Clinical Trial Results:
Phase 3B Recombinant Antihemophilic Factor Manufactured and Formulated without Added Human or Animal Proteins (rAHF-PFM): Evaluation of Immunogenicity, Efficacy, and Safety in Previously Untreated Patients with 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
|
|
EudraCT number |
2004-001623-38 |
Trial protocol |
AT |
Global end of trial date |
11 Sep 2009
|
|
Results information
|
|
Results version number |
v1(current) |
This version publication date |
13 Feb 2016
|
First version publication date |
13 Feb 2016
|
Other versions |
|
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
|
|||
|
Trial identification
|
|||
Sponsor protocol code |
060103
|
||
|
Additional study identifiers
|
|||
ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
|
Sponsors
|
|||
Sponsor organisation name |
Baxter Innovations GmbH
|
||
Sponsor organisation address |
Industriestrasse 67, Vienna, Austria, A-1221
|
||
Public contact |
Clinical Trial Registries and Results Disclosure, Baxter Innovations GmbH, ClinicalTrialsDisclosure@baxalta.com
|
||
Scientific contact |
Clinical Trial Registries and Results Disclosure, Baxter Innovations GmbH, ClinicalTrialsDisclosure@baxalta.com
|
||
Sponsor organisation name |
Baxter Healthcare Corporation
|
||
Sponsor organisation address |
One Baxter Way, Westlake Village, United States, CA 91362-3811
|
||
Public contact |
Clinical Trial Registries and Results Disclosure, Baxter Healthcare Corporation, ClinicalTrialsDisclosure@baxalta.com
|
||
Scientific contact |
Clinical Trial Registries and Results Disclosure, Baxter Healthcare Corporation, ClinicalTrialsDisclosure@baxalta.com
|
||
|
Paediatric regulatory details
|
|||
Is trial part of an agreed paediatric investigation plan (PIP) |
No
|
||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
Yes
|
||
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
|
||
|
Results analysis stage
|
|||
Analysis stage |
Final
|
||
Date of interim/final analysis |
11 Sep 2009
|
||
Is this the analysis of the primary completion data? |
Yes
|
||
Primary completion date |
11 Sep 2009
|
||
Global end of trial reached? |
Yes
|
||
Global end of trial date |
11 Sep 2009
|
||
Was the trial ended prematurely? |
No
|
||
|
General information about the trial
|
|||
Main objective of the trial |
The objectives of study 060103 were: To assess the immunogenicity of rAHF-PFM by determining the risk of FVIII inhibitor development; To assess in vivo incremental recovery of rAHF-PFM at the first study visit, at every other interval study visit, and at the study termination visit; To evaluate the hemostatic efficacy of rAHF-PFM in the management and prevention of acute bleeding events; To evaluate the hemostatic efficacy of rAHF-PFM during perioperative management, if surgery was required; To assess the safety of rAHF-PFM; To assess the incidence of the development of antibodies to CHO protein, murine IgG, and human VWF.
|
||
Protection of trial subjects |
This study was conducted in accordance with this protocol, the ICH Guideline for Good Clinical Practice, Title 21 of the U.S. Code of Federal Regulations, the European Directive, and the Declaration of Helsinki.
