Safety and Efficacy of Benefix in Patients With Hemophilia B in Usual Care Settings in China

Study Overview
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Brief Summary
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The purpose of this post-approval study is to evaluate the safety and efficacy of Benefix in subjects with hemophilia B in usual care settings in China.

Detailed Description
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The purpose of this post-approval study is to provide supplementary information relating to the use of BeneFIX in Chinese subjects with hemophilia B, especially on the safety and efficacy in different populations of Chinese hemophilia B patients, in particular in pediatric patients <6 years of age, pediatric patients ≥6 to ≤12 years of age, Previously Untreated Patients (PUPs) , subjects receiving prophylaxis treatment after enrollment in the study, and severe patients (FIX activity <1%).

Official Title
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An Open-label, Single-arm, Post-authorization Pragmatic Clinical Trial On The Safety And Efficacy Of Benefix (Nonacog Alfa, Recombinant Factor Ix) In Subjects With Hemophilia B In Usual Care Settings In China

Conditions
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HEMOPHILIA B

Intervention / Treatment
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* Drug: Benefix


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and/or female subjects with hemophilia B. Subjects/parents/legal representatives must be able to comply with study procedures (informed consent/assent process, clinical visits, reporting of infusion and bleed data, reporting of adverse events, etc) Exclusion Criteria: Presence of any other bleeding disorder in addition to hemophilia B. Subjects with a past history of, or current factor IX inhibitor. For laboratory-based assessments, any Bethesda inhibitor titer greater than the laboratory's normal range or ≥0.6 Bethesda Unit (BU)/mL. Subjects with known hypersensitivity to the active substance or to any of the excipients of BeneFIX. Subjects with a known hypersensitivity to Chinese Hamster Ovary cell proteins.
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Benefix<br>This is a single arm study. Subjects will be treated with Benefix by the investigator according to usual care in China and in accord with the China BeneFIX Package Insert. | Drug: Benefix<br>* Subjects will be treated by the investigator according to usual care in China and in accord with the China BeneFIX Package Insert. The treatment duration is approximately 6 months (±7 days) or approximately 50 Exposure Days (EDs) (±5 EDs) (see protocol definition on EDs) whichever occurs first.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Developed Factor IX Inhibitor | Factor IX (FIX) inhibitor development was defined as any Bethesda inhibitor titer greater than the laboratory's normal range or Bethesda inhibitor titer >=0.6 Bethesda Unit (BU)/mL. | Up to 6 months | 
| Number of Participants With Allergic Reactions | FIX product allergy was defined as a hypersensitivity reaction to a FIX product with symptoms such as hives, urticaria, tightness of chest, wheezing, hypotension, and anaphylaxis based on investigator's judgments. | Up to 6 months | 
| Number of Participants With Thrombotic Events | Thrombotic event was defined as any event associated with formation of a blood clot including catheter-associated thrombi and thrombotic complications. | Up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | An adverse event (AE) was any untoward medical occurrence in a clinical investigation participant administered a product or medical device, regardless of the causality with the treatment or usage. A serious adverse event (SAE) was any untoward occurrence at any dose that resulted in death; was life threatening (immediate risk of death); required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; resulted in congenital anomaly/birth defect. AEs included both serious and non-serious AEs. Treatment-emergent AEs were those with initial onset or increasing in severity after the first dose of study drug. | Up to 7 months (28 calendar days after end of 6-month or 50-exposure day study treatment) | 
| Annualized Bleeding Rates (ABRs) in Participants Receiving Prophylaxis Treatment With BeneFIX During Their Prophylaxis Period | For prophylaxis period, annualized bleeding rate (ABR) was derived for each participant by the following formula: ABR = number of bleeds in prophylaxis period / (number of days in prophylaxis period/365.25). A prophylaxis period was defined as time from first prophylaxis infusion through 6 calendar days after the day of last prophylaxis infusion, or the day of study conclusion visit, whichever was earlier. A break in the prophylaxis period was any period of 28 days or longer in which no prophylaxis infusions were given. For a prophylaxis regimen to have been qualified to have ABR calculated, the sum of its periods needed to be >=14 days. | Up to 6 months or 50 exposure days whichever occurred first | 
| Number of Spontaneous/Non-traumatic Breakthrough Bleeds Within 48 Hours of a Prophylaxis Dose of BeneFIX | The prophylaxis infusion time, bleed start time and bleed type (etiology) were used to determine the number of spontaneous, non-traumatic breakthrough bleeds that occurred <=48 hours after a prophylaxis infusion. If there was more than 1 bleed location (eg, ankle and joint) with identical bleed start date and time, it was treated as 1 bleed occurrence. | Up to 6 months or 50 exposure days whichever occurred first | 
| Annualized Bleeding Rates (ABRs) in Participants Receiving On-demand Treatment With BeneFIX During Their On-demand Period | For on-demand period, the annualized bleeding rate (ABR) was derived for each participant by the following formula: ABR = number of bleeds in on-demand period / (number of days in on-demand period/365.25). The on-demand period was defined as the entire time of enrollment in the study (ie, from the date of the enrollment visit through the day before the Final/Early Termination visit) except time in any prophylaxis period. The breaks in the prophylaxis period were considered on-demand periods. For an on-demand regimen to have been qualified to have ABR calculated, the sum of its periods needed to be >= 14 days. | Up to 6 months or 50 exposure days whichever occurred first | 
| Number of Infusions Resulted in the Following Response to On-demand Treatment of Bleeds: Excellent, Good, Moderate, no Response | Response was assessed using 4-point On-Demand Hemostasis Efficacy Rating Scale. Excellent means definite pain relief and/or improvement in signs of bleeding starting within 8 hours after an infusion, with no additional infusion administered; good means definite pain relief and/or improvement in signs of bleeding starting within 8 hours after an infusion, with at least one additional infusion administered for complete resolution of the bleeding episode, or definite pain relief and/or improvement in signs of bleeding starting after 8 hours following the infusion, with no additional infusion administered; moderate means probable or slight improvement starting after 8 hours following the infusion, with at least one additional infusion administered for complete resolution of the bleeding episode; no response means no improvement between infusions or during the 24 hour interval following an infusion, or condition worsens. Both first infusions and follow-up infusions were included. | Up to 6 months or 50 exposure days whichever occurred first | 
| Number of BeneFIX Infusions to Treat Each New Bleed | The number of BeneFIX infusions administered to treat each new bleed was calculated by adding the on-demand initial treatment and any on-demand follow-up treatments for the same bleed. If there was more than one bleed location (eg, ankle and joint) with identical bleed start date and time, it was treated as one bleed occurrence. | Up to 6 months or 50 exposure days whichever occurred first | 
| Average Infusion Dose and Total Factor IX Consumption in On-demand Setting | The total amount (international units [IU]) infused for each BeneFIX infusion was summed to calculate the total factor IX consumption for each participant. The average infusion dose for each participant was calculated as his total factor IX consumption (in IU) divided by the number of infusions administered. | Up to 6 months or 50 exposure days whichever occurred first | 
| Average Infusion Dose and Total Factor IX Consumption in Prophylaxis Setting | The total amount (international units [IU]) infused for each BeneFIX infusion was summed to calculate the total factor IX consumption for each participant. The average infusion dose for each participant was calculated as his total factor IX consumption (in IU) divided by the number of infusions administered. | Up to 6 months or 50 exposure days whichever occurred first | 
| Average Infusion Dose and Total Factor IX Consumption in Recovery Setting | The total amount (international units [IU]) infused for each BeneFIX infusion was summed to calculate the total factor IX consumption for each participant. The average infusion dose for each participant was calculated as his total factor IX consumption (in IU) divided by the number of infusions administered. | Up to 6 months or 50 exposure days whichever occurred first | 
| Percentage of Infusions With Less Than Expected Therapeutic Effects (LETEs) in On-demand Setting | Less than expected therapeutic effect (LETE) in the on-demand setting was defined as 2 successive no response ratings recorded after 2 successive BeneFIX drug infusions, respectively. | Up to 6 months or 50 exposure days whichever occurred first | 
| Percentage of Infusions With Less Than Expected Therapeutic Effects (LETEs) in Prophylaxis Setting | Less than expected therapeutic effect (LETE) in the prophylaxis setting was defined as occurrence of any spontaneous bleed within 48 hours after a regularly scheduled prophylactic dose of BeneFIX (which was not used to treat a bleed). | Up to 6 months or 50 exposure days whichever occurred first |