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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02172950
Recruitment Status : Active, not recruiting
First Posted : June 24, 2014
Last Update Posted : February 6, 2020
Sponsor:
Information provided by (Responsible Party):
CSL Behring

Tracking Information
First Submitted Date  ICMJE June 23, 2014
First Posted Date  ICMJE June 24, 2014
Last Update Posted Date February 6, 2020
Study Start Date  ICMJE October 13, 2014
Estimated Primary Completion Date July 1, 2025   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 7, 2019)
  • Incidence of inhibitor formation to FVIII in PTPs with 100 EDs to rVIII-SingleChain [ Time Frame: At the closest visit after 100 EDs (up to 5 years). ]
    Number of PTPs (with 100 EDs to rVIII-SingleChain) with inhibitor formation to FVIII
  • Incidence of high-titer inhibitor formation to FVIII in PUPs with at least 50 EDs of rVIII-SingleChain [ Time Frame: At the closest visit after 50 EDs (up to 5 years). ]
    Number of PUPs (with at least 50 EDs of rVIII-SingleChain) with high-titer inhibitor formation to FVIII. High-titer inhibitor is defined as an inhibitor titer of ≥ 5 Bethesda units/mL.
  • Treatment success for major bleeding episodes in PUPs [ Time Frame: Up to 5 years ]
    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.
  • Annualized spontaneous bleeding rate in PUPs [ Time Frame: Up to 5 years ]
    The annualized spontaneous bleeding rate for PUPs taking prophylaxis and on-demand treatment regimens.
Original Primary Outcome Measures  ICMJE
 (submitted: June 23, 2014)
Incidence rate of inhibitor formation to FVIII over 100 EDs. [ Time Frame: At the closest visit after 100 EDs (up to three years). ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 1, 2017)
  • Treatment success in PTPs [ Time Frame: Up to 5 years ]
    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".
  • Annualized bleeding rate in PTPs and PUPs [ Time Frame: Up to 5 years ]
    The annualized bleeding rate for PTPs and PUPs taking prophylaxis and on-demand treatment regimens
  • Percentage of bleeding episodes requiring 1, 2, 3, or > 3 injections of rVIII-SingleChain to achieve hemostasis in PTPs and PUPs [ Time Frame: Up to 5 years ]
  • Consumption of rVIII-SingleChain in PTPs and PUPs - injections [ Time Frame: Up to 5 years ]
    The number of rVIII-SingleChain injections per month and per year
  • Consumption of rVIII-SingleChain in PTPs and PUPs - IU/kg [ Time Frame: Up to 5 years ]
    rVIII-SingleChain consumption (IU/kg) per month and per year, and per event during prophylaxis, on-demand, and surgery.
  • Hemostatic efficacy of rVIII-SingleChain for PTPs and PUPs who undergo surgery [ Time Frame: From the start of surgery through the post-operative recovery (generally up to 14 days after 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".
  • Incidence of inhibitor formation to FVIII after 10 EDs and after 50 EDs in PTPs [ Time Frame: After 10 and after 50 exposure days ]
  • Percentage of PTPs and PUPs developing antibodies against rVIII-SingleChain [ Time Frame: 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 [ Time Frame: PTPs: At the closest visit after 100 EDs (up to 5 years). PUPs: At the closest visit after 50 EDs (up to 5 years). ]
  • Incidence of high-titer inhibitor formation to FVIII in PUPs after 10 EDs with rVIII-SingleChain [ Time Frame: At the closest visit after 10 EDs ]
    Number of PUPs (after 10 EDs of rVIII-SingleChain) with high-titer inhibitor formation to FVIII. High-titer inhibitor is defined as an inhibitor titer of ≥ 5 Bethesda units/mL.
  • Incidence of low-titer inhibitor formation to FVIII in PUPs [ Time Frame: At the closest visit after 10 and after 50 EDs (up to 5 years) ]
    Number of PUPs (after 10 and 50 EDs of rVIII-SingleChain) with low-titer inhibitor formation to FVIII. Low-titer inhibitor is defined as an inhibitor titer of less than 5 Bethesda units/mL.
