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

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ClinicalTrials.gov Identifier: NCT02093897
Recruitment Status : Completed
First Posted : March 21, 2014
Results First Posted : January 27, 2017
Last Update Posted : January 27, 2017
Sponsor:
Information provided by (Responsible Party):
CSL Behring

Study Type Interventional
Study Design Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Congenital Hemophilia A
Intervention Biological: rVIII-SingleChain
Enrollment 84
Recruitment Details This multicenter, multinational study enrolled subjects at 37 participating study centers in Australia, Europe, Georgia, Lebanon, Malaysia, Philippines, Switzerland, Thailand, Turkey, Ukraine, and the United States.
Pre-assignment Details Screening took place 4 to 28 days prior to first dose of study product (rVIII-SingleChain). A total of 88 subjects were screened, 4 of these did not fulfill all eligibility criteria and were therefore screening failures.
Arm/Group Title rVIII-SingleChain
Hide Arm/Group Description Subjects were assigned to either an on-demand or prophylaxis regimen and received rVIII-SingleChain as an intravenous (IV) infusion. Subjects assigned to a prophylaxis regimen were 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 was 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 received a single IV dose of 50 IU/kg of rVIII-SingleChain on Day 1 at the start of the PK evaluation period.
Period Title: Overall Study
Started [1] 84
Completed [2] 65
Not Completed 19
Reason Not Completed
Physician Decision             1
Planned age group closure - no's reached             17
Adverse event, non-fatal             1
[1]
A total of 5313 CSL627 infusions were administered to 84 subjects during the study.
[2]
As planned, groups were closed and subjects discontinued when 25 subjects reached 50 EDs per group.
Arm/Group Title rVIII-SingleChain
Hide Arm/Group Description Subjects were assigned to either an on-demand or prophylaxis regimen and received rVIII-SingleChain as an IV infusion. Subjects assigned to a prophylaxis regimen were 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 was based on the recommendations of the 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 received a single IV dose of 50 IU/kg of rVIII-SingleChain on Day 1 at the start of the PK evaluation period.
Overall Number of Baseline Participants 84
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 84 participants
<=18 years
84
 100.0%
Between 18 and 65 years
0
   0.0%
>=65 years
0
   0.0%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 84 participants
6.6  (3.11)
Gender  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 84 participants
Female
0
   0.0%
Male
84
 100.0%
Type of FVIII product used before enrollment   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 84 participants
Plasma product 33
Recombinant Product 49
Unknown 2
[1]
Measure Description: Type of FVIII product used by the subjects within the 12 months before enrollment into the study. This could have been a plasma FVIII product or a recombinant FVIII product.
Treatment modality of FVIII therapy before enrollment   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 84 participants
Prophylaxis 60
On-Demand 24
[1]
Measure Description: Treatment modality of FVIII therapy within the 12 months before enrollment, ie, routine prophylaxis or on-demand treatment. If a subject used both modalities, only the most recent one was counted.
1.Primary Outcome
Title Treatment Success
Time Frame Up to 1 year
Hide Outcome Measure Data
Hide Analysis Population Description
Efficacy Population
Arm/Group Title Efficacy Population
Hide Arm/Group Description:
The Efficacy Population consisted of all subjects who received at least 1 dose of rVIII-SingleChain as part of either a routine prophylaxis or on-demand regimen during the study. One subject was excluded from the efficacy population because of a pre-existing inhibitor to FVIII (confirmed by reexamination of a screening sample initially reported as negative due to laboratory error).
Overall Number of Participants Analyzed 83
Overall Number of Units Analyzed
Type of Units Analyzed: Treated bleeding events
347
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of treated bleeding events
96.3
(91.3 to 98.4)
2.Secondary Outcome
Title Annualized Bleeding Rate
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
The Efficacy Population comprised all subjects who received at least 1 rVIII-SingleChain dose for prophylaxis or on-demand treatment. One subject was excluded from the efficacy population because of a pre-existing inhibitor to FVIII (confirmed by reexamination of a screening sample initially reported as negative due to laboratory error).
Arm/Group Title On-demand Prophylaxis
Hide Arm/Group Description:
Subjects assigned to the on-demand treatment regimen treated themselves, or were treated by a caregiver/guardian, as needed for any bleeding episode and did not receive routine assigned infusions.
Subjects receiving routine prophylaxis treatment were initially treated with 15-50 IU/kg of rVIII-SingleChain every second day or 2 to 3 times per week, or at the investigator’s discretion, based upon available PK data, the FVIII treatment regimen used before enrollment and/or the subject’s bleeding phenotype. The dose or dosing frequency may have been adjusted if necessary.
Overall Number of Participants Analyzed 3 80
Median (Inter-Quartile Range)
Unit of Measure: Treated bleeding episodes per year
78.56
(35.12 to 86.62)
3.69
(0.00 to 7.20)
3.Secondary Outcome
Title Percentage of Bleeding Episodes Requiring 1, 2, 3, or More Than 3 Infusions of rVIII-SingleChain to Achieve Hemostasis.
Hide Description [Not Specified]
Time Frame Up to 1 year
Hide Outcome Measure Data
Hide Analysis Population Description
Efficacy Population
Arm/Group Title Efficacy Population
Hide Arm/Group Description:
The Efficacy Population consisted of all subjects who received at least 1 dose of rVIII-SingleChain as part of either a routine prophylaxis or on-demand regimen during the study. One subject was excluded from the efficacy population because of a pre-existing inhibitor to FVIII (confirmed by reexamination of a screening sample initially reported as negative due to laboratory error).
Overall Number of Participants Analyzed 83
Overall Number of Units Analyzed
Type of Units Analyzed: Number of Treated Bleeds
347
Measure Type: Number
Unit of Measure: Percentage (%) of bleeding episodes
Requiring 1 infusion 85.9
Requiring 2 infusions 9.8
Requiring 3 infusions 2.3
Requiring > 3 infusions 2.0
4.Secondary Outcome
Title Consumption of rVIII-SingleChain - IU/kg Per Subject Per Month
Hide Description [Not Specified]
Time Frame Up to 1 year
Hide Outcome Measure Data
Hide Analysis Population Description
The Efficacy Population comprised all subjects who received at least 1 rVIII-SingleChain dose for prophylaxis or on-demand treatment. One subject was excluded from the efficacy population because of a pre-existing inhibitor to FVIII (confirmed by reexamination of a screening sample initially reported as negative due to laboratory error).
Arm/Group Title On-demand Prophylaxis
Hide Arm/Group Description:
Subjects assigned to the on-demand treatment regimen treated themselves, or were treated by a caregiver/guardian, as needed for any bleeding episode and did not receive routine assigned infusions. Preventative and additional doses of rVIII-SingleChain were allowed. "Preventative dose" was defined as a dose taken before an activity or a minor procedure to prevent or minimize a bleeding episode, and "additional dose" was defined as a dose taken beyond the need to control hemostasis.
Subjects receiving routine prophylaxis treatment were initially treated with 15-50 IU/kg of rVIII-SingleChain every second day or 2 to 3 times per week, or at the investigator’s discretion, based upon available PK data, the FVIII treatment regimen used before enrollment and/or the subject’s bleeding phenotype. The dose or dosing frequency may have been adjusted if necessary. Preventative and additional doses of rVIII-SingleChain were allowed. "Preventative dose" was defined as a dose taken before an activity or a minor procedure to prevent or minimize a bleeding episode, and "additional dose" was defined as a dose taken beyond the need to control hemostasis.
Overall Number of Participants Analyzed 3 80
Median (Full Range)
Unit of Measure: IU/kg per subject per month
202
(126 to 231)
378
(153 to 1394)
5.Secondary Outcome
Title Consumption of rVIII-SingleChain - IU/kg Per Subject Per Year
Hide Description [Not Specified]
Time Frame Up to 1 year
Hide Outcome Measure Data
Hide Analysis Population Description
The Efficacy Population comprised all subjects who received at least 1 rVIII-SingleChain dose for prophylaxis or on-demand treatment. One subject was excluded from the efficacy population because of a pre-existing inhibitor to FVIII (confirmed by reexamination of a screening sample initially reported as negative due to laboratory error).
Arm/Group Title On-demand Prophylaxis
Hide Arm/Group Description:
Subjects assigned to the on-demand treatment regimen treated themselves, or were treated by a caregiver/guardian, as needed for any bleeding episode and did not receive routine assigned infusions. Preventative and additional doses of rVIII-SingleChain were allowed. "Preventative dose" was defined as a dose taken before an activity or a minor procedure to prevent or minimize a bleeding episode, and "additional dose" was defined as a dose taken beyond the need to control hemostasis.
Subjects receiving routine prophylaxis treatment were initially treated with 15-50 IU/kg of rVIII-SingleChain every second day or 2 to 3 times per week, or at the investigator’s discretion, based upon available PK data, the FVIII treatment regimen used before enrollment and/or the subject’s bleeding phenotype. The dose or dosing frequency may have been adjusted if necessary. Preventative and additional doses of rVIII-SingleChain were allowed. "Preventative dose" was defined as a dose taken before an activity or a minor procedure to prevent or minimize a bleeding episode, and "additional dose" was defined as a dose taken beyond the need to control hemostasis.
Overall Number of Participants Analyzed 3 80
Median (Full Range)
Unit of Measure: IU/kg per subject per year
2429
(1508 to 2771)
4541
(1839 to 16727)
6.Secondary Outcome
Title Consumption of rVIII-SingleChain - IU/kg Per Bleeding Event
Hide Description [Not Specified]
Time Frame Up to 1 year
Hide Outcome Measure Data
Hide Analysis Population Description
The Efficacy Population comprised all subjects who received at least 1 rVIII-SingleChain dose for prophylaxis or on-demand treatment. One subject was excluded from the efficacy population because of a pre-existing inhibitor to FVIII (confirmed by reexamination of a screening sample initially reported as negative due to laboratory error).
Arm/Group Title On-demand Prophylaxis
Hide Arm/Group Description:
Subjects assigned to the on-demand treatment regimen treated themselves, or were treated by a caregiver/guardian, as needed for any bleeding episode and did not receive routine assigned infusions. Preventative and additional doses of rVIII-SingleChain were allowed. "Preventative dose" was defined as a dose taken before an activity or a minor procedure to prevent or minimize a bleeding episode, and "additional dose" was defined as a dose taken beyond the need to control hemostasis.
Subjects receiving routine prophylaxis treatment were initially treated with 15-50 IU/kg of rVIII-SingleChain every second day or 2 to 3 times per week, or at the investigator’s discretion, based upon available PK data, the FVIII treatment regimen used before enrollment and/or the subject’s bleeding phenotype. The dose or dosing frequency may have been adjusted if necessary. Preventative and additional doses of rVIII-SingleChain were allowed. "Preventative dose" was defined as a dose taken before an activity or a minor procedure to prevent or minimize a bleeding episode, and "additional dose" was defined as a dose taken beyond the need to control hemostasis.
Overall Number of Participants Analyzed 3 80
Median (Full Range)
Unit of Measure: IU/kg per event
25.9
(21 to 78)
37.0
(16 to 282)
7.Secondary Outcome
Title Consumption of rVIII-SingleChain (On-demand Regimen) - Number of Infusions Per Subject Per Month
Hide Description [Not Specified]
Time Frame Up to 1 year
Hide Outcome Measure Data
Hide Analysis Population Description
Subjects assigned to the on-demand treatment regimen.
