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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Hemophilia A

Intervention / Treatment
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* Biological: BAY94-9027


Participation Criteria
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Eligibility Criteria
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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

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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1<br>On-demand treatment of BAY94-9027 at individual dose and number of infusions based upon location and severity of bleeds | Biological: BAY94-9027<br>* Intravenous infusion of BAY94-9027<br>|
| Experimental: Arm 2<br>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<br>* Intravenous infusion of BAY94-9027<br>|
| Experimental: Arm 3<br>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<br>* Intravenous infusion of BAY94-9027<br>|
| Experimental: Arm 4<br>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<br>* Intravenous infusion of BAY94-9027<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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). | On-demand: Weeks 0 -36 and Prophylaxis: Weeks 10 - 36 during Part A | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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. | On-demand: Weeks 0 -36 and Prophylaxis: Weeks 10 - 36 during Part A | 
| Annualized Number of Total Bleeds in On-demand Treatment Arm and in Each Prophylaxis Arm, Part A, Extension | Annualized number of total bleeds was defined as the annualized sum of spontaneous bleeds and trauma bleeds. | at least 100 total exposure days acquired, median time 3.9 years up to 7 years maximum | 
| Number of Participants Developed Human Coagulation Factor VIII (FVIII) Inhibitor - 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. | Weeks 0 to 36 during Part A | 
| Number of Bleeds Requiring 1, 2 or >= 3 Infusions to Control the Bleed - Part A | Number of bleeds requiring 1, 2 or >= 3 infusions to control the bleeding | Weeks 0 to 36 | 
| Number of Bleeds According to Locations - Part A | Bleed locations were categorised as joint, muscle, skin/mucosa, internal, others and missing. | Weeks 0 -36 | 
| Number of Bleeds Over Time Since Previous Prophylaxis Infusion - Part A |  | Weeks 0 to 36 | 
| Number of Bleeds According to Participant's Assessment of Response to Treatment - Part A | Response to treatment was assessed by participant as excellent, good, moderate, poor or missing during Part A of the study. | Weeks 0 to 36 during Part A | 
| Recombinant Human Factor VIII (rFVIII) Usage Expressed as Total Dose Per Kilogram Per Year - Part A | For prophylaxis patients, the dose is related to all infusions. | On-demand: Weeks 0 -36 and Prophylaxis: Weeks 10 - 36 during Part A | 
| Recombinant Human Factor VIII (rFVIII) Usage Expressed as Dose Per Kilogram Per Infusion - Part A | For prophylaxis patients, the dose per infusion related to prophylaxis infusion. | On-demand: Weeks 0 -36 and Prophylaxis: Weeks 10 - 36 during Part A | 
| 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 | 
| Number of Surgeries According to Physician's Assessment of Adequacy of Hemostasis in Major Surgery - 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. Adequacy of hemostasis was assessed as excellent, good, moderate or poor, by the surgeon or interventionalist during Part B of the study. | Day of surgery | 
| Recombinant Human Factor VIII (rFVIII) Usage Expressed as Dose Per Kilogram Per Infusion for Major Surgery - 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). | Up to 3 weeks post-surgery during Part B | 
| Recombinant Human Factor VIII (rFVIII) Usage Expressed as Number of Infusions for Major Surgery - 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. | Up to 3 weeks post-surgery during Part B | 
| Maximum Drug Plasma Concentration (Cmax) Following Single and Multiple Doses of BAY94-9027, Chromogenic Assay - Part A | Cmax: Maximum observed drug concentration following an infusion of 60 IU/kg | Weeks 0 and 36: pre-infusion (0 hours), post-infusion 15, 30 minutes, 1, 3, 6, 8, 24, 48, 72, 96 hours | 
| 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 | AUC: The total area under the plasma concentration versus time curve following an infusion of 60 IU/kg . | Weeks 0 and 36: pre-infusion (0 hours), post-infusion 15, 30 minutes, 1, 3, 6, 8, 24, 48, 72, 96 hours | 
| Terminal Elimination Half Life (t1/2) Following Single and Multiple Doses of BAY94-9027, Chromogenic Assay - Part A | t1/2: Terminal half-life is the time the plasma concentration during terminal phase is halved following an infusion of 60 IU/kg . | Weeks 0 and 36: pre-infusion (0 hours), post-infusion 15, 30 minutes, 1, 3, 6, 8, 24, 48, 72, 96 hours | 
| Overall Human Coagulation Factor VIII (FVIII) Recovery Value by Chromogenic Assay - 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 | Weeks 0 to 36 during Part A | 
| 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 | 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). | Week 0 (baseline) and Week 36 during Part A | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hemophilia A, factor VIII, prophylaxis