Randomised controlled trial of corneal vs. scleral rigid gas permeable contact lenses for keratoconus and other ectatic corneal disorders

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Randomised controlled trial of corneal vs. scleral rigid gas permeable contact lenses for keratoconus and other ectatic corneal disorders Alexander Levita,b,c,d,*, Martin Benwellc, Bruce J.W. Evansb,c a

Barnard and Levit Optometrists, Zamenhof House, 58 Clifton Gardens, London, NW11 7EL, UK Institute of Optometry, 56-62 Newington Causeway, London, SE1 6DS, UK c London South Bank University, School of Health and Social Care, 103 Borough Rd, London, SE1 0AA, UK d Ophthalmology Department, Central Middlesex Hospital, Acton Ln, Park Royal, London, NW10 7NS, UK b

ARTICLE INFO

ABSTRACT

Keywords: Keratoconus Corneal contact lenses Scleral contact lenses Corneal ectasia

Purpose: To compare the comfort and visual performance of corneal rigid gas permeable contact lenses (CoL) and scleral rigid gas permeable contact lenses (SL) in participants with corneal ectasia, successfully wearing “habitual” CoL. Methods: In a randomised controlled trial (RCT) with a 2 × 2 crossover, 34 participants were recruited and randomised into two groups. Group 1 (sequence AB), were fitted in period 1, with new CoL and after a 4-week washout period, in which habitual CoL were worn, were fitted with and crossed-over to SL, period 2. Group 2 (sequence BA), were first fitted with SL in period 1 and after a washout period of 4 weeks, crossed-over to new CoL, period 2. The median lengths in weeks of Periods 1 and 2 were: 17.5 (IQR 12.4) and 14.5 (IQR 6.2) respectively. The outcome measures for visual performance were best corrected visual acuity and the contrast sensitivity function. Vision related quality of life (Qol) was assessed using the National Eye Institute Visual Function Questioannaire-25 and reported subjective perception of vision (SPV) and reported subjective perception of comfort (SPC) scores, recorded on a scale from 1–10. The final outcome measure was the selection of the preferred lens type at the completion of the RCT. Results: For the 30 who completed the trial, significantly higher SPC scores were found for SL compared to CoL (p = 0.002). Significantly higher SPC scores for CoL were found in participants who selected CoL as their preferred lens for future use, compared to those who selected SL (p = 0.009). All other outcomes exhibited no significant difference between the experimental lenses. There was no significant difference (p=0.86) in the proportion preferring CoL (53%) and SL (47%). Conclusion: Significantly better comfort was reported for SL compared with CoL. Significantly higher comfort in CoL was found in those who preferred CoL, than those who preferred SL. Successful CoL wearers whose SPC in CoL is <7 are likely to achieve better comfort with SL. On average, successful CoL wearers found SL more comfortable and there are unlikely to be any significant visual or visual Qol advantage or disadvantage in refitting successful CoL wearers with keratoconus and other corneal ectasia disorders, with SL and vice versa.

1. Introduction In cases of uncorrected regular and irregular astigmatism, the formation of an aqueous ‘lens’ in the post-lens tear film of rigid contact lenses neutralises 90 % of corneal astigmatism [1,2]. CoL bear on the cornea only, SL vault the cornea bearing entirely on the sclera, preventing detrimental mechanical interaction with the cornea [3]. CoL are considered the gold standard in the management of keratoconus [4]. Despite recent resurgence, SL use is limited to relatively few practitioners [3] managing advanced disease or as a problem solver for

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failed alternative contact lenses [5,6]. CoL exhibit inherent positional instability on the keratoconic cornea and require steeper than standard central curvature to fit the cone and a transition to the flatter peripheral curves. This distributes the lens weight in the corneal mid-periphery moderating the mechanical pressure on the cone [2]. CoL may cause chronic corneal epithelial trauma, which has been associated with the pathogenesis and progression of keratoconus [7,8], which led to critical reviews and refinements of CoL fitting techniques [9,10,1]. There are three CoL fitting philosophies for keratoconus; apical bearing, apical clearance, and three-point touch,

Corresponding author at: Ophthalmology Department, Central Middlesex Hospital, Acton Ln, Park Royal, London, NW10 7NS, UK. E-mail addresses: [email protected] (A. Levit), [email protected] (M. Benwell), [email protected] (B.J.W. Evans).

https://doi.org/10.1016/j.clae.2019.12.007 Received 18 August 2019; Received in revised form 7 December 2019; Accepted 7 December 2019 1367-0484/ © 2019 British Contact Lens Association. Published by Elsevier Ltd. All rights reserved.

