Mineralocorticoid Antagonism to Stop Progression of Atrial Fibrillation (MONITOR-AF) Study

Study Overview
=================
Brief Summary
-----------------
This proposal details the implementation of an international (Singapore and New Zealand) multi-centre study to test a novel therapeutic strategy aimed at reducing the burden of atrial fibrillation - an important medical condition with major healthcare implications. Unique aspects of this study include i) a non-arrhythmic treatment target (mineralocorticoid receptor antagonism) -targeting the arrhythmogenic substrate of AF before it becomes permanently established, ii) the use of pacemaker monitoring capability to accurately document AF burden, thus increasing the power of the study and iii) multi-national collaborative, double blind design.

Official Title
-----------------
Mineralocorticoid Antagonism to Stop Progression of Atrial Fibrillation (MONITOR-AF) Study

Conditions
-----------------
Atrial Fibrillation

Intervention / Treatment
-----------------
* Drug: Spironolactone 25mg
* Drug: Placebo oral tablet


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age > 21 years (without child-bearing potential for women); With a permanent pacemaker capable of AF monitoring; Device documented AF in the last 12 months; Defined as: i. atrial high rate events (AHRE) > 220 bpm for >1% of the time; or ii. > 6 mins on at least one occasion Exclusion Criteria: Persistent (defined as sustained AF lasting continuously for 7 or more days) History of heart failure with indication for MRAs Any existing clinical indication for MRA or K+ sparing diuretic such as uncontrolled hypertension or oedema Contraindication to MRA Severe renal dysfunction (eGFR <30ml/min by CKD-Epi) Sustained hyperkalaemia (defined as K+ >5mmol/L in the absence of reversible cause) Receiving AF suppression pacing Women of child bearing potential Patients taking medications which may interact with the study drug or increase the level of potassium in the blood, include lithium, amiloride, cyclosporine, eplerenone, tacrolimus, and triamterene.

Ages Eligible for Study
-----------------
Minimum Age: 21 Years
Maximum Age: 100 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active<br>For patients randomized to active experimental arm: Spironolactone Patient will receive study drug for 18 months. Study drug dosages are 1 tablet alternate day, 1 tablet per day, or 2 tablets per day, with 1 tablet being 25mg spironolactone. Study drugs are titrated every 3 months based on patients' potassium and eGFR blood tests results. | Drug: Spironolactone 25mg<br>* Mineralocorticoid Receptor Antagonists<br>|
| Placebo Comparator: Control<br>For patients randomized to control arm: Placebo Patient will receive placebo for 18 months. Placebo dosages are 1 tablet alternate day, 1 tablet per day, or 2 tablets per day. Placebo are titrated every 3 months based on patients' potassium and eGFR blood tests results. | Drug: Placebo oral tablet<br>* Placebo<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Development of persistent AF (defined as the first episode of sustained AF lasting for more than 7 days) | Development of persistent AF (defined as the first episode of sustained AF lasting for more than 7 days) | 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of total time in AF. | Percentage of total time in AF. | 18 months | 
| Number of AF episodes | Number of AF episodes > 5 minutes duration recorded on pacemaker | 18 months | 
| Number of symptomatic AF episodes | Number of symptomatic AF episodes | 18 months | 
| Number of admissions for AF | Number of admissions for AF | 18 months | 
| Change in LA volumes in millimetre | Change in LA volumes in millimetre assessed by echo scan | 18 months | 
| Change in LV volumes in millimetre | Change in LV volumes in millimetre assessed by echo scan | 18 months | 
| Change in systolic and diastolic function | Change in systolic and diastolic function assessed by echo scan | 18 months | 
| Change in cardiac and systemic markers | Change in cardiac and systemic markers of stretch assessed by biomarkers blood tests - NT-proBNP | 18 months | 
| Change in cardiac and systemic markers of inflammation | Change in cardiac and systemic markers of inflammation assessed by biomarkers blood tests - hsCRP, myeloperoxidase, ST-2, GD-15, Galectin-3 | 18 months | 
| Change in cardiac and systemic markers of fibrosis | Change in cardiac and systemic markers of fibrosis assessed by biomarkers blood tests - PIIP, type 1 and II procollagen | 18 months |