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Trial registered on ANZCTR


Registration number
ACTRN12617001418369
Ethics application status
Approved
Date submitted
8/09/2017
Date registered
9/10/2017
Date last updated
3/12/2020
Date data sharing statement initially provided
13/08/2019
Type of registration
Retrospectively registered

Titles & IDs
Public title
Can metformin be safely used in patients with heart failure?
Scientific title
The safety and pharmacokinetics of metformin in heart failure
Secondary ID [1] 290200 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Chronic heart failure 300358 0
Condition category
Condition code
Cardiovascular 300225 300225 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Metformin hydrochloride (oral tablet immediate release formulation).
This study is both observational and interventional. The observational segment (Study A and Study B) will provide a platform for the safe intervention in Study C.

Study A and Study B:
Firstly, Study A, a cross-sectional survey will be conducted of patients with T2DM and heart failure, already on metformin. If the patient consents (patient information and consent form), one whole blood sample (4 mL) will be collected at the screening visit. This will be used to test for metformin concentrations, lactate concentrations, NT-ProBNP, biochemical parameters and genetic polymorphisms of transporters involved in the uptake and secretion of metformin.

Secondly, Study B, a cross-sectional survey will be conducted of patients without T2DM and heart failure, not on metformin. If the patient consents (patient information and consent form), one whole blood sample (4 mL) will be collected at the screening visit to analyse only NT-ProBNP and lactate concentrations.

In both Study A and B the patients will be recruited at the time of a clinic visit, for one visit only.

Study C - This section involves a larger interventional clinical trial dosing metformin in patients with heart failure, no T2DM and not already taking metformin. At the screening visit the patient’s demographics, medical conditions and current treatments will be recorded. The patients will also undergo a medical examination and blood collection for the determination of baseline plasma metformin concentrations to check that the patient is not currently taking metformin. Additionally, if the patient consents (separate patient information and consent form), one whole blood sample (4 mL) will be collected at the screening visit. This will be used to test for genetic polymorphisms of transporters involved in the uptake and secretion of metformin. Patients will start a low dose of metformin (500 mg once daily). The dose of metformin will be increased after 3 days to 1000 mg per day (500 mg twice daily) for 12 weeks. A patient diary will also be given to patients to record the times of drug administration for the entire study period.

Patients will attend study visits (for blood collection) at week 2, 4, 6, 8 and 12 after initiation of metformin dosing to monitor their on-going safety whilst on metformin. Blood collected at each of the study visits will be used to determine the same parameters as listed above. In addition, HbA1c will be assessed at weeks 8 and 12. The study doctors will review and sign off on all blood results from each patient. Any abnormal blood results will be followed up at an additional study visit in order to more closely monitor the patient’s safety. Patients will also have an opportunity to report any adverse effects they may be experiencing and/or any other concerns they may have at each study visit.

The procedures for the exit visit are the same for the screening visit as described above (with the exclusion of the metformin prescription). Patients will be asked to return any remaining tablets of metformin as well as their study diary at the exit visit.
Intervention code [1] 295958 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 299705 0
To establish the safety of metformin in patients with heart failure

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.

Study C - 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). 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] 299705 0
Within 3 hours of drug administration prior to 12pm. Venous blood samples and health status assessments will be collected on each study visit during week 0, 2, 4, 6, 8 and 12.
Primary outcome [2] 303591 0
Study A - To establish preliminary safety measures in patients with T2DM, heart failure and already on metformin
Timepoint [2] 303591 0
One study visit only with time and date of last metformin dose noted
Primary outcome [3] 303592 0
Study B - To measure the lactate concentrations and NT-ProBNP concentrations in patients with heart failure but no T2DM or on metformin
Timepoint [3] 303592 0
One study visit only
Secondary outcome [1] 327900 0
Metformin

This will be achieved by collection a minimum of 6 samples across 12 weeks. Several pharmacokinetic parameters will be calculated including AUC and Vd.
Timepoint [1] 327900 0
Study C - Within 3 hours of drug administration prior to 12pm. Venous blood samples will be collected on each study visit during week 0, 2, 4, 6, 8 and 12.

Study A - within 24 hours of their last dose. Venous blood samples will be collected on one visit only.
Secondary outcome [2] 338726 0
NT-ProBNP
Timepoint [2] 338726 0
Study C - Within 3 hours of drug administration prior to 12pm. Venous blood samples will be collected on each study visit during week 0 and 12.
Study A and B - Venous blood samples will be collected on one visit only.
Secondary outcome [3] 339525 0
HbA1C
Timepoint [3] 339525 0
Study C - Within 3 hours of drug administration prior to 12pm. Venous blood samples will be collected on each study visit during week 0 and 12.
Study A - Venous blood samples will be collected on one visit only.
Secondary outcome [4] 339526 0
Insulin
Timepoint [4] 339526 0
Study C - Within 3 hours of drug administration prior to 12pm. Venous blood samples will be collected on each study visit during week 0 and 12.
Study A - Venous blood samples will be collected on one visit only.
Secondary outcome [5] 339527 0
Glucose
Timepoint [5] 339527 0
Study C - Within 3 hours of drug administration prior to 12pm. Venous blood samples will be collected on each study visit during week 0 and 12.
Study A - Venous blood samples will be collected on one visit only.
Secondary outcome [6] 339528 0
Lactate
Timepoint [6] 339528 0
Study C - Within 3 hours of drug administration prior to 12pm. Venous blood samples will be collected on each study visit during week 0 and 12.
Study A and B - Venous blood samples will be collected on one visit only.
Secondary outcome [7] 373821 0
Metabolites relating to the effect of metformin in heart failure independant of T2DM. Metabolites of interest include BCAA's (leucine, isoleucine and valine) and free fatty acids. Pathways of interest will include glycolysis, central carbon pathways and lipids.
Timepoint [7] 373821 0
Study C - Within 3 hours of drug administration prior to 10am. Venous blood samples will be collected for week 0 and week 12. Study A and B will not be included in this outcome.

Eligibility
Key inclusion criteria
Study B & C - Patients with heart failure (NYHA Grade I-III, Preserved or Reduced Ejection Fraction)
Patients not currently taking metformin

Study A - Patients with heart failure (NYHA Grade I-III, Preserved or Reduced Ejection Fraction)
Patients currently taking metformin
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients who are currently on metformin

Patients who have type II diabetes mellitus (Study B & C Only)

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.

Patients with grade IV heart failure

Patients with chronic kidney disease ( creatinine clearance < 30 ml/min)

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
Single group
Other design features
Phase
Phase 4
Type of endpoint/s
Safety
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
26/07/2017
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
50
Accrual to date
20
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 6708 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment hospital [2] 14532 0
Liverpool Hospital - Liverpool
Recruitment postcode(s) [1] 14349 0
2010 - Darlinghurst
Recruitment postcode(s) [2] 27546 0
2170 - Liverpool

Funding & Sponsors
Funding source category [1] 294564 0
Government body
Name [1] 294564 0
Australian Research Council
Country [1] 294564 0
Australia
Funding source category [2] 294566 0
Hospital
Name [2] 294566 0
St Vincent's Hospital Sydney
Country [2] 294566 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] 293433 0
None
Name [1] 293433 0
Address [1] 293433 0
Country [1] 293433 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 296000 0
St Vincent's Hospital Human Research Ethics Committee
Ethics committee address [1] 296000 0
Research Office
Translational Research Centre
St Vincent's Hospital, Sydney,
97-105 Boundary Street
Darlinghurst, 2010, NSW.
Ethics committee country [1] 296000 0
Australia
Date submitted for ethics approval [1] 296000 0
19/11/2015
Approval date [1] 296000 0
16/02/2016
Ethics approval number [1] 296000 0

Summary
Brief summary
Type 2 diabetes increases the risk of heart failure by 50%. The risk of increased cardiac events in patients who are have diabetes and heart failure are high. Metformin has been shown to reduce all cause mortality in cardiovascular patients, especially reducing the risk of event such as myocardial infarction.

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

This study will consist of a study into the safety and pharmacokinetics of metformin in this patient group.

In the first arm patients (n=50) will receive 500 mg of metformin once per day for the first 3 days and then increased to 1000 mg (500mg twice daily) from day 4 up to 12 weeks.

We hypothesis that low dose metformin can be safely given to heart failure patients.
Trial website
N/A
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 69210 0
Prof Richard Day
Address 69210 0
Therapeutics Centre, Level 2 Xavier Building,
St Vincent's Hospital, Sydney,
390 Victoria Street, Darlinghurst, 2010, NSW,
Country 69210 0
Australia
Phone 69210 0
+61 2 8382 2331
Fax 69210 0
+61 2 8382 2724
Email 69210 0
[email protected]
Contact person for public queries
Name 69211 0
Gina Chowdhury
Address 69211 0
Therapeutics Centre, Level 2 Xavier Building,
St Vincent's Hospital, Sydney,
390 Victoria Street, Darlinghurst, 2010, NSW,
Country 69211 0
Australia
Phone 69211 0
+61 2 8382 2011
Fax 69211 0
+61 2 8382 2724
Email 69211 0
[email protected]
Contact person for scientific queries
Name 69212 0
Richard Day
Address 69212 0
Therapeutics Centre, Level 2 Xavier Building,
St Vincent's Hospital, Sydney,
390 Victoria Street, Darlinghurst, 2010, NSW,
Country 69212 0
Australia
Phone 69212 0
+61 2 8382 2331
Fax 69212 0
+61 2 8382 2724
Email 69212 0
[email protected]

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
No additional documents have been identified.