Hemophilia B
Conditions
Brief summary
This study will examine the safety and efficacy of a Recombinant Coagulation Factor IX Albumin Fusion Protein (rIX-FP) for the control and prevention of bleeding episodes in subjects who have previously received factor replacement therapy for hemophilia B. The study consists of a screening period, a pharmacokinetic (PK) period, followed by approximately a 5 month treatment period. Subjects will receive weekly routine prophylactic therapy and on-demand treatment for bleeding episodes. In addition, subjects who are not on routine factor replacement therapy prior to the study will receive only on-demand treatment for bleeding episodes.
Interventions
Study subjects will receive a single dose of 25IU/kg of rIX\_FP for pharmacokinetic analysis. Subjects will then be treated for approximately 5 months. The treatment dose will be based on the subject's PK profile and the subject's bleeding phenotype.
Sponsors
CSL Behring
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
12 Years to 65 Years
Healthy volunteers
No
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 obtained before undergoing any study specific procedures
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, abnormal kidney function, or liver disease * On-demand subjects experiencing less than 12 or 6 non-trauma induced bleeding episodes requiring treatment with a FIX product during the previous 6 or 3 months, respectively * Planned major surgical intervention during the study period
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Treatment-related Adverse Events | Approximately 20 weeks | The causal relationship of each adverse event to rIX-FP was assessed by the Investigator. |
| Number of Subjects With Inhibitors Against Factor IX (FIX) | Baseline, Day 10 and Weeks 4, 12 and 20 | The presence of inhibitors against FIX was assessed by the central laboratory by a FIX potency assay. To quantify anti-FIX neutralizing antibodies, the Bethesda assay with the Nijmegen modification was used, and the results expressed as Bethesda Units per mL (BU/mL). A positive inhibitor test is \>=0.6 BU/mL. |
| Number of Subjects Who Developed Antibodies to rIX-FP | Pre-dose, Day 10 and Weeks 4, 12, and 20 | Antibodies against rIX-FP were detected using a direct binding enzyme-linked immunosorbent assay (ELISA). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clearance of a Single Dose of rIX-FP | Pre-dose and up to 14 days after rIX-FP infusion | — |
| Area Under the Curve to the Last Sample With Quantifiable Drug Concentration (AUC0-t) After a Single Dose of rIX-FP | Pre-dose and up to 14 days after rIX-FP infusion. | The plasma concentrations of rIX-FP were measured as FIX activity using a validated, 1-stage assay in a central laboratory for a quantification range from 0.25 to 150% (or 0.25 IU/dL to 150 IU/dL). The PK population comprised all subjects who received at least 1 dose of rIX-FP and for whom a sufficient number of analyzable PK samples had been obtained in order to permit the evaluation of the PK profile of rIX-FP, and who did not receive a dose of rIX-FP or any other FIX product for the treatment of a bleed during the PK sampling period. |
| Breakthrough Bleeding Events | Week 9 to approximately Week 20 | Number of breakthrough bleeding events (spontaneous bleeding events) requiring treatment per subject in subjects receiving prophylactic treatment regimen with rIX-FP |
| Half-life (t1/2) of a Single Dose of rIX-FP | Pre-dose and up to 14 days after infusion | — |
| Incremental Recovery of rIX-FP at 30 Minutes Following Infusion of rIX-FP | 30 minutes after infusion | Incremental recovery (IU/mL/IU/kg) is defined as FIX activity (IU/mL) obtained 30 minutes following infusion, per dose of (IU/kg) infusion. FIX activity was measured at a central laboratory using validated one-stage clotting method. |
Countries
Bulgaria, Israel
Participant flow
Pre-assignment details
A total of 17 subjects were screened and enrolled in the study. Fifteen subjects participated in the pharmacokinetic (PK) evaluation period and were administered a dose of 25 IU/kg rIX-FP. Two subjects did not participate in the PK evaluation period because PK data for these 2 subjects were available from the previous phase 1 study (CSL654\_2001).
Participants by arm
| Arm | Count |
|---|---|
| Prophylactic For the PK evaluation, subjects received a single IV infusion of rIX-FP at a dose of 25 IU/kg. After completion of the PK evaluation period, subjects entered the treatment period and were administered a single IV infusion of rIX-FP once a week at a dose of 15 to 35 IU/kg, or at a dose determined by the investigator. The dose was adjusted up to 75 IU/kg to maintain the trough FIX activity level \> 1% between infusions. | 13 |
| On-demand For the PK evaluation, subjects received a single IV infusion of rIX-FP at a dose of 25 IU/kg. After completion of the PK evaluation period, subjects entered the treatment period and were administered 1 or more IV infusions of rIX-FP at a dose of at least 25 IU/kg to treat minor, moderate or major bleeding episodes. The dose of rIX-FP was calculated by the investigator. | 4 |
| Total | 17 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Sponsor decision | 0 | 2 |
Baseline characteristics
| Characteristic | Prophylactic | On-demand | Total |
|---|---|---|---|
| Age, Continuous | 23.2 years STANDARD_DEVIATION 9.4 | 35.8 years STANDARD_DEVIATION 9.7 | 26.1 years STANDARD_DEVIATION 10.7 |
| Age, Customized < 18 years | 3 participants | 0 participants | 3 participants |
| Age, Customized ≥ 18 years | 10 participants | 4 participants | 14 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 13 Participants | 4 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 14 / 17 |
| serious Total, serious adverse events | 0 / 17 |
Outcome results
Primary
Number of Subjects Who Developed Antibodies to rIX-FP
Antibodies against rIX-FP were detected using a direct binding enzyme-linked immunosorbent assay (ELISA).
Time frame: Pre-dose, Day 10 and Weeks 4, 12, and 20
Population: Safety Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Subjects | Number of Subjects Who Developed Antibodies to rIX-FP | 0 participants |
Primary
Number of Subjects With Inhibitors Against Factor IX (FIX)
The presence of inhibitors against FIX was assessed by the central laboratory by a FIX potency assay. To quantify anti-FIX neutralizing antibodies, the Bethesda assay with the Nijmegen modification was used, and the results expressed as Bethesda Units per mL (BU/mL). A positive inhibitor test is \>=0.6 BU/mL.
Time frame: Baseline, Day 10 and Weeks 4, 12 and 20
Population: Safety Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Subjects | Number of Subjects With Inhibitors Against Factor IX (FIX) | 0 participants |
Primary
Number of Subjects With Treatment-related Adverse Events
The causal relationship of each adverse event to rIX-FP was assessed by the Investigator.
Time frame: Approximately 20 weeks
Population: Safety Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Subjects | Number of Subjects With Treatment-related Adverse Events | 0 participants |
Secondary
Area Under the Curve to the Last Sample With Quantifiable Drug Concentration (AUC0-t) After a Single Dose of rIX-FP
The plasma concentrations of rIX-FP were measured as FIX activity using a validated, 1-stage assay in a central laboratory for a quantification range from 0.25 to 150% (or 0.25 IU/dL to 150 IU/dL). The PK population comprised all subjects who received at least 1 dose of rIX-FP and for whom a sufficient number of analyzable PK samples had been obtained in order to permit the evaluation of the PK profile of rIX-FP, and who did not receive a dose of rIX-FP or any other FIX product for the treatment of a bleed during the PK sampling period.
Time frame: Pre-dose and up to 14 days after rIX-FP infusion.
Population: PK population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| All Subjects | Area Under the Curve to the Last Sample With Quantifiable Drug Concentration (AUC0-t) After a Single Dose of rIX-FP | 2915 h*IU/dL | Geometric Coefficient of Variation 11.3 |
| On-demand | Area Under the Curve to the Last Sample With Quantifiable Drug Concentration (AUC0-t) After a Single Dose of rIX-FP | 2960 h*IU/dL | Geometric Coefficient of Variation 12.4 |
Secondary
Breakthrough Bleeding Events
Number of breakthrough bleeding events (spontaneous bleeding events) requiring treatment per subject in subjects receiving prophylactic treatment regimen with rIX-FP
Time frame: Week 9 to approximately Week 20
Population: Per protocol population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| All Subjects | Breakthrough Bleeding Events | 0.2 Events per subject | Standard Deviation 0.38 |
Secondary
Clearance of a Single Dose of rIX-FP
Time frame: Pre-dose and up to 14 days after rIX-FP infusion
Population: PK population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| All Subjects | Clearance of a Single Dose of rIX-FP | 0.749 mL/h/kg | Geometric Coefficient of Variation 14 |
| On-demand | Clearance of a Single Dose of rIX-FP | 0.699 mL/h/kg | Geometric Coefficient of Variation 10.6 |
Secondary
Half-life (t1/2) of a Single Dose of rIX-FP
Time frame: Pre-dose and up to 14 days after infusion
Population: PK population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| All Subjects | Half-life (t1/2) of a Single Dose of rIX-FP | 77.7 hours | Geometric Coefficient of Variation 25.2 |
| On-demand | Half-life (t1/2) of a Single Dose of rIX-FP | 138 hours | Geometric Coefficient of Variation 37.1 |
Secondary
Incremental Recovery of rIX-FP at 30 Minutes Following Infusion of rIX-FP
Incremental recovery (IU/mL/IU/kg) is defined as FIX activity (IU/mL) obtained 30 minutes following infusion, per dose of (IU/kg) infusion. FIX activity was measured at a central laboratory using validated one-stage clotting method.
Time frame: 30 minutes after infusion
Population: PK population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| All Subjects | Incremental Recovery of rIX-FP at 30 Minutes Following Infusion of rIX-FP | 1.47 IU/dL/IU/kg | Geometric Coefficient of Variation 8.2 |
| On-demand | Incremental Recovery of rIX-FP at 30 Minutes Following Infusion of rIX-FP | 1.35 IU/dL/IU/kg | Geometric Coefficient of Variation 4.9 |