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

• Sponsor: Bayer (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01580293
• Collaborator: (none)
• Enrollment: 145
• Locations: 59
• Arms: 4
• Actual Duration (Months): 90.9
• Patients Per Site: 2.5
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

Haemophilia A is an inherited disorder in which one of the proteins, Factor VIII, needed to form blood clots is missing or not present in sufficient levels. In a person with haemophilia A, the clotting process is slowed and the person experiences bleeds that can result in serious problems and potential disability.

The current standard treatment for severe haemophilia A is regularly scheduled infusion of FVIII to keep levels high enough to prevent bleeding. Due to the short half-life of FVIII, prophylaxis may require treatment as often as every other day.

In this trial safety and efficacy of a long-acting recombinant factor VIII molecule is evaluated in subjects with severe Hemophilia A.

120-140 patients will receive open label treatment with long-acting rFVIII either on-demand to treat bleeds or prophylactically for 36 weeks in the main trial plus an optional extension to continue treatment for at least 100 total exposure days (ED). Patients on prophylactic treatment will receive study drug at dosing intervals between once and twice a week depending on their observed bleeding. Patients will attend the treatment centre for routine blood samples and be required to keep an electronic diary.

Male patients aged 12-65, with severe hemophilia A, previously treated with FVIII for at least 50 exposure days may be eligible for this study.

Condition or Disease	Intervention/Treatment	Phase
Hemophilia A	Biological: BAY94-9027	Phase 2/Phase 3

Detailed Description

Subjects in prophylactic treatment arms will undergo clinical evaluation at 10 weeks. Those with adequate control of bleeding will undergo randomization to every 5 or 7 day infusion. Those with continued bleeding will remain in treatment arm and have an increase in dose.

Part B-major surgery - optional sub study included to collect information on efficacy of BAY94-9027 in major surgical setting. Due to rarity of surgery in this population, enrollment to this sub-study may be independent of participation in main study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 145 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II/III, Multicenter, Partially Randomized, Open Label Trial Investigating Safety and Efficacy of On-demand and Prophylactic Treatment With BAY94-9027 in Severe Hemophilia A
• Actual Study Start Date: Apr 23, 2012
• Actual Primary Completion Date: Jun 13, 2014
• Actual Study Completion Date: Nov 21, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm 1 On-demand treatment of BAY94-9027 at individual dose and number of infusions based upon location and severity of bleeds	Biological: BAY94-9027; Intravenous infusion of BAY94-9027
Experimental: Arm 2 Prophylaxis treatment of BAY94-9027; 2 infusions per week over 10 weeks followed by 2 infusions per week over 26 weeks in the main trial; and at least 1 day per week in the extension for at least 100 ED	Biological: BAY94-9027; Intravenous infusion of BAY94-9027
Experimental: Arm 3 Prophylaxis treatment of BAY94-9027; 2 infusions per week over 10 weeks followed by infusion every 5 days over 26 weeks in the main trial; and at least 1 day per week in the extension for at least 100 ED	Biological: BAY94-9027; Intravenous infusion of BAY94-9027
Experimental: Arm 4 Prophylaxis treatment of BAY94-9027; 2 infusions per week over 10 weeks followed by infusion every 7 days over 26 weeks in the main trial; and at least 1 day per week in the extension for at least 100 ED	Biological: BAY94-9027; Intravenous infusion of BAY94-9027

Outcome Measures

Primary Outcome Measures

1. 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 [On-demand: Weeks 0 -36 and Prophylaxis: Weeks 10 - 36 during Part A]

   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).

Secondary Outcome Measures

1. 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 [On-demand: Weeks 0 -36 and Prophylaxis: Weeks 10 - 36 during Part A]

   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.

2. Annualized Number of Total Bleeds in On-demand Treatment Arm and in Each Prophylaxis Arm, Part A, Extension [at least 100 total exposure days acquired, median time 3.9 years up to 7 years maximum]

   Annualized number of total bleeds was defined as the annualized sum of spontaneous bleeds and trauma bleeds.

