Omega‐3 and omega‐6 polyunsaturated fatty acids for dry eye disease

Laura E Downie; Sueko M Ng; Kristina B Lindsley; Esen K Akpek

doi:10.1002/14651858.CD011016.pub2

. 2019 Dec 18;2019(12):CD011016. doi: 10.1002/14651858.CD011016.pub2

Omega‐3 and omega‐6 polyunsaturated fatty acids for dry eye disease

Laura E Downie ^1,^✉, Sueko M Ng ², Kristina B Lindsley ³, Esen K Akpek ⁴

Editor: Cochrane Eyes and Vision Group

PMCID: PMC6917524 PMID: 31847055

Abstract

Background

Polyunsaturated fatty acid (PUFA) supplements, involving omega‐3 and/or omega‐6 components, have been proposed as a therapy for dry eye. Omega‐3 PUFAs exist in both short‐ (alpha‐linolenic acid [ALA]) and long‐chain (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) forms, which largely derive from certain plant‐ and marine‐based foods respectively. Omega‐6 PUFAs are present in some vegetable oils, meats, and other animal products.

Objectives

To assess the effects of omega‐3 and omega‐6 polyunsaturated fatty acid (PUFA) supplements on dry eye signs and symptoms.

Search methods

CENTRAL, Medline, Embase, two other databases and three trial registries were searched in February 2018, together with reference checking. A top‐up search was conducted in October 2019, but the results have not yet been incorporated.

Selection criteria

We included randomized controlled trials (RCTs) involving dry eye participants, in which omega‐3 and/or omega‐6 supplements were compared with a placebo/control supplement, artificial tears, or no treatment. We included head‐to‐head trials comparing different forms or doses of PUFAs.

Data collection and analysis

We followed standard Cochrane methods and assessed the certainty of the evidence using GRADE.

Main results

We included 34 RCTs, involving 4314 adult participants from 13 countries with dry eye of variable severity and etiology. Follow‐up ranged from one to 12 months. Nine (26.5%) studies had published protocols and/or were registered. Over half of studies had high risk of bias in one or more domains.

Long‐chain omega‐3 (EPA and DHA) versus placebo or no treatment (10 RCTs)

We found low certainty evidence that there may be little to no reduction in dry eye symptoms with long‐chain omega‐3 versus placebo (four studies, 677 participants; mean difference [MD] ‐2.47, 95% confidence interval [CI] ‐5.14 to 0.19 units). We found moderate certainty evidence for a probable benefit of long‐chain omega‐3 supplements in increasing aqueous tear production relative to placebo (six studies, 1704 participants; MD 0.68, 95% CI 0.26 to 1.09 mm/5 min using the Schirmer test), although we did not judge this difference to be clinically meaningful. We found low certainty evidence for a possible reduction in tear osmolarity (one study, 54 participants; MD ‐17.71, 95% CI ‐28.07 to ‐7.35 mOsmol/L). Heterogeneity was too substantial to pool data on tear break‐up time (TBUT) and adverse effects.

Combined omega‐3 and omega‐6 versus placebo (four RCTs)

For symptoms (low certainty) and ocular surface staining (moderate certainty), data from the four included trials could not be meta‐analyzed, and thus effects on these outcomes were unclear. For the Schirmer test, we found moderate certainty evidence that there was no intergroup difference (four studies, 455 participants; MD: 0.66, 95% CI ‐0.45 to 1.77 mm/5 min). There was moderate certainty for a probable improvement in TBUT with the PUFA intervention relative to placebo (four studies, 455 participants; MD 0.55, 95% CI 0.04 to 1.07 seconds). Effects on tear osmolarity and adverse events were unclear, with data only available from a single small study for each outcome.

Omega‐3 plus conventional therapy versus conventional therapy alone (two RCTs)

For omega‐3 plus conventional therapy versus conventional therapy alone, we found low certainty evidence suggesting an intergroup difference in symptoms favoring the omega‐3 group (two studies, 70 participants; MD ‐7.16, 95% CI ‐13.97 to ‐0.34 OSDI units). Data could not be combined for all other outcomes.

Long‐chain omega‐3 (EPA and DHA) versus omega‐6 (five RCTs)

For long‐chain omega‐3 versus omega‐6 supplementation, we found moderate certainty evidence for a probable improvement in dry eye symptoms (two studies, 130 participants; MD ‐11.88, 95% CI ‐18.85 to ‐4.92 OSDI units). Meta‐analysis was not possible for outcomes relating to ocular surface staining, Schirmer test or TBUT. We found low certainty evidence for a potential improvement in tear osmolarity (one study, 105 participants; MD ‐11.10, 95% CI ‐12.15 to ‐10.05 mOsmol/L). There was low level certainty regarding any potential effect on gastrointestinal side effects (two studies, 91 participants; RR 2.34, 95% CI 0.35 to 15.54).

Authors' conclusions

Overall, the findings in this review suggest a possible role for long‐chain omega‐3 supplementation in managing dry eye disease, although the evidence is uncertain and inconsistent. A core outcome set would work toward improving the consistency of reporting and the capacity to synthesize evidence.

Plain language summary

Omega‐3 and omega‐6 polyunsaturated fatty acid supplements for dry eye disease

What is the aim of this review?  Dry eye is a long‐term eye condition that can lead to eye discomfort and changes to vision. Omega‐3 and omega‐6 supplements, including the omega‐3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have been studied as a treatment for dry eye. This Cochrane Review summarizes the best available research evidence.

Key messages  More research is needed to gain a full understanding of the role of omega‐3 and omega‐6 supplements in treating dry eye disease, particularly with how to use this therapy to treat dry eye due to different causes and severities. There is also a need for more research to provide information about how the supplement characteristics (eg, dose, form, composition) affect clinical outcomes.

What was studied in the review?  The main outcome was improvement in dry eye symptoms, measured after at least one month of follow‐up. Secondary outcomes considered a range of clinical measures and side effects.

What are the main results of the review?  We included 34 randomized controlled trials (RCTs) involving more than 4314 adult participants from 13 countries.

Although much of the evidence was uncertain, long‐chain omega‐3 supplements may have little to no benefit, relative to placebo, on dry eye symptoms, but did improve some clinical signs. There was a beneficial effect on dry eye symptoms when omega‐3 supplements were combined with standard dry eye treatments (eg, artificial tears, eyelid warm compresses, corticosteroid eye drops) compared to standard treatment alone, and when long‐chain omega‐3 supplements were compared with omega‐6 supplements. The most common side effect was temporary gastrointestinal problems.

For combined omega‐3 and omega‐6 supplements, relative to placebo, there was no benefit for tear production, and a small amount of improvement in the stability of the tears. Effects on other clinical measures, including dry eye symptoms and side effects, could not be clearly determined. It is also unclear whether other types of supplement combinations are effective for treating dry eye. We have low to moderate confidence in the evidence for all outcomes.

These findings suggest that long‐chain omega‐3 supplements may have a role in managing dry eye, however the evidence is currently inconsistent and more research is needed.

How up‐to‐date is this review?  The Cochrane review authors searched for studies that had been published up to February 2018. A top‐up search was conducted in October 2019, but the results have not yet been incorporated.

Summary of findings

Background

Description of the condition

Dry eye disease, as recently defined in the Tear Film and Ocular Surface (TFOS) International Dry Eye WorkShop II (DEWS II) report, is a "multifactorial disease of the ocular surface characterized by loss of homeostasis of the tear film, and accompanied by ocular symptoms, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neuro‐sensory abnormalities play aetiological roles” (Craig 2017). Dry eye disease is highly prevalent. Based upon epidemiological studies, the prevalence of dry eye worldwide varies considerably depending on the study population, the definition of dry eye, and the diagnostic criteria used. In adults, the prevalence of dry eye signs, with the presence or absence of symptoms, has been reported to range from approximately 5% to 50% (Stapleton 2017). It has been estimated that in the United States, more than five million adults aged 50 years or older have clinically significant dry eye disease (Schaumberg 2003; Schaumberg 2009). A range of risk factors for the condition have been identified and include advancing age, female sex, race (in particular, Asian ethnicity), certain medical conditions (eg, connective tissue disease, Sjögren's syndrome, androgen deficiency, diabetes), contact lens wear, some systemic medications (eg, estrogen replacement therapy, antihistamines, anxiolytics, antidepressants, diuretics), and certain environmental conditions (eg, computer use, low ambient humidity, air pollution) (Stapleton 2017).

Dry eye disease typically is associated with symptoms of ocular discomfort, including foreign body sensation, dryness, irritation, burning, and light sensitivity (Lemp 1995; Miljanovic 2005). The condition can have a major negative impact on quality of life (Schiffman 2003). Dry eye disease also is highly correlated with anxiety and depression (Li 2011). In 2011, the direct economic burden of dry eye disease in the United States was estimated to be $3.4B per annum (Yu 2011). With respect to indirect costs, the burden of disease is due primarily to losses in workplace productivity (Yu 2011).

In terms of its etiology, dry eye disease involves perturbation(s) to the lacrimal functional unit comprising the lacrimal gland and its accessory glands, ocular surface components (eg, cornea, conjunctiva), meibomian glands, and eyelids and their associated sensory and motor innervation (Stern 1998). Under physiologic conditions, the integrated lacrimal functional unit regulates tear secretion, distribution, and clearance to maintain ocular surface integrity. Disruption to one or more of its components promotes loss of tear homeostasis and tear film dysfunction. Dry eye disease can be primarily aqueous deficient or evaporative in etiology (Craig 2017); the former involves primarily reduced lacrimal grand secretion, whereas the latter is due predominantly to abnormalities in the lipid‐secreting meibomian glands.

Clinically, the diagnosis of dry eye can be challenging, as objective clinical signs and self‐reported symptoms are not well correlated (Downie 2015a; Johnson 2009; Nichols 2004). Although more recent studies indicate that this might be so because some ocular surface and tear film parameters are too dynamic for reliable measurement at rest, and that subjecting patients to a desiccating stress correlates better with "real‐life" tear film function (Karakus 2018). In 2017, the TFOS DEWS II Diagnostic Methodology subcommittee report outlined a contemporary approach to dry eye diagnosis, factoring in the quality of research evidence for current tests and their clinical accessibility (Wolffsohn 2017). This approach involves consideration of both patient symptoms and key clinical signs that are indicative of loss of tear film homeostasis (ie, tear instability, tear hyperosmolarity, and ocular surface damage) (Downie 2015c; Wolffsohn 2017).

In terms of management and therapy for dry eye disease, both pharmacologic and non‐pharmacologic therapeutic options are available (AAO 2013; Jones 2017). Although the mainstay of therapy involves artificial tear drops to supplement the tear film, this modality provides only temporary symptomatic relief, and up to two‐thirds of dry eye sufferers remaining symptomatic despite adherence to treatment (Downie 2015b). Depending on disease severity, other management options include devices or procedures for tear retention (eg, punctal occlusion, moisture‐conserving spectacles, contact lenses), devices or procedures for tear stimulation (eg, intranasal neurogenic tear stimulation, vectored thermal pulsation), pharmacologic tear stimulation (ie, secretagogues), biological tear substitutes (eg, serum and salivary gland autotransplantation), anti‐inflammatory medications (eg, cyclosporine, lifitegrast, corticosteroids, tetracyclines), surgical approaches, dietary interventions, environmental modifications, and complementary therapies. As recently reviewed, there is currently a paucity of high‐quality randomized controlled trial (RCT) evidence for many of these treatment options (Jones 2017), and this poses a challenge for implementing best practice clinical care, particularly with regard to instituting specific treatments for patients with different dry eye subtypes.

Description of the intervention

Fatty acids are composed of a methyl group at one end, a hydrocarbon chain in the middle, and a carboxyl group at the other end. Polyunsaturated fatty acids (PUFAs) are fatty acids that have two or more double bonds in the hydrocarbon chain. Omega‐3 and omega‐6 PUFAs have their first double bond located at the 3‐ or 6‐carbon from the methyl end, respectively. Because humans are unable to synthesize either omega‐3 or omega‐6 PUFAs in vivo, these fatty acids must be obtained from the diet or through supplementation.

Omega‐3 PUFAs exist as both long‐chain (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) and short‐chain (α‐linolenic acid [ALA]) subtypes. Short‐chain omega‐3s are present in relatively high amounts in certain vegetable oils (eg, flaxseed oil, canola oil) and terrestrial plants (eg, walnuts, chia seeds). Long‐chain omega‐3s derive predominantly from oily fish (eg, salmon, mackerel, anchovies, sardines) and to a lesser extent from other marine sources (eg, oysters, mussels, prawns) (James 2000; Kris‐Etherton 2007). Within the body, short‐chain ALA can be converted to the long‐chain omega‐3 PUFAs (EPA and DHA), although the efficiency of this conversion may be age‐dependent (Brenna 2002). Omega‐6 PUFAs, such as arachidonic acid and linoleic acid, are present in some vegetable oils (eg, corn, safflower, sunflower seed), meats (eg, poultry), and other animal products (James 2000; Kris‐Etherton 2007).

The American Dietetic Association (ADA), jointly with the Dietitians of Canada (DC), recommend that dietary fat for adults should provide 20% to 35% of daily energy requirements, with an intake of omega‐3 PUFAs of 500 mg per day, which is equivalent to consuming approximately 8 oz (227 g) of oily fish per week (Kris‐Etherton 2007). Adequate intakes (AIs) for omega‐6 PUFAs, which are estimated to cover the needs of individuals based on age and gender, are 17 g per day for men aged 19 to 50 years, 14 g per day for men older than 50 years, 12 g per day for women aged 19 to 50 years, and 11 g per day for women older than 50 years (IOM 2002). The recommended range for omega‐6 PUFAs is 3% to 10% of energy intake (Kris‐Etherton 2007). Table 6 summarizes the classification, structure, common food sources, and dietary recommendations for omega‐3 and omega‐6 PUFAs.

