Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12614001180606
Ethics application status
Approved
Date submitted
2/10/2014
Date registered
11/11/2014
Date last updated
23/07/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
The renal handling of metformin in the setting of impaired kidney function
Scientific title
A pharmacokinetic study of renal clearance of metformin in patients with impaired renal function.
Secondary ID [1] 285429 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
renal disease 293188 0
type 2 diabetes 293225 0
Condition category
Condition code
Renal and Urogenital 293462 293462 0 0
Kidney disease
Metabolic and Endocrine 293494 293494 0 0
Diabetes

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The proposed research will be an open label, single dose pharmacokinetic study. Each volunteer will receive a single dose of metformin 500mg orally followed by 7 blood samples over 24 hours. The sampling schedule is based on the known pharmacokinetics of metformin (half life ~ 6 hours) with intensive sampling in the first 2 hours to capture drug absorption, followed by further sampling over 24 hours to capture drug excretion (e.g. 15-30 minutes, 30-60 minutes, 90-120 minutes, 4, 6, 8 and 24 hours for the measurement of metformin, gentamicin, creatinine (3 samples), urate (3 samples), and cystatin C (1 sample)). Timed urine samples (0-3, 3–8, 8–24 hours) will be collected to determine the renal clearances of metformin, urate, creatinine, and gentamicin. Note that urate will provide a control for tubular function. In addition, we
will administer a single dose of gentamicin 40mg by IV injection at the same time as the metformin dose. This a commonly used antibiotic but it being used here as a marker for glomerular filtration rate
(GFR). This will provide an accurate ‘control’ for GFR. Subjects will be stratified into 3 groups based on kidney
function; eGFR 1) > 60mL/min, 2) >30 and =< 60mL/min, 3) =<30mL/min. This will allow us to quantify the impact of
different stages of renal disease on metformin renal handling. We intend to recruit 45 subjects (15/group).
Intervention code [1] 290354 0
Treatment: Drugs
Comparator / control treatment
There is no control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 293282 0
metformin renal clearance - assessed by the measurement and analysis of plasma and urine concentrations of metformin (note that both plasma and urine concentrations are needed to assess this primary outcome)
Timepoint [1] 293282 0
Plasma concentrations measured post-dose at 15-30 minutes, 30-60 minutes, 90-120 minutes, 4, 6, 8 and 24 hours.
Timed urine concentrations measured at 0-3, 3–6, 6–24 hours.
Secondary outcome [1] 310709 0
Gentamicin clearance (a marker for GFR) - assessed by the measurement and analysis of plasma concentrations of gentamicin
Timepoint [1] 310709 0
Plasma concentrations measured post-dose at 15-30 minutes, 30-60 minutes, 90-120 minutes, 4, 6, 8 and 24 hours.
Secondary outcome [2] 310786 0
Creatinine clearance (the gold standard for assessing kidney function clinically) - assessed by the measurement and analysis of plasma and urine concentration of creatinine
Timepoint [2] 310786 0
Plasma concentrations measured post-dose at 15-30 minutes, 30-60 minutes, 90-120 minutes, 4, 6, 8 and 24 hours.
Timed urine concentrations measured at 0-3, 3–6, 6–24 hours.
Secondary outcome [3] 310787 0
urate renal clearance - assessed by the measurement and analysis of urate plasma and urine concentrations
Timepoint [3] 310787 0
Plasma concentrations measured post-dose at 15-30 minutes, 30-60 minutes, 90-120 minutes, 4, 6, 8 and 24 hours.
Timed urine concentrations measured at 0-3, 3–6, 6–24 hours.

Eligibility
Key inclusion criteria
1. Subjects with a measured eGFR either <=30mL/min, between >30 & <= 60mL/min and > 60 mL/min
2. Subjects who are >18 years of age.

Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Subjects who are unable or unwilling to give written informed consent
2. Subjects with Type 2 diabetes or who are currently taking metformin
3. Subjects with evidence of >25% change in eGFR in the past month
4. Significant asthma, heart failure or any condition associated with a fragile fluid balance (potential reaction to beta-blockade)
5. Pregnancy
6. Known allergy to medication classes; biguanides or aminoglycosides.
7. The concomitant use of drugs known or suspected to interact with the tubular transport of metformin or creatinine including: antibiotics (unless a 2 week washout), beta-blockers, calcium channel blockers, antiarrhythmic drugs, H2 blockers, thiazide diuretics (unless a 7 day washout), antituberculosis drugs, and probenecid.

