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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/study/NCT02234323
Registration number
NCT02234323
Ethics application status
Date submitted
29/08/2014
Date registered
9/09/2014
Titles & IDs
Public title
An Open Label Study to Determine the Safety and Efficacy of Replacement Factor VIII Protein (Known as rFVIIIFc) in Previously Untreated Males With Severe Hemophilia A
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Scientific title
An Open-Label, Multicenter Evaluation of the Safety and Efficacy of Recombinant Coagulation Factor VIII Fc Fusion Protein (rFVIIIFc; BIIB031) in the Prevention and Treatment of Bleeding in Previously Untreated Patients With Severe Hemophilia A
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Secondary ID [1]
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2013-005512-10
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Secondary ID [2]
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997HA306
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Universal Trial Number (UTN)
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Hemophilia A
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Condition category
Condition code
Blood
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0
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Clotting disorders
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Human Genetics and Inherited Disorders
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0
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Other human genetics and inherited disorders
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Other - rFVIIIFc
Experimental: rFVIIIFc - Participants were to receive rFVIIIFc as follows- Prophylaxis regimen (PR): rFVIIIFc 25-80 international units per kilogram (IU/kg), at 3- to 5-day intervals until participant reached greater than or equal to (\>=) 50 exposure days (ED: 24-hour period in which \>=1 injection/dose of rFVIIIFc was given), or study withdrawal/end of study. Adjustments to dose/dosing interval was done as needed by investigator; Treatment with an optional ER (Episodic regimen) can be initiated before PR at investigators discretion; ITI: rFVIIIFc 200 IU/kg, daily for participants who, after exposure to rFVIIIFc, had positive high titer inhibitor (\>=5.00 Bethesda Units per milliliter \[BU/mL\]) or positive low titer inhibitor (\>=0.60 and \<5.00 BU/mL) and had poorly controlled bleeding despite increased rFVIIIFc doses, or required bypassing agent to treat bleeding.
Treatment: Other: rFVIIIFc
Administered as specified in arm description
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Intervention code [1]
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Treatment: Other
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Percentage of Participants With Confirmed Inhibitor Development as Measured by the Nijmegen-Modified Bethesda Assay
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Assessment method [1]
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A positive/confirmed inhibitor result occurs when a participant has a value \>=0.6 BU/mL by central laboratory testing using Nijmegen-modified Bethesda assay, that is confirmed on re-testing of a separate sample collected \>=2 weeks after the initial sample. Confirmed inhibitor development was based on all participants who had reached \>=10 EDs and had \>=1 inhibitor test performed at or beyond this milestone or who had an inhibitor. Exposure day (ED) is a 24-hour period in which participant received \>=1 dose of rFVIIIFc injections. Participants who did not develop an inhibitor but reached the milestone number of EDs were included in the denominator during calculation of percentage. Additionally, any participant who developed an inhibitor following the initial rFVIIIFc administration was included in the numerator and denominator during calculation of percentage.
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Timepoint [1]
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Up to 3 years
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Secondary outcome [1]
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Annualized Number of Bleeding Episodes (Spontaneous and Traumatic) Per Participant (Annualized Bleeding Rate [ABR])
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Assessment method [1]
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ABR was annualized number of bleeding episodes during efficacy period (EP) per participant annualized to a 1-year interval of time. Bleeding episodes were classified as spontaneous if parent/caregiver/participant records bleeding event when there is no known contributing factor such as definite trauma or antecedent "strenuous" activity and as traumatic when there is known reason for bleed. ABR=(Number of bleeding episodes during EP divided by total number of days during EP)\*365.25. EP was sum of all intervals of time during which participants were treated with rFVIIIFc per treatment regimens of study excluding surgical/rehabilitation periods and large injection intervals (greater than \[\>\]28 days). Participants were included in summary of more than 1 treatment regimen if their regimen changed during study.
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Timepoint [1]
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Up to 3 years
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Secondary outcome [2]
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Annualized Number of Spontaneous Joint Bleeding Episodes
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Assessment method [2]
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Bleeding episodes were classified as spontaneous if parent/caregiver/participant records a bleeding event when there was no known contributing factor such as a definite trauma or antecedent "strenuous" activity. Annualized spontaneous joint bleeding episodes = (Total number of spontaneous joint bleeding episodes during EP divided by total number of days during EP)\*365.25. EP reflects sum of all intervals of time during which participants were treated with rFVIIIFc per treatment regimen excluding major and minor surgical/rehabilitation periods and large injection intervals (\> 28 days). Bleeding episodes were summarized by treatment regimen. Participants were included in summary of more than 1 treatment regimen if their regimen changed during study.
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Timepoint [2]
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Up to 3 years
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Secondary outcome [3]
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Number of rFVIIIFc Injections With Excellent or Good, Moderate or None Treatment Response Assessed Using a 4-Point Scale
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Assessment method [3]
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Using e-diary, each participant's parent/caregiver rated treatment response to any bleeding episode at approximately 8-12 hours from time of injection and prior to additional doses of rFVIIIFc given for same bleeding episodes, using 4-point scale: 1=Excellent: abrupt pain relief and/or improvement in signs of bleeding within approximately 8 hour after initial injection; 2=Good: definite pain relief and/or improvement in signs of bleeding within approximately 8 hour after injection, but possibly requiring more than 1 injection after 24-48 hour for complete resolution; 3=Moderate: Probable/slight beneficial effect within 8 hour after initial injection and requires more than 1 injection and 4=None: No improvement or condition worsens within approximately 8 hour after initial injection. Participants included in more than 1 treatment regimen if their regimen changed during study.
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Timepoint [3]
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Up to 3 years
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Secondary outcome [4]
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Total Number of Exposure Days (EDs)
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Assessment method [4]
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An ED was defined as a 24-hour period in which a participant received one or more doses of rFVIIIFc injections, with the time of the first injection of rFVIIIFc defined as the start of the ED. Participants who did not have a particular injection type were counted as having zero injections for that type.
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Timepoint [4]
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Up to 3 years
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Secondary outcome [5]
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Total Annualized rFVIIIFc Consumption Per Participant for the Prevention and Treatment of Bleeding Episodes
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Assessment method [5]
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Total annualized rFVIIIFc consumption (in IU/kg) was calculated for each participant as: Annualized consumption = (Total IU/kg of rFVIIIFc during EP divided by total number of days during EP)\*365.25. EP reflects the sum of all intervals of time during which participants are treated with rFVIIIFc according to the treatment regimens of the study excluding surgical/rehabilitation periods and large injection intervals (\>28 days). Participants were included in summary of more than 1 treatment regimen if their regimen changed during study.
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Timepoint [5]
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Up to 3 years
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Secondary outcome [6]
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Number of Injections of rFVIIIFc Required to Resolve a Bleeding Episode
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Assessment method [6]
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Number of Injections of rFVIIIFc required to resolve a bleeding episode during EP were reported. EP reflects the sum of all intervals of time during which participants were treated with rFVIIIFc according to the treatment regimens of the study excluding surgical/rehabilitation periods and large injection intervals (\>28 days). All injections given from the initial sign of a bleed, until the last date/time within the bleed window were counted. Participants were included in summary of more than 1 treatment regimen if their regimen changed during study.
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Timepoint [6]
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Up to 3 years
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Secondary outcome [7]
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Average Dose Per Injection of rFVIIIFc Required to Resolve a Bleeding Episode
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Assessment method [7]
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The average dose of rFVIIIFc per injection per bleeding episode was calculated as the average of all doses (IU/kg) administered to treat the bleeding episode during EP. EP begins with the first treatment regimen dose of rFVIIIFc and ends with the last dose (regardless of the reason for dosing). Surgery/rehabilitation periods were not included in the EP. Participants were included in summary of more than 1 treatment regimen if their regimen changed during study.
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Timepoint [7]
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Up to 3 years
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Secondary outcome [8]
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Change From Baseline in rFVIIIFc Incremental Recovery (IR)
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Assessment method [8]
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Blood samples were taken at trough (predose) and Cmax (maximum concentration) for assessment of incremental recovery, measured by the one-stage clotting assay. IR (International Units per deciliter \[IU/dL\] per IU/kg) = (Cmax for FVIII activity - Pre-dose FVIII activity) (IU/dL) divided by actual dose (IU/kg), where Cmax (maximum concentration) is 30-minute FVIII activity post-dose and FVIII activity less than (\<)0.5 IU/dL was set to 0 IU/dL for calculation of IR.
