Hemophilia B
Conditions
Brief summary
This study will examine the pharmacokinetics, safety and efficacy of rIX-FP for the control and prevention of bleeding episodes in children who have previously received factor replacement therapy for hemophilia B.
Interventions
BIOLOGICALrIX-FP
Recombinant Fusion Protein Linking Coagulation Factor IX with Albumin (rIX-FP)
Sponsors
CSL Behring
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
No minimum to 11 Years
Healthy volunteers
No
Inclusion criteria
* Male subjects, younger than 12 years old. * Severe hemophilia B (Factor IX \[FIX\] activity of ≤ 2%). * Body weight ≥ 10 kg. * Subjects who have received FIX products (plasma-derived and/or recombinant FIX) for \> 150 exposure days (EDs) (6 to \< 12 years), and \> 50 EDs (\< 6 years). * 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.
Exclusion criteria
* Known hypersensitivity to any FIX product or hamster protein. * Known congenital or acquired coagulation disorder other than congenital FIX deficiency. * Kidney or liver disease. * Recent life-threatening bleeding episode.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects Developing Inhibitors to Factor IX (FIX) | 12 months | Inhibitor formation was defined as any inhibitor (≥0.6 BU \[Bethesda Units\]/mL) identified and confirmed by retesting. |
| Incremental Recovery Following a Single Intravenous Dose of 50 IU/kg rIX-FP or Previous FIX Product | 30 minutes after infusion | Incremental recovery (IU/dL/IU/kg) is defined as the FIX activity (IU/dL) 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. Recovery values were baseline-corrected for pre-infusion plasma FIX activity. Incremental recovery was measured following a single intravenous dose of 50 IU/kg rIX-FP on Day 1. Analysis of previous FIX product was conducted at the beginning of the study in a subset of subjects who had no historical pharmacokinetic (PK) data of their previous FIX product. For the PK assessment, the previous FIX product was administered by IV infusion after approximately 4 days following the last FIX treatment, prior to any dosing of rIX-FP. The formal PK population consisted of subjects who received at least 1 dose of rIX-FP for PK assessment and for whom a sufficient number of analyzable PK samples had been obtained to permit the evaluation of the PK profile of rIX-FP. |
| Half-life (t1/2) Following a Single Intravenous Dose of 50 IU/kg rIX-FP or Previous FIX Product | Pre-dose, 30 minutes, 3, 24, 48, 72 120, 168, 240 and 336 hours post-dose | FIX activity was measured at a central laboratory using validated one-stage clotting method. FIX levels were not corrected for baseline values. |
| Area Under the Concentration Versus Time Curve From Time Point Zero to the Last Sample With Quantifiable Drug Concentration (AUClast) | Pre-dose, 30 minutes, 3, 24, 48, 72 120, 168, 240 and 336 hours post-dose | AUClast following a single intravenous dose of 50 IU/kg rIX-FP or previous FIX product. FIX activity was measured at a central laboratory using validated one-stage clotting method. FIX levels were not corrected for baseline values. |
| Clearance for FIX Activity Following a Single Intravenous Dose of 50 IU/kg rIX-FP or Previous FIX Product | Pre-dose, 30 minutes, 3, 24, 48, 72 120, 168, 240 and 336 hours post-dose | FIX activity was measured at a central laboratory using validated one-stage clotting method. FIX levels were not corrected for baseline values. Clearance is normalized for body weight. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects Developing Antibodies Against rIX-FP | 12 months | Antibodies to rIX-FP were measured using a direct-binding enzyme-linked immunosorbent assay (ELISA). |
| Number of Bleeding Episodes Requiring One, Two or More Than Two Infusions of rIX-FP to Achieve Hemostasis | Approximately 12 months | For each bleeding episode that required treatment, the number of episodes that required one, two or more than two infusions of rIX-FP to achieve hemostasis |
| Consumption of rIX-FP During Routine Prophylaxis | 12 months | Consumption of rIX-FP during routine prophylaxis is expressed as the total prophylaxis dose per month. |
| Number of Subjects With Treatment-related Adverse Events | 12 months | — |
Countries
Australia, Austria, Canada, Czechia, France, Germany, Israel, Italy, Russia, Spain
Participant flow
Recruitment details
Of the 18 sites that were activated, subjects were enrolled from 17 sites in 10 countries.
