Clinical Trial Results:
A Phase 3, Multicenter, Open Label Study of Efficacy and Safety of PEGylated rFVIII (BAX 855) in Previously Treated Patients With Severe Hemophilia A Undergoing Surgical or Other Invasive Procedures
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Summary
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EudraCT number |
2013-001359-11 |
Trial protocol |
GB BE LT BG ES DE NL |
Global end of trial date |
23 Sep 2016
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Results information
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Results version number |
v1(current) |
This version publication date |
06 Apr 2017
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First version publication date |
06 Apr 2017
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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 |
261204
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01913405 | ||
WHO universal trial number (UTN) |
- | ||
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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) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-001296-PIP01-12 | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
23 Sep 2016
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
23 Sep 2016
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Global end of trial reached? |
Yes
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Global end of trial date |
23 Sep 2016
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To evaluate the perioperative hemostatic efficacy of BAX 855 in male previously treated patients aged 2-75 years with severe hemophilia A (FVIII<1%) undergoing major or minor elective or minor emergency surgical, dental or other invasive procedures as determined by the Global Hemostatic Efficacy Assessment.
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Protection of trial subjects |
The study was conducted in accordance with the study protocol, the International Conference on Harmonization Guideline for Good Clinical Practice E6 (ICH GCP April 1996), Title 21 of the US Code of Federal Regulations (US CFR), the European Clinical Trial Directive (2001/20/EC and 2005/28/EC), and applicable national and local regulatory requirements. The enrollment of subjects <12years of age was limited to subjects participating in the pediatric study 261202. In the Russian Federation, all subjects were required to be >18 years old at the time of enrollment.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
20 Dec 2013
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United States: 8
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Country: Number of subjects enrolled |
Russian Federation: 2
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Country: Number of subjects enrolled |
United Kingdom: 1
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Country: Number of subjects enrolled |
Bulgaria: 6
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Country: Number of subjects enrolled |
Lithuania: 1
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Country: Number of subjects enrolled |
Spain: 3
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Country: Number of subjects enrolled |
Switzerland: 2
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Worldwide total number of subjects |
23
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EEA total number of subjects |
11
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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) |
1
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Adults (18-64 years) |
22
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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 |
Twelve study sites have enrolled subjects in seven countries (US, Russia, UK, Bulgaria, Lithuania, Spain, Switzerland). There were 30 surgical enrollments in a total of 23 unique subjects. Seven unique subjects enrolled more than once, of whom five received study product for more than one surgical procedure. | ||||||||||||
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Pre-assignment
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Screening details |
A total of 23 subjects provided informed consent and were screened for study participation. There were 3 screen failures, of which 2 participated and completed the study. 22 unique subjects (29 surgical enrollments) were exposed to study product. One subject discontinued prior to surgery and one subject discontinued after surgery. | ||||||||||||
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Pre-assignment period milestones
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Number of subjects started |
23 | ||||||||||||
Number of subjects completed |
22 | ||||||||||||
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Pre-assignment subject non-completion reasons
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Reason: Number of subjects |
Screen failure: 1 | ||||||||||||
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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 | ||||||||||||
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Arms
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Arm title
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Overall trial | ||||||||||||
Arm description |
Treatment with BAX855 for pre-surgical PK infusion, surgery and postoperative treatment. | ||||||||||||
Arm type |
Experimental | ||||||||||||
Investigational medicinal product name |
BAX 855
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Investigational medicinal product code |
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Other name |
Adynovate, Adynovi
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Subjects undergoing major surgery initially underwent a pharmacokinetic (PK) evaluation with BAX855 (60 +/-5 IU/kg), if PK parameters were not already available from a BAX855 parent study. For subjects undergoing minor surgery an individual IR was determined. Individual dosing based on the patients PK/IR parameters was outlined in the FVIII substitution plan. For the loading dose prior surgery the FVIII target levels were to be 80-100% of normal (major surgery) and 30-60% of normal (minor surgery). Subsequent infusions were preceeded by measurement of residual FVIII levels and the dose adjusted as needed. The following FVIII trough levels were to be targeted: Postoperative day 1-3: not below 80%, day 4-7: not below 50%, day 8 to discharge: not below 30%
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| Notes [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: A total of 23 subjects provided informed consent and were screened for study participation. One subject was a screen failure and did not enter the baseline period. Two other subjects were also screen failures but did enter the baseline period and were treated with study product. |
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Baseline characteristics reporting groups
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Reporting group title |
Overall trial
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Reporting group description |
Overall trial | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Full Analysis Set
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Subject analysis set type |
Full analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The FAS comprises all subjects with at least one available hemostatic assessment.
