A Trial Investigating Safety and Efficacy of Treatment With BAY94-9027 in Severe Hemophilia A (PROTECT-VIII)

• ClinicalTrials.gov Identifier: NCT01580293
• Recruitment Status: Completed
• First Posted: April 19, 2012
• Results First Posted: December 6, 2018
• Last Update Posted: December 2, 2020
• Sponsor: Bayer
• Information provided by (Responsible Party): Bayer

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Hemophilia A
• Intervention: Biological: BAY94-9027
• Enrollment: 145

Participant Flow

Recruitment Details	The study was conducted in 3 parts: Part A (main study [36-week treatment period] and an optional extension [at least 100 total exposure days]) and Part B for major surgeries (up to 3 weeks).
Pre-assignment Details	Of 149 participants screened in Part A, 134 were treated, reasons for non-inclusion were screen failure, consent withdrawal, and non-adherence to protocol visit windows. Participants selected either on-demand or prophylaxis treatment at start of study according to their preference. Randomization to prophylaxis arms occurred after week 10.

Arm/Group Title	BAY94-9027 On-demand Treatment, Part A	BAY94-9027 Prophylaxis Treatment, Part A	BAY949027 Treatment in Major Surgery, Part B
Arm/Group Description	Participants received on-demand treatment with BAY94-9027 as an intravenous (IV) infusion at a dose as indicated based upon location and severity of bleeds (a maximum of 60 international units per kilogram [IU/kg]). Participants entering extension either continued their on-demand treatment or switched to one of the prophylaxis regimens.	All participants started BAY94-9027 IV infusion, with 2x/week at a dose of 25 IU/kg for 10 weeks. Thereafter, participants with less than 2 spontaneous joint and/or muscle bleeds were randomized 1:1 to either every 5 or every 7 days dosing regimen. High bleeders continued 2x/week infusion (2x/week 'failed'). Participants qualified to be randomized but enrolled after randomized arms were filled, remained on 2x/week treatment (2x/week 'forced' group). Participants entering extension either continued their prophylaxis regimen or switched to one of the other prophylaxis regimens.	Participants who underwent major surgery received study drug during their hospital stay up to 3 weeks post surgery. Participants were treated according to the type of procedure, using tailored doses (a maximum of 60 IU/kg/infusion) expected to maintain acceptable therapeutic level of FVIII activity.
Period Title: Part A_Main Trial
Started [1]	20	114	0 [2]
Completed	18	108	0
Not Completed	2	6	0
Reason Not Completed
Adverse Event	0	2	0
Withdrawal by Subject	1	4	0
Non-adherence to the protocol	1	0	0
[1] Received Treatment; [2] Participants in Part B were not counted for Part A
Period Title: Part A_Extension
Started	14 [1]	107 [1]	0 [2]
Completed	14	95	0
Not Completed	0	12	0
Reason Not Completed
Adverse Event	0	2	0
Withdrawal by Subject	0	3	0
Lost to Follow-up	0	1	0
Other Reason	0	1	0
Completed Japan only	0	5	0
[1] Not all participants from main trial entered extension or remained in the same arm.; [2] Participants in Part B were not counted for part A
Period Title: Part B
Started [1]	0 [2]	0 [2]	19 [3]
Completed	0	0	17
Not Completed	0	0	2
Reason Not Completed
Withdrawal by Subject	0	0	1
Other reason	0	0	1
[1] Treated in Part B; [2] Time in Part A for 8 participants coming from Part A was not counted in part B.; [3] 11 participants were enrolled in Part B only, 8 participants switched from Part A to Part B.

Baseline Characteristics

Arm/Group Title		BAY94-9027 On-demand Treatment, Main Trial	BAY94-9027 Prophylaxis Treatment, 2x/Week Dropped, Main Trial	BAY94-9027 Prophylaxis Treatment, 2x/Week Failed, Main Trial	BAY94-9027 Prophylaxis Treatment, 2x/Week Forced, Main Trial	BAY94-9027 Prophylaxis Treatment, Every 5 Days, Main Trial	BAY94-9027 Prophylaxis Treatment, Every 7 Days, Main Trial	BAY94-9027 Treatment in Major Surgery, Part B Only	Total
Arm/Group Description		Participants received on-demand treatment with BAY94-9027 as an intravenous (IV)infusion at a dose as indicated based upon location and severity of bleeds (a maximum of 60 international units per kilogram [IU/kg]).	4 participants dropped out during week 0-10	All participants started BAY94-9027 IV infusion with 2x/week at a dose of 25 IU/kg for 10 weeks. High bleeders (with 2 or more muscle or joint bleeds in the first 10 weeks) continued 2x/week infusion (2x/week 'failed') at a dose of 30 to 40 IU/kg.	All participants started BAY94-9027 IV infusion with 2x/week at a dose of 25 IU/kg for 10 weeks. Participants with < 2 spontaneous joint and/or muscle bleeds were randomized 1:1 to either every 5 or every 7 days dosing regimen. Participants enrolled after randomization arms were filled continued 2x/week treatment at a dose of 30-40 IU/kg (2x/week 'forced').	All participants started BAY94-9027 IV infusion with 2x/week at a dose of 25 IU/kg for 10 weeks. Participants with < 2 spontaneous joint and/or muscle bleeds were randomized 1:1 to either every 5 or every 7 days dosing regimen, participants randomized to the every 5 days treatment arm were to begin treatment with 45 IU/kg every 5 days with the option to increase dose up to 60 IU/kg/infusion.	All participants started BAY94-9027 IV infusion with 2x/week at a dose of 25 IU/kg for 10 weeks. Participants <2 spontaneous joint and/or muscle bleeds were randomized 1:1 to either every 5 or every 7 days dosing regimen, participants randomized to the every 7 days treatment arm were to administer a dose of 60 IU/kg (maximum 6000 IU) every 7 days.	Participants treated in Part B only were included. Participants treated in Part A and continued in Part B were excluded. Participants who underwent major surgery received study drug during their hospital stay and up until hospital discharge or 3 weeks post-surgery, whichever came first. Participants were treated according to the type of procedure, using tailored doses (a maximum of 60 IU/kg) expected to maintain acceptable therapeutic level of FVIII activity.	Total of all reporting groups
Overall Number of Baseline Participants		20	4	13	11	43	43	11	145
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	20 participants	4 participants	13 participants	11 participants	43 participants	43 participants	11 participants	145 participants
		44.8 (13.5)	27.3 (14.2)	31.4 (11.6)	33.1 (11.0)	33.7 (13.0)	37.0 (13.5)	37.9 (13.7)	36.1 (13.5)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	20 participants	4 participants	13 participants	11 participants	43 participants	43 participants	11 participants	145 participants
	Female	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Male	20 100.0%	4 100.0%	13 100.0%	11 100.0%	43 100.0%	43 100.0%	11 100.0%	145 100.0%

Outcome Measures

1. Primary Outcome

Title	Annualized Number of Total Bleeds in On-demand Treatment Arm (Weeks 0 -36) and in Each Prophylaxis Arm (Weeks 10 - 36, Excluding Rescue Bleeds) - Part A, Main Trial
Description	Annualized number of total bleeds was defined as the annualized sum of spontaneous bleeds and trauma bleeds. A participant who had the one-time increase in dose frequency was regarded as rescued. A rescue bleed was a bleed that occured after the dose frequency was increased. Rescue bleeds and periods were not considered for the annualized bleeding rate (ABR).
Time Frame	On-demand: Weeks 0 -36 and Prophylaxis: Weeks 10 - 36 during Part A

Outcome Measure Data

Analysis Population Description

Intent to treat (ITT) population part A week 10-36, 4 participants dropped out during week 0-10.

Arm/Group Title	BAY94-9027 On-demand Treatment, Main Trial	BAY94-9027 Prophylaxis Treatment, 2x/Week Failed, Main Trial	BAY94-9027 Prophylaxis Treatment, 2x/Week Forced, Main Trial	BAY94-9027 Prophylaxis Treatment, Every 5 Days, Main Trial	BAY94-9027 Prophylaxis Treatment, Every 7 Days, Main Trial	BAY94-9027 Prophylaxis Treatment Total, Main Trial
Arm/Group Description:	Participants received on-demand treatment with BAY94-9027 as an intravenous (IV)infusion at a dose as indicated based upon location and severity of bleeds (a maximum of 60 international units per kilogram [IU/kg]).	All participants started BAY94-9027 IV infusion with 2x/week at a dose of 25 IU/kg for 10 weeks. High bleeders (with 2 or more muscle or joint bleeds in the first 10 weeks) continued 2x/week infusion (2x/week 'failed') at a dose of 30 to 40 IU/kg.	All participants started BAY94-9027 IV infusion with 2x/week at a dose of 25 IU/kg for 10 weeks. Participants with < 2 spontaneous joint and/or muscle bleeds were randomized 1:1 to either every 5 or every 7 days dosing regimen. Participants enrolled after randomization arms were filled continued 2x/week treatment at a dose of 30-40 IU/kg (2x/week 'forced').	All participants started BAY94-9027 IV infusion with 2x/week at a dose of 25 IU/kg for 10 weeks. Participants with < 2 spontaneous joint and/or muscle bleeds were randomized 1:1 to either every 5 or every 7 days dosing regimen, participants randomized to the every 5 days treatment arm were to begin treatment with 45 IU/kg every 5 days with the option to increase dose up to 60 IU/kg/infusion.	All participants started BAY94-9027 IV infusion with 2x/week at a dose of 25 IU/kg for 10 weeks. Participants <2 spontaneous joint and/or muscle bleeds were randomized 1:1 to either every 5 or every 7 days dosing regimen, participants randomized to the every 7 days treatment arm were to administer a dose of 60 IU/kg (maximum 6000 IU) every 7 days.	All participants receiving an schedule of prophylaxis treatment, all prophylaxis arms combined.
Overall Number of Participants Analyzed	20	13	11	43	43	110
Median (Inter-Quartile Range); Unit of Measure: bleeds
	23.42; (17.84 to 37.25)	4.11; (2.01 to 10.56)	1.93; (0.00 to 5.24)	1.93; (0.00 to 4.23)	3.85; (0.00 to 6.47)	2.09; (0.00 to 6.05)

2. Secondary Outcome

Title	Annualized Number of Joint Bleeds, Trauma, Spontaneous Bleeds in On-demand Treatment Arm (Weeks 0 -36) and in Each Prophylaxis Arm (Weeks 10 - 36, Excluding Rescue Bleeds) - Part A
Description	A participant who had the one-time increase in dose frequency was regarded as rescued. A rescue bleed was a bleed that occured after the dose frequency was increased. Rescue bleeds and periods were not considered for the ABR.
Time Frame	On-demand: Weeks 0 -36 and Prophylaxis: Weeks 10 - 36 during Part A

Outcome Measure Data

Analysis Population Description

ITT population part A week 10-36, 4 participants dropped out during week 0-10.

Arm/Group Title	BAY94-9027 On-demand Treatment, Main Trial	BAY94-9027 Prophylaxis Treatment, 2x/Week Failed, Main Trial	BAY94-9027 Prophylaxis Treatment, 2x/Week Forced, Main Trial	BAY94-9027 Prophylaxis Treatment, Every 5 Days, Main Trial	BAY94-9027 Prophylaxis Treatment, Every 7 Days, Main Trial	BAY94-9027 Prophylaxis Treatment Total, Main Trial
Arm/Group Description:	Participants received on-demand treatment with BAY94-9027 as an intravenous (IV)infusion at a dose as indicated based upon location and severity of bleeds (a maximum of 60 international units per kilogram [IU/kg]).	All participants started BAY94-9027 IV infusion with 2x/week at a dose of 25 IU/kg for 10 weeks. High bleeders (with 2 or more muscle or joint bleeds in the first 10 weeks) continued 2x/week infusion (2x/week 'failed') at a dose of 30 to 40 IU/kg.	All participants started BAY94-9027 IV infusion with 2x/week at a dose of 25 IU/kg for 10 weeks. Participants with < 2 spontaneous joint and/or muscle bleeds were randomized 1:1 to either every 5 or every 7 days dosing regimen. Participants enrolled after randomization arms were filled continued 2x/week treatment at a dose of 30-40 IU/kg (2x/week 'forced').	All participants started BAY94-9027 IV infusion with 2x/week at a dose of 25 IU/kg for 10 weeks. Participants with < 2 spontaneous joint and/or muscle bleeds were randomized 1:1 to either every 5 or every 7 days dosing regimen, participants randomized to the every 5 days treatment arm were to begin treatment with 45 IU/kg every 5 days with the option to increase dose up to 60 IU/kg/infusion.	All participants started BAY94-9027 IV infusion with 2x/week at a dose of 25 IU/kg for 10 weeks. Participants <2 spontaneous joint and/or muscle bleeds were randomized 1:1 to either every 5 or every 7 days dosing regimen, participants randomized to the every 7 days treatment arm were to administer a dose of 60 IU/kg (maximum 6000 IU) every 7 days.	All participants receiving an schedule of prophylaxis treatment, all prophylaxis arms combined.
Overall Number of Participants Analyzed	20	13	11	43	43	110
Median (Inter-Quartile Range); Unit of Measure: bleeds
Joint Bleeds	16.34; (11.61 to 30.30)	4.01; (1.98 to 8.03)	1.93; (0.00 to 5.24)	1.86; (0.00 to 3.99)	1.92; (0.00 to 6.26)	1.93; (0.00 to 5.24)
Trauma Bleeds	9.09; (3.08 to 15.53)	1.98; (0.00 to 5.80)	0.00; (0.00 to 1.93)	0.00; (0.00 to 2.09)	0.00; (0.00 to 0.00)	0.00; (0.00 to 1.98)
Spontaneous Bleeds	14.29; (7.26 to 22.71)	3.87; (0.00 to 4.11)	0.00; (0.00 to 1.93)	0.00; (0.00 to 3.99)	1.93; (0.00 to 6.33)	0.00; (0.00 to 4.17)

3. Secondary Outcome

Title	Annualized Number of Total Bleeds in On-demand Treatment Arm and in Each Prophylaxis Arm, Part A, Extension
Description	Annualized number of total bleeds was defined as the annualized sum of spontaneous bleeds and trauma bleeds.
Time Frame	at least 100 total exposure days acquired, median time 3.9 years up to 7 years maximum

Outcome Measure Data

Analysis Population Description

ITT extension population. Participants in each regimen stayed on this regimen without switch. Participants who switched regimen were analyzed in the variable frequency arm.

Arm/Group Title	BAY94-9027 On-demand Treatment, Extension	BAY94-9027 Prophylaxis Treatment, 2x/Week, Extension	BAY94-9027 Prophylaxis Treatment, Every 5 Days, Extension	BAY94-9027 Prophylaxis Treatment, Every 7 Days, Extension	BAY94-9027 Prophylaxis Treatment, Variable, Extension
Arm/Group Description:	On-demand participants entering the Part A extension either continued their on-demand treatment or switched to one of the prophylaxis regimens.	Prophylaxis participants entering the Part A extension were either to continue their prophylaxis regimen as it was at the conclusion of the main trial, or had the option of switching to one of the other prophylaxis regimens.	Prophylaxis participants entering the Part A extension were either to continue their prophylaxis regimen as it was at the conclusion of the main trial, or had the option of switching to one of the other prophylaxis regimens.	Prophylaxis participants entering the Part A extension were either to continue their prophylaxis regimen as it was at the conclusion of the main trial, or had the option of switching to one of the other prophylaxis regimens.	Participants changed their treatment regimens at least once after 1st week in extension.
Overall Number of Participants Analyzed	14	23	33	23	28
Median (Inter-Quartile Range); Unit of Measure: bleeds
	34.09; (20.33 to 36.63)	1.57; (0.79 to 3.61)	1.17; (0.00 to 4.57)	0.65; (0.00 to 1.68)	3.10; (1.13 to 5.86)

4. Secondary Outcome

Title	Number of Participants Developed Human Coagulation Factor VIII (FVIII) Inhibitor - Part A
Description	FVIII inhibitor testing was done according to the Nijmegen modified Bethesda assay. A positive inhibitor test was defined with a threshold of ≥0.6 Bethesda unit (BU) at the central laboratory.
Time Frame	Weeks 0 to 36 during Part A

Outcome Measure Data

Analysis Population Description

Part A safety population (N=134) included all participants who received at least 1 dose of study drug during Part A of the study.

Arm/Group Title	BAY94-9027 On-demand Treatment, Main Trial	BAY94-9027 Prophylaxis Treatment, Week 0-36, Main Trial
Arm/Group Description:	Participants received on-demand treatment with BAY94-9027 as an intravenous (IV)infusion at a dose as indicated based upon location and severity of bleeds (a maximum of 60 international units per kilogram [IU/kg]).	All participants in the prophylaxis arms started BAY94-9027 IV infusion, with 2x/week at a dose of 25 IU/kg for 10 weeks. Thereafter, participants with less than 2 spontaneous joint and/or muscle bleeds were randomized 1:1 to either every 5 or every 7 days dosing regimen. High bleeders continued 2x/week infusion (2x/week 'failed'). Participants qualified to be randomized, but enrolled after randomized arms were filled, remained on 2x/week treatment (2x/week 'forced' group).
Overall Number of Participants Analyzed	20	114
Measure Type: Count of Participants; Unit of Measure: Participants
	0 0.0%	0 0.0%

5. Secondary Outcome

Title	Number of Bleeds Requiring 1, 2 or >= 3 Infusions to Control the Bleed - Part A
Description	Number of bleeds requiring 1, 2 or >= 3 infusions to control the bleeding
Time Frame	Weeks 0 to 36

Outcome Measure Data

Analysis Population Description

Part A ITT population, analysis population includes participants who presented >=1 bleeding event.

Arm/Group Title	BAY94-9027 On-demand Treatment, Main Trial	BAY94-9027 Prophylaxis Treatment, Week 0-36, Main Trial
Arm/Group Description:	Participants received on-demand treatment with BAY94-9027 as an intravenous (IV)infusion at a dose as indicated based upon location and severity of bleeds (a maximum of 60 international units per kilogram [IU/kg]).	All participants in the prophylaxis arms started BAY94-9027 IV infusion, with 2x/week at a dose of 25 IU/kg for 10 weeks. Thereafter, participants with less than 2 spontaneous joint and/or muscle bleeds were randomized 1:1 to either every 5 or every 7 days dosing regimen. High bleeders continued 2x/week infusion (2x/week 'failed'). Participants qualified to be randomized, but enrolled after randomized arms were filled, remained on 2x/week treatment (2x/week 'forced' group).
Overall Number of Participants Analyzed	20	75
Overall Number of Units Analyzed; Type of Units Analyzed: Bleeds	386	316
Measure Type: Number; Unit of Measure: bleeds
1 infusion	307	262
2 infusions	45	22
Greater than or equal to (>=) 3 infusions	34	32

6. Secondary Outcome

Title	Number of Bleeds According to Locations - Part A
Description	Bleed locations were categorised as joint, muscle, skin/mucosa, internal, others and missing.
Time Frame	Weeks 0 -36

Outcome Measure Data

Analysis Population Description

Analysis population includes participants who presented >=1 bleeding event.

Arm/Group Title	BAY94-9027 On-demand Treatment, Main Trial	BAY94-9027 Prophylaxis Treatment, Week 0-36, Main Trial
Arm/Group Description:	Participants received on-demand treatment with BAY94-9027 as an intravenous (IV)infusion at a dose as indicated based upon location and severity of bleeds (a maximum of 60 international units per kilogram [IU/kg]).	All participants in the prophylaxis arms started BAY94-9027 IV infusion, with 2x/week at a dose of 25 IU/kg for 10 weeks. Thereafter, participants with less than 2 spontaneous joint and/or muscle bleeds were randomized 1:1 to either every 5 or every 7 days dosing regimen. High bleeders continued 2x/week infusion (2x/week 'failed'). Participants qualified to be randomized, but enrolled after randomized arms were filled, remained on 2x/week treatment (2x/week 'forced' group).
Overall Number of Participants Analyzed	20	75
Overall Number of Units Analyzed; Type of Units Analyzed: Bleeds	386	316
Measure Type: Number; Unit of Measure: bleeds
Missing	0	0
Joint	303	235
Muscle	54	59
Skin/Mucosa	12	12
Internal	7	7
Other	26	16

7. Secondary Outcome

Title	Number of Bleeds Over Time Since Previous Prophylaxis Infusion - Part A
Description	[Not Specified]
Time Frame	Weeks 0 to 36

Outcome Measure Data

Analysis Population Description

Analysis population includes participants who presented >=1 bleeding event.

Arm/Group Title	BAY94-9027 On-demand Treatment, Main Trial	BAY94-9027 Prophylaxis Treatment, Week 0-36, Main Trial
Arm/Group Description:	Participants received on-demand treatment with BAY94-9027 as an intravenous (IV)infusion at a dose as indicated based upon location and severity of bleeds (a maximum of 60 international units per kilogram [IU/kg]).	All participants in the prophylaxis arms started BAY94-9027 IV infusion, with 2x/week at a dose of 25 IU/kg for 10 weeks. Thereafter, participants with less than 2 spontaneous joint and/or muscle bleeds were randomized 1:1 to either every 5 or every 7 days dosing regimen. High bleeders continued 2x/week infusion (2x/week 'failed'). Participants qualified to be randomized, but enrolled after randomized arms were filled, remained on 2x/week treatment (2x/week 'forced' group).
Overall Number of Participants Analyzed	20	75
Overall Number of Units Analyzed; Type of Units Analyzed: Bleeds	386	316
Measure Type: Number; Unit of Measure: bleeds
<1 day	4	21
>=1 to <2 days	19	62
>=2 to <3 days	30	82
>=3 to <4 days	30	69
>=4 to <5 days	38	32
>=5 to <6 days	42	36
>=6 to <7 days	31	11
>=7 days	192	3

8. Secondary Outcome

Title	Number of Bleeds According to Participant's Assessment of Response to Treatment - Part A
Description	Response to treatment was assessed by participant as excellent, good, moderate, poor or missing during Part A of the study.
Time Frame	Weeks 0 to 36 during Part A

Outcome Measure Data

Analysis Population Description

Analysis population includes participants who presented >=1 bleeding event.

Arm/Group Title	BAY94-9027 On-demand Treatment, Main Trial	BAY94-9027 Prophylaxis Treatment, Week 0-36, Main Trial
Arm/Group Description:	Participants received on-demand treatment with BAY94-9027 as an intravenous (IV)infusion at a dose as indicated based upon location and severity of bleeds (a maximum of 60 international units per kilogram [IU/kg]).	All participants in the prophylaxis arms started BAY94-9027 IV infusion, with 2x/week at a dose of 25 IU/kg for 10 weeks. Thereafter, participants with less than 2 spontaneous joint and/or muscle bleeds were randomized 1:1 to either every 5 or every 7 days dosing regimen. High bleeders continued 2x/week infusion (2x/week 'failed'). Participants qualified to be randomized, but enrolled after randomized arms were filled, remained on 2x/week treatment (2x/week 'forced' group).
Overall Number of Participants Analyzed	20	75
Overall Number of Units Analyzed; Type of Units Analyzed: Bleeds	386	316
Measure Type: Number; Unit of Measure: bleeds
Excellent or Good	252	256
Excellent	81	107
Good	171	149
Moderate	115	47
Poor	16	7
Missing	3	6

9. Secondary Outcome

Title	Recombinant Human Factor VIII (rFVIII) Usage Expressed as Total Dose Per Kilogram Per Year - Part A
Description	For prophylaxis patients, the dose is related to all infusions.
Time Frame	On-demand: Weeks 0 -36 and Prophylaxis: Weeks 10 - 36 during Part A

Outcome Measure Data

Analysis Population Description

ITT population part A week 10-36, 4 participants dropped out during week 0-10.

Arm/Group Title	BAY94-9027 On-demand Treatment, Main Trial	BAY94-9027 Prophylaxis Treatment, 2x/Week Failed, Main Trial	BAY94-9027 Prophylaxis Treatment, 2x/Week Forced, Main Trial	BAY94-9027 Prophylaxis Treatment, Every 5 Days, Main Trial	BAY94-9027 Prophylaxis Treatment, Every 7 Days, Main Trial	BAY94-9027 Prophylaxis Treatment Total, Main Trial
Arm/Group Description:	Participants received on-demand treatment with BAY94-9027 as an intravenous (IV)infusion at a dose as indicated based upon location and severity of bleeds (a maximum of 60 international units per kilogram [IU/kg]).	All participants started BAY94-9027 IV infusion with 2x/week at a dose of 25 IU/kg for 10 weeks. High bleeders (with 2 or more muscle or joint bleeds in the first 10 weeks) continued 2x/week infusion (2x/week 'failed') at a dose of 30 to 40 IU/kg.	All participants started BAY94-9027 IV infusion with 2x/week at a dose of 25 IU/kg for 10 weeks. Participants with < 2 spontaneous joint and/or muscle bleeds were randomized 1:1 to either every 5 or every 7 days dosing regimen. Participants enrolled after randomization arms were filled continued 2x/week treatment at a dose of 30-40 IU/kg (2x/week 'forced').	All participants started BAY94-9027 IV infusion with 2x/week at a dose of 25 IU/kg for 10 weeks. Participants with < 2 spontaneous joint and/or muscle bleeds were randomized 1:1 to either every 5 or every 7 days dosing regimen, participants randomized to the every 5 days treatment arm were to begin treatment with 45 IU/kg every 5 days with the option to increase dose up to 60 IU/kg/infusion.	All participants started BAY94-9027 IV infusion with 2x/week at a dose of 25 IU/kg for 10 weeks. Participants <2 spontaneous joint and/or muscle bleeds were randomized 1:1 to either every 5 or every 7 days dosing regimen, participants randomized to the every 7 days treatment arm were to administer a dose of 60 IU/kg (maximum 6000 IU) every 7 days.	All participants receiving an schedule of prophylaxis treatment, all prophylaxis arms combined.
Overall Number of Participants Analyzed	20	13	11	43	43	110
Median (Full Range); Unit of Measure: IU/kg/year
	1518.5; (390 to 3655)	4421.4; (3759 to 5978)	3314.4; (2651 to 4062)	3482.9; (2936 to 6774)	3338.7; (2764 to 5789)	3421.0; (2651 to 6774)

10. Secondary Outcome

Title	Recombinant Human Factor VIII (rFVIII) Usage Expressed as Dose Per Kilogram Per Infusion - Part A
Description	For prophylaxis patients, the dose per infusion related to prophylaxis infusion.
Time Frame	On-demand: Weeks 0 -36 and Prophylaxis: Weeks 10 - 36 during Part A

Outcome Measure Data

Analysis Population Description

ITT population part A week 10-36, 4 participants dropped out during week 0-10.

Arm/Group Title	BAY94-9027 On-demand Treatment, Main Trial	BAY94-9027 Prophylaxis Treatment, 2x/Week Failed, Main Trial	BAY94-9027 Prophylaxis Treatment, 2x/Week Forced, Main Trial	BAY94-9027 Prophylaxis Treatment, Every 5 Days, Main Trial	BAY94-9027 Prophylaxis Treatment, Every 7 Days, Main Trial	BAY94-9027 Prophylaxis Treatment Total, Main Trial
Arm/Group Description:	Participants received on-demand treatment with BAY94-9027 as an intravenous (IV)infusion at a dose as indicated based upon location and severity of bleeds (a maximum of 60 international units per kilogram [IU/kg]).	All participants started BAY94-9027 IV infusion with 2x/week at a dose of 25 IU/kg for 10 weeks. High bleeders (with 2 or more muscle or joint bleeds in the first 10 weeks) continued 2x/week infusion (2x/week 'failed') at a dose of 30 to 40 IU/kg.	All participants started BAY94-9027 IV infusion with 2x/week at a dose of 25 IU/kg for 10 weeks. Participants with < 2 spontaneous joint and/or muscle bleeds were randomized 1:1 to either every 5 or every 7 days dosing regimen. Participants enrolled after randomization arms were filled continued 2x/week treatment at a dose of 30-40 IU/kg (2x/week 'forced').	All participants started BAY94-9027 IV infusion with 2x/week at a dose of 25 IU/kg for 10 weeks. Participants with < 2 spontaneous joint and/or muscle bleeds were randomized 1:1 to either every 5 or every 7 days dosing regimen, participants randomized to the every 5 days treatment arm were to begin treatment with 45 IU/kg every 5 days with the option to increase dose up to 60 IU/kg/infusion.	All participants started BAY94-9027 IV infusion with 2x/week at a dose of 25 IU/kg for 10 weeks. Participants <2 spontaneous joint and/or muscle bleeds were randomized 1:1 to either every 5 or every 7 days dosing regimen, participants randomized to the every 7 days treatment arm were to administer a dose of 60 IU/kg (maximum 6000 IU) every 7 days.	All participants receiving an schedule of prophylaxis treatment, all prophylaxis arms combined.
Overall Number of Participants Analyzed	20	13	11	43	43	110
Median (Full Range); Unit of Measure: IU/kg/infusion
	32.8; (23 to 58)	39.2; (33 to 42)	30.6; (29 to 41)	45.3; (39 to 58)	59.0; (51 to 64)	46.9; (29 to 64)

11. Secondary Outcome

Title	Number of Participants Requiring an Increase in Dose Frequency, or Dose Increase, During Weeks 10 to 36 - Part A
Description	[Not Specified]
Time Frame	Weeks 10 to 36 during Part A

Outcome Measure Data

Analysis Population Description

ITT population part A week 10-36, 4 participants dropped out during week 0-10.

Arm/Group Title	BAY94-9027 Prophylaxis Treatment, 2x/Week Failed, Main Trial	BAY94-9027 Prophylaxis Treatment, 2x/Week Forced, Main Trial	BAY94-9027 Prophylaxis Treatment, Every 5 Days, Main Trial	BAY94-9027 Prophylaxis Treatment, Every 7 Days, Main Trial	BAY94-9027 Prophylaxis Treatment Total, Main Trial
Arm/Group Description:	All participants started BAY94-9027 IV infusion with 2x/week at a dose of 25 IU/kg for 10 weeks. High bleeders (with 2 or more muscle or joint bleeds in the first 10 weeks) continued 2x/week infusion (2x/week 'failed') at a dose of 30 to 40 IU/kg.	All participants started BAY94-9027 IV infusion with 2x/week at a dose of 25 IU/kg for 10 weeks. Participants with < 2 spontaneous joint and/or muscle bleeds were randomized 1:1 to either every 5 or every 7 days dosing regimen. Participants enrolled after randomization arms were filled continued 2x/week treatment at a dose of 30-40 IU/kg (2x/week 'forced').	All participants started BAY94-9027 IV infusion with 2x/week at a dose of 25 IU/kg for 10 weeks. Participants with < 2 spontaneous joint and/or muscle bleeds were randomized 1:1 to either every 5 or every 7 days dosing regimen, participants randomized to the every 5 days treatment arm were to begin treatment with 45 IU/kg every 5 days with the option to increase dose up to 60 IU/kg/infusion.	All participants started BAY94-9027 IV infusion with 2x/week at a dose of 25 IU/kg for 10 weeks. Participants <2 spontaneous joint and/or muscle bleeds were randomized 1:1 to either every 5 or every 7 days dosing regimen, participants randomized to the every 7 days treatment arm were to administer a dose of 60 IU/kg (maximum 6000 IU) every 7 days.	All participants receiving an schedule of prophylaxis treatment, all prophylaxis arms combined.
Overall Number of Participants Analyzed	13	11	43	43	110
Measure Type: Count of Participants; Unit of Measure: Participants
Dose frequency increased	0 0.0%	0 0.0%	0 0.0%	11 25.6%	11 10.0%
Dose increased	2 15.4%	0 0.0%	7 16.3%	0 0.0%	9 8.2%

12. Secondary Outcome

Title	Number of Surgeries According to Physician's Assessment of Adequacy of Hemostasis in Major Surgery - Part B
Description	Major surgery was defined as any surgical or invasive procedure (elective or emergent) in which the overall bleeding risk was excessive, required a general anesthetic in an individual without a bleeding disorder, penetrated or exposed a major body cavity, resulted in substantial impairment of physical or physiological functions, or required special anatomic knowledge or manipulative skill. Adequacy of hemostasis was assessed as excellent, good, moderate or poor, by the surgeon or interventionalist during Part B of the study.
Time Frame	Day of surgery

Outcome Measure Data

Analysis Population Description

17 participants were included in the Part B ITT population.

Arm/Group Title	BAY949027 Treatment in Major Surgery, Part B
Arm/Group Description:	Participants who underwent major surgery received study drug during their hospital stay up to 3 weeks post surgery. Participants were treated according to the type of procedure, using tailored doses (a maximum of 60 IU/kg/infusion) expected to maintain acceptable therapeutic level of FVIII activity.
Overall Number of Participants Analyzed	17
Overall Number of Units Analyzed; Type of Units Analyzed: Surgeries	20
Measure Type: Number; Unit of Measure: surgeries
Good	13
Excellent	7
Moderate	0
Poor	0

13. Secondary Outcome

Title	Recombinant Human Factor VIII (rFVIII) Usage Expressed as Dose Per Kilogram Per Infusion for Major Surgery - Part B
Description	Major surgery was defined as any surgical or invasive procedure (elective or emergent) in which the overall bleeding risk was excessive, required a general anesthetic in an individual without a bleeding disorder, penetrated or exposed a major body cavity, resulted in substantial impairment of physical or physiological functions, or required special anatomic knowledge or manipulative skill. Total dose per kilogram per Infusion was expressed in international units per kilogram per infusion (IU/kg/infusion).
Time Frame	Up to 3 weeks post-surgery during Part B

Outcome Measure Data

Analysis Population Description

Part B ITT population

Arm/Group Title	BAY949027 Treatment in Major Surgery, Part B
Arm/Group Description:	Participants who underwent major surgery received study drug during their hospital stay up to 3 weeks post surgery. Participants were treated according to the type of procedure, using tailored doses (a maximum of 60 IU/kg/infusion) expected to maintain acceptable therapeutic level of FVIII activity.
Overall Number of Participants Analyzed	17
Overall Number of Units Analyzed; Type of Units Analyzed: Surgeries	20
Median (Full Range); Unit of Measure: IU/kg/infusion
	33.7; (22 to 51)

14. Secondary Outcome

Title	Recombinant Human Factor VIII (rFVIII) Usage Expressed as Number of Infusions for Major Surgery - Part B
Description	Major surgery was defined as any surgical or invasive procedure (elective or emergent) in which the overall bleeding risk was excessive, required a general anesthetic in an individual without a bleeding disorder, penetrated or exposed a major body cavity, resulted in substantial impairment of physical or physiological functions, or required special anatomic knowledge or manipulative skill.rFVIII usage expressed as number of infusions and IU/kg per year, as well as IU/kg per event (surgery) was assessed by investigator.
Time Frame	Up to 3 weeks post-surgery during Part B

Outcome Measure Data

Analysis Population Description

Part B ITT population

Arm/Group Title	BAY949027 Treatment in Major Surgery, Part B
Arm/Group Description:	Participants who underwent major surgery received study drug during their hospital stay up to 3 weeks post surgery. Participants were treated according to the type of procedure, using tailored doses (a maximum of 60 IU/kg/infusion) expected to maintain acceptable therapeutic level of FVIII activity.
Overall Number of Participants Analyzed	17
Overall Number of Units Analyzed; Type of Units Analyzed: Surgeries	20
Median (Full Range); Unit of Measure: infusions
	8.0; (3 to 39)

15. Secondary Outcome

Title	Maximum Drug Plasma Concentration (Cmax) Following Single and Multiple Doses of BAY94-9027, Chromogenic Assay - Part A
Description	Cmax: Maximum observed drug concentration following an infusion of 60 IU/kg
Time Frame	Weeks 0 and 36: pre-infusion (0 hours), post-infusion 15, 30 minutes, 1, 3, 6, 8, 24, 48, 72, 96 hours

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Analysis Set (PKS) with participants evaluable for this outcome, PKS included all participants with a valid profile of BAY94-9027 during Part A of the study.

Arm/Group Title	BAY94-9027 Treatment - Part A, Week 0	BAY94-9027 Treatment - Part A, Week 36
Arm/Group Description:	Part A, Week 0 included all PKS participants treated with a single (first) dose of BAY94-9027 as an IV infusion at Week 0.	Part A, Week 36 group included all PKS participants treated with multiple doses (last dose paired) of BAY94-9027 as an IV infusion at Week 36. Paired data were defined as the single dose data for the sub-set of participants who also had multiple dose PK data.
Overall Number of Participants Analyzed	22	15
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: IU/dL
	162.8; (14.74%)	177.1; (20.98%)

16. Secondary Outcome

Title	Area Under the Plasma Concentration Versus Time Curve From Zero to Infinity (AUC) Following Single and Multiple Doses of BAY94-9027, Chromogenic Assay - Part A
Description	AUC: The total area under the plasma concentration versus time curve following an infusion of 60 IU/kg .
Time Frame	Weeks 0 and 36: pre-infusion (0 hours), post-infusion 15, 30 minutes, 1, 3, 6, 8, 24, 48, 72, 96 hours

Outcome Measure Data

Analysis Population Description

PKS with participants evaluable for this outcome

Arm/Group Title	BAY94-9027 Treatment - Part A, Week 0	BAY94-9027 Treatment - Part A, Week 36
Arm/Group Description:	Part A, Week 0 included all PKS participants treated with a single (first) dose of BAY94-9027 as an IV infusion at Week 0.	Part A, Week 36 group included all PKS participants treated with multiple doses (last dose paired) of BAY94-9027 as an IV infusion at Week 36. Paired data were defined as the single dose data for the sub-set of participants who also had multiple dose PK data.
Overall Number of Participants Analyzed	22	15
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: h*IU/dL
	3707.5; (33.77%)	4130.8; (28.8%)

17. Secondary Outcome

Title	Terminal Elimination Half Life (t1/2) Following Single and Multiple Doses of BAY94-9027, Chromogenic Assay - Part A
Description	t1/2: Terminal half-life is the time the plasma concentration during terminal phase is halved following an infusion of 60 IU/kg .
Time Frame	Weeks 0 and 36: pre-infusion (0 hours), post-infusion 15, 30 minutes, 1, 3, 6, 8, 24, 48, 72, 96 hours

Outcome Measure Data

Analysis Population Description

PKS with participants evaluable for this outcome

Arm/Group Title	BAY94-9027 Treatment - Part A, Week 0	BAY94-9027 Treatment - Part A, Week 36
Arm/Group Description:	Part A, Week 0 included all PKS participants treated with a single (first) dose of BAY94-9027 as an IV infusion at Week 0.	Part A, Week 36 group included all PKS participants treated with multiple doses (last dose paired) of BAY94-9027 as an IV infusion at Week 36. Paired data were defined as the single dose data for the sub-set of participants who also had multiple dose PK data.
Overall Number of Participants Analyzed	22	15
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: Hours
	17.1; (27.05%)	19.6; (38.48%)

18. Secondary Outcome

Title	Overall Human Coagulation Factor VIII (FVIII) Recovery Value by Chromogenic Assay - Part A
Description	Recovery was calculated by the following formula: Recovery = (post-infusion FVIII activity - pre-infusion FVIII activity ) * weight / dose (in IU). Recovery is the increase of FVIII activity after the injection normalized by dose: IU/dl per IU/kg = kg/dL
Time Frame	Weeks 0 to 36 during Part A

Outcome Measure Data

Analysis Population Description

Part A ITT population

Arm/Group Title	BAY94-9027 On-demand Treatment, Main Trial	BAY94-9027 Prophylaxis Treatment, Week 0-36, Main Trial
Arm/Group Description:	Participants received on-demand treatment with BAY94-9027 as an intravenous (IV)infusion at a dose as indicated based upon location and severity of bleeds (a maximum of 60 international units per kilogram [IU/kg]).	All participants in the prophylaxis arms started BAY94-9027 IV infusion, with 2x/week at a dose of 25 IU/kg for 10 weeks. Thereafter, participants with less than 2 spontaneous joint and/or muscle bleeds were randomized 1:1 to either every 5 or every 7 days dosing regimen. High bleeders continued 2x/week infusion (2x/week 'failed'). Participants qualified to be randomized, but enrolled after randomized arms were filled, remained on 2x/week treatment (2x/week 'forced' group).
Overall Number of Participants Analyzed	20	112
Mean (Standard Deviation); Unit of Measure: Kilogram per deciliter
	2.67 (0.54)	2.68 (0.55)

19. Secondary Outcome

Title	Change From Baseline in Quality of Life by Hemophilia Specific Quality of Life Instrument or Questionnaire for Adults (Haemo-QoL-A) Overall Score at Week 36 - Part A
Description	Quality of life (QoL) was measured by the Haemo-QoL-A overall score, which ranged from 0 (the worst condition) to 100 (the best condition).
Time Frame	Week 0 (baseline) and Week 36 during Part A

Outcome Measure Data

Analysis Population Description

Part A ITT population with participants evaluable for this outcome

Arm/Group Title	BAY94-9027 On-demand Treatment, Main Trial	BAY94-9027 Prophylaxis Treatment, Week 0-36, Main Trial
Arm/Group Description:	Participants received on-demand treatment with BAY94-9027 as an intravenous (IV)infusion at a dose as indicated based upon location and severity of bleeds (a maximum of 60 international units per kilogram [IU/kg]).	All participants in the prophylaxis arms started BAY94-9027 IV infusion, with 2x/week at a dose of 25 IU/kg for 10 weeks. Thereafter, participants with less than 2 spontaneous joint and/or muscle bleeds were randomized 1:1 to either every 5 or every 7 days dosing regimen. High bleeders continued 2x/week infusion (2x/week 'failed'). Participants qualified to be randomized, but enrolled after randomized arms were filled, remained on 2x/week treatment (2x/week 'forced' group).
Overall Number of Participants Analyzed	19	97
Mean (Standard Deviation); Unit of Measure: scores on a scale
	-0.14 (9.70)	2.59 (7.98)

20. Other Pre-specified Outcome

Title	Change From Baseline in Overall Pain Severity and Interference Due to Pain at Week 36 - Part A
Description	Brief Pain Inventory (BPI) - Short Form (BPI-SF) was a 15-item, self-administered, validated tool developed to assess pain used in the study for patient reported outcomes. Scores ranged from 0 to 10 and a higher score indicates a higher level of pain/interference.
Time Frame	Week 0 (baseline) and Week 36 during Part A

Outcome Measure Data

Analysis Population Description

Analysis population includes participants evaluable in each category for this outcome.

Arm/Group Title		BAY94-9027 On-demand Treatment, Main Trial	BAY94-9027 Prophylaxis Treatment, Week 0-36, Main Trial
Arm/Group Description:		Participants received on-demand treatment with BAY94-9027 as an intravenous (IV)infusion at a dose as indicated based upon location and severity of bleeds (a maximum of 60 international units per kilogram [IU/kg]).	All participants in the prophylaxis arms started BAY94-9027 IV infusion, with 2x/week at a dose of 25 IU/kg for 10 weeks. Thereafter, participants with less than 2 spontaneous joint and/or muscle bleeds were randomized 1:1 to either every 5 or every 7 days dosing regimen. High bleeders continued 2x/week infusion (2x/week 'failed'). Participants qualified to be randomized, but enrolled after randomized arms were filled, remained on 2x/week treatment (2x/week 'forced' group).
Overall Number of Participants Analyzed		20	112
Mean (Standard Deviation); Unit of Measure: scores on a scale
Pain severity subscale	Number Analyzed	15 participants	78 participants
		-0.8 (1.8)	0.1 (1.39)
Interference subscale	Number Analyzed	15 participants	77 participants
		-0.99 (2.54)	-0.06 (1.39)

21. Other Pre-specified Outcome

Title	Change From Baseline in Work Productivity and Activity Impairment (WPAI) Questionnaire at Week 36 - Part A
Description	The WPAI is a validated instrument to assess the effect of hemophilia on ability to work, attend classes, and perform regular daily activities in participants aged 12 and above. The WPAI also contained classroom impairment questions (CIQ). The questionnaire was self-administered and comprised of nine questions that elicited information on work, classroom, and daily activity impairment during the previous seven days. WPAI outcomes that are overall work and activity impairment, transformed to impairment percentages (range from 0 to 100), with higher numbers indicating greater impairment and less productivity.
Time Frame	Week 0 (baseline) and Week 36 during Part A

Outcome Measure Data

Analysis Population Description

Analysis population includes participants evaluable in each category for this outcome.

Arm/Group Title		BAY94-9027 On-demand Treatment, Main Trial	BAY94-9027 Prophylaxis Treatment Total, Main Trial
Arm/Group Description:		Participants received on-demand treatment with BAY94-9027 as an intravenous (IV)infusion at a dose as indicated based upon location and severity of bleeds (a maximum of 60 international units per kilogram [IU/kg]).	All participants receiving an schedule of prophylaxis treatment, all prophylaxis arms combined.
Overall Number of Participants Analyzed		20	112
Mean (Standard Deviation); Unit of Measure: scores on a scale
Activity impairment	Number Analyzed	20 participants	108 participants
		4.74 (24.12)	-7.13 (20.00)
Overall work impairment	Number Analyzed	12 participants	62 participants
		4.44 (21.94)	-1.22 (21.94)

22. Other Pre-specified Outcome

Title	Recombinant Human Factor VIII (rFVIII) Usage Expressed as Number of Infusions- Part A
Description	For prophylaxis patients, the dose is related to all infusions.
Time Frame	On-demand: Weeks 0 -36 and Prophylaxis: Weeks 10 - 36 during Part A

Outcome Measure Data

Analysis Population Description

ITT population part A week 10-36, 4 participants dropped out during week 0-10.

Arm/Group Title	BAY94-9027 On-demand Treatment, Main Trial	BAY94-9027 Prophylaxis Treatment, 2x/Week Failed, Main Trial	BAY94-9027 Prophylaxis Treatment, 2x/Week Forced, Main Trial	BAY94-9027 Prophylaxis Treatment, Every 5 Days, Main Trial	BAY94-9027 Prophylaxis Treatment, Every 7 Days, Main Trial	BAY94-9027 Prophylaxis Treatment Total, Main Trial
Arm/Group Description:	Participants received on-demand treatment with BAY94-9027 as an intravenous (IV)infusion at a dose as indicated based upon location and severity of bleeds (a maximum of 60 international units per kilogram [IU/kg]).	All participants started BAY94-9027 IV infusion with 2x/week at a dose of 25 IU/kg for 10 weeks. High bleeders (with 2 or more muscle or joint bleeds in the first 10 weeks) continued 2x/week infusion (2x/week 'failed') at a dose of 30 to 40 IU/kg.	All participants started BAY94-9027 IV infusion with 2x/week at a dose of 25 IU/kg for 10 weeks. Participants with < 2 spontaneous joint and/or muscle bleeds were randomized 1:1 to either every 5 or every 7 days dosing regimen. Participants enrolled after randomization arms were filled continued 2x/week treatment at a dose of 30-40 IU/kg (2x/week 'forced').	All participants started BAY94-9027 IV infusion with 2x/week at a dose of 25 IU/kg for 10 weeks. Participants with < 2 spontaneous joint and/or muscle bleeds were randomized 1:1 to either every 5 or every 7 days dosing regimen, participants randomized to the every 5 days treatment arm were to begin treatment with 45 IU/kg every 5 days with the option to increase dose up to 60 IU/kg/infusion.	All participants started BAY94-9027 IV infusion with 2x/week at a dose of 25 IU/kg for 10 weeks. Participants <2 spontaneous joint and/or muscle bleeds were randomized 1:1 to either every 5 or every 7 days dosing regimen, participants randomized to the every 7 days treatment arm were to administer a dose of 60 IU/kg (maximum 6000 IU) every 7 days.	All participants receiving an schedule of prophylaxis treatment, all prophylaxis arms combined.
Overall Number of Participants Analyzed	20	13	11	43	43	110
Median (Full Range); Unit of Measure: infusions
	29; (9 to 76)	56.0; (52 to 71)	55.0; (47 to 59)	38.0; (3 to 58)	27.0; (5 to 63)	37.5; (3 to 71)

23. Other Pre-specified Outcome

Title	Recombinant Human Factor VIII (rFVIII) Usage Expressed as Dose Per Kilogram With Prophylaxis Treatment - Part A
Description	For prophylaxis patients, the dose per kilogram is related to prophylaxis infusions.
Time Frame	Weeks 10 - 36 during Part A

Outcome Measure Data

Analysis Population Description

ITT population part A week 10-36, 4 participants dropped out during week 0-10.

Arm/Group Title	BAY94-9027 Prophylaxis Treatment, 2x/Week Failed, Main Trial	BAY94-9027 Prophylaxis Treatment, 2x/Week Forced, Main Trial	BAY94-9027 Prophylaxis Treatment, Every 5 Days, Main Trial	BAY94-9027 Prophylaxis Treatment, Every 7 Days, Main Trial	BAY94-9027 Prophylaxis Treatment Total, Main Trial
Arm/Group Description:	All participants started BAY94-9027 IV infusion with 2x/week at a dose of 25 IU/kg for 10 weeks. High bleeders (with 2 or more muscle or joint bleeds in the first 10 weeks) continued 2x/week infusion (2x/week 'failed') at a dose of 30 to 40 IU/kg.	All participants started BAY94-9027 IV infusion with 2x/week at a dose of 25 IU/kg for 10 weeks. Participants with < 2 spontaneous joint and/or muscle bleeds were randomized 1:1 to either every 5 or every 7 days dosing regimen. Participants enrolled after randomization arms were filled continued 2x/week treatment at a dose of 30-40 IU/kg (2x/week 'forced').	All participants started BAY94-9027 IV infusion with 2x/week at a dose of 25 IU/kg for 10 weeks. Participants with < 2 spontaneous joint and/or muscle bleeds were randomized 1:1 to either every 5 or every 7 days dosing regimen, participants randomized to the every 5 days treatment arm were to begin treatment with 45 IU/kg every 5 days with the option to increase dose up to 60 IU/kg/infusion.	All participants started BAY94-9027 IV infusion with 2x/week at a dose of 25 IU/kg for 10 weeks. Participants <2 spontaneous joint and/or muscle bleeds were randomized 1:1 to either every 5 or every 7 days dosing regimen, participants randomized to the every 7 days treatment arm were to administer a dose of 60 IU/kg (maximum 6000 IU) every 7 days.	All participants receiving an schedule of prophylaxis treatment, all prophylaxis arms combined.
Overall Number of Participants Analyzed	13	11	43	43	110
Median (Full Range); Unit of Measure: IU/kg
	1986.9; (1733 to 2236)	1669.1; (1430 to 1947)	1704.3; (139 to 2049)	1530.2; (122 to 1788)	1644.9; (122 to 2236)

24. Other Pre-specified Outcome

Title	Number of Minor Surgeries According to Physician's Assessment of Adequacy of Hemostasis - Part A
Description	Minor surgery was defined as any surgical procedure that did not meet the definition of major, and included simple dental extractions, incision and drainage of abscesses, or simple excisions.
Time Frame	Weeks 0 to 36 during Part A

Outcome Measure Data

Analysis Population Description

Part A ITT population

Arm/Group Title	BAY94-9027 Treatment - Part A
Arm/Group Description:	This group included both on-demand and prophylaxis arms in Part A.
Overall Number of Participants Analyzed	10
Overall Number of Units Analyzed; Type of Units Analyzed: Minor surgeries	17
Measure Type: Number; Unit of Measure: minor surgeries
Excellent	9
Good	6
Missing	2

25. Other Pre-specified Outcome

Title	Number of Surgeries According to Physician's Assessment of Response to Hemostasis, Post-surgery - Part B Main Trial
Description	Response to treatment during surgery was assessed by investigator/surgeon as excellent, good, moderate, poor or missing during Part B of the study.
Time Frame	Up to 3 weeks post-surgery during Part B

Outcome Measure Data

Analysis Population Description

Part B ITT population

Arm/Group Title	BAY949027 Treatment in Major Surgery, Part B
Arm/Group Description:	Participants who underwent major surgery received study drug during their hospital stay up to 3 weeks post surgery. Participants were treated according to the type of procedure, using tailored doses (a maximum of 60 IU/kg/infusion) expected to maintain acceptable therapeutic level of FVIII activity.
Overall Number of Participants Analyzed	14
Overall Number of Units Analyzed; Type of Units Analyzed: Surgeries	17
Measure Type: Number; Unit of Measure: surgeries
Excellent	8
Good	5
Moderate	3
Missing	1

26. Other Pre-specified Outcome

Title	Number of Participants With Change/Drop in Hemoglobin/Hematocrit Laboratory Assessments - Part B
Description	Hematocrit is defined as the volume percentage (%) of red blood cells in blood.
Time Frame	Up to 3 weeks post-surgery during Part B

Outcome Measure Data

Analysis Population Description

Part B Safety population (N=17) included all participants who received at least 1 dose of study drug during Part B of the study.

Arm/Group Title	BAY949027 Treatment in Major Surgery, Part B
Arm/Group Description:	Participants who underwent major surgery received study drug during their hospital stay up to 3 weeks post surgery. Participants were treated according to the type of procedure, using tailored doses (a maximum of 60 IU/kg/infusion) expected to maintain acceptable therapeutic level of FVIII activity.
Overall Number of Participants Analyzed	17
Measure Type: Count of Participants; Unit of Measure: Participants
Hematocrit	6 35.3%
Hemoglobin	2 11.8%

27. Other Pre-specified Outcome

Title	Maximum Blood Loss During Major Surgery - Part B
Description	Major surgery was defined as any surgical or invasive procedure (elective or emergent) in which the overall bleeding risk was excessive, required a general anesthetic in an individual without a bleeding disorder, penetrated or exposed a major body cavity, resulted in substantial impairment of physical or physiological functions, or required special anatomic knowledge or manipulative skill.
Time Frame	day of surgery

Outcome Measure Data

Analysis Population Description

Part B ITT population with participants treated for major surgery

Arm/Group Title	BAY949027 Treatment in Major Surgery, Part B
Arm/Group Description:	Participants who underwent major surgery received study drug during their hospital stay up to 3 weeks post surgery. Participants were treated according to the type of procedure, using tailored doses (a maximum of 60 IU/kg/infusion) expected to maintain acceptable therapeutic level of FVIII activity.
Overall Number of Participants Analyzed	17
Overall Number of Units Analyzed; Type of Units Analyzed: Surgeries	20
Measure Type: Number; Unit of Measure: milliliter
	1000

28. Other Pre-specified Outcome

Title	Number of Participants Who Took Anti-fibrinolytic Medications During Major Surgery - Part B
Description	Major surgery was defined as any surgical or invasive procedure (elective or emergent) in which the overall bleeding risk was excessive, required a general anesthetic in an individual without a bleeding disorder, penetrated or exposed a major body cavity, resulted in substantial impairment of physical or physiological functions, or required special anatomic knowledge or manipulative skill.
Time Frame	Up to 3 weeks post-surgery during Part B

Outcome Measure Data

Analysis Population Description

Part B ITT population with participants treated for major surgery

Arm/Group Title	BAY949027 Treatment in Major Surgery, Part B
Arm/Group Description:	Participants who underwent major surgery received study drug during their hospital stay up to 3 weeks post surgery. Participants were treated according to the type of procedure, using tailored doses (a maximum of 60 IU/kg/infusion) expected to maintain acceptable therapeutic level of FVIII activity.
Overall Number of Participants Analyzed	17
Measure Type: Count of Participants; Unit of Measure: Participants
	8 47.1%

29. Other Pre-specified Outcome

Title	Volume of Blood Transfused in Major Surgery - Part B
Description	Major surgery was defined as any surgical or invasive procedure (elective or emergent) in which the overall bleeding risk was excessive, required a general anesthetic in an individual without a bleeding disorder, penetrated or exposed a major body cavity, resulted in substantial impairment of physical or physiological functions, or required special anatomic knowledge or manipulative skill.
Time Frame	Up to 3 weeks post-surgery during Part B

Outcome Measure Data

Analysis Population Description

Part B ITT population who had blood transfusions during major surgery

Arm/Group Title	BAY949027 Treatment in Major Surgery, Part B
Arm/Group Description:	Participants who underwent major surgery received study drug during their hospital stay up to 3 weeks post surgery. Participants were treated according to the type of procedure, using tailored doses (a maximum of 60 IU/kg/infusion) expected to maintain acceptable therapeutic level of FVIII activity.
Overall Number of Participants Analyzed	4
Overall Number of Units Analyzed; Type of Units Analyzed: Surgeries	5
Median (Full Range); Unit of Measure: milliliter
	865; (600 to 1380)

Adverse Events

Time Frame	Adverse event data were collected after the first dose of study drug and up to 7 days after the last dose over a period of approximately 5 years.
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	BAY94-9027 Treatment, Part A, Main Trial		BAY94-9027 Treatment, Part A, Extension		BAY94-9027 Treatment in Major Surgery, Part B
Arm/Group Description	Subjects entering Part A main trial were treated with BAY 94-9027 for either on-demand or prophylactic treatment.		Subjects in Part A extension either continued their regimen from main trial or switched to one of the other regimens at any time.		Subjects, either Part B subjects only or subjects from Part A/Part A Extension, who underwent major surgery received study drug during their hospital stay up to 3 weeks post-surgery. Subjects were treated according to the type of procedure, using tailored doses (a maximum of 60 IU/kg/infusion) expected to maintain acceptable therapeutic level of FVIII activity.
All-Cause Mortality
	BAY94-9027 Treatment, Part A, Main Trial		BAY94-9027 Treatment, Part A, Extension		BAY94-9027 Treatment in Major Surgery, Part B
	Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	0/134 (0.00%)		0/121 (0.00%)		0/22 (0.00%)
Serious Adverse Events
	BAY94-9027 Treatment, Part A, Main Trial		BAY94-9027 Treatment, Part A, Extension		BAY94-9027 Treatment in Major Surgery, Part B
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/134 (9.70%)		36/121 (29.75%)		2/22 (9.09%)
Blood and lymphatic system disorders
Anaemia * 1	0/134 (0.00%)	0	1/121 (0.83%)	1	0/22 (0.00%)	0
Cardiac disorders
Angina unstable * 1	0/134 (0.00%)	0	1/121 (0.83%)	1	0/22 (0.00%)	0
Eye disorders
Macular fibrosis * 1	0/134 (0.00%)	0	1/121 (0.83%)	1	0/22 (0.00%)	0
Gastrointestinal disorders
Anal fistula * 1	0/134 (0.00%)	0	1/121 (0.83%)	2	0/22 (0.00%)	0
Enterocolitis * 1	0/134 (0.00%)	0	1/121 (0.83%)	1	0/22 (0.00%)	0
Gastrointestinal haemorrhage * 1	0/134 (0.00%)	0	1/121 (0.83%)	1	0/22 (0.00%)	0
Inguinal hernia * 1	0/134 (0.00%)	0	2/121 (1.65%)	3	0/22 (0.00%)	0
Intestinal obstruction * 1	0/134 (0.00%)	0	1/121 (0.83%)	1	0/22 (0.00%)	0
Mouth haemorrhage * 1	0/134 (0.00%)	0	1/121 (0.83%)	1	0/22 (0.00%)	0
Pancreatitis acute * 1	1/134 (0.75%)	1	0/121 (0.00%)	0	0/22 (0.00%)	0
Retroperitoneal haematoma * 1	0/134 (0.00%)	0	1/121 (0.83%)	1	0/22 (0.00%)	0
Tooth impacted * 1	0/134 (0.00%)	0	2/121 (1.65%)	2	0/22 (0.00%)	0
Hepatobiliary disorders
Bile duct stone * 1	1/134 (0.75%)	1	0/121 (0.00%)	0	0/22 (0.00%)	0
Hepatic cirrhosis * 1	0/134 (0.00%)	0	1/121 (0.83%)	1	0/22 (0.00%)	0
Immune system disorders
Drug hypersensitivity * 1	1/134 (0.75%)	1	0/121 (0.00%)	0	0/22 (0.00%)	0
Infections and infestations
Anal abscess * 1	0/134 (0.00%)	0	1/121 (0.83%)	3	0/22 (0.00%)	0
Arthritis bacterial * 1	0/134 (0.00%)	0	1/121 (0.83%)	1	0/22 (0.00%)	0
Cellulitis * 1	0/134 (0.00%)	0	1/121 (0.83%)	1	0/22 (0.00%)	0
Device related infection * 1	1/134 (0.75%)	1	0/121 (0.00%)	0	0/22 (0.00%)	0
Gastroenteritis * 1	1/134 (0.75%)	1	0/121 (0.00%)	0	0/22 (0.00%)	0
Medical device site joint infection * 1	0/134 (0.00%)	0	1/121 (0.83%)	1	0/22 (0.00%)	0
Nasal vestibulitis * 1	0/134 (0.00%)	0	1/121 (0.83%)	1	0/22 (0.00%)	0
Pneumonia * 1	1/134 (0.75%)	1	0/121 (0.00%)	0	0/22 (0.00%)	0
Injury, poisoning and procedural complications
Alcohol poisoning * 1	1/134 (0.75%)	1	0/121 (0.00%)	0	0/22 (0.00%)	0
Contusion * 1	0/134 (0.00%)	0	1/121 (0.83%)	1	0/22 (0.00%)	0
Fall * 1	0/134 (0.00%)	0	1/121 (0.83%)	1	0/22 (0.00%)	0
Fibula fracture * 1	0/134 (0.00%)	0	1/121 (0.83%)	1	0/22 (0.00%)	0
Hand fracture * 1	0/134 (0.00%)	0	1/121 (0.83%)	1	0/22 (0.00%)	0
Head injury * 1	0/134 (0.00%)	0	2/121 (1.65%)	2	0/22 (0.00%)	0
Humerus fracture * 1	0/134 (0.00%)	0	1/121 (0.83%)	1	0/22 (0.00%)	0
Injury * 1	1/134 (0.75%)	1	0/121 (0.00%)	0	0/22 (0.00%)	0
Ligament rupture * 1	0/134 (0.00%)	0	1/121 (0.83%)	1	0/22 (0.00%)	0
Overdose * 1	1/134 (0.75%)	1	0/121 (0.00%)	0	0/22 (0.00%)	0
Periprosthetic fracture * 1	0/134 (0.00%)	0	1/121 (0.83%)	1	0/22 (0.00%)	0
Tendon rupture * 1	1/134 (0.75%)	1	0/121 (0.00%)	0	0/22 (0.00%)	0
Tibia fracture * 1	0/134 (0.00%)	0	1/121 (0.83%)	1	0/22 (0.00%)	0
Investigations
Anti factor VIII antibody positive * 1	0/134 (0.00%)	0	0/121 (0.00%)	0	2/22 (9.09%)	2
Colonoscopy * 1	1/134 (0.75%)	1	0/121 (0.00%)	0	0/22 (0.00%)	0
Liver function test increased * 1	0/134 (0.00%)	0	1/121 (0.83%)	2	0/22 (0.00%)	0
Musculoskeletal and connective tissue disorders
Arthralgia * 1	0/134 (0.00%)	0	1/121 (0.83%)	1	0/22 (0.00%)	0
Arthropathy * 1	1/134 (0.75%)	1	1/121 (0.83%)	2	0/22 (0.00%)	0
Back pain * 1	0/134 (0.00%)	0	2/121 (1.65%)	3	0/22 (0.00%)	0
Chondrocalcinosis pyrophosphate * 1	0/134 (0.00%)	0	1/121 (0.83%)	1	0/22 (0.00%)	0
Haemarthrosis * 1	1/134 (0.75%)	1	1/121 (0.83%)	1	0/22 (0.00%)	0
Haemophilic arthropathy * 1	1/134 (0.75%)	1	4/121 (3.31%)	5	0/22 (0.00%)	0
Osteoarthritis * 1	0/134 (0.00%)	0	1/121 (0.83%)	1	0/22 (0.00%)	0
Rotator cuff syndrome * 1	0/134 (0.00%)	0	1/121 (0.83%)	1	0/22 (0.00%)	0
Synovitis * 1	0/134 (0.00%)	0	1/121 (0.83%)	1	0/22 (0.00%)	0
Nervous system disorders
Epilepsy * 1	0/134 (0.00%)	0	1/121 (0.83%)	1	0/22 (0.00%)	0
Product Issues
Device malfunction * 1	1/134 (0.75%)	1	0/121 (0.00%)	0	0/22 (0.00%)	0
Psychiatric disorders
Depression * 1	0/134 (0.00%)	0	1/121 (0.83%)	1	0/22 (0.00%)	0
Renal and urinary disorders
Hydronephrosis * 1	0/134 (0.00%)	0	1/121 (0.83%)	1	0/22 (0.00%)	0
Nephrolithiasis * 1	0/134 (0.00%)	0	1/121 (0.83%)	1	0/22 (0.00%)	0
Renal colic * 1	0/134 (0.00%)	0	1/121 (0.83%)	1	0/22 (0.00%)	0
Ureterolithiasis * 1	0/134 (0.00%)	0	1/121 (0.83%)	1	0/22 (0.00%)	0
Skin and subcutaneous tissue disorders
Dermatitis exfoliative generalised * 1	0/134 (0.00%)	0	1/121 (0.83%)	1	0/22 (0.00%)	0
Surgical and medical procedures
Joint arthroplasty * 1	0/134 (0.00%)	0	1/121 (0.83%)	1	0/22 (0.00%)	0
Knee arthroplasty * 1	1/134 (0.75%)	1	0/121 (0.00%)	0	0/22 (0.00%)	0
Renal stone removal * 1	0/134 (0.00%)	0	1/121 (0.83%)	2	0/22 (0.00%)	0
Ureteral stent insertion * 1	0/134 (0.00%)	0	1/121 (0.83%)	1	0/22 (0.00%)	0
Vascular disorders
Haematoma * 1	0/134 (0.00%)	0	2/121 (1.65%)	2	1/22 (4.55%)	1
1 Term from vocabulary, MedDRA (22.1); * Indicates events were collected by non-systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	BAY94-9027 Treatment, Part A, Main Trial		BAY94-9027 Treatment, Part A, Extension		BAY94-9027 Treatment in Major Surgery, Part B
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	67/134 (50.00%)		74/121 (61.16%)		16/22 (72.73%)
Gastrointestinal disorders
Nausea * 1	5/134 (3.73%)	6	5/121 (4.13%)	7	2/22 (9.09%)	2
General disorders
Pyrexia * 1	1/134 (0.75%)	1	10/121 (8.26%)	13	3/22 (13.64%)	3
Infections and infestations
Influenza * 1	5/134 (3.73%)	9	8/121 (6.61%)	12	0/22 (0.00%)	0
Nasopharyngitis * 1	24/134 (17.91%)	34	25/121 (20.66%)	55	1/22 (4.55%)	1
Pharyngitis * 1	1/134 (0.75%)	1	7/121 (5.79%)	9	0/22 (0.00%)	0
Upper respiratory tract infection * 1	3/134 (2.24%)	3	12/121 (9.92%)	14	0/22 (0.00%)	0
Injury, poisoning and procedural complications
Limb injury * 1	3/134 (2.24%)	3	8/121 (6.61%)	8	0/22 (0.00%)	0
Procedural haemorrhage * 1	0/134 (0.00%)	0	0/121 (0.00%)	0	3/22 (13.64%)	3
Procedural hypotension * 1	0/134 (0.00%)	0	0/121 (0.00%)	0	2/22 (9.09%)	2
Procedural pain * 1	2/134 (1.49%)	2	7/121 (5.79%)	8	9/22 (40.91%)	10
Investigations
Haemoglobin decreased * 1	0/134 (0.00%)	0	2/121 (1.65%)	2	3/22 (13.64%)	3
Musculoskeletal and connective tissue disorders
Arthralgia * 1	11/134 (8.21%)	13	26/121 (21.49%)	40	2/22 (9.09%)	2
Back pain * 1	8/134 (5.97%)	10	14/121 (11.57%)	17	0/22 (0.00%)	0
Haemarthrosis * 1	2/134 (1.49%)	2	8/121 (6.61%)	8	1/22 (4.55%)	1
Musculoskeletal pain * 1	4/134 (2.99%)	4	7/121 (5.79%)	10	0/22 (0.00%)	0
Osteoarthritis * 1	0/134 (0.00%)	0	7/121 (5.79%)	12	0/22 (0.00%)	0
Pain in extremity * 1	5/134 (3.73%)	6	8/121 (6.61%)	11	0/22 (0.00%)	0
Nervous system disorders
Headache * 1	16/134 (11.94%)	28	14/121 (11.57%)	21	0/22 (0.00%)	0
Psychiatric disorders
Insomnia * 1	3/134 (2.24%)	3	1/121 (0.83%)	1	2/22 (9.09%)	2
Respiratory, thoracic and mediastinal disorders
Cough * 1	8/134 (5.97%)	11	9/121 (7.44%)	11	0/22 (0.00%)	0
Epistaxis * 1	8/134 (5.97%)	10	6/121 (4.96%)	6	0/22 (0.00%)	0
Skin and subcutaneous tissue disorders
Rash * 1	1/134 (0.75%)	1	3/121 (2.48%)	6	2/22 (9.09%)	2
Vascular disorders
Haematoma * 1	0/134 (0.00%)	0	3/121 (2.48%)	3	2/22 (9.09%)	2
1 Term from vocabulary, MedDRA (22.1); * Indicates events were collected by non-systematic assessment

Limitations and Caveats

Some registered "Secondary outcome measure" were re-classified as "Other Pre-specified" in line with protocol.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

• Name/Title: Therapeutic Area Head
• Organization: Bayer AG
• Phone: (+) 1-888-8422937
• EMail: clinical-trials-contact@bayer.com

Publications:

Baumann A, Piel I, Hucke F, Sandmann S, Hetzel T, Schwarz T. Pharmacokinetics, excretion, distribution, and metabolism of 60-kDa polyethylene glycol used in BAY 94-9027 in rats and its value for human prediction. Eur J Pharm Sci. 2019 Mar 15;130:11-20. doi: 10.1016/j.ejps.2019.01.015. Epub 2019 Jan 14.

Lalezari S, Reding MT, Pabinger I, Holme PA, Negrier C, Chalasani P, Shin HJ, Wang M, Tseneklidou-Stoeter D, Maas Enriquez M. BAY 94-9027 prophylaxis is efficacious and well tolerated for up to >5 years with extended dosing intervals: PROTECT VIII extension interim results. Haemophilia. 2019 Nov;25(6):1011-1019. doi: 10.1111/hae.13853. Epub 2019 Oct 17.

Reding MT, Ng HJ, Poulsen LH, Eyster ME, Pabinger I, Shin HJ, Walsch R, Lederman M, Wang M, Hardtke M, Michaels LA. Safety and efficacy of BAY 94-9027, a prolonged-half-life factor VIII. J Thromb Haemost. 2017 Mar;15(3):411-419. doi: 10.1111/jth.13597. Epub 2017 Feb 22.

• Responsible Party: Bayer
• ClinicalTrials.gov Identifier: NCT01580293
• Other Study ID Numbers: 13024; 2011-005210-11 ( EudraCT Number )
• First Submitted: March 28, 2012
• First Posted: April 19, 2012
• Results First Submitted: September 26, 2018
• Results First Posted: December 6, 2018
• Last Update Posted: December 2, 2020