3. Number of Participants Developed Human Coagulation Factor VIII (FVIII) Inhibitor - Part A [Weeks 0 to 36 during Part A]

   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.

4. Number of Bleeds Requiring 1, 2 or >= 3 Infusions to Control the Bleed - Part A [Weeks 0 to 36]

   Number of bleeds requiring 1, 2 or >= 3 infusions to control the bleeding

5. Number of Bleeds According to Locations - Part A [Weeks 0 -36]

   Bleed locations were categorised as joint, muscle, skin/mucosa, internal, others and missing.

6. Number of Bleeds Over Time Since Previous Prophylaxis Infusion - Part A [Weeks 0 to 36]

7. Number of Bleeds According to Participant's Assessment of Response to Treatment - Part A [Weeks 0 to 36 during Part A]

   Response to treatment was assessed by participant as excellent, good, moderate, poor or missing during Part A of the study.

8. Recombinant Human Factor VIII (rFVIII) Usage Expressed as Total Dose Per Kilogram Per Year - Part A [On-demand: Weeks 0 -36 and Prophylaxis: Weeks 10 - 36 during Part A]

   For prophylaxis patients, the dose is related to all infusions.

9. Recombinant Human Factor VIII (rFVIII) Usage Expressed as Dose Per Kilogram Per Infusion - Part A [On-demand: Weeks 0 -36 and Prophylaxis: Weeks 10 - 36 during Part A]

   For prophylaxis patients, the dose per infusion related to prophylaxis infusion.

10. Number of Participants Requiring an Increase in Dose Frequency, or Dose Increase, During Weeks 10 to 36 - Part A [Weeks 10 to 36 during Part A]

11. Number of Surgeries According to Physician's Assessment of Adequacy of Hemostasis in Major Surgery - Part B [Day of surgery]

    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.

12. Recombinant Human Factor VIII (rFVIII) Usage Expressed as Dose Per Kilogram Per Infusion for Major Surgery - Part B [Up to 3 weeks post-surgery during Part B]

    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).

13. Recombinant Human Factor VIII (rFVIII) Usage Expressed as Number of Infusions for Major Surgery - Part B [Up to 3 weeks post-surgery during Part B]

    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.

14. Maximum Drug Plasma Concentration (Cmax) Following Single and Multiple Doses of BAY94-9027, Chromogenic Assay - Part A [Weeks 0 and 36: pre-infusion (0 hours), post-infusion 15, 30 minutes, 1, 3, 6, 8, 24, 48, 72, 96 hours]

    Cmax: Maximum observed drug concentration following an infusion of 60 IU/kg

15. 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 [Weeks 0 and 36: pre-infusion (0 hours), post-infusion 15, 30 minutes, 1, 3, 6, 8, 24, 48, 72, 96 hours]

    AUC: The total area under the plasma concentration versus time curve following an infusion of 60 IU/kg .

16. Terminal Elimination Half Life (t1/2) Following Single and Multiple Doses of BAY94-9027, Chromogenic Assay - Part A [Weeks 0 and 36: pre-infusion (0 hours), post-infusion 15, 30 minutes, 1, 3, 6, 8, 24, 48, 72, 96 hours]

    t1/2: Terminal half-life is the time the plasma concentration during terminal phase is halved following an infusion of 60 IU/kg .

17. Overall Human Coagulation Factor VIII (FVIII) Recovery Value by Chromogenic Assay - Part A [Weeks 0 to 36 during Part A]

    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

18. 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 [Week 0 (baseline) and Week 36 during Part A]

    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).

Other Outcome Measures

1. Change From Baseline in Overall Pain Severity and Interference Due to Pain at Week 36 - Part A [Week 0 (baseline) and Week 36 during Part A]

   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.

2. Change From Baseline in Work Productivity and Activity Impairment (WPAI) Questionnaire at Week 36 - Part A [Week 0 (baseline) and Week 36 during Part A]

   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.

3. Recombinant Human Factor VIII (rFVIII) Usage Expressed as Number of Infusions- Part A [On-demand: Weeks 0 -36 and Prophylaxis: Weeks 10 - 36 during Part A]

   For prophylaxis patients, the dose is related to all infusions.

4. Recombinant Human Factor VIII (rFVIII) Usage Expressed as Dose Per Kilogram With Prophylaxis Treatment - Part A [Weeks 10 - 36 during Part A]

   For prophylaxis patients, the dose per kilogram is related to prophylaxis infusions.

5. Number of Minor Surgeries According to Physician's Assessment of Adequacy of Hemostasis - Part A [Weeks 0 to 36 during Part A]

   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.

6. Number of Surgeries According to Physician's Assessment of Response to Hemostasis, Post-surgery - Part B Main Trial [Up to 3 weeks post-surgery during Part B]

   Response to treatment during surgery was assessed by investigator/surgeon as excellent, good, moderate, poor or missing during Part B of the study.

7. Number of Participants With Change/Drop in Hemoglobin/Hematocrit Laboratory Assessments - Part B [Up to 3 weeks post-surgery during Part B]

   Hematocrit is defined as the volume percentage (%) of red blood cells in blood.

8. Maximum Blood Loss During Major Surgery - Part B [day of surgery]

   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.

9. Number of Participants Who Took Anti-fibrinolytic Medications During Major Surgery - Part B [Up to 3 weeks post-surgery during Part B]

   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.

10. Volume of Blood Transfused in Major Surgery - Part B [Up to 3 weeks post-surgery during Part B]

    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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Years to 65 Years
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male; 12-65 years of age

• Subjects with severe hemophilia A

• Previously treated with factor VIII for a minimum of 150 exposure days

Exclusion Criteria:

• Inhibitors to FVIII (current evidence or history)

• Any other inherited or acquired bleeding disorder in addition to Hemophilia A

• Platelet count < 100,000/mm3

• Creatinine > 2x upper limit of normal or AST/ALT (aspartate aminotransferase/alanine aminotransferase) > 5x upper limit of normal

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Tucson	Arizona	United States	85724-5024
2		Sacramento	California	United States	95817
3		San Diego	California	United States	92103-8651
4		Jacksonville	Florida	United States	32207
5		Miami	Florida	United States	33136
6		Chicago	Illinois	United States	60612
7		Detroit	Michigan	United States	48202
8		Minneapolis	Minnesota	United States	55455
9		Syracuse	New York	United States	13210
10		Cincinnati	Ohio	United States	45229-3039
11		Cleveland	Ohio	United States	44106-6007
12		Columbus	Ohio	United States	43205
13		Hershey	Pennsylvania	United States	17033
14		Richmond	Virginia	United States	23298-0155
15		Wien		Austria	1090
16		Brugge		Belgium	8000
17		London	Ontario	Canada	N6A 5W9
18		Medellín	Antioquia	Colombia
19		Barranquilla	Atlántico	Colombia
20		Aarhus N		Denmark	8200
21		BRON cedex		France	69677
22		Marseille		France	13005
23		Reims Cedex		France	51092
24		Rennes Cedex		France	35033
25		Heidelberg	Baden-Württemberg	Germany	69004
26		Bonn	Nordrhein-Westfalen	Germany	53127
27		Ramat Gan		Israel	5262000
28		Napoli	Campania	Italy	80131
29		Roma	Lazio	Italy	00161
30		Milano	Lombardia	Italy	20122
31		Torino	Piemonte	Italy	10126
32		Nagoya	Aichi	Japan	466-8560
33		Nishinomiya	Hyogo	Japan	663-8501
34		Kashihara	Nara	Japan	634-8522
35		Shinjuku-ku	Tokyo	Japan	160-0023
36		Suginami	Tokyo	Japan	167-0035
37		Hiroshima		Japan	734-8551
38		Busan	Busan Gwang''yeogsi	Korea, Republic of	49241
39		Daejeon		Korea, Republic of	35233
40		Seoul		Korea, Republic of	03722
41		Seoul		Korea, Republic of	05278
42		Amsterdam		Netherlands	1105 AZ
43		Den Haag		Netherlands	2545 CH
44		Groningen		Netherlands	9713 GZ
45		Maastricht		Netherlands	6229 HX
46		Oslo		Norway	0372
47		Wroclaw		Poland	50-367
48		Timisoara		Romania	300011
49		Singapore		Singapore	119228
50		Singapore		Singapore	169608
51		Singapore		Singapore	229 899
52		Changhua		Taiwan	50006
53		Taipei		Taiwan	10002
54		Taipei		Taiwan	11217
55		Ankara		Turkey	06100
56		Izmir		Turkey	35100
57		Newcastle Upon Tyne	Vale Of Glamorgan, The	United Kingdom	NE1 4LP
58		London		United Kingdom	SE1 7EH
59		Sheffield		United Kingdom	S10 2JF

Sponsors and Collaborators

• Bayer

Investigators

• Study Director: Bayer Study Director, Bayer

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Click here to find information about studies related to Bayer Healthcare products conducted in Europe

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
• First Posted: Apr 19, 2012
• Last Update Posted: Dec 2, 2020
• Last Verified: Nov 1, 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Bayer: Hemophilia A, factor VIII, prophylaxis
• Additional relevant MeSH terms: Hemophilia A; Factor VIII

Study Results

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 Detail	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	20	114	0
COMPLETED	18	108	0
NOT COMPLETED	2	6	0
Period Title: Part A_Main Trial
STARTED	14	107	0
COMPLETED	14	95	0
NOT COMPLETED	0	12	0
Period Title: Part A_Main Trial
STARTED	0	0	19
COMPLETED	0	0	17
NOT COMPLETED	0	0	2

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 Participants	20	4	13	11	43	43	11	145
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	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 (Count of Participants)
Female	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Male	20 100%	4 100%	13 100%	11 100%	43 100%	43 100%	11 100%	145 100%

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.
Measure Participants	20	13	11	43	43	110
Median (Inter-Quartile Range) [bleeds]	23.42	4.11	1.93	1.93	3.85	2.09

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.
Measure Participants	20	13	11	43	43	110
Joint Bleeds	16.34	4.01	1.93	1.86	1.92	1.93
Trauma Bleeds	9.09	1.98	0.00	0.00	0.00	0.00
Spontaneous Bleeds	14.29	3.87	0.00	0.00	1.93	0.00

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.
Measure Participants	14	23	33	23	28
Median (Inter-Quartile Range) [bleeds]	34.09	1.57	1.17	0.65	3.10

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).
Measure Participants	20	114
Count of Participants [Participants]	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).
Measure Participants	20	75
Measure bleeds	386	316
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).
Measure Participants	20	75
Measure bleeds	386	316
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
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).
Measure Participants	20	75
Measure bleeds	386	316
<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).
Measure Participants	20	75
Measure bleeds	386	316
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.
Measure Participants	20	13	11	43	43	110
Median (Full Range) [IU/kg/year]	1518.5	4421.4	3314.4	3482.9	3338.7	3421.0

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.
Measure Participants	20	13	11	43	43	110
Median (Full Range) [IU/kg/infusion]	32.8	39.2	30.6	45.3	59.0	46.9

11. Secondary Outcome

Title	Number of Participants Requiring an Increase in Dose Frequency, or Dose Increase, During Weeks 10 to 36 - Part A
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.
Measure Participants	13	11	43	43	110
Dose frequency increased	0 0%	0 0%	0 0%	11 100%	11 25.6%
Dose increased	2 10%	0 0%	7 53.8%	0 0%	9 20.9%

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.
Measure Participants	17
Measure surgeries	20
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.
Measure Participants	17
Measure surgeries	20
Median (Full Range) [IU/kg/infusion]	33.7

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.
Measure Participants	17
Measure surgeries	20
Median (Full Range) [infusions]	8.0

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.
Measure Participants	22	15
Geometric Mean (Geometric Coefficient of Variation) [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.
Measure Participants	22	15
Geometric Mean (Geometric Coefficient of Variation) [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.
Measure Participants	22	15
Geometric Mean (Geometric Coefficient of Variation) [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).
Measure Participants	20	112
Mean (Standard Deviation) [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).
Measure Participants	19	97
Mean (Standard Deviation) [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).
Measure Participants	20	112
Pain severity subscale	-0.8 (1.8)	0.1 (1.39)
Interference subscale	-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.
Measure Participants	20	112
Activity impairment	4.74 (24.12)	-7.13 (20.00)
Overall work impairment	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.
Measure Participants	20	13	11	43	43	110
Median (Full Range) [infusions]	29	56.0	55.0	38.0	27.0	37.5

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.
Measure Participants	13	11	43	43	110
Median (Full Range) [IU/kg]	1986.9	1669.1	1704.3	1530.2	1644.9

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.
Measure Participants	10
Measure minor surgeries	17
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.
Measure Participants	14
Measure surgeries	17
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.
Measure Participants	17
Hematocrit	6 30%
Hemoglobin	2 10%

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.
Measure Participants	17
Measure surgeries	20
Number [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.
Measure Participants	17
Count of Participants [Participants]	8 40%

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.
Measure Participants	4
Measure surgeries	5
Median (Full Range) [milliliter]	865

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.
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 (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/134 (0%)		0/121 (0%)		0/22 (0%)
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 (9.7%)		36/121 (29.8%)		2/22 (9.1%)
Blood and lymphatic system disorders
Anaemia	0/134 (0%)	0	1/121 (0.8%)	1	0/22 (0%)	0
Cardiac disorders
Angina unstable	0/134 (0%)	0	1/121 (0.8%)	1	0/22 (0%)	0
Eye disorders
Macular fibrosis	0/134 (0%)	0	1/121 (0.8%)	1	0/22 (0%)	0
Gastrointestinal disorders
Anal fistula	0/134 (0%)	0	1/121 (0.8%)	2	0/22 (0%)	0
Enterocolitis	0/134 (0%)	0	1/121 (0.8%)	1	0/22 (0%)	0
Gastrointestinal haemorrhage	0/134 (0%)	0	1/121 (0.8%)	1	0/22 (0%)	0
Inguinal hernia	0/134 (0%)	0	2/121 (1.7%)	3	0/22 (0%)	0
Intestinal obstruction	0/134 (0%)	0	1/121 (0.8%)	1	0/22 (0%)	0
Mouth haemorrhage	0/134 (0%)	0	1/121 (0.8%)	1	0/22 (0%)	0
Pancreatitis acute	1/134 (0.7%)	1	0/121 (0%)	0	0/22 (0%)	0
Retroperitoneal haematoma	0/134 (0%)	0	1/121 (0.8%)	1	0/22 (0%)	0
Tooth impacted	0/134 (0%)	0	2/121 (1.7%)	2	0/22 (0%)	0
Hepatobiliary disorders
Bile duct stone	1/134 (0.7%)	1	0/121 (0%)	0	0/22 (0%)	0
Hepatic cirrhosis	0/134 (0%)	0	1/121 (0.8%)	1	0/22 (0%)	0
Immune system disorders
Drug hypersensitivity	1/134 (0.7%)	1	0/121 (0%)	0	0/22 (0%)	0
Infections and infestations
Anal abscess	0/134 (0%)	0	1/121 (0.8%)	3	0/22 (0%)	0
Arthritis bacterial	0/134 (0%)	0	1/121 (0.8%)	1	0/22 (0%)	0
Cellulitis	0/134 (0%)	0	1/121 (0.8%)	1	0/22 (0%)	0
Device related infection	1/134 (0.7%)	1	0/121 (0%)	0	0/22 (0%)	0
Gastroenteritis	1/134 (0.7%)	1	0/121 (0%)	0	0/22 (0%)	0
Medical device site joint infection	0/134 (0%)	0	1/121 (0.8%)	1	0/22 (0%)	0
Nasal vestibulitis	0/134 (0%)	0	1/121 (0.8%)	1	0/22 (0%)	0
Pneumonia	1/134 (0.7%)	1	0/121 (0%)	0	0/22 (0%)	0
Injury, poisoning and procedural complications
Alcohol poisoning	1/134 (0.7%)	1	0/121 (0%)	0	0/22 (0%)	0
Contusion	0/134 (0%)	0	1/121 (0.8%)	1	0/22 (0%)	0
Fall	0/134 (0%)	0	1/121 (0.8%)	1	0/22 (0%)	0
Fibula fracture	0/134 (0%)	0	1/121 (0.8%)	1	0/22 (0%)	0
Hand fracture	0/134 (0%)	0	1/121 (0.8%)	1	0/22 (0%)	0
Head injury	0/134 (0%)	0	2/121 (1.7%)	2	0/22 (0%)	0
Humerus fracture	0/134 (0%)	0	1/121 (0.8%)	1	0/22 (0%)	0
Injury	1/134 (0.7%)	1	0/121 (0%)	0	0/22 (0%)	0
Ligament rupture	0/134 (0%)	0	1/121 (0.8%)	1	0/22 (0%)	0
Overdose	1/134 (0.7%)	1	0/121 (0%)	0	0/22 (0%)	0
Periprosthetic fracture	0/134 (0%)	0	1/121 (0.8%)	1	0/22 (0%)	0
Tendon rupture	1/134 (0.7%)	1	0/121 (0%)	0	0/22 (0%)	0
Tibia fracture	0/134 (0%)	0	1/121 (0.8%)	1	0/22 (0%)	0
Investigations
Anti factor VIII antibody positive	0/134 (0%)	0	0/121 (0%)	0	2/22 (9.1%)	2
Colonoscopy	1/134 (0.7%)	1	0/121 (0%)	0	0/22 (0%)	0
Liver function test increased	0/134 (0%)	0	1/121 (0.8%)	2	0/22 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	0/134 (0%)	0	1/121 (0.8%)	1	0/22 (0%)	0
Arthropathy	1/134 (0.7%)	1	1/121 (0.8%)	2	0/22 (0%)	0
Back pain	0/134 (0%)	0	2/121 (1.7%)	3	0/22 (0%)	0
Chondrocalcinosis pyrophosphate	0/134 (0%)	0	1/121 (0.8%)	1	0/22 (0%)	0
Haemarthrosis	1/134 (0.7%)	1	1/121 (0.8%)	1	0/22 (0%)	0
