A randomised, double-masked, placebo-controlled trial to evaluate the efficacy, safety, and tolerability of oral BI 1815368 in participants with centre-involved diabetic macular edema for 48 weeks of treatment (THULITE)

The primary objective of this study is to evaluate the dose-response relationship for BI 1815368 in participants with varying levels of vision impairment due to centre-involved diabetic macular edema (CI-DME). This objective is clinically relevant as it aims to determine the optimal dosing strategy for treating visual impairment associated with this diabetic retinal complication.

The secondary objectives include:

• Evaluation of the difference in proportions of participants achieving ≥15-letter gain in ETDRS (Early Treatment Diabetic Retinopathy Study) visual acuity compared with baseline across different dose regimens and placebo in the study eye at Week 48.

• Investigation of the safety profile of BI 1815368, defined as the occurrence of drug-related adverse events between baseline and end of study, and evaluation of the change in central subfield foveal thickness (CST) using spectral domain optical coherence tomography (SD-OCT) following administration of BI 1815368 at Week 48 compared with baseline across different dose regimens and placebo.

The clinical trial enrolled a total of **107 participants** diagnosed with **centre-involved diabetic macular edema** (CI-DME). The study population included both **male and female** adults aged **18 years and older**, specifically encompassing adults and elderly individuals. All participants had a confirmed diagnosis of **diabetes mellitus** (type 1 or type 2) with **HbA1c** levels below 12% and were required to be on stable diabetes medication for at least 30 days prior to enrollment. The study eye demonstrated CI-DME confirmed by **SD-OCT** with **central subfield thickness** (CST) of at least 320 µm for males and 305 µm for females. Participants exhibited varying degrees of **vision impairment**, with **best-corrected visual acuity** (BCVA) measured by **ETDRS letter score** ranging between 24 and 78 in the study eye, corresponding to a Snellen equivalent range of 20/320 to 20/32. The trial focused on patients with specific disease characteristics to evaluate the dose-response relationship of the investigational treatment in this population.

This is a randomized, double-masked, placebo-controlled clinical trial designed to evaluate the efficacy, safety, and tolerability of oral BI 1815368 in participants with centre-involved diabetic macular edema. The trial is classified as a Phase 2 study investigating a drug not currently authorized in the target population. The investigational medicinal product, BI 1815368, is administered orally in tablet form, with participants receiving either the active treatment or matching placebo. The active substance is of chemical origin and is manufactured by Boehringer Ingelheim International. The maximum treatment period is set at 48 weeks. The study is estimated to begin recruitment in October 2025 and is expected to conclude in September 2027.

The primary objective of this trial is to evaluate the dose-response relationship for BI 1815368 in participants with varying levels of vision impairment due to centre-involved diabetic macular edema. The primary endpoint is defined as the occurrence of a gain of at least 10 ETDRS letters compared with baseline in the study eye at Week 48. Secondary endpoints include the occurrence of a gain of at least 15 ETDRS letters compared with baseline at Week 48, the occurrence of drug-related adverse events over the treatment period through end of study, and the absolute change from baseline of central subfield thickness as measured by SD-OCT in the study eye at Week 48.

Eligible participants must be at least 18 years of age with a diagnosis of diabetes mellitus (type 1 or type 2) and HbA1c less than 12 percent, treated with stable medication for at least 30 days prior to Day 1. Centre-involved diabetic macular edema must be confirmed on SD-OCT with central subfield thickness of at least 320 micrometers for male participants and at least 305 micrometers for female participants in the study eye at screening. Best-corrected visual acuity in the study eye must be between 24 and 78 ETDRS letter score (Snellen equivalent range 20/320 to 20/32) at screening. Participants should have no already-set plans for major changes in diabetes medication at the time of screening and baseline. Additional inclusion criteria apply to ensure appropriate participant selection.

The trial involves a structured series of study visits throughout the 48-week treatment period. Participants undergo screening procedures to confirm eligibility based on the specified inclusion and exclusion criteria. Following successful screening, participants are randomized to receive either BI 1815368 or placebo and enter the treatment phase. Regular follow-up visits are conducted throughout the 48-week treatment period to monitor efficacy parameters, including visual acuity measurements and optical coherence tomography assessments, as well as to evaluate safety and tolerability. An end-of-study visit is performed to capture final efficacy and safety data. The expected length of participant involvement extends through the 48-week treatment period plus the time required for screening and the end-of-study assessment. Conditions that may lead to early termination from the study include occurrence of unacceptable adverse events, participant withdrawal of consent, protocol violations, or investigator decision based on safety concerns.

The experimental treatment in this clinical trial consists of BI 1815368, an investigational medicinal product of chemical origin manufactured by Boehringer Ingelheim International. BI 1815368 is formulated as an oral tablet and is administered via the oral route. The maximum treatment period with BI 1815368 is 48 weeks. The trial is designed to evaluate the dose-response relationship of BI 1815368 in participants with varying levels of vision impairment due to center-involved diabetic macular edema.

The comparator treatment used in this trial is BI 1815368 Placebo, which serves as the control intervention in this randomized, double-masked, placebo-controlled study. The placebo is designed to match the experimental treatment to maintain blinding throughout the study period. The use of placebo allows for the assessment of the efficacy, safety, and tolerability of the active investigational product compared to an inactive control.

Efficacy will be assessed using visual acuity and anatomical parameters in participants with **centre-involved diabetic macular edema**. The primary efficacy endpoint is the occurrence of a gain of at least 10 **ETDRS letters** compared with baseline in the study eye at Week 48. Secondary efficacy endpoints include the occurrence of a gain of at least 15 ETDRS letters compared with baseline in the study eye at Week 48, and the absolute change from baseline of **central subfield thickness** as measured by **spectral-domain optical coherence tomography** in the study eye at Week 48. Best-corrected visual acuity will be evaluated using the ETDRS letter score, with assessments conducted throughout the 48-week treatment period. Anatomical changes will be measured by spectral-domain optical coherence tomography to determine central subfield thickness at specified timepoints.