Arm/Group Title On-demand
Hide Arm/Group Description:
Subjects assigned to the on-demand treatment regimen treated themselves, or were treated by a caregiver/guardian, as needed for any bleeding episode and did not receive routine assigned infusions. Preventative and additional doses of rVIII-SingleChain were allowed. "Preventative dose" was defined as a dose taken before an activity or a minor procedure to prevent or minimize a bleeding episode, and "additional dose" was defined as a dose taken beyond the need to control hemostasis.
Overall Number of Participants Analyzed 3
Median (Full Range)
Unit of Measure: number of infusion per subject per month
7.58
(5.1 to 7.7)
8.Secondary Outcome
Title Consumption of rVIII-SingleChain (On-demand Regimen) - Number of Infusions Per Subject Per Year
Hide Description [Not Specified]
Time Frame Up to 1 year
Hide Outcome Measure Data
Hide Analysis Population Description
Subjects assigned to the on-demand treatment regimen.
Arm/Group Title On-demand
Hide Arm/Group Description:
Subjects assigned to the on-demand treatment regimen treated themselves, or were treated by a caregiver/guardian, as needed for any bleeding episode and did not receive routine assigned infusions. Preventative and additional doses of rVIII-SingleChain were allowed. "Preventative dose" was defined as a dose taken before an activity or a minor procedure to prevent or minimize a bleeding episode, and "additional dose" was defined as a dose taken beyond the need to control hemostasis.
Overall Number of Participants Analyzed 3
Median (Full Range)
Unit of Measure: number of infusions per subject per year
90.95
(60.9 to 92.3)
9.Secondary Outcome
Title Incremental Recovery
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
PK Population
Arm/Group Title Pharmacokinetic Population
Hide Arm/Group Description:
The Pharmacokinetic (PK) Population comprised those subjects who participated in the PK assessment and received at least 1 dose of rVIII-SingleChain and for whom a sufficient number of analyzable PK samples were obtained to permit the evaluation of the PK profile of rVIII-SingleChain.
Overall Number of Participants Analyzed 39
Mean (Standard Deviation)
Unit of Measure: (IU/dL)/(IU/kg)
1.63  (0.329)
10.Secondary Outcome
Title Half-life (t1/2) of rVIII-SingleChain
Hide 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.
Hide Outcome Measure Data
Hide Analysis Population Description
PK Population
Arm/Group Title Pharmacokinetic Population
Hide Arm/Group Description:
The PK Population comprised those subjects who participated in the PK assessment and received at least 1 dose of rVIII-SingleChain and for whom a sufficient number of analyzable PK samples were obtained to permit the evaluation of the PK profile of rVIII-SingleChain.
Overall Number of Participants Analyzed 39
Mean (Standard Deviation)
Unit of Measure: hour
10.3  (2.51)
11.Secondary Outcome
Title Area Under the Concentration Curve (AUC)
Hide 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.
Hide Outcome Measure Data
Hide Analysis Population Description
PK Population
Arm/Group Title Pharmacokinetic Population
Hide Arm/Group Description:
The PK Population comprised those subjects who participated in the PK assessment and received at least 1 dose of rVIII-SingleChain and for whom a sufficient number of analyzable PK samples were obtained to permit the evaluation of the PK profile of rVIII-SingleChain.
Overall Number of Participants Analyzed 39
Mean (Standard Deviation)
Unit of Measure: IU*h/dL
1050  (286)
12.Secondary Outcome
Title Clearance (Cl) of rVIII-SingleChain
Hide 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.
Hide Outcome Measure Data
Hide Analysis Population Description
PK Population
Arm/Group Title Pharmacokinetic Population
Hide Arm/Group Description:
The PK Population comprised those subjects who participated in the PK assessment and received at least 1 dose of rVIII-SingleChain and for whom a sufficient number of analyzable PK samples were obtained to permit the evaluation of the PK profile of rVIII-SingleChain.
Overall Number of Participants Analyzed 39
Mean (Standard Deviation)
Unit of Measure: mL/h/kg
4.86  (1.43)
13.Secondary Outcome
Title Number of Subjects With Inhibitor Formation to rVIII-SingleChain
Hide 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).
