Perfluorohexyloctane in dry eye disease: A systematic review of its efficacy and safety as a novel therapeutic agent

Revised Manuscript--Clean Copy No Highlighted Changes Click here to view linked References This is an Accepted Manuscript of an article published by Elsevier in Ocular Surface 30, 254 - 262 on October 2023, available at: https://doi.org/10.1016/j.jtos.2023.10.001 . It is deposited under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way. 1 2 3 4 5 Title 6 Perfluorohexyloctane in Dry Eye Disease: A Systematic Review of its Efficacy and Safety as a 7 Novel Therapeutic Agent 4 5 Authors 6 Antonio Ballesteros-Sánchez a, b, ⁎ , OD, MSc, PhD candidate 7 Concepción De-Hita-Cantalejo a, OD, PhD 8 María Carmen Sánchez-González a, OD, PhD 9 Zane Jansone-Langine c, d, OD, PhD 10 Maria Alvarez de Sotomayor e, PharmD, PhD 11 Josip Culig f, MD, PhD 12 José-María Sánchez-González a, OD, PhD 13 14 Affiliations 15 a Department of Physics of Condensed Matter, Optics Area, University of Seville, Seville, Spain. 16 b Department of Ophthalmology, Clínica Novovisión, Murcia, Spain. 17 c University of Latvia, Jelgavas street 1, Riga, Latvia. 18 d The Dr. Solomatin Eye Center, Marijas street 2, Riga, Latvia. 19 e Pharmacology Department, Faculty of Pharmacy, University of Seville, 41012 Seville, Spain. 20 f Department of Medicine and Clinical Pharmacology, University of Applied Health Sciences, 21 Zagreb, Croatia. 22 23 24 25 ⁎ 26 27 28 29 30 Corresponding author 31 Antonio Ballesteros-Sánchez, OD, MSc, PhD Candidate. Reina Mercedes Street. University of 32 Seville, Seville, Spain. Telephone: +34 617 70 05 30. E-mail: [email protected] 28 29 Abstract 30 Perfluorohexyloctane (F6H8), a physically and chemically inert synthetic compound, has 31 recently emerged as a promising candidate for the treatment of DED due to its unique 32 properties. A systematic review that only include full-length randomized controlled 33 studies (RCTs), reporting the effects of F6H8 in three databases, PubMed, Scopus and 34 Web of Science, was performed according to the PRISMA statement. The search period 35 was performed between June 1, 2023, and June 21, 2023. The Cochrane risk of bias tool 36 was used to analyze the quality of the studies selected. A total of six RCTs were included 37 in this systematic review. F6H8 tear substitutes treatment achieved a higher improvement 38 than control group interventions in most of the reported variables. The mean differences 39 between both groups were in favor of F6H8 and were as follow: eye dryness score (EDS) 40 base on a visual analogue scale (VAS) of -6.12 ± 4.3 points, ocular surface disease index 41 (OSDI) questionnaire score of -2.8 ± 2.3 points, lipid layer thickness (LLT) of 11.4 ± 10.4 42 μm, total corneal fluorescein staining (tCFS) of -0.8 ± 0.3 points and ocular treatment- 43 emergent adverse events (TEAEs) of -0.66 ± 1.7. Tear film break-up time (TBUT) was 44 the only variable in favor of control group with a mean of -0.5 ± 0.4 s. Patient satisfaction 45 after F6H8 tear substitutes treatment was high. Therefore, F6H8 tear substitutes improve 46 dry eye symptoms and signs with a satisfactory tolerability and could be recommended 47 in patients with DED. 48 49 50 51 52 53 KEYWORDS 54 perfluorohexyloctane; tear substitutes; dry eye disease; meibomian gland dysfunction. 55 1. Introduction 56 Dry eye disease (DED) is a prevalent ocular disease characterized by symptoms such as 57 ocular discomfort, visual disturbances, and tear film instability [1]. It affects a substantial 58 proportion of the population and presents significant challenges in terms of diagnosis and 59 management [2]. Despite the availability of various treatment options, there is a need for 60 more effective therapeutic agents to ameliorate symptoms and improve the quality of life 61 of patients with DED [3]. The multifactorial nature of DED presents complexities in its 62 treatment [4]. The underlying causes can include tear deficiency, excessive tear 63 evaporation, or a combination of both [5]. In addition, DED may coexist with conditions 64 such as meibomian gland dysfunction (MGD) or autoimmune diseases, complicating 65 management strategies [5–7]. These challenges suggest the need for novel therapeutic 66 agents that target specific mechanisms involved in the pathogenesis of DED [5,7,8]. 67 Perfluorohexyloctane (F6H8) has emerged as a promising candidate for the treatment of 68 DED [9,10]. F6H8 is a physically and chemically inert synthetic compound that has 69 unique properties that make it suitable for ocular applications [11]. Its excellent 70 biocompatibility [12–14], low surface tension [11,15], and high lipid affinity [14] make 71 it a potential therapeutic agent capable of addressing tear film instability and improving 72 ocular surface health in patients with DED [16]. F6H8 has been on the market since 2015 73 as an approved medical device in Europe, Australia, and New Zealand, and gained FDA 74 approval as a drug for use in the United States in 2023. The assessment of F6H8 efficacy 75 and safety in DED is of paramount significance [17]. By evaluating its therapeutic effects, 76 as well as adverse events and tolerability, it is possible to determine its potential benefits 77 and clinical relevance [18,19] 78 To date some published studies have evaluated the effects of F6H8 tear substitutes in DED 79 [9–14,18–20]. However, to the best of our knowledge, no systematic reviews have 80 explored the available literature regarding the benefits of F6H8 tear substitutes treatment. 81 Therefore, the objective of this systematic review is to evaluate the efficacy and safety of 82 F6H8 tear substitutes in the management of DED based on the available randomized 83 controlled trials (RCTs) Through this review, we aim to provide a comprehensive 84 overview of the current evidence on F6H8, enabling evidence-based decision making and 85 guiding future research directions. 86 2. Method of Literature Search 87 2.1 Data sources and search strategy 88 This systematic review was performed according to the Preferred Reporting Items for 89 Systematic Reviews and Meta-Analyses (PRISMA) [21,22]. We identified 56 articles 90 published before June 21, 2023, through the following databases: PubMed, Scopus and 91 Web of science. The data search strategy with Boolean operators was as follows: 92 (perfluorohexyloctane OR NOV03 OR F6H8 eye drops) AND (dry eye disease OR DED 93 OR evaporative dry eye OR EDE OR aqueous-deficient dry eye OR ADDE OR 94 meibomian gland dysfunction OR MGD). The references of the retrieved articles were 95 reviewed to identify other related studies if they met the inclusion criteria. 96 2.2 Study selection 97 All those 56 articles identified through the search strategy were considered and analyzed. 98 Duplicate studies were removed by DistillerSR software (DistillerSR Inc., Ottawa, 99 Canada) [23]. The remaining studies underwent additional screening stages, which 100 included title screening, abstract screening, and full-text screening. Studies unrelated to 101 the topic were excluded from the review during title and abstract screening. Full-text 102 screening studies that did not include F6H8 tear substitutes treatment was also excluded 103 from the review. These studies were reviewed by two investigators (ABS and JMSG) who 104 selected them according to the inclusion and exclusion criteria. The inclusion criteria were 105 as follows: human studies, full-length original articles and prospective randomized 106 controlled studies. The exclusion criteria included non-English publications and 107 unindexed journals. There were no restrictions placed on the country in which the study 108 was performed, the follow-up period, the sample size or results of the studies. 109 2.3 Quality assessment and data extraction 110 The data from each study were collected and summarized independently in tables 111 designed by two researchers (ABS and JMSG). The following information was obtained 112 from each article: (1) author and date of publication (year), (2) study design, (3) mean 113 follow-up of all patients in the whole procedure (expressed in months), (4) number of 114 patients, (5) mean age of the patients (expressed in years), (6) patient sex (male/female), 115 (7) number of eyes involved, (8) study group intervention, (9) control group intervention, 116 (10) F6H8 posology and (11) conflicts of interest. 117 Regarding the results of the studies, the following date were collected: (12) eye dryness 118 score based on a visual analog scale (EDS, values from 0 to 100) [24], (13) ocular surface 119 disease index (OSDI, values from 0 to 100) [25]; (14) tear break-up time (TBUT, 120 expressed in seconds, s); (15) lipid layer thickness (LLT, expressed in micron, μm); (16) 121 Schirmer test (ST, expressed in millimeters, mm]; (17) total corneal fluorescein staining 122 (tCFS), which tCFS was defined as the sum of fluorescein staining in 5 areas (inferior, 123 superior, central, nasal and temporal) with a maximum score of 15 points [20]. 124 Fluorescein staining in each area was assessed with the National Eye Institute scale from 125 grade 0 (no staining) to grade 3 (heavy staining) [26]; (18) meiboscore, which was defined 126 as the sum of meibomian gland expression in 5 central meibomian glands on the lower 127 eyelid with a maximum score of 15 points [27]. Meibomian gland expression was grade 128 from 0 to 3, where grade 0 is normal meibum, grade 1 is turbid oil meibum, grade 2 is 129 turbid and viscous oil appearance meibum and grade 3 is toothpaste-like consistency 130 meibum or no expression [18]; (19) ocular treatment-emergent adverse events (TEAEs) 131 (expressed as percentages); (20) patient satisfaction ranging from 0 (no acceptance) to 10 132 (high acceptance) and finally (21) authors judgment expressed by commenting in favor 133 or against of F6H8 tear substitutes treatment. Data synthesis was performed according to 134 the Cochrane guideline for synthesis without meta-analysis (SWiM) [28]. Baseline and 135 last visit values for all these variables were collected in the treatment (T) and control (C) 136 groups. Intra-group clinical outcomes were defined as “Last visit (LV) – Baseline (B) 137 differences”. Inter-group clinical outcomes were defined as “T group (LV–B) – C group (LV– 138 B) differences”. Mean ± SD for each variable were calculated to report intra-group and 139 inter-group clinical outcomes. 140 The literature that remained after full-text screening was examined to assess the quality 141 of the studies. To avoid the risk of bias, two dependable authors created a synopsis based 142 on the Cochrane risk of bias tool [29], which includes the following items: (1) random 143 sequence generation, (2) allocation concealment, (3) blinding of participants and 144 personnel, (4) blinding of outcome assessment, (5) incomplete outcome data, (6) selective 145 reporting and (7) other sources of bias. A third nonblinded assessor decided the quality of 146 the studies when disagreements occurred between the two assessors. 147 3. Results 148 3.1 Study characteristics 149 The study selection process of this systematic review is presented with a flowchart 150 diagram in Fig. 1. The design of the included studies was prospective randomized 151 controlled trials published between 2020 and 2023. This systematic review included 1965 152 eyes from 1965 patients with a mean age of 46.4 ± 16.1 years. The sex distribution was 153 1477 females (75.1%) and 488 males (24.9%). Patient follow-up, expressed in months, 154 ranged from 1 month [12] to 3 months [19], with a mean follow-up of 2 ± 0.6 months. 155 Regarding study group intervention, 4 studies used NOV03 (Novaliq GmbH, Heidelberg, 156 Germany) [13,14,18,20], 1 study used NovaTears (Novaliq GmbH, Heidelberg, 157 Germany) [12] and 1 study used EvoTears (Ursapharm GmbH, Saarbrücken, Germany) 158 [19]. Across the studies, various brand names such as NOV03, NovaTears, and EvoTears 159 were used. However, it should be noted that all these formulations are based on the active 160 ingredient F6H8. Different interventions were used in the control group, such as saline 161 solution (sodium chloride, NaCl 0.6% or 0.9%) [12–14,18,20], and cationic emulsion 162 (mineral oils, MOs 0.5%) [19]. Five studies had conflicts of interest by the authors 163 (supported by Novaliq GmbH, Heidelberg, Germany) [12–14,18,20]. More detailed study 164 characteristics and tear substitutes composition are presented in Table 1. 165 3.2 Outcomes 166 Regarding efficacy outcomes, 5 studies reported dry eye symptom outcomes [12– 167 14,18,20], of which 3 studies used the OSDI questionnaire [12,14,18], while all studies 168 used the EDS [12–14,18,20]. All studies also reported dry eye sign outcomes, of which 3 169 studies evaluated TBUT [12,14,18], 2 studies assessed LLT [12,19], 5 studies evaluated 170 tCFS [12–14,18,20] and 1 study assessed ST and meiboscore [14]. Regarding safety 171 outcomes, 5 studies reported ocular TEAEs [12–14,18,20], while patient satisfaction was 172 reported by 1 study [14]. 173 Intra-group clinical outcomes are presented in Tables 2 and 3. Regarding treatment group, 174 most of the outcomes achieved an improvement, with a mean EDS of -24 ± 10.3 points, 175 mean OSDI questionnaire score of -14.9 ± 10.9 points, mean TBUT of 3.6 ± 1,6 s, mean 176 LLT of 16.7 ± 4.2 μm and mean tCFS of -2.1 ± 0.9 points. The meiboscore also achieved 177 an improvement of -2.1 points, while ST showed a worsening of -1 mm. Regarding 178 control group, most of the outcomes also achieved an improvement, with a mean EDS of 179 -17.9 ± 6.4 points, mean OSDI questionnaire score of -12.2 ± 8.7 points, mean TBUT of 180 4.2 ± 2.1 s, mean LLT of 5.4 ± 6.3 μm and mean tCFS of -1.3 ± 0.7 points. The ST and 181 meiboscore also achieved an improvement of 0.3 mm and -1.8 points, respectively. 182 Inter-group clinical outcomes are presented in Table 4. Most of the outcomes were in 183 favor of the treatment group, with a mean EDS of -6.12 ± 4.3 points, mean OSDI 184 questionnaire score of -2.8 ± 2.3 points, mean LLT of 11.4 ± 10.4 μm and mean tCFS of 185 -0.8 ± 0.3 points. The meiboscore also achieved a treatment group improvement of -0.3 186 points compared to the control group. However, TBUT and ST were in favor of control 187 group with a mean of -0.5 ± 0.4 s and -1.3 mm, respectively. Regarding adverse events, 188 the treatment group reported that ocular TEAEs was 0.66 ± 1.7 % lower than the control 189 group. In addition, patient satisfaction was 0.9 points higher in the treatment group 190 compared to the control group. 191 3.3 Risk of bias 192 The risk of bias summary of the included studies is presented in Fig. 2. Risk of bias 193 assessment was classified into three evidence level groups: (1) studies with a low risk of 194 bias (Tauber et al. (2021) [18], Tauber et al. (2023) [20], Sheppard et al. [13] and Tian et 195 al. [14]), (2) studies with an unclear risk of bias (Schmidl et al. [12] and Habbe et al. [19]) 196 and (3) studies with a high risk of bias (no studies). The overall risk of bias summary of 197 the domains used in each study is presented in Fig. 3. The items used to assess the risk of 198 bias showed an overall low risk of bias, which was of 68%. Therefore, no study was 199 excluded due to risk of bias. The Robvis tool (NIHR, Bristol, UK) was used to create risk 200 of bias assessment figures [30]. 201 4. Discussion 202 Tear film hyperosmolarity is considered the trigger for the ocular surface inflammatory 203 mechanism resulting in the dry eye symptoms and signs [5,31,32]. Tear substitutes are 345 References 346 [1] Nelson JD, Craig JP, Akpek EK, Azar DT, Belmonte C, Bron AJ, et al. TFOS 347 DEWS II Introduction. Ocul Surf 2017;15:269–75. 348 https://doi.org/10.1016/j.jtos.2017.05.005. 349 [2] Stapleton F, Alves M, Bunya VY, Jalbert I, Lekhanont K, Malet F, et al. 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Author (Date) Assessment EDS (0-100) OSDI TBUT, s LLT, μm ST, mm (0-100) tCFS (0-15) Meiboscore (0-15) Ocular TEAEs, % Satisfaction (0-10) Schmidl et al. [12] 2020 Tauber et al. [18] 2021 Habbe et al. [19] 2023 Sheppard et al. [13] 2023 Tauber et al. [20] 2023 Tian et al. [14] 2023 Baseline 32 ± 14 40 ± 14 9.4 ± 5.4 71.4 ± 16.3 NR 3.8 ± 1,4 NR - - Last visit 20.2 ± 17.3 30.4 ± 21.6 14.8 ± 5.3 83 ± 16.4 NR 3.1 ± 1.6 NR 20.8 NR Difference LV-B -11.8 -9.6 5.7* 11.6 - -0.7 - - - Baseline 66.8 ± 21.7 54 ± 16.9 3 ± 0.9 NR 14.3 ± 8.8 6.7 ± 2 8 ± 3.9 - - Last visit 56.8 ± 18.7 51 ± 9.2 NR NR NR 5.8 ± 1.8 NR 11.7 NR Difference LV-B - 10.7* -3 - - - -0.9* - - - Baseline NR NR 9.9 ± 5.3 51.3 ± 6.7 NR NR NR - - Last visit NR NR 15.5 ± 5.6 50.4 ± 5.5 NR NR NR NR NR Difference LV-B - - 5.6* -0.9 - - - - - Baseline 64.3 ± 19.5 55.8 ± 17.2 3.1 ± 0.9 NR 12.8 ± 7.9 7.1 ± 2.1 8.1 ± 3.5 - - Last visit 45.3 ± 16.5 NR NR NR NR 6 ± 1.9 NR 12.3 NR Difference LV-B -19* - - - - -1.1* - - - Baseline 66.8 ± 18.7 54.4 ± 17 3.3 ± 0.8 NR 11 ± 7.6 6.7 ± 1.9 7.7 ± 3.2 - - Last visit 47.1 ± 17.4 NR NR NR NR 5.7 ± 2 NR 7.5 NR Difference LV-B -19.7* - - - - -1* - - - Baseline 65.6 ± 16.5 56.2 ± 16.6 2.8 ± 0.9 NR 13.2 ± 7 6.3 ± 1.7 8.4 ± 3.8 - - Last visit 37.3 ± 20.9 32.3 ± 17.3 4.1 ± 2.3 NR 13.5 ± 6.2 3.6 ± 2.4 6.6 ± 3.5 15.4 7.5 ± 2.0 Difference LV-B -28.3* -23.9* 1.3* - 0.3 -2.7* -1.8* - - Mean ± SD LV-B -17.9 ± 6.4a -12.2 ± 8.7a 4.2 ± 2.1a 5.4 ± 6.3a - -1.3 ± 0.7a - 13.5 ± 4.4b - B, Baseline; EDS, Eye dryness score based on a visual analog scale; LLT, Lipid layer thickness; LV, Last visit; NR, Not reported; OSDI, Ocular surface disease; SD, Standard deviation; ST, Schirmer test; TBUT, tear break-up time; tCFS, Total corneal fluorescein staining; TEAEs, Treatment-emergent adverse events. * Statistical significance level P < 0.05. a Mean ± SD values of the difference LV-B for each variable. b Mean ± SD LV value for ocular TEAEs Table 4 Click here to access/download;Table (Editable version);Table 4.docx Table 4 Inter-group differences [T group LV-B) – (C group LV-B)] outcomes. Author (Date) Assessment EDS OSDI TBUT, s LLT, μm ST, mm tCFS Meiboscore Ocular Satisfaction F/A B, Baseline; EDS, Eye dryness score based on a visual analog scale; F/A, Favor or against; LLT, Lipid layer thickness; LV, Last visit; NR, Not reported; OSDI, Ocular surface disease; SD, Standard deviation; ST, Schirmer test; TBUT, tear break-up time; tCFS, Total corneal fluorescein staining; TEAEs, Treatment-emergent adverse events. * Statistical significance level P < 0.05. a Inter-group differences [(T group LV) – (C group LV)] outcomes. (0-100) (0-100) (0-15) (0-15) TEAEs, % (0-10) Schmidl et al. [12] T difference LV-B -12.8 -10.6 5.1* 12.5 - -1.3 - 17.6 - 2020 C difference LV-B -11.8 -9.6 5.7* 11.6 - -0.7 - 20.8 - F Difference T-C -1 -1 -0.6 0.9 - -0.6 - -3.2a - Tauber et al. [18] T difference LV-B -11.8* -4.3 - - - -1.2* - 11.4 - 2021 C difference LV-B -10.7* -3 - - - -0.9* - 11.7 - F Difference T-C -1.1 -1.3 - - - -0.3 - -0.3a - Habbe et al. [19] T difference LV-B - - 4.5* 20.9* - - - NR - 2023 C difference LV-B - - 5.6* -0.9 - - - NR - F Difference T-C - - -1.1 21.8 - - - - - Sheppard et al. [13] T difference LV-B -29.5* - - - - -2.3* - 12.9 - 2023 C difference LV-B -19* - - - - -1.1* - 12.3 - F Difference T-C -10.5 - - - - -1.2 - -0.6a - Tauber et al. [20] Baseline -27.4* - - - - -2* - 9.6 - 2023 Last visit -19.7* - - - - -1* - 7.5 - F Difference T-C -7.7 - - - - -1 - 2.1a - Tian et al. [14] T difference LV-B -38.6* -29.9* 1.4* - -1* -3.8* -2.1* 14.1 8.4 2023 C difference LV-B -28.3* -23.9* 1.3* - 0.3 -2.7* -1.8* 15.4 7.5 F Difference T-C -10.3 -6 0.1 - -1.3 -1.1 -0.3 -1.3a 0.9a