Mazdutide as Adjuvant Therapy Following Sleeve Gastrectomy in Severe Obesity

Official title

Mazdutide as Adjuvant Therapy Following Sleeve Gastrectomy in Severe Obesity:A Multicenter, Randomized, Double-Blind, Placebo-Controlled Superiority Trial

Overview

The SMART study is a 96-week, multicenter, randomized, double-blind, placebo-controlled superiority clinical trial. A total of 256 severe obesity patients are randomized 1:1 to either receive the bariatric surgery plus GCG/GLP-1 dual receptor agonist group (receiving sleeve gastrectomy followed by subcutaneous injections of mazdutide weekly, with stepwise dose escalation to a maintenance dose per protocol) or the bariatric surgery plus placebo group (receiving matched procedure plus placebo injections). The primary objective is to evaluate the potential enhancing weight reduction effects of the combination therapy with bariatric surgery and mazdutide measured by the percentage change of excess weight loss.

Interventions

• Drug Sleeve gastrectomy plus early mazdutide initiation
  After sleeve gastrectomy is preformed, mazdutide injection (pre-filled auto-injector pen) is administered subcutaneously at the same time each week at 5th month post procedure. The treatment begins with a starting dose of 2.0 mg, followed by a titration schedule increasing by 2.0 mg every 4 weeks (2.0 mg → 4.0 mg). If well-tolerated, participants reached the target maintenance dose of 6.0 mg (4.0 mg → 6.0 mg)weekly for maintenance. The protocol permits adaptive dose downgrade to 4.0 mg weekly wh
• Drug Sleeve gastrectomy followed with early mazdutide placebo initation
  After sleeve gastrectomy is preformed, mazdutide placebo injection (pre-filled auto-injector pen) is administered subcutaneously at the same time each week at 5th month post procedure. The treatment begins with a starting dose of 2.0 mg placebo, followed by a titration schedule increasing by 2.0 mg every 4 weeks (2.0 mg → 4.0 mg). If well-tolerated, participants reached the target maintenance dose of 6.0 mg placebo(4.0 mg → 6.0 mg) weekly for maintenance. The protocol permits adaptive dose downg

Primary outcome measures

• the rate of excess weight loss(EWL%) compared to baseline [Time frame: At 48th week post procedure]

Secondary outcome measures (12)

• Assessing the change in BMI(kilogram/square meter, kg/m²） classification compared to baseline(Based on the BMI classification in Chinese adiposity diagnosis and treatment guideline 2024) [Time frame: At 48th week post procedure]
• Assessing the rate of total body weight loss(TBWL%) compared to baseline [Time frame: At 48th week post procedure]
• Assessing the change of waist circumference(centimeter, cm) compared to baseline [Time frame: at 48th week post procedure]
• Assessing the change of hip circumference(centimeter, cm) compared to baseline [Time frame: At 48th week post procedure]
• Assessing the change of blood pressure(incl. systolic blood pressure and diastolic blood pressure) compared to baseline（Hydrargyrum, mmHg） [Time frame: At 48th week post procedure]
• Assessing the percentage change（%） of body fat or fat-free mass compared to baseline [Time frame: At 48th week post procedure]
• Assessing the percentage change（%） of liver fat content or pancreatic fat content compared to baseline [Time frame: At 48th week post procedure]
• Assessing the percentage change(%) of triglyceride(TG), low-density lipoprotein cholesterol(LDL-C),total cholesterol(TC) or high-density lipoprotein cholesterol(HDL-C) compared to baseline [Time frame: At 48th week post procedure]
• Assessing the change of aspartate transaminase(AST) or alanine aminotransferase(ALT) compared to baseline [Time frame: At 48th week post procedure]
• Assessing the change(%) of serum uric acid compared to baseline [Time frame: At 48th week post procedure]
• Assessing the change of nutrition status (incl. albumin, victamin B12, folic acid or serum iron and so forth) compared to baseline [Time frame: At 48th week post procedure]
• Assessing the change of body weight related life quality(IWQOL-Lite) , upper GI symptom scale(GERDQ) or overall life quality scale(SF-36) compared to baseline [Time frame: At 48th week post procedure]

Eligibility criteria

Inclusion criteria

• Aged 18-70 years (inclusive), male or female;
• BMI≥37.5 kg/m2, with or without obesity-related complications;
• Planned to take sleeve gastrectomy
• Understand the trial protocol, voluntarily sign the informed consent form (ICF), and agree to follow all study requirements and restrictions.

Exclusion criteria

• Previous gastrointestinal surgery such as stomach and duodenum, or weight loss and metabolic surgery;
• History of thyroid C-cell carcinoma, multiple endocrine neoplasia (MEN) 2A or 2B, or relevant family history;
• ALT > 3.0 × ULN (if NAFLD is diagnosed at screening and within 6 months prior to screening, ALT ≤ 5.0 × ULN can be enrolled), or AST > 3.0 ×ULN, or total bilirubin (TBIL) > 2 × ULN
• Estimated glomerular filtration rate eGFR < 45 mL/min/1.73 m2 using the CKD-EPI equation
• Chronic anemia：Hemoglobin < 110 g/L (males) or < 100 g/L (females)；
• Have the following 12-lead electrocardiogram (ECGs) abnormalities at screening(<50 beats/min or >100 beats/min), 2nd or 3rd degree atrioventricular block, long QT syndrome or QTcF > 450 ms (males), QTcF > 470 ms (females), left or right bundle branch block, pre-excitation syndrome, or other significant arrhythmia (except sinus arrhythmia);
• Acute hyperglycemic/hypoglycemic events within 1 year, including:

diabetic ketoacidosis (DKA), hyperosmolar hyperglycemic state (HHS), and hypoglycemic coma, etc;

• Participants with previous severe myocardial infarction, stroke, acute and chronic heart failure, cardiac procedure such as percutaneous coronary intervention, coronary artery bypass grafting, or are not suitable for participation in this study after the investigator's assessment;
• Previous or confirmed mental illness at screening/randomization phase\[Previous moderate to severe depressionPHQ questionnaire (Depression Screening Scale) ≥ 15 points, C-SSRS questionnaire (Columbia Suicide Severity Scale) category 4 or 5 at screening or randomization, or "Yes" in suicidal behavior or suicidal ideation\];
• Previous specific infectious diseases, incl. acquired immunodeficiency syndrome, viral hepatitis B, viral hepatitis C, etc;
• End-stage disease with an expected survival of less than 5 years or previous/current malignancy;
• Use of GLP-1 receptor (GLP-1R) agonists or GLP-1R/GCGR agonists or GIPR/GLP-1R agonists or GIPR/GLP-1R/GCGR agonists within three months prior to screening;
• History of alcohol or drug abuse at screening;
• History of specific drugs use beyond 2 times, incl. moderate anticholinergics, antiparkinsonians, antiepileptic drugs, antipsychotics, benzodiazepines and sedatives, morphine and narcotic analgesics, stimulant drugs, medical marijuana, marijuana, and cannabidiol, etc.;
• Pregnant or lactating females, males or females of childbearing potential who are not willing to use contraception throughout the study and for 8 weeks after the end of the study;
• Having participated in other clinical investigators who have a conflict of interest with this study;
• The investigator suspects that the participant may be allergic to ingredients in the study drug or drugs of the same class;

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Triple blind

Primary purpose

Treatment

Study locations

China · 14 centers

• Beijing Friendship Hospital, Capital Medical University — Beijing
• Beijing Hospital — Beijing
• Peking University People's Unviersity — Beijing
• The Third Hospital of Central South University — Changsha
• West China Hospital of Sichuan University — Chengdu
• The First Affiliated Hospital of Jinan University(Guangzhou Overseas Chinese Hospital) — Guangzhou
• Qilu Hospital of Shandong University — Jinan
• Kunming First People's Hospital — Kunming
• … and 6 more centers

Identifiers

NCT: NCT07135141 · SMART trial

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