Clinical Trial Results:
A Postauthorization Safety Surveillance Study of Patients Switching to ReFacto AF From ReFacto or Other Factor VIII Products in Usual Care Settings
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Summary
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EudraCT number |
2008-007997-39 |
Trial protocol |
DE BE ES SE AT FI DK FR IT PT NL GB CZ GR HU |
Global end of trial date |
28 Mar 2013
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Results information
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Results version number |
v1(current) |
This version publication date |
30 May 2016
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First version publication date |
30 Jul 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 |
3082B2-4432-WW
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT00884390 | ||
WHO universal trial number (UTN) |
- | ||
Other trial identifiers |
Alias: B1831004 | ||
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Sponsors
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Sponsor organisation name |
Pfizer Inc.
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Sponsor organisation address |
235 E 42nd Street, New York, United States, NY 10017
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Public contact |
Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 800-718-1021, ClinicalTrials.gov_Inquiries@pfizer.com
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Scientific contact |
Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 800-718-1021, ClinicalTrials.gov_Inquiries@pfizer.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 |
19 Aug 2013
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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 |
28 Mar 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 the study was to evaluate the safety of ReFacto AF. The secondary objective was to evaluate the efficacy of ReFacto AF.
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Protection of trial subjects |
The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
07 May 2009
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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 |
Romania: 10
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Country: Number of subjects enrolled |
Netherlands: 6
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Country: Number of subjects enrolled |
Spain: 62
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Country: Number of subjects enrolled |
Sweden: 10
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Country: Number of subjects enrolled |
United Kingdom: 12
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Country: Number of subjects enrolled |
Austria: 3
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Country: Number of subjects enrolled |
Belgium: 8
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Country: Number of subjects enrolled |
Denmark: 4
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Country: Number of subjects enrolled |
Finland: 8
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Country: Number of subjects enrolled |
France: 16
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Country: Number of subjects enrolled |
Germany: 35
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Country: Number of subjects enrolled |
Greece: 3
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Country: Number of subjects enrolled |
Hungary: 20
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Country: Number of subjects enrolled |
Italy: 11
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Worldwide total number of subjects |
208
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EEA total number of subjects |
208
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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) |
42
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Adults (18-64 years) |
166
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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 |
Two hundred and eight (208) subjects were enrolled into the study (146 subjects into the ReFacto Switch group [Cohort 1: subjects who switched from ReFacto to ReFacto Albumin Free [AF]] and 62 subjects into the Other Switch group [Cohort 2: subjects who switched from other Factor VIII (FVIII) products other than ReFacto to ReFacto AF]). | |||||||||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
Study started on 07 May 2009 and ended on 28 March 2013. Overall, 208 subjects were enrolled into the study across 14 countries. | |||||||||||||||||||||||||||||||||
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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 |
Non-randomised - controlled
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Blinding used |
Not blinded | |||||||||||||||||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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ReFacto Switch | |||||||||||||||||||||||||||||||||
Arm description |
Subjects who switched from ReFacto to ReFacto AF. | |||||||||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||||||||
Investigational medicinal product name |
ReFacto AF
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Investigational medicinal product code |
PF-05208756
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Other name |
Moroctocog alfa (Albumin Free Cell Culture[AF-CC])
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Pharmaceutical forms |
Powder for solution for injection/infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Subjects who switched from ReFacto to ReFacto AF.
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Arm title
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Other Switch | |||||||||||||||||||||||||||||||||
Arm description |
Subjects who switched from other FVIII products other than ReFacto to ReFacto AF. | |||||||||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||||||||
Investigational medicinal product name |
ReFacto AF
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Investigational medicinal product code |
PF-05208756
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Other name |
Moroctocog alfa (AF-CC)
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Pharmaceutical forms |
Powder for solution for injection/infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Subjects who switched from other FVIII products other than ReFacto to ReFacto AF.
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Baseline characteristics reporting groups
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Reporting group title |
ReFacto Switch
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Reporting group description |
Subjects who switched from ReFacto to ReFacto AF. | ||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Other Switch
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Reporting group description |
Subjects who switched from other FVIII products other than ReFacto to ReFacto AF. | ||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
ReFacto Switch
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Reporting group description |
Subjects who switched from ReFacto to ReFacto AF. | ||
Reporting group title |
Other Switch
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Reporting group description |
Subjects who switched from other FVIII products other than ReFacto to ReFacto AF. | ||
Subject analysis set title |
Annualized Bleed Rate
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
Annualized Bleed Rate (ABR) by regimen at baseline is summarized for all subjects for on-demand regimen, preventive regimen and prophylaxis regimen, respectively.
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Subject analysis set title |
First Infusion Per Bleed
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
Includes the first infusion for an associated bleeding episode.
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Subject analysis set title |
All Subjects With Bleeds
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
Includes any infusion with an associated bleeding episode, regardless of the reason for treatment indicated on the case report form.
