An Open Label Study to Determine the Safety and Efficacy of Replacement Factor VIII Protein (Known as rFVIIIFc) in Previously Untreated Males With Severe Hemophilia A

An Open-Label, Multicenter Evaluation of the Safety and Efficacy of Recombinant Coagulation Factor VIII Fc Fusion Protein (rFVIIIFc; BIIB031) in the Prevention and Treatment of Bleeding in Previously Untreated Patients With Severe Hemophilia A

The primary objective of the study was to evaluate the safety of rFVIIIFc (BIIB031) in previously untreated participants (PUPs) with severe hemophilia A. The secondary objectives were to evaluate the efficacy of rFVIIIFc in the prevention and treatment of bleeding episodes in PUPs, to evaluate rFVIIIFc consumption for the prevention and treatment of bleeding episodes in PUPs, and to describe experience with the use of rFVIIIFc for immune tolerance induction (ITI) in participants with inhibitors.

Study Overview

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

• Study Type: Interventional
• Enrollment (Actual): 108
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Brisbane, Australia, 4029
    • Research Site
  • Parkville, Australia, 3052
    • Research Site
  • Perth, Australia, 6008
    • Research Site
  • Westmead, Australia, 2145
    • Research Site
• Brazil
  • Campinas, Brazil, 13083-878
    • Research Site
  • Canoas, Brazil, 92425-900
    • Research Site
  • Ribeirão Preto, Brazil, 14048-900
    • Research Site
  • Rio de Janeiro, Brazil, 20211-030
    • Research Site
  • São Paulo, Brazil, 01227-200
    • Research Site
• Canada
  • Hamilton, Canada, L8S 4K1
    • Research Site
  • London, Canada, N6A 4G5
    • Research Site
  • Toronto, Canada, M5G 1X8
    • Research Site
• France
  • Caen cedex 9, France, 14033
    • Research Site
  • Le Kremlin Bicêtre cedex, France, 94270
    • Research Site
  • Lille Cedex, France, 59037
    • Research Site
  • Nantes Cedex 1, France, 44093
    • Research Site
  • Strasbourg, France, 67200
    • Research Site
  • Toulouse cedex, France, 31059
    • Research Site
  • Tours cedex 9, France, 37044
    • Research Site
• Germany
  • Berlin, Germany, 13353
    • Research Site
  • Bonn, Germany, 53127
    • Research Site
  • Duesseldorf, Germany, 40225
    • Research Site
  • Frankfurt, Germany, 60590
    • Research Site
  • Hannöver, Germany, 30625
    • Research Site
• Ireland
  • Dublin, Ireland, D12 N512
    • Research Site
• Italy
  • Bari, Italy, 70123
    • Research Site
  • Florence, Italy, 50134
    • Research Site
  • Genova, Italy, 16148
    • Research Site
  • Milan, Italy, 20122
    • Research Site
  • Napoli, Italy, 80123
    • Research Site
  • Padova, Italy, 35128
    • Research Site
  • Rome, Italy, 161
    • Research Site
  • Rome, Italy, 165
    • Research Site
  • VI
    • Vicenza, VI, Italy, 36100
      • Research Site
• Netherlands
  • Leiden, Netherlands, 2333 ZA
    • Research Site
  • Utrecht, Netherlands, 3584 CX
    • Research Site
• New Zealand
  • Auckland, New Zealand, 1023
    • Research Site
  • Christchurch, New Zealand, 8011
    • Research Site
• Poland
  • Gdansk, Poland, 80-952
    • Research Site
  • Kraków, Poland, 30-663
    • Research Site
  • Lublin, Poland, 20-093
    • Research Site
  • Warszawa, Poland, 02-091
    • Research Site
• Spain
  • Barcelona, Spain, 08035
    • Research Site
  • Madrid, Spain, 28046
    • Research Site
• Sweden
  • Stockholm, Sweden, 171 76
    • Research Site
• United Kingdom
  • Cardiff, United Kingdom, CF14 4XW
    • Research Site
  • London, United Kingdom, WC1N3JH
    • Research Site
  • Sheffield, United Kingdom, S10 2TH
    • Research Site
  • Cambridgeshire
    • Cambridge, Cambridgeshire, United Kingdom, CB2 0QQ
      • Research Site
  • Hampshire
    • Basingstoke, Hampshire, United Kingdom, RG24 9NA
      • Research Site
  • London
    • Whitechapel, London, United Kingdom, E1 1BB
      • Research Site
• United States
  • Arkansas
    • Little Rock, Arkansas, United States, 72202
      • Research Site
  • California
    • Duarte, California, United States, 91010
      • Research Site
    • Sacramento, California, United States, 95817
      • Research Site
    • San Francisco, California, United States, 94143
      • Research Site
    • Torrance, California, United States, 90509
      • Research Site
  • Indiana
    • Indianapolis, Indiana, United States, 46260
      • Research Site
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • Research Site
  • Maine
    • Brewer, Maine, United States, 04412
      • Research Site
  • Michigan
    • East Lansing, Michigan, United States, 48823
      • Research Site
  • Minnesota
    • Minneapolis, Minnesota, United States, 55404
      • Research Site
  • Missouri
    • Saint Louis, Missouri, United States, 63104
      • Research Site
  • New York
    • Buffalo, New York, United States, 14209
      • Research Site
    • New York, New York, United States, 10065
      • Research Site
    • Rochester, New York, United States, 14621
      • Research Site
  • Ohio
    • Columbus, Ohio, United States, 43205
      • Research Site
  • Oregon
    • Portland, Oregon, United States, 97239
      • Research Site
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Research Site
  • Texas
    • Dallas, Texas, United States, 75230
      • Research Site
    • Dallas, Texas, United States, 75235
      • Research Site
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 5 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Key Inclusion Criteria:

• Ability of the participant's legally authorized representative (e.g. their parent or legal guardian) to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use confidential health information in accordance with national and local participant privacy regulations.
• Weight >=3.5 kg at the time of screening.
• Severe hemophilia A defined as less than (<) 1 IU/dL (<1%) endogenous FVIII documented in the medical record or as tested during the Screening Period.

Key Exclusion Criteria:

• Any exposure to blood components, factor VIII replacement products, including commercially available rFVIIIFc at any time prior to or during screening.
• History of positive inhibitor testing. A prior history of inhibitors was defined based on a patient's historical positive inhibitor test using the local laboratory Bethesda value for a positive inhibitor test (ie, equal to or above lower level of detection).
• History of hypersensitivity reactions associated with any rFVIIIFc administration.
• Other coagulation disorder(s) in addition to hemophilia A.
• Any concurrent clinically significant major disease that, in the opinion of the Investigator, would make the participant unsuitable for enrollment.
• Current systemic treatment with chemotherapy and/or other immunosuppressant drugs.

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

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: rFVIIIFc; Participants were to receive rFVIIIFc as follows- Prophylaxis regimen (PR): rFVIIIFc 25-80 international units per kilogram (IU/kg), at 3- to 5-day intervals until participant reached greater than or equal to (>=) 50 exposure days (ED: 24-hour period in which >=1 injection/dose of rFVIIIFc was given), or study withdrawal/end of study. Adjustments to dose/dosing interval was done as needed by investigator; Treatment with an optional ER (Episodic regimen) can be initiated before PR at investigators discretion; ITI: rFVIIIFc 200 IU/kg, daily for participants who, after exposure to rFVIIIFc, had positive high titer inhibitor (>=5.00 Bethesda Units per milliliter [BU/mL]) or positive low titer inhibitor (>=0.60 and <5.00 BU/mL) and had poorly controlled bleeding despite increased rFVIIIFc doses, or required bypassing agent to treat bleeding.

Biological: rFVIIIFc; Administered as specified in arm description; Other Names: Eloctate; BIIB031; efmoroctocog alfa; recombinant coagulation factor VIII Fc fusion protein; antihemophilic factor [recombinant]; Fc fusion protein

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Confirmed Inhibitor Development as Measured by the Nijmegen-Modified Bethesda Assay	A positive/confirmed inhibitor result occurs when a participant has a value >=0.6 BU/mL by central laboratory testing using Nijmegen-modified Bethesda assay, that is confirmed on re-testing of a separate sample collected >=2 weeks after the initial sample. Confirmed inhibitor development was based on all participants who had reached >=10 EDs and had >=1 inhibitor test performed at or beyond this milestone or who had an inhibitor. Exposure day (ED) is a 24-hour period in which participant received >=1 dose of rFVIIIFc injections. Participants who did not develop an inhibitor but reached the milestone number of EDs were included in the denominator during calculation of percentage. Additionally, any participant who developed an inhibitor following the initial rFVIIIFc administration was included in the numerator and denominator during calculation of percentage.	Up to 3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Annualized Number of Bleeding Episodes (Spontaneous and Traumatic) Per Participant (Annualized Bleeding Rate [ABR])	ABR was annualized number of bleeding episodes during efficacy period (EP) per participant annualized to a 1-year interval of time. Bleeding episodes were classified as spontaneous if parent/caregiver/participant records bleeding event when there is no known contributing factor such as definite trauma or antecedent "strenuous" activity and as traumatic when there is known reason for bleed. ABR=(Number of bleeding episodes during EP divided by total number of days during EP)*365.25. EP was sum of all intervals of time during which participants were treated with rFVIIIFc per treatment regimens of study excluding surgical/rehabilitation periods and large injection intervals (greater than [>]28 days). Participants were included in summary of more than 1 treatment regimen if their regimen changed during study.	Up to 3 years
Annualized Number of Spontaneous Joint Bleeding Episodes	Bleeding episodes were classified as spontaneous if parent/caregiver/participant records a bleeding event when there was no known contributing factor such as a definite trauma or antecedent "strenuous" activity. Annualized spontaneous joint bleeding episodes = (Total number of spontaneous joint bleeding episodes during EP divided by total number of days during EP)*365.25. EP reflects sum of all intervals of time during which participants were treated with rFVIIIFc per treatment regimen excluding major and minor surgical/rehabilitation periods and large injection intervals (> 28 days). Bleeding episodes were summarized by treatment regimen. Participants were included in summary of more than 1 treatment regimen if their regimen changed during study.	Up to 3 years
Number of rFVIIIFc Injections With Excellent or Good, Moderate or None Treatment Response Assessed Using a 4-Point Scale	Using e-diary, each participant's parent/caregiver rated treatment response to any bleeding episode at approximately 8-12 hours from time of injection and prior to additional doses of rFVIIIFc given for same bleeding episodes, using 4-point scale: 1=Excellent: abrupt pain relief and/or improvement in signs of bleeding within approximately 8 hour after initial injection; 2=Good: definite pain relief and/or improvement in signs of bleeding within approximately 8 hour after injection, but possibly requiring more than 1 injection after 24-48 hour for complete resolution; 3=Moderate: Probable/slight beneficial effect within 8 hour after initial injection and requires more than 1 injection and 4=None: No improvement or condition worsens within approximately 8 hour after initial injection. Participants included in more than 1 treatment regimen if their regimen changed during study.	Up to 3 years
Total Number of Exposure Days (EDs)	An ED was defined as a 24-hour period in which a participant received one or more doses of rFVIIIFc injections, with the time of the first injection of rFVIIIFc defined as the start of the ED. Participants who did not have a particular injection type were counted as having zero injections for that type.	Up to 3 years
Total Annualized rFVIIIFc Consumption Per Participant for the Prevention and Treatment of Bleeding Episodes	Total annualized rFVIIIFc consumption (in IU/kg) was calculated for each participant as: Annualized consumption = (Total IU/kg of rFVIIIFc during EP divided by total number of days during EP)*365.25. EP reflects the sum of all intervals of time during which participants are treated with rFVIIIFc according to the treatment regimens of the study excluding surgical/rehabilitation periods and large injection intervals (>28 days). Participants were included in summary of more than 1 treatment regimen if their regimen changed during study.	Up to 3 years
Number of Injections of rFVIIIFc Required to Resolve a Bleeding Episode	Number of Injections of rFVIIIFc required to resolve a bleeding episode during EP were reported. EP reflects the sum of all intervals of time during which participants were treated with rFVIIIFc according to the treatment regimens of the study excluding surgical/rehabilitation periods and large injection intervals (>28 days). All injections given from the initial sign of a bleed, until the last date/time within the bleed window were counted. Participants were included in summary of more than 1 treatment regimen if their regimen changed during study.	Up to 3 years
Average Dose Per Injection of rFVIIIFc Required to Resolve a Bleeding Episode	The average dose of rFVIIIFc per injection per bleeding episode was calculated as the average of all doses (IU/kg) administered to treat the bleeding episode during EP. EP begins with the first treatment regimen dose of rFVIIIFc and ends with the last dose (regardless of the reason for dosing). Surgery/rehabilitation periods were not included in the EP. Participants were included in summary of more than 1 treatment regimen if their regimen changed during study.	Up to 3 years
Change From Baseline in rFVIIIFc Incremental Recovery (IR)	Blood samples were taken at trough (predose) and Cmax (maximum concentration) for assessment of incremental recovery, measured by the one-stage clotting assay. IR (International Units per deciliter [IU/dL] per IU/kg) = (Cmax for FVIII activity - Pre-dose FVIII activity) (IU/dL) divided by actual dose (IU/kg), where Cmax (maximum concentration) is 30-minute FVIII activity post-dose and FVIII activity less than (<)0.5 IU/dL was set to 0 IU/dL for calculation of IR.	Baseline, Weeks 12, 24, 36, 48, 60, 72, 84, 96, 108 and 120
Number of Participants With Response to Immune Tolerance Induction (ITI)	Complete Success was defined as meeting all of the following criteria: Negative inhibitor titers in 2 consecutive determinations at least 4 weeks apart; IR >=66% of baseline in 2 consecutive determinations at least 4 weeks apart; Half life >=6 hours. Partial Success was defined as meeting the first criteria for complete success and one of the other 2 after 33 months of ITI.	Up to 3 years

Collaborators and Investigators

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

Publications and helpful links

General Publications

• Konigs C, Ozelo MC, Dunn A, Kulkarni R, Nolan B, Brown SA, Schiavulli M, Gunawardena S, Mukhopadhyay S, Jayawardene D, Winding B, Carcao M. First study of extended half-life rFVIIIFc in previously untreated patients with hemophilia A: PUPs A-LONG final results. Blood. 2022 Jun 30;139(26):3699-3707. doi: 10.1182/blood.2021013563.

Study record dates

Study Major Dates

• Study Start (Actual): January 12, 2015
• Primary Completion (Actual): September 23, 2019
• Study Completion (Actual): September 23, 2019

Study Registration Dates

• First Submitted: August 29, 2014
• First Submitted That Met QC Criteria: September 5, 2014
• First Posted (Estimate): September 9, 2014

Study Record Updates

• Last Update Posted (Actual): April 11, 2022
• Last Update Submitted That Met QC Criteria: March 15, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: Hemophilia; Hemophilia A; prophylaxis treatment; episodic treatment
• 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: 997HA306; 2013-005512-10 (EudraCT Number)

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