BAX 326 (rFIX) Continuation Study

Study Overview
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Brief Summary
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The purpose of this BAX 326 Continuation Study is to further investigate incremental recovery over time, the hemostatic efficacy, the safety, immunogenicity, and health-related quality of life (HR QoL) of BAX 326 in previously treated patients (PTPs) with severe and moderately severe hemophilia B who participated in BAX 326 pivotal study 250901 or BAX 326 pediatric study 251101.

Official Title
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BAX 326 (Recombinant Factor IX): Evaluation of Safety, Immunogenicity, and Hemostatic Efficacy in Previously Treated Patients With Severe (FIX Level < 1%) or Moderately Severe (FIX Level <= 2%) Hemophilia B - A Continuation Study

Conditions
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Hemophilia B

Intervention / Treatment
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* Biological: BAX 326 (Recombinant factor IX)


Participation Criteria
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Eligibility Criteria
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Main Inclusion Criteria: Subject and/or legal representative has/have voluntarily provided signed informed consent Subject has completed Baxter clinical study 250901 (pivotal study) or Baxter clinical study 251101 (pediatric study) Subject was 12 to 65 years old at the time of screening for Study 250901 or < 12 years old at the time of screening for Study 251101 Subject has severe (FIX level < 1%) or moderately severe (FIX level 1-2%) hemophilia B (based on the one stage activated partial thromboplastin time (aPTT) assay), as tested at screening at the central laboratory Subject has not developed an inhibitory FIX antibody during Baxter Pivotal Study 250901 or Pediatric Study 251101 Main Exclusion Criteria: Subject received factor IX product(s) other than BAX 326 upon completion of Baxter Pivotal Study 250901 or Pediatric Study 251101 Subject has been diagnosed with an acquired hemostatic defect other than hemophilia B For subjects transferring from Pivotal Study 250901: Subject's weight is < 35 kg or > 120 kg Subject is planned to take part in any other clinical study, with the exception of BAX 326 Surgery study as described in this protocol, during the course of the Continuation Study

Ages Eligible for Study
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Maximum Age: 65 Years

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BAX 326<br> | Biological: BAX 326 (Recombinant factor IX)<br>* The treatment with BAX 326 will be at the discretion of the investigator and will consist of either twice weekly prophylactic treatment with 50 IU/kg, modified prophylaxis, or on-demand treatment.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events Possibly or Probably Related to the Investigational Product | Possibly or probably related adverse events that occurred during or after first BAX326 infusion. | Assessed (based on patient diary) every 3 months until study completion (when BAX326 is licensed in the respective country or the participant has accumulated approximately 100 exposure days to BAX 326, whichever is last). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment of Bleeding Episodes: Number of Infusions Per Bleeding Episode Required Until Bleed Resolution | Number of Infusions of BAX326 that were required until bleed resolution. | Throughout the study from screening to study completion (when BAX326 is licensed in the respective country or the participant has accumulated approximately 100 exposure days to BAX 326, whichever is last). | 
| Treatment of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Resolution of Bleed | Overall clinical efficacy rating of bleeding episodes was done at resolution of bleed according these rating scale: Excellent=Full relief of pain and cessation of objective signs of bleeding after a single infusion. No additional infusion is required for the control of bleeding. Administration of further infusion would not affect the scoring. Good=Definite pain relief and/or improvement in signs of bleeding after a single infusion. Possibly requires more than 1 infusion for complete resolution. Fair=Probable and/or slight relief of pain and slight improvement in signs of bleeding after a single infusion. Required more than 1 infusion for complete resolution. None=No improvement or condition worsens. | Throughout the study from screening to study completion (when BAX326 is licensed in the respective country or the participant has accumulated approximately 100 exposure days to BAX 326, whichever is last). | 
| Annualized Bleed Rate During Prophylaxis Treatment | Annualized bleed rate (ABR) was calculated as (number of bleeding episodes/observed treatment period in days)*365.25 | For prophylactic treatment the period from first to last prophylactic infusion is considered. | 
| Consumption of BAX 326: Number of Infusions Per Month and Per Year | The number of infusions consumed per month and per year for the prophylactic and on-demand treatment regimens. | Throughout the study from screening to study completion (when BAX326 is licensed in the respective country or the participant has accumulated approximately 100 exposure days to BAX 326, whichever is last). | 
| Consumption of BAX 326: Weight Adjusted Consumption Per Month and Per Year | The weight adjusted consumption of BAX 326 per month and per year for the prophylactic and on-demand treatment regimens. | Throughout the study from screening to study completion (when BAX326 is licensed in the respective country or the participant has accumulated approximately 100 exposure days to BAX 326, whichever is last). | 
| Consumption of BAX326: Weight Adjusted Consumption Per Bleeding Episode | The weight adjusted consumption of BAX 326 per bleeding episode for the prophylactic and on-demand treatment regimens. Only infusions required until the resolution of bleed are considered. | Throughout the study from screening to study completion (when BAX326 is licensed in the respective country or the participant has accumulated approximately 100 exposure days to BAX 326, whichever is last). | 
| Development of Inhibitory and Total Binding Antibodies to Factor IX | Testing for inhibitory and total binding antibodies to Factor IX (FIX). Development during study means negative at screening and positive at any subsequent visit. Treatment emergent means more than 2-dilution increase as compared to the pre-study titer at screening. | Laboratory assessment for immunology were done at screening, at exposure day 1, at week 4 (± 1 week), at month 3 (±1 week), thereafter, every 3 months (± 1 week) and at study completion/termination. | 
| Development of Antibodies to Chinese Hamster Ovary Proteins (CHO Proteins) and rFurin | Testing for antibodies to CHO proteins and rFurin. Development during study means negative at screening and positive at any subsequent visit. Treatment emergent means more than 2-dilution increase as compared to the pre-study titer at screening. | Laboratory assessment for immunology were done at screening, at exposure day 1, at week 4 (± 1 week), at month 3 (±1 week), thereafter, every 3 months (± 1 week) and at study completion/termination. | 
| Occurrence of Severe Allergic Reactions and Thrombotic Events | The occurrence of severe allergic reactions and thrombotic events was assessed. | Throughout the study from screening to study completion (when BAX326 is licensed in the respective country or the participant has accumulated approximately 100 exposure days to BAX 326, whichever is last). | 
| Clinical Significant Changes in Routine Laboratory Parameters and Vital Signs | Hematology panel consists of complete blood count (hemoglobin, hematocrit, erythrocytes, leukocytes) with differential (ie, basophils, eosinophils, lymphocytes, monocytes, neutrophils), mean corpuscular volume, mean corpuscular hemoglobin concentration and platelet count. Clinical chemistry panel consists of sodium, potassium, chloride, bicarbonate, total protein, albumin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, alkaline phosphatase, blood urea nitrogen, creatinine and glucose. Vital signs include body temperature, respiratory rate, pulse rate, supine systolic and diastolic blood pressure. CS=clinically significant, NCS=not clinically significant. Change from Screening to End of Study is reported. | Measurements at screening and at study completion/termination are included in the analysis. | 
| Pharmacokinetics: Incremental Recovery (IR) Over Time | PK infusion with investigational product was administered after a wash out period of at least 5 days. Incremental recovery is calculated as IR30min = (C30min [IU/dL] - Cpre-infusion [IU/dL]) / dose per kg body weight [IU/kg] where C30min and Cpre-infusion relate to the unadjusted concentration values. | IR over time was measured as Baseline and at Completion/Termination visit within 30 minutes pre-infusion and at 30 (± 5) minutes post-infusion. | 
| Pharmacokinetics: Area Under the Plasma Concentration Versus Time Curve From Time 0 to Infinity (AUC 0-∞) | After a wash out period of at least 5 days PK infusion with investigational product was administered. AUC 0-∞ is defined as AUC 0-t + Ct/lambda z, where t is the time of last quantifiable concentration, Ct is the last quantifiable concentration. | PK assessments were done within 30 minutes pre-infusion and post-infusion at 30 (± 5) minutes, 9 hours (± 30 minutes), 24 (± 2) hours, 48 (± 2) hours and 72 (± 2) hours | 
| Pharmacokinetics: Elimination Phase Half-life (T1/2) | PK infusion with investigational product was administered after a wash out period of at least 5 days. Elimination phase half-life is calculated as T1/2=log e (2) / lambda z where the elimination rate constant (lambda z) will be obtained by log e - linear fitting using least squares deviation to at least the last 3 quantifiable concentrations above pre-infusion level. | PK assessments were done within 30 minutes pre-infusion and post-infusion at 30 (± 5) minutes, 9 hours (± 30 minutes), 24 (± 2) hours, 48 (± 2) hours and 72 (± 2) hours | 
| Pharmacokinetics: Mean Residence Time (MRT) | PK infusion with investigational product was administered after a wash out period of at least 5 days. Mean residence time is calculated as total area under the moment curve divided by the total area under the curve. MRT=(AUMC0-∞[h2*IU/dL])/(AUC0-∞[h*IU/dL]) - TI/2 where AUMC0-∞ is determined in a similar manner as AUC0-∞ and TI represents infusion duration in hours. | PK assessments were done within 30 minutes pre-infusion and post-infusion at 30 (± 5) minutes, 9 hours (± 30 minutes), 24 (± 2) hours, 48 (± 2) hours and 72 (± 2) hours | 
| Pharmacokinetics: Systemic Clearance (CL) | PK infusion with investigational product was administered after a wash out period of at least 5 days. Systemic clearance is balculated as the dose in IU/kg divided by the total AUC. CL= Dose[IU/kg] / AUC0-∞[h*IU/dL] | PK assessments were done within 30 minutes pre-infusion and post-infusion at 30 (± 5) minutes, 9 hours (± 30 minutes), 24 (± 2) hours, 48 (± 2) hours and 72 (± 2) hours | 
| Pharmacokinetics: Volume of Distribution at Steady State (Vss) | PK infusion with investigational product was administered after a wash out period of at least 5 days. Apparent steady state volume of distribution is calculated as Vss = CL * MRT CL=Systemic Clearance and MRT=Mean residence time | PK assessments were done within 30 minutes pre-infusion and post-infusion at 30 (± 5) minutes, 9 hours (± 30 minutes), 24 (± 2) hours, 48 (± 2) hours and 72 (± 2) hours | 
| Pharmacokinetics: Incremental Recovery (IR) | PK infusion with investigational product was administered after a wash out period of at least 5 days. Incremental recovery is calculated as IR30min = (C30min [IU/dL] - Cpre-infusion [IU/dL]) / dose per kg body weight [IU/kg] where C30min and Cpre-infusion relate to the unadjusted concentration values. | PK assessments were done within 30 minutes pre-infusion and post-infusion at 30 (± 5) minutes, 9 hours (± 30 minutes), 24 (± 2) hours, 48 (± 2) hours and 72 (± 2) hours. | 
| Changes in Health Related Quality of Life (HR QoL) Based on Questionnaire SF-36 | The Short Form (36) Health Survey (SF-36) is a 36-item validated, generic HR QoL instrument suitable for participants of 17 years of age or older. The SF-36 consists of eight scaled scores (vitality, physical functioning, bodily pain, general health, mental health, physical role functioning, emotional role functioning, social role functioning) which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight. The lower the score the more disability. The higher the score the less disability. The mental health component summary score ranged from 19.5 to 64.2 with higher scores indicating less disability. The physical health component summary scores ranged from 18.6 to 59.6 with higher scores indicating less disability. | Baseline at exposure day 1 and at study completion/termination. | 
| Changes in Health Related Quality of Life Using the Peds QL | The Pediatric Quality of Life Inventory (Peds QL) is a generic health related quality of life instrument designed specifically for a pediatric population and captures following domains: physical functioning, emotional functioning, social functioning and school functioning. The Peds-QL total score consist of all 23 items of all domains. Score range from 0-100 and higher scores indicate better quality of life (collected scores ranged from 44.6 to 98.9). The Peds-QL Physical Health Summary score consists of 8 items from the physical functioning domain. Score range from 0-100 and higher scores indicate better quality of life (collected scores ranged from 40.6 to 100.0) The Psychosocial Health Summary score consists of 15 items from the emotional, social and school functioning domains. Score range from 0 to 100 and higher scores indicate better quality of life (collected scores ranged from 46.7 to 100.0). | Baseline at exposure day 1 and at study completion/termination. | 
| Changes in Health Related Quality of Life (HR QoL) Based on Questionnaire Haemo-QoL and Haem-A-QoL | The Hemophilia Quality of Life Questionnaire (Haemo-QoL) and the Hemophilia Quality of Life Questionnaire for Adults (Haem-A-Qol) instruments have been developed and used in hemophilia A patients. As a hemophilia-specific instrument, this measure assesses very specific aspects of dealing with hemophilia. The areas covered by this instrument are: physical health, sports/leisure, school/work, dealing with hemophilia, and outlook for the future. Haemo-QoL is used for participants aged 8 to 16 years and total scores range from 0 to 100 with higher scores indicating low quality of life (collected scores ranged from 0.0 to 44.3) Haem-A-QoL is used for participants aged 17 years and older and total scores range from 0 to 100 with higher scores indicating low quality of life (collected scores ranged from 4.9 to 76.8). | Baseline at exposure day 1 and at study completion/termination. | 
| Changes in Health Related Quality of Life (HR QoL) Based on Questionnaire EQ-5D and Pain Score. | The EQ-5D captures overall HR QoL (phyiscal, mental and social functioning). A health utility score can be calculated from this measure, adult and proxy versions available. EQ-5D Visual Analog Scale (EQ-5D VAS):Respondents specify their level of agreement to a statement by indicating a position along a continuous line between two endpoints (scale range from 0 to 100). Score 0 corresponds to the worst health you can imagine and score 100 corresponds to the best health you can imagine (collected scores ranged from 10-100). EQ-5D Total Index is based on general population valuation surveys. Responses to 5 questions are converted to an Index value and score range from 0 to 1, with higher scores indicating better quality of life. Total Index was derived on US population (collected scores ranged from 0.4-1). General pain assessment (Pain score) is done through a visual analog scale (VAS), scores ranging from 0 to 100 with higher scores indicating more pain (collected scores ranged 0-87). | Baseline at exposure day 1 and at study completion/termination. |