Study of Recombinant Factor IX Fc Fusion Protein (rFIXFc) in Participants With Hemophilia B

NCT01027364 | Completed Phase 3 Results DMC

• 2 other identifiers: 998HB1022009-014295-21
• Study Type: interventional
• Target: 123
• Locations: 17 countries
• Sites: 51

Brief Summary

The primary objectives of the study were: to evaluate the safety and tolerability of rFIXFc; to evaluate the efficacy of rFIXFc in all treatment arms; to evaluate the effectiveness of prophylaxis over on-demand (episodic) therapy by comparing the annualized number of bleeding episodes between participants receiving rFIXFc on each prevention (prophylaxis) regimen and participants receiving rFIXFc on an episodic regimen. The secondary objectives of the study were: to evaluate and assess the pharmacokinetic (PK) parameter estimates of rFIXFc and rFIX (BeneFIX®) at baseline in the Sequential PK subgroup as well as rFIXFc at Week 26 (±1 week); to evaluate participants' response to treatment; to evaluate rFIXFc consumption.

Conditions

Severe Hemophilia B

Outcome Measures

Primary Outcomes (7)

• Number of Participants With Potentially Clinically Significant Laboratory Abnormalities

  Clinical laboratory evaluations included hematology and blood chemistry. Table does not include laboratory tests evaluated during the surgical/rehabilitation period. Because the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for participants in Arm 4 were included in listings and reviewed separately. Review of the listing was sufficient to assess this endpoint. ULN=upper limit of normal.

  up to 52 weeks ± 1 week

• Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)

  AE=any untoward medical occurrence that did not necessarily have a causal relationship with this treatment, and could be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of study product, whether related or not. TE=event present prior to receiving the first injection of BeneFIX or rFIXFc that subsequently worsened in severity or not present prior to receiving the first injection but subsequently appeared before last visit on study. Serious AE (SAE)=AE resulting in death, immediate risk of death, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity, or a congenital/anomaly/birth defect, or any other medically important event. Related=related, possibly related, and relationship missing. Data include AEs emergent during the surgical/rehabilitation period; AE data are included in each treatment arm only for the time each participant was enrolled in that arm.

  up to 52 weeks + 30 days ± 1 week

• Number of Participants With Non-serious Treatment-emergent Adverse Events (TEAEs) During the Surgical / Rehabilitation Period

  AE=any untoward medical occurrence that did not necessarily have a causal relationship with this treatment, and could be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of study product, whether related or not. TEAE=AE present prior to receiving the first injection of BeneFIX or rFIXFc that subsequently worsened in severity or was not present prior to receiving the first injection but subsequently appeared before last visit on study. Participants are counted once if they report multiple events in the same system organ class (SOC) or preferred term (PT). Coded using the Medical Dictionary for Regulatory Activities (MedDRA), version 15.0 dictionary. The following SOCs are abbreviated in the table: Immune System (IS); Injury, Poisoning, and Procedural (IPP); Metabolism and Nutrition (MN); Musculoskeletal and Connective Tissue (MCT); Respiratory, Thoracic and Mediastinal (RTM); Skin and Subcutaneous Tissue (SST).

  up to 52 weeks + 30 days ± 1 week

• Number of Participants With Treatment-emergent Serious Adverse Events (TESAEs) During the Surgical / Rehabilitation Period

  SAE=AE resulting in death, immediate risk of death, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity, or a congenital/anomaly/birth defect, or any other medically important event. TESAE=SAE present prior to receiving the first injection of BeneFIX or rFIXFc that subsequently worsened in severity or was not present prior to receiving the first injection but subsequently appeared before last visit on study. Participants are counted once if they report multiple events in the same system organ class (SOC) or preferred term (PT). Coded using the Medical Dictionary for Regulatory Activities (MedDRA), version 15.0 dictionary. The following SOC is abbreviated in the table: Injury, Poisoning, and Procedural (IPP).

  up to 52 weeks + 30 days ± 1 week

• Incidence Rate of FIX Inhibitor Development

  An inhibitor test result ≥0.6 Bethesda units (BU)/mL, identified and confirmed by re-testing of a second sample obtained within 2 to 4 weeks, was considered positive. Both tests were to be performed using the Nijmegen-modified Bethesda Assay by the central laboratory. The incidence rates along with the 95% CI were summarized for all titers for subjects with 50 or more exposure days (EDs) to rFIXFc and a valid inhibitor test after the 50th exposure. In addition, the incidence rates for all subjects regardless of their exposure days to rFIXFc were also summarized. The 95% CI was calculated using Clopper-Pearson exact method.

  up to 52 weeks ± 1 week

• Annualized Bleeding Rate

  Annualized bleeding episodes = (number of bleeding episodes / number of days in the respective period)\*365.25. In Arms 1 and 2, the efficacy period (EP) started with date and time of first prophylactic dose following a completed pharmacokinetic (PK) sampling period and ended with last dose administered (for prophylaxis or a bleeding episode). In Arm 3, the EP started following last PK sampling timepoint and ended with either date of last contact or date of last entry into the eDiary, whichever was later. The EP was interrupted for the repeat PK period in Arm 1 (sequential PK subgroup) and for all surgical/rehabilitation periods (for both major and minor surgeries) in all 3 arms. A bleeding episode started from the first sign of a bleed, and ended 72 hours after the last treatment for the bleeding, within which any symptoms of bleeding at the same location, or injections less than or equal to 72 hours apart, were considered the same bleeding episode.

  up to 52 weeks ± 1 week (efficacy period as defined in description)

• Comparison of Annualized Bleeding Rates

  Estimated with a factor for arm, based on whole study duration for all participants. Annualized bleeding episodes = (number of bleeding episodes / number of days in the respective period)\*365.25. In Arms 1 and 2, the efficacy period (EP) started with date and time of first prophylactic dose following a completed PK sampling period and ended with last dose administered (for prophylaxis or a bleeding episode). In Arm 3, the EP started following last PK sampling timepoint and ended with either date of last contact or date of last entry into the eDiary, whichever was later. The EP was interrupted for the repeat PK period in Arm 1 and for all surgical/rehabilitation periods in all 3 arms. A bleeding episode started from the first sign of a bleed, and ended 72 hours after the last treatment for the bleeding, within which any symptoms of bleeding at the same location, or injections less than or equal to 72 hours apart, were considered the same bleeding episode.

  up to 52 weeks ± 1 week (efficacy period as defined in description)

Secondary Outcomes (31)

• Participant Assessment of Response to Injections to Treat a Bleeding Episode

  up to 52 weeks ± 1 week

• Physicians' Global Assessments of Participants' Response to Treatment With rFIXFc

  up to 52 weeks ± 1 week

• Annualized rFIXFc Consumption Per Participant

  up to 52 weeks ± 1 week (efficacy period as defined in description)

• Average Weekly Dose For the Fixed Weekly Interval Prophylaxis Arm

  up to 52 weeks ± 1 week (efficacy period as defined in description)

• Average Dosing Interval For the Individualized Interval Prophylaxis Arm

  up to 52 weeks ± 1 week (efficacy period as defined in description)

Study Arms (4)

Fixed Weekly Interval

EXPERIMENTAL

50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling.

Drug: Factor IX (rFIXFc); Drug: rFIX

Individualized Interval

EXPERIMENTAL

100 IU/kg rFIXFc via IV injection once every 10 days initially, then at an interval derived from the baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial 10-day interval were to be made based on baseline PK assessments and trough levels, which were monitored at Weeks 4, 16, 26, and 39.

Drug: Factor IX (rFIXFc)

On Demand

EXPERIMENTAL

20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes

Drug: Factor IX (rFIXFc)

Surgery

EXPERIMENTAL

The surgical period and dosing are dependent on the type of surgery the participant undergoes. Participants who started the study in one of the other treatment arms prior to surgery will return to the original treatment arm. Participants who joined the study in the Surgery arm will be assigned to one of the other treatment arms following post-operative rehabilitation.

Drug: Factor IX (rFIXFc)

Interventions

Factor IX (rFIXFc) DRUG

Also known as: Recombinant Human Factor IX Fc Fusion Protein

Fixed Weekly Interval; Individualized Interval; On Demand; Surgery

rFIX DRUG

Also known as: Recombinant Factor IX, BeneFIX®

Fixed Weekly Interval

Eligibility Criteria

• Age: 12 Years+
• Sex: male
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Male and 12 years of age and older and weigh at least 40 kg
• Diagnosed with hemophilia B (baseline Factor IX level less than or equal to 2%)
• History of at least 100 exposure days to any Factor IX product
• Platelet count ≥100,000 cells/μL

You may not qualify if:

