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Acute Metabolic Effects of LAF 237 in Type 2 Diabetics

This study has been completed.
Sponsor:
Collaborator:
Novartis
Information provided by:
The University of Texas Health Science Center at San Antonio
ClinicalTrials.gov Identifier:
NCT00230464
First received: September 28, 2005
Last updated: January 3, 2006
Last verified: September 2005
History of Changes
  Purpose

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.


Condition Intervention Phase
Type 2 Diabetes Mellitus
 Drug: LAF 237
 Phase 3

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

Resource links provided by NLM:

U.S. FDA Resources

Further study details as provided by The University of Texas Health Science Center at San Antonio:

Primary Outcome Measures:
  • Rate of appearance of endogenous glucose

Secondary Outcome Measures:
  • Rate of dissapearance of glucose
  • Fasting glucose
  • Insulin secretion
  • Free fatty acids
  • Glucagon
  • Rate of appearance of oral glucose

Estimated Enrollment: 16
Study Start Date: November 2004
Estimated Study Completion Date: September 2005
Detailed 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.

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00230464

Locations
United States, Texas
Audie L Murphy VA Hospital
San Antonio, Texas, United States, 78229
Sponsors and Collaborators
The University of Texas Health Science Center at San Antonio
Novartis
Investigators
Principal Investigator: Ralph A DeFronzo, MD University of Texas
  More Information

No publications provided

ClinicalTrials.gov Identifier: NCT00230464     History of Changes
Other Study ID Numbers: CLAF237A2346
Study First Received: September 28, 2005
Last Updated: January 3, 2006
Health Authority: United States: Food and Drug Administration

Keywords provided by The University of Texas Health Science Center at San Antonio:
diabetes
rate of appearance of glucose
insulin secretion
glucagon

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Vildagliptin
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 16, 2013