BAX 326 Pediatric Study

Study Overview
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Brief Summary
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The purpose of this study is to assess BAX 326 pharmacokinetic parameters, to evaluate its hemostatic efficacy, safety, immunogenicity, and changes in health-related quality of life in pediatric patients.

Detailed Description
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The secondary outcome measure: Area Under the Plasma Concentration Versus Time Curve From 0 to 72 Hours (h) Post-infusion analysis was not done due to the different time-points for the last PK blood sample, AUC0-72 h was redundant and only total AUC was included in the PK analysis.

Official Title
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BAX 326 (Recombinant Factor IX): A Phase 2/3 Prospective, Uncontrolled, Multicenter Study Evaluating Pharmacokinetics, Efficacy, Safety, and Immunogenicity in Previously Treated Pediatric Patients With Severe (FIX Level < 1%) or Moderately Severe (FIX Level 1-2%) Hemophilia B

Conditions
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Hemophilia B

Intervention / Treatment
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* Biological: BAX326


Participation Criteria
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Eligibility Criteria
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Main Inclusion Criteria: Participant and/or legal representative has/have voluntarily provided signed informed consent Participant has severe (FIX level < 1%) or moderately severe (FIX level ≤ 2%) hemophilia B Participant is < 12 years old at the time of screening Participant has no evidence of a history of FIX inhibitors (based on the participant's medical records) Participant is immunocompetent as evidenced by a CD4 count ≥ 200 cells/mm^3 Main Exclusion Criteria: Participant has a detectable FIX inhibitor at screening, with a titer ≥ 0.6 Bethesda Unit (BU) Participant has a history of allergic reaction, e.g. anaphylaxis, following exposure to FIX concentrate(s) Participant has evidence of an ongoing or recent thrombotic disease Participant has an inherited or acquired hemostatic defect other than hemophilia B

Ages Eligible for Study
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Maximum Age: 12 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BAX326 < 6 years of age<br> | Biological: BAX326<br>* All participants underwent a pharmacokinetic evaluation with BAX326 (recombinant Factor IX) followed by twice weekly prophylactic treatment for 6 months or for at least 50 exposure days, whichever occurred last.<br>* Other names: RIXUBIS;|
| Experimental: BAX326 6 to <12 years of age<br> | Biological: BAX326<br>* All participants underwent a pharmacokinetic evaluation with BAX326 (recombinant Factor IX) followed by twice weekly prophylactic treatment for 6 months or for at least 50 exposure days, whichever occurred last.<br>* Other names: RIXUBIS;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events (AEs) Possibly or Probably Related to BAX326 |  | Throughout study period (approximately 17 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics (PK): Total Area Under the Plasma Concentration Versus Time Curve From 0 to 72 Hours Post-infusion Per Dose (AUC 0-72h/Dose) |  | Within 30 mins pre-infusion and 4 post-infusion timepoints | 
| Pharmacokinetics (PK): Total Area Under the Plasma Concentration Versus Time Curve From 0 to Infinity Post-infusion Per Dose (Total AUC/Dose) |  | Within 30 mins pre-infusion and 4 post-infusion timepoints. Refer to Population Description below for more details. | 
| Pharmacokinetics (PK): Mean Residence Time (MRT) | Computed as total area under the first moment curve (total AUMC) divided by the total area under the concentration versus time curve (total AUC) | Within 30 mins pre-infusion and 4 post-infusion timepoints. Refer to Population Description below for more details. | 
| Pharmacokinetics (PK): Factor IX (FIX) Clearance (CL) | Computed as the dose divided by total Area under the curve (AUC) | Within 30 mins pre-infusion and 4 post-infusion timepoints. Refer to Population Description below for more details. | 
| Pharmacokinetics (PK): Incremental Recovery (IR) | The rise in FIX activity in IU/dL per unit dose administered in IU/kg. Calculated as follows: (FIX activity at post-infusion minus FIX activity at pre-infusion) divided by weight-adjusted dose | Within 30 mins pre-infusion and 30 mins post-infusion | 
| Pharmacokinetics (PK): Elimination Phase Half-life (T 1/2) | Calculated as log_e2/λ, where λ is the regression slope in the terminal phase of the least absolute deviations regression model | Within 30 mins pre-infusion and 4 post-infusion timepoints. Refer to Population Description below for more details. | 
| Pharmacokinetics (PK): Volume of Distribution at Steady State (Vss) | Computed as Clearance (CL) * Mean residence time (MRT) | Within 30 mins pre-infusion and 4 post-infusion timepoints. Refer to Population Description below for more details. | 
| Pharmacokinetics (PK): Incremental Recovery (IR) Over Time | IR calculated as follows: (FIX activity at post-infusion minus FIX activity at pre-infusion) divided by weight-adjusted dose. IR is determined at baseline (PK analysis), Week 5, Week 13 and Week 26 timepoints. Number of participants contributing data (N) for this outcome measure is included in the category title in the order: pediatric participants > 6 years of age; pediatric participants 6 to <12 years of age; pharmacokinetic Full Analysis Set (PKFAS). | Within 30 mins pre-infusion and 30 mins post-infusion at baseline, Week 5, Week 13 and Week 26. | 
| Hemostatic Efficacy: Treatment of Bleeding Episodes: Number of Infusions Per Bleeding Episode |  | Throughout study period (approximately 17 months) | 
| Hemostatic Efficacy: Treatment of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Resolution of Bleed | Rating Scale for Treatment of bleeding episodes (4-point ordinal scale): - Excellent: Full relief of pain and cessation of objective signs of bleeding (eg, swelling, tenderness, and decreased range of motion in the case of musculoskeletal hemorrhage) after a single infusion. No additional infusion required for the control of bleeding. Administration of further infusions to maintain hemostasis did not affect this 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 single infusion. Required more than 1 infusion for complete resolution. - None: No improvement or condition worsens. | Throughout study period (approximately 17 months) | 
| Hemostatic Efficacy: Prophylaxis: Annualized Bleeding Rate (ABR) | The annualized bleeding rate (ABR) during prophylaxis was calculated only for participants who had adequate treatment time for bleeding rate assessment (i.e., more than 3 months of prophylaxis treatment). The observation period for prophylaxis was to be the time between the first and the last prophylactic infusions. The treatment period for surgery was to be excluded from the bleed rate calculation. ABR calculated as (Number of bleeding episodes/observed treatment period in days) * 365.25. | Throughout study period (approximately 17 months) | 
| Consumption of BAX326: Number of Infusions Per Month |  | Throughout study period (approximately 17 months) | 
| Consumption of BAX326: Number of Infusions Per Year |  | Throughout study period (approximately 17 months) | 
| Consumption of BAX326: Weight-adjusted Consumption Per Month |  | Throughout study period (approximately 17 months) | 
| Consumption of BAX326: Weight-adjusted Consumption Per Year (Annualized) |  | Throughout study period (approximately 17 months) | 
| Consumption of BAX326: Weight-adjusted Consumption Per Event | Event includes prophylactic infusions of study product and infusions of study product for treatment of bleeding episodes (BEs). | Throughout study period (approximately 17 months) | 
| Safety and Immunogenicity: Number of Participants Who Developed Inhibitory Antibodies to Factor IX (FIX) |  | Throughout study period (approximately 17 months) | 
| Safety and Immunogenicity: Number of Participants Who Developed Total Binding Antibodies to Factor IX (FIX) | If more than 2-dilution increase as compared to pre-study level at screening and titers verified for specificity in the confirmatory assay. AB=antibodies in category for outcome measure data. | Throughout study period (approximately 17 months) | 
| Safety: Number of Participants With Severe Allergic Reactions, e.g. Anaphylaxis |  | Throughout study period (approximately 17 months) | 
| Safety: Number of Participants With Thrombotic Events |  | Throughout study period (approximately 17 months) | 
| Safety: Number of Participants With Clinically Significant Changes in Routine Laboratory Parameters (Haematology and Clinical Chemistry), and Vital Signs | Categories consist of Clinically Significant (CS) changes in haemaotology parameters, clinical chemistry parameters and vital signs. Abbreviations in categories; Clin=clinical; params=parameters | Throughout study period (approximately 17 months) | 
| Safety: Number of Participants Who Developed Antibodies to Chinese Hamster Ovary (CHO) Proteins and Recombinant Furin (rFurin) | If more than 2-dilution increase as compared to pre-study level at screening and titers verified for specificity in the confirmatory assay. | Throughout study period (approximately 17 months) | 
| Health-related Quality of Life (HRQoL): PedsQL™ Change From Baseline in Total Score | For this study, the PedsQL™ questionnaires for participants 2 to 7 years of age (parent-proxy versions for age groups 2-4 years and 5-7 years) and PedsQL™ Child version for participants 8 to 12 years of age were used. The Peds-QL is a generic Health-Related Quality of Life (HR QoL) instrument designed specifically for a pediatric population. It captures the following domains: general health/activities, feelings/emotional, social functioning, school functioning. A 5-point score is used for each domain: from 0 (never) to 4 (almost always). Items are reversed scored and linearly transformed to a 0-100 scale as follows: 0=100, 1=75, 2=50, 3=25, 4=0 so that higher scores indicate better quality of life (QoL). The total score is the mean (average) of all scores from the 4 domains. The change from baseline in total score is reported- a positive score indicates a better QoL compared to baseline and a negative score indicates a poorer QoL compared to baseline. | Baseline and 6 months | 
| Health-related Quality of Life (HRQoL): Haemo-QoL, Change From Baseline in Total Score | The Haemo-QoL is a quality of life (QoL) assessment instrument for children and adolescents with haemophilia. As a hemophilia-specific instrument, this measure assesses very specific aspects of dealing with hemophilia. For the Haemo-QoL, higher scores indicate a worse quality of life. Scores on a scale range between 0 and 100. | Baseline and 6 months | 
| Health Resource Use: Number of Hospitalizations | The number of hospitalizations per participant. Number of participants contributing data (N) for this outcome measure is included in the category title in the order: pediatric participants < 6 years of age; pediatric participants 6 to <12 years of age; Full Analysis Set. | Baseline (Pharmacokinetic [PK] assessment), Week 5, Week 13 and Week 26 | 
| Health Resource Use: Length of Hospitalization | The length of hospitalization per participant. Number of participants contributing data (N) for this outcome measure is included in the category title in the order: pediatric participants < 6 years of age; pediatric participants 6 to <12 years of age; Full Analysis Set. | Baseline (Pharmacokinetic [PK] assessment), Week 5, Week 13 and Week 26 | 
| Health Resource Use: Unscheduled Doctor's Office Visits | The number of unscheduled doctor's Office visits per participant. Number of participants contributing data (N) for this outcome measure is included in the category title in the order: pediatric participants < 6 years of age; pediatric participants 6 to <12 years of age; Full Analysis Set. | Baseline (Pharmacokinetic [PK] assessment), Week 5, Week 13 and Week 26 | 
| Health Resource Use: Emergency Room Visits | The number of Emergency Room visits per participant. Number of participants contributing data (N) for this outcome measure is included in the category title in the order: pediatric participants < 6 years of age; pediatric participants 6 to <12 years of age; Full Analysis Set. | Baseline (Pharmacokinetic [PK] assessment), Week 5, Week 13 and Week 26 | 
| Health Resource Use: Days Lost From School | The number of days lost from school per participant. Number of participants contributing data (N) for this outcome measure is included in the category title in the order: pediatric participants < 6 years of age; pediatric participants 6 to <12 years of age; Full Analysis Set. | Baseline (Pharmacokinetic [PK] assessment), Week 5, Week 13 and Week 26 |