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NCT Number: NCT02586636

Impact of OCT1 on Metformin Tolerance

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.

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Key information

Conditions

Tolerance

Age range

18 year–80 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 4

Primary location

Ninewells Hospital

Dundee, Angus, DD19SY, United Kingdom

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

metformin

Drug

Metformin is given alongside omeprazole / placebo. Started at low dose and titrated gradually over four weeks according to the individual's tolerance of metformin. We anticipate that their tolerance of metformin will be reduced by loss of function variants in OCT1, and by concurrent use of OCT1 inhibiting drugs (in our study this is omeprazole).

Omeprazole

Drug

Given as concurrent treatment in one of the two treatment periods. Omeprazole treatment dose is fixed at 20mg twice daily for four weeks duration. Omeprazole, in our study, is used as an OCT1 inhibitor, and we hypothesise that this will reduce an individual's maximum tolerated dose of metformin during concurrent treatment. This will be compared to the other treatment period in which concurrent treatment is a placebo, and therefore, the maximum tolerated dose of metformin would not be affected.

Placebo

Drug

Given as concurrent treatment in one of the two treatment periods. Placebo treatment dose is fixed at one tablet twice daily (to match the dosing pattern of omeprazole) for four weeks duration. Omeprazole, in our study, is used as an OCT1 inhibitor, and we hypothesise that this will reduce an individual's maximum tolerated dose of metformin during concurrent treatment. This will be compared to the other treatment period in which concurrent treatment is a placebo, and therefore, the maximum tolerated dose of metformin would not be affected.

Primary outcomes

  1. Maximum tolerated dose of metformin

    Time frame: 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.

Sponsors and collaborators

Lead sponsor

NHS Tayside

Other Gov

Collaborators

  • University of Dundee

Registry information

Official study title

Impact of OCT1 Genotype and OCT1 Inhibiting Drugs on an Individual's Tolerance of Metformin

Acronym: ImpOCT

Important dates

Study start
2016
Primary completion
2018
Study completion
2018
First posted
Oct 26, 2015
Registry last updated
Jun 13, 2018

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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