Clinical trial NCT01619332: Clinical Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of LEZ763
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Type II Diabetes
Keywords: Healthy volunteers,
Diabetes
Glucose
Pharmacokinetics
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2012-06-14
Enrollment: 220
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility 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

Primary outcomes:
measure: Number of Patients with adverse events, serious adverse events and death
timeFrame: Day 28
measure: Pharmacokinetics of LEZ763 (Part I): area under the plasma concentration-time curve from time zero to infinity (AUCinf)
timeFrame: 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
measure: Pharmacokinetics of LEZ763 (Part I): area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast)
timeFrame: 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
measure: Pharmacokinetics of LEZ763 (Part I): Terminal elimination half-life (T1/2)
timeFrame: 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
measure: Pharmacokinetics of LEZ763 (Part I): Apparent systemic (or total body) clearance from plasma following extravascular administration (CL/F)
timeFrame: 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
measure: Pharmacokinetics of LEZ763 (Part I) : Observed maximum plasma concentration (Cmax) following drug administration
timeFrame: 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
measure: Pharmacokinetics of LEZ763 (Part I): time to reach the maximum concentration after drug administration (Tmax)
timeFrame: 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
measure: Pharmacokinetics of LEZ763 (Part II) : Observed maximum plasma concentration (Cmax) following drug administration
timeFrame: 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
measure: Pharmacokinetics of LEZ763 (Part II): time to reach the maximum concentration after drug administration (Tmax)
timeFrame: 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
measure: Pharmacokinetics of LEZ763 (Part II): Accumulation ratio(Racc)
timeFrame: 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
measure: Pharmacokinetics of LEZ763 (Part III) : Observed maximum plasma concentration (Cmax) following drug administration
timeFrame: 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
measure: Pharmacokinetics of LEZ763 (Part III): time to reach the maximum concentration after drug administration (Tmax)
timeFrame: 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
measure: Pharmacokinetics of LEZ763 (Part III): Area under the plasma concentration-time curve from time zero to the end of the dosing interval tau (AUCtau)
timeFrame: 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
measure: Pharmacokinetics of LEZ763 (Part III): Accumulation ratio(Racc)
timeFrame: 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
measure: Pharmacokinetics of LEZ763 and Sitagliptin (Part III): Observed maximum plasma concentration (Cmax) following drug administration
timeFrame: 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
measure: 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)
timeFrame: 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
measure: Pharmacokinetics of LEZ763 and Sitagliptin (Part III): Time to reach the maximum concentration after drug administration (Tmax)
timeFrame: 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
measure: Area under the effect curve (AUC0-4h) over the 4-hour post-dose period to measure glucose response following a standard mixed meal test
timeFrame: 4 hour post-dose Day 27
Secondary outcomes:
measure: Area under the serum Glucagon-like-peptide 1 (GLP-1) curve (AUC0-24 hours)
timeFrame: 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
measure: 2-hour value of post-prandial glucose
timeFrame: Day 1 of Part I, Day 1 and day 10 of Part II
measure: Change from baseline in Fasting C-peptide at Day 27 (Part III)
timeFrame: Baseline, Day 27
measure: Change from baseline in Fasting Insulin at Day 27 (Part III)
timeFrame: Baseline , Day 27
measure: Change from baseline in fasting plasma glucose at Day 27 (Part III)
timeFrame: Baseline , Day 27
measure: Change From Baseline in peak glucose level following meal Test at Day 27 (Part III)
timeFrame: Baseline , Day 27
measure: Peak effect (Emax) on postprandial GLP-1 (Part III)
timeFrame: Baseline , Day 27
measure: Change from baseline in Peptide YY (PYY) (Part III)
timeFrame: Baseline , Day 27
measure: Change from baseine in Gastric inhibit polypeptide (GIP) (Part III)
timeFrame: Baseline , Day 27
Other outcomes:
Locations:
city: Chula Vista
country: United States
facility: Novartis Investigative Site
state: California
city: Miami
country: United States
facility: Novartis Investigative Site
state: Florida
city: Orlando
country: United States
facility: Novartis Investigative Site
state: Florida
city: Cincinnati
country: United States
facility: Novartis Investigative Site
state: Ohio
city: Knoxville
country: United States
facility: Novartis Investigative Site
state: Tennessee
city: San Antonio
country: United States
facility: Novartis Investigative Site
state: Texas
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: