Trial Outcomes & Findings for 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 (NCT NCT02234323)

Last Updated: 2022-04-11

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

108 participants

Primary outcome timeframe

Up to 3 years

Results posted on

2022-04-11

Participant Flow

The study was conducted at 44 active centers in 13 countries between 12-Jan-2015 to 23-Sep-2019.

110 participants screened, 108 enrolled, 103 received drug.

Participant milestones

Participant milestones
Measure	Recombinant Coagulation Factor VIII Fc Fusion Protein Participants were to receive rFVIIIFc as follows -Prophylaxis regimen (PR): rFVIIIFc 25-80 international units per kilogram (IU/kg), at 3-5 day intervals until participant reached \>= 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.
All Enrolled STARTED	108
All Enrolled COMPLETED	103
All Enrolled NOT COMPLETED	5
All Treated STARTED	103
All Treated Episodic Treatment Regimen	81
All Treated Prophylactic Treatment Regimen	89
All Treated Immune Tolerance Induction (ITI)	15
All Treated COMPLETED	85
All Treated NOT COMPLETED	18

Reasons for withdrawal

Reasons for withdrawal
Measure	Recombinant Coagulation Factor VIII Fc Fusion Protein Participants were to receive rFVIIIFc as follows -Prophylaxis regimen (PR): rFVIIIFc 25-80 international units per kilogram (IU/kg), at 3-5 day intervals until participant reached \>= 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.
All Enrolled Not Treated: Completed study in database	2
All Enrolled Not Treated:Consent withdrawn by subject	2
All Enrolled Not Treated: Exceeded lab value limit	1
All Treated Death	1
All Treated Physician Decision	5
All Treated Lack of Efficacy	3
All Treated Exceeded lab value limit	2
All Treated Other	7

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Recombinant Coagulation Factor VIII Fc Fusion Protein n=103 Participants Participants were to receive rFVIIIFc as follows -PR: rFVIIIFc 25-80 IU/kg, at 3- to 5-day intervals until participant reached \>= 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 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 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.
Age, Continuous	0.58 years n=93 Participants
Sex: Female, Male Female	0 Participants n=93 Participants
Sex: Female, Male Male	103 Participants n=93 Participants
Race/Ethnicity, Customized White	79 Participants n=93 Participants
Race/Ethnicity, Customized Black or African-American	2 Participants n=93 Participants
Race/Ethnicity, Customized Asian	5 Participants n=93 Participants
Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander	2 Participants n=93 Participants
Race/Ethnicity, Customized Not reported due to confidentiality regulations	4 Participants n=93 Participants
Race/Ethnicity, Customized Other	11 Participants n=93 Participants

PRIMARY outcome

Timeframe: Up to 3 years

Population: Safety analysis set participants who 1) reached \>=10 EDs and had \>=1 inhibitor test performed at \>=10 EDs or who had inhibitor or 2) did not develop inhibitor but reached \>=10 EDs or 3) developed an inhibitor following the initial rFVIIIFc administration.

Outcome measures

Outcome measures
Measure	Recombinant Coagulation Factor VIII Fc Fusion Protein n=90 Participants Participants were to receive rFVIIIFc as follows -PR (Prophylaxis regimen): rFVIIIFc 25-80 IU/kg, at 3- to 5-day intervals until participant reached \>= 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 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 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.
Percentage of Participants With Confirmed Inhibitor Development as Measured by the Nijmegen-Modified Bethesda Assay	31.11 percentage of participants Interval 21.77 to 41.74

SECONDARY outcome

Timeframe: Up to 3 years

Population: Analysis performed on Full Analysis Set (FAS) participants within the EP. FAS included all enrolled participants with \>=1 dose of study treatment. Here, number analyzed signifies number of FAS participants analyzed in each treatment regimen.

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.

