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

• Status: Recruiting
• Trial end date: 2023-06-30
• Target enrollment: 0
• Participant gender: All

Summary

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.

• Phase: Phase 4
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Mina Chung, MD
• Collaborators: American Heart Association; The Cleveland Clinic
• Treatments: Metformin

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. New York Heart Association (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. History of lactic acidosis

10. History of hepatic dysfunction - bilirubin >1.5x upper limits of normal, unless due to Gilbert's syndrome

11. Planned antiarrhythmic (class I or III) drug change, AF ablation/PVI procedure or cardiac surgery over the first 3 mos of the study

12. AF ablation/PVI procedure performed in the past 6 months

13. Device changed or implanted in the past 3 months

14. For patients on dofetilide, corrected QT interval (QTc) >490 ms if QRS duration is 100 ms, adjusted QTc >490 ms. Adjusted QTc = QTc - (QRS duration - 100 ms).

15. Women who are pregnant, breast-feeding or of child-bearing potential and not willing or able to use an acceptable form of contraception.

16. 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. History of lactic acidosis

8. Hepatic dysfunction - bilirubin >1.5x ULN, unless due to Gilbert's syndrome

9. Planned antiarrhythmic (class I or III) drug change, cardiac surgery over the first 3 mos of the study

10. Device changed or implanted in the past 3 months

11. For patients on dofetilide with a pacemaker, QTc >490 ms if QRS duration isIf QRS duration is >100 ms, adjusted QTc >490 ms. Adjusted QTc = QTc - (QRS duration - 100 ms).

12. Women who are pregnant, breast-feeding or of child-bearing potential and not willing or able to use an acceptable form of contraception.

13. 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

14. Life expectancy less than 2 years due to concomitant disease.

15. Age <18 years old.