  • Incidence of total inhibitor formation to FVIII in PUPs [ Time Frame: At the closest visit after 10 and after 50 EDs (up to 5 years) ]
    Number of PUPs (after 10 and 50 EDs of rVIII-SingleChain) with inhibitor formation (both low- and high-titer inhibitors) to FVIII.
  • Treatment success for non-major bleeding episodes in PUPs [ Time Frame: Up to 5 years ]
    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.
  • Percentage of PUPs with clinically significant abnormal vital signs values after first rVIII-SingleChain injection [ Time Frame: At 1, 2, 3, and 6 hours after first rVIII-SingleChain injection ]
    Vital signs assessments include heart rate, blood pressure, and body temperature. Clinical significance of an abnormality will be assessed by the investigator
  • Percentage of PUPs with treatment-emergent clinically significant abnormal vital signs values [ Time Frame: Up to 5 years ]
    Vital signs assessments include heart rate, blood pressure, and body temperature. Clinical significance of an abnormality will be assessed by the investigator
Original Secondary Outcome Measures  ICMJE
 (submitted: June 23, 2014)
  • Treatment success [ Time Frame: Up to three years ]
    Rate of treatment success where treatment success of 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".
  • Annualized bleeding rate [ Time Frame: Up to three years ]
    The annualized bleeding rate for subjects taking prophylaxis and on-demand treatment regimens
  • The proportion of bleeding episodes requiring 1, 2, 3, or > 3 infusions of rVIII-SingleChain to achieve hemostasis [ Time Frame: Up to three years ]
  • Consumption of rVIII-SingleChain - infusions [ Time Frame: Up to three years ]
    The number of rVIII-SingleChain infusions per month and per year
  • Consumption of rVIII-SingleChain - IU/kg [ Time Frame: Up to three years ]
    rVIII-SingleChain consumption (IU/kg) per month and per year, and per event during prophylaxis, on-demand, and surgery.
  • Hemostatic efficacy of rVIII-SingleChain for subjects who undergo surgery [ Time Frame: From the start of surgery through the post-operative recovery (generally up to 14 days after 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".
  • The incidence rate of inhibitor formation to FVIII [ Time Frame: After 10 and after 50 exposure days ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE An Open-label Safety and Efficacy Study of Recombinant FVIII in Patients With Severe Hemophilia A
Official Title  ICMJE 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
Brief Summary 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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Hemophilia A
  • Severe Hemophilia A
Intervention  ICMJE Biological: rVIII‑SingleChain
Recombinant single-chain coagulation factor VIII
Other Name: CSL627
Study Arms  ICMJE
  • 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.
    Intervention: Biological: rVIII‑SingleChain
  • 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.
    Intervention: Biological: rVIII‑SingleChain
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: October 21, 2019)
245
Original Estimated Enrollment  ICMJE
 (submitted: June 23, 2014)
200
Estimated Study Completion Date  ICMJE July 1, 2025
Estimated Primary Completion Date July 1, 2025   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Ages  ICMJE Child, Adult, Older Adult
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   Austria,   Canada,   Czechia,   France,   Georgia,   Germany,   Hungary,   Ireland,   Italy,   Japan,   Lebanon,   Malaysia,   Netherlands,   Philippines,   Poland,   Portugal,   Romania,   South Africa,   Spain,   Switzerland,   Thailand,   Ukraine,   United Kingdom,   United States
Removed Location Countries Czech Republic,   Turkey
 
Administrative Information
NCT Number  ICMJE NCT02172950
Other Study ID Numbers  ICMJE CSL627_3001
2013-003262-13 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party CSL Behring
Study Sponsor  ICMJE CSL Behring
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Program Director CSL Behring
PRS Account CSL Behring
Verification Date February 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP