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

Early Phase 1

Completed

• Conditions: Hemophilia A With Inhibitor; Hemophilia B With Inhibitor
• Interventions: Biological: Eptacog alfa, activated

• Registration Number: NCT04789954
• Lead Sponsor: AryoGen Pharmed Co.

Brief Summary

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

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.

Study Timeline

• Study Start: 2020-12-29
• Study First Submitted: 2021-03-04
• Study First Submitted QC: 2021-03-06
• Study First Posted: 2021-03-10
• Primary Completion: 2021-08-13
• Study Completion: 2022-07-31
• Status Verified: 2022-09
• Last Update Submitted: 2022-09-09
• Last Update Posted: 2022-09-10

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Male
• Target Recruitment: 14

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
AryoSeven 30 μg/kg	Eptacog alfa, activated	Single dose, intravenously
AryoSeven 270 μg/kg	Eptacog alfa, activated	Single dose, intravenously
AryoSeven 10 μg/kg	Eptacog alfa, activated	Single dose, intravenously
AryoSeven 90 μg/kg	Eptacog alfa, activated	Single dose, intravenously
NovoSeven 30 μg/kg	Eptacog alfa, activated	Single dose, intravenously

Primary Outcome Measures

Name	Time	Method
Lag time of the thrombin generation curve	Up to 30 hours after AryoSeven and NovoSeven injection	Time to 16.7% of peak plasmatic concentration, in minutes.

Secondary Outcome Measures

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

Trial Locations

Locations (1)

Comprehensive Hemophilia Care Center; 🇮🇷 Teheran, Iran, Islamic Republic of