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

Study Overview
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Brief Summary
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The study will assess the pharmacokinetics (part A) safety, tolerability, and efficacy of prophylaxis treatment (2 to 3 times a week) (part B) with BAY81-8973 over a one year period (split into two six month treatment periods). The study will compare 2 different methods (assays) for measuring the amount of study drug, the chromogenic substrate assay per European Pharmacopeia (CS/EP) with the classical assay (Chromogenic Substrate Adjusted, CS/ADJ). During one six month period patients will receive the study drug where the dose has been measured using the (CS/EP) and during the other six months period the dose will be measured based on the Chromogenic Substrate Adjusted assay CS/ADJ)

Official Title
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A Two Part Randomized Cross-Over Trial to Evaluate the Pharmacokinetics, Efficacy, and Safety Profile of Plasma Protein-Free Recombinant FVIII Formulated With Sucrose (BAY81-8973) in Previously Treated Subjects With Severe Hemophilia A Under Prophylaxis Therapy

Conditions
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Blood Coagulation Disorders, Hemophilia A

Intervention / Treatment
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* Biological: Recombinant Factor VIII (BAY81-8973)
* Biological: Recombinant Factor VIII (Kogenate FS, BAY14-2222)
* Biological: Recombinant Factor VIII (BAY81-8973)
* Biological: Recombinant Factor VIII (BAY81-8973)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1: Recombinant Factor VIII (BAY81-8973) then Kogenate FS<br>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 | Biological: Recombinant Factor VIII (BAY81-8973)<br>* Single dose of BAY81-8973 crossed over to single dose of Kogenate FS<br>|
| Experimental: Arm 2: Kogenate FS then Recombinant Factor VIII (BAY81-8973)<br>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 | Biological: Recombinant Factor VIII (Kogenate FS, BAY14-2222)<br>* Single dose of Kogenate FS crossed over to Single dose of BAY81-8973<br>|
| Experimental: Arm 3: Recombinant Factor VIII by CS/EP then by CS/ADJ<br>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 | Biological: Recombinant Factor VIII (BAY81-8973)<br>* 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.<br>|
| Experimental: Arm 4: Recombinant Factor VIII by CS/ADJ then by CS/EP<br>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 | Biological: Recombinant Factor VIII (BAY81-8973)<br>* 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.<br>|
| Experimental: Arm 5: Recombinant Factor VIII by CS/EP<br>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 | Biological: Recombinant Factor VIII (BAY81-8973)<br>* 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<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A - Area Under the Drug Concentration-time Curve (AUC) | 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. | 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. | 
| Part A - Half-life (t 1/2) | 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. | Samples taken at pre-injection, and at 0.25, 0.5, 1, 3, 6, 8, 24, 30 and 48 hours post injection. | 
| Part B - Annualized Number of Total Bleeds | The annualized number of bleeds experienced by participants | 12 months after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part B - The in Vivo Recovery Values of Human Factor VIII (FVIII) | 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. | 15-30 minutes after the injection | 
| Part B - Annualized Number of Bleeds in Each 6-month Potency Assignment Period | The annualized number of bleeds experienced by participants in each of the two treatment periods | 6 months on each potency | 
| Part B - Control of Bleeding as Measured by the Number of Injections Required to Treat a Bleed | The number of injections needed by participants to stop a bleed | 6 months on each potency | 
| Part B - Changes From Baseline at 12 Months in Quality of Life (QoL) as Measured by Transformed Total Score of Haemo-QoL Questionnaire | 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. | Baseline and 12 months | 
| Part B - Changes From Baseline at 12 Months in Utility Index as Measured by EQ-5D Questionaire | 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. | Baseline and 12 months | 
| Part A - Number of Participants With Inhibitory Antibody Formation | A test to ensure that participants have not developed antibodies that will interfere with the action of BAY81-8973 | Up to 6 weeks after first injection of study drug | 
| Part B - Number of Participants With Incidence of Inhibitory Antibody Formation | A test to ensure that participants have not developed antibodies that will interfere with the action of BAY81-8973 | Up to 12 months after drug administration | 
| Part C - Number of Participants With Incidence of Inhibitory Antibody Formation | A test to ensure that participants have not developed antibodies that will interfere with the action of BAY81-8973 | before and 3 weeks after surgery | 
| Part A - Number of Participants With Incidence of Antibody Formation to Heat-shock Protein (HSP-70) | A test to analyze the formation of antibodies to HSP-70 | Up to 6 weeks after drug administration | 
| Part B - Number of Participants With Incidence of Antibody Formation to Heat-shock Protein (HSP-70) | A test to analyze the formation of antibodies to HSP-70 | Up to 12 months after drug administration | 
| Part C - Number of Participants With Incidence of Antibody Formation to Heat-shock Protein (HSP-70) | A test to analyze the formation of antibodies to HSP-70 | before and 3 weeks after surgery | 
| Part A - Number of Participants With Incidence of Antibody Formation to Host Cell Proteins (HCP) | A test to ensure that participants have not developed antibodies to HCP during the study | Up to 4 weeks after drug administration | 
| Part B - Number of Participants With Incidence of Antibody Formation to Host Cell Proteins (HCP) | A test to ensure that participants have not developed antibodies to HCP during the study | Up to 12 months after drug administration | 
| Part C - Number of Participants With Incidence of Antibody Formation to Host Cell Proteins (HCP) | A test to ensure that participants have not developed antibodies to HCP during the study | before and 3 weeks after surgery | 
| Part B - Number of Participants With Assessment of the Hemostasis During Major Surgery | An assessment made by surgeons of how effective BAY81-8973 was in stopping bleeding during major operations | An average of 1 month after start of treatment | 
| Part C - Number of Participants With Assessment of the Hemostasis During Major Surgery | An assessment made by surgeons of how effective BAY81-8973 was in stopping bleeding during major operations | at the time of surgery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hemophilia A, Factor VIII, Prophylaxis