Clinical Trial Protocol Iranian Registry of Clinical Trials

25 Sep 2021

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

Protocol summary AryoGEn Eptacog alfa(AryoSeven),IV 90 or 270 mcg perkg. NovoNordisk Eptacog alfa(Novoseven), IV 90 or Study aim 270 mcg per kg Bioequivalence according to Main outcome variables Pharmacokinetic,Pharmacodynamic parameters.Clinical PK:Area Under Curveinf(AUCinf) PD:Thrombin Generation response in controlling acute Assay,D-Dimer,F1.2 prothrombin fragments. bleeding.Immunogenicity,ADRs Design General information Patients enrolled are randomized to receive injections of either doses of AryoSeven or NovoSeven,separated by Reason for update washout period of 3 days.Blood samples for the PKPD Applying changes of protocol amendments Adding phase(atleast 5 ml) is collected 10 min prior dose blinding procedure Adding actual patient initiation and administration and at 10, 20min,1,3,5,8,12,24 and 30h end Adding the international sites where the study is after administration.For plasma sample stability study registered and only for maximum 10 patients,9ml blood instead of Acronym 5ml will be drawn during Visit 2 and 3 at timepoints1h UGA 2014-01 and 12h.Before second dose blood is taken for IRCT registration information immunogenicity test.Patients hospitalized at time of IRCT registration number: IRCT2017021831193N2 study medication administration and plasma Registration date: 2017-08-05, 1396/05/14 sampling.Patients will be followed for 12 months to Registration timing: prospective receive AryoSeven for bleedings at center or home(by patient at home or caregiver) with dose and duration of treatment decided by Investigator.Plasma sampling for Last update: 2021-02-07, 1399/11/19 determination of antibody formation against FVII will be Update count: 3 taken every 3 months at the center. Registration date Settings and conduct 2017-08-05, 1396/05/14 Multicenter(Tehran,Shiraz,Zahedan,Istanbul,Adana,Bursa )Randomized,Double blind,crossover.Blinding is Registrant information performed by independent third party who prepares and Name labels undistinguishable syringes according to Amirhossein Saadatirad randomization. Name of organization / entity Participants/Inclusion and exclusion criteria AryoGen Pharmed Over 12 years with congenital Hemophilia A or B with Country inhibitors over 5BU with over2 episodes of bleeding oer Iran (Islamic Republic of) year requiring treatment with FVII, not in bleeding Phone episode. without inhibitor to FVII and any other type of +98 26 3610 6480 congenital or acquired coagulopathy Email address Intervention groups [email protected]

1 Recruitment status affect the primary end point of the study. Recruitment complete Age Funding source From 12 years old AryoGen Pharmed Gender Male

Expected recruitment start date Phase 2018-09-17, 1397/06/26 3 Expected recruitment end date Groups that have been masked 2019-05-31, 1398/03/10 Actual recruitment start date Participant empty Care provider Actual recruitment end date Investigator empty Outcome assessor Trial completion date Data and Safety Monitoring Board empty Sample size Scientific title Target sample size: 48 A Randomized, Multicenter, Double blind, Single doses Randomization (investigator's opinion) Study Comparing the Pharmacodynamic, Randomized Pharmacokinetic and Safety of Biosimilar EPTACOG Alfa Randomization description with Novoseven®, in Patient with Hemophilia A or B with 1:1 manner stratified by center Inhibitors Blinding (investigator's opinion) Double blinded Public title Blinding description Pharmacodynamic, Pharmacokinetic Study ofAryoSeven Blinding is performed by an independent third party with Novoseven®, in Patient with Hemophilia A or B with operator (pharmacist or nurse, unblinded), who will Inhibitors prepare undistinguishable syringes with patient’s dosing Purpose and labelling. As soon as the patient is registered Treatment (centrally) and randomization code assigned, the central Inclusion/Exclusion criteria randomization office will inform the pharmacist or nurse Inclusion criteria: through email of the treatment assigned to the patient; -Confirmed diagnosis of congenital haemophilia A or B the pharmacist or nurse will prepare the study treatment with inhibitors to FVIII or FIX titer >5 Bethesda Units [BU] on the basis of the treatment assigned and body weight -With > 2 episodes of bleeding/year requiring treatment of patient (defined as weight on the date of admission). with FVII infusions, non in bleeding episode -Male The third party operator (pharmacist or nurse) will label subjects -Adult and children (>12 years) -Patients to be the study treatment syringes with with labels supplied by enrolled must also provide voluntary written informed AryoGen. consent to the protocol to be eligible for the study. For Placebo minor patients, parent/legal guardian will provide Not used consent and, when possible, patient assent will also be Assignment obtained. For compromised patients, their designated Crossover proxy must provide informed consent. -For the PK/PD Other design features phase, patients will be hospitalized at time of study medication administration for plasma sampling (2 times during the study). Secondary Ids Exclusion criteria: -Any other type of congenital or acquired coagulopathy, 1 such as: liver disease (hepatitis), vitamin k deficiency, uremia, malignancy. -Antibodies against Factor VII. - Registry name Ongoing bleeding prophylaxis regimens with Novoseven clinicaltrials.gov or planned to occur during the trial. -Patients who have Secondary trial Id received routine (prophylactic) treatment with rFVIIa in NCT03935334 the period between screening visit (visit 1) and visit 2 of Registration date this study (first dose administration). -Platelet count less 2019-05-02, 1398/02/12 than 100.000 platelets/mcL (at screening visit). -Any clinical sign or known history of arterial thrombotic event 2 or deep venous- thrombosis or pulmonary embolism. - HIV positive with current CD4+ count of less than Registry name 200/μL. -Liver cirrhosis. -Factor VIII/IX immune tolerance clinicaltrialsregister.eu induction regimen planned to occur during the trial. - Secondary trial Id Known hypersensitivity to the study medication. -Parallel 2019-002854-22 participation in another experimental drug trial. -Parallel Registration date participation in another marketed drug trial that may 2020-01-03, 1398/10/13

2 Ethics committees 1 Description of health condition studied 1 Hemophilia A with inhibitor ICD-10 code Ethics committee D66 Name of ethics committee ICD-10 code description Shiraz University of Medical Sciences Deficiency factor VIII (with functional defect) Street address Shiraz University of Medical Sciences 2 City Description of health condition studied Shiraz Hemophilia B with inhibitor Province ICD-10 code Fars D67 Postal code ICD-10 code description 7134814336 Hereditary factor IX deficiency (with functional defect) Approval date 2017-06-19, 1396/03/29 Primary outcomes Ethics committee reference number IR.SUMS.REC.1396.43 1 2 Description Pharmacokinetic parameter: the area under the plasma Ethics committee concentration time curve from time 0 to infinity, based Name of ethics committee on the last observed concentration (AUCinf) Iran University of Medical Sciences Timepoint Street address 10 min- prior to dose administration and at 10 min, 20 Iran University of Medical Sciences ,Shahid Hemmat min, 1 h, 3 h, 5 h, 8 h, 12 h, 24 h and 30 h after Highway AryoSeven or NovoSeven injection City Method of measurement Tehran Measurement of plasma level of factor VII clotting Province activity (FVII:C) determined by commercial Staclot® Tehran VIIa–recombinant tissue factor assay (Diagnostica Stago, Postal code Asniéres sur Seine, France)performed by a central lab. 1449614535 Approval date 2 2018-03-06, 1396/12/15 Description Ethics committee reference number Pharmacodynamic parameters:Thrombin Generation IR.IUMS.REC 1396.9-33058 Assay (TGA), D-Dimer, F1.2 prothrombin fragments Timepoint 3 Thrombin Generation Assay:10 min prior to dose administration and at 10 min,20 min,1h,3 h,5 h,8 h,12 Ethics committee h,24 h and 30 h after AryoSeven or NovoSeven Name of ethics committee injection.D-dimer and F1.2 prothrombin fragments- 10 Zahedan University of Medical Sciences min- prior to dose administration and at 20 min, 1 h, 5 h, Street address and 12 h and 24 h after on the same samples obtained Zahedan University of Medical Sciences, Dr. Hesabi for TGA sq. Zahedan, Iran Method of measurement City Validated analytical method performed by central lab Zahedan Province Secondary outcomes Sistan-va-Balouchestan Postal code 1 9816737789 Approval date Description 2018-12-19, 1397/09/28 Secondary PK parameters:AUClast, Cmax,tmax, Ethics committee reference number AUCextra;First order rate constant associated with the IR.ZAUMS.REC.1397.356 terminal (log-linear) portion of the curve (λz);Elimination half-life; MRT; CL; Vss Timepoint Health conditions studied 10 min- prior to dose administration and at 10 min, 20

3 min, 1 h, 3 h, 5 h, 8 h and 12 h, 24 h and 30 h after 3 AryoSeven or NovoSeven injection Description Method of measurement Novo Nordisk eptacog alfa (Novoseven 1 mg), Pharmacokinetic assessment by measurement of plasma intravenous 90 microgram per kg Lyophilized powder for level of factor VII clotting activity (FVII:C) determined by solution with provided solvent commercial Staclot® VIIa–recombinant tissue factor Category assay (Diagnostica Stago, Asniéres sur Seine, France)., Treatment - Drugs performed by a central lab

2 4 Description Description Novo Nordisk eptacog alfa (Novoseven 1 mg), Clinical parameters in controlling acute bleeding after intravenous 270 microgram per kg Lyophilized powder treatment with AryoSeven. for solution with provided solvent Timepoint Category 2 h, 6 h and 12 h post infusion (last AryoSeven dose). Treatment - Drugs Method of measurement 4 point scale (Excellent, Good, Moderate, None) by the investigator Recruitment centers

3 1 Description Recruitment center Immunogenicity assessment. Name of recruitment center Timepoint Iran Comprehensive Hemophilia Care Center At screening visit, after the second drug administration Full name of responsible person (visit 3) and then every 3 months for a year. Dr. Mohammadreza Baghaipour Method of measurement Street address PT based Bethesda assay Tehran, No. 3, N Felestin St City 4 Tehran Province Description Tehran Adverse events Postal code Timepoint 1415863675 at any time during the study Phone Method of measurement +98 21 8891 0001 Adverse events grading for severity, seriousness, Email expected or unexpected, relationship to the study drug, [email protected] action taken, outcome. 2 Intervention groups Recruitment center Name of recruitment center 1 Hemophilia Ward Shahid Dastgheib Hospital Description Full name of responsible person AryoGen eptacog alfa (AryoSeven 1.2 mg), intravenous Dr. Mohammad Reza Bordbar 90 microgram per kg single dose. Lyophilized powder for Street address solution with provided solvent Building no.7, Shahid Dastgheib Hospital, Hafez Category avenue, Shiraz, Iran Treatment - Drugs City Shiraz Province 2 Fars Description Postal code AryoGen eptacog alfa (AryoSeven 1.2 mg), intravenous 714563769 270 microgram per kg single dose. Lyophilized powder Phone for solution with provided solvent +98 71 3228 8064 Category Email Treatment - Drugs [email protected]

4 3 Person responsible for general inquiries

Recruitment center Contact Name of recruitment center Name of organization / entity Ali Asghar Hospital AryoGen Pharmed Full name of responsible person Full name of responsible person Dr. Majid Naderi Amirhossein Saadatirad Street address Position Ali Ashghar Hospital, Azadi st, Zahedan, Iran Project Manager of rFVIIa registration in Europe City Latest degree Zahedan Ph.D. Province Other areas of specialty/work Sistan-va-Balouchestan Medical Pharmacy Postal code Street address 9816743463 No 140, corner of Tajbakhsh street, 24th Km of Phone Tehran Karaj Makhsous road +98 54 3329 5784 City Email Garmdareh [email protected] Province Alborz Postal code Sponsors / Funding sources 3164819712 Phone +98 26 3610 6480 1 Fax Sponsor Email Name of organization / entity [email protected] AryoGen Pharmed Web page address Full name of responsible person Amirhossein Saadatirad Person responsible for scientific Street address inquiries No 140, Corner of Tajbakhsh street, 24th Km of Tehran Karaj Makhsous road Contact City Name of organization / entity Garmdareh Baqiyatallah Hospital Province Full name of responsible person Alborz Dr. Hasan Abolghasemi Postal code Position 3164819712 Full professor Phone Latest degree +98 26 3610 6480 Subspecialist Email Other areas of specialty/work [email protected] Pediatrics Grant name Street address Grant code / Reference number Mollasadra str, south Sheykh Bahaii str, Tehran City Is the source of funding the same sponsor Tehran organization/entity? Province Yes Tehran Title of funding source Postal code AryoGen Pharmed 1465915371 Proportion provided by this source Phone 100 009828882742 Public or private sector Fax Private Email Domestic or foreign origin [email protected] Domestic Web page address Category of foreign source of funding empty Person responsible for updating data Country of origin Type of organization providing the funding Contact Industry Name of organization / entity

5 AryoGen Pharmed Sharing plan Full name of responsible person Amirhossein Saadatirad Deidentified Individual Participant Data Set (IPD) Position Undecided - It is not yet known if there will be a plan to Project Manager of rFVIIa registration in Europe make this available Latest degree Study Protocol Ph.D. Other areas of specialty/work Undecided - It is not yet known if there will be a plan to Medical Pharmacy make this available Street address Statistical Analysis Plan No 140, corner of Tajbakhsh street, 24th Km of Undecided - It is not yet known if there will be a plan to Tehran Karaj Makhsous road make this available City Informed Consent Form Garmdareh No - There is not a plan to make this available Province Clinical Study Report Alborz Undecided - It is not yet known if there will be a plan to Postal code make this available 3164819712 Analytic Code Phone +98 26 3610 6480 Undecided - It is not yet known if there will be a plan to Fax make this available Email Data Dictionary [email protected] Undecided - It is not yet known if there will be a plan to Web page address make this available

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