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title rVIII-SingleChain
Hide Arm/Group Description:
Subjects were assigned to either an on-demand or prophylaxis regimen and received rVIII-SingleChain as an IV infusion. Subjects assigned to a prophylaxis regimen were 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 was based on the recommendations of the 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 received a single IV dose of 50 IU/kg of rVIII-SingleChain on Day 1 at the start of the PK evaluation period.
Overall Number of Participants Analyzed 84
Measure Type: Number
Unit of Measure: participants
0
Time Frame For the duration of the study, approximately 1 year, 5 months.
Adverse Event Reporting Description The Safety Population comprised all subjects treated with rVIII-SingleChain. A total of 5313 CSL627 infusions were administered to 84 subjects during the study.
 
Arm/Group Title rVIII-SingleChain
Hide Arm/Group Description Subjects were assigned to either an on-demand or prophylaxis regimen and received rVIII-SingleChain as an IV infusion. Subjects assigned to a prophylaxis regimen were 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 was based on the recommendations of the 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 received a single IV dose of 50 IU/kg of rVIII-SingleChain on Day 1 at the start of the PK evaluation period.
All-Cause Mortality
rVIII-SingleChain
Affected / at Risk (%)
Total   --/--    
Show Serious Adverse Events Hide Serious Adverse Events
rVIII-SingleChain
Affected / at Risk (%) # Events
Total   9/84 (10.71%)    
Blood and lymphatic system disorders   
Anaemia  1  1/84 (1.19%)  3
Gastrointestinal disorders   
Dyspepsia  1  1/84 (1.19%)  1
General disorders   
Device occlusion  1  1/84 (1.19%)  1
Systemic inflammatory response syndrome  1  1/84 (1.19%)  1
Infections and infestations   
Bacteraemia  1  1/84 (1.19%)  1
Pneumonia  1  1/84 (1.19%)  1
Injury, poisoning and procedural complications   
Hand fracture  1  1/84 (1.19%)  1
Laceration  1  1/84 (1.19%)  1
Splenic rupture  1  1/84 (1.19%)  1
Investigations   
Inhibiting antibodies positive  1 [1]  1/84 (1.19%)  1
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA (16.1)
[1]
Subject identified with pre-existing inhibitor to FVIII confirmed by reexamination of screening sample initially reported as negative due to laboratory error. Therefore, event is not a de-novo inhibitor developed during exposure to rVIII-SingleChain
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
rVIII-SingleChain
Affected / at Risk (%) # Events
Total   31/84 (36.90%)    
General disorders   
Pyrexia  1  5/84 (5.95%)  5
Infections and infestations   
Nasopharyngitis  1  14/84 (16.67%)  15
Injury, poisoning and procedural complications   
Head injury  1  5/84 (5.95%)  6
Musculoskeletal and connective tissue disorders   
Arthralgia  1  8/84 (9.52%)  8
Nervous system disorders   
Headache  1  7/84 (8.33%)  9
Respiratory, thoracic and mediastinal disorders   
Cough  1  7/84 (8.33%)  10
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA (16.1)
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
CSL agreements and restrictions on publishing may vary with individual investigators; however, CSL will not prohibit any investigator from publishing. CSL supports the publication of results from all centers of a multi-center trial and generally requires that reports based on single-site data not precede the primary publication of the entire clinical trial.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Clinical Trial Disclosure Manager
Organization: CSL Behring
Phone: Use email contact
EMail: clinicaltrials@cslbehring.com
Layout table for additonal information
Responsible Party: CSL Behring
ClinicalTrials.gov Identifier: NCT02093897     History of Changes
Other Study ID Numbers: CSL627_3002
2012-001336-65 ( EudraCT Number )
First Submitted: March 19, 2014
First Posted: March 21, 2014
Results First Submitted: August 23, 2016
Results First Posted: January 27, 2017
Last Update Posted: January 27, 2017