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| Name | Class |
|---|---|
| Ethicon, Inc. | INDUSTRY |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Bariatric Surgery | Active Comparator | Roux-en-Y Gastric Bypass (RYGB) and Sleeve Gastrectomy (SG) |
|
| Semaglutide | Active Comparator | Semaglutide, which is an incretin-based medication that has been approved for the treatment of obesity, will be used for this arm. |
|
| Tirzepatide | Active Comparator | Tirzepatide, which is an incretin-based medication that has been approved for the treatment of obesity, will be used for this arm. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Bariatric Surgery | Procedure | Patients receive either RYGB or SG. The surgical risk, the differential impact of each procedure on body weight and other obesity-related diseases, presence of other medical and mental problems, patient's behavioral factors (e.g., postoperative compliance, active smoking), medications, and goals will be considered when the patient and local medical team make a shared decision about the most appropriate surgical procedure. |
| Measure | Description | Time Frame |
|---|---|---|
| The mean percentage weight loss | The mean percentage weight loss at 52 weeks for the following 2 comparisons:
| First 52 weeks of the study |
| Measure | Description | Time Frame |
|---|---|---|
| Percentage of Participants Achieving Weight Loss Milestones (Body weight related end points) | Percentage of participants achieving ≥5%, ≥10%, ≥15%, ≥20%, ≥25%, ≥30%, and ≥35% weight loss from baseline | First 52 weeks of the study |
| Absolute Change in Weight (Body weight related end points) |
| Measure | Description | Time Frame |
|---|---|---|
| Cardiac ejection fraction (via cardiac MRI) | Ejection fraction of the heart evaluated via cardiac MRI measured in percentage | First 52 weeks of the study |
| Left ventricular mass (via cardiac MRI) | Left ventricular mass, evaluated via cardiac MRI measured in grams |
Inclusion Criteria:
Entry into the study would require that the patient:
Exclusion Criteria:
Significant cardiac or atherosclerotic disease (planned to undergo cardiac, coronary, carotid, or peripheral artery revascularization procedures in the next 12 months)
Severe uncompensated cardiopulmonary disease leading to American Society of Anesthesiologists Class IV or V
Classified as New York Heart Association Class IV
Left ventricular ejection fraction <25% at the time of screening (if already known)
Myocardial infarction, unstable angina, stroke, transient ischemic attack, heart surgery, coronary stent placement in the past 6 months
Prior bariatric surgery of any kind
• Intragastric balloon that has been removed at least 6 months prior to the first study visit is allowed.
History of solid organ transplant
Type 1 diabetes or autoimmune diabetes
eGFR < 30 mL/min/1.73 m2 or being on dialysis
History of deep vein thrombosis, pulmonary embolism, or venous thromboembolism
On therapeutic dose of anticoagulants such as warfarin or direct oral anticoagulants (DOACs)
Decompensated cirrhosis characterized by presence of ascites, hepatic encephalopathy, portal hypertension, or esophageal varices.
History of severe anemia defined as hemoglobin less than 8 g/dL
Use of investigational therapy
Liver transaminase level or alkaline phosphatase >200 U/L
Significant alcohol use (average >2 drinks/day)
Presence of active malignancy (except non-melanoma skin cancer)
Life expectancy less than 3 years due to concomitant diseases
Major mental health, psychological disorders, or substance abuse disorders that in the opinion of the investigators could disqualify the patient from bariatric surgery
Any condition or major illness that, in the investigator's judgment, places the subject at undue risk by participating in the study
Unable to understand the risks, benefits and compliance requirements of study
Lack capacity to give informed consent
Plans to move outside the primary location of study (northeast Ohio) within the next 12 months
Pregnant, breast-feeding or the intention of becoming pregnant or not using adequate contraceptive measures
Hypothalamic obesity
Continuous treatment with semaglutide (once weekly) or tirzepatide (once weekly) <60 days before screening
History of semaglutide (once weekly) or tirzepatide (once weekly) use in the past for obesity with lack of clinical response
Chronic use of systemic steroids
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.
Acute pancreatitis < 180 days before screening
History or presence of chronic pancreatitis
History of Crohn's disease
Known or suspected allergy to semaglutide, tirzepatide, excipients, or related products
A personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2)
Previous participation in this trial and got randomized to one of the study groups but did not proceed.
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| Name | Affiliation | Role |
|---|---|---|
| Ali Aminian | The Cleveland Clinic | Principal Investigator |
| Ali Aminian, MD | The Cleveland Clinic | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| The Cleveland Clinic | Cleveland | Ohio | 44195 | United States |
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| ID | Term |
|---|---|
| D009765 | Obesity |
| ID | Term |
|---|---|
| D050177 | Overweight |
| D044343 | Overnutrition |
| D009748 | Nutrition Disorders |
| D009750 | Nutritional and Metabolic Diseases |
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| ID | Term |
|---|---|
| D050110 | Bariatric Surgery |
| D015390 | Gastric Bypass |
| C000591245 | semaglutide |
| D000098860 | Tirzepatide |
| ID | Term |
|---|---|
| D049088 | Bariatrics |
| D000073319 | Obesity Management |
| D013812 | Therapeutics |
| D013514 | Surgical Procedures, Operative |
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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.
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| Semaglutide | Drug | Semaglutide will be initiated at a dose of 0.25 mg once weekly and will be increased during the dose-escalation period to reach a maintenance dose of up to 2.4 mg once weekly by week 16. If patients do not tolerate a dose during dose escalation, we will consider delaying dose escalation until next visit (for 4 weeks). Dosing for Semaglutide is the FDA-approved dosing schedule. The maintenance dose is 2.4 mg injected subcutaneously once-weekly. The protocol allows for dose reductions in case a participant does not tolerate the recommended target dose of 2.4 mg and may stay at the lower maintenance dose level (e.g., 1.7 mg once weekly), if needed. |
|
|
| Tirzepatide | Drug | Tirzepatide will be initiated at a dose of 2.5 mg once weekly and will be increased by 2.5 mg every week during the dose-escalation period to reach a maintenance dose of up to 15 mg once weekly by week 20. If patients do not tolerate a dose during dose escalation, we will consider delaying dose escalation until next visit (for 4 weeks). Dosing for Tirzepatide is the FDA-approved dosing schedule. The maintenance dose is 15 mg injected subcutaneously once-weekly. The protocol allows for dose reductions in case a participant does not tolerate the recommended target dose of 15 mg and may stay at the lower maintenance dose level (e.g., 10 mg once weekly), if needed. |
|
|
Mean absolute change in weight measured in kilograms from baseline to 52 weeks |
| First 52 weeks of the study |
| Absolute Change in BMI (Body weight related end points) | Absolute change in BMI measured in kg/m^2 from baseline to 52 weeks | First 52 weeks of the study |
| Excess Weight Loss Percentage (Body weight related end points) | Percentage of excess weight loss, calculated by dividing the difference between initial BMI and final BMI by the difference between initial BMI and a target BMI of 25 | First 52 weeks of the study |
| Change in Waist Circumference (Body weight related end points) | Change in waist circumferential measurement above the level of the iliac crests measured in centimeters from baseline to 52 weeks | First 52 weeks of the study |
| Systolic blood pressure trends | Mean and change in systolic blood pressure measured in mmHg | First 52 weeks of the study |
| Mean and change from baseline in lipid panel | Mean and change from baseline in total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and triglycerides measured in mg/dL | First 52 weeks of the study |
| Changes in glucose homeostasis markers in T2DM patients | Mean and change from baseline in blood glucose (measured in mg/dL) and HbA1c (as a percentage) in patients with T2DM | First 52 weeks of the study |
| Percentage of patients with T2DM meeting predefined HbA1c targets | Percentage of patients meeting different HbA1c targets, for example:
| First 52 weeks of the study |
| Changes in inflammatory marker, CRP | Mean and change from baseline in C-Reactive Protein (CRP) measured in mg/L | First 52 weeks of the study |
| Changes in Lipoprotein(a) | Mean and change from baseline in Lipoprotein(a) measured in mg/dL | First 52 weeks of the study |
| Change in cardiovascular and diabetes medications | Change in the number of cardiovascular and diabetes medications prescribed | First 52 weeks of the study |
| Change from baseline in quality of life metrics | Change from baseline in score of The 36-Item Short Form Health Survey (SF-36) (physical and mental components). Each item is given a score ranging from 0-100. Lower scores indicating poor outcomes. Final score is an average of all the items that were answered. Unanswered questions are not included in the final average. Research coordinator completes the survey with the patient. | First 52 weeks of the study |
| Change in body composition (via Seca mBCA 554 Bioimpedance Analysis) | Change in body composition (% fat mass and % fat-free mass) as measured by Seca mBCA 554 Bioimpedance Analysis to assess whether that weight loss is primarily caused by reduction in fat mass or not. | First 52 weeks of the study |
| Mean change in liver fat content (via MRI-PDFF) | Mean change from baseline in liver fat content as assessed by MRI-PDFF measured as a percentage | First 52 weeks of the study |
| Percentage of Participants Achieving ≥5%, ≥30%, ≥50% Absolute Reduction in Liver Fat Content (via MRI-PDFF) | Percentage of participants achieving at least 5%, 30%, or 50% relative reduction in liver fat content from baseline | First 52 weeks of the study |
| Percentage of Participants Achieving MRI-PDFF Normalization (via MRI-PDFF) | Percentage of participants achieving MRI-PDFF normalization, defined as a liver fat content of <5%, at week 52 | First 52 weeks of the study |
| First 52 weeks of the study |
| Pericardial fat fraction (via cardiac MRI) | fat fraction of the pericardium via cardiac MRI measured in percentage | First 52 weeks of the study |
| change in body weight (second phase of the study) | Change in body weight in percentage during the extension phase of the trial mimicking what can happen in the real-life setting | from week 52 to week 104 of the study |
| Cross-overing to bariatric surgery (second phase of the study) | Percentage of patients cross-over from nonsurgical arm to bariatric surgery | from week 52 to week 104 of the study |
| Anti-obesity medication after bariatric surgery (second phase of the study) | Percentage of patients receiving anti-obesity medications after bariatric surgery | from week 52 to week 104 of the study |
| Change in body weight in patients receiving combination therapy (second phase of the study) | Change in body weight in percentage during the extension phase of the trial in the patients who receive both bariatric surgery and anti-obesity medications | from week 52 to week 104 of the study |
| Safety end points | Complications related to obesity, bariatric surgery, as well as adverse events of semaglutide and tirzepatide in the trial will be recorded and evaluated. | Throughout the study, 104 weeks |
| D001835 |
| Body Weight |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D005763 |
| Gastroenterostomy |
| D000714 | Anastomosis, Surgical |
| D013505 | Digestive System Surgical Procedures |
| D000067757 | Glucagon-Like Peptide-1 Receptor |
| D000067756 | Glucagon-Like Peptide Receptors |
| D043562 | Receptors, G-Protein-Coupled |
| D011956 | Receptors, Cell Surface |
| D008565 | Membrane Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
| D011964 | Receptors, Gastrointestinal Hormone |
| D018000 | Receptors, Peptide |