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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
Scientific title
The pharmacokinetics and safety of metformin in patients with liver disease
Secondary ID [1] 298984 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Chronic liver disease 314222 0
Condition category
Condition code
Metabolic and Endocrine 312585 312585 0 0
Diabetes
Oral and Gastrointestinal 312717 312717 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon

Intervention/exposure
Study type
Interventional
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.
Intervention code [1] 315433 0
Treatment: Drugs
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.
Control group
Historical

Outcomes
Primary outcome [1] 321239 0
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).
Timepoint [1] 321239 0
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.
Secondary outcome [1] 374426 0
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.
Timepoint [1] 374426 0
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.

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.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 4
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
3/07/2014
Date of last participant enrolment
Anticipated
Actual
4/03/2016
Date of last data collection
Anticipated
Actual
31/08/2016
Sample size
Target
30
Accrual to date
Final
24
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 14679 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment postcode(s) [1] 27708 0
2010 - Darlinghurst

Funding & Sponsors
Funding source category [1] 303524 0
Government body
Name [1] 303524 0
National Health and Medical Research Council
Country [1] 303524 0
Australia
Primary sponsor type
Hospital
Name
St Vincent's Hospital, Sydney
Address
390 Victoria Street
Darlinghurst, NSW, 2010
Country
Australia
Secondary sponsor category [1] 303585 0
None
Name [1] 303585 0
Address [1] 303585 0
Country [1] 303585 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 304050 0
St Vincent's Hospital Human Research Ethics Committee
Ethics committee address [1] 304050 0
Research Office
Translational Research Centre
St Vincent's Hospital Sydney
97-105 Boundary Street
Darlinghurst, NSW, 2010
Ethics committee country [1] 304050 0
Australia
Date submitted for ethics approval [1] 304050 0
30/01/2014
Approval date [1] 304050 0
13/05/2014
Ethics approval number [1] 304050 0

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.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 95650 0
Prof Richard Day
Address 95650 0
Therapeutics Centre, Level 2 Xavier Building
St Vincent's Hospital, Sydney
390 Victoria Street, Darlinghurst, 2010, NSW
Country 95650 0
Australia
Phone 95650 0
+61 2 8382 2331
Fax 95650 0
+61 2 8382 2724
Email 95650 0
r.day@unsw.edu.au
Contact person for public queries
Name 95651 0
Dr Sophie Stocker
Address 95651 0
Therapeutics Centre, Level 2 Xavier Building
St Vincent's Hospital, Sydney
390 Victoria Street, Darlinghurst, 2010, NSW
Country 95651 0
Australia
Phone 95651 0
+61 2 8382 2617
Fax 95651 0
+61 2 8382 2724
Email 95651 0
sophie.stocker@svha.org.au
Contact person for scientific queries
Name 95652 0
Prof Richard Day
Address 95652 0
Therapeutics Centre, Level 2 Xavier Building
St Vincent's Hospital, Sydney
390 Victoria Street, Darlinghurst, 2010, NSW
Country 95652 0
Australia
Phone 95652 0
+61 2 8382 2331
Fax 95652 0
+61 2 8382 2724
Email 95652 0
r.day@unsw.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


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
SourceTitleYear of PublicationDOI
EmbaseThe safety and pharmacokinetics of metformin in patients with chronic liver disease.2020https://dx.doi.org/10.1111/apt.15635
N.B. These documents automatically identified may not have been verified by the study sponsor.