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

Type 2 Diabetes Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT01937598
• Other study ID #: 120-0569-DZBL-2012
• Secondary ID: 2013-001764-35
• Status: Recruiting
• Phase: Phase 3
• First received: August 27, 2013
• Last updated: September 4, 2013
• Start date: August 2013
• Est. completion date: February 2015

Study information

• Verified date: September 2013
• Source: Diabeteszentrum Bad Lauterberg im Harz
• Contact: Michael A. Nauck, Prof. Dr. med.
• Email: nauck[@]diabeteszentrum.de
• Is FDA regulated: No
• Health authority: Germany: Ethics CommissionGermany: Federal Institute for Drugs and Medical Devices
• Study type: Interventional

Clinical Trial Summary

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

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 16
• Est. completion date: February 2015
• Est. primary completion date: February 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 25 Years to 75 Years

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Basic Science

Related Conditions & MeSH terms

• Diabetes Mellitus, Type 2
• Type 2 Diabetes

Intervention

Drug:
• Sitagliptin

• 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.

Locations

Country	Name	City	State
Germany	Diabeteszentrum Bad Lauterberg	Bad Lauterberg

Sponsors (1)

Lead Sponsor	Collaborator
Michael A. Nauck

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incremental area under the plasma glucose (BG) concentration-time profile (AUC)	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.	Approximately 6 weeks (range 9 - 60 days / 8.5 weeks)	No
Secondary	AUC plasma glucose	Incremental AUC from 0 to 300 min	Approximately 6 weeks (range 9 - 60 days / 8.5 weeks)	No
Secondary	AUC insulin		Approximately 6 weeks (range 9 - 60 days / 8.5 weeks)	No
Secondary	AUC C-peptide		Approximately 6 weeks (range 9 - 60 days / 8.5 weeks)	No
Secondary	AUC glucagon		Approximately 6 weeks (range 9 - 60 days / 8.5 weeks)	No
Secondary	AUC total GLP-1		Approximately 6 weeks (range 9 - 60 days / 8.5 weeks)	No
Secondary	AUC total GIP		Approximately 6 weeks (range 9 - 60 days / 8.5 weeks)	No
Secondary	AUC active GLP-1		Approximately 6 weeks (range 9 - 60 days / 8.5 weeks)	No
Secondary	AUC active GIP		Approximately 6 weeks (range 9 - 60 days / 8.5 weeks)	No
Secondary	Velocity of gastric emptying	velocity of gastric emptying as determined through 13C-breath test with t½, lag time, gastric emptying coefficient and time course as main outcome parameters.	Approximately 6 weeks (range 9 - 60 days / 8.5 weeks)	No
Secondary	plasma glucose concentration 120 min after starting the meal;		Approximately 6 weeks (range 9 - 60 days / 8.5 weeks)	No