Antidiabetic Effects of Adding a DPP-4 Inhibitor (Sitagliptin) to Pre-Existing Treatment With an Incretin Mimetic (Liraglutide) in Patients With Type 2 Diabetes Treated With Metformin

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2013 by Diabeteszentrum Bad Lauterberg im Harz
Sponsor:
Information provided by (Responsible Party):
Michael A. Nauck, Diabeteszentrum Bad Lauterberg im Harz
ClinicalTrials.gov Identifier:
NCT01937598
First received: August 27, 2013
Last updated: September 4, 2013
Last verified: September 2013
  Purpose

Objectives: To quantify differences in control of glycemia (primary objective) and the secretion of endogenous incretin hormones (secondary objective) comparing sitagliptin or placebo added to pre-existing therapy with liraglutide and metformin


Condition Intervention Phase
Type 2 Diabetes
Drug: Sitagliptin
Drug: Placebo
Other: Mixed meal test
Drug: Liraglutide
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Basic Science
Official Title: Antidiabetic Effects of Adding a DPP-4 Inhibitor (Sitagliptin) to Pre-Existing Treatment With an Incretin Mimetic (Liraglutide) in Patients With Type 2 Diabetes Treated With Metformin

Resource links provided by NLM:


Further study details as provided by Diabeteszentrum Bad Lauterberg im Harz:

Primary Outcome Measures:
  • Incremental area under the plasma glucose (BG) concentration-time profile (AUC) [ Time Frame: Approximately 6 weeks (range 9 - 60 days / 8.5 weeks) ] [ Designated as safety issue: No ]
    Incremental area under the plasma glucose (BG) concentration-time profile (AUC) immediately before to 300 min after a mixed meal test. In addition, the time course of BG values will be analysed with an ANCOVA model for repeated measurements with placebo baseline values as covariate.


Secondary Outcome Measures:
  • AUC plasma glucose [ Time Frame: Approximately 6 weeks (range 9 - 60 days / 8.5 weeks) ] [ Designated as safety issue: No ]
    Incremental AUC from 0 to 300 min

  • AUC insulin [ Time Frame: Approximately 6 weeks (range 9 - 60 days / 8.5 weeks) ] [ Designated as safety issue: No ]
  • AUC C-peptide [ Time Frame: Approximately 6 weeks (range 9 - 60 days / 8.5 weeks) ] [ Designated as safety issue: No ]
  • AUC glucagon [ Time Frame: Approximately 6 weeks (range 9 - 60 days / 8.5 weeks) ] [ Designated as safety issue: No ]
  • AUC total GLP-1 [ Time Frame: Approximately 6 weeks (range 9 - 60 days / 8.5 weeks) ] [ Designated as safety issue: No ]
  • AUC total GIP [ Time Frame: Approximately 6 weeks (range 9 - 60 days / 8.5 weeks) ] [ Designated as safety issue: No ]
  • AUC active GLP-1 [ Time Frame: Approximately 6 weeks (range 9 - 60 days / 8.5 weeks) ] [ Designated as safety issue: No ]
  • AUC active GIP [ Time Frame: Approximately 6 weeks (range 9 - 60 days / 8.5 weeks) ] [ Designated as safety issue: No ]
  • Velocity of gastric emptying [ Time Frame: Approximately 6 weeks (range 9 - 60 days / 8.5 weeks) ] [ Designated as safety issue: No ]
    velocity of gastric emptying as determined through 13C-breath test with t½, lag time, gastric emptying coefficient and time course as main outcome parameters.

  • plasma glucose concentration 120 min after starting the meal; [ Time Frame: Approximately 6 weeks (range 9 - 60 days / 8.5 weeks) ] [ Designated as safety issue: No ]

Estimated Enrollment: 16
Study Start Date: August 2013
Estimated Study Completion Date: February 2015
Estimated Primary Completion Date: February 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Sitagliptin
Substance: Sitagliptin phosphate 1H2O Pharmaceutical form: tablets Source: MSD SHARP & DOHME GMBH, Doses: 100 mg, Route of administration: p.o. as a tablet
Drug: Sitagliptin Other: Mixed meal test
Subjects will be instructed to consume the mixed meal test within 20 minutes. The exact start and stop time of the mixed meal test consumption will be recorded in the CRF. The mixed meal test procedures will be identical for all subjects randomised in the study. To detect the plasma glucose excursion after mixed meal test, plasma glucose will be closely monitored
Drug: Liraglutide
Patients on metformin monotherapy will, after screening and randomization, enter a run-in period of 2 weeks with the additional treatment of liraglutide (0.6 mg/d for 1 week followed by 1.2 mg/d for another week) that will be continued for the entire duration of the study.
Other Names:
  • Liraglutide
  • (Source Victoza Prescribing Information, issued April 6, 2012, Version 3)
Placebo Comparator: Placebo
Substance: Placebo (sitagliptin) Pharmaceutical form: tablets Source: MSD SHARP & DOHME GMBH Doses: - Route of administration: p.o. as tablets
Drug: Placebo Other: Mixed meal test
Subjects will be instructed to consume the mixed meal test within 20 minutes. The exact start and stop time of the mixed meal test consumption will be recorded in the CRF. The mixed meal test procedures will be identical for all subjects randomised in the study. To detect the plasma glucose excursion after mixed meal test, plasma glucose will be closely monitored
Drug: Liraglutide
Patients on metformin monotherapy will, after screening and randomization, enter a run-in period of 2 weeks with the additional treatment of liraglutide (0.6 mg/d for 1 week followed by 1.2 mg/d for another week) that will be continued for the entire duration of the study.
Other Names:
  • Liraglutide
  • (Source Victoza Prescribing Information, issued April 6, 2012, Version 3)

Detailed Description:

This is a double blind, controlled, cross-over comparison of adding sitagliptin (or placebo) to pre-existing metformin+liraglutide therapy. Patients with type 2 diabetes mellitus (T2DM) on pre-existing treatment with metformin (≥ 1500 mg/d) monotherapy or metformin plus liraglutide (1.2 mg/d) will be studied. Patients on metformin monotherapy will, after screening and randomization, enter a run-in period of 2 weeks with the additional treatment of liraglutide (0.6 mg/d for 1 week followed by 1.2 mg/d for another week). At the end of this 2 weeks therapy, a mixed meal challenge will take place, with the assessment of glucose and hormone responses (insulin, C-peptide, glucagon, GLP-1, GIP) and gastric emptying as measured by 13C-octanoate breath tests. Prior to the meal tests, liraglutide will be administered at a dose of 1.2 mg per injection, which is the recommended dose for treatment. Sitagliptin will be used at a dose of 100 mg, which is recommended for clinical use.

  Eligibility

Ages Eligible for Study:   25 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Signed and dated written informed consent obtained before any study-related activities
  2. Male and female subjects with a diagnosis of type 2 diabetes mellitus according to ADA criteria at least 4 months prior to screening
  3. Medical history without major pathology (with the exception of type 2 diabetes) as judged by the investigator
  4. On a stable regimen of metformin for at least 1 month and liraglutide 1.2 mg for at least 1 week at the time-point of randomisation.
  5. Aged between 25 and 75 years, both inclusive
  6. Body mass index (BMI) between 22 and 40kg/m2, both inclusive
  7. HbA1c ≥ 6.5 and ≤ 8.5% (≥ 7.0 and ≤ 8.5% for patients without previous liraglutide treatment)
  8. Female must be post-menopausal, surgically sterilized or practicing an effective birth control

Exclusion criteria

  1. Subjects with type 1 diabetes, maturity onset diabetes of the young (MODY) or secondary forms of diabetes such as due to pancreatitis
  2. Current or previous treatment with insulin therapy (except for treatment at diabetes' diagnosis, within a clinical trial, for surgical procedures or during an acute illness, and no insulin administration within the 6 months before screening)
  3. Treatment with any hypoglycaemic medication other than metformin and liraglutide within one month prior to screening
  4. Subjects with known diabetic gastroparesis and / or prokinetic therapy
  5. Subjects that underwent surgery of the upper gastrointestinal tract
  6. Women who are pregnant, intending to become pregnant during the study period, currently lactating females, or women of child-bearing potential not using highly effective, medically approved birth control methods
  7. Subjects with any severe medical or surgical history of conditions likely to confound study assessments or study endpoints, for example but not limited to haemoglobinopathies, inflammatory bowel disease, cystic fibrosis, bariatric surgery and/or any surgery shortening the intestine, history of lactose intolerance, lactose- or glucose-galactose-malabsorption
  8. Subjects with a suspicion of medullary thyroid cancer or a multiple endocrine neoplasia
  9. Subjects with a personal or family history of medullar thyroid cancer or a multiple endocrine neoplasia
  10. Serious and/or unstable coronary heart disease (unstable angina, myocardial infarction within the preceding 6 months), congestive heart failure of New York Heart Association Class III or worse (severe limitation of physical activity; physical activity of low intensity resulting in fatigue, palpitation, or dyspnoea), second/third degree heart block, superior vena cava syndrome, uncontrolled hypertension, history of congenital QT-syndrome within family, history of stroke (within the preceding 6 months) or serious peripheral vascular disease
  11. History of arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia, or uncontrolled atrial fibrillation) that is symptomatic or requires treatment (grade 3), left bundle branch block, or asymptomatic sustained ventricular tachycardia are not allowed
  12. Marked diabetic complications: severe autonomic or sensory neuropathy including previously diagnosed gastroparesis; proliferative retinopathy
  13. Any respiratory disease leading to respiratory insufficiency and/or depression including but not limited to clinically significant: bronchial asthma, chronic obstructive pulmonary disease, that might impact to the breath test, as judged by the investigator
  14. Clinically significant vital signs including known bradycardia with pulse rate < 50/min or 12-lead ECG findings including QTc > 450 msec for males or QTc > 470 msec for women
  15. Clinically significant abnormal haematology, biochemistry, lipids, or urinalysis or coagulation screening tests, as judged by the Investigator
  16. Moderate or severe renal dysfunction defined as an estimated creatinine clearance (MDRD equation) GFR <50 ml/min.
  17. Clinical or laboratory evidence of hepatic dysfunction or disease; laboratory evidence defined as any of the following parameters: alkaline phosphatase, ALT, AST or bilirubin > 3x ULN. Isolated mild rise in bilirubin considered to be due to Gilbert's condition is allowed
  18. Uncontrolled high blood pressure (DBP > 95 mmHg and/or SBP > 160 mmHg), unless clearly documented to be white-coat hypertension
  19. History of any psychiatric condition that might impair the subject's ability to understand or to comply with the requirements of the study or to provide informed consent
  20. History of relevant drug and/or food allergies or a history of severe anaphylactic reaction
  21. Currently active or history of alcohol abuse (defined as an intake of more than 24 units of alcohol per week; one unit of alcohol equals approximately 250 mL of beer, 100 mL of wine or 35 mL of spirits) or drug addiction (including soft drugs like cannabis products)
  22. Use of concomitant medication which would be likely to interact with metformin, sitagliptin or liraglutide (according to the subject information leaflet). Participation in another clinical trial within the 3 months preceding screening or 5-half-lives of drug studied, whichever is longer, prior to study medication administration
  23. Malignancy within 5 years of study start, except for successfully treated local basal cell carcinomas
  24. Subjects known to be positive for Hepatitis B surface antigen or Hepatitis C antibodies (or diagnosed with active hepatitis according to local practice)
  25. Subject who has donated or lost more than 500 mL blood within 3 months prior to screening and has an Hb < 14 g/dl at screening
  26. History of hypersensitivity to the study medication or any of the excipients or to medicinal products with similar chemical structures
  27. Veins unsuitable for repeated venipuncture
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01937598

Contacts
Contact: Michael A. Nauck, Prof. Dr. med. nauck@diabeteszentrum.de

Locations
Germany
Diabeteszentrum Bad Lauterberg Recruiting
Bad Lauterberg, Germany, 37431
Contact: Michael A. Nauck       nauck@diabeteszentrum.de   
Sub-Investigator: Oleg Baranov         
Sponsors and Collaborators
Michael A. Nauck
Investigators
Principal Investigator: Michael A. Nauck, Prof. Dr. med. Diabeteszentrum Bad Lauterberg
  More Information

No publications provided

Responsible Party: Michael A. Nauck, Prof. Dr. med., Diabeteszentrum Bad Lauterberg im Harz
ClinicalTrials.gov Identifier: NCT01937598     History of Changes
Other Study ID Numbers: 120-0569-DZBL-2012, 2013-001764-35
Study First Received: August 27, 2013
Last Updated: September 4, 2013
Health Authority: Germany: Ethics Commission
Germany: Federal Institute for Drugs and Medical Devices

Keywords provided by Diabeteszentrum Bad Lauterberg im Harz:
Incretin, DPP-4 inhibitor

Additional relevant MeSH terms:
Diabetes Mellitus, Type 2
Diabetes Mellitus
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Sitagliptin
Liraglutide
Metformin
Hypoglycemic Agents
Glucagon-Like Peptide 1
Incretins
Dipeptidyl-Peptidase IV Inhibitors
Physiological Effects of Drugs
Pharmacologic Actions
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on September 16, 2014