Antidiabetic Effects of Adding a DPP-4 Inhibitor to Pre-Existing Treatment With an Incretin Mimetic in Patients With T2D
Condition: Type 2 Diabetes
MeSH terms: Diabetes Mellitus, Type 2
Intervention: Placebo; Mixed meal test; Liraglutide; Sitagliptin
Intervention description: Patients administered a single dose of placebo during a mixed meal challenge.; 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; 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.; Patients administered a single dose of Sitagliptin during a mixed meal challenge.
Intervention MeSH terms: Sitagliptin Phosphate; Liraglutide
Phase: Phase 3
Study type: Interventional
Primary purpose: Basic Science
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Enrollment: 16.0
Sex: All
Minimum age: 25 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: Incretin, DPP-4 inhibitor

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
    

Eligibility criteria:

        Inclusion Criteria:

          -  Signed & dated written informed consent

          -  Male & female subjects with a diagnosis of type 2 diabetes mellitus according to ADA
             criteria at least 4 months prior to screening

          -  Medical history without major pathology (with the exception of type 2 diabetes) as
             judged by the investigator

          -  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.

          -  Age: 25 - 75 years, both inclusive

          -  Body mass index (BMI): 22 - 40kg/m^2, both inclusive

          -  HbA1c ≥ 6.5 and ≤ 8.5% (≥ 7.0 and ≤ 8.5% for patients without previous liraglutide
             treatment)

          -  Female must be post-menopausal, surgically sterilized or practicing an effective birth
             control

        Exclusion criteria

          -  Subjects with type 1 diabetes, maturity onset diabetes of the young (MODY) or
             secondary forms of diabetes such as due to pancreatitis

          -  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)

          -  Treatment with any hypoglycaemic medication other than metformin and liraglutide
             within one month prior to screening

          -  Known of diabetic gastroparesis and / or prokinetic therapy

          -  Subjects that underwent surgery of the upper gastrointestinal tract

          -  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

          -  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

          -  A suspicion of medullary thyroid cancer or a multiple endocrine neoplasia

          -  A personal or family history of medullar thyroid cancer or a multiple endocrine
             neoplasia

          -  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

          -  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

          -  Marked diabetic complications: severe autonomic or sensory neuropathy including
             previously diagnosed gastroparesis; proliferative retinopathy

          -  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

          -  Clinically significant vital signs including known bradycardia with pulse rate <
             50/min or 12-lead ECG findings including QTc (corrected QT interval) > 450 msec for
             males or QTc > 470 msec for women

          -  Clinically significant abnormal haematology, biochemistry, lipids, or urinalysis or
             coagulation screening tests, as judged by the Investigator

          -  Moderate or severe renal dysfunction defined as an estimated creatinine clearance
             (MDRD equation) GFR (glomerular filtration rate) <50 ml/min.

          -  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 (upper Limit of normal). Isolated mild rise in bilirubin considered
             to be due to Gilbert's condition is allowed

          -  Uncontrolled high blood pressure (DBP (diastolic blood pressure) > 95 mmHg and/or SBP
             (systolic blood pressure) > 160 mmHg), unless clearly documented to be white-coat
             hypertension

          -  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

          -  History of relevant drug and/or food allergies or a history of severe anaphylactic
             reaction

          -  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)

          -  Use of concomitant medication which would be likely to interact with metformin,
             sitagliptin or liraglutide (according to the subject information leaflet).
             Participation in another study within the 3 months preceding screening or 5-half-lives
             of drug studied, whichever is longer, prior to study drug administration

          -  Malignancy within 5 years of study start, except for successfully treated local basal
             cell carcinomas

          -  Known to be positive for Hepatitis B surface antigen or Hepatitis C antibodies (or
             diagnosed with active hepatitis according to local practice)

          -  Subject who has donated or lost > 500 mL blood within 3 months prior to screening &
             has a Hb < 14 g/dl at screening

          -  History of hypersensitivity to the study drug or any of the excipients or to medicinal
             products with similar chemical structures

          -  Veins unsuitable for repeated venipuncture