Haemophilic arthropathy	1/134 (0.7%)	1	4/121 (3.3%)	5	0/22 (0%)	0
Osteoarthritis	0/134 (0%)	0	1/121 (0.8%)	1	0/22 (0%)	0
Rotator cuff syndrome	0/134 (0%)	0	1/121 (0.8%)	1	0/22 (0%)	0
Synovitis	0/134 (0%)	0	1/121 (0.8%)	1	0/22 (0%)	0
Nervous system disorders
Epilepsy	0/134 (0%)	0	1/121 (0.8%)	1	0/22 (0%)	0
Product Issues
Device malfunction	1/134 (0.7%)	1	0/121 (0%)	0	0/22 (0%)	0
Psychiatric disorders
Depression	0/134 (0%)	0	1/121 (0.8%)	1	0/22 (0%)	0
Renal and urinary disorders
Hydronephrosis	0/134 (0%)	0	1/121 (0.8%)	1	0/22 (0%)	0
Nephrolithiasis	0/134 (0%)	0	1/121 (0.8%)	1	0/22 (0%)	0
Renal colic	0/134 (0%)	0	1/121 (0.8%)	1	0/22 (0%)	0
Ureterolithiasis	0/134 (0%)	0	1/121 (0.8%)	1	0/22 (0%)	0
Skin and subcutaneous tissue disorders
Dermatitis exfoliative generalised	0/134 (0%)	0	1/121 (0.8%)	1	0/22 (0%)	0
Surgical and medical procedures
Joint arthroplasty	0/134 (0%)	0	1/121 (0.8%)	1	0/22 (0%)	0
Knee arthroplasty	1/134 (0.7%)	1	0/121 (0%)	0	0/22 (0%)	0
Renal stone removal	0/134 (0%)	0	1/121 (0.8%)	2	0/22 (0%)	0
Ureteral stent insertion	0/134 (0%)	0	1/121 (0.8%)	1	0/22 (0%)	0
Vascular disorders
Haematoma	0/134 (0%)	0	2/121 (1.7%)	2	1/22 (4.5%)	1
Other (Not Including 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	67/134 (50%)		74/121 (61.2%)		16/22 (72.7%)
Gastrointestinal disorders
Nausea	5/134 (3.7%)	6	5/121 (4.1%)	7	2/22 (9.1%)	2
General disorders
Pyrexia	1/134 (0.7%)	1	10/121 (8.3%)	13	3/22 (13.6%)	3
Infections and infestations
Influenza	5/134 (3.7%)	9	8/121 (6.6%)	12	0/22 (0%)	0
Nasopharyngitis	24/134 (17.9%)	34	25/121 (20.7%)	55	1/22 (4.5%)	1
Pharyngitis	1/134 (0.7%)	1	7/121 (5.8%)	9	0/22 (0%)	0
Upper respiratory tract infection	3/134 (2.2%)	3	12/121 (9.9%)	14	0/22 (0%)	0
Injury, poisoning and procedural complications
Limb injury	3/134 (2.2%)	3	8/121 (6.6%)	8	0/22 (0%)	0
Procedural haemorrhage	0/134 (0%)	0	0/121 (0%)	0	3/22 (13.6%)	3
Procedural hypotension	0/134 (0%)	0	0/121 (0%)	0	2/22 (9.1%)	2
Procedural pain	2/134 (1.5%)	2	7/121 (5.8%)	8	9/22 (40.9%)	10
Investigations
Haemoglobin decreased	0/134 (0%)	0	2/121 (1.7%)	2	3/22 (13.6%)	3
Musculoskeletal and connective tissue disorders
Arthralgia	11/134 (8.2%)	13	26/121 (21.5%)	40	2/22 (9.1%)	2
Back pain	8/134 (6%)	10	14/121 (11.6%)	17	0/22 (0%)	0
Haemarthrosis	2/134 (1.5%)	2	8/121 (6.6%)	8	1/22 (4.5%)	1
Musculoskeletal pain	4/134 (3%)	4	7/121 (5.8%)	10	0/22 (0%)	0
Osteoarthritis	0/134 (0%)	0	7/121 (5.8%)	12	0/22 (0%)	0
Pain in extremity	5/134 (3.7%)	6	8/121 (6.6%)	11	0/22 (0%)	0
Nervous system disorders
Headache	16/134 (11.9%)	28	14/121 (11.6%)	21	0/22 (0%)	0
Psychiatric disorders
Insomnia	3/134 (2.2%)	3	1/121 (0.8%)	1	2/22 (9.1%)	2
Respiratory, thoracic and mediastinal disorders
Cough	8/134 (6%)	11	9/121 (7.4%)	11	0/22 (0%)	0
Epistaxis	8/134 (6%)	10	6/121 (5%)	6	0/22 (0%)	0
Skin and subcutaneous tissue disorders
Rash	1/134 (0.7%)	1	3/121 (2.5%)	6	2/22 (9.1%)	2
Vascular disorders
Haematoma	0/134 (0%)	0	3/121 (2.5%)	3	2/22 (9.1%)	2

Limitations/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.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.