Hemophilia A or B With Inhibitor Clinical Trial
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.
| Verified date | July 2020 |
| Source | AryoGen Pharmed Co. |
| Contact | n/a |
| Is FDA regulated | No |
| Health authority | |
| Study type | Interventional |
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.
| Status | Completed |
| Enrollment | 48 |
| Est. completion date | February 3, 2021 |
| Est. primary completion date | January 31, 2021 |
| Accepts healthy volunteers | No |
| Gender | Male |
| Age group | 12 Years and older |
| Eligibility | 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 |
| Country | Name | City | State |
|---|---|---|---|
| Iran, Islamic Republic of | Hemophilia Center - Hematology & Oncology Dept. Shiraz University of Medical Science | Shiraz | |
| Iran, Islamic Republic of | Comprehensive Hemophilia Care Center | Teheran | |
| Iran, Islamic Republic of | Ali Asghar Hospital | Zahedan | |
| Turkey | Acibadem Adana Hastanesi, Pediatrik Hematoloji-Onkoloji Bölümü | Adana | |
| Turkey | Hacettepe Üniversitesi Çocuk Sagligi ve Hastaliklari Anabilim Dali Çocuk Hematolojisi Bilim Dali | Ankara | |
| Turkey | Uludag Üniversitesi Tip Fakültesi Çocuk Sagligi ve Hastaliklari Anabilim Dali/Hematoloji Bilim Dali | Bursa | |
| Turkey | Istanbul Üniversitesi Cerrahpasa Tip Fakültesi Çocuk Sagligi ve Hastaliklari Anabilim Dali Çocuk Hematoloji-Onkoloji B.D. | Istanbul | |
| Turkey | Ege Üniversitesi Tip Fakültesi Cocuk Sagligi ve Hastalikari Anabilim Dali ÇocukHematoloji Bilim Dali | Izmir |
| Lead Sponsor | Collaborator |
|---|---|
| AryoGen Pharmed Co. |
Iran, Islamic Republic of, Turkey,
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Primary | 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 | |
| Primary | 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 | Area under the plasma concentration-time curve from 0 to the last measurable time point (AUClast). | Measurement of plasma level of factor VII clotting activity (FVII:C) determined by commercial Staclot® VIIa-recombinant tissue factor assay | 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 | Maximum plasma concentration (Cmax) | Measurement of plasma level of factor VII clotting activity (FVII:C) determined by commercial Staclot® VIIa-recombinant tissue factor assay | 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 | Time of Cmax (tmax); | Measurement of plasma level of factor VII clotting activity (FVII:C) determined by commercial Staclot® VIIa-recombinant tissue factor assay | 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 | Fraction of the total AUCinf that was derived by extrapolation beyond tlast (AUCextra) | Measurement of plasma level of factor VII clotting activity (FVII:C) determined by commercial Staclot® VIIa-recombinant tissue factor assay | 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 | First order rate constant associated with the terminal (log-linear) portion of the curve (?z) | Measurement of plasma level of factor VII clotting activity (FVII:C) determined by commercial Staclot® VIIa-recombinant tissue factor assay | 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 | Elimination half-life | Measurement of plasma level of factor VII clotting activity (FVII:C) determined by commercial Staclot® VIIa-recombinant tissue factor assay | 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 | Mean residence time (MRT) | Measurement of plasma level of factor VII clotting activity (FVII:C) determined by commercial Staclot® VIIa-recombinant tissue factor assay | 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 | Clearance and CL/Dose (CL) | Measurement of plasma level of factor VII clotting activity (FVII:C) determined by commercial Staclot® VIIa-recombinant tissue factor assay | 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 | Volume of distribution (Vss) | Measurement of plasma level of factor VII clotting activity (FVII:C) determined by commercial Staclot® VIIa-recombinant tissue factor assay | 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 | Immunogenicity | The Prothrombin Time (PT) based Bethesda assay will be used. | On plasma samples obtained at screening visit, before the second dose/second drug administration, and then every 3 months for a year | |
| Secondary | Adverse Events | 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. | Adverse events (AEs) will be monitored throughout the trial, from the first dose administered up to 12 months follow-up. |