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Clinical Trial Results:
Phase 3, Prospective, Multi-center, Open Label Study to Investigate Safety, Immunogenicity, and Hemostatic Efficacy of PEGylated Factor VIII (BAX 855) in Previously Untreated Patients (PUPs) <6 years With Severe Hemophilia A (FVIII <1%)

Summary
EudraCT number	2015-002136-40
Trial protocol	GB BG ES CZ AT HU DE NL BE NO DK FI IT Outside EU/EEA
Global end of trial date	29 Oct 2024

Results information
Results version number	v1(current)
This version publication date	15 May 2025
First version publication date	15 May 2025
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

261203

ISRCTN number

US NCT number

NCT02615691

WHO universal trial number (UTN)

Sponsor organisation name

Takeda

Sponsor organisation address

500 Kendall Street, Cambridge, Massachusetts, United States, 02142

Public contact

Study Director, Takeda, TrialDisclosures@takeda.com

Scientific contact

Study Director, Takeda, TrialDisclosures@takeda.com

Is trial part of an agreed paediatric investigation plan (PIP)

Yes

EMA paediatric investigation plan number(s)

EMEA-001296-PIP01-12

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Yes

Analysis stage

Final

Date of interim/final analysis

29 Oct 2024

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

29 Oct 2024

Was the trial ended prematurely?

Main objective of the trial

The main objective of the trail was to determine safety including immunogenicity of BAX 855 based on the incidence of inhibitor development to FVIII (≥ 0.6 Bethesda unit (BU)/mL using the Nijmegen modification of the Bethesda assay).

Protection of trial subjects

Each participant signed an informed consent form (ICF) before participating in the study.

Background therapy

Evidence for comparator

Actual start date of recruitment

12 Nov 2015

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Canada: 2

Country: Number of subjects enrolled

France: 2

Country: Number of subjects enrolled

Italy: 3

Country: Number of subjects enrolled

Belgium: 3

Country: Number of subjects enrolled

Norway: 2

Country: Number of subjects enrolled

Spain: 1

Country: Number of subjects enrolled

Thailand: 12

Country: Number of subjects enrolled

Malaysia: 24

Country: Number of subjects enrolled

India: 3

Country: Number of subjects enrolled

Korea, Republic of: 2

Country: Number of subjects enrolled

Singapore: 2

Country: Number of subjects enrolled

Türkiye: 16

Country: Number of subjects enrolled

Taiwan: 1

Country: Number of subjects enrolled

Ukraine: 5

Country: Number of subjects enrolled

Ireland: 9

Country: Number of subjects enrolled

United States: 32

Country: Number of subjects enrolled

Hong Kong: 1

Worldwide total number of subjects

120

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

109

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Participants took part in the study at various investigative sites globally from 12 November 2015 to 29 October 2024.

Screening details

Previously untreated patients(PUPs)<6 years with severe hemophilia A(Factor VIII[FVIII]<1%)were treated with BAX 855 in Part A for >=100 exposure days(EDs) or until development of FVIII inhibitor.Then,participants who developed high or low titer FVIII inhibitors entered Part B.In Part B they underwent immune tolerance induction(ITI) with BAX 855.

Period 1 title

Part A: Main Study (5 years)

Is this the baseline period?

Yes

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

All Participants

Arm description

PUPs < 6 years of age with severe hemophilia A (FVIII < 1%) and < 3 EDs to ADVATE, BAX 855 or plasma transfusion were enrolled in a single arm group. Part A (Main Study): Participants age <3 years - who had not experienced two joint bleeds received on-demand treatment of 10-80 international units per kilogram (IU/kg) intravenously (IV) depending on the severity of the bleeding episode; and - who experienced maximum of two joint bleeds received prophylaxis treatment with dose of 25-80 IU/kg of BAX 855 IV (based on investigator discretion) once weekly for up to 100 EDs. Part B (ITI Portion): Participants who met the pre-defined Part B treatment criteria entered Part B of the study for ITI. Participants either received prophylaxis treatment of BAX 855 low dose 50 IU/kg IV, three times a week (Q3W) or high dose 100-200 IU/kg IV, daily at the discretion of the investigator according to the institution’s standard of care.

Arm type

Experimental

Investigational medicinal product name

PEGylated rFVIII

Investigational medicinal product code

BAX855

Other name

Pharmaceutical forms

Powder and solution for solution for injection

Routes of administration

Intravenous use

Dosage and administration details

For Part A: 10-50 IU/kg, up to 80 IU/kg, depending on the severity of the bleeding episode and for Part B: 25-50 IU/kg, up to 80 IU/kg at investigator discretion, at least once weekly.

Number of subjects in period 1	All Participants
Started	120
Part A: On-demand Treatment	80
Part A: Prophylaxis Treatment	112
Completed	106
Not completed	14
Physician decision	2
Consent withdrawn by subject	7
Adverse event, non-fatal	3
Reason Not Specified	2

Period 2 title

Part B: ITI Portion (3.5 years)

Is this the baseline period?

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

All Participants

Arm description

Arm type

Experimental

Investigational medicinal product name

PEGylated rFVIII

Investigational medicinal product code

BAX855

Other name

Pharmaceutical forms

Powder and solution for solution for injection

Routes of administration

Intravenous use

Dosage and administration details

For Part A: 10-50 IU/kg, up to 80 IU/kg, depending on the severity of the bleeding episode and for Part B: 25-50 IU/kg, up to 80 IU/kg at investigator discretion, at least once weekly.

Number of subjects in period 2	All Participants
Started	7
Part B:FVII Inhibitor Dose(50 IU/kg Q3W)	4 ^[1]
Part B:FVII Inhibitor100-200IU/kg Daily	3 ^[2]
Completed	7

Notes
[1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: A participant that received on-demand treatment first and then moved to prophylaxis treatment was counted for both on-demand and prophylaxis regimens. A participant that started with prophylaxis treatment was counted only for the prophylaxis regimen even if the participant received on-demand treatment while on the prophylaxis regimen.
[2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: A participant that received on-demand treatment first and then moved to prophylaxis treatment was counted for both on-demand and prophylaxis regimens. A participant that started with prophylaxis treatment was counted only for the prophylaxis regimen even if the participant received on-demand treatment while on the prophylaxis regimen.

Baseline characteristics

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Reporting group title

All Participants

Reporting group description

Reporting group values	All Participants	Total
Number of subjects	120
Age Categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	0.90 ( 0.717 )	-
Gender categorical
Units: Subjects
Female	0	0
Male	120	120
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	0
Asian	45	45
Native Hawaiian or Other Pacific Islander	0	0
Black or African American	7	7
White	61	61
More than one race	4	4
Unknown or Not Reported	3	3
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	6	6
Not Hispanic or Latino	114	114
Unknown or Not Reported	0	0

End points

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Reporting group title

All Participants

Reporting group description

Reporting group title

All Participants

Reporting group description

Subject analysis set title

Part A: Main Study

Subject analysis set type

Per protocol

Subject analysis set description

Participants age <3 years - who had not experienced two joint bleeds received on-demand treatment of 10-80 IU/kg IV depending on the severity of the bleeding episode; and - who experienced maximum of two joint bleeds received prophylaxis treatment with dose of 25-80 IU/kg of BAX 855 IV (based on investigator discretion) once weekly for up to 100 EDs.

Subject analysis set title

Part B: ITI Portion

Subject analysis set type

Per protocol

Subject analysis set description

Participants who met the pre-defined Part B treatment criteria entered in the Part B of the study for ITI. Participants either received prophylaxis treatment of low dose BAX 855 50 IU/kg IV, three times a week or high dose 100-200 IU/kg IV, daily at the discretion of the investigator according to the institution’s standard of care.

Subject analysis set title

Part A: Main Study: On-demand

Subject analysis set type

Per protocol

Subject analysis set description

Participants age <3 years and who had not experienced two joint bleeds received on-demand treatment of 10-80IU/kg of BAX 855 IV depending on the severity of the bleeding episode.

Subject analysis set title

Part A: Main Study: Prophylaxis

Subject analysis set type

Per protocol

Subject analysis set description

Participants age <3 years or after a maximum of two joint bleeds received prophylaxis treatment with dose of 25-80 IU/kg of BAX 855 IV (based on investigator discretion) once weekly for up to 100 EDs.

Subject analysis set title

Part B: ITI Portion (50 IU/kg Three Times Weekly Regimen)

Subject analysis set type

Per protocol

Subject analysis set description

Participants received prophylaxis treatment of 50 IU/kg BAX 855 IV three times in a week.

Subject analysis set title

Part B: ITI Portion (100-200 IU/kg Daily Regimen)

Subject analysis set type

Per protocol

Subject analysis set description

Participants received prophylaxis treatment of 100-200 IU/kg BAX 855 IV daily.

Primary: Number of Participants With FVIII Inhibitor Development

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End point title

Number of Participants With FVIII Inhibitor Development ^[1]

End point description

Number of participants who developed an inhibitor (at any time) confirmed by a central laboratory based on a second repeat blood sample draw within 2 weeks of site notification of an inhibitor and all participants who had not developed an inhibitor and had greater than or equal to (>=) 100 EDs when the sample for the last valid inhibitor test was drawn. The SAS included all participants in the enrolled population with at least one BAX 855 infusion. Included in the analysis were participants who had equal or greater than 100 EDs or developed a confirmed FVIII inhibitor.

End point type

Primary

End point timeframe

Throughout Part A of the study, approximately 5 years

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive analyses were planned for this endpoint.

End point values	Part A: Main Study
Number of subjects analysed	100
Units: participants	11

No statistical analyses for this end point

Primary: Number of Participants With Success of Immune Tolerance Induction (ITI)

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End point title

Number of Participants With Success of Immune Tolerance Induction (ITI) ^[2]

End point description

Success is defined as 1) a persistently negative inhibitor titer less than (<) 0.6 Bethesda unit (BU), 2) FVIII IR >=66% of the baseline value following a wash-out period of 84-96 hours, and 3) a FVIII half-life of >=6 hours. The FVIII Inhibitor Treatment Analysis Set (IAS) included all participants who received at least one FVIII inhibitor treatment with BAX 855 during the study after the date that participant moved to FVIII inhibitor treatment.

End point type

Primary

End point timeframe

Up to 33 months in Part B of the study

Notes
[2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive analyses were planned for this endpoint.

End point values	Part B: ITI Portion
Number of subjects analysed	7
Units: participants	5

No statistical analyses for this end point

Secondary: Number of Participants With Binding Immunoglobulin G (IgG) and Immunoglobulin M (IgM) Antibodies

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End point title

Number of Participants With Binding Immunoglobulin G (IgG) and Immunoglobulin M (IgM) Antibodies

End point description

Binding IgG and IgM antibodies (Ab) to FVIII , Factor VIII-Polyethylene glycol (PEG-FVIII) and Polyethylene glycol (PEG) was assessed. A participant that received on-demand treatment first and then moved to prophylaxis treatment was counted for both on-demand and prophylaxis regimens. A participant that started with prophylaxis treatment was counted only for the prophylaxis regimen even if the participant received on-demand treatment while on the prophylaxis regimen. Visits and their approximate time in weeks after baseline visit for individual participants: Visit 1(Week 5), Visit 2 (Week 10), Visit 3 (Week 15), Visit 4 (Week 20), Visit 5 (Week 30), Visit 6 (Week 40), Visit 7 (Week 55), Visit 8 (Week 75) and Study Completion Visit (Weeks 100-110). The SAS included all participants in the enrolled population with at least one BAX 855 infusion. 'n' indicates the number of participants with data available for analyses for each category. Study Completion is denoted as SC.

End point type

Secondary

End point timeframe

Throughout Part A of the study, approximately 5 years

End point values	Part A: Main Study: On-demand	Part A: Main Study: Prophylaxis
Number of subjects analysed	80	112
Units: participants
Screening- Binding IgG Ab to FVIII (n=75,40)	1	0
Screening- Binding IgM Ab to FVIII (n=75,40)	0	0
Screening- Binding IgG Ab to PEG-FVIII (n=75,40)	3	2
Screening- Binding IgM Ab to PEG-FVIII (n=75,40)	4	1
Screening- Binding IgG Ab to PEG (n=75,40)	0	0
Screening- Binding IgM Ab to PEG (n=75,40)	6	4
Baseline- Binding IgG Ab to FVIII (n=79,38)	2	1
Baseline- Binding IgM Ab to FVIII (n=79,38)	0	0
Baseline- Binding IgG Ab to PEG-FVIII (n=79,38)	7	3
Baseline- Binding IgM Ab to PEG-FVIII (n=79,38)	4	2
Baseline- Binding IgG Ab to PEG (n=79,38)	0	0
Baseline- Binding IgM Ab to PEG (n=79,38)	8	2
Visit 1- Binding IgG Ab to FVIII (n=47,62)	0	4
Visit 1- Binding IgM Ab to FVIII (n=47,62)	0	0
Visit 1- Binding IgG Ab to PEG-FVIII (n=47,62)	14	36
Visit 1- Binding IgM Ab to PEG-FVIII (n=47,62)	0	2
Visit 1- Binding IgG Ab to PEG (n=47,62)	4	8
Visit 1- Binding IgM Ab to PEG (n=47,62)	0	3
Visit 2- Binding IgG Ab to FVIII (n=20,76)	1	1
Visit 2- Binding IgM Ab to FVIII (n=20,76)	0	0
Visit 2- Binding IgG Ab to PEG-FVIII (n=20,76)	6	27
Visit 2- Binding IgM Ab to PEG-FVIII (n=20,76)	0	0
Visit 2- Binding IgG Ab to PEG (n=20,76)	2	3
Visit 2- Binding IgM Ab to PEG (n=20,76)	0	0
Visit 3- Binding IgG Ab to FVIII (n=11,86)	0	2
Visit 3- Binding IgM Ab to FVIII (n=11,86)	0	0
Visit 3- Binding IgG Ab to PEG-FVIII (n=11,86)	4	25
Visit 3- Binding IgM Ab to PEG-FVIII (n=11,86)	0	0
Visit 3- Binding IgG Ab to PEG (n=11,86)	1	4
Visit 3- Binding IgM Ab to PEG (n=11,86)	0	0
Visit 4- Binding IgG Ab to FVIII (n=5,87)	0	0
Visit 4- Binding IgM Ab to FVIII (n=5,87)	0	0
Visit 4- Binding IgG Ab to PEG-FVIII (n=5,87)	1	18
Visit 4- Binding IgM Ab to PEG-FVIII (n=5,87)	0	0
Visit 4- Binding IgG Ab to PEG (n=5,87)	0	1
Visit 4- Binding IgM Ab to PEG (n=5,87)	0	0
Visit 5- Binding IgG Ab to FVIII (n=3,94)	0	0
Visit 5- Binding IgM Ab to FVIII (n=3,94)	0	0
Visit 5- Binding IgG Ab to PEG-FVIII (n=3,94)	1	13
Visit 5- Binding IgM Ab to PEG-FVIII (n=3,94)	0	0
Visit 5- Binding IgG Ab to PEG (n=3,94)	0	1
Visit 5- Binding IgM Ab to PEG (n=3,94)	0	0
Visit 6- Binding IgG Ab to FVIII (n=1,94)	0	0
Visit 6- Binding IgM Ab to FVIII (n=1,94)	0	0
Visit 6- Binding IgG Ab to PEG-FVIII (n=3,94)	1	5
Visit 6- Binding IgM Ab to PEG-FVIII (n=3,94)	0	0
Visit 6- Binding IgG Ab to PEG (n=1,94)	0	0
Visit 6- Binding IgM Ab to PEG (n=1,94)	0	0
Visit 7- Binding IgG Ab to FVIII (n=1,93)	0	0
Visit 7- Binding IgM Ab to FVIII (n=1,93)	0	0
Visit 7- Binding IgG Ab to PEG-FVIII (n=1,93)	1	4
Visit 7- Binding IgM Ab to PEG-FVIII (n=1,93)	0	0
Visit 7- Binding IgG Ab to PEG (n=1,93)	0	0
Visit 7- Binding IgM Ab to PEG (n=1,93)	0	0
Visit 8- Binding IgG Ab to FVIII (n=1,90)	0	0
Visit 8- Binding IgM Ab to FVIII (n=1,90)	0	0
Visit 8- Binding IgG Ab to PEG-FVIII (n=1,90)	0	1
Visit 8- Binding IgM Ab to PEG-FVIII (n=1,90)	0	0
Visit 8- Binding IgG Ab to PEG (n=1,90)	0	0
Visit 8- Binding IgM Ab to PEG (n=1,90)	0	0
SC- Binding IgG Ab to FVIII (n=4,96)	0	1
SC- Binding IgM Ab to FVIII (n=4,96)	0	0
SC- Binding IgG Ab to PEG-FVIII(n=4,96)	1	2
SC- Binding IgM Ab to PEG-FVIII (n=4,96)	1	0
SC- Binding IgG Ab to PEG (n=4,96)	1	1
SC- Binding IgM Ab to PEG (n=4,96)	1	0

No statistical analyses for this end point

Secondary: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

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End point title

Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

End point description

AE:any untoward medical occurrence in participant administered investigational product(IP) that does not necessarily have causal relationship with treatment.SAE:any untoward clinical manifestation of signs,symptoms or outcomes(whether considered related to IP or not & at any dose)which results in death,is lifethreatening,requires inpatient hospitalization,prolongation of hospitalization,is important medical event.A participant that received on-demand treatment 1st & then moved to prophylaxis treatment was counted for both on-demand & prophylaxis regimens.A participant that started with prophylaxis treatment was counted only for that regimen even if the participant received on-demand treatment while on prophylaxis regimen.SAS:all participants in enrolled population with at least 1 BAX855 infusion for Part A of study & IAS:all participants who received at least 1 FVIII inhibitor treatment with BAX855 during study after date that participant moved to FVIII inhibitor treatment for Part B.

