T-iontoCL: Transepithelial Corneal Cross-linking Using Iontophoresis

• Sponsor: Fondazione G.B. Bietti, IRCCS (Other)
• Overall Status: Completed
• CT.gov ID: NCT02117999
• Collaborator: CNR Institute for chemical and physical processes (IPCF), Messina (Other)
• Enrollment: 30
• Location: 1
• Arms: 2
• Actual Duration (Months): 32
• Patients Per Site Per Month: 0.9

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Progressive Keratoconus	Device: Cross-linking with iontophoresis; Device: Standard corneal cross-linking	N/A

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 30 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Consecutive patients were randomized, using block randomization model, in one of the armConsecutive patients were randomized, using block randomization model, in one of the arm
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Randomized Clinical Trial Comparing Transepithelial Corneal Cross-linking Using Iontophoresis and Standard Corneal Cross-linking for the Treatment of Keratoconus
• Actual Study Start Date: Jan 1, 2014
• Actual Primary Completion Date: Jun 1, 2016
• Actual Study Completion Date: Sep 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cross-linking with iontophoresis Transepithelial cross-linking by using iontophoresis to administer riboflavin into the corneal stroma	Device: Cross-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.; Other Names: Ricrolin+
Active Comparator: Standard corneal cross-linking Standard corneal cross-linking includes de-epithelialization and stromal soaking by applying drops of riboflavin	Device: Standard 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.; Other Names: Ricrolin

Outcome Measures

Primary Outcome Measures

1. K-max [Changes from baseline in Kmax at 12 months]

   Measuring maximum keratometry (K-max), measured in diopters (D), derived from computerized videokeratography.

2. Corneal Endothelial Cell Density [Changes from baseline in ECD at 12 months]

   Endothelial cell density (ECD) will be evaluated using specular microscopy

Secondary Outcome Measures

1. 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.

2. Visual Acuity [Changes from baseline at 12 months.]

   Visual acuity tested using ETDRS

3. Contrast Sensitivity [Changes from baseline at 12 months.]

   Contrast sensitivity tested using Pelli-Robson chart

4. Central Retinal Thickness [Changes from baseline at 12 months.]

   Central retinal thickness (1 mm ETDRS map) will be measured before and after CXL procedures

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 46 Years
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Fondazione G.B. Bietti, IRCCS	Rome		Italy	00198

Sponsors and Collaborators

• Fondazione G.B. Bietti, IRCCS
• CNR Institute for chemical and physical processes (IPCF), Messina

Investigators

• Principal Investigator: Marco Lombardo, MD, PhD, Fondazione G.B. Bietti, IRCCS

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Inclusion and exclusion criteria to the present RCT are shown in the main website page

Publications

• Bikbova G, Bikbov M. Transepithelial corneal collagen cross-linking by iontophoresis of riboflavin. Acta Ophthalmol. 2014 Feb;92(1):e30-4. doi: 10.1111/aos.12235. Epub 2013 Jul 15.
• Eljarrat-Binstock E, Domb AJ. Iontophoresis: a non-invasive ocular drug delivery. J Control Release. 2006 Feb 21;110(3):479-89. Epub 2005 Dec 15. Review.
• Hao J, Li SK, Liu CY, Kao WW. Electrically assisted delivery of macromolecules into the corneal epithelium. Exp Eye Res. 2009 Dec;89(6):934-41. doi: 10.1016/j.exer.2009.08.001. Epub 2009 Aug 12.
• Meek KM, Hayes S. Corneal cross-linking--a review. Ophthalmic Physiol Opt. 2013 Mar;33(2):78-93. doi: 10.1111/opo.12032. Review.
• Spoerl E, Huhle M, Seiler T. Induction of cross-links in corneal tissue. Exp Eye Res. 1998 Jan;66(1):97-103.

• Responsible Party: Marco Lombardo, Dr. Marco Lombardo, Fondazione G.B. Bietti, IRCCS
• ClinicalTrials.gov Identifier: NCT02117999
• Other Study ID Numbers: SEA27; PON01_00110
• First Posted: Apr 21, 2014
• Last Update Posted: Aug 8, 2019
• Last Verified: Aug 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Marco Lombardo, Dr. Marco Lombardo, Fondazione G.B. Bietti, IRCCS: corneal cross-linking; transepithelial corneal cross-linking; iontophoresis; progressive keratoconus
• Additional relevant MeSH terms: Keratoconus

Study Results

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 Detail	Block randomization strategy was used to randomize units with comparable baseline Kmax values in either group.

Arm/Group Title	T-ionto CL	Standard CL
Arm/Group Description	Eyes undergoing transepithelial corneal cross-linking with iontophoresis	Eyes undergoing standard corneal cross-linking
Period Title: Overall Study
STARTED	20	10
Mean Kmax Change in Corneal Topography	20	10
COMPLETED	20	10
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Standard CL	T-ionto CL	Total
Arm/Group Description	Participants undergoing standard corneal cross-linking	Participants undergoing transepithelial corneal cross-linking with iontophoresis	Total of all reporting groups
Overall Participants	10	20	30
Overall eyes	12	22	34
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	29.4 (5.6)	31 (6.6)	30 (6)
Sex: Female, Male (eyes) [Count of Units]
Female	4	3	7
Male	8	19	27
Ethnicity (NIH/OMB) (eyes) [Count of Units]
Hispanic or Latino	0	0	0
Not Hispanic or Latino	12	22	34
Unknown or Not Reported	0	0	0
Race (NIH/OMB) (eyes) [Count of Units]
American Indian or Alaska Native	0	0	0
Asian	0	0	0
Native Hawaiian or Other Pacific Islander	0	0	0
Black or African American	0	0	0
White	12	22	34
More than one race	0	0	0
Unknown or Not Reported	0	0	0
Region of Enrollment (eyes) [Number]
Italy	12	22	34
family history of keratoconus (Count of Participants)
Count of Participants [Participants]	2 20%	3 15%	5 16.7%

Outcome Measures

1. Primary Outcome

Title	K-max
Description	Measuring maximum keratometry (K-max), measured in diopters (D), derived from computerized videokeratography.
Time Frame	Changes from baseline in Kmax at 12 months

Outcome Measure Data

Analysis Population Description

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/Group Title	Transepithelial Corneal Cross-linking Using Iontophoresis	Standard Corneal Cross-linking
Arm/Group Description	Transepithelial corneal cross-linking using iontophoresis Transepithelial corneal cross-linking using 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.	Standard corneal cross-linking Standard 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.
Measure Participants	22	12
Mean (Standard Deviation) [Diopters (D)]	-0.52 (1.30)	-0.82 (1.20)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Transepithelial Corneal Cross-linking Using Iontophoresis, Standard Corneal Cross-linking
	Comments	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.
	Type of Statistical Test	Non-Inferiority
	Comments	Sample size calculation was performed to detect a difference of 0.95 D between the average Kmax changes for the T-ionto CL and standard CL groups at 12 months, at a significance level of 5% and a power of 81%, assuming a standard deviation of 1.20 D.
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	ANOVA
	Comments

2. Primary Outcome

Title	Corneal Endothelial Cell Density
Description	Endothelial cell density (ECD) will be evaluated using specular microscopy
Time Frame	Changes from baseline in ECD at 12 months

Outcome Measure Data

Analysis Population Description

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/Group Title	Transepithelial Corneal Cross-linking Using Iontophoresis	Standard Corneal Cross-linking
Arm/Group Description	Transepithelial corneal cross-linking using iontophoresis Transepithelial corneal cross-linking using 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.	Standard corneal cross-linking Standard 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.
Measure Participants	22	12
Mean (Standard Deviation) [cells/mm2]	2675 (311)	2658 (321)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Transepithelial Corneal Cross-linking Using Iontophoresis, Standard Corneal Cross-linking
	Comments	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.
	Type of Statistical Test	Non-Inferiority
	Comments	sample size calculation was performed to detect a difference of 0.95 D between the average Kmax changes for the T-ionto CL and standard CL groups at 12 months, at a significance level of 5% and a power of 81%, assuming a standard deviation of 1.20 D. The sample size of the study was 34 cases (allocation ratio of 2:1)
Statistical Test of Hypothesis	p-Value	0.05
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	35
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Optical Aberrations
Description	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.

Outcome Measure Data

Analysis Population Description

Corneal high-order aberrations

Arm/Group Title	T-ionto CL	Standard CL
Arm/Group Description	Participants undergoing transepithelial corneal cross-linking with iontophoresis	Participants undergoing standard corneal cross-linking
Measure Participants	20	10
Mean (Standard Deviation) [micrometers]	2.19 (0.99)	2.21 (0.86)

4. Secondary Outcome

Title	Visual Acuity
Description	Visual acuity tested using ETDRS
Time Frame	Changes from baseline at 12 months.

Outcome Measure Data

Analysis Population Description

Corrected distance visual acuity

Arm/Group Title	T-ionto CL	Standard CL
Arm/Group Description	Participants undergoing transepithelial corneal cross-linking with iontophoresis	Participants undergoing standard corneal cross-linking
Measure Participants	20	10
Mean (Standard Deviation) [LogMAR]	0.03 (0.10)	0.01 (0.10)

5. Secondary Outcome

Title	Contrast Sensitivity
Description	Contrast sensitivity tested using Pelli-Robson chart
Time Frame	Changes from baseline at 12 months.

Outcome Measure Data

Analysis Population Description

Contrast-sensitivity function assessed by Pelli-Robson charts

Arm/Group Title	T-ionto CL	Standard CL
Arm/Group Description	Participants undergoing transepithelial corneal cross-linking with iontophoresis	Participants undergoing standard corneal cross-linking
Measure Participants	20	10
Mean (Standard Deviation) [log]	1.62 (0.08)	1.63 (0.06)

6. Secondary Outcome

Title	Central Retinal Thickness
Description	Central retinal thickness (1 mm ETDRS map) will be measured before and after CXL procedures
Time Frame	Changes from baseline at 12 months.

Outcome Measure Data

Analysis Population Description

1 mm central retinal thickness assessed by SD-OCT

Arm/Group Title	T-ionto CL	Standard CL
Arm/Group Description	Participants undergoing transepithelial corneal cross-linking with iontophoresis	Participants undergoing standard corneal cross-linking
Measure Participants	20	10
Mean (Standard Deviation) [micrometers]	275 (20)	277 (38)

Adverse Events

Time Frame	1 year
Adverse Event Reporting Description	no differences
Arm/Group Title	Transepithelial Corneal Cross-linking Using Iontophoresis		Standard Corneal Cross-linking
Arm/Group Description	Participants undergoing transepithelial corneal cross-linking using iontophoresis		Participants undergoing standard corneal cross-linking
All Cause Mortality
	Transepithelial Corneal Cross-linking Using Iontophoresis		Standard Corneal Cross-linking
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Transepithelial Corneal Cross-linking Using Iontophoresis		Standard Corneal Cross-linking
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/10 (0%)
Other (Not Including Serious) Adverse Events
	Transepithelial Corneal Cross-linking Using Iontophoresis		Standard Corneal Cross-linking
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		1/10 (10%)
Eye disorders
Corneal sub-epithelial infiltrates	0/20 (0%)	0	1/10 (10%)	1

Limitations/Caveats

Principal Investigator (PI) is NOT employed by the organization sponsoring the study. There is NOT an agreement between the PI and the Sponsor that restricts the PI's rights to discuss or publish trial results after the trial is completed.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.