NCT03603912

Brief Summary

Prospective randomized open-label blinded endpoint (PROBE) 2x2 factorial study of metformin extended release up to 750 mg BID and lifestyle and risk factor modification (LRFM) in CIED patients with at least 1 ≥5 minute episode of AF over the prior 3 months. Randomization will be stratified by pacemaker vs. ICD and rhythm at enrollment (sinus rhythm/atrial paced vs. AF).

Trial Health

75
On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment
175

participants targeted

Target at P25-P50 for phase_4 atrial-fibrillation

Timeline
7mo left

Started Aug 2018

Longer than P75 for phase_4 atrial-fibrillation

Geographic Reach
1 country

1 active site

Status
active not recruiting

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

Study Progress94%
Aug 2018Dec 2026

First Submitted

Initial submission to the registry

July 12, 2018

Completed
15 days until next milestone

First Posted

Study publicly available on registry

July 27, 2018

Completed
28 days until next milestone

Study Start

First participant enrolled

August 24, 2018

Completed
8.3 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

December 1, 2026

Expected
Same day until next milestone

Study Completion

Last participant's last visit for all outcomes

December 1, 2026

Last Updated

September 12, 2025

Status Verified

August 1, 2025

Enrollment Period

8.3 years

First QC Date

July 12, 2018

Last Update Submit

September 8, 2025

Conditions

Atrial Fibrillation

Outcome Measures

Primary Outcomes (1)

  • Change in AF burden

    Composite of change from baseline to 1 year of average daily AF burden % after a 3 month blanking period and survival at 1 year.

    1 year

Secondary Outcomes (32)

  • Total time of AF/3 mos

    3 months, 1 year, 2 years

  • Average %time in AF/day

    3 months, 1 year, 2 years

  • %change in average AF time/day

    Baseline to 3 months, 1 year, 2 years

  • Number of days of AF

    3 months, 1 year, 2 years

  • Number of AF episodes/month

    3 months, 1 year, 2 years

  • +27 more secondary outcomes

Study Arms (5)

Control

NO INTERVENTION

Written educational literature on healthy eating and exercise guideline

Metformin

EXPERIMENTAL

Metformin ER up to 750 mg twice daily

Drug: Metformin

Lifestyle/Risk Factor Modification

EXPERIMENTAL

Lifestyle/Risk Factor Modification (LRFM): Diet/nutrition, exercise, and risk factor modification

Behavioral: Lifestyle/Risk Factor Modification

Metformin + LRFM

EXPERIMENTAL

Metformin ER up to 750 mg twice daily + Lifestyle/Risk Factor Modification (LRFM) diet/nutrition, exercise, and risk factor modification

Drug: MetforminBehavioral: Lifestyle/Risk Factor Modification

No Atrial Fibrillation

NO INTERVENTION

Written educational literature on healthy eating and exercise guideline

Interventions

MetforminDRUG

Metformin ER 500 mg daily, titrated at 1 month intervals to 500 mg twice daily, then 750 mg twice daily, as tolerated, for 2 years.

Also known as: Metformin HCL
MetforminMetformin + LRFM
Lifestyle/Risk Factor ModificationBEHAVIORAL

Diet/nutrition counseling and exercise prescription with follow-up visits, sleep apnea screening and treatment if detected, optimization of guideline-directed medical therapies for hypertension, coronary artery disease (CAD), hyperlipidemia and heart failure (HF).

Also known as: LRFM
Lifestyle/Risk Factor ModificationMetformin + LRFM

Eligibility Criteria

Age18 Years+
Sexall
Healthy VolunteersNo
Age GroupsAdult (18-64), Older Adult (65+)

You may qualify if:

  • Permanent pacemaker or implantable cardioverter-defibrillator (ICD) (with or without cardiac resynchronization therapy (CRT) with an implanted atrial lead capable of providing AF diagnostics and remote monitoring.
  • Paroxysmal AF, or persistent AF with plans for conversion.
  • AF on cardiac implantable electrical device (CIED) over the past 3 months with at least 1 episode lasting ≥5 minutes.
  • If on an antiarrhythmic drug, then on a stable regimen for the past 3 months.

You may not qualify if:

  • Permanent AF with no plans to convert to sinus rhythm.
  • If in persistent AF, current episode \>12 months in duration (current long-standing persistent AF)
  • NYHA Functional Class IV heart failure
  • On metformin or other pharmacologic therapy for diabetes mellitus.
  • Use of anti-retroviral protease inhibitors (e.g. ombitasvir, paritaprevir, ritonavir, dasabuvir) or topiramate.
  • Known sensitivity to metformin
  • Moderate renal disease (eGFR \<45 ml/min/1.73 m2)
  • Significant alcohol use (average \>2 drinks/day)
  • Hepatic dysfunction - bilirubin \>1.5x ULN, unless due to Gilbert's syndrome
  • Planned antiarrhythmic (class I or III) drug change, AF ablation/PVI procedure or cardiac surgery over the first 3 mos of the study
  • AF ablation/PVI procedure performed in the past 6 months
  • Device changed or implanted in the past 3 months
  • For patients on dofetilide with a pacemaker, QTc \>490 ms if QRS duration is \</=100 ms. If QRS duration is \>100 ms, adjusted QTc \>490 ms. Adjusted QTc = QTc - (QRS duration - 100 ms).
  • Women who are pregnant, breast-feeding or of child-bearing potential and not willing or able to use an acceptable form of contraception.
  • Participants considered by the investigator to be unsuitable for the study for any of the following reasons: Not agreeable for treatment with metformin or anticipated to have poor compliance on study drug treatment; inability to follow diet or exercise instructions; unwilling to attend study follow-up visits
  • +21 more criteria

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (1)

Cleveland Clinic

Cleveland, Ohio, 44195, United States

Location

Related Publications (1)

  • Wass SY, Barnard J, Kim HS, Sun H, Telfer W, Schilling T, Barzilai B, Bruemmer D, Cho L, Huang J, Hussein A, Kashyap SR, Laffin L, Mehra R, Moravec C, Saliba W, Sanders P, Nissen S, Varma N, Smith J, Van Wagoner D, Chung MK. Upstream targeting for the prevention of atrial fibrillation: Targeting Risk Interventions and Metformin for Atrial Fibrillation (TRIM-AF)-rationale and study design. J Interv Card Electrophysiol. 2025 Jan;68(1):9-19. doi: 10.1007/s10840-024-01955-z. Epub 2024 Dec 13.

    PMID: 39671157DERIVED

MeSH Terms

Conditions

Atrial Fibrillation

Interventions

Metformin

Condition Hierarchy (Ancestors)

Arrhythmias, CardiacHeart DiseasesCardiovascular DiseasesPathologic ProcessesPathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

BiguanidesGuanidinesAmidinesOrganic Chemicals

Study Officials

  • Mina K Chung, MD

    The Cleveland Clinic

    PRINCIPAL INVESTIGATOR

Study Design

Study Type
interventional
Phase
phase 4
Allocation
RANDOMIZED
Masking
SINGLE
Who Masked
OUTCOMES ASSESSOR
Purpose
TREATMENT
Intervention Model
FACTORIAL
Sponsor Type
OTHER
Responsible Party
SPONSOR INVESTIGATOR
PI Title
Principal Investigator, Professor of Medicine

Study Record Dates

First Submitted

July 12, 2018

First Posted

July 27, 2018

Study Start

August 24, 2018

Primary Completion (Estimated)

December 1, 2026

Study Completion (Estimated)

December 1, 2026

Last Updated

September 12, 2025

Record last verified: 2025-08

Data Sharing

IPD Sharing
Will not share

Locations

US(1)