Feed-Back Suppression of Meal-Induced Glucagon-like Peptide 1 (GLP-1) Secretion

NCT02749032 | Completed Phase 1

• 1 other identifier: DZBL-2010-1
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

Brief Summary

The present study is a phase I, single-centre, double-blind, randomized, cross-over (3 treatments, 3 treatment periods and 6 sequences), stratified (background medication: metformin vs. diet-only), placebo-controlled study, comparing periods lasting 6-9 days on treatment with repeated doses of vildagliptin, sitagliptin, or placebo, with wash-out periods between treatment periods lasting 21 days minimum. The study was designed to directly compare the effects of vildagliptin and sitagliptin on incretin hormone responses, glycaemia, and insulin as well as glucagon secretory responses in patients with type 2 diabetes.

Conditions

Type 2 Diabetes

Outcome Measures

Primary Outcomes (1)

• GLP-1 feedback inhibition

  Comparison of the percentage reduction or its reciprocal value (times 100) in total GLP-1 (secretion, incremental values above baseline, 0-240 min following meal ingestion) between vildagliptin and sitagliptin treatment relative to placebo treatment.

  0-240 min following meal ingestion

Secondary Outcomes (6)

• Relationship of the GLP-1 feedback inhibition [%]

  0-240 min following meal ingestion

• Differences in glucagon secretion [pmol/l]

  0-240 min following meal ingestion

• Differences in insulin secretory responses - Insulin [pmol/l]

  0-240 min following meal ingestion

• Differences in insulin secretory responses - c-peptide [pmol/l]

  0-240 min following meal ingestion

• Differences in glucose concentrations [mmol/l]

  0-240 min following meal ingestion

Study Arms (6)

Vildagliptin - stratum diet/exercise

ACTIVE COMPARATOR

Vildagliptin (50 mg per tablet) was administered orally twice daily (15 minutes prior to breakfast or test meal, on the last day of treatment period) and without a defined temporal relation to dinner in the evening, irrespective of the stratum defined by the background diabetes treatment. Mixed meal test were performed in the morning after an overnight fast.

Other: Mixed meal test; Drug: Vildagliptin; Other: Diet and exercise

Vildagliptin - stratum metformin

ACTIVE COMPARATOR

Vildagliptin (50 mg per tablet) was administered orally twice daily (15 minutes prior to breakfast or test meal, on the last day of treatment period) and without a defined temporal relation to dinner in the evening, irrespective of the stratum defined by the background diabetes treatment. Mixed meal test were performed in the morning after an overnight fast.

Other: Mixed meal test; Drug: Vildagliptin; Drug: Metformin

Sitagliptin - stratum diet/exercise

ACTIVE COMPARATOR

The dosage of sitagliptin depended on the stratum defined by the background diabetes medication. In patients treated with diet and exercise (no other glucose-.lowering medication), sitagliptin was given as one 100 mg in the morning (15 minutes prior to breakfast or the test meal, on the last day of the treatment period), and a corresponding placebo tablet was administered in the evening (no temporal relation to dinner required). Mixed meal test were performed in the morning after an overnight fast.

Other: Mixed meal test; Drug: Sitagliptin; Other: Diet and exercise

Sitagliptin - stratum metformin

ACTIVE COMPARATOR

In patients treated with metformin, sitagliptin (50 mg per tablet) was administered orally twice daily (15 minutes prior to breakfast or test meal, on the last day of treatment period) and without a defined temporal relation to dinner in the evening. Mixed meal test were performed in the morning after an overnight fast.

Other: Mixed meal test; Drug: Sitagliptin; Drug: Metformin

Placebo - stratum diet/exercise

PLACEBO COMPARATOR

Placebo was administered orally twice daily: 15 minutes prior to breakfast or the test meal on the last day of treatment period) and one dose in the evening (no temporal relation to dinner required). Mixed meal test were performed in the morning after an overnight fast.

Other: Mixed meal test; Drug: Placebo; Other: Diet and exercise

Placebo - stratum metformin

PLACEBO COMPARATOR

Placebo was administered orally twice daily: 15 minutes prior to breakfast or the test meal on the last day of treatment period) and one dose in the evening (no temporal relation to dinner required). Mixed meal test were performed in the morning after an overnight fast.

Other: Mixed meal test; Drug: Placebo; Drug: Metformin

Interventions

Mixed meal test OTHER

Mixed meal test were performed in the morning after an overnight fast. The standardized mixed meal was composed of 2 eggs (100 g), 1 slice (50 g) of whole grain rye bread, 1 slice (50 g) of rye flour bread, 10 g of fat-reduced margarine, 20 g of boiled ham, and 25 g of diet jam, amounting to 450 kcal, 50 % carbohydrate, 20 % protein, and 30 % fat (based on calorie count). Patients were allowed to drink tea (black or fruit-based) or de-caffeinated coffee ad libitum.

Placebo - stratum diet/exercise; Placebo - stratum metformin; Sitagliptin - stratum diet/exercise; Sitagliptin - stratum metformin; Vildagliptin - stratum diet/exercise; Vildagliptin - stratum metformin

Vildagliptin DRUG

Vildagliptin (50 mg per tablet) was administered orally twice daily (15 minutes prior to breakfast or test meal, on the last day of treatment period) and without a defined temporal relation to dinner in the evening, irrespective of the stratum defined by the background diabetes treatment.

