Trial Outcomes & Findings for A Safety and Efficacy Study of a Recombinant Fusion Protein Linking Coagulation Factor IX With Albumin (rIX-FP) in Patients With Hemophilia B (NCT NCT01496274)

Last Updated: 2016-05-09

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE2/PHASE3

Target enrollment

63 participants

Primary outcome timeframe

Up to 26 weeks for on-demand regimen, and between 1 and 17 months for prophylaxis regimen.

Results posted on

2016-05-09

Participant Flow

Subjects were enrolled from 30 sites in 10 countries.

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.

Participant milestones

Participant milestones
Measure	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.	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.
Overall Study STARTED	40	23
Overall Study COMPLETED	37	18
Overall Study NOT COMPLETED	3	5

Reasons for withdrawal

Reasons for withdrawal
Measure	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.	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.
Overall Study Protocol Violation	0	1
Overall Study Adverse Event	1	1
Overall Study Withdrawal by Subject	2	0
Overall Study Lost to Follow-up	0	3

Baseline Characteristics

A Safety and Efficacy Study of a Recombinant Fusion Protein Linking Coagulation Factor IX With Albumin (rIX-FP) in Patients With Hemophilia B

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Prophylaxis n=40 Participants 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	On-demand n=23 Participants 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	Total n=63 Participants Total of all reporting groups
Age, Customized 0 to 11 years	0 participants n=5 Participants	0 participants n=7 Participants	0 participants n=5 Participants
Age, Customized 12 to 17 years	7 participants n=5 Participants	0 participants n=7 Participants	7 participants n=5 Participants
Age, Customized 18 to 64 years	33 participants n=5 Participants	23 participants n=7 Participants	56 participants n=5 Participants
Age, Customized 65 years and over	0 participants n=5 Participants	0 participants n=7 Participants	0 participants n=5 Participants
Sex: Female, Male Female	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Sex: Female, Male Male	40 Participants n=5 Participants	23 Participants n=7 Participants	63 Participants n=5 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	On-demand Arm, On-demand Regimen n=19 Participants Participants in the On-demand Arm, when receiving episodic treatment for bleeding episodes (on-demand regimen).	On-demand Arm, Prophylaxis Regimen n=19 Participants Participants in the On-demand Arm, when receiving routine weekly prophylaxis (prophylaxis regimen).	Safety Population The Safety population consisted of subjects who received at least 1 dose of rIX-FP during the study.	Prophylaxis Arm, 14-day Regimen Subjects received prophylactic rIX-FP every 14 days.
Change in Frequency of Spontaneous Bleeding Events Between On-demand and Prophylaxis Treatments (Annualized)	15.43 bleeds/year/subject Interval 7.98 to 17.96	0.00 bleeds/year/subject Interval 0.0 to 0.96	—	—

PRIMARY outcome

Timeframe: Up to 27.7 months (maximum)

Population: Safety Population

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.

Outcome measures

Outcome measures
Measure	On-demand Arm, On-demand Regimen n=63 Participants Participants in the On-demand Arm, when receiving episodic treatment for bleeding episodes (on-demand regimen).	On-demand Arm, Prophylaxis Regimen Participants in the On-demand Arm, when receiving routine weekly prophylaxis (prophylaxis regimen).	Safety Population The Safety population consisted of subjects who received at least 1 dose of rIX-FP during the study.	Prophylaxis Arm, 14-day Regimen Subjects received prophylactic rIX-FP every 14 days.
Number of Subjects Developing Inhibitors Against Factor IX (FIX) Participants with >=50 EDs to rIX-FP (n = 49)	0 participants Interval 0.0 to 7.3	—	—	—
Number of Subjects Developing Inhibitors Against Factor IX (FIX) All participants (n = 63)	0 participants Interval 0.0 to 5.7	—	—	—

SECONDARY outcome

Timeframe: For the duration of the study; median 20.27 months.

Population: Safety Population

The percentage of participants experiencing treatment-related adverse-events (TEAEs).

Outcome measures

Outcome measures
Measure	On-demand Arm, On-demand Regimen n=40 Participants Participants in the On-demand Arm, when receiving episodic treatment for bleeding episodes (on-demand regimen).	On-demand Arm, Prophylaxis Regimen n=23 Participants Participants in the On-demand Arm, when receiving routine weekly prophylaxis (prophylaxis regimen).	Safety Population n=63 Participants The Safety population consisted of subjects who received at least 1 dose of rIX-FP during the study.	Prophylaxis Arm, 14-day Regimen Subjects received prophylactic rIX-FP every 14 days.
The Frequency of Related Adverse Events Related TEAE	10.0 Percentage of participants	4.3 Percentage of participants	7.9 Percentage of participants	—
The Frequency of Related Adverse Events Not related TEAE	87.5 Percentage of participants	78.3 Percentage of participants	84.1 Percentage of participants	—

SECONDARY outcome

Timeframe: For the duration of the study; median 20.27 months.

Population: Safety Population

Outcome measures

Outcome measures
Measure	On-demand Arm, On-demand Regimen n=63 Participants Participants in the On-demand Arm, when receiving episodic treatment for bleeding episodes (on-demand regimen).	On-demand Arm, Prophylaxis Regimen Participants in the On-demand Arm, when receiving routine weekly prophylaxis (prophylaxis regimen).	Safety Population The Safety population consisted of subjects who received at least 1 dose of rIX-FP during the study.	Prophylaxis Arm, 14-day Regimen Subjects received prophylactic rIX-FP every 14 days.
Number of Subjects Developing Antibodies Against rIX-FP	0 participants	—	—	—

SECONDARY outcome

Timeframe: For the duration of the study; median 20.27 months.

Population: Efficacy Population

Number of injections required to achieve hemostasis expressed as a percentage of the bleeding episodes requiring treatment.

Outcome measures

Outcome measures
Measure	On-demand Arm, On-demand Regimen n=101 bleeding episodes requiring treatment Participants in the On-demand Arm, when receiving episodic treatment for bleeding episodes (on-demand regimen).	On-demand Arm, Prophylaxis Regimen n=220 bleeding episodes requiring treatment Participants in the On-demand Arm, when receiving routine weekly prophylaxis (prophylaxis regimen).	Safety Population n=37 bleeding episodes requiring treatment The Safety population consisted of subjects who received at least 1 dose of rIX-FP during the study.	Prophylaxis Arm, 14-day Regimen Subjects received prophylactic rIX-FP every 14 days.
Proportion of Bleeding Episodes Requiring One or ≤ Two Injections of rIX-FP to Achieve Hemostasis 1 injection	92.1 percentage of bleeding episodes treated	94.5 percentage of bleeding episodes treated	91.9 percentage of bleeding episodes treated	—
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	98.6 percentage of bleeding episodes treated	94.6 percentage of bleeding episodes treated	—

SECONDARY outcome

Timeframe: For the duration of the study; median 20.27 months

Population: Efficacy Population

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.

Outcome measures

Outcome measures
Measure	On-demand Arm, On-demand Regimen n=101 bleeding episodes requiring treatment Participants in the On-demand Arm, when receiving episodic treatment for bleeding episodes (on-demand regimen).	On-demand Arm, Prophylaxis Regimen n=257 bleeding episodes requiring treatment Participants in the On-demand Arm, when receiving routine weekly prophylaxis (prophylaxis regimen).	Safety Population The Safety population consisted of subjects who received at least 1 dose of rIX-FP during the study.	Prophylaxis Arm, 14-day Regimen Subjects received prophylactic rIX-FP every 14 days.
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	87.5 percentage of bleeding episodes	—	—
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	7.4 percentage of bleeding episodes	—	—
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	2.3 percentage of bleeding episodes	—	—
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	0.4 percentage of bleeding episodes	—	—
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	2.3 percentage of bleeding episodes	—	—

SECONDARY outcome

Timeframe: Median 269, 240, 386 and 316 days, respectively (see Description)

Population: Efficacy Population

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.

Outcome measures

Outcome measures
Measure	On-demand Arm, On-demand Regimen n=19 Participants Participants in the On-demand Arm, when receiving episodic treatment for bleeding episodes (on-demand regimen).	On-demand Arm, Prophylaxis Regimen n=40 Participants Participants in the On-demand Arm, when receiving routine weekly prophylaxis (prophylaxis regimen).	Safety Population n=7 Participants The Safety population consisted of subjects who received at least 1 dose of rIX-FP during the study.	Prophylaxis Arm, 14-day Regimen n=21 Participants Subjects received prophylactic rIX-FP every 14 days.
rIX-FP Consumed Per Month While Maintaining Assigned Prophylactic Treatment Interval During Routine Prophylaxis.	191.69 IU/kg/month Standard Deviation 36.33	202.68 IU/kg/month Standard Deviation 47.92	201.50 IU/kg/month Standard Deviation 42.56	157.44 IU/kg/month Standard Deviation 16.34

SECONDARY outcome

Timeframe: 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.

Pharmacokinetic (PK) data are presented for a single 50 IU/kg dose of rIX-FP.

Outcome measures

Outcome measures
Measure	On-demand Arm, On-demand Regimen n=27 Participants Participants in the On-demand Arm, when receiving episodic treatment for bleeding episodes (on-demand regimen).	On-demand Arm, Prophylaxis Regimen n=18 Participants Participants in the On-demand Arm, when receiving routine weekly prophylaxis (prophylaxis regimen).	Safety Population The Safety population consisted of subjects who received at least 1 dose of rIX-FP during the study.	Prophylaxis Arm, 14-day Regimen Subjects received prophylactic rIX-FP every 14 days.
Incremental Recovery of rIX-FP	1.29 (IU/dL)/(IU/kg) Standard Deviation 0.33	1.24 (IU/dL)/(IU/kg) Standard Deviation 0.25	—	—

SECONDARY outcome

Timeframe: 336 hours

PK data are presented for a single 50 IU/kg dose of rIX-FP.

Outcome measures

Outcome measures
Measure	On-demand Arm, On-demand Regimen n=26 Participants Participants in the On-demand Arm, when receiving episodic treatment for bleeding episodes (on-demand regimen).	On-demand Arm, Prophylaxis Regimen n=17 Participants Participants in the On-demand Arm, when receiving routine weekly prophylaxis (prophylaxis regimen).	Safety Population The Safety population consisted of subjects who received at least 1 dose of rIX-FP during the study.	Prophylaxis Arm, 14-day Regimen Subjects received prophylactic rIX-FP every 14 days.
Half-life (t1/2) of a Single Dose of rIX-FP	104.77 hour Standard Deviation 22.73	96.88 hour Standard Deviation 20.94	—	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	On-demand Arm, On-demand Regimen n=27 Participants Participants in the On-demand Arm, when receiving episodic treatment for bleeding episodes (on-demand regimen).	On-demand Arm, Prophylaxis Regimen n=18 Participants Participants in the On-demand Arm, when receiving routine weekly prophylaxis (prophylaxis regimen).	Safety Population The Safety population consisted of subjects who received at least 1 dose of rIX-FP during the study.	Prophylaxis Arm, 14-day Regimen Subjects received prophylactic rIX-FP every 14 days.
Area Under the Curve (AUC)	6534.15 IU*hr/dL Standard Deviation 1856.96	5963.30 IU*hr/dL Standard Deviation 1893.00	—	—

SECONDARY outcome

Timeframe: 336 hours

PK data are presented for a single 50 IU/kg dose of rIX-FP.

Outcome measures

Outcome measures
Measure	On-demand Arm, On-demand Regimen n=26 Participants Participants in the On-demand Arm, when receiving episodic treatment for bleeding episodes (on-demand regimen).	On-demand Arm, Prophylaxis Regimen n=17 Participants Participants in the On-demand Arm, when receiving routine weekly prophylaxis (prophylaxis regimen).	Safety Population The Safety population consisted of subjects who received at least 1 dose of rIX-FP during the study.	Prophylaxis Arm, 14-day Regimen Subjects received prophylactic rIX-FP every 14 days.
Clearance of a Single Dose of rIX-FP	50.19 mL/hr Standard Deviation 12.92	59.00 mL/hr Standard Deviation 19.37	—	—

SECONDARY outcome

Timeframe: Up to 14 days after surgery

Population: Surgical Population

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.

Outcome measures

Outcome measures
Measure	On-demand Arm, On-demand Regimen n=6 events Participants in the On-demand Arm, when receiving episodic treatment for bleeding episodes (on-demand regimen).	On-demand Arm, Prophylaxis Regimen Participants in the On-demand Arm, when receiving routine weekly prophylaxis (prophylaxis regimen).	Safety Population The Safety population consisted of subjects who received at least 1 dose of rIX-FP during the study.	Prophylaxis Arm, 14-day Regimen Subjects received prophylactic rIX-FP every 14 days.
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	—	—	—
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	—	—	—
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	—	—	—
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	—	—	—

SECONDARY outcome

Timeframe: During treatment, between median 240 and 386 days per subject.

Population: Efficacy Population

Median number of spontaneous bleeds per year per subject comparing 7-, 10- and 14- day prophylactic regimens.

