Progressive Keratoconus
Conditions
Keywords
corneal cross-linking, transepithelial corneal cross-linking, iontophoresis, progressive keratoconus
Brief summary
The purpose of the present Randomized Clinical Trial (RCT) is to compare the efficacy and safety of transepithelial corneal cross-linking using iontophoresis (T-ionto CL) to treat progressive keratoconus in comparison with standard cross-linking (standard CL).
Detailed description
Keratoconus is a progressive corneal ectatic disease causing visual impairment by inducing irregular astigmatism and corneal opacity. This disorder typically begins during the second decade of life and, in severe forms, may need a corneal transplantation. Corneal cross-linking with riboflavin and UV-A is a procedure intended to halt keratoconus progression. It generates additional chemical bonds between stromal proteins in order to stiffen the corneal tissue. Standard CL includes epithelial removal and stroma soaking with dextran-enriched 0.1% riboflavin solution for 30 minutes before being exposed to ultraviolet-A radiation using a 3mW/cm2 lamp for 30 minutes. Epithelial debridement exposes the cornea to a risk of side effects, such as pain for the first two post-operative days, temporary loss of visual acuity during the first three months, and serious complications, such as infection and stromal opacity due to corneal scarring. Iontophoresis is a non invasive technique in which a weak electric current is used to enhance the penetration of hypotonic 0.1% riboflavin-5-phosphate solution into the corneal stroma through the intact epithelium. After iontophoresis, the corneal tissue is irradiated using a 10 mW/cm2 for 9 minutes (T-ionto CL). From previous experimental work (Lombardo M. et al. JCRS 2014 and JCRS 2015), the investigators provided evidence that T-ionto CL increases the stiffness of human corneas with results almost comparable with standard CL. The new procedure holds the promise to be as effective as the standard procedure while minimizing all the related risks. It is object of the present clinical trial to randomize patients with progressive keratoconus to T-ionto CL and standard CL and compare efficacy and safety of treatments.
Interventions
DEVICECross-linking with iontophoresis
The procedure involves a constant current source and two electrodes. The active electrode is a bath tube, which includes a stainless steel grid, placed into the cup at a minimal distance from the cornea. The reservoir is filled with dextran-free, hypotonic riboflavin-5-phosphate solution. The generator applies a constant current of 1mA for a preset period of 5 min. After the riboflavin administration by iontophoresis, the cornea is irradiated using a UVA lamp of 10mW/cm2 for 9 minutes.
DEVICEStandard corneal cross-linking
In the standard CL, the epithelium is mechanically removed. Then, a solution of riboflavin is instilled each minute for 30 minutes. Corneas are irradiated using a UVA lamp of 3mW/cm2 for 30 minutes.
Sponsors
CNR Institute for chemical and physical processes (IPCF), Messina
Fondazione G.B. Bietti, IRCCS
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Consecutive patients were randomized, using block randomization model, in one of the arm
Eligibility
Sex/Gender
ALL
Age
18 Years to 46 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of progressive keratoconus
Exclusion criteria
* Anterior corneal curvature steeper than 61 D; * central corneal thickness \<400 um * corneal scarring; * descemetocele; * history of herpetic keratitis; * Concomitant eye diseases; * Inflammatory eye diseases; * Glaucoma; * Cataract; * Pregnancy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| K-max | Changes from baseline in Kmax at 12 months | Measuring maximum keratometry (K-max), measured in diopters (D), derived from computerized videokeratography. |
| Corneal Endothelial Cell Density | Changes from baseline in ECD at 12 months | Endothelial cell density (ECD) will be evaluated using specular microscopy |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Optical Aberrations | Changes from baseline at 12 months. | Optical aberrations of the eye will be measured using dynamic skyascopy. Corneal wavefront aberration will be measured using Placido disk topographer and Scheimpflug tomographer. |
| Visual Acuity | Changes from baseline at 12 months. | Visual acuity tested using ETDRS |
| Contrast Sensitivity | Changes from baseline at 12 months. | Contrast sensitivity tested using Pelli-Robson chart |
| Central Retinal Thickness | Changes from baseline at 12 months. | Central retinal thickness (1 mm ETDRS map) will be measured before and after CXL procedures |
Countries
Italy
Participant flow
Recruitment details
Eligible patients were randomized after enrolment, with allocation ratio of 2:1, into either the study or control group
Pre-assignment details
Block randomization strategy was used to randomize units with comparable baseline Kmax values in either group.
