Sulphonylurea Receptor Mutation and Responsiveness to Gliclazide - a Pilot Proof of Concept, Randomised Cross-over Study

Diabetes Clinical Trial

Official title:

Sulphonylurea Receptor Mutation and Responsiveness to Gliclazide - a Pilot Proof of Concept, Randomised Cross-over Study

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02201602
• Other study ID #: Gliclazide
• Status: Completed
• Phase: Phase 4
• First received: July 22, 2014
• Last updated: August 31, 2016
• Start date: August 2014
• Est. completion date: July 2016

Study information

• Verified date: August 2016
• Source: Khoo Teck Puat Hospital
• Contact: n/a
• Is FDA regulated: No
• Health authority: Singapore: Domain Specific Review BoardsSingapore: Health Sciences Authority
• Study type: Interventional

Clinical Trial Summary

Gliclazide has greater glucose lowering efficacy than glibenclamide among type 2 diabetes mellitus patients with minor haplotype (K23/A1369) at the KCNJ11/ABCC gene locations.

Description:

Sulphonylurea (SU) is a glucose-lowering agent used widely to treat type 2 diabetes mellitus (T2DM). SU promotes insulin secretion from the pancreatic islet beta cell via binding and inhibition of the ATP-sensitive potassium (KATP) channel. The KATP channel is made up of two subcomponents, an inner Kir6.2 K+ channel (coded by the KCNJ11 gene) and an outer SU receptor 1 (SUR1) (coded by the ABCC8 gene). Although all SUs are mechanistically similar in terms of increasing insulin secretion, they bind to distinct regions of Kir 6.2 and SUR1 to exert their function. Different types of SU (e.g. tolbutamide, glibenclamide, glipizide, glimepiride and gliclazide) can therefore be grouped by their binding sites (A/B/A+B site) on the KATP channel [3]. Interestingly, the KCNJ11 E23K (rs5219) variant was shown to confer susceptibility to T2DM and the ABCC8 S1369A (rs757110) variant was found to be in complete linkage disequilibrium with it i.e. inherited together as a genetic block (haplotype). A recent in vitro molecular study suggested that the minor haplotype (K23/A1369) of KATP channel is sensitive to inhibition by gliclazide (binds to A-site) but not glibenclamide (binds to A+B site), and that the increased responsiveness to gliclazide was largely due to the A1369 allele. Understanding how the response to these two SUs may vary with the presence of the minor haplotype (K23/A1369) would therefore be beneficial for customization of patient treatment to achieve better clinical outcomes.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 8
• Est. completion date: July 2016
• Est. primary completion date: June 2016
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 21 Years to 65 Years

Eligibility

Inclusion Criteria:

• Type 2 diabetes

• Age 21-65

• HbA1c >8.0% on two consecutive visits

Exclusion Criteria:

• Currently taking insulin at a regime more complex than basal insulin

• Not willing to perform self-blood glucose monitoring (SBGM)

• Renal impairment i.e. eGFR<50mls/min

• Pregnancy or unwilling to practice adequate contraception

• Taking other medications that may affect blood glucose e.g. systemic glucocorticoids.

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Diabetes

Intervention

Drug:
• Gliclazide

• Glibenclamide

Locations

Country	Name	City	State
Singapore	Khoo Teck Puat Hospital	Singapore

Sponsors (1)

Lead Sponsor	Collaborator
Khoo Teck Puat Hospital

Country where clinical trial is conducted

Singapore, 

References & Publications (2)

Gloyn AL, Weedon MN, Owen KR, Turner MJ, Knight BA, Hitman G, Walker M, Levy JC, Sampson M, Halford S, McCarthy MI, Hattersley AT, Frayling TM. Large-scale association studies of variants in genes encoding the pancreatic beta-cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) confirm that the KCNJ11 E23K variant is associated with type 2 diabetes. Diabetes. 2003 Feb;52(2):568-72. — View Citation

Hamming KS, Soliman D, Matemisz LC, Niazi O, Lang Y, Gloyn AL, Light PE. Coexpression of the type 2 diabetes susceptibility gene variants KCNJ11 E23K and ABCC8 S1369A alter the ATP and sulfonylurea sensitivities of the ATP-sensitive K(+) channel. Diabetes. 2009 Oct;58(10):2419-24. doi: 10.2337/db09-0143. Epub 2009 Jul 8. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Mean blood glucose level		6 days	No
Secondary	Glycemic variability	Glycemic variability will be assessed using the EasyGV software (http://www.phc.ox.ac.uk/research/diabetes/software/easygv/) which is capable of calculating 10 different measures of glycemic variability from continuous glucose monitoring data, such as Standard Deviation (SD) and M-value, mean amplitude of glycemic excursions (MAGE).	6 days	No