Clinical Trial Results:
ADVATE Antihemophilic Factor (Recombinant), Plasma/Albumin-Free Method (ADVATE rAHF-PFM): A Phase 4 Study Comparing Two Prophylactic Regimens In Subjects With Severe Or Moderately Severe Hemophilia A
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 |
2005-000347-29 |
Trial protocol |
GB AT HU CZ SI IT |
Global end of trial date |
16 Jun 2010
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Results information
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Results version number |
v1(current) |
This version publication date |
05 Mar 2016
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First version publication date |
05 Mar 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 |
060201
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT00243386 | ||
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, 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, United States, CA 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) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
Yes
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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 |
16 Jun 2010
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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 |
16 Jun 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 |
The primary objective of this study was to compare the rates of bleeding episodes between a standard prophylaxis regimen (20 to 40 IU/kg every 48 ± 6 hours) and a pharmacokinetics (PK)-driven prophylaxis regimen (20 to 80 IU/kg every 72 ± 6 hours).
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Protection of trial subjects |
This study was conducted in accordance with the standards of Good Clinical Practice (GCP) in effect at the time of the study.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
04 Jan 2006
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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 |
Austria: 1
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Country: Number of subjects enrolled |
Czech Republic: 6
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Country: Number of subjects enrolled |
Greece: 2
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Country: Number of subjects enrolled |
Hungary: 9
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Country: Number of subjects enrolled |
Italy: 4
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Country: Number of subjects enrolled |
Poland: 26
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Country: Number of subjects enrolled |
Russian Federation: 8
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Country: Number of subjects enrolled |
Slovenia: 1
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Country: Number of subjects enrolled |
United Kingdom: 2
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Country: Number of subjects enrolled |
United States: 23
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Worldwide total number of subjects |
82
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EEA total number of subjects |
51
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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) |
5
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Adolescents (12-17 years) |
8
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Adults (18-64 years) |
69
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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) at 21 European and 9 United States clinical sites beginning January 2006 and completing in June 2010 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
82 subjects were enrolled and screened. 7 were screen failures, 1 was withdrawn for non-compliance, and 1 requested withdrawal. Therefore, 73 of the 82 enrolled were treated with investigational product (rAFH-PFM). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
Pre-assignment period milestones
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Number of subjects started |
82 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
Number of subjects completed |
73 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
Pre-assignment subject non-completion reasons
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Reason: Number of subjects |
Consent withdrawn by subject: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reason: Number of subjects |
Screen Failure: 7 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reason: Number of subjects |
Withdrawn for non compliance: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
Period 1
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Period 1 title |
Overall study (Parts 1 and 2) (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
Blinding implementation details |
This open-label study had 2 parts
Part 1: Subjects underwent PK evaluation for 48 hours followed by on-demand treatment with rAFH-PFM for 6 months
Part 2: Subjects were randomized either to standard prophylaxis or PK-driven prophylaxis (both with rAFH-PFM) for 12 months.
Randomization in part 2 stratified based on presence of target joints [joint in which at least 4 bleeds occurred within 6 months or > 20 lifetime bleeds (0 target joints; 1-2 target joints; ≥ target joints) to reduce bias
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Arms
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Are arms mutually exclusive |
No
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Arm title
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All subjects | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
All subjects who were exposed to investigational product (rAHF-PFM). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
ADVATE
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Investigational medicinal product code |
rAHF-PFM
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Other name |
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Pharmaceutical forms |
Powder and solvent for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Standard Prophylaxis - 20-40 IU/kg every 48±6h; PK-driven Prophylaxis 20-80 IU/kg (determined by PK results) every 72±6h; On-demand - 10-100 IU/kg - dose and frequency dependent on severity and location of bleed
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Arm title
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On-Demand | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
On-demand regimen - rAHF-PFM was to be used for the treatment of bleeding episodes according to the severity and type of episode by the protocol-recommended dosing until the episode resolved: superficial (10-20 IU/kg every 12-14 hours), minor joint (20-40 IU/kg every 12-14 hours), deep muscle (30-60 IU/kg every 12-14 hours), major joint or life-threatening (60-100 IU/kg every 8-12 hours), genitourinary, GI, and intracranial (60-100 IU/kg every 8-12 hours). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
ADVATE