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Subject analysis set title |
Subjects Who Received at Least One Prophylactic Infusion
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
Subjects who had at least one prophylaxis dose, and at least one bleed.
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Subject analysis set title |
All Subjects
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
All enrolled subjects following a prophylaxis regimen at baseline.
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Subject analysis set title |
Subjects Following a Non-prophylaxis Regimen at Baseline
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
All enrolled subjects following an on-demand or preventive regimen at baseline.
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Subject analysis set title |
Subjects Following a Prophylaxis Regimen at Baseline
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
All enrolled subjects following a prophylaxis regimen at baseline.
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Subject analysis set title |
All Subjects With at Least One Bleed
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
All enrolled subjects with at least one bleed.
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Subject analysis set title |
All Subjects With at Least One Prophylaxis Infusion
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
All enrolled subjects with at least one prophylaxis infusion.
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End point title |
Number of Subjects With Clinically Significant Factor VIII Inhibitor Development [1] | ||||||||||||
End point description |
Number of subjects with clinically significant FVIII inhibitor development after switching from ReFacto to moroctocog alfa (AF-CC). Clinically significant inhibitors are defined as a central laboratory confirmed positive inhibitor (greater than or equal to [≥] 0.6 Bethesda unit [BU] using the Nijmegen modification of the Bethesda assay present at 2 consecutive blood draws within a 6-week interval) and within 28 days before the initial or within 28 days following the second positive FVIII inhibitor sample collection one of the following: the need for the subject to administer alternative hemostatic products in order to achieve sufficient efficacy, or ≥2 adverse event reports of decreased drug effect (or other adverse event indicating a decrease in the efficacy of the test article). All enrolled subjects who took at least 1 dose of ReFacto AF study drug were included in the safety and efficacy analyses.
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End point type |
Primary
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End point timeframe |
100 exposure days to study medication (approximately 2 years)
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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: Only descriptive data was planned to be reported for this endpoint. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Annualized Bleeding Rates (ABRs) | ||||||||||||||
End point description |
An ABR for each subject will be calculated as the number of bleeds requiring administration of FVIII replacement product (taken from the Infusion Log Diary case report form), divided by his total therapy duration (in days), then multiplied by 365.25. All enrolled subjects who took at least 1 dose of ReFacto AF study drug were included in the safety and efficacy analyses.
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End point type |
Secondary
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End point timeframe |
100 exposure days to study medication (approximately 2 years)
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Response Assessment of First On-demand Treatment of New Bleeds | ||||||||||||||||||
End point description |
A 4-point scale of assessment of ‘on-demand’ treatment is defined as:Excellent: Definite pain relief and/or improvement in signs of bleeding starting within 8 hours after an infusion, with no additional infusion administered.Good: Definite pain relief and/or improvement in signs of bleeding starting within 8 hours after an infusion, with at least one additional infusion administered for complete resolution of the bleeding episode; or, Definite pain relief and/or improvement in signs of bleeding starting after 8 hours following the infusion, with no additional infusion administered.Moderate: Probable or slight improvement starting after 8 hours following the infusion, with at least one additional infusion administered for complete resolution of the bleeding episode.No Response: No improvement at all between infusions or during the 24-hour interval following an infusion, or condition worsens. All enrolled subjects who took at least 1 dose of ReFacto AF study drug.
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End point type |
Secondary
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End point timeframe |
100 exposure days to study medication (approximately 2 years)
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Number of ReFacto AF Infusions to Treat Each New Bleed | ||||||||||||||||||
End point description |
The Infusion Log Diary case report form (CRF) was used to determine the number of test article infusions administered to treat a bleed. This was calculated by adding the initial (on-demand) infusion to any subsequent (on-demand) infusions for the same bleed (same bleed start date/time). The mean of infusions to produce an excellent, good, moderate and no response was reported. All enrolled subjects who took at least 1 dose of ReFacto AF study drug were included in the safety and efficacy analyses.
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End point type |
Secondary
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End point timeframe |
100 exposure days to study medication (approximately 2 years)
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Number of Bleeding Episodes Occurring Less Than Equal To (≤) 48 Hours After a Prophylaxis Infusion | ||||||
End point description |
First, the bleed start time from the Infusion Log Diary CRF was used to determine the number of breakthrough bleeds that occurred ≤48 hours after an infusion marked as “Prophylaxis” (which had no associated bleed). If there was more than 1 bleed location (i.e. ankle and joint) with identical bleed start date and time, it was treated as 1 bleed occurrence. If a response was given, or if a bleed time was given, but “On Demand” was not listed as “treatment type”, it was still counted as an on-demand bleed for analyses/summaries. Bleeding episodes were not categorized as spontaneous (atraumatic) or traumatic. All enrolled subjects who took at least 1 dose of ReFacto AF study drug were included in the safety and efficacy analyses.
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End point type |
Secondary
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End point timeframe |
100 exposure days to study medication (approximately 2 years)
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| No statistical analyses for this end point | |||||||
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End point title |
Number of Subjects With Breakthrough Bleeds | ||||||
End point description |
The number of subjects with any breakthrough bleed were reported. All enrolled Subjects who took at least 1 dose of ReFacto AF study drug were included in the safety and efficacy analyses.
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End point type |
Secondary
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End point timeframe |
100 exposure days to study medication (approximately 2 years)
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| No statistical analyses for this end point | |||||||
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End point title |
Total Factor Consumption (TFC) Following a Non-prophylaxis Regimen at Baseline for All Subjects | ||||||||||||||||||
End point description |
The total amount (in International Units [IU]) infused for each test article infusion recorded in the Infusion Log Diary CRF was summed to calculate the TFC for each subject. All enrolled subjects who took at least 1 dose of ReFacto AF study drug were included in the safety and efficacy analyses.
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End point type |
Secondary
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End point timeframe |
100 exposure days to study medication (approximately 2 years)
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
TFC Following a Prophylaxis Regimen at Baseline for All Subjects | ||||||||||||||||||
End point description |
The total amount (in IU) infused for each test article infusion recorded in the Infusion Log Diary CRF was summed to calculate the TFC for each subject. All enrolled subjects who took at least 1 dose of ReFacto AF study drug were included in the safety and efficacy analyses.
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End point type |
Secondary
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End point timeframe |
100 exposure days to study medication (approximately 2 years)
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Average Infusion Dose | ||||||||||||
End point description |
The average infusion dose for each subject was calculated as his total factor consumption (in IU) divided by the number of infusions administered. Summary statistics were reported for both of these variables separately for those subjects classified at baseline as following an on-demand regimen, and for those on a primary or secondary prophylaxis regimen. All enrolled subjects who took at least 1 dose of ReFacto AF study drug were included in the safety and efficacy analyses.
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End point type |
Secondary
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End point timeframe |
100 exposure days to study medication (approximately 2 years)
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Incidence of Less-Than-Expected-Therapeutic Effect (LETE) in the On-demand Setting | ||||||||
End point description |
The calculation of incidence of on-demand LETE used the number of bleeds identified as, or with a result of, LETE as the numerator (from the On Demand LETE CRF), and the denominator was the number of bleeding episodes treated in an on-demand setting. This denominator could include new bleeding episodes in prophylaxis subjects breakthrough bleeds), and if subsequent on-demand doses for such a bleed met the on-demand LETE criteria, then an on-demand LETE was reported. All enrolled subjects who took at least 1 dose of ReFacto AF study drug were included in the safety and efficacy analyses.
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End point type |
Secondary
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End point timeframe |
100 exposure days to study medication (approximately 2 years)
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| No statistical analyses for this end point | |||||||||
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End point title |
Incidence of Less-than-expected-therapeutic Effect (LETE) in the Prophylaxis Setting | ||||||||
End point description |
The calculation of incidence of prophylaxis LETE used the number of bleeds identified as, or with a result of, LETE as the numerator (from the Prophylactic LETE CRF), and the denominator was the number of routine prophylaxis infusions. Each infusion was classified in the infusion log (“Prophylaxis/ On Demand/ Preventive”), and subjects were instructed to select “On Demand” if the infusion was to treat a bleed, even if the subject typically followed a prophylaxis regimen. Only the infusions classified as “Prophylaxis” were counted in this denominator.
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End point type |
Secondary
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End point timeframe |
100 exposure days to study medication (approximately 2 years)
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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 |
Duration of participation in study (Baseline up to 28 days after last dose of investigational product)
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Adverse event reporting additional description |
The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event 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 |
15.0
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Reporting groups
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Reporting group title |
All Subjects
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Reporting group description |
The primary safety analysis was performed on all subjects who received at least 1 dose of ReFacto AF. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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28 May 2009 |
1) Modification of definition of “clinically significant FVIII inhibitor” to remove any association of this definition with LETEs.
2) Deleted definition of “lack of effect” to disassociate this term with “LETE”, so as to allow sites to report lack of effect as an AE. This was independent of occurrences of LETE.
3) Added an exclusion that subjects who have had previous exposure to ReFacto AF were not permitted to participate in this study.
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30 Aug 2010 |
1) Modified the time specified for the interim analysis. Previously, it was “An interim analysis will be conducted when approximately 50% of the subjects have achieved 50 EDs” and now it is “An interim analysis will be conducted before 2 years of enrollment, when data is available for 50% of the subjects who have achieved 50 EDs”.
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24 Mar 2011 |
1) The efficacy endpoint, number of spontaneous/breakthrough bleeds within 48 hours of a preventive or prophylaxis dose of ReFacto AF, ABR was modified to indicate that all bleeds reported within 48 hours of a prophylaxis dose would be included. |
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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. | |||
| The study was terminated early by agreement with the EMA (European Medicines Agency) before full recruitment was attained, but this is not considered to affect the overall results and the ability of the study to address its objectives. | |||
