- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03935334
Clinical Trial Comparing a Biosimilar Eptacog Alfa With Novoseven, in Patients With Hemophilia With Inhibitors
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 Overview
Status
Conditions
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 Type
Enrollment (Actual)
Phase
- Phase 3
Contacts and Locations
Study Locations
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Shiraz, Iran, Islamic Republic of
- Hemophilia Center - Hematology & Oncology Dept. Shiraz University of Medical Science
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Teheran, Iran, Islamic Republic of
- Comprehensive Hemophilia Care Center
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Zahedan, Iran, Islamic Republic of
- Ali Asghar Hospital
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Adana, Turkey
- Acibadem Adana Hastanesi, Pediatrik Hematoloji-Onkoloji Bölümü
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Ankara, Turkey
- Hacettepe Üniversitesi Çocuk Sağlığı ve Hastalıkları Anabilim Dalı Çocuk Hematolojisi Bilim Dalı
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Bursa, Turkey
- Uludağ Üniversitesi Tıp Fakültesi Çocuk Sağlığı ve Hastalıkları Anabilim Dalı/Hematoloji Bilim Dalı
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Istanbul, Turkey
- Istanbul Üniversitesi Cerrahpaşa Tip Fakültesi Çocuk Sağlığı ve Hastalıkları Anabilim Dalı Çocuk Hematoloji-Onkoloji B.D.
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Izmir, Turkey
- Ege Üniversitesi Tip Fakültesi Cocuk Sağliği ve Hastalikari Anabilim Dali ÇocukHematoloji Bilim Dali
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: TREATMENT
- Allocation: RANDOMIZED
- Interventional Model: CROSSOVER
- Masking: QUADRUPLE
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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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.
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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.
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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.
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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.
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
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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
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Measurement of plasma level of factor VII clotting activity (FVII:C) determined by commercial Staclot® VIIa-recombinant tissue factor assay (Diagnostics Stago, France).
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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
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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
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Measurement of plasma levels based on standard methods recommended by the Subcommittee on the control of anticoagulation of the ISTH
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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
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
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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
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Measurement of plasma level of factor VII clotting activity (FVII:C) determined by commercial Staclot® VIIa-recombinant tissue factor assay
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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
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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
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Measurement of plasma level of factor VII clotting activity (FVII:C) determined by commercial Staclot® VIIa-recombinant tissue factor assay
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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
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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
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Measurement of plasma level of factor VII clotting activity (FVII:C) determined by commercial Staclot® VIIa-recombinant tissue factor assay
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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
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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
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Measurement of plasma level of factor VII clotting activity (FVII:C) determined by commercial Staclot® VIIa-recombinant tissue factor assay
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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
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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
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Measurement of plasma level of factor VII clotting activity (FVII:C) determined by commercial Staclot® VIIa-recombinant tissue factor assay
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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
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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
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Measurement of plasma level of factor VII clotting activity (FVII:C) determined by commercial Staclot® VIIa-recombinant tissue factor assay
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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
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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
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Measurement of plasma level of factor VII clotting activity (FVII:C) determined by commercial Staclot® VIIa-recombinant tissue factor assay
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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
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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
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Measurement of plasma level of factor VII clotting activity (FVII:C) determined by commercial Staclot® VIIa-recombinant tissue factor assay
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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
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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
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Measurement of plasma level of factor VII clotting activity (FVII:C) determined by commercial Staclot® VIIa-recombinant tissue factor assay
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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
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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
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The Prothrombin Time (PT) based Bethesda assay will be used.
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On plasma samples obtained at screening visit, before the second dose/second drug administration, and then every 3 months for a year
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Adverse Events
Time Frame: Adverse events (AEs) will be monitored throughout the trial, from the first dose administered up to 12 months follow-up.
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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.
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Adverse events (AEs) will be monitored throughout the trial, from the first dose administered up to 12 months follow-up.
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Collaborators and Investigators
Sponsor
Study record dates
Study Major Dates
Study Start (ACTUAL)
Primary Completion (ACTUAL)
Study Completion (ACTUAL)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (ACTUAL)
Study Record Updates
Last Update Posted (ACTUAL)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- UGA 2014-01
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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