Trial to Evaluate the Efficacy and Safety of a New Full Length Recombinant Human FVIII for Hemophilia A (Leopold I)

• Part A - Area Under the Drug Concentration-time Curve (AUC) [ Time Frame: Samples taken at pre-injection, and at 0.25, 0.5, 1, 3, 6, 8, 24, 30 and 48 hours post injection. AUC calculated from time of injection to infinity. ]
  To examine the Pharmacokinetic (PK) characteristics of BAY 81-8973 and ensure that the new drug is similar to Kogenate FS. All results are based on the chromogenic assay.
• Part A - Half-life (t 1/2) [ Time Frame: Samples taken at pre-injection, and at 0.25, 0.5, 1, 3, 6, 8, 24, 30 and 48 hours post injection. ]
  To examine the PK characteristics of BAY81-8973 and ensure that the new drug is similar to Kogenate FS. All results are based on the chromogenic assay.
• Part B - Annualized Number of Total Bleeds [ Time Frame: 12 months after randomization ]
  The annualized number of bleeds experienced by participants

• Part A: Pharmacokinetics after a single dose [ Time Frame: 48 hours ]
• Part B: Number of all bleeds in one year [ Time Frame: 12 months ]

• Part B - The in Vivo Recovery Values of Human Factor VIII (FVIII) [ Time Frame: 15-30 minutes after the injection ]
  The amount of Factor VIII found in blood samples taken after the injection of the study drug at the beginning of the CS/EP treatment period.
• Part B - Annualized Number of Bleeds in Each 6-month Potency Assignment Period [ Time Frame: 6 months on each potency ]
  The annualized number of bleeds experienced by participants in each of the two treatment periods
• Part B - Control of Bleeding as Measured by the Number of Injections Required to Treat a Bleed [ Time Frame: 6 months on each potency ]
  The number of injections needed by participants to stop a bleed
• Part B - Changes From Baseline at 12 Months in Quality of Life (QoL) as Measured by Transformed Total Score of Haemo-QoL Questionnaire [ Time Frame: Baseline and 12 months ]
  A measure of how treatment with BAY81-8973 affected the daily life of participants. the scoring system has 100 points. 0 is the worst possible score. 100 is the best possible score. Positive changes from baseline indicate an improvement in quality of life and negative changes indicate a deterioration.
• Part B - Changes From Baseline at 12 Months in Utility Index as Measured by EQ-5D Questionaire [ Time Frame: Baseline and 12 months ]
  A measure of how treatment with BAY81-8973 affected the daily life of participants. 1.0 = Best possible score, -0.594 = Worst possible score. Positive changes from baseline indicate an improvement and negative changes indicate a deterioration.
• Part A - Number of Participants With Inhibitory Antibody Formation [ Time Frame: Up to 6 weeks after first injection of study drug ]
  A test to ensure that participants have not developed antibodies that will interfere with the action of BAY81-8973
• Part B - Number of Participants With Incidence of Inhibitory Antibody Formation [ Time Frame: Up to 12 months after drug administration ]
  A test to ensure that participants have not developed antibodies that will interfere with the action of BAY81-8973
• Part C - Number of Participants With Incidence of Inhibitory Antibody Formation [ Time Frame: before and 3 weeks after surgery ]
  A test to ensure that participants have not developed antibodies that will interfere with the action of BAY81-8973
• Part A - Number of Participants With Incidence of Antibody Formation to Heat-shock Protein (HSP-70) [ Time Frame: Up to 6 weeks after drug administration ]
  A test to analyze the formation of antibodies to HSP-70
• Part B - Number of Participants With Incidence of Antibody Formation to Heat-shock Protein (HSP-70) [ Time Frame: Up to 12 months after drug administration ]
  A test to analyze the formation of antibodies to HSP-70
• Part C - Number of Participants With Incidence of Antibody Formation to Heat-shock Protein (HSP-70) [ Time Frame: before and 3 weeks after surgery ]
  A test to analyze the formation of antibodies to HSP-70
• Part A - Number of Participants With Incidence of Antibody Formation to Host Cell Proteins (HCP) [ Time Frame: Up to 4 weeks after drug administration ]
  A test to ensure that participants have not developed antibodies to HCP during the study
• Part B - Number of Participants With Incidence of Antibody Formation to Host Cell Proteins (HCP) [ Time Frame: Up to 12 months after drug administration ]
  A test to ensure that participants have not developed antibodies to HCP during the study
• Part C - Number of Participants With Incidence of Antibody Formation to Host Cell Proteins (HCP) [ Time Frame: before and 3 weeks after surgery ]
  A test to ensure that participants have not developed antibodies to HCP during the study
• Part B - Number of Participants With Assessment of the Hemostasis During Major Surgery [ Time Frame: An average of 1 month after start of treatment ]
  An assessment made by surgeons of how effective BAY81-8973 was in stopping bleeding during major operations
• Part C - Number of Participants With Assessment of the Hemostasis During Major Surgery [ Time Frame: at the time of surgery ]
  An assessment made by surgeons of how effective BAY81-8973 was in stopping bleeding during major operations

• In vivo recovery (blood levels) of study drug 15 minutes after one dose [ Time Frame: 15 minutes ]
• Non-inferiority of study drug potency determinations as measured by bleeding rate [ Time Frame: 12 months ]
• Potential for inhibitory antibody formation during prophylactic treatment with study drug [ Time Frame: 12 months ]
• Potential for antibody formation to human heat shock protein 70 and hamster proteins during prophylactic treatment with study drug [ Time Frame: 12 months ]
• Surgical outcomes during prophylactic treatment with study drug [ Time Frame: 12 months ]
• Control of bleeding with study drug [ Time Frame: 12 months ]
• Quality of life and pharmacoeconomic parameters during prophylactic treatment with study drug [ Time Frame: 12 months ]