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Investigational medicinal product code |
rAHF-PFM
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Other name |
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Pharmaceutical forms |
Powder and solvent for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Standard Prophylaxis - 20-40 IU/kg every 48±6h; PK-driven Prophylaxis 20-80 IU/kg (determined by PK results) every 72±6h; On-demand - 10-100 IU/kg - dose and frequency dependent on severity and location of bleed
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Arm title
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Standard Prophylaxis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Standard prophylaxis regimen - subjects dosed at 20-40 IU/kg of rAHF-PFM every 48 ± 6 hours, exact regimen to be determined by the investigator. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
ADVATE
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Investigational medicinal product code |
rAHF-PFM
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Other name |
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Pharmaceutical forms |
Powder and solvent for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Standard Prophylaxis - 20-40 IU/kg every 48±6h; PK-driven Prophylaxis 20-80 IU/kg (determined by PK results) every 72±6h; On-demand - 10-100 IU/kg - dose and frequency dependent on severity and location of bleed
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Arm title
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PK-Driven Prophylaxis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Pharmacokinetic (PK)-Driven prophylaxis regimen - subjects dosed at 20-80 IU/kg of rAHF-PFM every 72 ± 6 hours, exact regimen to be determined by the sponsor. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
ADVATE
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Investigational medicinal product code |
rAHF-PFM
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Other name |
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Pharmaceutical forms |
Powder and solvent for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Standard Prophylaxis - 20-40 IU/kg every 48±6h; PK-driven Prophylaxis 20-80 IU/kg (determined by PK results) every 72±6h; On-demand - 10-100 IU/kg - dose and frequency dependent on severity and location of bleed
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Arm title
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Any Prophylaxis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Standard Prophylaxis: 20-40 IU/kg of rAHF-PFM every 48 ± 6 hours, exact regimen to be determined by the investigator. PK-Driven Prophylaxis: 20-80 IU/kg of rAHF-PFM every 72 ± 6 hours, exact regimen to be determined by the sponsor | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
ADVATE
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Investigational medicinal product code |
rAHF-PFM
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Other name |
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Pharmaceutical forms |
Powder and solvent for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Standard Prophylaxis - 20-40 IU/kg every 48±6h; PK-driven Prophylaxis 20-80 IU/kg (determined by PK results) every 72±6h; On-demand - 10-100 IU/kg - dose and frequency dependent on severity and location of bleed
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Baseline characteristics reporting groups [1]
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Reporting group title |
Overall study (Parts 1 and 2)
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Reporting group description |
Overall study (Parts 1 and 2) | |||||||||||||||||||||||||||||||||||||||
Notes [1] - The number of subjects reported to be in the baseline period is not equal to the worldwide number of subjects enrolled in the trial. It is expected that these numbers will be the same. Justification: The worldwide number of subjects enrolled only included subjects treated with study product (N=73) as per definition of enrolled in EudraCT (Enrolled=Treated). The number of subjects reported in the baseline period includes all subjects enrolled in the study i.e. signed informed consent (N=82). |
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End points reporting groups
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Reporting group title |
All subjects
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Reporting group description |
All subjects who were exposed to investigational product (rAHF-PFM). | ||
Reporting group title |
On-Demand
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Reporting group description |
On-demand regimen - rAHF-PFM was to be used for the treatment of bleeding episodes according to the severity and type of episode by the protocol-recommended dosing until the episode resolved: superficial (10-20 IU/kg every 12-14 hours), minor joint (20-40 IU/kg every 12-14 hours), deep muscle (30-60 IU/kg every 12-14 hours), major joint or life-threatening (60-100 IU/kg every 8-12 hours), genitourinary, GI, and intracranial (60-100 IU/kg every 8-12 hours). | ||
Reporting group title |
Standard Prophylaxis
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Reporting group description |
Standard prophylaxis regimen - subjects dosed at 20-40 IU/kg of rAHF-PFM every 48 ± 6 hours, exact regimen to be determined by the investigator. | ||
Reporting group title |
PK-Driven Prophylaxis
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Reporting group description |
Pharmacokinetic (PK)-Driven prophylaxis regimen - subjects dosed at 20-80 IU/kg of rAHF-PFM every 72 ± 6 hours, exact regimen to be determined by the sponsor. | ||
Reporting group title |
Any Prophylaxis
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Reporting group description |
Standard Prophylaxis: 20-40 IU/kg of rAHF-PFM every 48 ± 6 hours, exact regimen to be determined by the investigator. PK-Driven Prophylaxis: 20-80 IU/kg of rAHF-PFM every 72 ± 6 hours, exact regimen to be determined by the sponsor | ||
Subject analysis set title |
Subjects ≥14 Years
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Comprised of subjects ≥14 Years
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Subject analysis set title |
Subjects <14 Years
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Comprised of subjects <14 Years
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Subject analysis set title |
On-Demand Versus Standard Prophylaxis
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
On-demand: rAHF-PFM was to be used for the treatment of bleeding episodes according to the severity and type of episode by the protocol-recommended dosing until the episode resolved: superficial (10-20 IU/kg every 12-14 hours), minor joint (20-40 IU/kg every 12-14 hours), deep muscle (30-60 IU/kg every 12-14 hours), major joint or life-threatening (60-100 IU/kg every 8-12 hours), genitourinary, Gastrointestinal (GI), and intracranial (60-100 IU/kg every 8-12 hours).