End point type

Secondary

End point timeframe

Throughout Part A and Part B of the study, approximately 9 years

End point values	Part A: Main Study: On-demand	Part A: Main Study: Prophylaxis	Part B: ITI Portion (50 IU/kg Three Times Weekly Regimen)	Part B: ITI Portion (100-200 IU/kg Daily Regimen)
Number of subjects analysed	80	112	4	3
Units: participants
AEs	57	94	4	3
SAEs	18	35	1	3

No statistical analyses for this end point

Secondary: Number of Participants With At Least One Clinically Significant Changes in Clinical Laboratory Parameters

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End point title

Number of Participants With At Least One Clinically Significant Changes in Clinical Laboratory Parameters

End point description

Clinical laboratory parameters included hematology and clinical chemistry. Changes in laboratory values could be considered as AE if they were judged to be clinically significant. The SAS included all participants in the enrolled population with at least one BAX 855 infusion for Part A of the study and the IAS included all participants who received at least one FVIII inhibitor treatment with BAX 855 during the study after the date that participant moved to FVIII inhibitor treatment for Part B of the study.

End point type

Secondary

End point timeframe

Throughout Part A and Part B of the study, approximately 9 years

End point values	Part A: Main Study	Part B: ITI Portion
Number of subjects analysed	120	7
Units: participants	53	1

No statistical analyses for this end point

Secondary: Number of Participants With At Least One Clinically Significant Changes in Vital Signs

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End point title

Number of Participants With At Least One Clinically Significant Changes in Vital Signs

End point description

Vital signs were assessed based on body temperature, respiratory rate, blood pressure, and heart rate. The SAS included all participants in the enrolled population with at least one BAX 855 infusion for Part A of the study and the IAS included all participants who received at least one FVIII inhibitor treatment with BAX 855 during the study after the date that participant moved to FVIII inhibitor treatment for Part B of the study.

End point type

Secondary

End point timeframe

Throughout Part A and Part B of the study, approximately 9 years

End point values	Part A: Main Study	Part B: ITI Portion
Number of subjects analysed	120	7
Units: participants	0	0

No statistical analyses for this end point

Secondary: Annualized Bleeding Rate (ABR) for Prophylactic and On-demand Treatment and Immune Tolerance Induction (ITI)

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End point title

Annualized Bleeding Rate (ABR) for Prophylactic and On-demand Treatment and Immune Tolerance Induction (ITI)

End point description

ABR was assessed based upon each individual bleeding episode.Bleeding episode:subjective (pain consistent with a joint bleed) or objective evidence of bleeding which may or may not require treatment with FVIII.Bleeding occurring at multiple locations related to same injury(example,knee & ankle bleed following a fall) was counted as single bleeding episode.Mean total annualized bleed rate is reported.A participant that received on-demand treatment first & then moved to prophylaxis treatment was counted for both on-demand & prophylaxis regimens.A participant that started with prophylaxis treatment was counted only for that regimen even if participant received on-demand treatment while on the prophylaxis regimen.SAS:all participants in the enrolled population with at least 1 BAX855 infusion for Part A of study & IAS:all participants who received at least 1 FVIII inhibitor treatment with BAX855 during study after the date that participant moved to FVIII inhibitor treatment for Part B.

End point type

Secondary

End point timeframe

Throughout Part A and Part B of the study, approximately 9 years

End point values	Part A: Main Study: On-demand	Part A: Main Study: Prophylaxis	Part B: ITI Portion (50 IU/kg Three Times Weekly Regimen)	Part B: ITI Portion (100-200 IU/kg Daily Regimen)
Number of subjects analysed	80	112	4	3
Units: unique bleeds per year
arithmetic mean (standard deviation)	10.004 ( 15.533 )	4.536 ( 8.657 )	7.673 ( 8.965 )	6.432 ( 14.518 )

No statistical analyses for this end point

Secondary: Bleeding Episodes Categorized by Number of BAX 855 Infusions Required for Treatment

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End point title

Bleeding Episodes Categorized by Number of BAX 855 Infusions Required for Treatment

End point description

A bleeding episode is defined as subjective (pain consistent with a joint bleed) or objective evidence of bleeding which may or may not require treatment with FVIII. The number of BAX 855 infusions needed for each bleeding episode was determined by the participant, caregiver, clinician treating the participant, and is based upon the participant's response to treatment, using the Efficacy Rating Scale for Treatment of Bleeding Episodes. Number of bleeding episodes are categorized by number of infusions required to treat the bleeding episodes. A participant that received on-demand treatment first and then moved to prophylaxis treatment was counted for both on-demand and prophylaxis regimens. A participant that started with prophylaxis treatment was counted only for the prophylaxis regimen even if the participant received on-demand treatment while on the prophylaxis regimen. The SAS included all participants in the enrolled population with at least one BAX 855 infusion.

End point type

Secondary

End point timeframe

Throughout Part A of the study, approximately 5 years

End point values	Part A: Main Study: On-demand	Part A: Main Study: Prophylaxis
Number of subjects analysed	80 ^[3]	112 ^[4]
Units: bleeding episodes
number (not applicable)
Number of infusions per bleed: 0	7	14
Number of infusions per bleed: 1	302	312
Number of infusions per bleed: 2	43	44
Number of infusions per bleed: 3	18	19
Number of infusions per bleed: 4	4	1
Number of infusions per bleed: >4	5	6

Notes
[3] - Number of treated bleeds=379
[4] - Number of treated bleeds=396

No statistical analyses for this end point

Secondary: Number of Bleeds by Overall Hemostatic Efficacy Rating at 24 Hours After Initiation of Treatment

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End point title

Number of Bleeds by Overall Hemostatic Efficacy Rating at 24 Hours After Initiation of Treatment

End point description

Participant or caregiver rated overall treatment response using 4-point efficacy rating scale as Excellent:Full relief of pain & cessation of objective signs of bleeding after single infusion & no additional infusion is required for control of bleeding;Good:Definite pain relief &/or improvement in signs of bleeding after single infusion & possibly requires more than 1 infusion for complete resolution;Fair:Probable &/or slight relief of pain & slight improvement in signs of bleeding after single infusion & required more than 1 infusion for complete resolution & None:No improvement or condition worsens.Number of bleeds with each efficacy rating are reported.Participant that received on-demand treatment 1st & then moved to prophylaxis treatment was counted for both on-demand & prophylaxis regimens.Participant that started with prophylaxis treatment was counted only for that regimen even if the participant received on-demand treatment while on prophylaxis regimen.

End point type

Secondary

End point timeframe

At 24 hours after study drug administration during Part A of the study

End point values	Part A: Main Study: On-demand	Part A: Main Study: Prophylaxis
Number of subjects analysed	80 ^[5]	112 ^[6]
Units: bleeds
number (not applicable)
Excellent	76	102
Good	67	71
Fair	13	10
None	2	1

Notes
[5] - Number of treated bleeds=158
[6] - Number of treated bleeds=184

No statistical analyses for this end point

Secondary: Number of Bleeds by Overall Hemostatic Efficacy Rating at Bleed Resolution

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End point title

Number of Bleeds by Overall Hemostatic Efficacy Rating at Bleed Resolution

End point description

The participant or caregiver rated overall treatment response using a 4-point efficacy rating scale as Excellent:Full relief of pain & cessation of objective signs of bleeding after single infusion & no additional infusion is required for the control of bleeding; Good:Definite pain relief &/or improvement in signs of bleeding after a single infusion & possibly requires more than 1 infusion for complete resolution; Fair:Probable &/or slight relief of pain & slight improvement in signs of bleeding after single infusion & required more than 1 infusion for complete resolution & None:No improvement or condition worse.Number of bleeds with each efficacy rating are reported.Participant that received on-demand treatment first & then moved to prophylaxis treatment was counted for both on-demand & prophylaxis regimens.Participant that started with prophylaxis treatment was counted only for prophylaxis regimen even if the participant received on-demand treatment while on prophylaxis regimen.

End point type

Secondary

End point timeframe

From start of study treatment up to bleed resolution throughout Part A of the study (up to approximately 5 years)

End point values	Part A: Main Study: On-demand	Part A: Main Study: Prophylaxis
Number of subjects analysed	80 ^[7]	112 ^[8]
Units: bleeds
number (not applicable)
Excellent	166	166
Good	83	77
Fair	12	9
None	3	1

Notes
[7] - Number of treated bleeds=264
[8] - Number of treated bleeds=253

No statistical analyses for this end point

Secondary: Weight-adjusted Consumption of BAX 855: Average Number of Prophylactic Infusions

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End point title

Weight-adjusted Consumption of BAX 855: Average Number of Prophylactic Infusions

End point description

Weight-adjusted consumption of BAX 855 was determined based upon the record in participants diaries of the actual number of BAX 855 infusions as measured in the clinic. Average (Avg.) number (no.) of infusions per month and year are reported as categories. The SAS included all participants in the enrolled population with at least one BAX 855 infusion. Number analyzed (n) for each category is the number of participants with data available for analyses.

End point type

Secondary

End point timeframe

Throughout Part A and Part B of the study, approximately 9 years

End point values	Part A: Main Study: Prophylaxis
Number of subjects analysed	112
Units: infusions
arithmetic mean (standard deviation)
Avg. No. of Prophylactic Infusions/Month (n=111)	4.900 ( 1.877 )
Avg. No. of Prophylactic Infusions per Year (n=83)	57.067 ( 16.361 )

No statistical analyses for this end point

Secondary: Weight-adjusted Consumption of BAX 855: Average Prophylactic Dose

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End point title

Weight-adjusted Consumption of BAX 855: Average Prophylactic Dose

End point description

Weight-adjusted consumption of BAX 855 was determined based upon the record in participants diaries of the actual amount of BAX 855 infused as measured in the clinic. Average dose per prophylactic infusion, per month and per year are reported as categories. The SAS included all participants in the enrolled population with at least one BAX 855 infusion. Number analyzed (n) for each category is the number of participants with data available for analyses. n=112 for Average Dose [IU/kg] per Prophylactic Infusion; n=111 for Average Prophylactic Dose [IU/kg] per Month and n=83 for Average Prophylactic Dose [IU/kg] per Year.

End point type

Secondary

End point timeframe

Throughout Part A of the study, approximately 5 years

End point values	Part A: Main Study: Prophylaxis
Number of subjects analysed	112
Units: IU/kg
arithmetic mean (standard deviation)
Average Dose [IU/kg] per Prophylactic Infusion	45.514 ( 7.831 )
Average Prophylactic Dose [IU/kg] per Month	221.568 ( 85.925 )
Average Prophylactic Dose [IU/kg] per Year	2597.079 ( 783.089 )

No statistical analyses for this end point

Secondary: Weight-adjusted Consumption of BAX 855: Average Dose

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End point title

Weight-adjusted Consumption of BAX 855: Average Dose

End point description

Weight-adjusted consumption of BAX 855 was determined based upon the record in participants diaries of the actual amount of BAX 855 infused as measured in the clinic. Average dose to treat bleeding episode and average FVIII inhibitor treatment Dose [IU/kg] per Week, Month and per Year are reported as categories. A participant that received on-demand treatment first and then moved to prophylaxis treatment was counted for both on-demand and prophylaxis regimens. A participant that started with prophylaxis treatment was counted only for the prophylaxis regimen even if the participant received on-demand treatment while on the prophylaxis regimen. SAS was used. Number analyzed (n) for each category is the number of participants with data available for analyses. n for the categories: per bleeding episode (n=80,112,0,0), per Week(n=0,0,2,3), per Month(n=0,0,2,3), per Year(n=0,0,2,3).

End point type

Secondary

End point timeframe

Throughout Part A of the study, approximately 5 years

End point values	Part A: Main Study: On-demand	Part A: Main Study: Prophylaxis	Part B: ITI Portion (50 IU/kg Three Times Weekly Regimen)	Part B: ITI Portion (100-200 IU/kg Daily Regimen)
Number of subjects analysed	80	112	4	3
Units: IU/kg
arithmetic mean (standard deviation)
Average Dose [IU/kg] to Treat Bleeding Episode	55.445 ( 32.826 )	63.864 ( 44.818 )	99999 ( 99999 )	99999 ( 99999 )
Average FVIII Inhibitor Dose[IU/kg]/Week	99999 ( 99999 )	99999 ( 99999 )	123.510 ( 65.563 )	417.750 ( 319.694 )
Average FVIII Inhibitor Dose[IU/kg]/Month	99999 ( 99999 )	99999 ( 99999 )	537.038 ( 285.076 )	1816.427 ( 1390.068 )
Average FVIII Inhibitor Dose[IU/kg]/Year	99999 ( 99999 )	99999 ( 99999 )	6444.460 ( 3420.911 )	21797.128 ( 16680.821 )

No statistical analyses for this end point

Secondary: Number of Participants by Hemostatic Efficacy Rating in Case of Surgery

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End point title

Number of Participants by Hemostatic Efficacy Rating in Case of Surgery

End point description

Hemostatic efficacy assessed during & after any surgical/invasive procedures,& overall perioperatively.Operating surgeon assessed it compared to that expected for type of procedure performed in non-hemophilic population,prior to discharge from recovery room(intraoperative),on postoperative Day1&at discharge/14 days post-surgery(perioperative).Participants rated efficacy:1.Excellent:Postoperative blood loss≤100%than expected;2.Good:Postoperative blood loss up to50%more(101-150%)than expected;3.Fair:Postoperative blood loss50%(>150%)more than expected;4.None:Significant postoperative bleeding that due to inadequate therapeutic response despite proper dosing,necessitating rescue therapy.Perioperative ratings:based on amount of blood components required for transfusions versus expected.Categories=Participant-provided ratings.Invasive Procedure Analysis Set(IPRAS):participants receiving BAX 855 for≤1surgeries/invasive procedures in study.n=participants with data available for analyses.

End point type

Secondary

End point timeframe

Surgery Day 0 up to postoperative Day 14 or discharge (whichever occurs first)

End point values	All Participants
Number of subjects analysed	37
Units: participants
Intraoperative - Excellent (n=11)	10
Intraoperative - Good (n=11)	0
Intraoperative - Fair (n=11)	0
Intraoperative - None (n=11)	1
Postoperative - Excellent (n=11)	11
Postoperative - Good (n=11)	0
Postoperative - Fair (n=11)	0
Postoperative - None (n=11)	0
Perioperative - Excellent (n=11)	10
Perioperative - Good (n=11)	0
Perioperative - Fair (n=11)	0
Perioperative - None (n=11)	1

No statistical analyses for this end point

Secondary: Incremental Recovery (IR) of BAX 855

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End point title

Incremental Recovery (IR) of BAX 855

End point description

BAX 855 was administered in participants for the determination of FVIII IR at the study site at baseline and every study visit other than study visits at 5 EDs, 15 EDs and 30 EDs. The FVIII assays were done using following methods: 1-stage clotting FVIII activity and FVIII chromogenic activity. Data is reported for each of these methods as categories per visit. The Pharmacokinetic (PK) analysis set (PKAS) included all participants in the SAS who had at least one post-dose measurement of FVIII activity without protocol deviations and/or events with potential to affect concentration (FVIII activity levels). Number analyzed (n) is the number of participants with data available for analyses for each category. n=4 for the Preoperative Assessments Surgery timepoint.

