Mazdutide for Weight Management and Gout in Adults With Obesity

1. Informed consent is obtained before trial entry, and the subject fully understands the trial content, procedures, and potential adverse reactions; able to complete the study according to the protocol requirements.
2. Subjects (including male subjects) have no plans for pregnancy, sperm donation, or egg donation from 14 days before screening until 3 months after trial completion, and voluntarily agree to use effective contraception.
3. Aged 18 to 65 years (inclusive), male or female.
4. Obesity: BMI ≥ 30.0 kg/m².
5. Diagnosis of gout according to the 2015 ACR/EULAR classification criteria for gout, confirmed by the investigator; at least 2 gout flares in the past 6 months with supporting medical records/prescription documentation.
6. Subjects must have been on a stable dose of urate-lowering therapy (ULT) for at least 8 weeks prior to enrollment: allowed agents include allopurinol, febuxostat, or other oral ULTs recognized by local guidelines; dose unchanged in the past 8 weeks; or discontinued ULT in the past 8 weeks; not taking colchicine for gout flare prophylaxis.
7. Body weight change \< 5% in the past 6 months controlled by diet and exercise alone.
8. HbA1c ≤ 10.0%; background antidiabetic medications allowed: metformin, stable-dose insulin, sulfonylureas (SUs), SGLT2 inhibitors; prohibited: GLP-1 receptor agonists, DPP-4 inhibitors; background medications must be stable for ≥ 8 weeks prior to enrollment.
9. Subjects have received standardized gout management or healthy lifestyle education for ≥ 6 months prior to enrollment, including but not limited to urate-lowering therapy, dietary modification, alcohol control, weight management, and gout-related behavioral interventions. These management measures have been stable for at least 2 months prior to enrollment without significant off-protocol changes. Subjects agree to maintain their previous lifestyle and disease management habits during the study, without actively changing dietary patterns, alcohol intake, exercise intensity, or other factors that may affect gout flares, unless deemed medically necessary by the investigator.

Exclusion Criteria:

• 1. Persistent or significant lifestyle changes in the 6 months prior to enrollment, including substantial adjustment in alcohol consumption, extreme dietary pattern changes, initiation or discontinuation of systemic urate-lowering therapy, initiation or discontinuation of diuretics/uricosuric agents, etc. If the investigator determines that such changes may have a clinically meaningful impact on gout flares or uric acid levels, the subject will be excluded.

  2. Average daily smoking ≥ 5 cigarettes in the 3 months prior to screening, or inability to stop using any tobacco products during the trial.

  3. History of specific allergies (asthma, urticaria, eczema, etc.), allergic constitution, or allergy to GLP-1/GCG dual receptor agonists and excipients. Subjects judged unsuitable for enrollment due to allergy to the study drug or its excipients. Subjects who participated in other clinical trial drug studies within 3 months prior to enrollment and are judged unsuitable by the investigator.

  4. History of heavy alcohol use and unwillingness to abstain from alcohol throughout the study period: > 14 units of alcohol per week (1 unit ≈ 10 mL alcohol, approximately 285 mL beer at 3.5%, 25 mL spirits at 40%, or 100 mL wine at 10%).

  5. Body weight change > 5.0% (self-reported) in the 12 weeks prior to screening controlled by diet and exercise alone.

  6. ULT dose adjustment within 8 weeks prior to screening, or expected need for ULT adjustment during the study. Acute gout flare within 2 weeks prior to enrollment. Inability to maintain stable ULT dose during the study.

  7.Medication History:

  1. Use of any clinical trial drug within 3 months prior to enrollment.
  2. Use of other urate-lowering or uric acid-affecting drugs (e.g., lesinurad) within 2 weeks prior to randomization, or inability to discontinue other urate-lowering or uric acid-affecting drugs during the study.
  3. Use of aspirin > 325 mg daily within 2 weeks prior to enrollment, or unstable aspirin dosing, or expected use during the study.
  4. Use of any diuretics within 2 weeks prior to enrollment, or expected use during the study.
  5. Unstable dosing of medications for comorbid conditions within 4 weeks prior to enrollment, or expected adjustment of treatment regimen during the study.
  6. Use of any other prescription drugs, over-the-counter drugs, traditional Chinese medicine, or health supplements within 1 week prior to enrollment or within 5 drug half-lives (whichever is longer).

  7. Use of drugs or treatments that may cause significant weight gain or loss within 3 months:

     • Corticosteroids (short-term use \< 7 days or topical, inhaled, intraocular, or intranasal administration excluded);

       • Tricyclic antidepressants, atypical antipsychotics, and mood stabilizers (e.g., imipramine, chlorpromazine, amitriptyline, mirtazapine, clozapine, olanzapine, paroxetine, phenelzine, thioridazine, valproic acid and derivatives, lithium);

         • Orlistat, GLP-1 receptor agonists, or other weight-loss treatments beyond diet and exercise (e.g., weight-loss teas, traditional Chinese medicine weight-loss products, acupuncture for weight loss);

           • Other drugs or treatments that may significantly affect weight or uric acid (e.g., SGLT2 inhibitors). If SGLT2 inhibitors are used, dose adjustment must not exceed the stable dose at enrollment.

