Evaluation of Intravitreal BI 764524 in Moderately-Severe to Severe Non-Proliferative Diabetic Retinopathy: A Randomized, Sham-Controlled, Double-Masked Trial

The primary objective of this study is to demonstrate a non-flat dosing frequency-response curve and evaluate the dosing frequency-response relationship for **BI 764524** in patients with moderately-severe to severe non-proliferative **diabetic retinopathy**. The response is defined as the proportion of patients achieving a ≥2-step improvement from baseline in the Diabetic Retinopathy Severity Scale (DRSS) level in the study eye at Week 52. This objective is clinically relevant as it aims to assess the potential of BI 764524 to improve retinal health and prevent progression of diabetic retinopathy, which is a leading cause of vision impairment.

Secondary objectives include:

• Evaluating the proportion of patients developing vision-threatening complications, such as proliferative diabetic retinopathy (PDR), anterior segment neovascularisation (NV), or centre-involved diabetic macular edema (CI-DME) between baseline and Week 52. This involves demonstrating a non-flat dosing frequency-response curve and assessing the treatment effect in terms of relative risk reduction when comparing BI 764524 to sham.
• Estimating treatment differences between BI 764524 and sham for other secondary efficacy and safety endpoints, analyzed separately for each BI 764524 dosing regimen.

The clinical trial involves a total of **113 participants** diagnosed with **diabetic retinopathy**. The study population includes both male and female subjects aged **18 years and older**. Participants are required to have a diagnosis of diabetes mellitus under regular treatment, with an HbA1c level of less than 12%. The trial specifically targets individuals with moderately severe to severe non-proliferative diabetic retinopathy, as assessed by the Diabetic Retinopathy Severity Scale (DRSS) levels 47 to 53. The presence of retinal non-perfusion (RNP) is confirmed through ultra-widefield fluorescein angiography. Participants must have a best-corrected visual acuity of at least 49 letters on the ETDRS chart at a 4-meter distance, and their ocular media must be sufficiently clear to allow quality fundus imaging. The trial does not include a vulnerable population, and the selection process ensures that participants meet these specific health criteria to evaluate the dosing frequency-response relationship for the investigational drug BI 764524.

The clinical trial is designed as a **randomized**, sham-controlled, and double-masked study to evaluate the safety, tolerability, pharmacokinetics, and efficacy of three dosing regimens of intravitreal BI 764524 in patients with moderately-severe to severe **non-proliferative diabetic retinopathy**. The trial is expected to last for 72 weeks, with an estimated recruitment start date in October 2024 and an estimated end date in May 2027. Participants will be randomly assigned to receive either the active treatment, BI 764524, or a sham injection procedure. The primary objective is to demonstrate a non-flat dosing frequency-response curve and evaluate the dosing frequency-response relationship for BI 764524, with the primary endpoint being a ≥2-step improvement in the Diabetic Retinopathy Severity Scale (DRSS) level in the study eye at Week 52.

Study visits are structured to include an initial **screening** visit to assess eligibility based on criteria such as age, diagnosis of diabetes mellitus, and severity of diabetic retinopathy. Follow-up visits will occur at regular intervals to monitor the treatment's effects and any adverse events. The end-of-study visit will conclude the participant's involvement, assessing the final outcomes and any long-term effects of the treatment. The expected length of participant involvement is approximately 72 weeks, with conditions for early termination including significant adverse events or withdrawal of consent.

Inclusion criteria require participants to be male or female, aged 18 years or older, with a diagnosis of diabetes mellitus under regular treatment and moderately severe to severe non-proliferative diabetic retinopathy. Exclusion criteria are not specified in the provided data. The trial will assess both primary and secondary endpoints, including changes in visual acuity, central subfield thickness, and the occurrence of various ocular adverse events. The trial is categorized as a Phase 4 study, focusing on the safety and efficacy of a new therapy in patients with diabetic retinopathy.

The clinical trial involves the administration of **BI 764524**, an investigational medication formulated as a **solution for injection**. This pharmaceutical product is of biological origin, specifically a protein, and is developed by Boehringer Ingelheim International. The active substance, also named BI 764524, is administered via the **intravitreal route**. The trial evaluates three dosing regimens over a maximum treatment period of 48 weeks. The dosing frequency and response relationship are assessed, with the primary endpoint being a ≥2-step improvement in the Diabetic Retinopathy Severity Scale (DRSS) level at Week 52. The trial aims to establish a non-flat dosing frequency-response curve.

In addition to the experimental treatment, a **Sham Injection Procedure** is employed as a comparator in the study. This procedure serves as a placebo control to evaluate the efficacy and safety of BI 764524. The sham procedure does not involve the administration of an active pharmaceutical ingredient and is used to maintain the double-masked nature of the trial. The use of a sham control allows for the assessment of the treatment effect by comparing the proportion of patients achieving the primary endpoint between the BI 764524 and sham groups.

Efficacy in this clinical trial will be assessed primarily through the occurrence of a **≥2-step improvement** compared with baseline in the Diabetic Retinopathy Severity Scale (DRSS) level in the study eye at Week 52. This primary endpoint will be used to evaluate the treatment effect of BI 764524 compared to a sham injection procedure. The absolute differences in proportions between the treatment and control groups will be summarized to determine efficacy.

Secondary endpoints include several measures: the occurrence of vision-threatening complications (VTCs) in the study eye between baseline and Week 52, the absolute change from baseline in best-corrected visual acuity (BCVA) measured in ETDRS letters at Week 52, and the absolute change from baseline in central subfield thickness (CST) assessed by spectral domain optical coherence tomography (SD-OCT) at Week 52. Additional secondary endpoints involve the occurrence of a **≥2-step worsening** of DRSS, the development of proliferative diabetic retinopathy (PDR) and/or anterior segment neovascularization (NV), and the occurrence of center-involved diabetic macular edema (CI-DME) in the study eye between baseline and Week 52. Furthermore, the trial will monitor the occurrence of drug-related adverse events (AEs) and ocular AEs, including those of special interest, from baseline to the end of the study (EOS).