Hemophilia B
Conditions
Brief summary
This study will examine the safety, pharmacokinetics and efficacy of rIX-FP for the control and prevention of bleeding episodes in subjects who have previously received factor replacement therapy for hemophilia B.
Interventions
BIOLOGICALrIX-FP
Recombinant IX-FP (rIX-FP) is a fusion protein linking coagulation factor IX with albumin, and will be administered by intravenous administration
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 * On-demand subjects only, who have experienced a minimum average of 2 non-trauma induced bleeding episodes requiring treatment with a FIX product during the previous 6 or 3 months
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, kidney or liver dysfunction * Recent life-threatening bleeding episode
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Frequency of Spontaneous Bleeding Events Between On-demand and Prophylaxis Treatments (Annualized) | Up to 26 weeks for on-demand regimen, and between 1 and 17 months for prophylaxis regimen. | Subjects in the on-demand arm received on-demand dosing with rIX-FP for up to 26 weeks (on-demand regimen), and then received weekly prophylaxis with rIX-FP for the remainder of the study (prophylaxis regimen). The effectiveness of prophylaxis in comparison to on-demand therapy was investigated by comparing the same subject's annualized spontaneous bleeding rate (AsBR) during the on-demand regimen and during the prophylaxis regimen. |
| Number of Subjects Developing Inhibitors Against Factor IX (FIX) | Up to 27.7 months (maximum) | The number of participants developing inhibitors against factor IX (FIX) along with the 95% Clopper-Pearson confidence interval, are summarized for subjects with 50 or more exposure days (EDs) to rIX-FP, and for all participants in the study. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Bleeding Episodes Requiring One or ≤ Two Injections of rIX-FP to Achieve Hemostasis | For the duration of the study; median 20.27 months. | Number of injections required to achieve hemostasis expressed as a percentage of the bleeding episodes requiring treatment. |
| Investigator's Overall Clinical Assessment of Hemostatic Efficacy for Treatment of Bleeding Episodes, Based on a Four Point Ordinal Scales (Excellent, Good, Moderate, Poor/No Response) | For the duration of the study; median 20.27 months | Number of bleeding episodes requiring treatment that resulted in hemostatic efficacy of excellent, good, moderate, poor/no response, according to the Investigator's clinical assessment of hemostatic efficacy, expressed as a percentage of the bleeding episodes requiring treatment. |
| rIX-FP Consumed Per Month While Maintaining Assigned Prophylactic Treatment Interval During Routine Prophylaxis. | Median 269, 240, 386 and 316 days, respectively (see Description) | Time frame: For Prophylaxis Arm 7-, 10- and 14-day regimens, median 269, 240 and 386 days respectively. For On-demand Arm, prophylaxis regimen, median 316 days. |
| Incremental Recovery of rIX-FP | 336 hours | Pharmacokinetic (PK) data are presented for a single 50 IU/kg dose of rIX-FP. |
| The Frequency of Related Adverse Events | For the duration of the study; median 20.27 months. | The percentage of participants experiencing treatment-related adverse-events (TEAEs). |
| Area Under the Curve (AUC) | 336 hours | AUC to the last sample with quantifiable drug concentration (AUClast) of a single dose of rIX-FP. PK data are presented for a single 50 IU/kg dose of rIX-FP. |
| Clearance of a Single Dose of rIX-FP | 336 hours | PK data are presented for a single 50 IU/kg dose of rIX-FP. |
| Investigator's (or Surgeon's) Overall Clinical Assessment of Hemostatic Efficacy for Surgical Prophylaxis, Based on a Four Point Ordinal Scale (Excellent, Good, Moderate, Poor/No Response) | Up to 14 days after surgery | Number of surgical events treated prophylactically with rIX-FP that resulted in hemostatic efficacy of excellent, good, moderate, poor/no response, according to the Investigator's (surgeon's) overall assessment of hemostatic efficacy for surgical prophylaxis. |
| Annualized Spontaneous Bleeding Events Compared Between 7 Day Prophylactic and Extended Regimens | During treatment, between median 240 and 386 days per subject. | Median number of spontaneous bleeds per year per subject comparing 7-, 10- and 14- day prophylactic regimens. |
| Half-life (t1/2) of a Single Dose of rIX-FP | 336 hours | PK data are presented for a single 50 IU/kg dose of rIX-FP. |
| Number of Subjects Developing Antibodies Against rIX-FP | For the duration of the study; median 20.27 months. | — |
Countries
Austria, Bulgaria, France, Germany, Israel, Italy, Japan, Russia, Spain, United States
Participant flow
Recruitment details
Subjects were enrolled from 30 sites in 10 countries.
Pre-assignment details
A total of 69 subjects provided informed consent and were screened for study participation. Of these, 63 subjects were enrolled and treated with rIX-FP.
Participants by arm
| Arm | Count |
|---|---|
| Prophylaxis Routine weekly prophylaxis and episodic treatment for bleeding episodes. An individualized dosing interval may be tested in sub-group subjects during the 2nd part of the trial.
Subjects may participate in a surgical 'sub-study' in which rIX-FP may be administered prior to, during and after surgical intervention.
rIX-FP: Recombinant IX-FP (rIX-FP) is a fusion protein linking coagulation factor IX with albumin, and will be administered by intravenous administration | 40 |
| On-demand Episodic treatment for bleeding episodes for up to 26 weeks then switch to routine weekly prophylaxis for the remainder of the study.
Subjects may participate in a surgical 'sub-study' in which rIX-FP may be administered prior to, during and after surgical intervention.
rIX-FP: Recombinant IX-FP (rIX-FP) is a fusion protein linking coagulation factor IX with albumin, and will be administered by intravenous administration | 23 |
| Total | 63 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 |
| Overall Study | Lost to Follow-up | 0 | 3 |
| Overall Study | Protocol Violation | 0 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 0 |
Baseline characteristics
| Characteristic | Prophylaxis | On-demand | Total |
|---|---|---|---|
| Age, Customized 0 to 11 years | 0 participants | 0 participants | 0 participants |
| Age, Customized 12 to 17 years | 7 participants | 0 participants | 7 participants |
| Age, Customized 18 to 64 years | 33 participants | 23 participants | 56 participants |
| Age, Customized 65 years and over | 0 participants | 0 participants | 0 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 40 Participants | 23 Participants | 63 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 36 / 40 | 18 / 23 |
| serious Total, serious adverse events | 1 / 40 | 2 / 23 |
Outcome results
Primary
Change in Frequency of Spontaneous Bleeding Events Between On-demand and Prophylaxis Treatments (Annualized)
Subjects in the on-demand arm received on-demand dosing with rIX-FP for up to 26 weeks (on-demand regimen), and then received weekly prophylaxis with rIX-FP for the remainder of the study (prophylaxis regimen). The effectiveness of prophylaxis in comparison to on-demand therapy was investigated by comparing the same subject's annualized spontaneous bleeding rate (AsBR) during the on-demand regimen and during the prophylaxis regimen.
Time frame: Up to 26 weeks for on-demand regimen, and between 1 and 17 months for prophylaxis regimen.
Population: This analysis includes only the participants assigned to the on-demand arm who received at least 1 dose of rIX-FP in the on-demand regimen and at least 1 dose of rIX-FP in the prophylaxis regimen.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| On-demand Arm, On-demand Regimen | Change in Frequency of Spontaneous Bleeding Events Between On-demand and Prophylaxis Treatments (Annualized) | 15.43 bleeds/year/subject |
| On-demand Arm, Prophylaxis Regimen | Change in Frequency of Spontaneous Bleeding Events Between On-demand and Prophylaxis Treatments (Annualized) | 0.00 bleeds/year/subject |
Comparison: A test of null hypothesis that the ratio of AsBR (prophylaxis regimen/on-demand regimen) was ≥ 0.50 was conducted at the 1-sided 0.025 level. Matched pairs design with 19 subjects and 2 observations per subject.p-value: <0.0001Wilcoxon signed-rank test
Primary
Number of Subjects Developing Inhibitors Against Factor IX (FIX)
The number of participants developing inhibitors against factor IX (FIX) along with the 95% Clopper-Pearson confidence interval, are summarized for subjects with 50 or more exposure days (EDs) to rIX-FP, and for all participants in the study.
Time frame: Up to 27.7 months (maximum)
Population: Safety Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| On-demand Arm, On-demand Regimen | Number of Subjects Developing Inhibitors Against Factor IX (FIX) | Participants with >=50 EDs to rIX-FP (n = 49) | 0 participants |
| On-demand Arm, On-demand Regimen | Number of Subjects Developing Inhibitors Against Factor IX (FIX) | All participants (n = 63) | 0 participants |
Secondary
Annualized Spontaneous Bleeding Events Compared Between 7 Day Prophylactic and Extended Regimens
Median number of spontaneous bleeds per year per subject comparing 7-, 10- and 14- day prophylactic regimens.
Time frame: During treatment, between median 240 and 386 days per subject.
Population: Efficacy Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| On-demand Arm, On-demand Regimen | Annualized Spontaneous Bleeding Events Compared Between 7 Day Prophylactic and Extended Regimens | 0.00 bleeds/year/subject |
| On-demand Arm, Prophylaxis Regimen | Annualized Spontaneous Bleeding Events Compared Between 7 Day Prophylactic and Extended Regimens | 0.00 bleeds/year/subject |
| Safety Population | Annualized Spontaneous Bleeding Events Compared Between 7 Day Prophylactic and Extended Regimens | 0.00 bleeds/year/subject |
Secondary
Area Under the Curve (AUC)
AUC to the last sample with quantifiable drug concentration (AUClast) of a single dose of rIX-FP. PK data are presented for a single 50 IU/kg dose of rIX-FP.
Time frame: 336 hours
Population: The PK population comprised 46 subjects who received at least 1 dose of rIX-FP at 50 IU/kg. Data are presented for subjects from the PK population who had a sufficient number of analyzable PK samples for evaluation of the PK profile of rIX-FP.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| On-demand Arm, On-demand Regimen | Area Under the Curve (AUC) | 6534.15 IU*hr/dL | Standard Deviation 1856.96 |
| On-demand Arm, Prophylaxis Regimen | Area Under the Curve (AUC) | 5963.30 IU*hr/dL | Standard Deviation 1893 |
Secondary
Clearance of a Single Dose of rIX-FP
PK data are presented for a single 50 IU/kg dose of rIX-FP.
Time frame: 336 hours
Population: The PK population comprised 46 subjects who received at least 1 dose of rIX-FP at 50 IU/kg. Data are presented for subjects from the PK population who had a sufficient number of analyzable PK samples for evaluation of the PK profile of rIX-FP.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| On-demand Arm, On-demand Regimen | Clearance of a Single Dose of rIX-FP | 50.19 mL/hr | Standard Deviation 12.92 |
| On-demand Arm, Prophylaxis Regimen | Clearance of a Single Dose of rIX-FP | 59.00 mL/hr | Standard Deviation 19.37 |
Secondary
Half-life (t1/2) of a Single Dose of rIX-FP
PK data are presented for a single 50 IU/kg dose of rIX-FP.
Time frame: 336 hours
Population: The PK population comprised 46 subjects who received at least 1 dose of rIX-FP at 50 IU/kg. Data are presented for subjects from the PK population who had a sufficient number of analyzable PK samples for evaluation of the PK profile of rIX-FP.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| On-demand Arm, On-demand Regimen | Half-life (t1/2) of a Single Dose of rIX-FP | 104.77 hour | Standard Deviation 22.73 |
| On-demand Arm, Prophylaxis Regimen | Half-life (t1/2) of a Single Dose of rIX-FP | 96.88 hour | Standard Deviation 20.94 |
Secondary
Incremental Recovery of rIX-FP
Pharmacokinetic (PK) data are presented for a single 50 IU/kg dose of rIX-FP.
Time frame: 336 hours
Population: The PK population comprised 46 subjects who received at least 1 dose of rIX-FP at 50 IU/kg. Data are presented for subjects from the PK population who had a sufficient number of analyzable PK samples for evaluation of the PK profile of rIX-FP.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| On-demand Arm, On-demand Regimen | Incremental Recovery of rIX-FP | 1.29 (IU/dL)/(IU/kg) | Standard Deviation 0.33 |
| On-demand Arm, Prophylaxis Regimen | Incremental Recovery of rIX-FP | 1.24 (IU/dL)/(IU/kg) | Standard Deviation 0.25 |
Secondary
Investigator's (or Surgeon's) Overall Clinical Assessment of Hemostatic Efficacy for Surgical Prophylaxis, Based on a Four Point Ordinal Scale (Excellent, Good, Moderate, Poor/No Response)
Number of surgical events treated prophylactically with rIX-FP that resulted in hemostatic efficacy of excellent, good, moderate, poor/no response, according to the Investigator's (surgeon's) overall assessment of hemostatic efficacy for surgical prophylaxis.
