Title: KERALINK: Efficacy and safety of cross-linking in children with Keratoconus
Funder: Department of Health and Social Care

Abstract: The Keralink trial will examine efficacy and safety of corneal cross-linking (CXL) in children and young people, under 17 years, with progressive keratoconus, a disorder of shape of the cornea. In this age group no randomised controlled trial (RCT) has been undertaken. • Design: Multicentre single masked RCT - intervention arm to have CXL in one or both eyes followed by standard care, control arm to have standard care only. Follow-up for 18 months. • Target population: Progressive keratoconus patients aged <17 years. • Inclusion Criteria: •Aged 10-16 years with keratoconus progression confirmed in one or both eyes by Pentacam corneal topography. Progression will be defined as an increase of at least 1.5 dioptres in steepest keratometry value (Kmax) on corneal topography between two Pentacam examinations at least 3 months apart. •Patients and their parents/guardians must be sufficiently fluent in English to provide assent and informed consent and to complete the patient reported outcome measures •Patients must be willing to attend for follow up visits • Exclusion Criteria: •Advanced keratoconus as determined by apex corneal scarring •Apex corneal thickness <400µ •Maximum corneal curvature (Kmax) >60 dioptres •Rigid contact lens wear in both eyes and unable to abstain for 7 days pre-examinations •Corneal comorbidity •Down’s syndrome •Any clinical condition which the investigator considers would make the patient unsuitable for the trial, including pregnancy •Participation in other clinical trials which would materially impact on the Keralink study • Measurement of outcomes: Primary outcome measure is Kmax in the study eye at 18 months post randomisation Secondary outcomes will be (a) Keratoconus progression (yes/no) defined as >1.5D increase in Kmax from baseline (randomisation) to 18 months or requirement for change from spectacle to rigid contact lens correction of vision (b) Time to Keratoconus progression (c) uncorrected and best corrected visual acuity (measured as logMAR) (d) refraction (measured in dioptres of myopia and astigmatism) (e) central corneal thickness (ultrasound) (f) quality of life as assessed by CHU9D and VF-14 questionnaires • Sample size: A difference between the groups in the change in Kmax of 1.5D after 18 months would be a clinically important difference (based on Wittig-Silva et al. Ophthalmology 2014;121:812 - a RCT of CXL in adults). A sample size of 46 patients would be required to detect this difference at the 5% significance level with 90% power, assuming a SD of 1.5D. This estimate of SD is itself derived from data in the Wittig-Silva publication. If we specifically adjust the sample size to take account of 10% loss to follow up and up to 20% of the control arm cross-over to CXL or transplant, then our planned total sample size of 60 patients would still provide at least 80% power to detect the clinically important difference. • Project timetables including recruitment rate: Anticipated duration of the study is 42 months, allowing for 6 months trial set-up including regulatory approvals, 12 months recruitment in the 3 centres, 18 months follow-up of last recruited patients and 6 months for writing-up and trial completion. • Expertise in multidisciplinary team: Lead investigator and clinician collaborators in the 3 centres are consultant ophthalmologists; UCL Comprehensive Clinical Trials Unit, with additional context specific methodological expertise from Burr and Bunce, will support the trial in respect of trial design, organisation, staff recruitment, trial design and statistics advice; patient representation by the chair of the Keratoconus Group.

Lay abstract: Keratoconus is a long term eye disorder in which the normally round dome-shaped clear window of the eye (cornea) thins progressively leading to a cone-like bulge. This impairs the ability of the eye to focus and reduces vision. Corneal topography is an image analysis technique to map the shape of the cornea and can confirm keratoconus diagnosis even in very early disease. Onset is usually in teens or early 20s. In the early stages, spectacles or soft contact lenses are used. As the cornea becomes thinner and steeper, hard contact lenses, often uncomfortable and inconvenient, are required to correct vision. In advanced cases, corneal transplant surgery is needed. Keratoconus usually affects both eyes (although often unequally) and in most cases starts in late childhood or teens. As keratoconus progresses, it can impact greatly upon quality of life with reduced vision affecting the young person’s education, leisure activities and self-confidence and cause significant anxiety in parents. Our trial addresses a key priority from the views of over 2000 patients, their parents and clinicians – “What causes keratoconus to progress and can progression be prevented?” Corneal collagen cross-linking (CXL) is a new treatment that is believed to stop keratoconus getting worse. CXL involves removal of the epithelium (the surface layer) of the cornea, administration of riboflavin eye drops and exposure of the cornea to ultraviolet light. NICE, the body that approves new treatments for use in the NHS, has approved the use of CXL provided audit of outcomes is performed and encouraged further research on outcomes including visual acuity (clarity of vision), corneal topography and quality of life. Approval by NICE was based on evidence from studies in adults with limited data on children and young people (CYP). It is of particular interest to examine CXL in young patients as early onset is a risk factor for rapid progression and requirement for corneal transplant. If CXL works in stabilising keratoconus, this would avoid the need for hard contact lenses or corneal surgery, especially if the CXL effect is sustained lifelong. Two uncontrolled studies of CXL in keratoconus patients under 19 years are reported, each has limitations but do suggest that it does work. The Keralink study will examine, with a more robust design and longer follow-up, how safe is CXL and how well it works in CYP with progressive keratoconus compared with the usual care with spectacle/contact lens correction of vision. Patients under 17 with progressing keratoconus will be randomised to (a) receive CXL in one or both eyes followed by standard care or (b) standard care only (the control group). Follow-up will be for 18 months. The trial will recruit 60 CYP in Moorfields Eye Hospital (London), Sheffield and Liverpool. The main outcome measure will be the change in Kmax overall in the 2 groups between the start of the study and 18 months. Kmax is an indicator derived from corneal topography and changes in this measure indicate whether keratoconus is progressing or not. We will also measure Keratoconus progression (defined as more than 1.5 dioptres increase from entry into the study in Kmax) in individual patients, vision with and without glasses or contact lenses, refraction (the measurement for glasses or contact lenses), corneal thickness at the centre of the cornea, patient-reported visual function and quality of life. Safety of CXL will be monitored carefully.

Research activity codes: 6.1 PHARMACEUTICALS;6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: EYE