N=26 surgical enrollments in 21 unique subjects.
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Subject analysis set title |
Per-Protocol Analysis Set
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Subject analysis set type |
Per protocol | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The PPAS comprises all subjects with available intraoperative efficacy assessment performed by the surgeon within 60 minutes post-surgery, postoperative hemostatic control assessed by the operating surgeon postoperatively at 24 hours and perioperative hemostatic control assessed by the investigator during end of study visit. Only subjects who met all study entry criteria and who had no major protocol violation that impacted hemostatic efficacy assessment were included in the PPAS.
N=12 surgical enrollments in 11 unique subjects.
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Subject analysis set title |
Safety Analysis Set
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Subject analysis set type |
Safety analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The SAS comprises all subjects who received at least one infusion of BAX855.
N= 29 surgical enrollments in 22 unique subjects.
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Subject analysis set title |
Pharmacokinetic Analysis Set
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Subject analysis set type |
Sub-group analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The PKAS comprises only subjects who underwent a PK assessment.
N=25 surgical enrollments in 20 unique subjects.
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Subject analysis set title |
Major orthopedic surgery
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Subject analysis set type |
Sub-group analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Comprises all subjects treated with BAX855 for major orthopedic surgery.
N=14 surgical enrollments in 12 unique subjects.
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Subject analysis set title |
Major non-orthopedic surgery
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Subject analysis set type |
Sub-group analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Comprises all subjects treated with BAX855 for major non-orthopedic surgery.
N=7 surgical enrollments in 6 unique subjects.
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Subject analysis set title |
Minor surgery
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Subject analysis set type |
Sub-group analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Comprises all subjects treated with BAX855 for minor surgery.
N=5 surgical enrollments in 4 unique subjects.
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End points reporting groups
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Reporting group title |
Overall trial
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Reporting group description |
Treatment with BAX855 for pre-surgical PK infusion, surgery and postoperative treatment. | ||
Subject analysis set title |
Full Analysis Set
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
The FAS comprises all subjects with at least one available hemostatic assessment.
N=26 surgical enrollments in 21 unique subjects.
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Subject analysis set title |
Per-Protocol Analysis Set
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
The PPAS comprises all subjects with available intraoperative efficacy assessment performed by the surgeon within 60 minutes post-surgery, postoperative hemostatic control assessed by the operating surgeon postoperatively at 24 hours and perioperative hemostatic control assessed by the investigator during end of study visit. Only subjects who met all study entry criteria and who had no major protocol violation that impacted hemostatic efficacy assessment were included in the PPAS.
N=12 surgical enrollments in 11 unique subjects.
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Subject analysis set title |
Safety Analysis Set
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
The SAS comprises all subjects who received at least one infusion of BAX855.
N= 29 surgical enrollments in 22 unique subjects.
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Subject analysis set title |
Pharmacokinetic Analysis Set
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
The PKAS comprises only subjects who underwent a PK assessment.
N=25 surgical enrollments in 20 unique subjects.
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Subject analysis set title |
Major orthopedic surgery
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Comprises all subjects treated with BAX855 for major orthopedic surgery.
N=14 surgical enrollments in 12 unique subjects.
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Subject analysis set title |
Major non-orthopedic surgery
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Comprises all subjects treated with BAX855 for major non-orthopedic surgery.
N=7 surgical enrollments in 6 unique subjects.
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Subject analysis set title |
Minor surgery
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Comprises all subjects treated with BAX855 for minor surgery.
N=5 surgical enrollments in 4 unique subjects.
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End point title |
Global Hemostatic Efficacy Assessment score (GHEA) [1] | ||||||||||||||||||||||||||||||||||||||||||
End point description |
The GHEA is composed of three individual ratings:
a. Assessment of intraoperative hemostatic efficacy of BAX 855 performed by the operating surgeon;
b. Assessment of postoperative hemostatic efficacy of BAX 855 at postoperative Day 1 (approx. 24 hours post surgery) performed by the operating surgeon;
c. Assessment of perioperative hemostatic efficacy of BAX855 at Day 14 or discharge, whichever is first, performed by the investigator.
The scores of the individual ratings are added for the GHEA.
Treatment success is a GHEA score of excellent or good. Point estimates and corresponding two-sided exact (Clopper-Pearson) confidence intervals at 90% confidence level are calculated.
Number of subjects analysed is based on surgical enrollments and the same as number of surgeries.
Main analysis was done on the FAS with 24 surgeries with at least one available hemostatic assessment, supportive analysis was done on the PPAS with 12 surgeries with all hemostatic assessments available.
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End point type |
Primary
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End point timeframe |
Hemostatic efficacy assessments were performed intraoperatively, postoperatively on day 1 (approximately 24 hours after surgery) and perioperatively at day 14 or discharge (whichever was first).
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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: Per protocol, only descriptive statistics were collected for this endpoint. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||
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End point title |
Intraoperative blood loss | |||||||||||||||||||||||||||||||||||||||||||||
End point description |
Actual intraoperative blood loss was assessed at the end of surgery and was compared to the estimated volume of expected average and maximum blood loss in a hemostatically normal individual of the same sex, age and stature as the study subject. Expected intraoperative blood loss was predicted pre-operatively by the investigator/surgeon.
Number of subjects is counted based on surgical enrollment.
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End point type |
Secondary
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End point timeframe |
From initiation of surgery until end of surgery.
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| Notes [2] - n=26 for predicted average and maximum blood loss [3] - n=7 for predicted average and maximum blood loss |
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| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||||||||||||||
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End point title |
Postoperative blood loss | |||||||||||||||||||||||||||||||||||||||||||||
End point description |
Actual post-operative blood loss assessed at postoperative day 1 was compared to the estimated volume of expected average and maximum blood loss in a hemostatically normal individual of the same sex, age and stature as the study subject. Expected postoperative blood loss was predicted pre-operatively by the investigator/surgeon.
Number of subjects is counted based on surgical enrollment.
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End point type |
Secondary
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End point timeframe |
From completion of surgery until 24 hours after surgery.
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| Notes [4] - n=26 for predicted average and maximum blood loss [5] - n=14 for predicted average and maximum blood loss [6] - n=7 for predicted average and maximum blood loss [7] - n=5 for predicted average and maximum blood loss |
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| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||||||||||||||
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End point title |
Overall perioperative blood loss | |||||||||||||||||||||||||||||||||||||||||||||
End point description |
Actual overall perioperative blood loss (assessed at the end of surgery, at postoperative day 1 and until discharge or day 14 - whichever is first) was compared to the estimated volume of expected average and maximum blood loss in a hemostatically normal individual of the same sex, age and stature as the study subject. Expected perioperative blood loss was predicted pre-operatively by the investigator/surgeon.
Number of subjects is counted based on surgical enrollment.
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End point type |
Secondary
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End point timeframe |
From start of surgery until discharge or day 14, whichever occurred last.
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| Notes [8] - n=26 for predicted average and maximum blood loss [9] - n=7 for predicted average and maximum blood loss |
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| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||||||||||||||
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End point title |
Blood transfusion requirements | ||||||||||||||||||||
End point description |
Volume of blood, red blood cells, platelets, and other blood products transfused. Only packed red blood cells were transfused in this study.
Subjects are counted based on surgical enrollment.
No blood transfusions were required for minor surgeries and no blood transfusion were required intraoperatively for major surgeries.
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End point type |
Secondary
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End point timeframe |
From initiation of the surgery to 24 hours after completion of the surgery.
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| Notes [10] - Dispersion is not applicable as there is only 1 subject in the analysis set. |
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| No statistical analyses for this end point | |||||||||||||||||||||
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End point title |
Occurrence of bleeding episodes and additional need for surgical intervention | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Any clinically relevant bleeding episodes (as assessed by the investigator) and any need for additional surgical intervention were recorded. If the subject had not resumed his previous treatment after discharge, the occurrence and treatment of bleeding episodes were recorded in the subject's diary.
Only surgical enrollments that have encountered bleeding episodes are listed as subjects analysed.
The additional need for surgeries was assessed for all 26 surgical enrollments.
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End point type |
Secondary
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End point timeframe |
From start of surgery until the last intensified treatment after hospital discharge (or until hospital discharge if there was no intensified treatment).
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| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End point title |
Daily and total weight-adjusted consumption of BAX855 per subject | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Daily weight-adjusted BAX855 consumption is listed from preoperative loading dose until discharge. Total weight-adjusted BAX855 consumption is calculated from first study infusion (PK/IR) until end of study. PK infusions from previous studies are not included.
Subjects are counted based on their surgical enrollment.
