Study on the Dose-response Relationship of Pharmacodynamic Parameters in Patients With Hemophilia With Inhibitors

Study Overview
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Brief Summary
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Randomized, double-blind, single-dose, 5 ways crossover, exploratory clinical trial evaluating four different doses of AryoSeven (eptacog alfa, activated) and NovoSeven on selected pharmacodynamic parameters in patients with hemophilia with inhibitors.

Detailed Description
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Randomized, double-blind, single dose, 5 ways crossover, clinical trial evaluating four different doses (10 µg/kg, 30 µg/kg, 90 µg/kg, and 270 µg/kg) of AryoSeven (recombinant human FVII activated or eptacog alfa, activated) and one dose of NovoSeven (30 µg/kg) on selected pharmacodynamic parameters (PD) [Primary: Thrombin Generation Assay (TGA)] in male adult and adolescent (>12 years) patients with hemophilia A or B, with an inhibitors titer >5 Bethesda Units [BU] and not in bleeding status. This will be an exploratory study to evaluate dose-response relationship of PD markers as surrogate efficacy endpoints.

Official Title
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An Exploratory Study to Evaluate the Dose Response-Relationship of Pharmacodynamic Parameters of AryoSeven, in Patients With Hemophilia With Inhibitors

Conditions
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Hemophilia A With Inhibitor, Hemophilia B With Inhibitor

Intervention / Treatment
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* Biological: Eptacog alfa, activated


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed diagnosis of congenital haemophilia A or B with inhibitors to FVIII or FIX titer >5 Bethesda Units [BU] with > 2 episodes of bleeding/year requiring treatment with FVII infusions, not in bleeding episode Male adults and adolescents (>12 years) Patient informed consent has been obtained [Patients to be enrolled must also provide voluntary written informed consent to the protocol prior to screening to be eligible for the study. For adolescents, parent/legal guardian must provide consent and, wherever possible, patient assent will also be obtained. For compromised patients, their designated proxy must provide informed consent]. Patients willing and able to be hospitalized prior to time of study medication administration for plasma sampling (5 times during the study). Exclusion Criteria: Any other type of congenital or acquired coagulopathy, such as: liver disease (hepatitis), vitamin k deficiency, uremia, malignancy. Antibodies against Factor VII Ongoing bleeding prophylaxis regimens with AryoSeven/NovoSeven or planned to occur during the trial Platelet count less than 100.000 platelets/mcL (at screening visit) Any clinical sign or known history of arterial thrombotic event or deep venous- thrombosis or pulmonary embolism HIV positive with current CD4+ count of less than 200/µL Liver cirrhosis Factor VIII/IX immune tolerance induction regimen planned to occur during the trial Known hypersensitivity to the study medication Parallel participation in another experimental drug trial. Parallel participation in another marketed drug trial that may affect the primary end-point of the study. Concomitant diseases and/or medications, or any other conditions, that render the patient unsuitable for inclusion into the study in the judgement of the investigator.

Ages Eligible for Study
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Minimum Age: 12 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AryoSeven 10 μg/kg<br>Single dose, intravenously | Biological: Eptacog alfa, activated<br>* A dose sequence for each injection will be randomly selected from the following doses: 10 μg/kg, 30 μg/kg, 90 μg/kg, or 270 μg/kg, separated by a wash-out period of 3 days.<br>|
| Experimental: AryoSeven 30 μg/kg<br>Single dose, intravenously | Biological: Eptacog alfa, activated<br>* A dose sequence for each injection will be randomly selected from the following doses: 10 μg/kg, 30 μg/kg, 90 μg/kg, or 270 μg/kg, separated by a wash-out period of 3 days.<br>|
| Experimental: AryoSeven 90 μg/kg<br>Single dose, intravenously | Biological: Eptacog alfa, activated<br>* A dose sequence for each injection will be randomly selected from the following doses: 10 μg/kg, 30 μg/kg, 90 μg/kg, or 270 μg/kg, separated by a wash-out period of 3 days.<br>|
| Experimental: AryoSeven 270 μg/kg<br>Single dose, intravenously | Biological: Eptacog alfa, activated<br>* A dose sequence for each injection will be randomly selected from the following doses: 10 μg/kg, 30 μg/kg, 90 μg/kg, or 270 μg/kg, separated by a wash-out period of 3 days.<br>|
| Active Comparator: NovoSeven 30 μg/kg<br>Single dose, intravenously | Biological: Eptacog alfa, activated<br>* A dose sequence for each injection will be randomly selected from the following doses: 10 μg/kg, 30 μg/kg, 90 μg/kg, or 270 μg/kg, separated by a wash-out period of 3 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Lag time of the thrombin generation curve | Time to 16.7% of peak plasmatic concentration, in minutes. | Up to 30 hours after AryoSeven and NovoSeven injection | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Endogenous Thrombin Potential (PD parameter) | Area under the curve plasma levels of thrombin generation curve (in nmol/per minute) | Up to 30 hours after AryoSeven and NovoSeven injection | 
| Time to Peak (PD parameter) | Time to Peak of thrombin generation curve (in minutes) | Up to 30 hours after AryoSeven and NovoSeven injection | 
| Peak height (PD parameter) | Peak height of thrombin generation curve (in nmol/ml) | Up to 30 hours after AryoSeven and NovoSeven injection | 
| F1.2 prothrombin fragments (PD parameter) | Peak height (micg/L) | Up to 30 hours after AryoSeven and NovoSeven injection | 
| D-dimer (PD parameter) | Peak height (micg/L) | Up to 30 hours after AryoSeven and NovoSeven injection | 
| AUCinf (PK parameter) | Area under the plasma concentration time curve from time 0 to infinity, based on the last observed concentration; | Up to 30 hours after AryoSeven and NovoSeven injection | 
| Cmax (PK parameter) | Observed maximum plasma concentration | Up to 30 hours after AryoSeven and NovoSeven injection | 
| Time of Cmax (PK parameter) | Time of observed maximum plasma concentration | Up to 30 hours after AryoSeven and NovoSeven injection |