Randomized, Placebo‑Controlled Trial of Once‑Daily Oral Semaglutide (1.5, 4, 9 mg) for Weight Loss in Adults with Overweight or Obesity

The primary objective is to demonstrate the superiority of oral semaglutide (investigational doses) versus placebo, when added to a reduced‑calorie diet and increased physical activity, in achieving greater weight loss in adults with overweight and obesity. Demonstrating superior weight reduction is clinically relevant because it directly addresses a key modifiable risk factor for cardiometabolic disease.

Secondary objectives include:

• Evaluation of the effect of oral semaglutide compared with placebo on cardiometabolic parameters from baseline to week 60.
• Assessment of safety and tolerability of oral semaglutide versus placebo from baseline to week 67.

The trial enrolled 135 adult participants, both female and male, aged 18 years and older, who were classified as having overweight and obesity based on a body‑mass index of ≥27 kg/m² with at least one weight‑related comorbidity or a BMI of ≥30 kg/m². Subjects were selected from the patient population after providing informed consent and demonstrating a documented history of at least one unsuccessful dietary attempt to lose weight. All participants were required to follow a reduced‑calorie diet and increase physical activity as part of the study protocol. General health status permitted inclusion of individuals with common obesity‑associated conditions such as hypertension, dyslipidaemia, obstructive sleep apnoea, or cardiovascular disease, while vulnerable status was not excluded.

The study is a Phase III, randomized, double‑blind, placebo-controlled trial evaluating oral semaglutide (1.5 mg, 4 mg, or 9 mg tablets) versus matching placebo as an adjunct to a reduced‑calorie diet and increased physical activity in adults with overweight or obesity. Participants are screened for eligibility, provide informed consent, and undergo baseline assessments during the screening visit. Eligible subjects are then randomized and initiate study medication on Day 1. Subsequent follow‑up visits are scheduled at approximately weeks 4, 12, 24, 36, and 52 to record body weight, waist circumference, vital signs, laboratory parameters, and adverse events, and to reinforce diet and exercise counseling. An end‑of‑study visit at week 52 (or earlier if discontinuation occurs) completes the final efficacy and safety assessments. Overall participant involvement is expected to be 52 weeks, with the entire trial period spanning from August 2026 to February 2028. Early termination may occur due to serious adverse events, protocol non‑compliance, withdrawal of consent, pregnancy, or inability to maintain the required lifestyle interventions.

The investigational product consists of oral tablets of Rybelsus containing semaglutide. Three dosage strengths are utilized: 1.5 mg, 4 mg, and 9 mg per tablet. Each tablet is administered by the oral route once daily, in conjunction with a reduced‑calorie diet and increased physical activity as specified in the protocol.

The control arm receives a matching placebo tablet identical in appearance to the semaglutide tablets. The placebo is taken orally once daily, following the same schedule and dietary/physical‑activity recommendations as the active treatment arms.

All study medications are dispensed in blister packs to facilitate dosing compliance. Participants are instructed to ingest the tablet each morning on an empty stomach with a limited amount of water, at least 30 minutes before the first meal of the day. Dosing schedules are recorded in a patient diary, and compliance is assessed through pill‑count reconciliation at each study visit. Any missed doses are documented, and participants receive reminders to maintain adherence throughout the trial period.

The primary efficacy assessment is the relative change in body weight from baseline to the end of treatment. Body weight will be measured with calibrated scales at baseline and at each protocol‑specified visit.

Secondary efficacy parameters include:

• Achievement of body weight reduction ≥ 5 % (Yes/No)
• Achievement of body weight reduction ≥ 10 % (Yes/No)
• Achievement of body weight reduction ≥ 15 % (Yes/No)
• Change in waist circumference
• Change in high‑sensitivity C‑reactive protein (hsCRP)
• Change in glycaemic status
• Change in lipid profile: total cholesterol, HDL cholesterol, non‑HDL cholesterol, LDL cholesterol, VLDL cholesterol, triglycerides, free fatty acids
• Change in systolic blood pressure
• Change in diastolic blood pressure
• Change in fasting plasma glucose (FPG)
• Change in HbA1c
• Change in waist‑height ratio (WtHR)
• Number of treatment‑emergent adverse events
• Number of treatment‑emergent serious adverse events
• Number of treatment‑emergent adverse events leading to permanent discontinuation

These secondary endpoints will be evaluated using standard laboratory assays for biochemical markers, calibrated devices for anthropometric and blood pressure measurements, and predefined case report forms for adverse event reporting, all collected at the scheduled study visits defined in the protocol.