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: March 25, 2022
• Sponsor: Bioverativ, a Sanofi company
• Collaborator: Swedish Orphan Biovitrum
• Information provided by (Responsible Party): Sanofi ( Bioverativ, a Sanofi company )

Study Description

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

Study Design

• 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

Arms and Interventions

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

Outcome Measures

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.

Eligibility Criteria

• 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.

Contacts and Locations

Locations

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

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Nolan B, Klukowska A, Shapiro A, Rauch A, Recht M, Ragni M, Curtin J, Gunawardena S, Mukhopadhyay S, Jayawardene D, Winding B, Fischer K, Liesner R. Final results of the PUPs B-LONG study: evaluating safety and efficacy of rFIXFc in previously untreated patients with hemophilia B. Blood Adv. 2021 Jul 13;5(13):2732-2739. doi: 10.1182/bloodadvances.2020004085.

• 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
• Results First Posted: July 31, 2020
• Last Update Posted: March 25, 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

Keywords provided by Sanofi ( Bioverativ, a Sanofi company ):

prophylaxis treatment; episodic treatment

Additional relevant MeSH terms:

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