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

Phase 4Active Not RecruitingNCT03603912

Mina Chung, MD175 enrolled

Overview

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).

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

SINGLE

Enrollment

175

Conditions

Atrial Fibrillation

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.

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).

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Locations (1)

Cleveland Clinic

Cleveland, Ohio, United States

Outcomes

Primary Outcomes

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.

Time frame: 1 year