MIST (Metabolic Intervention With Semaglutide and THR-β Therapy) Trial

Prior treatment

• Weight change \>5% of total body weight within 6 months prior to screening or planned initiation of a weight loss program or use of weight-altering medication.
• Use of GLP-1 agonist treatment within the last 6 months prior to screening.
• Have current treatment with or history (within 3 months prior to screening) of treatment with medications that may cause significant weight gain.
• History of significant alcohol consumption for \>3 consecutive months within a year prior to screening.
• Current or past therapy with THR-β agonists (eg, resmetirom).
• Active untreated hyperthyroidism or hyperthyroidism currently treated with antithyroid medications including methimazole or propylthiouracil.
• History of bariatric surgery, fitting of a weight loss device, or intestinal bypass surgery within 5 years prior to screening.
• History of major surgery within 8 weeks prior to screening.

Other illness

• History or current diagnosis of type 1 or type 2 diabetes mellitus.
• Obesity induced by endocrine disorders such as Cushing's syndrome or monogenic or syndromic obesity such as Prader-Willi syndrome.
• History or current evidence of a pituitary disorder.
• Documented evidence or clinical signs/symptoms of advanced liver disease including liver cirrhosis, portal hypertension, or hepatic decompensation.
• Clinically relevant acute or chronic medical condition or unstable disease of the cardiovascular, gastrointestinal, hepatic, renal, endocrine, pulmonary, neurologic, psychiatric, immune or dermatologic system.

Lab values

• ALT or AST \>1.5×ULN, or ALP \>1.5×ULN at screening.

Other

• Clinically significant thyroid dysfunction including uncontrolled hypothyroidism or hyperthyroidism.

• Capable of providing written informed consent and complying with all trial procedures.
• Willing to comply with contraception requirements (as applicable to males and females of childbearing potential).
• Obese with BMI ≥30 kg/m\^2 and stable body weight within 6 months prior to screening.
• HbA1c ≤6.5%.
• Estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m\^2 (per CKD-EPI 2021 formula).
• If participant consents to enter the imaging substudy, has liver fat content by MRI-PDFF \>8% at baseline (Week 9).