An Open-label Safety and Efficacy Study of Recombinant FVIII in Patients With Severe Hemophilia A

A Phase III Open Label, Multicenter, Extension Study to Assess the Safety and Efficacy of Recombinant Coagulation Factor VIII (rVIII-SingleChain, CSL627) in Subjects With Severe Hemophilia A

This multicenter, open-label, phase 3 extension study will investigate the safety and efficacy of rVIII-SingleChain for prophylaxis and on-demand treatment of bleeding episodes in at least 200 previously treated patients (PTPs) with severe congenital hemophilia A and previous exposure to FVIII products who achieve at least 100 exposure days (EDs) to rVIII-SingleChain in this study, as well as in previously untreated patients (PUPs) with no previous exposure to any FVIII product who achieve at least 50 EDs to rVIII-SingleChain in this study. A substudy (open to both PTPs and PUPs) will investigate the use of rVIII-SingleChain in surgery. A substudy (open to PUPs who develop an inhibitor to rVIII-SingleChain) will investigate the use of rVIII-SingleChain in immune tolerance induction (ITI) therapy.

Study Overview

• Status: Completed
• Conditions: Hemophilia A; Severe Hemophilia A
• Intervention / Treatment: Biological: rVIII-SingleChain

• Study Type: Interventional
• Enrollment (Actual): 246
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Melbourne, Australia, 3052
    • Study Site 0360014
  • Nedlands, Australia, WA 6009
    • Study Site 0360028
  • Perth, Australia, WA 6000
    • Study Site 0360031
• Austria
  • Graz, Austria, 8036
    • Study Site 0400012
  • Linz, Austria, 4020
    • Study Site 0400003
  • Wien, Austria, 1090
    • Study Site 0400001
  • Wien, Austria, 1090
    • Study Site 0400002
• Canada
  • Saint John, Canada, E2L 4L2
    • Study Site 1240022
• Czechia
  • Hradec Kralove, Czechia, 500 05
    • Study Site 2030017
• France
  • Brest, France, 29609
    • Study Site 2500015
  • Le Kremlin Bicetre, France, 94270
    • Study Site 2500017
  • Lille Cedex, France, 59037
    • Study Site 2500028
  • Nantes, France, 44093
    • Study Site 2500018
  • Paris, France, 75015
    • Study Site 2500002
• Georgia
  • Tbilisi, Georgia, 0179
    • Study Site 2680001
• Germany
  • Bonn, Germany, 53127
    • Study Site 2760034
  • Frankfurt, Germany, 60596
    • Study Site 2760091
  • Giessen, Germany, 35385
    • Study Site 2760087
  • Hannover, Germany, 30625
    • Study Site 2760066
• Hungary
  • Debrecen, Hungary, 4032
    • Study Site 3480007
• Ireland
  • Dublin, Ireland, 12
    • Study Site 3720002
• Italy
  • Milano, Italy, 20122
    • Study Site 3800023
• Japan
  • Hyogo, Japan, 663-8501
    • Study Site 3920031
  • Nagoya, Japan, 466-8550
    • Study Site 3920029
  • Okayama, Japan, 710-8602
    • Study Site 3920064
  • Saitama, Japan, 339-8551
    • Study Site 3920033
  • Tokyo, Japan, 160-0023
    • Study Site 3920025
• Lebanon
  • Beirut, Lebanon, 165191
    • Study Site 4220007
• Malaysia
  • Kuala Lumpur, Malaysia, 50400
    • Study Site 4580001
• Netherlands
  • Amsterdam Zuidoost, Netherlands, 1105 AZ
    • Study Site 5280006
  • Nijmegen, Netherlands, 6500
    • Study Site 5280008
  • Utrecht, Netherlands, 3584
    • Study Site 5280007
• Philippines
  • Cebu City, Philippines, 6000
    • Study Site 6080001
  • Davao City, Philippines, 8000
    • Study Site 6080002
• Poland
  • Gdansk, Poland, 80-952
    • Study Site 6160013
  • Krakow, Poland, 31-531
    • Study Site 6160038
  • Rzeszow, Poland, 35-301
    • Study Site 6160035
  • Wroclaw, Poland, 50-367
    • Study Site 6160014
• Portugal
  • Porto, Portugal, 4200-319
    • Study Site 6200001
• Romania
  • Bucharest, Romania, 011026
    • Study Site 6420030
  • Timisoara, Romania, 300011
    • Study Site 6420037
• South Africa
  • Parktown, South Africa, 2193
    • Study Site 7100001
• Spain
  • A Coruna, Spain, 15006
    • Study Site 7240008
  • Barcelona, Spain, 08035
    • Study Site 7240021
  • Madrid, Spain, 28046
    • Study Site 7240007
  • Valencia, Spain, 46026
    • Study Site 7240023
• Switzerland
  • Luzern, Switzerland, 6000
    • Study Site 7560010
• Thailand
  • Bangkok, Thailand, 10330
    • Study Site 7640001
  • Bangkok, Thailand, 10700
    • Study Site 7640005
  • Chiang Mai, Thailand, 50200
    • Study Site 7640002
  • Khon Kaen, Thailand, 40002
    • Study Site 7640004
  • Songkhla, Thailand, 90110
    • Study Site 7640003
• Ukraine
  • Dnipropetrovsk, Ukraine, 49102
    • Study Site 8040007
  • Lviv, Ukraine, 79044
    • Study Site 8040005
• United Kingdom
  • London, United Kingdom, NW3 2QG
    • Study Site 8260008
• United States
  • California
    • San Diego, California, United States, 92103-8651
      • Study Site 8400213
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Study Site 8400241
  • Connecticut
    • Hartford, Connecticut, United States, 06106
      • Study Site 8400118
  • Florida
    • Miami, Florida, United States, 33136
      • Study Site 8400116
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Study Site 8400184
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • Study Site 8400204
  • Texas
    • Dallas, Texas, United States, 75390-9016
      • Study Site 8400240
    • Houston, Texas, United States, 77030
      • Study Site 8400041
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Study Site 8400154

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: ADULT; OLDER_ADULT; CHILD
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

PTPs:

• Males of any age who have been diagnosed with severe congenital hemophilia A (FVIII activity levels < 1%) and who participated in a previous CSL-sponsored clinical study with rVIII-SingleChain.
• Males 0 to <65 years age who have been diagnosed with severe congenital hemophilia A (FVIII activity levels < 1%), who have at least 50 EDs to any FVIII product, and who are not currently enrolled in a CSL-sponsored clinical study with rVIII-SingleChain.

PUPs:

• Males 0 to <18 years of who have been diagnosed with severe congenital hemophilia A (FVIII activity levels < 1%)
• No prior exposure to any Factor VIII product (with the exception of short-term use of blood products).

ITI substudy:

• PUPs who have developed a confirmed inhibitor to rVIII-SingleChain in the main study.

Exclusion Criteria:

• Known or suspected hypersensitivity to rVIII-SingleChain or to any excipients of rVIII-SingleChain or Chinese hamster ovary (CHO) proteins.
• Currently receiving a therapy not permitted during the study.
• Serum creatinine > 2 x upper limit of normal, alanine aminotransferase or aspartate aminotransferase > 5 x upper limit of normal at Screening (if specified)
• Any first-order family (eg, siblings) history of FVIII inhibitors
• For PTPs not rolling over directly from a CSL-sponsored clinical study with rVIII-SingleChain: any history of or current FVIII inhibitors

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: Previously treated patients (PTPs); The investigator will assign subjects to either prophylaxis or on-demand treatment regimens for rVIII-SingleChain by intravenous injection. The investigator will determine the rVIII-SingleChain dose and dosing schedule for the subject based upon the subject's pharmacokinetic (PK) profile, rVIII-SingleChain PK data, previous FVIII treatment regimen, and bleeding phenotype, if available.	Biological: rVIII-SingleChain; Recombinant single-chain coagulation factor VIII; Other Names: CSL627
EXPERIMENTAL: Previously untreated patients (PUPs); The investigator will assign subjects to either prophylaxis or on-demand treatment regimens for rVIII-SingleChain by intravenous injection. The investigator will determine the rVIII-SingleChain dose and dosing schedule at their discretion, taking into consideration the World Federation of Hemophilia (WFH) guidelines, the type of bleeding episode, location of the bleeding, subject's age, and other disease characteristics.	Biological: rVIII-SingleChain; Recombinant single-chain coagulation factor VIII; Other Names: CSL627

