Morbid Obesity
Conditions
Keywords
SANDWICH, Semaglutide, conversion of sleeve gastrectomy to Roux-en-Y gastric bypass, sleeve gastrectomy, Roux-en-Y gastric bypass, recurrent weight gain
Brief summary
Recurrent weight gain affects 15% to 40% of patients after metabolic and bariatric surgery (MBS). SG is the most performed operation worldwide, and long-term regain after SG is well documented. A 2026 international Delphi consensus has now standardized the definition. This trial uses that definition. So does our companion trial, RESURGE. We have two real treatments. Both work. Neither is enough. Conversion of SG to RYGB gives around 20% additional total weight loss at 12 months across all indications, and less when the indication is poor weight response rather than reflux. Drug therapy also works after MBS. Liraglutide beat placebo by about 8 percentage points in the BARI-OPTIMISE randomized trial. Semaglutide gives around 11% total weight loss and tirzepatide around 14% in pooled retrospective data, including specifically after SG. Most patients do not return to their nadir weight with either option alone. The field is already comparing the two strategies, but only retrospectively. Two 2025 multicenter cohorts compared conversion against GLP-1 therapy after SG. These studies cannot control diet, exercise, supplementation, co-medication, or adherence. They cannot settle the question. The societies agree on the pathway but admit the evidence is weak. The 2024 IFSO position statement and the 2026 ASMBS statement say the same thing: work up the anatomy first; operate when there is a structural problem; consider medical therapy when there is not; and consider combining drug therapy with revision. The 2024 IFSO international consensus goes further: with 92% agreement, it states that medications should generally be considered before revisional surgery for recurrent weight gain. Every one of those recommendations rests on consensus and retrospective data. None rests on a randomized trial. This protocol is that trial.
Detailed description
The biology says the combination should win. Revision restores restriction and corrects anatomy. It does not correct appetite biology. Patients with poor response after MBS show blunted satiety-hormone profiles, which is exactly what GLP-1 therapy replaces. The operation and the drug cover each other's weakness. They are complementary tools, not competitors. Medical therapy alone has a durability problem. When the drug stops, weight returns. SURMOUNT-4 showed rapid regain after tirzepatide withdrawal, and meta-analysis confirms the pattern across agents. Surgery provides the durable base. The drug adds effect where it is needed most: around the revision. That is the logic of the sandwich. The pre-operative phase has three jobs. It tests whether the patient tolerates and responds to the drug before we commit to a reoperation. It produces weight loss before revisional surgery, where technical difficulty and risk are higher than in primary surgery. And it gives strong medical responders a genuine chance to avoid the reoperation altogether. Some patients on active drug will lose enough weight before surgery to step off the operating list. We expect this. It is not a flaw and it is not contamination. It is a pre-specified secondary endpoint. It is also the first randomized test of the advice the guidelines already give: try medical therapy first when the anatomy is normal. Patients whose anatomy forces surgery are not in this trial at all; they go straight to the operating room, as they should. Every published combination series is confounded. Diet, exercise, supplements, other drugs, and adherence differ between patients and are rarely measured. This protocol standardizes all of them in both arms and measures them objectively. Section 8 lists each confounder and what we do about it.
Interventions
Weekly subcutaneous injections from identical, pharmacy-labelled pens. The active arm receives semaglutide 2.4 mg. Escalation: 0.25, 0.5, 1.0, 1.7, 2.4 mg at 4-week steps. If 2.4 mg is not tolerated, the patient stays on the highest tolerated dose of at least 1.0 mg. Patients who cannot tolerate 1.0 mg stop injections but stay in the trial and are analyzed in their arm.
DRUGPlacebo
Weekly subcutaneous injections from identical, pharmacy-labelled pens. The placebo arm receives matched placebo. Escalation: 0.25, 0.5, 1.0, 1.7, 2.4 mg at 4-week steps. If 2.4 mg is not tolerated, the patient stays on the highest tolerated dose of at least 1.0 mg. Patients who cannot tolerate 1.0 mg stop injections but stay in the trial and are analyzed in their arm.
Sponsors
General Committee of Teaching Hospitals and Institutes, Egypt
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* SG at least 2 years before screening. * Recurrent weight gain meeting the international Delphi consensus definition. Operational entry threshold for this trial: regain of at least 20% of the maximal weight lost, measured from nadir. * BMI of 35 kg/m² or more, or 30 kg/m² or more with at least one obesity-associated disease, and accepted for conversion to RYGB by the multidisciplinary team. * Upper endoscopy and contrast imaging completed. * Able to give written informed consent.
Exclusion criteria
* Anatomy. These patients need surgery regardless of drug response, so randomizing them is not ethical. They are operated outside the trial. This is the operational form of the rule: anatomical cause, direct surgery; no anatomical cause, eligible for the trial. * Staple-line leak or gastric fistula. * Sleeve stenosis or axial twist. * Hiatal hernia larger than 3 cm. * Los Angeles grade C or D esophagitis, or Barrett's esophagus. * Drug and general safety * GLP-1 receptor agonist use within the last 6 months, or previous intolerance. * History of pancreatitis. * Personal or family history of medullary thyroid carcinoma or MEN2. * Type 1 diabetes; eGFR below 30 mL/min/1.73 m²; active malignancy. * Pregnancy, breastfeeding, or pregnancy plans during the study. Women of childbearing potential must use reliable contraception. Per current labeling and the 2026 Standards, obesity pharmacotherapy is stopped at least 2 months before any planned conception. * Uncontrolled psychiatric disease or active substance use disorder. * Current smoking, unless cessation is completed before surgery per unit policy. * Any other anti-obesity medication within the last 3 months.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage total weight loss | Baseline till 30 months | Measured in kilograms at month 18 after randomization. Baseline is the randomization weight. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| BMI change | 0, 3, 6, 9, 12 months | Equation: BMI = weight (In kilograms) / \[height (In meters)\]\^2 |
| change in HbA1c | 0, 6, 12 months | An HbA1c level reflects your average blood sugar over the past two to three months, and any meaningful change typically takes at least 6 weeks to show because red blood cells live for about 3 months. Normal: Below 5.7% Prediabetes: 5.7% to 6.4% Diabetes: 6.5% or higher |
| systolic and diastolic blood pressure | 0, 6, 12 months | Normal blood pressure is less than 120 mm Hg systolic and less than 80 mm Hg diastolic. Systolic (Top Number): Measures the pressure in your arteries when your heart beats and contracts. Diastolic (Bottom Number): Measures the pressure in your arteries when your heart rests between beats. Normal: Less than 120 mm Hg systolic and less than 80 mm Hg diastolic. Elevated: 120-129 mm Hg systolic and less than 80 mm Hg diastolic. Stage 1 Hypertension (High Blood Pressure): 130-139 mm Hg systolic or 80-89 mm Hg diastolic. Stage 2 Hypertension: 140 mm Hg or higher systolic, or 90 mm Hg or higher diastolic. Hypertensive Crisis: Higher than 180 mm Hg systolic and/or higher than 120 mm Hg diastolic. This requires immediate emergency medical care |
| total cholesterol, LDL, HDL, and triglycerides | 0, 6, 12 months | Normal adult values for a lipid panel are measured in milligrams per deciliter (mg/dL): Total Cholesterol: Below 200 mg/dL is desirable. (Borderline high is 200-239 mg/dL, and high is 240 mg/dL and above.) LDL ("Bad") Cholesterol: Below 100 mg/dL is optimal. (130-159 mg/dL is borderline high, and 160-189 mg/dL or higher is high.) HDL ("Good") Cholesterol: 60 mg/dL and higher is protective. Levels below 40 mg/dL for men or below 50 mg/dL for women are considered low. Triglycerides: Below 150 mg/dL is normal. (Borderline high is 150-199 mg/dL, and high is 200-499 mg/dL.) |
| Operative time | At the time or during surgery | From the start till the end of the surgery measured in minutes |
| 30-day complications | postoperative till 30 days | The Clavien-Dindo Classification grades 30-day postoperative complications based on the level of medical or surgical therapy needed to treat them. Grade I: Any deviation from the normal postoperative course without the need for pharmacological treatment or surgical, endoscopic, and radiological interventions. Grade II: Requiring pharmacological treatment with drugs other than those allowed for Grade I, including blood transfusions and total parenteral nutrition. Grade III: Requiring surgical, endoscopic, or radiological intervention. Grade IIIa: Intervention not under general anesthesia. Grade IIIb: Intervention under general anesthesia. Grade IV: Life-threatening complication (including central nervous system complications) requiring intermediate care or intensive care unit (ICU) management. Grade V: Death of a patient. |
| change in GerdQ score | 0, 6, 12 months | A change in the GerdQ score reflects how gastroesophageal reflux disease (GERD) symptoms and their daily impact respond to treatment or evolve over time. Range: The total score spans from 0 to 18. Diagnosis Threshold: A score of 8 or higher indicates a high likelihood of GERD. Components: It evaluates four positive predictors (heartburn, regurgitation, sleep disturbance, and over-the-counter medication use) and two negative predictors (epigastric pain and nausea) over the past 7 days. Decrease in Score: A lowering score (especially moving from ≥ 8 to \< 8) typically indicates successful treatment response, reduced symptom frequency, and lower disease impact. Increase or No Change: A rising score or a score that remains persistently above 8 suggests ongoing treatment failure, unmanaged symptom triggers, or disease progression. |
| change in IWQOL-Lite-CT total and domain scores | 0, 6, 12 months | The IWQOL-Lite-CT (Impact of Weight on Quality of Life-Lite Clinical Trials Version) score ranges from 0 to 100, where 100 represents the best possible quality of life and functioning (meaning zero weight-related impairment). Total Score Range: 0-100 (higher = better quality of life) Domain/Composite Scores: 0-100 Raw scores are converted or transformed to a 0-100 scale for standard reporting. |
| change in fat mass and lean soft tissue mass | 0, 6, 12 months | (bioelectrical impedance analysis, standardized hydration instructions), with fat-free mass loss reported as a proportion of total weight change and hand-grip strength measured at weeks 0, 32, and 68, so that mass is interpreted together with function per the ESPEN/EASO sarcopenic-obesity framework and current meta-analytic evidence. |
| Hand-grip strength | 0, 6, 12 months | A hand grip strength test measures the maximum force of your hand and forearm muscles using a portable device called a handgrip dynamometer. Position yourself: Sit up straight with your feet flat on the floor. Place your arm by your side with your elbow bent at a 90-degree angle and your wrist in a neutral position. Hold the device: Adjust the handle so it fits comfortably in your hand. Squeeze hard: Squeeze the handles as hard as you can for about 3 to 5 seconds without moving your arm or resting the device against your body. Repeat trials: Take three measurements for each hand, resting for 15 to 30 seconds between attempts. Use either the highest score or the average of the trials. A normal hand grip strength score typically ranges from 40 to 56 kg (88 to 123 lbs) for adult men and 25 to 36 kg (55 to 79 lbs) for adult women aged 20-29. |
| Intraoperative adverse events | At the time or during surgery | Adverse intraoperative events (AIEs) occur in approximately 3% to 7% of bariatric surgeries and increase the relative risk of overall postoperative complications by about 90%. Organ Injuries: Unintentional lacerations or punctures to the liver, spleen, stomach, intestines, or major blood vessels during trocar placement or dissection. Intraoperative Bleeding: Significant hemorrhage from staple lines, mesentery, or the abdominal wall requiring intervention or transfusion. Anastomosis and Staple Line Issues: Leaks, bleeding, or technical difficulties during the creation of pouches or connections (such as in a Roux-en-Y Gastric Bypass), identified via intraoperative leak tests. Equipment Malfunction: Failures involving laparoscopic staplers, cameras, insufflation systems, or energy devices. Anesthesia-Related Events: Severe hemodynamic instability, difficult airway management, or allergic reactions linked to medications. |
| Safety of the drug phase | Baseline till 30 months | all adverse events, with events of special interest: pancreatitis, gallstones, severe gastrointestinal intolerance, hypoglycemia, dumping, aspiration at induction, venous thromboembolism, mortality. |
Countries
Egypt
Contacts
CONTACTMohamed Hany Ashour, Professor, MD
Outcome results
None listed