|
||
Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
01 Apr 2004
|
||
Long term follow-up planned |
No
|
||
Independent data monitoring committee (IDMC) involvement? |
Yes
|
||
|
Population of trial subjects
|
|||
Number of subjects enrolled per country |
|||
Country: Number of subjects enrolled |
Italy: 2
|
||
Country: Number of subjects enrolled |
United States: 35
|
||
Country: Number of subjects enrolled |
United Kingdom: 2
|
||
Country: Number of subjects enrolled |
Austria: 2
|
||
Country: Number of subjects enrolled |
Canada: 3
|
||
Country: Number of subjects enrolled |
Spain: 2
|
||
Country: Number of subjects enrolled |
France: 4
|
||
Country: Number of subjects enrolled |
Germany: 5
|
||
Worldwide total number of subjects |
55
|
||
EEA total number of subjects |
17
|
||
Number of subjects enrolled per age group |
|||
In utero |
0
|
||
Preterm newborn - gestational age < 37 wk |
0
|
||
Newborns (0-27 days) |
8
|
||
Infants and toddlers (28 days-23 months) |
47
|
||
Children (2-11 years) |
0
|
||
Adolescents (12-17 years) |
0
|
||
Adults (18-64 years) |
0
|
||
From 65 to 84 years |
0
|
||
85 years and over |
0
|
||
|
|||||||||||||||||||||
|
Recruitment
|
|||||||||||||||||||||
Recruitment details |
Recruitment was conducted in the U.S., Canada, and Europe at 24 study sites. | ||||||||||||||||||||
|
Pre-assignment
|
|||||||||||||||||||||
Screening details |
Participants screened for maximum 21 days. Study was not randomized; it was an open-label evaluation. Prior to initial infusion, a minimum washout period of 3 days was required. 11 participants who enrolled did not receive any rAHF-PFM infusions (3 withdrew consent, 6 screen failures, 1 non-compliance with screening, 1 pre-existing low hemoglobin) | ||||||||||||||||||||
|
Period 1
|
|||||||||||||||||||||
Period 1 title |
Overall Study (overall period)
|
||||||||||||||||||||
Is this the baseline period? |
Yes | ||||||||||||||||||||
Allocation method |
Not applicable
|
||||||||||||||||||||
Blinding used |
Not blinded | ||||||||||||||||||||
|
Arms
|
|||||||||||||||||||||
|
Arm title
|
PUPs | ||||||||||||||||||||
Arm description |
All treated subjects | ||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||
Investigational medicinal product name |
rAHF-PFM
|
||||||||||||||||||||
Investigational medicinal product code |
ADVATE
|
||||||||||||||||||||
Other name |
|||||||||||||||||||||
Pharmaceutical forms |
Infusion
|
||||||||||||||||||||
Routes of administration |
Intravenous use
|
||||||||||||||||||||
Dosage and administration details |
rAHF-PFM was to be dosed according to a therapeutic regimen which was determined by the investigator (ie: standard regimen [25 to 50 IU/kg body weight, 3 to 4 times per week]; a modified prophylactic regimen [dose and frequency selected by investigator] or on–demand treatment [dose selected by investigator]). The dosing regimen used to treat BEs was at the discretion of the investigator and in accordance with the institution’s standard of care for the type of BE diagnosed.
|
||||||||||||||||||||
|
|||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||
|
Baseline characteristics reporting groups
|
||||||||||||||||||||||||||||||||||||||||
Reporting group title |
PUPs
|
|||||||||||||||||||||||||||||||||||||||
Reporting group description |
All treated subjects | |||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||
|
|||
|
End points reporting groups
|
|||
Reporting group title |
PUPs
|
||
Reporting group description |
All treated subjects | ||
Subject analysis set title |
Did not Develop Factor VIII Inhibitor
|
||
Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Subjects in Immunogenicity Analysis Set who did not develop Factor VIII Inhibitor
|
||
Subject analysis set title |
Developed Factor VIII Inhibitor
|
||
Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Subjects in Immunogenicity Analysis Set who developed Factor VIII Inhibitor
|
||
|
|||||||||
End point title |
Factor VIII Inhibitor Development [1] | ||||||||
End point description |
Percentage of treated participants who developed factor VIII inhibitors
|
||||||||
End point type |
Primary
|
||||||||
End point timeframe |
Assessed during study period which was to be at least 75 exposure days or 3 years (whichever came first)
|
||||||||
| 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: Per protocol, descriptive statistics were collected for this endpoint. |
|||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||||||||
End point title |
Bleeding Episodes Treated With 1 to ≥4 Infusions | ||||||||||||||
End point description |
The number of bleeding episodes treated with 1, 2, 3, or ≥4 infusions of rAHF-PFM to achieve adequate hemostasis
|
||||||||||||||
End point type |
Secondary
|
||||||||||||||
End point timeframe |
Reported during study period which was to be at least 75 exposure days or 3 years (whichever came first)
|
||||||||||||||
|
|||||||||||||||
| No statistical analyses for this end point | |||||||||||||||
|
|||||||||||||||||
End point title |
Assessment of Hemostasis for Treatment of Bleeding Episodes | ||||||||||||||||
End point description |
Number of rAHF-PFM-treated bleeding episodes with treater 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; or None: No improvement or condition worsens.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Reported during study period which was to be at least 75 exposure days or 3 years (whichever came first)
|
||||||||||||||||
|
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||
End point title |
Annualized Rate of Bleeding Episodes | ||||||||
End point description |
Number of bleeding episodes per subject annualized over 1 year for all etiologies
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Reported during study period which was to be at least 75 exposure days or 3 years (whichever came first)
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||||||||
End point title |
Weekly rAHF-PFM Utilization | ||||||||||||||
End point description |
Weight-Adjusted Weekly Dose for Prophylaxis, On-Demand Treatment, and Perioperative Management. rAHF-PFM dose determined by the investigator (ie: standard regimen [25-50 IU/kg body weight, 3-4 times per week]; modified prophylactic regimen [dose and frequency selected by investigator] or on–demand treatment [dose selected by investigator]). Dosing to treat BEs was at investigator's discretion and in accordance with institution’s standard of care. rAHF-PFM was administered I.V. via bolus infusion, except for perioperative management when it was given either by continuous or bolus infusion.
|
||||||||||||||
End point type |
Secondary
|
||||||||||||||
End point timeframe |
Reported during study period which was to be at least 75 exposure days or 3 years (whichever came first)
|
||||||||||||||
|
|||||||||||||||
| No statistical analyses for this end point | |||||||||||||||
|
|||||||||||||
End point title |
In Vivo Incremental Recovery | ||||||||||||
End point description |
Change in factor VIII concentration from pre- to post-infusion at initial and termination study visits.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
30 minutes pre-infusion to 30 minutes post-infusion
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||||
End point title |
Assessment of Intra-operative Hemostasis | ||||||||||||||
End point description |
Number of surgical procedures managed with rAHF-PFM and with surgeon's assessment of hemostasis based on a 4-point ordinal scale: Excellent: ≤ average predicted blood loss for matched procedures in healthy individuals Good: > average predicted blood loss, but ≤ maximal predicted blood loss for matched procedures in healthy individuals Fair: > maximal predicted blood loss for matched procedures in healthy individuals, and hemostasis was achieved None: uncontrolled hemostasis with proper dosing, necessitating a change in treatment regimen
|
||||||||||||||
End point type |
Secondary
|
||||||||||||||
End point timeframe |
Assessed at the time of discharge from recovery room
|
||||||||||||||
|
|||||||||||||||
| No statistical analyses for this end point | |||||||||||||||
|
|||||||||||||||
End point title |
Assessment of Postoperative Hemostasis | ||||||||||||||
End point description |
Number of surgical procedures managed with rAHF-PFM and with investigator's assessment of hemostasis based on a 4-point ordinal scale: Excellent: hemostasis was as good as or better than other licensed factor VIII products for matched procedure Good: hemostasis was probably as good as other licensed factor VIII products for matched procedure Fair: hemostasis was clearly < optimal for matched procedure, without need to change regimen None: bleeding from inadequate response with proper dosing, necessitating a change in regimen
|
||||||||||||||
End point type |
Secondary
|
||||||||||||||
End point timeframe |
Assessed at the time of discharge from hospital or clinic
|
||||||||||||||
|
|||||||||||||||
| No statistical analyses for this end point | |||||||||||||||
|
|||||||||||||
End point title |
Assessment of Blood Loss During Surgical Procedures | ||||||||||||
End point description |
Percentage of actual intraoperative blood loss compared to preoperatively predicted average and maximal blood loss in hemostatically normal matched individuals (from institutional blood bank records)
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Predicted volumes preoperatively estimated and actual volumes intraoperatively recorded
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||
End point title |
Adverse Events Deemed Related to Treatment | ||||||
End point description |
Number of participants who reported AEs deemed related to treatment with rAHF-PFM
|
||||||
End point type |
Secondary
|
||||||
End point timeframe |
Reported during the study period which was to be at least 75 exposure days or 3 years (whichever came first)
|
||||||
|
|||||||
| No statistical analyses for this end point | |||||||
|
|||||||||||||
End point title |
Development of Antibodies to Heterologous Proteins | ||||||||||||
End point description |
Number of treated participants who developed antibodies to heterologous proteins (ie, Chinese Hamster Ovary Cell Protein, Murine IgG, or Recombinant Human VWF)
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Assessed at baseline, throughout the duration of the study, which was to be at least 75 exposure days or 3 years (whichever came first), and at the termination visit.
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||||||||
End point title |
Factor VIII Inhibitor Risk Factor: Genetic Risk Factor- Family History of Inhibitors | ||||||||||||||||||
End point description |
Number of treated participants who developed an inhibitor
|
||||||||||||||||||
End point type |
Post-hoc
|
||||||||||||||||||
End point timeframe |
Duration of study which was to be at least 75 exposure days or 3 years (whichever came first)
|
||||||||||||||||||
|
|||||||||||||||||||
Statistical analysis title |
Statistical analysis 1 | ||||||||||||||||||
Comparison groups |
Did not Develop Factor VIII Inhibitor v Developed Factor VIII Inhibitor
|
||||||||||||||||||
Number of subjects included in analysis |
50
|
||||||||||||||||||
Analysis specification |
Post-hoc
|
||||||||||||||||||
Analysis type |
|||||||||||||||||||
Method |
|||||||||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||||||||
Point estimate |
4.95
|
||||||||||||||||||
Confidence interval |
|||||||||||||||||||
level |
95% | ||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||
lower limit |
1.29 | ||||||||||||||||||
upper limit |
19.06 | ||||||||||||||||||
|
||||||||||||||||
End point title |
Factor VIII Inhibitor Risk Factor: Race | |||||||||||||||
End point description |
Number of treated participants who developed an inhibitor
|
|||||||||||||||
End point type |
Post-hoc
|
|||||||||||||||
End point timeframe |
Duration of study which was to be at least 75 exposure days or 3 years (whichever came first)
|
|||||||||||||||
|
||||||||||||||||
Statistical analysis title |
Statistical analysis 1 | |||||||||||||||
Comparison groups |
Did not Develop Factor VIII Inhibitor v Developed Factor VIII Inhibitor
|
|||||||||||||||
Number of subjects included in analysis |
50
|
|||||||||||||||
Analysis specification |
Post-hoc
|
|||||||||||||||
Analysis type |
||||||||||||||||
Method |
||||||||||||||||
Parameter type |
Odds ratio (OR) | |||||||||||||||
Point estimate |
4.18
|
|||||||||||||||
Confidence interval |
||||||||||||||||
level |
95% | |||||||||||||||
sides |
2-sided
|
|||||||||||||||
lower limit |
1.18 | |||||||||||||||
upper limit |
14.82 | |||||||||||||||
|
||||||||||||||||
End point title |
Factor VIII Inhibitor Risk Factor: Number of Participants with Intensive Treatment and High Dose (≤20 Exposure Days (EDs)) | |||||||||||||||
End point description |
Immunogenicity Analysis Set- Participants with 5 consecutive study days of a mean infusion dose of FVIII >50 IU/kg within ≤20 EDs who developed an inhibitor
|
|||||||||||||||
End point type |
Post-hoc
|
|||||||||||||||
End point timeframe |
Duration of study which was to be at least 75 exposure days or 3 years (whichever came first)
|
|||||||||||||||
|
||||||||||||||||
Statistical analysis title |
Statistical analysis 1 | |||||||||||||||
Comparison groups |
Did not Develop Factor VIII Inhibitor v Developed Factor VIII Inhibitor
|
|||||||||||||||
Number of subjects included in analysis |
50
|
|||||||||||||||
Analysis specification |
Post-hoc
|
|||||||||||||||
Analysis type |
||||||||||||||||
Method |
||||||||||||||||
Parameter type |
Odds ratio (OR) | |||||||||||||||
Point estimate |
4.5
|
|||||||||||||||
Confidence interval |
||||||||||||||||
level |
95% | |||||||||||||||
sides |
2-sided
|
|||||||||||||||
lower limit |
1.05 | |||||||||||||||
upper limit |
19.25 | |||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
Study period was to be at least 75 exposure days or 3 years (whichever came first)
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
Median days on study was 498 (range: 82 to 1360) days. Median days of rAHF-PFM exposure was 76 (range: 1 to 414) exposure days.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Dictionary used for adverse event reporting
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
12.1
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
PUPs
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Reporting group 1 description | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||
Substantial protocol amendments (globally) |
|||
| Were there any global substantial amendments to the protocol? No | |||
Interruptions (globally) |
|||
| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
|||
| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
