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
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|ClinicalTrials.gov Identifier: NCT02234323|
Recruitment Status : Completed
First Posted : September 9, 2014
Results First Posted : August 13, 2020
Last Update Posted : April 11, 2022
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|Condition or disease||Intervention/treatment||Phase|
|Hemophilia A||Biological: rFVIIIFc||Phase 3|
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||108 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|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|
|Actual Study Start Date :||January 12, 2015|
|Actual Primary Completion Date :||September 23, 2019|
|Actual Study Completion Date :||September 23, 2019|
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.
Administered as specified in arm description
- Percentage of Participants With Confirmed Inhibitor Development as Measured by the Nijmegen-Modified Bethesda Assay [ Time Frame: Up to 3 years ]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.
- Annualized Number of Bleeding Episodes (Spontaneous and Traumatic) Per Participant (Annualized Bleeding Rate [ABR]) [ Time Frame: Up to 3 years ]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.
- Annualized Number of Spontaneous Joint Bleeding Episodes [ Time Frame: Up to 3 years ]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.
- Number of rFVIIIFc Injections With Excellent or Good, Moderate or None Treatment Response Assessed Using a 4-Point Scale [ Time Frame: Up to 3 years ]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.
- Total Number of Exposure Days (EDs) [ Time Frame: Up to 3 years ]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.
- Total Annualized rFVIIIFc Consumption Per Participant for the Prevention and Treatment of Bleeding Episodes [ Time Frame: Up to 3 years ]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.
- Number of Injections of rFVIIIFc Required to Resolve a Bleeding Episode [ Time Frame: Up to 3 years ]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.
- Average Dose Per Injection of rFVIIIFc Required to Resolve a Bleeding Episode [ Time Frame: Up to 3 years ]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.
- Change From Baseline in rFVIIIFc Incremental Recovery (IR) [ Time Frame: Baseline, Weeks 12, 24, 36, 48, 60, 72, 84, 96, 108 and 120 ]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.
- Number of Participants With Response to Immune Tolerance Induction (ITI) [ Time Frame: Up to 3 years ]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.
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|Ages Eligible for Study:||up to 5 Years (Child)|
|Sexes Eligible for Study:||Male|
|Accepts Healthy Volunteers:||No|
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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02234323
Documents provided by Sanofi ( Bioverativ, a Sanofi company ):
|Responsible Party:||Bioverativ, a Sanofi company|
|Other Study ID Numbers:||
2013-005512-10 ( EudraCT Number )
|First Posted:||September 9, 2014 Key Record Dates|
|Results First Posted:||August 13, 2020|
|Last Update Posted:||April 11, 2022|
|Last Verified:||March 2022|
|Individual Participant Data (IPD) Sharing Statement:|
|Plan to Share IPD:||Yes|
|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|
Blood Coagulation Disorders, Inherited
Blood Coagulation Disorders
Coagulation Protein Disorders
Genetic Diseases, Inborn