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Trial registered on ANZCTR
Registration number
ACTRN12619001292167
Ethics application status
Approved
Date submitted
2/09/2019
Date registered
19/09/2019
Date last updated
19/09/2019
Date data sharing statement initially provided
19/09/2019
Date results information initially provided
19/09/2019
Type of registration
Retrospectively registered
Titles & IDs
Public title
The safety and disposition of metformin in people with liver disease
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Scientific title
The pharmacokinetics and safety of metformin in patients with liver disease
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Secondary ID [1]
298984
0
None
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Universal Trial Number (UTN)
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Chronic liver disease
314222
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Condition category
Condition code
Metabolic and Endocrine
312585
312585
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0
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Diabetes
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Oral and Gastrointestinal
312717
312717
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0
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Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Metformin hydrochloride (oral tablet immediate release formulation).
This prospective interventional study will be conducted in patients with varying degrees of liver disease who are not currently treated with metformin. Eligible patients will be prescribed a low oral dose of metformin (500 mg, immediate-release formulation, twice daily) for 6 weeks. Participants will be required to complete a diary describing the day and time of study medication ingestion.
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Intervention code [1]
315433
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Treatment: Drugs
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Comparator / control treatment
Results from the present study will be compared to data previously published examining the pharmacokinetics of metformin in healthy subjects and patients with type 2 diabetes mellitus.
Healthy subject data was obtained from Timmins et al Clin Pharmacokinet. 2005 where subjects were dosed with metformin extended release (500, 1000 and 1500 mg once daily) for 3 weeks followed by metformin extended release 2000 mg once daily or metformin immediate release 1000 mg twice daily for 2 weeks.
Type 2 diabetes mellitus data was obtained from Duong et al Clin Pharmacokinet. 2013 from patients receiving metformin (250-3000 mg/day) either the immediate or extended release formulation.
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Control group
Historical
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Outcomes
Primary outcome [1]
321239
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The primary objective of this study is to investigate the safety of metformin in patients with all-cause chronic liver disease, with varying degrees of liver fibrosis and cirrhosis, with or without type 2 diabetes mellitus by monitoring the concentrations of metformin and blood biochemistry (composite primary outcome).
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Assessment method [1]
321239
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Timepoint [1]
321239
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Venous blood samples will be obtained at Week 0 (screening visit), 1, 2, 3, 4, 5 and 6. These blood samples will be used to determine: metformin concentrations, lactate concentrations, creatinine concentrations, fasting glucose and insulin concentration, and blood biochemistry.
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Secondary outcome [1]
374426
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The secondary objective is to compare the pharmacokinetics of metformin in patients with chronic liver disease with healthy subjects, and patients with type 2 diabetes mellitus and no known history of chronic liver disease by monitoring plasma metformin concentrations and using these to estimate an individual's pharmacokinetic parameters (CLMet/F apparent clearance of metformin; Vc/F, apparent volume of distribution of metformin in the central compartment; CLMet/F:CLCr ratio of the apparent clearance of metformin to creatinine clearance) using a population pharmacokinetic analysis approach.
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Assessment method [1]
374426
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Timepoint [1]
374426
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The pharmacokinetics of metformin will be determined at Week 1, 2, 3, 4, 5 and 6 post initiation of the study medication in patients with chronic liver disease. An average of the pharmacokinetics of metformin over the course of the study will be determined and compared to steady-state pharmacokinetic of metformin in healthy subjects and patients with type 2 diabetes and no known history of chronic liver disease reported in the literature.
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Eligibility
Key inclusion criteria
Patients with chronic liver disease who are naïve to metformin treatment and do not have a diagnosis of type 2 diabetes mellitus.
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Minimum age
18
Years
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Maximum age
No limit
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key exclusion criteria
Significant renal impairment (eGFR < 30 mL/min), or women lactating, pregnant or of childbearing potential and unwilling to avoid becoming pregnant during the study.
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Non-randomised trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
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Who is / are masked / blinded?
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Intervention assignment
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Other design features
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Phase
Phase 4
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
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Date of first participant enrolment
Anticipated
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Actual
3/07/2014
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Date of last participant enrolment
Anticipated
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Actual
4/03/2016
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Date of last data collection
Anticipated
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Actual
31/08/2016
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Sample size
Target
30
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Accrual to date
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Final
24
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Recruitment in Australia
Recruitment state(s)
NSW
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Recruitment hospital [1]
14679
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St Vincent's Hospital (Darlinghurst) - Darlinghurst
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Recruitment postcode(s) [1]
27708
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2010 - Darlinghurst
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Funding & Sponsors
Funding source category [1]
303524
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Government body
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Name [1]
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National Health and Medical Research Council
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Address [1]
303524
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16 Marcus Clarke Street
Canberra, ACT, 2601
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Country [1]
303524
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Australia
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Primary sponsor type
Hospital
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Name
St Vincent's Hospital, Sydney
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Address
390 Victoria Street
Darlinghurst, NSW, 2010
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Country
Australia
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Secondary sponsor category [1]
303585
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None
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Name [1]
303585
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Address [1]
303585
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Country [1]
303585
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Ethics approval
Ethics application status
Approved
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Ethics committee name [1]
304050
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St Vincent's Hospital Human Research Ethics Committee
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Ethics committee address [1]
304050
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Research Office
Translational Research Centre
St Vincent's Hospital Sydney
97-105 Boundary Street
Darlinghurst, NSW, 2010
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Ethics committee country [1]
304050
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Australia
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Date submitted for ethics approval [1]
304050
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30/01/2014
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Approval date [1]
304050
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13/05/2014
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Ethics approval number [1]
304050
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Summary
Brief summary
Metformin is the first drug chosen to treat type 2 diabetes mellitus. However, the regulatory label warns against it use in people who also have chronic liver disease but there is little published data to support this warning. This study will investigate the safety and pharmacokinetics of metformin in patients with chronic liver disease (CLD) with or without type II diabetes mellitus (T2DM) who will be prescribed metformin (500 mg, immediate release, twice daily) for up to six weeks. We hypothesis that metformin at doses adjusted based on renal function can be safely administered to patients with CLD. Further, the pharmacokinetics of metformin in patients with CLD will be similar to those reported in patient with T2DM
and no CLD.
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Trial website
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
95650
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Prof Richard Day
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Address
95650
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Therapeutics Centre, Level 2 Xavier Building
St Vincent's Hospital, Sydney
390 Victoria Street, Darlinghurst, 2010, NSW
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Country
95650
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Australia
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Phone
95650
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+61 2 8382 2331
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Fax
95650
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+61 2 8382 2724
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Email
95650
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[email protected]
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Contact person for public queries
Name
95651
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Dr Sophie Stocker
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Address
95651
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Therapeutics Centre, Level 2 Xavier Building
St Vincent's Hospital, Sydney
390 Victoria Street, Darlinghurst, 2010, NSW
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Country
95651
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Australia
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Phone
95651
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+61 2 8382 2617
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Fax
95651
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+61 2 8382 2724
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Email
95651
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[email protected]
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Contact person for scientific queries
Name
95652
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Prof Richard Day
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Address
95652
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Therapeutics Centre, Level 2 Xavier Building
St Vincent's Hospital, Sydney
390 Victoria Street, Darlinghurst, 2010, NSW
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Country
95652
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Australia
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Phone
95652
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+61 2 8382 2331
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Fax
95652
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+61 2 8382 2724
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Email
95652
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[email protected]
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Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
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No/undecided IPD sharing reason/comment
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What supporting documents are/will be available?
No Supporting Document Provided
Results publications and other study-related documents
Documents added manually
No documents have been uploaded by study researchers.
Documents added automatically
Source
Title
Year of Publication
DOI
Embase
The safety and pharmacokinetics of metformin in patients with chronic liver disease.
2020
https://dx.doi.org/10.1111/apt.15635
N.B. These documents automatically identified may not have been verified by the study sponsor.
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