Evaluation of Long-term Effects of Semaglutide Versus Placebo on Diabetic Retinopathy Progression in Type 2 Diabetes Patients

The primary objective of this study is to evaluate the long-term effects of treatment with **semaglutide** compared to placebo, both added to standard-of-care, on the development and progression of diabetic retinopathy in subjects with type 2 diabetes (T2D). This is clinically relevant as diabetic retinopathy is a common complication of T2D, and understanding the impact of semaglutide on its progression could inform treatment strategies and improve patient outcomes.

The secondary objectives are to assess the effects of treatment with semaglutide compared to placebo, both added to standard-of-care, with regards to:

• Visual acuity
• Diabetic retinopathy manifestations, including the occurrence of diabetic macular oedema or proliferative diabetic retinopathy
• Diabetic retinopathy treatments, such as laser photocoagulation, intravitreal agents, and vitrectomy
• Modifiable risk factors for diabetic retinopathy, including glycaemia, blood pressure, and lipids

The clinical trial involves a total of **878 participants** diagnosed with **type 2 diabetes mellitus**. The study population includes both male and female subjects aged 18 years and older. Participants were selected based on specific inclusion criteria, including an HbA1c level ranging from 7.0% to 10.0% (53-86 mmol/mol). The trial does not involve a vulnerable population. The study aims to assess the long-term effects of semaglutide on diabetic retinopathy development and progression, with participants receiving either semaglutide or a placebo in addition to standard-of-care treatment. Lifestyle factors such as diet and physical activity were not specified as part of the selection criteria. The trial is a post-authorization safety study conducted as a commitment to the European Medicines Agency.

The clinical trial is designed to evaluate the long-term effects of **semaglutide** on diabetic retinopathy in individuals with type 2 diabetes. This study is a randomized, double-blind, placebo-controlled trial, conducted as a post-authorization safety study (PASS) to fulfill commitments to the European Medicines Agency. The trial will span approximately eight years, with an estimated recruitment start date in May 2019 and an anticipated end date in November 2027. Participants will be randomly assigned to receive either semaglutide or a placebo, both administered via subcutaneous injection using a pre-filled pen injector. The primary objective is to assess the development and progression of diabetic retinopathy over a five-year period, with the primary endpoint being the presence of three or more steps of ETDRS subject-level progression at year five.

Study visits are structured to ensure comprehensive monitoring and data collection. The inclusion visit, or screening visit, will confirm eligibility based on criteria such as age (≥18 years), a diagnosis of type 2 diabetes, and an HbA1c level between 7.0% and 10.0%. Following randomization, participants will attend regular follow-up visits to monitor their health status, adherence to the treatment regimen, and any adverse events. These visits will also include ophthalmic assessments to evaluate changes in visual acuity and the presence of diabetic retinopathy or macular edema. The end-of-study visit will occur at the conclusion of the five-year treatment period, where final assessments will be conducted to determine the long-term effects of the intervention.

Participant involvement is expected to last for the entire duration of the trial, approximately eight years, including the follow-up period. However, conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or non-compliance with the study protocol. The trial aims to provide valuable insights into the safety and efficacy of semaglutide in managing diabetic retinopathy, contributing to improved therapeutic strategies for individuals with type 2 diabetes.

The clinical trial involves the administration of **semaglutide**, marketed under the name Ozempic, which is provided as a **solution for injection** in a pre-filled pen. The pharmaceutical form is a solution for injection, specifically designed for subcutaneous administration. The pre-filled pen, known as the PDS290 pen-injector, contains semaglutide at a concentration of 1.34 mg/mL. This device allows for adjustable dosing, enabling the delivery of semaglutide in doses of 0.25 mg, 0.5 mg, and 1 mg. The pen-injector is equipped with an integrated 1.5 mL cartridge. The clinical batches of the product are produced in smaller batch sizes compared to the marketed product, and the maximum treatment period is 260 weeks. The administration frequency and specific dosing schedule are determined by the study protocol, and participant compliance is monitored throughout the trial.

The study also includes a **placebo** comparator, which is a solution for injection in a 1.5 mL pre-filled PDS290 pen injector. The placebo is designed to mimic the administration process of the active treatment without containing the active substance, semaglutide. The placebo is used to assess the long-term effects of semaglutide on diabetic retinopathy development and progression in subjects with type 2 diabetes, in comparison to standard-of-care therapy. The placebo administration follows the same route and frequency as the active treatment to ensure blinding and consistency in the trial design.

The efficacy of the clinical trial will be assessed by evaluating the long-term effects of **semaglutide** compared to placebo on the development and progression of diabetic retinopathy in subjects with type 2 diabetes. The primary endpoint for efficacy assessment is the presence of a ≥3 steps ETDRS (Early Treatment Diabetic Retinopathy Study) subject level progression at year 5, measured as a binary outcome (yes/no). Secondary endpoints include the time from randomization to the first occurrence of a ≥3 steps ETDRS progression or central-involved diabetic macular edema (ciDME) in either eye, measured in months.

Additional secondary endpoints involve changes from baseline at year 5 in visual acuity, assessed by the number of letters in both the worse and better seeing eyes. The occurrence of treatments for diabetic retinopathy or diabetic macular edema, such as laser photocoagulation, intravitreal injections, and vitrectomy, will also be recorded. Other secondary measures include changes in HbA1c levels, body weight, blood pressure, and lipid profiles. These parameters will be collected and analyzed at specified time points throughout the trial, with the final assessment occurring at the end of the treatment period, which is set for 260 weeks.