Clinical Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of LEZ763 - Full Text View

Purpose

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.

Condition	Intervention	Phase
Type II Diabetes	Drug: Placebo Drug: Sitagliptin Drug: LEZ763	Phase 2

Study Type:	Interventional
Study Design:	Endpoint Classification: Pharmacokinetics/Dynamics Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor) Primary Purpose: Treatment
Official Title:	A Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of LEZ763 Following Single and Multiple Ascending Doses in Healthy Subjects and Patients With Type 2 Diabetes

Resource links provided by NLM:

MedlinePlus related topics: Diabetes Diabetes Medicines Diabetes Type 2

Drug Information available for: Sitagliptin Sitagliptin phosphate

U.S. FDA Resources

Further study details as provided by Novartis:

Primary Outcome Measures:

Number of Patients with adverse events, serious adverse events and death [ Time Frame: Day 28 ] [ Designated as safety issue: No ]
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.
Pharmacokinetics of LEZ763 (Part I): area under the plasma concentration-time curve from time zero to infinity (AUCinf) [ 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 ] [ Designated as safety issue: No ]
Blood will be collected at multiple timepoints and will be analyzed for LEZ736 concentrations after single dose
Pharmacokinetics of LEZ763 (Part I): area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast) [ 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 ] [ Designated as safety issue: No ]
Blood will be collected at multiple timepoints and will be analyzed for LEZ736 concentrations after single dose
Pharmacokinetics of LEZ763 (Part I): Terminal elimination half-life (T1/2) [ 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 ] [ Designated as safety issue: No ]
Blood will be collected at multiple timepoints and will be analyzed for LEZ736 concentrations after single dose
Pharmacokinetics of LEZ763 (Part I): Apparent systemic (or total body) clearance from plasma following extravascular administration (CL/F) [ 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 ] [ Designated as safety issue: No ]
Blood will be collected at multiple timepoints and will be analyzed for LEZ736 concentrations after single dose
Pharmacokinetics of LEZ763 (Part I) : Observed maximum plasma concentration (Cmax) following drug administration [ 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 ] [ Designated as safety issue: No ]
Blood will be collected at multiple timepoints and will be analyzed for LEZ736 concentrations after single and multiple doses
Pharmacokinetics of LEZ763 (Part I): time to reach the maximum concentration after drug administration (Tmax) [ 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 ] [ Designated as safety issue: No ]
Blood will be collected at multiple timepoints and will be analyzed for LEZ736 concentrations after single dose
Pharmacokinetics of LEZ763 (Part II) : Observed maximum plasma concentration (Cmax) following drug administration [ 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 ] [ Designated as safety issue: No ]
Blood will be collected at multiple timepoints and will be analyzed for LEZ736 concentrations after multiple doses
Pharmacokinetics of LEZ763 (Part II): time to reach the maximum concentration after drug administration (Tmax) [ 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 ] [ Designated as safety issue: No ]
Blood will be collected at multiple timepoints and will be analyzed for LEZ736 concentrations after multiple doses
Pharmacokinetics of LEZ763 (Part II): Accumulation ratio(Racc) [ 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 ] [ Designated as safety issue: No ]
Blood will be collected at multiple timepoints and will be analyzed for LEZ736 concentrations after multiple doses
Pharmacokinetics of LEZ763 (Part III) : Observed maximum plasma concentration (Cmax) following drug administration [ 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 ] [ Designated as safety issue: No ]
Blood will be collected at multiple timepoints and will be analyzed for LEZ736 concentrations after multiple doses
Pharmacokinetics of LEZ763 (Part III): time to reach the maximum concentration after drug administration (Tmax) [ 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 ] [ Designated as safety issue: No ]
Blood will be collected at multiple timepoints and will be analyzed for LEZ736 concentrations after multiple doses
Pharmacokinetics of LEZ763 (Part III): Area under the plasma concentration-time curve from time zero to the end of the dosing interval tau (AUCtau) [ 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 ] [ Designated as safety issue: No ]
Blood will be collected at multiple timepoints and will be analyzed for LEZ736 concentrations after single and multiple doses
Pharmacokinetics of LEZ763 (Part III): Accumulation ratio(Racc) [ 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 ] [ Designated as safety issue: No ]
Blood will be collected at multiple timepoints and will be analyzed for LEZ736 concentrations after single and multiple doses
Pharmacokinetics of LEZ763 and Sitagliptin (Part III): Observed maximum plasma concentration (Cmax) following drug administration [ 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 ] [ Designated as safety issue: No ]
Blood will be collected at multiple timepoints and will be analyzed for LEZ736 concentrations after multiple doses
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) [ 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 ] [ Designated as safety issue: No ]
Blood will be collected at multiple timepoints and will be analyzed for LEZ736 concentrations after multiple doses
Pharmacokinetics of LEZ763 and Sitagliptin (Part III): Time to reach the maximum concentration after drug administration (Tmax) [ 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 ] [ Designated as safety issue: No ]
Blood will be collected at multiple timepoints and will be analyzed for LEZ736 concentrations after multiple doses
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 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Area under the serum Glucagon-like-peptide 1 (GLP-1) curve (AUC0-24 hours) [ 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 ] [ Designated as safety issue: No ]
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
2-hour value of post-prandial glucose [ Time Frame: Day 1 of Part I, Day 1 and day 10 of Part II ] [ Designated as safety issue: No ]
Change from baseline in Fasting C-peptide at Day 27 (Part III) [ Time Frame: Baseline, Day 27 ] [ Designated as safety issue: No ]
Change from baseline in Fasting Insulin at Day 27 (Part III) [ Time Frame: Baseline , Day 27 ] [ Designated as safety issue: No ]
Change from baseline in fasting plasma glucose at Day 27 (Part III) [ Time Frame: Baseline , Day 27 ] [ Designated as safety issue: No ]
Change From Baseline in peak glucose level following meal Test at Day 27 (Part III) [ Time Frame: Baseline , Day 27 ] [ Designated as safety issue: No ]
Peak effect (Emax) on postprandial GLP-1 (Part III) [ Time Frame: Baseline , Day 27 ] [ Designated as safety issue: No ]
Change from baseline in Peptide YY (PYY) (Part III) [ Time Frame: Baseline , Day 27 ] [ Designated as safety issue: No ]
Change from baseine in Gastric inhibit polypeptide (GIP) (Part III) [ Time Frame: Baseline , Day 27 ] [ Designated as safety issue: No ]

Estimated Enrollment:	280
Study Start Date:	January 2012
Estimated Study Completion Date:	April 2013
Estimated Primary Completion Date:	April 2013 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: LEZ763 Part I- Healthy volunteers enrolled into 6 single-ascending dose cohorts Part II- Healthy volunteers enrolled into 5 multiple-ascending dose cohorts. Part III- LEZ763 will be given orally once daily for 28 days in a randomized and blinded manner	Drug: LEZ763 LEZ763 will be given orally once daily for 28 days in a randomized and blinded manner
Placebo Comparator: Placebo Part I : Healthy volunteers enrolled in 6 single ascending dose cohorts to receive matching placebo of LEZ763. Part II: Healthy volunteers enrolled in 5 multiple ascending dose cohorts to receive matching placebo of LEZ763. Part III- Placebo will be given orally once daily for 28 days to patients assigned to placebo in a randomized and blinded manner	Drug: Placebo Placebo will be given orally once daily for 28 days to patients assigned to placebo in a randomized and blinded manner
Active Comparator: Sitagliptin Sitaglitpin will be given orally once daily for 28 days to patients assigned to this treatment in a randomized and blinded manner	Drug: Sitagliptin Sitaglitpin will be given orally once daily for 28 days to patients assigned to this treatment in a randomized and blinded manner

Eligibility

Ages Eligible for Study:	18 Years to 65 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	Yes

Criteria

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01619332

Contacts

Contact: Novartis Pharmaceuticals

+1(862)778-8300

Locations

United States, California
Novartis Investigative Site	Not yet recruiting
Chula Vista, California, United States, 91910
United States, Florida
Novartis Investigative Site	Recruiting
Miami, Florida, United States, 33126

Sponsors and Collaborators

Novartis Pharmaceuticals

Investigators

Study Director:

Novartis Pharmaceuticals

More Information

No publications provided

Responsible Party:	Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:	NCT01619332 History of Changes
Other Study ID Numbers:	CLEZ763X2201
Study First Received:	June 12, 2012
Last Updated:	November 20, 2012
Health Authority:	United States: Food and Drug Administration

Keywords provided by Novartis:

Healthy volunteers,
Diabetes
Glucose
Pharmacokinetics

Additional relevant MeSH terms:

Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Sitagliptin
Dipeptidyl-Peptidase IV Inhibitors

Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Hypoglycemic Agents
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on May 19, 2013