Clinical trial NCT03935334: Clinical Trial Comparing a Biosimilar Eptacog Alfa With Novoseven, in Patients With Hemophilia With Inhibitors
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.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hemophilia A or B With Inhibitor
Lead sponsor: AryoGen Pharmed Co.
Sponsor class: INDUSTRY
First posted: 2019-05-02
Enrollment: 48
Sex: MALE
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.

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.

Eligibility 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

Primary outcomes:
measure: Area under the plasma concentration time curve from time 0 to infinity, based on the last observed concentration (AUCinf)
timeFrame: 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
measure: Treatment response to Thrombin Generation Assay (TGA), D-Dimer, F1.2 prothrombin fragments.
timeFrame: 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:
measure: Area under the plasma concentration-time curve from 0 to the last measurable time point (AUClast).
timeFrame: 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
measure: Maximum plasma concentration (Cmax)
timeFrame: 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
measure: Time of Cmax (tmax);
timeFrame: 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
measure: Fraction of the total AUCinf that was derived by extrapolation beyond tlast (AUCextra)
timeFrame: 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
measure: First order rate constant associated with the terminal (log-linear) portion of the curve (λz)
timeFrame: 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
measure: Elimination half-life
timeFrame: 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
measure: Mean residence time (MRT)
timeFrame: 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
measure: Clearance and CL/Dose (CL)
timeFrame: 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
measure: Volume of distribution (Vss)
timeFrame: 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
measure: Immunogenicity
timeFrame: On plasma samples obtained at screening visit, before the second dose/second drug administration, and then every 3 months for a year
measure: Adverse Events
timeFrame: Adverse events (AEs) will be monitored throughout the trial, from the first dose administered up to 12 months follow-up.
Other outcomes:
Locations:
city: Shiraz
country: Iran, Islamic Republic of
facility: Hemophilia Center - Hematology & Oncology Dept. Shiraz University of Medical Science
city: Teheran
country: Iran, Islamic Republic of
facility: Comprehensive Hemophilia Care Center
city: Zahedan
country: Iran, Islamic Republic of
facility: Ali Asghar Hospital
city: Adana
country: Turkey
facility: Acibadem Adana Hastanesi, Pediatrik Hematoloji-Onkoloji Bölümü
city: Ankara
country: Turkey
facility: Hacettepe Üniversitesi Çocuk Sağlığı ve Hastalıkları Anabilim Dalı Çocuk Hematolojisi Bilim Dalı
city: Bursa
country: Turkey
facility: Uludağ Üniversitesi Tıp Fakültesi Çocuk Sağlığı ve Hastalıkları Anabilim Dalı/Hematoloji Bilim Dalı
city: Istanbul
country: Turkey
facility: Istanbul Üniversitesi Cerrahpaşa Tip Fakültesi Çocuk Sağlığı ve Hastalıkları Anabilim Dalı Çocuk Hematoloji-Onkoloji B.D.
city: Izmir
country: Turkey
facility: Ege Üniversitesi Tip Fakültesi Cocuk Sağliği ve Hastalikari Anabilim Dali ÇocukHematoloji Bilim Dali
Study officials:
affiliation: Consultant
name: Massimo Iacobelli, MD
role: STUDY_DIRECTOR
References: