Evaluation of the Safety and Efficacy of Oral Semaglutide in Managing Hyperglycemia in Post-Renal Transplant Patients: A Randomized, Placebo-Controlled Trial

The primary objective of this study is to determine whether **oral semaglutide** (Rybelsus) is non-inferior to placebo in regulating plasma glucose levels in patients experiencing hyperglycaemia following renal transplantation. This is clinically relevant as effective glucose regulation is crucial for preventing complications and improving outcomes in this patient population.

Secondary objectives include evaluating the effect of oral semaglutide on renal graft function, body weight, insulin usage, cardiovascular parameters, and safety parameters such as plasma semaglutide concentration, gastrointestinal side effects, and the dose of immunosuppressants. These assessments are important for understanding the broader impact of semaglutide on patient health and treatment safety.

The clinical trial focuses on patients with **hyperglycaemia after renal transplantation**. The study population includes both male and female participants, aged between 18 and 80 years. Participants are required to have a diagnosis of post-transplant hyperglycaemia, identified 10 to 15 days after transplantation, with fasting plasma glucose levels of at least 7.0 mmol/L or an oral glucose tolerance test showing plasma glucose levels of at least 11.1 mmol/L. Additionally, an estimated glomerular filtration rate (eGFR) greater than 15 ml/min/1.73 m² is necessary 10 to 15 days post-transplantation. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants. Participants must be willing and able to comply with the trial protocol, and written informed consent is required before any trial-related procedures are performed.

The clinical trial is designed to evaluate the **safety** and efficacy of oral **semaglutide** in patients experiencing hyperglycemia following renal transplantation. This is a randomized, double-blind, placebo-controlled trial, conducted in a Phase 4 setting. The trial aims to determine whether oral semaglutide, marketed as Rybelsus, is non-inferior to placebo in regulating plasma glucose levels when added to standard care. The trial is expected to run from September 2023 to September 2026, with participant involvement lasting up to 14 days of treatment.

Participants will be randomly assigned to receive either semaglutide tablets (3 mg, 7 mg, or 14 mg) or placebo tablets, all administered orally. The trial will include an initial screening visit to confirm eligibility based on criteria such as age (18-80 years), diagnosis of post-transplant hyperglycemia, and adequate renal function. Following the screening, eligible participants will undergo a baseline visit where initial assessments and randomization will occur.

Throughout the trial, participants will attend regular follow-up visits to monitor glucose levels and other health parameters using continuous glucose monitoring (CGM) and other laboratory tests. The primary endpoint is the mean sensor glucose level, while secondary endpoints include time in target glucose range, glucose variability, and various metabolic and cardiovascular parameters. The end-of-study visit will involve a comprehensive evaluation of the participant's health status and the collection of final data.

Participant involvement is expected to last for the duration of the treatment period, which is 14 days. Conditions that may lead to early termination from the study include significant adverse events, non-compliance with the trial protocol, or withdrawal of consent. The trial is conducted under strict ethical guidelines, ensuring the safety and well-being of all participants.

The clinical trial involves the administration of **Rybelsus** tablets, which contain the active substance **semaglutide**. The trial includes three different dosages of Rybelsus: 3 mg, 7 mg, and 14 mg tablets. Each tablet is administered orally. The maximum daily dose for the 3 mg and 14 mg tablets is 14 mg, while for the 7 mg tablets, it is 7 mg. The treatment period for each dosage is up to 14 days. The pharmaceutical form of the medication is a tablet, and it is not a paediatric formulation. The active substance, semaglutide, is a protein of other origin, and the product is manufactured by Novo Nordisk A/S. The administration of the medication is monitored to ensure compliance with the dosing schedule.

In addition to the experimental medication, a **placebo** is used as a comparator treatment in the study. The placebo is also in tablet form and is administered orally. It contains no active substance and serves as a control to evaluate the efficacy of the semaglutide tablets. The placebo is administered under the same conditions as the experimental medication, with a maximum treatment period of 14 days. The use of a placebo allows for a comparison of the effects of the active medication against a non-active substance, providing a baseline for assessing the efficacy of semaglutide in regulating plasma glucose levels in patients with hyperglycemia after renal transplantation.

The efficacy of oral **semaglutide** in patients with hyperglycemia following renal transplantation will be assessed through a series of primary and secondary endpoints. The primary endpoint is the mean sensor glucose level, measured in mmol/L, evaluated by continuous glucose monitoring (CGM). Secondary endpoints include a variety of parameters also evaluated by CGM, such as the percentage of time spent in target glucose ranges (3.9–10.0 mmol/L and 3.9–7.8 mmol/L), time in hyperglycemia at different levels, glucose variability, and glucose management indicators. Additional secondary endpoints encompass a wide range of clinical and laboratory measures, including HbA1c levels, body weight, body mass index (BMI), creatinine levels, estimated glomerular filtration rate (eGFR), blood pressure, pulse rate, urinary albumin-to-creatinine ratio, and plasma concentrations of cholesterol, LDL, HDL, triglycerides, semaglutide, insulin, and C-peptide. The study will also assess homeostatic model assessment (HOMA) for beta-cell function and insulin resistance, blood concentrations of cyclosporine and tacrolimus, dose-corrected plasma semaglutide concentration, and plasma levels of alanine transaminase (ALAT) and amylase.

Furthermore, the trial will evaluate gastrointestinal side effects using the Gastrointestinal Symptom Rating Scale (GSRS), which consists of 15 symptoms rated on a 7-point scale. The incidence of adverse events, serious adverse events, self-reported hypoglycemic episodes, out-of-target blood levels of tacrolimus and ciclosporin, and a 25% increase in creatinine from discharge will also be monitored. Other endpoints include the incidence of admissions, admissions due to dehydration, renal graft rejection, and renal graft failure, defined as a return to dialysis. These efficacy parameters will be collected and analyzed at specified time points throughout the trial to determine the non-inferiority of oral semaglutide compared to placebo in regulating plasma glucose levels in the target patient population.