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IRCT2017021831193N2 IRCT 2017-08-05 AryoGen Pharmed Pharmacodynamic, Pharmacokinetic Study ofAryoSeven with Novoseven®, in Patient with Hemophilia A or B with Inhibitors UGA 2014-01 A Randomized, Multicenter, Double blind, Single doses Study Comparing the Pharmacodynamic, Pharmacokinetic and Safety of Biosimilar EPTACOG Alfa with Novoseven®, in Patient with Hemophilia A or B with Inhibitors 2018-09-17 anticipated 48 Complete https://irct.ir/trial/24587 interventional Randomization: Randomized, Blinding: Double blinded, Placebo: Not used, Assignment: Crossover, Purpose: Treatment, Randomization description: 1:1 manner stratified by center, Blinding description: Blinding is performed by an independent third party operator (pharmacist or nurse, unblinded), who will prepare undistinguishable syringes with patient’s dosing and labelling. As soon as the patient is registered (centrally) and randomization code assigned, the central randomization office will inform the pharmacist or nurse through email of the treatment assigned to the patient; the pharmacist or nurse will prepare the study treatment on the basis of the treatment assigned and body weight of patient (defined as weight on the date of admission). The third party operator (pharmacist or nurse) will label the study treatment syringes with with labels supplied by AryoGen. 3 Condition 1: Hemophilia A with inhibitor. Condition 2: Hemophilia B with inhibitor. Intervention 1: AryoGen eptacog alfa (AryoSeven 1.2 mg), intravenous 90 microgram per kg single dose. Lyophilized powder for solution with provided solvent. Intervention 2: AryoGen eptacog alfa (AryoSeven 1.2 mg), intravenous 270 microgram per kg single dose. Lyophilized powder for solution with provided solvent. Intervention 3: Novo Nordisk eptacog alfa (Novoseven 1 mg), intravenous 90 microgram per kg Lyophilized powder for solution with provided solvent. Intervention 4: Novo Nordisk eptacog alfa (Novoseven 1 mg), intravenous 270 microgram per kg Lyophilized powder for solution with provided solvent. Undecided - It is not yet known if there will be a plan to make this available Justification or reason for indecision in sharing IPD is not decided yet
public Amirhossein Saadatirad
No 140, corner of Tajbakhsh street, 24th Km of Tehran Karaj Makhsous road
Garmdareh Iran (Islamic Republic of) 3164819712 +98 26 3610 6480 saadatirada@aryogen.com AryoGen Pharmed scientific Dr. Hasan Abolghasemi
Mollasadra str, south Sheykh Bahaii str, Tehran
Tehran Iran (Islamic Republic of) 1465915371 009828882742 Abolghasem@bmsu.ac.ir Baqiyatallah Hospital Iran (Islamic Republic of) Iran (Islamic Republic of) Iran (Islamic Republic of) -Confirmed diagnosis of congenital haemophilia 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 episode -Male subjects -Adult and children (>12 years) -Patients to be enrolled must also provide voluntary 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 time of study medication administration for plasma sampling (2 times during the study). 12 years no limit Male -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/mcL (at screening visit). -Any clinical sign or known history of 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 end point of the study. D66 D67 Deficiency factor VIII (with functional defect) Hereditary factor IX deficiency (with functional defect) Treatment - Drugs Treatment - Drugs Treatment - Drugs Treatment - Drugs AryoGen eptacog alfa (AryoSeven 1.2 mg), intravenous 90 microgram per kg single dose. Lyophilized powder for solution with provided solvent AryoGen eptacog alfa (AryoSeven 1.2 mg), intravenous 270 microgram per kg single dose. Lyophilized powder for solution with provided solvent Novo Nordisk eptacog alfa (Novoseven 1 mg), intravenous 90 microgram per kg Lyophilized powder for solution with provided solvent Novo Nordisk eptacog alfa (Novoseven 1 mg), intravenous 270 microgram per kg Lyophilized powder for solution with provided solvent Pharmacokinetic parameter: the area under the plasma concentration time curve from time 0 to infinity, based on the last observed concentration (AUCinf). Timepoint: 10 min- prior to dose administration and at 10 min, 20 min, 1 h, 3 h, 5 h, 8 h, 12 h, 24 h and 30 h after AryoSeven or NovoSeven injection. Method of measurement: Measurement of plasma level of factor VII clotting activity (FVII:C) determined by commercial Staclot® VIIa–recombinant tissue factor assay (Diagnostica Stago, Asniéres sur Seine, France)performed by a central lab. Pharmacodynamic parameters:Thrombin Generation Assay (TGA), D-Dimer, F1.2 prothrombin fragments. Timepoint: Thrombin Generation Assay:10 min prior to dose administration and at 10 min,20 min,1h,3 h,5 h,8 h,12 h,24 h and 30 h after AryoSeven or NovoSeven injection.D-dimer and F1.2 prothrombin fragments- 10 min- prior to dose administration and at 20 min, 1 h, 5 h, and 12 h and 24 h after on the same samples obtained for TGA. Method of measurement: Validated analytical method performed by central lab. Secondary PK parameters:AUClast, Cmax,tmax, AUCextra;First order rate constant associated with the terminal (log-linear) portion of the curve (λz);Elimination half-life; MRT; CL; Vss. Timepoint: 10 min- prior to dose administration and at 10 min, 20 min, 1 h, 3 h, 5 h, 8 h and 12 h, 24 h and 30 h after AryoSeven or NovoSeven injection. Method of measurement: Pharmacokinetic assessment by measurement of plasma level of factor VII clotting activity (FVII:C) determined by commercial Staclot® VIIa–recombinant tissue factor assay (Diagnostica Stago, Asniéres sur Seine, France)., performed by a central lab. Clinical parameters in controlling acute bleeding after treatment with AryoSeven. Timepoint: 2 h, 6 h and 12 h post infusion (last AryoSeven dose). Method of measurement: 4 point scale (Excellent, Good, Moderate, None) by the investigator. Immunogenicity assessment. Timepoint: At screening visit, after the second drug administration (visit 3) and then every 3 months for a year. Method of measurement: PT based Bethesda assay. Adverse events. Timepoint: at any time during the study. Method of measurement: Adverse events grading for severity, seriousness, expected or unexpected, relationship to the study drug, action taken, outcome. NCT03935334 clinicaltrials.gov 2019-002854-22 clinicaltrialsregister.eu AryoGen Pharmed Approved 2017-06-19 Shiraz University of Medical Sciences Shiraz University of Medical Sciences Shiraz Fars Iran (Islamic Republic of) Approved 2018-03-06 Iran University of Medical Sciences Iran University of Medical Sciences ,Shahid Hemmat Highway Tehran Tehran Iran (Islamic Republic of) Approved 2018-12-19 Zahedan University of Medical Sciences Zahedan University of Medical Sciences, Dr. Hesabi sq. Zahedan, Iran Zahedan Sistan-va-Balouchestan Iran (Islamic Republic of)