Clinical Trial Results:
A Non-controlled, Open-Label, Multicenter, Study of Efficacy of rFVIIIFc for Immune Tolerance Induction (ITI) in Severe Hemophilia A Subjects With Inhibitors Undergoing the First ITI Treatment
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Summary
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EudraCT number |
2017-000373-36 |
Trial protocol |
ES DE BE GB FR BG IT Outside EU/EEA |
Global end of trial date |
16 Feb 2021
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Results information
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Results version number |
v1(current) |
This version publication date |
28 Aug 2021
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First version publication date |
28 Aug 2021
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
LPS16473
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03093480 | ||
WHO universal trial number (UTN) |
- | ||
Other trial identifiers |
Bioverativ Therapeutics Inc.: 997HA402 | ||
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Sponsors
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Sponsor organisation name |
Bioverativ, a Sanofi company
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Sponsor organisation address |
225 Second Avenue, Waltham, Massachusetts (MA), United States, 02451
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Public contact |
Trial Transparency Team, Bioverativ, a Sanofi company, Contact-US@sanofi.com
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Scientific contact |
Trial Transparency Team, Bioverativ, a Sanofi company, Contact-US@sanofi.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 |
06 Apr 2021
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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 |
16 Feb 2021
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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 was to describe the time to tolerisation (i.e., immune tolerance induction [ITI] success) with Recombinant Coagulation Factor VIII Fc (rFVIIIFc) in subjects within a maximum of 48 weeks (12 months) of ITI treatment.
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Protection of trial subjects |
The study was conducted by investigators experienced in the treatment of paediatric subjects. The parent(s) or guardian(s) as well as the subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time. In addition to the consent form for the parent(s)/guardian(s), an assent form in age-appropriate language was provided and explained to the subject. Repeated invasive procedures were minimised. The number of blood samples as well as the amount of blood drawn were adjusted according to age and weight. All subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject is participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in accordance with the trial subjects’ written informed consent and applicable personal data protection laws.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
08 Dec 2017
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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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 |
Canada: 3
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Country: Number of subjects enrolled |
United States: 5
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Country: Number of subjects enrolled |
Spain: 1
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Country: Number of subjects enrolled |
United Kingdom: 1
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Country: Number of subjects enrolled |
Belgium: 2
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Country: Number of subjects enrolled |
Bulgaria: 3
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Country: Number of subjects enrolled |
Italy: 1
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Worldwide total number of subjects |
16
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EEA total number of subjects |
7
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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) |
7
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Children (2-11 years) |
8
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Adolescents (12-17 years) |
1
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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 |
The study was conducted at 14 active centres in 7 countries between 08-Dec-2017 to 16-Feb-2021. | ||||||||||
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Pre-assignment
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Screening details |
Total 16 paediatric subjects were screened, enrolled and received drug. | ||||||||||
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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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Arm title
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Recombinant Coagulation Factor VIII Fc (rFVIIIFc) | ||||||||||
Arm description |
Subjects were to receive rFVIIIFc at a dose of 200 international units (IU)/kilogram (kg) as once daily injections or divided on several injections per day at the discretion of the investigator, starting at baseline visit up to maximum of 48 Weeks in ITI Period. Subjects who met the criteria for ITI success entered the tapering period and received rFVIIIFc at a dose adjusted according to investigator judgment based on the FVIII activity levels and with the aim of tapering the rFVIIIFc dose to reach a prophylactic dosing regimen within 16 weeks (4 months). Follow-Up was for 32 weeks under an adjusted prophylactic regimen according to investigator judgment. | ||||||||||
Arm type |
Experimental | ||||||||||
Investigational medicinal product name |
rFVIIIFc
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Investigational medicinal product code |
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Other name |
ELOCTATE/ELOCTA; BIIB031; efmoroctocog alfa; antihemophilic factor [recombinant]; Fc fusion protein
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Pharmaceutical forms |
Powder for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
rFVIIIFc 200 IU/kg/day in ITI Period, 50 or 100 IU/kg (adjusted according to investigator judgement) in tapering period and prophylactic regimen in follow-up period intravenously.
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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: Tapering Period Full Analysis Set: includes subjects entering the tapering phase of the study. [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: Follow-Up Period Full Analysis Set: includes all subjects entering the follow-up phase in the study. |
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Baseline characteristics reporting groups
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Reporting group title |
Recombinant Coagulation Factor VIII Fc (rFVIIIFc)
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Reporting group description |
Subjects were to receive rFVIIIFc at a dose of 200 international units (IU)/kilogram (kg) as once daily injections or divided on several injections per day at the discretion of the investigator, starting at baseline visit up to maximum of 48 Weeks in ITI Period. Subjects who met the criteria for ITI success entered the tapering period and received rFVIIIFc at a dose adjusted according to investigator judgment based on the FVIII activity levels and with the aim of tapering the rFVIIIFc dose to reach a prophylactic dosing regimen within 16 weeks (4 months). Follow-Up was for 32 weeks under an adjusted prophylactic regimen according to investigator judgment. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Recombinant Coagulation Factor VIII Fc (rFVIIIFc)
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Reporting group description |
Subjects were to receive rFVIIIFc at a dose of 200 international units (IU)/kilogram (kg) as once daily injections or divided on several injections per day at the discretion of the investigator, starting at baseline visit up to maximum of 48 Weeks in ITI Period. Subjects who met the criteria for ITI success entered the tapering period and received rFVIIIFc at a dose adjusted according to investigator judgment based on the FVIII activity levels and with the aim of tapering the rFVIIIFc dose to reach a prophylactic dosing regimen within 16 weeks (4 months). Follow-Up was for 32 weeks under an adjusted prophylactic regimen according to investigator judgment. | ||
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End point title |
Time to Tolerisation With rFVIIIFc [1] | ||||||||
End point description |
Time required for subjects to achieve ITI success, where ITI success was defined as achieving all 3 of the following criteria: confirmed negative titers consisting of 2 consecutive negative inhibitor assessments within 2 weeks (less than [<] 0.6 Bethesda units/millilitre [mL] by the Nijmegen-modified Bethesda assay); incremental recovery (IR) greater than or equal to (>=) 66 percent (%) of the expected IR in 2 consecutive assessments; half-life (t½) >= 7 hours. Subjects who were in ITI full analysis set (includes all subjects receiving at least 1 infusion of rFVIIIFc) and achieved ITI success.
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End point type |
Primary
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End point timeframe |
Up to 48 Weeks
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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: As the endpoint was descriptive in nature, no statistical analysis was provided. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Number of Subjects With Immune Tolerance Induction Success | ||||||||
End point description |
Number of subjects who achieved ITI success, where ITI success was defined as achieving all 3 of the following criteria: confirmed negative titers consisting of 2 consecutive negative inhibitor assessments within 2 weeks (<0.6 Bethesda units/mL by the Nijmegen-modified Bethesda assay); IR >= 66% of the expected IR at 2 consecutive assessments; t½ >=7 hours. ITI full analysis set.
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End point type |
Secondary
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End point timeframe |
Up to 48 Weeks
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| No statistical analyses for this end point | |||||||||
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End point title |
Number of Subjects Who Experienced Relapse | ||||||||
End point description |
Number of subjects with ITI success who reaches the criteria for relapse (defined as confirmed positive inhibitor titer >= 0.6 BU/mL or abnormal recovery after tolerance was achieved, and t½ < 7 hours) evaluated during the Tapering or Follow-Up Periods. Tapering Full analysis set.
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End point type |
Secondary
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End point timeframe |
Up to 48 weeks (16 weeks Tapering period and 32 weeks follow-up period)
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| No statistical analyses for this end point | |||||||||
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End point title |
Annualised Bleeding Rates During Immune Tolerance Induction Period | ||||||||
End point description |
A bleeding episode started from the first sign of a bleed and ended no more than 72 hours after the last treatment for the bleed, within which any symptoms of bleeding at the same location or injections less than or equal to 72 hours apart were considered the same bleeding episode. Annualised bleeding rate for a subject during the ITI period was defined as the number of bleeding episodes divided by the length of the ITI period in days* 365.25. ITI full analysis set which excludes subjects who were observed for less than 90 days during the period.
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End point type |
Secondary
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End point timeframe |
Up to 48 weeks
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| No statistical analyses for this end point | |||||||||
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End point title |
Annualised Bleeding Rates After Immune Tolerance Induction Period | ||||||||||||
End point description |
A bleeding episode started from the first sign of a bleed and ended no more than 72 hours after the last treatment for the bleed, within which any symptoms of bleeding at the same location or injections less than or equal to 72 hours apart were considered the same bleeding episode. Annualised bleeding rate for a subject after the ITT period (for tapering and follow-up period) was defined as the number of bleeding episodes divided by the length of the period after the ITI period in days* 365.25. Tapering period full analysis set excluding subjects who were observed for less than 90 days in the period.
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End point type |
Secondary
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End point timeframe |
Up to 48 weeks (16 weeks Tapering period and 32 weeks follow-up period)
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) as a Measure of Safety and Tolerability | ||||||||||||||||
End point description |
An adverse event (AE) was any untoward medical occurrence that does not necessarily have a causal relationship with this treatment. An SAE was any untoward medical occurrence that at any dose: resulted in death; in the view of the investigator, places the subject at immediate risk of death (a life-threatening event); required inpatient hospitalisation or prolongation of existing hospitalisation; resulted in persistent or significant disability/incapacity; resulted in a congenital anomaly/birth defect; any other medically important event that, in the opinion of the investigator, may jeopardise the subject or may require intervention to prevent one of the other outcomes listed in the definition. ITI full analysis set.
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End point type |
Secondary
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End point timeframe |
Up to 2 Years
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Average Number of Days Missed From Work or School Per Month During Immune Tolerance Induction Period | ||||||||
End point description |
Average number of days missed from school or work per month for a period (counting in non-missing diary days) was defined as number of the missing school/work days in the period divided by number of days with data entry in the period. Number of days per month missed from school or work was reported for those who attend school or have a job. Subjects of ITI full analysis set and who attend school or have a job.
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End point type |
Secondary
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End point timeframe |
Up to 48 weeks
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| No statistical analyses for this end point | |||||||||
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End point title |
Average Number of Days Missed From Work or School Per Month After Immune Tolerance Induction Period | ||||||||
End point description |
Average number of days missed from school or work per month for a period (counting in non-missing diary days) was defined as number of the missing school/work days in the period divided by number of days with data entry in the period. Number of days per month missed from school or work was reported for those who attend school or have a job. Subjects of Tapering full analysis set and who attended school or have a job. Here, ‘99999’ was used as a space filler and signifies that the standard deviation was not estimable because only 1 subject was available for the analysis.
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End point type |
Secondary
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End point timeframe |
Up to 48 weeks (16 weeks Tapering period & 32 weeks Follow-up period)
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| No statistical analyses for this end point | |||||||||
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End point title |
Annualised Number of Hospitalisation Days During Immune Tolerance Induction Period | ||||||||
End point description |
Annualised number of hospitalisation days during a period for a subject was defined as the number of hospitalisation days divided by the length of the period in days * 365.25. ITI Full analysis set but excluding subjects who were observed for less than 90 days in the period.
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End point type |
Secondary
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End point timeframe |
Up to 48 weeks
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| No statistical analyses for this end point | |||||||||
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End point title |
Annualised Number of Hospitalisation Days After Immune Tolerance Induction Period | ||||||||
End point description |
Annualised number of hospitalisation days during a period for a subjects was defined as the number of hospitalisation days divided by the length of the period in days * 365.25. Tapering Period Full analysis set but excluding subjects who were observed for less than 90 days in the period.
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End point type |
Secondary
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End point timeframe |
Up to 48 weeks (16 weeks Tapering period & 32 weeks Follow-up period)
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| No statistical analyses for this end point | |||||||||
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End point title |
Adherence to Treatment Regimen Overall Study Period | ||||||||
End point description |
Adherence to treatment was based on prescribed daily dose for the overall study period which was defined as the percentage of administered doses versus the prescribed doses to a subjects for the entire study duration. ITI full analysis set.
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End point type |
Secondary
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End point timeframe |
Up to 2 Years
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| No statistical analyses for this end point | |||||||||
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End point title |
Annualised rFVIIIFc Consumption for Overall Study Period | ||||||||
End point description |
Annualised rFVIIIFc consumption for a treatment period was the total nominal rFVIIIFc (IU/kg) / length of period in days * 365.25. ITI Full analysis set.
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End point type |
Secondary
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End point timeframe |
Up to 2 Years
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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 |
All AEs were collected from signature of the informed consent form up to end of the study (up to 2 years) regardless of seriousness or relationship to investigational product.
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Adverse event reporting additional description |
Reported AEs were TEAEs i.e. defined as AEs that developed, worsened, or became serious on or after the first administration of rFVIIIFc. Analysis performed on ITI full analysis set.
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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 |
23.1
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Reporting groups
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Reporting group title |
Recombinant Coagulation Factor VIII Fc (rFVIIIFc)
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Reporting group description |
Subjects were to receive rFVIIIFc at a dose of 200 IU/kg as once daily injections or divided on several injections per day at the discretion of the investigator, starting at baseline visit up to maximum of 48 Weeks in ITI Period. Subjects who met the criteria for ITI success entered the tapering period and received rFVIIIFc at a dose adjusted according to investigator judgment based on the FVIII activity levels and with the aim of tapering the rFVIIIFc dose to reach a prophylactic dosing regimen within 16 weeks (4 months). Follow-Up was for 32 weeks under an adjusted prophylactic regimen according to investigator judgment. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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09 Feb 2018 |
Following changes were made: Primary reason for this amendment was to provide clarifications, consistency, and a few corrections. |
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11 Jul 2019 |
Following changes were made: Text was added as appropriate: “this study would enroll up to 17 subjects”, Or “approximately, 17 subjects would be treated.” Specific changes for Canada from Protocol 1.1 and 2.1 were added - the primary reason for this amendment was to reduce the number of subjects to be enrolled. Given the rarity of the disease and coupled with a low enrollment rate, a decision was made by the Sponsor to end enrollment at a total of 16 subjects in all countries, effective 12 Dec 2019. No safety concerns contributed to this decision. Clarified the timing for subjects moving from interim ITI visits to ITI outcome assessment visits, and clarified sample collection schedules for anti-drug antibodies. |
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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 | |||