• History of Factor IX inhibitors
• Kidney or liver dysfunction
• Diagnosed with another coagulation defect other than hemophilia B
• Prior history of anaphylaxis associated with any Factor IX or intravenous (IV) immunoglobulin administration

Sponsors & Collaborators

• Bioverativ Therapeutics Inc.: lead
• Swedish Orphan Biovitrum: collaborator

Study Sites (51)

Research Site

Phoenix, Arizona, United States

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Sacramento, California, United States

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Aurora, Colorado, United States

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Chicago, Illinois, United States

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Indianapolis, Indiana, United States

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East Lansing, Michigan, United States

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Philadelphia, Pennsylvania, United States

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Pittsburgh, Pennsylvania, United States

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Seattle, Washington, United States

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Camperdown, New South Wales, Australia

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Adelaide, South Australia, Australia

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Perth, Western Australia, Australia

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Brussels, Belgium

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Leuven, Belgium

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Campinas, Brazil

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Calgary, Alberta, Canada

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Toronto, Ontario, Canada

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Montreal, Quebec, Canada

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Vancouver, Canada

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Beijing, China

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Guangzhou, China

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Shanghai, China

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Tianjin, China

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Lyon, France

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Marseille, France

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Berlin, Germany

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Bonn, Germany

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Pokfulam, Hong Kong

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Shatin, Hong Kong

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Ludhiana, Punjab, India

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Vellore, Tamil Nadu, India

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Bangalore, India

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Pune, India

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Florence, Italy

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Milan, Italy

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Kasihara-City, Japan

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Kawasaki, Japan

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Kitakyushu, Japan

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Nagoya, Japan

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Suginami-ku, Japan

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Tokyo, Japan

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Lodz, Poland

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Warsaw, Poland

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Moscow, Russia

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Saint Petersburg, Russia

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Johannesburg, Gauteng, South Africa

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Cape Town, Western Cape, South Africa

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Malmo, Sweden

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Stockholm, Sweden

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Cambridge, United Kingdom

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London, United Kingdom

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Related Publications (2)

• Powell JS, Pasi KJ, Ragni MV, Ozelo MC, Valentino LA, Mahlangu JN, Josephson NC, Perry D, Manco-Johnson MJ, Apte S, Baker RI, Chan GC, Novitzky N, Wong RS, Krassova S, Allen G, Jiang H, Innes A, Li S, Cristiano LM, Goyal J, Sommer JM, Dumont JA, Nugent K, Vigliani G, Brennan A, Luk A, Pierce GF; B-LONG Investigators. Phase 3 study of recombinant factor IX Fc fusion protein in hemophilia B. N Engl J Med. 2013 Dec 12;369(24):2313-23. doi: 10.1056/NEJMoa1305074. Epub 2013 Dec 4.

  PMID: 24304002 RESULT

• Shapiro AD, Kulkarni R, Ragni MV, Chambost H, Mahlangu J, Oldenburg J, Nolan B, Ozelo MC, Foster MC, Willemze A, Barnowski C, Jain N, Winding B, Dumont J, Lethagen S, Barnes C, Pasi KJ. Post hoc longitudinal assessment of the efficacy and safety of recombinant factor IX Fc fusion protein in hemophilia B. Blood Adv. 2023 Jul 11;7(13):3049-3057. doi: 10.1182/bloodadvances.2022009230.

  PMID: 36848635 DERIVED

MeSH Terms

Conditions

Hemophilia B

Interventions

Factor IX

Condition Hierarchy (Ancestors)

Blood Coagulation Disorders, Inherited; Blood Coagulation Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, X-Linked

Intervention Hierarchy (Ancestors)

Enzyme Precursors; Enzymes and Coenzymes; Blood Coagulation Factors; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Protein Precursors; Biological Factors

Results Point of Contact

• Title: Bioverativ Study Medical Director
• Organization: Bioverativ

clinicaltrials@bioverativ.com

Study Officials

• Medical Director

  Bioverativ Therapeutics Inc.

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 4, 2009
• First Posted: December 7, 2009
• Study Start: December 1, 2009
• Primary Completion: July 1, 2012
• Study Completion: July 1, 2012
• Last Updated: December 19, 2020
• Results First Posted: September 4, 2014

Record last verified: 2018-08

Locations

GB (2); BR (1); IT (2); RU (2); FR (2); HK (2); PL (2); IN (4); US (9); BE (2); CA (4); ZA (2); SE (2); JP (6); DE (2); AU (3); CN (4)