besançon
State/Province
Doubs
ZIP/Postal Code
25030
Country
France
Facility Name
CHU de Toulouse - Hôpital Purpan
City
Toulouse
State/Province
Haute Garonne
ZIP/Postal Code
31059
Country
France
Facility Name
Hemostase Clinique - Institut Cœur-Poumons (4eme étage aile est)
City
Lille
State/Province
Nord
ZIP/Postal Code
59037
Country
France
Facility Name
Hôpital Necker - Enfants Malades
City
Paris
ZIP/Postal Code
75015
Country
France
Facility Name
Universitaetsklinikum Bonn AoeR
City
Bonn
State/Province
North Rhine-Westphalia
ZIP/Postal Code
53127
Country
Germany
Facility Name
Fondazione IRCCS CA' Granda Ospedale Maggiore Policlinico
City
Milano
ZIP/Postal Code
20122
Country
Italy
Facility Name
Azienda Ospedaliera Pediatrica Santobono Pausillipon
City
Napoli
ZIP/Postal Code
80122
Country
Italy
Facility Name
Ospedale San Bortolo di Vicenza
City
Vicenza
ZIP/Postal Code
36100
Country
Italy
Facility Name
Nagoya University Hospital
City
Nagoya-shi
State/Province
Aichi-Ken
ZIP/Postal Code
466-8550
Country
Japan
Facility Name
St. Marianna University School of Medicine Hospital
City
Kawasaki
State/Province
Kanagawa-Ken
ZIP/Postal Code
216-8511
Country
Japan
Facility Name
Nara Medical University Hospital
City
Kashihara-Shi
State/Province
Nara-Ken
ZIP/Postal Code
634-8521
Country
Japan
Facility Name
Hospital Universitari Vall d'Hebron
City
Barcelona
ZIP/Postal Code
8035
Country
Spain
Facility Name
Hospital Universitario La Paz
City
Madrid
ZIP/Postal Code
28046
Country
Spain
Facility Name
Hospital Universitari i Politecnic La Fe
City
Valencia
ZIP/Postal Code
46026
Country
Spain
Facility Name
St Thomas' Hospital
City
London
State/Province
Greater London
ZIP/Postal Code
SE1 7EH
Country
United Kingdom
Facility Name
John Radcliffe Hospital
City
Oxford
State/Province
Oxfordshire
ZIP/Postal Code
OX3 9DU
Country
United Kingdom
Facility Name
Royal Hospital for Children
City
Glasgow
State/Province
Strathclyde
ZIP/Postal Code
G514TF
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing 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

Learn more about this trial

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)

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