Standard Prophylaxis: 20-40 IU/kg of rAHF-PFM every 48 ± 6 hours, exact regimen to be determined by the investigator.
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Subject analysis set title |
On-Demand Versus PK-Driven Prophylaxis
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
On-demand: rAHF-PFM was to be used for the treatment of bleeding episodes according to the severity and type of episode by the protocol-recommended dosing until the episode resolved: superficial (10-20 IU/kg every 12-14 hours), minor joint (20-40 IU/kg every 12-14 hours), deep muscle (30-60 IU/kg every 12-14 hours), major joint or life-threatening (60-100 IU/kg every 8-12 hours), genitourinary, GI, and intracranial (60-100 IU/kg every 8-12 hours).
PK-driven prophylaxis: 20-80 IU/kg of rAHF-PFM every 72 ± 6 hours, exact regimen to be determined by the sponsor.
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Subject analysis set title |
On-Demand Versus Any Prophylaxis
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
On-demand: rAHF-PFM was to be used for the treatment of bleeding episodes according to the severity and type of episode by the protocol-recommended dosing until the episode resolved: superficial (10-20 IU/kg every 12-14 hours), minor joint (20-40 IU/kg every 12-14 hours), deep muscle (30-60 IU/kg every 12-14 hours), major joint or life-threatening (60-100 IU/kg every 8-12 hours), genitourinary, GI, and intracranial (60-100 IU/kg every 8-12 hours)
Prophylaxis:
•Standard prophylaxis: 20-40 IU/kg of rAHF-PFM every 48 ± 6 hours, exact regimen to be determined by the investigator
•PK-driven prophylaxis: 20-80 IU/kg of rAHF-PFM every 72 ± 6 hours, exact regimen to be determined by the sponsor
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Subject analysis set title |
Subjects with SAEs outside of 3 Treatment Arms
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
Subjects with SAEs that occurred after exposure to investigational product, but outside of the on-demand, standard prophylaxis and PK-driven prophylaxis treatment arms.
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Subject analysis set title |
On-Demand to Standard Prophylaxis
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Comprised of subjects who completed the on-demand and standard prophylaxis regimens.
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Subject analysis set title |
On-Demand to PK-Driven Prophylaxis
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Comprised of subjects who completed the on-demand and PK-driven prophylaxis regimens.
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Subject analysis set title |
On-Demand to Any Prophylaxis
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Comprised of subjects who completed the on-demand and any prophylaxis regimens.
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Subject analysis set title |
Subjects Assessed Before Treatment
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Subjects assessed before treatment with investigational product (rAFH-PFM).
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End point title |
Mean Transformed Annualized Bleed Rate Estimates From Each of the 1-year Prophylaxis Regimens [1] | ||||||||||||
End point description |
Subjects were randomized to receive 1 of the 2 following prophylaxis regimens (Study Part 2):
1. Standard prophylaxis (20-40 IU/kg (every 48 ±6 hours), exact regimen determined by investigator)
2. PK-driven prophylaxis (20-80 IU/kg (every 72 ±6 hours), exact regimen determined by sponsor)
Annualized bleed rates were transformed using the square root of the number of bleeding episodes observed (X = bleeds/year), X′ = √(X + 0.5). This transformation was performed to stabilize the variance and align the sample distribution with the assumption of normality inherent in using the t-test.
Population: Subjects in the efficacy per-protocol set comprising of all subjects who completed, according to the protocol, both the on-demand treatment regimen and the randomly assigned prophylactic regimen. Subjects did not have major protocol deviations that would impact the assessment of the primary efficacy endpoint.
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End point type |
Primary
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End point timeframe |
12 months ±2 weeks
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Notes [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Arms in the baseline period are not mutually exclusive. Refer to the description of arms in period 1 (baseline period). Please also note that it is not currently possible to enter statistics for some endpoints in this study due to limitations of EudraCT. All statistics are available for these study results in ClinicalTrials.gov (NCT00243386). |
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Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Statistical analysis description |
A t-test was used to compare the means of the transformed data. The null-hypothesis tested was H0: X'A(PK-driven prophylaxis) - X'B (standard prophylaxis) = 0 (i.e., no difference for treatment under the 2 prophylactic regimens. X' = (ABR+0.5)^(1/2)
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Comparison groups |
Standard Prophylaxis v PK-Driven Prophylaxis
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Number of subjects included in analysis |
53
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.6016 | ||||||||||||
Method |
t-test, 2 sided | ||||||||||||
Confidence interval |
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End point title |
Median Annualized Bleed Rate Estimates From Each of the 1 Year Prophylaxis Regimens [2] | ||||||||||||
End point description |
Subjects were randomized to receive 1 of the 2 following prophylaxis regimens (part 2 of the study):
1. Standard prophylaxis- infusions every 48 ±6 hours, dosed at 20 to 40 IU/kg.
2. PK-driven prophylaxis- infusions every 72 ±6 hours dosed at 20 to 80 IU/kg.
Population: Subjects in the efficacy intent-to-treat set comprising of all subjects in the prophylaxis treatment regimen who had at least 1 assessment (1 quarterly visit) or who had withdrawn after 3 bleeding episodes prior to reaching the first assessment period.
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End point type |
Primary
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End point timeframe |
12 months ±2 weeks
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Notes [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Arms in the baseline period are not mutually exclusive. Refer to the description of arms in period 1 (baseline period). |
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Statistical analysis title |
Statistical analysis 1 | ||||||||||||
Comparison groups |
Standard Prophylaxis v PK-Driven Prophylaxis
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Number of subjects included in analysis |
66
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.1467 | ||||||||||||
Method |
Wilcoxon-Rank Sum (Mann-Whitney) | ||||||||||||
Confidence interval |
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level |
95% |
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|||||||||
End point title |
Mean Difference of Transformed Annualized Bleeding Rate Between On-Demand and Standard Prophylaxis Treatment Regimens | ||||||||
End point description |
Annualized bleed rates were transformed using the square root of the number of bleeding episodes observed (X bleeds/year), X′ = √(X + 0.5). This transformation was performed to stabilize the variance and align the sample distribution with the assumption of normality inherent in using the paired t-test. Mean Difference of Transformed Annualized Bleeding Rate (TABR) = (On-Demand Treatment TABR) - (Standard Prophylaxis Treatment TABR). Participants from the On-Demand portion of the study were subsequently randomized to either Standard Prophylaxis or PK-Driven Prophylaxis, (i.e the same participants were analyzed across the two measurement time periods).
Population: Subjects in the efficacy intent-to-treat set comprising of all subjects in the prophylaxis treatment regimen who had at least 1 assessment (1 quarterly visit) or who had withdrawn after 3 bleeding episodes prior to reaching the first assessment period.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
On-demand 6 months (± 2 weeks); followed by Prophylaxis 12 months (± 2 weeks)
|
||||||||
|
|||||||||
No statistical analyses for this end point |
|
|||||||||
End point title |
Mean Difference of Transformed Annualized Bleeding Rate Between On-Demand and PK-Driven Prophylaxis Treatment Regimens | ||||||||
End point description |
Annualized bleed rates were transformed using the square root of the number of bleeding episodes observed (X bleeds/year), X′ = √(X + 0.5). This transformation was performed to stabilize the variance and align the sample distribution with the assumption of normality inherent in using the paired t-test. Mean Difference of Transformed Annualized Bleeding Rate (TABR) = (On-Demand Treatment TABR) - (PK-Driven Prophylaxis Treatment TABR) Participants from the On-Demand portion of the study were subsequently randomized to either Standard Prophylaxis or PK-Driven Prophylaxis, (i.e the same participants were analyzed across the two measurement time periods).
Population: Subjects in the efficacy intent-to-treat set comprising of all subjects in the prophylaxis treatment regimen who had at least 1 assessment (1 quarterly visit) or who had withdrawn after 3 bleeding episodes prior to reaching the first assessment period.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
On-demand 6 months (± 2 weeks); followed by Prophylaxis 12 months (± 2 weeks)
|
||||||||
|
|||||||||
No statistical analyses for this end point |
|
|||||||||
End point title |
Mean Difference of Transformed Annualized Bleeding Rate Between On-Demand and Any Prophylaxis Treatment Regimens | ||||||||
End point description |
Annualized bleed rates were transformed using the square root of the number of bleeding episodes observed (X bleeds/year), X′ = √(X + 0.5). This transformation was performed to stabilize the variance and align the sample distribution with the assumption of normality inherent in using the paired t-test. Mean Difference of Transformed Annualized Bleeding Rate (TABR) = (On-Demand Treatment TABR) - (Any Prophylaxis Treatment TABR). Any Prophylaxis = Standard or PK-Driven Prophylaxis Participants from the On-Demand portion of the study were subsequently randomized to either Standard Prophylaxis or PK-Driven Prophylaxis, (i.e the same participants were analyzed across the two measurement time periods).
Population: Subjects in the efficacy intent-to-treat set comprising of all subjects in the prophylaxis treatment regimen who had at least 1 assessment (1 quarterly visit) or who had withdrawn after 3 bleeding episodes prior to reaching the first assessment period.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
On-demand 6 months (± 2 weeks); Prophylaxis 12 months (± 2 weeks)
|
||||||||
|
|||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Total Weight-Adjusted Dose of rAHF-PFM Used Per Year for Each Prophylaxis Arm [3] | ||||||||||||
End point description |
Subjects were randomized to receive 1 of the 2 following prophylaxis regimens (part 2 of the study):
1. Standard prophylaxis- infusions every 48 ±6 hours, dosed at 20 to 40 IU/kg.
2. PK-driven prophylaxis- infusions every 72 ±6 hours dosed at 20 to 80 IU/kg.
Population: Subjects in the efficacy intent-to-treat set comprising of all subjects in the prophylaxis treatment regimen who had at least 1 assessment (1 quarterly visit) or who had withdrawn after 3 bleeding episodes prior to reaching the first assessment period.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
12 months ±2 weeks
|
||||||||||||
Notes [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Arms in the baseline period are not mutually exclusive. Refer to the description of arms in period 1 (baseline period). |
|||||||||||||
|
|||||||||||||
Statistical analysis title |
Statistical analysis 1 | ||||||||||||
Comparison groups |
PK-Driven Prophylaxis v Standard Prophylaxis
|
||||||||||||
Number of subjects included in analysis |
66
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.4924 | ||||||||||||
Method |
Wilcoxon-Rank Sum (Mann-Whitney) | ||||||||||||
Confidence interval |
|||||||||||||
level |
95% |
|
|||||||||||||||||||||||||||||
End point title |
Bleeding Episodes Treated With 1 to ≥4 Infusions [4] | ||||||||||||||||||||||||||||
End point description |
The number of bleeding episodes treated with 1, 2, 3, or ≥4 infusions of rAHF-PFM to achieve adequate hemostasis.
Population: Subjects in the efficacy intent-to-treat set comprising of all subjects in the prophylaxis treatment regimen who had at least 1 assessment (1 quarterly visit) or who had withdrawn after 3 bleeding episodes prior to reaching the first assessment period.
|
||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||
End point timeframe |
Throughout the study period (4 years and 5 months)
|
||||||||||||||||||||||||||||
Notes [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Arms in the baseline period are not mutually exclusive. Refer to the description of arms in period 1 (baseline period) for this endpoint. |
|||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||
End point title |
Assessment of Hemostasis for Treatment of Bleeding Episodes [5] | ||||||||||||||||||||||||||||||||
End point description |
Number of rAHF-PFM-treated bleeding episodes with an assessment of hemostasis (4-point ordinal scale):
Excellent: Full pain relief & bleeding cessation within ~8 hrs of 1 infusion. Additional infusions may have been given to maintain hemostasis;
Good: Definite pain relief and/or improvement in bleeding within ~8 hrs after infusion. Possibly requires >1 infusion for complete resolution;
Fair: Probable or slight relief of pain & slight improvement in bleeding within ~8 hrs after infusion. Requires >1 infusion for complete resolution;
None: No improvement or condition worsens.
Population: Subjects in the hemostatic efficacy rating set comprising of subjects who reported a bleeding episode that was treated with rAFH-PFM.
|
||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||
End point timeframe |
On-demand 6 months (± 2 weeks); Prophylaxis 12 months (± 2 weeks)
|
||||||||||||||||||||||||||||||||
Notes [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Arms in the baseline period are not mutually exclusive. Refer to the description of arms in period 1 (baseline period). |
|||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Total Area Under the Curve (AUC) | ||||||||||||
End point description |
Total AUC estimated by AUC 0-48h plus an area extrapolated from the log-linear regression model.
Population: Subjects in the pharmacokinetic (PK) intent-to-treat set comprising of subjects who provided at least 1 evaluable PK assessment.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Area Under the Curve | ||||||||||||
End point description |
Area under the factor VIII (FVIII) plasma concentration versus time curve (AUC) from 0 to 48 hours estimated using the linear trapezoidal method.
Population: Subjects in the pharmacokinetic (PK) intent-to-treat set comprising of subjects who provided at least 1 evaluable PK assessment.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Maximum Plasma Concentration (C-max) | ||||||||||||
End point description |
Maximal Factor VIII Concentration After Infusion.
Population: Subjects in the pharmacokinetic (PK) intent-to-treat set comprising of subjects who provided at least 1 evaluable PK assessment.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Within 1 hour post-infusion
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Adjusted Incremental Recovery (IR) | ||||||||||||
End point description |
Change in factor VIII concentration from pre- to post-infusion at initial and termination study visits. Adjusted IR defined as: [Cmax (IU/dL) – pre-infusion FVIII (IU/dL)]/dose (IU/kg).
Population: Subjects in the pharmacokinetic (PK) intent-to-treat set comprising of subjects who provided at least 1 evaluable PK assessment.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
30 minutes pre-infusion to 48 hours post-infusion
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Terminal Half-life | ||||||||||||
End point description |
Computed from the regression slope in the terminal phase of the model. Terminal half life is the time it takes for the plasma concentration or the amount of drug in the body to be reduced by 50%.
Population: Subjects in the pharmacokinetic (PK) intent-to-treat set comprising of subjects who provided at least 1 evaluable PK assessment.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Weight-Adjusted Clearance | ||||||||||||
End point description |
Computed as the weight-adjusted dose divided by total area under the curve (AUC).
Population: Subjects in the pharmacokinetic (PK) intent-to-treat set comprising of subjects who provided at least 1 evaluable PK assessment.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Mean Residence Time | ||||||||||||
End point description |
Computed as total Area Under the Moment Curve (AUMC) divided by the total area under the curve (AUC).
Population: Subjects in the pharmacokinetic (PK) intent-to-treat set comprising of subjects who provided at least 1 evaluable PK assessment.Population: Comprised of subjects who provided at least 1 evaluable pharmacokinetic (PK) assessment.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Volume of Distribution at Steady State | ||||||||||||
End point description |
Computed as weight-adjusted clearance * mean residence time.
Population: Subjects in the pharmacokinetic (PK) intent-to-treat set comprising of subjects who provided at least 1 evaluable PK assessment.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||
End point title |
Factor VIII Inhibitor Development [6] | ||||||
End point description |
Number of treated subjects who developed factor VIII inhibitors.
Population: All subjects in the safety analysis set comprising of all subjects who were exposed to rAHF-PFM.
|
||||||
End point type |
Secondary
|
||||||
End point timeframe |
Throughout study period (4 years and 5 months)
|
||||||
Notes [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Arms in the baseline period are not mutually exclusive. Refer to the description of arms in period 1 (baseline period). |
|||||||
|
|||||||
No statistical analyses for this end point |
|
|||||||
End point title |
Number of Subjects with AEs Related to Investigational Product (IP) [7] | ||||||
End point description |
Number of treated subjects with AEs judged to be possibly or probably related to treatment with IP.
Population: All subjects in the safety analysis set comprising of all subjects who were exposed to rAHF-PFM.
|
||||||
End point type |
Secondary
|
||||||
End point timeframe |
Throughout study period (4 years and 5 months)
|
||||||
Notes [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Arms in the baseline period are not mutually exclusive. Refer to the description of arms in period 1 (baseline period). |
|||||||
|
|||||||
No statistical analyses for this end point |
|
|||||||
End point title |
Number of Subjects who reported ≥1 AE Regardless of Relatedness to Investigational Product (IP) [8] | ||||||
End point description |
Number of treated subjects with 1 or more AE regardless of relatedness to IP.
Population: All subjects in the safety analysis set comprising of all subjects who were exposed to rAHF-PFM.
|
||||||
End point type |
Secondary
|
||||||
End point timeframe |
Throughout study period (4 years and 5 months)
|
||||||
Notes [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Arms in the baseline period are not mutually exclusive. Refer to the description of arms in period 1 (baseline period) . |
|||||||
|
|||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Number of Subjects who reported ≥1 AE Regardless of Relatedness to Investigational Product (IP) by treatment regimen [9] | ||||||||||||
End point description |
Population: All subjects in the safety analysis set comprising of all subjects who were exposed to rAHF-PFM.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Throughout the study period (4 years and 5 months)
|
||||||||||||
Notes [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Arms in the baseline period are not mutually exclusive. Refer to the description of arms in period 1 (baseline period). |
|||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Number of Subjects with SAEs by Preferred MedDRA Term and Treatment Regimen [10] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Number of Subjects with serious adverse events (SAEs) by Preferred MedDRA Term and Treatment Regimen (On-demand; Standard Prophylaxis and pharmacokinetic (PK)-driven Prophylaxis)
Population: All subjects in the safety analysis set comprising of all subjects who were exposed to rAHF-PFM.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Throughout the study period (4 years and 5 months)
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Notes [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Arms in the baseline period are not mutually exclusive. Refer to the description of arms in period 1 (baseline period). |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||
End point title |
AEs with onset ≤1 hour following the end of an infusion, regardless of relatedness [11] | ||||||
End point description |
Population: All subjects in the safety analysis set comprising of all subjects who were exposed to rAHF-PFM.
|
||||||
End point type |
Secondary
|
||||||
End point timeframe |
Throughout study period (4 years and 5 months)
|
||||||
Notes [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Arms in the baseline period are not mutually exclusive. Refer to the description of arms in period 1 (baseline period). |
|||||||
|
|||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||
End point title |
Number of Subjects with Severe SAEs and Severe non-SAEs by Preferred MedDRA Term and Treatment Regimen [12] | ||||||||||||||||||||||||||||||||
End point description |
This outcome is focused only on SEVERE serious adverse events (SAEs) and SEVERE non-SAEs.
Population: All subjects in the safety analysis set comprising of all subjects who were exposed to rAHF-PFM.
|
||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||
End point timeframe |
Throughout the study period (4 years and 5 months)
|
||||||||||||||||||||||||||||||||
Notes [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Arms in the baseline period are not mutually exclusive. Refer to the description of arms in period 1 (baseline period). |
|||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||
End point title |
Baseline Health-related Quality of Life (HRQoL) Scores: PF, RP, BP, GH, VT, SF, RE, MH, PCS, and MCS | ||||||||||||||||||||||||||||
End point description |
Physical Functioning (PF); Role Limitation Due to Physical Health (RP); Bodily Pain (BP); General Health (GH); Vitality (VT); Social Functioning (SF); Role Limitation Due to Emotional Problems (RE); Mental Health (MH), Physical Component Score (PCS); Mental Component Score (MCS). Baseline SF-36v1 Scores, where data available. Scores range 0-100, higher scores represent better health. There is no total overall score; scoring is done for subscores and summary scores. The raw data from the SF-36 items were transformed to norm based scores for each of the 8 HRQoL/SF-36 health domain scores.
Population: All subjects in pharmacoeconomic (PE) set comprising of subjects who completed a HRQoL assessment.
|
||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||
End point timeframe |
Baseline
|
||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Health-related Quality of Life (HRQoL) Scores: PF, RP, BP, GH, VT, SF, RE, MH, PCS, and MCS at the End of Treatment Regimens [13] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Physical Functioning (PF); Role Limitation Due to Physical Health (RP); Bodily Pain (BP); General Health (GH); Vitality (VT); Social Functioning (SF); Role Limitation Due to Emotional Problems (RE); Mental Health (MH), Physical Component Score (PCS); Mental Component Score (MCS). Baseline SF-36v1 Scores, where data available. Scores range 0-100, higher scores represent better health. There is no total overall score; scoring is done for subscores and summary scores. The raw data from the SF-36 items were transformed to norm based scores for each of the 8 HRQoL/SF-36 health domain scores.
Population: All subjects in pharmacoeconomic (PE) set comprising of subjects who completed a HRQoL assessment.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
End of on-demand treatment period (6 months) and at study termination (approximately 18 months)
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Notes [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Arms in the baseline period are not mutually exclusive. Refer to the description of arms in period 1 (baseline period). |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
HRQoL Scores Change From On-Demand Treatment Regimen Period Through Prophylaxis Period | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Differences in health domain scores = (End of on-demand treatment) – (End of prophylaxis regimen). A negative value for the median difference equates to a larger domain score for the prophylaxis regimen.
Physical Functioning (PF); Role Limitation Due to Physical Health (RP); Bodily Pain (BP); General Health (GH); Vitality (VT); Social Functioning (SF); Role Limitation Due to Emotional Problems (RE); Mental Health (MH), Physical Component Score (PCS); Mental Component Score (MCS).
Scores range 0-100, higher scores represent better health. There is no total overall score; scoring is done for subscores and summary scores. The raw data from the SF-36 items were transformed to norm based scores for each of the 8 HRQoL/SF-36 health domain scores.
Population: Subjects ≥14 years in pharmacoeconomic (PE) set comprising of subjects ≥14 years who completed a Health Related Quality of Life (HRQoL) assessment.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
End of on-demand treatment period (6 months) and at study termination (approximately 18 months)
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||
End point title |
Bodily Pain HRQoL Scores Change From On-Demand Period Through Prophylaxis Period | ||||||||
End point description |
After an on-demand treatment period, subjects were randomized to 1 of 2 prophylactic regimens for 12 months. The standard prophylactic regimen was dosed at 20 to 40 IU/kg every 48 ±6 hours, and the PK-driven prophylaxis regimen was dosed at 20 to 80 IU/kg every 72 ±6 hours.
Bodily Pain Health Related Quality of Life (HRQoL) Scores Change = (End of on-demand treatment) – (End of prophylaxis regimen). A negative value for the median difference equates to a larger domain score for the prophylaxis regimen.
Scores range 0-100, higher scores represent better health. There is no total overall score; scoring is done for subscores and summary scores. The raw data from the SF-36 items were transformed to norm based scores.
Population: Subjects ≥14 years in pharmacoeconomic (PE) set comprising of subjects ≥14 years who completed a HRQoL assessment.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
End of on-demand treatment period (6 months) and at study termination (approximately 18 months)
|
||||||||
|
|||||||||
No statistical analyses for this end point |
|
|||||||||
End point title |
Physical Component Scores (PCS) HRQoL Scores Change From On-Demand Period Through Prophylaxis Period | ||||||||
End point description |
After an on-demand treatment period, subjects were randomized to 1 of 2 prophylactic regimens for 12 months. The standard prophylactic regimen was dosed at 20 to 40 IU/kg every 48 ±6 hours, and the PK-driven prophylaxis regimen was dosed at 20 to 80 IU/kg every 72 ±6 hours.
PCS Health Related Quality of Life (HRQoL) Scores Change = (End of on-demand treatment) – (End of prophylaxis regimen) A negative value for the median difference equates to a larger domain score for the prophylaxis regimen. Scores range 0-100, higher scores represent better health. There is no total overall score; scoring is done for subscores and summary scores. The raw data from the SF-36 items were transformed to norm based scores.
Population: Subjects ≥14 years in pharmacoeconomic (PE) set comprising of subjects ≥14 years who completed a HRQoL assessment.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
End of on-demand treatment period (6 months) and at study termination (approximately 18 months)
|
||||||||
|
|||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||
End point title |
Median (IQR) Annualized Bleed Rates [14] | ||||||||||||||||||||
End point description |
Bleed rates (number of bleeding episodes per subject) were annualized to account for the varying number of days a subject may have actually been on each regimen.
Population: Subjects in the efficacy intent-to-treat set comprising of all subjects in the prophylaxis treatment segment who had at least 1 assessment (1 quarterly visit) or who had withdrawn after 3 bleeding episodes prior to reaching the first assessment period.
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End point type |
Post-hoc
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End point timeframe |
On-demand 6 months (± 2 weeks); Prophylaxis 12 months (± 2 weeks)
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Notes [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Arms in the baseline period are not mutually exclusive. Refer to the description of arms in period 1 (baseline period). |
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Statistical analysis title |
Statistical analysis 1 | ||||||||||||||||||||
Comparison groups |
On-Demand v Any Prophylaxis
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Number of subjects included in analysis |
106
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Analysis specification |
Post-hoc
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Analysis type |
superiority | ||||||||||||||||||||
P-value |
< 0.0001 | ||||||||||||||||||||
Method |
Wilcoxon Signed-Rank Test | ||||||||||||||||||||
Confidence interval |
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level |
95% |
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Adverse events information
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Timeframe for reporting adverse events |
Throughout the study period (4 years and 5 months)
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
N/A
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Reporting groups
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Reporting group title |
On-Demand
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Reporting group description |
On-demand: rAHF-PFM was to be used for the treatment of bleeding episodes according to the severity and type of episode by the protocol-recommended dosing until the episode resolved: superficial (10-20 IU/kg every 12-14 hours), minor joint (20-40 IU/kg every 12-14 hours), deep muscle (30-60 IU/kg every 12-14 hours), major joint or life-threatening (60-100 IU/kg every 8-12 hours), genitourinary, GI, and intracranial (60-100 IU/kg every 8-12 hours) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
PK-Driven Prophylaxis
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Reporting group description |
PK-driven prophylaxis regimen dosed at 20 to 80 IU/kg (every 72 ±6 hours) exact regimen to be determined by the sponsor | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
SAEs Outside of the 3 Treatment Arms
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Reporting group description |
Participants with SAEs that occurred after exposure to investigational product, but outside of the three treatment arms | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Standard Prophylaxis
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Reporting group description |
Standard prophylaxis regimen dosed at 20 to 40 IU/kg (every 48 ±6 hours), exact regimen to be determined by the investigator | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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30 May 2006 |
Provision of criteria for assessing the severity and cause of bleeding episodes and recording the anatomical site(s) affected. |
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20 Sep 2007 |
Change in inclusion criteria. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported | |||
Online references |
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http://www.ncbi.nlm.nih.gov/pubmed/22212248 |