A randomized clinical trial assessing theranostic-guided corneal cross-linking for treating keratoconus: the ARGO protocol

Anna Maria Roszkowska, Giuseppe Lombardo, Rita Mencucci, Vincenzo Scorcia, Giuseppe Giannaccare, Annarita Vestri, Danilo Alunni Fegatelli, Giuseppe Massimo Bernava, Sebastiano Serrao, Marco Lombardo, Anna Maria Roszkowska, Giuseppe Lombardo, Rita Mencucci, Vincenzo Scorcia, Giuseppe Giannaccare, Annarita Vestri, Danilo Alunni Fegatelli, Giuseppe Massimo Bernava, Sebastiano Serrao, Marco Lombardo

Abstract

The Assessment of theranostic guided riboflavin/UV-A corneal cross-linking for treatment of keratoconus (ARGO; registration number NCT05457647) clinical trial tests the hypothesis that theranostic-guided riboflavin/UV-A corneal cross-linking (CXL) can provide predictable clinical efficacy for halting keratoconus progression, regardless of treatment protocol, i.e., either with or without epithelial removal. Theranostics is an emerging therapeutic paradigm of personalized and precision medicine that enables real-time monitoring of image-guided therapy. In this trial, the theranostic software module of a novel UV-A medical device will be validated in order to confirm its accuracy in estimating corneal cross-linking efficacy in real time. During CXL procedure, the theranostic UV-A medical device will provide the operator with an imaging biomarker, i.e., the theranostic score, which is calculated by non-invasive measurement of corneal riboflavin concentration and its UV-A light mediated photo-degradation. ARGO is a randomized multicenter clinical trial in patients aged between 18 and 40 years with progressive keratoconus aiming to validate the theranostic score by assessing the change of the maximum keratometry point value at 1-year postoperatively. A total of 50 participants will be stratified with allocation ratio 1:1 using a computer-generated stratification plan with blocks in two treatment protocols, such as epithelium-off or epithelium-on CXL. Following treatment, participants will be monitored for 12 months. Assessment of safety and performance of theranostic-guided corneal cross-linking treatment modality will be determined objectively by corneal tomography, corneal endothelial microscopy, visual acuity testing and slit-lamp eye examination.

Keywords: Corneal cross-linking; Keratoconus; Riboflavin; Theranostics.

Conflict of interest statement

Roszkowska AM, Mencucci R, Scorcia V, Giannaccare G, Vestri A, Alunni Fegatelli D, Bernava GM and Serrao S: none.Lombardo M and Lombardo G are co-inventors of the patents IT102016000007349, EP3407920B1 and CN201680080266.9 for theranostic-guided corneal cross-linking.

The authors Roszkowska AM, Mencucci R, Scorcia V, Giannaccare G, Vestri A, Alunni Fegatelli D, Bernava GM and Serrao S have no relevant financial or non-financial interests to disclose. Lombardo M and Lombardo G are co-inventors of the Patents IT102016000007349, EP3407920B1 and CN201680080266.9 for theranostic-guided corneal cross-linking.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Main treatment steps of investigational theranostic-guided CXL procedure. A The patient lies supine looking at the fixation light of the system. The UV-A device drives the operator through the main procedure steps of theranostic-guided CXL, inviting her/him to proceed to the next phase by pressing the footswitch; B focusing phase; C dosing phase and D UV-A irradiation phase. The Placido disk of the system allows for a precise focusing of the UV-A beam onto the area of the cornea to treat. At pre-specified intervals during dosing and UV-A photo-therapy phases, the system tracks the concentration of riboflavin into the cornea and provides the operator with real time quantitative information on treatment performance. The theranostic score provides an estimation of treatment efficacy
Fig. 2
Fig. 2
During theranostic-guided UV-A irradiation of the cornea enriched with riboflavin, the system calculates the theranostic score. In A, B a representative case of epithelium-on investigational theranostic-guided CXL procedure. The theranostic medical device is able to quantify the amount of UV-A light mediated photo-degradation of riboflavin providing a real time estimate (i.e., theranostic score) that correlates with the induced corneal stiffening effect of CXL. Calculation of the theranostic score takes into account the corneal riboflavin dose prior to start UV-A photo-therapy phase, the amount of riboflavin photo-degraded by UV-A light therapy and the corneal thickness
Fig. 3
Fig. 3
Representative Placido disc corneal topographies of two study cases (AOF01 and AON03) treated by investigational theranostic-guided Epi-OFF (A) and Epi-ON (B) CXL procedures respectively. The tangential maps at 3 months postoperatively and at the preoperative state are shown in (#1) and (#2) respectively. The difference tangential maps show − 1.31 D and − 1.64 D Kmax flattening after Epi-OFF and Epi-ON CXL protocols respectively. The theranostic score was 0.97 and 0.99 respectively. “OD” and “OS” indicate “right eye” and “left eye” respectively

References

    1. Armstrong BK, Smith SD, Coc IR, Agarwal P, Mustapha N, Navon S. Screening for keratoconus in a high-risk adolescent population. Ophthalmic Epidemiolog. 2021;28(3):191–197. doi: 10.1080/09286586.2020.1804593.
    1. Ozalp O, Atalay E, Yıldırım N. Prevalence and risk factors for keratoconus in a university-based population in Turkey. J Cataract Refract Surg. 2021;47:1524–1529. doi: 10.1097/j.jcrs.0000000000000669.
    1. Kristianslund O, Hagem AM, Thorsrud A, Drolsum L. Prevalence and incidence of keratoconus in Norway: a nationwide register study. Acta Ophthalmol. 2021;99(5):e694–e699. doi: 10.1111/aos.14668.
    1. Godefrooij DA, de Wit GA, Uiterwaal CS, Imhof SM, Wisse RPL. Age-specific incidence and prevalence of keratoconus: a nationwide registration study. Am J Ophthalmol. 2017;175:169–117. doi: 10.1016/j.ajo.2016.12.015.
    1. Hagem AM, Thorsrud A, Sabdvik GF, Drolsum L. Randomized study of collagen cross-linking with conventional versus accelerated UVA irradiation using riboflavin with hydroxypropyl methylcellulose: two-year results. Cornea. 2019;38:203–209. doi: 10.1097/ICO.0000000000001791.
    1. Hashemi H, Ambrosio R, Jr, Vinciguerra R, Inciguerra P, Robert CJ, Ghaffari R, Asgari S Two-year changes in corneal stiffness parameters after accelerated corneal cross-linking. J Biomech. 2019;93:209–212. doi: 10.1016/j.jbiomech.2019.06.011.
    1. Lombardo M, Serrao S, Schiano-Lomoriello LG, D, Two years outcomes of a randomized controlled trial of transepithelial corneal cross-linking with iontophoresis for keratoconus. J Cataract Refract Surg. 2019;45(7):992–1000. doi: 10.1016/j.jcrs.2019.01.026.
    1. Stojanovic A, Zhou W, Utheim TP. Corneal collagen cross-linking with and without epithelial removal: a contralateral study with 0.5% hypotonic riboflavin Solution. Biomed Res Int. 2014;2014:754182. doi: 10.1155/2014/619398.
    1. Lombardo M, Micali N, Villari V, Serrao S, Pucci G, Barberi R, Lombardo G. Ultraviolet A—visible spectral absorbance of the human cornea after transepithelial soaking with dextran-enriched and dextran-free riboflavin 0.1% ophthalmic solutions. J Cataract Refract Surg. 2015;41:2283–2290. doi: 10.1016/j.jcrs.2015.11.007.
    1. Godefrooij DA, Gans R, Imhof SM, Wisse RPL. Nationwide reduction in the number of corneal transplantations for keratoconus following the implementation of cross-linking. Acta Ophthalmol. 2016;94:675–678. doi: 10.1111/aos.13095.
    1. Li J, Ji P, Lin X. Efficacy of corneal collagen cross-linking for treatment of keratoconus: a meta-analysis of randomized controlled trials. PLoS ONE. 2015;10(5):e0127079. doi: 10.1371/journal.pone.0127079.
    1. Chunyu T, Xiujun P, Zhengjun F, Xia Z, Feihu Z. Corneal collagen cross-linking in keratoconus: a systematic review and meta-analysis. Sci Rep. 2014;4:5652. doi: 10.1038/srep05652.
    1. Kobashi H, Hieda O, Itoi M, Kamyia K, Kato N, Shimazaki J, Tsubota K. Keratoconus group of Japan. Corneal cross-linking for paediatric keratoconus: a systematic review and meta-analysis. J Clin Med. 2021;10(12):2626. doi: 10.3390/jcm10122626.
    1. Shalchi Z, Wang X, Nanavaty MA. Safety and efficacy of epithelium removal and transepithelial corneal collagen crosslinking for keratoconus. Eye. 2015;29:15–29. doi: 10.1038/eye.2014.230.
    1. Dhawan S, Rao K, Natrajan S. Complications of Corneal Collagen Cross-Linking. J Ophthalmol. 2011;2011:869015. doi: 10.1155/2011/869015.
    1. Koller T, Mrochen M, Seiler T. Complication and failure rates after corneal crosslinking. J Cataract Refract Surg. 2009;35:1358–1362. doi: 10.1016/j.jcrs.2009.03.035.
    1. Serrao S, Lombardo G, Lombardo M. Adverse events after riboflavin/UV-A corneal cross-linking: a literature review. Int Ophthalmol. 2022;42(1):337–348. doi: 10.1007/s10792-021-02019-1.
    1. Spoerl E, Hoyer A, Pillunat LE, et al. Corneal cross-linking and safety issues. Open Ophthalmol J. 2011;5:14–16. doi: 10.2174/1874364101105010014.
    1. Wen D, Song B, Li Q, Tu R, Huang Y, Wang Q, McAlinden C, OʼBrart D, Huang J Comparison of epithelium-Off versus transepithelial corneal collagen cross-linking for keratoconus: a systematic review and meta-analysis. Cornea. 2018;37(8):1018–1024. doi: 10.1097/ICO.0000000000001632.
    1. Zhang X, Zhao J, Li M, Tian M, Shen Y, Zhou X. Conventional and transepithelial corneal cross-linking for patients with keratoconus. PLoS ONE. 2018;13(4):e0195105. doi: 10.1371/journal.pone.0195105.
    1. Ng SM, Ren M, Lindsley KB, Hawkins BS, Kuo IC (2021) Transepithelial versus epithelium-of corneal crosslinking for progressive keratoconus. Cochrane Database Syst Rev 3:CD013512
    1. Nath S, Shen C, Koziarz A, Banfield L, Nowrouzi-Kia B, Fava MA, Hodge WG. Transepithelial versus epithelium-off corneal collagen cross-linking for corneal ectasia: a systematic review and meta-analysis. Ophthalmology. 2021;128(8):1150–1160. doi: 10.1016/j.ophtha.2020.12.023.
    1. D'Oria F, Palazón A, Alio JL. Corneal collagen cross-linking epithelium-on vs. epithelium-off: a systematic review and meta-analysis. Eye Vis. 2021;8(1):34. doi: 10.1186/s40662-021-00256-0.
    1. Lombardo M, Pucci G, Barberi R, Lombardo G. Interaction of ultraviolet light with the cornea: clinical implications for corneal crosslinking. J Cataract Refract Surg. 2015;41:446–459. doi: 10.1016/j.jcrs.2014.12.013.
    1. Lombardo G, Micali N, Villari V, Serrao S, Lombardo M. All-optical method to assess stromal concentration of riboflavin in conventional and accelerated UV-A irradiation of the human cornea. Invest Opthalmol Vis Sci. 2016;57:476–483. doi: 10.1167/iovs.15-18651.
    1. Baiocchi S, Mazzotta C, Cerretani D, Caporossi T, Caporossi A. Corneal crosslinking: riboflavin concentration in corneal stroma exposed with and without epithelium. J Cataract Refract Surg. 2009;35:893–899. doi: 10.1016/j.jcrs.2009.01.009.
    1. Holmström B, Oster G. Riboflavin as an electron donor in photochemical reactions. J Am Chem Soc. 1961;83:1867–1871. doi: 10.1021/ja01469a022.
    1. Brummer G, Littlechild S, McCall S, Zhang Y, Conrad GW. The role of nonenzymatic glycation and carbonyls in collagen cross-linking for the treatment of keratoconus. Invest Ophthalmol Vis Sci. 2011;52:6363–6369. doi: 10.1167/iovs.11-7585.
    1. Zhang Y, Conrad AH, Conrad GW. Effects of ultraviolet-A and riboflavin on the interaction of collagen and proteoglycans during corneal cross-linking. J Biol Chem. 2011;286:13011–13022. doi: 10.1074/jbc.M110.169813.
    1. Sel S, Nass N, Pötzsch S, Trau S, Simm A, Kalinski T, Duncker GIW, Kruse FE, Auffarth GU, Brömme HJ. UVA irradiation of riboflavin generates oxygen-dependent hydroxyl radicals. Redox Rep. 2014;19(72):79.
    1. McCall AS, Kraft S, Edelhauser HF, Kidder GW, Lundquist RR, Bradshaw HE, Dedeic Z, Dionne MJC, Clement EM, Conrad GW. Mechanisms of corneal tissue cross-linking in response to treatment with topical riboflavin and long-wavelength ultraviolet radiation (UVA) Invest Ophthalmol Vis Sci. 2010;51:129–138. doi: 10.1167/iovs.09-3738.
    1. Kamaev P, Friedman MD, Sherr E, Muller D. Photochemical kinetics of corneal cross-linking with riboflavin. Invest Ophthalmol Vis Sci. 2012;53:2360–2367. doi: 10.1167/iovs.11-9385.
    1. Lombardo G, Villari V, Micali N, et al. Non-invasive optical method for real-time assessment of intracorneal riboflavin concentration and efficacy of corneal cross-linking. J Biophotonics. 2018;11(7):e201800028. doi: 10.1002/jbio.201800028.
    1. Lombardo M, Lombardo G. Non-invasive and real time assessment of riboflavin consumption in standard and accelerated corneal cross-linking. J Cataract Refract Surg. 2019;45:80–86. doi: 10.1016/j.jcrs.2018.07.062.
    1. Lombardo G, Serrao S, Lombardo M. Comparison between standard and transepithelial corneal crosslinking using a theranostic UV-A device. Graefes Arch Clin Exp Ophthalmol. 2020;258(4):829–834. doi: 10.1007/s00417-019-04595-6.
    1. Lombardo G, Bernava GM, Serrao S, Lombardo M (2022) Theranostic-guided corneal cross-linking: pre-clinical evidence on a new treatment paradigm for keratoconus. J Biophoton 15(12):e202200218
    1. Zhang X, Sun L, Chen Y, Li M, Tian M, Zhou X. One-year outcomes of pachymetry and epithelium thicknesses after accelerated (45 mW/cm2) transepithelial corneal collagen cross-linking for keratoconus patients. Sci Rep. 2016;6:32692. doi: 10.1038/srep32692.
    1. Artola A, Piñero DP, Ruiz-Fortes P, Soto-Negro R, Pérez-Cambrodí RJ. Clinical outcomes at one year following keratoconus treatment with accelerated transepithelial cross-linking. Int J Ophthalmol. 2017;10(4):652–655.
    1. Tian M, Jian W, Sun L, Shen Y, Zhang X, Zhou X. One-year follow-up of accelerated transepithelial corneal collagen cross-linking for progressive pediatric keratoconus. BMC Ophthalmol. 2018;18(1):75. doi: 10.1186/s12886-018-0739-9.
    1. Kır MB, Türkyılmaz K, Öner V. Transepithelial high-intensity cross-linking for the treatment of progressive keratoconus: 2-year outcomes. Curr Eye Res. 2017;42(1):28–31. doi: 10.3109/02713683.2016.1148742.
    1. Huang J, Shen Y, Jian W, Xu H, Li M, Zhao J, Zhou X, Liao H. Two-year topographic and densitometric outcomes of accelerated (45 mW/cm2) transepithelial corneal cross-linking for keratoconus: a case-control study. BMC Ophthalmol. 2018;18(1):337. doi: 10.1186/s12886-018-0999-4.
    1. Ferdi AC, Nguyen V, Gore DM, Allan BD, Rozema JJ, Watson SL. Keratoconus natural progression: a systematic review and meta-analysis of 11529 Eyes. Ophthalmology. 2019;126:935–945. doi: 10.1016/j.ophtha.2019.02.029.
    1. Craig JA, Mahon J, Yellowlees A, Barata T, Glanville J, Arber M, Mandava L, Powell J, Figueiredo F. Epithelium-off photochemical corneal collagen cross-linkage using riboflavin and ultraviolet a for keratoconus and keratectasia: a systematic review and meta-analysis. Ocul Surf. 2014;12(3):202–214. doi: 10.1016/j.jtos.2014.05.002.
    1. Wen D, Li Q, Song B, Tu R, Wang Q, O'Brart DPS, McAlinden C, Huang J. Comparison of standard versus accelerated corneal collagen cross-linking for keratoconus: a meta-analysis. Invest Ophthalmol Vis Sci. 2018;59(10):3920–3931. doi: 10.1167/iovs.18-24656.
    1. Hersh PS, Stulting RD, Muller D, Durrie DS, Rajpal RK. United States Crosslinking Study Group. United States multicenter clinical trial of corneal collagen crosslinking for keratoconus treatment. Ophthalmology. 2017;124(9):1259–1270. doi: 10.1016/j.ophtha.2017.03.052.
    1. Hersh PS, Stulting RD, Muller D, Durrie DS, Rajpal RK. U.S. Crosslinking Study Group. U.S. Multicenter clinical trial of corneal collagen crosslinking for treatment of corneal ectasia after refractive surgery. Ophthalmology. 2017;124(10):1475–1484. doi: 10.1016/j.ophtha.2017.05.036.
    1. Jiang LZ, Jiang W, Qiu SY. Conventional vs. pulsed-light accelerated corneal collagen cross-linking for the treatment of progressive keratoconus: 12-month results from a prospective study. Exp Ther Med. 2017;14(5):4238–4244.
    1. Kobashi H, Rong SS. Corneal collagen cross-linking for keratoconus: systematic review. Biomed Res Int. 2017;2017:8145651. doi: 10.1155/2017/8145651.
    1. Kobashi H, Tsubota K. Accelerated versus standard corneal cross-linking for progressive keratoconus: a meta-analysis of randomized controlled trials. Cornea. 2020;39(2):172–180. doi: 10.1097/ICO.0000000000002092.
    1. Mazzotta C, Traversi C, Paradiso AL, Latronico ME, Rechichi M. Pulsed light accelerated crosslinking versus continuous light accelerated crosslinking: one-year results. J Ophthalmol. 2014;2014:604731. doi: 10.1155/2014/604731.
    1. McAnena L, Doyle F, O'Keefe M. Cross-linking in children with keratoconus: a systematic review and meta-analysis. Acta Ophthalmol. 2017;95(3):229–239. doi: 10.1111/aos.13224.
    1. Meiri Z, Keren S, Rosenblatt A, Sarig T, Shenhav L, Varssano D. Efficacy of corneal collagen cross-linking for the treatment of keratoconus: a systematic review and meta-analysis. Cornea. 2016;35(3):417–428. doi: 10.1097/ICO.0000000000000723.
    1. Shajari M, Kolb CM, Agha B, Steinwender G, Müller M, Herrmann E, Schmack I, Mayer WJ, Kohnen T. Comparison of standard and accelerated corneal cross-linking for the treatment of keratoconus: a meta-analysis. Acta Ophthalmol. 2019;97(1):e22–e35. doi: 10.1111/aos.13814.
    1. Tomita M, Mita M, Huseynova T. Accelerated versus conventional corneal collagen crosslinking. J Cataract Refract Surg. 2014;40(6):1013–1020. doi: 10.1016/j.jcrs.2013.12.012.
    1. Wittig-Silva C, Chan E, Islam FM, Wu T, Whiting M, Snibson GR. A randomized, controlled trial of corneal collagen cross-linking in progressive keratoconus. Three-Year Results Ophthalmology. 2014;121:812–821.
    1. Al Fayez MF, Alfayez S, Alfayez Y. Transepithelial versus epithelium-off corneal collagen cross-linking for progressive keratoconus: a prospective randomized controlled trial. Cornea. 2015;34(10):S53–56. doi: 10.1097/ICO.0000000000000547.
    1. Soeters N, et al. Transepithelial versus epithelium-off corneal cross-linking for the treatment of progressive keratoconus: a randomized controlled trial. Am J Ophthalmol. 2015;159(5):821–8.e3. doi: 10.1016/j.ajo.2015.02.005.
    1. Hashemian H, et al. Evaluation of corneal changes after conventional versus accelerated corneal cross-linking: a randomized controlled trial. J Refract Surg. 2014;30(12):837–842. doi: 10.3928/1081597X-20141117-02.
    1. Lombardo M, et al. Randomized controlled trial comparing transepithelial corneal cross-linking using iontophoresis with the Dresden protocol in progressive keratoconus. Ophthalmology. 2017;124:804–812. doi: 10.1016/j.ophtha.2017.01.040.

Source: PubMed

Sponsorer og samarbeidspartnere

Medisinsk tilstand

Legemiddelintervensjoner

3
Abonnere