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| Name | Class |
|---|---|
| Ethicon, Inc. | INDUSTRY |
| iRhythm Technologies, Inc. | INDUSTRY |
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Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. It is estimated that between 3 and 6 million Americans are currently living with AF, while 12 million people in the United States will have AF in 2030. Obesity and its comorbidities such as type 2 diabetes (T2DM), hypertension, and obstructive sleep apnea (OSA) are major risk factors for development and progression of AF. Metabolic and Bariatric Surgery (MBS) is the most effective currently available treatment for obesity. Patients typically lose 20 to 35 percent of body weight after surgery which is often sustained for many years. MBS can improve all 5 major risk factors of AF including obesity, hypertension, T2DM, OSA, and systemic inflammation.
The purpose of the study is to understand if MBS can affect the severity of AF and the toll AF's symptoms take on patients.
This is randomized trial of 100 patients with BMI ≥35 kg/m2 and AF. Patients who met the initial screening criteria (including presence of at least 1% AF burden during a 2-week monitoring period with an ambulatory cardiac monitor) will be invited for possible enrollment. Patients will then be randomized 1:1 to MBS group versus nonsurgical control group and will be followed for 12 months (phase 1) and then for an additional 18 months (phase 2).
Interventions include Roux-en-Y Gastric Bypass or Sleeve Gastrectomy surgical procedures based on the shared medical decision between the bariatric surgeon and patients considering the patient's conditions. In the control group, patients are allowed to take anti-obesity medications (AOMs) that are not contraindicated in patients with AF at the discretion of obesity medicine specialists.
Lifestyle and risk factor modification in both groups will consist of targeted and personalized diet plans, exercise, and risk factor reduction, including optimal therapies for T2DM, hypertension, dyslipidemia, heart failure, coronary artery disease, and OSA.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Metabolic Surgery | Active Comparator | Roux-en-Y Gastric Bypass (RYGB) and Sleeve Gastrectomy (SG) |
|
| Control group (nonsurgical standard of care for obesity) | Other | In the Control group, the subjects will be receiving standard of care for nonsurgical management of obesity, including possible AOMs that are not contraindicated in patients with AF at the discretion of obesity medicine specialists. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Roux-en-Y Gastric Bypass or Sleeve Gastrectomy | Procedure | Patients receive either RYGB or SG. The surgical risk, differential impact of each procedure on body weight and other obesity-related diseases, presence of other medical and mental problems, patient's behavioral factors (e.g., postoperative compliance, active smoking), medications, and goals will be considered when the patient and local medical team make a shared decision about the most appropriate surgical procedure. |
| Measure | Description | Time Frame |
|---|---|---|
| Relative change in total duration of being in atrial fibrillation (AF) | Relative change from baseline to 52 weeks in the percentage total duration of being in AF during a 2-week monitoring period (i.e., %burden), assessed by the Zio XT Patch (iRhythm). | First 52 weeks of the study |
| Measure | Description | Time Frame |
|---|---|---|
| Presence of at least 1 AF episode | Presence of at least 1 AF episode (present or absent) in a 2-week monitoring time by Zio XT Patch at 52 weeks. | First 52 weeks of the study |
| Change in number of AF episodes (≥30 seconds) |
| Measure | Description | Time Frame |
|---|---|---|
| Percentage of Participants Achieving Weight Loss Milestones | Percentage of participants achieving ≥ 5%, ≥ 10%, ≥ 15%, ≥ 20%, ≥ 25%, ≥ 30%, ≥ 35% weight loss from baseline (yes/no) | First 52 weeks of the study |
| Excess Weight Loss Percentage |
INCLUSION CRITERIA
Entry into the study would require that the patient:
Is a candidate for general anesthesia
Is eligible for metabolic surgery (RYGB or SG)
Is ≥18 and ≤80 years old
has a BMI ≥35 and ≤65 kg/m2
has AF criteria, which:
Patients without history of prior AF ablation/PVI procedure or with history of prior failed AF ablation/PVI procedure are eligible for the study.
Patients with and without T2DM are eligible for the study. Patients with T2DM should have been on a stable dose of anti-diabetic medication (including insulin) for at least 3 months prior to entry, with HbA1c ≤12%.
Have the ability and willingness to participate in the study and agree to any of the arms involved in the study.
Able to understand the options and to comply with the requirements of each arm.
Have a negative urine pregnancy test at screening and randomization visits for women of childbearing potential.
Women, of childbearing age, must agree to use reliable method of contraception for 2 years.
EXCLUSION CRITERIA
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Chytaine Hall | Contact | 216-445-3983 | hallc1@ccf.org | |
| Ali Aminian | Contact | 2164450045 | aminiaa@ccf.org |
| Name | Affiliation | Role |
|---|---|---|
| Ali Aminani | Bariatric Research Medical Director | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| The Cleveland Clinic | Cleveland | Ohio | 44195 | United States |
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| ID | Term |
|---|---|
| D001281 | Atrial Fibrillation |
| D009765 | Obesity |
| D024821 | Metabolic Syndrome |
| ID | Term |
|---|---|
| D001145 | Arrhythmias, Cardiac |
| D006331 | Heart Diseases |
| D002318 | Cardiovascular Diseases |
| D010335 | Pathologic Processes |
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| ID | Term |
|---|---|
| D015390 | Gastric Bypass |
| D050110 | Bariatric Surgery |
| D024043 | Collagen Type II |
| D013812 | Therapeutics |
| ID | Term |
|---|---|
| D049088 | Bariatrics |
| D000073319 | Obesity Management |
| D005763 | Gastroenterostomy |
| D000714 | Anastomosis, Surgical |
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METSAFE is a randomized open-label blinded-endpoint single-center controlled efficacy/safety study with 2 parallel groups of patients with obesity and AF who will either receive metabolic surgery or nonsurgical obesity care for 30 months. The study has 2 phases: the first 12 months and the subsequent 18 months.
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Patients and investigators will not be blinded to treatment assignment. However, the clinical assessors of cardiac rhythm recorders are blinded to the study arms; Assessment of the primary endpoint will be based on the blinded downloads and interpretation of Zio XT Patch (iRhythm) data yielding the AF burden.
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| Anti-Obesity Medication (AOM) treatment | Drug | Implementation of obesity pharmacotherapy in the nonsurgical group includes initial assessment of side effects and response, followed by achieving a clinically meaningful weight loss (5% weight loss) after three months. Once this goal is reached, AOMs will be continued throughout the study. If a weight plateau is reached within the first AOM, then another AOM may be added in combination in a stepwise fashion. The choice of AOMs considered may include metformin, topiramate, liraglutide, dulaglutide, semaglutide, tirzepatide, and empagliflozin. |
|
Change in Zio XT Patch derived variables from baseline to 52 weeks including number of AF episodes (≥30 seconds) in a 2-week monitoring time.
| First 52 weeks of the study |
| Change in number of AF espisodes longer than 6 minutes | Change in Zio XT Patch derived variables from baseline to 52 weeks including number of AF episodes longer than 6 minutes in a 2-week monitoring time. | First 52 weeks of the study |
| Change in the longest AF duration | Change in Zio XT Patch derived variables from baseline to 52 weeks including the longest AF duration in a 2-week monitoring time. | First 52 weeks of the study |
| Change in the second longest AF duration | Change in Zio XT Patch derived variables from baseline to 52 weeks including the second longest AF duration in a 2-week monitoring time. | First 52 weeks of the study |
| Change in the AF type | Change in the AF type (e.g. regression from or progression to persistent form of AF) | First 52 weeks of the study |
| Change in AF Symptom burden | Change in AF Symptom burden and severity assessed by the Toronto AF Severity Score (AFSS) | First 52 weeks of the study |
| Relapse of AF after ablation | Number of relapses of AF after ablation in each group *Since more ablation is expected in the second phase of study, this end point will be more relevant in the phase 2 of study. | Throughout the study, 130 weeks |
| Change in cardiac structure | Change in cardiac structure assessed by transthoracic echocardiography including LA and LV size, morphology, and function | First 52 weeks of the study |
| Change in weight | Percent and absolute changes in body weight and BMI | First 52 weeks of the study |
Percentage of excess weight loss, calculated by dividing the difference between initial BMI and final BMI by the difference between initial BMI and a target BMI of 25
| First 52 weeks of the study |
| Change in waist circumference | Change in waist circumferential measurement above the level of the iliac crests measured in centimeters from baseline to 52 weeks | First 52 weeks of the study |
| Change in physical activity | Change in physical activity, tracked by a commercial wearable device | First 52 weeks of the study |
| Systolic blood pressure trends | Mean and change in systolic blood pressure in mmHg | First 52 weeks of the study |
| Change in glucose homeostasis markers in T2DM patients | Mean and change from baseline in blood glucose and HbA1c in patients with T2DM | First 52 weeks of the study |
| Percentage of patients with T2DM meeting predefined HbA1c targets | Percentage of patients meeting predefined HbA1c targets:
| First 52 weeks of the study |
| change in anti-diabetic medication | Changes in doses or drugs being used for diabetes | First 52 weeks of the study |
| Mean and change from baseline in lipid panel | Mean and change from baseline in total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and triglycerides | First 52 weeks of the study |
| Changes in inflammatory markers (CRP) | Mean and change from baseline in C-Reactive Protein (CRP) in mg/L | First 52 weeks of the study |
| change in antihypertensive therapy | Percentage of patients with escalation or de-escalation of antihypertensive therapy | First 52 weeks of the study |
| change in antiarrhythmic therapy | Change in antiarrhythmic medications taken by the patient | First 52 weeks of the study |
| Count of Direct Current cardioversions | Number of Direct Current (DC) Cardioversions | First 52 weeks of the study |
| Count of AF ablation/pulmonary vein isolation procedures | Number of AF ablation/pulmonary vein isolation (PVI) procedures (for increase in burden or persistence) | Throughout the study, 130 weeks |
| Other cardiovascular therapy changes | Change in other cardiovascular medications | First 52 weeks of the study |
| Change in Quality of life metrics | Change from baseline in QoL metrics using Short Form Health Survey (SF-36) | First 52 weeks of the study |
| Change in body composition (via Seca mBCA 554 Bioimpedance Analysis) | Change in body composition (% fat mass and % fat-free mass) as measured by Seca mBCA 554 Bioimpedance Analysis to examine correlation of changes in body composition with AF-related outcomes. | First 52 weeks of the study |
| Change in Apnea-Hypopnea Index in polysomnoraphy | Change in Apnea-Hypopnea Index (AHI) in polysomnography to assess the possible positive effects of weight loss on OSA and to examine their correlation with AF-related outcomes | First 52 weeks of the study |
| Count of major clinical outcomes | Number of major clinical outcomes including all-cause mortality, cardiovascular mortality, stroke, transient ischemic attack, myocardial infarction, hospitalization for unstable angina, and hospitalization for heart failure. | Throughout the study, 130 weeks |
| Safety end points | Complications specifically related to obesity, AF, metabolic surgery, as well as adverse events of cardiovascular medications and interventions in the trial will be recorded and evaluated. | Throughout the study, 130 weeks |
| D013568 |
| Pathological Conditions, Signs and Symptoms |
| D050177 | Overweight |
| D044343 | Overnutrition |
| D009748 | Nutrition Disorders |
| D009750 | Nutritional and Metabolic Diseases |
| D001835 | Body Weight |
| D012816 | Signs and Symptoms |
| D007333 | Insulin Resistance |
| D006946 | Hyperinsulinism |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D013514 |
| Surgical Procedures, Operative |
| D013505 | Digestive System Surgical Procedures |
| D024022 | Fibrillar Collagens |
| D003094 | Collagen |
| D001704 | Biopolymers |
| D011108 | Polymers |
| D046911 | Macromolecular Substances |
| D016326 | Extracellular Matrix Proteins |
| D012596 | Scleroproteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |