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

Mina Chung, MD

Status and phase: Active, not recruiting; Phase 4

Conditions: Atrial Fibrillation

Treatments: Behavioral: Lifestyle/Risk Factor Modification; Drug: Metformin

Study type: Interventional

Funder types: Other

Identifiers

NCT03603912

18-757

Details and patient eligibility

About

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).

Full description

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.

Enrollment: 175 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

TRIM-AF Cohorts

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.

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

Inclusion Criteria:

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. 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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Factorial Assignment

Masking: Single Blind

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175 participants in 5 patient groups

Control

No Intervention group

Description:

Written educational literature on healthy eating and exercise guideline

Metformin

Experimental group

Description:

Metformin ER up to 750 mg twice daily

Treatment:

Drug: Metformin

Lifestyle/Risk Factor Modification

Experimental group

Description:

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

Treatment:

Behavioral: Lifestyle/Risk Factor Modification

Metformin + LRFM

Experimental group

Description:

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

Treatment:

Drug: Metformin

Behavioral: Lifestyle/Risk Factor Modification

No Atrial Fibrillation

No Intervention group

Description:

Written educational literature on healthy eating and exercise guideline