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Timepoint [8]
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Baseline, Weeks 12, 24, 36, 48, 60, 72, 84, 96, 108 and 120
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Secondary outcome [9]
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Number of Participants With Response to Immune Tolerance Induction (ITI)
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Assessment method [9]
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Complete Success was defined as meeting all of the following criteria: Negative inhibitor titers in 2 consecutive determinations at least 4 weeks apart; IR \>=66% of baseline in 2 consecutive determinations at least 4 weeks apart; Half life \>=6 hours. Partial Success was defined as meeting the first criteria for complete success and one of the other 2 after 33 months of ITI.
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Timepoint [9]
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Up to 3 years
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Eligibility
Key inclusion criteria
Key
* Ability of the participant's legally authorized representative (e.g. their parent or legal guardian) to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use confidential health information in accordance with national and local participant privacy regulations.
* Weight >=3.5 kg at the time of screening.
* Severe hemophilia A defined as less than (<) 1 IU/dL (<1%) endogenous FVIII documented in the medical record or as tested during the Screening Period.
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Minimum age
No limit
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Maximum age
5
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Sex
Males
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Can healthy volunteers participate?
No
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Key exclusion criteria
* Any exposure to blood components, factor VIII replacement products, including commercially available rFVIIIFc at any time prior to or during screening.
* History of positive inhibitor testing. A prior history of inhibitors was defined based on a patient's historical positive inhibitor test using the local laboratory Bethesda value for a positive inhibitor test (ie, equal to or above lower level of detection).
* History of hypersensitivity reactions associated with any rFVIIIFc administration.
* Other coagulation disorder(s) in addition to hemophilia A.
* Any concurrent clinically significant major disease that, in the opinion of the Investigator, would make the participant unsuitable for enrollment.
* Current systemic treatment with chemotherapy and/or other immunosuppressant drugs.
Note: Other protocol defined Inclusion/Exclusion criteria may apply.
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Study design
Purpose of the study
Treatment
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Allocation to intervention
NA
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Single group
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Other design features
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Phase
Phase 3
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
12/01/2015
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
23/09/2019
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Sample size
Target
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Accrual to date
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Final
108
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Recruitment in Australia
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Research Site - Brisbane
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Research Site - Parkville
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Research Site - Westmead
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Recruitment postcode(s) [1]
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4029 - Brisbane
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Recruitment postcode(s) [2]
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3052 - Parkville
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Recruitment postcode(s) [3]
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6008 - Perth
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Recruitment postcode(s) [4]
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2145 - Westmead
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Recruitment outside Australia
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Arkansas
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Sheffield
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Funding & Sponsors
Primary sponsor type
Commercial sector/industry
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Name
Bioverativ, a Sanofi company
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Swedish Orphan Biovitrum
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Ethics approval
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Summary
Brief summary
The primary objective of the study was to evaluate the safety of rFVIIIFc (BIIB031) in previously untreated participants (PUPs) with severe hemophilia A. The secondary objectives were to evaluate the efficacy of rFVIIIFc in the prevention and treatment of bleeding episodes in PUPs, to evaluate rFVIIIFc consumption for the prevention and treatment of bleeding episodes in PUPs, and to describe experience with the use of rFVIIIFc for immune tolerance induction (ITI) in participants with inhibitors.
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Trial website
https://clinicaltrials.gov/study/NCT02234323
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Trial related presentations / publications
Konigs C, Ozelo MC, Dunn A, Kulkarni R, Nolan B, Brown SA, Schiavulli M, Gunawardena S, Mukhopadhyay S, Jayawardene D, Winding B, Carcao M. First study of extended half-life rFVIIIFc in previously untreated patients with hemophilia A: PUPs A-LONG final results. Blood. 2022 Jun 30;139(26):3699-3707. doi: 10.1182/blood.2021013563. Erratum In: Blood. 2023 Mar 23;141(12):1495. doi: 10.1182/blood.2022019369.
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Public notes
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Contacts
Principal investigator
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Contact person for scientific queries
Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
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What data in particular will be shared?
Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org
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When will data be available (start and end dates)?
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Available to whom?
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Available for what types of analyses?
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How or where can data be obtained?
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What supporting documents are/will be available?
No Supporting Document Provided
Type
Other Details
Attachment
Study protocol
https://cdn.clinicaltrials.gov/large-docs/23/NCT02234323/Prot_000.pdf
Statistical analysis plan
https://cdn.clinicaltrials.gov/large-docs/23/NCT02234323/SAP_001.pdf
Results publications and other study-related documents
No documents have been uploaded by study researchers.
Results are available at
https://clinicaltrials.gov/study/NCT02234323