Clinical Trial Results:
An Open-Label, Multicenter Evaluation of Safety, Pharmacokinetics, and Efficacy of Recombinant Coagulation Factor VIII Fc Fusion Protein, BIIB031, in the Prevention and Treatment of Bleeding Episodes in Pediatric Subjects With Hemophilia A
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Summary
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EudraCT number |
2011-003073-28 |
Trial protocol |
GB IE NL PL |
Global end of trial date |
05 Dec 2013
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Results information
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Results version number |
v1 |
This version publication date |
05 Feb 2016
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First version publication date |
24 Jan 2015
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Other versions |
v2 |
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 |
8HA02PED
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Additional study identifiers
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ISRCTN number |
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US NCT number |
NCT01458106 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Biogen Idec
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Sponsor organisation address |
225 Binney Street , Cambridge, United States, 02142
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Public contact |
Biogen Idec Study Medical Director, Biogen Idec, clinicaltrials@biogenidec.com
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Scientific contact |
Biogen Idec Study Medical Director, Biogen Idec, clinicaltrials@biogenidec.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-001114-PIP01-10 | ||
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 |
05 Dec 2013
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
05 Dec 2013
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The primary objective of the study is to evaluate the safety of recombinant coagulation factor VIII FC fusion protein (rFVIIIFc) in previously treated pediatric subjects with hemophilia A. Secondary objectives of this study in this study population are as follows: to evaluate the efficacy of rFVIIIFc for prevention and treatment of bleeding episodes; to evaluate and assess the pharmacokinetics (PK) of rFVIIIFc; and to evaluate rFVIIIFc consumption for prevention and treatment of bleeding episodes.
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Protection of trial subjects |
Only subjects who met the eligibility criteria were randomized into the trial.
The first dose of rFVIIIFc was administered under medical supervision in the clinic and subjects were tested for inhibitor formation at screening and at each clinic visit prior to dosing. Medications and resuscitation equipment for the emergency management of anaphylactic reactions were available in the room where the subject's first injection was performed. In addition, the subject was provided with specific instructions by the Investigator on what to do if such an event occurred while at home, including how to seek emergency medical treatment.
In addition to scheduled clinic visits, at least one telephone call was planned midway between visits for study site staff to check on each subject’s status.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
01 Nov 2012
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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 |
Netherlands: 1
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Country: Number of subjects enrolled |
Poland: 3
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Country: Number of subjects enrolled |
United Kingdom: 20
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Country: Number of subjects enrolled |
Ireland: 8
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Country: Number of subjects enrolled |
Australia: 6
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Country: Number of subjects enrolled |
Hong Kong: 2
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Country: Number of subjects enrolled |
South Africa: 11
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Country: Number of subjects enrolled |
United States: 20
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Worldwide total number of subjects |
71
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EEA total number of subjects |
32
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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) |
1
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Children (2-11 years) |
70
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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 |
- | |||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
Subject eligibility for the study was determined up to 8 weeks prior to the Baseline Visit. This period could be extended if the subject had a bleeding episode requiring coagulation factor VIII (FVIII) treatment within 5 days prior to the first dose of prestudy FVIII or rFVIIIFc in cases where prestudy FVIII PK assessment was exempted. | |||||||||||||||||||||||||||
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Period 1
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Period 1 title |
Overall study (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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Are arms mutually exclusive |
Yes
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Arm title
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Subjects < 6 Years Old | |||||||||||||||||||||||||||
Arm description |
PK subgroup: After a Washout Period of ≥ 72 hours, at the Baseline Visit (28 ± 7 days prior to Day 1), subjects receive a single IV injection of prestudy FVIII over 5 (± 2) minutes at a dose of 50 IU/kg, rounded up to the nearest 250 IU increment, for a PK assessment. Following a second Washout Period of ≥ 72 hours, subjects receive a single IV injection of rFVIIIFc over 5 (± 2) minutes at a dose of 50 IU/kg for PK assessment. The first prophylactic dose of rFVIIIFc is administered at a starting dose of 25 IU/kg IV injection on Day 1 and 50 IU/kg on Day 4. Dose increases to a maximum of 80 IU/kg, and frequency of administration to a minimum interval of once every 2 days, are allowed as indicated. Non-PK subgroup: On Day 1, a first prophylactic dose of rFVIIIFc of 25 IU/kg IV injection is given, followed by a dose of 50 IU/kg on Day 4. Dose increases to a maximum of 80 IU/kg, and frequency of administration to a minimum interval of once every 2 days, are allowed as indicated. | |||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||
Investigational medicinal product name |
Recombinant FVIIIFc
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Investigational medicinal product code |
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Other name |
BIIB031, ELOCTATE, rFVIIIFc, antihemophilic factor (recombinant) Fc fusion protein, recombinant coagulation factor VIII Fc fusion protein, efmoroctocog alfa
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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 |
Study site staff members were instructed to refer to the Directions for Handling and Administration Manual located in the Pharmacy Manual for specific instructions on the handling, preparation, administration, and disposal of the study treatment. Subjects were instructed to refer to the Information for Patients for instruction on the preparation and administration of rFVIIIFc. Vials of rFVIIIFc were combined as needed, based on the actual labeled potency to achieve the subject's calculated dose. Partial vial use was allowed, in order to achieve the calculated dose.
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Investigational medicinal product name |
Factor VIII
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Investigational medicinal product code |
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Other name |
FVIII
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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 |
Prestudy treatment was any current FVIII treatment prescribed by the Investigator. Prestudy drug for the PK assessment was prepared and administered according to the manufacturer’s prescribing information. Vials of prestudy FVIII were combined as needed, based on the nominal labeled potency (e.g., 250 IU, 500 IU, and 1000 IU), to achieve the participant's calculated dose.
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Arm title
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Subjects 6 to < 12 Years Old | |||||||||||||||||||||||||||
Arm description |
PK subgroup: After a Washout Period of ≥ 72 hours, at the Baseline Visit (28 ± 7 days prior to Day 1), subjects receive a single IV injection of prestudy FVIII over 5 (± 2) minutes at a dose of 50 IU/kg, rounded up to the nearest 250 IU increment, for a PK assessment. Following a second Washout Period of ≥ 72 hours, subjects receive a single IV injection of rFVIIIFc over 5 (± 2) minutes at a dose of 50 IU/kg for PK assessment. The first prophylactic dose of rFVIIIFc is administered at a starting dose of 25 IU/kg IV injection on Day 1 and 50 IU/kg on Day 4. Dose increases to a maximum of 80 IU/kg, and frequency of administration to a minimum interval of once every 2 days, are allowed as indicated. Non-PK subgroup: On Day 1, a first prophylactic dose of rFVIIIFc of 25 IU/kg IV injection is given, followed by a dose of 50 IU/kg on Day 4. Dose increases to a maximum of 80 IU/kg, and frequency of administration to a minimum interval of once every 2 days, are allowed as indicated. | |||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||
Investigational medicinal product name |
Recombinant FVIIIFc
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Investigational medicinal product code |
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Other name |
BIIB031, ELOCTATE, rFVIIIFc, antihemophilic factor (recombinant) Fc fusion protein, recombinant coagulation factor VIII Fc fusion protein, efmoroctocog alfa
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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 |
Study site staff members were instructed to refer to the Directions for Handling and Administration Manual located in the Pharmacy Manual for specific instructions on the handling, preparation, administration, and disposal of the study treatment. Subjects were instructed to refer to the Information for Patients for instruction on the preparation and administration of rFVIIIFc. Vials of rFVIIIFc were combined as needed, based on the actual labeled potency to achieve the subject's calculated dose. Partial vial use was allowed, in order to achieve the calculated dose.
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Investigational medicinal product name |
Factor VIII
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Investigational medicinal product code |
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Other name |
FVIII
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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 |
Prestudy treatment was any current FVIII treatment prescribed by the Investigator. Prestudy drug for the PK assessment was prepared and administered according to the manufacturer’s prescribing information. Vials of prestudy FVIII were combined as needed, based on the nominal labeled potency (e.g., 250 IU, 500 IU, and 1000 IU), to achieve the participant's calculated dose.
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| Notes [1] - 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: Number of subjects participating in the Subgroup. [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: Number of subjects participating in the Subgroup. [3] - 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: Number of subjects participating in the Subgroup. |
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Baseline characteristics reporting groups
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Reporting group title |
Subjects < 6 Years Old
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Reporting group description |
PK subgroup: After a Washout Period of ≥ 72 hours, at the Baseline Visit (28 ± 7 days prior to Day 1), subjects receive a single IV injection of prestudy FVIII over 5 (± 2) minutes at a dose of 50 IU/kg, rounded up to the nearest 250 IU increment, for a PK assessment. Following a second Washout Period of ≥ 72 hours, subjects receive a single IV injection of rFVIIIFc over 5 (± 2) minutes at a dose of 50 IU/kg for PK assessment. The first prophylactic dose of rFVIIIFc is administered at a starting dose of 25 IU/kg IV injection on Day 1 and 50 IU/kg on Day 4. Dose increases to a maximum of 80 IU/kg, and frequency of administration to a minimum interval of once every 2 days, are allowed as indicated. Non-PK subgroup: On Day 1, a first prophylactic dose of rFVIIIFc of 25 IU/kg IV injection is given, followed by a dose of 50 IU/kg on Day 4. Dose increases to a maximum of 80 IU/kg, and frequency of administration to a minimum interval of once every 2 days, are allowed as indicated. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Subjects 6 to < 12 Years Old
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Reporting group description |
PK subgroup: After a Washout Period of ≥ 72 hours, at the Baseline Visit (28 ± 7 days prior to Day 1), subjects receive a single IV injection of prestudy FVIII over 5 (± 2) minutes at a dose of 50 IU/kg, rounded up to the nearest 250 IU increment, for a PK assessment. Following a second Washout Period of ≥ 72 hours, subjects receive a single IV injection of rFVIIIFc over 5 (± 2) minutes at a dose of 50 IU/kg for PK assessment. The first prophylactic dose of rFVIIIFc is administered at a starting dose of 25 IU/kg IV injection on Day 1 and 50 IU/kg on Day 4. Dose increases to a maximum of 80 IU/kg, and frequency of administration to a minimum interval of once every 2 days, are allowed as indicated. Non-PK subgroup: On Day 1, a first prophylactic dose of rFVIIIFc of 25 IU/kg IV injection is given, followed by a dose of 50 IU/kg on Day 4. Dose increases to a maximum of 80 IU/kg, and frequency of administration to a minimum interval of once every 2 days, are allowed as indicated. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Subjects < 6 Years Old
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Reporting group description |
PK subgroup: After a Washout Period of ≥ 72 hours, at the Baseline Visit (28 ± 7 days prior to Day 1), subjects receive a single IV injection of prestudy FVIII over 5 (± 2) minutes at a dose of 50 IU/kg, rounded up to the nearest 250 IU increment, for a PK assessment. Following a second Washout Period of ≥ 72 hours, subjects receive a single IV injection of rFVIIIFc over 5 (± 2) minutes at a dose of 50 IU/kg for PK assessment. The first prophylactic dose of rFVIIIFc is administered at a starting dose of 25 IU/kg IV injection on Day 1 and 50 IU/kg on Day 4. Dose increases to a maximum of 80 IU/kg, and frequency of administration to a minimum interval of once every 2 days, are allowed as indicated. Non-PK subgroup: On Day 1, a first prophylactic dose of rFVIIIFc of 25 IU/kg IV injection is given, followed by a dose of 50 IU/kg on Day 4. Dose increases to a maximum of 80 IU/kg, and frequency of administration to a minimum interval of once every 2 days, are allowed as indicated. | ||
Reporting group title |
Subjects 6 to < 12 Years Old
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Reporting group description |
PK subgroup: After a Washout Period of ≥ 72 hours, at the Baseline Visit (28 ± 7 days prior to Day 1), subjects receive a single IV injection of prestudy FVIII over 5 (± 2) minutes at a dose of 50 IU/kg, rounded up to the nearest 250 IU increment, for a PK assessment. Following a second Washout Period of ≥ 72 hours, subjects receive a single IV injection of rFVIIIFc over 5 (± 2) minutes at a dose of 50 IU/kg for PK assessment. The first prophylactic dose of rFVIIIFc is administered at a starting dose of 25 IU/kg IV injection on Day 1 and 50 IU/kg on Day 4. Dose increases to a maximum of 80 IU/kg, and frequency of administration to a minimum interval of once every 2 days, are allowed as indicated. Non-PK subgroup: On Day 1, a first prophylactic dose of rFVIIIFc of 25 IU/kg IV injection is given, followed by a dose of 50 IU/kg on Day 4. Dose increases to a maximum of 80 IU/kg, and frequency of administration to a minimum interval of once every 2 days, are allowed as indicated. | ||
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End point title |
Occurrence of FVIII Inhibitor Development [1] | ||||||||||||||||||
End point description |
An inhibitor test result ≥0.6 Bethesda units (BU)/mL, confirmed on 2 separate samples drawn 2 to 4 weeks apart, was considered positive. Both tests were to be performed by the central laboratory using the Nijmegen-modified Bethesda Assay. Incidences were summarized for any positive inhibitor for subjects with ≥50 exposure days (EDs) to rFVIIIFc. In addition, the incidence for all subjects, regardless of their EDs to rFVIIIFc, was also summarized. An exact 95% CI for the proportion of subjects with a confirmed inhibitor was calculated using the Clopper-Pearson method for a binomial proportion. Safety Analysis Set: subjects who received at least 1 dose of prestudy FVIII, or at least 1 dose of rFVIIIFc.
