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

Study Overview
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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.

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

Conditions
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Atrial Fibrillation

Intervention / Treatment
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* Drug: Metformin
* Behavioral: Lifestyle/Risk Factor Modification


Participation Criteria
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Eligibility Criteria
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TRIM-AF Cohorts Inclusion Criteria: 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. Paroxysmal AF, or persistent AF with plans for conversion. AF on cardiac implantable electrical device (CIED) over the past 3 months with at least 1 episode lasting ≥5 minutes. If on an antiarrhythmic drug, then on a stable regimen for the past 3 months. Exclusion Criteria: Permanent AF with no plans to convert to sinus rhythm. If in persistent AF, current episode >12 months in duration (current long-standing persistent AF) NYHA Functional Class IV heart failure On metformin or other pharmacologic therapy for diabetes mellitus. Use of anti-retroviral protease inhibitors (e.g. ombitasvir, paritaprevir, ritonavir, dasabuvir) or topiramate. Known sensitivity to metformin Moderate renal disease (eGFR <45 ml/min/1.73 m2) Significant alcohol use (average >2 drinks/day) Hepatic dysfunction - bilirubin >1.5x ULN, unless due to Gilbert's syndrome Planned antiarrhythmic (class I or III) drug change, AF ablation/PVI procedure or cardiac surgery over the first 3 mos of the study AF ablation/PVI procedure performed in the past 6 months Device changed or implanted in the past 3 months 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). Women who are pregnant, breast-feeding or of child-bearing potential and not willing or able to use an acceptable form of contraception. 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 Life expectancy less than 2 years due to concomitant disease. Age <18 years old. TRIM - No AF Cohort Inclusion Criteria: Permanent pacemaker or ICD (with or without CRT) with an implanted atrial lead capable of providing AF diagnostics and remote monitoring. No AF on CIED over the past 6 months. No history of AF. Age >/=18 years old. Exclusion Criteria: History of AF. NYHA Functional Class IV heart failure On metformin or other pharmacologic therapy for diabetes mellitus. Use of anti-retroviral protease inhibitors (e.g. ombitasvir, paritaprevir, ritonavir, dasabuvir) or topiramate. Moderate renal disease (eGFR <45 ml/min/1.73 m2) Significant alcohol use (average >2 drinks/day) Hepatic dysfunction - bilirubin >1.5x ULN, unless due to Gilbert's syndrome Planned antiarrhythmic (class I or III) drug change, cardiac surgery over the first 3 mos of the study Device changed or implanted in the past 3 months 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). Women who are pregnant, breast-feeding or of child-bearing potential and not willing or able to use an acceptable form of contraception. 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 Life expectancy less than 2 years due to concomitant disease. Age <18 years old.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Single


Arms and Interventions

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

What is the study measuring?
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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 |