Outcome measures

Outcome measures
Measure	Recombinant Coagulation Factor VIII Fc Fusion Protein n=101 Participants Participants were to receive rFVIIIFc as follows -PR (Prophylaxis regimen): rFVIIIFc 25-80 IU/kg, at 3- to 5-day intervals until participant reached \>= 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 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 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.
Annualized Number of Bleeding Episodes (Spontaneous and Traumatic) Per Participant (Annualized Bleeding Rate [ABR]) Episodic Treatment	2.24 episodes per participant per year Interval 0.0 to 39.8
Annualized Number of Bleeding Episodes (Spontaneous and Traumatic) Per Participant (Annualized Bleeding Rate [ABR]) Prophylaxis Treatment	1.49 episodes per participant per year Interval 0.0 to 18.7
Annualized Number of Bleeding Episodes (Spontaneous and Traumatic) Per Participant (Annualized Bleeding Rate [ABR]) ITI Treatment	0.00 episodes per participant per year Interval 0.0 to 6.6

SECONDARY outcome

Timeframe: Up to 3 years

Population: Analysis was performed on FAS which included participants within EP. Here, number analyzed signifies number of FAS participants who were analyzed in each treatment regimen.

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.

Outcome measures

Outcome measures
Measure	Recombinant Coagulation Factor VIII Fc Fusion Protein n=101 Participants Participants were to receive rFVIIIFc as follows -PR (Prophylaxis regimen): rFVIIIFc 25-80 IU/kg, at 3- to 5-day intervals until participant reached \>= 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 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 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.
Annualized Number of Spontaneous Joint Bleeding Episodes Episodic Treatment	0.00 episodes per participant per year Interval 0.0 to 0.0
Annualized Number of Spontaneous Joint Bleeding Episodes Prophylaxis Treatment	0.00 episodes per participant per year Interval 0.0 to 0.0
Annualized Number of Spontaneous Joint Bleeding Episodes ITI Treatment	0.00 episodes per participant per year Interval 0.0 to 0.0

SECONDARY outcome

Timeframe: Up to 3 years

Population: Analysis performed on FAS participants within the EP and based on all injections. Here, number analyzed signifies number of responses to injections reported for each treatment regimen.

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.

Outcome measures

Outcome measures
Measure	Recombinant Coagulation Factor VIII Fc Fusion Protein n=579 responses to injections Participants were to receive rFVIIIFc as follows -PR (Prophylaxis regimen): rFVIIIFc 25-80 IU/kg, at 3- to 5-day intervals until participant reached \>= 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 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 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.
Number of rFVIIIFc Injections With Excellent or Good, Moderate or None Treatment Response Assessed Using a 4-Point Scale Episodic Regimen · Excellent or Good	102 responses to injections
Number of rFVIIIFc Injections With Excellent or Good, Moderate or None Treatment Response Assessed Using a 4-Point Scale Episodic Regimen · Moderate	16 responses to injections
Number of rFVIIIFc Injections With Excellent or Good, Moderate or None Treatment Response Assessed Using a 4-Point Scale Episodic Regimen · None	2 responses to injections
Number of rFVIIIFc Injections With Excellent or Good, Moderate or None Treatment Response Assessed Using a 4-Point Scale Episodic Regimen · Response not provided	118 responses to injections
Number of rFVIIIFc Injections With Excellent or Good, Moderate or None Treatment Response Assessed Using a 4-Point Scale Prophylaxis Regimen · Excellent or Good	163 responses to injections
Number of rFVIIIFc Injections With Excellent or Good, Moderate or None Treatment Response Assessed Using a 4-Point Scale Prophylaxis Regimen · Moderate	27 responses to injections
Number of rFVIIIFc Injections With Excellent or Good, Moderate or None Treatment Response Assessed Using a 4-Point Scale Prophylaxis Regimen · None	14 responses to injections
Number of rFVIIIFc Injections With Excellent or Good, Moderate or None Treatment Response Assessed Using a 4-Point Scale Prophylaxis Regimen · Response not provided	89 responses to injections
Number of rFVIIIFc Injections With Excellent or Good, Moderate or None Treatment Response Assessed Using a 4-Point Scale ITI Regimen · Excellent or Good	20 responses to injections
Number of rFVIIIFc Injections With Excellent or Good, Moderate or None Treatment Response Assessed Using a 4-Point Scale ITI Regimen · Moderate	14 responses to injections
Number of rFVIIIFc Injections With Excellent or Good, Moderate or None Treatment Response Assessed Using a 4-Point Scale ITI Regimen · None	3 responses to injections
Number of rFVIIIFc Injections With Excellent or Good, Moderate or None Treatment Response Assessed Using a 4-Point Scale ITI Regimen · Response not provided	11 responses to injections

