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

Phase 4

Active, not recruiting

• Conditions: Atrial Fibrillation
• Interventions: Behavioral: Lifestyle/Risk Factor Modification; Drug: Metformin

• Registration Number: NCT03603912
• Lead Sponsor: Mina Chung, MD

Brief Summary

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

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.

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study First Submitted: 2018-07-12
• Study First Submitted QC: 2018-07-20
• Study First Posted: 2018-07-27
• Study Start: 2018-08-24
• Status Verified: 2024-08
• Last Update Submitted: 2024-08-28
• Last Update Posted: 2024-08-29
• Primary Completion: 2025-08
• Study Completion: 2025-12

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 175

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.

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: FACTORIAL

Arm && Interventions

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

Primary Outcome Measures

Name	Time	Method
Change in AF burden	1 year	Composite of change from baseline to 1 year of average daily AF burden % after a 3 month blanking period and survival at 1 year.

Secondary Outcome Measures

Name	Time	Method
Total time of AF/3 mos	3 months, 1 year, 2 years	Total time of AF per 3 month period
Average %time in AF/day	3 months, 1 year, 2 years	Average percent time in AF/day
%change in average AF time/day	Baseline to 3 months, 1 year, 2 years	Percent change in average AF time/day from baseline
Number of days of AF	3 months, 1 year, 2 years	Number of days of AF over the time period
Number of AF episodes/month	3 months, 1 year, 2 years	Number of AF episodes/month over the time period
Longest duration of AF at each 3 mo. period	3 months, 1 year, 2 years	Longest duration at each 3 mo. period over the time period
Change in AF burden without blanking period	1 year	Composite of change from baseline to 1 year of average daily AF burden % and survival at 1 year.
AF density	1 year, 2 years	a measure of AF temporal aggregation, calculated using daily AF burden time over the study period
Change in LDL	Baseline, 1 year, 2 years	Change in LDL from baseline
Time to next AF and to persistent AF	Up to 2 years	Time to next AF and to persistent AF with and without a 3 mo. blanking period
Incidence of Persistent AF	3 months, 1 year, 2 years	Development of persistent AF over the study period
Cardioversion for AF	3 months, 1 year, 2 years	Electrical cardioversion procedures over the study period
AF ablation/pulmonary vein isolation (PVI) for increase in burden or persistent AF	3 months, 1 year, 2 years	Occurrence of AF ablation/PVI procedures over the study period.
Change of antiarrhythmic drug	3 months, 1 year, 2 years	Change or new initiation of class I or III antiarrhythmic drug over the study period.
Change in Atrial Fibrillation Symptom Score (AFSS)	Baseline, 1 year, 2 years	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)
Change in Short Form-36 (SF-36) scores	Baseline, 1 year, 2 years	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.
Change in BMI	Baseline, 1 year, 2 years	Change in body mass index (BMI, kg/m2) from baseline (calculated from weight, height)
Change in physical assessment questionnaire scores: Rapid Assessment of Physical Activity (RAPA)	Baseline, 1 year, 2 years	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)
Change in GPCOG questionnaire score	Baseline, 1 year, 2 years	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
Change in body fat composition	baseline, 1 year, 2 years	Change in body fat composition (%) from baseline.
Change in weight	baseline, 1 year, 2 years	Change in weight (pounds) from baseline
Change in waist/hip ratio	Baseline, 1 year, 2 years	Change in waist/hip ratio from baseline
Change in HbA1c	Baseline, 1 year, 2 years	Change in HbA1c (%) from baseline
Change in HDL	Baseline, 1 year, 2 years	Change in HDL from baseline
Change in total cholesterol	Baseline, 1 year, 2 years	Change in total cholesterol from baseline
Change in triglycerides	Baseline, 1 year, 2 years	Change in triglycerides from baseline
Change in Homeostatic Model Assessment - Insulin Resistance (HOMA-IR)	Baseline, 1 year, 2 years	Change in HOMA-IR from baseline (calculated from fasting blood sugar and insulin)
Composite Major Adverse Cardiovascular Events (MACE)	1 year, 2 years	Composite incidence of cardiovascular death, nonfatal stroke, nonfatal myocardial infarction
All-cause mortality	1 year, 2 years	Incidence of all-cause death
Stroke	1 year, 2 years	Incidence of stroke
Transient ischemic attack	1 year, 2 years	Incidence of transient ischemic attack
Activity by implanted device	3 months, 1 year, 2 years	Daily activity as measured by the sensors in the implanted pacemaker or defibrillator device (hours/day)

Trial Locations

Locations (1)

Cleveland Clinic; 🇺🇸 Cleveland, Ohio, United States