Clinical Trial Results:
A diagnostic interventional, controlled, cross-sectional evaluation of joint status using MRI in subjects with severe hemophilia A treated with primary prophylaxis, secondary prophylaxis, or on-demand therapy
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Summary
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EudraCT number |
2009-010147-14 |
Trial protocol |
DE GB GR ES IT |
Global end of trial date |
31 Dec 2010
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Results information
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Results version number |
v1(current) |
This version publication date |
22 Jul 2016
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First version publication date |
22 Jul 2016
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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 |
BAY14-2222/12948
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT00927667 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Bayer AG
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Sponsor organisation address |
Kaiser-Wilhelm-Allee, Leverkusen, Germany, D-51368
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Public contact |
Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
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Scientific contact |
Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.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? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
14 Apr 2011
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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 |
31 Dec 2010
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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 bone and cartilage damage at different ages using magnetic resonance imaging (MRI) in four index joints of subjects with severe hemophilia A in relation to previous treatment schedule of primary or secondary prophylaxis with start at different ages, comparing to subjects who received only on-demand therapy.
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Protection of trial subjects |
The conduct of this investigation met all local legal and regulatory requirements. The investigation was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and the International Conference on Harmonization (ICH) guideline E6: Good Clinical Practice (GCP). Three different versions of informed consent forms (1 for test subjects, 1 for minors, and 1 for adults or legal representatives of minors) explaining the procedures of the investigation including the potential hazards were reviewed and approved by the IEC/IRB before their use. Before entering the investigation, the informed consent form was read by and explained to all subjects or their legally authorized representative. Each subject had ample opportunity to ask questions and was assured of the right to withdraw from the investigation at any time without any disadvantage and without having to provide a reason for this decision.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
09 Jun 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 |
Germany: 66
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Country: Number of subjects enrolled |
Spain: 9
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Country: Number of subjects enrolled |
United Kingdom: 2
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Country: Number of subjects enrolled |
Greece: 20
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Country: Number of subjects enrolled |
Italy: 22
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Country: Number of subjects enrolled |
Sweden: 10
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Worldwide total number of subjects |
129
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EEA total number of subjects |
129
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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) |
11
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Adults (18-64 years) |
118
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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 |
Study was conducted at fifteen study center in Germany, Greece, Italy, Spain, Sweden, United Kingdom, from 09 JUN 2009 (first subject first visit) to 31 DEC 2010 (last subject last visit). | ||||||||||||||||||
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Pre-assignment
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Screening details |
In addition to 28 test subjects who underwent MRIs for the quality assessment of MRIs at each center, a total of 129 investigational subjects were recruited. All investigational subjects underwent the MRIs on 1 study Visit. 11 of all recruited subjects were excluded from the Per-protocol (PP) population due to major protocol deviation. | ||||||||||||||||||
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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 | ||||||||||||||||||
Blinding implementation details |
Blinding was applicable to analysis of MRIs only. Central readers were blinded to bleeding and treatment history.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Group 1 | ||||||||||||||||||
Arm description |
Subjects with a history of treatment using primary prophylaxis (starting before the age of 2 years and prior to the occurrence of a second joint bleed) and continuing for at least 10 years and presently on prophylaxis therapy without any therapy interruption or missing documentation for more than 12 consecutive months. | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
Recombinant FVIII (rFVIII) or plasma-derived FVIII (pdFVIII) products
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
Regular prophylaxis treatment for hemophilia. No interventional drug was administered in the study.
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Arm title
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Group 2 | ||||||||||||||||||
Arm description |
Subjects with a history of prophylactic treatment starting between the age of 2 to less than 6 years and after the occurrence of at least one joint bleed, continuing for at least 10 years and presently on prophylaxis therapy without any therapy interruption or missing documentation for more than 12 consecutive months. | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
Recombinant FVIII (rFVIII) or plasma-derived FVIII (pdFVIII) products
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
Regular prophylaxis treatment for hemophilia. No interventional drug was administered in the study.
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Arm title
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Group 3 | ||||||||||||||||||
Arm description |
Subjects with a history of prophylactic treatment starting between the age of 6 to less than 12 years and continuing for at least 10 years and presently on prophylaxis therapy without any therapy interruption or missing documentation for more than 12 consecutive months | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
Recombinant FVIII (rFVIII) or plasma-derived FVIII (pdFVIII) products
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
Regular prophylaxis treatment for hemophilia. No interventional drug was administered in the study.
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Arm title
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Group 4 | ||||||||||||||||||
Arm description |
Subjects with a history of prophylactic treatment starting between the age of 12 to 18 years and continuing for at least 10 years and presently on prophylaxis therapy without any therapy interruption or missing documentation for more than 12 consecutive months. | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
Recombinant FVIII (rFVIII) or plasma-derived FVIII (pdFVIII) products
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
Regular prophylaxis treatment for hemophilia. No interventional drug was administered in the study.
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Arm title
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Group 5 | ||||||||||||||||||
Arm description |
Subjects with a history of only on-demand treatment (ie, received never a regimen of regular prophylactic FVIII therapy lasting longer than 8 consecutive months) with more than 12 bleeds/year in the previous 5 years. | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
Recombinant FVIII (rFVIII) or plasma-derived FVIII (pdFVIII) products
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
Regular on-demand treatment for hemophilia. No interventional drug was administered in the study.
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Baseline characteristics reporting groups
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Reporting group title |
Group 1
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Reporting group description |
Subjects with a history of treatment using primary prophylaxis (starting before the age of 2 years and prior to the occurrence of a second joint bleed) and continuing for at least 10 years and presently on prophylaxis therapy without any therapy interruption or missing documentation for more than 12 consecutive months. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Group 2
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Reporting group description |
Subjects with a history of prophylactic treatment starting between the age of 2 to less than 6 years and after the occurrence of at least one joint bleed, continuing for at least 10 years and presently on prophylaxis therapy without any therapy interruption or missing documentation for more than 12 consecutive months. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Group 3
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Reporting group description |
Subjects with a history of prophylactic treatment starting between the age of 6 to less than 12 years and continuing for at least 10 years and presently on prophylaxis therapy without any therapy interruption or missing documentation for more than 12 consecutive months | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Group 4
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Reporting group description |
Subjects with a history of prophylactic treatment starting between the age of 12 to 18 years and continuing for at least 10 years and presently on prophylaxis therapy without any therapy interruption or missing documentation for more than 12 consecutive months. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Group 5
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Reporting group description |
Subjects with a history of only on-demand treatment (ie, received never a regimen of regular prophylactic FVIII therapy lasting longer than 8 consecutive months) with more than 12 bleeds/year in the previous 5 years. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Group 1
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Reporting group description |
Subjects with a history of treatment using primary prophylaxis (starting before the age of 2 years and prior to the occurrence of a second joint bleed) and continuing for at least 10 years and presently on prophylaxis therapy without any therapy interruption or missing documentation for more than 12 consecutive months. | ||
Reporting group title |
Group 2
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Reporting group description |
Subjects with a history of prophylactic treatment starting between the age of 2 to less than 6 years and after the occurrence of at least one joint bleed, continuing for at least 10 years and presently on prophylaxis therapy without any therapy interruption or missing documentation for more than 12 consecutive months. | ||
Reporting group title |
Group 3
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Reporting group description |
Subjects with a history of prophylactic treatment starting between the age of 6 to less than 12 years and continuing for at least 10 years and presently on prophylaxis therapy without any therapy interruption or missing documentation for more than 12 consecutive months | ||
Reporting group title |
Group 4
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Reporting group description |
Subjects with a history of prophylactic treatment starting between the age of 12 to 18 years and continuing for at least 10 years and presently on prophylaxis therapy without any therapy interruption or missing documentation for more than 12 consecutive months. | ||
Reporting group title |
Group 5
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Reporting group description |
Subjects with a history of only on-demand treatment (ie, received never a regimen of regular prophylactic FVIII therapy lasting longer than 8 consecutive months) with more than 12 bleeds/year in the previous 5 years. | ||
Subject analysis set title |
Secondary prophylaxis (Group 3 + Group 4)
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
In the age group of subjects of 27-35 years, subjects on secondary prophylaxis started at an age between 6-18 years (= Group 3 + Group 4 combined; n=17)
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Subject analysis set title |
On-demand (Group 5)
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
In the age group of subjects of 27-35 years, subjects treated on-demand (n=12).
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Subject analysis set title |
Per Protocol
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
11 of the 129 recruited subjects had at least 1 major protocol deviation and were, therefore, excluded from the PP population, which the primary analysis was based on.
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End point title |
Maximum ankle MRI Score according to the Additive part of the Compatible MRI Scales [1] | ||||||||||||
End point description |
A MRI scoring scheme including a 10 step progressive scale and a 20 step additive scale with identical definitions of mutual steps is presented. The progressive (P) score equals the highest value reached with the progressive scale. The additive (A) score equals the sum of points accumulated with the additive scale. The maximum values are 10 and 20, respectively. Higher scores represent worse joint status.
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End point type |
Primary
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End point timeframe |
At MRI visit
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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 statistics was performed. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Compatible Additive MRI Score a for the maximally affected index joint | ||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
4 index joints (2 ankles, 2 knees). '99999' indicates the results were not applicable because no subjects were enrolled in those age groups.
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End point type |
Secondary
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End point timeframe |
At MRI visit
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| Notes [2] - PP population [3] - PP population [4] - PP population [5] - PP population [6] - PP population |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||
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End point title |
Compatible Progressive MRI Score a for the maximally affected index joint | ||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
'99999' indicates the results were not applicable because no subjects were enrolled in those age groups.
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End point type |
Secondary
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End point timeframe |
At MRI visit
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| Notes [7] - PP population [8] - PP population [9] - PP population [10] - PP population [11] - PP population |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||
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End point title |
Basic MRI Score a for the maximally affected index joint | ||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
'99999' indicates the results were not applicable because no subjects were enrolled in those age groups.
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End point type |
Secondary
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End point timeframe |
At MRI visit
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| Notes [12] - PP population [13] - PP population [14] - PP population [15] - PP population [16] - PP population |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||
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End point title |
Extended MRI Score a for the maximally affected index joint | ||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
'99999' indicates the results were not applicable because no subjects were enrolled in those age groups.
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End point type |
Secondary
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End point timeframe |
At MRI visit
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| Notes [17] - PP population [18] - PP population [19] - PP population [20] - PP population [21] - PP population |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||
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End point title |
Annualized number of joint bleeds in the previous 5 years - All joints | ||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
'99999' indicates the results were not applicable because no subjects were enrolled in those age groups.
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End point type |
Secondary
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End point timeframe |
in previous 5 years
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| Notes [22] - PP population [23] - PP population [24] - PP population [25] - PP population [26] - PP population |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||
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End point title |
Annualized number of joint bleeds in the previous 5 years - Index joints | ||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
'99999' indicates the results were not applicable because no subjects were enrolled in those age groups.
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End point type |
Secondary
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End point timeframe |
in the previous 5 years
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| Notes [27] - PP population [28] - PP population [29] - PP population [30] - PP population [31] - PP population |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||
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End point title |
Gilbert Score: Physical examination joint score for the mean of index joints | ||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
The orthopedic examination of the hemophilia subject included evaluation of hemorrhages, pain and joint function. Joint function was evaluated in absence of active bleeding episode by rating each joint (elbows, knees, and ankles) on an 18-point scale: 12 (8 points for elbows) points for physical examination, 3 points for pain and 3 points for bleeding. A joint score of zero (0) reflects a normal, unaffected joint. '99999' indicates the results were not applicable because no subjects were enrolled in those age groups.
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End point type |
Secondary
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End point timeframe |
At Screening / Enrollment visit
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| Notes [32] - PP population [33] - PP population [34] - PP population [35] - PP population [36] - PP population |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||
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End point title |
Gilbert Score: Physical examination joint score for the mean of six Joints | ||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
'99999' indicates the results were not applicable because no subjects were enrolled in those age groups.
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End point type |
Secondary
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End point timeframe |
At Screening / Enrollment visit
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| Notes [37] - PP population [38] - PP population [39] - PP population [40] - PP population [41] - PP population |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||
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End point title |
Compatible Additive MRI Score a for the mean of all index joints | ||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
'99999' indicates the results were not applicable because no subjects were enrolled in those age groups.
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End point type |
Secondary
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End point timeframe |
At MRI visit
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| Notes [42] - PP population [43] - PP population [44] - PP population [45] - PP population |
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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 obtaining informed consent until end of study
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
13
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Reporting groups
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Reporting group title |
Group 1
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Reporting group description |
Subjects with a history of treatment using primary prophylaxis (starting before the age of 2 years and prior to the occurrence of a second joint bleed) and continuing for at least 10 years and presently on prophylaxis therapy without any therapy interruption or missing documentation for more than 12 consecutive months. | ||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Group 2
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Reporting group description |
Subjects with a history of prophylactic treatment starting between the age of 2 to less than 6 years and after the occurrence of at least one joint bleed, continuing for at least 10 years and presently on prophylaxis therapy without any therapy interruption or missing documentation for more than 12 consecutive months. | ||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Group 3
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Reporting group description |
Subjects with a history of prophylactic treatment starting between the age of 6 to less than 12 years and continuing for at least 10 years and presently on prophylaxis therapy without any therapy interruption or missing documentation for more than 12 consecutive months | ||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Group 4
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Reporting group description |
Subjects with a history of prophylactic treatment starting between the age of 12 to 18 years and continuing for at least 10 years and presently on prophylaxis therapy without any therapy interruption or missing documentation for more than 12 consecutive months. | ||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Group 5
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Reporting group description |
Subjects with a history of only on-demand treatment (ie, received never a regimen of regular prophylactic FVIII therapy lasting longer than 8 consecutive months) with more than 12 bleeds/year in the previous 5 years. | ||||||||||||||||||||||||||||||||||||||||||
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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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04 May 2009 |
A. Coordinating radiologist’s name and designation of function corrected
B. Observations and measurements at screening and enrollment visit of the test subject completed
C. MRI Scale:
- two more MRI scales added
- number of blinded readers changed from two to three
- adjudication procedure in case of discrepancies changed
- MRI Scale used for calculation of primary variable changed from Compatible
- MRI Scales to Extended MRI scale
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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. | |||
| Decimal places were automatically truncated if last decimal equals zero. | |||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/25470205 |
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