Corneal Crosslinking in Patients With Keratoconus and Post-Refractive Ectasia

• Sponsor: Price Vision Group (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01143389
• Collaborator: (none)
• Enrollment: 510
• Location: 1
• Arms: 2
• Duration (Months): 88
• Patients Per Site Per Month: 5.8

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the effectiveness of using riboflavin and UV light to treat progressive keratoconus or post-refractive corneal ectasia.

Condition or Disease	Intervention/Treatment	Phase
Keratoconus; Post-Refractive Ectasia	Drug: Riboflavin; Device: UVX light	Phase 2

Detailed Description

The primary objective of this study is to evaluate two riboflavin-dosing regimens for corneal collagen cross-linking to slow the progressive changes in corneal curvature in eyes with progressive keratoconus or post-refractive ectasia.

Study Design

• Study Type: Interventional
• Actual Enrollment: 510 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Evaluation of Two Riboflavin Dosing Regimens for Corneal Collagen Cross-Linking in Eyes With Progressive Keratoconus or Ectasia
• Study Start Date: May 1, 2010
• Actual Primary Completion Date: May 30, 2017
• Actual Study Completion Date: Aug 30, 2017

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Riboflavin 0.1% eyedrops every 5 minutes The eye will be irradiated for 30 minutes with UVX light, during which time instillation of riboflavin will continue (1 drop every 5 minutes for this arm).	Drug: Riboflavin; Riboflavin 0.1% eye drops are applied before and during irradiation of the cornea.; Device: UVX light; UVX 365 nm wavelength light source is applied with continued application of riboflavin.
Active Comparator: Riboflavin 0.1% eyedrops every 2 minutes The eye will be irradiated for 30 minutes with UVX light, during which time instillation of riboflavin will continue (1 drop every 2 minutes for this arm).	Drug: Riboflavin; Riboflavin 0.1% eye drops are applied before and during irradiation of the cornea.; Device: UVX light; UVX 365 nm wavelength light source is applied with continued application of riboflavin.

Outcome Measures

Primary Outcome Measures

1. Change in Maximum Keratometry From Baseline to 6 Months After Treatment [6 months]

   Change in maximum keratometry (Kmax) between baseline and 6 months after treatment, measured by corneal tomography.

Secondary Outcome Measures

1. Pachymetry [6 months]

   Minimum corneal thickness measured by corneal tomography

2. Corrected Distance Visual Acuity (CDVA) [6 months]

   Corrected distance visual acuity (CDVA) reported in logarithm of the minimum angle of resolution (logMAR). Lower numbers represent better vision; 0.0 corresponds to 20/20 vision. Each increase of 0.1 on the logMAR scale corresponds to one less line read on the eye chart.

3. Uncorrected Distance Visual Acuity (UDVA) [6 months]

   Uncorrected distance visual acuity reported in logarithm of the minimum angle of resolution units. Lower numbers represent better vision; 0.0 corresponds to 20/20 vision without any type of correction such as glasses. Each increase of 0.1 on the logMAR scale corresponds to one less line read on the eye chart.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 10 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. 10 years of age or older

2. Having documented ectasia on topography or tomography after previous refractive surgery OR progressive keratoconus defined as one or more of the following changes over a period of 36 months or less before randomization:

3. An increase of ≥ 1.00 D in the steepest keratometry value (or sim K)

4. An increase of ≥ 1.00 D in regular astigmatism evaluated by subjective manifest refraction

5. A myopic shift (decrease in the spherical equivalent) of ≥ 0.50 D on subjective manifest refraction

6. Documented decrease in visual acuity associated with irregular astigmatism and topographic features of ectasia.

7. Subjects with keratoconus diagnosis only:

1. Axial topography consistent with keratoconus b. Presence of central or inferior steepening on the Pentacam map. c. Presence of one or more slit lamp findings associated with keratoconus, such as: i. Fleischer ring ii. Vogt striae iii. Corneal thinning iv. Corneal scarring

1. Contact Lens Wearers Only: Removal of contact lenses for the required period of time prior to the screening refraction:

Contact Lens Type Minimum Discontinuation Time Soft 3 Days Soft Extended Wear 1 Week Soft Toric 2 Weeks Rigid gas permeable 2 Weeks

1. Signed written informed consent

Exclusion Criteria:

• 1. Any keratoconus patient over 21 years of age without evidence of progression of his corneal deformity.

1. Patients with excessively thin corneas. 3. Previous ocular condition in the eyes to be treated that may predispose the eye for future complications, for example:

1. History of corneal disease (e.g., herpes simplex, herpes zoster keratitis, recurrent erosion syndrome, corneal melt, corneal dystrophy, etc.) b. Clinically significant corneal scarring in the proposed treatment zone 4. A history of chemical injury or delayed epithelial healing in the eye(s) to be treated.

1. A known sensitivity to treatment medications. 6. Patients with a current condition that, in the treating physician's opinion, would interfere with or prolong epithelial healing.

2. Pregnancy (including plan to become pregnant) or lactation during the course of the study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Price Vision Group	Indianapolis	Indiana	United States	46260

Sponsors and Collaborators

• Price Vision Group

Investigators

• Principal Investigator: Francis W Price, MD, Price Vision Group

Study Documents (Full-Text)

• Study Protocol - Sep 16, 2016
• Statistical Analysis Plan - Sep 12, 2017

More Information

Additional Information:

• Price Vision Group Website

Publications

• Caporossi A, Baiocchi S, Mazzotta C, Traversi C, Caporossi T. Parasurgical therapy for keratoconus by riboflavin-ultraviolet type A rays induced cross-linking of corneal collagen: preliminary refractive results in an Italian study. J Cataract Refract Surg. 2006 May;32(5):837-45.
• Mazzotta C, Traversi C, Baiocchi S, Sergio P, Caporossi T, Caporossi A. Conservative treatment of keratoconus by riboflavin-uva-induced cross-linking of corneal collagen: qualitative investigation. Eur J Ophthalmol. 2006 Jul-Aug;16(4):530-5.
• Raiskup-Wolf F, Hoyer A, Spoerl E, Pillunat LE. Collagen crosslinking with riboflavin and ultraviolet-A light in keratoconus: long-term results. J Cataract Refract Surg. 2008 May;34(5):796-801. doi: 10.1016/j.jcrs.2007.12.039.
• Wittig-Silva C, Whiting M, Lamoureux E, Lindsay RG, Sullivan LJ, Snibson GR. A randomized controlled trial of corneal collagen cross-linking in progressive keratoconus: preliminary results. J Refract Surg. 2008 Sep;24(7):S720-5. doi: 10.3928/1081597X-20080901-15.

• Responsible Party: Price Vision Group
• ClinicalTrials.gov Identifier: NCT01143389
• Other Study ID Numbers: 2010-0243
• First Posted: Jun 14, 2010
• Last Update Posted: Jun 6, 2018
• Last Verified: May 1, 2018

• Keywords provided by Price Vision Group: Keratoconus; Ectasia; cross linking; collagen cross linking
• Additional relevant MeSH terms: Keratoconus; Dilatation, Pathologic; Riboflavin

Study Results

Participant Flow

Arm/Group Title	Riboflavin 0.1% Eyedrops Every 5 Minutes	Riboflavin 0.1% Eyedrops Every 2 Minutes
Arm/Group Description	The eye will be irradiated for 30 minutes with UVX light, during which the instillation of riboflavin will continue (1 drop every 5 minutes for this arm). Riboflavin: Riboflavin 0.1% eye drops are applied before and during irradiation of the cornea. UVX light: UVX 365 nm wavelength light source is applied with continued application of riboflavin.	The eye will be irradiated for 30 minutes with UVX light, during which the instillation of riboflavin will continue (1 drop every 2 minutes for this arm). Riboflavin: Riboflavin 0.1% eye drops are applied before and during irradiation of the cornea. UVX light: UVX 365 nm wavelength light source is applied with continued application of riboflavin.
Period Title: Overall Study
STARTED	253	257
COMPLETED	227	232
NOT COMPLETED	26	25

