Semaglutide 2.4mg for low responders after bariatric surgery

The primary objective of this study is to evaluate the **weight change** from 3 to 18 months post-bariatric surgery in low responders treated with **Semaglutide** 2.4 mg combined with a lifestyle intervention. This is clinically relevant as it aims to determine the efficacy of Semaglutide in enhancing weight loss outcomes compared to a placebo group receiving the same lifestyle intervention.

Secondary objectives include: - Studying weight loss at various intervals (3, 6, 12, and 18 months) post-surgery, both before and after the initiation of Semaglutide treatment. - Evaluating **metabolic health** at multiple time points, including before surgery and after the start of Semaglutide. - Assessing health-related quality of life and gastrointestinal symptoms at specified intervals. - Evaluating changes in **cardiorespiratory fitness** levels before and after treatment. - Investigating changes in liver fat and stiffness using vibration-controlled transient elastography. - Describing the persistence of therapy and the average weekly dose of Semaglutide.

The clinical trial focuses on individuals diagnosed with **obesity** who have undergone bariatric surgery. The study population includes both male and female participants aged between 18 and 74 years. Participants are required to have a body mass index (BMI) of at least 35.0 kg/m² prior to surgery and must have undergone a primary (banded) Roux-en-Y gastric bypass (RYGB) or (banded) sleeve gastrectomy (SG). The trial does not involve a vulnerable population. Participants are selected based on their placement in the lowest quartile of total weight loss (%TWL) three months post-surgery and are enrolled in a specialized module at the Dutch Obesity Clinic. The sponsor has not provided the total number of participants involved in the study. Lifestyle interventions are a key component of the trial, with a focus on weight change from 3 to 18 months post-surgery, comparing those treated with Semaglutide 2.4 mg to those receiving a placebo.

The clinical trial is designed to evaluate the efficacy of **semaglutide** 2.4 mg in patients with **obesity** who are low responders after bariatric surgery. This is a randomized, double-blind, placebo-controlled trial with a primary objective to assess the change in percentage total weight loss (%TWL) from 3 to 18 months post-surgery. The trial will involve a lifestyle intervention alongside the administration of semaglutide or placebo. The study is expected to last until January 30, 2026, with recruitment starting on December 4, 2023.

Participants will be involved in the study for a maximum of 68 weeks, during which they will attend several study visits. The initial visit will be a screening visit to confirm eligibility based on criteria such as age (18-74 years), pre-surgery BMI (≥35.0 kg/m²), and surgical history (primary banded RYGB or sleeve gastrectomy). Following the screening, participants will be randomized to receive either semaglutide or placebo. Subsequent follow-up visits will occur at 3, 6, 12, and 18 months post-surgery to monitor %TWL, metabolic health, quality of life, and other secondary endpoints.

The end-of-study visit will coincide with the 18-month post-surgery mark, where final assessments will be conducted. Participants may be withdrawn from the study early if they experience significant adverse effects, fail to comply with the study protocol, or choose to withdraw consent. The trial will utilize a prefilled, fixed, multi-dose pen-injector for subcutaneous injection of semaglutide, ensuring precise dosing and ease of use. The primary endpoint is the change in %TWL from 3 to 18 months, while secondary endpoints include metabolic health parameters, quality of life assessments, and cardiorespiratory fitness, among others.

The clinical trial involves the administration of **Semaglutide**, a pharmaceutical product developed by Novo Nordisk A/S. The experimental medication is formulated as a **solution for injection** and is identified by the product name "Semaglutide B 3.0 mg/ml PDS290." The active substance, semaglutide, is administered via subcutaneous injection using a prefilled, fixed, multi-dose pen-injector designed for single-patient use. The maximum daily dose of semaglutide is 2.4 mg, with a total maximum dose of 163.2 mg over a treatment period of 68 weeks. The dosing schedule is structured to ensure consistent administration, and participant compliance is monitored throughout the trial.

In addition to the experimental treatment, the study includes a comparator group receiving a placebo alongside a lifestyle intervention. The placebo is administered in a manner consistent with the semaglutide treatment to maintain blinding and ensure the integrity of the trial results. The primary objective of the trial is to evaluate the weight change, specifically the percentage of total weight loss, in low responders after bariatric surgery when treated with semaglutide compared to those receiving placebo. The trial design incorporates rigorous monitoring of dosing schedules and participant adherence to ensure the reliability and validity of the study outcomes.

Efficacy in this clinical trial will be assessed primarily through the change in **% total weight loss (TWL)** from 3 to 18 months after bariatric surgery. This period corresponds to 15 months or 68 weeks after the initiation of treatment with Semaglutide 2.4 mg. Body weight measurements, a standard part of the treatment protocol, will be used to calculate %TWL at specified intervals: 3, 6, 12, and 18 months post-surgery. Secondary endpoints include assessments of metabolic health, quality of life, gastrointestinal symptoms, cardiorespiratory fitness, liver fat, and liver stiffness, as well as therapy persistence.

Metabolic health will be evaluated using parameters such as blood pressure, HbA1c, glucose, triglycerides, and cholesterol levels (LDL, HDL, and total cholesterol). Hypertension and dyslipidemia will be monitored at all follow-up points to determine improvements or remission in comorbid conditions. Gastrointestinal symptoms and eating habits will be assessed through adverse event reporting and the "eating habits and physical problems" scales of the BODY-Q questionnaire, which will also evaluate health-related quality of life (HRQoL) at baseline and at 3, 6, 12, and 18 months.

Cardiorespiratory fitness will be measured using the Åstrand test, where participants cycle on a submaximal level for 6 minutes on a cycle ergometer. VO2max will be calculated by integrating patient characteristics with test outcomes. Liver fat and stiffness will be assessed using vibration-controlled transient elastography at the start of the study and after 68 weeks of Semaglutide treatment, with results expressed in kPa. Additionally, the study will track the number and percentage of patients adhering to the dose escalation protocol, those maintaining a 2.4 mg weekly dose for 52 weeks, and the average weekly dose across all participants.