Clinical Trial Protocol Iranian Registry of Clinical Trials

24 Sep 2021

A randomized, two-armed, parallel, double-blind, active-controlled, non- inferiority clinical trial to compare eﬃcacy and safety of test-liraglutide (CinnaGen Co., Iran) to innovator liraglutide product (Victoza®, Novo Nordisk, Denmark) in patients with type II diabetes (T2D)

Protocol summary mg/day subcutaneous liraglutide for a week and then 1.2 mg/day up to 3 weeks and finally 1.8 mg/day to the end Study aim of week 26 Comparing the efficacy and safety of Cinnagen liraglutide Main outcome variables and Novo Nordisk Victoza® in type II diabetes patients Change in HbA1c after 26 weeks of treatment Design randomized, two-armed, parallel, double-blind, active- General information controlled, non-inferiority clinical trial of 300 type II diabetes patients Reason for update Settings and conduct Protocol changes:Blood test and antidrug antibody 2 cities (Tehran and Karaj) and 17centers will participate presence evaluating (week 0 week 12 and week 26) in this study. The patients will be included in the study HbA1c equal or greater than 7 and equal or smaller than after declaring informed consent and meeting specific 10.5 18–80years of age Subjects with type 2 diabetes inclusion/exclusion criteria. Initially, the patients will be treated for ≥ 3 months with a stable metformin dose of given a randomization code and will be allocated ≥1500 mg and at least half the maximum dose of a randomly to one of the two intervention groups. The sulfonylurea or non-sulfonylurea insulin secretagogues study drugs will be used in exact identical shape, box, agent(Half of maximum dose) breast-feeding Female and labels so the investigator, the patient, and data who intends to become pregnant during the clinical trial analyzer will be completely unaware of the drug which period Dr. Mahsan Seifoddin-Melli Bank Hospital Dr. certain patient has received. Subsequently, the patient Mohammad Khaledi- Lolagar Hospital will be injected daily and Evaluation and clinical Acronym examination will be performed in 7 visits and will be IRCT registration information monitored for 6 months after the first injection. IRCT registration number: IRCT20150303021315N15 Participants/Inclusion and exclusion criteria Registration date: 2019-09-13, 1398/06/22 Subjects with type 2 diabetes treated for ≥3 months with Registration timing: registered_while_recruiting a stable metformin dose of ≥1500mg and at least half the maximum dose of a insulin secretagogues agent; 18–80years old; 7≤HbA1c≤10.5; BMI:20-45 Kg/m2 and Last update: 2020-09-29, 1399/07/08 informed consent; no Hypersensitivity to liraglutide or Update count: 3 any formulation component, no Insulin treatment during Registration date the previous 3 months; Impaired liver or renal 2019-09-13, 1398/06/22 function:Uncontrolled hypertension; Malignancy; History or family history of Medullary Thyroid Carcinoma or MEN Registrant information syndrome type 2; History of pancreatic cancer and Name pancreatitis; Recent MI; Pregnancy or Previous exposure Nassim Anjidani to exenatide or liraglutide. Name of organization / entity Intervention groups Orchid Pharmed either liraglutide (cinnagen) or victoza group receive 0.6 Country

1 Iran (Islamic Republic of) endocrine neoplasia syndrome type 2 (MEN2) History of Phone pancreatic cancer and pancreatitis History of recent MI, +98 21 4347 3000 uncontrolled CHF, and unstable Angina within last 3 Email address months History or known case of severe non-proliferative [email protected] diabetic retinopathy or proliferative diabetic retinopathy Pregnancy or breast-feeding Female who intends to Recruitment status become pregnant during the clinical trial period Previous Recruitment complete exposure to exenatide or liraglutide. Funding source Age From 18 years old to 80 years old Expected recruitment start date Gender 2019-06-10, 1398/03/20 Both Expected recruitment end date 2021-05-02, 1400/02/12 Phase Actual recruitment start date 3 empty Groups that have been masked Actual recruitment end date empty Participant Trial completion date Care provider empty Investigator Outcome assessor Scientific title Data analyser A randomized, two-armed, parallel, double-blind, active- controlled, non-inferiority clinical trial to compare Sample size efficacy and safety of test-liraglutide (CinnaGen Co., Iran) Target sample size: 300 to innovator liraglutide product (Victoza®, Novo Nordisk, Randomization (investigator's opinion) Denmark) in patients with type II diabetes (T2D) Randomized Randomization description Public title The randomization plan of the patients will be carried out Comparing Efficacy and Safety of CinnaGen-liraglutide centrally using an R-CRAN software version 3.2.3. Blocks Versus Victoza® in Patients with Type II Diabetes (with the size 2 or 4) will be made using permuted block Purpose randomization for a total of 300 patients (1:1 allocation Treatment ratio). After randomization procedure, a code will be Inclusion/Exclusion criteria allocated to each patient that will be used as patient Inclusion criteria: Subjects with type 2 diabetes treated for ≥ 3 months identifier throughout the study. The assigned code will with a stable metformin dose of ≥1500 mg and at least be denoted by 4 initials (corresponding to the first two half the maximum dose of a sulfonylurea or non- letters of first name, first two letters of surname) and 4 sulfonylurea insulin secretagogues agent(Half of numbers (center code). Moreover, the described code is maximum dose) 18–80years of age HbA1c equal or followed by study unique identification code consisting of greater than 7 and equal or smaller than 10.5 Body mass first two letters of the generic name of the index (BMI) of 20-45 kg/m2 investigational product and study phase number, Exclusion criteria: respectively (LI3), and four numbers (corresponding to Lack of consent for being in the trial and not complying the randomization number), e.g. ABCD0001LI3-0001. The with 26-weeks follow-up period Hypersensitivity to randomization number will be assigned in a consecutive liraglutide or any component of the formulation way. (excipients include Disodium phosphate dehydrate, Blinding (investigator's opinion) Propylene glycol, Phenol, Water for injection) Insulin Double blinded treatment during the previous 3 months (except short- Blinding description term treatment for intercurrent illness) Impaired liver The medication compartment of both Victoza® and test- function (alanine aminotransferase concentrations equal liraglutide (CinnaGen) will be placed in similar pen- to or greater than 2.5 times upper normal range). injector containers, in a way that they cannot be Impaired renal function (eGFR smaller than 60 differentiated by the appearance. Additionally, The mL/min/1.73 m2) Uncontrolled hypertension (equal or center researcher and the patient are not aware of the greater than 160/100 mmHg) Malignancy Using any drug grouping. drugs apart from OGLAs likely to affect glucose Placebo concentrations, including androgens, hyperglycemia- Not used associated agents, hypoglycemia-associated agents, Assignment MAO inhibitors, quinolone antibiotics, salicylates (Anti- Parallel inflammatory dose). Current use of a dipeptidyl Other design features peptidase-4 inhibitor (DPP-4i) Treatment with systemic corticosteroids within last three months History or family history of Medullary Thyroid Carcinoma (MTC) Multiple Secondary Ids

2 1 Primary outcomes Registry name ClinicalTrial.gov 1 Secondary trial Id Description NCT03421119 Change in HbA1c after 26 weeks of treatment Registration date Timepoint 2018-02-02, 1396/11/13 Screening, baseline, week 12, and week 26 Method of measurement Ethics committees By High-performance liquid chromatography (HPLC)

Secondary outcomes 1

Ethics committee 1 Name of ethics committee Ethics committee of Iran University of Medical Description Sciences Percentages of subjects achieving HbA1c < 7.0% Timepoint Street address Screening, baseline, week 12, and week 26 Near Milad Tower, Shahid Hemmat Highway Method of measurement City -By High-performance liquid chromatography(HPLC) Tehran Province Tehran 2 Postal code Description 1449614535 Percentages of subjects achieving HbA1c ≤ 6.5% Approval date Timepoint 2019-01-23, 1397/11/03 Screening, baseline week 12, and week 26 Ethics committee reference number Method of measurement IR.IUMS.REC.1396.31731 By High-performance liquid chromatography(HPLC)

2 3 Description Ethics committee Changes in body weight Name of ethics committee Timepoint Ethics Committee of Alborz University of Medical Screening, baseline week 12, and week 26 Sciences Method of measurement Street address Scales Hassan Abad, Karaj, Alborz Province City 4 Karaj Province Description Alborz Changes in mean FBS Postal code Timepoint 1462364641 Baseline, week 12, and week 26 Method of measurement Approval date Laboratory Test 2019-06-15, 1398/03/25 Ethics committee reference number IR.ABZUMS.REC.1398.052 5 Description Health conditions studied Changes in mean PPBS Timepoint Baseline, week 12, and week 26 1 Method of measurement Laboratory Test Description of health condition studied type 2 diabetes ICD-10 code 6 E11 Description ICD-10 code description Changes in Systolic Blood Pressure Type 2 diabetes mellitus Timepoint

3 Screening, baseline, week 4, week 8, week 12, and week 13 26 Description Method of measurement Adverse events with special focus on the incidence, Medical examination severity, and duration of gastrointestinal disturbances, nausea, vomiting, diarrhea; kidney function (BUN, SCr), 7 liver function (ALT, AST, ALP), serum levels of Amylase and Lipase, tachycardia/palpitation, and antibody Description formation Changes in Diastolic Blood Pressure Timepoint Timepoint Screening, baseline, week 4, week 8, week 12, week 16, Screening, baseline, week 4, week 8, week 12, and week week 20, and week 26 26 Method of measurement Method of measurement evaluation adverse events and adverse drug reaction Medical examination 14 8 Description Description Change in quality of life Changes in Lipid profiles Timepoint Timepoint Baseline, week 12 and week 26 Baseline, week 12, and week 26 Method of measurement EQ5D questionnaire Method of measurement Laboratory Test 15 9 Description Medication adherence Description Timepoint Change in Pulse Rate Baseline, week 12 and week 26 Timepoint Method of measurement Screening, baseline, week 4, week 8, week 12, and week Morisky questionnaire 26 Method of measurement 16 Medical examination Description Cost-effectiveness 10 Timepoint Description Baseline, week 4, week 8, week 12, week 16, week 20 Change in eGFR and week 26 Timepoint Method of measurement Screening, baseline, week 12, and week 26 Cost-effectiveness questionnaire Method of measurement Laboratory Test 17 Description 11 Fear of injection Timepoint Description Baseline, week 12 and week 26 Change in ALT Method of measurement Timepoint D-FISQ questionnaire Screening, Baseline, week 12, and week 26 Method of measurement Intervention groups Laboratory Test

1 12 Description Description Liraglutide (produced by CinnaGen Co.) pen-injector (18 Change in liver AST mg/3 ml), subcutaneous injection of 0.6 mg every day for Timepoint one week, followed by a dose of 1.2 mg per day for up to Baseline, week 12, and week 26 three weeks. Then, 1.8 mg daily subcutaneous injection Method of measurement will be performed until the end of week 26. Laboratory Test Category

4 Treatment - Drugs 3 Recruitment center 2 Name of recruitment center Description Dr Mohajerani Office Victoza® (produced by Novo Nordisk Company) pen- Full name of responsible person injector (18 mg/3 ml), subcutaneous injection of 0.6 mg Mohammadreza Mohajeri Tehrani every day for one week, followed by a dose of 1.2 mg per Street address day for up to three weeks. Then, 1.8 mg daily No.103, Shokr-allah St, In front of Tehran Heart subcutaneous injection will be performed until the end of Center, North Kargar Ave week 26. City Category Tehran Treatment - Drugs Province Tehran Postal code Recruitment centers 1593748711 Phone 1 +98 21 8802 5450 Email Recruitment center [email protected] Name of recruitment center Institute of Endocrinology and Metabolism Research andTraining Center 4 Full name of responsible person Recruitment center Mohammad Ebrahim Khamseh Name of recruitment center Street address Shahid Rajaei Hospital Behafarin ST, Karimkhan AVE, Vali-asr Sq Full name of responsible person City Zahra Ghaem maghami Tehran Street address Province Valiasr Ave, Niayesh Intersection Tehran City Postal code tehran 1593748711 Province Phone Tehran +98 21 8894 5246 Postal code Fax 1593748711 +98 21 8894 5173 Phone Email +98 21 2392 2197 [email protected] Email [email protected] 2 Recruitment center 5 Name of recruitment center Recruitment center Dr Esteghamati Office Name of recruitment center Full name of responsible person Dr Monavari Office Alireza Esteghamati Full name of responsible person Street address Arezou monavari Unit 13, 2nd floor, ebne sina Building, before shariati Street address St, motahhari St No. 11, Bahar Medical building, Shahid taheri Alley, City Bahar Ave Tehran City Province karaj Tehran Province Postal code Alborz 1593748711 Postal code Phone 1593748711 +98 21 8841 7918 Phone Fax +98 26 3225 6438 Email Email [email protected] [email protected]

5 6 9 Recruitment center Recruitment center Name of recruitment center Name of recruitment center Taban Clinic Dr Khannakhjavani Oﬃce Full name of responsible person Full name of responsible person Ramin malbousbaf Manouchehr Khan Nakhjavani Street address Street address No.100, End of Derakhti Blvd, Dadman Blvd, Shahrak- No. 82, Fajr Street (Jam), Motahhari Street e-Qarb City City Tehran Tehran Province Province Tehran Tehran Postal code Postal code 1487474884 1593748711 Phone Phone +98 21 8883 0323 +98 21 2237 7250 Email Email [email protected] [email protected]

10 7 Recruitment center Recruitment center Name of recruitment center Name of recruitment center Personal Office Dr Zamanzadeh Office Full name of responsible person Full name of responsible person Amir Kamran Nikoosokhan Mehran Zaman zadeh Street address Street address First Floor, No. 17, Shohada Alley, Above Motahhari, No.10, third floor, Tooran(135) medical building, West Mirzaee Shirazi Street hoveyzeh St, North Sohrevardi City City Tehran Tehran Province Province Tehran Tehran Postal code Postal code 1493846644 1593748711 Phone Phone +98 21 8874 7090 +98 21 8872 8237 Email Email [email protected] [email protected]