2. Table 1. Omega‐3 and omega‐6 polyunsaturated fatty acids ‐ structure, common food sources, and recommendations.

Polyunsaturated fatty acid (PUFA) classification		Structure (number of carbons:number of double bonds)	Example food sources	Recommendations from the American Dietetic Association and Dietitians of Canada (Kris‐Etherton 2007)
Omega‐3	Alpha‐linolenic acid (ALA)	C18:3	Flaxseed, canola oil, soybean oil	0.6% to 1.2% of total energy intake for ALA 500 mg (approximately 8 oz [227 g] of cooked fish per week) for sufficient omega‐3 long‐chain PUFA (EPA or DHA) intake
	Eicosapentaenoic acid (EPA)	C20:5	Oily fish
	Docosahexaenoic acid (DHA)	C22:6	Oily fish
Omega‐6	Linoleic acid (LA)	C18:2	Soybean oil, safflower oil, corn oil	3% to 10% of total energy intake; range of 11 to 17 g per day depending on age and sex
Omega‐6	Arachidonic acid (AA)	C20:4	Meat, poultry, eggs

Oral long‐chain omega‐3 PUFAs (EPA and DHA) compared with placebo or no treatment for dry eye
Patient or population: people with dry eye^a Settings: primary care setting Intervention: oral long‐chain omega‐3 PUFAs (EPA and DHA)^b Comparison: placebo or no treatment^c
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No. of participants  (studies)	Certainty of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo or no treatment	Oral long‐chain omega‐3 PUFAs
Change in dry eye symptoms, measured using the OSDI score (ranging from 0 to 100 units, with a reduction in scores indicating clinical improvement) at 1‐month (with actual follow‐up ranging from 1 to 12 months)	The pooled summary estimate from four studies (Asbell 2018; Deinema 2017; Goyal 2017; Kangari 2013) indicated little to no reduction in symptoms of dry eye (mean difference [MD] ‐2.47 OSDI units, 95% CI ‐5.14 to 0.19 units, n=677, I² = 48%). Three additional studies (Bhargava 2015a; Bhargava 2016a; Bhargava 2016b) reported a significant difference in mean symptom score at the end of the follow‐up period, quantified using the Dry Eye Questionnaire and Scoring System (DESS).			1785  (7 studies)	⊕⊕⊝⊝  low^d	In addition, symptom score data were reported only as P‐values or in a non‐numeric form in two studies (Kawakita 2013;  Pinazo‐Durán 2013), or included non‐dry eye participants (as in Kawashima 2016).
Change in ocular surface staining at 1‐month (with actual follow‐up ranging from 8 weeks to 12 months)	Two studies found no evidence of a difference between groups for change in corneal fluorescein staining score (Deinema 2017: MD ‐0.31, 95% CI ‐0.66 to 0.04 units, quantified using the Oxford scale; Asbell 2018: MD 0.1, 95% CI ‐0.2 to 0.4 units; P = 0.61, quantified using an unspecified grading scale). Goyal 2017 reported that the control group had a higher rate of conjunctival staining with lissamine green (43.4%) compared with the omega‐3 treatment group (14%), at 3‐months of follow‐up (P=0.009). Kawakita 2013 considered combined corneal and conjunctival staining using rose bengal, and reported that the fish oil (omega‐3) group were “significantly improved to those in the placebo group" after 8 and 12 weeks of treatment.			681 (4 studies)	⊕⊕⊝⊝  low^d	No relevant combinable  data were available for this outcome.
Change in Schirmer test (aqueous tear production, measured in mm/5 min, with higher scores indicating more tear production) at 1‐month (with actual follow‐up ranging from 1 to 6 months)	The pooled summary estimate from six studies (Asbell 2018; Bhargava 2015a; Bhargava 2016a; Bhargava 2016b; Deinema 2017; Kangari 2013) showed an improvement in Schirmer test score with long‐chain omega‐3 supplementation relative to the control (MD 0.68, 95% CI 0.26 to 1.09 mm/5 min, n=1704, I² = 16%). In addition, one study (Kawakita 2013, n=26) described no significant inter‐group difference in Schirmer test score, but did not provide quantitative data.			1730  (7 studies)	⊕⊕⊕⊝  moderate^e	For one additional study, we could not incorporate data into the analyses due to unit of analysis errors (Goyal 2017). Two other trials did not separately report data for dry eye participants versus non‐dry eye (healthy) controls (Kawashima 2016; Pinazo‐Durán 2013).
Change in tear film stability, measured using tear break‐up time (TBUT) with fluorescein (in seconds, with higher scores indicating greater tear film stability) at 1‐month (with actual follow‐up ranging from 45 days to 12 months)	Four studies (Bhargava 2015a; Bhargava 2016a; Bhargava 2016b; Deinema 2017) reported a significantly improved TBUT with the omega‐3 PUFA intervention compared with placebo, and 1 study (Asbell 2018) reported no significant difference between treatment groups. Meta‐analysis was not performed due to substantial heterogeneity (I² = 98%).			1640 (5 studies)	⊕⊕⊝⊝  low^d	The remaining studies were not included in the analysis due to insufficient data reporting (Kangari 2013;  Kawakita 2013; Pinazo‐Durán 2013) or the presence of an unit of analysis error (Goyal 2017).
Change in tear osmolarity (measured in mOsmol/L, with reductions in osmolarity indicating clinical improvement) at 1‐month (with actual follow‐up at 3 months)	Deinema 2017 reported that the mean difference in tear osmolarity was significantly reduced (improved) relative to baseline in the omega‐3 group relative to the placebo group at day 90 (MD: ‐17.71, 95% CI ‐28.07 to ‐7.35 mOsmol/L).			54 (1 study)	⊕⊕⊝⊝  low^d
Adverse event: gastrointestinal disorders at 1‐month (with actual follow‐up ranging from 3 to 12 months)	Three studies (Asbell 2018; Bhargava 2016a; Deinema 2017) reported that gastrointestinal disorders were reported in between 5% and 19% of participants in the omega‐3 group and between 0% and 24% of participants in the placebo group. Meta‐analysis was not performed due to substantial heterogeneity (I² = 76%).			719  (3 studies)	⊕⊕⊝⊝  low^f	The presence or absence of adverse events was not indicated in three studies (Goyal 2017; Kawakita 2013;  Pinazo‐Durán 2013).
The basis for the assumed risk* (ie, the median control group risk across studies) is provided in the footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; DESS: Dry Eye Questionnaire and Scoring System; DHA: docosahexaenoic acid; EPA: eicosapentaenoic acid; MD: mean difference; OSDI: Ocular Surface Disease Index; PUFA: polyunsaturated fatty acid; RCT: randomized controlled trial; RR: risk ratio; TBUT: tear break‐up time.
GRADE Working Group grades of evidence.  High quality: further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: we are very uncertain about the estimate. ^aDry eye associated with computer vision syndrome (Bhargava 2015a), rosacea (Bhargava 2016a), visual display terminal use (Bhargava 2016b), and post laser‐assisted in situ keratomileusis (LASIK) (Goyal 2017). The remaining studies included patients with non‐specific causes of dry eye. ^bDaily dose of EPA and DHA varied substantially between studies, ranging from a daily value of EPA of 85 mg to 2000 mg, and DHA of 108 mg to 1000 mg (see Table 2 for details). ^cAll studies used a placebo intervention, except for Pinazo‐Durán 2013 (no treatment). ^dDowngraded one level for each of risk of bias and inconsistency. ^eDowngraded one level for risk of bias. ^fDowngraded one level for each of inconsistency and imprecision.

Combined oral omega‐3 and omega‐6 PUFAs compared with placebo for dry eye
Patient or population: people with dry eye^a Settings: primary care setting Intervention: combined oral omega‐3 and omega‐6 PUFAs^b Comparison: placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No. of participants  (studies)	Certainty of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo	Combined oral omega‐3 and omega‐6 PUFAs
Symptoms of dry eye at 1‐month (with actual follow‐up ranging from 3 to 6 months)	The Oral sea buckthorn oil study 2010 evaluated eight dry eye symptoms, and reported that the PUFA intervention was more efficacious in reducing ocular burning (P = 0.05) than placebo at 3 months of follow‐up. Creuzot 2006 assessed eight dry eye symptoms, and reported that the number of participants who had specific symptoms ameliorated was significantly greater in the PUFA supplement group compared with the placebo group for conjunctival hyperemia (P = 0.045), reflex lacrimation (P = 0.047), sensations of dryness (P = 0.059), and discomfort (P = 0.091). Creuzot‐Garcher 2011 assessed six dry eye symptoms and reported no significant inter‐group difference except in one sub‐domain (sensation of eye fatigue; P = 0.044). Brignole‐Baudouin 2011 quantified five dry eye symptoms to derive a 'global subjective dry eye score' and reported that neither the global score, nor the analysis of each symptom showed a significant difference between groups at the 3‐month study endpoint.			Not explicitly reported (4 studies)	⊕⊕⊝⊝  low^c	No relevant combinable  data were available for this outcome, as studies either did not provide quantitative data or used different measurement scales.
Ocular surface staining at 1‐month (with actual follow‐up ranging from 3 to 6 months)	No significant intergroup difference was observed for corneal fluorescein staining at the study endpoint of 3 months (Brignole‐Baudouin 2011), and 6 months (Creuzot‐Garcher 2011).    Creuzot 2006 reported that the PUFA supplement had an effect on corneal fluorescein staining, whereby at six months of follow‐up, 32% of participants had no corneal staining compared with 25% of participants in the placebo group.			Not explicitly reported (3 studies)	⊕⊕⊕⊝  moderate^d	No relevant combinable  data were available for this outcome, as studies either did not provide quantitative data or used different rating scales.
Schirmer test (aqueous tear production, measured in mm/5 min, with higher scores indicating more tear production) at 1‐month (with actual follow‐up ranging from 3 to 6 months)	The pooled summary estimate from four studies (Brignole‐Baudouin 2011; Creuzot 2006; Creuzot‐Garcher 2011; Oral sea buckthorn oil study 2010) showed no difference between the PUFA and placebo supplement groups (MD 0.66, 95% CI ‐0.45 to 1.77 mm/5 min, n=455, I² = 0%).			455  (4 studies)	⊕⊕⊕⊝  moderate^d
Change in tear film stability, measured using tear break‐up time (TBUT) with fluorescein (in seconds, with higher scores indicating greater tear film stability) at 1‐month (with actual follow‐up ranging from 3 to 6 months)	The pooled summary estimate from four studies (Brignole‐Baudouin 2011) indicated a significant improvement with combined omega‐3 and omega‐6 supplementation relative to placebo (MD 0.55, 95% CI 0.04 to 1.07 seconds, n=455, I² = 0%).			455 (4 studies)	⊕⊕⊕⊝  moderate^d
Change in tear osmolarity (measured in mOsmol/L, with reductions in osmolarity indicating clinical improvement) at 1‐month (with actual follow‐up at 3 months)	In Oral sea buckthorn oil study 2010, tear osmolarity was reported to increase in both groups, but the increase (worsening) was significantly greater in the placebo group after adjustment for "significant" covariates (P = 0.04).			83 to 96 (1 study)	⊕⊕⊝⊝  low^e
Adverse event: gastrointestinal disorders at 1‐month (with actual follow‐up at 3 months)	Brignole‐Baudouin 2011 reported that four (6.0%) participants in the PUFA intervention group and five (7.1%) participants in the placebo group experienced treatment‐related, non‐ocular adverse events.			138 (1 study)	⊕⊕⊝⊝  low^e
The basis for the assumed risk* (ie, the median control group risk across studies) is provided in the footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). ALA: alpha‐linolenic acid; CI: confidence interval; DHA: docosahexaenoic acid; EPA: eicosapentaenoic acid; MD: mean difference; PUFA: polyunsaturated fatty acid; RCT: randomized controlled trial; TBUT: tear break‐up time.
GRADE Working Group grades of evidence.  High quality: further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: we are very uncertain about the estimate. ^aDry eye in individuals with (non‐specific) dry eye (Oral sea buckthorn oil study 2010), mild to moderate dry eye disease (Brignole‐Baudouin 2011; Creuzot 2006), or moderate dry eye disease (Creuzot‐Garcher 2011). ^bDaily dose of EPA from 28 mg to 427.5 mg; DHA from 285 mg to 392 mg; "omega‐6" 15 mg; γ‐linolenic 82 mg; linoleic acid 126. ^cDowngraded one level for risk of bias and one level for inconsistency. ^dDowngraded one level for risk of bias. ^eDowngraded one level for risk of bias and one level for imprecision.

Oral omega‐3 PUFAs plus conventional therapy versus conventional therapy alone, for dry eye
Patient or population: people with dry eye^a Settings: primary care setting Intervention: oral omega‐3 PUFAs plus conventional therapy^b Comparison: conventional therapy^c
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No. of participants  (studies)	Certainty of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Conventional therapy	Oral omega‐3 PUFAs plus conventional therapy
Dry eye symptoms, measured using the OSDI score (ranging from 0 to 100 units, with a reduction in scores indicating clinical improvement) at 1‐month (with actual follow‐up ranging from 1 month to 3 months)	The pooled summary estimate from two studies (Korb 2015; Mohammadpour 2017) showed a significantly improved (lower) OSDI score at the study endpoint with omega‐3 supplementation plus conventional therapy, relative to conventional therapy alone (MD ‐7.16, 95% CI ‐13.97 to ‐0.34, n=70, I² = 0%).			70  (2 studies)	⊕⊕⊝⊝  low^d,e	Both studies reported OSDI at the study endpoint, rather than as change from baseline.
Change in ocular surface staining at 1‐month	‐	‐	‐	‐	‐	Neither study addressed this outcome.
Change in Schirmer test (aqueous tear production, measured in mm/5 min) at 1‐month of follow‐up	‐	‐	‐	‐	‐	There were no relevant combinable  data available for this outcome. One study (Mohammadpour 2017), with a unit of analysis error, reported no significant intra‐ or inter‐group differences in Schirmer test scores at the study endpoint.
Change in tear film stability, measured using tear break‐up time (TBUT) with fluorescein (in seconds) at 1‐month	‐	‐	‐	‐	‐	There were no relevant combinable  data available for this outcome. One study (Mohammadpour 2017), with a unit of analysis error, reported that the mean "TBUT improved in both (intervention) groups (p<0.001). However, TBUT was affected significantly more in the treatment group compared with the control group, p=0.038" (see Effects of interventions for further detail).
Change in tear osmolarity (measured in mOsmol/L, with reductions in osmolarity indicating clinical improvement) at 1‐month	‐	‐	‐	‐	‐	There were no relevant combinable  data available for this outcome. One study (Mohammadpour 2017), with a unit of analysis error, reported that the mean tear osmolarity significantly improved from 315.40 ± 17.06 to 296.90 ± 14.39 in the omega‐3 treatment group (P < 0.001) but not in the control group (P = 0.157) (see Effects of interventions for further detail).
Adverse events at 1‐month	‐	‐	‐	‐	‐	There were no relevant combinable  data available for this outcome. One study (Korb 2015) reported that "a total of two adverse events (infectious mononucleosis and sinusitis) were reported for a single patient in the combination treatment group (omega‐3s plus conventional therapy); neither was considered to be treatment related."
The basis for the assumed risk* (ie, the median control group risk across studies) is provided in the footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; DHA: docosahexaenoic acid; EPA: eicosapentaenoic acid; MD: mean difference; OSDI: Ocular Surface Disease Index; PUFA: polyunsaturated fatty acid.
GRADE Working Group grades of evidence.  High quality: further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: we are very uncertain about the estimate. ^aEvaporative dry eye ‐ Korb 2015 ‐ and dry eye secondary to cataract surgery ‐ Mohammadpour 2017. ^bIn Korb 2015, the "Intervention" consisted of lid hygiene with hypoallergenic eyelid cleansing wipes (Systane Lid Wipes; Alcon Laboratories, Inc., Fort Worth, TX, USA) once daily; instilled 1 drop of lipid emulsion eye drops formulated to restore lipid, aqueous, and mucin components of the tear film (Systane Balance; Alcon) 4 times daily; and 2 oral vitamin supplements containing 1000 mg of omega‐3 fatty acids (Systane Vitamin Omega‐3 Healthy Tears; Alcon), daily for 3 months (daily dose of 2000 mg of omega‐3 fatty acids). In Mohammadpour 2017, the "Intervention" consisted of standard therapy plus omega‐3 dietary supplement (1000 mg every 8 hours, Advanced Canada, each capsule containing 180 mg EPA and 120 mg DHA) every 8 hours (daily dose of 510 mg EPA and 360 mg DHA). ^cIn Korb 2015, the "Comparison" (conventional therapy) consisted of a warm wet microfiber compress (from Terry World Textiles, LLC, Santa Monica, CA, USA) to both eyelids for 8 minutes once daily, for 3 months. In Mohammadpour 2017, conventional therapy consisted of artificial tears (every 4 hours) and betamethasone 0.1% eye drops (every 8 hours). ^dDowngraded one level for risk of bias. ^eDowngraded one level for imprecision.

Study ID Study design	Condition(s) included	Total number of randomized participants	Intervention(s) studied					Follow‐up period
Aragona 2005 Randomized, parallel‐group, controlled trial	Moderate to severe dry eye disease associated with primary Sjögren’s syndrome	40	Omega‐6 supplementation: oral sachets containing linoleic acid 112 mg and γ‐linolenic acid 15 mg, twice daily (daily dose of linoleic acid 224 mg and γ‐linolenic acid 30 mg)				Placebo oral sachets, twice daily Each placebo sachet contained placebo with only non‐active excipients (matched to the omega‐6 arm), as follows  ‐ Fructose 2383.3 mg  ‐ Monohydrate citric acid 50 mg  ‐ Aspartame 12.5 mg  ‐ Silicon dioxide 6 mg  ‐ Bigrade aroma 45 mg  ‐ Citrus aroma 131 mg	1 month
Asbell 2018 Randomized, controlled trial	Moderate to severe dry eye disease	535	Omega‐3 supplementation^a: 5 soft gelatin oral capsules per day containing triglyceride omega‐3 PUFAs (400 mg EPA and 200 mg DHA) (daily dose of 2000 mg EPA and 1000 mg DHA)				Placebo (5 oral 1000 mg olive oil capsules), comprising 68% oleic acid, 13% palmitic acid, and 11% linoleic acid^a (daily dose of 5000 mg olive oil)	12 months
Barabino 2003 Randomized, parallel‐group, controlled trial	Dry eye disease	26	Omega‐6 supplementation^b: oral tablets containing linoleic acid 28.5 mg and γ‐linolenic acid 15 mg, twice daily (daily dose of linoleic acid 57 mg and γ‐linolenic acid 30 mg)				Placebo ("specially made tablets containing a low quantity of sugar at the same dose as the study group") oral tablets twice daily^b	45 days
Bhargava 2013 Randomized, parallel‐group, controlled trial	Dry eye syndrome	518	Omega‐3 supplementation: oral 500 mg soft gel capsule containing EPA 325 mg and DHA 175 mg, twice daily (daily dose of EPA 650 mg and DHA 350 mg)				Placebo oral capsules (500 mg), containing corn oil, twice daily	3 months
Bhargava 2015a Randomized, parallel‐group, controlled trial	Dry eye associated with computer vision syndrome	478	Omega‐3 supplementation: oral capsule containing EPA 180 mg and DHA 120 mg, 2 capsules/time, twice daily (daily dose of 720 mg EPA and 480 mg DHA)				Placebo capsules containing olive oil (dose not reported), twice daily	3 months
Bhargava 2015b Randomized, parallel‐group, controlled trial	Dry eye associated with contact lens wear	496 females	Omega‐3 supplementation: oral capsule containing EPA 180 mg and DHA 120 mg, 2 capsules/time, twice daily (daily dose of 720 mg EPA and 480 mg DHA)				Placebo oral capsules containing corn oil (dose not reported), twice daily	6 months
Bhargava 2016a Randomized, parallel‐group, controlled trial	Dry eye in rosacea patients	130	Omega‐3 supplementation: oral capsule containing EPA 180 mg and DHA 120 mg, 2 capsules/time, twice daily (daily dose of 720 mg EPA and 480 mg DHA)				Placebo oral capsules containing olive oil (dose not reported), 2 capsules/time, twice daily	6 months
Bhargava 2016b Randomized, parallel‐group, controlled trial	Dry eye in visual display terminal users	522	Omega‐3 supplementation: oral capsule containing EPA 180 mg and DHA 120 mg, 4 capsules/time, twice daily (daily dose of 1440 mg EPA and 960 mg DHA)				Placebo oral capsules containing olive oil (dose not reported), 4 capsules/time, twice daily	45 days
Brignole‐Baudouin 2011 Randomized, parallel‐group, controlled trial	Mild to moderate dry eye syndrome	138	Combined omega‐3 and omega‐6 supplementation: oral soft gel capsule containing fish oil (omega‐3 average of 285 mg, including EPA 142.5 mg and DHA 95 mg, and omega‐6 average of 5 mg), 3 capsules daily (daily dose of omega‐3: 855 mg including EPA 427.5 mg and DHA 285 mg, and omega‐6: 15 mg)				Placebo oral soft gel capsule containing medium‐chain triglycerides (daily dose: 575 mg)	3 months
Creuzot 2006 Randomized, parallel‐group, controlled trial	Mild to moderate dry eye syndrome	71	Combined omega‐3 and omega‐6 supplementation: oral capsule containing omega‐3 PUFAs (DHA 196 mg and EPA 14 mg), omega‐6 PUFA (γ‐linolenic acid 41 mg or linoleic acid 63 mg), various vitamins (C, E, B6, B9, B12), and a trace element (zinc) (Nutrilarm, Laboratoires Thea), twice daily (daily dose of EPA 28 mg and DHA 392 mg as omega‐3 PUFAs, and γ‐linolenic acid 82 mg or linoleic acid 126 mg as omega‐6 PUFAs)				Placebo oral capsule containing oleic acid (dose not reported) twice daily (2 capsules per day)	6 months
Creuzot‐Garcher 2011 Randomized, parallel‐group, controlled trial	Moderate dry eye	181	Combined omega‐3 and omega‐6 supplementation: oral capsule containing omega‐3 PUFAs (DHA 196 mg and EPA 14 mg), omega‐6 PUFA (γ‐linolenic acid 41 mg or linolenic acid 63 mg), various vitamins (C, E, B6, B9, B12), and a trace element (zinc) (Nutrilarm, Laboratoires Thea), twice daily (daily dose of EPA 28 mg and DHA 392 mg as omega‐3 PUFAs, and γ‐linolenic acid 82 mg or linolenic acid 126 mg as omega‐6 PUFAs)				Placebo oral capsule (composition not reported) twice daily (2 capsules per day)	6 months
Deinema 2017 Randomized, parallel‐group, controlled trial	Mild to moderate dry eye disease	60	Omega‐3 supplementation: fish oil capsules (triglyceride omega‐3 PUFAs) (daily dose of 1000 mg EPA and 500 mg DHA)		Omega‐3 supplementation: krill oil capsules (phospholipid omega‐3 PUFAs) (daily dose of 945 mg EPA and 510 mg DHA)		Placebo oral capsules (daily dose of 1500 mg)	90 days
Epitropoulos 2016 Randomized, parallel‐group, controlled trial	Dry eye disease associated with meibomian gland dysfunction	122	Omega‐3 supplementation: oral capsules containing re‐esterified omega‐3 PUFAs: 420 mg EPA and 140 mg DHA (daily dose of 1680 mg EPA and 560 mg DHA)				Control oral capsules containing 3136 mg linoleic acid (safflower oil, omega‐6 fatty acid)	12 weeks
Gilbard 2008 Randomized, parallel‐group, controlled trial	Sjögren’s syndrome	61	Omega‐3 supplementation: TheraTears Nutrition (no other details reported, although this product contains EPA, DHA, and ALA)				Placebo oral capsules containing wheat germ oil (dose not reported)	Not reported
Goyal 2017 Randomized, controlled trial	Dry eye associated with LASIK	60	Omega‐3 supplementation: oral capsule containing 180 mg EPA and 120 mg DHA, 2 capsules/time, twice daily (daily dose of 720 mg EPA and 480 mg DHA)				Placebo oral capsule containing vitamin E (daily dose of 400 mg)	13 weeks
Kangari 2013 Randomized, parallel‐group, controlled trial	Dry eye syndrome	73	Omega‐3 supplementation: oral capsule containing EPA 180 mg and DHA 120 mg, twice daily (daily dose of EPA 360 mg and DHA 240 mg)				Placebo oral capsule (1 g) containing medium‐chain triglycerides, twice daily	1 month
Kawakita 2013 Randomized, controlled trial	Dry eye	27	Omega‐3 supplementation: oral soft gel capsule containing EPA 83 mg and DHA 36 mg 3 times daily, 5 capsules/time, 3 times daily (15 capsules/d) (daily dose of EPA 1245 mg and DHA 540 mg)				Placebo oral capsules containing mainly medium‐chain triglycerides (dose not reported)	3 months
Kawashima 2016 Randomized, controlled trial	Dry eye^c	40^c	Omega‐3 supplementation: oral capsules containing 40.5 mg EPA and 27 mg DHA, 2 capsules/time, once daily (daily dose of 81 mg EPA and 54 mg DHA)				"Vehicle" (no further details provided), 2 capsules/time, once daily	8 weeks
Kokke 2008 Randomized, parallel‐group, controlled trial	Dry eye associated with soft contact lens wear	76 females	Omega‐6 supplementation: oral capsule containing evening primrose oil (linoleic acid about 57 mg and γ‐linolenic acid 50 mg, Equazen UK Ltd.), 6 capsules daily (daily dose of linoleic acid about 342 mg and γ‐linolenic acid 300 mg				Placebo capsule containing olive oil (78.0% oleic acid, 11.2% palmitic acid, and 5.6% mainly linoleic acid), 6 capsules daily	6 months
Korb 2015 Randomized, controlled trial	Lipid deficient/evaporative dry eye	26	Omega‐3 supplementation^d: oral 1000 mg capsule of "omega‐3 fatty acids" (unspecified)				No oral capsules; warm wet microfiber compress to both eyelids for 8 minutes once daily	3 months
Macsai 2008 Randomized, controlled trial	Simple obstructive meibomian gland dysfunction and blepharitis	38	Omega‐3 supplementation^e: flaxseed oil oral 1000 mg capsules 2 capsules/time, 3 times daily (daily dose of 6 g flaxseed oil, comprising approximately 55% ALA, 15% linoleic acid, and 19% oleic acid. Total daily dose of omega‐3 fatty acids: 3.3 g)				Olive oil oral capsules (dose not reported), 6 capsules daily^e	1 year
Manthorpe 1984 Randomized, cross‐over, controlled trial	Keratoconjunctivitis sicca associated with primary Sjögren’s syndrome	36	Omega‐6 supplementation: oral capsule (500 mg) containing cis‐linoleic acid 365 mg and γ‐linolenic acid 45 mg, Efamol twice daily (3 capsules at a time) plus a tablet containing vitamin C 125 mg, pyridoxine 25 mg, niacin 25 mg, and ZnSo4 5 mg (Efavit) twice daily (3 tablets at a time) (daily dose of linoleic acid 2190 mg and γ‐linolenic acid 270 mg)				"Placebo" oral 500 mg capsule (composition not reported), dosed twice daily (3 capsules at a time)	3 weeks in each cross‐over phase
Mohammadpour 2017 Randomized, controlled trial	Post cataract surgery dry eye	48	Omega‐3 supplementation^f: oral 1000 mg (Advanced Canada containing 180 mg EPA and 120 mg DHA), every 8 hours (daily dose of 510 mg EPA and 360 mg DHA)				"Standard therapy" alone, comprising artificial tears every 4 hours and betamethasone 0.1% eye drops every 8 hours	1 month
NCT01107964	Dry eye syndrome	27	Omega‐3 supplementation of 4 g/d (1 g capsule, 4 times daily) containing omega‐3 acid ethyl esters (exact dose not specified)				Placebo oral capsule (1 g) containing corn oil, 4 times daily (dose not specified)	45 days
Oleñik 2013 Randomized, parallel‐group, controlled trial	Symptomatic meibomian gland dysfunction, no tear instability	64	Omega‐3 supplementation^g: oral capsule containing EPA 42.5 mg, DHA 350 mg, and DPA 30 mg (Brudysec 1.5 g, Brudy Lab SL), 1 capsule/time, 3 times daily (daily dose of EPA 127.5 mg, DHA 1050 mg, DPA 90 mg)				Placebo oral 500 mg capsule containing sunflower oil, 1 capsule/time, 3 times daily	3 months
Oral sea buckthorn oil study 2010 Randomized, parallel‐group, controlled trial	Dry eye symptoms	100	Combined omega‐3 and omega‐6 supplementation: oral capsule (1000 mg) containing sea buckthorn oil (Aromtech Ltd.), 1 capsule/time, twice daily				Placebo oral capsule containing palm and coconut oil triacylglycerols of medium‐chain fatty acids, 1 capsule/time, twice daily	3 months
Oxholm 1986 Randomized, cross‐over, controlled trial	Keratoconjunctivitis sicca associated with primary Sjögren’s syndrome	28	Omega‐6 supplementation: oral capsule (500 mg) containing evening primrose oil (primarily comprising linoleic acid 365 mg and γ‐linolenic acid 45 mg, Efamol), 6 capsules daily (daily dose of 3 g of Efamol containing linoleic acid 2190 mg and γ‐linolenic acid 270 mg)				"Placebo" oral capsule (500 mg, composition not reported), 6 capsules daily	8 weeks in each cross‐over phase
Papas 2007 Randomized, parallel‐group, controlled trial	Dry eye associated with Sjögren’s syndrome	41	Omega‐3 supplementation: omega‐3 supplement containing a flaxseed and fish oil blend (TheraTears Nutrition, Advanced Vision Research); daily dose not reported				Germ seed oil oral capsule (composition and dose not reported)	3 months
Pinazo‐Durán 2013 Randomized controlled trial	Mild to moderate dry eye	30	Omega‐3 supplementation^g: oral 1.5 g capsule containing EPA 42.5 mg, DHA 350 mg, DPA 30 mg (Brudysec 1.5 g, Brudy Laboratories), 2 capsules daily (daily dose of EPA 85 mg, DHA 700 mg, DPA 60 mg)				No treatment	3 months
Pinheiro 2007 Randomized, parallel‐group, controlled trial	Keratoconjunctivitis sicca associated with rheumatoid arthritis or systemic lupus erythematosus	38	Omega‐3 supplementation: flaxseed oil capsules, 1 capsule plus 1 placebo capsule (daily dose of flaxseed oil 1 g)			Omega‐3 supplementation: flaxseed oil, 2 capsules (daily dose of flaxseed oil 2 g)	Placebo oral capsule containing 950 mg synthetic mineral oil and 50 mg evening primrose oil, 2 capsules daily	6 months
Reeder 2006 Randomized, parallel‐group, controlled trial	Dry eye	20	Omega‐3 supplementation: omega‐3 supplement containing flaxseed oil and fish oil (TheraTears Nutrition); daily dose not reported				Oral capsule containing flaxseed oil (1000 mg)	2 months
Sheppard 2013 Randomized, parallel‐group, controlled trial	Moderate to severe keratoconjunctivitis sicca in postmenopausal women	38 females	Combined omega‐3 and omega‐6 supplementation^h: oral capsules containing omega‐6 PUFAs (γ‐linolenic acid 177.5 mg, linoleic acid 177.5 mg, and arachidonic acid < 0.75 mg) and omega‐3 PUFAs (EPA 31.5 mg, DPA 24.75 mg, DPA 9.75 mg), 2 capsules/time, twice daily (daily dose of omega‐3s: ALA 196 mg, EPA 126 mg, DHA 99 mg, and DPA 39 mg; and omega‐6s: linoleic acid 710 mg, γ‐linolenic acid 240 mg, and arachidonic acid < 3 mg)				Placebo oral capsule, with a main ingredient of sunflower oil, 2 capsules/time, twice daily^h	6 months
Theander 2002 Randomized, parallel‐group, controlled trial	Dry eye associated with primary Sjögren’s syndrome	90	Omega‐6 supplementation: oral γ‐linolenic acid 800 mg daily (Scotia Pharmaceutical Ltd.)	Omega‐6 supplementation: oral γ‐linolenic acid 1600 mg daily (Scotia Pharmaceutical Ltd.)			Placebo, containing mostly corn oil (dose not reported)	6 months
Wojtowicz 2011 Randomized, parallel‐group, controlled trial	Dry eye, some with concomitant meibomitis or meibomian gland dysfunction	36	Omega‐3 supplementation: oral capsules containing fish oil 1600 mg (containing EPA 450 mg and DHA 300 mg) and flaxseed oil (1000 mg) daily (TheraTears Nutrition, Advanced Vision Research)				Placebo oral capsules containing wheat germ oil (dose not reported)	3 months

Main PUFA intervention		Daily dose	Comparison (daily dose)	Study
Omega‐3, ‐6, or combined versus placebo/no treatment	Long‐chain omega‐3 versus placebo or no treatment (10 RCTs)	EPA 2000mg DHA 1000mg (triglyceride form)	Olive oil, 5000mg	Asbell 2018
		EPA 720mg DHA 480mg	Olive oil (dose not reported)	Bhargava 2015a (computer vision syndrome)
		EPA 720mg DHA 480mg	Olive oil (dose not reported)	Bhargava 2016a (rosacea)
		EPA 1440mg DHA 960mg	Olive oil (dose not reported)	Bhargava 2016b (visual display terminal users)
		Fish oil EPA 1000mg DHA 500mg (triglyceride form)	Olive oil (1500mg)	Deinema 2017
		Krill oil EPA 945mg DHA 510mg (phospholipid form)	Olive oil (1500mg)	Deinema 2017
		EPA 720mg DHA 480mg	Vitamin E (400mg)	Goyal 2017 (LASIK‐induced dry eye)
		EPA 360mg DHA 240mg	Medium‐chain triglycerides (2 x 1g capsules)	Kangari 2013
		EPA 1245mg DHA 540mg	Medium‐chain triglycerides (does not reported)	Kawakita 2013
		EPA 81mg DHA 54mg	"Vehicle" (no further details provided)	Kawashima 2016 (note: also included non‐dry eye subjects)
		EPA 85mg DHA 700mg DPA 60 mg	No treatment	Pinazo‐Durán 2013
	Short‐chain omega‐3 (flaxseed oil) versus placebo (two RCTs)	6000mg, equivalent to 3300mg omega‐3 fatty acids	Olive oil (dose not reported)	Macsai 2008
		1000mg flaxseed oil	Placebo (950mg synthetic mineral oil and 50mg evening primrose oil)	Pinheiro 2007 (systemic lupus erythematosus or rheumatoid arthritis)
		2000mg flaxseed oil
	Omega‐6 versus placebo (six RCTs)	Linoleic acid 224 mg γ‐linolenic acid 30 mg	Control (non‐active excipients only)	Aragona 2005 (Sjögren’s syndrome)
		Linoleic acid 57 mg γ‐linolenic acid 30 mg	Control ("specially made tablets containing a low quantity of sugar at the same dose as the study group")	Barabino 2003
		Linoleic acid about 342mg γ‐linolenic acid 300mg	Olive oil (dose not reported)	Kokke 2008
		Linoleic acid 2190mg γ‐linolenic acid 270mg	"Placebo" 500mg capsule (composition not reported)	Manthorpe 1984 (cross‐over trial) ‐ Sjögren’s syndrome
		Linoleic acid 2190mg γ‐linolenic acid 270 mg (Efamol)	“Placebo" 500mg capsule (composition not reported)	Oxholm 1986 (cross‐over trial) ‐ Sjögren’s syndrome
		γ‐linolenic acid 800mg	Corn oil (dose not reported)	Theander 2002 (Sjögren’s syndrome)
		γ‐linolenic acid 1600mg	Corn oil (dose not reported)	Theander 2002 (Sjögren’s syndrome)
	Combined omega‐3 and omega‐6 PUFAs versus placebo (four RCTs)	2000 mg (comprising long‐chain omega‐3 and omega‐6 PUFAs)	Control (medium‐chain fatty acids)	Oral sea buckthorn oil study 2010
		EPA 427.5 mg DHA 285 mg (total omega‐3 PUFAs 855 mg) Omega‐6 15 mg	Medium‐chain triglycerides (575mg)	Brignole‐Baudouin 2011
		Linoleic acid 126 mg γ‐linolenic acid 82 mg EPA 28 mg DHA 392 mg	Oleic aid (dose not reported)	Creuzot 2006
		linoleic acid 126 mg γ‐linolenic acid 82mg EPA 28mg DHA 392mg	Placebo (composition and dose not reported)	Creuzot‐Garcher 2011
Omega with conventional treatment versus conventional treatment	Oral omega‐3 plus conventional therapy versus conventional therapy alone (two RCTs)	EPA 510mg DHA 360mg Plus artificial tears, and Betamethasone 0.1% eye drops (every 8 hours)	Artificial tears (every 4 hours) and betamethasone 0.1% eye drops (every 8 hours)	Mohammadpour 2017 (post‐cataract surgery)
		2000 mg of omega‐3 fatty acid (Systane Vitamin Omega‐3 Healthy Tears; Alcon), lid hygiene (once daily), and lipid emulsion eye drops (once daily)	Warm compresses (8 minutes/time, once daily)	Korb 2015
Comparison of different combinations of omega 3 and 6 with each other	Long‐chain omega‐3 versus omega‐6 (five RCTs)	EPA 650mg DHA 350mg	Corn oil 1000mg	Bhargava 2013
		EPA 720mg DHA 480mg	Corn oil (dose not reported)	Bhargava 2015b (contact lens wearers)
		EPA 1680mg DHA 560mg (re‐esterified omega‐3 PUFAs)	Linoleic acid, safflower oil (3136 mg/d)	Epitropoulos 2016
		4 × 1 g capsules of "omega‐3‐ acid ethyl esters" (exact dose of EPA and DHA not reported)	Corn oil (4 × 1g capsules; dose not reported)	NCT01107964
		EPA 127.5mg DHA 1050mg DPA 90mg	Sunflower oil (3 × 500mg capsules; dose not reported)	Oleñik 2013
	Combined long‐ and short‐chain (flaxseed) omega‐3 versus combined omega‐3 and omega‐6 (three RCTs)	Fish oil 1600mg (containing EPA 450mg and DHA 300mg) Flaxseed oil 1000 mg (TheraTears Nutrition)	Wheat germ oil (dose not reported)	Gilbard 2008 (abstract only) ‐ Sjögren’s syndrome Wojtowicz 2011
		Fish oil and flaxseed oil blend (dose not reported) TheraTears Nutrition	Germ seed oil (dose not reported)	Papas 2007 (abstract only) ‐ Sjögren’s syndrome
	Combined omega‐3 and omega‐6 PUFAs versus omega‐6 alone (one RCT)	Linoleic acid 710mg γ‐linolenic acid 240mg Arachidonic acid < 3mg EPA 126mg DHA 99mg DPA 39mg	Sunflower oil (dose not reported)	Sheppard 2013 (post‐menopausal women)
	Combined long‐ and short‐chain (flaxseed) omega‐3 versus short‐chain omega‐3 alone (one RCT)	Fish oil and flaxseed oil blend (dose not reported) TheraTears Nutrition	Flaxseed oil 1000mg	Reeder 2006 (abstract only)

Study	Corneal fluorescein	Conjunctival fluorescein	Corneal lissamine green	Conjunctival lissamine green	Corneal rose bengal	Conjunctival rose bengal
Aragona 2005	Scale not specified (scored from 0 to 15)	NA	NA	NA	NA	NA
Asbell 2018	Scale not specified (scored from 0 to 15)	NA	NA	Scale not specified (scored from 0 to 6)	NA	NA
Barabino 2003	NA	NA	NA	van Bijsterveld scale	NA	NA
Bhargava 2013	NA	NA	NA	NA	van Bijsterveld scale (graded from 0 to 9)
Brignole‐Baudouin 2011	Oxford scale	NA	NA	van Bijsterveld scale	NA	NA
Creuzot 2006	Oxford scale	NA	NA	van Bijsterveld scale	NA	NA
Creuzot‐Garcher 2011	Oxford scale		NA	van Bijsterveld scale	NA	NA
Deinema 2017	Oxford scale	NA	NA	Oxford scale	NA	NA
Epitropoulos 2016	Oxford scale	NA	NA	NA	NA	NA
Goyal 2017	National Eye Institute/Industry workshop scale	NA	NA	National Eye Institute/Industry workshop scale	NA	NA
Kawakita 2013	Scale not specified (scored from 0 to 9)		NA	NA	Scale not specified (scored from 0 to 9)
Kawashima 2016	Japanese diagnostic criteria		NA	NA	NA	NA
Kokke 2008	CCLRU scale	CCLRU scale	NA	NA	van Bijsterveld scale	van Bijsterveld scale
NCT01107964	NA	NA	Scale not specified (scored from 0 to 9)		NA	NA
Macsai 2008	National Eye Institute/Industry workshop scale	NA	NA	NA	NA	Six regions of conjunctiva, each graded from 0 to 3
Manthorpe 1984	NA	NA	NA	NA	van Bijsterveld scale
Oleñik 2013	Oxford scale	Oxford scale	NA	NA	NA	NA
Oxholm 1986	NA	NA	NA	NA	van Bijsterveld scale
Sheppard 2013	Scale not specified	NA	NA	Scale not specified	NA	NA
Theander 2002	NA	NA	van Bijsterveld scale		NA	NA
Wojtowicz 2011	NA	NA	National Eye Institute/Industry workshop scale	NA	NA	NA

Study ID	Number of participants and study population	Adverse event(s)	Serious adverse event(s)
Aragona 2005	40 participants with moderate to severe dry eye disease associated with primary Sjögren’s syndrome	None	None
Asbell 2018	535 participants with moderate to severe dry eye disease	"The percentage of patients with at least one non‐serious adverse event was similar in the active supplement group and the placebo group (61.9% and 60.8%, respectively; p=0.87), as was the percentage of patients with an episode of bleeding (2.0% and 1.6%, respectively; p=1.00). A higher percentage of patients reported diarrhoea in the active supplement group than in the placebo group (4.9% and 1.6%, respectively; p=0.09)" Based on data available in the online Appendix 45 (out of 349) participants in the "active" supplement group had 66 events; and 19 (out of 186) participants in the "placebo" group had 22 events related to gastrointestinal disorders 45 (out of 349) participants in the "active" supplement group had 56 events; and 24 (out of 186) participants in the "placebo" group had 33 events related to "eye disorders." This included 3 (out of 349) participants in the "active" supplement group and 2 (out of 349 participants) in the "placebo" group reporting blurred vision 8 (out of 349) participants in the "active" supplement group had 8 events; and 3 out of 186 people in the "placebo" group had 3 events that were diagnosed as a neoplasm (benign, malignant, or unspecified, including cysts)	"The percentage of patients with at least one serious adverse event was 6.0% in the active supplement group and 8.1% in the placebo group (p = 0.31)" Based on data available in the online Appendix 4 (out of 349) participants in the "active" supplement group and 2 out of 186 people in the "placebo" group were diagnosed with a neoplasm (benign, malignant, or unspecified, including cysts) 3 (out of 349) participants in the "active" supplement group and no (out of 186) participants in the "placebo" group experienced gastrointestinal disorders that were classed as "serious" adverse events
Barabino 2003	26 participants with dry eye disease	"No obvious adverse effects associated with systemic LA and GLA were recorded"	Not reported
Bhargava 2015a	478 participants with dry eye associated with computer vision syndrome	Adverse events were not explicitly reported, although it was stated that 6 participants in the omega‐3 intervention group dropped out due to gastric intolerance	Not reported
Bhargava 2015b	496 participants with dry eye associated with contact lens wear	Adverse events were not explicitly reported, although non‐compliance and gastric intolerance were the reason for 14 participants dropping out of the omega‐3 intervention group	Not reported
Bhargava 2016a	130 participants with dry eye due to rosacea	4 participants in the placebo group (n = 65) experienced transient skin rashes that were not severe enough to warrant discontinuation from the study. Eight participants in the omega‐3 intervention group (n = 65) experienced gastric intolerance	Not reported
Bhargava 2016b	522 visual display terminal users with dry eye	A total of 26 participants in the omega‐3 group (n = 256) discontinued the study due to gastrointestinal upset	Not reported
Brignole‐Baudouin 2011	137 participants with mild to moderate dry eye disease	"The number of participants with product‐related non‐ocular adverse events was similar in both groups (fatty acids n = 4 from 67 participants; placebo group n = 5 from 70 participants). In the fatty acid group, these were mainly mild gastrointestinal disorders. Four subjects were withdrawn prematurely because of adverse events, two in each group"	"No product‐related serious adverse events or product‐related ocular adverse events were reported. In the placebo group, there were two unrelated serious adverse events: hospitalization for moderate skin rash with complete recovery and pleural carcinoma. In the fatty acid group, one subject had moderate gastralgia and meteorism and another subject had mild nausea and diarrhoea, both completely recovered"
Deinema 2017	60 participants with mild to moderate dry eye disease	"The three (olive oil, fish oil and krill oil) interventions were generally well tolerated. Of the 53 adverse events noted, 51 were considered mild (i.e., awareness of symptoms or signs but well tolerated) and 2 were graded as moderate (i.e., discomfort interfering with normal activity)." "The most frequently reported adverse events were colds (24.5%), sore throat (11.3%), headache/migraine (11.3%), and gastrointestinal events (e.g., nausea, abdominal discomfort, bloating, stomach cramps, heartburn, and gastroenteritis; 13.2%). Based on the principal investigator’s (L.E.D.’s) assessment, 72% were deemed to have no potential association with the study supplements and 28% of the adverse events were considered to be potentially related to the study supplements" Based on data available in the online Supplementary Material: there was 1 event (from 19 participants) in the "fish oil" supplement group; 1 event (from 18 participants) in the "krill oil" supplement group; and 4 events (from 17 participants) in the "placebo group" related to gastrointestinal disorders	None
Kangari 2013	73 participants with dry eye syndrome	Adverse events were not explicitly reported, although it was stated that "in the treatment group, 3 subjects stopped the medication because of digestion problems"	Not reported
Kawashima 2016	40 participants with dry eye	"None of the 40 subjects (0.0%) in either group reported any adverse events or side effects"	None
Korb 2015	26 participants with lipid deficient/evaporative dry eye	"A total of two adverse events (infectious mononucleosis and sinusitis) were reported for a single patient in the combination treatment group (omega‐3s + conventional therapy); neither was considered to be treatment related"	None
Manthorpe 1984	36 participants with keratoconjunctivitis sicca associated with primary Sjögren’s syndrome	"The following symptoms were evident in 47% of patients after intake of Efamol/Efavit: Sudden universal flushing which usually began in the face and throat, sensation of heat, increase in pulse frequency and fear. A few patients thought that their last minutes had arrived! The symptoms disappeared gradually within 15‐30 min. The symptoms are due to niacin and by changing the Efavit tablets to ZnSO4 and vitamin C tablets the symptoms disappeared. The type and frequency of other side‐effects were equal among the Efamol/Efavit and placebo treatment periods"	Not reported
NCT01107964	27 participants with dry eye syndrome	Two participants in the omega‐3 acid ethyl ester group (from n = 13) and 1 participant in the placebo group (from n = 14) experienced adverse events. These consisted of (a) omega‐3 group: diarrhea (n = 1) and breast tenderness (n = 1); (b) placebo group: dyspepsia (n = 1) (Note: "Events were collected by a non‐systematic assessment")	None
Oleñik 2013	64 participants with symptomatic meibomian gland dysfunction and no tear instability	2 participants from the omega‐3 + vitamin + mineral supplement group (n = 33) experienced "digestive upset." None of the participants in the placebo group (n = 31) experienced adverse events	None
Oxholm 1986	28 participants with keratoconjunctivitis sicca associated with primary Sjögren’s syndrome	"Three patients complained of transient nausea and softening of stools during the period of Efamol treatment"	None
Sheppard 2013	38 postmenopausal women participants with moderate to severe keratoconjunctivitis sicca	"There were no reported ocular adverse events directly attributed to either the study supplement or placebo. One supplement‐treated patient withdrew after a rash appeared ˜2 weeks after the initiation of treatment"	None. "(There were) no significant systemic adverse events were reported, including dyspepsia, dysgeusia, nausea, vomiting, anorexia, diarrhoea, constipation, bruising, or increased infections"
Theander 2002	90 participants with dry eye associated with primary Sjögren’s syndrome	"Only mild gastrointestinal side effects were reported, most often subsiding after some weeks despite continuous medication. 53% of the placebo‐treated and 56% of the GLA treated patients experienced some sort of gastrointestinal complaints. Some patients complained about weight gain. There was a tendency towards increased weight, especially in the GLA treated patients, who, however, did not reach statistical significance. No significant changes in any of the laboratory parameters were detected during the study"	Not reported

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Dry eye symptoms, measured using the OSDI score [OSDI] units	4	677	Mean Difference (IV, Random, 95% CI)	‐2.47 [‐5.14, 0.19]
2 DESS: mean score at study endpoint [DESS units]	3		Mean Difference (IV, Random, 95% CI)	Subtotals only
3 Schirmer test (tear production) (mm/5 min)	6	1826	Mean Difference (IV, Random, 95% CI)	0.68 [0.26, 1.09]
4 Tear break‐up time (TBUT) measured using fluorescein (seconds)	5		Mean Difference (IV, Random, 95% CI)	Subtotals only
5 Conjunctival impression cytology (CIC) score: mean score at study endpoint (Nelson grade)	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
6 Adverse event: gastrointestinal disorders	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Schirmer test (tear production) (mm/5 min)	4	455	Mean Difference (IV, Random, 95% CI)	0.66 [‐0.45, 1.77]
2 TBUT: Mean change from baseline (seconds)	4	455	Mean Difference (IV, Random, 95% CI)	0.55 [0.04, 1.07]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Dry eye symptoms, measured using the OSDI score [OSDI] units	2	130	Mean Difference (IV, Fixed, 95% CI)	‐11.88 [‐18.85, ‐4.92]
2 DESS: mean score at study endpoint [DESS units]	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
3 Schirmer test (tear production) (mm/5 min)	4		Mean Difference (IV, Random, 95% CI)	Subtotals only
4 Tear break‐up time (TBUT) measured using fluorescein (seconds)	5		Mean Difference (IV, Random, 95% CI)	Subtotals only
5 Adverse event: gastrointestinal disorders	2	91	Risk Ratio (M‐H, Fixed, 95% CI)	2.34 [0.35, 15.54]

Methods	Study design: randomized, parallel‐group, controlled trial Study site(s): single center Number of participants randomized (total and per group): 80 eyes of 40 participants (ie, 40 eyes of 20 participants per treatment group) Unit of randomization (individual or eye): individual Exclusions after randomization: none Losses to follow‐up: none Unit of analysis (individual or eye): individual (right eye) Reported power calculation? (Y/N): N Reported subgroup analysis? (Y/N): N
Participants	Baseline characteristics Country: Italy Age (mean ± SD, range): 36.6 ± 6.7 years for total; 36.9 ± 7.9 years for treatment group; 36.3 ± 5.5 years for control group Gender: 2 men and 18 women in the treatment group; 1 man and 19 women in the control group Inclusion criteria: 1. Age more than 18 years 2. Primary Sjögren’s syndrome, as defined by the American‐European Consensus Group 3. Ability and willingness to participate in the study 4. Stable disease and general therapy for at least 1 month 5. No local treatment other than preservative‐free cellulose‐derivative eye drops 6. Moderate to severe dry eye, as defined by tear basal secretion less than 5 mm/5 min, tear break‐up time (TBUT) less than 7 seconds, and signs of corneal damage demonstrated by corneal fluorescein staining (at least 2+ according to Lemp) Exclusion criteria: 1. Any systemic disease different from Sjögren’s syndrome 2. Menopausal status 3. Presence of systemic treatment with drugs such as β‐blocking agents, benzodiazepines, hormones, or antihistamine agents that could interfere with tear production 4. Use of non‐steroidal anti‐inflammatory drugs (NSAIDs) or steroids Equivalence of baseline characteristics? (Y/N): Y
Interventions	Intervention #1 (treatment group): oral sachets containing linoleic acid 112 mg and γ‐linolenic acid 15 mg, twice daily Intervention #2 (control group'): oral placebo sachets, twice daily Length of follow‐up: 1 month of treatment and 15 days after suspension of treatment Notes: sachets were diluted in water; participants were instructed to follow their usual diets; participants were allowed to continue their general and local therapies
Outcomes	Primary outcome(s): PGE₁ content (mg/mL) of tears at study endpoint Secondary outcome(s): subjective dry eye symptoms (burning, itching, foreign body sensation, dryness, mucous discharge, and photophobia); TBUT; corneal fluorescein staining; tear basal secretion (Schirmer test with anaesthesia) at study endpoint Adverse events reported? (Y/N): Y Measurement time points (including intervals at which outcomes were assessed): baseline, 1 month of treatment, and 15 days after suspension of treatment Other issues with outcome assessment (eg, quality control for outcomes, if any): none
Notes	Study dates: not reported Funding source(s): "supported by grants from the National Research Council and Bausch & Lomb" Conflicts of interest: 2 authors were affiliated with Bausch & Lomb (E, F); "The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked 'advertisement' in accordance with 18 U.S.C. §1734 solely to indicate this fact" Publication language: English Registered on clinical trials registry? (Y/N): N
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Once recruited, patients were randomly divided into two groups, according to a table of random numbers, and assigned, in a double masked manner, to the treatments"
Allocation concealment (selection bias)	Unclear risk	Allocation concealment was not reported
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	"Once recruited, patients were randomly divided into two groups, according to a table of random numbers, and assigned, in a double masked manner, to the following treatments" Details of masking about participants and personnel were not reported
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	"The tear content of PGE₁ was evaluated in a masked manner by enzyme immunoassay (EIA), using a commercial kit" (primary outcome. Self‐reported symptoms were graded by means of a questionnaire administered at the beginning of each examination by a different observer (RS) from the one who performed the examinations (PA)" "The statistical analysis of the results was performed in a masked manner"
Incomplete outcome data (attrition bias)   All outcomes	Low risk	There were no missing data
Selective reporting (reporting bias)	Unclear risk	No access to study protocol or clinical trials registry
Other bias	High risk	"Supported by grants from the National Research Council and Bausch & Lomb" Two of the authors were affiliated with Bausch & Lomb (E, F) "The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked 'advertisement' in accordance with 18 U.S.C. §1734 solely to indicate this fact"

Methods	Study design: randomized, parallel‐group, controlled trial Study site(s): multi‐center (2 sites) Number randomized (total and per group): 518 eyes of 518 participants; 264 eyes of 264 participants in the treatment group; 254 eyes of 254 participants in the control group Unit of randomization (individual or eye): individual Exclusions after randomization: 6 participants, due to faulty impression cytology slides Losses to follow‐up: 12 participants Unit of analysis (individual or eye): individual (1 eye per participant was enrolled) Reported power calculation? (Y/N): Y (80% power) Reported subgroup analysis? (Y/N): Y (patients with Sjögren’s syndrome, contact lens users, video display terminals, chronic blepharitis, and acne rosacea)
Participants	Baseline characteristics Country: India Age (mean ± SD, range): 38.8 ± 4.1 years in the treatment group; 40.1± 6.8 years in the control group Gender: 254 men and 268 women total Inclusion criteria: 1. Aged more than 16 years 2. Symptoms of dry eye 3. TBUT less than 10 s 4. Presence of lid margin scaling, telangiectasia, collarette and meibomian gland plugging on slit‐lamp examination Exclusion criteria: 1. Any pre‐existing ocular disease other than dry eye syndrome 2. Current treatment with oral tetracyclines or corticosteroids 3. Past history of herpetic eye disease, liver disease, diabetes, or laser keratomileusis (LASIK) 4. Pregnant or lactating mothers 5. Cognitive or psychiatric disorder 6. Postmenopausal women 7. HIV 8. Hepatitis B and C 9. Inability to swallow soft gel capsules 10. Current treatment with aspirin or anticoagulant therapy 11. Allergy to fluorescein 12. Malignancy or chronic infection of the lacrimal gland Equivalence of baseline characteristics? (Y/N): Y (personal communication)
Interventions	Intervention #1 (treatment group): oral 500 mg capsule containing eicosapentaenoic acid (EPA) 325 mg and docosahexaenoic acid (DHA) 175 mg, twice daily Intervention #2 (control group): oral placebo capsules containing corn oil twice daily (daily dose: 1000 mg/d) Length of follow‐up: 3 months Notes: topical medications and contact lens use were discontinued before enrollment
Outcomes	Primary outcome(s): change from baseline in subjective symptoms Secondary outcome(s): change from baseline in Schirmer test and TBUT; rose bengal score (RBS) and conjunctival impression cytology (CIC) scores (for cellular changes and goblet cell density, measured using Nelson grade) at study endpoint Adverse events reported? (Y/N): N Measurement time points (specify intervals at which outcomes were assessed): baseline, months 1, 2, and 3 Other issues with outcome assessment (eg, quality control for outcomes, if any): none
Notes	Study dates: not reported Funding source(s): not reported Conflicts of interest: not reported Publication language: English Registered on clinical trials registry? (Y/N): N
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Patients were randomly assigned to one of two groups by parallel assignment. The allocation codes were generated by a DOS based computer software"
Allocation concealment (selection bias)	Low risk	"The allocation was concealed in green colored envelopes that were opened by health care staff not involved in patient care" "software (Disk operating system based) generates codes (sequentially numbered and coloured) which were sealed in envelopes and were opened by a third party who were not involved in patient care" (personal communication)
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	"Double blind" study "The two types of capsules and packs were similar to each other (omega‐3 dietary supplementation)" "The subjects were masked to the contents" Software (disk operating system based) generates codes (sequentially numbered and colored), which were sealed in envelopes and were opened by a third party who was not involved in patient care (personal communication)
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	"At each visit, each subject underwent a detailed ocular examination by an independent investigator (not a study ophthalmologist)" Independent investigator performed all tests (including tear film tests) and was masked to information obtained from the dry eye questionnaire (personal communication)
Incomplete outcome data (attrition bias)   All outcomes	High risk	12/518 (2.3%) participants were lost to follow‐up, and 6/518 (1.2%) were excluded from the analysis due to faulty impression cytology slides; it was not reported which treatment group these individuals belonged to
Selective reporting (reporting bias)	Unclear risk	No access to study protocol or clinical trials registry
Other bias	Unclear risk	Information regarding funding source and conflict of interest was not reported

