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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 : August 13, 2020
Sponsor:
Collaborator:
Swedish Orphan Biovitrum
Information provided by (Responsible Party):
Sanofi ( Bioverativ, a Sanofi company )

Tracking Information
First Submitted Date  ICMJE August 29, 2014
First Posted Date  ICMJE September 9, 2014
Results First Submitted Date  ICMJE July 28, 2020
Results First Posted Date  ICMJE August 13, 2020
Last Update Posted Date August 13, 2020
Actual Study Start Date  ICMJE January 12, 2015
Actual Primary Completion Date September 23, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 28, 2020)
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.
Original Primary Outcome Measures  ICMJE
 (submitted: September 5, 2014)
Number of participants with inhibitor development [ Time Frame: For the duration of study participation, approximately 3 years ]
Participants will be tested for development of inhibitors at timepoints throughout the study based on exposure days (ED). One ED is equivalent to a 24 hour period in which rFVIIIFc is dosed
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 28, 2020)
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: September 5, 2014)
  • Annualized number of bleeding episodes per participant [ Time Frame: For the duration of study participation, approximately 3 years ]
  • Annualized number of spontaneous joint bleeding episodes per participant [ Time Frame: For the duration of study participation, approximately 3 years ]
  • Number of injections required to resolve a bleeding episode [ Time Frame: For the duration of study participation, approximately 3 years ]
  • Dose per injection of rFVIIIFc required to resolve a bleeding episode [ Time Frame: For the duration of study participation, approximately 3 years ]
  • Response to treatment with rFVIIIFc for bleeding episodes, using the 4-point bleeding response scale [ Time Frame: For the duration of study participation, approximately 3 years ]
  • Number of EDs per participant per year [ Time Frame: For the duration of study participation, approximately 3 years ]
  • Annualized rFVIIIFc consumption per participant for the prevention and treatment of bleeding episodes [ Time Frame: For the duration of study participation, approximately 3 years ]
  • rFVIIIFc incremental recovery (IR) as measured by the one-stage aPTT clotting assay and the two-stage chromogenic assay [ Time Frame: For the duration of study participation, approximately 3 years ]
    Samples for incremental recovery taken when the participant is in a non-bleeding state.
  • Response to immune tolerance induction (ITI) with rFVIIIFc (success, partial success, failure, early withdrawal) [ Time Frame: Until immune tolerance is achieved or up to 33 months ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE 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
Official Title  ICMJE 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
Brief 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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Hemophilia A
Intervention  ICMJE 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
Study Arms  ICMJE 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.
Intervention: Biological: rFVIIIFc
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: October 4, 2018)
108
Original Estimated Enrollment  ICMJE
 (submitted: September 5, 2014)
125
Actual Study Completion Date  ICMJE September 23, 2019
Actual Primary Completion Date September 23, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.

Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Ages  ICMJE up to 5 Years   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   Brazil,   Canada,   France,   Germany,   Ireland,   Italy,   Netherlands,   New Zealand,   Poland,   Spain,   Sweden,   United Kingdom,   United States
Removed Location Countries Denmark
 
Administrative Information
NCT Number  ICMJE NCT02234323
Other Study ID Numbers  ICMJE 997HA306
2013-005512-10 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Qualified researchers may request access to participant 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. Participant 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://www.clinicalstudydatarequest.com/
Responsible Party Sanofi ( Bioverativ, a Sanofi company )
Study Sponsor  ICMJE Bioverativ, a Sanofi company
Collaborators  ICMJE Swedish Orphan Biovitrum
Investigators  ICMJE Not Provided
PRS Account Sanofi
Verification Date July 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP