Rossi 2018.

Study characteristics
Methods	Study design: parallel‐group, randomized controlled trial (3 arms) Number randomized (total and per group): 30 eyes of 30 participants; 10 eyes of 10 participants each group Unit of randomization (individual or eye): individual (1 eye per participant) Number analyzed (total and per group): 30 eyes of 30 participants; 10 eyes of 10 participants each group Unit of analysis (individual or eye): individual (1 per participant) Exclusions and losses to follow‐up (total and per group): none (personal communication) How were missing data handled?: not applicable Length of follow‐up: 12 months Reported power calculation (Y/N), if yes, sample size and power: not reported
Participants	Country: Italy Setting: University of Campania Baseline characteristics 1. Epithelium‐off CXL, n = 10 Age (mean ± SD, range): 30.4 ± 3 years Gender: 5 men and 5 women Maximum K: 57.89 ± 4.51 D (personal communication) CDVA (logMAR): 0.28 ± 0.13 (personal communication) 2. Transepithelial CXL, n = 10 Age (mean ± SD, range): 27.2 ± 5.5 years Gender: 5 men and 5 women Maximum K: 57.25 ± 6.49 D (personal communication) CDVA (logMAR): 0.22 ± 0.04 (personal communication) 3. Iontophoresis‐transepithelial CXL, n = 10 Age (mean ± SD, range): 28 ± 3.8 years Gender: 6 men and 4 women Maximum K: 53.55 ± 4.06 D (personal communication) CDVA (logMAR): 0.28 ± 0.12 (personal communication) Overall, n = 30 Age (mean ± SD, range): 28.5 ± 4.4 years Gender: 16 men and 14 women Maximum K: 56.2 ± 5.5 D CDVA (logMAR): 0.26 ± 0.11 Inclusion criteria: age >= 18 years; progressive keratoconus with a documented clinical and instrumental (topographic, pachymetric, or aberrometric) worsening in the previous 6 months of observation; thinnest corneal point >= 400 μm in epi‐off CXL and >= 360 μm epi‐on and iontophoresis‐CXL, a clear cornea on slit‐lamp and the absence of scar or severe Vogt striae, which can be considered predictive risk factors for postoperative haze development. The parameters defined to establish keratoconus progression were: worsening of UDVA and/or CDVA of more than 1 Snellen line, an increase in central corneal astigmatism of at least 1.00 D, an increase in the maximum cone apex curvature of at least 1.00 D, a reduction of at least 10 μm or more in the thinnest point. Exclusion criteria: any coexisting ocular disease or corneal opacities possibly affecting visual acuity; previous intraocular surgery; history of herpetic keratitis; severe dry eye; concomitant autoimmune diseases; any lens or retinal disease Baseline equivalence: baseline comparable
Interventions	1. Transepithelial CXL 1 drop of 1% pilocarpine administered 30 minutes before treatment. Cornea anesthetized with single‐dose anesthetic eye drops (4% lidocaine) 20 min before UV radiation. Corneal epithelial removal not performed. Corneal imbibition obtained with 0.1% riboflavin in 15% dextran solution supplemented with trometamol and ethylenediaminetetraacetic acid (EDTA) (Ricrolin TE; Sooft, Italy) by instillation of 2 drops every 5 min for 30 min at 3.0 mW/cm2. 2. Transepithelial CXL using iontophoresis Topical anesthesia instilling 4% lidocaine every 5 min 5 times before treatment. Pilocarpine 1% was instilled 30 min before the procedure. Impregnation of the cornea with a riboflavin hypotonic solution (specifically designed for I‐CXL, consisting of 0.1% riboflavin, no dextran, and the addition of EDTA and trometamol; Ricrolin+; Sooft, Italy) performed using the iontophoresis device. System formed by 2 electrodes and a connection cable: return electrode in the artificial system is a stainless steel wire; the electrode negative is a grid of steel contained in a corneal applicator (Iontofor CXL, Sooft, Italy). Eye adherence of the corneal applicator maintained with a vacuum system; the grid steel (negative electrode) was covered with riboflavin 0.1% (Ricrolin+; Sooft, Italy) Electrical generator with power of 1 mA (total time that the riboflavin solution was administered by iontophoresis: 5 min) Corneal irradiation performed with a source of UVA 370 nm (UV‐X System; Peschke Meditrade GmbH, Hüenenberg, Switzerland) at 10 mW/cm2 for 10 min. Hypotonic riboflavin 0.1% drops continued every 2 min during UVA exposure. 3. Epithelium‐off CXL Topical anesthesia: 4% lidocaine and 1.0% pilocarpine instilled Mechanical corneal epithelium removal over 9.0 mm Riboflavin (0.1% in 20% dextran solution; Ricrolin; Sooft, Italy) administered topically every 2 min for 30 min, which continued every 2 min during UVA exposure. Cornea exposed to UVA 370‐nanometer light (UV‐X System; Peschke Meditrade GmbH, Hünenberg, Switzerland) for 30 min at an irradiance of 3.0 mW/ cm2. "All patients were discharged with topical tobramycin to apply four times a day for 1 week, dexamethasone phosphate 0.1% four times a day for 2 weeks, then tapering to zero. Orally, amino acids (Aminoftal, SOOFT, Italy) were administered for 2 weeks... . Topical hyaluronic 3 times a day was administered for 3 months. All patients were operated by same surgeon."
Outcomes	Primary outcome: examination (spherical error, spherical equivalent), corneal topography (corneal astigmatism, flattest meridian keratometry, steepest meridian keratometry, mean keratometry, apex keratometry, superior‐inferior corneal symmetry index), aberrometry (spherical aberration, coma and root‐mean‐square), central corneal thickness and endothelial cell density. All intra‐ and postoperative adverse events were recorded. Secondary outcomes: not distinguished Adverse outcomes: no ocular or systemic adverse event was observed. No corneal edema, no haze, and no re‐epithelialization delay were noticed. Eye pain was reported in participants in the epi‐off CXL group in the early postoperative correlated with the sudden corneal de‐epithelialization. Measurement time points: 12 months Other issues with outcome assessment (e.g. quality control for outcomes, if any): none
Notes	Study period: not reported Publication language: English Trial registration: not found Conflicts of interest: "The authors declare that they have no conflict of interest." Funding source: "The study had no funding." (personal communication)
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Randomization was done by a computer‐generated random number list prepared by an investigator with no clinical involvement" (personal communication)
Allocation concealment (selection bias)	Unclear risk	Allocation concealment before assignment was not reported.
Blinding of participants and personnel (performance bias) All outcomes	High risk	"Patient and the surgeon responsible for the treatment were aware of the allocated arm, technicians and physicians performing the other clinical investigations and data analysts were kept blinded to the allocation." (personal communication)
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"Patient and the surgeon responsible for the treatment were aware of the allocated arm, technicians and physicians performing the other clinical investigations and data analysts were kept blinded to the allocation." (personal communication)
Incomplete outcome data (attrition bias) All outcomes	Low risk	"No patients were lost in our study. All the participants had the scheduled follow up examinations." (personal communication)
Selective reporting (reporting bias)	Unclear risk	Neither protocol nor trial registry was available.
Other bias	Low risk	None identified.