Clinical Trial Details (PDF Generation Date :- Thu, 26 Jul 2018 10:07:49 GMT) CTRI Number CTRI/2008/091/000256 [Registered on: 23/02/2010] - Last Modified On 20/11/2015 Post Graduate Thesis Type of Trial Type of Study Study Design Public Title of Study Scientific Title of Study No Interventional Drug Randomized, Parallel Group, Placebo Controlled Trial A clinical trial to study the tolerability and safety of ZYT1, an investigational drug in human volunteers A randomized, double blind placebo control phase 1 clinical study to evaluate the safety, tolerability and pharmacokinetics of ZYT1, a selective TR beta agonist following oral administrations in healthy volunteers Secondary IDs if Any Secondary ID Identifier Details of Principal Investigator or overall Trial Coordinator (multi-center study) Details Contact Person (Scientific Query) Details Contact Person (Public Query) ZYT1/1001 Ver. 04,dated 20th April 2012 Protocol Number Details of Principal Investigator Dr Tanvi Shah Phone 91-2717-250801 Fax 91-2717-250606 Zydus Research Center Sarkhej Bavla N.H. No.8A, Moraiya Ahmadabad GUJARAT 382213 tanvishah@zyduscadila.com Details Contact Person (Scientific Query) DrRHJani Sr. Vice President Cadila Healthcare Limited Phone 91-22-26186052 Fax 91-22-26151735 Senior Vice President, Clinical R&D, Cadila Healthcare Limited Zydus Cadila House, Plot No. 360, TPS 5, Service Road, Vile Parle (E) Mumbai MAHARASHTRA 400057 rhjani@zyduscadila.com Details Contact Person (Public Query) DrRHJani Sr. Vice President Cadila Healthcare Limited Clinical R&D, Zydus Cadila House, Plot No. 360, TPS 5, Service Road, Vile Parle (E) Mumbai MAHARASHTRA 400057 page 1 / 5
Source of Monetary or Material Support Primary Sponsor Details of Secondary Sponsor Countries of Recruitment Sites of Study Details of Ethics Committee Regulatory Clearance Status from DCGI Health Condition / Problems Studied Intervention / Comparator Agent Inclusion Criteria Phone 91-22-26186052 Fax 91-22-26151735 rhjani@zyduscadila.com Source of Monetary or Material Support > Zydus research Center, Cadila Healthcare Limited, Ahmedabad Primary Sponsor Details Zydus Research Center Zydus Research Center Cadila Healthcare Ltd. Sarkhej-Bavla N. H. No. 8 A, Moraiya, Ahmedabad 382 213, Type of Sponsor List of Countries of Principal Investigator Dr. Alpeshkumar Patel Pharmaceutical industry-n of Site Site Phone/Fax/ Zydus Research Center, Zydus Research Center,Sarkhej Bavla N.H. No.8A, Moraiya-382213 Ahmadabad GUJARAT +91-2717-250801 alpeshkumar@zydusca dila.com of Committee Approval Status Date of Approval Is Independent Ethics Committee? Dr Alpesh Kumar Approved 25/04/2012 Yes Patel,Independent Ethics committee,aditya Status Date Approved/Obtained 19/11/2008 Health Type Healthy Human Volunteers Condition Treatment of obesity and lipid disorders Type Details Intervention ZYT1 From 0.5mg oral administration Comparator Agent Placebo once Age From Age To Gender Details 18.00 Year(s) 45.00 Year(s) Both Inclusion Criteria 1.Age: 18-45 years 2.Mentally, physically and legally eligible to give informed consent. 3.Male and female volunteers weighing between 50-75kg and 45-75kg respectively. 4.Ability to communicate effectively with the study personnel. 5.Willingness to adhere to the protocol requirements. 6.Normal Thyroid Function Tests (free and total T3, free and total T4 and TSH) 7.Lipid criteria: Low density lipoprotein (LDL) cholesterol up to 160mg/dL and triglyceride (TG) level up to 500mg/dL 8.For gender effect study, only females with history of sterility or one year menopause or use of long acting non-hormonal contraceptive page 2 / 5