Pre-assignment details
Subjects \<12 years of age with severe hemophilia B (FIX activity of ≤2%) were planned to be enrolled in the study, including 11 to 12 subjects in each age group (6 to \<12 years and \<6 years of age). Of 29 subjects screened, 27 subjects were enrolled and treated with rIX-FP.
Participants by arm
| Arm | Count |
|---|---|
| Age < 6 Years Subjects less than 6 years of age who received a single dose of 50 IU/kg rIX-FP on Day 1 during the pharmacokinetic phase of the study.
Subjects received weekly (7-day) routine prophylaxis treatment with an initial weekly dose of 35 to 50 IU/kg rIX-FP, which may have been adjusted based on protocol-specified criteria. | 12 |
| Age 6 to <12 Years Subjects between 6 and less than 12 years of age who received a single dose of 50 IU/kg rIX-FP on Day 1 during the pharmacokinetic phase of the study.
Subjects received weekly (7-day) routine prophylaxis treatment with an initial weekly dose of 35 to 50 IU/kg rIX-FP, which may have been adjusted based on protocol-specified criteria. | 15 |
| Total | 27 |
Baseline characteristics
| Characteristic | Age < 6 Years | Age 6 to <12 Years | Total |
|---|---|---|---|
| Age, Continuous | 3.2 years STANDARD_DEVIATION 1.7 | 8.1 years STANDARD_DEVIATION 1.41 | 5.9 years STANDARD_DEVIATION 2.93 |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 12 Participants | 15 Participants | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 23 / 27 |
| serious Total, serious adverse events | 4 / 27 |
Outcome results
Primary
Area Under the Concentration Versus Time Curve From Time Point Zero to the Last Sample With Quantifiable Drug Concentration (AUClast)
AUClast following a single intravenous dose of 50 IU/kg rIX-FP or previous FIX product. FIX activity was measured at a central laboratory using validated one-stage clotting method. FIX levels were not corrected for baseline values.
Time frame: Pre-dose, 30 minutes, 3, 24, 48, 72 120, 168, 240 and 336 hours post-dose
Population: PK Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| rIX-FP | Area Under the Concentration Versus Time Curve From Time Point Zero to the Last Sample With Quantifiable Drug Concentration (AUClast) | rIX-FP Assessment (n = 27, 12, 15) | 4156.7037 IU*hr/dL | Standard Deviation 1204.09549 |
| rIX-FP | Area Under the Concentration Versus Time Curve From Time Point Zero to the Last Sample With Quantifiable Drug Concentration (AUClast) | Previous FIX Assessment (n = 16, 7, 9) | 718.9386 IU*hr/dL | Standard Deviation 230.52884 |
| Age < 6 Years | Area Under the Concentration Versus Time Curve From Time Point Zero to the Last Sample With Quantifiable Drug Concentration (AUClast) | rIX-FP Assessment (n = 27, 12, 15) | 3891.4820 IU*hr/dL | Standard Deviation 1252.99415 |
| Age < 6 Years | Area Under the Concentration Versus Time Curve From Time Point Zero to the Last Sample With Quantifiable Drug Concentration (AUClast) | Previous FIX Assessment (n = 16, 7, 9) | 676.5414 IU*hr/dL | Standard Deviation 316.91381 |
| Age 6 to <12 Years | Area Under the Concentration Versus Time Curve From Time Point Zero to the Last Sample With Quantifiable Drug Concentration (AUClast) | rIX-FP Assessment (n = 27, 12, 15) | 4368.8810 IU*hr/dL | Standard Deviation 1162.09967 |
| Age 6 to <12 Years | Area Under the Concentration Versus Time Curve From Time Point Zero to the Last Sample With Quantifiable Drug Concentration (AUClast) | Previous FIX Assessment (n = 16, 7, 9) | 751.9143 IU*hr/dL | Standard Deviation 146.70454 |
Primary
Clearance for FIX Activity Following a Single Intravenous Dose of 50 IU/kg rIX-FP or Previous FIX Product
FIX activity was measured at a central laboratory using validated one-stage clotting method. FIX levels were not corrected for baseline values. Clearance is normalized for body weight.
Time frame: Pre-dose, 30 minutes, 3, 24, 48, 72 120, 168, 240 and 336 hours post-dose
Population: PK Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| rIX-FP | Clearance for FIX Activity Following a Single Intravenous Dose of 50 IU/kg rIX-FP or Previous FIX Product | rIX-FP Assessment (n = 26, 11, 15) | 1.1119 mL/hr/kg | Standard Deviation 0.31373 |
| rIX-FP | Clearance for FIX Activity Following a Single Intravenous Dose of 50 IU/kg rIX-FP or Previous FIX Product | Previous FIX Assessment (n = 16, 7, 9) | 6.4007 mL/hr/kg | Standard Deviation 2.14434 |
| Age < 6 Years | Clearance for FIX Activity Following a Single Intravenous Dose of 50 IU/kg rIX-FP or Previous FIX Product | rIX-FP Assessment (n = 26, 11, 15) | 1.1841 mL/hr/kg | Standard Deviation 0.32924 |
| Age < 6 Years | Clearance for FIX Activity Following a Single Intravenous Dose of 50 IU/kg rIX-FP or Previous FIX Product | Previous FIX Assessment (n = 16, 7, 9) | 7.1576 mL/hr/kg | Standard Deviation 2.78944 |
| Age 6 to <12 Years | Clearance for FIX Activity Following a Single Intravenous Dose of 50 IU/kg rIX-FP or Previous FIX Product | rIX-FP Assessment (n = 26, 11, 15) | 1.0589 mL/hr/kg | Standard Deviation 0.30203 |
| Age 6 to <12 Years | Clearance for FIX Activity Following a Single Intravenous Dose of 50 IU/kg rIX-FP or Previous FIX Product | Previous FIX Assessment (n = 16, 7, 9) | 5.8119 mL/hr/kg | Standard Deviation 1.37641 |
Primary
Half-life (t1/2) Following a Single Intravenous Dose of 50 IU/kg rIX-FP or Previous FIX Product
FIX activity was measured at a central laboratory using validated one-stage clotting method. FIX levels were not corrected for baseline values.
Time frame: Pre-dose, 30 minutes, 3, 24, 48, 72 120, 168, 240 and 336 hours post-dose
Population: PK Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| rIX-FP | Half-life (t1/2) Following a Single Intravenous Dose of 50 IU/kg rIX-FP or Previous FIX Product | rIX-FP Assessment (n = 26, 11, 15) | 91.4492 hours | Standard Deviation 15.9754 |
| rIX-FP | Half-life (t1/2) Following a Single Intravenous Dose of 50 IU/kg rIX-FP or Previous FIX Product | Previous FIX Assessment (n = 16, 7, 9) | 18.6291 hours | Standard Deviation 6.15551 |
| Age < 6 Years | Half-life (t1/2) Following a Single Intravenous Dose of 50 IU/kg rIX-FP or Previous FIX Product | rIX-FP Assessment (n = 26, 11, 15) | 89.6124 hours | Standard Deviation 11.17364 |
| Age < 6 Years | Half-life (t1/2) Following a Single Intravenous Dose of 50 IU/kg rIX-FP or Previous FIX Product | Previous FIX Assessment (n = 16, 7, 9) | 19.8816 hours | Standard Deviation 8.01073 |
| Age 6 to <12 Years | Half-life (t1/2) Following a Single Intravenous Dose of 50 IU/kg rIX-FP or Previous FIX Product | rIX-FP Assessment (n = 26, 11, 15) | 92.7962 hours | Standard Deviation 19.02537 |
| Age 6 to <12 Years | Half-life (t1/2) Following a Single Intravenous Dose of 50 IU/kg rIX-FP or Previous FIX Product | Previous FIX Assessment (n = 16, 7, 9) | 17.6550 hours | Standard Deviation 4.52497 |
Primary
Incremental Recovery Following a Single Intravenous Dose of 50 IU/kg rIX-FP or Previous FIX Product
Incremental recovery (IU/dL/IU/kg) is defined as the FIX activity (IU/dL) 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. Recovery values were baseline-corrected for pre-infusion plasma FIX activity. Incremental recovery was measured following a single intravenous dose of 50 IU/kg rIX-FP on Day 1. Analysis of previous FIX product was conducted at the beginning of the study in a subset of subjects who had no historical pharmacokinetic (PK) data of their previous FIX product. For the PK assessment, the previous FIX product was administered by IV infusion after approximately 4 days following the last FIX treatment, prior to any dosing of rIX-FP. The formal PK population consisted of subjects who received at least 1 dose of rIX-FP for PK assessment and for whom a sufficient number of analyzable PK samples had been obtained to permit the evaluation of the PK profile of rIX-FP.
Time frame: 30 minutes after infusion
Population: PK Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| rIX-FP | Incremental Recovery Following a Single Intravenous Dose of 50 IU/kg rIX-FP or Previous FIX Product | rIX-FP Assessment (n = 27, 12, 15) | 1.0114 (IU/dL)/(IU/kg) | Standard Deviation 0.22711 |
| rIX-FP | Incremental Recovery Following a Single Intravenous Dose of 50 IU/kg rIX-FP or Previous FIX Product | Previous FIX Assessment (n = 17, 8, 9) | 0.7379 (IU/dL)/(IU/kg) | Standard Deviation 0.19768 |
| Age < 6 Years | Incremental Recovery Following a Single Intravenous Dose of 50 IU/kg rIX-FP or Previous FIX Product | rIX-FP Assessment (n = 27, 12, 15) | 0.9506 (IU/dL)/(IU/kg) | Standard Deviation 0.20432 |
| Age < 6 Years | Incremental Recovery Following a Single Intravenous Dose of 50 IU/kg rIX-FP or Previous FIX Product | Previous FIX Assessment (n = 17, 8, 9) | 0.6764 (IU/dL)/(IU/kg) | Standard Deviation 0.1398 |
| Age 6 to <12 Years | Incremental Recovery Following a Single Intravenous Dose of 50 IU/kg rIX-FP or Previous FIX Product | rIX-FP Assessment (n = 27, 12, 15) | 1.0600 (IU/dL)/(IU/kg) | Standard Deviation 0.23934 |
| Age 6 to <12 Years | Incremental Recovery Following a Single Intravenous Dose of 50 IU/kg rIX-FP or Previous FIX Product | Previous FIX Assessment (n = 17, 8, 9) | 0.7925 (IU/dL)/(IU/kg) | Standard Deviation 0.23219 |
Primary
Number of Subjects Developing Inhibitors to Factor IX (FIX)
Inhibitor formation was defined as any inhibitor (≥0.6 BU \[Bethesda Units\]/mL) identified and confirmed by retesting.
Time frame: 12 months
Population: Safety Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| rIX-FP | Number of Subjects Developing Inhibitors to Factor IX (FIX) | 0 participants |
Secondary
Consumption of rIX-FP During Routine Prophylaxis
Consumption of rIX-FP during routine prophylaxis is expressed as the total prophylaxis dose per month.
Time frame: 12 months
Population: Efficacy Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| rIX-FP | Consumption of rIX-FP During Routine Prophylaxis | 205.071 IU/kg/month | Standard Deviation 41.155 |
| Age < 6 Years | Consumption of rIX-FP During Routine Prophylaxis | 213.517 IU/kg/month | Standard Deviation 44.3848 |
| Age 6 to <12 Years | Consumption of rIX-FP During Routine Prophylaxis | 198.314 IU/kg/month | Standard Deviation 38.5693 |
Secondary
Number of Bleeding Episodes Requiring One, Two or More Than Two Infusions of rIX-FP to Achieve Hemostasis
For each bleeding episode that required treatment, the number of episodes that required one, two or more than two infusions of rIX-FP to achieve hemostasis
Time frame: Approximately 12 months
Population: Efficacy Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| rIX-FP | Number of Bleeding Episodes Requiring One, Two or More Than Two Infusions of rIX-FP to Achieve Hemostasis | 1 infusion | 94 bleeding episodes |
| rIX-FP | Number of Bleeding Episodes Requiring One, Two or More Than Two Infusions of rIX-FP to Achieve Hemostasis | 2 infusions | 9 bleeding episodes |
| rIX-FP | Number of Bleeding Episodes Requiring One, Two or More Than Two Infusions of rIX-FP to Achieve Hemostasis | > 2 infusions | 3 bleeding episodes |
| rIX-FP | Number of Bleeding Episodes Requiring One, Two or More Than Two Infusions of rIX-FP to Achieve Hemostasis | 1 or 2 infusions | 103 bleeding episodes |
| Age < 6 Years | Number of Bleeding Episodes Requiring One, Two or More Than Two Infusions of rIX-FP to Achieve Hemostasis | 1 or 2 infusions | 45 bleeding episodes |
| Age < 6 Years | Number of Bleeding Episodes Requiring One, Two or More Than Two Infusions of rIX-FP to Achieve Hemostasis | 1 infusion | 40 bleeding episodes |
| Age < 6 Years | Number of Bleeding Episodes Requiring One, Two or More Than Two Infusions of rIX-FP to Achieve Hemostasis | > 2 infusions | 0 bleeding episodes |
| Age < 6 Years | Number of Bleeding Episodes Requiring One, Two or More Than Two Infusions of rIX-FP to Achieve Hemostasis | 2 infusions | 5 bleeding episodes |
| Age 6 to <12 Years | Number of Bleeding Episodes Requiring One, Two or More Than Two Infusions of rIX-FP to Achieve Hemostasis | 1 or 2 infusions | 58 bleeding episodes |
| Age 6 to <12 Years | Number of Bleeding Episodes Requiring One, Two or More Than Two Infusions of rIX-FP to Achieve Hemostasis | 2 infusions | 4 bleeding episodes |
| Age 6 to <12 Years | Number of Bleeding Episodes Requiring One, Two or More Than Two Infusions of rIX-FP to Achieve Hemostasis | > 2 infusions | 3 bleeding episodes |
| Age 6 to <12 Years | Number of Bleeding Episodes Requiring One, Two or More Than Two Infusions of rIX-FP to Achieve Hemostasis | 1 infusion | 54 bleeding episodes |
Secondary
Number of Subjects Developing Antibodies Against rIX-FP
Antibodies to rIX-FP were measured using a direct-binding enzyme-linked immunosorbent assay (ELISA).
Time frame: 12 months
Population: Safety Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| rIX-FP | Number of Subjects Developing Antibodies Against rIX-FP | 0 participants |
Secondary
Number of Subjects With Treatment-related Adverse Events
Time frame: 12 months
Population: Safety Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| rIX-FP | Number of Subjects With Treatment-related Adverse Events | Any adverse event | 26 participants |
| rIX-FP | Number of Subjects With Treatment-related Adverse Events | Treatment-related adverse event | 0 participants |