Time frame: Up to 14 days after surgery
Population: Surgical Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| On-demand Arm, On-demand Regimen | Investigator's (or Surgeon's) Overall Clinical Assessment of Hemostatic Efficacy for Surgical Prophylaxis, Based on a Four Point Ordinal Scale (Excellent, Good, Moderate, Poor/No Response) | Moderate | 0 events |
| On-demand Arm, On-demand Regimen | Investigator's (or Surgeon's) Overall Clinical Assessment of Hemostatic Efficacy for Surgical Prophylaxis, Based on a Four Point Ordinal Scale (Excellent, Good, Moderate, Poor/No Response) | Poor/No response | 0 events |
| On-demand Arm, On-demand Regimen | Investigator's (or Surgeon's) Overall Clinical Assessment of Hemostatic Efficacy for Surgical Prophylaxis, Based on a Four Point Ordinal Scale (Excellent, Good, Moderate, Poor/No Response) | Excellent | 6 events |
| On-demand Arm, On-demand Regimen | Investigator's (or Surgeon's) Overall Clinical Assessment of Hemostatic Efficacy for Surgical Prophylaxis, Based on a Four Point Ordinal Scale (Excellent, Good, Moderate, Poor/No Response) | Good | 0 events |
Secondary
Investigator's Overall Clinical Assessment of Hemostatic Efficacy for Treatment of Bleeding Episodes, Based on a Four Point Ordinal Scales (Excellent, Good, Moderate, Poor/No Response)
Number of bleeding episodes requiring treatment that resulted in hemostatic efficacy of excellent, good, moderate, poor/no response, according to the Investigator's clinical assessment of hemostatic efficacy, expressed as a percentage of the bleeding episodes requiring treatment.
Time frame: For the duration of the study; median 20.27 months
Population: Efficacy Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| On-demand Arm, On-demand Regimen | Investigator's Overall Clinical Assessment of Hemostatic Efficacy for Treatment of Bleeding Episodes, Based on a Four Point Ordinal Scales (Excellent, Good, Moderate, Poor/No Response) | Good | 20.8 percentage of bleeding episodes |
| On-demand Arm, On-demand Regimen | Investigator's Overall Clinical Assessment of Hemostatic Efficacy for Treatment of Bleeding Episodes, Based on a Four Point Ordinal Scales (Excellent, Good, Moderate, Poor/No Response) | Poor/No response | 0 percentage of bleeding episodes |
| On-demand Arm, On-demand Regimen | Investigator's Overall Clinical Assessment of Hemostatic Efficacy for Treatment of Bleeding Episodes, Based on a Four Point Ordinal Scales (Excellent, Good, Moderate, Poor/No Response) | Moderate | 3.0 percentage of bleeding episodes |
| On-demand Arm, On-demand Regimen | Investigator's Overall Clinical Assessment of Hemostatic Efficacy for Treatment of Bleeding Episodes, Based on a Four Point Ordinal Scales (Excellent, Good, Moderate, Poor/No Response) | Missing | 5.0 percentage of bleeding episodes |
| On-demand Arm, On-demand Regimen | Investigator's Overall Clinical Assessment of Hemostatic Efficacy for Treatment of Bleeding Episodes, Based on a Four Point Ordinal Scales (Excellent, Good, Moderate, Poor/No Response) | Excellent | 71.3 percentage of bleeding episodes |
| On-demand Arm, Prophylaxis Regimen | Investigator's Overall Clinical Assessment of Hemostatic Efficacy for Treatment of Bleeding Episodes, Based on a Four Point Ordinal Scales (Excellent, Good, Moderate, Poor/No Response) | Missing | 2.3 percentage of bleeding episodes |
| On-demand Arm, Prophylaxis Regimen | Investigator's Overall Clinical Assessment of Hemostatic Efficacy for Treatment of Bleeding Episodes, Based on a Four Point Ordinal Scales (Excellent, Good, Moderate, Poor/No Response) | Excellent | 87.5 percentage of bleeding episodes |
| On-demand Arm, Prophylaxis Regimen | Investigator's Overall Clinical Assessment of Hemostatic Efficacy for Treatment of Bleeding Episodes, Based on a Four Point Ordinal Scales (Excellent, Good, Moderate, Poor/No Response) | Good | 7.4 percentage of bleeding episodes |
| On-demand Arm, Prophylaxis Regimen | Investigator's Overall Clinical Assessment of Hemostatic Efficacy for Treatment of Bleeding Episodes, Based on a Four Point Ordinal Scales (Excellent, Good, Moderate, Poor/No Response) | Moderate | 2.3 percentage of bleeding episodes |
| On-demand Arm, Prophylaxis Regimen | Investigator's Overall Clinical Assessment of Hemostatic Efficacy for Treatment of Bleeding Episodes, Based on a Four Point Ordinal Scales (Excellent, Good, Moderate, Poor/No Response) | Poor/No response | 0.4 percentage of bleeding episodes |
Secondary
Number of Subjects Developing Antibodies Against rIX-FP
Time frame: For the duration of the study; median 20.27 months.
Population: Safety Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| On-demand Arm, On-demand Regimen | Number of Subjects Developing Antibodies Against rIX-FP | 0 participants |
Secondary
Proportion of Bleeding Episodes Requiring One or ≤ Two Injections of rIX-FP to Achieve Hemostasis
Number of injections required to achieve hemostasis expressed as a percentage of the bleeding episodes requiring treatment.
Time frame: For the duration of the study; median 20.27 months.
Population: Efficacy Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| On-demand Arm, On-demand Regimen | Proportion of Bleeding Episodes Requiring One or ≤ Two Injections of rIX-FP to Achieve Hemostasis | 1 injection | 92.1 percentage of bleeding episodes treated |
| On-demand Arm, On-demand Regimen | Proportion of Bleeding Episodes Requiring One or ≤ Two Injections of rIX-FP to Achieve Hemostasis | 1 or 2 injections | 100.0 percentage of bleeding episodes treated |
| On-demand Arm, Prophylaxis Regimen | Proportion of Bleeding Episodes Requiring One or ≤ Two Injections of rIX-FP to Achieve Hemostasis | 1 injection | 94.5 percentage of bleeding episodes treated |
| On-demand Arm, Prophylaxis Regimen | Proportion of Bleeding Episodes Requiring One or ≤ Two Injections of rIX-FP to Achieve Hemostasis | 1 or 2 injections | 98.6 percentage of bleeding episodes treated |
| Safety Population | Proportion of Bleeding Episodes Requiring One or ≤ Two Injections of rIX-FP to Achieve Hemostasis | 1 injection | 91.9 percentage of bleeding episodes treated |
| Safety Population | Proportion of Bleeding Episodes Requiring One or ≤ Two Injections of rIX-FP to Achieve Hemostasis | 1 or 2 injections | 94.6 percentage of bleeding episodes treated |
Secondary
rIX-FP Consumed Per Month While Maintaining Assigned Prophylactic Treatment Interval During Routine Prophylaxis.
Time frame: For Prophylaxis Arm 7-, 10- and 14-day regimens, median 269, 240 and 386 days respectively. For On-demand Arm, prophylaxis regimen, median 316 days.
Time frame: Median 269, 240, 386 and 316 days, respectively (see Description)
Population: Efficacy Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| On-demand Arm, On-demand Regimen | rIX-FP Consumed Per Month While Maintaining Assigned Prophylactic Treatment Interval During Routine Prophylaxis. | 191.69 IU/kg/month | Standard Deviation 36.33 |
| On-demand Arm, Prophylaxis Regimen | rIX-FP Consumed Per Month While Maintaining Assigned Prophylactic Treatment Interval During Routine Prophylaxis. | 202.68 IU/kg/month | Standard Deviation 47.92 |
| Safety Population | rIX-FP Consumed Per Month While Maintaining Assigned Prophylactic Treatment Interval During Routine Prophylaxis. | 201.50 IU/kg/month | Standard Deviation 42.56 |
| Prophylaxis Arm, 14-day Regimen | rIX-FP Consumed Per Month While Maintaining Assigned Prophylactic Treatment Interval During Routine Prophylaxis. | 157.44 IU/kg/month | Standard Deviation 16.34 |
Secondary
The Frequency of Related Adverse Events
The percentage of participants experiencing treatment-related adverse-events (TEAEs).
Time frame: For the duration of the study; median 20.27 months.
Population: Safety Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| On-demand Arm, On-demand Regimen | The Frequency of Related Adverse Events | Related TEAE | 10.0 Percentage of participants |
| On-demand Arm, On-demand Regimen | The Frequency of Related Adverse Events | Not related TEAE | 87.5 Percentage of participants |
| On-demand Arm, Prophylaxis Regimen | The Frequency of Related Adverse Events | Related TEAE | 4.3 Percentage of participants |
| On-demand Arm, Prophylaxis Regimen | The Frequency of Related Adverse Events | Not related TEAE | 78.3 Percentage of participants |
| Safety Population | The Frequency of Related Adverse Events | Related TEAE | 7.9 Percentage of participants |
| Safety Population | The Frequency of Related Adverse Events | Not related TEAE | 84.1 Percentage of participants |