Impact of OCT1 on Metformin Tolerance

Phase 4

Completed

• Conditions: Tolerance
• Interventions: Drug: Metformin; Drug: Omeprazole; Drug: Placebo

• Registration Number: NCT02586636
• Lead Sponsor: NHS Tayside

Brief Summary

Metformin is the first-line treatment for medical management of Type 2 Diabetes. Up to 25% of patients experience significant gastrointestinal symptoms and in approximate 5%, side-effects result in the discontinuation of metformin. It would be of great clinical significance if the underlying cause of this intolerance was identified.

Recent data has highlighted a metformin transporter in the gut - Organic Cation Transporter 1(OCT1) - as a potential culprit for the variability in metformin tolerance. Across a diabetic population, up to one in four people were shown to have a single reduced function allele for OCT1, with approximately 8% having two reduced function alleles. This may increase the risk of the individual experiencing metformin-associated side-effects, potentially due to accumulation within the cells lining the intestine. The investigators aim to show that loss of function of OCT1, either due to genetic variation or drug inhibition of OCT1, may lead to an increase in the symptoms associated with metformin intolerance.

The study is being undertaken at the Clinical Research Centre in Ninewells Hospital, Dundee. The investigators will recruit participants from the GoDARTS study (Genetics of Diabetes and Audit Research Tayside Study). The participants will be healthy controls, i.e. non-diabetic, and recruited according to their genotype of OCT1 (information from GoDARTS). The volunteers will then enter a matched cross-over study with two treatment periods. Metformin is taken during both treatment periods alongside either Omeprazole (a proton pump inhibitor used to prevent excess stomach acid, known to interact with OCT1) or placebo. The metformin dose is increased gradually during each period, to a maximum tolerated dose. The investigators expect to see a lower maximum tolerated dose in individuals with loss of function genotype, or in those taking concurrent omeprazole compared to placebo. The study will last approximately 9 weeks. Volunteers have 3 visits to the CRC, and weekly phone call interviews.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2015-10-22
• Study First Submitted QC: 2015-10-23
• Study First Posted: 2015-10-26
• Study Start: 2016-03
• Primary Completion: 2018-04-09
• Study Completion: 2018-04-09
• Status Verified: 2018-06
• Last Update Submitted: 2018-06-12
• Last Update Posted: 2018-06-13

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 61

Inclusion Criteria

• Aged 18 - 80
• White European (to limit genetic variation as much as possible)
• Non-diabetic
• No previous treatment with metformin
• No known gastrointestinal pathology e.g. inflammatory bowel disease, IBS, coeliac
• No daily treatment with PPI, anti-spasmodic, or anti-motility drugs
• No daily OCT1 inhibiting drugs
• Able to complete the symptom severity score and Bristol stool chart independently i.e. no cognitive impairment or visual impairment
• Normal renal function - eGFR>60
• Known OCT1 genotype - either normal ("wild type") or two reduced function alleles.

Exclusion Criteria

• Does not meet inclusion criteria
• Heterozygous OCT1 genotype i.e. only one reduced function allele
• Recent involvement (<30 days) in a CTIMP
• Pregnancy or planning to conceive
• Inability/unwillingness to comply with the protocol

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
OCT1 -/-	Placebo	Cohort of patients with two loss of function alleles for OCT1. The participants within this group will receive metformin at increasing dose to a maximum tolerated dose over two distinct four week treatment periods. The concurrent treatment order of omeprazole and placebo will be randomised within the cohort.
OCT wt/wt	Placebo	Cohort of patients with two "normal" or wild type alleles for OCT1. The participants within this group will receive metformin at increasing dose to a maximum tolerated dose over two distinct four week treatment periods. The concurrent treatment order of omeprazole and placebo will be randomised within the cohort.
OCT1 -/-	Metformin	Cohort of patients with two loss of function alleles for OCT1. The participants within this group will receive metformin at increasing dose to a maximum tolerated dose over two distinct four week treatment periods. The concurrent treatment order of omeprazole and placebo will be randomised within the cohort.
OCT1 -/-	Omeprazole	Cohort of patients with two loss of function alleles for OCT1. The participants within this group will receive metformin at increasing dose to a maximum tolerated dose over two distinct four week treatment periods. The concurrent treatment order of omeprazole and placebo will be randomised within the cohort.
OCT wt/wt	Omeprazole	Cohort of patients with two "normal" or wild type alleles for OCT1. The participants within this group will receive metformin at increasing dose to a maximum tolerated dose over two distinct four week treatment periods. The concurrent treatment order of omeprazole and placebo will be randomised within the cohort.
OCT wt/wt	Metformin	Cohort of patients with two "normal" or wild type alleles for OCT1. The participants within this group will receive metformin at increasing dose to a maximum tolerated dose over two distinct four week treatment periods. The concurrent treatment order of omeprazole and placebo will be randomised within the cohort.

Primary Outcome Measures

Name	Time	Method
Maximum tolerated dose of metformin	At the completion of the study, after approximately 1.5 years.	Each treatment period consists of four weeks. Metformin dose titrated gradually in presence of omeprazole or placebo.

Trial Locations

Locations (1)

Ninewells Hospital; 🇬🇧 Dundee, Angus, United Kingdom