Clinical trial NCT03603912: Targeting Risk Interventions and Metformin for Atrial Fibrillation (TRIM-AF)
Official title: Upstream Targeting for the Prevention of Atrial Fibrillation: Targeting Risk Interventions and Metformin for Atrial Fibrillation (TRIM-AF)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE4
Conditions: Atrial Fibrillation
Lead sponsor: The Cleveland Clinic
Sponsor class: OTHER
Collaborators: name: American Heart Association
name: The Cleveland Clinic
First posted: 2018-07-27
Enrollment: 175
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

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.

Eligibility 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. 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.

Primary outcomes:
measure: Change in AF burden
timeFrame: 1 year
Secondary outcomes:
measure: Total time of AF/3 mos
timeFrame: 3 months, 1 year, 2 years
measure: Average %time in AF/day
timeFrame: 3 months, 1 year, 2 years
measure: %change in average AF time/day
timeFrame: Baseline to 3 months, 1 year, 2 years
measure: Number of days of AF
timeFrame: 3 months, 1 year, 2 years
measure: Number of AF episodes/month
timeFrame: 3 months, 1 year, 2 years
measure: Longest duration of AF at each 3 mo. period
timeFrame: 3 months, 1 year, 2 years
measure: Change in AF burden without blanking period
timeFrame: 1 year
measure: AF density
timeFrame: 1 year, 2 years
measure: Time to next AF and to persistent AF
timeFrame: Up to 2 years
measure: Incidence of Persistent AF
timeFrame: 3 months, 1 year, 2 years
measure: Cardioversion for AF
timeFrame: 3 months, 1 year, 2 years
measure: AF ablation/pulmonary vein isolation (PVI) for increase in burden or persistent AF
timeFrame: 3 months, 1 year, 2 years
measure: Change of antiarrhythmic drug
timeFrame: 3 months, 1 year, 2 years
measure: Change in Atrial Fibrillation Symptom Score (AFSS)
timeFrame: Baseline, 1 year, 2 years
measure: Change in Short Form-36 (SF-36) scores
timeFrame: Baseline, 1 year, 2 years
measure: Change in physical assessment questionnaire scores: Rapid Assessment of Physical Activity (RAPA)
timeFrame: Baseline, 1 year, 2 years
measure: Change in GPCOG questionnaire score
timeFrame: Baseline, 1 year, 2 years
measure: Change in weight
timeFrame: baseline, 1 year, 2 years
measure: Change in body fat composition
timeFrame: baseline, 1 year, 2 years
measure: Change in BMI
timeFrame: Baseline, 1 year, 2 years
measure: Change in waist/hip ratio
timeFrame: Baseline, 1 year, 2 years
measure: Change in HbA1c
timeFrame: Baseline, 1 year, 2 years
measure: Change in total cholesterol
timeFrame: Baseline, 1 year, 2 years
measure: Change in LDL
timeFrame: Baseline, 1 year, 2 years
measure: Change in HDL
timeFrame: Baseline, 1 year, 2 years
measure: Change in triglycerides
timeFrame: Baseline, 1 year, 2 years
measure: Change in Homeostatic Model Assessment - Insulin Resistance (HOMA-IR)
timeFrame: Baseline, 1 year, 2 years
measure: Composite Major Adverse Cardiovascular Events (MACE)
timeFrame: 1 year, 2 years
measure: All-cause mortality
timeFrame: 1 year, 2 years
measure: Stroke
timeFrame: 1 year, 2 years
measure: Transient ischemic attack
timeFrame: 1 year, 2 years
measure: Activity by implanted device
timeFrame: 3 months, 1 year, 2 years
Other outcomes:
Locations:
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
Study officials:
affiliation: The Cleveland Clinic
name: Mina K Chung, MD
role: PRINCIPAL_INVESTIGATOR
References: