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

A Phase 3b Open-label, Multicenter, Safety and Efficacy Extension Study of a Recombinant Coagulation Factor IX Albumin Fusion Protein (rIX-FP) in Subjects With Hemophilia B

This study will examine the long-term safety and efficacy of rIX-FP for the control and prevention of bleeding episodes in children and adults with severe hemophilia B. The study will include subjects who have not previously been treated with Factor IX products, subjects who previously completed a CSL-sponsored rIX-FP lead-in study and subjects requiring major non-emergency surgery who have not previously completed a CSL-sponsored rIX-FP lead-in study.

A surgical prophylaxis substudy will examine the efficacy of rIX-FP in subjects with hemophilia B who are undergoing non-emergency major or minor surgery. An additional substudy will examine the safety and PK of subcutaneous (SC) administration of rIX-FP.

Study Overview

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

• Study Type: Interventional
• Enrollment (Actual): 97
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Victoria
    • Parkville, Victoria, Australia, 3052
      • Royal Children's Hospital
    • Westmead, Victoria, Australia, 2145
      • The Children's Hospital Westmead
• Austria
  • Vienna, Austria, 1090
    • Department of Pediatrics, Medical University of Vienna
  • Vienna, Austria, 1090
    • Medical University of Vienna, Vienna General Hospital
• Bulgaria
  • Sofia, Bulgaria, 1233
    • SHAT "Joan Pavel" ODD [Hemorrhagic Diathesis & Anemia]
• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L8L 2X2
      • McMaster University
• Czechia
  • Brno, Czechia, 62500
    • Fakultni nemocnice Brno
  • Ostrava-Poruba, Czechia, 708 52
    • Fakultni Nemocrice Ostrava
  • Praha, Czechia, 15006
    • Fakultni nemocnice v Motole
• France
  • Brest, France, 29609
    • CHRU Hopital Morvan
  • Bron Cedex, France, 69677
    • Hôpital Louis Pradel
  • Le Kremlin-Bicetre, France, 94275
    • Hopital Bicetre - Centre de Traitement del'Hemophilia
  • Marseille Cedex, France, 13385
    • Hopital d'Enfants La Timonepital
  • Paris, France, 75015
    • Hopital Necker-Enfants Malades
• Germany
  • Bonn, Germany, 53127
    • Institut fur experimentelle Hamatologie
  • Bremen, Germany, 28177
    • Prof. Hess Kinderklinik
  • Duisburg, Germany, 47051
    • CRC Coagulation Research Centre GmbH
  • Dusseldorf, Germany, 40225
    • Heinrich Heine University Dusseldorf
  • Hamburg, Germany, 20246
    • Universtatsklinikum Hamburg-Eppendorf
  • Hannover, Germany, 30159
    • Werlhof-Institute for Haemostasis and Thrombosis
  • Heidelberg, Germany
    • Kurpfalzkrankenhaus Heidlerberg GmbH
• Israel
  • Tel Aviv, Israel
    • Chaim Sheba Medical Center
• Italy
  • Milano, Italy, 20122
    • IRCCS Ospedale Maggiore[Centro emofilia e Trobosi]
  • Parma, Italy, 43126
    • UOS Gestione e Organizzazione Funzlone Hub Emofilia
  • Vicenza, Italy, 36100
    • Centro Malattie Emorragiche e Trombotiche Ospedale
• Japan
  • Kashihara, Japan, 634-8522
    • Nara Medical University Hospital
  • 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, 160-0023
    • Tokyo Medical University Hospital
  • Tokyo, Japan, 167-0035
    • Ogikubo Hospital
  • Yokohama, Japan, 241-0811
    • St. Marianna University, School of Medicine, Seibu Hospital
• Malaysia
  • Kuala Lumpur, Malaysia, 50400
    • National Blood Center
• Philippines
  • Cebu, Philippines, 6000
    • Perpetual Succour Hospital
• South Africa
  • Parktown, South Africa, 2193
    • Haemophilia Comprehensive Care Centre
• Spain
  • A Coruna, Spain
    • C.H.U. A Coruña
  • Barcelona, Spain, 08035
    • Hospital Vall Hebron
  • Madrid, Spain, 28046
    • H.U. La Paz
• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado
  • Indiana
    • Indianapolis, Indiana, United States, 46260
      • Indiana Hemophilia & Thrombosis Center Inc.
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Hospital of the University of Pennsylvania
  • Utah
    • Salt Lake City, Utah, United States, 84103
      • University of Utah

