Clinical Trial Results:
A Phase 3, Prospective, Open-label, Randomized Study to Evaluate Safety and Efficacy of Recombinant Activated FVII BI (rFVIIa BI) in the Treatment of Acute Bleeding Episodes per an On-demand Regimen in Patients with Hemophilia A or B with Inhibitors.
Due to the EudraCT – Results system being out of service between 31 July 2015 and 12 January 2016, these results have been published in compliance with revised timelines.
Summary
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EudraCT number |
2011-006294-26 |
Trial protocol |
ES BE PL |
Global end of trial date |
11 Nov 2014
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Results information
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Results version number |
v1(current) |
This version publication date |
13 Feb 2016
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First version publication date |
13 Feb 2016
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Other versions |
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 |
021101
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01757405 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Baxalta Innovations GmbH
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Sponsor organisation address |
Industriestrasse 67, Vienna, Austria, A-1221
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Public contact |
Clinical Trial Registries and Results Disclosure, Baxalta Innovations GmbH, ClinicalTrialsDisclosure@baxalta.com
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Scientific contact |
Clinical Trial Registries and Results Disclosure, Baxalta Innovations GmbH, ClinicalTrialsDisclosure@baxalta.com
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Sponsor organisation name |
Baxalta US Inc.
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Sponsor organisation address |
One Baxter Way, Westlake Village, CA, United States, 91362
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Public contact |
Clinical Trial Registries and Results Disclosure, Baxalta US Inc., ClinicalTrialsDisclosure@baxalta.com
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Scientific contact |
Clinical Trial Registries and Results Disclosure, Baxalta US Inc., ClinicalTrialsDisclosure@baxalta.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-001382-PIP01-12 | ||
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 |
17 Mar 2015
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
11 Nov 2014
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Global end of trial reached? |
Yes
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Global end of trial date |
11 Nov 2014
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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 safety and efficacy of rFVIIa BI in the treatment of acute bleeding episodes per an on demand regimen in hemophilia A or B patients with inhibitors
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Protection of trial subjects |
This study was conducted in accordance with the clinical protocol, the International Conference on Harmonisation Guideline for Good Clinical Practice E6 (ICH GCP, April 1996), Title 21 of the US Code of Federal Regulations (US CFR), the European Clinical Trial Directive (2001/20/EC and 2005/28/EC), and applicable national and local regulatory requirements.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
20 Feb 2013
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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 |
Romania: 2
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Country: Number of subjects enrolled |
Ukraine: 17
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Country: Number of subjects enrolled |
Russian Federation: 7
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Country: Number of subjects enrolled |
United States: 1
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Country: Number of subjects enrolled |
Serbia: 2
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Country: Number of subjects enrolled |
Poland: 4
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Country: Number of subjects enrolled |
Spain: 3
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Country: Number of subjects enrolled |
Japan: 2
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Worldwide total number of subjects |
38
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EEA total number of subjects |
9
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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) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
7
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Adults (18-64 years) |
31
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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 |
Subjects were enrolled (signed informed consent) from 16 sites in 9 countries. | ||||||||||||||||||
Pre-assignment
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Screening details |
A total of 40 subjects provided informed consent and were screened for study participation, of which there was 1 screen failure. 39 subjects (in pre-assignment period) were randomized where 1 subject withdrew after randomization prior to treatment, therefore 38 subjects were enrolled and treated with rFVIIa BI. | ||||||||||||||||||
Pre-assignment period milestones
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Number of subjects started |
39 [1] | ||||||||||||||||||
Number of subjects completed |
38 | ||||||||||||||||||
Pre-assignment subject non-completion reasons
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Reason: Number of subjects |
subject w/d after randomization prior to treatment: 1 | ||||||||||||||||||
Notes [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: A total of 40 subjects provided informed consent and were screened for study participation, of which there was 1 screen failure. 39 subjects (in pre-assignment period) were randomized where 1 subject withdrew after randomization prior to treatment, therefore 38 subjects were enrolled and treated with rFVIIa BI. |
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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 |
Randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Arm 1: up to 3 x 90 μg/kg rFVIIa BI | ||||||||||||||||||
Arm description |
Bleeding episodes treated with up to 3 doses of 90 μg/kg of recombinant activated factor VII BI (rFVIIa BI) every 3 hours as on-demand intravenous bolus infusions. | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
rFVIIa BI
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Investigational medicinal product code |
BAX817
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Other name |
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Pharmaceutical forms |
Powder for solution for infusion
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Routes of administration |
Intravenous bolus use
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Dosage and administration details |
either up to 3 x 90 μg/kg rFVIIa BI (ARM 1) OR 1 x 270 μg/kg rFVIIa BI (ARM 2)
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Arm title
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Arm 2: 1 x 270 μg/kg rFVIIa BI | ||||||||||||||||||
Arm description |
Bleeding episodes treated with 1 dose of 270 μg/kg of recombinant activated factor VII BI (rFVIIa BI) as on-demand intravenous bolus infusion. | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
rFVIIa BI
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Investigational medicinal product code |
BAX817
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Other name |
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Pharmaceutical forms |
Powder for solution for infusion
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Routes of administration |
Intravenous bolus use
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Dosage and administration details |
either up to 3 x 90 μg/kg rFVIIa BI (ARM 1) OR 1 x 270 μg/kg rFVIIa BI (ARM 2)
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Baseline characteristics reporting groups
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Reporting group title |
Arm 1: up to 3 x 90 μg/kg rFVIIa BI
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Reporting group description |
Bleeding episodes treated with up to 3 doses of 90 μg/kg of recombinant activated factor VII BI (rFVIIa BI) every 3 hours as on-demand intravenous bolus infusions. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Arm 2: 1 x 270 μg/kg rFVIIa BI
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Reporting group description |
Bleeding episodes treated with 1 dose of 270 μg/kg of recombinant activated factor VII BI (rFVIIa BI) as on-demand intravenous bolus infusion. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Arm 1: up to 3 x 90 μg/kg rFVIIa BI
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Reporting group description |
Bleeding episodes treated with up to 3 doses of 90 μg/kg of recombinant activated factor VII BI (rFVIIa BI) every 3 hours as on-demand intravenous bolus infusions. | ||
Reporting group title |
Arm 2: 1 x 270 μg/kg rFVIIa BI
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Reporting group description |
Bleeding episodes treated with 1 dose of 270 μg/kg of recombinant activated factor VII BI (rFVIIa BI) as on-demand intravenous bolus infusion. |
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End point title |
Percentage of bleeding episodes with "Treatment Success". | ||||||||||||
End point description |
"Treatment Success" defined as no additional haemostatic product required within 12 hours of the first dose of rFVIIa BI per bleeding episode, other than the prescribed dosing regimen (either up to 3 x 90 μg/kg doses of rFVIIa B [Arm 1] OR - 1 x 270 μg/kg dose rFVIIa BI [Arm 2]).
There were a total of 289 bleeding episodes in Arm 1 and 256 bleeding episodes in Arm 2.
The analysis was conducted on subjects in the Full Analysis Dataset.
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End point type |
Primary
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End point timeframe |
From first exposure to rFVIIa BI until the end of the study, up to 6 months (day 180) per subject.
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Statistical analysis title |
Equivalence test of successfully treated BEs | ||||||||||||
Statistical analysis description |
Equivalence test of successfully treated bleeding episodes (BEs) between or within treatment arms. Denoting the success rates in the two treatment groups by p1 and p2 , the null hypotheses of H01 : p1/p2 < 0.83 and H02 : p1/p2 > 1.20 was implicitly tested against the one-sided alternatives Ha1: 0.83 ≤ p1/p2 and Ha2 : p1/p2 ≤ 1.20, by comparing the 90% two-sided confidence interval (CI) of the ratio of success proportions to the equivalence region defined as [0.83, 1.20].
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Comparison groups |
Arm 2: 1 x 270 μg/kg rFVIIa BI v Arm 1: up to 3 x 90 μg/kg rFVIIa BI
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Number of subjects included in analysis |
38
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Analysis specification |
Pre-specified
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Analysis type |
equivalence [1] | ||||||||||||
Method |
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Parameter type |
Ratio of success proportion | ||||||||||||
Point estimate |
1.21
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Confidence interval |
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level |
90% | ||||||||||||
sides |
2-sided
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lower limit |
1.15 | ||||||||||||
upper limit |
1.28 | ||||||||||||
Notes [1] - Equivalence of treatment success proportions in all bleeding episodes for the two treatment groups was determined by comparing the 90% two-sided CI of the ratio of success proportions to the equivalence region defined as [0.83, 1.20]. |
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End point title |
Treatment Response based on a four-point scale. | ||||||||||||||||||||||||||||||
End point description |
Subject or investigator used a four point rating scale:-
EXCELLENT - full relief of pain and cessation of objective signs of bleeding (swelling, tenderness, decrease in range of motion [for muscle bleeds]) within 9 hours of treatment initiation. No additional infusion required to control bleeding, other than prescribed dosing regimen.
GOOD - Substantial relief of pain and/or cessation of objective signs of bleeding within 9 hours of treatment initiation. No additional infusion required to control bleeding, other than prescribed dosing regimen.
MODERATE - slight relief of pain and slight improvement of signs of bleeding within 9 hours of treatment initiation. Requires additional infusion beyond treatment regimen.
NONE - No improvement or condition worsens.
SUCCESSFUL = EXCELLENT or GOOD.
There were 289 bleeding episodes in Arm 1 ( up to 3 x 90 μg/kg rFVIIa BI) and 256 bleeding episodes in Arm 2 (1 x 270 μg/kg rFVIIa BI).
Analysis conducted on subjects in Full Analysis Dataset.
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End point type |
Secondary
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End point timeframe |
From first exposure to rFVIIa BI until the end of the study, up to 6 months (day 180) per subject.
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No statistical analyses for this end point |
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End point title |
Percentage of clinical responders for all acute bleeding episodes at 24 hours after rFVIIa BI infusion | ||||||||||||
End point description |
Clinical responders defined as sustained bleeding control, (no additional hemostatic medication including rFVIIa BI required between 12 and 24 hours after first infusion of the successfully treated bleeding episode).
There were a total of 289 bleeding episodes in Arm 1 (up to 3 x 3 x 90 μg/kg rFVIIa BI) and 256 bleeding episodes in Arm 2 (1 x 270 μg/kg rFVIIa BI).
The analysis was conducted on subjects in the Full Analysis Dataset.
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End point type |
Secondary
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End point timeframe |
From first exposure to rFVIIa BI until the end of the study, up to 6 months (day 180) per subject.
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No statistical analyses for this end point |
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End point title |
Safety and Tolerability of Treatment Regimens by Clinical Assessment of Adverse Events (AEs) per Subject | |||||||||||||||||||||||||||
End point description |
Safety was determined by the number of AEs (both serious AEs [SAEs] and non-serious AEs [nsAE]). Tolerability was determined by the number of AEs related to rFVIIa BI (both SAEs and nsAEs) as determined by causality assessment of the AEs by the investigator. An AE was deemed Related if the investigator judged the AE to be "possibly related" or "probably related" to rFVIIa BI.
The percentage of subjects with AEs were presented by seriousness (SAE, nsAE), severity (Mild, Moderate or Severe) and causality (Related or Not Related to rFVIIa BI).
The analysis was conducted on subjects in the Safety Analysis Dataset.
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End point type |
Secondary
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End point timeframe |
From first exposure to rFVIIa BI until the end of the study, up to 6 months (day 180) per subject.
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No statistical analyses for this end point |
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End point title |
Safety and Tolerability of Treatment Regimens by Clinical Assessment of Adverse Events (AEs) | |||||||||||||||||||||||||||
End point description |
Safety was determined by the number of AEs (both serious AEs [SAEs] and non-serious AEs [nsAE]). Tolerability was determined by the number of AEs related to rFVIIa BI (both SAEs and nsAEs) as determined by causality assessment of the AEs by the investigator. An AE was deemed Related if the investigator judges the AE to be "possibly related" or "probably related" to rFVIIa BI.
The percentage of AEs were presented by seriousness (SAE, nsAE), severity (Mild, Moderate or Severe) and causality (Related or Not Related [to rFVIIa BI]).
The analysis was conducted on subjects in the Safety Analysis Dataset.
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End point type |
Secondary
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End point timeframe |
From first exposure to rFVIIa BI until the end of the study, up to 6 months (day 180) per subject.
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No statistical analyses for this end point |
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End point title |
Percentage of Subjects with Inhibitor Development to FVII | ||||||||||||
End point description |
Development of rFVII inhibitors or FVIIa binding antibodies during the study.
The analysis was conducted on subjects in the Safety Analysis Dataset.
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End point type |
Secondary
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End point timeframe |
From first exposure to rFVIIa BI until the end of the study, up to 6 months (day 180) per subject.
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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 exposure of rFVIIa BI until the end of the study, up to 6 months (day 180) per subject.
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Adverse event reporting additional description |
The population consisted of subjects who received at least one dose of rFVIIa BI during the study.
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
17.1
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Reporting groups
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Reporting group title |
Arm 1: up to 3 x 90 μg/kg rFVIIa BI
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Reporting group description |
Subjects who received at least 1 dose of 90 μg/kg of rFVIIa BI as on-demand intravenous bolus infusion during the study. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Arm 2: 1 x 270 μg/kg rFVIIa BI
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Reporting group description |
Subjects who received at least 1 dose of 270 ug/kg of rFVIIa BI as on-demand intravenous bolus infusion during the study. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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? No | |||
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 |