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

Atrial Fibrillation Clinical Trial

— TRIM-AF  

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03603912
• Other study ID #: 18-757
• Status: Active, not recruiting
• Phase: Phase 4
• Start date: August 24, 2018
• Est. completion date: December 2025

Study information

• Verified date: February 2024
• Source: The Cleveland Clinic
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 270
• Est. completion date: December 2025
• Est. primary completion date: August 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Atrial Fibrillation

Intervention

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.

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).

Locations

Country	Name	City	State
United States	Cleveland Clinic	Cleveland	Ohio

Sponsors (3)

Lead Sponsor	Collaborator
Mina Chung, MD	American Heart Association, The Cleveland Clinic

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Total time of AF/3 mos	Total time of AF per 3 month period	3 months, 1 year, 2 years
Secondary	Average %time in AF/day	Average percent time in AF/day	3 months, 1 year, 2 years
Secondary	%change in average AF time/day	Percent change in average AF time/day from baseline	Baseline to 3 months, 1 year, 2 years
Secondary	Number of days of AF	Number of days of AF over the time period	3 months, 1 year, 2 years
Secondary	Number of AF episodes/month	Number of AF episodes/month over the time period	3 months, 1 year, 2 years
Secondary	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
Secondary	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
Secondary	AF density	a measure of AF temporal aggregation, calculated using daily AF burden time over the study period	1 year, 2 years
Secondary	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
Secondary	Incidence of Persistent AF	Development of persistent AF over the study period	3 months, 1 year, 2 years
Secondary	Cardioversion for AF	Electrical cardioversion procedures over the study period	3 months, 1 year, 2 years
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Change in weight	Change in weight (pounds) from baseline	baseline, 1 year, 2 years
Secondary	Change in body fat composition	Change in body fat composition (%) from baseline.	baseline, 1 year, 2 years
Secondary	Change in BMI	Change in body mass index (BMI, kg/m2) from baseline (calculated from weight, height)	Baseline, 1 year, 2 years
Secondary	Change in waist/hip ratio	Change in waist/hip ratio from baseline	Baseline, 1 year, 2 years
Secondary	Change in HbA1c	Change in HbA1c (%) from baseline	Baseline, 1 year, 2 years
Secondary	Change in total cholesterol	Change in total cholesterol from baseline	Baseline, 1 year, 2 years
Secondary	Change in LDL	Change in LDL from baseline	Baseline, 1 year, 2 years
Secondary	Change in HDL	Change in HDL from baseline	Baseline, 1 year, 2 years
Secondary	Change in triglycerides	Change in triglycerides from baseline	Baseline, 1 year, 2 years
Secondary	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
Secondary	Composite Major Adverse Cardiovascular Events (MACE)	Composite incidence of cardiovascular death, nonfatal stroke, nonfatal myocardial infarction	1 year, 2 years
Secondary	All-cause mortality	Incidence of all-cause death	1 year, 2 years
Secondary	Stroke	Incidence of stroke	1 year, 2 years
Secondary	Transient ischemic attack	Incidence of transient ischemic attack	1 year, 2 years
Secondary	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