Baseline Characteristics

Arm/Group Title	Riboflavin 0.1% Eyedrops Every 5 Minutes	Riboflavin 0.1% Eyedrops Every 2 Minutes	Total
Arm/Group Description	The eye will be irradiated for 30 minutes with UVX light, during which time instillation of riboflavin will continue (1 drop every 5 minutes for this arm). Riboflavin: Riboflavin 0.1% eye drops are applied before and during irradiation of the cornea. UVX light: UVX 365 nm wavelength light source is applied with continued application of riboflavin.	The eye will be irradiated for 30 minutes with UVX light, during which time instillation of riboflavin will continue (1 drop every 2 minutes for this arm). Riboflavin: Riboflavin 0.1% eye drops are applied before and during irradiation of the cornea. UVX light: UVX 365 nm wavelength light source is applied with continued application of riboflavin.	Total of all reporting groups
Overall Participants	253	257	510
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	32 (12)	32 (13)	32 (13)
Sex: Female, Male (Count of Participants)
Female	62 24.5%	61 23.7%	123 24.1%
Male	191 75.5%	196 76.3%	387 75.9%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	10 4%	13 5.1%	23 4.5%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	28 11.1%	24 9.3%	52 10.2%
White	215 85%	220 85.6%	435 85.3%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	253 100%	257 100%	510 100%
Keratoconus/ectasia classification (Count of Participants)
Keratoconus mild (flat K <51D and astigmatism <8D)	140 55.3%	139 54.1%	279 54.7%
Keratoconus moderate	43 17%	43 16.7%	86 16.9%
Keratoconus severe (flat K >56D by tomography)	20 7.9%	21 8.2%	41 8%
Ectasia after refractive surgery	50 19.8%	54 21%	104 20.4%

Outcome Measures

1. Primary Outcome

Title	Change in Maximum Keratometry From Baseline to 6 Months After Treatment
Description	Change in maximum keratometry (Kmax) between baseline and 6 months after treatment, measured by corneal tomography.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

Per protocol population

Arm/Group Title	Riboflavin 0.1% Eyedrops Every 5 Minutes	Riboflavin 0.1% Eyedrops Every 2 Minutes
Arm/Group Description	The eye will be irradiated for 30 minutes with UVX light, during which the instillation of riboflavin will continue (1 drop every 5 minutes for this arm). Riboflavin: Riboflavin 0.1% eye drops are applied before and during irradiation of the cornea. UVX light: UVX 365 nm wavelength light source is applied with continued application of riboflavin.	The eye will be irradiated for 30 minutes with UVX light, during which the instillation of riboflavin will continue (1 drop every 2 minutes for this arm). Riboflavin: Riboflavin 0.1% eye drops are applied before and during irradiation of the cornea. UVX light: UVX 365 nm wavelength light source is applied with continued application of riboflavin.
Measure Participants	227	232
Mean (Standard Deviation) [diopters]	0.76 (2.4)	0.97 (3.2)

2. Secondary Outcome

Title	Pachymetry
Description	Minimum corneal thickness measured by corneal tomography
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

Per protocol

Arm/Group Title	Riboflavin 0.1% Eyedrops Every 5 Minutes	Riboflavin 0.1% Eyedrops Every 2 Minutes
Arm/Group Description	The eye will be irradiated for 30 minutes with UVX light, during which the instillation of riboflavin will continue (1 drop every 5 minutes for this arm). Riboflavin: Riboflavin 0.1% eye drops are applied before and during irradiation of the cornea. UVX light: UVX 365 nm wavelength light source is applied with continued application of riboflavin.	The eye will be irradiated for 30 minutes with UVX light, during which the instillation of riboflavin will continue (1 drop every 2 minutes for this arm). Riboflavin: Riboflavin 0.1% eye drops are applied before and during irradiation of the cornea. UVX light: UVX 365 nm wavelength light source is applied with continued application of riboflavin.
Measure Participants	227	232
Mean (Standard Deviation) [microns]	438 (51)	434 (20)

3. Secondary Outcome

Title	Corrected Distance Visual Acuity (CDVA)
Description	Corrected distance visual acuity (CDVA) reported in logarithm of the minimum angle of resolution (logMAR). Lower numbers represent better vision; 0.0 corresponds to 20/20 vision. Each increase of 0.1 on the logMAR scale corresponds to one less line read on the eye chart.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

Per protocol

Arm/Group Title	Riboflavin 0.1% Eyedrops Every 5 Minutes	Riboflavin 0.1% Eyedrops Every 2 Minutes
Arm/Group Description	The eye will be irradiated for 30 minutes with UVX light, during which the instillation of riboflavin will continue (1 drop every 5 minutes for this arm). Riboflavin: Riboflavin 0.1% eye drops are applied before and during irradiation of the cornea. UVX light: UVX 365 nm wavelength light source is applied with continued application of riboflavin.	The eye will be irradiated for 30 minutes with UVX light, during which the instillation of riboflavin will continue (1 drop every 2 minutes for this arm). Riboflavin: Riboflavin 0.1% eye drops are applied before and during irradiation of the cornea. UVX light: UVX 365 nm wavelength light source is applied with continued application of riboflavin.
Measure Participants	227	232
Mean (Standard Deviation) [logMAR]	0.32 (0.29)	0.31 (0.28)

4. Secondary Outcome

Title	Uncorrected Distance Visual Acuity (UDVA)
Description	Uncorrected distance visual acuity reported in logarithm of the minimum angle of resolution units. Lower numbers represent better vision; 0.0 corresponds to 20/20 vision without any type of correction such as glasses. Each increase of 0.1 on the logMAR scale corresponds to one less line read on the eye chart.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

Per protocol

Arm/Group Title	Riboflavin 0.1% Eyedrops Every 5 Minutes	Riboflavin 0.1% Eyedrops Every 2 Minutes
Arm/Group Description	The eye will be irradiated for 30 minutes with UVX light, during which the instillation of riboflavin will continue (1 drop every 5 minutes for this arm). Riboflavin: Riboflavin 0.1% eye drops are applied before and during irradiation of the cornea. UVX light: UVX 365 nm wavelength light source is applied with continued application of riboflavin.	The eye will be irradiated for 30 minutes with UVX light, during which the instillation of riboflavin will continue (1 drop every 2 minutes for this arm). Riboflavin: Riboflavin 0.1% eye drops are applied before and during irradiation of the cornea. UVX light: UVX 365 nm wavelength light source is applied with continued application of riboflavin.
Measure Participants	227	232
Mean (Standard Deviation) [logMAR]	0.95 (0.53)	0.91 (0.55)

Adverse Events

Time Frame	6 months
Arm/Group Title	Riboflavin 0.1% Eyedrops Every 5 Minutes		Riboflavin 0.1% Eyedrops Every 2 Minutes
Arm/Group Description	The eye will be irradiated for 30 minutes with UVX light, during which the instillation of riboflavin will continue (1 drop every 5 minutes for this arm). Riboflavin: Riboflavin 0.1% eye drops are applied before and during irradiation of the cornea. UVX light: UVX 365 nm wavelength light source is applied with continued application of riboflavin.		The eye will be irradiated for 30 minutes with UVX light, during which the instillation of riboflavin will continue (1 drop every 2 minutes for this arm). Riboflavin: Riboflavin 0.1% eye drops are applied before and during irradiation of the cornea. UVX light: UVX 365 nm wavelength light source is applied with continued application of riboflavin.
All Cause Mortality
	Riboflavin 0.1% Eyedrops Every 5 Minutes		Riboflavin 0.1% Eyedrops Every 2 Minutes
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/253 (0%)		0/257 (0%)
Serious Adverse Events
	Riboflavin 0.1% Eyedrops Every 5 Minutes		Riboflavin 0.1% Eyedrops Every 2 Minutes
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/253 (0%)		0/257 (0%)
Other (Not Including Serious) Adverse Events
	Riboflavin 0.1% Eyedrops Every 5 Minutes		Riboflavin 0.1% Eyedrops Every 2 Minutes
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/253 (4.7%)		13/257 (5.1%)
Eye disorders
Loss of 2 or more logMAR lines of corrected distance visual acuity (CDVA) relative to baseline	12/253 (4.7%)	12	13/257 (5.1%)	13

Limitations/Caveats

Limitations included the 6-month follow up duration and the reduced reproducibility of measurement techniques in eyes with ectasia as compared with normal eyes.

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.