Mazdutide as Adjuvant Therapy Following Sleeve Gastrectomy in Severe Obesity (SMART)

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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Severe Obesity
• Intervention / Treatment: Drug: Sleeve gastrectomy plus early mazdutide initiation; Drug: Sleeve gastrectomy followed with early mazdutide placebo initation

• Study Type: Interventional
• Enrollment (Estimated): 256
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: ZhongTao Zhang, MD, PhD; Phone Number: +86 010 63139361; Email: zhangzht@ccmu.edu.cn
• Study Contact Backup: Name: Mengyi Li, MD, PhD; Phone Number: +86 010 63139361; Email: limengyi@ccmu.edu.cn

Study Locations

• China
  • Beijing, China
    • Beijing Friendship Hospital, Capital Medical University
  • Beijing, China
    • Beijing Hospital
    • Principal Investigator: Lixin Guo
    • Contact: Lixing Guo; Phone Number: +86 13901317569; Email: glx1218@163.com
  • Beijing, China
    • Peking University People's Unviersity
    • Principal Investigator: Linong Ji, MD,PhD
    • Contact: Linong Li, MD,PhD; Phone Number: +86 010 63139361; Email: jiln@bjmu.edu.cn
    • Contact: Zhaohui Zhong; Phone Number: +86 13691102568; Email: zhongzhaohui@pkuph.edu.cn
    • Principal Investigator: Zhaohui Zhong
    • Principal Investigator: Yingying Luo
  • Changsha, China
    • The Third Hospital of Central South University
    • Contact: Liyong Zhu; Phone Number: +86 19373109453; Email: zly8128@csu.edu.cn
    • Principal Investigator: Liyong Zhu
  • Chengdu, China
    • West China Hospital of Sichuan University
    • Contact: Yi Chen; Phone Number: +86 13881823928
    • Principal Investigator: Yi Chen
  • Guangzhou, China
    • The First Affiliated Hospital of Jinan University(Guangzhou Overseas Chinese Hospital)
    • Contact: Jingge Yang; Phone Number: +86 13560099502; Email: dukeyjg@126.com
    • Principal Investigator: Jingge Yang
  • Jinan, China
    • QiLU Hospital of ShanDong University
    • Contact: Shaozhuang Liu; Phone Number: +86 18560085165; Email: liushaozhuang@sdu.edu.cn
    • Principal Investigator: Shaozhuang Liu
  • Kunming, China
    • Kunming First People's Hospital
    • Contact: JianHui Yin; Phone Number: +86 15877990129; Email: 1551389142@qq.com
    • Principal Investigator: Jianhui Yin
  • Nanjing, China
    • Nanjing Drum Tower Hospital
    • Contact: Xitai Sun; Phone Number: +86 13815424927; Email: sunxitai@hotmail.com
    • Principal Investigator: Xitai Sun
  • Shanghai, China
    • Huadong Hospital Affiliated to Fudan University
    • Contact: Yan Gu; Phone Number: +86 13661756660; Email: yangu@fudan.edu.cn
    • Principal Investigator: Yan Gu
  • Shanghai, China
    • Shanghai Sixth People's Hospital to Shanghai Jiao Tong University School of Medicine
    • Contact: Jianzhong Di; Phone Number: +86 18930177207; Email: dijianzhong@163.com
    • Principal Investigator: Jianzhong Di
  • Shijiazhuang, China
    • The Second Hospital of Hebei Medical University
    • Principal Investigator: Tao Li
    • Contact: Tao Li; Phone Number: +86 13930483525; Email: litao18353@163.com
  • Tianjing, China
    • Tianjin Medical University General Hospital
    • Contact: Xiaoyu Liang; Phone Number: +86 13802036941; Email: liangxiaoyu2025@hotmail.com
    • Principal Investigator: Xiaoyu Liang
  • Wuhan, China
    • Zhongnan Hospital of Wuhan University
    • Principal Investigator: Zhen Li
    • Contact: Zhen Li; Phone Number: +86 15071396243; Email: kamei_li@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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;

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sleeve gastrectomy plus mazdutide group; Participants will receive weekly subcutaneous injections of mazdutide at 5th month post sleeve gastrectomy(starting at 2.0 mg, with stepwise dose escalation to a target maintenance dose of 6.0 mg and optional adaptive downgrade to 4.0 mg if necessary)	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 when clinically indicated, such as intolerance. The total intervention is maintained until 48 weeks post procedure.
Placebo Comparator: Sleeve gastrectomy plus mazdutide placebo group; Participants will receive weekly subcutaneous injections of matched placebo at 5th month post sleeve gastrectomy	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 downgrade to 4.0 mg weekly when clinically indicated, such as intolerance. The total intervention is maintained until 48 weeks post procedure.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
the rate of excess weight loss(EWL%) compared to baseline	EWL%=[preoperative weight-post operative weight]/[preoperative weight -ideal body weight]x100%, ideal weight=height²(m²)x25kg/m²	At 48th week post procedure

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)	BMI classification in China: BMI 18.5-24 kg/m² healthy; 24<BMI<28 kg/m² overweight, 28<BMI<32.5 kg/m² mild obesity, 32.5<BMI<37.5 kg/m² moderately obese, BMI>37.5 kg/m² severe or extremely severe obesity	At 48th week post procedure
Assessing the rate of total body weight loss(TBWL%) compared to baseline	Total body weight loss (TBWL) is the pre-op weight minus the post op body weight	At 48th week post procedure
Assessing the change of waist circumference(centimeter, cm) compared to baseline	waist circumference is measured with centimeter(cm)	at 48th week post procedure
Assessing the change of hip circumference(centimeter, cm) compared to baseline	Hip circumference is measured with centimeter(cm).	At 48th week post procedure
Assessing the change of blood pressure(incl. systolic blood pressure and diastolic blood pressure) compared to baseline（Hydrargyrum, mmHg）	Blood pressure is measured with mmHg.	At 48th week post procedure
Assessing the percentage change（%） of body fat or fat-free mass compared to baseline	Body fat or fat-free mass is measured by dual energy X-ray absorptiometry(DEXA)	At 48th week post procedure
Assessing the percentage change（%） of liver fat content or pancreatic fat content compared to baseline	Liver fat content or pancreatic fat content is measured with Magnetic resonance imaging-derived proton density fat fraction(MRI-PDFF)	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	TG(millimoles per liter, mmol/L) , LDL-C(millimoles per liter, mmol/L) ,TC(millimoles per liter, mmol/L) or HDL-C(millimoles per liter, mmol/L) is tested in the lab of study sites with local standards according to Chinese Guidelines for Lipid Management	At 48th week post procedure
Assessing the change of aspartate transaminase(AST) or alanine aminotransferase(ALT) compared to baseline		At 48th week post procedure
Assessing the change(%) of serum uric acid compared to baseline	serum uric acid(micromoles per liter, µmol/L) is tested in the lab of study sites according to Chinese National Standards	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	Albumin(gram per liter, g/L), folic acid(nanomoles per liter,nmol/L), Victamin B12(picomole per liter, pmol/L), serum iron(milligrams per liter, mg/L) is tested in the lab of study sites according to Chinese National Standards	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	IWQOL-Lite Score ranges among 31-105, the higher the score, the poorer the quality of life; When GerdQ score ≥8 points, it means the risk of gastroesophageal reflux is high; SF-36 score includes 8 dimensions, and the total score equals mean transformed scores of 8 dimensions, the higher the score, the higher the quality of life, transformed score of each dimension=［（actual score-the lowest possible score）/general average possible score］×100	At 48th week post procedure
Assessing the rate(%) of procedure-related or drug-related complications, re-admission, or major cardiovascular adverse events	Procedure-related complications include gastroesophageal reflux disease, malnutrition and so on; Drug-related complications include nausea, vomiting, diarrhea and so on	At 48th week post procedure
Assessing the rate(%) of body weight regain among participants	'Body weight rebounded over 15% compared to nadir weight' is referred to as weight regain	At 96th week post procedure

Collaborators and Investigators

• Sponsor: Beijing Friendship Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): September 30, 2025
• Primary Completion (Estimated): September 30, 2027
• Study Completion (Estimated): September 30, 2029

Study Registration Dates

• First Submitted: August 12, 2025
• First Submitted That Met QC Criteria: August 20, 2025
• First Posted (Actual): August 21, 2025

Study Record Updates

• Last Update Posted (Actual): August 21, 2025
• Last Update Submitted That Met QC Criteria: August 20, 2025
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nutrition Disorders; Overnutrition; Body Weight; Overweight; Obesity; Obesity, Morbid
• Other Study ID Numbers: SMART trial (Allergan)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No