Please cite this article as: Alexander Levit, Martin Benwell and Bruce J.W. Evans, Contact Lens and Anterior Eye, https://doi.org/10.1016/j.clae.2019.12.007

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which have been described in detail elsewhere [11,1,12,2]. However, Edrington et al., found apical bearing in 88 % and apical clearance in 12 %, of 808 patients in the Collaborative Longitudinal Evaluation of Keratoconus (CLEK) study [13]. The CLEK researchers reported that 53 % of eyes with apical bearing CoL exhibited corneal scarring, which was associated with decreased visual acuity and visual Qol [14], supporting Korb et al. These authors recommended to fit CoL with apical clearance to minimise corneal morbidity [15]. However, this recommendation was shown by Gundel et al., to cause significant corneal steepening in 14 eyes (47 %), consistent with worsening keratoconus [16]. Exacerbation of keratoconus was associated with increased risks of scarring [17,18], reduced visual acuity [18] and a reduction in Qol [19–21]. McMonnies concluded that the risk of scarring from flat-fitting CoL must be balanced against the risk of keratoconus progression caused by apical clearance. However, optimal divided support fit is difficult to achieve and maintain, due to the high level of accuracy required and the dynamic-progressive nature of keratoconus [25]. It seems reasonable to consider SL, which by vaulting the cornea prevent mechanical corneal insult [3,26,27], as management of choice for keratoconus. The recommendation to utilise modern SL only in advanced disease [6] or if all other options fail [28] was also expressed by earlier researchers [29–33]. Some modern researchers demonstrated high satisfaction when patients with keratoconus were refitted with SL from CoL [34,35] and suggested that scleral lenses are fitted earlier, possibly as the first option in keratoconus [35]. Modern SL design benefitted from recent findings of the non-rotationally symmetrical shaped sclera, with gradually increasing asymmetry along the 15 mm chord centred on the corneal apex [36]. Further improvements include the development of non-rotationally symmetrical haptics, which optimise lens weight distribution by scleral alignment and may improve visual acuity [37]. Refinements, include the application of front surface toric and wavefront corrections [38] in the rotationally stable lenses [39]. Known complications of SL wear include, difficulties with lens handling [40], limbal corneal bullae [41], suction due to lens seal-off, conjunctival prolapse, corneal epithelial bogging [42], mid-day lens fogging [43,44], hypoxia in SL fitted with excessive corneal clearance [45], increase in inflammatory bio-markers from post lens tear stagnation [46] and increased risk of glaucoma [47,48]. Research comparing SL with CoL is sparse and includes retrospective analyses of participants who were selected to be refitted with SL due to clinical needs [5,31,34,35,49], but no randomised controlled trials (RCT). A prospective randomised controlled trial is required to provide the strongest empirical evidence when comparing the 2 lens types. The RCT described here was conducted to establish whether significant differences in a number of outcome measures could be established, when comparing the performance of CoL versus SL in participants with corneal ectasia, who had been successfully managed with habitual CoL wear. It was hoped that the findings of this research may help to formulate the scope of SL utility in the management of keratoconus and other ectatic corneal disorders.

wearers, who are asymptomatic, with no clinical indications for refitting with alternative contact lenses. 3. Age 18–69. Exclusion criteria were patients with keratoconus who are satisfied with their unaided vision in both eyes and patients with additional eye disease which affects their vision. The research design chosen was RCT with a 2 × 2 crossover. RCT represents the gold standard quantitative design for evaluating healthcare interventions [51,52], the crossover compares intra-subject differences between the two randomised groups. This avoids problems of comparability with regard to confounding variables such as gender, race, age and other individual idiosyncrasy, as participants are their own controls [53], receiving different treatments during different time periods, by crossing over from one treatment to another during the course of the trial (Table 1). In a crossover design the analysis should take account of the period and sequence effects, which may be confounded with treatment effects, [53,54]. It is reasonable to assume that randomisation minimises sequence effects: the period effect must be accounted for due to possible changes of the participants during the intervals between the measurements, or through habituation to the measurement itself [55]. The possibility of a differential carryover effect must also be accounted for, although it is unlikely in chronic conditions such as keratoconus, under non-curative management, such as contact lenses and with the incorporation of a washout period [53,54]. The sample size was calculated conservatively, to enable a parallel study analysis should the crossover not be completed for all participants. LogMAR data from previous studies of contact lens correction in keratoconus [56–59,38], with 0.10 logMAR taken as a clinically significant change [60,61]. The sample size calculation indicated a minimum sample size of 15. The experimental contact lens was the SL, Zenlens™ manufactured in Boston XO2 material (Alden Optical / Bausch and Lomb, Kingstonupon-Thames, UK), the control was the CoL Rose K2™ manufactured in Menicon Z material (David Thomas/ Menicon, Northampton UK). These were fitted according to manufacturers' recommendations [62–64], to give optimal divided support in CoL and corneal clearance (≥200 μm) with scleral alignment in SL. Participants used their habitual lens solutions. The primary outcome measure was the monocular BCVA, using letter by letter logMAR scoring [65–67]. The secondary outcome measures were CSF, measured by the CSV-1000E [68]. Both visual outcomes were measured by repeated, 3 times each eye, forced choice method [69], by a masked examiner, with standardized uniform retro illumination of 85 cd/m² [70]. The other secondary outcomes were the validated Qol questionnaire [71,72] previously used in keratoconic contact lens wearers [19,20,73]. The SPV and SPC scales are non-validated, numeric rating scales, developed by the chief investigator and were graded at the end of the wearing period with each lens type. Each participant was asked by the chief investigator to “grade, from 1 to 10 (worst-best), their perception of their own comfort and vision in each eye with the experimental lens. Grade 1 being equivalent to a level of comfort / vision quality that is consistent with the lens being unwearable / unusable, respectively and grade 10, lens cannot be felt / optimal”, respectively. Although this approach is widely used in healthcare practice, we found no reported use of this scale in keratoconus research. The participants’ choice of one of the experimental lenses for future wear, was the final outcome. SPSS version 21 (IBM) was used for all statistical calculations. Analysis for normality was performed on all data and appropriate statistical tests for parametric and non-parametric data were employed in the descriptive and inferential statistics. Due to significantly higher logMAR Kendall’s tau correlation between the right and left eyes [0.663 (p = 0.01)] versus right and random left eye correlation [-0.102 (p = 0.478)], including both right and left eye monocular data as individual datapoints from each participant was inappropriate [74]. Therefore, the statistical analyses for the carryover, period and treatment effects were

