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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
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:
Collaborator:
Swedish Orphan Biovitrum
Information provided by (Responsible Party):
Sanofi ( Bioverativ, a Sanofi company )

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.

Condition or disease Intervention/treatment Phase
Hemophilia B Biological: rFIXFc Phase 3

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 33 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : November 13, 2014
Actual Primary Completion Date : August 20, 2019
Actual Study Completion Date : August 20, 2019


Arm Intervention/treatment
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.
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




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   up to 17 Years   (Child)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
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.


Information from the National Library of Medicine

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): NCT02234310


Locations
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United States, California
Research Site
Sacramento, California, United States, 95817
United States, District of Columbia
Research Site
Washington, District of Columbia, United States, 20010
United States, Georgia
Research Site
Atlanta, Georgia, United States, 30322
United States, Indiana
Research Site
Indianapolis, Indiana, United States, 46260
United States, Kentucky
Research Site
Louisville, Kentucky, United States, 40202
United States, Louisiana
Research Site
New Orleans, Louisiana, United States, 70112
United States, Michigan
Research Site
East Lansing, Michigan, United States, 48823
Research Site
Traverse City, Michigan, United States, 49684
United States, Ohio
Research Site
Columbus, Ohio, United States, 43205
United States, Oregon
Research Site
Portland, Oregon, United States, 97239
United States, Pennsylvania
Research Site
Pittsburgh, Pennsylvania, United States, 15213
Australia, New South Wales
Research Site
Westmead, New South Wales, Australia, 2145
Denmark
Research Site
Aarhus, Denmark, 8200
France
Hopital Cardiologique - CHU Lille
Lille, Nord, France, 59037
Research Site
Lyon Cedex 3, Rhone, France, 69437
Ireland
Research Site
Dublin, Ireland, D12 N512
Italy
Research Site
Milano, Italy, 20122
Research Site
Napoli, Italy, 80122
Research Site
Parma, Italy, 43126
Research Site
Roma, Italy, 00165
Netherlands
Research Site
Utrecht, Netherlands, 3584 CX
New Zealand
Research Site
Auckland, New Zealand, 1023
Poland
Research Site
Warszawa, Poland, 02-091
Sweden
Research Site
Malmo, Sweden, 205 02
United Kingdom
Research Site
Cambridge, Cambridgeshire, United Kingdom, CB2 0QQ
Research Site
Whitechapel, London, United Kingdom, E1 1BB
Research Site
London, United Kingdom, WC1N3JH
Sponsors and Collaborators
Bioverativ, a Sanofi company
Swedish Orphan Biovitrum
  Study Documents (Full-Text)

Documents provided by Sanofi ( Bioverativ, a Sanofi company ):
Study Protocol  [PDF] August 6, 2018
Statistical Analysis Plan  [PDF] March 1, 2019

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Responsible Party: Bioverativ, a Sanofi company
ClinicalTrials.gov Identifier: NCT02234310    
Other Study ID Numbers: 998HB303
2013-003629-27 ( EudraCT Number )
First Posted: September 9, 2014    Key Record Dates
Results First Posted: July 31, 2020
Last Update Posted: July 31, 2020
Last Verified: July 2020
Individual Participant Data (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/
Keywords provided by Sanofi ( Bioverativ, a Sanofi company ):
prophylaxis treatment
episodic treatment
Additional relevant MeSH terms:
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Hemophilia A
Hemophilia B
Blood Coagulation Disorders, Inherited
Blood Coagulation Disorders
Hematologic Diseases
Coagulation Protein Disorders
Hemorrhagic Disorders
Genetic Diseases, Inborn
Genetic Diseases, X-Linked