Impact of OCT1 on Metformin Tolerance (ImpOCT)

June 12, 2018 updated by: Laura McCreight, NHS Tayside

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

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

61

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United Kingdom
    • Angus
      • Dundee, Angus, United Kingdom, DD19SY
        • Ninewells Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 80 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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 Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Other: OCT1 -/-
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.
Drug: Metformin
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).
Drug: Omeprazole
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.
Drug: Placebo
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.
Other: OCT wt/wt
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.
Drug: Metformin
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).
Drug: Omeprazole
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.
Drug: Placebo
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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
At the completion of the study, after approximately 1.5 years.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

NHS Tayside

Collaborators

University of Dundee

Investigators

  • Study Chair: Ewan R Pearson, MBBCh, PhD, University of Dundee / NHS Tayside

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

March 1, 2016

Primary Completion (Actual)

April 9, 2018

Study Completion (Actual)

April 9, 2018

Study Registration Dates

First Submitted

October 22, 2015

First Submitted That Met QC Criteria

October 23, 2015

First Posted (Estimate)

October 26, 2015

Study Record Updates

Last Update Posted (Actual)

June 13, 2018

Last Update Submitted That Met QC Criteria

June 12, 2018

Last Verified

June 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2015DM13

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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