Back to resultsClinical Trial Comparing a Biosimilar Eptacog Alfa With Novoseven, in Patients With Hemophilia With Inhibitors
Primary Purpose
Hemophilia A or B With Inhibitor
Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Biosimilar eptacog alfa, activated (AryoSeven)
Eptacog alfa, activated (Novoseven)
Sponsored by
About this trial
This is an interventional treatment trial for Hemophilia A or B With Inhibitor
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
Sites / Locations
- Hemophilia Center - Hematology & Oncology Dept. Shiraz University of Medical Science
- Comprehensive Hemophilia Care Center
- Ali Asghar Hospital
- Acibadem Adana Hastanesi, Pediatrik Hematoloji-Onkoloji Bölümü
- Hacettepe Üniversitesi Çocuk Sağlığı ve Hastalıkları Anabilim Dalı Çocuk Hematolojisi Bilim Dalı
- Uludağ Üniversitesi Tıp Fakültesi Çocuk Sağlığı ve Hastalıkları Anabilim Dalı/Hematoloji Bilim Dalı
- Istanbul Üniversitesi Cerrahpaşa Tip Fakültesi Çocuk Sağlığı ve Hastalıkları Anabilim Dalı Çocuk Hematoloji-Onkoloji B.D.
- Ege Üniversitesi Tip Fakültesi Cocuk Sağliği ve Hastalikari Anabilim Dali ÇocukHematoloji Bilim Dali
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Active Comparator
Arm Label
Eptacog alfa, biosimilar (AryoSeven)
Novoseven
Arm Description
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.
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.
Outcomes
Primary Outcome Measures
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).
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
Secondary Outcome Measures
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
Maximum plasma concentration (Cmax)
Measurement of plasma level of factor VII clotting activity (FVII:C) determined by commercial Staclot® VIIa-recombinant tissue factor assay
Time of Cmax (tmax);
Measurement of plasma level of factor VII clotting activity (FVII:C) determined by commercial Staclot® VIIa-recombinant tissue factor assay
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
First order rate constant associated with the terminal (log-linear) portion of the curve (λz)
Measurement of plasma level of factor VII clotting activity (FVII:C) determined by commercial Staclot® VIIa-recombinant tissue factor assay
Elimination half-life
Measurement of plasma level of factor VII clotting activity (FVII:C) determined by commercial Staclot® VIIa-recombinant tissue factor assay
Mean residence time (MRT)
Measurement of plasma level of factor VII clotting activity (FVII:C) determined by commercial Staclot® VIIa-recombinant tissue factor assay
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
Volume of distribution (Vss)
Measurement of plasma level of factor VII clotting activity (FVII:C) determined by commercial Staclot® VIIa-recombinant tissue factor assay
Immunogenicity
The Prothrombin Time (PT) based Bethesda assay will be used.
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.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT03935334
Brief Title
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
2. Study Status
Record Verification Date
July 2020
Overall Recruitment Status
Completed
Study Start Date
July 23, 2018 (Actual)
Primary Completion Date
January 31, 2021 (Actual)
Study Completion Date
February 3, 2021 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
AryoGen Pharmed Co.
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. 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.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hemophilia A or B With Inhibitor
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Crossover Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes 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.
Allocation
Randomized
Enrollment
48 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Eptacog alfa, biosimilar (AryoSeven)
Arm Type
Experimental
Arm Description
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.
Arm Title
Novoseven
Arm Type
Active Comparator
Arm Description
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.
Intervention Type
Biological
Intervention Name(s)
Biosimilar eptacog alfa, activated (AryoSeven)
Intervention Description
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.
Intervention Type
Biological
Intervention Name(s)
Eptacog alfa, activated (Novoseven)
Intervention Description
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.
Primary Outcome Measure Information:
Title
Area under the plasma concentration time curve from time 0 to infinity, based on the last observed concentration (AUCinf)
Description
Measurement of plasma level of factor VII clotting activity (FVII:C) determined by commercial Staclot® VIIa-recombinant tissue factor assay (Diagnostics Stago, France).
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
Title
Treatment response to Thrombin Generation Assay (TGA), D-Dimer, F1.2 prothrombin fragments.
Description
Measurement of plasma levels based on standard methods recommended by the Subcommittee on the control of anticoagulation of the ISTH
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
Secondary Outcome Measure Information:
Title
Area under the plasma concentration-time curve from 0 to the last measurable time point (AUClast).
Description
Measurement of plasma level of factor VII clotting activity (FVII:C) determined by commercial Staclot® VIIa-recombinant tissue factor assay
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
Title
Maximum plasma concentration (Cmax)
Description
Measurement of plasma level of factor VII clotting activity (FVII:C) determined by commercial Staclot® VIIa-recombinant tissue factor assay
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
Title
Time of Cmax (tmax);
Description
Measurement of plasma level of factor VII clotting activity (FVII:C) determined by commercial Staclot® VIIa-recombinant tissue factor assay
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
Title
Fraction of the total AUCinf that was derived by extrapolation beyond tlast (AUCextra)
Description
Measurement of plasma level of factor VII clotting activity (FVII:C) determined by commercial Staclot® VIIa-recombinant tissue factor assay
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
Title
First order rate constant associated with the terminal (log-linear) portion of the curve (λz)
Description
Measurement of plasma level of factor VII clotting activity (FVII:C) determined by commercial Staclot® VIIa-recombinant tissue factor assay
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
Title
Elimination half-life
Description
Measurement of plasma level of factor VII clotting activity (FVII:C) determined by commercial Staclot® VIIa-recombinant tissue factor assay
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
Title
Mean residence time (MRT)
Description
Measurement of plasma level of factor VII clotting activity (FVII:C) determined by commercial Staclot® VIIa-recombinant tissue factor assay
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
Title
Clearance and CL/Dose (CL)
Description
Measurement of plasma level of factor VII clotting activity (FVII:C) determined by commercial Staclot® VIIa-recombinant tissue factor assay
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
Title
Volume of distribution (Vss)
Description
Measurement of plasma level of factor VII clotting activity (FVII:C) determined by commercial Staclot® VIIa-recombinant tissue factor assay
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
Title
Immunogenicity
Description
The Prothrombin Time (PT) based Bethesda assay will be used.
Time Frame
On plasma samples obtained at screening visit, before the second dose/second drug administration, and then every 3 months for a year
Title
Adverse Events
Description
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.
Time Frame
Adverse events (AEs) will be monitored throughout the trial, from the first dose administered up to 12 months follow-up.
10. Eligibility
Sex
Male
Minimum Age & Unit of Time
12 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Massimo Iacobelli, MD
Organizational Affiliation
Consultant
Official's Role
Study Director
Facility Information:
Facility Name
Hemophilia Center - Hematology & Oncology Dept. Shiraz University of Medical Science
City
Shiraz
Country
Iran, Islamic Republic of
Facility Name
Comprehensive Hemophilia Care Center
City
Teheran
Country
Iran, Islamic Republic of
Facility Name
Ali Asghar Hospital
City
Zahedan
Country
Iran, Islamic Republic of
Facility Name
Acibadem Adana Hastanesi, Pediatrik Hematoloji-Onkoloji Bölümü
City
Adana
Country
Turkey
Facility Name
Hacettepe Üniversitesi Çocuk Sağlığı ve Hastalıkları Anabilim Dalı Çocuk Hematolojisi Bilim Dalı
City
Ankara
Country
Turkey
Facility Name
Uludağ Üniversitesi Tıp Fakültesi Çocuk Sağlığı ve Hastalıkları Anabilim Dalı/Hematoloji Bilim Dalı
City
Bursa
Country
Turkey
Facility Name
Istanbul Üniversitesi Cerrahpaşa Tip Fakültesi Çocuk Sağlığı ve Hastalıkları Anabilim Dalı Çocuk Hematoloji-Onkoloji B.D.
City
Istanbul
Country
Turkey
Facility Name
Ege Üniversitesi Tip Fakültesi Cocuk Sağliği ve Hastalikari Anabilim Dali ÇocukHematoloji Bilim Dali
City
Izmir
Country
Turkey
12. IPD Sharing Statement
Plan to Share IPD
No
Learn more about this trial
Clinical Trial Comparing a Biosimilar Eptacog Alfa With Novoseven, in Patients With Hemophilia With Inhibitors
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