A Study to Test Whether BI 764524 Helps People With an Eye Condition Called Diabetic Retinopathy

CRIMSON: A Multicentre, Randomised, Sham-controlled (and Active Controlled in the USA), Double-masked, 72-week Trial to Study the Safety, Tolerability, Pharmacokinetics, and Efficacy of 3 Dosing Regimens of Intravitreal BI 764524 in Patients With Moderate to Severe Non-proliferative Diabetic Retinopathy

This study is open to adults with diabetic retinopathy. People who have non-proliferative diabetic retinopathy of moderate or high severity can join the study.

The purpose of this study is to find out whether a medicine called BI 764524 helps people with diabetic retinopathy. The study also aims to find a suitable treatment plan for BI 764524. Participants are put into 5 groups by chance. Participants in groups 1, 2, and 3 get BI 764524. Over 1 year, they get a different number of injections of the same dose of BI 764524 injected into 1 eye. During some visits, participants may get a sham control, which is done like an eye injection but without a needle, so that participants will not know how many injections of BI 764524 they received. Participants in group 4 only get a sham control. Participants in group 5 (only in the USA) get aflibercept or sham injections during some visits. Aflibercept is a medicine already used to treat diabetic retinopathy.

Participants are in the study for one and a half years. During this time, they visit the study site at least 16 times. During this time, doctors regularly do eye exams and visual tests to assess the severity of participants' eye condition. After 1 year of treatment, researchers look at the number of participants with eye improvements. To do so, they compare eye damage and certain severe eye problems between the groups of participants. The doctors also regularly check participants' health and take note of any unwanted effects.

General inclusion criteria

• Diagnosis of diabetes mellitus (DM) under regular treatment with Haemoglobin A1c (HbA1c) (glycated haemoglobin) (HbA1c) <12%; DM should be under regular investigation by a trained specialist as per local standard of care prior to and during the trial
• Age ≥18 years at time of signing Informed Consent Form (ICF)

Ocular inclusion criteria: study eye

• Moderate to severe non-proliferative diabetic retinopathy (NPDR) (Diabetic Retinopathy Severity Scale (DRSS) level 43 to 53) as assessed by Ultra-widefield colour fundus photography (UWF-CFP) images (within the 7-field grid) and confirmed by the central reading centre (CRC) at screening. Patient staged at DRSS level of 43 based on UWF-CFP images can be included only if:

  • They are participating in the standard 7-field CFP sub-study of the trial, and
  • They are staged as DRSS level of 47 to 53 on standard 7-field CFP imaging, as confirmed by the CRC at screening.

• Ultra-widefield fluorescein angiography (UWF-FA) image gradable for presence of retinal non-perfusion (RNP) as confirmed by the CRC at screening

• Visual acuity: best corrected visual acuity (BCVA) letter score of ≥49 letters (approximate Snellen equivalent of 20/100 or better) using ETDRS chart at starting distance of 4 meter (m) at screening and reconfirmed at baseline

• Sufficiently clear ocular media, adequate pupillary dilation, and fixation to permit quality fundus imaging

Main exclusion criteria in study eye:

- Evidence of active retinal neovascularisation (NV) on clinical exam and/or UWF-CFP images within the 7-field grid, confirmed by the CRC grading.

The following are permitted if, based on the assessment of the investigator, do not require acute treatment:

• Small neovascular lesions within the ETDRS 7-field that are detected only on UWF-FA, but not on clinical exam or UWF-CFP

• Neovascularisations outside of the ETDRS 7-field on ultra-widefield imaging

  • Evidence of active NV of the iris (small iris tufts are not an exclusion) or in the anterior chamber angle
  • Prior pan-retinal photocoagulation (PRP). Peripheral scatter or targeted laser treatment in up to 1 quadrant outside the ETDRS 7-field area is permitted if it was performed at least 6 months prior to Day 1
  • CI-DME, defined as central subfield thickness (CST) ≥320 micrometer (μm) as measured by Heidelberg Spectralis optical coherence tomography (OCT) and confirmed by central reading centre (CRC) at screening (equivalent measurements from other OCT machines may be accepted); participants with a CST of 320-330 μm can be included if, in the opinion of the investigator, the participant is not expected to require treatment for CI-DME during the duration of the study (e.g. no profound impact on BCVA, stable CST, etc.). CST must be re-confirmed at baseline. A CRC confirmation of the baseline CST is not required.
  • Previous treatment in the study eye for NPDR and/or diabetic macular edema (DME) with intravitreal (IVT) anti-vascular endothelial growth factor (VEGF) (including anti-VEGF/Ang2) or short acting corticosteroid drugs (e.g. triamcinolone) within 6 months prior to Day 1 or >4 treatments within the last 18 months (referred to elsewhere as 'previous IVT treatment').
  • Any previous IVT treatment other than anti-VEGF and short-acting steroids. Previous dexamethasone IVT drug delivery system (Ozurdex) or fluocinolone acetonide intravitreal implant (Iluvien) is not allowed
  • Refractive error of more than -8 dioptres of myopia (spherical equivalent) in the study eye. For patients having undergone refractive or cataract surgery in the study eye, either the pre-operative refractive error or the axial length measurement should be used, at the investigator's discretion. Axial length should be less than 26 mm
  • Any concurrent or past ocular condition in the study eye which, in the judgement of the investigator, could:

• Require medical or surgical intervention during the study period to prevent or treat vision loss (e.g. advanced cataract, history of retinal detachment or macular hole (Stage 3 or 4) in the study eye)

• Could likely contribute to a significant loss of BCVA during the study period if left untreated (e.g. advanced epiretinal membrane and/or vitreomacular traction, active or history of optic neuritis in either eye)

• Contraindicate the use of the investigational drug, or may render the patient at high risk for treatment complications (e.g. active infectious or non-infectious conjunctivitis/keratitis in either eye; history of recurrent infectious or inflammatory ocular disease in either eye (e.g. uveitis)

• May affect interpretation of the study results (e.g. central atrophy of the retinal pigment epithelium or photoreceptors; age-related macular degeneration, hereditary retinal degenerative diseases, myopic macular degeneration, past, current or planned use of medications known to be toxic to the retina, lens or optic nerve (e.g. deferoxamine, chloroquine/hydroxychloroquine, chlorpromazine, phenothiazines, tamoxifen, nicotinic acid, and ethambutol); history of central serous chorioretinopathy, ischemic optic neuropathy or retinal vascular occlusion