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

Study Overview
=================
Brief Summary
-----------------
This study will examine the safety, pharmacokinetics and efficacy of rIX-FP for the control and prevention of bleeding episodes in subjects who have previously received factor replacement therapy for hemophilia B.

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

Conditions
-----------------
Hemophilia B

Intervention / Treatment
-----------------
* Biological: rIX-FP


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male subjects, 12 to 65 years old Severe hemophilia B (FIX activity of ≤ 2%) Subjects who have received FIX products (plasma-derived and/or recombinant FIX) for > 150 exposure days (EDs) No history of FIX inhibitor formation, no detectable inhibitors at Screening and no family history of inhibitors against FIX Written informed consent for study participation On-demand subjects only, who have experienced a minimum average of 2 non-trauma induced bleeding episodes requiring treatment with a FIX product during the previous 6 or 3 months Exclusion Criteria: Known hypersensitivity to any FIX product or hamster protein Known congenital or acquired coagulation disorder other than congenital FIX deficiency HIV positive subjects with a CD4 count < 200/mm3 Low platelet count, kidney or liver dysfunction Recent life-threatening bleeding episode

Ages Eligible for Study
-----------------
Minimum Age: 12 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Prophylaxis<br>Routine weekly prophylaxis and episodic treatment for bleeding episodes. An individualized dosing interval may be tested in sub-group subjects during the 2nd part of the trial. Subjects may participate in a surgical 'sub-study' in which rIX-FP may be administered prior to, during and after surgical intervention. | Biological: rIX-FP<br>* Recombinant IX-FP (rIX-FP) is a fusion protein linking coagulation factor IX with albumin, and will be administered by intravenous administration<br>|
| Experimental: On-demand<br>Episodic treatment for bleeding episodes during the first 6 months then switch to routine weekly prophylaxis for a further 6 months Subjects may participate in a surgical 'sub-study' in which rIX-FP may be administered prior to, during and after surgical intervention. | Biological: rIX-FP<br>* Recombinant IX-FP (rIX-FP) is a fusion protein linking coagulation factor IX with albumin, and will be administered by intravenous administration<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Frequency of Spontaneous Bleeding Events Between On-demand and Prophylaxis Treatments (Annualized) | Subjects in the on-demand arm received on-demand dosing with rIX-FP for up to 26 weeks (on-demand regimen), and then received weekly prophylaxis with rIX-FP for the remainder of the study (prophylaxis regimen). The effectiveness of prophylaxis in comparison to on-demand therapy was investigated by comparing the same subject's annualized spontaneous bleeding rate (AsBR) during the on-demand regimen and during the prophylaxis regimen. | Up to 26 weeks for on-demand regimen, and between 1 and 17 months for prophylaxis regimen. | 
| Number of Subjects Developing Inhibitors Against Factor IX (FIX) | The number of participants developing inhibitors against factor IX (FIX) along with the 95% Clopper-Pearson confidence interval, are summarized for subjects with 50 or more exposure days (EDs) to rIX-FP, and for all participants in the study. | Up to 27.7 months (maximum) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Frequency of Related Adverse Events | The percentage of participants experiencing treatment-related adverse-events (TEAEs). | For the duration of the study; median 20.27 months. | 
| Number of Subjects Developing Antibodies Against rIX-FP |  | For the duration of the study; median 20.27 months. | 
| Proportion of Bleeding Episodes Requiring One or ≤ Two Injections of rIX-FP to Achieve Hemostasis | Number of injections required to achieve hemostasis expressed as a percentage of the bleeding episodes requiring treatment. | For the duration of the study; median 20.27 months. | 
| Investigator's Overall Clinical Assessment of Hemostatic Efficacy for Treatment of Bleeding Episodes, Based on a Four Point Ordinal Scales (Excellent, Good, Moderate, Poor/No Response) | Number of bleeding episodes requiring treatment that resulted in hemostatic efficacy of excellent, good, moderate, poor/no response, according to the Investigator's clinical assessment of hemostatic efficacy, expressed as a percentage of the bleeding episodes requiring treatment. | For the duration of the study; median 20.27 months | 
| rIX-FP Consumed Per Month While Maintaining Assigned Prophylactic Treatment Interval During Routine Prophylaxis. | Time frame: For Prophylaxis Arm 7-, 10- and 14-day regimens, median 269, 240 and 386 days respectively. For On-demand Arm, prophylaxis regimen, median 316 days. | Median 269, 240, 386 and 316 days, respectively (see Description) | 
| Incremental Recovery of rIX-FP | Pharmacokinetic (PK) data are presented for a single 50 IU/kg dose of rIX-FP. | 336 hours | 
| Half-life (t1/2) of a Single Dose of rIX-FP | PK data are presented for a single 50 IU/kg dose of rIX-FP. | 336 hours | 
| Area Under the Curve (AUC) | AUC to the last sample with quantifiable drug concentration (AUClast) of a single dose of rIX-FP. PK data are presented for a single 50 IU/kg dose of rIX-FP. | 336 hours | 
| Clearance of a Single Dose of rIX-FP | PK data are presented for a single 50 IU/kg dose of rIX-FP. | 336 hours | 
| Investigator's (or Surgeon's) Overall Clinical Assessment of Hemostatic Efficacy for Surgical Prophylaxis, Based on a Four Point Ordinal Scale (Excellent, Good, Moderate, Poor/No Response) | Number of surgical events treated prophylactically with rIX-FP that resulted in hemostatic efficacy of excellent, good, moderate, poor/no response, according to the Investigator's (surgeon's) overall assessment of hemostatic efficacy for surgical prophylaxis. | Up to 14 days after surgery | 
| Annualized Spontaneous Bleeding Events Compared Between 7 Day Prophylactic and Extended Regimens | Median number of spontaneous bleeds per year per subject comparing 7-, 10- and 14- day prophylactic regimens. | During treatment, between median 240 and 386 days per subject. |