Theranostic Guided Riboflavin/UV-A Corneal Cross-linking (ARGO)

This is a clinical study consisting of a study arm to assess the performance of the theranostic software module (Research Use Only) of a CE marked (CE1936) UV-A medical device, C4V CHROMO4VIS™, in order to validate its use for theranostic-guided corneal cross-linking treatment of keratoconus and corneal ectasia. The study hypothesis is that theranostic-guided riboflavin/UV-A corneal cross-linking with the C4V CHROMO4VIS™ system is safe and can estimate treatment efficacy during operation, regardless of treatment protocol, i.e., either with or without epithelial removal.

Keratoconus is a naturally-occurring ocular condition characterized by progressive thinning and steepening of the central cornea, resulting in corneal optical irregularities with increasing myopia, irregular astigmatism, corneal opacity and consequential loss of visual acuity. Riboflavin/UV-A corneal cross-linking is a procedure used to biomechanically stabilize the weak cornea in keratoconus and to slow down or halt the clinical progression of this disease. Theranostics is an emerging therapeutic paradigm that enables monitoring of image-guided therapy in clinic through the use of a theranostic module that makes use of real-time non-invasive molecular analysis of the tissue being treated to achieve optimal treatment outcomes in the management of disease. The theranostic software module of the C4V CHROMO4VIS™ medical device is able to measure the concentration of riboflavin into the cornea during treatment and to provide the surgeon with an objective assessment of treatment efficacy. The scope of this study is to validate the theranostic imaging biomarker score by assessing the change of corneal topography Kmax value at 1-year postoperatively. The 1-year follow-up is long enough to provide scientific evidence of the safety and efficacy of the theranostic UV-A medical device in question. A pre-operative examination will ensure that every interested and willing participant fulfils the inclusion criteria of this study. Post-operative examinations will be carried out after 1 week, 1 month, 3 months, 6 months and 12 months. This is a multi-center clinical trial. Eligible participants will be stratified with allocation ratio 1:1 into either treatment protocol (EpiOn and EpiOFF Thera-CXL) using a computer-generated stratification plan with blocks. Two different blocks are created, which include eyes with Kmax steeper or flatter than 54.0 D to allocate patients with comparable baseline Kmax values in either treatment protocol.

One study arm receiving riboflavin/UV-A corneal cross-linking with either standard, Epi-OFF, or transepithelial, Epi-ON, treatment protocol. Only one eye of each participant is designated as the study eye.

Participant receives stratification to either corneal cross-linking protocol after consent form signature. Outcome assessor is masked. All participants wear contact lens after treatment until first postoperative eye examination at 1 week.

One study arm receiving riboflavin/UV-A corneal cross-linking with either standard, Epi-OFF, or transepithelial, Epi-ON, treatment protocol. Only one eye of each participant is designated as the study eye.

Corneal cross-linking procedure will be performed using the theranostic software module of the C4V CHROMO4VIS™ system in all participants. Participants will receive a single dose of the 0.22% riboflavin ophthalmic solution, RitSight™. Application of the riboflavin eye drop will be done for 15 minutes for the EpiOFF CXL treatment and 20 minutes for the EpiON CXL treatment. Estimates of riboflavin concentration into the cornea will be monitored by the C4V CHROMO4VIS™ system during the dosing phase of treatment. Once the dosing phase is completed, the C4V CHROMO4VIS™ system provides the Operator the access to the UV-A irradiation of the cornea with 5.4 J/cm2 total energy dose and 7.00 mm light beam diameter in all participants. Estimates of treatment efficacy by calculation of theranostic score will be performed by the C4V CHROMO4VIS™ system during UV-A irradiation.

The aim of this study is to validate the Theranostic Imaging Biomarker for theranostic-guided corneal corneal cross-linking (CXL) in patients with keratoconus

Assess the Theranostic Imaging Biomarker for theranostic-guided corneal corneal cross-linking (CXL) in patients with keratoconus

Inclusion Criteria: criteria for inclusion in the clinical trial are those currently referred to as the golden standard for the treatment of corneal cross-linking. The criterion to determine progression of keratoconus is based on providing at least one of the following evidences: at least two Placido disk corneal topography measurements showing at least +1.00 D steepening of the Kmax value in the last year or longer interval period. at least two manifest refraction measurements showing at least -0.50 D change in spherical equivalent refraction in the last year or longer interval period. at least two central corneal thickness (CCT) measurements showing at least -10 µm change in in the last year or longer interval period. Exclusion Criteria: Anterior corneal curvature steeper than 63 D; Corneal thickness thinner than 400 µm; Corneal scarring; Descemetocele; History of herpetic keratitis; Concomitant eye diseases; Inflammatory eye diseases; Glaucoma; Cataract; Nistagmus; Pregnancy; Breast feeding.

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Lombardo G, Bernava GM, Serrao S, Lombardo M. Theranostic-guided corneal cross-linking: Preclinical evidence on a new treatment paradigm for keratoconus. J Biophotonics. 2022 Dec;15(12):e202200218. doi: 10.1002/jbio.202200218. Epub 2022 Sep 16.

Roszkowska AM, Lombardo G, Mencucci R, Scorcia V, Giannaccare G, Vestri A, Alunni Fegatelli D, Bernava GM, Serrao S, Lombardo M. A randomized clinical trial assessing theranostic-guided corneal cross-linking for treating keratoconus: the ARGO protocol. Int Ophthalmol. 2023 Jul;43(7):2315-2328. doi: 10.1007/s10792-022-02628-4. Epub 2022 Dec 31.