Study to Determine the Safety and Efficacy of rFIXFc in Previously Untreated Males With Severe Hemophilia B (PUPs B-LONG)

• ClinicalTrials.gov Identifier: NCT02234310
• Recruitment Status: Completed
• First Posted: September 9, 2014
• Results First Posted: July 31, 2020
• Last Update Posted: July 31, 2020
• Sponsor: Bioverativ, a Sanofi company
• Collaborator: Swedish Orphan Biovitrum
• Information provided by (Responsible Party): Sanofi ( Bioverativ, a Sanofi company )

Tracking Information

• First Submitted Date: July 17, 2014
• First Posted Date: September 9, 2014
• Results First Submitted Date: July 15, 2020
• Results First Posted Date: July 31, 2020
• Last Update Posted Date: July 31, 2020
• Actual Study Start Date: November 13, 2014
• Actual Primary Completion Date: August 20, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 15, 2020)

Percentage of Participants With Confirmed Inhibitor Development as Measured by the Nijmegen-Modified Bethesda Assay [ Time Frame: Up to 3 years ]

Development of an inhibitor was defined as an inhibitor test result of >= 0.60 Bethesda units per milliliter (BU/mL) that was confirmed by a second test result of >=0.60 BU/mL from a separate sample, drawn 2 to 4 weeks after the date when the original sample was drawn, with both tests performed by the central laboratory using Nijmegen-modified Bethesda assay.

Original Primary Outcome Measures (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 rFIXFc is dosed.

Current Secondary Outcome Measures (submitted: July 15, 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 normalized 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 traumatic when there is known reason for bleed. ABR=(Number of bleeding episodes during EP/total number of days during EP)*365.25. EP reflects the sum of all intervals of time during which participants were treated with rFIXFc per treatment regimens 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 is 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 efficacy period (EP) divided by total number of days during EP)*365.25. EP reflects the sum of all intervals of time during which participants were treated with rFIXFc per treatment regimen excluding major and minor 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 rFIXFc 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 (BE) at approximately 8 to 12 hours from time of injection and prior to additional doses of rFIXFc given for same BE using 4-point scale:- 1=Excellent: abrupt pain relief and/or improvement in signs of bleeding within approximately 8 hours after initial injection; 2=Good: definite pain relief and/or improvement in signs of bleeding within approx. 8 hours after injection, but possibly requiring more than 1 injection after 24-48 hours for complete resolution; 3=Moderate: Probable/slight beneficial effect within 8 hours after initial injection and requires more than 1 injection and 4=None: No improvement or condition worsens within approx. 8 hours after initial injection. Participants were included in summary of 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 rFIXFc injections, with the time of the first injection of rFIXFc defined as the start of the ED. Participant who did not have a particular injection type were counted as having zero injections for that type.
• Total Annualized rFIXFc Consumption Per Participant for the Prevention and Treatment of Bleeding Episodes [ Time Frame: Up to 3 years ]
  Total annualized rFIXFc consumption (in IU/kg) was calculated for each participant as: Annualized consumption = (Total IU/kg of rFIXFc during efficacy period (EP) divided by total number of days during EP)*365.25. EP reflects the sum of all intervals of time during which participants were treated with rFIXFc 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 rFIXFc Required to Resolve a Bleeding Episode [ Time Frame: Up to 3 years ]
  Number of injections of rFIXFc required to resolve a bleeding episode during efficacy period (EP) were reported. EP reflects the sum of all intervals of time during which participants were treated with rFIXFc 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 rFIXFc Required to Resolve a Bleeding Episode [ Time Frame: Up to 3 years ]
  The average dose of rFIXFc per injection per bleeding episode was calculated as the average of all doses (IU/kg) administered to treat the bleeding episode during efficacy period (EP). EP begins with the first treatment regimen dose of rFIXFc and ends with the last dose (regardless of the reason for dosing). Surgery/rehabilitation periods are 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 rFIXFc Incremental Recovery (IR) [ Time Frame: Baseline, Weeks 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, and 144 ]
  Blood samples were taken at trough 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 FIX activity - Pre-dose FIX activity) (IU/dL)/ Actual dose (IU/kg), where Cmax is 30 minute FIX activity post-dose and FIX activity less than (<)0.5 IU/dL was set to 0 IU/dL for calculation of IR.

Original Secondary Outcome Measures (submitted: September 5, 2014)

• Annualized Number of Bleeding Episodes (Spontaneous and Traumatic) 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 ]
• Response to Treatment for Bleeding Episodes [ Time Frame: For the duration of study participation, approximately 3 years ]
  Response to treatment for bleeding episodes uses a 4-point bleeding response scale that the investigator completes for bleeding episodes treated in the clinic, and the parent or caregiver completes for all other bleeding episodes.
• Total Number of Exposure Days per Participant per Year [ Time Frame: For the duration of study participation, approximately 3 years ]
• Total Annualized BIIB029 Consumption per Participant for the Prevention and Treatment of Bleeding Episodes [ Time Frame: For the duration of study participation, approximately 3 years ]
• Number of Injections of BIIB029 Required to Resolve a Bleeding Episode [ Time Frame: For the duration of study participation, approximately 3 years ]
• Dose per Injection of BIIB029 Required to Resolve a Bleeding Episode [ Time Frame: For the duration of study participation, approximately 3 years ]
• BIIB029 Incremental Recovery [ Time Frame: Predose; within 30 minutes of the injection and at 10 (±5) minutes post dose ]
  Blood samples will be taken at trough for assessment of incremental recovery, measured by the one-stage clotting assay.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study to Determine the Safety and Efficacy of rFIXFc in Previously Untreated Males With Severe Hemophilia B
• Official Title: An Open-Label, Multicenter Evaluation of the Safety and Efficacy of Recombinant Coagulation Factor IX Fc Fusion Protein (rFIXFc; BIIB029) in the Prevention and Treatment of Bleeding in Previously Untreated Patients With Severe Hemophilia B
• Brief Summary: The primary objective of the study was to evaluate the safety of recombinant coagulation factor IX Fc fusion protein (rFIXFc, BIIB029) in previously untreated patients (PUPs) with severe hemophilia B. Secondary objectives were to evaluate the efficacy of rFIXFc in the prevention and treatment of bleeding episodes in PUPs, and to evaluate rFIXFc consumption for prevention and treatment of bleeding episodes in PUPs.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Hemophilia B

Intervention

Biological: rFIXFc

Adjustments to the dose and interval of rFIXFc was made in this study based on investigator discretion using available pharmacokinetic (PK) data, subsequent FIX trough and peak levels, level of physical activity, and bleeding pattern, in accordance with local standards of care for a prophylactic regimen. There was an option to start study dosing as episodic treatment (on-demand).

Other Names:

• BIIB029
• Alprolix
• recombinant coagulation factor IX Fc fusion protein

Study Arms

Experimental: Recombinant Coagulation Factor IX Fc Fusion Protein (rFIXFc)

Participants received rFIXFc intravenous (IV) injection as follows: Prophylactic treatment regimen: started with rFIXFc 50 International Units per kilogram (IU/kg) weekly until a participant reached at least 50 exposure days (ED=24-hour period in which greater than or equal to (>=1) injection/dose of rFIXFc was given) to rFIXFc, withdrawal from study or end of study. Adjustments to dose and dosing interval was based on incremental recovery, subsequent Factor IX (FIX) levels, physical activity, bleeding pattern, in accordance with local standards of care for prophylactic regimen (PR). Treatment with episodic (on demand) regimen can be initiated before PR at investigators discretion. Episodic (On demand; optional): rFIXFc at individual doses based on participant's clinical condition, type and severity of bleeding event until PR.

Intervention: Biological: rFIXFc

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: October 4, 2018): 33
• Original Estimated Enrollment (submitted: September 5, 2014): 60
• Actual Study Completion Date: August 20, 2019
• Actual Primary Completion Date: August 20, 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

Key Inclusion Criteria:

• Weight >=3.5 kilogram at the time of informed consent.
• Severe hemophilia B was defined as less than or equal to (<=)2 International Units per deciliter (IU/dL) (<=2 percent [%]) endogenous FIX documented in the medical record or as tested during the Screening Period.

Key Exclusion Criteria:

• History of positive inhibitor testing. A prior history of inhibitors was defined based on a participant's historical positive inhibitor test using the local laboratory Bethesda value for a positive inhibitor test (that is equal to or above lower limit of detection).
• History of hypersensitivity reactions associated with any rFIXFc administration.
• Exposure to blood components or injection with a coagulation factor IX (FIX) concentrate (including plasma derived) other than rFIXFc.
• Injection with commercially available rFIXFc more than 28 days prior to Screening.
• More than 3 injections of commercially available rFIXFc prior to confirmation of eligibility.
• Other coagulation disorders in addition to hemophilia B.
• Any concurrent clinically significant major disease that, in the opinion of the Investigator, would have made the participant unsuitable for enrollment (example HIV infection with cluster of differentiation 4 (CD4) lymphocyte count less than (<)200 cells/microliter (mcL) or a viral load greater than (>)200 particles/mcL, or any other known congenital or acquired immunodeficiency).
• Current systemic treatment with chemotherapy and/or other immunosuppressant drugs. Use of steroids for treatment of asthma or management of acute allergic episodes or otherwise life-threatening episodes was allowed. Treatment in these circumstances should not have exceeded a 14-day duration.
• Participation within the past 30 days in any other clinical study involving investigational treatment.
• Current enrollment in any other clinical study involving investigational treatment.
• Inability to comply with study requirements.
• Other unspecified reasons that, in the opinion of the Investigator or Bioverativ, would have made the participant unsuitable for enrollment.

NOTE: Other protocol-defined inclusion/exclusion criteria may apply.

Sex/Gender

• Sexes Eligible for Study: Male

• Ages: up to 17 Years (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Denmark, France, Ireland, Italy, Netherlands, New Zealand, Poland, Sweden, United Kingdom, United States
• Removed Location Countries: Belgium, Canada, Germany, Spain, Switzerland

Administrative Information

• NCT Number: NCT02234310
• Other Study ID Numbers: 998HB303; 2013-003629-27 ( EudraCT Number )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• 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: Bioverativ, a Sanofi company
• Collaborators: Swedish Orphan Biovitrum
• Investigators: Not Provided
• PRS Account: Sanofi
• Verification Date: July 2020