Pivotal Study (Pharmacokinetics, Efficacy, Safety) of BAX 326 (rFIX) in Hemophilia B Patients

Baxalta now part of Shire86 enrolled

Overview

The purpose of this pivotal Phase 1/3 study is to determine the pharmacokinetic (PK) parameters, the hemostatic efficacy, and the safety of BAX 326, a recombinant factor IX, in previously treated patients (PTPs) with severe and moderately severe hemophilia B.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

Conditions

Hemophilia B

Interventions

BAX 326BIOLOGICAL

* Study Part 1: Pharmacokinetic (PK) Crossover with BAX326 and BeneFIX * Study Part 2: Open-label evaluation of prophylaxis and on-demand BAX326 only * Study Part 3: Open-label repeat of PK evaluation (repeat Study Part 1) with BAX326 only and same study participants as Study Part 1

BeneFIXBIOLOGICAL

* Study Part 1: Pharmacokinetic (PK) Crossover with BAX326 and BeneFIX. * BeneFIX only used in Part 1 of this study. * Study Part 2 and 3 only utilized BAX326

Eligibility

Sex: ALLMin age: 12 YearsMax age: 65 Years

Medical Language ↔ Plain English

Main Inclusion Criteria: * Participant is 12 to 65 years old at the time of screening * Participant and/or legal representative has/have provided signed informed consent * Participant has severe (factor IX (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 * Participant is previously treated with plasma-derived or recombinant FIX concentrate(s) for a minimum of 150 exposure days (EDs) (based on the participant's medical records); if a verifiable, documented history is unavailable, the participant can be enrolled if s/he has 100-150 EDs to any FIX product that are not fully documented and has participated in Study 050901 for at least 50 EDs to Immunine prior to enrollment (not valid for US and Japan). * Participant has no evidence of a history of FIX inhibitors * If the participant is to receive prophylactic treatment, the participant is willing to receive prophylactic treatment over a period of 6 months. * If the participant is to receive on-demand treatment, the participant has ≥12 documented bleeding episodes requiring treatment within 12 months prior to enrollment and is willing to receive on-demand treatment for the duration of this study. Main Exclusion Criteria: * The participant has a history of FIX inhibitors with a titer ≥0.6 Bethesda Units (BU) (as determined by the Nijmegen modification of the Bethesda assay or the assay employed in the respective local laboratory) at any time prior to screening * The participant has a detectable FIX inhibitor at screening, with a titer ≥0.6 BU as determined by the Nijmegen modification of the Bethesda assay in the central laboratory * The participant's weight is \< 35 kg or \> 120 kg * The participant has a history of allergic reaction, eg, anaphylaxis, following exposure to FIX concentrate(s) * The participant has a known hypersensitivity to hamster proteins or recombinant furin (rFurin) * The participant has ongoing or recent evidence of a thrombotic disease, fibrinolysis or disseminated intravascular coagulation (DIC)

Locations (25)

Unnamed facility

Rosario, Argentina

Unnamed facility

Brasília, Brazil

Unnamed facility

São Paulo, Brazil

Outcomes

Primary Outcomes

Study Part 1- Area Under the Plasma Concentration Versus Time Curve From 0 to 72 Hours Per Dose

Computed using the linear trapezoidal method. The concentration at 72 hours was interpolated from the two nearest sampling time points or extrapolated using the last quantifiable concentration and the terminal rate constant λz. λz was estimated from the slope of natural log-linear fitting to latter quantifiable concentrations, with largest adjusted R\^2.

Time frame: 72 hours

Secondary Outcomes

Study Parts 1 and 3: Area Under the Plasma Concentration/Time Curve From Time 0 to Infinity Per Dose (AUC0-∞/ Dose)

Defined as (AUC0-t + Ct)/ λz/ dose, where t is the time of last quantifiable concentration, Ct is the last quantifiable concentration. λz will be estimated from the slope of natural log-linear fitting to latter quantifiable concentrations, with largest adjusted R\^2. The objective of Study Part 3 was to re-evaluate the Pharmacokinetic (PK) parameters for BAX 326 after a period of 6 months of treatment, in participants who accumulated at least 30 EDs to BAX 326, and to compare them with those determined in the same participants participating in Study Part 1.

Time frame: 0-30 minutes before infusion up to 72 hours post-infusion

Study Parts 1 and 3: Mean Residence Time (MRT)

Computed as Area under the moment curve 0-∞ (AUMC0-∞) / AUC0-∞- TI/2, where AUMC0-∞ will be determined in a similar manner as AUC0-∞ and TI represents infusion duration \[hr\] The objective of Study Part 3 was to re-evaluate the Pharmacokinetic (PK) parameters for BAX 326 after a period of 6 months of treatment, in participants who accumulated at least 30 EDs to BAX 326, and to compare them with those determined in the same participants participating in Study Part 1.

Time frame: 0-30 minutes before infusion up to 72 hours post-infusion

Study Parts 1 and 3: Clearance (CL)

Computed as Dose/ AUC0-∞. The objective of Study Part 3 was to re-evaluate the Pharmacokinetic (PK) parameters for BAX 326 after a period of 6 months of treatment, in participants who accumulated at least 30 EDs to BAX 326, and to compare them with those determined in the same participants participating in Study Part 1.

Data from ClinicalTrials.gov

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Unnamed facility

Sofia, Bulgaria

Unnamed facility

Santiago, Chile

Unnamed facility

Bogotá, Colombia

Unnamed facility

Cali, Colombia

Unnamed facility

Prague, Czechia

Unnamed facility

Hiroshima, Japan

Unnamed facility

Nara, Japan

...and 15 more locations

Time frame: 0-30 minutes before infusion up to 72 hours post-infusion

Study Parts 1 and 3: Incremental Recovery at Cmax (IR at Cmax)

Defined as (Cmax - Cpre-infusion)/Dose, where maximum concentration (Cmax) will be determined as the highest concentration achieved within one hour after infusion. The objective of Study Part 3 was to re-evaluate the Pharmacokinetic (PK) parameters for BAX 326 after a period of 6 months of treatment, in participants who accumulated at least 30 EDs to BAX 326, and to compare them with those determined in the same participants participating in Study Part 1.

Time frame: 0-30 minutes before infusion up to 1 hour post-infusion

Incremental Recovery (IR) at 30 Minutes Over Time

IR at 30 Minutes was measured at the following time points during the study: - Part 1 or Part 2, Exposure Day (ED) 1. (If participant was present for Study Part 1, then ED 1 from Part 1 was used. If Participant entered study in Study Part 2, then ED 1 from Part 2 was used.) - Part 2: Week 5 - Part 2: Week 13 - Part 2 or Part 3: Week 26 (Week 26 of study participation) - Study Completion or Termination Visit

Time frame: 0-30 minutes before infusion and 30 minutes post-infusion

Change in Incremental Recovery (IR) at 30 Minutes Over Time

The median changes in IR at 30 Minutes, calculated as the change in IR value from exposure day 1 (ED1).

Time frame: 0-30 minutes before infusion and 30 minutes post-infusion

Study Parts 1 and 3: Half Life (T 1/2)

Elimination phase half-life will be determined as ln2/ λz. The objective of Study Part 3 was to re-evaluate the Pharmacokinetic (PK) parameters for BAX 326 after a period of 6 months of treatment, in participants who accumulated at least 30 EDs to BAX 326, and to compare them with those determined in the same participants participating in Study Part 1.

Time frame: 0-30 minutes before infusion up to 72 hours post-infusion

Study Parts 1 and 3: Volume of Distribution at Steady State (Vss)

Vss computed as CL·MRT. The objective of Study Part 3 was to re-evaluate the Pharmacokinetic (PK) parameters for BAX 326 after a period of 6 months of treatment, in participants who accumulated at least 30 EDs to BAX 326, and to compare them with those determined in the same participants participating in Study Part 1.

Time frame: 0-30 minutes before infusion up to 72 hours post-infusion

Study Part 2: Annualized Bleed Rate (ABR) During Treatment With BAX326

ABR during prophylaxis (twice-weekly) in Part 2 was calculated as (Number of bleeding episodes/observed treatment period in days) \* 365.25. The treatment period on prophylaxis was defined as time between the first and the last prophylactic infusions and ABR on prophylaxis was calculated for participants who received a minimum of 3 months of prophylactic treatment with BAX326.

Time frame: Study Part 2 = 26 weeks ± 1 week (Note: Study Part 1 = 2-4 weeks)

Bleeding Episodes Treated With 1, 2 or ≥3 Infusions of BAX326 by Bleeding Site and Cause

The number of bleeding episodes treated with 1, 2, or ≥3 infusions of BAX326 to achieve adequate hemostasis. Only infusions required until resolution of bleed were considered.

Time frame: Study Part 2 = 26 weeks ± 1 week (Study Part 2 began at week 3-5)

Hemostatic Efficacy at Resolution of All Bleeding Episodes (BEs) Treated With BAX326 by Bleeding Site and Cause

Rating Scale for Treatment of BEs (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.

Time frame: At bleed resolution throughout the study period of 22 months (Study Parts 1, 2, and 3)

Total Weight-adjusted Dose Per Bleeding Episode (BEs) of All BEs Treated With BAX326 by Bleeding Site and Cause

Time frame: Study Part 2 = 26 weeks ± 1 week (Note: Study Part 1 = 2-4 weeks)

Consumption of BAX326 Per Event Per Participant

Weight-adjusted consumption of BAX326 by event per participant, i.e., for prophylactic treatment and for treatment of bleeds until resolution of bleed.

Time frame: Study Part 2 = 26 weeks ± 1 week (Note: Study Part 1 = 2-4 weeks)

Consumption of BAX326 Per Participant: Median Number of Infusions Per Month

Time frame: Study Part 1 = 2-4 weeks, Study Part 2 = 26 weeks ± 1 week (Prophylaxis and On-Demand period), Study Part 3 = 1 week (Total = 29-31 weeks)

Consumption of BAX326 Per Participant: Median Weight-adjusted Consumption Per Month

Time frame: Study Part 1 = 2-4 weeks, Study Part 2 = 26 weeks ± 1 week (Prophylaxis and On-Demand period), Study Part 3 = 1 week (Total = 29-31 weeks)

Number of Participants Who Developed Inhibitory Antibodies to Factor IX (FIX)

Time frame: Study Part 1 = 2-4 weeks, Study Part 2 = 26 weeks ± 1 week, Study Part 3 = 1 week (Total = 29-31 weeks)

Occurrence of Total Binding Antibodies of Indeterminate Specificity (Within Assay Variability)

Occurrence of total binding antibodies of indeterminate specificity (within assay variability) to FIX, antibodies to CHO proteins and rFurin is defined by a dilution of 2 or less increase as compared to levels at screening visit (e.g. negative to 1:20 or 1:40).

Time frame: Study Part 1 = 2-4 weeks, Study Part 2 = 26 weeks ± 1 week, Study Part 3 = 1 week (Total = 29-31 weeks)

Occurrence of Treatment Related Total Binding Antibodies

Occurrence of treatment related total binding antibodies to Factor IX (FIX), antibodies to Chinese hamster ovary (CHO) proteins, and recombinant furin (rFurin) is defined by more than 2-dilution increase as compared to levels at screening visit and confirmed specificity (e.g. negative to 1:80)

Time frame: Study Part 1 = 2-4 weeks, Study Part 2 = 26 weeks ± 1 week, Study Part 3 = 1 week (Total = 29-31 weeks)

Number of Participants Who Experienced Severe Allergic Reactions (e.g. Anaphylaxis)

Time frame: Study Part 1 = 2-4 weeks, Study Part 2 = 26 weeks ± 1 week, Study Part 3 = 1 week (Total = 29-31 weeks)

Number of Participants Who Experienced Thrombotic Events

Time frame: Study Part 1 = 2-4 weeks, Study Part 2 = 26 weeks ± 1 week, Study Part 3 = 1 week (Total = 29-31 weeks)

Number of Participants With Clinically Significant Changes in Laboratory Parameters: Clinical Chemistry

Clinically significant changes in chemistry assessments for Alanine Aminotransferase, Albumin, Alkaline Phosphatase, Aspartate Aminotransferase, Bicarbonate, Bilirubin, Blood Urea Nitrogen, Chloride, Glucose, Potassium, Protein (Serum), Sodium. Clinically Significant (CS) defined as: -1. The abnormal value constitutes an adverse event (AE) and, -2. The abnormal value is a symptom of or related to a disease that is already recorded as an AE in Case Report Form (CRF).

Time frame: Study Part 1 = 2-4 weeks, Study Part 2 = 26 weeks ± 1 week, Study Part 3 = 1 week (Total = 29-31 weeks)

Number of Participants With Clinically Significant Changes in Laboratory Parameters: Hematology

Clinically significant changes in hematology assessments for Basophils, Basophils/Leukocytes, Eosinophils, Eosinophils/Leukocytes, Erythrocyte Mean Corpuscular Hemoglobin Concentration, Erythrocyte Mean Corpuscular Volume, Erythrocytes, Hematocrit, Hemoglobin, Leukocytes, Lymphocytes, Lymphocytes/Leukocytes, Monocytes, Monocytes/Leukocytes, Neutrophils, Neutrophils/Leukocytes, Platelets,

Time frame: Study Part 1 = 2-4 weeks, Study Part 2 = 26 weeks ± 1 week, Study Part 3 = 1 week (Total = 29-31 weeks)

Number of Participants With Clinically Significant Changes in Laboratory Parameters: Vital Signs

Clinically significant changes in vital signs assessments for pulse rate, systolic/diastolic blood pressure, respiratory rate, body temperature

Time frame: Study Part 1 = 2-4 weeks, Study Part 2 = 26 weeks ± 1 week, Study Part 3 = 1 week (Total = 29-31 weeks)

Number of Participants With Clinically Significant Changes in Laboratory Parameters: Thrombogenic Markers

Clinically significant changes in thrombogenic markers assessments for thrombin-antithrombin (TAT), prothrombin fragment 1.2, and D-dimer as evaluated by an independent Data Monitoring Committee (DMC)

Time frame: Study Part 1 = 2-4 weeks, Study Part 2 = 26 weeks ± 1 week, Study Part 3 = 1 week (Total = 29-31 weeks)

Number of Adverse Events (AEs) After BAX326 Treatment

Time frame: Study Part 1 = 2-4 weeks, Study Part 2 = 26 weeks ± 1 week, and Study Part 3 = 1 week (Total = 29-31 weeks)

Number of Participants With Adverse Events (AEs) After BAX326 Treatment

Time frame: Study Part 1 = 2-4 weeks, Study Part 2 = 26 weeks ± 1 week, and Study Part 3 = 1 week (Total = 29-31 weeks)

EuroQoL (Quality of Life)-5 Dimensions (EQ-5D) Total Index Scores

EQ-5D is a participant answered questionnaire scoring 5 dimensions - mobility, self-care, usual activities, pain/discomfort and anxiety/depression. The EQ-5D total score ranges from 0 (worst health state) to 1 (perfect health state) and 1 reflects the best outcome.