Clinical Ophthalmology
`
`Open Access Full Text Article
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`Dovepress
`open access to scientific and medical research
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`R E V I E W
`
`A Decade of Effective Dry Eye Disease
`Management with Systane Ultra (Polyethylene
`Glycol/Propylene Glycol with Hydroxypropyl
`Guar) Lubricant Eye Drops
`
`Sruthi Srinivasan
`Venkiteshwar Manoj
`
`Clinical Development and Medical Affairs,
`Alcon Research, LLC, Johns Creek,
`GA, USA
`
`Correspondence: Sruthi Srinivasan
`Clinical Development and Medical Affairs,
`Alcon Research, LLC, 11460 Johns Creek
`Parkway, Johns Creek, GA, 30097, USA
`Tel +1 678 415-5315
`Email sruthi.srinivasan@alcon.com
`
`Abstract: Dry eye disease (DED) is a multifactorial ocular condition characterized by a loss
`of homeostasis of the tear film resulting in ocular symptoms of discomfort, irritation, and
`visual disturbance, all of which significantly impact the patients’ social and occupational
`quality of life. While management of DED depends on the severity of symptoms and signs,
`use of artificial tear products (ATPs) that replace or supplement the deficient natural tear film
`is the mainstay treatment option. In this review, we present a decade of evidence on Systane
`Ultra® (polyethylene glycol [PEG]/propylene glycol [PG] with hydroxypropyl guar [HP
`guar]) in effectively managing DED. The active demulcents in Systane Ultra®—PEG, PG,
`along with HP guar gelling technology—provide optimal ocular surface protection and
`lubrication to heal damaged areas of the cornea caused by DED and, therefore, are recom-
`mended for patients with both aqueous and/or mucin layer deficiencies. Over the years,
`several clinical studies have shown that PEG/PG with HP guar provides long-lasting relief
`from dry eye and has often been chosen as a standard or comparator against other ATPs.
`Here, we describe the salient features of PEG/PG with HP guar—its constituents and their
`mechanisms of action. Furthermore, we summarize results from a systematic literature search
`that identified 23 relevant publications further emphasizing on the effectiveness and safety of
`PEG/PG with HP guar in alleviating the signs and symptoms of DED.
`Keywords: artificial tear products, dry eye disease, PEG/PG with HP guar
`
`Dry Eye Disease: Prevalence, Definition, Burden,
`and Management
`Dry eye disease (DED), also known as keratoconjunctivitis sicca, is a critical and
`significant public health issue affecting ~344 million people worldwide and more
`than 30 million in the United States alone [https://www.tfosdewsreport.org/, last
`accessed 10 February 2020]. The estimated prevalence of DED ranges from 5% to
`34% in individuals over 50 years old and is more common in women; however,
`with increased use of electronic/media devices the risk of DED in the younger
`population is on the rise.1,2
`In 2017, the Tear Film & Ocular Surface Society’s Dry Eye Workshop II (TFOS
`DEWS II) report defined DED as a “multifactorial disease of the tears and ocular
`surface that results in symptoms of discomfort, visual disturbance, and tear film
`instability with potential damage to the ocular surface”. It is accompanied by
`
`Received: 3 March 2021
`Accepted: 23 April 2021
`Published: 9 June 2021
`
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`Clinical Ophthalmology 2021:15 2421–2435
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`increased osmolarity of the tear film and inflammation of
`the ocular surface.3,4 Patients with DED may complain of
`ocular discomfort including redness, burning and stinging,
`ocular dryness, photophobia, foreign body sensation, grit-
`tiness, and visual disturbance, all of which significantly
`affect the quality of lives of patients (reporting up to 34%
`impairment in daily activities).5,6 Etiologically, DED is
`classified into (i) aqueous-tear deficiency, characterized
`by lack of tear secretion from the lacrimal glands, and
`(ii) evaporative DED, involving excessive evaporative loss
`of tears due to meibomian gland deficiencies.2 However,
`most DED (>80%) are mixed conditions characterized by
`both lacrimal and meibomian gland deficiencies.7
`With the increasing burden of DED and its impact on
`patients’ daily and social lives that worsens with age, it is
`this condition appropriately.4
`important
`to manage
`Depending on severity of the disease, the treatment and
`management of DED include patient education (about the
`condition, management, and prognosis); modifications in
`the environmental, dietary, and lifestyle-related factors;
`artificial tear substitutes; punctal plugs; lid warming and
`intranasal stimulation devices; topical and/or systemic
`anti-inflammatory medications, such as cyclosporine,
`diquafosol, and lifitegrast; and surgery.8 Treatment goals
`include relieving the signs and symptoms of the disease,
`improving patients’ comfort, re-establishing ocular surface
`damage.7,9
`homeostasis,
`and minimizing
`corneal
`Irrespective of the severity grade of DED, over-the-
`counter (OTC) eye drops, or artificial tear products
`(ATPs) are the mainstay and first-line treatment for DED
`providing immediate symptomatic relief.4,10
`
`Artificial Tear Products
`ATPs are lubricant eye drops used to treat the dryness and
`irritation associated with DED. These buffered formula-
`tions, with or without preservatives, contain electrolytes,
`surfactants, and one or more lubricants that may be guar-
`or cellulose-based derivatives including hydroxypropyl
`guar (HP guar), glycerin, dextran, polyvinyl alcohol, poly-
`ethylene glycol [PEG] 400, propylene glycol [PG], sodium
`hyaluronate, and polyvinylpyrrolidone to enhance or
`replace the tear film.8–12
`The numerous commercially available ATPs are pri-
`marily hypotonic or isotonic buffered solutions contain-
`ing other excipients (eg, electrolytes, surfactants, and
`various types of viscosity agents). Most target to replen-
`ish either the aqueous or lipid layer of the tear film and
`there is no consensus on the therapeutic efficacy of one
`
`over the other.13 The ideal artificial tear is one that can
`spread uniformly and evenly, minimize friction during
`blinks, has minimal blurring upon instillation, is safe and
`convenient to use, and effectively improves the signs and
`symptoms of dry eye.12 Further, an ideal ATP should
`also have the potential to restore deficiencies in both,
`aqueous and lipid, layers of the tear film to address
`patient’s dry eye symptoms, regardless of the deficiency
`(lacrimal or meibomian) within the tear film that may be
`causing the symptoms.
`Here, we describe the constituents, mechanisms of
`action, and clinical evidence of PEG/PG with HP guar
`that is formulated with an intelligent delivery system and
`offers symptomatic relief to consumers/patients across the
`wide spectrum of DED.
`
`Systane Ultra (PEG/PG with HP
`GUAR)
`Systane Ultra® (PEG/PG with HP guar; Alcon, Fort
`Worth, TX, USA) has been commercially available since
`2008. PEG/PG with HP guar is commercially available in
`several countries across four markets (Asia-Pacific,
`Europe/Middle East/Africa, Latin America/Caribbean,
`and North America) worldwide, and provides immediate
`comfort, extended ocular surface protection, and symptom
`relief for DED due to insufficient quantity or quality of
`natural tears.14
`
`Formulation
`The active ingredients of PEG/PG with HP guar lubricant eye
`drops are the hydrophilic demulcents 0.4% PEG 400 and
`0.3% PG, which have lower viscosity than cellulose
`derivatives.14 The lubricant drops also contain HP guar,
`a natural polysaccharide gelling agent, and are buffered with
`borate and sorbitol. Moreover, these lubricant formulations
`containing PEG/PG with HP guar are free of preservatives.
`
`HP Guar
`The HP guar technology was originally developed for
`ophthalmic use in contact lens multi-purpose solutions
`(UNIQUE pH™, Alcon Laboratories, Inc., Fort Worth,
`Texas, USA). Use of HP guar, a water-soluble natural
`polysaccharide excipient, in PEG/PG with HP guar lubri-
`cant drops increases the viscosity of the eye drop owing to
`its high molecular weight (1000–5000 kDa).8,12,14
`Although Systane Ultra and Systane Original have
`similar HP guar concentrations and 2-hour viscosities
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`(range, 4300–5800 Cps), the pH of Systane Ultra (pH 7.9)
`is higher than that of Systane Original (pH 7.0). Moreover,
`sorbitol is included in Systane Ultra but not in Systane
`Original. Upon exposure to the higher pH (~7.5) of the
`ocular surface and tears, HP guar’s interaction with borate
`and divalent ions in the tear film allows the formation of
`the protective viscoelastic matrix on the ocular surface to
`provide prolonged retention of the active demulcents,
`thereby protecting the ocular surface. Further, this gel
`matrix mimics the mucin in the tear film and reduces the
`friction between the eyelid and ocular surface during
`blinks.8,12,14
`HP guar molecules preferentially bind to desiccated or
`damaged hydrophobic regions of the cornea; this allows
`protective layer to limit further damage and time for sur-
`face epithelial cells to undergo repair and renewal.14–16
`A preclinical study using in vivo (desiccated corneas of
`anesthetized rabbits) and in vitro (immortalized human
`corneal epithelial cells and Chang conjunctival cells) mod-
`els, based on methylene blue uptake, showed that HP guar,
`PEG, and PG effectively and uniformly formed a layer on
`the ocular surface providing protection from desiccation,
`thereby allowing recovery of the damaged epithelium.16 In
`another preclinical in vivo study, the effect of lubricant
`drops containing PEG/PG with HP guar on precorneal
`mucous layer was evaluated over 7 days in New Zealand
`white rabbits (N = 16).17 Their right eyes were treated with
`PEG/PG/HP guar and the left eyes were randomized to
`receive PEG/PG/HP guar with Polyquad, 0.1% hyaluro-
`nate sodium, 0.5% carboxymethyl cellulose (CMC), and
`phosphate-buffered
`saline.
`The
`study
`showed
`a significantly thicker mucous in eyes treated with PEG/
`PG/HP guar drops compared with PEG/PG/HP guar with
`Polyquad (P< 0.001 vs all). Interestingly, no significant
`difference was noted in the mucous layer between the eyes
`treated with PEG/PG/HP guar and PEG/PG/HP guar with
`Polyquad.17
`In a clinical study of 87 patients with DED,
`Christensen et al15 demonstrated that, compared to control
`(CMC sodium; Refresh Tears® Lubricant Eye Drops,
`Allergan, Irvine, CA, USA), PEG/PG with HP guar lubri-
`cant significantly reduced conjunctival (P= 0.025) and
`temporal corneal staining (P= 0.024). Furthermore,
`patients reported a reduction in DED symptoms in the
`morning (P= 0.015) and evening (P= 0.023), lower fre-
`quencies of foreign body sensation (P= 0.033), and felt
`their eyes were “refreshed longer” (P=0.037); thereby
`confirming that PEG/PG with HP guar lubricant drops
`
`were more effective at alleviating signs and symptoms of
`dry eye than CMC sodium alone (Refresh Tears).15
`Tear instability and increased evaporation in all types
`of DED results in tear film hyperosmolarity (one of the
`key characteristics of the disease). A clinical study by Ng
`et al18 in 31 patients with DED (with Ocular Surface
`Disease Index questionnaire [OSDI] ≥20 and mean tear
`osmolarity ≥300 mOsm/L in at least one eye) showed that
`treatment with PEG/PG with HP guar for 3 weeks (4
`times/day [QID] for 3 weeks) showed a significant reduc-
`tion in tear osmolarity scores (mean, standard deviation
`[SD]: 314.6 [11.9] mOsm/L vs 307.7 [15.7] mOsm/L, P<
`0.05) compared to baseline. Furthermore, significant
`improvements were observed in dry eye conditions and
`symptoms at Week 3 (mean OSDI score: P≤ 0.01; non-
`invasive tear break-up time [NIBUT]: P< 0.05; central
`corneal staining: P< 0.05) from baseline. The study further
`noted that, unlike other hypotonic drops, the reduction in
`tear osmolarity was observed even 15 minutes after instil-
`lation with PEG/PG with HP guar.18
`In 2015, a pre-clinical study by Rangarajan et al
`explored a potential synergistic benefit of combining HP
`guar with another naturally viscoelastic hydrophilic poly-
`mer, hyaluronic acid (HA), that has also been shown to
`reduce ocular surface damage in DED patients.19,20 It was
`observed that in human corneal epithelial cells, hydration
`protection against desiccation and protection by surface
`retention were significantly greater with HA/HP guar vs
`HP guar or HA alone (P< 0.001). Also, protection with HP
`guar alone was significantly greater vs HA alone
`(P=0.016). Post surfactant-insult, cell viability, cell barrier
`protection, tissue hydration, and lubricity were also sig-
`nificantly greater with dual-polymer formulation than HP
`guar or HA alone.20 Overall, these findings confirm that
`HP guar in lubricant eye drops improves the adherence
`and retention of the ATP, improves tear stability and tissue
`hydration, and minimizes tear evaporation, thereby low-
`ering tear osmolarity and corneal dryness to provide long-
`lasting relief from DED symptoms.
`
`Preservatives in PEG/PG with HP Guar
`The treatment options for DED are constantly evolving;
`however, use of lubricant eye drops is a constant through
`different stages of the disease to provide symptomatic
`relief. With the long-term and continuous usage of these
`lubricant drops, the ATPs should be sterile to prevent
`unwanted effects on the ocular surface, and hence preser-
`vatives are added
`to ATP
`formulations
`for
`their
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`antimicrobial properties.21,22 Furthermore, considering the
`long-term and frequent usage of the ATPs, it is important
`that the preservatives added to the ATPs are well tolerated
`with minimal or no side effects.21
`The most commonly used preservative in prescription
`topical ophthalmic drops, including ATPs, is benzalkonium
`chloride (BAK), which demonstrates pan-antimicrobial
`properties; however, BAK-containing formulations have
`shown to have deleterious effects on the ocular surface and
`are not widely used in OTC ocular lubricants or artificial
`tears.21–23 Over the last decade, PEG/PG with HP guar
`lubricant eye drops have shown to provide relief from the
`symptoms of dry eye without the use of certain preservatives
`that have adverse effects. Unlike many OTC eye drops, the
`preservative used in PEG/PG with HP guar is polyquater-
`nium or Polyquad, a hydrophilic cationic polymer that was
`initially developed and used as an antimicrobial disinfectant
`in contact lens solutions. The large molecular size of
`Polyquad is key to its function, while it effectively disrupts
`microbial membranes, its sheer size exclusion prevents cyto-
`toxicity in mammalian cells.21,24 Polyquad has shown to be
`effective against Pseudomonas aeruginosa, Serratia marces-
`cens, Staphylococcus aureus, and the fungus Candida
`albicans.25 With more than 30 years of usage, safety con-
`cerns raised with Polyquad are minimal – it does not
`adversely affect the ocular surface and has shown to offer
`comparable
`tolerability
`to a preservative-free eye
`drops.17,21,22
`The concerns over the use of preservatives in ATPs, in
`addition to physician and patient preferences, have led to
`the development of preservative-free formulations. While
`preservative-based eye drops have a longer shelf life, pre-
`servative-free drops typically come in disposable single-
`dose sterile vials that reduce the risk of contamination and
`eliminate the need for preservatives. PEG/PG with HP
`
`guar preservative-free lubricant eye drops relieve dry eye
`symptoms with a preservative-free formula and are avail-
`able in convenient, single-use sterile vials that provide
`immediate and long-lasting DED symptom relief similar
`to its preserved formulation.17 Lubricant eye drops are
`now also available in multi-dose preservative-free formu-
`lations that are cost effective and easy to use.21,22,26
`
`Mechanism of Action
`PEG/PG with HP guar lubricant eye drops are maintained at
`a pH of 7.9 where HP guar, borate, and sorbitol exist in a state
`of dynamic equilibrium where sorbitol optimizes the viscosity
`of the drop.12 During instillation, the pressure exerted on the
`bottle reduces the drop viscosity and once instilled, the con-
`centration of sorbitol decreases owing to its water solubility,
`allowing for efficient and uniform spreading. The borate ions
`in Systane interact with galactomannan on the surface of the
`eye to form a protective cross-linked bio-adhesive gel.12,14,27
`Further, the ionic properties of the tear film increase the
`density of the borate/HP guar crosslinks and fortify this low
`viscosity gel matrix to allow retention of active demulcents
`for tear film stability and lubrication, decrease evaporation of
`the tear film, and protect the ocular surface (Figure 1). The
`borate/HP guar gel matrix also reduces friction between
`blinks to provide prolonged relief and comfort.14
`The aforementioned properties make PEG/PG with HP
`guar an ideal lubricating drop with a longer retention time
`and sustained lubrication for aqueous-deficient, evapora-
`tive, and mixed DED conditions.
`
`Clinical Studies of PEG/PG with HP
`Guar
`A literature search was conducted independently by the
`authors on the PubMed database; following removal of
`duplicates, a total of 304 articles were identified using
`
`Figure 1 Mechanism of action of PEG/PG with HP GUAR. Image courtesy with permission from Alcon.
`Abbreviations: HP GUAR, hydroxypropyl-guar; PEG, polyethylene glycol; PG, propylene glycol.
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`the following search strings: (i) (Systane Ultra) AND (dry
`eye disease OR DED OR dry eye syndrome OR DES or
`dry eye); (ii) ([polyethylene glycol OR PEG] AND [pro-
`pylene glycol OR PG] AND [hydroxypropyl guar OR HP
`guar OR HPG]) AND (dry eye disease OR DED OR dry
`eye syndrome OR DES or dry eye); (iii) (Systane Ultra)
`AND (artificial tears OR ocular lubricants OR lubricant
`eye drops OR ATP); (iv) ([polyethylene glycol OR PEG]
`AND [propylene glycol OR PG] AND [hydroxypropyl
`guar OR HP guar OR HPG]) AND (artificial tears OR
`ocular lubricants OR lubricant eye drops OR ATP); and (v)
`(dry eye OR DED) AND (artificial tears AND lubricant).
`Multiple reports of the same dataset were assessed, and
`only the most updated articles were included. Only
`English
`language articles were
`included. Abstracts
`retrieved from the search were screened and a total of 20
`relevant articles were identified, with consensus, by the
`authors were further evaluated and reviewed. In addition, 3
`relevant abstracts on the use of PEG/PG with HP guar in
`DED identified from Google Scholar Search were also
`identified and reviewed. Data from the studies reporting
`on the use of PEG/PG with HP guar in dry eye conditions,
`including the study design, patient population, lubricant
`dosage, and endpoints assessed are summarized
`in
`Figure 2.
`Over the last 10 years, clinical studies have demon-
`strated that the use of PEG/PG with HP guar is associated
`with improvements in the signs and symptoms of dry eye
`and is well tolerated in patients with DED (Table 1). Here,
`we present an overview of key clinical studies conducted
`with PEG/PG with HP guar in patients with dry eye.
`
`Efficacy and Safety of PEG/PG with HP
`Guar (Systane Ultra)
`A 6-week, controlled, randomized, prospective, double-
`masked, multisite, parallel-group study conducted by
`Davitt et al28 on 113 patients with DED evaluated the
`efficacy and safety of PEG/PG with HP guar (vs saline) in
`improving the signs and symptoms of DED. The study
`demonstrated a reduction in the severity of dry eye with no
`untoward safety issues.28 Use of PEG/PG with HP guar
`lubricant eye drops reduced both corneal and conjunctival
`staining as early as Day 7, with significant reduction in mean
`corneal staining (P= 0.0009) by Day 14 and in mean con-
`junctival staining (P= 0.0475) by Day 28 that was sustained
`until end of the study. Furthermore, with PEG/PG with HP
`guar use patients also reported significant reductions in the
`
`mean scores for the ocular symptoms of dryness and OSDI
`vs baseline. The authors concluded that PEG/PG with HP
`guar lubricant was efficacious and well tolerated when used
`QID for 6 weeks in patients with dry eyes.28
`The efficacy of ATPs in relieving symptoms of dry eye
`typically rely on patient reporting, which may be
`subjective.29 Therefore, in addition to patient-reported
`scores, clinicians evaluate signs of ocular damage by
`staining for specific ocular surface antigens that are altered
`during DED. Human leukocyte antigen-DR isotype (HLA-
`DR) is one such biomarker for increased inflammation on
`the ocular surface associated with DED.30,31 Fernandez
`et al32 showed that treatment with PEG/PG with HP guar
`for 30 days significantly reduced HLA-DR expression (P=
`0.02), corneal staining (P= 0.01), OSDI score (P= 0.02),
`and tear firm breakup time (TFBUT; P= 0.01), suggesting
`a reduction in surface inflammation and thereby an
`improvement in the signs and symptoms of DED.
`In 2017, Labetoulle et al33 demonstrated that PEG/PG
`with HP guar decreased ocular surface staining based on
`the mean change in total ocular surface staining (TOSS)
`score from baseline at Day 35 (mean [SD]: −2.2 [0.33]
`points), thereby alleviating the signs and symptoms in
`patients with DED. Further, patient-reported scores from
`the study indicated that DED treatment with PEG/PG with
`HP guar was effective, convenient, and well tolerated over
`3 months of treatment.33 Asbell et al34 showed that PEG/
`PG with HP guar eye drops instilled QID or PRN to DED
`patients (N = 97) reduced corneal staining but the differ-
`ence between the two dosing regimens for reduction in
`TOSS score was not statistically significant (mean [SD]:
`−1.19 [0.26] for QID vs −0.94 [0.24] for PRN; P= 0.184).
`However, the Impact of Dry Eye on Everyday Life
`(IDEEL) symptom-bother score favored QID dosing, sug-
`gesting that the regular use of artificial tears may provide
`improved symptom relief vs PRN use in DED. Overall,
`both regimens were well tolerated with no new safety
`findings.34
`As mentioned earlier, Ng et al showed a significant (P<
`0.05) reduction in osmolarity (15 minutes after instilla-
`tion), in addition to improvements in dry eye symptoms
`(conjunctival hyperemia, ocular surface staining, and cen-
`tral corneal staining) using PEG/PG with HP guar QID
`over 3 weeks in DED patients (N = 31).18 More recently,
`a study by Aguilar et al35 demonstrated the efficacy of
`PEG/PG with HP guar (thrice daily) at Day 90 (vs base-
`line) in reducing squamous metaplasia (based on mean ±
`SD goblet cell density score: 0.8 ± 0.5 vs 1.2 ± 0.5; P<
`
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`Figure 2 Flow chart for literature search for publication screening and inclusion. *Search strings used: (i) (Systane Ultra) AND (dry eye disease OR DED OR dry eye
`syndrome OR DES or dry eye); (ii) ([polyethylene glycol OR PEG] AND [propylene glycol OR PG] AND [hydroxypropyl guar OR HP guar OR HPG]) AND (dry eye disease
`OR DED OR dry eye syndrome OR DES or dry eye); (iii) (Systane Ultra) AND (artificial tears OR ocular lubricants OR lubricant eye drops OR ATP); (iv) ([polyethylene
`glycol OR PEG] AND [propylene glycol OR PG] AND [hydroxypropyl guar OR HP guar OR HPG]) AND (artificial tears OR ocular lubricants OR lubricant eye drops OR
`ATP); and (v) (dry eye OR DED) AND (artificial tears AND lubricant). †After removing duplicates.
`
`0.0001), improving TFBUT (6.8 vs 5.8; P< 0.0001), cor-
`neal staining (0.3 vs 3.1; P < 0.00010), and conjunctival
`staining (0.9 vs 3.6; P < 0.0001), thereby allowing normal-
`ization of the ocular surface in patients with DED.
`
`Comparator Studies: PEG/PG with HP
`Guar vs Other ATPs/Treatments
`With more than a decade of effectively alleviating the
`signs and symptoms of dry eye without any major safety
`concerns, PEG/PG with HP guar is frequently used as
`
`a standard/comparator while assessing the effectiveness
`of other lubricant eye drops in DED.
`
`PEG/PG with HP Guar vs Optive
`PEG/PG with HP guar has been compared with Optive®
`Tears (CMC and glycerin; Allergan; https://www.allergan.
