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

• ClinicalTrials.gov Identifier: NCT03935334
• Recruitment Status: Recruiting
• First Posted: May 2, 2019
• Last Update Posted: May 2, 2019
• Sponsor: AryoGen Pharmed Co.
• Information provided by (Responsible Party): AryoGen Pharmed Co.

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Hemophilia A or B With Inhibitor	Biological: Biosimilar eptacog alfa, activated (AryoSeven); Biological: Eptacog alfa, activated (Novoseven)	Phase 3

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 48 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: Blinding will be performed by an independent third party operator (nurse/pharmacist, unblinded), who will prepare undistinguishable syringes with patient's dosing and labelling.
• Primary Purpose: Treatment
• Official 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.
• Actual Study Start Date: July 23, 2018
• Estimated Primary Completion Date: November 2019
• Estimated Study Completion Date: November 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: Eptacog alfa, biosimilar (AryoSeven); 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); 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.
Active Comparator: Novoseven; 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); 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.

Outcome Measures

Primary Outcome Measures :

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 Outcome Measures :

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.

Eligibility Criteria

• Ages Eligible for Study: 12 Years and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Contacts

Contact: Amirhossein Saadatirad, PhD; +98(26)36106480-84; saadatirada@aryogen.com

Locations

Iran, Islamic Republic of

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

Shiraz, Iran, Islamic Republic of

Contact: Mohammadreza Bordbar, MD

Comprehensive Hemophilia Care Center; Recruiting

Teheran, Iran, Islamic Republic of

Contact: Mohammad Reza Baghaipour, MD

Ali Asghar Hospital; Recruiting

Zahedan, Iran, Islamic Republic of

Contact: Majid Naderi, MD

Turkey

Acibadem Adana Hastanesi, Pediatrik Hematoloji-Onkoloji Bölümü; Recruiting

Adana, Turkey

Contact: Bulent Antmen, MD

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

Ankara, Turkey

Contact: Ş. Selin Aytaç Eyupuglu, MD

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

Bursa, Turkey

Contact: Melike Sezgin Evim, MD

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

Istanbul, Turkey

Contact: Bulent Zulfikar, MD

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

Izmir, Turkey

Contact: Kaan Kavakli

Sponsors and Collaborators

AryoGen Pharmed Co.

Investigators

• Study Director: Massimo Iacobelli, MD; Consultant

More Information

• Responsible Party: AryoGen Pharmed Co.
• ClinicalTrials.gov Identifier: NCT03935334 History of Changes
• Other Study ID Numbers: UGA 2014-01
• First Posted: May 2, 2019
• Last Update Posted: May 2, 2019
• Last Verified: May 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Hemophilia A; Blood Coagulation Disorders, Inherited; Blood Coagulation Disorders; Hematologic Diseases; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn