Mazdutide for Reducing Atrial Fibrillation Recurrence After Catheter Ablation in Obese Patients

1. Aged 18-75 years (inclusive);

2. BMI ≥ 28 kg/m², with waist circumference ≥ 90 cm for male subjects and ≥ 85 cm for female subjects;

3. Patients with non-valvular atrial fibrillation (AF) undergoing their first AF catheter ablation and maintaining sinus rhythm within 24 hours post-ablation;

4. Anteroposterior diameter of the left atrium (excluding transverse and superoinferior diameters) measured from the parasternal long-axis view on echocardiography < 55 mm;

5. Agree to randomization as specified in this study and be able to complete follow-up assessments as required.

### Surgery-related

1. AF caused by reversible etiologies;

2. Left ventricular ejection fraction (LVEF) < 30 % on echocardiography;

3. Unstable angina, acute myocardial infarction, or percutaneous coronary intervention (PCI) within the preceding 1 month;

4. Patients with severe coronary artery stenosis without prior PCI;

5. Stroke, transient ischemic attack (TIA), intracerebral hemorrhage, or any embolic event within the preceding 1 month;

6. Severe congenital heart disease, such as tetralogy of Fallot, corrected transposition of the great arteries, etc.;

7. Hypertrophic cardiomyopathy;

8. Moderate or greater aortic stenosis, moderate or greater mitral stenosis;

9. Severe hepatic dysfunction (Child-Pugh Class 3), renal insufficiency (eGFR < 30 mL/min/1.73 m²), or a history of renal dialysis, kidney transplantation, or nephrectomy;

10. Prior cardiac surgery, including coronary artery bypass grafting, mechanical or bioprosthetic valve replacement, etc.;

11. Post-implantation of intracardiac devices, such as pacemaker implantation, left atrial appendage closure, patent foramen ovale closure, atrial septal defect transcatheter closure, etc.;

12. Contraindications to anticoagulant therapy;

13. Presence of an inferior vena cava filter, or contraindications to right- or left-heart catheterization (e.g., left atrial thrombus, etc.).

### Medications or treatments received prior to screening

14. Self-reported body weight change > 5 % within 90 days before screening;

15. Use (past or current) of anti-obesity medications within 90 days before screening, including sibutramine hydrochloride, orlistat, phentermine, phenylpropanolamine, mazindol, diethylpropion, lorcaserin, phentermine-topiramate combination, naltrexone-bupropion combination, and GLP-1 receptor agonists (liraglutide, benaglutide, semaglutide, tirzepatide, mazdutide), etc.;

16. Use of weight-altering medications within 90 days before screening: systemic corticosteroids (intravenous, oral, or intra-articular administration), tricyclic antidepressants, psychotropic or sedative agents (e.g., imipramine, amitriptyline, mirtazapine, paroxetine, phenelzine, chlorpromazine, thioridazine, clozapine, olanzapine, valproic acid and its derivatives, lithium salts), etc.;

17. Use of weight-modulating Chinese herbal medicines, health supplements, or meal replacements within 90 days before screening.

### Medical history or documented evidence of any of the following disorders

18. Prior bariatric-metabolic surgery or planned bariatric-metabolic surgery within 1 year;

19. Obesity secondary to underlying diseases or medications: e.g., hypercortisolism (Cushing's syndrome), obesity due to pituitary-hypothalamic injury, obesity following dose reduction/discontinuation of anti-obesity drugs, monogenic obesity, etc.;

20. Confirmed type 1 diabetes mellitus;

21. Prior severe hypoglycaemia or recurrent symptomatic hypoglycaemic episodes (≥ 2 events within 6 months before screening);

22. History of retinopathy;

23. Abnormal thyroid function (including TSH ≤ 0.1 mIU/L or ≥ 10 mIU/L) within 7 days before screening, or history of thyroid surgery;

24. Personal or family history of pancreatitis;

25. Personal or family history of medullary thyroid carcinoma;

26. Personal or family history of multiple endocrine neoplasia syndrome type 2;

27. History of malignant neoplasm or malignant tumour in remission;

28. History of moderate-to-severe depression; or history of severe psychiatric disorders including schizophrenia, bipolar disorder, etc.;

29. Prior suicidal ideation or suicidal behaviour;

30. Limb deformity or amputation precluding accurate measurement of height and body weight;

31. Post-procedural 12-lead ECG showing sinus heart rate < 50 beats/min, second- or third-degree atrioventricular block, long-QT syndrome, or QTcF > 450 ms (male), QTcF > 470 ms (female);

32. Contraindications or known hypersensitivity to mazdutide.

### Exclusion by laboratory values at screening

33. Serum calcitonin ≥ 50 ng/L (pg/mL);

34. Fasting triglycerides ≥ 5.64 mmol/L (500 mg/dL);

35. Serum amylase or lipase > 2.0 × upper limit of normal (ULN).

### Other criteria

36. Pregnant or lactating women; subjects (male or female) of child-bearing potential who plan pregnancy within 1 year or decline contraception throughout the study period and for 8 weeks after study completion;

37. Life expectancy < 1 year due to malignancy, severe organ failure, or other conditions;

38. Any other conditions that, in the investigator's judgement, render the subject unsuitable for study participation.