Study to Evaluate the Safety and Efficacy of Epi-on Corneal Cross-linking in Eyes With Progressive Keratoconus

Study Overview
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Brief Summary
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To evaluate the safety and efficacy of epithelium-on corneal collagen cross-linking (CXL) in impeding the progression of, and/or reducing corneal curvature (Kmax) in eyes with progressive keratoconus. Epithelium-on CXL uses a formulation that allows the riboflavin to penetrate the cornea without the need to remove the epithelium, the outer most layer of the cornea.

Detailed Description
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Up to 275 study eyes with progressive keratoconus will be enrolled. Study eyes will be randomized in a 2:1 ratio to receive CXL treatment or sham/control treatment.The primary efficacy endpoint is a difference of ≥ 1 diopter between treatment groups in the mean change in Kmax from baseline to Month 6.

Official Title
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A Phase III, Multi-center Study to Evaluate the Safety and Efficacy of Epithelium-on Corneal Collagen Cross-linking in Eyes With Progressive Keratoconus

Conditions
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Progressive Keratoconus

Intervention / Treatment
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* Drug: Paracel 1
* Drug: Paracel Placebo
* Drug: Paracel 2 R0185
* Device: KXL High Power System (2 J)
* Device: KXL High Power System (10 J)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Be between 12 and 55 years of age, male or female, of any race; Provide written informed consent and sign a HIPAA form. Subjects who are under the age of 18 (or have not yet reached the age of majority per local regulations) will need to sign an assent form as well as having a parent or legal guardian sign an informed consent Ability to read English or Spanish to complete the NEI-VFQ 25 questionnaire; Willingness and ability to follow all instructions and comply with schedule for follow-up visits; For females capable of becoming pregnant, agree to have urine pregnancy testing performed prior to randomization of each study eye and prior to treatment of a cross-over eye; must not be lactating, and must agree to use a medically acceptable form of birth control for at least one week prior to the randomization visit, one week prior to treatment of a cross-over eye, and continue to use the method for one month following the last treatment. Acceptable forms for birth control are spermicide with barrier, oral contraceptive, injectable or implantable method of contraception, transdermal contraceptive, intrauterine device, or surgical sterilization of partner. For non-sexually active females, abstinence will be considered an acceptable form of birth control. Women considered capable of becoming pregnant include all females who have experienced menarche and have not experienced menopause (as defined by amenorrhea for greater than 12 consecutive months) or have not undergone successful surgical sterilization (e.g. hysterectomy, bilateral tubal ligation, or bilateral oophorectomy); Having topographic and clinical evidence of keratoconus defined as thefollowing: Axial topography consistent with keratoconus Maximum corneal curvature, as measured by Kmax of ≥ 47.00 D; Presence of central or inferior steepening on the Pentacam topography map Presence of one or more findings associated with keratoconus, such as Fleischer ring Vogt striae Corneal thinning Corneal scarring Scissoring of the retinoscopic reflex Having a diagnosis of progressive keratoconus, defined as one or more of the following changes over a period of 18 months or less: An increase of ≥ 1.00 D in Kmax or simK An increase of ≥ 1.00 D in regular astigmatism on subjective manifest refraction A myopic shift (towards greater negative sphere) of 0.50 D or more on subjective manifest refraction or as evaluated by comparing eyeglass or contact lens prescriptions to current subjective manifest refraction [NOTE: subjects with a clear history of progression but without prior documentation may be screened and followed for a period of time to confirm and document progression] BSCVA of ≥ 1 letter and ≤ 85 letters on ETDRS chart Contact Lens Wearers Only: Removal of contact lenses is required for a 1 week period prior to the screening visit(s) and subject must agree to remain out of their contact lenses from the time of treatment until the 1-month visit is completed. A contact lens wearer is defined as someone who has worn contact lenses in the eye to be treated in the last 30 days. Exclusion Criteria: Contraindications, sensitivity or known allergy to the use of the test article(s) or their components; If female, be pregnant, nursing or planning a pregnancy or have a positive urine pregnancy test prior to the randomization or treatment of either eye or during the course of the study; Eyes classified as either normal, atypical normal, or keratoconus suspect on the severity grading scheme; A history of previous corneal surgery, limbal relaxing incision procedure, or insertion of Intacs in the eye(s) to be treated; Corneal pachymetry that is < 325 microns at the thinnest point measured by Pentacam in the eye to be treated; Eyes which are aphakic, or eyes which are pseudophakic and do not have a UV blocking lens implanted; Previous ocular condition (other than refractive error) in the eye to be treated that may predispose the eye for future complications. For example: History of corneal disease (e.g., herpes simplex, herpes zoster keratitis, corneal melt, corneal dystrophy, etc.); Clinically significant corneal scarring in the cross-linking treatment zone that is not related to keratoconus or, in the Investigator's opinion, will interfere with the cross-linking procedure; A history of delayed epithelial healing in the eye to be treated or a current condition that may interfere with or prolong epithelial healing; Subjects with nystagmus or any other condition that would prevent a steady gaze during the treatment or other diagnostic tests; A history of previous corneal cross-linking treatment in the eye to be treated; Have used an investigational drug or device within 30 days of screening or be concurrently enrolled in another investigational drug or device trial within 30 days of the study.

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Epithelium-on CXL Treatment Group<br>Study eye receives Paracel 1, Paracel 2 R0185 and irradiated using KXL High Power System (10 J) | Drug: Paracel 1<br>* Two drops every 60 seconds for 4 minutes<br>* Other names: 0.250% riboflavin ophthalmic solution;Drug: Paracel 2 R0185<br>* Two drops every 30 seconds for 6 minutes<br>* Other names: 0.185% riboflavin ophthalmic solution;Device: KXL High Power System (10 J)<br>* 30 mW/cm2 for 11 minutes 6 seconds with an on/off cycle of 1 second UVA on/1 second UVA off (total UVA does of 10 J/cm2)<br>* Other names: UVA Irradiation;|
| Sham Comparator: Sham Treatment/Control Group<br>Sham eye receives Paracel Placebo and irradiated using KXL High Power System (2 J) | Drug: Paracel Placebo<br>* Two drops of Paracel Placebo every 60 seconds for 4 minutes followed by two drops every 30 seconds for 6 minutes<br>* Other names: 0.0% riboflavin ophthalmic solution;Device: KXL High Power System (2 J)<br>* 6 mW/cm2 for 11 minutes 6 seconds with an on/off cycle of 1 second UVA on/1 second UVA off (total UVA does of 2 J/cm2)<br>* Other names: Ultraviolet-A (UVA) Irradiation;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Kmax | Mean difference of at least 1 diopter in Kmax change from baseline between treatment groups | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Kmax | Change from baseline in Kmax between treatment groups | 12 months |