2. Methods This research was approved by the NHS National Research Ethics Service of London-Camden and King’s Cross as well as the research ethics committees of London South Bank University and the Institute of Optometry. The study was registered with ClinicalTrials.gov and was in full compliance with Good Clinical Practice guidelines and the Declaration of Helsinki. Thirty-four participants were recruited from a clinic specialising in corneal ectatic disorders in a North London Hospital Eye Service Clinic (Fig. 1). The inclusion criteria were 1. Previous diagnosis of corneal ectasia by clinic ophthalmologists, which was confirmed by recognised corneal topography criteria [50]. 2. Candidates are successful CoL 2

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Fig. 1. Research flow diagram according to Consolidated Standards of Reporting Trials (CONSORT) [51,75]. Table 1 Sequence of Randomisation and crossover.

Table 2 Ethnicity demographics (age data presented as mean ± standard deviation).

Keratoconus Contact Lens Clinic Population Selection + Informed Consent Selected Participants Randomisation [Period 0] Group 1 (AB) Group 2 (BA) Baseline measurements and CoL fitting Baseline measurements and SL fitting Period 1 [Group 1, lens A], [Group 2 lens B] Median length 17.5 Interquartile Range (IQR) 12.4 weeks Outcome measures + refitting in SL Outcome measures + refitting in CoL Washout Period: wear of original CoL Length of 4 weeks Crossover to SL Crossover to CoL Period 2 [Group 1, lens B], [Group 2 lens A] Median length 14.5 (IQR 6.2) weeks Outcome measures, completion final lens Outcome measures, completion final choice lens choice

Race

N

%

Black African Asian Indian Black Afro Caribbean Caucasian white

5 13 3 9

16.7 43.3 10.0 30.0

% % % %

Age (years)

AAD (years)

43.8 ± 16.4 36.8 ± 12.1 32.3 ± 3.2 31.9 ± 7.0

18.8 22.5 22.3 25.2

± ± ± ±

3.4 4.5 4.7 9.9

ADD – Age at diagnosis.

median duration of CoL wear was 14.5 years (IQR = 12), neither of which varied with sex (p = 0.190). Participant ethnicities were broadly classified into 4 groups [76] (Table 2). 3.2. Corneal characteristics Keratoconus was the most prevalent corneal ectatic disorder, with 54 (93.1 %) of eyes affected. Two eyes (3.4 %) exhibited pellucid marginal degeneration. Of the 54 eyes with keratoconus, at the baseline assessment 33 eyes (56.9 %) featured a nipple type cone, 21 (36.2 %) eyes featured the oval type [77]. CXL treatment had been applied to 6 eyes (10.3 %) and 2 eyes (3.4 %) had been treated with Intrastromal Corneal Ring Segments (ICRS). Three corneal parameters were measured, Kmax maximal radius of curvature, pachymetry and Surface Regularity Index (SRI), Kmax Mean = 6.2 mm (±0.60), Pachymetry Mean=445.11 μm (±48.72). SRI Median = 1.54DS, (IQR = 0.40).