8 11 Recruitment center Recruitment center Name of recruitment center Name of recruitment center Dr Hossein Panah Oﬃce Lolagar Hospital Full name of responsible person Full name of responsible person Farhad hosein panah Zahra Banazadeh Street address Street address No. 178, Lower Tehran Clinic, Ghaem Magham Street South Khosh street, diabetes st City City Tehran Tehran Province Province Tehran Tehran Postal code Postal code 1593748711 1492374646 Phone Phone +98 21 4425 7406 +98 21 6683 5000 Email Email [email protected] [email protected]

6 12 15 Recruitment center Recruitment center Name of recruitment center Name of recruitment center Personal Oﬃce Shariat Razavi Hospital Full name of responsible person Full name of responsible person Hassan Ganjizadeh Hedayat Allah Rezvanfar Street address Street address No. 52, Fathi Shaghaghi Street, Yousef Abad Shahid Abdollahi Street, South Mehr Abad City City Tehran Tehran Province Province Tehran Tehran Postal code Postal code 1539474621 1465820317 Phone Phone +98 21 8810 9722 +98 21 6687 6031 Email Email [email protected] [email protected]

13 16 Recruitment center Recruitment center Name of recruitment center Name of recruitment center Personal Office Shohadaye Yaft Abad Hospital Full name of responsible person Full name of responsible person Habib Moazami Goudarzi Mitra Najafipour Moghadam Street address Street address Ehsan Building, opposite Ghaem Hospital, Student South Al Ghadir Boulevard, Al Ghadir Square, Moallem Boulevard Square, City City Karaj Tehran Province Province Alborz Tehran Postal code Postal code 1450312891 1436824005 Phone Phone +98 26 3271 8706 +98 21 6678 3120 Email Email [email protected] Mnajafi[email protected]

17 14 Recruitment center Recruitment center Name of recruitment center Name of recruitment center Melli Bank Hospital Firouz Abadi Hospital Full name of responsible person Full name of responsible person Mahsan Seifoddin Fatemeh Tajik Rostami Street address Street address Ferdowsi St., Central Oﬃce Building, Bank Melli Fadaiyane Eslam Street, Shahre rey Hospital City City Tehran Tehran Province Province Tehran Tehran Postal code Postal code 1455457210 3376311359 Phone Phone +98 21 5104 8000 +98 21 6142 0000 Email Email [email protected] [email protected]

7 Sponsors / Funding sources Phone +98 21 4347 3000 Email 1 [email protected] Sponsor Name of organization / entity Person responsible for scientiﬁc CinnaGen Company Full name of responsible person inquiries haleh Hamedifar Street address Contact CinnaGen research and production Company. Simin Name of organization / entity Dasht Industrial Park, Karaj, Alborz, Iran Institute of Endocrinology and Metabolism Research City and Training Center Karaj Full name of responsible person Province Mohammad Ebrahim Khamseh Alborz Position Postal code Iran univercity of medical science prof- coordinating 6670337 263 98 investigator Phone Latest degree +98 26 3667 0334 Subspecialist Email Other areas of specialty/work [email protected] General Practitioner Grant name Street address Grant code / Reference number Behafarin ST, Karimkhan AVE, Vali-asr Sq Is the source of funding the same sponsor City organization/entity? Tehran Yes Province Title of funding source Tehran CinnaGen Company Postal code Proportion provided by this source 100 1593748711 Public or private sector Phone Private +98 21 8894 5246 Domestic or foreign origin Email Domestic [email protected] 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 OrchidPharmed Co. Person responsible for general inquiries Full name of responsible person Nassim Anjidani Contact Position Name of organization / entity Pharm.D./Medical Department Manager Orchid Pharmed Co. Latest degree Full name of responsible person Medical doctor Nassim Anjidani Other areas of specialty/work Position Medical Pharmacy Pharmacist (PharmD), Medical Manager Street address Latest degree No. 42, Atar St, Attar Sq Medical doctor City Other areas of specialty/work Medical Pharmacy Tehran Street address Province No. 42, Atar St, Attar Sq Tehran City Postal code Tehran 1994766411 Province Phone Tehran +98 21 4347 3000 Postal code Email 1994766411 [email protected]

8 Sharing plan Informed Consent Form Undecided - It is not yet known if there will be a plan to Deidentiﬁed Individual Participant Data Set (IPD) make this available Undecided - It is not yet known if there will be a plan to Clinical Study Report Undecided - It is not yet known if there will be a plan to make this available make this available Study Protocol Analytic Code Undecided - It is not yet known if there will be a plan to Undecided - It is not yet known if there will be a plan to make this available make this available Statistical Analysis Plan Data Dictionary Undecided - It is not yet known if there will be a plan to Undecided - It is not yet known if there will be a plan to make this available make this available