A Safety and Efficacy Extension Study of a Recombinant Fusion Protein Linking Coagulation Factor IX With Albumin (rIX-FP) in Patients With Hemophilia B

Study Overview
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Brief Summary
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This study will examine the long-term safety and efficacy of rIX-FP for the control and prevention of bleeding episodes in children and adults with severe hemophilia B. The study will include subjects who have not previously been treated with Factor IX products, subjects who previously completed a CSL-sponsored rIX-FP lead-in study and subjects requiring major non-emergency surgery who have not previously completed a CSL-sponsored rIX-FP lead-in study. A surgical prophylaxis substudy will examine the efficacy of rIX-FP in subjects with hemophilia B who are undergoing non-emergency major or minor surgery. An additional substudy will examine the safety and PK of subcutaneous (SC) administration of rIX-FP.

Official Title
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A Phase 3b Open-label, Multicenter, Safety and Efficacy Extension Study of a Recombinant Coagulation Factor IX Albumin Fusion Protein (rIX-FP) in Subjects With Hemophilia B

Conditions
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Hemophilia B

Intervention / Treatment
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* Biological: rIX-FP


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Main study inclusion criteria: For previously treated subjects, either: Completed a CSL-sponsored rIX-FP (CSL654) study, including study CSL654_3001 [NCT01496274] or study CSL654_3002 [NCT01662531]. Or: Scheduled to have a major non-emergency surgery within approximately 8 weeks from the anticipated date of receiving the first rIX-FP injection. Not previously completed a CSL-sponsored rIX-FP lead-in study. Male, 12 to 70 years of age. Documented severe hemophilia B (FIX activity of ≤ 2%), or confirmed at screening by the central laboratory. Subjects who have received FIX products (plasma-derived and / or recombinant FIX) for > 150 exposure days (EDs), confirmed by their treating physician. No confirmed history of FIX inhibitor formation at screening by the central laboratory For previously untreated subjects: Male, up to 18 years of age. Documented severe hemophilia B (FIX activity of ≤ 2%), or confirmed at screening by the central laboratory. Never previously been treated with FIX clotting factor products (except previous exposure to blood components). No confirmed history of FIX inhibitor formation Surgery substudy inclusion criterion: Must require non-emergency surgery Subcutaneous substudy inclusion criteria: Male, at least 18 years of age. Subjects currently enrolled in Study CSL654_3003 Subjects who have received rIX-FP for ≥ 100 EDs (single-dose cohorts) or for ≥ 50 EDs (repeated-dose cohort) Exclusion criteria: Main study exclusion criteria: Currently receiving a therapy not permitted during the study. Any issue that, in the opinion of the investigator, would render the subject unsuitable for participation in the study. For subjects who have previously completed a CSL-sponsored rIX-FP study: Unwilling to participate in the study for a total of 100 exposure days. For subjects requiring major non-emergency surgery who have not previously completed a CSL-sponsored rIX-FP lead-in study: Known hypersensitivity (ie, allergic reaction or anaphylaxis) to any FIX product or hamster protein. Known congenital or acquired coagulation disorder other than congenital FIX deficiency. Currently receiving IV immunomodulating agents such as immunoglobulin or chronic systemic corticosteroid treatment. Low platelet count, kidney or liver disease. Human immunodeficiency virus positive with a CD4 count < 200/mm3. For previously untreated subjects: Known congenital or acquired coagulation disorder other than congenital FIX deficiency (except for vitamin K deficiency of the newborn). Known kidney or liver dysfunction or any condition which, in the investigator's opinion, place the patient at unjustifiable risk. The surgical substudy does not have any additional exclusion criteria, although subject(s) in France will not be eligible for the surgery sub-study. Subcutaneous substudy exclusion criteria: Intravenous use of rIX-FP within 14 days of subcutaneous administration of rIX-FP. Life-threatening bleeding episode or major surgery during the 3 months prior to substudy entry

Ages Eligible for Study
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Maximum Age: 70 Years

Sexes Eligible for Study
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Male

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: rIX-FP<br>Subjects will administer rIX-FP by intravenous infusion as routine prophylaxis, prevention, and on-demand treatment during a treatment period of approximately 3 years. The routine prophylaxis treatment interval for previously treated patients may be changed at each scheduled 6-month follow-up assessment. On-demand treatment with rIX-FP will be used for all bleeding episodes requiring treatment. Subjects (other than those in France) may participate in a surgical 'substudy' in which rIX-FP may be administered before, during and after surgery. An additional substudy will examine the safety and PK of subcutaneous administration of rIX-FP. For previously untreated patients, subjects will administer rIX-FP intravenously as weekly prophylaxis and/or on-demand treatment during the first 12 months, and as weekly routine prophylaxis thereafter. The dose of rIX-FP administered will be based on the subject's previous rIX-FP use and/or pharmacokinetic data. | Biological: rIX-FP<br>* Recombinant Fusion Protein Linking Coagulation Factor IX with Albumin (rIX-FP)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Number of Participants Who Developed Inhibitors Against Factor IX (FIX) |  | For PTPs: up to 5 years or the time it takes to achieve 100 exposure days (EDs). For PUPs: up to 3 years or the time it takes to achieve 50 EDs. | 
| Mean Incremental Recovery of a 50 IU/kg Dose of CSL654 in Previously Untreated Patients (PUPs) | Incremental Recovery: The increase in plasma concentration per IU/kg of factor administered. | Approximately 30 minutes after infusion of CSL654 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Annualized Bleeding Rate (ABR) by Prophylaxis Regimen in Previously Treated Patients (PTPs) |  | For PTPs: up to 5 years or the time it takes to achieve 100 exposure days (EDs). | 
| Spontaneous ABR by Prophylaxis Regimen in PTPs |  | For PTPs: up to 5 years or the time it takes to achieve 100 exposure days (EDs). | 
| Average Amount of CSL654 (rIX-FP) Consumed Per Month Per Subject During Routine Prophylaxis Treatment. |  | For PTPs: up to 5 years or the time it takes to achieve 100 exposure days (EDs). For PUPs: up to 3 years or the time it takes to achieve 50 EDs. | 
| Percentage of Participants With at Least One Treatment Emergent Adverse Event (TEAE) and the Percentage of Participants With at Least One CSL654-related TEAE |  | For PTPs: up to 5 years or the time it takes to achieve 100 exposure days (EDs). For PUPs: up to 3 years or the time it takes to achieve 50 EDs. | 
| Number of Participants With Investigator's Overall Clinical Assessment of Hemostatic Efficacy for the Treatment of Major Bleeding Events With CSL654 in PUPs | The investigator will rate the efficacy of the rIX-FP treatment based on a hemostatic efficacy four point rating scale of excellent, good, moderate, or poor/no response. | Up to 3 years or the time it takes to achieve 50 EDs | 
| Total ABR for On-demand Regimen vs. 14-Day Regimen in PTPs |  | For PTPs: up to 5 years or the time it takes to achieve 100 exposure days (EDs). | 
| Spontaneous ABR for On-demand Regimen vs. 14-Day Regimen in PTPs |  | For PTPs: up to 5 years or the time it takes to achieve 100 exposure days (EDs). | 
| Total ABR for Subjects >=12 Years: 7-Day Regimen vs. 14-Day Regimen in PTPs |  | For PTPs: up to 5 years or the time it takes to achieve 100 exposure days (EDs). | 
| Spontaneous ABR for Subjects >=12 Years: 7-Day Regimen vs. 14-Day Regimen in PTPs |  | For PTPs: up to 5 years or the time it takes to achieve 100 exposure days (EDs). | 
| Total ABR for Subjects >=12 Years: 7-Day Regimen vs. (10 or 14)-Day Regimen in PTPs |  | For PTPs: up to 5 years or the time it takes to achieve 100 exposure days (EDs). | 
| Spontaneous ABR for Subjects >=12 Years: 7-Day Regimen vs. (10 or 14)-Day Regimen in PTPs |  | For PTPs: up to 5 years or the time it takes to achieve 100 exposure days (EDs). |