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

Upstream Targeting for the Prevention of Atrial Fibrillation: Targeting Risk Interventions and Metformin for Atrial Fibrillation (TRIM-AF)

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).

Study Overview

• Status: Active, not recruiting
• Conditions: Atrial Fibrillation
• Intervention / Treatment: Drug: Metformin; Behavioral: Lifestyle/Risk Factor Modification

Detailed 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.

• Study Type: Interventional
• Enrollment (Estimated): 270
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Single

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Control; Written educational literature on healthy eating and exercise guideline
Experimental: Metformin; Metformin ER up to 750 mg twice daily	Drug: 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.; Other Names: Metformin HCL
Experimental: Lifestyle/Risk Factor Modification; Lifestyle/Risk Factor Modification (LRFM): Diet/nutrition, exercise, and risk factor modification	Behavioral: 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).; Other Names: LRFM
Experimental: Metformin + LRFM; Metformin ER up to 750 mg twice daily + Lifestyle/Risk Factor Modification (LRFM) diet/nutrition, exercise, and risk factor modification	Drug: 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.; Other Names: Metformin HCL; Behavioral: 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).; Other Names: LRFM
No Intervention: No Atrial Fibrillation; Written educational literature on healthy eating and exercise guideline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total time of AF/3 mos	Total time of AF per 3 month period	3 months, 1 year, 2 years
Average %time in AF/day	Average percent time in AF/day	3 months, 1 year, 2 years
%change in average AF time/day	Percent change in average AF time/day from baseline	Baseline to 3 months, 1 year, 2 years
Number of days of AF	Number of days of AF over the time period	3 months, 1 year, 2 years
Number of AF episodes/month	Number of AF episodes/month over the time period	3 months, 1 year, 2 years
Longest duration of AF at each 3 mo. period	Longest duration at each 3 mo. period over the time period	3 months, 1 year, 2 years
Change in AF burden without blanking period	Composite of change from baseline to 1 year of average daily AF burden % and survival at 1 year.	1 year
AF density	a measure of AF temporal aggregation, calculated using daily AF burden time over the study period	1 year, 2 years
Time to next AF and to persistent AF	Time to next AF and to persistent AF with and without a 3 mo. blanking period	Up to 2 years
Incidence of Persistent AF	Development of persistent AF over the study period	3 months, 1 year, 2 years
Cardioversion for AF	Electrical cardioversion procedures over the study period	3 months, 1 year, 2 years
AF ablation/pulmonary vein isolation (PVI) for increase in burden or persistent AF	Occurrence of AF ablation/PVI procedures over the study period.	3 months, 1 year, 2 years
Change of antiarrhythmic drug	Change or new initiation of class I or III antiarrhythmic drug over the study period.	3 months, 1 year, 2 years
Change in Atrial Fibrillation Symptom Score (AFSS)	Changes in Atrial Fibrillation Symptom Score (AFSS) from baseline - Global well-being (1-10), AF duration (1-8, lower denotes longer duration AF), AF severity (1-10, higher denotes more severe AF), ER visits (0-7), Hospitalizations (0-7), Specialist visits (0-7)	Baseline, 1 year, 2 years
Change in Short Form-36 (SF-36) scores	Change in SF-36 scores from baseline. SF-36 has 8 scaled scores; scores are weighted sums of the questions in each section. Scores range from 0-100 with lower scores indicating more disability, higher scores indicating less disability. Sections are: Vitality, physical functioning, bodily pain, general health perceptions, physical role functioning, emotional role functioning, social role functioning, mental health.	Baseline, 1 year, 2 years
Change in physical assessment questionnaire scores: Rapid Assessment of Physical Activity (RAPA)	Change in physical assessment questionnaire score from baseline. RAPA 1 Aerobic score 1-7, high more active. RAPA 2 Strength & Flexibility score 0-3 (higher more strength and flexibility)	Baseline, 1 year, 2 years
Change in GPCOG questionnaire score	Change in General Practitioner assessment of Cognition (GPCOG) questionnaire score from baseline. Step 1: Score 0-4 Cognitive impairment is indicated; 5-8 More information required; 9 No significant cognitive impairment	Baseline, 1 year, 2 years
Change in weight	Change in weight (pounds) from baseline	baseline, 1 year, 2 years
Change in body fat composition	Change in body fat composition (%) from baseline.	baseline, 1 year, 2 years
Change in BMI	Change in body mass index (BMI, kg/m2) from baseline (calculated from weight, height)	Baseline, 1 year, 2 years
Change in waist/hip ratio	Change in waist/hip ratio from baseline	Baseline, 1 year, 2 years
Change in HbA1c	Change in HbA1c (%) from baseline	Baseline, 1 year, 2 years
Change in total cholesterol	Change in total cholesterol from baseline	Baseline, 1 year, 2 years
Change in LDL	Change in LDL from baseline	Baseline, 1 year, 2 years
Change in HDL	Change in HDL from baseline	Baseline, 1 year, 2 years
Change in triglycerides	Change in triglycerides from baseline	Baseline, 1 year, 2 years
Change in Homeostatic Model Assessment - Insulin Resistance (HOMA-IR)	Change in HOMA-IR from baseline (calculated from fasting blood sugar and insulin)	Baseline, 1 year, 2 years
Composite Major Adverse Cardiovascular Events (MACE)	Composite incidence of cardiovascular death, nonfatal stroke, nonfatal myocardial infarction	1 year, 2 years
All-cause mortality	Incidence of all-cause death	1 year, 2 years
Stroke	Incidence of stroke	1 year, 2 years
Transient ischemic attack	Incidence of transient ischemic attack	1 year, 2 years
Activity by implanted device	Daily activity as measured by the sensors in the implanted pacemaker or defibrillator device (hours/day)	3 months, 1 year, 2 years

Collaborators and Investigators

• Sponsor: Mina Chung, MD
• Collaborators: The Cleveland Clinic; American Heart Association
• Investigators: Principal Investigator: Mina K Chung, MD, The Cleveland Clinic

Study record dates

Study Major Dates

• Study Start (Actual): August 24, 2018
• Primary Completion (Estimated): August 1, 2025
• Study Completion (Estimated): December 1, 2025

Study Registration Dates

• First Submitted: July 12, 2018
• First Submitted That Met QC Criteria: July 20, 2018
• First Posted (Actual): July 27, 2018

Study Record Updates

• Last Update Posted (Estimated): February 9, 2024
• Last Update Submitted That Met QC Criteria: February 7, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Arrhythmias, Cardiac; Atrial Fibrillation; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: 18-757

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes