Clinical Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of LEZ763

Type II Diabetes Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01619332
• Other study ID #: CLEZ763X2201
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: March 2012
• Est. completion date: September 2013

Study information

• Verified date: March 2016
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 220
• Est. completion date: September 2013
• Est. primary completion date: September 2013
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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

Related Conditions & MeSH terms

• Diabetes Mellitus, Type 2
• Type II Diabetes

Intervention

Drug:
• Placebo
Placebo will be given orally once daily for 28 days to patients assigned to placebo in a randomized and blinded manner
• Sitagliptin
Sitaglitpin will be given orally once daily for 28 days to patients assigned to this treatment in a randomized and blinded manner
• LEZ763
LEZ763 will be given orally once daily for 28 days in a randomized and blinded manner

Locations

Country	Name	City	State
United States	Novartis Investigative Site	Chula Vista	California
United States	Novartis Investigative Site	Cincinnati	Ohio
United States	Novartis Investigative Site	Knoxville	Tennessee
United States	Novartis Investigative Site	Miami	Florida
United States	Novartis Investigative Site	Orlando	Florida
United States	Novartis Investigative Site	San Antonio	Texas

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	Day 28
Primary	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	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
Primary	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	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
Primary	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	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
Primary	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	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
Primary	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	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
Primary	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	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
Primary	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	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
Primary	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	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
Primary	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	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
Primary	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	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
Primary	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	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
Primary	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	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
Primary	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	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
Primary	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	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
Primary	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	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
Primary	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	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
Primary	Area under the effect curve (AUC0-4h) over the 4-hour post-dose period to measure glucose response following a standard mixed meal test		4 hour post-dose Day 27
Secondary	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	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
Secondary	2-hour value of post-prandial glucose		Day 1 of Part I, Day 1 and day 10 of Part II
Secondary	Change from baseline in Fasting C-peptide at Day 27 (Part III)		Baseline, Day 27
Secondary	Change from baseline in Fasting Insulin at Day 27 (Part III)		Baseline , Day 27
Secondary	Change from baseline in fasting plasma glucose at Day 27 (Part III)		Baseline , Day 27
Secondary	Change From Baseline in peak glucose level following meal Test at Day 27 (Part III)		Baseline , Day 27
Secondary	Peak effect (Emax) on postprandial GLP-1 (Part III)		Baseline , Day 27
Secondary	Change from baseline in Peptide YY (PYY) (Part III)		Baseline , Day 27
Secondary	Change from baseine in Gastric inhibit polypeptide (GIP) (Part III)		Baseline , Day 27

External Links

•   Results for CLEZ763X2201 from the Novartis Clinical Trials website