Acute Metabolic Effects of LAF 237 in Type 2 Diabetics

Type 2 Diabetes Mellitus Clinical Trial

Official title:

A Double-Blind, Placebo-Controlled, Randomized, Crossover Study to Explore the Acute Effects of LAF 237 on the Rate of Appearance and Disappearance of Glucose During the Overnight Post-Absorptive Period in Type 2 Diabetics

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00230464
• Other study ID #: CLAF237A2346
• Status: Completed
• Phase: Phase 3
• First received: September 28, 2005
• Last updated: January 3, 2006
• Start date: November 2004
• Est. completion date: September 2005

Study information

• Verified date: September 2005
• Source: The University of Texas Health Science Center at San Antonio
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

Incretin hormones (GIP and GLP-1) stimulate insulin release in a glucose dependant manner, hence are necessary for maintenance of normal glucose tolerance. Both GIP and GLP-1 are degraded and inactivated by DPP-4.

LAF 237 is an inhibitor of DPP-4 that has been shown to increase meal-stimulated levels of intact GLP-1 in animals and patients with T2DM..

The purpose of the current study is to explore the acute effects of LAF237 on the rate of appearance and disappearance of glucose in type 2 diabetics. Secondary objectives include the effect on FPG, insulin secretion rates, glucagon and FFA levels, and rate of glucose entry from the GI tract.

Description:

Study Design Double blind, placebo-controlled, randomized, two –period crossover study. Sixteen (16) both sexes diabetic patients will be enrolled and randomized to receive one of two treatment sequences (LAF-placebo or placebo-LAF).

At screening, patients will begin a weight maintaining diet containing 50% carbohydrates, 30% protein and 20% fat.

Within 7 days from screening patients will be scheduled for treatment 1. Patients will begin a 10-hour overnight fast on Day -1 at ~21h00. Patients will be admitted to GCRC next day. Fasting plasma glucose sample will be drawn and following this the patient will be served a standard breakfast containing 1/5 of their caloric allotment (50% carbohydrates, 30% protein and 20% fat). At noon patient will be fed a standard lunch containing 2/5 of their caloric allotment (50% carbohydrates, 30% protein and 20% fat). At 14h30 (-210) an infusion of 3-3H glucose will be started and continued until 08h00 next day (20 µCi x FPG/100 continuous, 0.20/min). At 17h30 (-30) patients will ingest 100 mg of LAF237 or placebo with 200 ml of water. At 18h00 (time zero) patients will be served a dinner (2/5 of their caloric allotment). The carbohydrates (glucose) in the meal will be labeled with 75 µCi of [1-14C]-glucose.

At -60, -50, -40, -35, -30, -20, -10, -5, and 0 minutes before dinner plasma samples for determination of glucose, insulin, C-peptide, glucagons, GLP-1, GIP, FFA, lactate, and amino acid concentrations and 3-3H glucose radioactivity will be drawn. Following dinner, further blood samples will be drawn every 15 minutes for 3.5 hours (18h00-21h30) and every 30 minutes for the next 10.5 hours (22h00-08h00 Day 2). Post dinner samples will be analyzed for the above parameter as well as for 14C glucose radioactivity. At 08h00 on Day 2, both catheters will be removed and the patients will be fed breakfast and then released from the site.

In addition to blood samples, urine from dinner time until 08h00 on Day 2 will be collected.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 16
• Est. completion date: September 2005
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

1. Age 18-75 years with type 2 diabetes, males or females (non-pregnant)

2. Time of diagnosis: within 6 months prior to screening, or 1 month prior to screening with no detectable anti-GAD Abs

3. Normal physical exam, EKG, blood tests, and urinalysis

4. HbA1c=7-11% at screening

5. FPG=160-280 mg/dl at screening

6. Diabetes controlled by diet and exercise alone or by stable dosage of metformin or sulfonylurea

7. BMI=22-45 kg/m2 and with a stable (+/- 2.5 kg) weight for the last 6 months

8. Compliant to study requirements & written consent.

Exclusion Criteria:

1. Pregnant or lactating female

2. History of: type 1 DM, pancreatic injury, secondary diabetes (Cushing, acromegaly), acute metabolic complications (ketoacidosis or hyperosmolar state) within the past 6 months, torsades des pointes, ventricular tachycardia or ventricular fibrillation

3. Any of the following within the past 6 months: MI, CABG, unstable angina

4. ECG abnormalities: second degree AV block (Mobitz 1 and 2), third degree AV block, prolonged QTc (>450 ms)

5. Use of the following medications: class Ia ,Ib, Ic or III antiarrhythmics, insulin, thiazolidinediones, corticosteroids

6. Investigational drug treatment within 4 weeks prior to screening unless local health authority guidelines mandate a longer period

7. Fasting triglycerides >700 mg/dl at screening

8. Diabetic complications

9. Renal disease (creatinine >1.5 mg/dl-males or >1.4 mg/dl-female), renal failure, hepatic dysfunction, thyrotoxicosis

10. History of gastrointestinal surgery (partial bowel resections, partial gastric resections)

11. Donation of one unit of blood within 2 weeks or transfusion within 8 weeks prior to screening

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double-Blind, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Diabetes Mellitus, Type 2
• Type 2 Diabetes Mellitus

Intervention

Drug:
• LAF 237

Locations

Country	Name	City	State
United States	Audie L Murphy VA Hospital	San Antonio	Texas

Sponsors (2)

Lead Sponsor	Collaborator
The University of Texas Health Science Center at San Antonio	Novartis

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Rate of appearance of endogenous glucose
Secondary	Rate of dissapearance of glucose
Secondary	Fasting glucose
Secondary	Insulin secretion
Secondary	Free fatty acids
Secondary	Glucagon
Secondary	Rate of appearance of oral glucose