`com.au/en-au/products/list/optive-lubricant-eye-drops
`-15mL, last accessed 07-February 2020) across four dif-
`ferent studies.28,33,36,37
`Davitt et al28 were the first to compare the efficacy and
`safety of PEG/PG with HP guar with that of Optive in
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`Table 1 Clinical Studies Using PEG/PG with HP Guar Lubricant Eye Drops in DED
`
`Publication
`
`No. of DED Patients Treated
`with PEG/PG with HP-Guar
`
`No of Patients Treated with
`Comparator
`
`Endpoints
`
`Results
`
`Davitt et al,
`201028
`
`n = 52
`
`Optive (CMC/glycerin) n = 53
`
`Corneal staining
`
`P < 0.0009 at day 14; P = 0.0106
`at day 42 compared with Optive
`
`Conjunctival
`staining
`
`P = 0.0475 at day 14; P = 0.00009
`at day 42 compared with Optive
`
`Ocular symptoms
`score
`
`No significant differences
`between groups
`
`TFBUT
`
`OSDI scores
`
`VF-14 scores
`
`n = 16 moderate-to-severe DED
`
`None
`
`Corneal staining
`
`P < 0.0001 relative to baseline
`
`Fernandez
`et al, 201532
`
`Labetoulle
`et al, 201733
`
`n = 43
`
`Optive (osmoprotective CMC/
`glycerin) n = 41
`
`Asbell et al,
`201834
`
`N = 97 1 drop 4x/day (n = 34) vs as
`needed (n = 63)
`
`Ng et al,
`201818
`
`n = 28
`
`None
`
`None
`
`Conjunctival
`staining
`
`No change
`
`TFBUT
`
`P < 0.0001 relative to baseline
`
`DEWS score
`
`P < 0.0001 relative to baseline
`
`OSDI score
`
`P = 0.02 relative to baseline
`
`Cells expressing
`HLA-DR
`
`TOSS score
`
`IDEEL score
`
`P = 0.02 relative to baseline
`
`No significant differences
`between groups
`
`TOSS score
`
`No differences between groups
`
`IDEEL score
`
`Tear osmolarity
`
`NITBUT
`
`Corneal staining
`
`Conjunctival
`hyperemia
`
`Conjunctival
`staining
`
`P < 0.05 relative to baseline in
`worse eye
`
`Improvements not significant
`
`P < 0.0001 at days 30, 60, 90
`relative to baseline
`
`(Continued)
`
`Aguilar et al,
`201835
`
`n = 49
`
`None
`
`Goblet cell density
`
`Corneal staining
`
`Conjunctival
`staining
`
`TFBUT
`
`Clinical Ophthalmology 2021:15
`
`2427
`https://doi.org/10.2147/OPTH.S294427
`DovePress
`
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`

`Srinivasan and Manoj
`
`Dovepress
`
`Table 1 (Continued).
`
`Publication
`
`No. of DED Patients Treated
`with PEG/PG with HP-Guar
`
`No of Patients Treated with
`Comparator
`
`Endpoints
`
`Results
`
`Torkildsen,
`200936
`
`N = 48
`
`Optive (osmoprotective CMC/
`glycerin) n = 48 Crossover
`study
`
`IVAD
`
`P = 0.0365 at 90 min compared
`with Optive
`
`No significant differences
`between groups
`
`Median time at
`BCVA
`
`Reading rate
`
`Functional blink
`rate
`
`Guillon et al,
`201137
`
`N = 27
`
`Optive (osmoprotective CMC/
`glycerin) n = 27
`
`VA
`
`Torkildsen
`et al, 201738
`
`N = 41
`
`Rohto (PG/povidone) n = 39
`
`Corcoran
`et al, 201739
`
`N = 33 (+15 without DED)
`
`Rohto (PG/povidone) n = 33
`(+15 without DED)
`
`OSDI scores
`
`Subjective vision
`scores
`
`Subjective comfort
`scores
`
`Ocular comfort
`scores
`
`Corneal staining
`
`Conjunctival
`staining
`
`TFBUT
`
`Ora Calibra
`Ocular
`Discomfort Scale
`
`4-Symptom
`Questionnaire
`
`Ora Calibra
`Quality of Life
`Questionnaire
`
`Cooling score
`
`Corneal staining
`
`Schirmer’s score
`
`OSDI
`
`Superior to comparator in static
`and time-controlled visual
`performance for high-contrast
`optotypes
`
`No significant differences
`between groups
`
`No significant differences
`between groups
`
`No significant differences
`between groups
`
`(Continued)
`
`2428
`
`Clinical Ophthalmology 2021:15
`https://doi.org/10.2147/OPTH.S294427
`DovePress
`
`Slayback Exhibit 1059, Page 8 of 15
`Slayback v. Eye Therapies - IPR2022-00142
`
`

`

`Dovepress