Targeting Risk Interventions and Metformin for Atrial Fibrillation (TRIM-AF)

NCT ID: NCT03603912

Last Updated: 2025-09-12

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

ACTIVE_NOT_RECRUITING

Clinical Phase

PHASE4

Total Enrollment

175 participants

Study Classification

INTERVENTIONAL

Study Start Date

2018-08-24

Study Completion Date

2026-12-31

Brief Summary

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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).

Detailed Description

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The purpose of this study is to perform a prospective, randomized study for the reduction of atrial fibrillation (AF) burden and progression, targeting metabolic upstream therapies. The study aims to determine if metformin and/or lifestyle/risk factor modifications reduce AF burden and progression. A secondary aim will attempt to determine clinical, genomic, and biomarker predictors of AF progression that can be used to personalize upstream therapies. This is a prospective randomized open-label blinded endpoint (PROBE) 2x2 factorial study of metformin extended release up to 750 mg twice daily and lifestyle and risk factor modification (LRFM) in patients with implanted pacemakers or defibrillators with atrial leads and at least 1 ≥5 minute episode of AF over the prior 3 months.

Conditions

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Atrial Fibrillation

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

FACTORIAL

Primary Study Purpose

TREATMENT

Blinding Strategy

SINGLE

Outcome Assessors

Study Groups

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Control

Written educational literature on healthy eating and exercise guideline

Group Type NO_INTERVENTION

No interventions assigned to this group

Metformin

Metformin ER up to 750 mg twice daily

Group Type EXPERIMENTAL

Metformin

Intervention Type DRUG

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.

Lifestyle/Risk Factor Modification

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

Group Type EXPERIMENTAL

Lifestyle/Risk Factor Modification

Intervention Type BEHAVIORAL

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).

Metformin + LRFM

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

Group Type EXPERIMENTAL

Metformin

Intervention Type DRUG

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.

Lifestyle/Risk Factor Modification

Intervention Type BEHAVIORAL

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).

No Atrial Fibrillation

Written educational literature on healthy eating and exercise guideline

Group Type NO_INTERVENTION

No interventions assigned to this group

Interventions

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Metformin

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.

Intervention Type DRUG

Lifestyle/Risk Factor Modification

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).

Intervention Type BEHAVIORAL

Other Intervention Names

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Metformin HCL LRFM

Eligibility Criteria

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Inclusion Criteria

1. 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.
2. Paroxysmal AF, or persistent AF with plans for conversion.
3. AF on cardiac implantable electrical device (CIED) over the past 3 months with at least 1 episode lasting ≥5 minutes.
4. If on an antiarrhythmic drug, then on a stable regimen for the past 3 months.


1. Permanent pacemaker or ICD (with or without CRT) with an implanted atrial lead capable of providing AF diagnostics and remote monitoring.
2. No AF on CIED over the past 6 months.
3. No history of AF.
4. Age \>/=18 years old.

Exclusion Criteria

1. Permanent AF with no plans to convert to sinus rhythm.
2. If in persistent AF, current episode \>12 months in duration (current long-standing persistent AF)
3. NYHA Functional Class IV heart failure
4. On metformin or other pharmacologic therapy for diabetes mellitus.
5. Use of anti-retroviral protease inhibitors (e.g. ombitasvir, paritaprevir, ritonavir, dasabuvir) or topiramate.
6. Known sensitivity to metformin
7. Moderate renal disease (eGFR \<45 ml/min/1.73 m2)
8. Significant alcohol use (average \>2 drinks/day)
9. Hepatic dysfunction - bilirubin \>1.5x ULN, unless due to Gilbert's syndrome
10. Planned antiarrhythmic (class I or III) drug change, AF ablation/PVI procedure or cardiac surgery over the first 3 mos of the study
11. AF ablation/PVI procedure performed in the past 6 months
12. Device changed or implanted in the past 3 months
13. 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).
14. Women who are pregnant, breast-feeding or of child-bearing potential and not willing or able to use an acceptable form of contraception.
15. 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
16. Life expectancy less than 2 years due to concomitant disease.
17. Age \<18 years old.

TRIM - No AF Cohort


1. History of AF.
2. NYHA Functional Class IV heart failure
3. On metformin or other pharmacologic therapy for diabetes mellitus.
4. Use of anti-retroviral protease inhibitors (e.g. ombitasvir, paritaprevir, ritonavir, dasabuvir) or topiramate.
5. Moderate renal disease (eGFR \<45 ml/min/1.73 m2)
6. Significant alcohol use (average \>2 drinks/day)
7. Hepatic dysfunction - bilirubin \>1.5x ULN, unless due to Gilbert's syndrome
8. Planned antiarrhythmic (class I or III) drug change, cardiac surgery over the first 3 mos of the study
9. Device changed or implanted in the past 3 months
10. 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).
11. Women who are pregnant, breast-feeding or of child-bearing potential and not willing or able to use an acceptable form of contraception.
12. 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
13. Life expectancy less than 2 years due to concomitant disease.
14. Age \<18 years old.
Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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American Heart Association

OTHER

Sponsor Role collaborator

The Cleveland Clinic

OTHER

Sponsor Role collaborator

Mina Chung, MD

OTHER

Sponsor Role lead

Responsible Party

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Mina Chung, MD

Principal Investigator, Professor of Medicine

Responsibility Role SPONSOR_INVESTIGATOR

Principal Investigators

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Mina K Chung, MD

Role: PRINCIPAL_INVESTIGATOR

The Cleveland Clinic

Locations

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Cleveland Clinic

Cleveland, Ohio, United States

Site Status

Countries

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United States

References

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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.

Reference Type DERIVED
PMID: 39671157 (View on PubMed)

Other Identifiers

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18-757

Identifier Type: -

Identifier Source: org_study_id

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