A Clinical Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of ZYD1, Following Subcutaneous Administration in Healthy Volunteers (ZYD1)

A Randomized, Double-blind, Placebo-controlled Phase I Clinical Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of ZYD1, a Selective Glucagon-like Peptide (GLP) 1 Agonist, Following Subcutaneous Administration in Healthy Volunteers.

ZYD1 is a novel GLP-1 receptor agonist. The ZYD1 exhibits increased stability to proteolytic cleavage, especially against dipeptidyl peptidase-4 (DPP-IV).

ZYD1 is a potent antidiabetic agent without gastrointestinal side-effects. A first in human (FIH) Phase I study intends to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of ZYD1 in normal healthy adult volunteers.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes Mellitus
• Intervention / Treatment: Drug: ZYD1; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 56
• Phase: Phase 1

Contacts and Locations

Study Locations

• India
  • Gujarat
    • Ahmedabad, Gujarat, India, 382213
      • Zydus Research Centre, Survey No. 396/403, Opp. Sarvotam Hotel, Nr. Nova Petrochemicals, Sarkhej-Bavla N.H. No. 8A, Village : Moraiya,

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age: 18-45 years
2. Mentally, physically, and legally eligible to give informed consent
3. Male and female volunteers weighing between 50-75 kg and 45-75 kg respectively
4. Ability to communicate effectively with the study personnel
5. Willingness to adhere to the protocol requirements
6. For gender effect study, only females with history of sterility or at least 1 year menopause or use of long acting nonhormonal contraceptive measures (e.g., intrauterine device) will be recruited.

Exclusion Criteria:

1. Presence or history of hypersensitivity to any of the active or inactive ingredients of ZYD1 formulation
2. Presence or history of pancreatitis at any time (Serum Amylase/Serum Lipase more than upper normal limit (UNL))
3. Presence or history of severe gastrointestinal disease in the last 6 months
4. Presence or history of renal insufficiency at any time (serum creatinine above the upper limit of the reference range)
5. Active liver disease and/or liver transaminases greater than 1.5 X UNL
6. Subject with personal or family history of medullary thyroid cancer
7. Subject with personal or family history of multiple endocrine neoplasia syndrome type 2
8. Subject with serum calcitonin >50 ng/L
9. 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)
10. Abnormal bleeding time (BT), clotting time (CT), prothrombin time (PT), and activated partial prothrombin time (APTT) tests on the day of check in
11. History or presence of any medication in the last 14 days including any medication known to interact with the Cytochrome P (CYP) 450 system
12. History or presence of significant alcoholism or drug abuse within the past 1 year
13. History or presence of significant smoking (more than 10 cigarettes per day) or consumption of tobacco products (more than 10 times per day)
14. Difficulty with donating blood
15. Systolic blood pressure more than 140 mmHg and less than 100 mmHg and diastolic blood pressure more than 90 mmHg and less than 60 mmHg
16. Pulse rate less than 60/minute and more than 100/minute
17. Any clinically significant abnormal X-ray or laboratory findings during screening
18. History or presence of any clinically significant electrocardiogram (ECG) abnormalities during screening
19. Major illness and/or major surgery in last 3 months
20. Volunteers who have participated in any drug research study other than the present trial within past 3 months
21. Volunteers who have donated one unit (350 ml) of blood in the past 3 months

22. For gender effect study, female volunteers with following criteria will not be recruited:

    • History of pregnancy or lactation in the past 3 months
    • Fertile female volunteers not protected against pregnancy by adequate long-term anti-fertility device or history of less than 1 year of menopause
    • Using hormonal contraceptives
    • Using hormone replacement therapy
    • Unable to give assurance for protection against pregnancy for 3 months after the participation in this trial
    • Positive urine pregnancy test on the day of check-in

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ZYD1; Tablet ZYD1 5 to 50 mg subcutaneously Once a day (OD) or BID depending upon the pharmacokinetic profile obtained in Plan I (Single dose study)	Drug: ZYD1; Plan I - Tablet ZYD1 - 0.5, 1 , 2, 5, 10, 25 and 50 mg subcutaneously OD after overnight fasting. Plan II - Tablet ZYD1 - 0.5, 1 , 2, 5, 10 and 25 mg subcutaneously OD after overnight fasting. Plan III - Tablet ZYD1 2/5 mg subcutaneously OD after overnight fasting depending on results of Plan I.; Other Names: Selective GLP-1 agonist
Placebo Comparator: Placebo; Tablet Placebo 5 to 50 mg subcutaneously OD or BID depending upon the pharmacokinetic profile obtained in Plan I (Single dose study)	Drug: Placebo; Plan I - Tablet Placebo - 0.5, 1 , 2, 5, 10, 25 and 50 mg subcutaneously OD after overnight fasting. Plan II - Tablet Placebo - 0.5, 1 , 2, 5, 10 and 25 mg subcutaneously OD after overnight fasting. Plan III - Tablet Placebo 2/5 mg subcutaneously OD after overnight fasting depending on results of Plan I.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To evaluate Safety and tolerability of ZYD1	The safety and tolerability shall be evaluated using physical examinations, standard laboratory tests (hematology, biochemistry and urine examination), and electrocardiogram (ECG). Spontaneously reported and solicited adverse events will also be used for safety parameters.	21 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetics (PK) and Pharmacodynamic (PD) effect after single and multiple subcutaneous dose administrations in healthy adult male volunteers Gender effect study.	PK parameters evaluated for Plan I and Plan III: Cmax, Tmax, Area Under Curve (AUC)0-t, AUC 0-inf, T1/2, z, Clearance(CL), Volume of distribution (Vd) Plan II: Cmin, Tmin, Cavg, % Fluctuation, Accumulation Index, Clss, Cmax, Vd or Vss For urine data (Plans I, II, and III): Amount recovered, % recovered The following PD parameters (Plan I-III) will be evaluated: Plasma glucose, Serum insulin, C-Peptide, Glucagon Gender effects: PK and PD effect in female volunteers at preselected single dose will be compared with the results of single-dose study in male volunteers.	1. For Plan I and III - Pre-dose (before dosing), 0.5, 1, 2, 3, 4, 6 ,8, 10, 12, 24, 48, 72 and 120 hrs post dose 2. Plan II - Day 01 - Pre-dose, 1, 2, 3, 4 and 8 hours following first dosing. Day 02 to 06 - Pre-dose of each . Day 07 - Pre-dose, 1, 2, 3,

Collaborators and Investigators

• Sponsor: Zydus Lifesciences Limited
• Investigators: Study Director: Rajendrakumar H Jani, PhD(Medical), Senior Vice President - Cadila Healthcare Limited; Principal Investigator: Kevinkumar Kansagra, MD, Zydus Research Centre

Study record dates

Study Major Dates

• Study Start: February 1, 2011
• Primary Completion (Actual): March 1, 2012
• Study Completion (Actual): June 1, 2012

Study Registration Dates

• First Submitted: March 5, 2012
• First Submitted That Met QC Criteria: October 25, 2013
• First Posted (Estimate): October 31, 2013

Study Record Updates

• Last Update Posted (Estimate): October 31, 2013
• Last Update Submitted That Met QC Criteria: October 25, 2013
• Last Verified: October 1, 2013

More Information

Terms related to this study

• Keywords: Selective GLP-1 agonist
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2
• Other Study ID Numbers: ZYD1/1001; CTRI/2011/04/001684 (Other Identifier: Clinical Trial Registration India)