SECONDARY outcome

Timeframe: Up to 3 years

Population: Analysis performed on safety analysis set.

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.

Outcome measures

Outcome measures
Measure	Recombinant Coagulation Factor VIII Fc Fusion Protein n=103 Participants Participants were to receive rFVIIIFc as follows -PR (Prophylaxis regimen): rFVIIIFc 25-80 IU/kg, at 3- to 5-day intervals until participant reached \>= 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 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 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.
Total Number of Exposure Days (EDs)	100.0 days Interval 0.0 to 649.0

SECONDARY outcome

Timeframe: Up to 3 years

Population: Analysis performed on FAS participants within the EP. Here, number analyzed signifies number of FAS participants who were analyzed in each treatment regimen.

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.

Outcome measures

Outcome measures
Measure	Recombinant Coagulation Factor VIII Fc Fusion Protein n=101 Participants Participants were to receive rFVIIIFc as follows -PR (Prophylaxis regimen): rFVIIIFc 25-80 IU/kg, at 3- to 5-day intervals until participant reached \>= 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 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 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.
Total Annualized rFVIIIFc Consumption Per Participant for the Prevention and Treatment of Bleeding Episodes Episodic Treatment	197.6 IU per kilogram per participant per year Interval 0.0 to 3177.0
Total Annualized rFVIIIFc Consumption Per Participant for the Prevention and Treatment of Bleeding Episodes Prophylaxis Treatment	5384.4 IU per kilogram per participant per year Interval 0.0 to 40126.0
Total Annualized rFVIIIFc Consumption Per Participant for the Prevention and Treatment of Bleeding Episodes ITI Treatment	67310.0 IU per kilogram per participant per year Interval 33323.0 to 78871.0

SECONDARY outcome

Timeframe: Up to 3 years

Population: Analysis performed on FAS participants within the EP. Here, number analyzed signifies number of FAS participants who were analyzed in each treatment regimen.

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.

Outcome measures

Outcome measures
Measure	Recombinant Coagulation Factor VIII Fc Fusion Protein n=101 Participants Participants were to receive rFVIIIFc as follows -PR (Prophylaxis regimen): rFVIIIFc 25-80 IU/kg, at 3- to 5-day intervals until participant reached \>= 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 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 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.
Number of Injections of rFVIIIFc Required to Resolve a Bleeding Episode Episodic Treatment	1.0 injections Interval 1.0 to 13.0
Number of Injections of rFVIIIFc Required to Resolve a Bleeding Episode Prophylaxis Treatment	1.0 injections Interval 1.0 to 7.0
Number of Injections of rFVIIIFc Required to Resolve a Bleeding Episode ITI Treatment	1.0 injections Interval 1.0 to 22.0

SECONDARY outcome

Timeframe: Up to 3 years

Population: Analysis performed on FAS participants within the EP. Here, number analyzed signifies number of FAS participants who were analyzed in each treatment regimen.

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.

Outcome measures

Outcome measures
Measure	Recombinant Coagulation Factor VIII Fc Fusion Protein n=101 Participants Participants were to receive rFVIIIFc as follows -PR (Prophylaxis regimen): rFVIIIFc 25-80 IU/kg, at 3- to 5-day intervals until participant reached \>= 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 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 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.
Average Dose Per Injection of rFVIIIFc Required to Resolve a Bleeding Episode Episodic Treatment	45.45 IU/kg Interval 19.2 to 106.0
Average Dose Per Injection of rFVIIIFc Required to Resolve a Bleeding Episode Prophylaxis Treatment	48.08 IU/kg Interval 17.9 to 144.0
Average Dose Per Injection of rFVIIIFc Required to Resolve a Bleeding Episode ITI Treatment	189.44 IU/kg Interval 76.9 to 250.0

SECONDARY outcome

Timeframe: Baseline, Weeks 12, 24, 36, 48, 60, 72, 84, 96, 108 and 120

Population: Analysis performed on FAS participants within the EP. Here number analyzed signifies number of FAS participants with available data for each visit.

