Clinical Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of LEZ763

Sponsor

Novartis Pharmaceuticals (Industry)

Overall Status

Completed

CT.gov ID

NCT01619332

Collaborator

(none)

220

Enrollment

Locations

Arms

Duration (Months)

36.7

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Type II Diabetes	Drug: Placebo Drug: Sitagliptin Drug: LEZ763	Phase 1/Phase 2

Study Design

Study Type:

Interventional

Actual Enrollment :

220 participants

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, 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

Study Start Date :

Mar 1, 2012

Actual Primary Completion Date :

Sep 1, 2013

Actual Study Completion Date :

Sep 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
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

Arm

Intervention/Treatment

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

Outcome Measures

Primary Outcome Measures

Number of Patients with adverse events, serious adverse events and death [Day 28]
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) [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]
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) [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]
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) [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]
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) [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]
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 [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]
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) [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]
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 [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]
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) [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]
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) [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]
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 [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]
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) [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]
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) [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]
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) [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]
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 [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]
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) [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]
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) [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]
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 [4 hour post-dose Day 27]

Secondary Outcome Measures

Area under the serum Glucagon-like-peptide 1 (GLP-1) curve (AUC0-24 hours) [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]
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 [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) [Baseline, Day 27]
Change from baseline in Fasting Insulin at Day 27 (Part III) [Baseline , Day 27]
Change from baseline in fasting plasma glucose at Day 27 (Part III) [Baseline , Day 27]
Change From Baseline in peak glucose level following meal Test at Day 27 (Part III) [Baseline , Day 27]
Peak effect (Emax) on postprandial GLP-1 (Part III) [Baseline , Day 27]
Change from baseline in Peptide YY (PYY) (Part III) [Baseline , Day 27]
Change from baseine in Gastric inhibit polypeptide (GIP) (Part III) [Baseline , Day 27]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

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

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Chula Vista	California	United States	91910
2	Novartis Investigative Site	Miami	Florida	United States	33126
3	Novartis Investigative Site	Orlando	Florida	United States	32809
4	Novartis Investigative Site	Cincinnati	Ohio	United States	45227
5	Novartis Investigative Site	Knoxville	Tennessee	United States	37920
6	Novartis Investigative Site	San Antonio	Texas	United States	78209