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Pharmacokinetic, Efficacy, and Safety Study of Recombinant Factor VIII Single Chain (rVIII-SingleChain) in Children With Severe Hemophilia A

Primary Purpose

Congenital Hemophilia A

Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
rVIII-SingleChain
Sponsored by
CSL Behring
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Congenital Hemophilia A

Eligibility Criteria

undefined - 11 Years (Child)MaleDoes not accept healthy volunteers

Inclusion Criteria:

  • Diagnosis of severe hemophilia A defined as < 1% Factor VIII (FVIII) concentration (FVIII:C) documented in medical records,
  • Males < 12 years of age,
  • Subjects who have received > 50 EDs with a FVIII product,
  • Prior PK data (at least incremental recovery and half-life) from previous FVIII exposure for subjects participating in the PK part
  • Investigator believes that the subject is willing and able to adhere to all protocol requirements. Investigator believes that the subject's parent(s) or legally acceptable representative(s) is / are willing and able to adhere to all protocol requirements.

Exclusion Criteria:

  • Any history of or current FVIII inhibitors
  • Use of an Investigational Medical Product (IMP) within 30 days prior to the first rVIII-SingleChain administration,
  • Administration of any cryoprecipitate, whole blood or plasma within 30 days prior to administration of rVIII-SingleChain,
  • Known hypersensitivity (allergic reaction or anaphylaxis) to any FVIII product or hamster protein,
  • Subject currently receiving IV immunomodulating agents such as immunoglobulin or chronic systemic corticosteroid treatment,
  • Subject with serum aspartate aminotransferase (AST) or serum alanine aminotransferase (ALT) values >5 times (x) the upper limit of normal (ULN) at Screening,
  • Subjects with serum creatinine values >2 x ULN at Screening,
  • Evidence of thrombosis, including deep vein thrombosis, stroke, pulmonary embolism, myocardial infarction and arterial embolus within 3 months before Day 1,
  • Experienced life-threatening bleeding episode or had major surgery or an orthopedic surgical procedure during the 3 months before rVIII-SingleChain administration.

Sites / Locations

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Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

rVIII-SingleChain

Arm Description

Subjects will be assigned to either an on-demand or prophylaxis regimen and will receive rVIII-SingleChain as an intravenous (IV) infusion. Subjects assigned to a prophylaxis regimen will be treated with 15 to 50 IU/kg of rVIII-SingleChain every second day or 2 to 3 times per week, or at the investigator's discretion, based on available PK data, the FVIII treatment regimen used before enrollment and/or the subject's bleeding phenotype. The dose for on-demand treatment of a bleeding episode is based on the recommendations of the World Federation of Hemophilia (WFH), with a minimum dose of 15 IU/kg. All subjects were to be treated for a minimum of 50 EDs. For the PK evaluation, the subjects will receive a single IV dose of 50 IU/kg of rVIII-SingleChain on Day 1 at the start of the PK evaluation period.

Outcomes

Primary Outcome Measures

Treatment Success
Rate of treatment success where treatment success of a bleeding episode is defined as a rating of "excellent" or "good" based on the investigator's overall clinical assessment of hemostatic efficacy (using a 4-point scale of excellent, good, moderate or poor/no response) on the on-demand and prophylaxis regimens combined. The rate of success was based on the number of treated bleeding events; there were 347 treated bleeding events in the Efficacy Population.

