METFORMIN FOR ATRIAL FIBRILLATION (MAFT)

January 18, 2024 updated by: Eslam Abbas, MBChB, MSc, Arab Contractors Medical Centre

The Efficacy And Safety Of Metformin For The Treatment Of Atrial Fibrillation

The aim of this multicenter, pragmatic, open-label, randomized, placebo-controlled clinical trial is to test whether repurposing metformin for the treatment of atrial fibrillation will be effective in decreasing patients' hospitalization, adverse major cardiovascular events, and non-cancer death.

Participants will be randomized into 2 study arms (385 participant each), whereby:

  • The Metformin Group (MG): will receive metformin oral tablets in addition to the standard rate/rhythm control strategy and anticoagulation.
  • The Placebo Control Group (PCG): will receive placebo oral tablets as a control group in addition to the standard rate/rhythm control strategy and anticoagulation.

Then both arms will be compared according to the these endpoints:

  • The primary endpoint is hospitalization due to an episodic AF or an AF with a rapid or slow ventricular response (in the case of permanent AF).
  • The secondary endpoint is a composite of non-fatal major cardiovascular adverse events or non-cancer death.

The non-fatal major cardiovascular adverse events include:

  • Hospitalization due to heart failure.
  • Non-fatal myocardial infarction.
  • Non-fatal stroke.
  • Hospitalization due to unstable angina.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Detailed Description

  • Type of The Study: Interventional, Placebo-Controlled Clinical Trial.
  • Therapeutic Area: Cardiology, Arrhythmia.
  • Purpose: Treatment.
  • Aim: Whether repurposing metformin for the treatment of atrial fibrillation will be effective in decreasing patients' hospitalization, adverse major cardiovascular events, and non-cancer death.
  • Assignment: Parallel.
  • Allocation: Randomized.
  • Masking: Pragmatic, Open-Label.
  • Duration: 12 months of follow-up.
  • Rationale: Atrial fibrillation (AF) is the most common heart arrhythmia [1], in which atria contract rapidly and irregularly and the contraction of atria and ventricles is no longer coordinated. Current guidelines for the treatment of AF recommend medication to avoid blood clotting and stroke, control heart rate, and restore sinus rhythm. However, the available treatments show limited efficiency and may have side effects associated with increased morbidity and mortality [2], emphasizing an urgent need for new or repurposed therapies. Lal and colleagues [3] reported an integrative approach-combining transcriptomics, iPSCs, and epidemiological evidence-to identify and repurpose metformin, a main first-line medication for the treatment of type 2 diabetes, as an effective risk reducer for atrial fibrillation. Interestingly, metformin enhances the life span in invertebrate and vertebrate laboratory models [4], and similar gene-expression-based drug-repurposing studies targeting aging identified metformin, among others, as a pro-longevity agent [5]. Diabetes and AF are both age-associated and often co-morbid conditions. Metformin is being tested in the Targeting Aging with Metformin (TAME) trial [6] to develop effective next-generation drugs to increase healthspan and lifespan. Additionally, metformin seems to be associated with a lower risk of atrial fibrillation and ventricular arrhythmias as compared with another anti-diabetic drug category which is sulfonylureas [7]. The potential antiarrhythmic role of metformin in patients with AF could be due to the effects of metformin on preventing the structural and electrical remodeling of the left atrium via attenuating intracellular reactive oxygen species, activating 5' adenosine monophosphate-activated protein kinase, improving calcium homeostasis, attenuating inflammation, increasing connexin-43 gap junction expression, and restoring small conductance calcium-activated potassium channels current [8]. Despite the solid preclinical, integrative, and retrospective analyses, the effect of metformin on patients with AF regarding morbidity and mortality has not be established using a perspective, randomized, controlled trial.
  • Inclusion Criteria: Age more than 20 years and less than 65 years, willing and able to provide written informed consent prior to performing study procedures, and diagnosed by atrial fibrillation (first detected, paroxysmal, persistent, longstanding persistent, or permanent).
  • Exclusion Criteria: Critically-ill patients who are admitted to ICU, advanced congestive heart failure, liver cell failure, chronic kidney disease with eGFR <45 mL/min/1.73 m², diabetic ketoacidosis with or without coma, concomitant treatment with carbonic anhydrase inhibitors, septicemia, shock, hypoxia, dehydration, blood dyscrasias, pregnancy, lactation, chronic muscle diseases, acute trauma or burns within 2 weeks, and history of allergy to the implemented drugs.

  • Methods: 770 enrolled AF patients who are candidates for metformin treatment according to the study criteria at the time of presentation, will undergo the following at the time of enrollment and during the bimonthly follow-ups:

    • General and Local cardiac examination.
    • CBC.
    • Chemistry Panel including KFTs, LFTs.
    • Serum electrolytes levels.
    • Resting surface 12 leads ECG.
    • Baseline echocardiography.

  • Interventions:

    • Drug: metformin 850 mg oral tablets. Prescribed: Once daily PO with meals and 200 mL of water. The dose can be up-titrated to 1500-2000 mg divided q8-12hr with meals in enrolled diabetic patients as a monotherapy or combined with sulfonylurea.

Other Name: Glucophage.

  • Drug: Placebo oral tablets. Prescribed: Once daily PO with meals and 200 mL of water. Other Name: Placebo

    - Study Arms:

  • The Metformin Group (MG): 385 patients will receive metformin oral tablets in addition to the standard rate/rhythm control strategy and anticoagulation.
  • The Placebo Control Group (PCG): 385 patients will receive placebo oral tablets as a control group in addition to the standard rate/rhythm control strategy and anticoagulation.

Endpoints:

  • The primary endpoint is hospitalization due to an episodic AF or an AF with a rapid or slow ventricular response (in the case of permanent AF).
  • The secondary endpoint is a composite of non-fatal major cardiovascular adverse events or non-cancer death.

The non-fatal major cardiovascular adverse events include:

  • Hospitalization due to heart failure.
  • Non-fatal myocardial infarction.
  • Non-fatal stroke.

  • Hospitalization due to unstable angina.

    • Safety: In terms of safety, a composite of metformin side effects comprising GIT symptoms, hypoglycemia, and lactic acidosis will be considered.

  • Ethics: The study will be conducted in compliance with human studies committees' regulations of the authors' institutions and COPE guidelines, including patient consent as appropriate.
  • Competing Interests: The authors will declare any commercial or financial relationships that could be construed as a potential conflict of interest.

Study Type

Interventional

Enrollment (Estimated)

770

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Willing and able to provide written informed consent prior to performing study procedures.

  • Atrial fibrillation (first detected, paroxysmal, persistent, longstanding persistent, or permanent)*.

    * Types of atrial fibrillation:

  • First detected: only one diagnosed episode.
  • Paroxysmal: recurrent episodes that stop on their own in less than seven days.
  • Persistent: recurrent episodes that last more than seven days.
  • Longstanding persistent: recurrent episodes that last more than twelve months.
  • Permanent: atrial fibrillation that has been accepted, and for which a solely rate control strategy has been decided upon.

Exclusion Criteria:

  • Critically-ill patients who are admitted to ICU.
  • Advanced congestive heart failure.
  • Liver cell failure.
  • Chronic kidney disease with eGFR <45 mL/min/1.73 m².
  • Diabetic ketoacidosis with or without coma.
  • Concomitant treatment with carbonic anhydrase inhibitors.
  • Septicemia.
  • Shock.
  • Hypoxia.
  • Dehydration.
  • Blood Dyscrasias.
  • Alcoholism.
  • Pregnancy.
  • Lactation.
  • Chronic muscle diseases.
  • Acute trauma or burns within 2 weeks.
  • History of allergy to the implemented drugs.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: The Metformin Group (MG)

The group (n=385) will receive metformin oral tablets in addition to the standard rate/rhythm control strategy and anticoagulation.

• Drug: metformin 850 mg oral tablets. Prescribed: Once daily PO with meals and 200 mL of water. The dose can be up-titrated to 1500-2000 mg divided q8-12hr with meals in enrolled diabetic patients as a monotherapy or combined with sulfonylurea.

Other Name: Glucophage.
Drug: Metformin
Metformin 850 mg oral tablets. Prescribed: Once daily PO with meals and 200 mL of water. The dose can be up-titrated to 1500-2000 mg divided q8-12hr with meals in enrolled diabetic patients as a monotherapy or combined with sulfonylurea.
Other Names:
  • Glucophage, Glumetza, and Riomet.
Placebo Comparator: The Placebo Control Group (PCG)

The group (n=385) will receive placebo oral tablets in addition to the standard rate/rhythm control strategy and anticoagulation.

• Drug: Placebo oral tablets. Prescribed: Once daily PO with meals and 200 mL of water. Other Name: Placebo
Drug: Placebo
Placebo oral tablets. Prescribed: Once daily PO with meals and 200 mL of water.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Primary Endpoint
Time Frame: 12 months since randomization
The primary endpoint is hospitalization due to an episodic AF or an AF with a rapid or slow ventricular response (in the case of permanent AF).
12 months since randomization

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Secondary Endpoint
Time Frame: 12 months since randomization

The secondary endpoint is a composite of non-fatal major cardiovascular adverse events or non-cancer death.

The non-fatal major cardiovascular adverse events include:

  • Hospitalization due to heart failure.
  • Non-fatal myocardial infarction.
  • Non-fatal stroke.
  • Hospitalization due to unstable angina.
12 months since randomization

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Arab Contractors Medical Centre

Investigators

  • Principal Investigator: Eslam Abbas, MBBCh, MSC, Arab Contractors Medical Centre, and Dar El Salam Cancer Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

June 1, 2024

Primary Completion (Estimated)

January 1, 2025

Study Completion (Estimated)

April 1, 2025

Study Registration Dates

First Submitted

May 18, 2023

First Submitted That Met QC Criteria

May 18, 2023

First Posted (Actual)

May 26, 2023

Study Record Updates

Last Update Posted (Actual)

January 22, 2024

Last Update Submitted That Met QC Criteria

January 18, 2024

Last Verified

January 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • #18101829

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Data can be shared with researchers who submit a proposal with a valuable research question as assessed by the clinical research office of Al-Azhar University. Requests should be directed to the corresponding authors.

IPD Sharing Time Frame

Data that underlie the results reported in this study will be available upon publication.

IPD Sharing Access Criteria

Data can be shared with researchers who submit a proposal with a valuable research question.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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