Treatment of Keratoconus With Advanced CXL-II

Phase 2

• Conditions: Keratoconus
• Interventions: Procedure: Topography-based CXL (KXL2); Procedure: Conventional pulsed CXL (pCXL); Drug: Riboflavin; Device: Avedro KXL II

• Registration Number: NCT02514200
• Lead Sponsor: Umeå University

Brief Summary

The purpose of this study is to determine whether individualized, topography-based corneal crosslinking for keratoconus can improve the optical outcomes of the treatment.

Detailed Description

The study is designed as a prospective, open label, randomized controlled trial involving patients aged 12 years or older of both genders with uni- or bilateral keratoconus planned for routine corneal crosslinking (CXL) at the Department of Clinical Sciences / Ophthalmology, Umeå University Hospital, Umeå, Sweden. The study involves 25+25 eyes with keratoconus, which are randomized to receive either conventional pulsed crosslinking with a uniform, universal 8 mm treatment pattern of 5.4 J/cm2 (pCXL; n=25), or a modified treatment - individualized topography-based corneal crosslinking (KXL2; n=25). In the latter treatment zone has an individualized arcuate shape and spares a 2 mm central optical zone. The size of the treatment zone is based on Pentacam HR® corneal tomography, and is determined by the transition zone where the corneal curvature drops off by ≥2D. The energy distribution is based on the maximum corneal steepness (Kmax) value retrieved from the Pentacam HR® tomography: ≤47.0D - 7.2 J/cm2; 47.1-52.0D - 10 J/cm2; ≥52.1D - 15 J/cm2. Thus, the thin protruding areas of the cornea are crosslinked, whereas the parts with a more normal shape are not. The aim is to potentially improve the optical outcome after the treatment.

Patients are randomized to either of the two treatment arms utilizing a computer list of unique random numbers between 1 and 50; an even number will be treated with KXL2 and an uneven number with pCXL. Bilateral inclusion is allowed, and the second eye to be treated will be assigned to the other group, i.e. eye number two will not get the same treatment as eye number 1.

All patients are informed about the procedures and provide oral and written consent before inclusion in the study.

At baseline, before treatment, each eye is evaluated with autorefractometer measurement (Oculus Parc-1®), uncorrected and best spectacle-corrected LogMAR visual acuity, Oculus Pentacam HR® Scheimpflug photography, Oculus CorVis® high-speed Scheimpflug photography, corneal endothelial photography with a specular microscope camera, Goldmann applanation tonometry and biomicroscopy.

For the Pentacam HR® rotating Scheimpflug camera, each eye is photographed using the "25 pictures" program under standardized, mesopic light conditions. Multiple variables will be analyzed, and individual photographs also will be analyzed manually for light backscatter and for the occurrence of a demarcation line, by a masked observer. The corneal biomechanical characteristics are assessed with data from the Oculus CorVis®, and corneal endothelial morphometry, including endothelial cell density is assessed manually and automatically from specular microscopy photographs taken with the Topcon SP-2000 endothelial camera. All investigations are repeated at 1 month, 3 months, 6 months and 12 months after the treatment.

Study Timeline

• Study Start: 2014-03
• Study First Submitted: 2015-07-30
• Study First Submitted QC: 2015-07-30
• Study First Posted: 2015-08-03
• Status Verified: 2017-12
• Last Update Submitted: 2018-05-15
• Last Update Posted: 2018-05-16
• Primary Completion: 2019-10
• Study Completion: 2019-10

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 50

Inclusion Criteria

1. Patients planned for corneal crosslinking.
2. Uni-or bilateral keratoconus diagnosis based on the Amsler-Krumeich grading and the "Total Deviation" keratoconus quantification value from the "Belin-Ambrosio enhanced ectasia" measurements of the Pentacam HR® Scheimpflug camera, and an altered red reflex and/or an irregular cornea seen as distortion of the keratometric mires.
3. Progression of the keratoconus in the eye in question, documented with Scheimpflug photography using the Oculus Pentacam HR® Scheimpflug camera and/or repeated subjective refraction and keratometry.
4. Minimum corneal thickness of 400 μm at the thinnest point after epithelial removal.
5. ≥12 years of age
6. No ocular abnormalities except keratoconus
7. No previous ocular surgery
8. No cognitive insufficiency interfering with the informed consent.

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Exclusion Criteria

1. Age under 12
2. Any corneal abnormalities except keratoconus
3. Previous ocular surgery
4. Cognitive insufficiency

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Topography-based CXL (KXL2)	Topography-based CXL (KXL2)	Individualized pulsed topography-based corneal crosslinking; 1 second on, 1 second off; 7.2J/cm2 - 15.0J/cm2; arcuate treatment zone. The Avedro KXL II™ System is used for the crosslinking after epithelial debridement in topical anesthesia and application of topical riboflavin every 3 minutes for 10 minutes.
Topography-based CXL (KXL2)	Avedro KXL II	Individualized pulsed topography-based corneal crosslinking; 1 second on, 1 second off; 7.2J/cm2 - 15.0J/cm2; arcuate treatment zone. The Avedro KXL II™ System is used for the crosslinking after epithelial debridement in topical anesthesia and application of topical riboflavin every 3 minutes for 10 minutes.
Conventional pulsed CXL (pCXL)	Conventional pulsed CXL (pCXL)	Conventional pulsed corneal crosslinking; 1 second on, 1 second off; 5.4 J/cm2; 8 mm central treatment zone. The Avedro KXL II™ System is used for the crosslinking after epithelial debridement in topical anesthesia and application of topical riboflavin every 3 minutes for 10 minutes.
Conventional pulsed CXL (pCXL)	Avedro KXL II	Conventional pulsed corneal crosslinking; 1 second on, 1 second off; 5.4 J/cm2; 8 mm central treatment zone. The Avedro KXL II™ System is used for the crosslinking after epithelial debridement in topical anesthesia and application of topical riboflavin every 3 minutes for 10 minutes.
Topography-based CXL (KXL2)	Riboflavin	Individualized pulsed topography-based corneal crosslinking; 1 second on, 1 second off; 7.2J/cm2 - 15.0J/cm2; arcuate treatment zone. The Avedro KXL II™ System is used for the crosslinking after epithelial debridement in topical anesthesia and application of topical riboflavin every 3 minutes for 10 minutes.
Conventional pulsed CXL (pCXL)	Riboflavin	Conventional pulsed corneal crosslinking; 1 second on, 1 second off; 5.4 J/cm2; 8 mm central treatment zone. The Avedro KXL II™ System is used for the crosslinking after epithelial debridement in topical anesthesia and application of topical riboflavin every 3 minutes for 10 minutes.

Primary Outcome Measures

Name	Time	Method
Change from baseline in refraction	1, 3, 6 and 12 months after the treatment	Change from baseline in refractive errors, including lower and higher order aberrations in the cornea.

Secondary Outcome Measures

Name	Time	Method
Change from baseline in corneal endothelial morphometry	1, 3, 6 and 12 months after the treatment	Change from baseline in corneal endothelial morphometry, including cell density.
Change from baseline in ETDRS LogMAR visual acuity	1, 3, 6 and 12 months after the treatment	Changes from baseline in uncorrected and best spectacle corrected visual acuity assessed with the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol, graded in logarithmic values of the minimal angle of resolution.
Change from baseline in corneal densitometry	1, 3, 6 and 12 months after the treatment	Change from baseline in corneal densitometry (corneal light backscatter), assessed with the Oculus Pentacam HR® rotating Scheimpflug camera.; assessed with the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol, graded in logarithmic values of the minimal angle of resolution.
Change from baseline in corneal biomechanical stability measured with GAT	1, 3, 6 and 12 months after the treatment	Change from baseline in biomechanical stability assessed with the Goldmann applanation tonometer (GAT).
Change from baseline in corneal biomechanical stability measured with CorVis®	1, 3, 6 and 12 months after the treatment	Change from baseline in biomechanical stability assessed with the Oculus CorVis high-speed Scheimpflug camera.