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.

Outcome measures

Outcome measures
Measure	Recombinant Coagulation Factor VIII Fc Fusion Protein n=101 Participants Participants were to receive rFVIIIFc as follows -PR (Prophylaxis regimen): rFVIIIFc 25-80 IU/kg, at 3- to 5-day intervals until participant reached \>= 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 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 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.
Change From Baseline in rFVIIIFc Incremental Recovery (IR) Change at Week 12	-0.5 IU/dL per IU/kg Interval -1.26 to -0.26
Change From Baseline in rFVIIIFc Incremental Recovery (IR) Change at Week 24	-0.7 IU/dL per IU/kg Interval -1.5 to 0.05
Change From Baseline in rFVIIIFc Incremental Recovery (IR) Change at Week 36	-0.4 IU/dL per IU/kg Interval -1.06 to 0.27
Change From Baseline in rFVIIIFc Incremental Recovery (IR) Change at Week 48	-0.5 IU/dL per IU/kg Interval -1.09 to -0.05
Change From Baseline in rFVIIIFc Incremental Recovery (IR) Change at Week 60	-0.4 IU/dL per IU/kg Interval -1.06 to 0.04
Change From Baseline in rFVIIIFc Incremental Recovery (IR) Change at Week 72	-0.8 IU/dL per IU/kg Interval -1.1 to -0.24
Change From Baseline in rFVIIIFc Incremental Recovery (IR) Change at Week 84	-0.6 IU/dL per IU/kg Interval -1.55 to 0.01
Change From Baseline in rFVIIIFc Incremental Recovery (IR) Change at Week 96	-0.6 IU/dL per IU/kg Interval -1.21 to -0.34
Change From Baseline in rFVIIIFc Incremental Recovery (IR) Change at Week 108	-1.5 IU/dL per IU/kg Interval -2.68 to -0.31
Change From Baseline in rFVIIIFc Incremental Recovery (IR) Change at Week 120	-0.6 IU/dL per IU/kg Interval -0.6 to -0.6

SECONDARY outcome

Timeframe: Up to 3 years

Population: Analysis performed on ITI analysis set which was defined as all participants who consented to and initiated the ITI sub-study.

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.

Outcome measures

Outcome measures
Measure	Recombinant Coagulation Factor VIII Fc Fusion Protein n=15 Participants Participants were to receive rFVIIIFc as follows -PR (Prophylaxis regimen): rFVIIIFc 25-80 IU/kg, at 3- to 5-day intervals until participant reached \>= 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 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 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.
Number of Participants With Response to Immune Tolerance Induction (ITI) Complete Success	5 Participants
Number of Participants With Response to Immune Tolerance Induction (ITI) Partial Success	2 Participants
Number of Participants With Response to Immune Tolerance Induction (ITI) Early Withdrawal	3 Participants
Number of Participants With Response to Immune Tolerance Induction (ITI) ITI Ongoing at end of Study	5 Participants

Adverse Events

Recombinant Coagulation Factor VIII Fc Fusion Protein

Serious events: 60 serious events

Other events: 85 other events

Deaths: 1 deaths

Serious adverse events

Serious adverse events
Measure	Recombinant Coagulation Factor VIII Fc Fusion Protein n=103 participants at risk Participants were to receive rFVIIIFc as follows -PR: rFVIIIFc 25-80 IU/kg, at 3- to 5-day intervals until participant reached \>= 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 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 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.
Injury, poisoning and procedural complications Head injury	7.8% 8/103 • Number of events 13 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Injury, poisoning and procedural complications Palate injury	0.97% 1/103 • Number of events 1 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Injury, poisoning and procedural complications Post procedural haemorrhage	0.97% 1/103 • Number of events 1 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Blood and lymphatic system disorders Factor viii inhibition	27.2% 28/103 • Number of events 29 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Blood and lymphatic system disorders Febrile neutropenia	0.97% 1/103 • Number of events 1 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Blood and lymphatic system disorders Spontaneous haematoma	0.97% 1/103 • Number of events 1 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Cardiac disorders Supraventricular tachycardia	0.97% 1/103 • Number of events 1 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Gastrointestinal disorders Tongue haemorrhage	0.97% 1/103 • Number of events 1 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
General disorders Device related thrombosis	0.97% 1/103 • Number of events 1 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
General disorders Pyrexia	3.9% 4/103 • Number of events 4 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Infections and infestations Bacterial sepsis	0.97% 1/103 • Number of events 1 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Infections and infestations Gastroenteritis norovirus	0.97% 1/103 • Number of events 1 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Infections and infestations Haematoma infection	0.97% 1/103 • Number of events 1 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Infections and infestations Meningitis aseptic	0.97% 1/103 • Number of events 1 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Infections and infestations Parainfluenzae virus infection	1.9% 2/103 • Number of events 2 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Infections and infestations Pneumonia	1.9% 2/103 • Number of events 2 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Infections and infestations Rotavirus infection	0.97% 1/103 • Number of events 1 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Infections and infestations Staphylococcal bacteraemia	0.97% 1/103 • Number of events 2 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Infections and infestations Staphylococcal infection	1.9% 2/103 • Number of events 2 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Infections and infestations Staphylococcal skin infection	0.97% 1/103 • Number of events 1 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Infections and infestations Vascular device infection	1.9% 2/103 • Number of events 3 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Infections and infestations Viral infection	1.9% 2/103 • Number of events 2 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Infections and infestations Viral upper respiratory tract infection	1.9% 2/103 • Number of events 2 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Injury, poisoning and procedural complications Concussion	0.97% 1/103 • Number of events 4 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Injury, poisoning and procedural complications Contusion	0.97% 1/103 • Number of events 1 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Injury, poisoning and procedural complications Craniocerebral injury	1.9% 2/103 • Number of events 2 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Injury, poisoning and procedural complications Facial bones fracture	0.97% 1/103 • Number of events 1 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Injury, poisoning and procedural complications Fall	10.7% 11/103 • Number of events 19 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Injury, poisoning and procedural complications Skin laceration	0.97% 1/103 • Number of events 1 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Injury, poisoning and procedural complications Traumatic haematoma	0.97% 1/103 • Number of events 1 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Injury, poisoning and procedural complications Vascular access site haematoma	0.97% 1/103 • Number of events 1 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Musculoskeletal and connective tissue disorders Haemarthrosis	1.9% 2/103 • Number of events 2 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Musculoskeletal and connective tissue disorders Haematoma muscle	0.97% 1/103 • Number of events 1 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Musculoskeletal and connective tissue disorders Soft tissue haemorrhage	0.97% 1/103 • Number of events 1 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Nervous system disorders Febrile convulsion	1.9% 2/103 • Number of events 2 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Nervous system disorders Haemorrhage intracranial	1.9% 2/103 • Number of events 2 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Nervous system disorders Intraventricular haemorrhage	0.97% 1/103 • Number of events 1 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Product Issues Device issue	0.97% 1/103 • Number of events 1 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Psychiatric disorders Mental status changes	0.97% 1/103 • Number of events 1 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Respiratory, thoracic and mediastinal disorders Asthma	0.97% 1/103 • Number of events 1 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Surgical and medical procedures Arteriovenous fistula operation	0.97% 1/103 • Number of events 1 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Surgical and medical procedures Central venous catheter removal	0.97% 1/103 • Number of events 1 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Surgical and medical procedures Central venous catheterisation	25.2% 26/103 • Number of events 30 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Surgical and medical procedures Ventriculo-peritoneal shunt	0.97% 1/103 • Number of events 1 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Vascular disorders Deep vein thrombosis	0.97% 1/103 • Number of events 1 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Vascular disorders Haematoma	2.9% 3/103 • Number of events 3 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Vascular disorders Poor venous access	2.9% 3/103 • Number of events 3 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Vascular disorders Subgaleal haematoma	0.97% 1/103 • Number of events 1 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.

Other adverse events

Other adverse events
Measure	Recombinant Coagulation Factor VIII Fc Fusion Protein n=103 participants at risk Participants were to receive rFVIIIFc as follows -PR: rFVIIIFc 25-80 IU/kg, at 3- to 5-day intervals until participant reached \>= 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 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 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.
Blood and lymphatic system disorders Iron deficiency anaemia	9.7% 10/103 • Number of events 10 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Gastrointestinal disorders Constipation	8.7% 9/103 • Number of events 9 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Gastrointestinal disorders Diarrhoea	17.5% 18/103 • Number of events 23 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Gastrointestinal disorders Teething	11.7% 12/103 • Number of events 23 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Gastrointestinal disorders Vomiting	18.4% 19/103 • Number of events 20 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
General disorders Pyrexia	30.1% 31/103 • Number of events 47 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Infections and infestations Conjunctivitis	7.8% 8/103 • Number of events 8 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Infections and infestations Ear infection	18.4% 19/103 • Number of events 28 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Infections and infestations Gastroenteritis	6.8% 7/103 • Number of events 7 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Infections and infestations Hand-foot-and-mouth disease	5.8% 6/103 • Number of events 6 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Infections and infestations Influenza	9.7% 10/103 • Number of events 14 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Infections and infestations Nasopharyngitis	30.1% 31/103 • Number of events 54 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Infections and infestations Otitis media	9.7% 10/103 • Number of events 11 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Infections and infestations Rhinitis	6.8% 7/103 • Number of events 11 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Infections and infestations Upper respiratory tract infection	27.2% 28/103 • Number of events 41 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Infections and infestations Varicella	5.8% 6/103 • Number of events 6 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Infections and infestations Viral infection	16.5% 17/103 • Number of events 32 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Infections and infestations Viral upper respiratory tract infection	10.7% 11/103 • Number of events 27 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Injury, poisoning and procedural complications Contusion	8.7% 9/103 • Number of events 16 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Injury, poisoning and procedural complications Fall	50.5% 52/103 • Number of events 146 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Injury, poisoning and procedural complications Head injury	27.2% 28/103 • Number of events 63 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Injury, poisoning and procedural complications Limb injury	7.8% 8/103 • Number of events 9 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Injury, poisoning and procedural complications Lip injury	5.8% 6/103 • Number of events 6 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Injury, poisoning and procedural complications Mouth injury	8.7% 9/103 • Number of events 10 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Injury, poisoning and procedural complications Skin abrasion	6.8% 7/103 • Number of events 19 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Injury, poisoning and procedural complications Skin laceration	8.7% 9/103 • Number of events 13 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Injury, poisoning and procedural complications Vaccination complication	5.8% 6/103 • Number of events 6 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Respiratory, thoracic and mediastinal disorders Cough	12.6% 13/103 • Number of events 20 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Respiratory, thoracic and mediastinal disorders Rhinorrhoea	8.7% 9/103 • Number of events 9 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Skin and subcutaneous tissue disorders Eczema	5.8% 6/103 • Number of events 9 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
Skin and subcutaneous tissue disorders Rash	9.7% 10/103 • Number of events 12 • All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product. Reported AEs are treatment-emergent AEs i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.

Additional Information

Trial Transparency Team

Bioverativ, a Sanofi company

Phone: 800-633-1610

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The Sponsor supports publication of clinical trial results but may request that investigators temporarily delay or alter publications in order to protect proprietary information. The Sponsor may also require that the results of multicenter studies be published only in their entirety and not as individual site data.
Publication restrictions are in place

Restriction type: OTHER