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Inhibitor Formation to FVIII in Previously Treated Patients (PTPs) With 100 Exposure Days (EDs) to CSL627		At the closest visit after 100 EDs (up to 5 years).
Number of Previously Untreated Patients (PUPs) With High-titer Inhibitor Formation to FVIII With at Least 50 EDs to CSL627	High-titer inhibitor is defined as an inhibitor titer of ≥ 5 Bethesda units/mL.	At the closest visit after 50 EDs (up to 5 years).
Percent Treatment Success for Major Bleeding Episodes in PUPs	Percentage of major bleeding episodes treated successfully where treatment success for a bleeding episode is defined as a rating of "excellent" or "good" on the investigator's clinical assessment of hemostatic efficacy 4-point scale "excellent, good, moderate or poor/no response". Major bleeding episodes are defined as bleeding episodes for which a subject is required to seek treatment at the hemophilia center or that threatens the subject's life or loss of limb.	Up to 5 years
Annualized Spontaneous Bleeding Rate in PUPs	The annualized spontaneous bleeding rate for PUPs taking prophylaxis and on-demand treatment regimens.	Up to 5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Bleeding Episodes Treated Successfully in PTPs	Percentage of bleeding episodes treated successfully where treatment success for a bleeding episode is defined as a rating of "excellent" or "good" on the investigator's clinical assessment of hemostatic efficacy 4-point scale "excellent, good, moderate or poor/no response".	Up to 5 years
Annualized Bleeding Rate in PTPs and PUPs	The annualized bleeding rate for PTPs and PUPs taking prophylaxis and on-demand treatment regimens	Up to 5 years
Percentage of Bleeding Episodes Requiring 1, 2, 3, or > 3 Injections of CSL627 to Achieve Hemostasis in PTPs and PUPs		Up to 5 years
Mean Number of On-demand Infusions of CSL627		Up to 5 years
Mean On-demand Dose Administered of CSL627		Up to 5 years
Mean Prophylaxis Dose Administered of CSL627		Up to 5 years
Mean Total Amount of CSL627 Administered During Surgery Period in PTPs		Day of surgery up to 336 hours post-surgery
Total Amount of CSL627 Administered During Surgery Period in PUPs		Day of surgery up to 336 hours post-surgery
Hemostatic Efficacy of rVIII-SingleChain for PTPs and PUPs Who Undergo Surgery	The investigator will rate the efficacy of the rVIII-SingleChain treatment during surgery based on a hemostatic efficacy four point rating scale of "excellent, good, moderate or poor/no response".	From the start of surgery through the post-operative recovery (generally up to 14 days after surgery)
Incidence of Inhibitor Formation to FVIII in PTPs After 10 EDs and After 50 EDs		Up to 5 years
Percentage of PTPs and PUPs Developing Antibodies Against CSL627		PTPs: At the closest visit after 100 EDs (up to 5 years). PUPs: At the closest visit after 50 EDs (up to 5 years).
Percentage of PTPs and PUPs Developing Antibodies to Chinese Hamster Ovary (CHO) Proteins		PTPs: At the closest visit after 100 EDs (up to 5 years). PUPs: At the closest visit after 50 EDs (up to 5 years).
Number of PUPs With High-titer Inhibitor Formation to FVIII After 10 EDs With CSL627	High-titer inhibitor is defined as an inhibitor titer of ≥ 5 Bethesda units/mL.	At the closest visit after 10 EDs (up to 5 years)
Number of PUPs With Low-titer Inhibitor Formation to FVIII After 10 EDs and After 50 EDs With CSL627	Low-titer inhibitor is defined as an inhibitor titer of less than 5 Bethesda units/mL.	At the closest visit after 10 and after 50 EDs (up to 5 years)
Incidence of Total Inhibitor Formation to FVIII in PUPs		Up to 5 years
Percent Treatment Success for Non-major Bleeding Episodes in PUPs	Percentage of bleeding episodes treated successfully where treatment success for a bleeding episode is defined as a rating of "excellent" or "good" on the investigator's clinical assessment of hemostatic efficacy 4-point scale "excellent, good, moderate or poor/no response". Non-major bleeding episodes are those not requiring treatment at the hemophilia center or not threatening subject's life or loss of limb.	Up to 5 years
Percentage of PUPs With Clinically Significant Abnormal Vital Signs Values After First Infusion of CSL627	Vital signs assessments include heart rate, blood pressure, and body temperature. Clinical significance of an abnormality will be assessed by the investigator.	Up to 6 hours after first infusion
Percentage of PUPs With Treatment-emergent Clinically Significant Abnormal Vital Signs Values	Vital signs assessments include heart rate, blood pressure, and body temperature. Clinical significance of an abnormality will be assessed by the investigator.	Up to 5 years

Collaborators and Investigators

• Sponsor: CSL Behring

Study record dates

Study Major Dates

• Study Start: October 13, 2014
• Primary Completion (ACTUAL): January 19, 2021
• Study Completion (ACTUAL): January 19, 2021

Study Registration Dates

• First Submitted: June 23, 2014
• First Submitted That Met QC Criteria: June 23, 2014
• First Posted (ESTIMATE): June 24, 2014

Study Record Updates

• Last Update Posted (ACTUAL): October 27, 2021
• Last Update Submitted That Met QC Criteria: September 29, 2021
• Last Verified: September 1, 2021

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; Blood Coagulation Disorders; Hemophilia A
• Other Study ID Numbers: CSL627_3001; 2013-003262-13 (EUDRACT_NUMBER)