A Randomized, Double-blind, Placebo-controlled Phase I Clinical Study to Evaluate the Safety, Tolerability and Pharmacokinetics of ZYDPLA1, a Novel DPP- IV Inhibitor, Following Oral Administration in Healthy Volunteers
Overview
- Phase
- Phase 1
- Intervention
- ZYDPLA1 tablet
- Conditions
- Diabetes Mellitus
- Sponsor
- Zydus Lifesciences Limited
- Enrollment
- 84
- Locations
- 1
- Primary Endpoint
- Safety and tolerability assessed by monitoring adverse events, clinical, laboratory, electrocardiogram, and vital signs examinations.
- Status
- Completed
- Last Updated
- 10 years ago
Overview
Brief Summary
This First in Human (FIH) Phase I study intends to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of ZYDPLA1 in normal healthy adult volunteers.
Detailed Description
Glucose-dependent insulinotropic polypeptide (GIP) and Glucagon-like peptide (GLP-1) are incretin hormones, which stimulate glucose dependent insulin secretion, inhibit glucagon secretion, delay gastric emptying, suppress appetite and improve peripheral glucose uptake and disposal. Dipeptidyl peptidase-IV (DPP-IV) is a serine protease, which selectively cleaves the first two amino acids of GIP and GLP-1 thereby making it inactive. Inhibition of DPP-IV activity elevates endogenous GIP, GLP-1 and insulin levels thereby improving glucose excursion and exhibits antidiabetic activity. Since no orally active GLP-1 agonists are available, clinically orally bioavailable DPP-IV inhibitors hold great potential for the treatment of type 2 diabetes mellitus. Cadila Healthcare Ltd. developed a novel and orally bioavailable DPP-IV inhibitor (ZYDPLA1). In-vitro studies confirm selective DPPIV inhibitory activity of the ZYDPLA1. Pre-clinical in vivo pharmacodynamic, absorption, distribution, metabolism and excretion (ADME) \& toxicological studies showed the promising antidiabetic activity, good exposure and safety profile of ZYDPLA1(in various animal models). Hence a randomized, double-blind, placebo-controlled first in man trial proposed to evaluate the safety and tolerability of ZYDPLA1 in healthy volunteers. This study included 4 plans: i) single dose escalation study ii) multiple dose escalation study, iii) gender effect study and iv) food effect study.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Healthy male or female between 18 and 65 years of age.
- •Male subjects must agree to use one of the contraception methods during the study. Male contraceptive options include: Vasectomy, Abstinence requiring the use of contraceptives if becoming sexually active, or double barrier method (condom with spermicide, diaphragm or cervical cap). No Sperm donation for at least up to 90 days after last investigational product.
- •BMI within the range 18.0 - 30.0 kg/m2 BMI value should be rounded off to one significant digit after decimal point. BMI values should be rounded to the nearest integer (ex. 30.4 rounds down to 30, while 17.5 rounds up to 18).
- •Capable of giving written informed consent, which includes compliance with protocol.
- •Corrected QT interval (QTc) interval \< 450msec (as measured by QTcF)
- •For gender effect study, only females with history of sterility or at least 1 year menopause or use of long acting non hormonal contraceptive measures (e.g., intrauterine device) will be recruited. Surgical sterility is defined as either bilateral tubal ligation/occlusion, bilateral oophorectomy or hysterectomy.
- •Negative Urine drug screen including amphetamine, barbiturates, benzodiazepines, cannabinoid, cocaine, opiates, methadone and phencyclidine within 28 days prior to initiation of the study and prior to check-in.
Exclusion Criteria
- •Presence or history of pancreatitis at any time {Serum Amylase/Serum Lipase more than significant upper normal limit (≥1.5 times UNL)}
- •Presence or history of severe gastrointestinal disease in the last 6 months
- •Presence or history of renal insufficiency at any time {Serum creatinine more than upper normal limit (UNL)}
- •Active liver disease and/or liver transaminases greater than 1.5 times UNL
- •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)
- •History or presence of any medication in the last 14 days
- •History or presence of significant alcoholism or drug abuse within the past 1 year
- •History or presence of significant smoking (more than 10 cigarettes per day) or consumption of tobacco products (more than 10 times per day)
- •Difficulty with donating blood or difficulty in accessibility of veins.
- •Intolerance to venipuncture.
Arms & Interventions
ZYDPLA1 tablet
ZYDPLA1 tablets: Route of administration: Oral Dosage (Single Ascending Study): 1 mg, 5mg, 20mg, 50mg, 100mg, 200mg Multiple Ascending Study: 100mg, 200mg Food effect and Gender effect study: 200mg
Intervention: ZYDPLA1 tablet
Placebo
Placebo tablets: Route of administration: Oral Dosage (Single Ascending Study): 1 mg, 5mg, 20mg, 50mg, 100mg, 200mg Multiple Ascending Study: 100mg, 200mg Food effect and Gender effect study: 200mg
Intervention: Placebo tablet
Outcomes
Primary Outcomes
Safety and tolerability assessed by monitoring adverse events, clinical, laboratory, electrocardiogram, and vital signs examinations.
Time Frame: 28 Days (Plan II)
Secondary Outcomes
- Glucagon(28 Days)
- Pharmacokinetic assessment: Maximum plasma concentration (Cmax)(14 Days (Plan I, III, and IV))
- Area under the curve from the time of dosing to the last measurable concentration (AUC0-t)(28 Days (Plan II))
- Terminal half life (t1/2)(28 Days (Plan II))
- Elimination rate constant (λz)(28 Days (Plan II))
- Secondary parameters: Plasma glucose(14 Days)
- Maximum plasma concentration (Cmax)(28 Days (Plan II))
- Area under the curve from the time of dosing to the infinity (AUC 0-inf)(28 Days (Plan II))
- Accumulation index(28 Days (Plan II))
- Pharmacodynamic effect (Plan I, III, and IV) assessment by monitoring primary parameters: Plasma DPPIV(14 Days)
- Serum insulin(28 Days)
- C-peptide(28 Days)
- Pharmacodynamic effect (Plan II) assessment by monitoring primary parameters: Plasma DPPIV(28 Days)
- Glucagon-like peptide-1 (active and total)(28 Days)
- Plasma glucose(28 Days)
- Time to reach maximum plasma concentration (Tmax)(28 Days (Plan II))
- Clearance (CL)(28 Days (Plan II))
- Volume of distribution (Vd)(28 Days (Plan II))