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

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.

Study Overview

• Status: Unknown
• Conditions: Atrial Fibrillation
• Intervention / Treatment: Drug: Placebo oral tablet; Drug: Spironolactone 25mg

• Study Type: Interventional
• Enrollment (Anticipated): 184
• Phase: Phase 2

Contacts and Locations

Study Locations

• Singapore
  • Singapore, Singapore, 308433
    • Not yet recruiting
    • Tan Tock Seng Hospital
    • Contact: Wee Kian Kenny Tan; Email: Kenny_WK_TAN@ttsh.com.sg
  • Singapore, Singapore, 529889
    • Not yet recruiting
    • Changi General Hospital
    • Contact: Vern Hsen Tan; Email: tan.vern.hsen@singhealth.com.sg
  • Singapore, Singapore, 119074
    • Recruiting
    • National University Hospital
    • Contact: Pipin Kojodjojo; Email: pipin_kojodjojo@nuhs.edu.sg
  • Singapore, Singapore, 609606
    • Recruiting
    • Ng Teng Fong General Hospital
    • Contact: Pipin Kojodjojo; Email: pipin_kojodjojo@nuhs.edu.sg

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 100 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Active; 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; Mineralocorticoid Receptor Antagonists
Placebo Comparator: Control; 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; Placebo

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

Collaborators and Investigators

• Sponsor: National University Hospital, Singapore
• Collaborators: University of Otago

Study record dates

Study Major Dates

• Study Start (Actual): May 23, 2018
• Primary Completion (Anticipated): May 31, 2022
• Study Completion (Anticipated): May 31, 2022

Study Registration Dates

• First Submitted: June 12, 2019
• First Submitted That Met QC Criteria: March 30, 2020
• First Posted (Actual): March 31, 2020

Study Record Updates

• Last Update Posted (Actual): March 31, 2020
• Last Update Submitted That Met QC Criteria: March 30, 2020
• Last Verified: June 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Arrhythmias, Cardiac; Atrial Fibrillation; Physiological Effects of Drugs; Hormones, Hormone Substitutes, and Hormone Antagonists; Natriuretic Agents; Diuretics; Hormone Antagonists; Mineralocorticoid Receptor Antagonists; Diuretics, Potassium Sparing; Spironolactone
• Other Study ID Numbers: Monitor-AF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No