NCT03445702

Brief Summary

Metformin is associated with a high degree of gastrointestinal intolerance, which limits the effective use of the medication. It is proposed to be an inhibitor of liver mitochondrial glycerophosphate dehydrogenase which results in partial blockade of mitochondrial complex 1 and inhibition of metabolism of lactate to pyruvate. There is also evidence that it is accumulated in gastrointestinal cells, and that there are certain genotypes associated with inclusion or lack of exclusion of the metformin from these cells. To validate this hypothesis investigators propose to give metformin after a standard meal test to see if there is the accumulation of lactic acid in those with gastrointestinal intolerance to metformin, compared to those without intolerance, and to determine if these elevations of lactic acid and GI symptoms are associated with genetic predispositions. Aims:

  1. 1.To determine if the GI intolerance to metformin is associated with post meal elevations of lactic acid.
  2. 2.To determine if individuals with gastrointestinal symptoms and elevated lactate/pyruvate ratios have genetic variation in the organic cation transporters.

Trial Health

87
On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment
15

participants targeted

Target at below P25 for early_phase_1 diabetes-mellitus-type-2

Timeline
Completed

Started Oct 2018

Typical duration for early_phase_1 diabetes-mellitus-type-2

Geographic Reach
1 country

1 active site

Status
completed

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

First Submitted

Initial submission to the registry

February 19, 2018

Completed
7 days until next milestone

First Posted

Study publicly available on registry

February 26, 2018

Completed
8 months until next milestone

Study Start

First participant enrolled

October 15, 2018

Completed
2 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

October 27, 2020

Completed
Same day until next milestone

Study Completion

Last participant's last visit for all outcomes

October 27, 2020

Completed
Last Updated

October 28, 2020

Status Verified

October 1, 2020

Enrollment Period

2 years

First QC Date

February 19, 2018

Last Update Submit

October 27, 2020

Conditions

Diabetes Mellitus, Type 2Metformin Adverse Reaction

Outcome Measures

Primary Outcomes (1)

  • Lactate to pyruvate ratio

    Meal tolerance test. Absolute levels and ratios of L/P will be compared pre and post metformin and between group by analysis of variance for repeated measures where the covariance is group (tolerant or intolerant) and drug (metformin vs placebo).

    2 weeks

Secondary Outcomes (1)

  • Genomic testing

    2 weeks

Study Arms (4)

Metformin intolerant & metformin

EXPERIMENTAL

Metformin 1000mg once

Drug: Metformin

Metformin intolerant & placebo

PLACEBO COMPARATOR

Placebo 1000mg once

Drug: Placebo

Metformin tolerant & metformin

ACTIVE COMPARATOR

Metformin 1000mg once

Drug: Metformin

Metformin tolerant and placebo

PLACEBO COMPARATOR

Placebo 1000mg once

Drug: Placebo

Interventions

MetforminDRUG

Metformin 1000mg once

Also known as: Glucophage
Metformin intolerant & metforminMetformin tolerant & metformin
PlaceboDRUG

Sugar pill manufactured to mimic metformin 1000mg

Metformin intolerant & placeboMetformin tolerant and placebo

Eligibility Criteria

Age40 Years - 70 Years
Sexall
Healthy VolunteersYes
Age GroupsAdult (18-64), Older Adult (65+)

You may qualify if:

  • Diabetes mellitus
  • Tolerance to meformin
  • Intolerance to metformin

You may not qualify if:

  • Those not competent to provide informed consent
  • Known systemic allergy (not intolerance) to metformin
  • Congestive heart failure NYHA class III-IV
  • Renal impairment,EGFRr\<45ml/min
  • Liver cirrhosis

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (1)

Saint Louis University

St Louis, Missouri, 63110, United States

Location

Related Publications (10)

  • Ferrannini E. The target of metformin in type 2 diabetes. N Engl J Med. 2014 Oct 16;371(16):1547-8. doi: 10.1056/NEJMcibr1409796. No abstract available.

    PMID: 25317875BACKGROUND

  • Madiraju AK, Erion DM, Rahimi Y, Zhang XM, Braddock DT, Albright RA, Prigaro BJ, Wood JL, Bhanot S, MacDonald MJ, Jurczak MJ, Camporez JP, Lee HY, Cline GW, Samuel VT, Kibbey RG, Shulman GI. Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature. 2014 Jun 26;510(7506):542-6. doi: 10.1038/nature13270. Epub 2014 May 21.

    PMID: 24847880BACKGROUND

  • Bailey CJ, Wilcock C, Scarpello JH. Metformin and the intestine. Diabetologia. 2008 Aug;51(8):1552-3. doi: 10.1007/s00125-008-1053-5. Epub 2008 Jun 5. No abstract available.

    PMID: 18528677BACKGROUND

  • Bailey CJ, Wilcock C, Day C. Effect of metformin on glucose metabolism in the splanchnic bed. Br J Pharmacol. 1992 Apr;105(4):1009-13. doi: 10.1111/j.1476-5381.1992.tb09093.x.

    PMID: 1504710BACKGROUND

  • Buse JB, DeFronzo RA, Rosenstock J, Kim T, Burns C, Skare S, Baron A, Fineman M. The Primary Glucose-Lowering Effect of Metformin Resides in the Gut, Not the Circulation: Results From Short-term Pharmacokinetic and 12-Week Dose-Ranging Studies. Diabetes Care. 2016 Feb;39(2):198-205. doi: 10.2337/dc15-0488. Epub 2015 Aug 18.

    PMID: 26285584BACKGROUND

  • Tarasova L, Kalnina I, Geldnere K, Bumbure A, Ritenberga R, Nikitina-Zake L, Fridmanis D, Vaivade I, Pirags V, Klovins J. Association of genetic variation in the organic cation transporters OCT1, OCT2 and multidrug and toxin extrusion 1 transporter protein genes with the gastrointestinal side effects and lower BMI in metformin-treated type 2 diabetes patients. Pharmacogenet Genomics. 2012 Sep;22(9):659-66. doi: 10.1097/FPC.0b013e3283561666.

    PMID: 22735389BACKGROUND

  • Pawlyk AC, Giacomini KM, McKeon C, Shuldiner AR, Florez JC. Metformin pharmacogenomics: current status and future directions. Diabetes. 2014 Aug;63(8):2590-9. doi: 10.2337/db13-1367.

    PMID: 25060887BACKGROUND

  • Wang L, Weinshilboum R. Metformin pharmacogenomics: biomarkers to mechanisms. Diabetes. 2014 Aug;63(8):2609-10. doi: 10.2337/db14-0609. No abstract available.

    PMID: 25060891BACKGROUND

  • Davidson J, Howlett H. New prolonged-release metformin improves gastrointestinal tolerability. British Journal of Diabetes & Vascular Disease 2004; 4: 273.

    BACKGROUND

  • Blonde L, Dailey GE, Jabbour SA, Reasner CA, Mills DJ. Gastrointestinal tolerability of extended-release metformin tablets compared to immediate-release metformin tablets: results of a retrospective cohort study. Curr Med Res Opin. 2004 Apr;20(4):565-72. doi: 10.1185/030079904125003278.

    PMID: 15119994BACKGROUND

MeSH Terms

Conditions

Diabetes Mellitus, Type 2

Interventions

Metformin

Condition Hierarchy (Ancestors)

Diabetes MellitusGlucose Metabolism DisordersMetabolic DiseasesNutritional and Metabolic DiseasesEndocrine System Diseases

Intervention Hierarchy (Ancestors)

BiguanidesGuanidinesAmidinesOrganic Chemicals

Study Design

Study Type
interventional
Phase
early phase 1
Allocation
RANDOMIZED
Masking
QUADRUPLE
Who Masked
PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
Masking Details
Investigators, participants, research coordinator will be blinded to intervention provided to subject
Purpose
SCREENING
Intervention Model
CROSSOVER
Model Details: Randomized, double blinded, placebo controlled crossover trial
Sponsor Type
OTHER
Responsible Party
PRINCIPAL INVESTIGATOR
PI Title
MD

Study Record Dates

First Submitted

February 19, 2018

First Posted

February 26, 2018

Study Start

October 15, 2018

Primary Completion

October 27, 2020

Study Completion

October 27, 2020

Last Updated

October 28, 2020

Record last verified: 2020-10

Locations

US(1)