Clinical Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of LEZ763

Phase 2CompletedNCT01619332

Novartis Pharmaceuticals220 enrolled

Overview

This study is a three part study to assess the safety and efficacy of LEZ763 on normal healthy volunteers and patients with Type 2 Diabetes.

Study Type

INTERVENTIONAL

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

220

Conditions

Type II Diabetes

Interventions

PlaceboDRUG

Placebo will be given orally once daily for 28 days to patients assigned to placebo in a randomized and blinded manner

SitagliptinDRUG

Sitaglitpin will be given orally once daily for 28 days to patients assigned to this treatment in a randomized and blinded manner

LEZ763DRUG

LEZ763 will be given orally once daily for 28 days in a randomized and blinded manner

Eligibility

Sex: ALLMin age: 18 YearsMax age: 65 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion criteria: * All subjects: (suggest this will reduce duplication) * Male or female aged 18-65 yr, * Subjects must weigh at least 50 kg to participate in the study. Body mass index (BMI) must be within the range of 18-37 kg/m2 (inclusive * Only postmenopausal females or female subjects who report surgical sterilization (women without child bearing potential) will be allowed in this study. * Subjects with stable conventional sleep-wake cycle Normal Healthy Volunteers * Healthy male or female subjects, * must be in good health (as determined by past medical history, physical examination, vital signs, electrocardiogram, and laboratory tests at Screening). Type II Diabetic Patients * Type 2 diabetes diagnosed by American Diabetes Association criteria for at least 3 months prior to screening. * Patients either drug naïve or on stable dose of metformin (stable dose for at least 4 weeks prior to Screening). The metformin dose should remain constant during the course of the study. * HbA1c 6.5 to 9.5 % inclusive at screening Exclusion criteria: All subjects: * Smokers (use of tobacco products in the previous 3 months). * Donation or loss of 400 mL or more of blood within 8 weeks prior to first dosing, or longer if required by local regulation. * Significant illness within two weeks prior to dosing. * Have (or have history of) drug or alcohol abuse within the 12 months prior to dosing or evidence of such abuse as indicated by the laboratory assays conducted during the screening or baseline evaluations Normal Healthy Volunteers • History of diabetes, or adrenal disorders. Type II Diabetic Patients * Type 1 diabetes mellitus; positive anti-GAD antibodies; acquired or secondary forms of diabetes such as those resulting from pancreatic surgery/injury, cystic fibrosis related diabetes * Evidence of clinically significant diabetic complications (such nephropathy, retinopathy, neuropathy) Other protocol defined inclusion/exclusion criteria may apply

Locations (6)

Novartis Investigative Site

Chula Vista, California, United States

Novartis Investigative Site

Miami, Florida, United States

Novartis Investigative Site

Orlando, Florida, United States

Novartis Investigative Site

Cincinnati, Ohio, United States

Outcomes

Primary Outcomes

Number of Patients with adverse events, serious adverse events and death

An adverse event is the appearance or worsening of any undesirable sign, symptom, or medical condition occurring after starting the study drug even if the event is not considered to be related to study drug. Adverse events will also be determined on the basis of clinical laboratory assessments, electrocardiographic evaluations and vital signs determinations.

Time frame: Day 28

Pharmacokinetics of LEZ763 (Part I): area under the plasma concentration-time curve from time zero to infinity (AUCinf)

Blood will be collected at multiple timepoints and will be analyzed for LEZ736 concentrations after single dose

Time frame: pre-dose, and 0.5, 0.66, 0.75, 1, 1.5, 2, 2.5, 3, 3.5 4, 6, 8, 12 hours post-dose on Day 1; 24 and 36 hours Day 2; Day 3, Day 4

Pharmacokinetics of LEZ763 (Part I): area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast)

Blood will be collected at multiple timepoints and will be analyzed for LEZ736 concentrations after single dose

Time frame: pre-dose, and 0.5, 0.66, 0.75, 1, 1.5, 2, 2.5, 3, 3.5 4, 6, 8, 12 hours post-dose on Day 1; 24 and 36 hours Day 2; Day 3, Day 4

Pharmacokinetics of LEZ763 (Part I): Terminal elimination half-life (T1/2)

Blood will be collected at multiple timepoints and will be analyzed for LEZ736 concentrations after single dose

Time frame: pre-dose, and 0.5, 0.66, 0.75, 1, 1.5, 2, 2.5, 3, 3.5 4, 6, 8, 12 hours post-dose on Day 1; 24 and 36 hours Day 2; Day 3, Day 4

Pharmacokinetics of LEZ763 (Part I): Apparent systemic (or total body) clearance from plasma following extravascular administration (CL/F)

Blood will be collected at multiple timepoints and will be analyzed for LEZ736 concentrations after single dose

Time frame: pre-dose, and 0.5, 0.66, 0.75, 1, 1.5, 2, 2.5, 3, 3.5 4, 6, 8, 12 hours post-dose on Day 1; 24 and 36 hours Day 2; Day 3, Day 4

Data from ClinicalTrials.gov

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Novartis Investigative Site

Knoxville, Tennessee, United States

Novartis Investigative Site

San Antonio, Texas, United States

Pharmacokinetics of LEZ763 (Part I) : Observed maximum plasma concentration (Cmax) following drug administration

Blood will be collected at multiple timepoints and will be analyzed for LEZ736 concentrations after single and multiple doses

Time frame: pre-dose, and 0.5, 0.66, 0.75, 1, 1.5, 2, 2.5, 3, 3.5 4, 6, 8, 12 hours post-dose on Day 1; 24 and 36 hours Day 2; Day 3, Day 4

Pharmacokinetics of LEZ763 (Part I): time to reach the maximum concentration after drug administration (Tmax)

Blood will be collected at multiple timepoints and will be analyzed for LEZ736 concentrations after single dose

Time frame: pre-dose, and 0.5, 0.66, 0.75, 1, 1.5, 2, 2.5, 3, 3.5 4, 6, 8, 12 hours post-dose on Day 1; 24 and 36 hours Day 2; Day 3, Day 4

Pharmacokinetics of LEZ763 (Part II) : Observed maximum plasma concentration (Cmax) following drug administration

Blood will be collected at multiple timepoints and will be analyzed for LEZ736 concentrations after multiple doses

Time frame: pre-dose, and 0.5, 0.66, 0.75, 1, 1.5, 2, 2.5, 3, 3.5 4, 6, 8, 12 hours post-dose on Day 1 and Day 10

Pharmacokinetics of LEZ763 (Part II): time to reach the maximum concentration after drug administration (Tmax)

Blood will be collected at multiple timepoints and will be analyzed for LEZ736 concentrations after multiple doses

Time frame: pre-dose, and 0.5, 0.66, 0.75, 1, 1.5, 2, 2.5, 3, 3.5 4, 6, 8, 12 hours post-dose on Day 1 and Day 10

Pharmacokinetics of LEZ763 (Part II): Accumulation ratio(Racc)

Blood will be collected at multiple timepoints and will be analyzed for LEZ736 concentrations after multiple doses

Time frame: pre-dose, and 0.5, 0.66, 0.75, 1, 1.5, 2, 2.5, 3, 3.5 4, 6, 8, 12 hours post-dose on Day 1 and Day 27

Pharmacokinetics of LEZ763 (Part III) : Observed maximum plasma concentration (Cmax) following drug administration

Blood will be collected at multiple timepoints and will be analyzed for LEZ736 concentrations after multiple doses

Time frame: pre-dose, and 0.5, 0.66, 0.75, 1, 1.5, 2, 2.5, 3, 3.5 4, 6, 8, 12 hours post-dose on Day 1 and Day 27

Pharmacokinetics of LEZ763 (Part III): time to reach the maximum concentration after drug administration (Tmax)

Blood will be collected at multiple timepoints and will be analyzed for LEZ736 concentrations after multiple doses

Time frame: pre-dose, and 0.5, 0.66, 0.75, 1, 1.5, 2, 2.5, 3, 3.5 4, 6, 8, 12 hours post-dose on Day 1 and Day 27

Pharmacokinetics of LEZ763 (Part III): Area under the plasma concentration-time curve from time zero to the end of the dosing interval tau (AUCtau)

Blood will be collected at multiple timepoints and will be analyzed for LEZ736 concentrations after single and multiple doses

Time frame: pre-dose, and 0.5, 0.66, 0.75, 1, 1.5, 2, 2.5, 3, 3.5 4, 6, 8, 12 hours post-dose on Day 1 and Day 27

Pharmacokinetics of LEZ763 (Part III): Accumulation ratio(Racc)

Blood will be collected at multiple timepoints and will be analyzed for LEZ736 concentrations after single and multiple doses

Time frame: pre-dose, and 0.5, 0.66, 0.75, 1, 1.5, 2, 2.5, 3, 3.5 4, 6, 8, 12 hours post-dose on Day 1 and Day 27

Pharmacokinetics of LEZ763 and Sitagliptin (Part III): Observed maximum plasma concentration (Cmax) following drug administration

Blood will be collected at multiple timepoints and will be analyzed for LEZ736 concentrations after multiple doses

Time frame: pre-dose, and 0.5, 0.66, 0.75, 1, 1.5, 2, 2.5, 3, 3.5 and 4 hours post-dose on Day 28

Pharmacokinetics of LEZ763 and Sitagliptin (Part III): Area under the plasma concentration-time curve from time zero to the end of the dosing interval tau (AUCtau)

Blood will be collected at multiple timepoints and will be analyzed for LEZ736 concentrations after multiple doses

Time frame: pre-dose, and 0.5, 0.66, 0.75, 1, 1.5, 2, 2.5, 3, 3.5 and 4 hours post-dose on Day 28

Pharmacokinetics of LEZ763 and Sitagliptin (Part III): Time to reach the maximum concentration after drug administration (Tmax)

Blood will be collected at multiple timepoints and will be analyzed for LEZ736 concentrations after multiple doses

Time frame: pre-dose, and 0.5, 0.66, 0.75, 1, 1.5, 2, 2.5, 3, 3.5 and 4 hours post-dose on Day 28

Area under the effect curve (AUC0-4h) over the 4-hour post-dose period to measure glucose response following a standard mixed meal test

Time frame: 4 hour post-dose Day 27

Secondary Outcomes

Area under the serum Glucagon-like-peptide 1 (GLP-1) curve (AUC0-24 hours)

GLP-1 Biomarker measures will be evaluated at pre-dose, and 0.5, 0.66, 0.75, 1, 1.5, 2, 2.5, 3, 3.5 and 4 hours post-dose

Time frame: Pre-dose, and 0.5, 0.66, 0.75, 1, 1.5, 2, 2.5, 3, 3.5 and 4 hours post-dose on Day -1, Day 1, Day 27, and Day 28

2-hour value of post-prandial glucose

Time frame: Day 1 of Part I, Day 1 and day 10 of Part II

Change from baseline in Fasting C-peptide at Day 27 (Part III)

Time frame: Baseline, Day 27

Change from baseline in Fasting Insulin at Day 27 (Part III)

Time frame: Baseline , Day 27

Change from baseline in fasting plasma glucose at Day 27 (Part III)

Time frame: Baseline , Day 27

Change From Baseline in peak glucose level following meal Test at Day 27 (Part III)

Time frame: Baseline , Day 27

Peak effect (Emax) on postprandial GLP-1 (Part III)

Time frame: Baseline , Day 27

Change from baseline in Peptide YY (PYY) (Part III)

Time frame: Baseline , Day 27

Change from baseine in Gastric inhibit polypeptide (GIP) (Part III)

Time frame: Baseline , Day 27