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 70 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion criteria:

Main study inclusion criteria:

For previously treated subjects, either:

• Completed a CSL-sponsored rIX-FP (CSL654) study, including study CSL654_3001 [NCT01496274] or study CSL654_3002 [NCT01662531].

Or:

• Scheduled to have a major non-emergency surgery within approximately 8 weeks from the anticipated date of receiving the first rIX-FP injection.
• Not previously completed a CSL-sponsored rIX-FP lead-in study.
• Male, 12 to 70 years of age.
• Documented severe hemophilia B (FIX activity of ≤ 2%), or confirmed at screening by the central laboratory.
• Subjects who have received FIX products (plasma-derived and / or recombinant FIX) for > 150 exposure days (EDs), confirmed by their treating physician.
• No confirmed history of FIX inhibitor formation at screening by the central laboratory

For previously untreated subjects:

• Male, up to 18 years of age.
• Documented severe hemophilia B (FIX activity of ≤ 2%), or confirmed at screening by the central laboratory.
• Never previously been treated with FIX clotting factor products (except previous exposure to blood components).
• No confirmed history of FIX inhibitor formation

Surgery substudy inclusion criterion:

• Must require non-emergency surgery

Subcutaneous substudy inclusion criteria:

• Male, at least 18 years of age.
• Subjects currently enrolled in Study CSL654_3003
• Subjects who have received rIX-FP for ≥ 100 EDs (single-dose cohorts) or for ≥ 50 EDs (repeated-dose cohort)

Exclusion criteria:

Main study exclusion criteria:

• Currently receiving a therapy not permitted during the study.
• Any issue that, in the opinion of the investigator, would render the subject unsuitable for participation in the study.

For subjects who have previously completed a CSL-sponsored rIX-FP study:

• Unwilling to participate in the study for a total of 100 exposure days.

For subjects requiring major non-emergency surgery who have not previously completed a CSL-sponsored rIX-FP lead-in study:

• Known hypersensitivity (ie, allergic reaction or anaphylaxis) to any FIX product or hamster protein.
• Known congenital or acquired coagulation disorder other than congenital FIX deficiency.
• Currently receiving IV immunomodulating agents such as immunoglobulin or chronic systemic corticosteroid treatment.
• Low platelet count, kidney or liver disease.
• Human immunodeficiency virus positive with a CD4 count < 200/mm3.

For previously untreated subjects:

• Known congenital or acquired coagulation disorder other than congenital FIX deficiency (except for vitamin K deficiency of the newborn).
• Known kidney or liver dysfunction or any condition which, in the investigator's opinion, place the patient at unjustifiable risk.

The surgical substudy does not have any additional exclusion criteria, although subject(s) in France will not be eligible for the surgery sub-study.

Subcutaneous substudy exclusion criteria:

• Intravenous use of rIX-FP within 14 days of subcutaneous administration of rIX-FP.
• Life-threatening bleeding episode or major surgery during the 3 months prior to substudy entry

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: rIX-FP; Subjects will administer rIX-FP by intravenous infusion as routine prophylaxis, prevention, and on-demand treatment during a treatment period of approximately 3 years. The routine prophylaxis treatment interval for previously treated patients may be changed at each scheduled 6-month follow-up assessment. On-demand treatment with rIX-FP will be used for all bleeding episodes requiring treatment. Subjects (other than those in France) may participate in a surgical 'substudy' in which rIX-FP may be administered before, during and after surgery. An additional substudy will examine the safety and PK of subcutaneous administration of rIX-FP. For previously untreated patients, subjects will administer rIX-FP intravenously as weekly prophylaxis and/or on-demand treatment during the first 12 months, and as weekly routine prophylaxis thereafter. The dose of rIX-FP administered will be based on the subject's previous rIX-FP use and/or pharmacokinetic data.

Biological: rIX-FP; Recombinant Fusion Protein Linking Coagulation Factor IX with Albumin (rIX-FP)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total Number of Participants Who Developed Inhibitors Against Factor IX (FIX)		For PTPs: up to 5 years or the time it takes to achieve 100 exposure days (EDs). For PUPs: up to 3 years or the time it takes to achieve 50 EDs.
Mean Incremental Recovery of a 50 IU/kg Dose of CSL654 in Previously Untreated Patients (PUPs)	Incremental Recovery: The increase in plasma concentration per IU/kg of factor administered.	Approximately 30 minutes after infusion of CSL654

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total Annualized Bleeding Rate (ABR) by Prophylaxis Regimen in Previously Treated Patients (PTPs)		For PTPs: up to 5 years or the time it takes to achieve 100 exposure days (EDs).
Spontaneous ABR by Prophylaxis Regimen in PTPs		For PTPs: up to 5 years or the time it takes to achieve 100 exposure days (EDs).
Average Amount of CSL654 (rIX-FP) Consumed Per Month Per Subject During Routine Prophylaxis Treatment.		For PTPs: up to 5 years or the time it takes to achieve 100 exposure days (EDs). For PUPs: up to 3 years or the time it takes to achieve 50 EDs.
Percentage of Participants With at Least One Treatment Emergent Adverse Event (TEAE) and the Percentage of Participants With at Least One CSL654-related TEAE		For PTPs: up to 5 years or the time it takes to achieve 100 exposure days (EDs). For PUPs: up to 3 years or the time it takes to achieve 50 EDs.
Number of Participants With Investigator's Overall Clinical Assessment of Hemostatic Efficacy for the Treatment of Major Bleeding Events With CSL654 in PUPs	The investigator will rate the efficacy of the rIX-FP treatment based on a hemostatic efficacy four point rating scale of excellent, good, moderate, or poor/no response.	Up to 3 years or the time it takes to achieve 50 EDs
Total ABR for On-demand Regimen vs. 14-Day Regimen in PTPs		For PTPs: up to 5 years or the time it takes to achieve 100 exposure days (EDs).
Spontaneous ABR for On-demand Regimen vs. 14-Day Regimen in PTPs		For PTPs: up to 5 years or the time it takes to achieve 100 exposure days (EDs).
Total ABR for Subjects >=12 Years: 7-Day Regimen vs. 14-Day Regimen in PTPs		For PTPs: up to 5 years or the time it takes to achieve 100 exposure days (EDs).
Spontaneous ABR for Subjects >=12 Years: 7-Day Regimen vs. 14-Day Regimen in PTPs		For PTPs: up to 5 years or the time it takes to achieve 100 exposure days (EDs).
Total ABR for Subjects >=12 Years: 7-Day Regimen vs. (10 or 14)-Day Regimen in PTPs		For PTPs: up to 5 years or the time it takes to achieve 100 exposure days (EDs).
Spontaneous ABR for Subjects >=12 Years: 7-Day Regimen vs. (10 or 14)-Day Regimen in PTPs		For PTPs: up to 5 years or the time it takes to achieve 100 exposure days (EDs).

Collaborators and Investigators

• Sponsor: CSL Behring

Study record dates

Study Major Dates

• Study Start (Actual): February 6, 2014
• Primary Completion (Actual): June 2, 2021
• Study Completion (Actual): June 2, 2021

Study Registration Dates

• First Submitted: January 29, 2014
• First Submitted That Met QC Criteria: February 2, 2014
• First Posted (Estimate): February 4, 2014

Study Record Updates

• Last Update Posted (Actual): July 14, 2022
• Last Update Submitted That Met QC Criteria: July 12, 2022
• Last Verified: July 1, 2022

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_3003; 2012-005489-37 (EudraCT Number)