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Trial registered on ANZCTR


Registration number
ACTRN12616000675426
Ethics application status
Approved
Date submitted
17/05/2016
Date registered
24/05/2016
Date last updated
8/05/2017
Type of registration
Retrospectively registered

Titles & IDs
Public title
Can metformin be used safely in dialysis patients?
Scientific title
The safety and pharmacokinetics of metformin in type 2 diabetes patients undergoing dialysis for end stage kidney disease.
Secondary ID [1] 289236 0
None.
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Type 2 diabetes mellitus 298807 0
End stage kidney disease. 298808 0
Condition category
Condition code
Metabolic and Endocrine 298855 298855 0 0
Diabetes
Renal and Urogenital 298856 298856 0 0
Kidney disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Arm 1 (Pharmacokinetic sub-study): Patients on haemodialysis (n=5) will receive 500 mg of metformin hydrochloride (oral tablet, immediate release formulation) after each dialysis session (3 dialysis sessions per week, 1500 mg/ week) for 12 weeks.

Arm 2 and 3 ( Extended Pharmacokinetic study and Safety study): Patients on haemodialysis (n=10, n=50) will receive 250 mg of metformin hydrochloride (oral tablet, immediate release formulation) after each dialysis session (3 dialysis sessions per week, 750 mg/ week) for 24 weeks. These two arms differ only in the timings of blood sampling for pharmacokinetic analysis at each study visit.

Patients will take their doses within 30 minutes of dialysis ending along with their normal medication. Nursing staff take record of all the doses administered, this is be used to determine compliance.
Intervention code [1] 294773 0
Treatment: Drugs
Comparator / control treatment
No control group.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 298333 0
To establish the safety of metformin in patients undergoing haemodialysis.


At each study visit, all patients will have their health status assessed, including any significant changes in their blood results (lactate, biocarbonate and/or anion gap). They will be asked about the occurrence of any severe gastrointestinal events (vomiting and/or diarrhoea) which may indicate lactic acidosis. If lactic acidosis is suspected (symptoms of lactic acidosis in association with low bicarbonate and high anion gap concentrations), arterial pH will be measured.

In addition, the safety of metformin will also be judged by the plasma concentrations of lactate (upper limit 5 mmol/L) and metformin (upper limit 5 mg/L). For Arms 2 and 3 if plasma lactate or metformin concentrations are above their respective limits, metformin will be either ceased or the dosage reduced, based on the treating clinician's judgment. Should a patient’s metformin dose require adjustment during the study, the patient will be monitored more closely again, as from the beginning of the protocol.
Timepoint [1] 298333 0
Arm 1: 12 weeks after the commencement of metformin therapy.

Arm 2 & 3: 24 weeks after the commencement of metformin therapy.
Secondary outcome [1] 323872 0
To describe the pharmacokinetics of metformin in patients on haemodialysis.

This will be achieved by collected a number of blood samples for the quantification of metformin. Dialyzer clearance, fraction of dose extracted, Cmax, AUC and time to steady state will be calculated for both plasma and blood.

Timepoint [1] 323872 0
Arm 1: Serial arterial (blood going into the dialyzer) and venous (blood going out of the dialyzer) samples will be collected throughout the dialysis session at the end of weeks 1, 2, 3, 4, 8 and 12. In addition after the first dose, at the end of week 1 and 8 bloods will be collected at 4, 24 and 42 (pre-dialysis) hours post dose. The serial samples taken throughout the dialysis session will be used to determine the rate and extent of metformin removal through the dialyzer. The samples taken post-dose will be used to determine the stability of metformin concentrations between dialysis sessions.

Arm 2: Arterial and venous samples will be collected at the start and end of dialysis on weeks 1, 2, 4, 6, 8, 12, 16, 20, 24 of metformin therapy. The purpose of this study is to provide more information on the rate and extent of metformin removal through the dialysis machine and determine the time to steady state.

Arm 3: A single venous sample will be collected at the start of the dialysis session on weeks 1, 2, 4, 6, 8, 12, 16, 20, 24 of metformin therapy.

Eligibility
Key inclusion criteria
Patients with type 2 diabetes mellitus and end-stage kidney disease.
Patients currently undergoing either haemodialysis or peritoneal dialysis.
Patients not currently taking metformin.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Women lactating, pregnant or of childbearing potential who are not willing to avoid becoming pregnant during the study.

Patients with a history of a psychological illness or condition such as to interfere with the patient's ability to understand the requirements of the study.

Patients with a history of lactic acidosis.

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
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Arm 1 will be recruited and treated first, to determine the short-term safety of metformin and some basic pharmacokinetic characteristics.

Arm 2 and 3 will be recruited after the completion of Arm 1.
Phase
Phase 4
Type of endpoint(s)
Safety
Statistical methods / analysis
Lactate concentrations will be analysed using a repeat-meansures ANOVA to determine any trends. A 20% increase in lactate concentrations from baseline will be considered clinically significant.

To calculate the sample size we took the average plasma lactate concentration to be 1.8 mmol/L with a standard deviation, 0.8 mmol/L (taken from a previous study Duong et al., 2013. Clin Pharmacokinect. 52(5): 373-384). The number of patients required to demonstrate a clinically significant change (20%) from baseline is n= 80 (type 1 error rate - 5%, study power - 0.8).

Pharmacokinetic parameters will be calculated using standard equations.

Recruitment
Recruitment status
Stopped early
Data analysis
Data collected is being analysed
Reason for early stopping/withdrawal
Safety concerns
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 5804 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst

Funding & Sponsors
Funding source category [1] 293613 0
Charities/Societies/Foundations
Name [1] 293613 0
Diabetes Australia Research Trust
Address [1] 293613 0
Level 1, 101 Northbourne Ave
TURNER ACT 2612
Country [1] 293613 0
Australia
Primary sponsor type
Hospital
Name
St Vincent's Hospital Sydney
Address
390 Victoria Street, Darlinghurst, 2010, NSW.
Country
Australia
Secondary sponsor category [1] 292432 0
None
Name [1] 292432 0
Address [1] 292432 0
Country [1] 292432 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295054 0
St Vincent's Hospital Human Research Ethics Committee
Ethics committee address [1] 295054 0
Research Office, Level 6 deLacy Building,
St Vincent's Hospital, Sydney,
390 Victoria Street,
Darlinghurst, 2010, NSW.
Ethics committee country [1] 295054 0
Australia
Date submitted for ethics approval [1] 295054 0
30/01/2014
Approval date [1] 295054 0
17/06/2014
Ethics approval number [1] 295054 0
HREC14/SVH/020

Summary
Brief summary
Type 2 diabetes is a leading cause of end-stage kidney disease (ESKD). The risk of cardiovascular complications is high in diabetic dialysed patients. Metformin has been shown to reduce these complications. However, it is not used in these patients due to the risk (very low) of acidosis.

To address this urgent health problem, we aim to investigate the safety of low dose metformin in these patients.

This study will consist of 3 arms, the pharmacokinetics arm, the extended pharmacokinetics arm and the safety arm.

In the first arm patients (n=5) will receive 500 mg of metformin after dialysis for 12 weeks.

In the second (n=10) and thrid arm (n=50) patients will receive 250 mg of metformin after dialysis (3 dialysis session per week) for 24 weeks.

We hypothesis that low dose metformin can be safely given to dialysis patients.
Trial website
N/A
Trial related presentations / publications
Smith FC, Gangaram SV, Kumar SS, et al. The safe use of metformin patients with end-stage kidney disease on haemodialysis. [Abstract number 532]. APSA-ASCEPT Joint Scientific Meeting 2015, Hobart, 29 Nov – 2 Dec.

Gangaram SV, Kumar SS, Graham GG, et al. Metformin pharmacokinetics in haemodialysis. [Abstract number 581]. ASCEPT-MPGPCR Joint Scientific Meeting 2014, Melbourne, 7-11 Dec.
Public notes

Contacts
Principal investigator
Name 65914 0
Prof Richard Day
Address 65914 0
Therapeutics Centre, Level 2 Xavier Building,
St Vincent's Hospital, Sydney,
390 Victoria Street, Darlinghurst, 2010, NSW,
Australia.
Country 65914 0
Australia
Phone 65914 0
+61 2 8382 2331
Fax 65914 0
+61 2 8382 2724
Email 65914 0
r.day@unsw.edu.au
Contact person for public queries
Name 65915 0
Miss Felicity Smith
Address 65915 0
Therapeutics Centre, Level 2 Xavier Building,
St Vincent's Hospital, Sydney,
390 Victoria Street, Darlinghurst, 2010, NSW,
Australia.
Country 65915 0
Australia
Phone 65915 0
+61 2 8382 2011
Fax 65915 0
+61 2 8382 2724
Email 65915 0
felicity.smith@unsw.edu.au
Contact person for scientific queries
Name 65916 0
Prof Richard Day
Address 65916 0
Therapeutics Centre, Level 2 Xavier Building,
St Vincent's Hospital, Sydney,
390 Victoria Street, Darlinghurst, 2010, NSW,
Australia.
Country 65916 0
Australia
Phone 65916 0
+61 2 8382 2331
Fax 65916 0
+61 2 8382 2724
Email 65916 0
r.day@unsw.edu.au

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary