Soeters 2015.

Study characteristics
Methods	Study design: parallel‐group, randomized controlled trial Number randomized (total and per group): 61 eyes of 61 participants in total; 26 eyes of 26 participants to epi‐off CXL group, and 35 eyes of 35 participants to trans‐CXL group Unit of randomization (individual or eye): individual (1 eye per participant) Number analyzed (total and per group): not explicitly reported Unit of analysis (individual or eye): individual (1 eye per participant) Exclusions and losses to follow‐up (total and per group): 4 (6%) participants in total; 2 participants in each group were lost to follow‐up at the last follow‐up visit. 2 moved abroad; 1 received follow‐up care at another hospital; and 1 was retreated with epi‐off CXL 10 months after the initial trans‐CXL treatment. How were missing data handled?: not reported Length of follow‐up: 12 months Reported power calculation (Y/N), if yes, sample size and power: Y, power 80%, sample size 29 each group
Participants	Country: the Netherlands Setting: University Medical Center Utrecht, the Netherlands Baseline characteristics 1. Epithelium‐off CXL, n = 26 Age (mean ± SD, range): 25.9 ± 7.6 (18 to 44) years Gender: 19 men and 7 women Maximum K: 57.8 ± 7.1 D CDVA (logMAR): 0.3 ± 0.3 2. Transepithelial CXL, n = 35 Age (mean ± SD, range): 26.9 ± 8 (18 to 48) years Gender: 28 men and 7 women Maximum K: 56.4 ± 5.0 D CDVA (logMAR): 0.3 ± 0.3 Overall, n = 61 Age (mean ± SD, range): 26.5 ± 7.8 (18 to 48) years Gender: 47 men and 14 women Maximum K: 57.0 ± 6.0 D CDVA (logMAR): 0.3 ± 0.3 Inclusion criteria: age > 18 years, a clear central cornea, documented progression as defined by an increase in Kmax, Ksteep, mean keratometry, and/or topographic cylinder value by > 0.5 D over the previous 6 to 12 months Exclusion criteria: minimal pachymetry of less than 400 mm prior to UVA irradiation, pregnancy or breastfeeding, history of previous ocular infection Baseline equivalence: comparable, except a lower spherical equivalent (P = 0.04) and logMAR UDVA (P = 0.03) in the trans‐CXL group
Interventions	1. Transepithelial CXL Local anesthetic eye drops (oxybuprocaine 0.4% and tetracaine 1%) applied 3 times during 5 minutes, and Ricrolin TE solution (consisting of riboflavin 0.1% eye drops with dextran T500 15 mg and EDTA; Sooft Italia) instilled every 2 minutes for 15 minutes. Eyelid speculum placed and a silicone ring positioned between the eyelids; the ring filled with RicrolinTE and used to retain a Ricrolin "pool" on the cornea (silicone ring removed after 15 minutes). Cornea rinsed with balanced salt solution and pachymetry performed. UVA irradiation performed during 30 minutes while Ricrolin TE solution reapplied to the cornea every 5 minutes. 2. Epithelium‐off CXL Dresden protocol adjusted while avoiding the eyelid speculum during riboflavin instillation. Epithelial removal (9 mm) performed using a blunt knife. After pachymetry measurements, isotonic riboflavin 0.1% solution with 20% dextran (Medio Cross) applied every 3 minutes for 30 minutes, with no eyelid speculum in place. In case of pachymetry < 400 mm, hypo‐osmolar riboflavin additionally applied every 20 seconds for 5 minutes and repeated up to 2 times until the required pachymetry value of > 400 mm was achieved. With an eyelid speculum in place, UVA irradiation was performed for 30 minutes, during which isotonic riboflavin drops were given every 5 minutes.
Outcomes	Primary outcome: clinical stabilization of keratoconus 1 year after CXL, defined as a Kmax increase of no more than 1 D over the preoperative Kmax value Secondary outcomes: manifest refraction, UDVA, CDVA, corneal tomography; keratometry, demarcation line, endothelial cell density Adverse outcomes: Transepithelial CXL: no adverse events were recorded Epithelium‐off CXL: adverse events occurred in 4 of 26 eyes (15%). 1 eye developed a herpes simplex keratitis 1 week post‐CXL, which was adequately treated and did not result in visual acuity loss (pre‐ and post‐CXL decimal CDVA was 0.8) or scarring; 1 eye developed a sterile infiltrate, though a clear cornea was seen at the 1‐month follow‐up; 1 eye had epithelial healing problems and a small central haze spot in the anterior stroma 1 week post‐CXL, possibly associated with his periocular eczema (pre‐CXL decimal CDVA was 0.6; after 1 year, 0.8); 1 eye showed delayed epithelial healing leading to a ‘‘cloudy stroma’’ at the 3‐month follow‐up and a deep stromal haze at the 6‐month follow‐up (pre‐ and post‐CXL decimal CDVA was 0.1). Measurement time points: 1, 3, 6, and 12 months Other issues with outcome assessment (e.g. quality control for outcomes, if any): none
Notes	Study period: enrollment from 30 May 2011 through 4 September 2013 Publication language: English Trial registration: NCT02349165 Conflicts of interest: "The authors report no conflicts of interest in this work." Funding source: "N. Soeters, R.P.L. Wisse, and D.A. Godefrooij were supported by the Dr F.P. Fischer Stichting (Amersfoort, TheNetherlands). N. Soeters was supported by Stichting Nederlands Oogheelkundig Onderzoek (SNOO, Rotterdam, The Netherlands). The funding organizations had no role in the design or conduct of this research. They provided unrestricted grants."
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of random sequence generation was not reported. "Patients were randomized using a simple unrestricted randomization procedure to either transepithelial CXL or epi‐off CXL."
Allocation concealment (selection bias)	Unclear risk	Authors reported that "sealed envelopes in a box" were used (personal communication), but allocation concealment remains unclear.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label study (NCT02349165). "The unequal sample size in this (non‐double‐masked) study can be considered a limitation"
Blinding of outcome assessment (detection bias) All outcomes	High risk	Open‐label study (NCT02349165). "The unequal sample size in this (non‐double‐masked) study can be considered a limitation"
Incomplete outcome data (attrition bias) All outcomes	Low risk	4 (6.7%) participants did not complete 1‐year follow‐up (2 lost to follow‐up; 2 protocol deviation). Although intention‐to‐treat analysis was not explicitly reported, the description indicates that outcomes for all participants were included in the analysis.
Selective reporting (reporting bias)	Unclear risk	All prespecified outcomes were reported in the final report, except the data for demarcation line depth at 6 months.
Other bias	High risk	Participants in trans‐CXL group had lower spherical equivalent (P = 0.04) and logMAR UDVA (P = 0.03) at baseline.