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NCT Number: NCT03935334

Clinical Trial Comparing a Biosimilar Eptacog Alfa With Novoseven, in Patients With Hemophilia With Inhibitors

The purpose of this multicentre, randomized, double-blinded, single dose, two-way cross-over study, is to compare the pharmacokinetics (PK) and pharmacodynamic (PD) of two different doses of the biosimilar eptacog alfa (activated) with Novoseven in 48 patients, adult and children (>12 years), not bleeding, with hemophilia A or B with inhibitors. Patients will be randomized to receive either a single dose of eptacog alfa biosimilar 90 μg/kg or 270 μg/kg and one single dose of NovoSeven 90 μg/kg or 270 μg/kg, or vice versa, with doses separated by a washout period. All patients will be followed 12 months and will receive biosimilar eptacog alfa, on demand, for every bleeding episode that should occur - or - for prophylaxis, with the aim of monitoring of inhibiting antibody formation, lack of efficacy and collection of safety data.

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Key information

Conditions

Hemophilia A or B With Inhibitor Blood Coagulation Disorders Blood Coagulation Disorders, Inherited Coagulation Protein Disorders Congenital, Hereditary, and Neonatal Diseases and Abnormalities Genetic Diseases, Inborn Hematologic Diseases Hemic and Lymphatic Diseases Hemophilia A Hemorrhagic Disorders

Age range

12 year and older

Sex eligibility

Male

Study type

Interventional

Phase

Phase 3

Primary location

Hemophilia Center - Hematology & Oncology Dept. Shiraz University of Medical Science, Shiraz, Iran

Loading trial locations.

About this study

Forty-eight patients enrolled, not bleeding, will be randomized to receive two injections separated by a washout period of 3 days (t1/2 = 2.3h). Patients are centrally registered and randomized to receive in a 2x2 cross-over setting either a single dose of two for the following products: A: AryoSeven 90 µg/kg and B: NovoSeven 90 µg/kg - or - C: AryoSeven 270 µg/kg and D: NovoSeven 270 µg/kg.

Patients will be hospitalized at the time of study medication administration and plasma sampling. Before any treatment, a blood sample will be obtained in all patients for testing for immunogenicity.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Confirmed diagnosis of congenital hemophilia 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, non in bleeding status
  • male subjects
  • adult and children (>12 years)
  • written informed consent to the protocol to be eligible for the study. For minor patients, parent/legal guardian will provide consent and, when possible, patient assent will also be obtained. For compromised patients, their designated proxy must provide informed consent.
  • For the PK/PD phase, patients will be hospitalized at the time of study medication administration for plasma sampling (2 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 Novoseven or planned to occur during the trial
  • Patients who have received routine (prophylactic) treatment with rFVIIa in the period between screening visit (visit 1) and visit 2 of this study (first dose administration)
  • Platelet count less than 100.000 platelets/microliter (at screening visit)
  • Any clinical sign or known history of an 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 endpoint of the study

Treatment and study plan

Biosimilar eptacog alfa, activated (AryoSeven)

Biological

A single dose of eptacog alfa biosimilar (AryoSeven) 90 μg/kg or 270 μg/kg. Then, in an open follow up phase of 12 months, for every bleeding episode patients will receive eptacog alfa biosimilar, on demand, for one of more days until resolution of bleeding, based on the Investigator's decision - or - prophylaxis with eptacog alfa biosimilar, with dose, frequency, and duration of treatment based on the Investigator's decision. The modality of treatment (on demand or prophylaxis) will be decided by the Investigator.

Eptacog alfa, activated (Novoseven)

Biological

A single dose of eptacog alfa (Novoseven) 90 μg/kg or 270 μg/kg. Then, in an open follow up phase of 12 months, for every bleeding episode patients will receive eptacog alfa biosimilar, on demand, for one of more days until resolution of bleeding, based on the Investigator's decision - or - prophylaxis with eptacog alfa biosimilar, with dose, frequency, and duration of treatment based on the Investigator's decision. The modality of treatment (on demand or prophylaxis) will be decided by the Investigator.

Primary outcomes

  1. Area under the plasma concentration time curve from time 0 to infinity, based on the last observed concentration (AUCinf)

    Time frame: Ten minutes prior to dose administration and at 10 minutes, 20 minutes, 1 hour, 3 hours, 5 hours, 8 hours, 12 hours, 24 hours and 30 hours after AryoSeven and NovoSeven injection

    Measurement of plasma level of factor VII clotting activity (FVII:C) determined by commercial Staclot® VIIa-recombinant tissue factor assay (Diagnostics Stago, France).

  2. Treatment response to Thrombin Generation Assay (TGA), D-Dimer, F1.2 prothrombin fragments.

    Time frame: Ten minutes prior to dose administration and at 10 minutes, 20 minutes, 1 hour, 3 hours, 5 hours, 8 hours, 12 hours, 24 hours and 30 hours after AryoSeven and NovoSeven injection

    Measurement of plasma levels based on standard methods recommended by the Subcommittee on the control of anticoagulation of the ISTH

Secondary outcomes

  1. Area under the plasma concentration-time curve from 0 to the last measurable time point (AUClast).

    Time frame: Ten minutes prior to dose administration and at 10 minutes, 20 minutes, 1 hour, 3 hours, 5 hours, 8 hours, 12 hours, 24 hours and 30 hours after AryoSeven and NovoSeven injection

    Measurement of plasma level of factor VII clotting activity (FVII:C) determined by commercial Staclot® VIIa-recombinant tissue factor assay

  2. Maximum plasma concentration (Cmax)

    Time frame: Ten minutes prior to dose administration and at 10 minutes, 20 minutes, 1 hour, 3 hours, 5 hours, 8 hours, 12 hours, 24 hours and 30 hours after AryoSeven and NovoSeven injection

    Measurement of plasma level of factor VII clotting activity (FVII:C) determined by commercial Staclot® VIIa-recombinant tissue factor assay

  3. Time of Cmax (tmax);

    Time frame: Ten minutes prior to dose administration and at 10 minutes, 20 minutes, 1 hour, 3 hours, 5 hours, 8 hours, 12 hours, 24 hours and 30 hours after AryoSeven and NovoSeven injection

    Measurement of plasma level of factor VII clotting activity (FVII:C) determined by commercial Staclot® VIIa-recombinant tissue factor assay

  4. Fraction of the total AUCinf that was derived by extrapolation beyond tlast (AUCextra)

    Time frame: Ten minutes prior to dose administration and at 10 minutes, 20 minutes, 1 hour, 3 hours, 5 hours, 8 hours, 12 hours, 24 hours and 30 hours after AryoSeven and NovoSeven injection

    Measurement of plasma level of factor VII clotting activity (FVII:C) determined by commercial Staclot® VIIa-recombinant tissue factor assay

  5. First order rate constant associated with the terminal (log-linear) portion of the curve (λz)

    Time frame: Ten minutes prior to dose administration and at 10 minutes, 20 minutes, 1 hour, 3 hours, 5 hours, 8 hours, 12 hours, 24 hours and 30 hours after AryoSeven and NovoSeven injection

    Measurement of plasma level of factor VII clotting activity (FVII:C) determined by commercial Staclot® VIIa-recombinant tissue factor assay

  6. Elimination half-life

    Time frame: Ten minutes prior to dose administration and at 10 minutes, 20 minutes, 1 hour, 3 hours, 5 hours, 8 hours, 12 hours, 24 hours and 30 hours after AryoSeven and NovoSeven injection

    Measurement of plasma level of factor VII clotting activity (FVII:C) determined by commercial Staclot® VIIa-recombinant tissue factor assay

  7. Mean residence time (MRT)

    Time frame: Ten minutes prior to dose administration and at 10 minutes, 20 minutes, 1 hour, 3 hours, 5 hours, 8 hours, 12 hours, 24 hours and 30 hours after AryoSeven and NovoSeven injection

    Measurement of plasma level of factor VII clotting activity (FVII:C) determined by commercial Staclot® VIIa-recombinant tissue factor assay

  8. Clearance and CL/Dose (CL)

    Time frame: Ten minutes prior to dose administration and at 10 minutes, 20 minutes, 1 hour, 3 hours, 5 hours, 8 hours, 12 hours, 24 hours and 30 hours after AryoSeven and NovoSeven injection

    Measurement of plasma level of factor VII clotting activity (FVII:C) determined by commercial Staclot® VIIa-recombinant tissue factor assay

  9. Volume of distribution (Vss)

    Time frame: Ten minutes prior to dose administration and at 10 minutes, 20 minutes, 1 hour, 3 hours, 5 hours, 8 hours, 12 hours, 24 hours and 30 hours after AryoSeven and NovoSeven injection

    Measurement of plasma level of factor VII clotting activity (FVII:C) determined by commercial Staclot® VIIa-recombinant tissue factor assay

  10. Immunogenicity

    Time frame: On plasma samples obtained at screening visit, before the second dose/second drug administration, and then every 3 months for a year

    The Prothrombin Time (PT) based Bethesda assay will be used.

  11. Adverse Events

    Time frame: Adverse events (AEs) will be monitored throughout the trial, from the first dose administered up to 12 months follow-up.

    Information about all adverse events, whether volunteered by the patient, discovered by investigator questioning, or detected through physical examination, laboratory test or other means, will be collected, recorded and followed as appropriate.

Sponsors and collaborators

Lead sponsor

AryoGen Pharmed Co.

Industry

Registry information

Official study title

A Randomized, Multicenter, Double-blind Clinical Trial Comparing Pharmacodynamic, Pharmacokinetic and Safety of a Biosimilar Eptacog Alfa (AryoSeven) and Novoseven®, in Patients With Hemophilia A or B With Inhibitors.

Important dates

Study start
2018
Primary completion
2021
Study completion
2021
First posted
May 2, 2019
Registry last updated
Feb 4, 2021

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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