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Type 2 DiabetesPhase 4NCT02291666

Evaluation of CYP450 Activities in Diabetic Patients vs. Non-diabetic Subjects

A Phase 4 study testing CRCHUM-MT cocktail in people with Type 2 Diabetes, run by Centre hospitalier de l'Université de Montréal (CHUM) at 1 site in Canada.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

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. Read more about this study

Who is it for?
Ages 18 to 80 yearsHealthy volunteers can take part
Conditions the study is for
Type 2 Diabetes
What is being tested?
CRCHUM-MT cocktail
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
73 participants
Where
1 siteCanada
Study dates
Apr 2015to Jul 2019
Phase
Phase 4
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 80 years
  • All sexes
  • Healthy volunteers accepted
  • Adult, Older adult

Who may be able to join

  • Participants will be ≥18 years old
  • Body weight index ≤35,
  • Non-smokers (>3 months)
  • Patients with type 2 diabetes and good glycemic control (A1C<7) or poor glycemic control (A1C>7.0) and healthy non-diabetic subjects will be eligible.

Who cannot join

  • Subjects with estimated glomerular filtration (MDRD) <50mL/min/1.73m2
  • ALT and AST 3 times above the upper limit of normal
  • Organ transplant recipient, inflammatory illnesses (i.e., polyarthritis, severe cirrhosis, infectious diseases, heart failure, HIV, hepatitis)
  • Previous history of or an active cancer (except non-melanoma skin cancer)
  • Uncontrolled thyroid functions
  • Pregnant
Show all 10Show fewer
  • History of drug or alcohol abuse
  • Subjects with a history of or current inflammatory bowel diseases including ulcerous colitis and Crohn's disease, and bariatric surgery
  • Drugs known to modulate CYP450 activities, subject taking one of the following therapies will be excluded: antibiotics, antivirals, anticancers, CYP450 inducers (carbamazepine, phenobarbital, phenytoin, rifampin, St-John's wort), CYP450 inhibitors (amiodarone, fluvoxamine, fluoxetine, verapamil), immunosuppressors, warfarin, INFs, antibodies or grapefruit juice (<2-4 weeks) , CYP450 drugs with strong affinity for the selected isoform and with a long half-life, CYP450 mechanism-based inhibitors or an investigational drug
  • Intolerance or hypersensitivity to probe drugs in the CRCHUM-MT cocktail or chlorzoxazone/acetaminophen

Trial locations and contacts

1 site in 1 country.

Canada1 site
  • Centre hospitalier de l'Université de Montréal (CHUM)

    Montreal, Quebec, H2X0A9

Other trials in Canada

About this study

Official title: Effects of Type 2 Diabetes on CYP450s Activities; Intersubject Variability in Drug Metabolism.

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.

Read more

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.

Read the detailed description

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.

Conditions
Type 2 Diabetes
Being tested
CRCHUM-MT cocktail
Keywords
Cytochromes p450, drug metabolism, pharmacokinetics, diabetes, probe markers
Medical subject headings
Diabetes Mellitus, Type 2, Diabetes Mellitus

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • CRCHUM-MT cocktailDrug

    Also called omeprazole, Losec, caffeine, Wake-up

Study groups in NCT02291666
Study groupRoleWhat they receive
T2D patients with A1C ≤7.0ExperimentalCRCHUM-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.
Receives: Drug: CRCHUM-MT cocktail
T2D patients with A1C>7.0ExperimentalCRCHUM-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.
Receives: Drug: CRCHUM-MT cocktail
Non T2D subjectsActive comparatorCRCHUM-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.
Receives: Drug: CRCHUM-MT cocktail

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Metabolic ratio

    The metabolite/probe-drug (parent compound) ratio will be used as a metabolic index of CYP activity.

    Measured: 12 hours

Secondary outcomes (2)
  1. Oral clearance

    CLo will be determined by noncompartmental analysis

    Measured: 12 hours

  2. Renal clearance

    CLr will be determined by noncompartmental analysis (Ae0-t of compound/AUC0-t compound)

    Measured: 12 hours

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted14 Nov 2014 (estimated)
  2. Study startApr 2015
  3. Primary completionJul 2019
  4. Study completionJul 2019

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 4
Primary purpose
Basic science
Allocation
Non-randomised
Intervention model
Parallel groups
Masking
Single blind
Who is masked
Outcomes assessor
Enrolment
73 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02291666
Sponsor's protocol ID
CE 14.066
Status last verified
Jul 2017
First submitted
30 Oct 2014
Last updated
23 Jul 2019
Results posted
No
Data monitoring committee
Yes

Publications

  • Gravel S, Chiasson JL, Turgeon J, Grangeon A, Michaud V. Modulation of CYP450 Activities in Patients With Type 2 Diabetes. Clin Pharmacol Ther. 2019 Dec;106(6):1280-1289. doi: 10.1002/cpt.1496. Epub 2019 Jul 9.

    PubMed 31099895
  • Gravel S, Chiasson JL, Dallaire S, Turgeon J, Michaud V. Evaluating the impact of type 2 diabetes mellitus on CYP450 metabolic activities: protocol for a case-control pharmacokinetic study. BMJ Open. 2018 Feb 8;8(2):e020922. doi: 10.1136/bmjopen-2017-020922.

    PubMed 29439084

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing CRCHUM-MT cocktail in people with Type 2 Diabetes, run by Centre hospitalier de l'Université de Montréal (CHUM) at 1 site in Canada.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 4 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 23 Jul 2019. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Metabolic ratio (time frame: 12 hours). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02291666, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 Jul 2019.

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