Long-Term Safety and Efficacy of rFIXFc in the Prevention and Treatment of Bleeding Episodes in Previously Treated Participants With Hemophilia B

Participants will follow either a prophylaxis or on-demand regimen. The starting dose in this study will be determined by the clinical profile of the patient in the preceding studies, B-LONG 998HB102 (NCT01027364) and Kids B-LONG study 9HB02PED (NCT01440946)

• rFIXFc (Biological), also known as coagulation factor IX (recombinant) Fc fusion protein, Alprolix, BIIB029: Administered as specified in the treatment arm.

Primary outcomes

• Number of Participants With Any Positive Inhibitor Development [Approximately 5 years]: An inhibitor test result greater than or equal to (>=)0.6 Bethesda units per milliliter (BU/mL), confirmed on 2 separate samples drawn 2 to 4 weeks apart, was considered positive. Both tests were to be performed by the central laboratory using the Nijmegen-modified Bethesda Assay. Data was summarized by treatment regimen for participants from Study 998HB102 and by age cohort (<6 years and 6 to <12 years old) and treatment regimen for participants from Study 9HB02PED per planned analysis. Participants were included in summary of more than 1 treatment regimen if their regimen changed during study.

Secondary outcomes

• Annualized Bleeding Rate (ABR) [Approximately 5 years]: ABR is annualized number of bleeding episodes per participant per year. Bleeding episodes were classified as spontaneous if participant records bleeding event when there is no known contributing factor such as definite trauma/antecedent strenuous activity and classified as traumatic if participant records bleeding event when there is known reason for bleed. ABR=(Number of bleeding episodes during efficacy period/number of days during efficacy period)*365.25. Efficacy period reflects 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. ABR was summarized by treatment regimen for participants from study 998HB102 and by age cohort (<6 years and 6 to <12 years old) and treatment regimen for participants from study 9HB02PED per planned analysis. Participants were included in summary of more than 1 treatment regimen if their regimen changed during study.
• Annualized Spontaneous Joint Bleeding Episodes [Approximately 5 years]: Bleeding episodes were classified as spontaneous if participant records a bleeding event when there is no known contributing factor such as definite trauma/antecedent strenuous activity. In addition, location of bleed (joint, internal, skin/mucosa or muscle) were also collected. Annualized spontaneous joint bleeding episodes=(Number of spontaneous joint bleeding episodes during efficacy period/number of days during efficacy period)*365.25. Efficacy period reflects 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. Bleeding episodes were summarized by treatment regimen for participants from study 998HB102 and by age cohort (<6 years and 6 to <12 years old) and treatment regimen for participants from study 9HB02PED as per planned analysis. Participants were included in summary of more than 1 treatment regimen if their regimen changed during study.
• Total Number of Exposure Days (EDs) [Approximately 5 years]: An exposure day is a 24-hour period in which one or more rFIXFc injections are given. The total number of days of exposure to rFIXFc were summarized by treatment regimen for participants from study 998HB102 and by age cohort (<6 years and 6 to <12 years old) and treatment regimen for participants from study 9HB02PED as per planned analysis. Participants were included in summary of more than 1 treatment regimen if their regimen changed during study.
• Annualized rFIXFc Consumption (International Units Per Kilogram [IU/kg]) [Approximately 5 years]: Annualized consumption = (total international unit per kilogram \[IU/kg\] of study treatment received during the efficacy period / total number of days during the efficacy period) multiplied by 365.25. Efficacy period reflects 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. Annualized consumption was summarized by treatment regimen for participants from study 998HB102 and by age cohort (<6 years and 6 to <12 years old) and treatment regimen for participants from study 9HB02PED as per planned analysis. Participants were included in summary of more than 1 treatment regimen if their regimen changed during study.
• Physicians' Global Assessment of Participant's Response to rFIXFc Regimen Using a 4-Point Scale [Approximately 5 years]: Participants were assessed for response to their rFIXFc regimen using following 4-point scale: 1=Excellent: bleeding episodes responded to less than or equal to (<=)usual number of injections or dose of rFIXFc or rate of breakthrough bleeding during prophylaxis was <= that usually observed; 2=Effective: most bleeding episodes responded to same number of injections and dose, but some required more injections or higher doses, or there was minor increase in rate of breakthrough; 3=Partially Effective: bleeding episodes most often required more injections and/or higher doses than expected or adequate breakthrough bleeding prevention during prophylaxis required more frequent injections and/or higher doses and 4=Ineffective: routine failure to control hemostasis/hemostatic control require additional agents. Total number of scale responses =total count of scale responses for all participants; multiple responses per participant including those at scheduled and unscheduled visits are counted.
• Participant's Assessment of Response (Excellent or Good Response) to rFIXFc Injections for the Treatment of Bleeding Episodes Using a 4-Point Scale [Approximately 5 years]: Using eDiary, participant received rating for treatment response to any bleeding episode (BE) using 4-point scale- 1=Excellent: Abrupt pain relief and/or improvement in signs of bleeding within approximately (approx.) 8 hours (h) after initial injection (inj.); 2=Good: Definite pain relief and/or improvement in signs of bleeding within approx. 8h after an injection, but possibly requiring more than 1 injection after 24-48h for complete resolution; 3=Moderate: Probable/slight beneficial effect within 8h after initial injection and requires more than 1 injection and 4=None: No improvement, or condition worsens within approx. 8h after initial injection. This assessment was to be made approx. 8 to 12h from time the injection was given to treat BE and prior to any additional doses of rFIXFc given for same bleeding episode. Percentages are based on the number of bleeding episodes for which a response (excellent or good) was provided for the first injection during the efficacy period.

Sex: Male

Key Inclusion Criteria:

* Subjects who have completed studies 998HB102 (NCT01027364) or 9HB02PED (NCT01440946) or other studies with rFIXFc
* Ability to understand the purposes \& risks of the study and provide signed and dated informed consent.

Key Exclusion Criteria:

* High-titer inhibitor (>/=5.00 BU/mL)

NOTE: Other protocol defined Inclusion/ Exclusion criteria may apply.

Participant flow

Outcome results

• Number of Participants With Any Positive Inhibitor Development (Primary), Count of participants, Participants: rFIXFc (9HB02PED [<6 Years Old]) 0; rFIXFc (9HB02PED [6 to <12 Years]) 0; rFIXFc (Participants From 998HB102) 0
• Annualized Bleeding Rate (ABR) (Secondary), Median, episodes per participant per year: rFIXFc (9HB02PED [<6 Years Old Age Cohort]) 1.04 (0.00 to 2.28); rFIXFc (9HB02PED [6 to <12 Years Old Age Cohort]) 1.14 (0.54 to 2.34); rFIXFc (Participants From Study 998HB102) 2.26 (0.40 to 5.16)
• Annualized Spontaneous Joint Bleeding Episodes (Secondary), Median, episodes per participant per year: rFIXFc (9HB02PED [<6 Years Old Age Cohort]) 0.00 (0.00 to 1.06); rFIXFc (9HB02PED [6 to <12 Years Old Age Cohort]) 0.00 (0.00 to 1.40); rFIXFc (Participants From Study 998HB102) 0.38 (0.00 to 2.25)
• Total Number of Exposure Days (EDs) (Secondary), Median, days: rFIXFc (9HB02PED [<6 Years Old Age Cohort]) 55.00 (8.0 to 176.0); rFIXFc (9HB02PED [6 to <12 Years Old Age Cohort]) 165.00 (3.0 to 202.0); rFIXFc (Participants From Study 998HB102) 169.00 (4.0 to 327.0)
• Annualized rFIXFc Consumption (International Units Per Kilogram [IU/kg]) (Secondary), Median, IU per kilogram per participant per year: rFIXFc (9HB02PED [<6 Years Old Age Cohort]) 3382.5 (2930.9 to 3667.4); rFIXFc (9HB02PED [6 to <12 Years Old Age Cohort]) 3212.0 (2838.5 to 3344.4); rFIXFc (Participants From Study 998HB102) 2598.0 (2129.8 to 3370.9)
• Physicians' Global Assessment of Participant's Response to rFIXFc Regimen Using a 4-Point Scale (Secondary), Count of units, Responses: rFIXFc (Participants From 9HB02PED) 131; rFIXFc (Participants From 998HB102) 622
• Participant's Assessment of Response (Excellent or Good Response) to rFIXFc Injections for the Treatment of Bleeding Episodes Using a 4-Point Scale (Secondary), Count of units, Injections: rFIXFc (9HB02PED [<6 Years Old Age Cohort]) 60; rFIXFc (9HB02PED [6 to <12 Years Old Age Cohort]) 47; rFIXFc (Participants From 998HB102) 342

Adverse events

Time frame: From signing of Informed Consent Form (ICF) through follow-up (approximately 5 years)

Serious adverse events by term

Other adverse events by term

• Results publication: Astermark J, Hermans C, Ezzalfani M, Sidhom A, Barbier S, Kragh N, Falk A, Eriksson D. Recombinant factor IX Fc prophylaxis reduces pain and increases levels of physical activity, with sustained, long-term improvements in patients with hemophilia B: post hoc analysis of phase III trials using patient-reported outcomes. Ther Adv Hematol. 2023 May 29;14:20406207231170701. doi: 10.1177/20406207231170701. eCollection 2023. PMID 37283819
• Results publication: 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
• Results publication: Shapiro AD, Pasi KJ, Ozelo MC, Kulkarni R, Barnowski C, Winding B, Szamosi J, Lethagen S. Extending recombinant factor IX Fc fusion protein dosing interval to 14 or more days in patients with hemophilia B. Res Pract Thromb Haemost. 2018 Nov 29;3(1):109-113. doi: 10.1002/rth2.12163. eCollection 2019 Jan. PMID 30656283

• Study Protocol (PDF, 2013-11-13)
• Statistical Analysis Plan (PDF, 2017-09-05)

• Medical Director, Study director, Bioverativ Therapeutics Inc.