Diabetes Mellitus, Type 2
Conditions
Brief summary
Proton pump inhibitors (PPIs) are treatment of choice for different gastrointestinal disorders common in type 2 diabetes. Sulfonylureas (SUs) are anti-diabetes agents particularly widely used in developing countries. Gliclazide, a recommended SU drug, is metabolised in part by CYP2C19, the main enzyme responsible for the PPI metabolism. A randomised, placebo-controlled, two-sequence, two-period crossover study will be performed to explore whether gliclazide pharmacokinetics (PK) and pharmacodynamics (PD) are altered upon co-administration with omeprazole. Sixteen healthy volunteers, CYP2C19 extensive/ultrarapid metabolisers (EM/UM), will receive placebo or omeprazole alone for 4 days, and concomitantly with single dose of gliclazide on day 5. Plasma concentration of gliclazide will be measured for 24 hours, and plasma glucose and insulin levels up to 12 hours after gliclazide administration.
Interventions
DRUGOmeprazole
Omeprazole (20 mg) will be administered orally once daily for 5 days in one of the two treatment periods.
DRUGPlacebo oral tablet
Placebo will be administered orally once daily for 5 days in one of the two treatment periods.
DRUGGliclazide
Gliclazide (40 mg) will be administered orally once, concomitantly with omeprazole or placebo on day 5.
Sponsors
General Hospital Prim. Dr. Abdulah Nakas
University of Dundee
Wellcome Trust
University of Sarajevo
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
MALE
Age
18 Years to 30 Years
Healthy volunteers
Yes
Inclusion criteria
* Men * Age 18-30 years * Non-smokers * CYP2C19 extensive/ultrarapid metabolisers
Exclusion criteria
* medical history of hepatic, renal, gastrointestinal and hematologic disease or any acute or chronic disease, or drug allergy to sulfonylureas or PPIs or history of drug abuse * abnormalities in physical examination, ECG and routine clinical laboratory tests (including fasting blood glucose concentration) * medication use during the 14 days prior and during the study period * grapefruit, grapefruit juice, alcohol, beverages or food containing methylxanthines use during 72 h prior and during the study period
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Gliclazide AUC | 24 hours | Area under the concentration-time curve (AUC) up to the last concentration measured |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Glucose | 12 hours | Change in glucose concentration - incremental area under the glucose concentration-time curve from 0 to 12 h |
| Insulin | 12 hours | Change in insulin concentration - incremental area under the insulin concentration-time curve from 0 to 12 h |
Countries
Bosnia and Herzegovina
Participant flow
Recruitment details
A total of 37 volunteers were recruited in the period between March 4th, 2019 and May 29th, 2019. On May 30th, 2019, volunteers were screened for CYP2C19 genotype status at the General Hospital in Sarajevo, B&H.
Pre-assignment details
From 23 individuals, CYP2C19 EM/UM metabolisers, 16 were available for further health status assessment. One participant did not meet inclusion criteria and a total of 15 volunteers were randomised.
Participants by arm
| Arm | Count |
|---|---|
| Omeprazole, Then Placebo Healthy volunteers, CYP2C19 extensive/ultrarapid metabolisers, will receive 20 mg of omeprazole alone for 4 days, and concomitantly with single dose of gliclazide on day 5. After a wash-out period, they will receive placebo under same conditions in a cross-over manner.
Omeprazole: Omeprazole (20 mg) will be administered orally once daily for 5 days in one of the two treatment periods.
Placebo oral tablet: Placebo will be administered orally once daily for 5 days in one of the two treatment periods.
Gliclazide: Gliclazide (40 mg) will be administered orally once, concomitantly with omeprazole or placebo on day 5. | 7 |
| Placebo, Then Omeprazole Healthy volunteers, CYP2C19 extensive/ultrarapid metabolisers, will receive placebo alone for 4 days, and concomitantly with single dose of gliclazide on day 5. After a wash-out period, they will receive omeprazole under same conditions in a cross-over manner.
Omeprazole: Omeprazole (20 mg) will be administered orally once daily for 5 days in one of the two treatment periods.
Placebo oral tablet: Placebo will be administered orally once daily for 5 days in one of the two treatment periods.
Gliclazide: Gliclazide (40 mg) will be administered orally once, concomitantly with omeprazole or placebo on day 5. | 8 |
| Total | 15 |
Baseline characteristics
| Characteristic | Omeprazole, Then Placebo | Placebo, Then Omeprazole | Total |
|---|---|---|---|
| Age, Continuous | 22.9 years STANDARD_DEVIATION 3.3 | 21.9 years STANDARD_DEVIATION 2.2 | 22.3 years STANDARD_DEVIATION 2.7 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 7 Participants | 8 Participants | 15 Participants |
| Region of Enrollment Bosnia and Herzegovina | 7 participants | 8 participants | 15 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 7 Participants | 8 Participants | 15 Participants |
| Weight | 82.2 kilograms STANDARD_DEVIATION 12.5 | 75.7 kilograms STANDARD_DEVIATION 10.8 | 78.7 kilograms STANDARD_DEVIATION 11.7 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 15 | 0 / 15 |
| other Total, other adverse events | 0 / 15 | 0 / 15 |
| serious Total, serious adverse events | 0 / 15 | 0 / 15 |
Outcome results
Primary
Gliclazide AUC
Area under the concentration-time curve (AUC) up to the last concentration measured
Time frame: 24 hours
Population: A total of 14 participants who completed both study periods were included in the analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Gliclazide + Omeprazole | Gliclazide AUC | 3.73 μgh/mL |
| Gliclazide + Placebo | Gliclazide AUC | 3.29 μgh/mL |
Comparison: The main evaluated outcome was systemic exposure to gliclazide, expressed as AUC(0-t). The geometric mean was calculated for gliclazide AUC(0-24). The ratio of the geometric means with 90% CIs was assessed by linear mixed models between the two treatment assignments: gliclazide and omeprazole co-administration to that of gliclazide and placebo. The obtained 90% CI was compared with the equivalence 0.8-1.25 range.90% CI: [0.86, 1.48]
Secondary
Glucose
Change in glucose concentration - incremental area under the glucose concentration-time curve from 0 to 12 h
Time frame: 12 hours
Population: A total of 14 participants who completed both study periods were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Gliclazide + Omeprazole | Glucose | 4.6 mmol x h/L | Standard Deviation 4.3 |
| Gliclazide + Placebo | Glucose | 4.0 mmol x h/L | Standard Deviation 3 |
p-value: 0.636t-test, 2 sided
Secondary
Insulin
Change in insulin concentration - incremental area under the insulin concentration-time curve from 0 to 12 h
Time frame: 12 hours
Population: A total of 14 participants who completed both study periods were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Gliclazide + Omeprazole | Insulin | 231.6 mIU x h/L | Standard Deviation 93.8 |
| Gliclazide + Placebo | Insulin | 265.9 mIU x h/L | Standard Deviation 78.2 |
p-value: 0.055t-test, 2 sided