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

NCT03935334 | Completed Phase 3

• 1 other identifier: UGA 2014-01
• Study Type: interventional
• Target: 48
• Locations: 2 countries
• Sites: 8

Brief Summary

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.

Conditions

Hemophilia A or B With Inhibitor

Outcome Measures

Primary Outcomes (2)

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

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

  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

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

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

  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

Secondary Outcomes (11)

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

  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

• Maximum plasma concentration (Cmax)

  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

• Time of Cmax (tmax);

  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

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

  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

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

  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

Study Arms (2)

Eptacog alfa, biosimilar (AryoSeven)

EXPERIMENTAL

Patients will be randomized to receive, in a 2x2 crossover setting, either a single dose of biosimilar eptacog alfa, activated (AryoSeven) of 90 μg/kg or 270 μg/kg, or eptacog alfa, activated (Novoseven) of 90 μg/kg or 270 μg/kg, or vice-versa, separated by a washout period of 3 days.

Biological: Biosimilar eptacog alfa, activated (AryoSeven)

Novoseven

ACTIVE COMPARATOR

Patients will be randomized to receive, in a 2x2 crossover setting, either a single dose of biosimilar eptacog alfa, activated (AryoSeven) of 90 μg/kg or 270 μg/kg, or eptacog alfa, activated (Novoseven) of 90 μg/kg or 270 μg/kg, or vice-versa, separated by a washout period of 3 days.

Biological: Eptacog alfa, activated (Novoseven)

Interventions

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, biosimilar (AryoSeven)

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.

Novoseven

Eligibility Criteria

• Age: 12 Years+
• Sex: male
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).

You may not qualify if:

• 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

Sponsors & Collaborators

• AryoGen Pharmed Co.: lead

Study Sites (8)

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

Shiraz, Iran

Location

Comprehensive Hemophilia Care Center

Tehran, Iran

Location

Ali Asghar Hospital

Zahedan, Iran

Location

Acibadem Adana Hastanesi, Pediatrik Hematoloji-Onkoloji Bölümü

Adana, Turkey (Türkiye)

Location

Hacettepe Üniversitesi Çocuk Sağlığı ve Hastalıkları Anabilim Dalı Çocuk Hematolojisi Bilim Dalı

Ankara, Turkey (Türkiye)

Location

Uludağ Üniversitesi Tıp Fakültesi Çocuk Sağlığı ve Hastalıkları Anabilim Dalı/Hematoloji Bilim Dalı

Bursa, Turkey (Türkiye)

Location

Istanbul Üniversitesi Cerrahpaşa Tip Fakültesi Çocuk Sağlığı ve Hastalıkları Anabilim Dalı Çocuk Hematoloji-Onkoloji B.D.

Istanbul, Turkey (Türkiye)

Location

Ege Üniversitesi Tip Fakültesi Cocuk Sağliği ve Hastalikari Anabilim Dali ÇocukHematoloji Bilim Dali

Izmir, Turkey (Türkiye)

Location

MeSH Terms

Conditions

Hemophilia A

Interventions

recombinant FVIIa

Condition Hierarchy (Ancestors)

Blood Coagulation Disorders, Inherited; Blood Coagulation Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Study Officials

• Massimo Iacobelli, MD

  Consultant

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Blinding will be performed by an independent third party operator (nurse/pharmacist, unblinded), who will prepare undistinguishable syringes with patient's dosing and labelling.
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 29, 2019
• First Posted: May 2, 2019
• Study Start: July 23, 2018
• Primary Completion: January 31, 2021
• Study Completion: February 3, 2021
• Last Updated: February 4, 2021

Record last verified: 2020-07

Data Sharing

• IPD Sharing: Will not share

Locations

TU (5); IR (3)