Evaluation of Oral Semaglutide Efficacy and Safety in Hyperglycemic Patients Post-Renal Transplantation: 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 the management of hyperglycaemia, which can impact the overall health and transplant success in these patients.

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 post-transplantation.

The clinical trial involves participants diagnosed with **hyperglycaemia after renal transplantation**. The study population includes both male and female subjects aged between 18 and 80 years. Participants are required to have a diagnosis of post-transplant hyperglycaemia 10 to 15 days following 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. Selection criteria include the ability and willingness to comply with the trial protocol, and written informed consent is required before any trial-related procedures are performed. Participants' general health status is not specified beyond the inclusion criteria, and no specific lifestyle considerations such as diet or physical activity are mentioned.

The clinical trial is designed to evaluate the **safety** and efficacy of oral **semaglutide** in patients experiencing **hyperglycaemia** after 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-of-care treatment. The trial is expected to run from September 2023 to September 2026, with participant involvement lasting up to 14 days, corresponding to the maximum treatment period for the investigational product.

Participants will undergo a series of study visits, beginning with an inclusion visit where eligibility is confirmed based on criteria such as age (18-80 years), diagnosis of post-transplant hyperglycaemia, and an estimated glomerular filtration rate (eGFR) greater than 15 ml/min/1.73 m². Following the inclusion visit, participants will be randomized to receive either semaglutide or placebo tablets, administered orally. The primary endpoint is the mean sensor glucose level evaluated by continuous glucose monitoring (CGM). Secondary endpoints include various measures of glucose control, body weight, blood pressure, and incidence of adverse events.

Follow-up visits will be scheduled to monitor the participants' response to treatment, assess safety, and collect data on secondary endpoints. The end-of-study visit will conclude the trial for each participant, during which final assessments will be conducted. Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with the trial protocol, or withdraw consent. The trial's design ensures rigorous monitoring and data collection to support the evaluation of semaglutide's efficacy and safety in this specific patient population.

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 the 7 mg tablet has a maximum daily dose of 7 mg. The treatment period for each dosage is up to 14 days. The pharmaceutical form of Rybelsus 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 trial aims to evaluate the safety and efficacy of oral semaglutide in patients with hyperglycemia following renal transplantation.

In addition to the experimental medication, a **placebo** is used as a comparator 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 assess the efficacy of the semaglutide tablets. The placebo is administered under the same conditions as the active treatment, with a maximum treatment period of 14 days. The use of a placebo allows for a more accurate assessment of the semaglutide's effects by providing a baseline for comparison.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment regimen. The trial's primary objective is to determine whether oral semaglutide, compared with placebo, is non-inferior in regulating plasma glucose levels in patients with hyperglycemia after renal transplantation. The study is conducted under strict clinical guidelines to ensure the safety and well-being of all participants.

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 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 homeostatic model assessment (HOMA) will be used to evaluate beta-cell function and insulin resistance.

Further assessments will include blood concentrations of cyclosporine and tacrolimus, dose-corrected plasma semaglutide concentration, plasma alanine transaminase (ALAT), plasma amylase, and gastrointestinal side effects using the Gastrointestinal Symptom Rating Scale (GSRS). 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. Additionally, the incidence of admissions, admissions due to dehydration, renal graft rejection, and renal graft failure (defined as return to dialysis) will be recorded. These efficacy parameters will be collected and analyzed at specified intervals throughout the trial to determine the non-inferiority of oral semaglutide compared to placebo in regulating plasma glucose levels in the target patient population.