Outcome measures

Outcome measures
Measure	On-demand Arm, On-demand Regimen n=38 Participants Participants in the On-demand Arm, when receiving episodic treatment for bleeding episodes (on-demand regimen).	On-demand Arm, Prophylaxis Regimen n=7 Participants Participants in the On-demand Arm, when receiving routine weekly prophylaxis (prophylaxis regimen).	Safety Population n=21 Participants The Safety population consisted of subjects who received at least 1 dose of rIX-FP during the study.	Prophylaxis Arm, 14-day Regimen Subjects received prophylactic rIX-FP every 14 days.
Annualized Spontaneous Bleeding Events Compared Between 7 Day Prophylactic and Extended Regimens	0.00 bleeds/year/subject Interval 0.0 to 0.0	0.00 bleeds/year/subject Interval 0.0 to 0.0	0.00 bleeds/year/subject Interval 0.0 to 1.0	—

Adverse Events

Prophylaxis

Serious events: 1 serious events

Other events: 36 other events

Deaths: 0 deaths

On-demand

Serious events: 2 serious events

Other events: 18 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Prophylaxis n=40 participants at risk 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.	On-demand n=23 participants at risk 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.
Nervous system disorders ACQUIRED EPILEPTIC APHASIA	0.00% 0/40 • For the duration of the study, up to 27.7 months. The Safety analysis population consisted of subjects who received at least 1 dose of rIX-FP during the study. Adverse Event (AE) data are treatment-emergent data unless otherwise noted. The total number of participants in the number affected by Other (non-serious) AEs, is the total number of participants experiencing at least one non-serious AE.	4.3% 1/23 • Number of events 1 • For the duration of the study, up to 27.7 months. The Safety analysis population consisted of subjects who received at least 1 dose of rIX-FP during the study. Adverse Event (AE) data are treatment-emergent data unless otherwise noted. The total number of participants in the number affected by Other (non-serious) AEs, is the total number of participants experiencing at least one non-serious AE.
Musculoskeletal and connective tissue disorders SYNOVITIS	0.00% 0/40 • For the duration of the study, up to 27.7 months. The Safety analysis population consisted of subjects who received at least 1 dose of rIX-FP during the study. Adverse Event (AE) data are treatment-emergent data unless otherwise noted. The total number of participants in the number affected by Other (non-serious) AEs, is the total number of participants experiencing at least one non-serious AE.	4.3% 1/23 • Number of events 1 • For the duration of the study, up to 27.7 months. The Safety analysis population consisted of subjects who received at least 1 dose of rIX-FP during the study. Adverse Event (AE) data are treatment-emergent data unless otherwise noted. The total number of participants in the number affected by Other (non-serious) AEs, is the total number of participants experiencing at least one non-serious AE.
Musculoskeletal and connective tissue disorders PAIN IN EXTREMITY	2.5% 1/40 • Number of events 1 • For the duration of the study, up to 27.7 months. The Safety analysis population consisted of subjects who received at least 1 dose of rIX-FP during the study. Adverse Event (AE) data are treatment-emergent data unless otherwise noted. The total number of participants in the number affected by Other (non-serious) AEs, is the total number of participants experiencing at least one non-serious AE.	0.00% 0/23 • For the duration of the study, up to 27.7 months. The Safety analysis population consisted of subjects who received at least 1 dose of rIX-FP during the study. Adverse Event (AE) data are treatment-emergent data unless otherwise noted. The total number of participants in the number affected by Other (non-serious) AEs, is the total number of participants experiencing at least one non-serious AE.
Musculoskeletal and connective tissue disorders MUSCLE HAEMORRHAGE	2.5% 1/40 • Number of events 1 • For the duration of the study, up to 27.7 months. The Safety analysis population consisted of subjects who received at least 1 dose of rIX-FP during the study. Adverse Event (AE) data are treatment-emergent data unless otherwise noted. The total number of participants in the number affected by Other (non-serious) AEs, is the total number of participants experiencing at least one non-serious AE.	0.00% 0/23 • For the duration of the study, up to 27.7 months. The Safety analysis population consisted of subjects who received at least 1 dose of rIX-FP during the study. Adverse Event (AE) data are treatment-emergent data unless otherwise noted. The total number of participants in the number affected by Other (non-serious) AEs, is the total number of participants experiencing at least one non-serious AE.

Other adverse events

Additional Information

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Results disclosure agreements

Principal investigator is a sponsor employee CSL agreements and restrictions on publishing may vary with individual investigators; however, CSL will not prohibit any investigator from publishing. CSL supports the publication of results from all centers of a multi-center trial and generally requires that reports based on single-site data not precede the primary publication of the entire clinical trial.
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