Clinical Trial Results:
A Phase 3 prospective, uncontrolled, multicenter study evaluating pharmacokinetics, efficacy, safety, and immunogenicity of BAX 855 (pegylated full-length recombinant FVIII) in previously treated pediatric patients with severe hemophilia A
Summary
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EudraCT number |
2014-000742-30 |
Trial protocol |
LT ES BG RO NL GB |
Global end of trial date |
23 Oct 2015
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Results information
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Results version number |
v1(current) |
This version publication date |
22 Apr 2016
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First version publication date |
22 Apr 2016
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
261202
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02210091 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Baxalta Innovations GmbH
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Sponsor organisation address |
Industriestrasse 67, Vienna, Austria, 1221
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Public contact |
Clinical Trial Registries and Results Disclosure, Baxalta Innovations GmbH, ClinicalTrialsDisclosure@baxalta.com
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Scientific contact |
Clinical Trial Registries and Results Disclosure, Baxalta Innovations GmbH, ClinicalTrialsDisclosure@baxalta.com
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Sponsor organisation name |
Baxalta US Inc.
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Sponsor organisation address |
One Baxter Way, Westlake Village, United States, CA 91362
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Public contact |
Clinical Trial Registries and Results Disclosure, Baxalta US Inc., ClinicalTrialsDisclosure@baxalta.com
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Scientific contact |
Clinical Trial Registries and Results Disclosure, Baxalta US Inc., ClinicalTrialsDisclosure@baxalta.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
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? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
23 Oct 2015
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
23 Oct 2015
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Global end of trial reached? |
Yes
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Global end of trial date |
23 Oct 2015
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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 assess the incidence of FVIII inhibitory antibodies (≥0.6 Bethesda units [BU] using the Nijmegen modification of the Bethesda assay).
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Protection of trial subjects |
This study was conducted in accordance with the protocol, the ICH Guideline for Good Clinical Practice E6 (ICH GCP, April 1996), Title 21 of the United States Code of Federal Regulations, the European Clinical Trial Directive (2001/20/EC and 2005/28/EC) and applicable national and local regulatory requirements. Justification for enrollment of pediatric subjects is based on the requirements outlined in the ICH M3 and E11 guidelines. The clinical development program for BAX 855 followed the EMA guidance outlined in EMA/CHMP/BPWP/144533/2009. In line with this guidance the pediatric study did not start before the data of 20 previously treated patients (PTPs) ≥12 years of age that had been treated for at least 50 exposure days (EDs) and the pharmacokinetic (PK) data of at least 12 PTPs ≥12 years of age were available (study 261201), were reviewed by an independent data monitoring committee (DMC) and a decision to start the study was obtained. For the PK evaluation, a population PK approach was used to reduce the number of blood draws: the 3 post-infusion blood draws over 96 hours were randomly selected from 3 choices for each blood draw.
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Background therapy |
- | ||
Evidence for comparator |
Prior to receiving prophylactic treatment with BAX 855, a subgroup of subjects within each age cohort underwent PK assessments with ADVATE followed by BAX 855 to compare the PK parameters of BAX 855 with ADVATE. | ||
Actual start date of recruitment |
31 Oct 2014
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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: 22
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Country: Number of subjects enrolled |
Malaysia: 9
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Country: Number of subjects enrolled |
Hong Kong: 1
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Country: Number of subjects enrolled |
Taiwan: 1
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Country: Number of subjects enrolled |
Korea, Republic of: 3
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Country: Number of subjects enrolled |
Bulgaria: 3
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Country: Number of subjects enrolled |
Netherlands: 3
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Country: Number of subjects enrolled |
Spain: 5
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Country: Number of subjects enrolled |
Ukraine: 5
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Country: Number of subjects enrolled |
United Kingdom: 8
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Country: Number of subjects enrolled |
Turkey: 6
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Worldwide total number of subjects |
66
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EEA total number of subjects |
19
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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) |
2
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Children (2-11 years) |
64
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
0
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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 |
52 sites participated in this study. 39 study sites enrolled subjects and 13 sites were initiated but were inactive. | ||||||||||||||||||
Pre-assignment
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Screening details |
A total of 73 subjects provided informed consent and were screened for study participation. There were 9 screen failures. Among these, 2 subjects were screen failures at first screening but entered the study later. 66 subjects were dosed in the prophylactic part of the study, of which 31 subjects were also dosed in the PK part prior to prophylaxis. | ||||||||||||||||||
Pre-assignment period milestones
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Number of subjects started |
73 [1] | ||||||||||||||||||
Number of subjects completed |
66 | ||||||||||||||||||
Pre-assignment subject non-completion reasons
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Reason: Number of subjects |
Screen failures: 7 | ||||||||||||||||||
Notes [1] - The number of subjects reported to have started the pre-assignment 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 73 subjects provided informed consent and were screened for study participation. There were 9 screen failures. Among these, 2 subjects were Screen failures at first screening but entered the study later. 66 subjects were dosed in the prophylactic part of the study, of which 31 subjects were also dosed in the PK part prior to prophylaxis. |
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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 | ||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Pediatric subjects <6 years of age | ||||||||||||||||||
Arm description |
Subjects were to be treated with prophylactic infusions of BAX 855 at a dose of 50 ±10 IU/kg administered twice weekly (at 3- and 4-day intervals or 3.5-day intervals) for a minimum of 50 exposure days to BAX855 or approximately 6 months, whichever occurred last. | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
BAX 855
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Powder and solvent for solution for injection/infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Dose of 50 ±10 IU/kg twice weekly for prophylaxis
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Arm title
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Pediatric subjects 6 to <12 years of age | ||||||||||||||||||
Arm description |
Subjects were to be treated with prophylactic infusions of BAX 855 at a dose of 50 ±10 IU/kg administered twice weekly (at 3- and 4-day intervals or 3.5-day intervals) for a minimum of 50 exposure days to BAX855 or approximately 6 months, whichever occurred last. | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
BAX 855
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Powder and solvent for solution for injection/infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Dose of 50 ±10 IU/kg twice weekly for prophylaxis
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Baseline characteristics reporting groups
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Reporting group title |
Overall trial
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Reporting group description |
Prophylactic Part (main study part) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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 full analysis set contains all subjects who received at least one dose of BAX 855 in either the PK part of the study or the prophylaxis part of the study. All efficacy analyses were performed on the full analysis set (FAS). The FAS is the primary analysis set.
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Subject analysis set title |
ADVATE Safety Analysis Set
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Subject analysis set type |
Safety analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The ADVATE safety analysis set contains all subjects who received at least one dose of ADVATE in the PK part of the study.
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Subject analysis set title |
BAX 855 Safety Analysis Set
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Subject analysis set type |
Safety analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The BAX 855 safety analysis set contains all subjects who received at least one dose of BAX 855.
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Subject analysis set title |
Pharmacokinetic (PK) Full Analysis Set
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Subject analysis set type |
Sub-group analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The pharmacokinetic full analysis set (PKFAS) contains all subjects who had been treated with at least 1 dose of ADVATE (60 ±5 IU/kg) and 1 dose of BAX 855 (60 ±5 IU/kg) in the PK part of the study (prior to prophylactic treatment) and had at least 1 PK concentration available for population PK and non-compartmental analysis.
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Subject analysis set title |
Pharmacokinetic (PK) Analysis Set - ADVATE
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Subject analysis set type |
Sub-group analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
This analysis set contains all subjects who had been treated with at least 1 dose of ADVATE (60 ±5 IU/kg) and 1 dose of BAX 855 (60 ±5 IU/kg) in the PK part of the study (prior to prophylactic treatment) and had at least 1 PK concentration available for population PK and non-compartmental analysis.
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Subject analysis set title |
Pharmacokinetic (PK) Analysis Set - BAX 855
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Subject analysis set type |
Sub-group analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
This analysis set contains all subjects who had been treated with at least 1 dose of ADVATE (60 ±5 IU/kg) and 1 dose of BAX 855 (60 ±5 IU/kg) in the PK part of the study (prior to prophylactic treatment) and had at least 1 PK concentration available for population PK and non-compartmental analysis.
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Subject analysis set title |
PK Analysis Set - BAX 855 - subjects <6 years of age
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Subject analysis set type |
Sub-group analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
This analysis set contains all subjects <6 years of age who had been treated with at least 1 dose of ADVATE (60 ±5 IU/kg) and 1 dose of BAX 855 (60 ±5 IU/kg) in the PK part of the study (prior to prophylactic treatment) and had at least 1 PK concentration available for population PK and non-compartmental analysis.
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Subject analysis set title |
PK Analysis Set - BAX 855 - subjects 6 to <12 years of age
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Subject analysis set type |
Sub-group analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
This analysis set contains all subjects 6 to <12 years of age who had been treated with at least 1 dose of ADVATE (60 ±5 IU/kg) and 1 dose of BAX 855 (60 ±5 IU/kg) in the PK part of the study (prior to prophylactic treatment) and had at least 1 PK concentration available for population PK and non-compartmental analysis.
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Subject analysis set title |
PK Analysis Set - ADVATE - subjects <6 years of age
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Subject analysis set type |
Sub-group analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
This analysis set contains all subjects <6 years of age who had been treated with at least 1 dose of ADVATE (60 ±5 IU/kg) and 1 dose of BAX 855 (60 ±5 IU/kg) in the PK part of the study (prior to prophylactic treatment) and had at least 1 PK concentration available for population PK and non-compartmental analysis.
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Subject analysis set title |
PK Analysis Set- ADVATE - subjects 6 to <12 years of age
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Subject analysis set type |
Sub-group analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
This analysis set contains all subjects 6 to <12 years of age who had been treated with at least 1 dose of ADVATE (60 ±5 IU/kg) and 1 dose of BAX 855 (60 ±5 IU/kg) in the PK part of the study (prior to prophylactic treatment) and had at least 1 PK concentration available for population PK and non-compartmental analysis.
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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 |
This analysis set contains all subjects in the Full Analysis Set (FAS) who fulfilled the following compliance criteria for prophylactic treatment: -) Infusion interval of 5 or more days did not occur more than five times in the observation period, -) the dose per infusion was below 40 IU/kg in no more than 10% of the infusions in the observation period, -) the dose per infusion was above 80 IU/kg in no more than 10% of the infusions in the observation period. The Per Protocol Analysis Set was a supportive analysis set.
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End points reporting groups
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Reporting group title |
Pediatric subjects <6 years of age
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Reporting group description |
Subjects were to be treated with prophylactic infusions of BAX 855 at a dose of 50 ±10 IU/kg administered twice weekly (at 3- and 4-day intervals or 3.5-day intervals) for a minimum of 50 exposure days to BAX855 or approximately 6 months, whichever occurred last. | ||
Reporting group title |
Pediatric subjects 6 to <12 years of age
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Reporting group description |
Subjects were to be treated with prophylactic infusions of BAX 855 at a dose of 50 ±10 IU/kg administered twice weekly (at 3- and 4-day intervals or 3.5-day intervals) for a minimum of 50 exposure days to BAX855 or approximately 6 months, whichever occurred last. | ||
Subject analysis set title |
Full Analysis Set
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
The full analysis set contains all subjects who received at least one dose of BAX 855 in either the PK part of the study or the prophylaxis part of the study. All efficacy analyses were performed on the full analysis set (FAS). The FAS is the primary analysis set.
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Subject analysis set title |
ADVATE Safety Analysis Set
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
The ADVATE safety analysis set contains all subjects who received at least one dose of ADVATE in the PK part of the study.
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Subject analysis set title |
BAX 855 Safety Analysis Set
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
The BAX 855 safety analysis set contains all subjects who received at least one dose of BAX 855.
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Subject analysis set title |
Pharmacokinetic (PK) Full Analysis Set
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
The pharmacokinetic full analysis set (PKFAS) contains all subjects who had been treated with at least 1 dose of ADVATE (60 ±5 IU/kg) and 1 dose of BAX 855 (60 ±5 IU/kg) in the PK part of the study (prior to prophylactic treatment) and had at least 1 PK concentration available for population PK and non-compartmental analysis.
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Subject analysis set title |
Pharmacokinetic (PK) Analysis Set - ADVATE
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
This analysis set contains all subjects who had been treated with at least 1 dose of ADVATE (60 ±5 IU/kg) and 1 dose of BAX 855 (60 ±5 IU/kg) in the PK part of the study (prior to prophylactic treatment) and had at least 1 PK concentration available for population PK and non-compartmental analysis.
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Subject analysis set title |
Pharmacokinetic (PK) Analysis Set - BAX 855
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
This analysis set contains all subjects who had been treated with at least 1 dose of ADVATE (60 ±5 IU/kg) and 1 dose of BAX 855 (60 ±5 IU/kg) in the PK part of the study (prior to prophylactic treatment) and had at least 1 PK concentration available for population PK and non-compartmental analysis.
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Subject analysis set title |
PK Analysis Set - BAX 855 - subjects <6 years of age
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
This analysis set contains all subjects <6 years of age who had been treated with at least 1 dose of ADVATE (60 ±5 IU/kg) and 1 dose of BAX 855 (60 ±5 IU/kg) in the PK part of the study (prior to prophylactic treatment) and had at least 1 PK concentration available for population PK and non-compartmental analysis.
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Subject analysis set title |
PK Analysis Set - BAX 855 - subjects 6 to <12 years of age
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
This analysis set contains all subjects 6 to <12 years of age who had been treated with at least 1 dose of ADVATE (60 ±5 IU/kg) and 1 dose of BAX 855 (60 ±5 IU/kg) in the PK part of the study (prior to prophylactic treatment) and had at least 1 PK concentration available for population PK and non-compartmental analysis.
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Subject analysis set title |
PK Analysis Set - ADVATE - subjects <6 years of age
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
This analysis set contains all subjects <6 years of age who had been treated with at least 1 dose of ADVATE (60 ±5 IU/kg) and 1 dose of BAX 855 (60 ±5 IU/kg) in the PK part of the study (prior to prophylactic treatment) and had at least 1 PK concentration available for population PK and non-compartmental analysis.
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Subject analysis set title |
PK Analysis Set- ADVATE - subjects 6 to <12 years of age
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
This analysis set contains all subjects 6 to <12 years of age who had been treated with at least 1 dose of ADVATE (60 ±5 IU/kg) and 1 dose of BAX 855 (60 ±5 IU/kg) in the PK part of the study (prior to prophylactic treatment) and had at least 1 PK concentration available for population PK and non-compartmental analysis.
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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 |
This analysis set contains all subjects in the Full Analysis Set (FAS) who fulfilled the following compliance criteria for prophylactic treatment: -) Infusion interval of 5 or more days did not occur more than five times in the observation period, -) the dose per infusion was below 40 IU/kg in no more than 10% of the infusions in the observation period, -) the dose per infusion was above 80 IU/kg in no more than 10% of the infusions in the observation period. The Per Protocol Analysis Set was a supportive analysis set.
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End point title |
Incidence of FVIII inhibitory antibodies (≥0.6 Bethesda units [BU] using the Nijmegen modification of the Bethesda assay) [1] | ||||||||||||
End point description |
Inhibitory antibodies were measured by the Nijmegen modification of the Bethesda assay at each study visit. The number of subjects included in the analysis was the sum of subjects that developed inhibitory antibodies to FVIII and the number of subjects that did not develop inhibitory antibodies to FVIII, had 50 or more exposure days and had a FVIII inhibitory test result after 50 exposure days. Per protocol, descriptive statistics were collected for this endpoint.
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End point type |
Primary
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End point timeframe |
Throughout the study period (1 year), approximately 6 months per subject
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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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Notes [2] - 29 subjects <6 years of age included in this analysis [3] - 28 subjects 6 to <12 years of age included in this analysis [4] - 57 subjects included in this analysis |
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No statistical analyses for this end point |
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End point title |
Annualized bleeding rate | ||||||||||||||||||||||||||||||||||||||||
End point description |
The annualized bleeding rate (ABR) was assessed based upon each individual bleeding episode, spontaneous or traumatic, recorded in the subject´s diary and/or recorded in the physician/nurse/study site notes.
In the Full Analysis Set (n=66), the point estimate for the overall mean ABR was 3.04 (95% confidence interval [CI] 2.208 – 4.186). Point estimates for the mean ABR were 2.37 (95% CI 1.486 – 3.778) in subjects <6 years of age (n=32) and 3.75 (95% CI 2.429 –5.781) in subjects 6 to <12 years of age (n=34).
Point estimates for the mean annualized spontaneous bleeding rate were 1.164 (95% CI 0.740 - 1.832) in the FAS (n=66), 1.018 (95% CI 0.523 - 1.978) in the younger (n=32) and 1.316 (95% CI 0.710 - 2.438) in the older (n=34) age cohort.
Point estimates for the mean annualized rate of joint bleeds were 1.103 (95% CI 0.637 - 1.910) in the FAS (n=66), 0.862 (95% CI 0.381 - 1.946) in the younger (n=32) and 1.355 (95% CI 0.648 - 2.833) in the older age cohort (n=34).
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End point type |
Secondary
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End point timeframe |
During prophylactic treatment: approx. 6 months per subject
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No statistical analyses for this end point |
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End point title |
Consumption of BAX 855: number of prophylactic infusions per month and per year (annualized) per subject | ||||||||||||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
During prophylactic treatment: approx. 6 months per subject
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No statistical analyses for this end point |
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End point title |
Consumption of BAX 855: weight-adjusted dose of prophylactic infusions per month and per year (annualized) per subject | ||||||||||||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
During prophylactic treatment: approx. 6 months per subject
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No statistical analyses for this end point |
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End point title |
Consumption of BAX 855: number of infusions per bleeding episode | ||||||||||||||||
End point description |
Of 66 subjects in the BAX855 Safety Analysis Set, 34 experienced bleeding episodes which were treated, 15 in the <6 year age group, 19 in the 6 to <12 year age group.
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End point type |
Secondary
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End point timeframe |
During prophylactic treatment: approx. 6 months per subject
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No statistical analyses for this end point |
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End point title |
Consumption of BAX 855: weight-adjusted dose per bleeding episode | ||||||||||||||||
End point description |
Of 66 subjects in the BAX855 Safety Analysis Set, 34 experienced bleeding episodes which were treated, 15 in the <6 year age group, 19 in the 6 to <12 year age group.
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End point type |
Secondary
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End point timeframe |
During prophylactic treatment: approx. 6 months per subject
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No statistical analyses for this end point |
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End point title |
Hemostatic efficacy at resolution of bleed | ||||||||||||||||||||||||||||
End point description |
A total of 70 treated bleeding episodes occurred in 34 subjects: 25 treated bleeding episodes in 15 subjects <6 years of age and 45 treated bleeding episodes in 19 subjects 6 to <12 years of age.
Rating Scale for Treatment of Bleeding Episodes (BEs) (4-point ordinal scale):
EXCELLENT: Full relief of pain and cessation of objective signs of bleeding (eg, swelling, tenderness, and decreased range of motion in the case of musculoskeletal hemorrhage) after a single infusion. No
additional infusion required for the control of bleeding. Administration of further infusions to maintain hemostasis did not affect this scoring.
GOOD: Definite pain relief and/or improvement in signs of bleeding after a single infusion. Possibly requires more than 1 infusion for complete resolution.
FAIR: Probable and/or slight relief of pain and slight improvement in signs of bleeding after single infusion. Required more than 1 infusion for complete resolution.
NONE: No improvement or condition worsens.
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End point type |
Secondary
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End point timeframe |
During prophylactic treatment: approx. 6 months per subject
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Notes [5] - 15 subjects <6 years of age had 25 bleeding episodes which were treated. [6] - 19 subjects 6 to <12 years of age had 45 bleeding episodes which were treated. [7] - A total of 70 treated bleeding episodes occurred in 34 of 66 subjects in the FAS. |
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No statistical analyses for this end point |
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End point title |
Serious adverse events (SAEs) possibly or probably related to BAX 855 | ||||||||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Throughout the study period (1 year), approximately 6 months per subject
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No statistical analyses for this end point |
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End point title |
Non-serious AEs possibly or probably related to BAX 855 | ||||||||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Throughout the study period (1 year), approximately 6 months per subject
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No statistical analyses for this end point |
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End point title |
Clinically significant changes in vital signs | ||||||||||||
End point description |
Vital signs: body temperature, respiratory rate (breaths/min), pulse rate (beats/min), and systolic and diastolic blood pressure (mmHg). For each abnormal vital sign value, the investigator had to decide if he/she deemed this to be an AE.
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End point type |
Secondary
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End point timeframe |
Throughout the study period (1 year), approximately 6 months per subject
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No statistical analyses for this end point |
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End point title |
Clinically significant changes in clinical laboratory parameters (hematology, clinical chemistry, lipids) | ||||||||||||||||||||||||
End point description |
The HEMATOLOGY PANEL consisted of complete blood count: hemoglobin, hematocrit, erythrocytes (ie, red blood cell count), leukocytes (ie, white blood cell count) with differential (ie, basophils, eosinophils, lymphocytes, monocytes, and neutrophils), mean corpuscular volume, mean corpuscular hemoglobin concentration, and platelet count.
The CLINICAL CHEMISTRY PANEL consisted of sodium, potassium, chloride, bicarbonate, total protein, albumin, ALT, aspartate aminotransferase (AST), total bilirubin, alkaline phosphatase, blood urea nitrogen, creatinine, and glucose.
The LIPID PANEL consisted of cholesterol, very low density lipoprotein, low density lipoprotein, high density lipoprotein, and triglycerides.
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End point type |
Secondary
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End point timeframe |
Throughout the study period (1 year), approximately 6 months per subject
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No statistical analyses for this end point |
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End point title |
Positive post-baseline binding antibodies to FVIII, PEG-FVIII, polyethylene glycol (PEG), and Chinese hamster ovary (CHO) proteins | ||||||||||||||||||||||||||||||||||||||||
End point description |
Binding antibodies to FVIII and PEG-FVIII, as well as to PEG, were measured using enzyme-linked immunosorbent assay (ELISA). Both immunoglobulin G (IgG) and immunoglobulin M (IgM) binding antibodies for FVIII, BAX 855, and PEG were routinely tested. Based on the variability of these tests, only samples with titers ≥1:80 could be confirmed and were evaluated as positive. Furthermore, only increases of more
than 2 titer steps between pre- and post-treatment samples were considered positive for treatment-related antibody development.
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End point type |
Secondary
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End point timeframe |
Throughout the study period (1 year), approximately 6 months per subject
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Notes [8] - For 1 of 34 subjects in the 6 to <12 year age group of the SAS, no data are available. [9] - For 1 of 66 subjects in the SAS (6 to <12 year age group), no data are available. |
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No statistical analyses for this end point |
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End point title |
Pharmacokinetics (PK): Area under the plasma concentration versus time curve from 0 to ∞ hours post-infusion (AUC0-∞) | ||||||||||||||||||||||||||||||||||||||||||
End point description |
The first infusion given for PK assessment was ADVATE and the second infusion was BAX 855. All subjects undergoing PK assessment were to have a 72-hour washout period prior to administration of ADVATE or BAX 855. The timing of the infusion (morning or afternoon) and the timing of the second and third post-infusion blood draws were to be determined at randomization. All subjects had samples drawn at 15-30 minutes post-infusion. The second post-infusion sample was either 7 hours (if am PK dose) or 4 hours post infusion (if pm PK dose), or on Day 1 in the morning or Day 1 in the afternoon. The third post-infusion sample was either on Day 2, Day 3 or Day 4. A nonlinear mixed effects model approach (population PK) was implemented to analyze PK data.
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End point type |
Secondary
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End point timeframe |
(1) up to 30 minutes pre-infusion; (2) up to 30 min post-infusion, (3) Day 0 either 4 or 7 hours post infusion or Day 1; (4) Either Day 2, Day 3, or Day 4
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No statistical analyses for this end point |
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End point title |
Pharmacokinetics (PK): Mean residence time (MRT) | ||||||||||||||||||||||||||||||||||||||||||
End point description |
The first infusion given for PK assessment was ADVATE and the second infusion was BAX 855. All subjects undergoing PK assessment were to have a 72-hour washout period prior to administration of ADVATE or BAX 855. The timing of the infusion (morning or afternoon) and the timing of the second and third post-infusion blood draws were to be determined at randomization. All subjects had samples drawn at 15-30 minutes post-infusion. The second post-infusion sample was either 7 hours (if am PK dose) or 4 hours post infusion (if pm PK dose), or on Day 1 in the morning or Day 1 in the afternoon. The third post-infusion sample was either on Day 2, Day 3 or Day 4. A nonlinear mixed effects model approach (population PK) was implemented to analyze PK data.
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End point type |
Secondary
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End point timeframe |
(1) up to 30 minutes pre-infusion; (2) up to 30 min post-infusion, (3) Day 0 either 4 or 7 hours post infusion or Day 1; (4) Either Day 2, Day 3, or Day 4
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No statistical analyses for this end point |
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End point title |
Pharmacokinetics (PK): Clearance (CL) | ||||||||||||||||||||||||||||||||||||||||||
End point description |
The first infusion given for PK assessment was ADVATE and the second infusion was BAX 855. All subjects undergoing PK assessment were to have a 72-hour washout period prior to administration of ADVATE or BAX 855. The timing of the infusion (morning or afternoon) and the timing of the second and third post-infusion blood draws were to be determined at randomization. All subjects had samples drawn at 15-30 minutes post-infusion. The second post-infusion sample was either 7 hours (if am PK dose) or 4 hours post infusion (if pm PK dose), or on Day 1 in the morning or Day 1 in the afternoon. The third post-infusion sample was either on Day 2, Day 3 or Day 4. A nonlinear mixed effects model approach (population PK) was implemented to analyze PK data.
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End point type |
Secondary
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End point timeframe |
(1) up to 30 minutes pre-infusion; (2) up to 30 min post-infusion, (3) Day 0 either 4 or 7 hours post infusion or Day 1; (4) Either Day 2, Day 3, or Day 4
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No statistical analyses for this end point |
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End point title |
Pharmacokinetics (PK): Incremental recovery (IR) | ||||||||||||||||||||||||||||||||||||||||||
End point description |
The first infusion given for PK assessment was ADVATE and the second infusion was BAX 855. All subjects undergoing PK assessment were to have a 72-hour washout period prior to administration of ADVATE or BAX 855. The timing of the infusion (morning or afternoon) and the timing of the second and third post-infusion blood draws were to be determined at randomization. All subjects had samples drawn at 15-30 minutes post-infusion. The second post-infusion sample was either 7 hours (if am PK dose) or 4 hours post infusion (if pm PK dose), or on Day 1 in the morning or Day 1 in the afternoon. The third post-infusion sample was either on Day 2, Day 3 or Day 4. A nonlinear mixed effects model approach (population PK) was implemented to analyze PK data.
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End point type |
Secondary
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End point timeframe |
(1) up to 30 minutes pre-infusion; (2) up to 30 min post-infusion, (3) Day 0 either 4 or 7 hours post infusion or Day 1; (4) Either Day 2, Day 3, or Day 4
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No statistical analyses for this end point |
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End point title |
Pharmacokinetics (PK): Incremental recovery (IR) of BAX 855 over time - one stage clotting assay | ||||||||||||||||||||||||||||||||
End point description |
Pre- and post-infusion levels of Factor VIII (FVIII) following infusion of BAX 855 were used to determine IR.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 5 (or 10-15 EDs, whichever occurs last), Week 12, and Month 6 (Completion/Termination)
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Notes [10] - Baseline: n=15, Week 5: n=27, Week 12: n=26, Month 6: n=27 [11] - Baseline: n=16, Week 5: n=30, Week 12: n=31, Month 6: n=28 [12] - Baseline: n=31, Week 5: n=57, Week 12: n=57, Month 6: n=55 |
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No statistical analyses for this end point |
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End point title |
Pharmacokinetics (PK): Incremental recovery (IR) of BAX 855 over time - chromogenic assay | ||||||||||||||||||||||||||||||||
End point description |
Pre- and post-infusion levels of Factor VIII (FVIII) following infusion of BAX 855 were used to determine IR.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 5 (or 10-15 EDs, whichever occurs last), Week 12, and Month 6 (Completion/Termination)
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Notes [13] - Baseline: n=15, Week 5: n=27, Week 12: n=26, Month 6: n=27 [14] - Baseline: n=16, Week 5: n=30, Week 12: n=31, Month 6: n=28 [15] - Baseline: n=31, Week 5: n=57, Week 12: n=57, Month 6: n=55 |
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No statistical analyses for this end point |
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End point title |
Pharmacokinetics (PK): Plasma half-life (T 1/2) | ||||||||||||||||||||||||||||||||||||||||||
End point description |
The first infusion given for PK assessment was ADVATE and the second infusion was BAX 855. All subjects undergoing PK assessment were to have a 72-hour washout period prior to administration of ADVATE or BAX 855. The timing of the infusion (morning or afternoon) and the timing of the second and third post-infusion blood draws were to be determined at randomization. All subjects had samples drawn at 15-30 minutes post-infusion. The second post-infusion sample was either 7 hours (if am PK dose) or 4 hours post infusion (if pm PK dose), or on Day 1 in the morning or Day 1 in the afternoon. The third post-infusion sample was either on Day 2, Day 3 or Day 4. A nonlinear mixed effects model approach (population PK) was implemented to analyze PK data.
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End point type |
Secondary
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End point timeframe |
(1) up to 30 minutes pre-infusion; (2) up to 30 min post-infusion, (3) Day 0 either 4 or 7 hours post infusion or Day 1; (4) Either Day 2, Day 3, or Day 4
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No statistical analyses for this end point |
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End point title |
Pharmacokinetics (PK): Volume of distribution at steady state (Vss) | ||||||||||||||||||||||||||||||||||||||||||
End point description |
The first infusion given for PK assessment was ADVATE and the second infusion was BAX 855. All subjects undergoing PK assessment were to have a 72-hour washout period prior to administration of ADVATE or BAX 855. The timing of the infusion (morning or afternoon) and the timing of the second and third post-infusion blood draws were to be determined at randomization. All subjects had samples drawn at 15-30 minutes post-infusion. The second post-infusion sample was either 7 hours (if am PK dose) or 4 hours post infusion (if pm PK dose), or on Day 1 in the morning or Day 1 in the afternoon. The third post-infusion sample was either on Day 2, Day 3 or Day 4. A nonlinear mixed effects model approach (population PK) was implemented to analyze PK data.
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End point type |
Secondary
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End point timeframe |
(1) up to 30 minutes pre-infusion; (2) up to 30 min post-infusion, (3) Day 0 either 4 or 7 hours post infusion or Day 1; (4) Either Day 2, Day 3, or Day 4
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No statistical analyses for this end point |
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End point title |
Pharmacokinetics (PK): Plasma half-life ratio of BAX 855 to ADVATE | ||||||||||||
End point description |
This is a descriptive summary of the ratio of plasma half-life in the same subject for BAX 855 compared to ADVATE based on the final covariate model (first observation tabulation). In the one-stage clotting assay, the mean half-life of BAX 855 was 1.30 times longer compared to ADVATE. In the chromogenic assay, the mean half-life of BAX 855 was 1.50 times longer compared to ADVATE.
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End point type |
Post-hoc
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End point timeframe |
(1) up to 30 minutes pre-infusion; (2) up to 30 min post-infusion, (3) Day 0 either 4 or 7 hours post infusion or Day 1; (4) Either Day 2, Day 3, or Day 4
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No statistical analyses for this end point |
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Adverse events information
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Timeframe for reporting adverse events |
Throughout the study period (1 year), approximately 6 months per subject
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Adverse event reporting additional description |
AEs were continuously monitored but specifically discussed and reviewed at these time points: pre- and post-PK infusion, at the baseline visit, during prophylactic treatment at these visits: Week 5 (or 10-15 exposure days (EDs)), Week 12, Week 20 (by phone); at the study completion visit at Month 6 or after at least 50 EDs, whichever occurred last
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
18.1
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Reporting groups
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Reporting group title |
BAX 855 Safety Analysis Set (n=66)
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Reporting group description |
The BAX 855 safety analysis set contains all subjects who received at least one dose of BAX 855. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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18 Nov 2014 |
-) The inclusion criterion “The subject has severe hemophilia A (FVIII <1%) as determined by the central laboratory” was amended to: “The subject has severe hemophilia A (FVIII <1%) as determined by the central laboratory, or a historical FVIII level <1% as determined at any local laboratory and/or a FVIII gene mutation consistent with severe hemophilia A”. Reason for change: To avoid potential risk of bleeding episodes in the washout period.
-) Text regarding dose adjustment of BAX 855 for prophylactic treatment was amended as follows: Original text: “Based on the Investigator’s clinical evaluation, the dose may be increased for subjects receiving prophylactic treatment at any time to ensure patient safety is adequately managed.” Revised text: “Based on the Investigator’s clinical evaluation, the dose may be increased up to a maximum of 80 IU/kg but not exceeding plasmatic FVIII peak levels of 200% for subjects receiving prophylactic treatment at any time to ensure patient safety is adequately managed.” Reason for change: To provide a maximum dose for prophylactic treatment.
-) Addition of the following serious adverse event (SAE) criterion: “Hospitalization for planned port placement or removal is not
considered an SAE, however, any hospitalization required for an emergency port removal is considered an SAE”. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |