Artificial Tears: A Systematic Review

Figures & data

Table 1 Randomised Clinical Trials That Have Used Artificial Tears for the Treatment of Dry Eye Disease

Paper	Design	Comparators	Participants Completing	Age (Years)	Duration (Dosing)	Tests Showing Significant Difference	Tests Not Differentiating Products	Tests Showing Significant Difference	Tests Showing no Change	General Comments
						Cross Comparator		Compared to Baseline
Amran et al 2014^Citation69	Randomized, open-label, multi-center study	Cationic Emulsion - Cationorm PVA-Povidone - Refresh	N = 44 N = 35	61.3 ± 15.4 61.9 ± 12.5	4 weeks (4x/day)	Symptoms, TBUT, eyelid erythema, Conjunctival staining with Cationic	Schirmer’s Corneal staining			Sub-analysis with MGD participants CLINICAL TRIAL NOT REGISTERED
Aragona et al 2020^Citation48	Randomized, double-masked, multi-center study	CMC + HA - Optive Fusion UD CMC - Refresh Optive Sensitive/Optive UD	N = 180 N = 184	59.4 ± 13.8 57.5 ± 13.7	90 days (2x/day)	Lower ocular pain/discomfort CMC-HA	OSDI TBUT Ocular surface staining Schirmer’s II	OSDI Symptoms (VAS) TBUT Ocular surface staining	Schirmer’s II	10% minor AE CLINICAL TRIAL NOT REGISTERED
Baeyens et al 2012^Citation74	Randomized, double-masked, multi-center study	SH 0.18% - Vismed Carbomer 0.3% NaCL	N = 100 N = 96 N = 96	59.3 ± 15.0 (across groups)	84 days	Symptoms & Corneal staining with SH vs saline	Symptoms, corneal and conjunctival staining, Schirmer’s, TBUT SH vs carbomer	Symptoms Corneal staining	Conjunctival staining, Schirmer’s, TBUT	CLINICAL TRIAL NOT REGISTERED
Barabino et al 2014^Citation104	Randomized, double-masked, multi-center study	CMC 0.5% / glycerin 0.9% - Optive HA 0.2% / tamarind seed polysaccharide 0.2% - Xiloial	N = 25 N = 23	57.1 ± 17.4 52.2 ± 14.9	3 months (4x/day)	Symptoms with HA+TS	TBUT Ocular surface staining Schirmer’s	OSDI TBUT Ocular surface staining	Schirmer’s	CLINICAL TRIAL NOT REGISTERED
Baudouin et al 2012^Citation57	Randomized, investigator-masked, multi-center study	CMC 0.5% and Osmoprotectant – Optive SH 0.18% - Vismed Multi	N = 37 N = 29	58.1 ± 14.2 55.4 ± 13.4	3 months	None	Osmolarity, Schirmer’s-I, OSDI, staining	Osmolarity, Schirmer’s-I, OSDI, staining	None	Clinical Trial NCT00987727 - only symptom primary and secondary outcomes and day 35 data missing Cochrane Risk of Bias R?C?M-O?I-S-B?
Benelli et al 2010^Citation62	Randomized, investigator-masked, single-center study	CMC 0.5% - Cellufresh PEG 400 2.5% - Blink Intensive HP‐guar 0.18%/PEG 400/PG - Systane	N = 20 N = 20 N = 20	Not stated	30 days (up to 4x/day)	Osmolarity with PEG400	VA Aberrometry Staining TBUT Schirmer’s	Aberrometry	Osmolarity VA Staining TBUT Schirmer’s	CLINICAL TRIAL NOT REGISTERED
Brignole et al 2005^Citation40	Randomized, masked-observer, single-center study	CMC 1% - Celluvisc SH 0.18% - Vismed	N = 11 N = 10	69 ± 2 57 ± 2	2 months (3x/day)	CD44, comfort (only at day 7), keratitis recovery with SH	All other inflammatory markers, cornea and conjunctival staining, TBUT, corneal topography, tear meniscus height	Symptoms and ocular surface staining	None	Moderate dry eye and keratitis patients CLINICAL TRIAL NOT REGISTERED
Brodwall et al 1997^Citation105	Randomized, investigator-masked, single-center study	Polyacrylic acid 0.2% - Visco Tears PVA 1.4%	N = 38 N = 41	60.2 61.8	4 weeks (Drops/day a study variable; avg 3–5)	Symptoms (16/27 study days), hyperaemia, Rose Bengal staining, compliance with polyacrylic acid	TBUT Schirmer’s	Symptoms & signs (unspecified)	TBUT Schirmer’s	CLINICAL TRIAL NOT REGISTERED
Bron et al 1998^Citation106	Randomized, double masked, multi-center study	Carbomer 940 0.2% - Lacrinorm/GelTears, Laboratoire Chauvin Carbomer 940 0.2% - Viscotears/Vidisic/Lacrigel	N = 92 N = 87	58.6 ± 16.2 64.0 ± 14.0	4 weeks (4x/day)	None	Symptoms TBUT, Schirmer’s, corneal and conjunctival staining	Symptoms TBUT, Schirmer’s, fluorescein/ lissamine green staining	None	AEs in n=21 Lacrinorm group and 17 Viscotears group CLINICAL TRIAL NOT REGISTERED
Calvao-Santos et al 2011^Citation41	Randomized, open-label, single-center study	Tears Again [lipidic] Opticol [aqueous] Optive [mucin] No treatment	N = 7 N = 6 N = 7 N = 7	24 to 53 years	30 days (not stated)	None	OSDI TBUT Schirmer’s	Symptoms, Schirmer’s for tears again	TBUT	Patients with digital eye strain. Compared drops primarily acting on one tear layer CLINICAL TRIAL NOT REGISTERED
Chiambaretta et al 2017^Citation50	Randomized, investigator-masked, multi-center study	HA-trehalose HA	N = 52 N = 49	60.0 ± 12.2 58.5 ± 13.4	84 days (3–6x/day; average 4)	Symptoms with HA-trehalose	Cornea & conjunctival staining	OSDI [Schirmer’s, TBUT, staining, hyperaemia, no statistics presented]	None	AEs: 3 with HA-trehalose vs 24 with HA Clinical Trial NCT02023268 - only staining as primary outcome and day 35 data missing Cochrane Risk of Bias R?C-M-O?I?S-B?
Christensen et al 2004^Citation61	Randomized, double-masked, multi-center study	PEG 400 0.4% / PG/HP‐guar 0.3% - Systane CMC 0.5% - Refresh Tears	N = 42 N = 45	58.5 59.5	6 weeks (4x/day)	Lissamine green staining, dryness, refreshed and FB symptoms with 0.5% PEG	Fluorescein staining, use ratings, ocular signs or symptom frequency	Corneal & conjunctival staining only with 0.4% PEG	Conjunctival staining with CMC	CLINICAL TRIAL NOT REGISTERED
Cohen et al 2014^Citation63	Randomized, double-masked, multi-center study	CMC 1% - Refresh LiquiGel PEG 400 0.4%/ PG/HP‐Guar 0.3% - Systane Gel	N = 70 N = 67	57.5±16.6 56.5±15.0	6 weeks (4x/day)	Corneal staining with PEG	Conjunctival staining, TBUT, symptoms	Corneal staining	Lissamine green staining, TBUT, symptoms	CLINICAL TRIAL NOT REGISTERED
Comez et al 2013^Citation107	Randomized, patient-masked, 2 group contralateral, single-center study	PG 0.3% and PEG 0.4% - Systane SH 15% - Eyestil HPMC - Tears Naturale CMC 0.5% - Refresh Tears	N = 17 N = 13	47.4±14.5 46.3±15.5	12 weeks (5x/day)	None	OSDI, Osmolarity, Schirmer’s, TBUT	OSDI, osmolarity, Schirmer’s, TBUT	None	~30% drop-out CLINICAL TRIAL NOT REGISTERED
Craig et al 2021^Citation4	Randomized, double-masked, multi-center study	Aminomethylpropanol, HP-guar - Systane Ultra Dimyristoyl phosphatidylglycerol, HP-guar, mineral oil, polyoxl 40 stearate - Systane Complete	N = 49 N = 50	43 ± 17 45 ± 16	6 months (4x/day +)	Lipid thickness	Symptoms, TMH, lipid, osmolarity, hyperaemia, expressibility, blinking	Symptoms (OSDI, DEQ-5, SANDE) NIBUT, LWE Cornea & conjunctival staining	TMH, osmolarity, hyperaemia, expressibility, blinking	Symptoms improved @1+ month, LWE @ 2+ months, lipid @ 3+ months staining @ 4+ months. 1 in 3 had no benefit in signs or symptoms. Those with lipid layer grade ≤ 3 benefit more from lipid-based drop Clinical Trial ACTRN12619000390189 - additional questionnaire, acuity and lid data presented Cochrane Risk of Bias R+C+M+O+I+S-B+
Dausch et al 2006^Citation76	Randomized, investigator-masked, cross-over, multi-center study	Liposomes - Tears Again Carbomer triglycerides - Liposic	N = 74 with deficient lipid layer	n=1 <25 years n=9 25–45 years n=16 46–60 years n=49 >60 years	6 weeks (3x/day)	Symptoms, LIPCOF, TBUT, Schirmer’s, lid margin inflammation with Tears Again		Symptoms, LIPCOF, TBUT, Schirmer’s, lid margin inflammation	-	Photo sequence of phospholipid liposomes sprayed on eyelid reaching ocular surface CLINICAL TRIAL NOT REGISTERED
Davitt et al 2010^Citation64	Randomized, double-masked, single-center study	PEG 400/PG/HP‐guar CMC 0.5% - Optive	N = 52 N = 53	33 x 18–64 years, 19 x ≥65 years 41x 18–64 years, 12 x ≥65 years	6 weeks (4x/day)	Cornea & conjunctival staining with PEG 400/PG/HP‐guar group	Symptoms, TBUT	Symptoms	TBUT	CLINICAL TRIAL NOT REGISTERED
Diaz-Llopis et al 2019^Citation108	Randomized, investigator-masked, multi-center study	Seawater spray - Quinton CMC 0.5% -Viscofresh	N = 60 N = 60	68.1 ± 6.3 66.8 ± 8.4	12 weeks (5x/day)	OSDI, IL-1 β and IL-6 with seawater spray	Cornea & conjunctival staining, Schirmer I, osmolarity, TBUT, TMH	OSDI, Cornea & conjunctival staining	Schirmer I, osmolarity, TBUT, TMH	CLINICAL TRIAL NOT REGISTERED
Downie et al 2020^Citation109	Randomized, double-masked, multi-center study	CMC, glycerin, flaxseed oil and castor oil and osmoprotectants (levocarnitine, Erythritol & trehalose) (OM3) Refresh Optive Advanced	N = 120 N = 122	54.3 ± 17.3 52.8 ± 16.7	90 days (2x/day +)	Combined corneal / conjunctival staining with OM3	OSDI TBUT	OSDI TBUT Combined corneal / conjunctival staining	None	AEs (OM3 0% vs ROA 4.1%) Clinical Trial NCT02553772 Cochrane Risk of Bias R+C+M+O+I+S+B?
Dumbleton et al 2009^Citation110	Randomized, double-masked, single-center study	PEG 400 0.25% - Blink gel tears CMC 1% - Refresh Liquigel	N = 56 N = 54	46.3 ± 19.3 47.2 ± 19.1	30 days (3x/day)	Symptoms with PEG	Phenol red test, TMH, NIBUT, hyperaemia, corneal and conjunctival staining		Hyperaemia, corneal and conjunctival staining	No notable AE’s CLINICAL TRIAL NOT REGISTERED
Essa et al 2018^Citation3	Randomized, investigator- masked, crossover, single-center study	SH 0.4% - Clinitas Soothe SH 0.15% - Hyabak Phospholipid liposomes -Tears Again CMC - TheraTears	N = 50 (for all treatments)	60.8 ± 14.2	4 weeks (drops/day a study variable; average 2–3)	None	OSDI NIBUT FBUT TMH Phenol Red LIPCOF Ocular surface staining Lipid layer grading Osmolarity (baseline visit only)	OSDI LIPCOF Conjunctival staining	NIBUT FBUT TMH Phenol Red Lipid layer grading	Artificial tears performed similarly. However, osmolarity balanced preferred in those with low baseline tear volume and lipisomal spray for those with lipid layer deficiency. Clinical Trial NCT02420834 Cochrane Risk of Bias R?C?M-O?I+S+B?
Fogt et al 2019^Citation111	Randomized, observer- masked, crossover, non-dispensing, single-center study	Omega 3 - Refresh Optive MEGA-3 Refresh Optive	N = 19 with thin lipid	46.5 ± 8.7	60 minutes (Single application)	Lipid layer thickness (overall), Symptoms with MEGA-3	None	Lipid layer thickness Symptoms	Symptoms Schirmer’s	Clinical Trial NCT03380624 - 15 min data missing Cochrane Risk of Bias R?C?M-O?I+S-B?
Fondi et al 2018^Citation112	Randomized, patient-masked, crossover single-center study	SH and trehalose - Thealoz Duo HA, trehalose and carbomer - Thealoz Duo Gel	N = 40 (for both treatment)	43.7 ± 12.3	1 week (actual 3.2 ± 2.6x/day HT & 1.9 ± 2.2x/day HTC-gel)	None	Corneal / conjunctival staining TBUT Sleep quality	Corneal / conjunctival staining TBUT Sleep quality	None	Clinical Trial NCT02980913 Cochrane Risk of Bias R?C?M-O?I?S+B?
Garcia-Lazaro et al 2011^Citation67	Randomized, investigator masked, cross‐over, single-center study	PEG 400 2.5% - Blink Intensive Tears HPMC 0.3% - Artific Tears	N = 20	57.5 ± 8.4	1 month (3x/day)	Tear meniscus volume with PEG	None	Tear meniscus volume	None	CLINICAL TRIAL NOT REGISTERED
Gensheimer et al 2012^Citation113	Randomized, double-masked, contralateral, non-dispensing, single-center study	Glycerin 1% with PLL-g-PEG - Eyeon PG 0.3% and PEG 0.4% - Systane	N = 16	44.5	120 mins (single application)	NIBUT, TBUT with glycerine	None	NIBUT with glycerine	TBUT	CLINICAL TRIAL NOT REGISTERED
Gokul et al 2018^Citation54	Randomized, double-masked, contralateral, non-dispensing, single-center study	Systane Balance Systane Ultra	N = 30	27 ± 9	30 mins (following 2.5 mins in adverse conditions)	Lipid thickness with liposomal Systane Balance	NIBUT	Lipid thickness, NIBUT	Glare acuity, temperature variation, TMH	CLINICAL TRIAL NOT REGISTERED
Grene et al 1992^Citation66	Randomized, double-masked, single-center study	CMC 1.0% - Celluvisc Lubricant HPMC 0.3% - Tears Naturale 2	N=28? N=28? severe	??	2 months (8x/day)	Symptoms, corneal erosions and impression cytology grades with CMC	Schirmer’s Corneal & conjunctival staining Lid & conjunctival swelling	Corneal staining, Symptoms, impression cytology grade (CMC only)	Schirmer’s	CLINICAL TRIAL NOT REGISTERED
Iester et al 2000^Citation70	Randomized, open-label?, multi-center, study	HPMC 0.3% HA 0.4%	N = 55 N = 58	56.4 ± 12.8 52.2 ± 10.6	2–3 months (6x/day)	Symptoms, Tear ferning Osmolarity, impression cytology With HA	TBUT Staining Schirmer’s I	TBUT, staining, Schirmer’s I, symptoms Impression cytology	-	Ferning, osmolarity and impression cytology only measured in ~33% of sample each CLINICAL TRIAL NOT REGISTERED
Jacobi et al 2012^Citation114	Randomized, open-label? Single-center study	HP-Guar - Systane UD Tamarindus indica seed polysaccharide 1% - VISINE INTENSIV	N=14 N=14	44 ± 8 overall	3 months (5x/day)	TBUT with HP-Guar	OSDI Schirmer’s II LIPCOF Corneal & conjunctival (rose Bengal)	TBUT LIPCOF OSDI with HP-Guar	Schirmer’s II LIPCOF Corneal & conjunctival (rose Bengal)	CLINICAL TRIAL NOT REGISTERED
Jerkins et al 2020^Citation115	Randomized, double-masked, multi-center study	Systane Balance Refresh Optive advanced	N = 117 N = 114	56.7 ± 14.7 55.6 ± 16.4	35 days (4x/day)	TBUT with Systane	Symptoms	Symptoms TBUT	None	2 lipid based drops Clinical Trial NCT02776670 - exploratory lid wiper epitheliopathy and questionnaire additionally reported Cochrane Risk of Bias R+C+M?O?I-S+B?
Johnson et al 2006^Citation60	Randomized, double-masked, contralateral, single-center study	SH 0.1% SH 0.3% NaCL 0.9%	N = 13 (for all treatments)	Range 21–34	6 hours (single application)	NIBUT (0.3% SH performed better than 0.1% SH)	Symptoms	Symptoms NIBUT	None	CLINICAL TRIAL NOT REGISTERED
Johnson et al 2008^Citation56	Randomized, double-masked study, single-center study	Carbomer 934 0.3% - Lacryvisc SH 0.18% - Vismed	N = 33 N = 32	Median 36 Median 39 Range 21–64	1 month (drops/day a study variable; median 2.1–2.3)	Corneal & conjunctival staining with SH	Symptoms NIBUT TBUT	Symptoms Corneal & conjunctival staining	NIBUT TBUT	CLINICAL TRIAL NOT REGISTERED
Khaireddin and Schmidt, 2010^Citation116	Randomized, multi-center study	HA - Vismed light Phospholipid - Tears Again	N = 103 N=113 Evaporative	n=9 <25 years, n=26 25–45 years, n=42 46–60 years, n=139 >60 years	3 months 3x/day +	LIPCOF, lid inflammation NIBUT with Tears Again	Schirmer’s	LIPCOF, lid Inflammation NIBUT	Schirmer’s	CLINICAL TRIAL NOT REGISTERED
Khanal et al 2007^Citation117	Randomized, investigator-masked, single-center study	Castor oil 0.1.25% HPMC 0.32% - Artelac Single Dose Unit	N = 27 N = 26	Unclear from text	1 month (3x/day)	Tear evaporation with HPMC	Schirmer’s, osmolarity	Tear evaporation; Lipid layer with caster oil	Schirmer’s, osmolality	CLINICAL TRIAL NOT REGISTERED
Labetoulle et al 2018^Citation118	Randomized, double-masked, multi-center study	HP-Guar - HA dual-polymer – Systane Hydration SH 0.15% - Hyabak	N = 50 N = 49	61.7 ± 12.3 56.7 ± 14.3	6 weeks (4x/day)	None	Symptoms, TBUT, ocular surface staining	Ocular surface staining	Symptoms, TBUT	Fluorescein dye only Clinical Trial NCT02470429 - exploratory end points additionally reported in n=30 Cochrane Risk of Bias R+C+M?O?I+S+B?