measures (e.g., Intra uterine device) will be recruited. Exclusion Criteria Method of Generating Random Sequence Method of Concealment Blinding/Masking Details Computer generated randomization Exclusion Criteria Sequentially numbered, sealed, opaque envelopes Participant and Investigator Blinded 1.Presence or history of hypersensitivity to any of the active or inactive ingredients of ZYT1 formulation. 2.History of thyroid disorders (any form) within 24 weeks prior to the recruitment in the study. 3.Active liver disease and/or liver transaminases greater than 1.5 X upper limit of normal (ULN). 4.Renal insufficiency (serum creatinine > 1.5mg/dL). 5.History of myocarditis, hypertrophic cardiomyopathy, valvular heart disease, restrictive cardiomyopathy, constrictive pericarditis, myocardial infarction, ischemic heart disease, stroke, congestive heart failure, cardiac arrhythmia or coronary revascularization procedure at any time. 6.Subject who has QTc 450 (male) or 470 (female). 7.History or presence of musculo-skeletal disorders (e.g., myopathies, myolysis, fractures due to osteoporosis, etc.) 8.History or presence of other systemic disorders or diseases (e.g., respiratory, gastrointestinal, endocrine, immunological, dermatological, neurological, psychiatric disease or any other body system involvement). 9.Subjects taking other hormonal therapies e.g., glucocorticoids, androgens or growth hormones. 10.Use of thyroid supplements (levothyroxine, liothyronine, etc.) or any preparation containing thyromimetic agents within 24 weeks prior to study entry. 11.History of coagulopathy or use of anticoagulants such as warfarin. 12.History or presence of chronic medications or any medications in the last 14 days. 13.History or presence of significant alcoholism or drug abuse within the past one-year. 14.History or presence of significant smoking (more than 10 cigarettes per day) or consumption of tobacco products (more than 10 times per day). 15.Difficulty with donating blood. 16.Systolic blood pressure more than 140mmHg and less than 100mmHg and diastolic blood pressure more than 90mmHg and less than 60mmHg. 17.Pulse rate less than 60/minute and more than 100/minute. 18.Any clinically significant abnormal X-ray or laboratory findings during screening. 19.History or presence of any clinically significant ECG abnormalities during screening. 20.Major illness and/or Major surgery in last 3 months. 21.Volunteers who have participated in any drug research study other than the present trial within past 3 months. 22.Volunteers who have donated one unit (350ml) of blood in the past 3 months. 23.For gender effect study, female volunteers with following criteria will not be recruited: a.history of pregnancy or lactation in the past 3 months b.fertile female volunteers not protected against pregnancy by adequate long-term anti- fertility device or history of less than one year of menopause c.using hormonal contraceptives d.using hormone replacement therapy e.unable to give assurance for protection against pregnancy for 3 months after the participation in this trial f.history of osteoporosis or history of fracture in the past 6 months g.positive urine pregnancy test on the day of check-in Primary Outcome Outcome Timepoints To evaluate- 1.Safety and tolerability of ZYT1. 2.Pharmacokinetics (PK) of ZYT1 after single and multiple oral dose administrations in healthy adult male volunteers. 3.Pharmacodynamic (PD) effect, if captured, in multiple dose study. 1.FOR PLAN I, III, IV: Blood Sampling for PK analysis-pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 and 120 hrs post dose. 2.FOR PLAN II: Pharmacodynamic assessment-pre-dose on Day 01, 05 and 10 Blood Sampling for PK page 3 / 5
4.Effect of food on pharmacokinetics in male volunteers. 5.Gender effects: Pharmacokinetics and safety parameters in female volunteers at pre-selected single dose will be compared with the results of single dose study in male volunteers. analysis-?day 1, 5, 9: pre-dose, 0.5hr, 1hr, 2hrs, 3hrs, 4hrs, 6hrs, 8hrs, 12hrs of dosing?day 2 to 13: predose?day 14: pre-dose, 0.5hr, 1hr, 2hrs, 3hrs, 4hrs, 6hrs, 8hrs, 12hrs, 24hrs, 48hrs, 72hrs and 120 hrs of dosing. Secondary Outcome Outcome Timepoints Target Sample Size Phase of Trial Phase 1 Date of First Enrollment () Date of First Enrollment (Global) Estimated Duration of Trial Recruitment Status of Trial (Global) Recruitment Status of Trial () Publication Details Brief Summary Total Sample Size=8 Sample Size from =8 06/02/2010 No Date Specified Years=0 Months=6 Days=0 Not Applicable Other (Terminated) This is a randomized, double blind placebo control phase 1 clinical study to evaluate the safety, tolerability and pharmacokinetics of ZYT1, a selective TR beta agonist following oral administrations in healthy volunteers. The primary objectives of this study is to evaluate- 1.Safety and tolerability of ZYT1. 2.Pharmacokinetics (PK) of ZYT1 after single and multiple oral dose administrations in healthy adult male volunteers. 3.Pharmacodynamic (PD) effect, if captured, in multiple dose study. 4.Effect of food on pharmacokinetics in male volunteers. 5.Gender effects: Pharmacokinetics and safety parameters in female volunteers at pre-selected single dose will be compared with the results of single dose study in male volunteers. Note 1: The safety and tolerability shall be evaluated using physical examinations, Standard laboratory tests (hematology, biochemistry and urine examination), electrocardiogram (ECG) and thyroid scanning. Spontaneously reported and solicited adverse events will also be used for safety parameters. Note 2: Although, it is not possible to predict the pharmacodynamic behavior of ZYT1, an attempt will be made to assess the pharmacodynamic (PD) effects of ZYT1 after multiple dose oral administrations. The study is divided into four plans as given below: (1) Plan I: Single dose escalation trial (2) Plan II: Multiple dose escalation trial (3) Plan III: Food effect trial (4) Plan IV: Gender Effect trial Pan I, Single dose study: 1. Objective of Plan I study is to evaluate safety, tolerability and PKof ZYT1 in healthy volunteers. 2. At each dose level, blood samples will be withdrawn for PK and safety studies 3. Healthy male volunteers will be given a single oral dose of either ZYT1 or placebo in the overnight fasting condition. 4. In first panel (S1), 6 volunteers will be given 0.5 mg ZYT1 and 2 will receive placebo. 5. In second panel (S2), 8 healthy male volunteers will be recruited. In this panel, 6 volunteers will receive 1 mg ZYT1 and 2 will receive placebo. 6. In third panel (S3) of 8 healthy volunteers, 6 will receive 2 mg ZYT1 and 2 will be given placebo. 7. During further dose escalations, each subsequent panels (S4, S5,?) shall consist of 8 healthy volunteers, 6 of the 8 volunteers will receive next higher dose of ZYT1 and 2 will receive placebo 8. In each dose group volunteers will be dosed on 2 different days (first 4 subjects and then on other day 4 subjects) to avoid exposure of more number of volunteers together. Out of 4 volunteers, 3 will be given ZYT1 and 1 will be given placebo as per randomization. There would be at least one day gap between enrolment of 4 subjects for each panel. 9. This escalation scheme, as a precaution, shall prevent the exposure of more number of subjects to successive higher doses. 10. After completion of each dose study, the safety and PK data will be circulated to DSMB/IEC and further decision for dose escalation will be taken subsequently. 11. The single dose escalation shall continue till either 64 mg dose or maximum tolerated dose or pharmacokinetic saturation is reached (dose linearity ceased), which ever is earlier. Further decisions will be taken after the review by the Data Safety Monitoring Board (DSMB). Plan II, Multiple dose study: 1. Objective of Plan II study is to evaluate safety, tolerability, PK and, if demonstrated, capture the Pharmcodynamics of ZYT1 in healthy volunteers. 2. At each dose level, blood samples will be withdrawn for PK, PDand safety page 4 / 5
