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Trial registered on ANZCTR


Registration number
ACTRN12616001188426
Ethics application status
Approved
Date submitted
18/07/2016
Date registered
30/08/2016
Date last updated
22/08/2019
Date data sharing statement initially provided
22/08/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A clnical trIal comparing the effect of treatment with oral spironolactone compared with a placebo on the frequency and duration of atrIal fibrillation in patients with an implanted cardiac device in New Zealand.
Scientific title
A double blind, randoMIsed controlled cliNical trIal comparing the effect of treatment with oral MRA (spironolactone) versus placebo on the frequency and duration of atrIal fibrillation in patients with an implanted cardiac device in New Zealand: MINIMIZE-AF
Secondary ID [1] 289700 0
None
Universal Trial Number (UTN)
U111111843974
Trial acronym
MINIMIZE-AF
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Atrial Fibrillation 299515 0
Condition category
Condition code
Cardiovascular 299492 299492 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
We will test the ability of the oral mineralocorticoid receptor antagonist (MRA), spironolactone, to prevent Atrial Fibrillation (AF) by performing a randomised controlled clinical trial and using monitoring features of implanted pacemakers to accurately document AF. Participants will be randomised 1:1 to receive either placebo or spironolactone 50mg per day for 18 months.
The dose of the study drug will be adjusted by the study doctor every 3 months during the 18 month intervention period according to renal function (eGFR) and potassium (K+) biochemistry levels.
.
The starting drug dose will be 25mg/d, titrated to 50mg/d after 4 weeks if K+ is <5mmol/L
If the baseline eGFR is 30-50ml/min/1.73m2, the starting dose will be 25mg on alternate days and titrated to 25mg daily at 4 weeks if K+ <5mmol/L
The dose will be halved if K+ increases into the range 5.5 - 6mmol/L or eGFR falls <15ml/min/1.73m2. Following dose reduction, blood tests will be repeated K+ / eGFR in 72hrs and doses continued if K+ <5 and eGFR >30ml/min/1.73m2
Study drug withheld if K+>6mmol/L, restart at half dose only if K+<5mmol/L at 72hrs
Study drug withheld if eGFR <15ml/min/1.73m2 and restarted once eGFR > 30ml/min/1.73m2
Medications will be counted as a check on adherence at all study visits.
Intervention code [1] 295327 0
Treatment: Drugs
Comparator / control treatment
placebo tablets: ingredients lactose, microcrystalline cellulose and magnesium stearate
Control group
Placebo

Outcomes
Primary outcome [1] 298970 0
Total burden (frequency and duration) of episodic AF assessed by uploaded pacemaker monitoring records,
Timepoint [1] 298970 0
Pacemaker records will be uploaded at baseline and every 3 months for 18 months to allow measurement of time in AF.
Primary outcome [2] 298971 0
This is a composite primary outcome to determine the effect of MRA treatment on echocardiographic measures of left atrial remodeling including atrial size and mechanical function
Timepoint [2] 298971 0
Echocardiography will be performed at baseline and every 3 months for 18 months.
Primary outcome [3] 298972 0
To determine the effect of MRA treatment on biological markers of cardiac loading from blood sample. e.g., BNP/NT-proBNP, aldosterone, plasma renin activity, angiotensin-II..
Timepoint [3] 298972 0
At baseline, 12 and 18 months.
Secondary outcome [1] 325778 0
Renal function by eGFR from serum samples.
Timepoint [1] 325778 0
Renal function will be assessed at baseline and 3 monthly for 18 months.
Secondary outcome [2] 326813 0
Hyperkalaemia
Timepoint [2] 326813 0
Plasma potassium levels (K+) will be measured at baseline, 1 month, 3 months and 3 monthly for 18 months. .

Eligibility
Key inclusion criteria
Patients with an implanted cardiac device capable of recording the frequency and duration of AF events and with
evidence of AF or AHRE within the 6months
prior to recruitment will be eligible.
Inclusion criteria: age >18 years (without childbearing
potential for women); with an implantable device capable of
AF or AHRE monitoring; and with device documented AF or AHRE (defined as AHRE >220 bpm for >2% of the time
or for > 5mins on at least one occasion) in the last 6months.
Minimum age
19 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Permanent AF,
Receiving AF suppression pacing
History of heart failure with indication for MRAs
A clinical indication for MRA or K+ sparing diuretic
Contraindication to MRA
Severe renal dysfunction
Sustained hyperkalaemia in the absence of reversible cause

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Randomisation will done by a telephone based interface using a computer generated randomisation sequence in permuted blocks. Randomisation will be stratified by patient age (< or >/= 70 years), whether they are dependent on ventricular pacing or not (complete heart block etc) and by known duration < 6-months or >/= 6-months of paroxysmal AF or AHRE events to avoid potential confounding related to these risk factors for permanent AF. Use of anti-arrhythmic and anti-hypertensive therapy will not be stratified and is expected to be adequately controlled by overall randomisation.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
a computer generated randomisation sequence in permuted blocks
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
Intervention assignment
Parallel
Other design features
none
Phase
Phase 4
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
The primary outcome, percentage of time in AF over the 18 months will be compared between randomised groups using 1-way ANOVA, or Mann-Whitney U tests if the assumptions for parametric analyses are not met. The relationship of the time since randomisation and treatment effect will be explored using repeated-measures ANOVA. The secondary outcomes of AF episodes and admission will be compared between groups using Poisson regression models. The changes over 18 months in functional, hormonal and inflammation markers will be compared between groups using 1-way ANOVA, with any of these measures showing extreme non-normality log-transformed prior to analysis. A two-tailed p-value <0.05 will be taken to indicate statistical significance.

Power analysis and sample size:
Based on local experience using telemetry data from a cohort of patients relevant to the study, a power calculation has been undertaken. The mean % time in AF extrapolated over 18 months for this group – who were not receiving an MRA and have had >2% time in AF in the last 6 months, was 18% with a standard deviation of approximately 12%. To show an absolute 6% decline in this rate (from 18% to 12%, relative risk reduction of 0.66) with 80% power (2-tailed alpha=0.05) would require a sample size of 65 patients per group, 130 in total. There may be some attrition of patients over the 18 months of the study (15%), therefore a total of 150 patients will be recruited.

Recruitment
Recruitment status
Recruiting
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 outside Australia
Country [1] 8038 0
New Zealand
State/province [1] 8038 0
Canterbury

Funding & Sponsors
Funding source category [1] 294081 0
Government body
Name [1] 294081 0
Health Research Council of New Zeakand
Address [1] 294081 0
PO Box 5541, Wellesley Street, Auckland 1141
Country [1] 294081 0
New Zealand
Primary sponsor type
University
Name
University of Otago
Address
PO Box 4345
Christchurch 8140
Country
New Zealand
Secondary sponsor category [1] 292911 0
None
Name [1] 292911 0
none
Address [1] 292911 0
none
Country [1] 292911 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295496 0
Southern Health and Disability Ethics Committee
Ethics committee address [1] 295496 0
Ministry of Health
Ethics Department
Freyberg Building
Reception – Ground Floor
20 Aitken Street
Wellington 6011
Ethics committee country [1] 295496 0
New Zealand
Date submitted for ethics approval [1] 295496 0
19/07/2016
Approval date [1] 295496 0
24/08/2016
Ethics approval number [1] 295496 0

Summary
Brief summary
Atrial fibrillation (AF) is an irregular heart rhythm that is common and is associated with impaired heart function, stroke and increased risk of hospitalisation or death. Aldosterone and other substances that activate mineralocorticoid receptors usually play a role in maintaining blood pressure and blood volume, but recent evidence suggest that they may also contribute to the development of AF. The proposed study will test whether blockade of mineralocorticoid receptors with an oral medication called spironolactone that is already proven to be beneficial for subjects with heart failure, can also reduce AF in subjects who already have a cardiac pacemaker. Using the cardiac pacemaker will allow more accurate detection of the total number and duration of episodes of AF. Participants in the study will receive either daily spironolactone or placebo tablets for 18 months and the difference in number of AF episodes will be identified from pacemaker recordings
Trial website
none
Trial related presentations / publications
none
Public notes
none

Contacts
Principal investigator
Name 67490 0
Prof Richard Troughton
Address 67490 0
Department of Medicine
University of Otago, Christchurch
PO Box 4345
Christchurch 8140
Country 67490 0
New Zealand
Phone 67490 0
+6433640640
Fax 67490 0
+6433641115
Email 67490 0
richard.troughton@cdhb.health.nz
Contact person for public queries
Name 67491 0
Ms Lorraine Skelton
Address 67491 0
Department of Medicine
University of Otago, Christchurch
PO Box 4345
Christchurch 8140
Country 67491 0
New Zealand
Phone 67491 0
+6433641063
Fax 67491 0
+6433641115
Email 67491 0
lorraine.skelton@cdhb.health.nz
Contact person for scientific queries
Name 67492 0
Prof Richard Troughton
Address 67492 0
Department of Medicine
University of Otago, Christchurch
PO Box 4345
Christchurch 8140
Country 67492 0
New Zealand
Phone 67492 0
+6433640640
Fax 67492 0
+6433641115
Email 67492 0
richard.troughton@cdhb.health.nz

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
Summary results
No Results