Participants by arm
| Arm | Count |
|---|---|
| Standard CL Participants undergoing standard corneal cross-linking | 10 |
| Standard CL Participants undergoing standard corneal cross-linking | 12 |
| T-ionto CL Participants undergoing transepithelial corneal cross-linking with iontophoresis | 20 |
| T-ionto CL Participants undergoing transepithelial corneal cross-linking with iontophoresis | 22 |
| Total | 64 |
Baseline characteristics
| Characteristic | Standard CL | T-ionto CL | Total |
|---|---|---|---|
| Age, Continuous | 29.4 years STANDARD_DEVIATION 5.6 | 31 years STANDARD_DEVIATION 6.6 | 30 years STANDARD_DEVIATION 6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 eyes | 0 eyes | 0 eyes |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 eyes | 22 eyes | 34 eyes |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 eyes | 0 eyes | 0 eyes |
| family history of keratoconus | 2 Participants | 3 Participants | 5 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 eyes | 0 eyes | 0 eyes |
| Race (NIH/OMB) Asian | 0 eyes | 0 eyes | 0 eyes |
| Race (NIH/OMB) Black or African American | 0 eyes | 0 eyes | 0 eyes |
| Race (NIH/OMB) More than one race | 0 eyes | 0 eyes | 0 eyes |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 eyes | 0 eyes | 0 eyes |
| Race (NIH/OMB) Unknown or Not Reported | 0 eyes | 0 eyes | 0 eyes |
| Race (NIH/OMB) White | 12 eyes | 22 eyes | 34 eyes |
| Region of Enrollment Italy | 12 eyes | 22 eyes | 34 eyes |
| Sex: Female, Male Female | 4 eyes | 3 eyes | 7 eyes |
| Sex: Female, Male Male | 8 eyes | 19 eyes | 27 eyes |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 20 | 1 / 10 |
| serious Total, serious adverse events | 0 / 20 | 0 / 10 |
Outcome results
Primary
Corneal Endothelial Cell Density
Endothelial cell density (ECD) will be evaluated using specular microscopy
Time frame: Changes from baseline in ECD at 12 months
Population: Analysis of changes from baseline in each group was made using the paired Student t-test. Treatment effects were assessed using repeated measures ANOVA between groups and time (3 days, 7 days, 1-, 3-, 6- and 12-months). The outcome measures over time were corrected for baseline values.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Transepithelial Corneal Cross-linking Using Iontophoresis | Corneal Endothelial Cell Density | 2675 cells/mm2 | Standard Deviation 311 |
| Standard Corneal Cross-linking | Corneal Endothelial Cell Density | 2658 cells/mm2 | Standard Deviation 321 |
Comparison: Analysis of changes from baseline in each group was made using the paired Student t-test. Treatment effects were assessed using repeated measures ANOVA between groups and time (3 days, 7 days, 1-, 3-, 6- and 12-months). The outcome measures over time were corrected for baseline values.p-value: 0.05ANOVA
Primary
K-max
Measuring maximum keratometry (K-max), measured in diopters (D), derived from computerized videokeratography.
Time frame: Changes from baseline in Kmax at 12 months
Population: Analysis of changes from baseline in each group was made using the paired Student t-test. Treatment effects were assessed using repeated measures ANOVA between groups and time (3 days, 7 days, 1-, 3-, 6- and 12-months). The outcome measures over time were corrected for baseline values.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Transepithelial Corneal Cross-linking Using Iontophoresis | K-max | -0.52 Diopters (D) | Standard Deviation 1.3 |
| Standard Corneal Cross-linking | K-max | -0.82 Diopters (D) | Standard Deviation 1.2 |
Comparison: Analysis of changes from baseline in each group was made using the paired Student t-test. Treatment effects were assessed using repeated measures ANOVA between groups and time (3 days, 7 days, 1-, 3-, 6- and 12-months). The outcome measures over time were corrected for baseline values. The relationship between the change in Kmax at 12 months and baseline parameters was assessed using Pearson's correlation analysis for either group.p-value: <0.05ANOVA
Secondary
Central Retinal Thickness
Central retinal thickness (1 mm ETDRS map) will be measured before and after CXL procedures
Time frame: Changes from baseline at 12 months.
Population: 1 mm central retinal thickness assessed by SD-OCT
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Transepithelial Corneal Cross-linking Using Iontophoresis | Central Retinal Thickness | 275 micrometers | Standard Deviation 20 |
| Standard Corneal Cross-linking | Central Retinal Thickness | 277 micrometers | Standard Deviation 38 |
Secondary
Contrast Sensitivity
Contrast sensitivity tested using Pelli-Robson chart
Time frame: Changes from baseline at 12 months.
Population: Contrast-sensitivity function assessed by Pelli-Robson charts
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Transepithelial Corneal Cross-linking Using Iontophoresis | Contrast Sensitivity | 1.62 log | Standard Deviation 0.08 |
| Standard Corneal Cross-linking | Contrast Sensitivity | 1.63 log | Standard Deviation 0.06 |
Secondary
Optical Aberrations
Optical aberrations of the eye will be measured using dynamic skyascopy. Corneal wavefront aberration will be measured using Placido disk topographer and Scheimpflug tomographer.
Time frame: Changes from baseline at 12 months.
Population: Corneal high-order aberrations
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Transepithelial Corneal Cross-linking Using Iontophoresis | Optical Aberrations | 2.19 micrometers | Standard Deviation 0.99 |
| Standard Corneal Cross-linking | Optical Aberrations | 2.21 micrometers | Standard Deviation 0.86 |
Secondary
Visual Acuity
Visual acuity tested using ETDRS
Time frame: Changes from baseline at 12 months.
Population: Corrected distance visual acuity
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Transepithelial Corneal Cross-linking Using Iontophoresis | Visual Acuity | 0.03 LogMAR | Standard Deviation 0.1 |
| Standard Corneal Cross-linking | Visual Acuity | 0.01 LogMAR | Standard Deviation 0.1 |