DUTCH Weight Control in Atrial Fibrillation Study

The primary objective of this randomized controlled trial is to demonstrate the superiority of once-weekly 2.4 mg **semaglutide** administered subcutaneously over placebo in achieving sinus rhythm at one year in patients with obesity and first detected, symptomatic persistent **atrial fibrillation** (AF). This is clinically relevant as achieving sinus rhythm can significantly improve patient outcomes by reducing symptoms and the risk of complications associated with AF.

Secondary objectives include:

• Quantifying the impact of weight reduction on AF-related symptoms using the modified EHRA score over a 52-week period.
• Assessing the effect on weight-related parameters such as weight, waist circumference, and BMI over the same timeframe.
• Evaluating the impact of weight reduction on quality of life using the EQ-5D-5L.
• Determining the effect of weight reduction on AF-related hospitalizations.
• Assessing the impact on other cardio-metabolic risk factors, including hypertension, glycemic control, and lipid profiles.
• Evaluating the intervention's impact on work productivity using the Work Productivity and Activity Index.
• Assessing the effect on exercise motivation using the Behavioral Regulation and Exercise Questionnaire 2.
• Evaluating the cost-effectiveness of rhythm control in new-onset persistent AF in obese patients.
• Quantifying the impact on the number of planned electrical cardioversions.
• Assessing the intervention's impact on inflammation using CRP levels.
• Evaluating the effect on NT-pro BNP levels over the 52-week period.

The clinical trial involves participants diagnosed with **obesity** and first detected, symptomatic persistent **atrial fibrillation**. The study population includes both male and female subjects aged 18 years and older. Participants are required to have a body mass index (BMI) of at least 30 kg/m², or a BMI of 27 kg/m² with at least one weight-related comorbidity such as hypertension, dyslipidemia, obstructive sleep apnea, or cardiovascular disease. The trial does not include a vulnerable population. Participants are expected to have scheduled electrical cardioversion and must provide written informed consent. The sponsor has not provided information regarding the total number of participants. The selection criteria ensure that the study population is representative of individuals who are likely to benefit from the intervention being tested, with a focus on those who have recently been diagnosed with persistent atrial fibrillation and meet the specified obesity criteria.

The clinical trial is designed as a **randomized**, double-blind, placebo-controlled study to evaluate the efficacy of once-weekly 2.4 mg **semaglutide** administered subcutaneously in patients with **obesity** and first detected, symptomatic persistent **atrial fibrillation** (AF). The primary objective is to demonstrate the superiority of semaglutide over placebo in achieving sinus rhythm at one year. The trial is expected to commence recruitment in June 2024 and conclude by June 2026, with a total duration of 52 weeks for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (≥18 years), obesity (BMI ≥30 kg/m² or BMI ≥27 kg/m² with a weight-related comorbidity), and scheduled electrical cardioversion. Following randomization, participants will receive either semaglutide or placebo via subcutaneous injection. Follow-up visits will be conducted at regular intervals to monitor the participants' health status, adherence to the treatment regimen, and any adverse events. The end-of-study visit will occur at the 12-month mark, where the primary and secondary endpoints will be assessed, including rhythm outcome status and changes in AF-related symptoms, quality of life, and various metabolic parameters.

Participant involvement is expected to last for the entire 52-week treatment period unless early termination is warranted. Conditions that may lead to early withdrawal include the occurrence of serious adverse events, non-compliance with the study protocol, or withdrawal of consent. The trial will employ rigorous monitoring to ensure participant safety and data integrity throughout the study duration.

The clinical trial involves the administration of **Semaglutide B 3.0 mg/ml PDS290**, which is an experimental medication formulated as a **solution for injection**. The active substance in this medication is **semaglutide**, and it is manufactured by Novo Nordisk A/S. The medication is administered via **subcutaneous injection**. The dosing regimen involves a maximum daily dose of 0.34 mg, with a total maximum dose of 2.4 mg over a treatment period of 52 weeks. The primary objective of the trial is to evaluate the efficacy of semaglutide in achieving sinus rhythm in patients with obesity and first detected, symptomatic persistent atrial fibrillation.

In addition to the experimental medication, a **placebo** is used as a comparator in this randomized controlled trial. The placebo is referred to as **PDS290 Semaglutide placebo**. It is designed to match the experimental medication in appearance and administration route, which is also via subcutaneous injection. The use of a placebo allows for the assessment of the true efficacy of semaglutide by providing a control group for comparison.

Efficacy in the clinical trial titled "DUTCH Weight Control in Atrial Fibrillation Study" will be assessed using both primary and secondary endpoints. The primary endpoints include the one-year rhythm outcome status, ranked by severity, and the occurrence of specific events within 12 months after randomization. These events include persistent **atrial fibrillation** (AF) on the ECG at the 12-month visit, catheter ablation for AF, arrhythmic death, and any serious adverse event due to an anti-arrhythmic drug. The second primary endpoint will be statistically assessed as a binary variable.

Secondary endpoints will evaluate changes in various parameters from the index visit to 12 months post-index visit. These include changes in AF-related symptoms measured by the modified EHRA score, quality of life assessed by the EQ-5D-5L, and work productivity using the Work Productivity and Activity Index. Additional secondary endpoints involve the number of hospitalizations and unscheduled hospital visits due to AF recurrence or adverse events of anti-arrhythmic drugs, as well as changes in physical and biochemical measures such as waist circumference, weight, BMI, blood pressure, HbA1c, lipid levels, CRP, and NT-pro BNP. The trial will also assess changes in exercise motivation using the Behavioral Regulation and Exercise Questionnaire 2 and the total cost of healthcare expenditures related to AF management.