INTERGLIKOM: Interaction Between Omeprazole and Gliclazide in CYP2C19 Normal/ Ultrarapid Metabolisers

• Sponsor: University of Sarajevo (Other)
• Overall Status: Completed
• CT.gov ID: NCT04198948
• Collaborator: General Hospital Prim. Dr. Abdulah Nakas (Other), University of Dundee (Other), Wellcome Trust (Other)
• Enrollment: 15
• Location: 1
• Arms: 2
• Actual Duration (Months): 5.1
• Patients Per Site Per Month: 3

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus, Type 2	Drug: Omeprazole; Drug: Placebo oral tablet; Drug: Gliclazide	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 15 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Single (Participant)
• Primary Purpose: Basic Science
• Official Title: Interaction Between Omeprazole and Gliclazide in CYP2C19 Normal/ Ultrarapid Metabolisers
• Actual Study Start Date: Mar 4, 2019
• Actual Primary Completion Date: Aug 5, 2019
• Actual Study Completion Date: Aug 5, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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.	Drug: Omeprazole; Omeprazole (20 mg) will be administered orally once daily for 5 days in one of the two treatment periods.; Drug: Placebo oral tablet; Placebo will be administered orally once daily for 5 days in one of the two treatment periods.; Drug: Gliclazide; Gliclazide (40 mg) will be administered orally once, concomitantly with omeprazole or placebo on day 5.
Experimental: 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.	Drug: Omeprazole; Omeprazole (20 mg) will be administered orally once daily for 5 days in one of the two treatment periods.; Drug: Placebo oral tablet; Placebo will be administered orally once daily for 5 days in one of the two treatment periods.; Drug: Gliclazide; Gliclazide (40 mg) will be administered orally once, concomitantly with omeprazole or placebo on day 5.

Outcome Measures

Primary Outcome Measures

1. Gliclazide AUC [24 hours]

   Area under the concentration-time curve (AUC) up to the last concentration measured

Secondary Outcome Measures

1. Glucose [12 hours]

   Change in glucose concentration - incremental area under the glucose concentration-time curve from 0 to 12 h

2. Insulin [12 hours]

   Change in insulin concentration - incremental area under the insulin concentration-time curve from 0 to 12 h

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 30 Years
• Sexes Eligible for Study: Male
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	General Hospital Prim. Dr. Abdulah Nakas	Sarajevo		Bosnia and Herzegovina	71000

Sponsors and Collaborators

• University of Sarajevo
• General Hospital Prim. Dr. Abdulah Nakas
• University of Dundee
• Wellcome Trust

Investigators

• Principal Investigator: Tanja Dujic, PhD, University of Sarajevo
• Principal Investigator: Aida Kulo Cesic, PhD, University of Sarajevo

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Sep 14, 2018

More Information

Publications

• Dujic T, Zhou K, Donnelly LA, Leese G, Palmer CNA, Pearson ER. Interaction between variants in the CYP2C9 and POR genes and the risk of sulfonylurea-induced hypoglycaemia: A GoDARTS Study. Diabetes Obes Metab. 2018 Jan;20(1):211-214. doi: 10.1111/dom.13046. Epub 2017 Aug 25.
• Furuta T, Iwaki T, Umemura K. Influences of different proton pump inhibitors on the anti-platelet function of clopidogrel in relation to CYP2C19 genotypes. Br J Clin Pharmacol. 2010 Sep;70(3):383-92. doi: 10.1111/j.1365-2125.2010.03717.x.
• Kalra S, Aamir AH, Raza A, Das AK, Azad Khan AK, Shrestha D, Qureshi MF, Md Fariduddin, Pathan MF, Jawad F, Bhattarai J, Tandon N, Somasundaram N, Katulanda P, Sahay R, Dhungel S, Bajaj S, Chowdhury S, Ghosh S, Madhu SV, Ahmed T, Bulughapitiya U. Place of sulfonylureas in the management of type 2 diabetes mellitus in South Asia: A consensus statement. Indian J Endocrinol Metab. 2015 Sep-Oct;19(5):577-96. doi: 10.4103/2230-8210.163171. Review.
• Schopman JE, Simon AC, Hoefnagel SJ, Hoekstra JB, Scholten RJ, Holleman F. The incidence of mild and severe hypoglycaemia in patients with type 2 diabetes mellitus treated with sulfonylureas: a systematic review and meta-analysis. Diabetes Metab Res Rev. 2014 Jan;30(1):11-22. doi: 10.1002/dmrr.2470. Review.
• Semiz S, Dujic T, Ostanek B, Prnjavorac B, Bego T, Malenica M, Marc J, Causevic A. Analysis of CYP2C9*2, CYP2C19*2, and CYP2D6*4 polymorphisms in patients with type 2 diabetes mellitus. Bosn J Basic Med Sci. 2010 Nov;10(4):287-91.
• Shao H, Ren XM, Liu NF, Chen GM, Li WL, Zhai ZH, Wang DW. Influence of CYP2C9 and CYP2C19 genetic polymorphisms on pharmacokinetics and pharmacodynamics of gliclazide in healthy Chinese Han volunteers. J Clin Pharm Ther. 2010 Jun;35(3):351-60. doi: 10.1111/j.1365-2710.2009.01134.x.
• Sun XM, Tan JC, Zhu Y, Lin L. Association between diabetes mellitus and gastroesophageal reflux disease: A meta-analysis. World J Gastroenterol. 2015 Mar 14;21(10):3085-92. doi: 10.3748/wjg.v21.i10.3085. Review.
• Wedemeyer RS, Blume H. Pharmacokinetic drug interaction profiles of proton pump inhibitors: an update. Drug Saf. 2014 Apr;37(4):201-11. doi: 10.1007/s40264-014-0144-0. Review.
• Zhang Y, Si D, Chen X, Lin N, Guo Y, Zhou H, Zhong D. Influence of CYP2C9 and CYP2C19 genetic polymorphisms on pharmacokinetics of gliclazide MR in Chinese subjects. Br J Clin Pharmacol. 2007 Jul;64(1):67-74. Epub 2007 Feb 12.

• Responsible Party: Tanja Dujic, PhD, Associate Professor, University of Sarajevo
• ClinicalTrials.gov Identifier: NCT04198948
• Other Study ID Numbers: 0101-3678/18; 209943/Z/17/Z
• First Posted: Dec 13, 2019
• Last Update Posted: Aug 18, 2021
• Last Verified: Jul 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Diabetes Mellitus, Type 2; Gliclazide; Omeprazole

Study Results

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 Detail	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.

Arm/Group Title	Omeprazole, Then Placebo	Placebo, Then Omeprazole
Arm/Group Description	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.	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.
Period Title: First Period
STARTED	7	8
COMPLETED	7	8
NOT COMPLETED	0	0
Period Title: First Period
STARTED	7	8
COMPLETED	7	8
NOT COMPLETED	0	0
Period Title: First Period
STARTED	7	8
COMPLETED	7	7
NOT COMPLETED	0	1

Baseline Characteristics

Arm/Group Title	Omeprazole, Then Placebo	Placebo, Then Omeprazole	Total
Arm/Group Description	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.	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.	Total of all reporting groups
Overall Participants	7	8	15
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	22.9 (3.3)	21.9 (2.2)	22.3 (2.7)
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%
Male	7 100%	8 100%	15 100%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	7 100%	8 100%	15 100%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
Bosnia and Herzegovina	7 100%	8 100%	15 100%
Weight (kilograms) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilograms]	82.2 (12.5)	75.7 (10.8)	78.7 (11.7)

Outcome Measures

1. Primary Outcome

Title	Gliclazide AUC
Description	Area under the concentration-time curve (AUC) up to the last concentration measured
Time Frame	24 hours

Outcome Measure Data

Analysis Population Description

A total of 14 participants who completed both study periods were included in the analysis.

Arm/Group Title	Gliclazide + Omeprazole	Gliclazide + Placebo
Arm/Group Description	Participants received 20 mg of omeprazole alone for 4 days, and concomitantly with single dose of gliclazide on day 5.	Participants received placebo alone for 4 days, and concomitantly with single dose of gliclazide on day 5.
Measure Participants	14	14
Geometric Mean (95% Confidence Interval) [μgh/mL]	3.73	3.29

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Gliclazide + Omeprazole, Gliclazide + Placebo
	Comments	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.
	Type of Statistical Test	Equivalence
	Comments	Sample size calculation was performed using SAS Proc Power procedure for equivalence test in 2x2 crossover design. For an equivalence range of 80-125%, the within-subject coefficient of variation for the AUC values for gliclazide of 7.8% based on previous PK studies, and expected test/reference geometric mean ratios between 87-115%, 14 volunteers (7 individuals per sequence) are required to show the lack of interaction with 85% power.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric least square mean ratio
	Estimated Value	1.13
	Confidence Interval	(2-Sided) 90%; 0.86 to 1.48
	Parameter Dispersion	Type: Value:
	Estimation Comments	The TOST (two one-sided test) test of equivalence showed that the geometric mean ratio and 90% CI for gliclazide AUC(0-24) between omeprazole and placebo phase was 1.13 (0.86-1.48), with upper confidence limit above the usual 1.25 boundary.

2. Secondary Outcome

Title	Glucose
Description	Change in glucose concentration - incremental area under the glucose concentration-time curve from 0 to 12 h
Time Frame	12 hours

Outcome Measure Data

Analysis Population Description

A total of 14 participants who completed both study periods were included in the analysis.

Arm/Group Title	Gliclazide + Omeprazole	Gliclazide + Placebo
Arm/Group Description	Participants received 20 mg of omeprazole alone for 4 days, and concomitantly with single dose of gliclazide on day 5.	Participants received placebo alone for 4 days, and concomitantly with single dose of gliclazide on day 5.
Measure Participants	14	14
Mean (Standard Deviation) [mmol x h/L]	4.6 (4.3)	4.0 (3.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Gliclazide + Omeprazole, Gliclazide + Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.636
	Comments
	Method	t-test, 2 sided
	Comments

3. Secondary Outcome

Title	Insulin
Description	Change in insulin concentration - incremental area under the insulin concentration-time curve from 0 to 12 h
Time Frame	12 hours

Outcome Measure Data

Analysis Population Description

A total of 14 participants who completed both study periods were included in the analysis.

Arm/Group Title	Gliclazide + Omeprazole	Gliclazide + Placebo
Arm/Group Description	Participants received 20 mg of omeprazole alone for 4 days, and concomitantly with single dose of gliclazide on day 5.	Participants received placebo alone for 4 days, and concomitantly with single dose of gliclazide on day 5.
Measure Participants	14	14
Mean (Standard Deviation) [mIU x h/L]	231.6 (93.8)	265.9 (78.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Gliclazide + Omeprazole, Gliclazide + Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.055
	Comments
	Method	t-test, 2 sided
	Comments

Adverse Events

Time Frame	Five days for each intervention.
Arm/Group Title	Gliclazide + Omeprazole		Gliclazide + Placebo
Arm/Group Description	Participants received 20 mg of omeprazole alone for 4 days, and concomitantly with single dose of gliclazide on day 5.		Participants received placebo alone for 4 days, and concomitantly with single dose of gliclazide on day 5.
All Cause Mortality
	Gliclazide + Omeprazole		Gliclazide + Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/15 (0%)
Serious Adverse Events
	Gliclazide + Omeprazole		Gliclazide + Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/15 (0%)
Other (Not Including Serious) Adverse Events
	Gliclazide + Omeprazole		Gliclazide + Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/15 (0%)

Limitations/Caveats

Participants received half of the 80 mg gliclazide tablet registered as an immediate-release formulation in Bosnia and Herzegovina (Diprian®, Hemofarm d.o.o. Banja Luka, B&H). However, the concentration-time profiles showed modified-release pattern and incomplete elimination within 24h; thus Cmax, tmax, t1/2, and AUC0-∞ could not be determined. The obtained PK profiles were used at the end for validation of physiologically based pharmacokinetic simulation of omeprazole-gliclazide interaction.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.