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| Name | Class |
|---|---|
| University of Roma La Sapienza | OTHER |
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This is a clinical study consisting of a study arm to validate accuracy and precision of the combined use of theranostic imaging biomarkers, riboflavin score and theranostic score, to assess and predict efficacy of corneal cross-linking in flattening the corneal topography Kmax value at 12-months postoperatively. The objective of the study is 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 through the use of a theranostic module that makes use of real-time non-invasive molecular imaging analysis of the tissue being treated to achieve optimal treatment outcomes in the management of disease on a personal basis.
The theranostic software module of the C4V CHROMO4VIS™ medical device is able to measure the concentration of riboflavin into the cornea during treatment (i.e., the riboflavin score) and to provide the surgeon with an objective assessment of treatment efficacy (i.e., the theranostic score).
The scope of this study is to validate the combined use of the theranostic imaging biomarkers in predicting the flattening 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 ensures that every interested and willing participant fulfils the inclusion criteria of this study. Masked post-operative examinations are carried out after 1 week, 1 month, 3 months, 6 months and 12 months.
This is a multi-center clinical trial. Eligible participants are stratified with allocation ratio 1:1 into either treatment protocol (epi-off CXL and epi-on 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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Riboflavin/UV-A corneal cross-linking monitored by theranostic software module | Experimental | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Riboflavin/UV-A corneal cross-linking | Device | Corneal cross-linking procedure is performed using the C4V CHROMO4VIS™ medical device equipped with theranostic software module in all participants. Participants will receive a single dose of the 0.22% riboflavin ophthalmic solution, RitSight™. Application of the riboflavin eye drop is done for 15 minutes for the epi-off CXL treatment and 20 minutes for the epi-on CXL treatment. Estimates of riboflavin concentration into the cornea are monitored by the C4V CHROMO4VIS™ system during the dosing phase of treatment. Once the pre-set dosing phase is completed, the C4V CHROMO4VIS™ system provides the Operator the access to the UV-A light irradiation of the cornea with 5.4 J/cm2 total energy dose (10 mW/cm2 for 9 min.) and 7.00 mm light beam diameter in all participants. Estimates of treatment efficacy by calculation of theranostic score are performed by the C4V CHROMO4VIS™ system during UV-A light irradiation. |
| Measure | Description | Time Frame |
|---|---|---|
| Validation of the Theranostic Scores | The aim of this study is to validate the combined use of theranostic imaging biomarkers in predicting the propsensity of corneal corneal cross-linking (CXL) in flattening the Kmax at 1-year. The accuracy and precision (95% CI) of the combined use of the theranostic imaging biomarkers to predict CXL treatment outcome are determined by calculating the percentage of correctly classified eyes and the positive predictive value (PPV) respectively. | 12 months |
| Measure | Description | Time Frame |
|---|---|---|
| Corneal Topography | Change of Maximum Keratometry value of Placido disc corneal topography. The secondary outcome measure of efficacy was assessed by measuring changes of Kmax value (D) from baseline to 12 months postoperatively. | 12 months |
| Endothelial Cell Density |
| Measure | Description | Time Frame |
|---|---|---|
| Manifest Refraction | Change of Manifest Spherical Equivalent Refraction (MSER). This outcome was assessed by measuring change of MSER (D) from baseline to 12 months postoperatively. | 12 months |
| Corrected Distance Visual Acuity |
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:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Vincenzo Scorcia, MD | Azienda Ospedaliera Universitaria Mater Domini - Università Magna Graecia di Catanzaro | Principal Investigator |
| Marco Lombardo, MD, PhD | Studio Italiano di Oftalmologia | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Azienda Ospedaliera Universitaria Mater Domini - Università Magna Graecia di Catanzaro | Catanzaro | 88100 | Italy | |||
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 29451741 | Background | Lombardo G, Villari V, Micali NL, Leone N, Labate C, De Santo MP, Lombardo M. Non-invasive optical method for real-time assessment of intracorneal riboflavin concentration and efficacy of corneal cross-linking. J Biophotonics. 2018 Jul;11(7):e201800028. doi: 10.1002/jbio.201800028. Epub 2018 Apr 10. | |
| 30360937 | Background |
| Label | URL |
|---|---|
| Updates on clinical trial RSKC001 | View source |
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| ID | Title | Description |
|---|---|---|
