Clinical Trial Results:
BAX 326 (recombinant factor IX): A Phase 3 Prospective, Multicenter Study Evaluating Efficacy and Safety in Previously Treated Patients With Severe (FIX level < 1%) or Moderately Severe (FIX level 1-2%) Hemophilia B Undergoing Surgical or Other Invasive Procedures
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.
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Summary
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EudraCT number |
2011-000413-39 |
Trial protocol |
GB CZ SE BG PL |
Global end of trial date |
15 May 2014
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Results information
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Results version number |
v1(current) |
This version publication date |
27 Feb 2016
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First version publication date |
27 Feb 2016
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
251002
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01507896 | ||
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-001139-PIP01-11 | ||
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 |
14 Oct 2014
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
15 May 2014
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Global end of trial reached? |
Yes
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Global end of trial date |
15 May 2014
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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 haemostatic efficacy and safety of BAX326 in the peri- and postoperative setting in subjects with severe (FIX level < 1%) or moderately severe (FIX level 1-2%) haemophilia B undergoing major or minor elective or emergency surgical, dental or other invasive procedures.
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Protection of trial subjects |
This study was conducted in accordance with the clinical protocol, the International Conference on Harmonisation 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.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
19 Dec 2011
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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 |
Bulgaria: 6
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Country: Number of subjects enrolled |
Czech Republic: 1
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Country: Number of subjects enrolled |
Poland: 8
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Country: Number of subjects enrolled |
Romania: 1
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Country: Number of subjects enrolled |
Russian Federation: 17
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Country: Number of subjects enrolled |
Ukraine: 3
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Country: Number of subjects enrolled |
Chile: 4
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Country: Number of subjects enrolled |
Colombia: 1
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Worldwide total number of subjects |
41
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EEA total number of subjects |
16
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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) |
40
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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 |
Enrollment was conducted at 10 clinical sites in 8 countries (Bulgaria, Czech Republic, Poland, Romania, Russia, Ukraine, Chile, Colombia). A total of 30 subjects were enrolled in the study; 38 surgical procedures were performed with BAX326. | ||||||||||||||||
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Pre-assignment
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Screening details |
Of 30 subjects enrolled, one discontinued prior to receiving BAX326; however, this subject was re-enrolled later and received treatment with BAX326. 28 subjects underwent 38 surgical procedures (7 subjects had at least 2 surgeries and were re-enrolled for each new surgical procedure); another 2 subjects discontinued after PK assessment with BAX326. | ||||||||||||||||
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Pre-assignment period milestones
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Number of subjects started |
41 | ||||||||||||||||
Number of subjects completed |
40 | ||||||||||||||||
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Pre-assignment subject non-completion reasons
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Reason: Number of subjects |
Consent withdrawn by subject: 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 BAX326 (38 subjects underwent surgery, another 2 subjects only had a pharmacokinetic evaluation) | ||||||||||||||||
Arm type |
Experimental | ||||||||||||||||
Investigational medicinal product name |
BAX326 (recombinant factor IX)
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Investigational medicinal product code |
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Other name |
Rixubis
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Pharmaceutical forms |
Powder and solvent for solution for injection
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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 BAX326, if PK parameters were not already available from the predecessor pivotal study (1 infusion). Following the loading dose(s) with BAX326 prior to surgery, subjects received BAX326 as a bolus infusion. The regimen was to be determined by the intensity and duration of the haemostatic challenge. The dose was to be tailored to raise FIX concentration to 80%-100% of normal for major surgeries and to 30%-60% of normal for minor surgeries to ensure that the recommended pre-infusion FIX activity levels were maintained in the perioperative period.
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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: Total of enrolled subjects (including re-enrolled subjects) = 41. One subject discontinued before treatment; two subjects discontinued after treatment. [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left. Justification: Subjects undergoing major surgery initially underwent a pharmacokinetic (PK) evaluation with BAX326, if PK parameters were not already available from the predecessor pivotal study (1 infusion). |
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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 |
Comprises all subjects (incl. re-enrolled subjects) who were exposed to investigational product (IP) during the study who provide data suitable for the hemostatic efficacy analysis
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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 |
Comprises all subjects (incl. re-enrolled subjects) exposed to IP during the study
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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 |
Comprises subjects in the Full Analysis Set who do not have major protocol deviations that are associated with efficacy endpoints or serious breaches of protocol; there was 1 major protocol deviation among the 21 subjects who underwent major surgery, which brings the number of subjects undergoing major surgery in the per-protocol analaysis set to 20.
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Subject analysis set title |
PK Analysis Set
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Subject analysis set type |
Sub-group analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Comprises subjects in the Full Analysis Set who had a presurgical PK assessment
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Subject analysis set title |
Subjects undergoing major surgery
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Subject analysis set type |
Sub-group analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The 21 major surgeries in the Full Analysis Set comprised 14 major, orthopedic surgeries (eg, joint replacement) and 7 non-orthopedic surgeries (3 abdominal, 3 dental, 1 excision of tumor from soft tissue).
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Subject analysis set title |
Subjects undergoing minor surgery
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Subject analysis set type |
Sub-group analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The 17 minor surgeries in the Full/Per-Protocol Analysis Set comprised 5 orthopedic surgeries (4 intraarticular infiltration, 1 synoviorthesis) and 12 non-orthopedic surgeries (11 dental, 1 intra-articular injection).
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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 BAX326 (38 subjects underwent surgery, another 2 subjects only had a pharmacokinetic evaluation) | ||
Subject analysis set title |
Full Analysis Set
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Comprises all subjects (incl. re-enrolled subjects) who were exposed to investigational product (IP) during the study who provide data suitable for the hemostatic efficacy analysis
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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 |
Comprises all subjects (incl. re-enrolled subjects) exposed to IP during the study
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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 |
Comprises subjects in the Full Analysis Set who do not have major protocol deviations that are associated with efficacy endpoints or serious breaches of protocol; there was 1 major protocol deviation among the 21 subjects who underwent major surgery, which brings the number of subjects undergoing major surgery in the per-protocol analaysis set to 20.
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Subject analysis set title |
PK Analysis Set
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Comprises subjects in the Full Analysis Set who had a presurgical PK assessment
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Subject analysis set title |
Subjects undergoing major surgery
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
The 21 major surgeries in the Full Analysis Set comprised 14 major, orthopedic surgeries (eg, joint replacement) and 7 non-orthopedic surgeries (3 abdominal, 3 dental, 1 excision of tumor from soft tissue).
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Subject analysis set title |
Subjects undergoing minor surgery
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
The 17 minor surgeries in the Full/Per-Protocol Analysis Set comprised 5 orthopedic surgeries (4 intraarticular infiltration, 1 synoviorthesis) and 12 non-orthopedic surgeries (11 dental, 1 intra-articular injection).
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End point title |
Intraoperative hemostatic efficacy [1] | |||||||||||||||||||||||||||||||||||
End point description |
The intraoperative hemostatic efficacy was to be assessed by the operating surgeon according to the following criteria (4-point ordinal scale):
- Excellent: Intraoperative blood loss was less than or equal to that expected for the type of procedure performed in a hemostatically normal subject (≤ 100% )
- Good: Intraoperative blood loss was up to 50% more than expected for the type of procedure performed in a hemostatically normal subject (101 – 150%)
- Fair: Intraoperative blood loss was more than 50% of that expected for the type of procedure performed in a hemostatically normal subject (> 150%)
- None: Uncontrolled hemorrhage that was the result of inadequate therapeutic response despite proper dosing, necessitating a change of FIX concentrate
Descriptive statistics: The intraoperative (at the end of surgery) hemostatic efficacy assessments were summarized by percentage of subjects in each efficacy categories (“excellent”, “good”, “fair” and “none”).
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End point type |
Primary
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End point timeframe |
At completion of surgery
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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, descriptive statistics were collected for this endpoint. |
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End point title |
Actual intraoperative blood loss [2] | ||||||||||||||||||||
End point description |
Actual intraoperative blood loss was summarized using descriptive statistics including median and range.
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End point type |
Primary
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End point timeframe |
At completion of surgery
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| Notes [2] - 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. |
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| No statistical analyses for this end point | |||||||||||||||||||||
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End point title |
Actual intraoperative blood loss compared to average and maximum blood loss predicted preoperatively by the operating surgeon [3] | ||||||||||||||||||||||||||||||
End point description |
Predicted average/maximum blood loss minus actual blood loss. The differences from the expected average and maximum blood loss was summarized using descriptive statistics including median and range.
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End point type |
Primary
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End point timeframe |
At completion of surgery
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| Notes [3] - 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. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
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End point title |
Postoperative hemostatic efficacy at drain removal | ||||||||||||||||||||||||||||
End point description |
Only 14 subjects who underwent major surgery had a drain placed. The postoperative hemostatic efficacy was to be assessed by the operating surgeon according to the following criteria (4-point ordinal scale):
- Excellent: Volume in drain was less than or equal than that expected for the type of procedure performed in a hemostatically normal subject (≤ 100% )
- Good: Volume in drain was up to 50% more than expected for the type of procedure performed in a hemostatically normal subject (101% - 150%)
- Fair: Volume in drain was more than 50% of that expected for the type of procedure performed in a hemostatically normal subject (> 150%)
- None: Uncontrolled bleeding that was the result of inadequate therapeutic response despite proper dosing, necessitating a change of FIX concentrate
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End point type |
Secondary
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End point timeframe |
At drain removal (if a drain was placed)
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||
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End point title |
Postoperative hemostatic efficacy at postoperative day 3 | |||||||||||||||||||||||||||||||||||
End point description |
If no drain was placed, the postoperative hemostatic efficacy was to be assessed for major surgeries by the operating surgeon on postoperative day 3 according to the following criteria (4-point ordinal scale):
- Excellent: Postoperative hemostasis achieved with BAX 326 was as good or better than that expected for the type of surgical procedure performed in a hemostatically normal subject
- Good: Postoperative hemostasis achieved with BAX 326 was probably as good as that expected for the type of surgical procedure performed in a hemostatically normal subject
- Fair: Postoperative hemostasis with BAX 326 was clearly less than optimal for the type of procedure performed but was maintained without the need to change the FIX concentrate
- None: Subject experienced uncontrolled bleeding that was the result of inadequate therapeutic response despite proper dosing, necessitating a change of FIX concentrate
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End point type |
Secondary
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End point timeframe |
At postoperative day 3 (approximately 72 hours postoperatively)
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| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||||
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End point title |
Postoperative hemostatic efficacy on day of discharge | |||||||||||||||||||||||||||||||||||
End point description |
On the day of discharge from hospital, the hemostatic efficacy was to be assessed by the investigator, ie, hemophilia physician. The rating criteria for "excellent", "good", "fair" and "none" were the same as for postoperative day 3.
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End point type |
Secondary
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End point timeframe |
At discharge from hospital
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| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||||
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End point title |
Actual postoperative blood loss | ||||||||||||||||
End point description |
Postoperative blood loss was based on the drainage fluid and was only assessed for subjects who had a drain placed (n=14).
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End point type |
Secondary
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End point timeframe |
At drain removal
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Actual postoperative blood loss compared to average and maximum blood loss predicted preoperatively by the operating surgeon | ||||||||||||||||||||||||
End point description |
Predicted average/maximum blood loss minus actual blood loss; was only assessed for subjects with major surgery who had a drain placed (n=14).
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End point type |
Secondary
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End point timeframe |
At drain removal
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
Daily weight-adjusted dose of BAX326 per subject | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Daily weight-adjusted doses of BAX326 per subject were recorded from the day of surgery until postoperative day 11+. The number of subjects in the FAS and the reporting groups who were exposed to daily doses of BAX326 after surgery decreases towards day 11.
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End point type |
Secondary
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||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
From initiation of surgery until the time of discharge (minor surgery: 1-3 days, major surgery: approximately 2 weeks)
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Notes [4] - Day2:n=29,Day3:n=26,Day4:n=24,Day5:n=23,Day6:n=21,Day7:n=21,Day8:n=19,Day9:n=19,D10:n=18,D11+:n=15 [5] - Day2:n=28,Day3:n=25,Day4:n=23,Day5:n=22,Day6:n=20,Day7:n=20,Day8:n=18,Day9:n=18,D10:n=17,D11+:n=15 [6] - Day 6: n=20, Day 7: n=20, Day 8: n=19, Day 9: n=19, Day 10: n=18, Day 11+: n=15 [7] - Day 2: n=8, Day 3: n=5, Day 4: n=3, Day 5: n=2, Day 6: n=1, Day 7: n=1, Days 8-11: n=0 |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
End point title |
Total weight-adjusted dose of BAX326 per subject | ||||||||||||||||||||||||||||||
End point description |
Assessed for the intra- and postoperative periods
|
||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||
End point timeframe |
From initiation of surgery until the time of discharge (minor surgery: 1-3 days, major surgery: approximately 2 weeks)
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||
End point title |
Number of units of blood product transfused | ||||||||||||||||||||||||
End point description |
Blood product transfusions consisted of packed red blood cells (PRBC) or fresh frozen plasma (FFP) or both. Six subjects who underwent major orthopedic surgery received blood product transfusions in the intraoperative period; 2 of these subjects also received blood product infusions in the postoperative period.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
From initiation of surgery until the time of discharge (minor surgery: 1-3 days, major surgery: approximately 2 weeks)
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
| Notes [8] - Only 2 subjects received blood product transfusions in the postoperative period. [9] - Only 1 subject received blood product transfusions in the postoperative period. [10] - Only 2 subjects received blood product transfusions in the postoperative period. |
|||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||
|
|||||||||||||||||||||||||
End point title |
Amount of blood product transfused (in mL) | ||||||||||||||||||||||||
End point description |
Blood product transfusions consisted of packed red blood cells (PRBC) or fresh frozen plasma (FFP) or both. Six subjects who underwent major orthopedic surgery received blood product transfusions in the intraoperative period; 2 of these subjects also received blood product infusions in the postoperative period.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
From initiation of surgery until the time of discharge (minor surgery: 1-3 days, major surgery: approximately 2 weeks)
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
| Notes [11] - Only 2 subjects received blood product transfusions in the postoperative period. [12] - Only 1 subject received blood product transfusions in the postoperative period. [13] - Only 2 subjects received blood product transfusions in the postoperative period. |
|||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||
|
|||||||
End point title |
Safety: Development of inhibitory antibodies to FIX | ||||||
End point description |
|||||||
End point type |
Secondary
|
||||||
End point timeframe |
Entire study duration: approx. 2.5 years; study participation per subject: mean of 43.3 days (standard deviation: 30.1 days (range: 4-110 days)
|
||||||
|
|||||||
| No statistical analyses for this end point | |||||||
|
|||||||
End point title |
Safety: Development of total binding antibodies to FIX | ||||||
End point description |
If more than 2-dilution increase as compared to pre-study level at screening
|
||||||
End point type |
Secondary
|
||||||
End point timeframe |
Entire study duration: approx. 2.5 years; study participation per subject: mean of 43.3 days (standard deviation: 30.1 days (range: 4-110 days)
|
||||||
|
|||||||
| No statistical analyses for this end point | |||||||
|
|||||||
End point title |
Safety: Adverse events (AEs) related to BAX326 | ||||||
End point description |
|||||||
End point type |
Secondary
|
||||||
End point timeframe |
Entire study duration: approx. 2.5 years; study participation per subject: mean of 43.3 days (standard deviation: 30.1 days (range: 4-110 days)
|
||||||
|
|||||||
| No statistical analyses for this end point | |||||||
|
|||||||
End point title |
Safety: Occurrence of thrombotic events | ||||||
End point description |
|||||||
End point type |
Secondary
|
||||||
End point timeframe |
Entire study duration: approx. 2.5 years; study participation per subject: mean of 43.3 days (standard deviation: 30.1 days (range: 4-110 days)
|
||||||
|
|||||||
| No statistical analyses for this end point | |||||||
|
|||||||||
End point title |
Presurgical Pharmacokinetics (PK): Area under the plasma concentration versus time curve from 0 to 72 hours post-infusion per dose (AUC 0-72h/dose) | ||||||||
End point description |
AUC0-72h [IU·hr/dL] (area under the plasma concentration/time curve from time 0 to 72 hours) was computed using the linear trapezoidal method. The concentration at 72 hours was interpolated from the two nearest sampling time points or extrapolated using the last quantifiable concentration and the terminal rate constant λz. λz was estimated from the slope of natural log-linear fitting to latter quantifiable concentrations,
with largest adjusted R2.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
0.5 hour (h) before start of PK infusion to 72±2 h after the infusion
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Presurgical PK: Total area under the plasma concentration versus time curve per dose (total AUC/dose) | ||||||||
End point description |
AUC0-inf [IU·hr/dL] (area under the plasma concentration/time curve from time 0 to infinity) was defined as AUC0-t + Ct / λz, where t is the time of last quantifiable concentration, and Ct is the last quantifiable concentration.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
0.5 hour (h) before start of PK infusion to 72±2 h after the infusion
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Presurgical PK: Mean residence time (MRT) | ||||||||
End point description |
MRT [hr] was computed as AUMC0-inf / AUC0-∞, where AUMC0-inf was determined in a similar manner as AUC0-inf.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
0.5 hour (h) before start of PK infusion to 72±2 h after the infusion
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Presurgical PK: Factor IX clearance (CL) | ||||||||
End point description |
CL [dL/(kg·hr)] (clearance) was computed as Dose / AUC0-inf.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
0.5 hour (h) before start of PK infusion to 72±2 h after the infusion
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Presurgical PK: Incremental recovery (IR) at 30 min | ||||||||
End point description |
IR [IU/dL:IU/kg] was defined as (C post-infusion - C pre-infusion) / Dose, where C post-infusion is the measured concentration achieved at 30±5 minutes for pre-surgical PK and at 15±5 minutes for loading dose.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
0.5 hour (h) before start of PK infusion and at 0.5 h ± 5 min after the infusion
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Presurgical PK: Elimination phase half-life (T 1/2) | ||||||||
End point description |
T1/2 [hr] (elimination phase half-life) was determined as ln2 / λz.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
0.5 hour (h) before start of PK infusion to 72±2 h after the infusion
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Presurgical PK: Volume of distribution at steady state (Vss) | ||||||||
End point description |
Vss [dL/kg] (volume of distribution at steady state) was computed as CL·MRT.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
0.5 hour (h) before start of PK infusion to 72±2 h after the infusion
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Presurgical PK: Incremental recovery (IR) at 15±5 minutes following loading dose prior to surgery | ||||||||
End point description |
|||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Within 60 minutes prior to surgery and 15±5 minutes after loading dose/rebolus, if applicable
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||
|
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
Entire study duration: approx. 2.5 years; study participation per subject: mean of 43.3 days (standard deviation: 30.1 days (range: 4-110 days)
|
||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||
|
Dictionary used for adverse event reporting
|
|||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
N/A
|
||||||||||||||||||||||||||||||||||||||||||||||||
|
Reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Safety Analysis Set
|
||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Comprises all subjects exposed to investigational product during the study (n=40) | ||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||
| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||
|
|||
Substantial protocol amendments (globally) |
|||
| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
11 Oct 2011 |
- Design was modified so that subjects taking part in the BAX326 pediatric study (251101) could also be recruited into the surgery study.
- Occurrence of thrombotic events was added as a safety endpoint. A daily clinical evaluation of thrombosis following surgery was added to the schedule of study procedures and assessments.
- Subjects could undergo 2 parallel surgeries, such as bilateral knee replacement, but prior approval had to be obtained from the sponsor. |
||
26 Feb 2013 |
- Tailoring of dose was specified ‘to raise FIX concentration to at least 80%-100% of normal for major surgeries and to at least 30%-60% of normal for minor surgeries to ensure that the recommended pre-infusion FIX levels are maintained in the perioperative period’.
- To ensure that subjects were hemostatically sufficiently covered on the day of surgery, the results of the pre-infusion FIX activity had to be available within 4 hours of infusion of BAX 326, and a second FIX activity level had to be determined within 12 hours of surgery, preferably within 6-8 h.
- In case of major surgery, the subject’s individual PK parameters, in particular IR and half-life, determined as part of the PK assessment, had to be available prior to the start of surgery, to determine the adequate dose and dose frequency.
- The formula for calculating the required units was revised as follows due to a revised IR based on the PK data of the BAX326 pivotal study (from 0.8 to 0.9) in subjects ≥12 years of age: ‘body weight (kg) x desired FIX rise (% or (IU/dL)) x 1.1 IU/kg’ (previously 1.3 IU/kg).
- Dosing adjustments based on aPTT values were no longer allowed. The following text was added: ‘ALL subsequent infusions of BAX 326 must be preceded by measurement of residual FIX levels and the dose adjusted as needed – dosing adjustments based on aPTT values are not allowed’. Postoperative aPTT assessments were removed from the protocol.
- In the event that high doses of BAX326 were required, it was recommended that these should be administered in 1-3 infusions over 24 hours, most commonly in 2 infusions, to avoid supraphysiological peaks.
- For subjects transitioning to the surgery study from the BAX326 pivotal, continuation, or pediatric study, the transition stages from one study to another were clarified.
- In the event that at least 3 pediatric subjects <12 years of age had been enrolled, a separate analysis of the pediatric cohort would have had to be performed. |
||
12 Apr 2013 |
- The previous number of approximately 30 elective or emergency surgical, dental or other invasive procedures in approximately 30 subjects was increased to 40 procedures/subjects. |
||
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 | |||
Online references |
|||
| http://www.ncbi.nlm.nih.gov/pubmed/24697870 |
|||