End point type

Secondary

End point timeframe

Pre-infusion within 30 minutes; and post-infusion at 15-30 minutes and 24-48 hours (Up to 9 years)

End point values	All Participants
Number of subjects analysed	119
Units: (IU/dL)/(IU/kg)
geometric mean (geometric coefficient of variation)
Baseline-1-Stage Clotting (n=99)	1.546 ( 46.991 )
Baseline-Chromogenic (n=100)	1.594 ( 55.555 )
Visit 1-1-Stage Clotting (n=45)	1.452 ( 49.680 )
Visit 1-Chromogenic (n=45)	1.651 ( 43.755 )
Visit 2-1-Stage Clotting (n=88)	1.345 ( 72.207 )
Visit 2-Chromogenic (n=88)	1.451 ( 57.891 )
Visit 3-1-Stage Clotting (n=47)	1.439 ( 61.369 )
Visit 3-Chromogenic (n=47)	1.586 ( 54.653 )
Visit 4-1-Stage Clotting (n=79)	1.558 ( 33.938 )
Visit 4-Chromogenic (n=79)	1.802 ( 31.897 )
Visit 5-1-Stage Clotting (n=56)	1.588 ( 51.122 )
Visit 5-Chromogenic (n=54)	1.916 ( 28.373 )
Visit 6-1-Stage Clotting (n=87)	1.714 ( 34.037 )
Visit 6-Chromogenic (n=87)	1.809 ( 46.022 )
Visit 7-1-Stage Clotting (n=89)	1.742 ( 46.707 )
Visit 7-Chromogenic (n=88)	1.965 ( 20.272 )
Visit 8-1-Stage Clotting (n=83)	1.634 ( 43.470 )
Visit 8-Chromogenic (n=82)	1.893 ( 36.334 )
Study Completion-1-Stage Clotting (n=89)	1.819 ( 25.513 )
Study Completion-Chromogenic (n=90)	1.979 ( 23.846 )
Preoperative Assessments Surgery-1-Stage Clotting	1.481 ( 42.457 )
Preoperative Assessments Surgery-Chromogenic	1.716 ( 45.340 )

No statistical analyses for this end point

Secondary: Blood Loss Per Participant in Case of Surgery

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End point title

Blood Loss Per Participant in Case of Surgery

End point description

The intraoperative blood loss was measured by determining the volume of blood and fluid removal through suction into the collection container (waste box and/or cell saver) and the estimated blood loss into swabs and towels during the procedure, per the anesthesiologist's record. Post-operatively, blood loss was determined by the drainage volume collected, which mainly consisted of drainage fluid via vacuum or gravity drain, as applicable. The assessment was done for the intra-operative time period (prior to discharge from recovery room) and for the post-operative time period (from completion of the procedure until approximately 24 hours post-surgery). The IPRAS included all participants who were treated with BAX 855 for one or more surgeries or invasive procedures in the context of the study. Number analyzed are the participants who experienced blood loss.

End point type

Secondary

End point timeframe

Surgery Day 0 up to postoperative Day 14 or discharge (whichever occurs first)

End point values	All Participants
Number of subjects analysed	37
Units: milliliters (mL)
arithmetic mean (standard deviation)
Observed Intra-Operative Blood Loss (n=17)	4.8 ( 5.43 )
Observed Post-Operative Blood Loss (n=0)	99999 ( 99999 )

No statistical analyses for this end point

Secondary: Half-life (T1/2) of BAX 855

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End point title

Half-life (T1/2) of BAX 855

End point description

The Half-life to determine FVIII half-life was an optional assessment that was planned to be performed at baseline, Visit 1, or Visit 2. As pre-specified in the protocol, the determination of FVIII half-life by abbreviated PK at baseline was optional and was not performed.

End point type

Secondary

End point timeframe

Pre-infusion, Post-infusion: 15-30 minutes and 24-48 hours at Baseline

End point values	All Participants
Number of subjects analysed	0 ^[9]
Units: hours
median (full range (min-max))	( to )

Notes
[9] - Determination of FVIII half-life by abbreviated PK at baseline was optional and was not performed.

No statistical analyses for this end point

Secondary: Immune Tolerance Induction (ITI) – Number of Participants With Partial Success and Failure of ITI

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End point title

Immune Tolerance Induction (ITI) – Number of Participants With Partial Success and Failure of ITI

End point description

Partial success defined as which meet two of following criteria, 1) inhibitor titer <0.6 BU (confirmed by a central laboratory with a second blood specimen obtained within 2 months), 2) FVIII in vivo recovery >=66% of baseline value (confirmed within a two month period), and 3) FVIII half-life >=6 hours. Failure defined as the failure to meet the criteria for partial success. FVIII inhibitor treatment analysis set (IAS) included all participants who received at least one FVIII inhibitor treatment with BAX 855 during the study after the date that participant moved to FVIII inhibitor treatment.

End point type

Secondary

End point timeframe

Up to 33 months in Part B of the study

End point values	Part B: ITI Portion
Number of subjects analysed	7
Units: participants
Partial Success	1
Failure	1

No statistical analyses for this end point

Secondary: Immune Tolerance Induction (ITI) - Number of Participants With At Least One Catheter-related Complication

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End point title

Immune Tolerance Induction (ITI) - Number of Participants With At Least One Catheter-related Complication

End point description

Number of participants with catheter-related complications are reported. IAS included all participants who received at least one FVIII inhibitor treatment with BAX 855 during the study after the date that participant moved to FVIII inhibitor treatment for Part B of the study.

End point type

Secondary

End point timeframe

Up to 33 months in Part B of the study

End point values	Part B: ITI Portion (50 IU/kg Three Times Weekly Regimen)	Part B: ITI Portion (100-200 IU/kg Daily Regimen)
Number of subjects analysed	4	3
Units: participants	0	2

No statistical analyses for this end point

Secondary: Immune Tolerance Induction (ITI) – Number of Participants With Binding Immunoglobulin G (IgG) and Immunoglobulin M (IgM) Antibodies

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End point title

Immune Tolerance Induction (ITI) – Number of Participants With Binding Immunoglobulin G (IgG) and Immunoglobulin M (IgM) Antibodies

End point description

Binding IgG and IgM antibodies to Factor VIII (FVIII), Factor VIII-Polyethylene glycol (PEG-FVIII) and Polyethylene glycol (PEG) are reported as categories per visit. The IAS included all participants who received at least one FVIII inhibitor treatment with BAX 855 during the study after the date that participant moved to FVIII inhibitor treatment. Follow-Up Visit is denoted as FU and Treatment Completion is denoted as TC.

End point type

Secondary

End point timeframe

Up to 33 months in Part B of the study

End point values	Part B: ITI Portion (50 IU/kg Three Times Weekly Regimen)	Part B: ITI Portion (100-200 IU/kg Daily Regimen)
Number of subjects analysed	4	3
Units: participants
Screening- Binding IgG Ab to FVIII (n=2,1)	0	1
Screening- Binding IgM Ab to FVIII (n=2,1)	0	0
Screening- Binding IgG Ab to PEG-FVIII (n=2,1)	0	1
Screening- Binding IgM Ab to PEG-FVIII (n=2,1)	0	0
Screening- Binding IgG Ab to PEG (n=2,1)	0	1
Screening- Binding IgM Ab to PEG (n=2,1)	0	0
First Infusion- Binding IgG Ab to FVIII (n=2,2)	2	0
First Infusion- Binding IgM Ab to FVIII (n=2,2)	0	0
First Infusion- Binding IgG Ab to PEG-FVIII(n=2,2)	2	1
First Infusion- Binding IgM Ab to PEG-FVIII(n=2,2)	0	0
First Infusion- Binding IgG Ab to PEG (n=2,2)	0	0
First Infusion- Binding IgM Ab to PEG (n=2,2)	0	0
Visit 1(Week 2) - Binding IgG Ab to FVIII (n=4,3)	2	1
Visit 1(Week 2) - Binding IgM Ab to FVIII (n=4,3)	0	0
Visit 1 (Week 2)-Binding IgGAb to PEG-FVIII(n=4,3)	0	2
Visit 1 (Week 2)-Binding IgMAb to PEG-FVIII(n=4,3)	0	0
Visit 1 (Week 2) - Binding IgG Ab to PEG (n=4,3)	0	2
Visit 1 (Week 2) - Binding IgM Ab to PEG (n=4,3)	0	0
Visit 2 (Week 4) - Binding IgG Ab to FVIII (n=4,3)	1	1
Visit 2 (Week 4) - Binding IgM Ab to FVIII (n=4,3)	0	0
Visit 2 (Week 4)-Binding IgGAb to PEG-FVIII(n=4,3)	1	1
Visit 2 (Week 4)-Binding IgMAb to PEG-FVIII(n=4,3)	0	0
Visit 2 (Week 4) - Binding IgG Ab to PEG (n=4,3)	0	0
Visit 2 (Week 4) - Binding IgM Ab to PEG (n=4,3)	0	0
FU Month 1- Binding IgG Ab to FVIII (n=2,2)	1	0
FU Month 1- Binding IgM Ab to FVIII (n=2,2)	0	0
FU Month 1- Binding IgG Ab to PEG-FVIII (n=2,2)	0	0
FU Month 1- Binding IgM Ab to PEG-FVIII (n=2,2)	0	0
FU Month 1- Binding IgG Ab to PEG (n=2,2)	0	0
FU Month 1- Binding IgM Ab to PEG (n=2,2)	0	0
FU Month 2- Binding IgG Ab to FVIII (n=4,2)	1	0
FU Month 2- Binding IgM Ab to FVIII (n=4,2)	0	0
FU Month 2- Binding IgG Ab to PEG-FVIII (n=4,2)	0	0
FU Month 2- Binding IgM Ab to PEG-FVIII (n=4,2)	0	0
FU Month 2- Binding IgG Ab to PEG (n=4,2)	0	0
FU Month 2- Binding IgM Ab to PEG (n=4,2)	0	0
FU Month 3- Binding IgG Ab to FVIII (n=4,2)	0	0
FU Month 3- Binding IgM Ab to FVIII (n=4,2)	0	0
FU Month 3- Binding IgG Ab to PEG-FVIII (n=4,2)	1	0
FU Month 3- Binding IgM Ab to PEG-FVIII (n=4,2)	0	0
FU Month 3- Binding IgG Ab to PEG (n=4,2)	0	0
FU Month 3- Binding IgM Ab to PEG (n=4,2)	0	0
FU Month 4- Binding IgG Ab to FVIII (n=3,2)	0	0
FU Month 4-Binding IgM Ab to FVIII (n=3,2)	0	0
FU Month 4- Binding IgG Ab to PEG-FVIII (n=3,2)	0	0
FU Month 4- Binding IgM Ab to PEG-FVIII (n=3,2)	0	0
FU Month 5- Binding IgG Ab to FVIII (n=3,2)	1	0
FU Month 5- Binding IgM Ab to FVIII (n=3,2)	0	0
FU Month 5- Binding IgG Ab to PEG-FVIII (n=3,2)	0	0
FU Month 5- Binding IgM Ab to PEG-FVIII (n=3,2)	0	0
FU Month 5- Binding IgG Ab to PEG (n=3,2)	0	0
FU Month 5- Binding IgM Ab to PEG (n=3,2)	0	0
FU Month 6- Binding IgG Ab to FVIII (n=4,2)	0	0
FU Month 6- Binding IgM Ab to FVIII (n=4,2)	0	0
FU Month 6- Binding IgG Ab to PEG-FVIII (n=4,2)	0	0
FU Month 6- Binding IgM Ab to PEG-FVIII (n=4,2)	0	0
FU Month 6- Binding IgG Ab to PEG (n=4,2)	0	0
FU Month 6- Binding IgM Ab to PEG (n=4,2)	0	0
FU Month 7-Binding IgG Ab to FVIII (n=3,2)	0	0
FU Month 7-Binding IgM Ab to FVIII (n=3,2)	0	0
FU Month 7-Binding IgG Ab to PEG-FVIII (n=3,2)	0	0
FU Month 7-Binding IgM Ab to PEG-FVIII (n=3,2)	0	0
FU Month 7-Binding IgG Ab to PEG (n=3,2)	0	0
FU Month 7-Binding IgM Ab to PEG (n=3,2)	0	0
FU Month 8-Binding IgG Ab to FVIII (n=3,1)	0	0
FU Month 8-Binding IgM Ab to FVIII (n=3,1)	0	0
FU Month 8-Binding IgG Ab to PEG-FVIII (n=3,1)	0	0
FU Month 8-Binding IgM Ab to PEG-FVIII (n=3,1)	0	0
FU Month 8-Binding IgG Ab to PEG (n=3,1)	0	0
FU Month 8-Binding IgM Ab to PEG (n=3,1)	0	0
FU Month 9-Binding IgG Ab to FVIII (n=2,1)	0	0
FU Month 9-Binding IgM Ab to FVIII (n=2,1)	0	0
FU Month 9-Binding IgG Ab to PEG-FVIII (n=2,1)	0	0
FU Month 9-Binding IgM Ab to PEG-FVIII (n=2,1)	0	0
FU Month 9-Binding IgG Ab to PEG (n=2,1)	0	0
FU Month 9-Binding IgM Ab to PEG (n=2,1)	0	0
FU Month 10- Binding IgG Ab to FVIII (n=1,1)	0	0
FU Month 10- Binding IgM Ab to FVIII (n=1,1)	0	0
FU Month 10- Binding IgG Ab to PEG-FVIII (n=1,1)	0	0
FU Month 10- Binding IgM Ab to PEG-FVIII (n=1,1)	0	0
FU Month 10- Binding IgG Ab to PEG (n=1,1)	0	0
FU Month 10- Binding IgM Ab to PEG (n=1,1)	0	0
FU Month 11- Binding IgG Ab to FVIII (n=4,1)	0	0
FU Month 11- Binding IgM Ab to FVIII (n=4,1)	0	0
FU Month 11- Binding IgG Ab to PEG-FVIII (n=4,1)	0	0
FU Month 11- Binding IgM Ab to PEG-FVIII (n=4,1)	0	0
FU Month 11- Binding IgG Ab to PEG (n=4,1)	0	0
FU Month 11- Binding IgM Ab to PEG (n=4,1)	0	0
FU Month 12- Binding IgG Ab to FVIII (n=4,1)	0	0
FU Month 12- Binding IgM Ab to FVIII (n=4,1)	0	0
FU Month 12- Binding IgG Ab to PEG-FVIII (n=4,1)	0	0
FU Month 12- Binding IgM Ab to PEG-FVIII (n=4,1)	0	0
FU Month 12- Binding IgG Ab to PEG (n=4,1)	0	0
FU Month 12- Binding IgM Ab to PEG (n=4,1)	0	0
FU Month 13- Binding IgG Ab to FVIII (n=2,1)	0	0
FU Month 13- Binding IgM Ab to FVIII (n=2,1)	0	0
FU Month 13- Binding IgG Ab to PEG-FVIII (n=2,1)	0	0
FU Month 13- Binding IgM Ab to PEG-FVIII (n=2,1)	0	0
FU Month 13- Binding IgG Ab to PEG (n=2,1)	0	0
FU Month 13- Binding IgM Ab to PEG (n=2,1)	0	0
FU Month 14- Binding IgG Ab to FVIII (n=1,1)	0	0
FU Month 14- Binding IgM Ab to FVIII (n=1,1)	0	0
FU Month 14- Binding IgG Ab to PEG-FVIII (n=1,1)	0	0
FU Month 14- Binding IgM Ab to PEG-FVIII (n=1,1)	0	0
FU Month 14- Binding IgG Ab to PEG (n=1,1)	0	0
FU Month 14- Binding IgM Ab to PEG (n=1,1)	0	0
FU Month 15- Binding IgG Ab to FVIII (n=1,1)	0	0
FU Month 15- Binding IgM Ab to FVIII (n=1,1)	0	0
FU Month 15- Binding IgG Ab to PEG-FVIII (n=1,1)	0	0
FU Month 15- Binding IgM Ab to PEG-FVIII (n=1,1)	0	0
FU Month 15- Binding IgG Ab to PEG (n=1,1)	0	0
FU Month 15- Binding IgM Ab to PEG (n=1,1)	0	0
FU Month 16- Binding IgG Ab to FVIII (n=1,1)	0	0
FU Month 16- Binding IgM Ab to FVIII (n=1,1)	0	0
FU Month 16- Binding IgG Ab to PEG-FVIII (n=1,1)	0	0
FU Month 16- Binding IgM Ab to PEG-FVIII (n=1,1)	0	0
FU Month 16- Binding IgG Ab to PEG (n=1,1)	0	0
FU Month 16- Binding IgM Ab to PEG (n=1,1)	0	0
FU Month 17- Binding IgG Ab to FVIII (n=1,1)	0	0
FU Month 17- Binding IgM Ab to FVIII (n=1,1)	0	0
FU Month 17- Binding IgG Ab to PEG-FVIII (n=1,1)	0	0
FU Month 17- Binding IgM Ab to PEG-FVIII (n=1,1)	0	0
FU Month 17- Binding IgG Ab to PEG (n=1,1)	0	0
FU Month 17- Binding IgM Ab to PEG (n=1,1)	0	0
FU Month 18- Binding IgG Ab to FVIII (n=1,1)	0	0
FU Month 18- Binding IgM Ab to FVIII (n=1,1)	0	0
FU Month 18- Binding IgG Ab to PEG-FVIII (n=1,1)	0	0
FU Month 18- Binding IgM Ab to PEG-FVIII (n=1,1)	0	0
FU Month 18- Binding IgG Ab to PEG (n=1,1)	0	0
FU Month 18- Binding IgM Ab to PEG (n=1,1)	0	0
FU Month 19- Binding IgG Ab to FVIII (n=1,0)	0	0
FU Month 19- Binding IgM Ab to FVIII (n=1,0)	0	0
FU Month 19- Binding IgG Ab to PEG-FVIII (n=1,0)	0	0
FU Month 19- Binding IgM Ab to PEG-FVIII (n=1,0)	0	0
FU Month 19- Binding IgG Ab to PEG (n=1,0)	0	0
FU Month 19- Binding IgM Ab to PEG (n=1,0)	0	0
FVIII Inhibitor TC- Binding IgG Ab to FVIII(n=0,0)	0	0
FVIII Inhibitor TC- Binding IgM Ab to FVIII(n=0,0)	0	0
FVIII InhibitorTC-Binding IgGAb toPEG-FVIII(n=0,0)	0	0
FVIII InhibitorTC-Binding IgMAb toPEG-FVIII(n=0,0)	0	0
FVIII Inhibitor TC- Binding IgG Ab to PEG (n=0,0)	0	0
FVIII Inhibitor TC- Binding IgM Ab to PEG (n=0,0)	0	0

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Up to approximately 9 years

Adverse event reporting additional description

SAS and IAS is used. Participant that received on-demand treatment 1st and then moved to prophylaxis treatment was counted for both on-demand and prophylaxis regimens. Participant that started with prophylaxis treatment was counted only for the prophylaxis regimen even if participant received on-demand treatment while on the prophylaxis regimen.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

27.0

Reporting group title

Part A: Main Study: On-demand

Reporting group description

Participants age <3 years and who had not experienced two joint bleeds received on-demand treatment of 10-80IU/kg of BAX 855 IV depending on the severity of the bleeding episode.

Reporting group title

Part B: ITI Portion (100-200 IU/kg Daily Regimen)

Reporting group description

Participants received prophylaxis treatment of 100-200 IU/kg BAX 855 IV daily.

Reporting group title

Part B: ITI Portion (50 IU/kg Three Times Weekly Regimen)

Reporting group description

Participants received prophylaxis treatment of 50 IU/kg BAX 855 IV three times in a week.

Reporting group title

Part A: Main Study: Prophylaxis

Reporting group description

Serious adverse events	Part A: Main Study: On-demand	Part B: ITI Portion (100-200 IU/kg Daily Regimen)	Part B: ITI Portion (50 IU/kg Three Times Weekly Regimen)	Part A: Main Study: Prophylaxis
Total subjects affected by serious adverse events
subjects affected / exposed	18 / 80 (22.50%)	3 / 3 (100.00%)	1 / 4 (25.00%)	35 / 112 (31.25%)
number of deaths (all causes)	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0
Vascular disorders
Haematoma
subjects affected / exposed	1 / 80 (1.25%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 112 (0.89%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhage
subjects affected / exposed	1 / 80 (1.25%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 112 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Vascular device occlusion
subjects affected / exposed	0 / 80 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 112 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	0 / 80 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	4 / 112 (3.57%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	0 / 80 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 112 (0.89%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pharyngeal haemorrhage
subjects affected / exposed	0 / 80 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	1 / 112 (0.89%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Irritability
subjects affected / exposed	0 / 80 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 112 (0.89%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Accidental exposure to product
subjects affected / exposed	0 / 80 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 112 (0.89%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Extradural haematoma
subjects affected / exposed	1 / 80 (1.25%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 112 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Head injury
subjects affected / exposed	1 / 80 (1.25%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 112 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lip injury
subjects affected / exposed	0 / 80 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 112 (0.89%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Mouth injury
subjects affected / exposed	1 / 80 (1.25%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 112 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Post procedural haemorrhage
subjects affected / exposed	0 / 80 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 112 (0.89%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Road traffic accident
subjects affected / exposed	1 / 80 (1.25%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 112 (0.89%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin laceration
subjects affected / exposed	1 / 80 (1.25%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 112 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Subcutaneous haematoma
subjects affected / exposed	1 / 80 (1.25%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 112 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tongue injury
subjects affected / exposed	0 / 80 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 112 (0.89%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Tachycardia
subjects affected / exposed	0 / 80 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 112 (0.89%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Febrile convulsion
subjects affected / exposed	0 / 80 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 112 (0.89%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhage intracranial
subjects affected / exposed	0 / 80 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 112 (0.89%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Immune thrombocytopenia
subjects affected / exposed	0 / 80 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 112 (0.89%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Factor VIII inhibition
subjects affected / exposed	5 / 80 (6.25%)	1 / 3 (33.33%)	0 / 4 (0.00%)	6 / 112 (5.36%)
occurrences causally related to treatment / all	4 / 5	1 / 1	0 / 0	6 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Strabismus
subjects affected / exposed	0 / 80 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 112 (0.89%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Intussusception
subjects affected / exposed	0 / 80 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 112 (0.89%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tongue haemorrhage
subjects affected / exposed	0 / 80 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 112 (0.89%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Mouth haemorrhage
subjects affected / exposed	0 / 80 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 112 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gingival bleeding
subjects affected / exposed	0 / 80 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 112 (0.89%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	1 / 80 (1.25%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 112 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastritis
subjects affected / exposed	0 / 80 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 112 (0.89%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tongue ulceration
subjects affected / exposed	0 / 80 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 112 (0.89%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Nail bed bleeding
subjects affected / exposed	0 / 80 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 112 (0.89%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 80 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 112 (0.89%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemarthrosis
subjects affected / exposed	5 / 80 (6.25%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 112 (0.00%)
occurrences causally related to treatment / all	0 / 5	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Muscle haemorrhage
subjects affected / exposed	2 / 80 (2.50%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 112 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haematoma muscle
subjects affected / exposed	0 / 80 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	3 / 112 (2.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Bacterial infection
subjects affected / exposed	0 / 80 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 112 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	0 / 80 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 112 (0.89%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 80 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 112 (0.89%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia influenzal
subjects affected / exposed	1 / 80 (1.25%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 112 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Device related sepsis
subjects affected / exposed	0 / 80 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 112 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Croup infectious
subjects affected / exposed	0 / 80 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 112 (0.89%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis viral
subjects affected / exposed	0 / 80 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 112 (0.89%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 80 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	2 / 112 (1.79%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	0 / 80 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 112 (0.89%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pharyngitis
subjects affected / exposed	0 / 80 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 112 (0.89%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 80 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	2 / 112 (1.79%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Systemic viral infection
subjects affected / exposed	0 / 80 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 112 (0.89%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tonsillitis
subjects affected / exposed	0 / 80 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 112 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular device infection
subjects affected / exposed	0 / 80 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 112 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Part A: Main Study: On-demand	Part B: ITI Portion (100-200 IU/kg Daily Regimen)	Part B: ITI Portion (50 IU/kg Three Times Weekly Regimen)	Part A: Main Study: Prophylaxis
Total subjects affected by non serious adverse events
subjects affected / exposed	47 / 80 (58.75%)	2 / 3 (66.67%)	4 / 4 (100.00%)	77 / 112 (68.75%)
Investigations
Bacillus test positive
subjects affected / exposed	0 / 80 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 112 (0.00%)
occurrences all number	0	1	0	0
Injury, poisoning and procedural complications
Skin wound
subjects affected / exposed	0 / 80 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 112 (0.00%)
occurrences all number	0	0	1	0
Head injury
subjects affected / exposed	1 / 80 (1.25%)	1 / 3 (33.33%)	0 / 4 (0.00%)	3 / 112 (2.68%)
occurrences all number	1	1	0	3
Blood and lymphatic system disorders
Iron deficiency anaemia
subjects affected / exposed	5 / 80 (6.25%)	0 / 3 (0.00%)	0 / 4 (0.00%)	6 / 112 (5.36%)
occurrences all number	5	0	0	6
Anaemia
subjects affected / exposed	0 / 80 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	2 / 112 (1.79%)
occurrences all number	0	1	0	2
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	17 / 80 (21.25%)	1 / 3 (33.33%)	1 / 4 (25.00%)	31 / 112 (27.68%)
occurrences all number	36	2	1	54
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	5 / 80 (6.25%)	0 / 3 (0.00%)	1 / 4 (25.00%)	9 / 112 (8.04%)
occurrences all number	6	0	1	9
Constipation
subjects affected / exposed	3 / 80 (3.75%)	1 / 3 (33.33%)	1 / 4 (25.00%)	2 / 112 (1.79%)
occurrences all number	3	1	1	2
Oral discomfort
subjects affected / exposed	0 / 80 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 112 (0.00%)
occurrences all number	0	0	1	0
Vomiting
subjects affected / exposed	5 / 80 (6.25%)	0 / 3 (0.00%)	1 / 4 (25.00%)	6 / 112 (5.36%)
occurrences all number	6	0	1	7
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	7 / 80 (8.75%)	1 / 3 (33.33%)	0 / 4 (0.00%)	16 / 112 (14.29%)
occurrences all number	7	1	0	28
Rhinorrhoea
subjects affected / exposed	4 / 80 (5.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	7 / 112 (6.25%)
occurrences all number	6	0	0	11
Skin and subcutaneous tissue disorders
Pruritus
subjects affected / exposed	0 / 80 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 112 (0.00%)
occurrences all number	0	0	1	0
Rash
subjects affected / exposed	3 / 80 (3.75%)	1 / 3 (33.33%)	0 / 4 (0.00%)	3 / 112 (2.68%)
occurrences all number	3	1	0	4
Dermatitis allergic
subjects affected / exposed	0 / 80 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 112 (0.00%)
occurrences all number	0	0	1	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 80 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 112 (0.00%)
occurrences all number	0	0	1	0
Infections and infestations
Nasopharyngitis
subjects affected / exposed	6 / 80 (7.50%)	0 / 3 (0.00%)	2 / 4 (50.00%)	18 / 112 (16.07%)
occurrences all number	10	0	2	27
Otitis media
subjects affected / exposed	5 / 80 (6.25%)	0 / 3 (0.00%)	0 / 4 (0.00%)	7 / 112 (6.25%)
occurrences all number	8	0	0	8
Gastroenteritis
subjects affected / exposed	3 / 80 (3.75%)	0 / 3 (0.00%)	0 / 4 (0.00%)	7 / 112 (6.25%)
occurrences all number	3	0	0	7
Influenza
subjects affected / exposed	3 / 80 (3.75%)	0 / 3 (0.00%)	0 / 4 (0.00%)	8 / 112 (7.14%)
occurrences all number	3	0	0	8
Ear infection
subjects affected / exposed	4 / 80 (5.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	7 / 112 (6.25%)
occurrences all number	8	0	0	13
COVID-19
subjects affected / exposed	1 / 80 (1.25%)	1 / 3 (33.33%)	0 / 4 (0.00%)	5 / 112 (4.46%)
occurrences all number	1	1	0	5
Pharyngitis
subjects affected / exposed	1 / 80 (1.25%)	0 / 3 (0.00%)	0 / 4 (0.00%)	6 / 112 (5.36%)
occurrences all number	1	0	0	9
Rhinitis
subjects affected / exposed	5 / 80 (6.25%)	0 / 3 (0.00%)	0 / 4 (0.00%)	7 / 112 (6.25%)
occurrences all number	5	0	0	12
Viral infection
subjects affected / exposed	3 / 80 (3.75%)	0 / 3 (0.00%)	1 / 4 (25.00%)	12 / 112 (10.71%)
occurrences all number	4	0	1	16
Scarlet fever
subjects affected / exposed	0 / 80 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 112 (0.00%)
occurrences all number	0	0	1	0
Vessel puncture site cellulitis
subjects affected / exposed	0 / 80 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 112 (0.00%)
occurrences all number	0	1	0	0
Vascular device infection
subjects affected / exposed	0 / 80 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 112 (0.00%)
occurrences all number	0	1	0	0
Upper respiratory tract infection
subjects affected / exposed	12 / 80 (15.00%)	0 / 3 (0.00%)	2 / 4 (50.00%)	27 / 112 (24.11%)
occurrences all number	15	0	3	54

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Were there any global substantial amendments to the protocol? Yes

26 Nov 2015

The following changes were made as per Amendment 3: 1. The definition of high-titer inhibitor was changed from ≥5 BU to ˃5 BU, to comply with standard definition of high-titer FVIII inhibitor. 2. The use of anti-cluster of differentiation 20 (CD20) chimeric monoclonal antibody rituximab with BAX 855 during ITI/inhibitor treatment was allowed. 3. The definitions of ITI/inhibitor treatment success, partial success, and failure were revised. 4. The inclusion criteria for Part B (ITI/inhibitor treatment) were revised. 5. The duration of Part B was revised. 6. Section on BAX 855 dosing for PK assessment was newly added to provide guidance on half-life determination in Part A but also Part B as half-life constitutes a criterion for ITI/inhibitor treatment success.

08 Feb 2018

The following changes were made as per Amendment 4: 1. The total number of Advate exposures was limited to 2 EDs total, including prior to enrollment and during the screening period. 2. The ITI/inhibitor treatment failure definition was updated to be conditional on the absence of an infection that could explain a failure of inhibitory titers to decrease, in the opinion of the investigator. 3. Wording was added that unless consent is withdrawn, participants may be contacted by the investigator after the trial completion visit for up to 3 months for supplemental clinical information related to the trial, if needed. 4. Wording was added that any site changes/corrections to participant diary data need to be supported by source documentation.

21 Jun 2021

The following changes were made as per Amendment 8: 1. The definition of target joint was amended to be consistent with International Society on Thrombosis and Haemostasis (ISTH) 2014 criteria. 2. A new section was added due to the coronavirus disease 2019 (COVID-19) pandemic that added the provision to include remote source document verification (rSDV), if needed, at sites where it was allowed. 3. Optional extension of access sections was added to describe the terms and conditions under which participants who completed the protocol may have continued access to BAX 855.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: Phase 3, Prospective, Multi-center, Open Label Study to Investigate Safety, Immunogenicity, and Hemostatic Efficacy of PEGylated Factor VIII (BAX 855) in Previously Untreated Patients (PUPs) <6 years With Severe Hemophilia A (FVIII <1%)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of Participants With FVIII Inhibitor Development

Primary: Number of Participants With FVIII Inhibitor Development

Primary: Number of Participants With Success of Immune Tolerance Induction (ITI)

Primary: Number of Participants With Success of Immune Tolerance Induction (ITI)

Secondary: Number of Participants With Binding Immunoglobulin G (IgG) and Immunoglobulin M (IgM) Antibodies

Secondary: Number of Participants With Binding Immunoglobulin G (IgG) and Immunoglobulin M (IgM) Antibodies

Secondary: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

Secondary: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

Secondary: Number of Participants With At Least One Clinically Significant Changes in Clinical Laboratory Parameters

Secondary: Number of Participants With At Least One Clinically Significant Changes in Clinical Laboratory Parameters

Secondary: Number of Participants With At Least One Clinically Significant Changes in Vital Signs

Secondary: Number of Participants With At Least One Clinically Significant Changes in Vital Signs

Secondary: Annualized Bleeding Rate (ABR) for Prophylactic and On-demand Treatment and Immune Tolerance Induction (ITI)

Secondary: Annualized Bleeding Rate (ABR) for Prophylactic and On-demand Treatment and Immune Tolerance Induction (ITI)

Secondary: Bleeding Episodes Categorized by Number of BAX 855 Infusions Required for Treatment

Secondary: Bleeding Episodes Categorized by Number of BAX 855 Infusions Required for Treatment

Secondary: Number of Bleeds by Overall Hemostatic Efficacy Rating at 24 Hours After Initiation of Treatment

Secondary: Number of Bleeds by Overall Hemostatic Efficacy Rating at 24 Hours After Initiation of Treatment

Secondary: Number of Bleeds by Overall Hemostatic Efficacy Rating at Bleed Resolution

Secondary: Number of Bleeds by Overall Hemostatic Efficacy Rating at Bleed Resolution

Secondary: Weight-adjusted Consumption of BAX 855: Average Number of Prophylactic Infusions

Secondary: Weight-adjusted Consumption of BAX 855: Average Number of Prophylactic Infusions

Secondary: Weight-adjusted Consumption of BAX 855: Average Prophylactic Dose

Secondary: Weight-adjusted Consumption of BAX 855: Average Prophylactic Dose

Secondary: Weight-adjusted Consumption of BAX 855: Average Dose

Secondary: Weight-adjusted Consumption of BAX 855: Average Dose

Secondary: Number of Participants by Hemostatic Efficacy Rating in Case of Surgery

Secondary: Number of Participants by Hemostatic Efficacy Rating in Case of Surgery

Secondary: Incremental Recovery (IR) of BAX 855

Secondary: Incremental Recovery (IR) of BAX 855

Secondary: Blood Loss Per Participant in Case of Surgery

Secondary: Blood Loss Per Participant in Case of Surgery

Secondary: Half-life (T1/2) of BAX 855

Secondary: Half-life (T1/2) of BAX 855

Secondary: Immune Tolerance Induction (ITI) – Number of Participants With Partial Success and Failure of ITI

Secondary: Immune Tolerance Induction (ITI) – Number of Participants With Partial Success and Failure of ITI

Secondary: Immune Tolerance Induction (ITI) - Number of Participants With At Least One Catheter-related Complication

Secondary: Immune Tolerance Induction (ITI) - Number of Participants With At Least One Catheter-related Complication

Secondary: Immune Tolerance Induction (ITI) – Number of Participants With Binding Immunoglobulin G (IgG) and Immunoglobulin M (IgM) Antibodies

Secondary: Immune Tolerance Induction (ITI) – Number of Participants With Binding Immunoglobulin G (IgG) and Immunoglobulin M (IgM) Antibodies

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
Phase 3, Prospective, Multi-center, Open Label Study to Investigate Safety, Immunogenicity, and Hemostatic Efficacy of PEGylated Factor VIII (BAX 855) in Previously Untreated Patients (PUPs) <6 years With Severe Hemophilia A (FVIII <1%)