| FG000 | Riboflavin/UV-A Corneal Cross-linking Monitored by Theranostic Software Module | 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. Riboflavin/UV-A corneal cross-linking: Corneal cross-linking procedure is performed using the C4V CHROMO4VIS™ system equipped with theranostic software module in all participants. Participants will receive a single dose of the 0.22% riboflavin ophthalmic solution, RitSight™. Application of the riboflavin eye drop is done for 15 minutes for the EpiOFF CXL treatment and 20 minutes for the EpiON CXL treatment. Estimates of riboflavin concentration into the cornea are monitored by the C4V CHROMO4VIS™ system during the dosing phase of treatment. Once the pre-set 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 (10 mW/cm2 for 9 min.) and 7.00 mm light beam diameter in all participants. Estimates of treatment efficacy by calculation of theranostic score are performed by the C4V CHROMO4VIS™ system during UV-A irradiation. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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Participants had confirmed diagnosis of progressive keratoconus using Placido disc corneal topography
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| ID | Title | Description |
|---|---|---|
| BG000 | Riboflavin/UV-A Corneal Cross-linking Monitored by Theranostic Software Module | 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. Riboflavin/UV-A corneal cross-linking: Corneal cross-linking procedure is performed using the C4V CHROMO4VIS™ system equipped with theranostic software module in all participants. Participants will receive a single dose of the 0.22% riboflavin ophthalmic solution, RitSight™. Application of the riboflavin eye drop is done for 15 minutes for the EpiOFF CXL treatment and 20 minutes for the EpiON CXL treatment. Estimates of riboflavin concentration into the cornea are monitored by the C4V CHROMO4VIS™ system during the dosing phase of treatment. Once the pre-set 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 (10 mW/cm2 for 9 min.) and 7.00 mm light beam diameter in all participants. Estimates of treatment efficacy by calculation of theranostic score are performed by the C4V CHROMO4VIS™ system during UV-A irradiation. |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Validation of the Theranostic Scores | The aim of this study is to validate the combined use of theranostic imaging biomarkers in predicting the propsensity of corneal corneal cross-linking (CXL) in flattening the Kmax at 1-year. The accuracy and precision (95% CI) of the combined use of the theranostic imaging biomarkers to predict CXL treatment outcome are determined by calculating the percentage of correctly classified eyes and the positive predictive value (PPV) respectively. | Posted | Number | 95% Confidence Interval | Percentage | 12 months | Eyes | Eyes |
|
1-week, 1-month, 3-months, 6-months and 12-months,.
Corneal haze was the only adverse events recorded.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Riboflavin/UV-A Corneal Cross-linking Monitored by Theranostic Software Module | 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. Riboflavin/UV-A corneal cross-linking: corneal cross-linking procedure is performed using the C4V CHROMO4VIS™ system equipped with theranostic software module in all participants. Participants will receive a single dose of the 0.22% riboflavin ophthalmic solution, RitSight™. Application of the riboflavin eye drop is done for 15 minutes for the epi-off CXL treatment and 20 minutes for the epi-on CXL treatment. Estimates of riboflavin concentration into the cornea are monitored by the C4V CHROMO4VIS™ system during the dosing phase of treatment. Once the pre-set 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 (10 mW/cm2 for 9 min.) and 7.00 mm light beam diameter in all participants. Estimates of treatment efficacy by calculation of theranostic score are performed by the C4V CHROMO4VIS™ system during UV-A irradiation. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Corneal Haze | Eye disorders | MeDRA | Systematic Assessment | Frequency of corneal haze was maximum at 1 month |
This study assessed CXL efficacy by measuring the change of the Kmax index, which was aligned with commonly used approaches in the field.
The list of adverse events may not be fully comprehensive as the first postoperative visit was scheduled at 7 days after treatment, excluding immediate postoperative events, such as eye pain, stromal oedema, corneal striae and conjunctival hyperaemia, from the assessment.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Marco Lombardo, Study Director | Studio Italiano di Oftalmologia | +393313438300 | studiolombardo@visioeng.it |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jun 28, 2021 | Oct 30, 2024 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D007640 | Keratoconus |
| ID | Term |
|---|---|
| D003316 | Corneal Diseases |
| D005128 | Eye Diseases |
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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. If both eyes of a study participant are eligible, the eye with worst CDVA is enrolled and treated.
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Outcome assessor is masked. Statistician is masked. Participant receives stratification to either corneal cross-linking protocol after consent form signature.
All participants wear contact lens after treatment until first postoperative eye examination at 1 week, when the corneal epithelium is completely healed.
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|
Change of Endothelial Cell Density (ECD) of the cornea. The secondary outcome measure of safety was assessed by measuring change of ECD (cell/mm^2) from baseline to 12 months postoperatively. |
| 12 months |
Change of Corrected Distance Visual Acuity (CDVA) measured with ETDRS chart and expressed in LogMAR.
This outcome was assessed by measuring changes of CDVA from baseline to 12 months postoperatively.
A negative change means improvement in CDVA after treatment.
| 12 months |
| Uncorrected Distance Visual Acuity | Change of Uncorrected Distance Visual Acuity (UDVA) measured with ETDRS chart and expressed in LogMAR. This outcome was assessed by measuring changes of UDVA from baseline to 12 months postoperatively. A negative change means improvement in UDVA after treatment. | 12 months |
| Central Corneal Thickness | Change of Central Corneal Thickness (CCT). This outcome was assessed by measuring changes of CCT from baseline to 12 months postoperatively. | 12 months |
| Stratification Groups | Change of primary and secondary outcome measures in either stratification group (epi-off CXL protocol and epi-on CXL protocol). These exploratory outcome measures included the following assessment: assessmentg of changes of Kmax value (D) at 12-months postoperatively in either stratification group. | 12 months |
| Azienda Ospedaliera Universitaria Careggi, Università di Firenze |
| Florence |
| 50134 |
| Italy |
| Azienda Ospedaliera Universitaria Policlinico G. Martino, Università di Messina | Messina | 98124 | Italy |
| Lombardo M, Lombardo G. Noninvasive real-time assessment of riboflavin consumption in standard and accelerated corneal crosslinking. J Cataract Refract Surg. 2019 Jan;45(1):80-86. doi: 10.1016/j.jcrs.2018.07.062. Epub 2018 Oct 22. |
| 31900647 | Background | 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 Apr;258(4):829-834. doi: 10.1007/s00417-019-04595-6. Epub 2020 Jan 3. |
| 26868750 | Background | Lombardo G, Micali NL, 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 Ophthalmol Vis Sci. 2016 Feb;57(2):476-83. doi: 10.1167/iovs.15-18651. |
| 25542349 | Background | 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 Feb;41(2):446-59. doi: 10.1016/j.jcrs.2014.12.013. Epub 2014 Dec 23. |
| 36059083 | Background | 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. |
| 36587174 | Background | 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. |
| 38908553 | Result | Roszkowska AM, Scorcia V, Mencucci R, Giannaccare G, Lombardo G, Alunni Fegatelli D, Vestri A, Bifezzi L, Bernava GM, Serrao S, Lombardo M. Assessment of the Predictive Ability of Theranostics for Corneal Cross-linking in Treating Keratoconus: A Randomized Clinical Trial. Ophthalmology. 2024 Dec;131(12):1403-1415. doi: 10.1016/j.ophtha.2024.06.012. Epub 2024 Jun 20. |
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| Sex: Female, Male | Count of Participants | Participants |
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| Secondary | Corneal Topography | Change of Maximum Keratometry value of Placido disc corneal topography. The secondary outcome measure of efficacy was assessed by measuring changes of Kmax value (D) from baseline to 12 months postoperatively. | Posted | Mean | Standard Deviation | diopters | 12 months | Eyes | Eyes |
|
|
|
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| Secondary | Endothelial Cell Density | Change of Endothelial Cell Density (ECD) of the cornea. The secondary outcome measure of safety was assessed by measuring change of ECD (cell/mm^2) from baseline to 12 months postoperatively. | Posted | Mean | Standard Deviation | cells/mm^2 | 12 months | Eyes | Eyes |
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| Other Pre-specified | Manifest Refraction | Change of Manifest Spherical Equivalent Refraction (MSER). This outcome was assessed by measuring change of MSER (D) from baseline to 12 months postoperatively. | Posted | Mean | Standard Deviation | diopters | 12 months |
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| Other Pre-specified | Corrected Distance Visual Acuity | Change of Corrected Distance Visual Acuity (CDVA) measured with ETDRS chart and expressed in LogMAR. This outcome was assessed by measuring changes of CDVA from baseline to 12 months postoperatively. A negative change means improvement in CDVA after treatment. | Posted | Mean | Standard Deviation | LogMAR | 12 months | Eyes | Eyes |
|
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| Other Pre-specified | Uncorrected Distance Visual Acuity | Change of Uncorrected Distance Visual Acuity (UDVA) measured with ETDRS chart and expressed in LogMAR. This outcome was assessed by measuring changes of UDVA from baseline to 12 months postoperatively. A negative change means improvement in UDVA after treatment. | Posted | Mean | Standard Deviation | LogMAR | 12 months | Eyes | Eyes |
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| Other Pre-specified | Central Corneal Thickness | Change of Central Corneal Thickness (CCT). This outcome was assessed by measuring changes of CCT from baseline to 12 months postoperatively. | Posted | Mean | Standard Deviation | micrometers | 12 months | Eyes | Eyes |
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| Other Pre-specified | Stratification Groups | Change of primary and secondary outcome measures in either stratification group (epi-off CXL protocol and epi-on CXL protocol). These exploratory outcome measures included the following assessment: assessmentg of changes of Kmax value (D) at 12-months postoperatively in either stratification group. | Posted | Mean | Standard Deviation | diopters | 12 months | Eyes | Eyes |
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| 0 |
| 50 |
| 0 |
| 50 |
| 6 |
| 50 |
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