             8. Patients with secondary hyperuricemia (e.g., due to renal disease, hematologic malignancy, chemotherapy, or drug-induced) or history of idiopathic uricaciduria (e.g., Lesch-Nyhan syndrome, phosphoribosylpyrophosphate (PRPP) synthetase hyperactivity, familial juvenile hyperuricemic nephropathy, congenital hereditary hyperuricemia); or history of xanthinuria.

             9. Past and Current Medical History - any of the following will exclude:

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  1. Other joint diseases that may confound gouty arthritis diagnosis, such as rheumatoid arthritis, septic arthritis, traumatic arthritis, psoriatic arthritis, etc.
  2. History of malignant tumors (regardless of cure status).
  3. Active infection at screening, serious infection requiring IV antimicrobial therapy or hospitalization within 12 weeks prior to randomization, or any infection requiring oral antibiotic therapy within 2 weeks prior to randomization.
  4. Gastrointestinal dysfunction such as peptic ulcer, irritable bowel syndrome, inflammatory bowel disease; history of conditions affecting gastric emptying (e.g., gastric bypass, pyloric stenosis), or prior gastrointestinal surgery (except procedures with minimal effect on GI motility such as polypectomy, appendectomy, and hemorrhoid surgery); history of acute or chronic pancreatitis; history of acute cholecystitis or symptomatic/requiring-treatment chronic cholecystitis or gallstones (subjects with prior cholecystectomy may be enrolled if judged suitable by the investigator); history of chronic malabsorption syndrome or cholestasis.
  5. Major surgery within 3 months prior to randomization, bariatric surgery (except liposuction > 1 year prior); planned surgery during the study.
  6. Myocardial infarction, unstable angina, percutaneous coronary intervention, coronary artery bypass grafting, stroke, intracerebral hemorrhage, subarachnoid hemorrhage, or transient ischemic attack within 12 months prior to randomization.
  7. Unstable hypertension within 1 month prior to screening, defined as: systolic BP ≥ 160 mmHg and/or diastolic BP ≥ 100 mmHg (if on antihypertensive medication, must be stable for 1 month).
  8. Other unstable cardiovascular, hepatic, renal, gastrointestinal, immune, hematologic, endocrine, metabolic, psychiatric, and/or psychological conditions that may affect study participation.
  9. Blood donation (or blood loss) ≥ 400 mL within 3 months prior to randomization, or receipt of blood transfusion.

  10. Endocrine diseases or history that may significantly affect weight (e.g., Cushing's syndrome, hypothyroidism or hyperthyroidism), except hypothyroidism if thyroid hormone replacement dose has been stable for at least 3 months.

      10. History of severe hypoglycemia or recurrent symptomatic hypoglycemia (≥ 2 episodes in 6 months); secondary obesity due to disease or medication, including: elevated cortisol (e.g., Cushing's syndrome), obesity due to pituitary and hypothalamic injury, obesity due to weight-loss drug withdrawal/discontinuation; history of or screening evidence of retinopathy; history of or screening evidence of malignant tumors (except cured skin basal cell carcinoma and cervical carcinoma in situ).

      11. Clinically significant 12-lead ECG abnormalities at screening: second- or third-degree atrioventricular block, long QT syndrome, or QTcF > 450 ms in males or > 470 ms in females; left or right bundle branch block, pre-excitation syndrome, or other clinically significant arrhythmias (sinus arrhythmia excluded); or heart rate \< 50 bpm or > 100 bpm.

      12. Any screening laboratory abnormality meeting the following criteria (re-measurement within one week allowed if clinically justified, with documentation): serum calcitonin ≥ 20 ng/L (pg/mL); ALT ≥ 3.0 × ULN and/or AST ≥ 3.0 × ULN and/or total bilirubin ≥ 1.5 × ULN; eGFR \< 60 mL/min/1.73 m²; thyroid dysfunction (TSH > 6 mIU/L or \< 0.4 mIU/L); fasting triglycerides ≥ 5.64 mmol/L (500 mg/dL); serum amylase or lipase > 2.0 × ULN; INR above the upper limit of normal range; hemoglobin \< 110 g/L (males) or \< 100 g/L (females).

      13. Use of any of the following within 3 months prior to screening: GLP-1 receptor agonists, GLP-1R/GCGR agonists, GIPR/GLP-1R agonists, or GIPR/GLP-1R/GCGR agonists; drugs affecting weight, including systemic corticosteroids (IV, oral, or intra-articular), tricyclic antidepressants, psychotropic or sedative medications (e.g., imipramine, amitriptyline, mirtazapine, paroxetine, phenelzine, chlorpromazine, thioridazine, clozapine, olanzapine, valproic acid, valproic acid derivatives, lithium); weight-affecting traditional Chinese medicines, health supplements, meal replacements; past or current use of weight-loss medications such as sibutramine, orlistat, phentermine, phenylpropanolamine, fenfluramine, phendimetrazine, bupropion, lorcaserin, phentermine/topiramate combination, naltrexone/bupropion combination; use of any alcohol-containing products within 48 hours prior to dosing, or positive alcohol screening.

      14. Positive hepatitis B surface antigen, positive hepatitis C antibody, positive HIV antibody, or positive syphilis screening.

      15. Positive drug abuse screening, history of drug abuse within the past 5 years, or drug use within 3 months prior to the trial.

      16. Pregnant or lactating females, or positive pregnancy test. 17. Subjects unable to participate for their own reasons. 18. Any other factors, in the investigator's judgment, that may affect the efficacy or safety evaluation of this study and render the subject unsuitable for participation.