Vildagliptin - stratum diet/exercise; Vildagliptin - stratum metformin

Sitagliptin DRUG

The dosage of sitagliptin depended on the stratum defined by the background diabetes medication. In patients treated with diet and exercise (no other glucose-.lowering medication), sitagliptin was given as one 100 mg in the morning (15 minutes prior to breakfast or the test meal, on the last day of the treatment period), and a corresponding placebo tablet was administered in the evening (no temporal relation to dinner required).

Sitagliptin - stratum diet/exercise; Sitagliptin - stratum metformin

Placebo DRUG

Placebo was administered orally twice daily: 15 minutes prior to breakfast or the test meal on the last day of treatment period) and one dose in the evening (no temporal relation to dinner required).

Placebo - stratum diet/exercise; Placebo - stratum metformin

Metformin DRUG

For patients continuing with pre-existing metformin treatment, 1000 mg film coated tablets from commercial sources. In half of the patients (stratum: metformin as background medication), metformin was administered orally twice daily at 1000 mg of active compound during of after breakfast and dinner.

Placebo - stratum metformin; Sitagliptin - stratum metformin; Vildagliptin - stratum metformin

Diet and exercise OTHER

Patients treated their diabetes mellitus type 2 with diet/exercise only

Placebo - stratum diet/exercise; Sitagliptin - stratum diet/exercise; Vildagliptin - stratum diet/exercise

Eligibility Criteria

• Age: 30 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• diabetes mellitus type 2 for more than one year, as defined by the American Diabetes Association
• body-mass-index between 20.0 and 40.0 kg/m² (inclusive),
• glycohaemoglobin (HbA1c) ≤ 8.5%,
• normal vital signs after 10 minutes resting in the supine position: systolic blood pressure 96 mmHg -159 mmHg; diastolic blood pressure 46 mmHg-99 mmHg; heart rate 46-99 bpm
• laboratory parameters within the normal range, or abnormalities judged to be clinically irrelevant by the investigator (serum estimated glomerular filtration rate was enforced to be \> 60 ml/min; hepatic enzymes and bilirubin (unless the subject has documented Gilbert syndrome) had to be \> 3-fold the upper limit of normal)
• women of childbearing potential (less than two years post-menopausal or not surgically sterile for more than 3 months), had to prove a negative serum β-human chorionic gonadotropin (HCG) pregnancy test at screening and a negative urine β-HCG pregnancy test at day 1 on each of the treatment periods, had to use a highly effective method of birth control (failure rate less than 1% per year)
• normal or clinically irrelevant findings in medical history and physical examination

You may not qualify if:

• any glucose-lowering drug therapy other than metformin during 3 months before the first treatment period
• any history or presence of clinically relevant cardiovascular, pulmonary, gastro-intestinal, hepatic, renal, metabolic (apart from diabetes mellitus type 2), haematological, neurological, psychiatric, systemic, ocular, gynaecologic, or infectious disease; any acute infectious disease or signs of acute illness
• symptoms of a clinically significant illness in the 3 months before the study, which, according to the investigator's opinion, could interfere with the purposes of the study
• congestive heart failure of New York Heart Association (NYHA) functional class III-IV
• Regular use of any medication other than metformin in the last month before study start with the exception of thyroid hormones, lipid-lowering and antihypertensive drugs, and, if female, with the exception of hormonal contraception or menopausal hormone replacement therapy
• participation in a trial with any investigational drug during the past three months
• presence or history of a drug allergy or clinically significant allergic disease according to the investigator's judgment including any known hypersensitivity to DPP-4 inhibitors
• presence of drug or alcohol abuse (alcohol consumption \> 40 grams / day)
• if female, pregnancy (defined as positive β-HCG blood test), breast-feeding

Sponsors & Collaborators

• Michael A. Nauck: lead

Study Sites (1)

Diabeteszentrum Bad Lauterberg

Bad Lauterberg im Harz, Lower Saxony, 37431, Germany

Location

MeSH Terms

Conditions

Diabetes Mellitus, Type 2

Interventions

Vildagliptin; Sitagliptin Phosphate; Metformin; Diet; Exercise

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Nitriles; Organic Chemicals; Pyrrolidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Triazoles; Azoles; Pyrazines; Biguanides; Guanidines; Amidines; Nutritional Physiological Phenomena; Diet, Food, and Nutrition; Physiological Phenomena; Motor Activity; Movement; Musculoskeletal Physiological Phenomena; Musculoskeletal and Neural Physiological Phenomena

Study Officials

• Michael A. Nauck, Prof.

  Diabeteszentrum Bad Lauterberg

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Prof. Dr. med. Michael A. Nauck

Study Record Dates

• First Submitted: April 8, 2016
• First Posted: April 22, 2016
• Study Start: November 1, 2011
• Primary Completion: March 1, 2014
• Last Updated: April 22, 2016

Record last verified: 2016-04

Locations

DE (1)