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Table 1 Characteristics of the 15 studies included in the review

From: Corneal collagen cross-linking epithelium-on vs. epithelium-off: a systematic review and meta-analysis

Authors, year Country Design Population/Sample size Comparison Epi-on CXL protocol Outcomes measures Follow-up
Vinciguerra et al. 2019 [47] Italy Prospective comparative non-randomized clinical study Adult with progressive keratoconuss /n = 60 20 S-CXL
20 I-CXL
20 I-SCXL
I-CXL:
Constant current set at 1 mA for 5 min, Ricrolin + , UVA 10 mW/cm2 for 9 min
CDVA, refraction, topography, HOAs, pachymetry, ECD 24 months
Lombardo et al. 2019 [48] Italy Prospective unmasked randomized controlled trial Adult with progressive keratoconus /
n = 34
12 standard CXL
22 T-ionto CXL
T-ionto CXL:
Current intensity set at 1.0 mA for 5 min, Ricrolin + , UVA 10 mW/cm2 for 9 min
UDVA, CDVA, refraction, contrast sensitivity, topography ECD, pachymetry, HOAs 24 months
Al Zubi et al. 2019 [49] Jordan Randomized control trial Adult with progressive keratoconus /
n = 80
40 epi-off CXL
40 transepithelial CXL
Transepithelial CXL:
0.1% riboflavin in 20% dextran for 30 min, UVA 3 mW/ cm2 for 30 min
UDVA, CDVA, pachymetry, topography 12 months
Iqbal et al. 2019 [50] Egypt Prospective multicenter controlled trial Pediatric with progressive keratoconus /
n = 271
91 S-CXL
92 A-CXL
88 T-CXL
T-CXL:
0.25% riboflavin, benzalkonium chloride and hydroxypropyl methylcellulose for 4.5 min, riboflavin 0.22% for 6 min, UVA 45 mW/cm2 for 5:20 min (pulsed)
UDVA, CDVA, refraction, topography, pachymetry 24 months
Rossi et al. 2018 [51] Italy Prospective clinical study Adult with progressive keratoconus /
n = 30
10 epi-off CXL
10 epi-on CXL
10 I-CXL
Epi-on CXL:
Ricrolin TE for 30 min, UVA 3 mW/ cm2 for 30 min
I-CXL:
Current intensity set at 1.0 mA for 5 min, Ricrolin + , UVA 10 mW/cm2 for 10 min
UDVA, CDVA, refraction, topography, HOAs, pachymetry, ECD 12 months
Jouve et al. 2017 [52] France Prospective observational non-randomized clinical study Adult with progressive keratoconus /
n = 80
40 C-CXL
40 I-CXL
I-CXL:
Current intensity set at 1.0 mA for 5 min, Ricrolin + , UVA 10 mW/cm2 for 9 min
CDVA, topography, pachymetry, confocal microscopy, demarcation line depth 24 months
Henriquez et al. 2017 [53] Peru Prospective cohort study Pediatric with progressive keratoconus /
n = 61
25 epi-off CXL
36 A-epi-on CXL
A-epi-on CXL:
0.25% riboflavin with 1.0% phosphate hydroxypropyl methylcellulose with 0.007% benzalkonium chloride for 30 min, UVA 18 mW/cm2 for 5 min
UCVA, BCVA, refraction, pachymetry, topography 12 months
Godefrooij et al. 2017 [54] Netherlands Noninferiority randomized clinical trial Adult with progressive keratoconus /
n = 61
26 epi-off CXL
35 transepithelial CXL
Transepithelial CXL:
Ricrolin TE for 30 min, UVA 3 mW/ cm2 for 30 min
UDVA, CDVA, refraction, HOAs, topography, pachymetry, ECD, demarcation line depth 12 months
Rush et al. 2017 [55] USA Prospective randomized controlled clinical trial Adult with progressive keratoconus /
n = 144
64 epi-off CXL
80 transepithelial CXL
Transepithelial CXL:
Riboflavin 0.25%, hydroxypropyl methylcellulose 1.2% and benzalkonium chloride 0.01% for 30 min, UVA 3 mW/ cm2 for 30 min
BCVA, topography, pachymetry 24 months
Eraslan et al. 2017 [56] Turkey Prospective comparative non-randomized interventional study Pediatric with progressive keratoconus /
n = 36
18 epi-off CXL
18 epi-on CXL
Epi-on CXL:
0.25% riboflavin, 1.2% hydroxypropyl methylcellulose and 0.01% benzalkonium chloride for 30 min, UVA 3 mW/cm2 for 30 min
UDVA, CDVA, topography, HOAs, pachymetry, demarcation line depth 24 months
Bikbova et al. 2016 [57] Russia Randomized controlled clinical study Adult with progressive keratoconus /
n = 149
73 standard CXL
76 transepithelial CXL
Transepithelial CXL:
Current intensity gradually increased from 0.2 to 1.0 mA for 10 min, Riboflavin 0.1%, UVA 3 mW/cm2 for 30 min
UDVA, CDVA, keratometry, topography, pachymetry, demarcation line depth, confocal microscopy 24 months
Vinciguerra et al. 2016 [58] Italy Prospective comparative non-randomized interventional study Adult with progressive keratoconus /
n = 40
20 S-CXL
20 I-CXL
I-CXL:
Constant current set at 1 mA for 5 min, Ricrolin, UVA 10 mW/cm2 for 9 min
CDVA, refraction, topography, HOAs, pachymetry, ECD 12 months
Al Fayez et al. 2015 [59] Saudi Arabia Prospective randomized parallel-group trial Adult with progressive keratoconus /
n = 70
36 epi-off CXL
34 transepithelial CXL
Transepithelial CXL:
Tetracaine 1% with benzalkonium chloride 0.02% every 2 min for 30 min, UVA 3 mW/cm2 for 30 min
UDVA, CDVA, pachymetry, ECD, topography, IOP 36 months
Rossi et al. 2015 [60] Italy Noninferiority randomized clinical trial Adult with progressive keratoconus/
n = 20
10 epi-off CXL
10 transepithelial CXL
Transepithelial CXL:
Ricrolin TE for 30 min, UVA 3 mW/ cm2 for 30 min
UDVA, CDVA, refraction, topography, HOAs, CCT, ECD 12 months
Soeters et al. 2015 [61] Netherlands Noninferiority randomized clinical trial Adult with progressive keratoconus /
n = 61
26 epi-off CXL
35 transepithelial CXL
Transepithelial CXL:
Ricrolin TE for 30 min, UVA 3 mW/ cm2 for 30 min
UDVA, CDVA, refraction, topography, pachymetry, ECD, demarcation line depth 12 months
  1. A-CXL accelerated epithelium-off cross-linking; A-epi-on CXL accelerated transepithelial corneal collagen cross-linking; BCVA best-corrected visual acuity; CDVA corrected distance visual acuity; CXL corneal collagen cross-linking; ECD endothelial cell density; HOA higher-order aberration; I-CXL iontophoresis corneal collagen cross-linking; I-SCXL iontophoresis with epithelium removal corneal collagen cross-linking; S-CXL standard corneal collagen cross-linking; T-CXL transepithelial epithelium-off cross-linking; T-ionto CXL transepithelial iontophoresis corneal cross-linking; UDVA uncorrected distance visual acuity
  2. In all the included trials, the control group was treated according to the standard epi-off CXL (Dresden protocol): central epithelial debridement, 0.1% riboflavin for 30 min, UVA 3 mW/cm2 for 30 min, total energy dose 5.4 J/cm2