Clinical Trial Results:
A Phase III Open-label Pharmacokinetic, Efficacy and Safety Study of rVIII-SingleChain in a Pediatric Population with Severe Hemophilia A
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Summary
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EudraCT number |
2012-001336-65 |
Trial protocol |
HU DE ES NL IT PT PL AT IE FR |
Global end of trial date |
24 Aug 2015
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Results information
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Results version number |
v2(current) |
This version publication date |
06 Apr 2017
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First version publication date |
09 Sep 2016
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Other versions |
v1 |
Version creation reason |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
CSL627_3002
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02093897 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
CSL Behring GmbH
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Sponsor organisation address |
Emil-von-Behring-Str. 76, Marburg, Germany, 35041
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Public contact |
Clin.Trial Registration Coordinator, CSL Behring GmbH, clinicaltrials@cslbehring.com
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Scientific contact |
Clin.Trial Registration Coordinator, CSL Behring GmbH, clinicaltrials@cslbehring.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-001215-PIP01-11 | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
21 Sep 2015
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
24 Aug 2015
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To evaluate the efficacy of recombinant single-chain FVIII (rVIII-SingleChain) in the treatment of major and minor bleeding episodes based on the investigator’s 4-point assessment scale.
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Protection of trial subjects |
This study was carried out in accordance with the International Conference on Harmonisation Good Clinical Practice guidelines, standard operating procedures for clinical research and development at CSL Behring and any other relevant procedures and applicable international and national regulatory requirements. The study protocol and all amendments were approved by the Independent Ethics Committee / Institutional Review Board of the participating centers. Before undergoing Screening procedures for possible enrollment into the study, the subjects’ legally acceptable representative was informed, in an understandable form, about the nature, scope, and possible consequences of the study.
The investigator was responsible for obtaining a subject’s legally acceptable representative written informed consent to participate in the study. The investigator could cease study treatment and withdraw the subject, or the subject could withdraw himself from participation in the study at any time. If a subject was withdrawn from the study or further participation was declined, the subject would continue to have access to medical care and would be treated according to routine medical practice, but would no longer receive the investigational medicinal product.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
26 Mar 2014
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Australia: 3
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Country: Number of subjects enrolled |
Georgia: 5
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Country: Number of subjects enrolled |
Lebanon: 6
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Country: Number of subjects enrolled |
Malaysia: 4
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Country: Number of subjects enrolled |
Philippines: 8
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Country: Number of subjects enrolled |
Romania: 1
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Country: Number of subjects enrolled |
Switzerland: 1
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Country: Number of subjects enrolled |
Thailand: 10
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Country: Number of subjects enrolled |
Turkey: 8
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Country: Number of subjects enrolled |
Ukraine: 6
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Country: Number of subjects enrolled |
United States: 4
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Country: Number of subjects enrolled |
Netherlands: 6
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Country: Number of subjects enrolled |
Poland: 2
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Country: Number of subjects enrolled |
Portugal: 2
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Country: Number of subjects enrolled |
Spain: 2
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Country: Number of subjects enrolled |
Austria: 3
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Country: Number of subjects enrolled |
France: 7
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Country: Number of subjects enrolled |
Germany: 5
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Country: Number of subjects enrolled |
Italy: 1
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Worldwide total number of subjects |
84
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EEA total number of subjects |
29
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
2
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Children (2-11 years) |
82
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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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. | ||||||||||||||
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Pre-assignment
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Screening 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. | ||||||||||||||
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Period 1
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Period 1 title |
Overall trial (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||
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Arms
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Arm title
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rVIII-SingleChain | ||||||||||||||
Arm 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. A total of 5313 CSL627 infusions were administered to 84 subjects during the study. As planned, groups were closed and subjects discontinued when 25 subjects reached 50 EDs per group. | ||||||||||||||
Arm type |
Experimental | ||||||||||||||
Investigational medicinal product name |
rVIII-SingleChain
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Investigational medicinal product code |
CSL627
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Other name |
Recombinant Single-Chain Factor VIII
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Pharmaceutical forms |
Powder and solvent for solution for injection/infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
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.
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Baseline characteristics reporting groups
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Reporting group title |
Overall trial
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Reporting group description |
- | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
rVIII-SingleChain
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Reporting 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. A total of 5313 CSL627 infusions were administered to 84 subjects during the study. As planned, groups were closed and subjects discontinued when 25 subjects reached 50 EDs per group. | ||
Subject analysis set title |
On-demand
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set 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).
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; data from such doses are included in the analysis of 'Consumption of rVIII-SingleChain' end points. "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.
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Subject analysis set title |
Prophylaxis
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set 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 (1 subject was excluded from the efficacy population as described previously). Subjects receiving routine prophylaxis treatment were initially treated with 15-50 IU/kg of rVIII-SingleChain every 2nd 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; data from such doses are included in the analysis of 'Consumption of rVIII-SingleChain' end points. "Preventative dose" was a dose taken before an activity or a minor procedure to prevent or minimize a bleeding episode and "additional dose" was a dose taken beyond the need to control hemostasis.
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Subject analysis set title |
Efficacy Population
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set 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).
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Subject analysis set title |
Pharmacokinetic Population
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set 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.
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End point title |
Treatment success [1] | ||||||||
End point 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.
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End point type |
Primary
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End point timeframe |
Up to 1 year
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Primary endpoint data were analysed descriptively and no statistical analyses were planned or conducted. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Annualized bleeding rate | ||||||||||||
End point 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.
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End point type |
Secondary
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End point timeframe |
Up to 1 year
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Percentage of bleeding episodes requiring 1, 2, 3 or > 3 infusions of rVIII-SingleChain to achieve hemostasis | ||||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Up to 1 year
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| Notes [2] - Number of treated bleeds = 347 |
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Consumption of rVIII-SingleChain - IU/kg per subject per month | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Up to 1 year
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Consumption of rVIII-SingleChain - IU/kg per subject per year | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Up to 1 year
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Consumption of rVIII-SingleChain - IU/kg per bleeding event | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Up to 1 year
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Consumption of rVIII-SingleChain (on-demand regimen) - number of infusions per subject per month | ||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Up to 1 year
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| No statistical analyses for this end point | |||||||||
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End point title |
Consumption of rVIII-SingleChain (on-demand regimen) - number of infusions per subject per year | ||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Up to 1 year
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| Notes [3] - Subjects assigned to the on-demand treatment regimen. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Incremental recovery | ||||||||
End point description |
Incremental recovery expressed as (IU/dL)/(IU/kg) corrected for subject's predose plasma FVIII activity measured using the chromogenic substrate assay.
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End point type |
Secondary
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End point timeframe |
At 1 hour after the start of infusion
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| No statistical analyses for this end point | |||||||||
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End point title |
Half-life (t1/2) of rVIII-SingleChain | ||||||||
End point description |
Half-life (t1/2) of rVIII-SingleChain, baseline uncorrected; plasma FVIII activity measured using the chromogenic substrate assay.
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End point type |
Secondary
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End point timeframe |
Immediately before dosing, and at approximately 1, 5, 10, 24, and 48 hours after dosing.
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| No statistical analyses for this end point | |||||||||
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End point title |
Area under the concentration curve (AUC) | ||||||||
End point description |
AUC to the last sample with quantifiable drug concentration (AUC0–t), baseline uncorrected; plasma FVIII activity measured using the chromogenic substrate assay.
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End point type |
Secondary
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End point timeframe |
Immediately before dosing, and at approximately 1, 5, 10, 24, and 48 hours after dosing.
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| No statistical analyses for this end point | |||||||||
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End point title |
Clearance (Cl) of rVIII-SingleChain | ||||||||
End point description |
Clearance (Cl) of rVIII-SingleChain, baseline uncorrected; plasma FVIII activity measured using the chromogenic substrate assay.
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End point type |
Secondary
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End point timeframe |
Immediately before dosing, and at approximately 1, 5, 10, 24, and 48 hours after dosing.
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| No statistical analyses for this end point | |||||||||
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End point title |
Number of subjects with inhibitor formation to rVIII-SingleChain | ||||||
End point 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.
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End point type |
Secondary
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End point timeframe |
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).
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| No statistical analyses for this end point | |||||||
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Adverse events information
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Timeframe for reporting adverse events |
For the duration of the study, approximately 1 year, 5 months.
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Adverse event reporting additional 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.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
16.1
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Reporting groups
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Reporting group title |
rVIII-SingleChain
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Reporting group description |
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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21 May 2013 |
- Extended duration of study participation to allow at least 50 EDs
- Increased cohort size of subjects screened for participation
- Added assessment for Chinese hamster ovary (CHO) antibodies
- Defined preventative dosing and additional dosing
- Added collection of additional subject information including blood group and hemophilia A gene defect
- Updated Independent Data and Safety Monitoring Committee responsibilities |
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28 Mar 2014 |
- Identified change in Coordinating Investigator
- Incorporated a change in PK collection time points as recommended by Food and Drug Administration (FDA)
- Updated Independent Data and Safety Monitoring Committee data review information |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