Number of subjects=surgeries (n) varies on each postoperative day as described in the categories for non-orthopedic major surgery (NOS), orthopedic major surgery (OS) and minor surgery (MS) and the full analysis set (FAS). 99.999 is listed if result is not available due to n=0 or standard deviation is not available due to n=1.
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End point type |
Secondary
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End point timeframe |
From initial loading dose until discharge for daily weight-adjusted dose and from first infusion (PK/IR) until end of study for total weight-adjusted dose.
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| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End point title |
Presurgical PK - Area under the plasma concentration/time curve | ||||||||||||||||
End point description |
The area under the plasma concentration/time curve from time 0 to infinity (AUC 0-inf) and the area under the first movement curve from time 0 to infinity (AUMC 0-inf) was calculated as the sum of AUC and AUMC from time 0 to the time of the last quantifiable concentration plus a tail area correction calculated as Ct/λz and Ct/λz(t+1/λz), respectively, where Ct is the last quantifiable concentration, t is the time of last quantifiable concentration and λz is the terminal or disposition rate constant.
The area under the plasma concentration/time curve from time 0 to 96 hours postinfusion (AUC 0-96h) was computed using the linear trapezoidal rule. For the calculation of AUC 0-96h the levels at 96 hours were linearly interpolated/extrapolated from the 2 nearest sampling time points.
Number of subjects is counted based on surgical enrollment.
Main analysis was done on the one-stage clotting assay results, supportive analysis was done on the chromogenic assay results.
|
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End point type |
Secondary
|
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End point timeframe |
PK measurements were done within 30 minutes pre-infusion, and post infusion at 15 (± 5) minutes, 3 hours (± 30 minutes), 9 hours (± 30 minutes), 32 (± 2) hours, 56 (± 4) hours and 96 (± 4) hours.
|
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|
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| No statistical analyses for this end point | |||||||||||||||||
|
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End point title |
Presurgical PK - Terminal Half-Life | ||||||||||||
End point description |
Terminal or disposition half-life (HL) was calculated as log e(2)/λz where the terminal or disposition rate constant (λz) was estimated as the slope of a log-linear least squares regression model.
Number of subjects is counted based on surgical enrollment.
Main analysis was done on the one-stage clotting assay results, supportive analysis was done on the chromogenic assay results.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
PK measurements were done within 30 minutes pre-infusion, and post infusion at 15 (± 5) minutes, 3 hours (± 30 minutes), 9 hours (± 30 minutes), 32 (± 2) hours, 56 (± 4) hours and 96 (± 4) hours.
|
||||||||||||
|
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| No statistical analyses for this end point | |||||||||||||
|
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End point title |
Presurgical PK - Mean residence time (MRT) | ||||||||||||
End point description |
Mean residence time (MRT) was calculated as total area under the moment curve divided by the total area under the curve.
Number of subjects is counted based on surgical enrollment.
Main analysis was done on the one-stage clotting assay results, supportive analysis was done on the chromogenic assay results.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
PK measurements were done within 30 minutes pre-infusion, and post infusion at 15 (± 5) minutes, 3 hours (± 30 minutes), 9 hours (± 30 minutes), 32 (± 2) hours, 56 (± 4) hours and 96 (± 4) hours.
|
||||||||||||
|
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| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Presurgical PK - Clearance (CL) | ||||||||||||
End point description |
Systemic clearance (CL) was calculated as the dose in IU/kg divided by the total AUC.
Number of subjects is counted based on surgical enrollment.
Main analysis was done on the one-stage clotting assay results, supportive analysis was done on the chromogenic assay results.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
PK measurements were done within 30 minutes pre-infusion, and post infusion at 15 (± 5) minutes, 3 hours (± 30 minutes), 9 hours (± 30 minutes), 32 (± 2) hours, 56 (± 4) hours and 96 (± 4) hours.
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Presurgical PK - Apparent volume of distribution at steady state (Vss) | ||||||||||||
End point description |
Apparent steady state volume of distribution (Vss) was calculated as dose multiplied with AUMC(0-inf) divided by AUC(0-inf) to square.
Number of subjects is counted based on surgical enrollment.
Main analysis was done on the one-stage clotting assay results, supportive analysis was done on the chromogenic assay results.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
PK measurements were done within 30 minutes pre-infusion, and post infusion at 15 (± 5) minutes, 3 hours (± 30 minutes), 9 hours (± 30 minutes), 32 (± 2) hours, 56 (± 4) hours and 96 (± 4) hours.
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
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End point title |
Presurgical PK - Incremental recovery | ||||||||||||||||
End point description |
Incremental recovery (IR) was calculated as C post infusion minus C pre-infusion divided by the dose.
Number of subjects is counted based on surgical enrollment.
Main analysis was done on the one-stage clotting assay results, supportive analysis was done on the chromogenic assay results.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
PK measurements were done within 30 minutes pre-infusion, and post infusion at 15 (± 5) minutes, 3 hours (± 30 minutes), 9 hours (± 30 minutes), 32 (± 2) hours, 56 (± 4) hours and 96 (± 4) hours.
|
||||||||||||||||
|
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| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||||||||||||||||||
End point title |
Summary of safety outcome measures (development of antibodies, thrombotic events, severe allergic reactions and other IP related AEs) | ||||||||||||||||||||||||||||
End point description |
Development of treatment emerging binding antibodies to FVIII IgG, FVIII IgM, BAX855 IgG, BAX855 IgM, PEG IgG, PEG IgM and CHO proteins was assessed as well as any thrombotic events and severe allergic reactions and any other Adverse Events related to the investigational product. Unique subjects with a safety outcome measure are counted.
|
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End point type |
Secondary
|
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End point timeframe |
From screening visit to end of study visit.
|
||||||||||||||||||||||||||||
|
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||
|
|||||||||||||||
End point title |
Changes in vital signs - Pulse rate | ||||||||||||||
End point description |
Changes in vital signs were assessed 15 minutes after the PK/IR infusion compared to the pre-infusion values.
Number of subjects is counted based on surgical enrollment. The 15 minutes post-infusion measurement includes 1 hour post infusion assessments for two subjects.
|
||||||||||||||
End point type |
Secondary
|
||||||||||||||
End point timeframe |
Vital signs measurement prior to the PK/IR infusion and 15 minutes post-infusion.
|
||||||||||||||
|
|||||||||||||||
| Notes [11] - n=25 for pre-infusion measurement |
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| No statistical analyses for this end point | |||||||||||||||
|
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End point title |
Changes in vital signs - Blood pressure | ||||||||||||||||||||
End point description |
Changes in vital signs were assessed 15 minutes after the PK/IR infusion compared to the pre-infusion values.
Number of subjects is counted based on surgical enrollment. The 15 minutes post-infusion measurement includes 1 hour post infusion assessments for two subjects.
|
||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
Vital signs measurement prior to the PK/IR infusion and 15 minutes post-infusion.
|
||||||||||||||||||||
|
|||||||||||||||||||||
| Notes [12] - n=25 for pre-infusion measurement |
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| No statistical analyses for this end point | |||||||||||||||||||||
|
|||||||||||||||
End point title |
Changes in vital signs - Respiratory rate | ||||||||||||||
End point description |
Changes in vital signs were assessed 15 minutes after the PK/IR infusion compared to the pre-infusion values.
Number of subjects is counted based on surgical enrollment. The 15 minutes post-infusion measurement includes 1 hour post infusion assessments for two subjects.
|
||||||||||||||
End point type |
Secondary
|
||||||||||||||
End point timeframe |
Vital signs measurement prior to the PK/IR infusion and 15 minutes post-infusion.
|
||||||||||||||
|
|||||||||||||||
| Notes [13] - n=25 for pre-infusion measurement |
|||||||||||||||
| No statistical analyses for this end point | |||||||||||||||
|
|||||||||||||||
End point title |
Changes in vital signs - Temperature | ||||||||||||||
End point description |
Changes in vital signs were assessed 15 minutes after the PK/IR infusion compared to the pre-infusion values.
Number of subjects is counted based on surgical enrollment. The 15 minutes post-infusion measurement includes 1 hour post infusion assessments for two subjects.
|
||||||||||||||
End point type |
Secondary
|
||||||||||||||
End point timeframe |
Vital signs measurement prior to the PK/IR infusion and 15 minutes post-infusion.
|
||||||||||||||
|
|||||||||||||||
| Notes [14] - n=25 for pre-infusion measurement |
|||||||||||||||
| No statistical analyses for this end point | |||||||||||||||
|
|||||||||||||||||
End point title |
Clinically significant changes in routine labor parameters (hematology and chemistry) | ||||||||||||||||
End point description |
Changes in clinical chemistry and hematology parameters from a normal or abnormal not clinically significant (ncs) result at screening to an abnormal and clinically significant (cs) result at the end of study assessment (EOS) are listed. Changes did occur in the following laboratory parameters: Alanine Aminotransferase (ALT) (U/L), Hemoglobin (g/L), Hematocrit, Erythrocytes(TI/L), Eosinophils/Leucocytes. Number of subjects is counted based on surgical enrollment.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Laboratory assessment were done throughout the study from screening to study completion/termination.
|
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|
|||||||||||||||||
| Notes [15] - ALT: n=27, Hematocrit: n=25 |
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| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Adverse events information
|
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Timeframe for reporting adverse events |
Throughout the entire study period (2 years and 9 months).
For each subject the duration of treatment and therefore for the entire study period depended on the nature of each subject’s invasive procedure (ranged from 43 days to 162 days).
|
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Adverse event reporting additional description |
Adverse Events (AEs) were recorded throughout the entire study period from screening to completion/termination. AEs that occurred during or after treatment are summarized here, AEs that occurred prior to study treatment were listed separately and are not included.
|
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Dictionary used for adverse event reporting
|
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
19.1
|
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|
Reporting groups
|
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Reporting group title |
Safety Analysis Set
|
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Reporting group description |
The Safety Analysis Set comprises all subjects who received at least one infusion of BAX855. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
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|
|||
Substantial protocol amendments (globally) |
|||
| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
19 Jul 2013 |
The overall study duration was extended from 24 to 41 months. The recruitment period was extended from 18 to 34 months. Pediatric PTPs transitioning from the pediatric study with BAX855 were excluded from participation in this study. Information was added to justify the inclusion of adolescents in this study with two ICH guidelines referenced. The level of detectable FVIII inhibitory antibodies which would exclude a subject from participation was changed from ≥ 0.6 BU using the Nijmegen modification of the Bethesda assay to ≥0.4 BU (due to validation of the central laboratory for this value). The wash-out period for the PK assessment was changed from 96 to 72 hours. Criteria were listed that would require a repetition of the PK assessment (e.g. bleeding episode prior to 72-hour timepoint, 2 or more PK blood sample results not evaluable). A requirement for a 72-hour wash-out period before the immunogenicity tests was added. The requirement that major surgery may only be started when the required target FVIII level (range 80-150%) has been attained was removed (as test results may not have been available within 60 minutes in most standard laboratories). In the assessment scales for ntraoperative and postoperative efficacy, the description of products for rescue therapy was deleted from the rating criterion 'none'. Viral serology tests (HBV, HCV, HIV) were added to the laboratory tests to be performed at the end-of-study/termination visit (in alignment with the pivotal study). A planned safety review was added which was to be performed upon completion of BAX855 pivotal study 261201 and was to include all major and minor surgeries performed until that time. |
||
30 Jan 2014 |
Overall study duration decreased from 41 to 36 months.Recruitment period changed from 34 to 33 months.Targeted accrual changed to approx. 50 surgical/invasive procedures in approx. 40 subjects, to include at least 10 major procedures in at least 5 subjects. Age range changed from previously 12-65 years to 2-75 years. Enrollment of subjects < 12 years of age limited to subjects participating in the BAX855 pediatric study. For newly recruited subjects the age range 12-75 years applies. Inclusion crit. were split according to whether subjects were transitioning form another BAX 855 study or were newly recruited. Emergency procedures now allowed in this study, provided these were minor emergency surgeries. Only subjects transitioning from another BAX855 study were allowed to undergo minor emergency surgery, newly recruited subjects had to undergo major procedures. If IR<1.5 in the parent study or after screening, no participation in this study. FVIII activity analysis at the central lab to be performed by 1-stage clotting and chromogenic assay. PK not required for minor surgeries and major surgeries if done in previous study, IR sufficient for subsequent dosing. Rating from EOS done at day 14, wording of definitions changed slightly. Changes in virology status removed from sec.outcome measures and not assessed at EOS. Antibodies to murine IgG not assessed. Wash-out for immunogenicity was 72h (FVIII) and 96h (BAX855). Addition of single dose vials with nominal potency of 3000 IU rFVIII. Instructions for use of vials, potencies and lots given. Dosing schedule changed (instead of PK guided dosing target levels provided). Surgery to start after normalization of aPTT and dose adjustments based on FVIII activity. Short half life removed from criteria for withdrawal. Detailed info for thrombosis prophy and topical hemostatics. Subject diary added. ECG and thrombotic markers removed. Vital signs timepoints changed and removed at EOS. Blood pressure measured in supine position. |
||
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 | |||
