A Phase 4 interventional study of CRCHUM-MT cocktail in Type 2 Diabetes, sponsored by Centre hospitalier de l'Université de Montréal (CHUM). Completed at 1 site in Canada. Open to participants aged 18 Years to 80 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2019-07-23.
Sponsored by Centre hospitalier de l'Université de Montréal (CHUM) · Phase 4, Interventional, and Basic science
Type 2 diabetes (T2D) could modulate CYP450 activities involved in drug-metabolism and cardiovascular homeostasis. We propose to carry out, for the first time, a comprehensive characterization of the effects of T2D on the expression and activity of major CYP450s. In our studies, patients with T2D will be studied since hyperglycaemia and/or hyperinsulinemia are believed to modulate CYP450s. This vicious cycle puts patients at risk of micro- and macro-vascular complications and inadequately controlled T2D due to high intersubject variability in drug disposition and action.
Characterization of the effects of T2D on drug metabolism capacity will be performed using a cocktail of CYP450 probe drugs.
CYP450 phenotype will be determined in 3 groups of patients (n=126 patients): 1) 42 T2D patients with good glycemic control; 2) 42 T2D patients with poor glycemic control; and 3) 42 non-T2D healthy subjects following a single oral administration of a cocktail of CYP450 probe drugs. Subjects will receive the CRCHUM-MT cocktail consisting of caffeine (CYP1A2), bupropion (CYP2B6), tolbutamide (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), midazolam (CYP3A4/5) and chlorxozaxone (which will be administered separately) (CYP2E1). Serial blood samples will be drawn and urine collected. Metabolic ratios will be calculated and compared between three groups of subjects. Other co-variables to be studied include T2D biomarkers at baseline (glucose, insulin, HbA1c), medications, genetic polymorphisms and inflammatory markers.
Our cocktail probe drug approach should allow us to demonstrate the effects of T2D on the activity of major CYP450s. Moreover, this project will indicate to us whether glycemic control should be considered as a covariate of intersubject variability in drug metabolism capacity.
Patients with type 2 diabetes (T2D) require various therapeutic approaches (diet, exercise and drugs) to ensure glycaemic control while minimizing the risk of hypoglycaemia. T2D is also associated with vascular morbidities necessitating multiple drugs to prevent cardiovascular complications. Clinical practice reveals that T2D patients show highly variable responses to different drugs. Variable drug dosages and effects are observed for drugs such as clopidogrel, warfarin, cyclosporine and tacrolimus, as well as for anti-hypertensive, cholesterol lowering and antidiabetic drugs. These observations strongly suggest that T2D modulates factors regulating drug disposition and/or drug effects.
The hypothesis underlying this proposal is: T2D and its abnormalities alter the expression and activities of CYP450s involved in the disposition of drugs used to treat T2D and associated comorbidities.
The overall objective of this project is to investigate the effects of T2D on the activity of several CYP450 isozymes. Primary objective: To compare CYP450 activities between diabetic and non-diabetic subjects following a single oral administration of a cocktail of CYP450 probe drugs. The secondary objective: To evaluate and compare CYP450 activities according to the glycemic control (T2D patients with good glycemic control; T2D patients with poor glycemic control; and non-diabetic healthy subjects).
Study design; Patients (n=126) will be recruited to constitute 3 groups: Group I, 42 confirmed T2D with HbA1c ≤7.0; Group II, 42 patients with poor glycemic control HbA1c>7.0, and Group III, 42 sexed-matched non-T2D healthy subjects. This design will allow us to compare CYP450 activities between T2D patients with good glycemic control, T2D patients with poor glycemic control, and non-diabetic healthy subjects. Participants will be ≥18 years old, with a body weight index ≤35, and be non-smokers (>3 months). Subjects will be recruited at the CHUM outpatient clinic. The T2D diagnosis will be established according to the Canadian clinical guidelines. After an overnight fast, participants will be admitted to the CRCHUM's Clinical Research Unit (they will be not hospitalized). Subjects will receive the CRCHUM-MT cocktail; 100mg caffeine, 100mg bupropion, 250mg tolbutamide, 20mg omeprazole, 30mg dextromethorphan and 2mg midazolam to phenotype for CYP1A2, 2B6, 2C9, 2C19, 2B6, 2D6 and 3A4/5, respectively. Serial blood samples will be drawn and urine collected over 8 hours following drug administration. At the end of study day, subjects will be discharged from the CRCHUM's Clinical Research Unit and an oral 250mg dose of chlorzoxazone (CYP2E1) will be given and urine collected overnight for 12 hours.
A blood sample will be taken for pharmacogenetic analysis for relevant drug metabolizing enzymes. Additional blood samples will be collected just before the administration of the cocktail to measure insulin, glycaemia and HbA1c levels, biomarkers and inflammatory markers.
The subjects will be instructed not to take any medication, caffeine or theobromine containing products on the morning of study day. Their regular medication will be administered 4 hours after the administration of the cocktail if indicated. The subjects in whom our probe marker drugs are used daily will still be enrolled as metabolic ratios and will be determined to establish CYP450 activities.
Pharmacokinetic parameters such as oral clearance, metabolic clearance and renal clearance will be determined by noncompartmental analysis. Metabolic ratios will be calculated and compared between three groups of subjects.
9,359 studies on the registry are indexed under Diabetes Mellitus, Type 2; 1,318 are open to participants now.
This study's enrollment of 73 is close to the median of 80 across 7,525 interventional studies indexed under Diabetes Mellitus, Type 2.
Browse Diabetes Mellitus, Type 2 studies →Centre hospitalier de l'Université de Montréal (CHUM) is the lead sponsor of 370 studies on the registry; 110 are open to participants now.
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Exclusion Criteria:
CRCHUM-MT cocktail; a single oral dose of the CRCHUM-MT cocktail will be administered; 100mg caffeine, 75mg bupropion, 150mg tolbutamide, 20mg omeprazole, 30mg dextromethorphan, 2mg midazolam and at night, one oral 250mg dose of chlorzoxazone will be taken separately.
Drug: CRCHUM-MT cocktail
CRCHUM-MT cocktail; a single oral dose of the CRCHUM-MT cocktail will be administered; 100mg caffeine, 75mg bupropion, 150mg tolbutamide, 20mg omeprazole, 30mg dextromethorphan, 2mg midazolam and at night, one oral 250mg dose of chlorzoxazone will be taken separately.
Drug: CRCHUM-MT cocktail
CRCHUM-MT cocktail; a single oral dose of the CRCHUM-MT cocktail will be administered; 100mg caffeine, 75mg bupropion, 150mg tolbutamide, 20mg omeprazole, 30mg dextromethorphan, 2mg midazolam and at night, one oral 250mg dose of chlorzoxazone will be taken separately.
Drug: CRCHUM-MT cocktail
Also known as: omeprazole, Losec, caffeine, Wake-up, bupropion, Wellbutrin, Zyban, dextromethorphan, midazolam, tolbutamide, chlorzoxazone, Acetazone
Metabolic ratio
The metabolite/probe-drug (parent compound) ratio will be used as a metabolic index of CYP activity.
Time frame: 12 hours
Oral clearance
CLo will be determined by noncompartmental analysis
Time frame: 12 hours
Renal clearance
CLr will be determined by noncompartmental analysis (Ae0-t of compound/AUC0-t compound)
Time frame: 12 hours
This study is completed, as verified in Jul 2017. You cannot join it, but the record below documents what was studied.
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Centre hospitalier de l'Université de Montréal (CHUM)