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End point type |
Primary
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End point timeframe |
Up to Week 26 +/- 7 days, or up to 50 exposure days (EDs) if reached prior to Week 26
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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: The incidence of confirmed inhibitor formation from the central laboratory was summarized for each age cohort and a 95% CI was calculated for each incidence for this endpoint, as presented in this data table. No further statistical analyses were planned. |
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| Notes [2] - Safety Analysis Set; n=subjects with given number of exposure days who had a valid inhibitor test. [3] - Safety Analysis Set; n=subjects with given number of exposure days who had a valid inhibitor test. |
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Annualized Bleeding Rate | ||||||||||||
End point description |
Annualized bleeding rate=(number of bleeding episodes during the efficacy period/total number of days during the efficacy period)*365.25. The efficacy period begins with the first prophylactic dose of rFVIIIFc and ends with the last dose (for prophylaxis or a bleed); surgery/rehabilitation periods and PK evaluation periods are not included. A bleeding episode started from the first sign of a bleed and ended ≤72 hours after the last treatment for the bleed, within which any symptoms of bleeding at the same location or injections ≤72 hours apart were considered the same bleeding episode. Any injection to treat the bleeding episode taken >72 hours after the preceding one was considered the first injection to treat a new bleeding episode at the same location. Any bleeding at a different location was considered a separate bleeding episode, regardless of time from last injection. Full Analysis Set: subjects who received ≥1 dose of rFVIIIFc.
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End point type |
Secondary
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End point timeframe |
Up to Week 26 +/- 7 days (efficacy period as defined in description)
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| Notes [4] - Full Analysis Set; based on the number of subjects whose efficacy period was ≥1 day in duration. [5] - Full Analysis Set; based on the number of subjects whose efficacy period was ≥1 day in duration. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Annualized Joint Bleeding Rate (Spontaneous) | ||||||||||||
End point description |
Annualized bleeding rate for spontaneous joint bleed=(number of bleeding episodes meeting those criteria during the efficacy period/total number of days during the efficacy period)*365.25. The efficacy period begins with the first prophylactic dose of rFVIIIFc and ends with the last dose (for prophylaxis or a bleed); surgery/rehabilitation periods and PK evaluation periods are not included. A bleeding episode started from the first sign of a bleed and ended ≤72 hours after the last treatment for the bleed, within which any symptoms of bleeding at the same location or injections ≤72 hours apart were considered the same bleeding episode. Any injection to treat the bleeding episode taken >72 hours after the preceding one was considered the first injection to treat a new bleeding episode at the same location. Any bleeding at a different location was considered a separate bleeding episode, regardless of time from last injection. Full Analysis Set: subjects who received ≥1 dose of rFVIIIFc.
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End point type |
Secondary
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End point timeframe |
Up to Week 26 +/- 7 days (efficacy period as defined in description)
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| Notes [6] - Full Analysis Set; based on the number of participants whose efficacy period was ≥1 day in duration. [7] - Full Analysis Set; based on the number of participants whose efficacy period was ≥1 day in duration. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Subject Assessment of Response to Injections to Treat a Bleeding Episode | |||||||||||||||||||||||||||
End point description |
Subject's assessment (provided by the caregiver) of the response to the first rFVIIIFc injection for each bleeding episode. Percentages were based on the number of first injections for which a response was provided, using the following 4-point scale: excellent=abrupt pain relief and/or improvement in signs of bleeding within approximately 8 hours after the initial injection; good=definite pain relief and/or improvement in signs of bleeding within approximately 8 hours after a single injection, but possibly requiring more than one injection after 24 to 48 hours for complete resolution; moderate=probable or slight beneficial effect within approximately 8 hours after the initial injection and requiring more than one injection; no response=no improvement, or condition worsened, within approximately 8 hours after the initial injection. Full Analysis Set: subjects who received at least 1 dose of rFVIIIFc; based on the number of injections with an evaluation.
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End point type |
Secondary
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End point timeframe |
Up to Week 26 +/- 7 days
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| Notes [8] - Full Analysis Set; percentages are based on the number of injections (total number of injections=35) [9] - Full Analysis Set; percentages are based on the number of injections (total number of injections=46) |
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| No statistical analyses for this end point | ||||||||||||||||||||||||||||
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End point title |
Annualized rFVIIIFc Consumption Per Subject | ||||||||||||||||||
End point description |
Consumption is calculated for the efficacy period. The efficacy period begins with the first prophylactic dose of rFVIIIFc and ends with the last dose (for prophylaxis or a bleed). Surgery/rehabilitation periods and PK evaluation periods are not included in the efficacy period. Annualized consumption = (total IU/kg of study treatment received during the efficacy period/total number of days during the efficacy period)*365.25. Consumption was calculated overall for all subjects and for the last 3 months (91 days) on study, counted backwards from the end of the efficacy period, for subjects with at least 24 weeks on study. Full Analysis Set: subjects who received at least 1 dose of rFVIIIFc. 'Overall' = number of subjects with evaluable data in the efficacy period overall; 'Last 3 months on Study' = number of subjects with ≥24 weeks on study.
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End point type |
Secondary
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End point timeframe |
Up to Week 26 +/- 7 days (efficacy period as defined in description)
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| Notes [10] - Full Analysis Set;n=subjects with evaluable data in the efficacy period overall or ≥24 wks on study. [11] - Full Analysis Set;n=subjects with evaluable data in the efficacy period overall or ≥24 wks on study. |
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Number of Days From Last Treatment Injection to a Spontaneous Bleeding Episode | ||||||||||||||||||
End point description |
The number of days from the last prophylaxis injection to the onset of a new spontaneous bleeding episode, analyzed across all evaluable bleeding episodes per subject and per episode, based on the efficacy period. Evaluable bleeding episodes are those for which both a date and time are available for both the onset of the bleeding episode and the previous prophylactic injection. The efficacy period begins with the first prophylactic dose of rFVIIIFc and ends with the last dose (for prophylaxis or a bleed). Surgery/rehabilitation periods and PK evaluation periods are not included in the efficacy period. For 'Per subject' values, the number of days from the last prophylactic injection to a spontaneous bleeding episode is averaged across all evaluable spontaneous bleeding episodes per subject. Full Analysis Set: subjects who received at least 1 dose of rFVIIIFc; number of subjects and number of episodes were determined for subjects with at least 1 evaluable spontaneous bleeding episode.
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End point type |
Secondary
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End point timeframe |
Up to Week 26 +/- 7 days (efficacy period as defined in description)
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| Notes [12] - Full Analysis Set; the number of evaluable spontaneous bleeding episodes analyzed was 17. [13] - Full Analysis Set; the number of evaluable spontaneous bleeding episodes analyzed was 19. |
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Number of Injections Required for Resolution of a Bleeding Episode | ||||||||||||||||||
End point description |
The number of injections required to resolve a bleeding episode per subject and per episode, based on the efficacy period. The efficacy period begins with the first prophylactic dose of rFVIIIFc and ends with the last dose (for prophylaxis or a bleed). Surgery/rehabilitation periods and PK evaluation periods are not included in the efficacy period. All injections given from the initial sign of a bleed, until the last date/time within the bleed window are counted. The resolution of a bleed is defined as no sign of bleeding following injection for the bleed. For 'Per subject' values, the number of injections required to resolve each bleed is averaged across all bleeding episodes per subject. Full Analysis Set: subjects who received at least 1 dose of rFVIIIFc; number of subjects and number of episodes were determined for subjects with at least 1 evaluable bleeding episode.
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
Up to Week 26 +/- 7 days (efficacy period as defined in description)
|
||||||||||||||||||
|
|||||||||||||||||||
| Notes [14] - Full Analysis Set; the number of bleeding episodes analyzed was 38. [15] - Full Analysis Set; the number of bleeding episodes analyzed was 48. |
|||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||
|
|||||||||||||||||||
End point title |
Total Dose Required for Resolution of a Bleeding Episode | ||||||||||||||||||
End point description |
The total dose required to resolved a bleeding episode per participant and per episode, based on the efficacy period. The efficacy period begins with the first prophylactic dose of rFVIIIFc and ends with the last dose (for prophylaxis or a bleed). Surgery/rehabilitation periods and PK evaluation periods are not included in the efficacy period. For 'Per bleeding episode' values, for each bleeding episode, the total dose is the sum of the doses (IU/kg) administered across all injections given to treat that bleeding episode. For 'Per participant' values, the total dose (IU/kg) used to resolve each bleed is averaged across all bleeding episodes per participant. Full Analysis Set: subjects who received at least 1 dose of rFVIIIFc; number of subjects and number of episodes were determined for subjects who had complete information on the dose administered to treat a bleeding episode.
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
Up to Week 26 +/- 7 days (efficacy period as defined in description)
|
||||||||||||||||||
|
|||||||||||||||||||
| Notes [16] - Full Analysis Set; the number of bleeding episodes analyzed was 38. [17] - Full Analysis Set; the number of bleeding episodes analyzed was 48. |
|||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||
|
|||||||||||||
End point title |
Maximum Plasma Activity (Cmax; One-stage Activated Partial Thromboplastin Time [aPTT] Clotting Assay) | ||||||||||||
End point description |
Maximum plasma activity during a dosing interval for participants in the PK subgroup. The values for Cmax were adjusted to the nominal dose of 50 IU/kg. The 95% confidence interval on the geometric mean is based on the t-statistic back-transformed from the log scale. PK Analysis Set: All subjects in the PK subgroup with adequate PK data, defined as complete and evaluable PK samples through 72 hours after rFVIIIFc dosing. Complete means the availability of the 72-hour sample and at least enough other samples to allow for all the PK parameters to be estimated.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline (28 ±7 days prior to Day 1) Prestudy FVIII Dosing: predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours post-dose. Day 1 (rFVIIIFc Dosing): predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours, 72 ±7 hours post-dose
|
||||||||||||
|
|||||||||||||
| Notes [18] - All subjects in the PK subgroup with adequate PK data [19] - All subjects in the PK subgroup with adequate PK data |
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Maximum Plasma Activity (Cmax; Two-stage Chromogenic Assay) | ||||||||||||
End point description |
Maximum plasma activity during a dosing interval for participants in the PK subgroup. The values for Cmax were adjusted to the nominal dose of 50 IU/kg. The 95% confidence interval on the geometric mean is based on the t-statistic back-transformed from the log scale. PK Analysis Set: All subjects in the PK subgroup with adequate PK data, defined as complete and evaluable PK samples through 72 hours after rFVIIIFc dosing. Complete means the availability of the 72-hour sample and at least enough other samples to allow for all the PK parameters to be estimated.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline (28 ±7 days prior to Day 1) Prestudy FVIII Dosing: predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours post-dose. Day 1 (rFVIIIFc Dosing): predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours, 72 ±7 hours post-dose
|
||||||||||||
|
|||||||||||||
| Notes [20] - All subjects in the PK subgroup with adequate PK data [21] - All subjects in the PK subgroup with adequate PK data |
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Elimination Half Life (t1/2; One-stage aPTT Clotting Assay) | ||||||||||||
End point description |
Time required for the activity of the drug to reach half of its original value for participants in the PK subgroup. The 95% confidence interval on the geometric mean is based on the t-statistic back-transformed from the log scale. PK Analysis Set: All subjects in the PK subgroup with adequate PK data, defined as complete and evaluable PK samples through 72 hours after rFVIIIFc dosing. Complete means the availability of the 72-hour sample and at least enough other samples to allow for all the PK parameters to be estimated.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline (28 ±7 days prior to Day 1) Prestudy FVIII Dosing: predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours post-dose. Day 1 (rFVIIIFc Dosing): predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours, 72 ±7 hours post-dose
|
||||||||||||
|
|||||||||||||
| Notes [22] - All subjects in the PK subgroup with adequate PK data [23] - All subjects in the PK subgroup with adequate PK data |
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Elimination Half Life (t1/2; Two-stage Chromogenic Assay) | ||||||||||||
End point description |
Time required for the activity of the drug to reach half of its original value for participants in the PK subgroup. The 95% confidence interval on the geometric mean is based on the t-statistic back-transformed from the log scale. PK Analysis Set: All subjects in the PK subgroup with adequate PK data, defined as complete and evaluable PK samples through 72 hours after rFVIIIFc dosing. Complete means the availability of the 72-hour sample and at least enough other samples to allow for all the PK parameters to be estimated.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline (28 ±7 days prior to Day 1) Prestudy FVIII Dosing: predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours post-dose. Day 1 (rFVIIIFc Dosing): predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours, 72 ±7 hours post-dose
|
||||||||||||
|
|||||||||||||
| Notes [24] - All subjects in the PK subgroup with adequate PK data [25] - All subjects in the PK subgroup with adequate PK data |
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Clearance (CL; One-stage aPTT Clotting Assay) | ||||||||||||
End point description |
Rate at which the body removes the drug, measured as the volume of the plasma cleared of drug per unit time per unit weight for participants in the PK subgroup. The 95% confidence interval on the geometric mean is based on the t-statistic back-transformed from the log scale. PK Analysis Set: All subjects in the PK subgroup with adequate PK data, defined as complete and evaluable PK samples through 72 hours after rFVIIIFc dosing. Complete means the availability of the 72-hour sample and at least enough other samples to allow for all the PK parameters to be estimated.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline (28 ±7 days prior to Day 1) Prestudy FVIII Dosing: predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours post-dose. Day 1 (rFVIIIFc Dosing): predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours, 72 ±7 hours post-dose
|
||||||||||||
|
|||||||||||||
| Notes [26] - All subjects in the PK subgroup with adequate PK data [27] - All subjects in the PK subgroup with adequate PK data |
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Clearance (CL; Two-stage Chromogenic Assay) | ||||||||||||
End point description |
Rate at which the body removes the drug, measured as the volume of the plasma cleared of drug per unit time per unit weight for participants in the PK subgroup. The 95% confidence interval on the geometric mean is based on the t-statistic back-transformed from the log scale. PK Analysis Set: All subjects in the PK subgroup with adequate PK data, defined as complete and evaluable PK samples through 72 hours after rFVIIIFc dosing. Complete means the availability of the 72-hour sample and at least enough other samples to allow for all the PK parameters to be estimated.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline (28 ±7 days prior to Day 1) Prestudy FVIII Dosing: predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours post-dose. Day 1 (rFVIIIFc Dosing): predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours, 72 ±7 hours post-dose
|
||||||||||||
|
|||||||||||||
| Notes [28] - All subjects in the PK subgroup with adequate PK data [29] - All subjects in the PK subgroup with adequate PK data |
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Volume at Steady State (Vss; One-stage aPTT Clotting Assay) | ||||||||||||
End point description |
Volume of distribution at steady state for participants in the PK subgroup. The 95% confidence interval on the geometric mean is based on the t-statistic back-transformed from the log scale. PK Analysis Set: All subjects in the PK subgroup with adequate PK data, defined as complete and evaluable PK samples through 72 hours after rFVIIIFc dosing. Complete means the availability of the 72-hour sample and at least enough other samples to allow for all the PK parameters to be estimated.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline (28 ±7 days prior to Day 1) Prestudy FVIII Dosing: predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours post-dose. Day 1 (rFVIIIFc Dosing): predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours, 72 ±7 hours post-dose
|
||||||||||||
|
|||||||||||||
| Notes [30] - All subjects in the PK subgroup with adequate PK data [31] - All subjects in the PK subgroup with adequate PK data |
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Volume at Steady State (Vss; Two-stage Chromogenic Assay) | ||||||||||||
End point description |
Volume of distribution at steady state for participants in the PK subgroup. The 95% confidence interval on the geometric mean is based on the t-statistic back-transformed from the log scale. PK Analysis Set: All subjects in the PK subgroup with adequate PK data, defined as complete and evaluable PK samples through 72 hours after rFVIIIFc dosing. Complete means the availability of the 72-hour sample and at least enough other samples to allow for all the PK parameters to be estimated.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline (28 ±7 days prior to Day 1) Prestudy FVIII Dosing: predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours post-dose. Day 1 (rFVIIIFc Dosing): predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours, 72 ±7 hours post-dose
|
||||||||||||
|
|||||||||||||
| Notes [32] - All subjects in the PK subgroup with adequate PK data [33] - All subjects in the PK subgroup with adequate PK data |
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Dose Normalized Area Under the Curve (DNAUC; One-stage aPTT Clotting Assay) | ||||||||||||
End point description |
Dose normalized area under the FVIII activity-time curve for participants in the PK subgroup. The 95% confidence interval on the geometric mean is based on the t-statistic back-transformed from the log scale. PK Analysis Set: All subjects in the PK subgroup with adequate PK data, defined as complete and evaluable PK samples through 72 hours after rFVIIIFc dosing. Complete means the availability of the 72-hour sample and at least enough other samples to allow for all the PK parameters to be estimated.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline (28 ±7 days prior to Day 1) Prestudy FVIII Dosing: predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours post-dose. Day 1 (rFVIIIFc Dosing): predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours, 72 ±7 hours post-dose
|
||||||||||||
|
|||||||||||||
| Notes [34] - All subjects in the PK subgroup with adequate PK data [35] - All subjects in the PK subgroup with adequate PK data |
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Dose Normalized Area Under the Curve (DNAUC; Two-stage Chromogenic Assay) | ||||||||||||
End point description |
Dose normalized area under the FVIII activity-time curve for participants in the PK subgroup. The 95% confidence interval on the geometric mean is based on the t-statistic back-transformed from the log scale. PK Analysis Set: All subjects in the PK subgroup with adequate PK data, defined as complete and evaluable PK samples through 72 hours after rFVIIIFc dosing. Complete means the availability of the 72-hour sample and at least enough other samples to allow for all the PK parameters to be estimated.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline (28 ±7 days prior to Day 1) Prestudy FVIII Dosing: predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours post-dose. Day 1 (rFVIIIFc Dosing): predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours, 72 ±7 hours post-dose
|
||||||||||||
|
|||||||||||||
| Notes [36] - All subjects in the PK subgroup with adequate PK data [37] - All subjects in the PK subgroup with adequate PK data |
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Mean Residence Time (MRT; One-stage aPTT Clotting Assay) | ||||||||||||
End point description |
The average time that a drug molecule is present in the systemic circulation for participants in the PK subgroup. The 95% confidence interval on the geometric mean is based on the t-statistic back-transformed from the log scale. PK Analysis Set: All subjects in the PK subgroup with adequate PK data, defined as complete and evaluable PK samples through 72 hours after rFVIIIFc dosing. Complete means the availability of the 72-hour sample and at least enough other samples to allow for all the PK parameters to be estimated.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline (28 ±7 days prior to Day 1) Prestudy FVIII Dosing: predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours post-dose. Day 1 (rFVIIIFc Dosing): predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours, 72 ±7 hours post-dose
|
||||||||||||
|
|||||||||||||
| Notes [38] - All subjects in the PK subgroup with adequate PK data [39] - All subjects in the PK subgroup with adequate PK data |
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Mean Residence Time (MRT; Two-stage Chromogenic Assay) | ||||||||||||
End point description |
The average time that a drug molecule is present in the systemic circulation for participants in the PK subgroup. The 95% confidence interval on the geometric mean is based on the t-statistic back-transformed from the log scale. PK Analysis Set: All subjects in the PK subgroup with adequate PK data, defined as complete and evaluable PK samples through 72 hours after rFVIIIFc dosing. Complete means the availability of the 72-hour sample and at least enough other samples to allow for all the PK parameters to be estimated.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline (28 ±7 days prior to Day 1) Prestudy FVIII Dosing: predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours post-dose. Day 1 (rFVIIIFc Dosing): predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours, 72 ±7 hours post-dose
|
||||||||||||
|
|||||||||||||
| Notes [40] - All subjects in the PK subgroup with adequate PK data [41] - All subjects in the PK subgroup with adequate PK data |
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Incremental Recovery (IR; One-stage aPTT Clotting Assay) | ||||||||||||
End point description |
The rise in FVIII activity in IU/dL per unit dose administered in IU/kg for participants in the PK subgroup. The 95% confidence interval on the geometric mean is based on the t-statistic back-transformed from the log scale. PK Analysis Set: All subjects in the PK subgroup with adequate PK data, defined as complete and evaluable PK samples through 72 hours after rFVIIIFc dosing. Complete means the availability of the 72-hour sample and at least enough other samples to allow for all the PK parameters to be estimated.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline (28 ±7 days prior to Day 1) Prestudy FVIII Dosing: predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours post-dose. Day 1 (rFVIIIFc Dosing): predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours, 72 ±7 hours post-dose
|
||||||||||||
|
|||||||||||||
| Notes [42] - All subjects in the PK subgroup with adequate PK data [43] - All subjects in the PK subgroup with adequate PK data |
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Incremental Recovery (IR; Two-stage Chromogenic Assay) | ||||||||||||
End point description |
The rise in FVIII activity in IU/dL per unit dose administered in IU/kg for participants in the PK subgroup. The 95% confidence interval on the geometric mean is based on the t-statistic back-transformed from the log scale. PK Analysis Set: All subjects in the PK subgroup with adequate PK data, defined as complete and evaluable PK samples through 72 hours after rFVIIIFc dosing. Complete means the availability of the 72-hour sample and at least enough other samples to allow for all the PK parameters to be estimated.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline (28 ±7 days prior to Day 1) Prestudy FVIII Dosing: predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours post-dose. Day 1 (rFVIIIFc Dosing): predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours, 72 ±7 hours post-dose
|
||||||||||||
|
|||||||||||||
| Notes [44] - All subjects in the PK subgroup with adequate PK data [45] - All subjects in the PK subgroup with adequate PK data |
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Time at Maximum Activity (Tmax; One-stage aPTT Clotting Assay) | ||||||||||||
End point description |
Time at which maximum activity (Cmax) is observed for participants in the PK subgroup. The 95% confidence interval on the geometric mean is based on the t-statistic back-transformed from the log scale. PK Analysis Set: All subjects in the PK subgroup with adequate PK data, defined as complete and evaluable PK samples through 72 hours after rFVIIIFc dosing. Complete means the availability of the 72-hour sample and at least enough other samples to allow for all the PK parameters to be estimated.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline (28 ±7 days prior to Day 1) Prestudy FVIII Dosing: predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours post-dose. Day 1 (rFVIIIFc Dosing): predose; 30 ±5 min, 3 hours ±30 min, 24
±3 hours, 48 ±4 hours, 72 ±7 hours post-dose
|
||||||||||||
|
|||||||||||||
| Notes [46] - All subjects in the PK subgroup with adequate PK data [47] - All subjects in the PK subgroup with adequate PK data |
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Time at Maximum Activity (Tmax; Two-stage Chromogenic Assay) | ||||||||||||
End point description |
Time at which maximum activity (Cmax) is observed for participants in the PK subgroup. The 95% confidence interval on the geometric mean is based on the t-statistic back-transformed from the log scale. PK Analysis Set: All subjects in the PK subgroup with adequate PK data, defined as complete and evaluable PK samples through 72 hours after rFVIIIFc dosing. Complete means the availability of the 72-hour sample and at least enough other samples to allow for all the PK parameters to be estimated.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline (28 ±7 days prior to Day 1) Prestudy FVIII Dosing: predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours post-dose. Day 1 (rFVIIIFc Dosing): predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours, 72 ±7 hours post-dose
|
||||||||||||
|
|||||||||||||
| Notes [48] - All subjects in the PK subgroup with adequate PK data [49] - All subjects in the PK subgroup with adequate PK data |
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Lambda Z (One-stage aPTT Clotting Assay) | ||||||||||||
End point description |
First order rate constant associated with the terminal portion of the curve (lambda z) for participants in the PK subgroup. The 95% confidence interval on the geometric mean is based on the t-statistic back-transformed from the log scale. PK Analysis Set: All subjects in the PK subgroup with adequate PK data, defined as complete and evaluable PK samples through 72 hours after rFVIIIFc dosing. Complete means the availability of the 72-hour sample and at least enough other samples to allow for all the PK parameters to be estimated.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline (28 ±7 days prior to Day 1) Prestudy FVIII Dosing: predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours post-dose. Day 1 (rFVIIIFc Dosing): predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours, 72 ±7 hours post-dose
|
||||||||||||
|
|||||||||||||
| Notes [50] - All subjects in the PK subgroup with adequate PK data [51] - All subjects in the PK subgroup with adequate PK data |
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Lambda Z (Two-stage Chromogenic Assay) | ||||||||||||
End point description |
First order rate constant associated with the terminal portion of the curve (lambda z) for participants in the PK subgroup. The 95% confidence interval on the geometric mean is based on the t-statistic back-transformed from the log scale. PK Analysis Set: All subjects in the PK subgroup with adequate PK data, defined as complete and evaluable PK samples through 72 hours after rFVIIIFc dosing. Complete means the availability of the 72-hour sample and at least enough other samples to allow for all the PK parameters to be estimated.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline (28 ±7 days prior to Day 1) Prestudy FVIII Dosing: predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours post-dose. Day 1 (rFVIIIFc Dosing): predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours, 72 ±7 hours post-dose
|
||||||||||||
|
|||||||||||||
| Notes [52] - All subjects in the PK subgroup with adequate PK data [53] - All subjects in the PK subgroup with adequate PK data |
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Volume at Terminal Phase (Vz; One-stage aPTT Clotting Assay) | ||||||||||||
End point description |
Volume of distribution estimated from the terminal phase for participants in the PK subgroup. The 95% confidence interval on the geometric mean is based on the t-statistic back-transformed from the log scale. PK Analysis Set: All subjects in the PK subgroup with adequate PK data, defined as complete and evaluable PK samples through 72 hours after rFVIIIFc dosing. Complete means the availability of the 72-hour sample and at least enough other samples to allow for all the PK parameters to be estimated.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline (28 ±7 days prior to Day 1) Prestudy FVIII Dosing: predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours post-dose. Day 1 (rFVIIIFc Dosing): predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours, 72 ±7 hours post-dose
|
||||||||||||
|
|||||||||||||
| Notes [54] - All subjects in the PK subgroup [55] - All subjects in the PK subgroup |
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Volume at Terminal Phase (Vz; Two-stage Chromogenic Assay) | ||||||||||||
End point description |
Volume of distribution estimated from the terminal phase for participants in the PK subgroup. The 95% confidence interval on the geometric mean is based on the t-statistic back-transformed from the log scale. PK Analysis Set: All subjects in the PK subgroup with adequate PK data, defined as complete and evaluable PK samples through 72 hours after rFVIIIFc dosing. Complete means the availability of the 72-hour sample and at least enough other samples to allow for all the PK parameters to be estimated.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline (28 ±7 days prior to Day 1) Prestudy FVIII Dosing: predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours post-dose. Day 1 (rFVIIIFc Dosing): predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours, 72 ±7 hours post-dose
|
||||||||||||
|
|||||||||||||
| Notes [56] - All subjects in the PK subgroup with adequate PK data [57] - All subjects in the PK subgroup with adequate PK data |
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Area Under the Curve to the Last Measurable Timepoint (AUClast; One-stage aPTT Clotting Assay) | ||||||||||||
End point description |
Dose-normalized area under the FVIII activity-time curve to the last measurable timepoint for participants in the PK subgroup. The 95% confidence interval on the geometric mean is based on the t-statistic back-transformed from the log scale. PK Analysis Set: All subjects in the PK subgroup with adequate PK data, defined as complete and evaluable PK samples through 72 hours after rFVIIIFc dosing. Complete means the availability of the 72-hour sample and at least enough other samples to allow for all the PK parameters to be estimated.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline (28 ±7 days prior to Day 1) Prestudy FVIII Dosing: predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours post-dose. Day 1 (rFVIIIFc Dosing): predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours, 72 ±7 hours post-dose
|
||||||||||||
|
|||||||||||||
| Notes [58] - All subjects in the PK subgroup with adequate PK data [59] - All subjects in the PK subgroup with adequate PK data |
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Area Under the Curve to the Last Measurable Timepoint (AUClast; Two-stage Chromogenic Assay) | ||||||||||||
End point description |
Dose-normalized area under the FVIII activity-time curve to the last measurable timepoint for participants in the PK subgroup. The 95% confidence interval on the geometric mean is based on the t-statistic back-transformed from the log scale. PK Analysis Set: All subjects in the PK subgroup with adequate PK data, defined as complete and evaluable PK samples through 72 hours after rFVIIIFc dosing. Complete means the availability of the 72-hour sample and at least enough other samples to allow for all the PK parameters to be estimated.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline (28 ±7 days prior to Day 1) Prestudy FVIII Dosing: predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours post-dose. Day 1 (rFVIIIFc Dosing): predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours, 72 ±7 hours post-dose
|
||||||||||||
|
|||||||||||||
| Notes [60] - All subjects in the PK subgroup with adequate PK data [61] - All subjects in the PK subgroup with adequate PK data |
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Area Under the Curve to Infinity (AUCinf; One-stage aPTT Clotting Assay) | ||||||||||||
End point description |
Dose normalized area under the FVIII activity-time curve to infinity for participants in the PK subgroup. The 95% confidence interval on the geometric mean is based on the t-statistic back-transformed from the log scale. PK Analysis Set: All subjects in the PK subgroup with adequate PK data, defined as complete and evaluable PK samples through 72 hours after rFVIIIFc dosing. Complete means the availability of the 72-hour sample and at least enough other samples to allow for all the PK parameters to be estimated.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline (28 ±7 days prior to Day 1) Prestudy FVIII Dosing: predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours post-dose. Day 1 (rFVIIIFc Dosing): predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours, 72 ±7 hours post-dose
|
||||||||||||
|
|||||||||||||
| Notes [62] - All subjects in the PK subgroup with adequate PK data [63] - All subjects in the PK subgroup with adequate PK data |
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Area Under the Curve to Infinity (AUCinf; Two-stage Chromogenic Assay) | ||||||||||||
End point description |
Dose normalized area under the FVIII activity-time curve to infinity for participants in the PK subgroup. The 95% confidence interval on the geometric mean is based on the t-statistic back-transformed from the log scale. PK Analysis Set: All subjects in the PK subgroup with adequate PK data, defined as complete and evaluable PK samples through 72 hours after rFVIIIFc dosing. Complete means the availability of the 72-hour sample and at least enough other samples to allow for all the PK parameters to be estimated.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline (28 ±7 days prior to Day 1) Prestudy FVIII Dosing: predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours post-dose. Day 1 (rFVIIIFc Dosing): predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours, 72 ±7 hours post-dose
|
||||||||||||
|
|||||||||||||
| Notes [64] - All subjects in the PK subgroup with adequate PK data [65] - All subjects in the PK subgroup with adequate PK data |
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Percentage of AUCinf Extrapolated From the Last Data Point to Infinity (%AUCext; One-stage aPTT Clotting Assay) | ||||||||||||
End point description |
Percentage of AUCinf extrapolated from the last data point to infinity for participants in the PK subgroup. The 95% confidence interval on the geometric mean is based on the t-statistic back-transformed from the log scale. PK Analysis Set: All subjects in the PK subgroup with adequate PK data, defined as complete and evaluable PK samples through 72 hours after rFVIIIFc dosing. Complete means the availability of the 72-hour sample and at least enough other samples to allow for all the PK parameters to be estimated.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline (28 ±7 days prior to Day 1) Prestudy FVIII Dosing: predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours post-dose. Day 1 (rFVIIIFc Dosing): predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours, 72 ±7 hours post-dose
|
||||||||||||
|
|||||||||||||
| Notes [66] - All subjects in the PK subgroup with adequate PK data [67] - All subjects in the PK subgroup with adequate PK data |
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Percentage of AUCinf Extrapolated From the Last Data Point to Infinity (%AUCext; Two-stage Chromogenic Assay) | ||||||||||||
End point description |
Percentage of AUCinf extrapolated from the last data point to infinity for participants in the PK subgroup. The 95% confidence interval on the geometric mean is based on the t-statistic back-transformed from the log scale. PK Analysis Set: All subjects in the PK subgroup with adequate PK data, defined as complete and evaluable PK samples through 72 hours after rFVIIIFc dosing. Complete means the availability of the 72-hour sample and at least enough other samples to allow for all the PK parameters to be estimated.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline (28 ±7 days prior to Day 1) Prestudy FVIII Dosing: predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours post-dose. Day 1 (rFVIIIFc Dosing): predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours, 72 ±7 hours post-dose
|
||||||||||||
|
|||||||||||||
| Notes [68] - All subjects in the PK subgroup with adequate PK data [69] - All subjects in the PK subgroup with adequate PK data |
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||||||||||||||
End point title |
Physician’s Global Assessment of the Subject’s Response to His rFVIIIFc Regimen | ||||||||||||||||||||||||
End point description |
Investigators assessed each subject’s response to his rFVIIIFc regimen using a 4-point scale: excellent=bleeding episodes responded to ≤ the usual number of injections or ≤ the usual dose of rFVIIIFc or the rate of breakthrough bleeding during prophylaxis was ≤ that usually observed; effective=most bleeding episodes responded to the same number of injections and dose, but some required more injections or higher doses, or there was a minor increase in the rate of breakthrough bleeding; partially effective=bleeding episodes most often required more injections and/or higher doses than expected, or adequate breakthrough bleeding prevention during prophylaxis required more frequent injections and/or higher doses; ineffective=routine failure to control hemostasis, or hemostatic control required additional agents. Percentages are based on the total number of responses; multiple responses per subject are counted. Full Analysis Set: subjects who received at least 1 dose of rFVIIIFc.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Up to Week 26 +/- 7 days
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
| Notes [70] - Full Analysis Set; percentages are based on the number of responses (total number of responses=141). [71] - Full Analysis Set; percentages are based on the number of responses (total number of responses=165). |
|||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||
|
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|
Adverse events information
|
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Timeframe for reporting adverse events |
Serious adverse events (AEs): from informed consent up to 21 days after last treatment visit (LTV); AEs: from Baseline (28 ± 7 days prior to Day 1) for PK Subgroup or from Day 1 (first dose of rFVIIIFc) for non-PK subgroup, up to 14 (+7) days after LTV.
|
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Adverse event reporting additional description |
Length of rFVIIIFc dosing was up to 26 weeks ± 7 days. Serious and non-serious AEs that were treatment-emergent with respect to rFVIIIFc are presented for those participants who were treated with rFVIIIFc. Data are presented for the Full Analysis Set (subjects who received at least 1 dose of rFVIIIFc).
|
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
15.0
|
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Reporting groups
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Reporting group title |
Subjects < 6 Years Old
|
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Reporting group description |
PK subgroup: After a Washout Period of ≥ 72 hours, at the Baseline Visit (28 ± 7 days prior to Day 1), subjects receive a single IV injection of prestudy FVIII over 5 (± 2) minutes at a dose of 50 IU/kg, rounded up to the nearest 250 IU increment, for a PK assessment. Following a second Washout Period of ≥ 72 hours, subjects receive a single IV injection of rFVIIIFc over 5 (± 2) minutes at a dose of 50 IU/kg for PK assessment. The first prophylactic dose of rFVIIIFc is administered at a starting dose of 25 IU/kg IV injection on Day 1 and 50 IU/kg on Day 4. Dose increases to a maximum of 80 IU/kg, and frequency of administration to a minimum interval of once every 2 days, are allowed as indicated. Non-PK subgroup: On Day 1, a first prophylactic dose of rFVIIIFc of 25 IU/kg IV injection is given, followed by a dose of 50 IU/kg on Day 4. Dose increases to a maximum of 80 IU/kg, and frequency of administration to a minimum interval of once every 2 days, are allowed as indicated. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Subjects 6 to < 12 Years Old
|
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Reporting group description |
PK subgroup: After a Washout Period of ≥ 72 hours, at the Baseline Visit (28 ± 7 days prior to Day 1), subjects receive a single IV injection of prestudy FVIII over 5 (± 2) minutes at a dose of 50 IU/kg, rounded up to the nearest 250 IU increment, for a PK assessment. Following a second Washout Period of ≥ 72 hours, subjects receive a single IV injection of rFVIIIFc over 5 (± 2) minutes at a dose of 50 IU/kg for PK assessment. The first prophylactic dose of rFVIIIFc is administered at a starting dose of 25 IU/kg IV injection on Day 1 and 50 IU/kg on Day 4. Dose increases to a maximum of 80 IU/kg, and frequency of administration to a minimum interval of once every 2 days, are allowed as indicated. Non-PK subgroup: On Day 1, a first prophylactic dose of rFVIIIFc of 25 IU/kg IV injection is given, followed by a dose of 50 IU/kg on Day 4. Dose increases to a maximum of 80 IU/kg, and frequency of administration to a minimum interval of once every 2 days, are allowed as indicated. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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|||
Substantial protocol amendments (globally) |
|||
| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
27 Apr 2012 |
The primary reason for this amendment was to revise the PK sampling schedule based on recommendations from the US Food and Drug Administration. The 96-hour sample was removed and a 48-hour sample was added. |
||
09 Apr 2013 |
The primary reasons for this amendment were as follows:
- Added an interim PK analyses. Data from the interim PK analyses were used to support marketing authorization in specific countries (e.g., US) for individuals under the age of 12. In addition, these PK data were used to inform the design of a clinical study in previously untreated patients that was required by the EU.
- Increased the sample size from approximately 60 subjects dosed to approximately 68 subjects to be dosed to ensure that 25 subjects per cohort complete the PK assessments and had valid inhibitor test results following at least 50 EDs to rFVIIIFc.
- Modified the statistical analysis:
o Clarified the demography and baseline disease characteristics, efficacy, PK, and safety methods of analysis;
o Removed sensitivity analysis of annualized bleeding episodes and annualized consumption for the prophylactic period, excluding PK profiling, surgical, nonmedical, and any irregular treatment due to increase in activity level (e.g., during summer camp);
o Added analysis for the following efficacy assessments: total dose, Investigator's assessment of subject's overall response to rFVIIIFc regimen.
- Clarified dose and interval titration. The clarification allowed for adequate prophylactic dosing based on both PK results and bleeding patterns by adjusting dose and/or interval and accounted for known pediatric PK differences for rFVIII products, accommodating subtle differences in standards of care at the different participating sites.
- Modified text to note that major surgeries were to be classified as SAEs.
- Recategorized endpoints for patient-reported and health outcomes from secondary endpoints to exploratory endpoints, and notified that these will be analyzed in a separate report. |
||
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 | |||
