Clinical trial NCT06803888: Bariatric Surgery vs. Semaglutide vs. Tirzepatide
Official title: Efficacy and Safety of Bariatric Surgery, Semaglutide Once Weekly, and Tirzepatide Once Weekly in Patients With Obesity
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Obesity and Obesity-related Medical Conditions
Keywords: Bariatric Surgery
Tirzepatide
Semaglutide
Obesity
GLP-1 Receptor Agonist
Mounjaro
Wegovy
Zepbound
Ozempic
Sleeve Gastrectomy
Roux-en-Y gastric bypass
Lead sponsor: The Cleveland Clinic
Sponsor class: OTHER
Collaborators: name: Ethicon, Inc.
First posted: 2025-01-31
Enrollment: 125
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This is a randomized non-blinded controlled efficacy/safety study with 3 parallel groups who will either receive bariatric surgery (RYGB or SG), semaglutide, or tirzepatide. The study has 2 phases: the first 12 months for the assessment of the primary endpoint, and the second 12 months as the extension phase of the study to mimic the real-life setting. Findings at the end of each phase will be separately reported.
Primary purpose: TREATMENT

Brief summary: The recent introduction of the new generation of anti-obesity medications (AOMs) will change the future of obesity treatment. These highly effective medications, such as high-dose semaglutide and tirzepatide, are hormone analogues that augment the incretin function and exert multiple physiological effects by activating glucagon-like peptide-1 (GLP-1) and/or glucose-dependent insulinotropic polypeptide (GIP) distributed in various organs. These medications provide an average of 15-22% weight reduction in one-year trials, which had not been seen in the past with medical therapy. While the literature suggests that bariatric surgery is superior to these new highly effective medications, there is no head-to-head comparison between the most common bariatric operations (Roux-en-Y gastric bypass \[RYGB\] and sleeve gastrectomy \[SG\]) with semaglutide (once weekly) and tirzepatide (once weekly). The goal of this Randomized Clinical Trial (RCT) is to compare these effective therapies in patients with severe obesity to provide the best evidence to inform clinical decisions in treating patients with obesity.

Detailed description: This is a randomized, non-blinded, controlled efficacy/safety study with 3 parallel groups who will either receive bariatric surgery (RYGB or SG), semaglutide, or tirzepatide. The study has 2 phases: the first 12 months for the assessment of the primary endpoint ( mean percentage weight loss) and the second 12 months as the extension phase of the study to mimic the real-life setting. Findings at the end of each phase will be separately reported.

A randomized trial of 125 patients with a BMI of 35-65 kg/m2 who sought treatment for obesity at Cleveland Clinic will be performed. Patients who meet the ASMBS/IFSO 2022 guidelines for bariatric surgery will be invited for possible enrollment. Interested and eligible patients will be randomized to receive their already chosen bariatric surgery (RYGB or SG), tirzepatide. or semaglutide in 2:2:1 ratio.

The study is not intended to compare RYGB vs SG head-to-head. RYGB and SG constitute one group as a bariatric surgery group. The assignment of RYGB or SG is not based on a randomized design. Each patient and surgical team will make a shared decision about the most appropriate surgical procedure. The study is also not intended to compare semaglutide vs tirzepatide head-to-head.

In the second or extension phase of the study, participants are followed from month 12 to month 24, regardless of the treatment that they receive. In this phase, the study medications (semaglutide and tirzepatide) will not be provided by the study. The goal of this phase is to provide valuable insights into A) access to AOMs and the durability of effects in the real-life setting, B) cross-over from AOMs to bariatric surgery, and C) adjuvant pharmacotherapy after bariatric surgery.

Eligibility criteria: Inclusion Criteria:

Entry into the study would require that the patient:

1. Is a candidate for general anesthesia
2. Is eligible for bariatric surgery (RYGB or SG) based on ASMBS/IFSO 2022 guidelines
3. Is ≥18 and ≤70 years old (both inclusive)
4. has a BMI ≥35 and ≤65 kg/m2 (both inclusive)
5. Patients with and without T2DM are eligible for the study. Patients with T2DM should have been on a stable dose of anti-diabetic medication (including insulin but not semaglutide or tirzepatide) for at least 3 months prior to entry, with HbA1c ≤12%.
6. No weight loss \> 20 lbs. in 3 months before screening (self-reported)
7. Has the ability and willingness to participate in the study, provide informed consent, and agree to any of the arms involved in the study.
8. Is able to understand the options and to comply with the requirements of each arm.
9. Has a negative urine pregnancy test at randomization visit for women of childbearing potential.
10. Women of childbearing age must agree to use reliable method of contraception for 2 years.

Exclusion Criteria:

1. Significant cardiac or atherosclerotic disease (planned to undergo cardiac, coronary, carotid, or peripheral artery revascularization procedures in the next 12 months)
2. Severe uncompensated cardiopulmonary disease leading to American Society of Anesthesiologists Class IV or V
3. Classified as New York Heart Association Class IV
4. Left ventricular ejection fraction \<25% at the time of screening (if already known)
5. Myocardial infarction, unstable angina, stroke, transient ischemic attack, heart surgery, coronary stent placement in the past 6 months
6. Prior bariatric surgery of any kind

   • Intragastric balloon that has been removed at least 6 months prior to the first study visit is allowed.
7. History of solid organ transplant
8. Type 1 diabetes or autoimmune diabetes
9. eGFR \< 30 mL/min/1.73 m2 or being on dialysis
10. History of deep vein thrombosis, pulmonary embolism, or venous thromboembolism
11. On therapeutic dose of anticoagulants such as warfarin or direct oral anticoagulants (DOACs)
12. Decompensated cirrhosis characterized by presence of ascites, hepatic encephalopathy, portal hypertension, or esophageal varices.
13. History of severe anemia defined as hemoglobin less than 8 g/dL
14. Use of investigational therapy
15. Liver transaminase level or alkaline phosphatase \>200 U/L
16. Significant alcohol use (average \>2 drinks/day)
17. Presence of active malignancy (except non-melanoma skin cancer)
18. Life expectancy less than 3 years due to concomitant diseases
19. Major mental health, psychological disorders, or substance abuse disorders that in the opinion of the investigators could disqualify the patient from bariatric surgery
20. Any condition or major illness that, in the investigator's judgment, places the subject at undue risk by participating in the study
21. Unable to understand the risks, benefits and compliance requirements of study
22. Lack capacity to give informed consent
23. Plans to move outside the primary location of study (northeast Ohio) within the next 12 months
24. Pregnant, breast-feeding or the intention of becoming pregnant or not using adequate contraceptive measures
25. Hypothalamic obesity
26. Continuous treatment with semaglutide (once weekly) or tirzepatide (once weekly) \<60 days before screening
27. History of semaglutide (once weekly) or tirzepatide (once weekly) use in the past for obesity with lack of clinical response
28. Chronic use of systemic steroids
29. Uncontrolled thyroid disease: thyroid stimulating hormone (TSH) \> 6.0 mIU/L or \< 0.1 mIU/L

    • Note: Patients receiving treatment for hypothyroidism can be included if their thyroid hormone replacement dose has been stable for at least 3 months.
30. Acute pancreatitis \< 180 days before screening
31. History or presence of chronic pancreatitis
32. History of Crohn's disease
33. Known or suspected allergy to semaglutide, tirzepatide, excipients, or related products
34. A personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2)
35. Previous participation in this trial and got randomized to one of the study groups but did not proceed.

Primary outcomes:
measure: The mean percentage weight loss
timeFrame: First 52 weeks of the study
Secondary outcomes:
measure: Percentage of Participants Achieving Weight Loss Milestones (Body weight related end points)
timeFrame: First 52 weeks of the study
measure: Absolute Change in Weight (Body weight related end points)
timeFrame: First 52 weeks of the study
measure: Absolute Change in BMI (Body weight related end points)
timeFrame: First 52 weeks of the study
measure: Excess Weight Loss Percentage (Body weight related end points)
timeFrame: First 52 weeks of the study
measure: Change in Waist Circumference (Body weight related end points)
timeFrame: First 52 weeks of the study
measure: Systolic blood pressure trends
timeFrame: First 52 weeks of the study
measure: Mean and change from baseline in lipid panel
timeFrame: First 52 weeks of the study
measure: Changes in glucose homeostasis markers in T2DM patients
timeFrame: First 52 weeks of the study
measure: Percentage of patients with T2DM meeting predefined HbA1c targets
timeFrame: First 52 weeks of the study
measure: Changes in inflammatory marker, CRP
timeFrame: First 52 weeks of the study
measure: Changes in Lipoprotein(a)
timeFrame: First 52 weeks of the study
measure: Change in cardiovascular and diabetes medications
timeFrame: First 52 weeks of the study
measure: Change from baseline in quality of life metrics
timeFrame: First 52 weeks of the study
measure: Change in body composition (via Seca mBCA 554 Bioimpedance Analysis)
timeFrame: First 52 weeks of the study
measure: Mean change in liver fat content (via MRI-PDFF)
timeFrame: First 52 weeks of the study
measure: Percentage of Participants Achieving ≥5%, ≥30%, ≥50% Absolute Reduction in Liver Fat Content (via MRI-PDFF)
timeFrame: First 52 weeks of the study
measure: Percentage of Participants Achieving MRI-PDFF Normalization (via MRI-PDFF)
timeFrame: First 52 weeks of the study
Other outcomes:
measure: Cardiac ejection fraction (via cardiac MRI)
timeFrame: First 52 weeks of the study
measure: Left ventricular mass (via cardiac MRI)
timeFrame: First 52 weeks of the study
measure: Pericardial fat fraction (via cardiac MRI)
timeFrame: First 52 weeks of the study
measure: change in body weight (second phase of the study)
timeFrame: from week 52 to week 104 of the study
measure: Cross-overing to bariatric surgery (second phase of the study)
timeFrame: from week 52 to week 104 of the study
measure: Anti-obesity medication after bariatric surgery (second phase of the study)
timeFrame: from week 52 to week 104 of the study
measure: Change in body weight in patients receiving combination therapy (second phase of the study)
timeFrame: from week 52 to week 104 of the study
measure: Safety end points
timeFrame: Throughout the study, 104 weeks
Locations:
city: Cleveland
country: United States
facility: The Cleveland Clinic
state: Ohio
Study officials:
affiliation: The Cleveland Clinic
name: Ali Aminian
role: PRINCIPAL_INVESTIGATOR
References: