Overweight or ObesityPhase 3SEMINAL-AFNCT06499857
Semaglutide for Metabolic Intervention and Adipose Loss to Treat Atrial Fibrillation
A Phase 3 study testing Semaglutide in people with Overweight or Obesity and Atrial Fibrillation, run by University of Chicago at 2 sites in United States.
Trial summary
The goal of the study is to learn how a weight loss medication called semaglutide, which is used to treat obesity, in addition to standard AF treatment might affect AF, atrial fibrillation severity, and whether it changes the risk of atrial fibrillation recurring after standard AF treatments. Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Overweight or Obesity, Atrial Fibrillation
- What is being tested?
- Semaglutide
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 200 participants
- Where
- 2 sitesUnited States
- Study dates
- 14 Apr 2025to Jun 2028
- Phase
- Phase 3
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Age 18-75 years
- BMI greater than or equal to 30 kg/m2
- Paroxysmal AF or persistent AF, in whom catheter ablation (CA) for AF is expected within 1 year (A group) or in whom catheter ablation is NOT expected within 1 year (M group)
- Ability to provide informed consent before any trial-related activities.
- Patients with type 2 diabetes mellitus (T2DM) will be included:
- If HbA1c (glycated hemoglobin) is less than or equal to 10 %
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- If the subject is taking basal insulin only or oral hypoglycemic agents or a combination of those.
- Patients on SGLT2-inhibitors and TZDs (Thiazolidinedione) will be included if they have been on a stable dose of these medications for at least 6 months
- The following protocol will be adopted to adjust insulin secretagogues (sulfonylureas or meglitinides) and insulin during the study (adapted from the Look Ahead Study).
- Patients will be asked to check their blood glucose (BG) 4 x day (before meals and at bed time) during the dose escalation and dose stabilization phases (weeks 0 to 20) and recommendation of dose adjustments will be immediately sent to their treating physician according to the dose adjustment scale below:
- 2 blood sugars <100 mg/dl- reduce meds [insulin secretagogues (sulfonylureas or meglitinides) and basal insulin] by 0-50 %
- 3 blood sugars 80-100 mg/dl- reduce meds [insulin secretagogues (sulfonylureas or meglitinides) and basal insulin] by 25-75%
- 3 blood sugars <80 mg/dl > 2 x week or severe hypoglycemia or symptomatic hypoglycemia- reduce meds [insulin secretagogues (sulfonylureas or meglitinides) and basal insulin] by 50-100 %
- Randomization to treatment (active and placebo) will be stratified to balance patients with T2DM across the study arms. After completion of the trial a prespecified subgroup analysis of the patients enrolled affected by T2DM will be performed.
- For women of child-bearing potential, use of appropriate contraception will be required.
- In patients that are prescribed amiodarone, standard care practices will be implemented to evaluate for liver and thyroid side effects with baseline liver and thyroid function tests via blood draw and evaluation every 6 months.
Who cannot join
- Current use of GLP-1 RA (glucagon-like peptide receptor agonists) or DPP4 (Dipeptidyl peptidase-4)-inhibitors or use within the last 90 days prior to screening
- Current antiobesity medication use or use within the last 90 days prior to screening
- A self-reported change in body weight of > 5 kg (11 lb.) within 30 days before screening
- History of bariatric surgery
- History of type I diabetes mellitus
- Current use of prandial insulin
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- Hospitalization for unstable angina, or TIA (Transient ischemic attack) < 30 days prior to screening
- Pulmonary embolism < 90 days before screening
- MI (myocardial infarction), stroke, etc. < 90 months prior to screening
- Uncontrolled thyroid disease: TSH (Thyroid-stimulating hormone) > 10.0 mIU/L (Milli-international Units Per Liter) or < 0.4 mIU/L (Milli-international Units Per Liter) at screening
- Active malignancy
- Active enrollment in another investigational study that includes any kind of intervention
- The receipt of any investigational drug within 90 days prior to this trial.
- Inability to comply with study procedures
- Acute pancreatitis < 180 days before screening
- History or presence of chronic pancreatitis
- CKD (Chronic Kidney Disease) stage 4 (GFR <30 ml/min)
- A personal or family history of medullary thyroid carcinoma (MTC) or Multiple Endocrine Neoplasia syndrome type 2 (MEN 2)
- A prior serious hypersensitivity reaction to semaglutide or to any of the excipients in WEGOVY
- Chronic inflammatory conditions requiring immunosuppression and/or on glucocorticoids
- Previous participation in this trial (received at least one dose of study drug or placebo)
- Pregnant, breast-feeding or planning pregnancy
Trial locations and contacts
2 sites in 1 country. Contact the study team or a site near you to ask about taking part.
United States2 sites, 2 recruiting
- Recruiting
University of Chicago
Chicago, Illinois, 60637
Silvana Pannain, MD, 773-702-3275, spannain@bsd.uchicago.edu
Andrew Beaser, MD, 773-702-9324, abeaser@bsd.uchicago.edu
- Not yet recruiting
The University of Arizona College of Medicine- Phoenix
Phoenix, Arizona, 85004
Roderick Tung, MD, 602-521-3090, rodericktung@arizona.edu
About this study
The goal of the study is to learn how a weight loss medication called semaglutide, which is used to treat obesity, in addition to standard AF treatment might affect AF, atrial fibrillation severity, and whether it changes the risk of atrial fibrillation recurring after standard AF treatments.
Read the detailed description
Obesity and atrial fibrillation (AF) pose a significant burden on healthcare systems worldwide. Obesity is an established independent risk factor for both the development of AF, as well as increased disease severity and adverse outcomes. According to a meta-analysis of 51 studies involving 60,000 individuals, every 5-unit increment in BMI confers an additional 19%-29% risk of incident AF, a 10% risk of post-operative AF, and a 13% risk of post-ablation AF. The estimated prevalence of AF in the United States is approximately 5.2 million, and is expected to increase to 12.1 million by the year 2030, likely explained by mirroring the growth of the obesity epidemic. While many associations have been made, the underlying pathophysiological mechanisms linking obesity and AF are incompletely understood.
Two large longitudinal cohort studies demonstrated that obesity contributes to disease progression to persistent or permanent forms of AF. Importantly, significant weight loss achieved by bariatric surgery has been associated with a reduction in the risk of new-onset AF by 29% in the prospective matched cohort Swedish Obese Study. Weight loss achieved with intensive lifestyle modification has also been shown to impact AF burden. However, these studies have not systematically investigated the biological mechanisms underlying weight loss and AF.
The novelty of the proposed study is that it will be the first to examine the impact of weight loss with semaglutide 2.4 mg on biological signaling and cardiac remodeling in relation to reductions in AF burden. Additionally, the proposed study will be the first to evaluate the effect of pharmacological weight loss on the risk of arrhythmia recurrence, combined with antiarrhythmic drugs (AAD) and/or catheter ablation (CA), which are the current first-line strategies for rhythm maintenance in patients with obesity. That is relevant as obesity is a chronic and relapsing health condition as demonstrated in multiple large intensive lifestyle modification studies which show a significant weight loss in the short term but minimal weight reduction in the long-term follow up. Pharmacotherapy has been shown to be superior to lifestyle modification to achieve larger and maintained weight loss.
Therefore, The investigators propose the first-ever double-blinded placebo controlled randomized clinical study to assess the efficacy and impact of an anti-obesity medication on atrial fibrillation in patients receiving contemporary therapies for atrial fibrillation.
- Conditions
- Overweight or Obesity, Atrial Fibrillation
- Being tested
- Semaglutide, Placebo
- Medical subject headings
- Overweight, Obesity, Atrial Fibrillation
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
SemaglutideDrug
3ml pen-injector containing semaglutide 3.0mg/ml solution for subcutaneous use.
PlaceboDrug
3ml pen-injector containing placebo solution for subcutaneous use.
| Study group | Role | What they receive |
|---|---|---|
| Semaglutide | Active comparator | Participants will have a 2 in 3 chance of receiving semaglutide (2.4 mg). Receives: Drug: Semaglutide |
| Placebo | Placebo comparator | Participants will have a 1 in 3 chance of receiving placebo. Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Time to first AF event detected by routine outpatient monitoring
Defined by length of time detected by routine outpatient monitoring (Holter, mobile telemetry, or implantable loop recorder).
Measured: Baseline to Week 68
Change from baseline in AF burden detected by routine outpatient monitoring.
Defined as the percentage of time spent in atrial fibrillation as detected by routine outpatient monitoring (Holter, mobile telemetry, or implantable loop recorder).
Measured: Baseline to Week 68
Secondary outcomes (16)
Weight loss
Change in Weight (kilograms) measured.
Measured: Baseline to Week 68
Change in waist circumference
Change waist circumference (cm) measured.
Measured: Baseline to Week 68
Change in epicardial and/or pericardial adipose tissue volume
Decrease measured by Cardiovascular magnetic resonance
Measured: Baseline to Week 68
Change in left and right ventricular size (mass)
Change in left and right ventricular size derived from time volume curves, and left and right atrial volumes (mL) measured by cardiovascular magnetic resonance
Measured: Baseline to Week 68
Change in left and right ventricular size (volume)
Change in left and right ventricular size derived from time volume curves, and left and right atrial volumes (mL) measured by cardiovascular magnetic resonance
Measured: Baseline to Week 68
Change in left and right ventricular function (ejection fraction)
Change in left and right ventricular function derived from time volume curves, and left and right atrial volumes (mL) measured by cardiovascular magnetic resonance
Measured: Baseline to Week 68
Change in left ventricular strain
Change in left ventricular strain derived from time volume curves, and left and right atrial volumes (mL) measured by cardiovascular magnetic resonance
Measured: Baseline to Week 68
Change in left ventricular diastolic parameters
Change in left ventricular strain diastolic parameters measured by cardiovascular magnetic resonance
Measured: Baseline to Week 68
Change in LV (left ventricular) myocardial fibrosis
Decrease in LV (%)myocardial fibrosis burden as measured by changes in native myocardial T1 times (milliseconds) measured by Cardiovascular magnetic resonance
Measured: Baseline to Week 68
Change in sympathetic activity and in circulating cytokines and adipokines
Decrease in systemic inflammation as measured by the levels of circulating cytokines and adipokines such as [CRP(C-reactive protein), TNF(Tumor necrosis factor), IL-6 (Interleukin 6), IL-1 alpha beta IL-8, IL-10, 16-18 monocyte chemoattractant protein (MCP-1), VEGF (Vascular endothelial growth factor)] (pg/mL) and adipokines (leptin, adiponectin, resistin, and visfatin) (pg/mL).
Measured: Baseline to Week 68
Change in Autonomic tone as determined by heart rate variability
HRV (milliseconds) will measured from baseline to Week 68 by outpatient rhythm monitoring
Measured: Baseline to Week 68
Changes from baseline through Week 68 of Atrial conduction times
Estimated by simple P wave duration (milliseconds) measured by 12-lead ECG
Measured: Baseline to Week 68
Changes in Body mass composition
Change in Body mass composition (percentage) measured by bio-impedance
Measured: Baseline to Week 68
Changes in Metabolic effects
Metabolic effects measured by CMP/HgA1C (mg/dL and %)
Measured: Baseline to Week 68
Left atrial and myocardial stress
Change measured by Serum BNP (pg/mL), which reflects left atrial and myocardial stress
Measured: Baseline to Week 68
Changes from baseline through Week 68 of novel Patient Reported Outcome Assessment.
Detection of within-patient changes on impact of health on an individual's everyday life reported in a novel Patient-Reported Outcome Assessment between baseline and Week 68.
Measured: Baseline to Week 68
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 Jul 2024
- Study start14 Apr 2025
- Primary completionDec 2027 (estimated)
- Study completionJun 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Overweight or ObesityStudies of the same condition, open and under way.
- More trials run by University of ChicagoThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Parallel Assignment Prospective, Randomized and Blinded
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 200 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University of Chicago
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Silvana Pannain, MD, Principal investigator, University of Chicago
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06499857
- Sponsor's protocol ID
- IRB23-0889
- Acronym
- SEMINAL-AF
- Status last verified
- Nov 2025
- First submitted
- 24 Apr 2024
- Last updated
- 14 Nov 2025
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 14 Nov 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Semaglutide for Metabolic Intervention and Adipose Loss to Treat Atrial Fibrillation
- ClinicalTrials.gov ID
- NCT06499857
- Acronym / sponsor ID
- SEMINAL-AF / IRB23-0889
- Conditions
- Overweight or Obesity, Atrial Fibrillation
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 200 participants (estimated)
- Lead sponsor
- University of ChicagoUniversity, hospital or other
- Study start
- 14 Apr 2025 (actual)
- Primary completion
- Dec 2027 (estimated)
- Study completion
- Jun 2028 (estimated)
- First posted
- 15 Jul 2024 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The goal of the study is to learn how a weight loss medication called semaglutide, which is used to treat obesity, in addition to standard AF treatment might affect AF, atrial fibrillation severity, and whether it changes the risk of atrial fibrillation recurring after standard AF treatments.
Detailed description
Obesity and atrial fibrillation (AF) pose a significant burden on healthcare systems worldwide. Obesity is an established independent risk factor for both the development of AF, as well as increased disease severity and adverse outcomes. According to a meta-analysis of 51 studies involving 60,000 individuals, every 5-unit increment in BMI confers an additional 19%-29% risk of incident AF, a 10% risk of post-operative AF, and a 13% risk of post-ablation AF. The estimated prevalence of AF in the United States is approximately 5.2 million, and is expected to increase to 12.1 million by the year 2030, likely explained by mirroring the growth of the obesity epidemic. While many associations have been made, the underlying pathophysiological mechanisms linking obesity and AF are incompletely understood.
Two large longitudinal cohort studies demonstrated that obesity contributes to disease progression to persistent or permanent forms of AF. Importantly, significant weight loss achieved by bariatric surgery has been associated with a reduction in the risk of new-onset AF by 29% in the prospective matched cohort Swedish Obese Study. Weight loss achieved with intensive lifestyle modification has also been shown to impact AF burden. However, these studies have not systematically investigated the biological mechanisms underlying weight loss and AF.
The novelty of the proposed study is that it will be the first to examine the impact of weight loss with semaglutide 2.4 mg on biological signaling and cardiac remodeling in relation to reductions in AF burden. Additionally, the proposed study will be the first to evaluate the effect of pharmacological weight loss on the risk of arrhythmia recurrence, combined with antiarrhythmic drugs (AAD) and/or catheter ablation (CA), which are the current first-line strategies for rhythm maintenance in patients with obesity. That is relevant as obesity is a chronic and relapsing health condition as demonstrated in multiple large intensive lifestyle modification studies which show a significant weight loss in the short term but minimal weight reduction in the long-term follow up. Pharmacotherapy has been shown to be superior to lifestyle modification to achieve larger and maintained weight loss.
Therefore, The investigators propose the first-ever double-blinded placebo controlled randomized clinical study to assess the efficacy and impact of an anti-obesity medication on atrial fibrillation in patients receiving contemporary therapies for atrial fibrillation.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 2
- Model description
- Parallel Assignment Prospective, Randomized and Blinded
| Arm | Type | Receives |
|---|---|---|
| Semaglutide | Active comparator | Drug: SemaglutideParticipants will have a 2 in 3 chance of receiving semaglutide (2.4 mg). |
| Placebo | Placebo comparator | Drug: PlaceboParticipants will have a 1 in 3 chance of receiving placebo. |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (16 listed)
- Age 18-75 years
- BMI greater than or equal to 30 kg/m2
- Paroxysmal AF or persistent AF, in whom catheter ablation (CA) for AF is expected within 1 year (A group) or in whom catheter ablation is NOT expected within 1 year (M group)
- Ability to provide informed consent before any trial-related activities.
- Patients with type 2 diabetes mellitus (T2DM) will be included:
Key exclusion criteria (22 listed)
- Current use of GLP-1 RA (glucagon-like peptide receptor agonists) or DPP4 (Dipeptidyl peptidase-4)-inhibitors or use within the last 90 days prior to screening
- Current antiobesity medication use or use within the last 90 days prior to screening
- A self-reported change in body weight of > 5 kg (11 lb.) within 30 days before screening
- History of bariatric surgery
- History of type I diabetes mellitus
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Semaglutide3ml pen-injector containing semaglutide 3.0mg/ml solution for subcutaneous use. | Drug | Semaglutide |
| Placebo3ml pen-injector containing placebo solution for subcutaneous use. | Drug | Placebo |
Primary outcome
Time to first AF event detected by routine outpatient monitoring
Time frame: Baseline to Week 68
Defined by length of time detected by routine outpatient monitoring (Holter, mobile telemetry, or implantable loop recorder).
Change from baseline in AF burden detected by routine outpatient monitoring.
Time frame: Baseline to Week 68
Defined as the percentage of time spent in atrial fibrillation as detected by routine outpatient monitoring (Holter, mobile telemetry, or implantable loop recorder).
16 secondary outcomes
Weight loss
Time frame: Baseline to Week 68
Change in waist circumference
Time frame: Baseline to Week 68
Change in epicardial and/or pericardial adipose tissue volume
Time frame: Baseline to Week 68
Change in left and right ventricular size (mass)
Time frame: Baseline to Week 68
Change in left and right ventricular size (volume)
Time frame: Baseline to Week 68
Change in left and right ventricular function (ejection fraction)
Time frame: Baseline to Week 68
Change in left ventricular strain
Time frame: Baseline to Week 68
Change in left ventricular diastolic parameters
Time frame: Baseline to Week 68
Change in LV (left ventricular) myocardial fibrosis
Time frame: Baseline to Week 68
Change in sympathetic activity and in circulating cytokines and adipokines
Time frame: Baseline to Week 68
Change in Autonomic tone as determined by heart rate variability
Time frame: Baseline to Week 68
Changes from baseline through Week 68 of Atrial conduction times
Time frame: Baseline to Week 68
Changes in Body mass composition
Time frame: Baseline to Week 68
Changes in Metabolic effects
Time frame: Baseline to Week 68
Left atrial and myocardial stress
Time frame: Baseline to Week 68
Changes from baseline through Week 68 of novel Patient Reported Outcome Assessment.
Time frame: Baseline to Week 68
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 14 Nov 2025.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Silvana Pannain, MD principal investigator
University of Chicago
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Semaglutide in people with Overweight or Obesity and Atrial Fibrillation, run by University of Chicago at 2 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 16 inclusion and 22 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 14 Nov 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Silvana Pannain, MD (773-702-3275, spannain@bsd.uchicago.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Time to first AF event detected by routine outpatient monitoring (time frame: Baseline to Week 68). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Nov 2025.