Secondary Outcome Measures

Annualized Bleeding Rate
The annualized bleeding rate was defined as the number of bleeding episodes requiring treatment divided by the efficacy evaluation period in days, x 365.25, and is presented separately for the on-demand regimen and the prophylaxis regimens.
Percentage of Bleeding Episodes Requiring 1, 2, 3, or More Than 3 Infusions of rVIII-SingleChain to Achieve Hemostasis.
Consumption of rVIII-SingleChain - IU/kg Per Subject Per Month
Consumption of rVIII-SingleChain - IU/kg Per Subject Per Year
Consumption of rVIII-SingleChain - IU/kg Per Bleeding Event
Consumption of rVIII-SingleChain (On-demand Regimen) - Number of Infusions Per Subject Per Month
Consumption of rVIII-SingleChain (On-demand Regimen) - Number of Infusions Per Subject Per Year
Incremental Recovery
Incremental recovery expressed as (IU/dL)/(IU/kg) corrected for subject's predose plasma FVIII activity measured using the chromogenic substrate assay.
Half-life (t1/2) of rVIII-SingleChain
Half-life (t1/2) of rVIII-SingleChain, baseline uncorrected; plasma FVIII activity measured using the chromogenic substrate assay.
Area Under the Concentration Curve (AUC)
AUC to the last sample with quantifiable drug concentration (AUC0-t), baseline uncorrected; plasma FVIII activity measured using the chromogenic substrate assay.
Clearance (Cl) of rVIII-SingleChain
Clearance (Cl) of rVIII-SingleChain, baseline uncorrected; plasma FVIII activity measured using the chromogenic substrate assay.
Number of Subjects With Inhibitor Formation to rVIII-SingleChain
The number of subjects who develop inhibitors to rVIII-SingleChain, defined as a rVIII-SingleChain antibody titer of at least 0.6 Bethesda Units (BU) per mL after receiving study drug.

Full Information

First Posted
March 19, 2014
Last Updated
December 5, 2016
Sponsor
CSL Behring
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1. Study Identification

Unique Protocol Identification Number
NCT02093897
Brief Title
Pharmacokinetic, Efficacy, and Safety Study of Recombinant Factor VIII Single Chain (rVIII-SingleChain) in Children With Severe Hemophilia A
Official Title
A Phase III Open-label Pharmacokinetic, Efficacy and Safety Study of rVIII-SingleChain in a Pediatric Population With Severe Hemophilia A
Study Type
Interventional

2. Study Status

Record Verification Date
December 2016
Overall Recruitment Status
Completed
Study Start Date
March 2014 (undefined)
Primary Completion Date
August 2015 (Actual)
Study Completion Date
August 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
CSL Behring

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This is an international, multicenter, open-label study to assess the efficacy, safety, and pharmacokinetic (PK) profile of rVIII-SingleChain in pediatric patients with severe hemophilia A. A minimum of 25 previously treated subjects ≥ 6 to < 12 years of age and at least 25 subjects < 6 years of age who have undergone > 50 exposure days (EDs) with a previous Factor VIII (FVIII) product are planned to be enrolled. Subjects will be assigned to either an on-demand or prophylaxis treatment regimen and will receive rVIII-SingleChain at a dose to be determined by the investigator. Hemostatic efficacy will be assessed by the subject/caregiver and the investigator who will assess overall efficacy by a 4-point scale.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Congenital Hemophilia A

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
84 (Actual)

8. Arms, Groups, and Interventions

Arm Title
rVIII-SingleChain
Arm Type
Experimental
Arm Description
Subjects will be assigned to either an on-demand or prophylaxis regimen and will receive rVIII-SingleChain as an intravenous (IV) infusion. Subjects assigned to a prophylaxis regimen will be treated with 15 to 50 IU/kg of rVIII-SingleChain every second day or 2 to 3 times per week, or at the investigator's discretion, based on available PK data, the FVIII treatment regimen used before enrollment and/or the subject's bleeding phenotype. The dose for on-demand treatment of a bleeding episode is based on the recommendations of the World Federation of Hemophilia (WFH), with a minimum dose of 15 IU/kg. All subjects were to be treated for a minimum of 50 EDs. For the PK evaluation, the subjects will receive a single IV dose of 50 IU/kg of rVIII-SingleChain on Day 1 at the start of the PK evaluation period.
Intervention Type
Biological
Intervention Name(s)
rVIII-SingleChain
Other Intervention Name(s)
Recombinant Factor VIII single chain, CSL627
Primary Outcome Measure Information:
Title
Treatment Success
Description
Rate of treatment success where treatment success of a bleeding episode is defined as a rating of "excellent" or "good" based on the investigator's overall clinical assessment of hemostatic efficacy (using a 4-point scale of excellent, good, moderate or poor/no response) on the on-demand and prophylaxis regimens combined. The rate of success was based on the number of treated bleeding events; there were 347 treated bleeding events in the Efficacy Population.
Time Frame
Up to 1 year
Secondary Outcome Measure Information:
Title
Annualized Bleeding Rate
Description
The annualized bleeding rate was defined as the number of bleeding episodes requiring treatment divided by the efficacy evaluation period in days, x 365.25, and is presented separately for the on-demand regimen and the prophylaxis regimens.
Time Frame
Up to 1 year
Title
Percentage of Bleeding Episodes Requiring 1, 2, 3, or More Than 3 Infusions of rVIII-SingleChain to Achieve Hemostasis.
Time Frame
Up to 1 year
Title
Consumption of rVIII-SingleChain - IU/kg Per Subject Per Month
Time Frame
Up to 1 year
Title
Consumption of rVIII-SingleChain - IU/kg Per Subject Per Year
Time Frame
Up to 1 year
Title
Consumption of rVIII-SingleChain - IU/kg Per Bleeding Event
Time Frame
Up to 1 year
Title
Consumption of rVIII-SingleChain (On-demand Regimen) - Number of Infusions Per Subject Per Month
Time Frame
Up to 1 year
Title
Consumption of rVIII-SingleChain (On-demand Regimen) - Number of Infusions Per Subject Per Year
Time Frame
Up to 1 year
Title
Incremental Recovery
Description
Incremental recovery expressed as (IU/dL)/(IU/kg) corrected for subject's predose plasma FVIII activity measured using the chromogenic substrate assay.
Time Frame
At 1 hour after the start of infusion
Title
Half-life (t1/2) of rVIII-SingleChain
Description
Half-life (t1/2) of rVIII-SingleChain, baseline uncorrected; plasma FVIII activity measured using the chromogenic substrate assay.
Time Frame
Immediately before dosing, and at approximately 1, 5, 10, 24, and 48 hours after dosing.
Title
Area Under the Concentration Curve (AUC)
Description
AUC to the last sample with quantifiable drug concentration (AUC0-t), baseline uncorrected; plasma FVIII activity measured using the chromogenic substrate assay.
Time Frame
Immediately before dosing, and at approximately 1, 5, 10, 24, and 48 hours after dosing.
Title
Clearance (Cl) of rVIII-SingleChain
Description
Clearance (Cl) of rVIII-SingleChain, baseline uncorrected; plasma FVIII activity measured using the chromogenic substrate assay.
Time Frame
Immediately before dosing, and at approximately 1, 5, 10, 24, and 48 hours after dosing.
Title
Number of Subjects With Inhibitor Formation to rVIII-SingleChain
Description
The number of subjects who develop inhibitors to rVIII-SingleChain, defined as a rVIII-SingleChain antibody titer of at least 0.6 Bethesda Units (BU) per mL after receiving study drug.
Time Frame
At screening, then after dosing at approximately monthly intervals for 6 months, then every 3 months until reaching 50 EDs, and at the end of study visit (up to approximately 12 months).

10. Eligibility

Sex
Male
Maximum Age & Unit of Time
11 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Diagnosis of severe hemophilia A defined as < 1% Factor VIII (FVIII) concentration (FVIII:C) documented in medical records, Males < 12 years of age, Subjects who have received > 50 EDs with a FVIII product, Prior PK data (at least incremental recovery and half-life) from previous FVIII exposure for subjects participating in the PK part Investigator believes that the subject is willing and able to adhere to all protocol requirements. Investigator believes that the subject's parent(s) or legally acceptable representative(s) is / are willing and able to adhere to all protocol requirements. Exclusion Criteria: Any history of or current FVIII inhibitors Use of an Investigational Medical Product (IMP) within 30 days prior to the first rVIII-SingleChain administration, Administration of any cryoprecipitate, whole blood or plasma within 30 days prior to administration of rVIII-SingleChain, Known hypersensitivity (allergic reaction or anaphylaxis) to any FVIII product or hamster protein, Subject currently receiving IV immunomodulating agents such as immunoglobulin or chronic systemic corticosteroid treatment, Subject with serum aspartate aminotransferase (AST) or serum alanine aminotransferase (ALT) values >5 times (x) the upper limit of normal (ULN) at Screening, Subjects with serum creatinine values >2 x ULN at Screening, Evidence of thrombosis, including deep vein thrombosis, stroke, pulmonary embolism, myocardial infarction and arterial embolus within 3 months before Day 1, Experienced life-threatening bleeding episode or had major surgery or an orthopedic surgical procedure during the 3 months before rVIII-SingleChain administration.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Program Director
Organizational Affiliation
CSL Behring
Official's Role
Study Director
Facility Information:
Facility Name
Study Site
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
Facility Name
Study Site
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60612
Country
United States
Facility Name
Study Site
City
Melbourne
State/Province
Victoria
ZIP/Postal Code
3052
Country
Australia
Facility Name
Study Site
City
Linz
ZIP/Postal Code
4020
Country
Austria
Facility Name
Study Site
City
Vienna
ZIP/Postal Code
1090
Country
Austria
Facility Name
Study Site
City
Brest
ZIP/Postal Code
29609
Country
France
Facility Name
Study Site
City
Le Kremlin Bicetre
ZIP/Postal Code
94270
Country
France
Facility Name
Study Site
City
Lille Cedex
ZIP/Postal Code
59037
Country
France
Facility Name
Study Site
City
Nantes
ZIP/Postal Code
44093
Country
France
Facility Name
Study Site
City
Paris
ZIP/Postal Code
75015
Country
France
Facility Name
Study Site
City
Tbilisi
ZIP/Postal Code
0177
Country
Georgia
Facility Name
Study Site
City
Bonn
ZIP/Postal Code
53127
Country
Germany
Facility Name
Study Site
City
Bremen
ZIP/Postal Code
28177
Country
Germany
Facility Name
Study Site
City
Frankfurt/Main
ZIP/Postal Code
60590
Country
Germany
Facility Name
Study Site
City
Hannover
ZIP/Postal Code
30159
Country
Germany
Facility Name
Study Site
City
Milano
ZIP/Postal Code
20122
Country
Italy
Facility Name
Study Site
City
Beirut
ZIP/Postal Code
11072240
Country
Lebanon
Facility Name
Study Site
City
Kuala Lumpur
ZIP/Postal Code
50400
Country
Malaysia
Facility Name
Study Site
City
Amsterdam
ZIP/Postal Code
1105 AZ
Country
Netherlands
Facility Name
Study Site
City
Njmegen
ZIP/Postal Code
6525 GA
Country
Netherlands
Facility Name
Study Site
City
Utrecht
ZIP/Postal Code
3584 CX
Country
Netherlands
Facility Name
Study Site
City
Cebu City
ZIP/Postal Code
6000
Country
Philippines
Facility Name
Study Site
City
Davao City
ZIP/Postal Code
8000
Country
Philippines
Facility Name
Study Site
City
Rzeszow
ZIP/Postal Code
35-310
Country
Poland
Facility Name
Study Site
City
Oporto
ZIP/Postal Code
4202-451
Country
Portugal
Facility Name
Study Site
City
Timisoara
ZIP/Postal Code
300011
Country
Romania
Facility Name
Study Site
City
Madrid
ZIP/Postal Code
28046
Country
Spain
Facility Name
Study Site
City
Lucerne
ZIP/Postal Code
6000
Country
Switzerland
Facility Name
Study Site
City
Bangkok
ZIP/Postal Code
10330
Country
Thailand
Facility Name
Study Site
City
Bangkok
ZIP/Postal Code
10700
Country
Thailand
Facility Name
Study Site
City
Chiang Mai
ZIP/Postal Code
50200
Country
Thailand
Facility Name
Study Site
City
Khon Kaen
ZIP/Postal Code
40002
Country
Thailand
Facility Name
Study Site
City
Songkla
ZIP/Postal Code
90110
Country
Thailand
Facility Name
Study Site
City
Adana
ZIP/Postal Code
01330
Country
Turkey
Facility Name
Study Site
City
Istanbul
ZIP/Postal Code
34098
Country
Turkey
Facility Name
Study Site
City
Izmir
ZIP/Postal Code
35100
Country
Turkey
Facility Name
Study Site
City
Lviv
ZIP/Postal Code
79044
Country
Ukraine

12. IPD Sharing Statement

Learn more about this trial

Pharmacokinetic, Efficacy, and Safety Study of Recombinant Factor VIII Single Chain (rVIII-SingleChain) in Children With Severe Hemophilia A

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