• Blood Coagulation Disorders
• Hemophilia A

• Biological: Recombinant Factor VIII (BAY81-8973)
  Single dose of BAY81-8973 crossed over to single dose of Kogenate FS
• Biological: Recombinant Factor VIII (Kogenate FS, BAY14-2222)
  Single dose of Kogenate FS crossed over to Single dose of BAY81-8973
• Biological: Recombinant Factor VIII (BAY81-8973)
  Participants received IV injections of BAY81-8973 at 20-50 IU/kg 2-3 times per week with BAY81-8973 measured by Chromogenic Substrate Assay Potency Per European Pharmacopeia (CS/EP) for 6 months and by Chromogenic Substrate Assay/Adjusted to Label Potency (CS/ADJ) for 6 months, sequence according to randomization.
• Biological: Recombinant Factor VIII (BAY81-8973)
  Participants received a loading dose of approximately 50 IU/kg of BAY 81-8973 before the first surgical incision followed by further treatment with BAY 81-8973 according to surgical requirements for up to 3 weeks

• Experimental: Arm 1: Recombinant Factor VIII (BAY81-8973) then Kogenate FS
  Part A - Arm 1: Participants first received one single intravenous (IV) injection of BAY81-8973 50 IU/kg, then 1 single IV injection of Kogenate FS (BAY14-2222) 50 IU/kg with a wash-out period of at least 2-3 days in between
  Intervention: Biological: Recombinant Factor VIII (BAY81-8973)
• Experimental: Arm 2: Kogenate FS then Recombinant Factor VIII (BAY81-8973)
  Part A - Arm 2: Participants first received one single intravenous (IV) injection of Kogenate FS (BAY14-2222) 50 IU/kg, then 1 single IV injection of BAY81-8973 50 IU/kg with a wash-out period of at least 2-3 days in between
  Intervention: Biological: Recombinant Factor VIII (Kogenate FS, BAY14-2222)
• Experimental: Arm 3: Recombinant Factor VIII by CS/EP then by CS/ADJ
  Part B - Arm 3: Participants received IV injection of BAY81-8973 at 20-50 IU/kg 2-3 times per week with BAY81-8973 measured by Chromogenic Substrate Assay Potency Per European Pharmacopeia for 6 months and then crossed over to study drug measured by Chromogenic Substrate Assay/Adjusted to Label Potency for 6 months
  Intervention: Biological: Recombinant Factor VIII (BAY81-8973)
• Experimental: Arm 4: Recombinant Factor VIII by CS/ADJ then by CS/EP
  Part B - Arm 4:. Participants received IV injection of BAY81-8973 at 20-50 IU/kg 2-3 times per week with BAY81-8973 measured by Chromogenic Substrate Assay/Adjusted to Label Potency for 6 months and then crossed over to study drug measured by Chromogenic Substrate Assay Per European Pharmacopeia for 6 months
  Intervention: Biological: Recombinant Factor VIII (BAY81-8973)
• Experimental: Arm 5: Recombinant Factor VIII by CS/EP
  Part C - Arm 5: Participants received a loading dose of approximately 50 IU/kg of BAY 81-8973 before the first surgical incision followed by further treatment with BAY 81-8973 according to surgical requirements for up to 3 weeks
  Intervention: Biological: Recombinant Factor VIII (BAY81-8973)

• Kitchen S, Katterle Y, Beckmann H, Maas Enriquez M. Chromogenic assay for BAY 81-8973 potency assignment has no impact on clinical outcome or monitoring in patient samples. J Thromb Haemost. 2016 Jun;14(6):1192-9. doi: 10.1111/jth.13322. Epub 2016 May 3.
• Oldenburg J, Windyga J, Hampton K, Lalezari S, Tseneklidou-Stoeter D, Beckmann H, Maas Enriquez M. Safety and efficacy of BAY 81-8973 for surgery in previously treated patients with haemophilia A: results of the LEOPOLD clinical trial programme. Haemophilia. 2016 May;22(3):349-53. doi: 10.1111/hae.12839. Epub 2016 Mar 1.
• Saxena K, Lalezari S, Oldenburg J, Tseneklidou-Stoeter D, Beckmann H, Yoon M, Maas Enriquez M. Efficacy and safety of BAY 81-8973, a full-length recombinant factor VIII: results from the LEOPOLD I trial. Haemophilia. 2016 Sep;22(5):706-12. doi: 10.1111/hae.12952. Epub 2016 Jun 24.

Inclusion Criteria:

• Male, aged 12 to 65 years
• Severe hemophilia A defined as < 1% FVIII:C
• >/= 150 days of previous treatment with FVIII in lifetime
• Currently receiving on-demand or any type of prophylaxis treatment regimen with any FVIII product
• No history of or current FVIII inhibitors

Exclusion Criteria:

• Presence of another bleeding disease that is different from hemophilia A (e.g., von Willebrand disease, hemophilia B)
• Low platelet count, abnormal kidney function, or liver disease
• Received treatment with immune suppressing drugs within the last 3 months prior or requires treatment during the study. (Some drugs for hepatitis C, Human immunodeficiency virus (HIV), and steroids are allowed)
• Receiving or has received other experimental drugs within 3 months prior to study entry
• Allergy to Factor VIII or hamsters or mouse protein