performed on the mean scores of the right and left eyes of each participant. For participants with only one eye fitted, that eye was analysed. 3. Results 3.1. Demographic data, descriptive statistics Research flow chart outlining recruitment and group allocation is presented below (Fig. 1). The sex distribution was 77 % (n = 23) males with median age of 34, (IQR = 13) and 23 % (n = 7) females, who were significantly older (p = 0.01), median age of 45 (IQR = 14) years. The population age range was 22–68 years with a median of 36 (IQR = 16) years. The study was completed by 13 and 17 participants in group 1 and 2 respectively (Fig. 1). Data were analysed from 56 eyes, using for each of the 26 bilateral participants averaged right and left eye visual data and 4 eyes of monocular participants. The median age at diagnosis (AAD) was 22y and the estimated

3.3. Randomised demographics No significant differences were observed in any of the demographics between the two randomized groups (Table 3), except corneal pachymetry, which was significantly lower (39.6 μm thinner) in group 1 [Mean = 423.20 (±45.10)] than in group 2 [Mean = 462.77 (±44.73)] (p = 0.002). 3

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Table 3 Randomised demographics. Measure

Groups

Difference p value

Group 1 N Gender Age Age at Diagnosis Duration Ethnicities Corneal metrics

Male Female

Mean (StdDev)

11 2

CoL wear Black African Asian Indian Black Afro Caribbean Caucasian white Kmax *Pachymetry SRI

3 5 1 4

39.5 (14.2) 23.2 (5.0)

Group 2 Median (IQR)

N 12 5

10.0 (22.0)

6.04 (0.47) 423.2 (45.1) 1.59 (0.24)

2 8 2 5

Mean (StdDev)

Median (IQR) 0.109

38.8 (9.3) 16.47 (6.63)

6.31 (0.59) 462.8 (44.7)

20.0 (8.0)

1.47 (0.48)

0.872 0.363 0.363 0.613

0.068 *0.002 0.252

4. Main outcomes, inferential statistics

4.1. Visual acuity

A possible carryover effect was identified for CSF only, described in more detail below. Graphical and statistical analyses [53,54] were used to investigate treatment effects (i.e., whether SL or CoL were superior). The summary of the main outcome measures is presented in Table 4.

The raw individual BCVA scores of the crossover group-by-period analysis are plotted in Fig. 2. The BCVA achieved with CoL was not significantly different to that with SL (p = 0.563) (Table 4 and Fig. 2).

Table 4 Inferential crossover statistics summary. Group 1 Measure ETDRS logMAR

CSF logCS all CPD

CSF logCS 6 CPD

Qol all Domains

Mean (StdDev)

Median (IQR)

T

Treatment effect Carryover effect C Period effect P

Treatment effect T Treatment effect P1 (G1) Treatment effect P1 (G2) Carryover effect C Period effect P Treatment effect T Treatment effect P1 (G1) Treatment effect P1 (G2) Treatment effect T Carryover effect C Period effect P

−0.01 (0.08) 0.14 (0.27)

0.0177 (0.08) A B

A B

Group 2

−0.035 (0.215) 1.46 (0.13) 1.56 (0.51) 2.89 (0.31)

Mean (StdDev)

0.0006 (0.07)

Median (IQR)

p value

0.00 (0.10) 0.03 (0.17)

0.563 0.281 0.541

0.03 (0.135)

0.05 (0.24)

−0.0285 (0.16) 1.75 (0.17) 1.84 (0.16)

3.15 (0.25)

0.316 0.070 0.00 (0.12)

0.0641 (0.14)

1.67 (10.53) 182.0 (20.23)

−0.92 (1.37)

−1.235 (1.98)

0.019* 0.711 0.104 0.110

−1.74 (9.23) 178.1 (32.97)

0.483 0.245 0.343

Qol Ocular pain

Treatment effect T Carryover effect C Period effect P

12.5 (37.5) 175 (56.25) 0.02 (0.21)

0.00 (25.0) 150.0 (75.0) 0.04 (0.16)

0.170 0.263 0.563

SPC

Treatment effect T Carryover effect C Period effect P

1.0 (2.25) 17.0 (1.50)

−1.0 (2.50) 16.0 (4.0)

0.002* 0.183 0.63

−0.50 (1.75) 16.0 (3.25) −0.50 (1.75)

0.213 0.592 0.157

−0.923 (±1.37)

SPV

Treatment effect T Carryover effect C Period effect P

Final lens choice

CoL SL

16 (53.3 %) 14 (46.7 %)

SPC CoL

CoL chosen 16 (53 %) SL chosen 14 (46.7 %)

Median (IQR) 9.0 (1.75) Median (IQR) 7.0 (1.54)

0.00 (0.50) 16.0 (4.75) 0.00 (0.50)

T

−1.235 (1.98)

0.009*

: Treatment effect was calculated by the difference between group 1 and 2 intrasubject scores difference in the 2 periods (Period 2 – Period 1) [54]. : Carry over effect was calculated by the difference between the intrasubject sums of scores of group 1 and 2 in the 2 periods (Period 1 + Period 1) [54]. P : Period effect was calculated by the difference between group 1 and 2 in the intrasubject scores difference between lens A (CoL) and lens B (SL) (A–B) [54]. A, B, Parallel group analysis calculated the difference in scores between the 2 groups in period 1 only. A = CoL, B = SL [54]. * P ≤ 0.05 Statistically significant. C

4

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with the literature as previous workers seem to have assumed that Qol data are normally distributed. There was no evidence of a significant differential carryover effect (p = 0.245) or period effect (p = 0.343). There was no significant difference (p = 0.483) between the experimental contact lenses with respect to their effect on the total (across all domains) Qol. 4.4. Subjective measures of comfort and vision There was no differential carryover effect (p = 0.183) and (p = 0.592) in SPC and SPV respectively and no significant period effect (p = 0.630) and (p = 0.157) in SPC and SPV respectively. The analysis of treatment effect indicates that the higher subjective perception of comfort score achieved with SL was statistically significant (p = 0.002) (Figs. 5 and 6). With respect to the SPV, no significant treatment effect difference was found (p = 0.213). Due to the statistically significant difference between the experimenta lenses in the SPC, an analysis of the conceptually related Qol ocular pain domain was performed (Table 4). The analysis supported the SPC findings, exhibiting better ocular pain scores with SL in group 1 only, but this did not reach statistical significance (p = 0.170). 4.5. Final lens choice At the end of the second experimental sequence participants were asked to choose either CoL or SL for future contact lens wear. Fourteen (46.7 %) participants chose SL and 16 (53.3 %) chose CoL as their preferred option. A Fisher’s exact test confirmed no statistically significant preference for one lens type (p = 0.86). The only statistically significant outcome in this experiment was the better SPC in SL compared to CoL. It was therefore decided to determine whether there was a significant association between the SPC in the experimental lenses and final lens choice (Table 4). We found a significantly higher SPC when wearing CoL in participants who chose CoL compared with the SPC in those who chose SL, both by parametric (p = 0.006) and non-parametric (p = 0.009) analyses. It is of note that no participant who selected to remain in CoL exhibited SPC < 7.0 in these lenses (Fig. 6). The higher SPC in SL in participants who chose SL [Median = 9.750, IQR = 1.3] compared to participants who chose CoL [Median = 9.00, IQR = 1.0], approached but did not reach statistical significance (p = 0.052). Despite the absence of a statistically significant carryover effect in the SPC, as a precaution it was decided to explore whether the sequence of contact lens wear had an effect on the SPC in CoL or the final lens choice. No statistically significant effect was found (p = 0.198). Similarly, a χ2 analysis confirmed that the sequence of lens wear had no significant effect on the final lens choice (p = 0.713).

Fig. 2. Mean OD/OS logMAR period 1 vs period 2, both groups, centroids (solid black).

4.2. Contrast sensitivity function The OD/OS averages of the LogCS data for CoL and SL revealed similar results across all spatial frequencies (Fig. 3) and the data were therefore averaged across spatial frequencies. The raw individual average OD/OS, mean of all CPD LogCS scores of both groups in both periods are presented in Fig. 4. The significant differential carryover effect (p = 0.019) is most likely an incidental finding (see discussion). As a precaution the analysis of the CSF data with respect to the treatment effect was performed in two ways: as a crossover trial, using data from both periods and as a parallel group trial, using data from the first period only. With both approaches, there was no significant treatment effect (p = 0.316and p = 0.070) respectively). 4.3. Visual quality of life Qol data were not normally distributed across the 12 domains investigated. However, means and SD were calculated for comparison

5. Discussion This is the first RCT comparing the performance of CoL and SL. A significantly better SPC score was observed for SL than CoL and significantly better SPC in CoL for participants who preferred CoL as their final lens choice, compared with those who preferred SL. No significant differences were found for visual performance and Qol between the two lens types. The main outcome measures are summarised in Table 4. 5.1. Best corrected visual acuity The BCVA results indicate that in patients with irregular cornea disorders such as keratoconus, who are successful CoL wearers, with no clinical indications for refitting with alternative contact lenses such as SL, the logMAR visual acuity is expected to be equivalent in both CoL and SL.

Fig. 3. LogCS scores and standard deviation CoL vs SL. 5

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Fig. 4. Individual participant’s logCS scores in group 1 periods 1[CoL] and 2 [SL] and Group 2 Periods 1 [SL] and 2 [CoL].

Fig. 5. Boxplots of subjective comfort scores in CoL and SL.

5.2. Contrast sensitivity Fig. 6. SPC in CoL in participants who chose CoL and SL.

The research population’s numerical scores of CS were lower at all four spatial frequencies than normative data [68,78]. A comparison with other keratoconic CoL wearers [79], exhibits lower scores in the Wei et al., (2011) keratoconic population, at 12 and 18 CPD, which may be due to the differences in the level of keratoconus, negatively affecting the higher resolution demands, at 12 and 18 CPD [logMAR 0.50 and 0.20 respectively]. The indication of a carryover effect for logCS scores (p = 0.019) is most likely related to the absolute differences in the logCS scores between the two groups (Fig. 5) and not due to period interaction.

Nevertheless, it was decided to analyse the LogCS treatment effect both according to a crossover study protocol and as a parallel group RCT. These analyses were concordant, confirming that there is no statistically significant difference in the performance of the two lens types, (p = 0.317) and (p = 0.070) respectively. Both methods of assessing visual performance in this research, the BCVA and the CSF, indicated that there was no statistically significant difference between the two experimental lenses with respect to 6

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participants’ visual performance. Similar visual results may be found in published research, [56–59,38]. Other research exploring CSF visual performance in both lens types; in CoL [79] and SL wearers [80] (28 keratoconic, 4 PMD and 8 corneal grafts), reported an identical mean logCS to this study. In their comprehensive review of optical considerations for SL, Vincent and Fadel (2019) acknowledged that, when used to manage complex corneal shapes, SL may provide superior visual acuity than CoL. However, they caution that the unique interaction between SL and the ocular adnexa may also lead to altered optical performance [37]. The visual outcomes in this research do not support the findings of Baran et al., (2012) and Bergmanson et al., (2016), who found superior visual performance in SL compared with CoL [34,35], nor the findings of Pullum and Buckley (1997), who reported that in some patients who were critical observers, vision was inferior when refitted into SL compared to their previous habitual CoL [31]. The most likely explanation for this difference is the study design and the population demographics. The present research is a crossover RCT, whereas the 3 studies mentioned above were retrospective analyses of participants who were selected to be refitted with SL due to clinical needs. The visual outcome results in the present research also indicate that patients who may require refitting from CoL to SL and vice versa, due to nonvisual clinical indications, such as reduced lens tolerance, should not be disadvantaged with respect to their vision from being refitted with either lens type.

5.5. Final lens choice Fourteen (47 %) of participants chose SL and 16 participants chose CoL (53 %). It is notable that despite the absence of significant differences in visual and visual Qol measures, almost 50 % of these habitual wearers of CoL chose to change to SL. Further analysis revealed significantly higher SPC in CoL compared to SL, in the participants who chose CoL as their preferred lenses (p < 0.01). This suggests that the SPC in CoL may be an important indicator of CoL performance in the population of this research. The possibility that the sequence of lens wear may have influenced final lens choice was excluded by the statistical equivalence in the number of participants choosing CoL and SL in the two randomised groups (p = 0.713). It is of note that the SPC score in 75 % (n = 12) of participants who chose CoL was ≥8, and none scored <7. Furthermore, in 57 % (n = 8) of previously successful CoL wearers, the SPC score was ≤7, and given an alternative they all chose SL. The other 43 % (n = 6), who chose SL despite scoring ≥7 in CoL, most likely chose SL due to a combination of other factors, such as improved vision and equal or better comfort. 5.6. Clinical significance The use of SL in advanced corneal ectasia management and /or as a problem solver [27,86,35], is well documented in the literature [29,87,31,32,88,89,5,35,90]. Due to significant advances in technology in recent years, the use of SL has undergone a revival in specialist contact lens practice [3,5]. This research attempted to determine whether the utility of SL may be expanded, as suggested by Bergmanson et al., (2016), from a problem solver to a first-choice lens for a neophyte keratoconic and/or a superior management option for a successful CoL wearer [35]. To address this question the participants selected for this research were all experienced, successful CoL wearers. Refitting these participants with SL enabled optimal comparison conditions between the two lens types. The SPC revealed significantly better comfort scores in SL. This finding is of significance because for the first time, well adapted, habitual CoL wearers are shown to exhibit better comfort scores with SL in a RCT. Furthermore, although SL are better tolerated by patients unable to tolerate CoL [5,35,49], the present research indicates that 47 % of successful, habitual CoL wearers, who demonstrate equivalent visual and Qol outcomes in both lens types, preferred SL for their future use. The most likely explanation for this, is that even in individuals who are successful and well adapted CoL wearers, the particular SL fitting features, may contribute to the significantly better comfort and frequent preference of SL. These fitting features include corneal clearance and therefore absence of lens cornea interaction, minimal lens mobility and eyelid interaction and the continued lubrication of the ocular surface covered by the lens. The clinical conundrum of how to effectively identify those successful CoL wearers who are most likely to benefit from being refitted with SL may to some degree have been answered by the SPC findings. Research participants who chose to remain in CoL had significantly higher comfort scores of ≥7.0, than those who switched to SL. If the present results can be replicated and the SPC is validated, then this method may be considered appropriate for the selection of patients for refitting with SL if their SPC score in CoL is < 7, even if no other indication for refitting is apparent. The finding in the present research that the CoL and SL, do not differ significantly in visual performance and visual Qol, may support practitioners’ decision to refit existing CoL wearers with SL and vice versa, or to fit a neophyte with either contact lens type, expecting equivalent lens performance with respect to vision and Qol and therefore, base their choice on other clinical aspects. In a neophyte such clinical aspects

5.3. Visual quality of life An assessment of Qol has been widely used in the monitoring of treatment efficacy in ocular disorders. The visual Qol impairment in keratoconus is equivalent in its severity to categories 3 and 4 macular degeneration [19]. Baran et al., (2012) re-fitted 43 keratoconics from CoL to SL and found a mean 27.6/100 points improvement in Qol scores, across the 12 domains (p < 0.001) [34]. Other researchers confirmed that CoL improved Qol in keratoconics [81]. Kymes et al., (2004) found significant score differences in Qol between keratoconic and non-keratoconic CoL wearers, for all 12 domains, (p < 0.05). The current research exhibited slightly better Qol scores compared with the keratoconics in Kymes et al., (2004), but still lower scores than the normative data of non-keratoconic CoL wearers in Walline et al., (2000) [19,82]. The current research found no significant difference in Qol with the two lens types (p = 0.483). This indicates that there would most likely be no significant advantage or disadvantage in the Qol, if successful CoL wearers with keratoconus are refitted with SL and vice versa. 5.4. Subjective measures of comfort and vision Numerical scales were found to be useful, repeatable and accurate when the visual quality is generally high [83] and may also be used for recording comfort levels due to ocular dryness [84]. The measurement of the sensation of experienced discomfort is inherently variable. Jalbert et al., reviewed the scales used to assess contact lens comfort and recommended that improved instruments need to be developed [85], since most studies used questionnaires validated for use in dry eye patients. The current research indicates that overall participants reported significantly (p = 0.002) better comfort in SL, with no period or lens wear sequence effects influencing this result. In view of the significant SPC finding, the Qol ocular pain domain, which represents general ocular pain in eye diseases although not directly related to perception of contact lens comfort, was compared in isolation, in the two experimental lenses. This analysis suggested better ocular pain scores in SL, which did not reach statistical significance (p = 0.170). 7

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may include an existing high ocular sensitivity, the presence of allergies, ocular surface disorders, dry eye disease, environmental dryness or other idiosyncratic features of ocular sensitivity. The above conclusions and recommendations may extend the utility of SL fitting not only beyond problem solving but also as recommended by Visser et al., (2016), that SL may achieve better vision and longer wearing time / comfort when factors which cause reduced lens tolerance are present. These factors include advanced corneal irregularity, significant tear film deficiency or an elevated corneal scar [6]. This recommendation may be extended to include reduced SPC in CoL to a level <7. The equivalence of the two lens types with respect to visual performance and visual Qol is important considering the challenge of fitting CoL in a way that does not risk compromising corneal integrity in corneal ectatic disorders [16,24,25,91]. Due to complete corneal vaulting it is reasonable to expect that SL may be more likely to avoid these problems. If there are long-term physiological advantages to SL, then the short-term equivalence in visual performance and visual Qol of SL and CoL demonstrated in the present research, may lead to the conclusion that SL may indeed be considered as the lens option of first choice in corneal ectatic disorders management. Further research is suggested to validate the SPC in keratoconic CoL wearers. In addition, due to the significantly better comfort achieved in SL in the population of this research, a crossover RCT comparing CoL to SL in neophyte keratoconics, would more specifically clarify the viability of using SL as a lens of first choice.

calculated power is 0.833 and α = 0.05. The specialist clinical setting of this research has both strengths and limitations. The strengths of such a setting are, the access to the specific population required for this research and minimisation of bias associated with non-specialist clinical settings with respect to disease severity range and experience of the treating professionals. The limitations of this setting are the challenges of allocating the extra time required for the additional examinations and the reliance on the contact lens fitting skills of a single practitioner, the chief investigator. The inequality between the genders in the population, may be significant due to poorer contact lens tolerance by older female participants [96,97] and alleviation of these symptoms by SL [6]. However, these effects are likely to be minimised by the crossover design. 7. Conclusions This research revealed significantly higher subjective comfort scores in SL than in CoL and also that participants who chose CoL as their future lenses, had significantly higher subjective comfort scores in CoL. Furthermore, no participant with SPC < 7, chose to remain in CoL. These findings indicate that for some wearers, SL afford superior comfort to CoL and habitual wearers of CoL are likely to prefer SL if their SPC with CoL is < 7. Patients with corneal ectasia managed with CoL, whose SPC are <7, may benefit from alternative contact lenses, such as SL even if no other clinical indications for refitting are present. If these findings are replicated and validated, the SPC instrument may be used routinely to establish whether an alternative contact lens management may be appropriate to further improve the contact lens experience of successful CoL wearers.

6. Strengths and limitations The main strength of this research is its design, as the causal inferences afforded by RCT provide the strongest empirical evidence of a treatment’s efficacy. The randomisation of participants and concealment of their allocation ensured that allocation bias and confounding of unknown variables were minimised. This was further enhanced by minimisation of the detection bias by performing visual data collection by practitioners who did not examine the participants and were naive to the type of lenses worn at the time. Furthermore, the chronicity of keratoconus and the non-curative nature of the experimental lenses, were appropriate for the crossover aspect of this research [92], which minimised the confounds of individual idiosyncrasies such as gender, age, race and disease severity [53,54]. As noted above, the research was single-masked. Participants could not be masked to the lens type; however, the research team took care to use neutral language in describing the lens options and not to suggest that one lens types may be preferable to the other. The potential disadvantages of RCTs were not significant in this research, dropout / attrition rate was low (4 participants; 12 %), the ethical considerations were appropriately addressed prior to the study commencement and there was sufficient prior knowledge about the clinically meaningful levels of improvement and expected variation of improvement in the sample size calculation [93]. The sample size was calculated conservatively to allow for the possibility of analysing the results from period 1 only as a parallel group RCT, in the unlikely event of discovering a significant differential carryover effect. Other limitations were the use of a non-validated tool for comfort assessment and the imbalance between the two randomised groups in the number of participants who completed the study (13 and 17 participants, in group 1 and 2, respectively), which occurred by chance and not due to any inherent differences between the two lens types. This imbalance also had no effect on the significance and power of the study. To maintain α = 0.05 and 0.80 power, the detectable change in visual acuity would alter from ±0.10 to ±0.107, which is insignificant since the H0 was rejected with the lower ±0.10 value. The effect on logCS outcome may be established by a post-hoc power calculation, taking the significant mean logCS difference as the normative value of 0.191 [94,95] and the current research’s standard deviation ±0.17, the

Disclosure The authors have no proprietary or commercial interest in the devices that were mentioned in this manuscript and used during the research work. This research did not receive any grant from funding agencies in the public, commercial, or not-for-profit sectors. All contact lenses were provided free-of-charge by the manufacturers, but the manufacturers had no input at any stage of the research. Acknowledgements The authors wish to thank Menicon David Thomas contact lens laboratory for manufacturing and supplying free of charge the CoL used in this research and to Bausch & Lomb and Alden Optical for manufacturing and supplying free of charge the SL used in this research. Special thanks to the research coordinator optometrist Mr Anthony Stanton and the clinical assistant optometrist Mr Daniel Gorjian for their help in research management and as naive data collectors. Thanks also to Dr Robert Marks, who designed and constructed the data entry system used in this research and Daniel Levit for his help with computer technology and to the consultant ophthalmic surgeon Mr Simon Levy for acting as research safety officer. We thank Dr Richard Armstrong for statistical advice at an early stage of the study. References [1] L. Szczotka-Flyn, W.J. Benjamin, G.E. Lowter, W.J. Benjamin (Ed.), Patients with keratoconus and irregular astigmatism, 2nd ed., Butterworth Heinemann, Elsevier, St. Louis, Misouri, 2006, pp. 1523–1558. [2] A. Watts, K. Colby, J.L. Alió (Ed.), Contact lenses for keratoconus, 1st ed, Springer, Switzerland, 2017, pp. 187–194, , https://doi.org/10.1007/978-3-319-43881-8_16. [3] E. van der Worp, D. Bornman, D.L. Ferreira, M. Faria-Ribeiro, N. Garcia-Porta, J.M. Gonzalez-Meijome, Modern scleral contact lenses: a review, Cont Lens Anterior Eye 37 (2014) 240–250 doi:10.1016/j.clae.2014.02.002. [4] D. Robertson, D.H. Cavanagh, Contact lens applications in corneal disease, in: J.H. Krachmer, M.J. Mannis, E.J. Holland (Eds.), Cornea fundamentals, diagnosis and management, 3rd ed, Mosby Elsevier, USA, 2011, pp. 1217–1229.

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