Semaglutide for the Reduction of Arrhythmia Burden in Overweight AF Patients

Study Overview
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Brief Summary
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The purpose of this pilot study is to assess the feasibility of a double-blind, randomized placebo-controlled trial of semaglutide 2.4 mg subcutaneously once weekly on top of standard care compared to standard care alone.

Detailed Description
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The SOCRATES-AF pilot study is a prospective, parallel-group, double-blind, randomized controlled trial in patients with paroxysmal or early persistent atrial fibrillation and overweight and obesity. The primary objective is to assess the feasibility of a double-blind, randomized placebo-controlled trial of semaglutide 2.4 mg subcutaneously (s.c.) once weekly on top of current standard care (lifestyle and risk factor management, oral anticoagulant and rate control therapy) versus current standard care alone in overweight or obese patients with symptomatic paroxysmal or early persistent AF. To assess recurrences of atrial fibrillation all participants will receive an implantable cardiac monitor.

Official Title
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Semaglutide for the Reduction of Arrhythmia Burden in Overweight and Obese Patients With Atrial Fibrillation (Pilot Study)

Conditions
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Atrial Fibrillation, Overweight and Obesity

Intervention / Treatment
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* Drug: Semaglutide Injectable Product
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent before any study-related activity ≥ 18 years of age at the time of signing informed consent Body mass index (BMI) ≥ 30 kg/m2 Body mass index (BMI) ≥ 27 kg/m2 and at least 1 concomitant cardiometabolic risk factor (hypertension, dyslipidemia, or obstructive sleep apnea) Symptomatic paroxysmal or early persistent atrial fibrillation (Paroxysmal AF: Self- terminating, in most cases within 48 hours up to 7 days. AF episodes that are cardioverted within 7 days with a documented 12 lead ECG showing sinus rhythm within the last 12 months; early persistent AF: AF episodes lasting longer than 7 days, including episodes that are terminated by cardioversion, either with drugs or by direct current cardioversion, after 7 days or more. Early persistent AF in this trial is defined as persistent AF with first-time electrical cardioversion (ECV) or a maximum of 1 previous ECVs.) Exclusion Criteria: General exclusion criteria Age ≥75 years History of type 1 or 2 diabetes (history of gestational diabetes is allowed) Known or suspected hypersensitivity to study medication or related products Treatment with GLP-1 receptor agonists within the last 3 months before randomisation Treatment with dipeptidyl peptidase-4 (DPP-4) inhibitors Alcohol/drug abuse Pregnant or breastfeeding women Fertile women not using chemical (tablet/pill, depot injection of progesterone, sub- dermal gestagen implantation, hormonal vaginal ring or transdermal hormonal patch) or mechanical (spirals) contraceptives Active malignancy, unless in complete remission for ≥5 years Family or personal history of multiple endocrine neoplasia type 2 (MEN2) or familial medullary thyroid carcinoma (FMTC) Personal history of non-familial medullary thyroid carcinoma Inflammatory bowel diseases Acute or chronic pancreatitis Obesity induced by other endocrinologic disorders (e.g. Cushing's Syndrome) Current history of treatment with medications that may cause significant weight gain, within the last 3 months before screening, including systemic corticosteroids (except for a short course of treatment, i.e. 7-10 days), tri-cyclic antidepressants, atypical antipsychotic and mood stabilizers (e.g. imipramine, amitriptyline, mirtazapine, paroxetine, phenelzine, chlorpromazine, thioridazine, clozapine, olanzapine, valproic acid and its derivatives, and lithium) Diet attempts using herbal supplements or over-the-counter medications within 3 months before screening Current participation (or within the last 3 months) in an organised weight reduction programme or currently using or used within 3 months before screening: pramlintide, sibutramine, orlistat, zonisamide, topiramate, phentermine (either by prescription or as part of a clinical trial) Severe chronic obstructive pulmonary disease Uncontrolled treated/untreated hypertension (systolic >180 mmHg and/or diastolic >105 mmHg) Previous or planned surgical treatment for obesity Life expectancy <2.5 years Other concomitant disease or treatment that according to the investigator's assessment makes the subject unsuitable for study participation Participation in any other clinical intervention trial Previous participation in the SOCRATES-AF pilot study Inability to sign informed consent Exclusion criteria related to a cardiac condition Previous or planned AF ablation Previous use of continuous prophylactic class I or III antiarrhythmic drugs Long-standing persistent or permanent AF Overall clinical history of persistent AF ≥5 years ECG suggestive of malignant ventricular arrhythmia Prolonged corrected QT-interval (>500 ms), unless caused by bundle branch block Myocardial infarction (MI) within the last 3 months before screening Coronary revascularization within the last 3 months before screening Planned coronary revascularisation Cardiac surgery within the last 12 months before screening Obstructive hypertrophic cardiomyopathy Clinically significant valvular heart disease Left ventricular (LV) dysfunction (HFrEF with left ventricular ejection fraction (LVEF) <45%) unless elicited by AF Hospitalization due to decompensated heart disease within 30 days prior to randomization Congestive heart failure (NYHA class IV) Current myocardial or pericardial infection Permanent pacemaker (PM) in use or implantable cardioverter defibrillator (ICD) Patient cannot be prescribed non-vitamin K oral anticoagulant (NOAC) perform physical exercise for medical or personal reasons Exclusion criteria based on laboratory abnormalities Liver disease with increased plasma alanine aminotransferase (ALAT) levels of more than three times the upper limit of normal Renal dysfunction (eGFR <30 ml/min), dialysis or kidney transplant Clinically manifest thyroid dysfunction requiring therapy. After successful treatment of thyroid dysfunction, subjects may be enrolled, when thyroid function is controlled. HbA1c >6.5% measured at screening

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: Parallel Assignment
Interventional Model Description: Investigator-driven, prospective, parallel-group, double-blind, randomized controlled clinical trial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Intervention group<br>Semaglutide 2.4 mg subcutaneously once weekly in addition to standard AF care with lifestyle and risk factor management focusing on cardiovascular risk reduction | Drug: Semaglutide Injectable Product<br>* Subcutaneous injection of Semaglutide 2.4 mg once weekly<br>* Other names: Semaglutide plus lifestyle and cardiovascular risk factor management;|
| Placebo Comparator: Control group<br>Placebo treatment with volume-matched placebo s.c. once weekly in addition to standard AF care with lifestyle and risk factor management focusing on cardiovascular risk reduction | Drug: Placebo<br>* Subcutaneous injection of volume-matched placebo once weekly<br>* Other names: Lifestyle and risk factor management alone;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants to Complete Recruitment | Recruit 100 patients at an average recruitment rate of 2 patients per centre per month | Up to 68 weeks, until end of treatment | 
| Number of Participants to Complete Follow-up | Achieve complete follow-up on 90% or more of patients | Up to 75 weeks, until final follow-up | 
| Total Resource Requirement | Determine the resource requirements, i.e. primarily time spent per included patient, to achieve the recruitment and follow-up goals | Up to 75 weeks, until final follow-up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of Semaglutide in Reducing AF Recurrences in Obese AF Patients | Collect preliminary information on the effect of semaglutide 2.4 mg s.c. once weekly on top of standard care on reducing AF recurrences in obese subjects with symptomatic paroxysmal or early persistent atrial fibrillation | Up to 75 weeks, until final follow-up | 
| Incidence of adverse effects of Semaglutide in overweight and obese AF patients | Collect preliminary information on adverse drug effects, which may lead to discontinuation or dose reduction | Up to 75 weeks, until final follow-up | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Atrial fibrillation, Overweight, Obesity, Semaglutide, Glucagon-like peptide-1 (GLP-1) receptor agonist, Implantable cardiac monitor