Type 2 diabetes mellitus MedDRA version: 20.1 Level: LLT Classification code 10045242 Term: Type II diabetes mellitus System Organ Class: 100000004861
Conditions
Interventions
Trade Name: Ezetimibe
Product Name: Ezetimibe
Product Code: Ezetimibe
Pharmaceutical Form: Film-coated tablet
Sponsors
Academic Medical Center
Eligibility
Sex/Gender
Male
Inclusion criteria
Inclusion criteria: In order to be eligible to participate in this study, a subject must meet all of the following criteria: - Ability to provide informed consent - Age: 18 years or older at the time of signing the informed consent - Male Specific inclusion criteria for the healthy lean subject group: - BMI between 18,5-25 kg/m2 or BMI between 25 and 30 kg/m2 with a waist circumference between between 79 cm and 94 cm - HOMA-IR index: = 2.0 (measured as fasting insulin (pmol/L) x fasting glucose (mmol/L)) / 135) Specific inclusion criteria for the type 2 diabetes mellitus (T2D) patient group: - T2D treated with diet and/or medication only (medication not changed in the past 3 months) - HbA1c 53-64 mmol/mol - BMI above 25 kg/m2 Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 40 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 40
Exclusion criteria
Exclusion criteria: A potential subject who meets any of the following criteria will be excluded from participation in this study: - Use of medication that interferes with bile acid metabolism (colesevelam, colestimide, ursodeoxycholic acid). - Diabetes treatment with dipeptidyl peptidase-4 inhibitors, GLP-1 receptor agonists or insulin - Hypercholesterolemia treatment with statins or fibrates unless on a stable dose for at least 3 months prior to screening - Use of nicotinic acid or derivates of nicotinic acid within 4 weeks prior to screening - Use of other drugs such as the following: vitamin K antagonists, ciclosporine, antacids containing aluminium hydroxide or aluminium oxide - Cholecystectomy - Gastro-intestinal disorders, including gallstone disease - Nefropathy checked by blood chemistry (creatinine, eGFR) - Liver disease checked by blood chemistry (ASAT, ALAT, GGT, AF, bilirubin) - Weight increase or decrease >10% in previous 3 months - Alcohol use >3 units/day - Tobacco use - XTC, cannabis, cocaine or opioids abuse - Likely to leave the study before its completion - Participation in other intervention studies
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To study the effects of gDCA on postprandial GLP-1 secretion, inflammation responses and hyperlipidemia in healthy lean male subjects and male T2D patients. The primary objective of phase 1 is to determine safety of long-term gDCA administration in healthy volunteers. ;Secondary Objective: The secondary objectives are to evaluate the effect of gDCA and ezetimibe on cholesterol elimination assessed as total faecal sterol concentration and plasma lipid profile/composition and the effect of different formulations on the gDCA bioavailability. ;Primary end point(s): Phase 1 The first phase of the study will be a pilot study where we investigate the metabolism and safety of long-term administration of gDCA compared to long-term administration of gDCA formulated in enteric-coated capsules (enteric-coated gDCA). In the past no safety study is performed or published investigating the metabolism of prolonged administration of (enteric-coated) glycine conjugated gDCA. Therefore we will include 20 healthy male volunteers in this phase. Ten subjects will receive 10 mg/kg/day gDCA for 30 days, the other group (N=10) will receive 10 mg/kg/day enteric-coated gDCA for 30 days. Subjects undergo a MMT at day 1, day 15 and day 30 in the AMC. After the last subject completed the study, the data will be analyses in the laboratory and discussed by the DSMB. After advise of the DSMB the project team will decide on phase 2. Phase 2 At the second phase we include 10 T2D male patients. The 10 T2D patients will receive 10 mg/kg/day gDCA or enteric-coated gDCA. The dosage and which form of gDCA (normal or enteric-coated) will be based on the results of the pilot study (phase 1) regarding safety. Subjects undergo a MMT at day 1, day 15 and day 30 in the AMC. Phase 3 In the third (final) phase we want to include 10 T2D male patients. The 10 T2D patients receive 10 mg/kg/day (enteric-coated) gDCA and 20 mg ezetimibe per day for 30 days. Subjects undergo a MMT at day 1, day | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): • Bile acid metabolism - CA, CDCA, DCA, LCA and conjugates, FGF19,C4) • Glucoregulatory and gut hormones - Glucose, glucagon and c-peptide • Resting energy expenditure - Basal metabolic rate - kcal/kg/day, protein-, carbohydrate- and fat oxidation) • Body composition (% fat mass and lean mass) • Microbiome - Gut microbiota composition • Appetite - Visual analogue scale scores + quantity of food consumed •Total faecal sterol concentration - FNS + faecal bile acid concentration • Bioavailability/pharmacokinetic parameters - Clearance, volume of distribution, absorption rate, mean residence time, elimination half-life between gDCA and enteric-coated gDCA. ;Timepoint(s) of evaluation of this end point: Visit 1: Day 1: baseline mixed meal test + stool sampling Visit 2: Day 15: second mixed meal test + stool sampling Visit 3: Day 31: third mixed meal test + stool sampling | — |
Countries
Netherlands
Contacts
Public ContactM.R. Soeters principal investigator
Academic Medical Center
Outcome results
None listed