Powered by TCPDF (www.tcpdf.org) PDF of Trial studies. 3. Healthy male overnight fasted volunteers will be given oral dose of either ZYT1 or placebo daily for 14 days. 4. In the first panel (M1), ZYT1 0.5 mg and placebo will be administered daily for 14 days to 6 and 2 volunteers respectively. 5. In second panel (M2), 8 healthy male volunteers will be recruited. In this panel, 6 volunteers will receive 1mg ZYT1and 2 will receive placebo daily for 14 days. 6. In third panel (M3) of 8 healthy volunteers, 6 will receive 2 mg ZYT1 and 2 will be given placebo. 7. During further dose escalations, each subsequent panels (M4, M5,?) shall consist of 8 healthy volunteers, 6 of the 8 volunteers will receive next higher dose of ZYT1 and 2 will receive placebo daily for 14 days. 8. In each dose group volunteers will be dosed on 2 different days (first 4 subjects and then on other day 4 subjects) to avoid exposure of more number of volunteers together.out of 4 volunteers, 3 will be given ZYT1 and 1 will be given placebo as per randomization. There would be at least one day gap between enrolment of 4 subjects for each panel. 9. This escalation scheme, as a precaution, shall prevent the exposure of more number of subjects to successive higher doses. 10. After completion of each dose study, the safety and PK data will be circulated to DSMB/IEC and further decision for dose escalation will be taken subsequently. 11. The multiple dose escalation shall continue till either 16 mg dose or maximum tolerated dose or pharmacokinetic saturation is reached (dose linearity ceased), which ever is earlier. Further decisions will be taken after the review by DSMB. 12. At the end of the study (Day 15), weight, fasting blood glucose, triglycerides, total cholesterol, high density lipoprotein (HDL), LDL, very low density lipoprotein (VLDL), free fatty acids and lipoprotein A will be compared with baseline (Day 01). Plan III, Food effect study: 1. Effect of food on pharmacokinetics will be studied in a cross over study, with selected dose after completion of Panel S5 of Plan I and based on limit of detection of the investigational medicinal product (IMP) in analytical methods. 2. A cross over study (with an appropriate wash out period) will be conducted to evaluate the food effect on the PK parameters of ZYT1. 3. In the food effect study, 8 male volunteers will be enrolled in the study. Out of these, 6 will be given a single dose of ZYT1 and 2 will be given a placebo in both the periods. 4. In period I (fasted condition), subjects will be administered the investigational product following an overnight fast of at least 10 hours. 5. In period II (fed condition), subjects will be given a test meal 30 minutes prior to the administration of the investigational product following an overnight fast of at least 10 hours. Study subjects will eat this meal in 30 minutes or less; however, the investigational product will be administered 30 minutes after the start of the meal. The test meal is a high-fat (approximately 50 percent of the total caloric content of the meal) and high-calorie (approximately 800 to 1000 calories) meal, which derives approximately 150, 250, and 500-600 calories from protein, carbohydrate, and fat respectively. The diet chart is given in annexure I. 6. Blood will be withdrawn for safety studies and also for PK study Plan IV, Gender effect study: 1. The gender effect study will be conducted after the completion of Panel S5 of single dose safety and tolerability study 2. Eight female volunteers will be enrolled in the study. 3. Out of 8 volunteers, 6 will be given a single dose of ZYT1 and 2 will be given a placebo to assess the effects of gender difference on safety, tolerability and pharmacokinetics. 4. Dose will be selected based on the safety and tolerability of Plan I and limit of detection of the IMP in analytical methods. page 5 / 5