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)
Subjects will be approached, recruited and enrolled either by convenience sampling from a known cohort of renal patients (under the care of a co-investigator) or from print advertisements. All subjects under go the same study procedures, i.e. they will receive a single 500mg dose of metformin - there is no treatment allocation.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
not applicable
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 4
Type of endpoint/s
Pharmacokinetics
Statistical methods / analysis
non-linear mixed effects modelling to compare the pharmacokinetics of metformin in subjects with different degrees of renal function.

We intend to recruit 15 subjects into each renal function group for a total of 45 subjects. There are no published studies designed to investigate the relationship between GFR and metformin renal clearance and therefore no basis for a sample size calculation. A previous study looking at the pathways of renal drug elimination using a cocktail of markers included 12 subjects total, while a previous study by our research group examining tubular function in those with impaired renal function used 45 subjects.

Recruitment
Recruitment status
Stopped early
Data analysis
Data collected is being analysed
Reason for early stopping/withdrawal
Participant recruitment difficulties
Date of first participant enrolment
Anticipated
24/11/2014
Actual
24/11/2014
Date of last participant enrolment
Anticipated
26/02/2016
Actual
27/11/2017
Date of last data collection
Anticipated
Actual
27/11/2017
Sample size
Target
45
Accrual to date
Final
32
Recruitment outside Australia
Country [1] 6387 0
New Zealand
State/province [1] 6387 0
Otago

Funding & Sponsors
Funding source category [1] 290035 0
University
Name [1] 290035 0
University of Otago Research Grant
Country [1] 290035 0
New Zealand
Primary sponsor type
Individual
Name
Dr Dan Wright
Address
PO Box 56, School of Pharmacy
University of Otago, Dunedin, New Zealand 9056
Country
New Zealand
Secondary sponsor category [1] 288726 0
None
Name [1] 288726 0
none
Address [1] 288726 0
none
Country [1] 288726 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 291743 0
Health and Disability Ethics Committees (HDEC)
Ethics committee address [1] 291743 0
Ministry of Health
No 1 The Terrace
PO Box 5013
Wellington 6145
Ethics committee country [1] 291743 0
New Zealand
Date submitted for ethics approval [1] 291743 0
03/10/2014
Approval date [1] 291743 0
20/10/2014
Ethics approval number [1] 291743 0

Summary
Brief summary
Metformin is the first-line treatment for Type-2 diabetes. There is currently no clear consensus on the safe prescribing of metformin in patients with impaired renal function and concern that these individuals are at increased risk of serious side effects. The renal handling of metformin in patients with kidney dysfunction is poorly understood. This project aims to clarify the impact of kidney function on metformin renal handling. This information will provide the scientific basis for a revised dosing guideline for patients with renal impairment.
Trial website
nil
Trial related presentations / publications
nil to date
Public notes
nil
Attachments [1] 198 198 0 0
/AnzctrAttachments/367192-Protocol_metforminstudy_FINAL.pdf

Contacts
Principal investigator
Name 51826 0
Dr Daniel Wright
Address 51826 0
PO Box 56, School of Pharmacy
University of Otago, Dunedin, New Zealand 9056
Country 51826 0
New Zealand
Phone 51826 0
+6434797290
Fax 51826 0
Email 51826 0
[email protected]
Contact person for public queries
Name 51827 0
Dr Daniel Wright
Address 51827 0
PO Box 56, School of Pharmacy
University of Otago, Dunedin, New Zealand 9056
Country 51827 0
New Zealand
Phone 51827 0
+6434797290
Fax 51827 0
Email 51827 0
[email protected]
Contact person for scientific queries
Name 51828 0
Dr Daniel Wright
Address 51828 0
PO Box 56, School of Pharmacy
University of Otago, Dunedin, New Zealand 9056
Country 51828 0
New Zealand
Phone 51828 0
+6434797290
Fax 51828 0
Email 51828 0
[email protected]

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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