Clinical Trial Results:
A Multicentre, Interventional, Non-randomized, Open-label, Single-group Phase III Study to Evaluate Plasma-Derived Antihaemophilic Factor/von Willebrand Factor Concentrate (Biostate®) for Immune Tolerance Induction in Male Paediatric Subjects With Haemophilia A (</=2%) Who Have Developed High-titre Antibodies to Factor VIII (Factor VIII Inhibitors)
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Summary
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EudraCT number |
2010-020113-85 |
Trial protocol |
DE FR AT GR IT |
Global end of trial date |
10 Dec 2013
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Results information
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Results version number |
v1(current) |
This version publication date |
13 Jul 2016
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First version publication date |
06 Aug 2015
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Other versions |
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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 |
CSLCT-BIO-10-67
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01445197 | ||
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 |
Clinical Trial Disclosure Manager, CSL Behring, clinicaltrials@cslbehring.com
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Scientific contact |
Clinical Trial Disclosure Manager, CSL Behring, clinicaltrials@cslbehring.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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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? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
16 Apr 2014
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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 |
10 Dec 2013
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
The primary objective of this study was to determine the proportion of subjects who achieve a complete response (success) following immune tolerance induction (ITI) treatment with Biostate.
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Protection of trial subjects |
This study was carried out in accordance with the International Conference on Harmonisation (ICH) Good Clinical Practice guidelines, and standard operating procedures for clinical research and development at CSL Behring (CSLB). The study protocol and all amendments were approved by the Independent Ethics Committee(s) (IECs) / Institutional Review Board(s) (IRBs) of the participating centers. Before undergoing screening procedures for possible enrollment into the study, subjects were informed, in an understandable form, about the nature, scope, and possible consequences of the study. The investigator was responsible for obtaining a subject’s written informed consent to participate in the study.
The investigator may cease study treatment and withdraw the subject, or the subject may withdraw himself from participation in the study at any time. If a subject is withdrawn from the study or further participation is declined, the subject will continue to have access to medical care and will be treated according to routine medical practice, but will no longer receive the investigational medicinal product (IMP).
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
07 Dec 2012
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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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 |
Germany: 1
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Worldwide total number of subjects |
1
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EEA total number of subjects |
1
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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) |
1
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Children (2-11 years) |
0
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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 |
- | ||||||||
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Pre-assignment
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Screening details |
The study included a Screening period of up to 28 days (plus an optional waiting period of up to 11 months). If the waiting period of up to 11 months was added at the discretion of the investigator to allow the subject’s inhibitor titre to decrease prior to the start of ITI treatment, the screening period duration was up to 12 months in total. | ||||||||
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Period 1
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Period 1 title |
Overall Study (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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Biostate | ||||||||
Arm description |
During ITI treatment, Biostate was administered intravenously at a daily dose of approximately 200 international units (IU)/kg body weight (b.w.), preferably split into 2 doses of 100 IU/kg b.w. per day. | ||||||||
Arm type |
Experimental | ||||||||
Investigational medicinal product name |
Human coagulation Factor VIII / von Willebrand Factor
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Investigational medicinal product code |
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Other name |
Biostate®, Voncento®
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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 |
Doses were administered as bolus intravenous injections at a rate not exceeding 6 mL/min.
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Baseline characteristics reporting groups
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Reporting group title |
Biostate
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Reporting group description |
During ITI treatment, Biostate was administered intravenously at a daily dose of approximately 200 international units (IU)/kg body weight (b.w.), preferably split into 2 doses of 100 IU/kg b.w. per day. | |||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Biostate
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Reporting group description |
During ITI treatment, Biostate was administered intravenously at a daily dose of approximately 200 international units (IU)/kg body weight (b.w.), preferably split into 2 doses of 100 IU/kg b.w. per day. | ||
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End point title |
Number of Subjects Who Achieve Complete, Partial, and No Response (ITI Failure) to Treatment [1] | ||||||||||||
End point description |
Complete Response = The following criteria were met in the given order: 1. An undetectable inhibitor titre (<0.6 BU/mL) at 2 consecutive assessments, tested at intervals of 2 weeks (±3 days); 2. After the subject was placed on prophylaxis and after a 48-hour wash-out period, FVIII plasma recovery of ≥66% of predicted and FVIII half-life of ≥6 hours based on blood samples taken prior to and at 10 min, 30 min, 2, 8, 12 (optional), and 24 hrs after administration of 50 IU/kg b.w. Biostate. ITI Failure = One of the following 2 conditions was fulfilled: 1. For a non-overlapping 6-month period, a reduction in the inhibitor titre of ≥20% based on 2 measurements taken 2 weeks (±3 days) apart was not achieved; 2. after 30 months of ITI treatment, the inhibitor titre was >5.0 BU/mL. Partial Response = If subject at the end of ITI treatment met neither the criteria for complete response nor those for ITI failure, the outcome for that subject was to be regarded as partial response.
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End point type |
Primary
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End point timeframe |
Up to approximately 9 months
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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: Because the study was terminated and only 1 subject was enrolled into the study, the primary objective could not be assessed with any further statistical analysis. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Summary of Overall Treatment-Emergent Adverse Events (AEs) and Serious AEs | ||||||||||||||||||||||
End point description |
An AE was defined as any untoward medical occurrence in a subject administered an IMP (whether it is the study or any reference product[s]), which does not necessarily have a causal relationship with the IMP. An SAE was defined as any untoward medical occurrence that at any dose: results in death; is life-threatening; requires in-patient hospitalisation or prolongation of existing hospitalization; results in persistent or significant disability or incapacity; is a congenital anomaly or birth defect; is medically significant. Treatment-emergent events were defined as those occurring after the first dose of IMP.
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End point type |
Secondary
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End point timeframe |
From first IMP dose through Final Visit (3 months [±2 weeks]) after complete response or the final dose of IMP (total study duration was up to approximately 9 months). AE/SAEs considered related to a study procedure were recorded from informed consent.
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| No statistical analyses for this end point | |||||||||||||||||||||||
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End point title |
Number of Subjects With Clinically Significant Markers of Activation of Coagulation | ||||||
End point description |
Thrombogenic risk was assessed by reporting the number of subjects with clinical symptoms or increased markers of activation of coagulation (eg, fibrin fragments, thrombin-antithrombin complex [TAT]).
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End point type |
Secondary
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End point timeframe |
Up to approximately 9 months
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| No statistical analyses for this end point | |||||||
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End point title |
Summary of Bleeding Events | ||||||||||||||
End point description |
The frequency, nature and location of bleeding events were recorded in the subject’s e-diary and/or the electronic case report form (eCRF). A major bleeding event was classified as one for which a subject was required to visit the Hemophilia Treatment Center to seek treatment recommendations from the treating physician. Major bleeding events may include: cerebral bleeding, severe bleeding into muscle or mucosal bleeding of the gastrointestinal tract (excluding nasal or oral bleeding) and bleeding events in target joints or those associated with swelling, pain, a decreased range of motion and an intensified treatment (use of bypassing agents for > 3 days). All other bleeding events were classified as minor unless the Investigator assessment noted otherwise.
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End point type |
Secondary
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End point timeframe |
Up to approximately 9 months
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Number of Catheter-related Complications | ||||||
End point description |
Occurrence of catheter-related complications (eg, line infections) were recorded in the subject’s e-diary.
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End point type |
Secondary
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End point timeframe |
up to approximately 9 months
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| No statistical analyses for this end point | |||||||
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End point title |
Time to Complete Response (Success) | ||||||
End point description |
The time point for complete response (success) was defined as the time when recovery is ≥ 66% of predicted, FVIII half-life is ≥ 6 hours, and a titre of < 0.6 BU/mL is confirmed, after the subject had been placed in prophylaxis.
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End point type |
Secondary
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End point timeframe |
Up to approximately 38 months (30-month treatment period plus approximately 8 months for establishing complete response)
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| Notes [2] - The subject in this study did not achieve a complete response. |
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| No statistical analyses for this end point | |||||||
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End point title |
Time to Inhibitor Titre <0.6 BU/mL for the First Time | ||||||
End point description |
Time to the first instance of an inhibitor titre of <0.6 BU/mL, as assessed by the central laboratory.
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End point type |
Secondary
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End point timeframe |
30 months
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| Notes [3] - The subject in this study did not reach an inhibitor titre of <0.6 BU/mL. |
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| No statistical analyses for this end point | |||||||
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End point title |
FVIII Inhibition Titres | ||||||||||||||||||||||||||||||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Screening through End-of-study (EOS; total study duration was up to approximately 9 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 |
From first IMP dose through Final Visit (3 months [±2 weeks]) after complete response or the final dose of IMP (total study duration was up to approximately 9 months). AE/SAEs considered related to a study procedure were recorded from informed consent.
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Adverse event reporting additional description |
All events presented were treatment-emergent (defined as those occurring after the first dose of IMP).
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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 |
13.1
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Reporting groups
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Reporting group title |
Biostate
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Reporting group description |
During ITI treatment, Biostate was administered intravenously at a daily dose of approximately 200 international units (IU)/kg body weight (b.w.), preferably split into 2 doses of 100 IU/kg b.w. per day. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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23 Sep 2011 |
Following discussion with External Expert and comments from competent authorities:
- Recalculation of sample size
- Dosing range introduced
- Day 14 Visit introduced
- Dose reduction scheme clarified
- Definition major bleedings added
- Orthopedic score (Gilbert Score) added
- Editorial changes: consistent use of terms, consistent use of American English vs British English
- Change of study team members |
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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. | |||
| Because the study was terminated due to lack of enrolment and overall feasibility, and only 1 subject was enrolled into the study, the primary objective could not be assessed and no conclusions about the efficacy of Biostate in ITI can be drawn. | |||
