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 201469 | 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 202048 | 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 201274 | 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 2014104 | 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 201257 | 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 201062 | 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 200540 | 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 1997105 | 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 1998106 | 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 201141 | 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 201750 | 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 200461 | 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 201463 | 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 2013107 | 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 20214 | 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 200676 | 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 201064 | 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 2019108 | 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 2020109 | 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 2009110 | 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 20183 | 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 2019111 | 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 2018112 | 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 201167 | 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 2012113 | 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 201854 | 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 199266 | 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 200070 | 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 2012114 | 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 2020115 | 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 200660 | 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 200856 | 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, 2010116 | 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 2007117 | 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 2018118 | 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 2020119 | 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 201158 | 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 201952 | 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 199671 | 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 201843 | 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 202055 | 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, 1998120 | 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 200765 | 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 201759 | 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 201647 | 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 201542 | 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 201853 | 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 202177 | 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 201668 | 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 2017121 | 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 201739 | 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 201551 | 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, 200778 | 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 201579 | 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 201549 | 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 2018122 | 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 2013123 | 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, 200846 | 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 2020124 | 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 |
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| Waduthantri et al 2012125 | 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 200773 | 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 2010126 | 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 200872 | 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.