Lahia et al 2020^Citation119	Randomized, double-masked, single-center study	Sacha inchi microemulsion (SIME) HA 0.2%	N = 26 N = 26	53.3 ± 12.6 overall	1 month (3x/day)	Ocular protection index with SIME	Symptoms, Corneal & conjunctival staining, TBUT	Symptoms, osmolarity in hyperosmolar subgroup. Corneal and conjunctival (nasal) staining, TBUT & lid redness only with SIME	Osmolarity, Conjunctival temporal staining	Fluorescein dye only Clinical Trial NCT03569202 Cochrane Risk of Bias R+C+M+O+I+S+B+
Lee et al 2011^Citation58	Randomized, observer-masked, single-center study	CMC 0.5% - Refresh Plus SH 0.1% - Hynex	N = 33 N = 32	39 ± 14.6 37 ± 13.4	2 months (6x/day)	None	Corneal & conjunctival staining TBUT Symptoms	Cornea & conjunctival staining TBUT Symptoms	None	Fluorescein staining only CLINICAL TRIAL NOT REGISTERED
Lievens et al 2019^Citation52	Randomized, double-masked, multi-center study	CMC 1.0% and glycerin 0.9% CMC 1.0%	N = 94 N = 94	≥ 18 years of age	1 month (2x/day +)	Symptoms Corneal staining TBUT With CMC-GLY at day 7 only	Symptoms Corneal staining TBUT at all other time points	Symptoms, corneal staining, and TBUT	None	Clinical Trial NCT02280473 Cochrane Risk of Bias R+C+M+O+I+S+B+
Marner et al 1996^Citation71	Randomized, open-label, crossover, multi-center study	Carbomer gel - Lubrithal PVA 1.4% - Lacril/Liquifilm	N=54 (for all treatment)	64.3, range 38–89	2 weeks (drops/day a study variable (carbomer 3.9 vs PVA 4.6x)	Symptoms, TBUT. Instillation frequency with carbomer	Schirmer’s I Ocular surface staining, Corneal sensitivity	Schirmer’s I, TBUT, ocular surface staining, symptoms	None	Rose Bengal only used AEs 33% with carbomer, 8% with PVA CLINICAL TRIAL NOT REGISTERED
Mihaltz et al 2018^Citation43	Randomized, investigator-masked, single-center study	Carbomer, triglycerides - Artelac Lipids UD SH - Artelac Splash Edo UD	N=10 N=13	55.5 ± 11.3 53.8 ± 17.9	3 months (4x/day +)	None	Schirmer’s, TBUT, Ocular surface staining Symptoms MG dropout aberrations	Schirmer’s, TBUT, Ocular surface staining	None	Lipid drops better for those with >50% MG dropout improving Schirmer’s & aberrations CLINICAL TRIAL NOT REGISTERED
Muntz et l 2020^Citation55	Randomized, double-masked, contralateral crossover, single-center study	Lipid, PG, HP-guar and mineral oil - Systane Complete PEG 400, PG and HP-guar - Systane Ultra	N = 28 (for all treatments)	29 ± 9	Single application – adverse environment	Symptoms, lipid layer quality, NIBUT with Systane complete	TMH Hyperaemia	Symptoms, NIBUT, Lipid layer quality only with Systane Complete	TMH Hyperaemia	Clinical Trial ACTRN12619000361101 Cochrane Risk of Bias R+C+M+O+I+S+B?
Nelson and Farris, 1998^Citation120	Randomized, double-masked, multi-center study	PVA 1.4% - Liquifilm SH 0.1%	N = 16 N = 20	52.3 ± 16.4 64.8 ± 10.8	8 weeks 8x/day +	-	Symptoms, Osmolality, TBUT, rose bengal staining, Schirmer’s I, impression cytology	Symptoms, Osmolality, TBUT, rose bengal staining, Schirmer’s I	Impression cytology	CLINICAL TRIAL NOT REGISTERED
Ousler et al 2007^Citation65	Randomized, double-masked crossover, single-center study	PEG & HP-Guar - Systane CMC - Refresh Tears CMC - Refresh Endura	N = 50	62.7	Single application	TBUT, Ocular protection index with Systane	Blink rate	No comparison presented		No difference between CMC products CLINICAL TRIAL NOT REGISTERED
Park et al 2017^Citation59	Randomized, investigator-masked, multi-center study	SH 0.1% SH 0.15% SH 0.3% Cyclosporine 0.05%	N = 43 N = 41 N = 47 N = 45	44.1 ± 13.9 46.2 ± 14.0 44.8 ± 16.2 45.2 ± 15.4	12 weeks (5–6x/day)	Schirmer’s (0.15% SH group)	Corneal & conjunctival staining TBUT	Corneal & conjunctival staining TBUT	Schirmer’s	AEs 13% 0.1% SH. 20% 0.15% SH, 13% 0.3% SH, 31% 0.05% CS group. Clinical Trial KCT0001796 Cochrane Risk of Bias R+C?M-O?I+S+B?
Perez-Balbuena et al 2016^Citation47	Randomized, double-masked, multi-center study	Xanthan gum 0.09% and chondroitin sulfate 0.1% PEG 400 0.4% and PG 0.3%	N = 76 N = 72	49.9 ± 16.0 45.5 ± 12.7	2 months (4x/day)	None	Schirmer’s, TBUT, Symptoms, Corneal & conjunctival staining	Schirmer’s, TBUT, Symptoms	Corneal & conjunctival staining	Clinical Trial NCT01657253 Cochrane Risk of Bias R+C?M+O?I+S+B+
Pinto-Bonilla et 2015^Citation42	Randomized, open-label, crossover, single-center study	Trehalose and SH 1.5mg/mL -Thealoz Duo PEG & HP-guar - Systane	N = 9 N = 8	45.3 ± 11.8 53.8 ± 14.6	1 week (5x/day) (Actual 3.7±0.9 / 3.5±0.9)	None	Symptoms, Corneal & conjunctival staining, Schirmer’s, TBUT	Symptoms	Schirmer’s TBUT, Corneal & conjunctival staining	CLINICAL TRIAL NOT REGISTERED
Postorino et al 2018^Citation53	Randomized, investigator-masked, single-center study	HA crosslinked + CoQ10 HA 0.15% crosslinked	N = 20 N = 20	60.2 ± 13.6 60.9 ± 12.5	3 months (4x/day)	Symptoms, MGD assessment, corneal / conjunctival staining, epithelial hyperreflectivity and keratocytes with HA + CoQ10	Symptoms, corneal aesthesiometry TBUT	OSDI MGD assessment, corneal / conjunctival staining, epithelial hyperreflectivity and keratocytes with HA + CoQ10 only	Corneal aesthesiometry TBUT	Fluorescein staining only Clinical Trial NCT03074344 - meibomian gland assessment and confocal additionally reported Cochrane Risk of Bias R+C+M-O?I?S-B?
Pult et al 2021^Citation77	Randomized, double-masked, crossover, multi-center study	Phospholipid 0.98% - Tears Again Phospholipid 0.12% - Ocuvers	N=30 (all treatments)	33.2±1.8	Single application	Symptoms, NIBUT with high concentration lipid	None	Symptoms, NIBUT with high concentration lipid only	None	CLINICAL TRIAL NOT REGISTERED
Robert et al 2016^Citation68	Randomized, investigator masked, multi-center study	Cationic Emulsion (Cation Norm) SH 0.18% - Vismed	N = 37 N = 37 Moderate to severe	60.0 ± 14.6 65.3 ± 11.1	3 months (4x/day)	Symptoms at 1 month with SH	TBUT, Schirmer’s, Corneal & conjunctival staining, Osmolarity, Impression cytology	Symptoms, Corneal & conjunctival staining	Schirmer’s, TBUT, Osmolarity, Impression cytology	AE’s 18% CE, 27% HS >10% drop-out Clinical Trial EudraCT 2011-A00955-36 Cochrane Risk of Bias R+C?M-O?I+S+B?
Safarzadeh et al 2017^Citation121	Randomized patient-masked, single-center study	Dextran 70, 1 mg/mL and HPMC – Tears Naturale Dextran 70, 0.1 mg/mL and 0.3 g HPMC – Tearlose	N = 41 N = 47	44.1 ± 6.3 45.8 ± 8.4	4 weeks (2x/day)	None	Symptoms, TBUT, Schirmer’s Corneal & conjunctival staining	Symptoms, TBUT, Corneal & conjunctival staining	Schirmer’s	Fluorescein staining only CLINICAL TRIAL NOT REGISTERED
Sanchez et al 2017^Citation39	Randomized, investigator-masked, single-center study	CMC 0.5% (Viscofresh) HA 0.15% (Lubristil)	N = 7 N = 8	51.8 ± 14.1 71.8 ± 12.2	1 month (4x/day)	TBUT, corneal staining, and HLA-DR with CMC	Schirmer’s Other inflammatory markers	HLA-DR, TBUT & corneal staining with CMC	Schirmer’s, Tear clearance,	No Aes CLINICAL TRIAL NOT REGISTERED
Schmidl et al 2015^Citation51	Randomized, double-masked, single-center study	Trehalose and SH 1.5mg/mL -Thealoz Duo SH, 0.15% - Hyabak NaCL 0.9% - Hydrabak	N = 20 N = 20 N = 20	43.6 ± 13.3 42.9 ± 12.0 41.8 ± 9.9	240 minutes Single application	Tear film thickness (SH+trehalose to 240min and SH to 40min only)	TBUT, Schirmer’s	Tear film thickness (both SH products)	TBUT, Schirmer’s	CLINICAL TRIAL NOT REGISTERED
Simmons and Vehige, 2007^Citation78	Randomized, double-masked, crossover and parallel groups, multi-center studies	CMC 1.0% CMC 0.5% (Refresh Tears)	N = 43 single application Parallel N = 53 N = 50	Mean 62 Not stated	60 minute (single-application) 1 month (4x/day)	Ocular protection index (low viscosity to 20min, high viscosity to 30min). Corneal & conjunctival staining with higher viscosity	Symptoms	Symptoms, Corneal and conjunctival staining	None	Fluorescein staining only. More AEs with high viscosity – visual disturbance 23vs4%; discharge 13vs2% CLINICAL TRIAL NOT REGISTERED
Simmons et al 2015^Citation79	Randomized, investigator-masked, multi-center study	CMC (Refresh Optive Advanced Sensitive), unit dose CMC (Refresh Optive Sensitive), unit dose CMC (Refresh Optive Advanced Sensitive), multi-dose CMC (Refresh Optive Sensitive), multi-dose	N = 105 N = 103 N = 51 N = 56	54.4 ± 14.8 55.8 ± 14.1 55.2 ± 14.5 53.5 ± 13.9	30 days (2x/day +)	None	Symptoms, TBUT, Corneal & conjunctival staining Schirmer’s	OSDI TBUT	Corneal & conjunctival staining, Schirmer’s	No clinically significant differences in safety, effectiveness, and acceptability between lipid and aqueous artificial tears Clinical Trial NCT01459588 Cochrane Risk of Bias R+C?M-O?I+S+B?
Simmons et al 2015^Citation49	Randomized, double-masked, multi-center study	CMC 0.5% + 0.1% HA (Optive Fusion) CMC 0.5% + 0.15HA CMC 0.5% (Refresh Tears)	N = 87 N = 87 N = 90	59.6 ± 14.5 59.2 ± 16.3 60.0 ± 13.3	3 months (2x/day +) (actual 4.3, 3.9, 3.8x/day)	Some symptoms with Fusion Corneal staining with Fusion vs Refresh	Conjunctival staining	Symptoms, Corneal & Conjunctival staining	None	Investigational formulations Clinical Trial NCT01294384 - visual disturbance questionnaire additionally reported Cochrane Risk of Bias R+C+M+O?I+S-B?
Szegedi et al 2018^Citation122	Randomized, patient-masked, single-center study	SH 0.18% + triglycerides, and phospholipids SH 0.18% - Vismed sodium chloride 0.9% - Hydrabak	N = 20? N = 20? N = 20?	34.6 ± 11.7 40.5 ± 9.9 39.2 ± 12.8	40 minutes Single-application	Tear film thickness 40min vs 20min vs 0min with phospholipids	TBUT, Corneal staining, Lipid thickness	Tear film thickness, TBUT, Corneal staining, Lipid thickness	None	Clinical Trial NCT03161080 Cochrane Risk of Bias R?C?M-O-I+S+B?
Tomlison et al 2013^Citation123	Randomized, double-masked, crossover, single-center study	CMC 0.5% - Refresh Tears CMC 0.5%/castor oil - Optive Plus Glycerin 1%/castor oil - Refresh Ultra	N = 18 with dry eye N = 19 controls For all treatments	41 ± 14 30 ± 12	2 weeks 3x/day	Evaporation for both CMCs	Symptoms, TBUT, NIBUT (except for controls), osmolarity	Symptoms, evaporation, TBUT, NIBUT (except for controls), osmolarity	Lipid thickness	Measures taken after adaptation to environmental centre CLINICAL TRIAL NOT REGISTERED
Troiano and Monaco, 2008^Citation46	Randomized, patient-masked, crossover, single-center study	HA 0.4% 300mOsm/L HA 0.4% 150mOsm/L	N = 28 For all treatments	55.5 ± 7.3	7 days 4x/day	Foreign body and dryness symptoms and ocular surface staining with 150mOsm/L	None	Symptoms, hyperaemia, ocular surface staining	None	Reducing osmolarity effective Rose Bengal staining only CLINICAL TRIAL NOT REGISTERED
van Setten et al 2020^Citation124	Substitution, open-label, multi-center study	High molecular weight HA 0.15% - Comfort Shield Over habitual controls	N = 44 N = 40	57.7 ± 14.4 59.5 ± 12.5	8 weeks Actual 8.2 vs 6.5			Symptoms, Visual acuity, nerve fibre length with high molecular weight HA	Corneal staining, TBUT, Schirmer’s, Lid wiper epitheliopathy, mucotaneous junction, osmolarity	Change from habitual optimal artificial tears. No change with controls CLINICAL TRIAL NOT REGISTERED
Waduthantri et al 2012^Citation125	Randomized, double-masked, single-center study	CMC 0.5% - Refresh Tears PEG 400 0.4% / PG/HP-guar 0.3% - Systane Ultra	N = 15 N = 15	54.7 ± 5.8 55.9 ± 5.3	6 weeks 4x/day	None	Symptoms Schirmer’s TBUT, Corneal staining	Symptoms	Schirmer’s TBUT, Corneal staining	Clinical Trial NCT00796926 - meibography, osmolarity and tear meniscus height not reported Cochrane Risk of Bias R+C?M+O+I+S-B+
Wang et al 2007^Citation73	Randomized, open label, single-center study	Carbomer - Vidisic Ophthalmic Gel Cellulose - Artelac Ophthalmic Solution Mineral oil (lanolin) -Duratears Ointment	N = 22 N = 23 N = 22	55.9 ± 15.7 50.1 ± 14.3 60.3 ± 11.2	4 weeks (4x/day for Carbomer and Cellulose) (1x/day before sleep for mineral oil)	Schirmer’s with Carbomer and Cellulose & TBUT with Carbomer	Schirmer’s	Symptoms, TBUT, Schirmer’s		Fluorescein staining only, but not reported in results CLINICAL TRIAL NOT REGISTERED
Wang et al 2010^Citation126	Randomized, open label, single-center study	Carbomer + lipid gel - Liposic Ophthalmic Liquid Gel HP-guar gel - Systane Lubricant Eye Drops	N = 15 N = 15	40.4 ± 15.0 49.5 ± 12.2	2 months (4x/day)	Symptoms & Schirmer’s with Carbomer + lipid	TBUT	Symptoms Schirmer’s TBUT	None	Fluorescein staining only, but not analysed in results CLINICAL TRIAL NOT REGISTERED
Xiao et al 2008^Citation72	Randomized, investigator-masked, single-center study	Carbomer‐based 0.4% gel CMC 1.0%	N = 30 N = 30	46.7 ± 2.3 46.6 ± 2.1	3 months 3x/day +	Symptoms, TBUT, Schirmer’s, corneal staining, ocular residence time with carbomer gel	None	Symptoms, TBUT, Schirmer’s corneal staining (but no statistics presented)	None	Method relating to precorneal residence time missing. Fluorescein staining only. CLINICAL TRIAL NOT REGISTERED

Notes: Grey box = no statistical comparison made; ? = not certain from paper. Cochrane Risk of Bias Tool Rating:³⁵ “+”: low risk; “-”: high risk; “?”: unclear risk; for Random sequence generation (selection bias), allocation Concealment (selection bias); Masking of participants/researchers (performance bias), masking of Outcome assessment (detection bias), Incomplete outcome data (attrition bias), Selective reporting (reporting bias), other Biases (respectively). CLINICAL TRIAL NOT REGISTERED - based on a search of the main registries and paper. © Aston University.

Abbreviations: CoQ10, coenzyme Q10; CMC, carboxymethylcellulose/ carmellose sodium; HA, hyaluronic acid/ hyaluronan; HPMC, Hydroxypropyl methylcellulose; HP-Guar, Hydroxypropyl guar; NaCL, sodium chloride; NIBUT, non-invasive tear breakup time; PEG, polyethylene glycol; PG, propylene glycol; PVA, polyvinyl alcohol; SH, sodium hyaluronate; TBUT, fluorescein tear breakup time; TMH, tear meniscus height; LIPCOF, Lid parallel conjunctival folds.

Figure 1 PRISMA 2020 flow diagram of the systematic review search results.

Notes: PRISMA figure adapted from Liberati A, Altman D, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Journal of clinical epidemiology. 2009;62(10). Creative Commons.¹²⁷

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