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

Hemophilia A Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02234323
• Other study ID #: 997HA306
• Secondary ID: 2013-005512-10
• Status: Completed
• Phase: Phase 3
• Start date: January 12, 2015
• Est. completion date: September 23, 2019

Study information

• Verified date: March 2022
• Source: Sanofi
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 108
• Est. completion date: September 23, 2019
• Est. primary completion date: September 23, 2019
• Accepts healthy volunteers: No
• Gender: Male
• Age group: N/A to 5 Years

Eligibility

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.

Related Conditions & MeSH terms

• Hemophilia A

Intervention

Biological:
• rFVIIIFc
Administered as specified in arm description

Locations

Country	Name	City	State
Australia	Research Site	Brisbane
Australia	Research Site	Parkville
Australia	Research Site	Perth
Australia	Research Site	Westmead
Brazil	Research Site	Campinas
Brazil	Research Site	Canoas
Brazil	Research Site	Ribeirão Preto
Brazil	Research Site	Rio de Janeiro
Brazil	Research Site	São Paulo
Canada	Research Site	Hamilton
Canada	Research Site	London
Canada	Research Site	Toronto
France	Research Site	Caen cedex 9
France	Research Site	Le Kremlin Bicêtre cedex
France	Research Site	Lille Cedex
France	Research Site	Nantes Cedex 1
France	Research Site	Strasbourg
France	Research Site	Toulouse cedex
France	Research Site	Tours cedex 9
Germany	Research Site	Berlin
Germany	Research Site	Bonn
Germany	Research Site	Duesseldorf
Germany	Research Site	Frankfurt
Germany	Research Site	Hannöver
Ireland	Research Site	Dublin
Italy	Research Site	Bari
Italy	Research Site	Florence
Italy	Research Site	Genova
Italy	Research Site	Milan
Italy	Research Site	Napoli
Italy	Research Site	Padova
Italy	Research Site	Rome
Italy	Research Site	Rome
Italy	Research Site	Vicenza	VI
Netherlands	Research Site	Leiden
Netherlands	Research Site	Utrecht
New Zealand	Research Site	Auckland
New Zealand	Research Site	Christchurch
Poland	Research Site	Gdansk
Poland	Research Site	Kraków
Poland	Research Site	Lublin
Poland	Research Site	Warszawa
Spain	Research Site	Barcelona
Spain	Research Site	Madrid
Sweden	Research Site	Stockholm
United Kingdom	Research Site	Basingstoke	Hampshire
United Kingdom	Research Site	Cambridge	Cambridgeshire
United Kingdom	Research Site	Cardiff
United Kingdom	Research Site	London
United Kingdom	Research Site	Sheffield
United Kingdom	Research Site	Whitechapel	London
United States	Research Site	Brewer	Maine
United States	Research Site	Buffalo	New York
United States	Research Site	Columbus	Ohio
United States	Research Site	Dallas	Texas
United States	Research Site	Dallas	Texas
United States	Research Site	Duarte	California
United States	Research Site	East Lansing	Michigan
United States	Research Site	Indianapolis	Indiana
United States	Research Site	Little Rock	Arkansas
United States	Research Site	Louisville	Kentucky
United States	Research Site	Milwaukee	Wisconsin
United States	Research Site	Minneapolis	Minnesota
United States	Research Site	New York	New York
United States	Research Site	Philadelphia	Pennsylvania
United States	Research Site	Portland	Oregon
United States	Research Site	Rochester	New York
United States	Research Site	Sacramento	California
United States	Research Site	Saint Louis	Missouri
United States	Research Site	San Francisco	California
United States	Research Site	Torrance	California

Sponsors (2)

Lead Sponsor	Collaborator
Bioverativ, a Sanofi company	Swedish Orphan Biovitrum

Countries where clinical trial is conducted

United States,  Australia,  Brazil,  Canada,  France,  Germany,  Ireland,  Italy,  Netherlands,  New Zealand,  Poland,  Spain,  Sweden,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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