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

A Phase II/III Open-label, Multicenter, Safety and Efficacy Study of a Recombinant Coagulation Factor IX Albumin Fusion Protein (rIX-FP) in Subjects With Hemophilia B

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.

Study Overview

• Status: Completed
• Conditions: Hemophilia B
• Intervention / Treatment: Biological: rIX-FP

• Study Type: Interventional
• Enrollment (Actual): 63
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Austria
  • Wien, Austria
    • AKH Wien [Hämatologie, Hämostaseol
• Bulgaria
  • Sophia, Bulgaria, 1233
    • SHAT "Joan Pavel" OOD [Hemorrhagic Diathesis and Anemia]
• France
  • Brest, France, 29609
    • Centre Hospitalier Universitaire de Brest/CHU Morvan
  • Le Kremlin-Bicêtre, France, 94275
    • C.R.T.H. Hôp. Bicêtre-Hémophilie
  • Lyon, France, 03 69437
    • CHU de Lyon - Hôpital Edouard Herriot [Hemophilie]
  • Paris, France, 75015
    • Hôpital Necker-CRTH
• Germany
  • Bonn, Germany
    • Instit. für Experimentelle - Hämato & Transfusionsmedizin
  • Bremen, Germany, 28205
    • Zentralkrankenhaus Prof. Hess-Kinderklinik
  • Frankfurt, Germany
    • Unikinderklinik Frankfurt/Main [Kinderheilkunde]
  • Hamburg, Germany, 20246
    • Universitätsklinikum Hamburg-Eppendorf, Abt für Pädiatr. Hämatologie
  • Hannover, Germany
    • Werlhof-Inst. Hannover
• Israel
  • Tel Aviv, Israel
    • Chaim Sheba Medical Center
• Italy
  • Milano, Italy
    • IRCCS Ospedale Maggiore[Centro emofilia e Trombosi]
  • Parma, Italy, 43126
    • A.O.U. di Parma [Centro di Rif. Reg. per la cura dell'Emofil
  • Vicenza, Italy, 36100
    • Osp. S.Bortolo ULSS N.6 [Terapie Cell. ed Ematologia]
• Japan
  • Kashihara, Japan, 634-8522
    • Nara Medical University Hospital [PEDIATRICS]
  • Kitakyushu, Japan
    • University of Occupational and Environmental Health
  • Nagoya, Japan, 466-8550
    • Nagoya University Hospital
  • Nishinomiya, Japan
    • The Hospital of Hyogo College of Medicine
  • Tokyo, Japan, 167-0035
    • Ogikubo Hospital
  • Tokyo, Japan
    • Tokyo Medical University Hospital
  • Yokohama, Japan, 241-0811
    • St. Marianna University, School of Medicine, Yokohama Seibu
• Russian Federation
  • Kirov, Russian Federation, 610027
    • FGU "Kirov Research Institute of Haemotology and Blood Trans
• Spain
  • A Coruna, Spain
    • C.H.U. A Coruña [Hematología]
  • Barcelona, Spain
    • H.U.Vall d'Hebrón [Hemofillia]
  • Madrid, Spain, 28046
    • H.U. La Paz [Coagulopatias Congénitas]
• United States
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
  • Indiana
    • Indianapolis, Indiana, United States, 46260
      • Indiana Hemophilia and Thrombosis Center, Inc.
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Hospital of the University of Pennsylvania
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53201
      • BloodCenter of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 65 years (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: 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.	Biological: rIX-FP; Recombinant IX-FP (rIX-FP) is a fusion protein linking coagulation factor IX with albumin, and will be administered by intravenous administration
EXPERIMENTAL: On-demand; Episodic treatment for bleeding episodes during the first 6 months then switch to routine weekly prophylaxis for a further 6 months Subjects may participate in a surgical 'sub-study' in which rIX-FP may be administered prior to, during and after surgical intervention.	Biological: rIX-FP; Recombinant IX-FP (rIX-FP) is a fusion protein linking coagulation factor IX with albumin, and will be administered by intravenous administration

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Up to 26 weeks for on-demand regimen, and between 1 and 17 months for prophylaxis regimen.
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.	Up to 27.7 months (maximum)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Frequency of Related Adverse Events	The percentage of participants experiencing treatment-related adverse-events (TEAEs).	For the duration of the study; median 20.27 months.
Number of Subjects Developing Antibodies Against rIX-FP		For the duration of the study; median 20.27 months.
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.	For the duration of the study; median 20.27 months.
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.	For the duration of the study; median 20.27 months
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.	Median 269, 240, 386 and 316 days, respectively (see Description)
Incremental Recovery of rIX-FP	Pharmacokinetic (PK) data are presented for a single 50 IU/kg dose of rIX-FP.	336 hours
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.	336 hours
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.	336 hours
Clearance of a Single Dose of rIX-FP	PK data are presented for a single 50 IU/kg dose of rIX-FP.	336 hours
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.	Up to 14 days after surgery
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.	During treatment, between median 240 and 386 days per subject.

Collaborators and Investigators

• Sponsor: CSL Behring

Publications and helpful links

General Publications

• Santagostino E, Martinowitz U, Lissitchkov T, Pan-Petesch B, Hanabusa H, Oldenburg J, Boggio L, Negrier C, Pabinger I, von Depka Prondzinski M, Altisent C, Castaman G, Yamamoto K, Alvarez-Roman MT, Voigt C, Blackman N, Jacobs I; PROLONG-9FP Investigators Study Group. Long-acting recombinant coagulation factor IX albumin fusion protein (rIX-FP) in hemophilia B: results of a phase 3 trial. Blood. 2016 Apr 7;127(14):1761-9. doi: 10.1182/blood-2015-09-669234. Epub 2016 Jan 11.

Study record dates

Study Major Dates

• Study Start: February 1, 2012
• Primary Completion (ACTUAL): July 1, 2014

Study Registration Dates

• First Submitted: December 19, 2011
• First Submitted That Met QC Criteria: December 19, 2011
• First Posted (ESTIMATE): December 21, 2011

Study Record Updates

• Last Update Posted (ESTIMATE): May 9, 2016
• Last Update Submitted That Met QC Criteria: April 3, 2016
• Last Verified: April 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Hematologic Diseases; Blood Coagulation Disorders, Inherited; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Blood Coagulation Disorders; Hemophilia A; Hemophilia B
• Other Study ID Numbers: CSL654_3001; 2011-002415-28 (EUDRACT_NUMBER)