Methods	Study design: randomized, parallel‐group, controlled trial Study site(s): multi‐center (3 sites) Number randomized (total and per group): 478 participants in total Unit of randomization (individual or eye): individual Exclusions after randomization: 6 participants due to gastric intolerance (in the omega‐3 treatment group); and 6 participants due to faulty impression cytology slides Losses to follow‐up: 10 in total Unit of analysis (individual or eye): individual (1 eye selected at random) Reported power calculation? (Y/N): Y (90% power) Reported subgroup analysis? (Y/N): N
Participants	Baseline characteristics Country: India Age (mean ± SD, range): 22.8 ± 2.5 years in the treatment group; 23.7 ± 6.8 years in the control group Gender: 219 men and 237 women, in total Inclusion criteria: 1. Symptomatic computer users (using computers for > 3 hours/d for minimum 1 year) on the basis of a questionnaire of dry eye‐related symptoms (Dry Eye Scoring System, DESS) Exclusion criteria: 1. Current ocular infection 2. Past history of laser in situ keratomileusis (LASIK) 3. Allergic conjunctivitis 4. Contact lens wear 5. Herpetic eye disease 6. Diabetes 7. Liver disease 8. Pregnant or lactating mothers 9. HIV and hepatitis B or C 10. Patients with inability to swallow soft gel capsules 11. Aspirin or anticoagulant therapy 12. Allergic to fluorescein 13. Systemic (tetracyclines and corticosteroids) or topical medications (other than artificial tear supplements) that could affect tear film or meibomian gland function Equivalence of baseline characteristics? (Y/N): N (symptoms of dry eye, P = 0.028; conjunctival impression cytology, P = 0.013)
Interventions	Intervention #1 (treatment group): oral capsule containing EPA 180 mg and DHA 120 mg, 2 capsules/time, twice daily (daily dose of 720 mg EPA and 480 mg DHA) Intervention #2 (control group): olive oil (dose not reported) Length of follow‐up: 3 months Notes: participants were instructed not to use artificial tear preparations, 2 hours before testing
Outcomes	Primary outcome(s): "decrease from baseline in" symptoms of dry eye Secondary outcome(s): Schirmer test with anesthesia; TBUT; Nelson grade (for cellular morphology and goblet cell density). Although these outcomes were described to be measured as "change from baseline," the manuscript reports endpoint data Adverse events reported? (Y/N): Y Measurement time points (specify intervals at which outcomes were assessed): baseline, 1, 2, and 3 months Other issues with outcome assessment (eg, quality control for outcomes, if any): none
Notes	Study dates: not reported Funding source(s): "we do not have any financial interest" Conflicts of interest: "none" Publication language: English Registered on clinical trials registry? (Y/N): N
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"The allocation codes were generated by a DOS based software"
Allocation concealment (selection bias)	Low risk	"The codes were sealed in blue coloured envelopes and were opened by health care personnel not involved in patient care"
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	"The subjects as well as the investigators were masked to the contents. The two types of capsules and packs were similar to each other"
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	"the subjects underwent a detailed ocular examination by an independent investigator (SK), who was not a study surgeon" "The independent investigator (SK) was masked to the information obtained from the questionnaire" Study does not explicitly state that outcome assessors were masked to assignments
Incomplete outcome data (attrition bias)   All outcomes	High risk	"Statistical analysis was performed on an intent to treat basis" However, we noted that 22/474 (4.6%) randomized participants were not included in the final analysis
Selective reporting (reporting bias)	Unclear risk	No access to study protocol or clinical trials registry
Other bias	High risk	Participant treatment group baselines were not equivalent for the primary outcome measure (ie, dry eye symptom score; P = 0.028)

Methods	Study design: randomized, parallel‐group, controlled trial Study site(s): multi‐center (3 sites) Number randomized (total and per group): 522 participants in total; 256 participants in the omega‐3 treatment group; 266 participants in the placebo group Unit of randomization (individual or eye): individual Exclusions after randomization: 26 in total; 22 (irregularly taking supplements because of bad taste and gastric intolerance) and 4 (inability to continue the trial) Losses to follow‐up: not reported Unit of analysis (individual or eye): individual (1 eye selected at random) Reported power calculation? (Y/N): Y (90% power) Reported subgroup analysis? (Y/N): N
Participants	Baseline characteristics Country: India Age (mean ± SD, range): 28.9 ± 4.2 years in the omega‐3 treatment group; 29.6 ± 5.5 years in the control group Gender: not reported Inclusion criteria: 1. Symptomatic visual display terminal (VDT) users experiencing dry eye symptoms based on their response to the Dry Eye Scoring System questionnaire Exclusion criteria: 1. Allergic conjunctivitis 2. History of laser in situ keratomileusis 3. Contact lens wear 4. Other causes of dry eye in the office‐going population, software professionals, or university students 5. Inability to swallow soft gel capsules 6. On a regular course of aspirin or anticoagulants (cyclo‐oxygenase‐2 inhibitors) 7. Allergic to fluorescein Equivalence of baseline characteristics? (Y/N): Y
Interventions	Intervention #1 (treatment group): oral capsule containing EPA 180 mg and DHA 120 mg, 4 capsules/time, twice daily (daily dose of 1440 mg EPA and 960 mg DHA) Intervention #2 (control group): olive oil (dose not reported) Length of follow‐up: 45 days Notes: systemic (tetracyclines and corticosteroids) or topical medications (other than artificial tear supplements) that could affect tear film or meibomian gland function (beta‐blockers, benzodiazepines, and antihistamines) were discontinued 3 weeks before the intervention commenced. Moreover, patients were instructed not to use artificial tear preparations 2 hours before testing
Outcomes	Primary outcome(s): "improvement in" symptoms of dry eye, but reported as endpoint data Secondary outcome(s): "improvement in" Schirmer test with anesthesia, TBUT, and Nelson grade on conjunctival impression cytology, but reported as endpoint data in the manuscript Adverse events reported? (Y/N): Y Measurement time points (specify intervals at which outcomes were assessed): baseline, 30 and 45 days Other issues with outcome assessment (eg, quality control for outcomes, if any): none
Notes	Study dates: not reported Funding source(s): "the authors have no funding or conflicts of interest to disclose" Conflicts of interest: "the authors have no funding or conflicts of interest to disclose" Publication language: English Registered on clinical trials registry? (Y/N): N
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"The allocation codes were generated by disk operating system–based software"
Allocation concealment (selection bias)	Low risk	"The codes were sealed in green envelopes and were opened by a health care personnel not involved in patient care"
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	"Double masked" "The subjects were masked to the contents. The two types of capsules and packs were similar to each other"
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	"A detailed ocular examination was performed by an independent investigator (who was not a study surgeon, K.S.)" "The independent investigator (K.S.) was masked to the information obtained from the questionnaire" It is unclear whether the outcome assessor was masked to the treatment allocation
Incomplete outcome data (attrition bias)   All outcomes	Low risk	"All dropouts (n=26) were included for analysis based on the last‐observation‐carried‐forward method"
Selective reporting (reporting bias)	Unclear risk	No access to study protocol or clinical trials registry
Other bias	Low risk	No other apparent sources of bias

Methods	Study design: randomized, controlled trial Study site(s): multicenter (27 sites) Number randomized (total and per group): 535 participants in total; 349 participants in the omega‐3 treatment group; 186 participants in the placebo group Unit of randomization (individual or eye): individual Exclusions after randomization: none Losses to follow‐up: 47 participants in total; 25 participants in the omega‐3 treatment group; 22 participants in the control group Unit of analysis (individual or eye): eye ("Generalized estimating equations were used for ocular measures to accommodate the correlation between eyes in the same person") Reported power calculation? (Y/N): Y (90% power) Reported subgroup analysis? (Y/N): Y (severity of dry eye)
Participants	Baseline characteristics Country: United States of America Age (mean ± SD, range): 58.3 ± 13.5 years in the omega‐3 treatment group; 57.5 ± 12.6 years in the control group Gender: 65 men and 284 women in the omega‐3 treatment group; 36 men and 150 women in the control group Inclusion criteria: 1. Sign and date the informed consent form approved by the IRB 2. ≥ 18 years of age 3. Demonstrate at least 2 of the 4 following signs in the same eye at 2 consecutive visits. The same signs must be present in the same eye on both visits: (screening visit: 7 to 21 days before randomization, and visit 00 [baseline visit]: day of randomization) a. Conjunctival staining present ≥ 1 (out of possible score of 6 per eye) b. Corneal fluorescein staining present ≥ 4 (out of a possible score of 15 per eye) c. Tear film break‐up time (TBUT) ≤ 7 seconds d. Schirmer test ≥ 1 to ≤ 7 mm/5 min 4. Demonstrate symptoms of dry eye disease (OSDI score greater than 22 (≥ 23 to ≤ 80) at screening visit and at least 18 (≥ 18 to ≤ 80) at randomization visit 5. Have dry eye‐related ocular symptoms for at least 6 months before the screening visit and use or desire to use artificial tears on average 2 times per day in the 2 weeks preceding the screening visit 6. Intraocular pressure (IOP) ≥ 5 mmHg and ≤ 22 mmHg in each eye 7. Women of child‐bearing potential must agree to use a reliable method of contraception during study participation and must demonstrate a negative urine pregnancy test at the screening visit 8. Be willing/able to return for all study visits and to follow instructions from the study investigator and his/her staff 9. Be able to swallow large, soft gel capsules 10. Demonstrate compliance with taking soft gels as directed during the run‐in period (≥ 90% taken, by pill count) Exclusion criteria: 1. Allergic to ingredients of active or placebo pills (fish, shellfish, olive oil) 2. Contact lens wearers who are unwilling to discontinue use for 2 weeks before the baseline visit and for the duration of the study 3. Pregnant or nursing/lactating 4. Participation in a study of an investigational drug or device within the 30 days preceding the screening visit 5. Current diagnosis of any of the following ocular conditions: i) Infection (eg, bacterial, viral, protozoan, or fungal infection of the cornea, conjunctiva, lacrimal gland, lacrimal sac, or eyelids) or ii) Inflammation (eg, retinitis, macular inflammation, choroiditis, uveitis, scleritis, episcleritis, keratitis) 6. History of ocular herpetic keratitis 7. Ocular surgery (including cataract surgery) within 6 months of the screening visit 8. Previous LASIK surgery or any other corneal surgery 9. Use of glaucoma medication or history of surgery for glaucoma 10. Eyelid abnormalities that affect lid function (eg, lagophthalmos, blepharospasm, ectropion, entropion, severe trichiasis) 11. Extensive ocular surface scarring or condition that may compromise ocular surface integrity such as Stevens‐Johnson syndrome, prior chemical burn, recurrent corneal erosions, persistent corneal epithelial defects, prior ocular trauma, etc. 12. Dry eye due to seasonal allergic conjunctivitis, or other acute or seasonal diagnosis 13. Current use of EPA/DHA supplements in excess of 1200 mg/d 14. History of liver disease 15. Currently on anticoagulation therapy such as heparin and warfarin. Use of clopidogrel (Plavix) or aspirin does not exclude the patient 16. Patients with hemophilia, thrombocytopenia, or other bleeding tendencies 17. History of atrial fibrillation 18. Uncontrolled ocular or systemic disease 19. Cognitive or psychiatric deficit that precludes informed consent or ability to perform requirements of the investigation Equivalence of baseline characteristics? (Y/N): N (equivalence for all parameters, except for a higher mean EPA level in the active supplement group than in the placebo group [0.63% vs 0.56%; P = 0.047], but this was not a primary outcome measure.) The paper also states that "In accordance with the protocol, an analysis of the mean change in the OSDI score with adjustment for the baseline EPA level was performed because of an imbalance between trial groups in the EPA level (P<0.10)"
Interventions	Intervention #1 (treatment group): 5 soft gelatin capsules per day (daily dose of 2000 mg EPA and 1000 mg DHA) Intervention #2 (control group): 5000 mg per day of refined olive oil Length of follow‐up: 12 months Notes: patients who were regularly using treatments for dry eye disease (including omega‐3 fatty acid supplements: eicosapentaenoic acid [EPA] plus docosahexaenoic acid [DHA] at a dose of <1200 mg daily), systemic medications that are known to cause ocular dryness, systemic glucocorticoids, or other immunosuppressive agents were allowed to continue those treatments if they committed to using them for the next 12 months. Patients with a history of thyroid disease, Sjögren’s syndrome, rheumatoid arthritis, or inflammatory diseases could be included in the trial if they were otherwise eligible
Outcomes	Primary outcome(s): mean change from baseline in OSDI Secondary outcome(s): changes in the percentages of EPA and DHA in total fatty acids in red cells (by weight), changes in signs of dry eye disease (as assessed by conjunctival lissamine green staining score, corneal fluorescein staining score, tear break‐up time, and the result on Schirmer test with anesthesia), changes in scores on physical health and mental health subscales of the Medical Outcomes Study 36‐Item Short Form Health Survey (SF‐36; scores range from 0 to 100, with higher scores indicating better health‐related quality of life), changes in scores on the discomfort and pain interference subscales of the Brief Ocular Discomfort Index (BODI; scores range from 0 to 100, with higher scores indicating greater discomfort), changes in treatments used for dry eye disease, changes in visual acuity and intraocular pressure (safety outcomes) Adverse events reported? (Y/N): Y Measurement time points (specify intervals at which outcomes were assessed): baseline, 3 months, 6 months, and 12 months Other issues with outcome assessment (eg, quality control for outcomes, if any): none
Notes	Study dates: October 2014 to July 2016 Funding source(s): "Supported by cooperative agreements (U10EY022879 and U10EY022881) from the National Eye Institute, National Institutes of Health (NIH), and by grant supplements from the NIH" Conflicts of interest: the lead author has multiple financial relationships, including personal fees, grants, and non‐financial support from multiple companies Publication language: English Registered on clinical trials registry? (Y/N): Y (clinicaltrials.gov, NCT02128763)
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Randomization was performed with the use of a web‐based module and was stratified according to clinical center with a permuted block method with randomly chosen block sizes"
Allocation concealment (selection bias)	Low risk	"Personnel at the Investigational Drug Service, University of Pennsylvania, mailed the supplements directly to the patients"
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	"All patients, clinical staff, and laboratory personnel were unaware of the trial‐group assignments" "The active and placebo capsules contained 3 mg of vitamin E (alpha‐tocopherol), as an antioxidant, as well as masking flavor and lemon flavor"
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	"All patients, clinical staff, and laboratory personnel were unaware of the trial‐group assignments"
Incomplete outcome data (attrition bias)   All outcomes	High risk	Although the paper states that "analyses were performed according to the intention‐to‐treat principle," it is evident that 36/535 (6.7%) who were randomized were not included in the final analysis. It is also stated that "propensity scores and the regression method of multiple imputation were used for missing OSDI scores at month 6 or 12 [ref 11]"; however imputation does appear to have been performed for the other outcome measures.
Selective reporting (reporting bias)	High risk	Some prespecified outcomes listed on the clinical trials registry entry (eg, frequency of artificial tears used, contrast sensitivity, tear cytokine level(s), ocular redness) were not reported in the paper
Other bias	High risk	The lead author (PA) has multiple financial relationships, including personal fees, grants, and non‐financial support from multiple companies

Methods	Study design: randomized controlled trial Study site(s): single center Number randomized (total and per group): 38 participants in total; 18 participants in the flaxseed group; 20 participants in the control group Unit of randomization (individual or eye): individual Exclusions after randomization: 1 participant, because of a new diagnosis of Sjögren's syndrome Losses to follow‐up: 7 patients Unit of analysis (individual or eye): individual (OSDI); eye (other outcomes) Reported power calculation? (Y/N): N Reported subgroup analysis? (Y/N): N
Participants	Baseline characteristics Country: United States Age (mean ± SD, range): 46.9 ± 8.6 years in the flaxseed group; 54.5± 9.5 years in the control group Gender: 4 men and 14 women in the flaxseed group; 2 men and 18 women in the control group Inclusion criteria: 1. Over the age of 18 2. Diagnosis of moderate to severe chronic blepharitis and simple obstructive meibomian gland dysfunction and greater than 3 months' duration of ocular symptoms consistent with blepharitis, dry eye, and meibomian gland disease 3. Had not taken oral tetracycline drugs (including doxycycline and minocycline) or oral corticosteroids for at least 3 months and had discontinued all topical medications for at least 1 month before study enrollment Exclusion criteria: 1. Patients on a regular course of aspirin or COX‐2 inhibitors 2. Patients who were on anticoagulant therapies or who had blood disorders 3. Pre‐existing ocular disease or pathology 4. Systemic disease requiring anticoagulation 5. Long‐term use of non‐steroidal anti inflammatory agents or COX‐2 inhibitors 6. Use of dietary fatty acid (FA) supplementation, including omega‐3 or omega‐6 FAs, for 1 month before day 0 Equivalence of baseline characteristics? (Y/N): N (the flaxseed oil group had more visible meibomian gland orifices; participants in the flaxseed group were slightly younger)
Interventions	Intervention #1 (flaxseed group): flaxseed oil (1000 mg) 6 capsules daily, equivalent to a daily dose of 3300 mg omega‐3 fatty acids Intervention #2 (control group): placebo (olive oil), 6 capsules daily (dose not reported) Length of follow‐up: 1 year Notes: participants were asked to maintain their normal dietary habits during the course of the study; patients were also counseled to continue their daily eyelash hygiene
Outcomes	Primary outcome(s): "change (from baseline) in" TBUT; meibum score; OSDI Secondary outcome(s): "change (from baseline) in" Schirmer test with anesthesia; corneal fluorescein staining; conjunctival rose bengal staining; percentage of gland orifice blockage; grading of gross meibum character; blood fatty acid analysis; meibum lipid content. Adverse events reported? (Y/N): N Measurement time points (specify intervals at which outcomes were assessed): baseline, every 3 month for a total period of 1 year Other issues with outcome assessment (eg, quality control for outcomes, if any): this study has a unit of analysis issue, whereby both eyes from participants were included in the analyses of ocular outcomes, without apparent statistical adjustment for within‐person (between‐eye) correlation
Notes	Study dates: not reported Funding source(s): "supported by the Pearl Vision Foundation, Dallas, Texas; an unrestricted grant from Research for the Prevention of Blindness, Inc, to the Department of Ophthalmology, Northwestern University; and private contributions to the Ophthalmology Research Fund, Evanston Northwestern Healthcare, Division of Ophthalmology. The Natrol Corporation provided the flaxseed and olive oil capsules" Conflicts of interest: none Publication language: English Registered on clinical trials registry? (Y/N): N
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Subject numbers were preassigned to the control or study group with the aid of the random number generator in Microsoft Excel"
Allocation concealment (selection bias)	Low risk	"This (randomization) list was not incorporated into any documentation, and only research staff members not involved in patient care had access to these assignments"
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	This study was reported as a "double‐masked" trial "Subjects were masked to the contents of the oil capsule. Both flaxseed and olive oil have similar properties in appearance and texture" "This list was not incorporated into any documentation, and only research staff members not involved in patient care had access to these assignments"
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	This study was reported to be a "double‐masked" study, but details of masking of outcome assessors were not reported
Incomplete outcome data (attrition bias)   All outcomes	High risk	"An intent‐to‐treat analysis has been done by assuming that patients lost to follow up had no change" However, ITT analysis was followed only for some outcomes, not for all analyses
Selective reporting (reporting bias)	Unclear risk	Protocol was not available
Other bias	High risk	"The Natrol Corporation provided the flaxseed and olive oil capsules" Unit of randomization was the individual participant, but the analysis was performed by using the eye of single participants without taking into account the non‐independence of eyes (unit of analysis error); baseline data were not equivalent between groups

Methods	Study design: randomized, cross‐over, controlled trial Study site(s): not reported if single or multi‐center Number randomized (total and per group): 36 participants Unit of randomization (individual or eye): individual Exclusions after randomization: not explicitly reported, but 1 or 2 patients were not included in the analysis according to the graphs in the manuscript Losses to follow‐up: none reported Number analyzed (total and per group): 36 participants in total Unit of analysis (individual or eye): not reported Reported power calculation? (Y/N): N Reported subgroup analysis? (Y/N): N
Participants	Baseline characteristics Country: Denmark Age (mean ± SD, range): median 39 years in men, and 51 years in women, range 34 to 76 Gender: 3 men and 33 women Inclusion criteria: 1. Primary Sjögren’s syndrome based on the Copenhagen criteria 2. Keratoconjunctivitis sicca defined as at least 2 of the following 3 objective tests for each organ proved abnormal; Schirmer test, TBUT, and lissamine green staining by the van Bijsterveld score 3. Xerostomia examined by lip biopsy; unstimulated sialometry values; salivary gland scintigraphy Exclusion criteria: not reported Equivalence of baseline characteristics? (Y/N): not applicable (cross‐over)
Interventions	Intervention #1 (active treatment group): oral capsule containing cis‐linoleic acid 365 mg and γ‐linolenic acid 45 mg, Efamol twice daily (3 capsules at a time) plus tablet containing vitamin C 125 mg, pyridoxine 25 mg, niacin 25 mg, and ZnSo₄ 5 mg(Efavit), twice daily, 3 tablets at a time. Daily dose of linoleic acid 2190 mg and γ‐linolenic acid 270 mg Intervention #2 (control group): "placebo" (composition not reported) 500 mg capsule (dose not reported) and tablets, twice daily, 3 capsules at a time Length of follow‐up: 3 weeks in each phase, with 1‐week washout between phases; 7 weeks in total Notes: participants on NSAIDs were asked to reduce their usual intake, if possible, or to continue at the same dosage as usual. All other medications were kept constant during the trial, with the exception of bromhexine, which was discontinued at least 2 weeks before the start of the investigation
Outcomes	Primary and secondary outcome measures were not clearly distinguished Specified outcome(s): change from baseline in: Schirmer test; TBUT; van Bijsterveld score; subjective feeling of dryness in mouth and eyes; biscuit‐eating time; amount of snake‐like nuclear chromatin in conjunctival epithelial cells; tear lysozyme concentration; saliva Na+ and K+ concentrations Adverse events reported? (Y/N): Y Measurement time points (specify intervals at which outcomes were assessed): baseline, week 3 in each phase Other issues with outcome assessment (eg, quality control for outcomes, if any): none
Notes	Study dates: not reported Funding source(s): not reported Conflicts of interest: not reported Publication language: English Registered on clinical trials registry? (Y/N): N
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of randomization was not reported
Allocation concealment (selection bias)	Unclear risk	Allocation concealment was not reported
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	"Double‐blind" study but details of masking about personnel were not reported "All patients received three capsules of Egamol and three tablets of Efavit twice daily or placebo of identical appearance and number"
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	"Double‐blind" study, but details of masking about outcome assessors were not reported
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	"All completed the investigation," but data in the graphs suggest that 1 or 2 participants were not included in the analyses
Selective reporting (reporting bias)	Unclear risk	No access to study protocol or clinical trials registry
Other bias	High risk	In this cross‐over design, there was only 1‐week washout period between intervention phases, which is likely inadequate; information regarding funding source and conflict of interest was not reported

Study	Reason for exclusion
Ahluwalia 2001	Wrong intervention
Arici 2006	Wrong intervention
Costa 2012	Wrong intervention
Downie 2018b	Wrong participant population
Gadaria‐Rathod 2013	No relevant outcomes
Hom 2016	Not a RCT
Jackson 2011	Wrong intervention
Kawabata 2011	Wrong participant population
Kaya 2016	Not a RCT
Kwon 2017	Not a RCT
Macrì 2001	Wrong participant population
Macrì 2002	Wrong participant population
Macrì 2003	Wrong participant population
McMonnies 2019	Wrong study design (commentary)
NCT00803452	Wrong intervention
NCT01059019	Wrong patient population
NCT01213342	Study terminated (researchers left institution)
NCT01364311	Study was withdrawn
NCT01630551	Withdrawn with no participants enrolled
No author listed	Wrong study design (letter to editor)
No authors listed	Wrong study design (letter to editor)
Ong 2013	Wrong participant population
Pinna 2007	Wrong participant population (not explicitly defined as 'dry eye')
Querques 2007	Wrong participant population
Scuderi 2012	Wrong intervention
Sharma 2006	Wrong intervention
Tellez‐Vazquez 2016	Not a RCT
Wang 2016	Wrong participant population
Yoon 2012	Wrong intervention

Trial name or title	Public title: dietary supplements and ocular (eye) comfort Scientific title: a randomized placebo‐controlled double‐masked study to investigate the effects of dietary supplementation with a combination of omega oils on ocular comfort including symptoms of dry eye
Methods	Study design: randomized, parallel‐group, controlled trial Study site(s): not reported Number randomized (total and per group): 80 participants (planned) Unit of randomization (individual or eye): not reported Exclusions after randomization: not reported Losses to follow‐up: not reported Number analyzed (total and per group): not reported Unit of analysis (individual or eye): not reported Reported power calculation? (Y/N): N Reported subgroup analysis? (Y/N): N
Participants	Participant characteristics Country: Australia Age (mean ± SD, range): not reported Gender: not reported Inclusion criteria: 1. Willing to comply with the dosage and study visit schedule 2. Contact lens wearers and non‐contact lens wearers 3. At least 18 years old Exclusion criteria: 1. Current consumption of omega oil dietary supplements 2. Moderate or severe dry eye disease 3. Systematic disease that would preclude participants from safely ingesting dietary supplementation with omega oils 4. No S3 or above ocular medications 5. No use of any anticoagulants or blood thinning medications Equivalence of baseline characteristics? (Y/N): not reported
Interventions	Intervention #1: capsules containing eicosapentaenoic acid ˜ 550 mg, docosahexaenoic acid ˜ 120 mg, and liolenic acids per 3 capsules per day Intervention #2 (control): placebo capsules containing paraffin oil, 3 capsules per day Length of follow‐up: 3 months Notes: none
Outcomes	Primary outcome(s): subjective ocular comfort assessed using validated questionnaires (OCI, OSDI, SESOD, numerical rating scales, WHS, DEQ) Secondary outcome(s): non‐invasive TBUT; tear osmometry; phenol red thread test; lipid layer thickness and meibum composition; cell and nerve morphology using impression cytology and confocal microscopy Adverse events reported? (Y/N): not reported Measurement time points (specify intervals at which outcomes were assessed): baseline, 1 and 3 months Other issues with outcome assessment (eg, quality control for outcomes, if any): none
Starting date	March 2011
Contact information	Dr. Isabelle Jalbert School of Optometry and Vision Science  The University of New South Wales  UNSW Sydney NSW, Australia 2052
Notes	Date of last participant enrollment: March 6, 2012 Date clinical trial registry last updated: November 12, 2013 Recruitment status: completed Other notes: study sponsored by Blackmores Limited

Trial name or title	Public title: the impact of omega‐3 on dry eye Scientific title: the impact of omega‐3 fatty acids supplements on dry eye
Methods	Study design: randomized, parallel‐group, controlled trial Study site(s): not reported Number randomized (total and per group): 42 participants Unit of randomization (individual or eye): not reported Exclusions after randomization: not reported Losses to follow‐up: not reported Number analyzed (total and per group): not reported Unit of analysis (individual or eye): not reported Reported power calculation? (Y/N): N Reported subgroup analysis? (Y/N): N
Participants	Participant characteristics Country: Iran Age (mean ± SD, range): between 40 and 65 years (planned) Gender: both (planned) Inclusion criteria: subjects with tear break up time of less than 10 seconds Exclusion criteria: subjects with blood coagulation problems and those who take blood thinning medications such as warfarin or Coumadin; subject with the history of stomach ulcer, hemorrhage, or surgery in the past three months; history of allergies to fish oil or gelatinous capsules. Equivalence of baseline characteristics? (Y/N): not reported
Interventions	Intervention #1: omega‐3 capsule twice daily Intervention #2 (control): placebo gelatinous capsule twice daily Length of follow‐up: 1 month Notes: none
Outcomes	Primary outcome(s): OSDI; TBUT; Schimer test Secondary outcome(s): not listed Adverse events reported? (Y/N): not reported Measurement time points (specify intervals at which outcomes were assessed): baseline; 1 month Other issues with outcome assessment (eg, quality control for outcomes, if any): none
Starting date	April 2012
Contact information	Dr. Haleh Kangari College of Rehabilitation Corner of Bakhshifard Street, Damavand Ave. , Emam Hossein Square 1616913111, Tehran, Iran (Islamic Republic of)
Notes	Date of last participant enrollment: not reported Date clinical trial registry last updated: February 22, 2018 Recruitment status: completed Actual completion date: not reported, but completed Other notes: study sponsored by Shahid Beheshti University of Medical Sciences

Trial name or title	Public title: impact of omega‐3 supplement on dry eye treatment Scientific title: clinical trial comparing the effects of omega‐3 supplements and artificial tear drops on dry eye symptoms after surgery, cataract emulsification methods
Methods	Study design: randomized, parallel‐group, controlled trial Study site(s): single‐center Number randomized (total and per group): 60 eyes (planned) Unit of randomization (individual or eye): not reported Exclusions after randomization: not reported Losses to follow‐up: not reported Number analyzed (total and per group): not reported Unit of analysis (individual or eye): not reported Reported power calculation? (Y/N): N Reported subgroup analysis? (Y/N): N
Participants	Baseline characteristics Country: Iran Age (mean ± SD, range): not reported Gender: not reported Inclusion criteria: 1. Dry eye symptoms following phacoemulsification cataract surgery 2. Index of 30 or more from the Ocular Surface Disease Questionnaire 3. Schirmer test of 10 millimeters or less 4. TBUTof 7 seconds or less 5. Lack of eye trauma 6. Absence of uveitis Exclusion criteria: 1. Historic eye surgeries 2. Using contact lenses 3. Suffering from systemic diseases such as Sjögren's syndrome and diabetic retinopathy that causes dry eye Equivalence of baseline characteristics? (Y/N): not reported
Interventions	Intervention #1: omega‐3 capsules (Vita Natural Fish Oil Capsules) containing eicosapentaenoic acid 180 mg and docosahexaenoic acid 120 mg, 3 times daily Intervention #2 (control): no oral capsule Length of follow‐up: 3 months Notes: participants in both groups were instructed to instil a drop of artificial tears every 6 hours
Outcomes	Primary outcome(s): OSDI; visual acuity; Schirmer test; TBUT Secondary outcome(s): none Adverse events reported? (Y/N): not reported Measurement time points (specify intervals at which outcomes were assessed): not reported Other issues with outcome assessment (eg, quality control for outcomes, if any): none
Starting date	First enrollment: August 7, 2013
Contact information	Dr. Mehrdad Mohammadpour Eye Research Center Farabi Hospital Ghazvin Square South Kargar Avenue, Enghelab Square, Tehran, Iran.
Notes	Notes: reported to be "not blinded" Recruitment status: reported to be "complete" on February 22, 2018 (last update) Other notes: study sponsored by Vice Chancellor for research, Tehran University of Medical Science

Trial name or title	Public title: effect of complementary supplementation Camelina Oil on the improvement of dry eye disease in patients with dry eye Scientific title: effect of complementary supplementation Camelina Oil on the improvement of dry eye disease in patients with dry eye
Methods	Study design: randomized, parallel‐group, controlled trial Study site(s): not reported Number randomized (total and per group): 60 participants (planned) Unit of randomization (individual or eye): not reported Exclusions after randomization: not reported Losses to follow‐up: not reported Number analyzed (total and per group): not reported Unit of analysis (individual or eye): not reported Reported power calculation? (Y/N): N Reported subgroup analysis? (Y/N): N
Participants	Participant characteristics Country: Iran Age (mean ± SD, range): between 18 and 65 years (planned) Gender: both (planned) Inclusion criteria: patients with moderate dry eye; ability to take oral capsules; fill in the consent form; ability to visit for examination Exclusion criteria: eye Schirmer test less than 5 mm; TBUT eyes less than 5 seconds; excessive corneal opacification; the presence of corneal ulcer at least in that eye; pregnancy or breastfeeding; corticosteroid use or systemic anti‐inflammatory treatment simultaneously; taking any oral supplement; a clear change in diet during the last month or during treatment; any eye surgery over the past 6 months in the affected eye Equivalence of baseline characteristics? (Y/N): not reported
Interventions	Intervention #1: capsule containing paraffin oil, two grams, twice a day accompanied by breakfast and lunch Intervention #2 (control): capsule containing Comelina oil, 2 grams, twice a day accompanied by breakfast and lunch Length of follow‐up: 3 months Notes: none
Outcomes	Primary outcome(s): Schirmer test; TBUT Secondary outcome(s): not listed Adverse events reported? (Y/N): not reported Measurement time points (specify intervals at which outcomes were assessed): not reported Other issues with outcome assessment (eg, quality control for outcomes, if any): none
Starting date	November 2018
Contact information	Mahdieh Reyhani Tabriz University of Medical Sciences Hospital Bina,Tehran, 1786521, Tehran, Iran (Islamic Republic of)
Notes	Date of last participant enrollment : recruitment pending Date clinical trial registry last updated: May 21, 2019 Recruitment status: pending Other notes: study sponsored by Tabriz University of Medical Sciences

Trial name or title	Public title: evaluation the effect of intra nasal viola odorata almond oil drop on dry eye disease Scientific title: evaluation the effect of intra nasal viola odorata almond oil drop on dry eye disease
Methods	Study design: randomized, parallel‐group, controlled trial Study site(s): not reported Number randomized (total and per group): 60 participants (planned) Unit of randomization (individual or eye): not reported Exclusions after randomization: not reported Losses to follow‐up: not reported Number analyzed (total and per group): not reported Unit of analysis (individual or eye): not reported Reported power calculation? (Y/N): N Reported subgroup analysis? (Y/N): N
Participants	Participant characteristics Country: Iran Age (mean ± SD, range): age between 30 to 70 years Gender: both (planned) Inclusion criteria: age between 30 to 70 years; Tear Break Up Time less than 10 seconds at least in one eye; Schirmer test less than 10 millimeter at least in one eye without Local anesthesia; 2 symptoms of feeling eye dryness, foreign body sensation, eye burning Exclusion criteria: any active eye infection; pregnancy or lactation; any anatomic disorder like entropion or ectropion; incoordination of patients; important surface diseases of eyes which affects test results; history of eye trauma during the past 2 months; moderate to severe blepharitis; refraction surgery or laser therapy of eyes during the past month
Interventions	Intervention #1: daily treatment with artificial tear and viola odorata almond oil drop intranasal 2 drops in each nostril at night before sleeping category Intervention #2 (control): daily treatment with artificial tear and normal saline drop intranasal 2 drops in each nostril at night before sleeping Length of follow‐up: 6 weeks Notes: none Equivalence of baseline characteristics? (Y/N): not reported
Outcomes	Primary outcome(s): eye dryness based on the score of questionnaire Secondary outcome(s): not listed Adverse events reported? (Y/N): not reported Measurement time points (specify intervals at which outcomes were assessed): not reported Other issues with outcome assessment (eg, quality control for outcomes, if any): none
Starting date	January 2018
Contact information	Dr Ali Davati Shahed University Beginning of Tehran Qom freeway‐Shahed university, 33191‐18651, Tehran, Iran (Islamic Republic of)
Notes	Date of last participant enrollment: February 19, 2019 (recruitment) Date clinical trial registry last updated: January 28, 2019 Recruitment status: completed Other notes: study sponsored by Shahed University

Trial name or title	Public title: the effect of a unique omega‐3 supplement on dry mouth and dry eye in Sjogren's patients Scientific title: the effect of a unique omega‐3 supplement on dry mouth and dry eye in Sjogren's patients
Methods	Study design: randomized, parallel‐group, controlled trial Study site(s): not reported Number randomized (total and per group): 65 participants (planned) Unit of randomization (individual or eye): not reported Exclusions after randomization: not reported Losses to follow‐up: not reported Number analyzed (total and per group): not reported Unit of analysis (individual or eye): not reported Reported power calculation? (Y/N): N Reported subgroup analysis? (Y/N): N
Participants	Participant characteristics Country: United States of America Age (mean ± SD, range): not reported Gender: not reported Inclusion criteria: subjects with Sjogren's syndrome as defined by the European Criteria and a positive blood test or lip biopsy Exclusion criteria: had less than 10 teeth; received periodontal therapy in the past 12 months or antibiotic therapy in the past 1 month; required pre‐medication with antibiotics had advanced periodontitis, an infectious or wasting disease; already supplementing with omega‐3s; participating in another clinical trial Equivalence of baseline characteristics? (Y/N): not reported
Interventions	Intervention #1: omega‐3 supplement (TheraTears Nutrition, Advanced Vision Research, USA) containing 750 mg of long‐chain omega‐3s (450 mg of eicosapentaenoic acid [EPA] and 300 mg of docosahexaenoic acid [DHA]) and 1000 mg of flaxseed oil, once a day Intervention #2 (control): placebo Length of follow‐up: 3 months Notes: none
Outcomes	Primary outcome(s): increased oral and ocular comfort Secondary outcome(s): increased salivary flow and improvement in gingival index Adverse events reported? (Y/N): not reported Measurement time points (specify intervals at which outcomes were assessed): 3 months Other issues with outcome assessment (eg, quality control for outcomes, if any): none
Starting date	July 2005
Contact information	Dr Athena Papas Tufts University School of Dental Medicine One Kneeland Street Room 508, Boston, United States of America 02111
Notes	Date of last participant enrollment: September 4, 2007 Date clinical trial registry last updated: April 11, 2008 Recruitment status: no longer recruited Other notes: study sponsored by Advanced Vision Research

PERMALINK

Omega‐3 and omega‐6 polyunsaturated fatty acids for dry eye disease

Laura E Downie

Sueko M Ng

Kristina B Lindsley

Esen K Akpek

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Description of the condition

Description of the intervention

2. Table 1. Omega‐3 and omega‐6 polyunsaturated fatty acids ‐ structure, common food sources, and recommendations.

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Adverse outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

"Summary of findings" tables

Summary of findings for the main comparison. Oral long‐chain omega‐3 PUFAs (ie, EPA and DHA) versus placebo or no treatment.

Summary of findings 2. Combined oral omega‐3 and omega‐6 PUFAs versus placebo.

Summary of findings 3. Oral omega‐3 PUFAs plus conventional therapy versus conventional therapy alone.

Results

Description of studies

Results of the search

1.

Included studies

1. Table 2. Summary of study design, participants, interventions, and follow‐up period.

Types of studies

Types of participants

Types of interventions

3. Table 3. Summary of interventions.

Outcome measures

Primary outcome

Secondary outcomes

Ocular surface staining

4. Table 4. Summary of ocular surface staining procedures and grading scales.

Aqueous tear production

Tear film stability

Change in the frequency of use of artificial tears

Change in conjunctival goblet cell density

Change in the proportion of participants with improved blurred vision symptoms

Change in ocular surface inflammatory biomarkers, including human leukocyte antigen‐DR (HLA‐DR) and lymphocytic cell infiltration

Adverse events

5. Table 5. Summary of adverse effects.

Excluded studies

Risk of bias in included studies

2.

3.

Allocation

Sequence generation

Trial name or title	Public title: evaluation of combined Eyepeace and Eye Nutrients study Scientific title: Investigate the improvements in tear film/ocular surface and visual recovery in laser and intraocular lens (IOL) refractive surgery patients preoperative using the Eyepeace (Eyelid massager) and Eye Nutrients (omega fatty acid supplement)
Methods	Study design: randomized, parallel‐group, controlled trial Study site(s): not reported Number randomized (total and per group): 225 participants (planned) Unit of randomization (individual or eye): not reported Exclusions after randomization: not reported Losses to follow‐up: not reported Number analyzed (total and per group): not reported Unit of analysis (individual or eye): not reported Reported power calculation? (Y/N): N Reported subgroup analysis? (Y/N): N
Participants	Participant characteristics Country: United Kingdom Age (mean ± SD, range): 18 years of age or older (planned) Gender: both (planned) Inclusion criteria: aged 18 or overHave otherwise healthy eyes; are prepared not to wear contact lens for 3 months of the trial; have a NITBUT <10s; OSDI score: greater than or equal to 12; symptom frequency at least "some of the time"; presence of cloudy fluid expressed from at least 1 of the central 8 glands on the lower/upper lid and/or presence of poor expressibility from at least 2‐3 of the central 8 glands on the lower lid Exclusion criteria: conjunctivitis; meibomian cysts; styes; damage to the cornea; ocular injury; cataract or laser refractive surgery in the past 6 months; increased intraocular pressure (primary or secondary); any chronic disease of the eye Equivalence of baseline characteristics? (Y/N): not reported
Interventions	Intervention #1: Eyepeace eyelid massage: once a day, to be started 1 week prior to laser or intraocular lens surgery, to be stopped one day prior to surgery eye nutrients: two capsules a day, to be started 1 week prior to laser or intraocular lens surgery, to be stopped 3 months after surgery Intervention #2: eye nutrients: two capsules a day, to be started 1 week prior to laser or intraocular lens surgery, to be stopped 3 months after surgery Intervention #3: no Eyepeace or eye nutrients Length of follow‐up: 3 months Notes: none
Outcomes	Primary outcome(s): tear film lipid layer thickness Secondary outcome(s): TBUT; meibomian gland function; ocular redness/hyperaemia; MMP‐9; corneal sensitivity; corneal staining; tear volume; dry eye symptoms; visual satisfaction; longitudinal progress of the patient’s dry eye symptoms and adherence to dry eye treatment, Adverse events reported? (Y/N): not reported Measurement time points (specify intervals at which outcomes were assessed):2 weeks, 1 month, 2 months and 3 months Other issues with outcome assessment (eg, quality control for outcomes, if any): none
Starting date	March 2018
Contact information	Proffesor Jonathan Moore Cathedral Eye Clinic 89‐91 Academy Street, Belfast, BT1 2LS, United Kingdom
Notes	Date of last participant enrollment: April 1, 2018 Date clinical trial registry last updated: February 13, 2018 Recruitment status: no longer recruiting Other notes: study sponsored by Cathedral Eye Research

Trial name or title	Public title: oral supplementation of omega‐3 and omega‐6 in dry eye syndrome Scientific title: a 3‐month, multicenter, double‐masked, randomized, controlled clinical study to investigate the efficacy of Medilar™ in patients suffering from dry eye syndrome
Methods	Study design: randomized, parallel‐group, controlled trial Study site(s): multi‐center (2 sites) Number randomized (total and per group): 140 participants Unit of randomization (individual or eye): not reported Exclusions after randomization: not reported Losses to follow‐up: not reported Number analyzed (total and per group): not reported Unit of analysis (individual or eye): not reported Reported power calculation? (Y/N): N Reported subgroup analysis? (Y/N): N
Participants	Participant characteristics Country: France and Italy Age (mean ± SD, range): not reported Gender: males and females Inclusion criteria: 1. Legally adult outpatients, both males and females  2. Having given written informed consent  3. Suffering from dry eye syndrome as defined by the presence of  3.1. At least 2 of the following 4 objective tests corresponding to the scores below  3.1.1. Schirmer I values less than 10 mm/5 min  3.1.2. Break‐up time values less than 10 s  3.1.3. Fluorescein staining of the cornea score greater than or equal to 1 and less than 4  3.1.5. Van Bijsterveld score greater than or equal to 3 and less than or equal to 6 (Lissamine green)  3.2. Score of at least 1, for at least 2 of the following 5 subjective tests (scored 0 to 3)  3.2.1. Foreign body sensation  3.2.2. Dryness  3.2.3. Burning  3.2.4. Stinging  3.2.5. Photophobia  4. Stable systemic treatment (unchanged for 1 month or longer) Exclusion criteria: 1. Aged younger than 18 years  2. Severe dry eye (lissamine green greater than 6 or corneal staining greater than or equal to 4)  3. Uncontrolled evolutive systemic disease  4. Patients with an implantable cardioverter‐defibrillator (ICD)  5. Uncontrolled inflammatory disease (treated with varying doses of steroids or non‐steroidal anti‐inflammatory substances)  6. Change in systemic treatment within the last month  7. Expected change in treatment of concomitant disease  8. Patients treated with anticoagulants or predisposed to bleeding or hemorrhage  9. Drastic change in food and/or food supplements within the last month  10. Other food supplement with eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)  11. Patients with a history of recurrent ocular herpes and/or recurrent uveitis  12. Evidence of acute ocular infection and/or intraocular inflammation within 1 month before the start of this study  13. Patients who have undergone ocular surgery within the last 6 months  14. Change in ocular treatment within the last month  15. Patients currently using any ophthalmic medication including any ocular ointment except artificial tear preparation and eye cleaning solution for treatment of dry eye syndrome  16. Patients treated with topical ocular, steroidal, or non‐steroidal anti‐inflammatory treatment within the last month  17. Patients treated with ocular topical cyclosporine within the last month  18. Occlusion therapy with lacrimal or punctum plugs within the last 3 months  19. Patients currently wearing contact lenses  20. Pregnant or lactating women  21. Women of child‐bearing potential considering becoming pregnant during the course of the study and those not taking precautions to avoid pregnancy  22. Patients for whom, in the physician's opinion, any of the protocol procedures may pose a special risk not outweighed by the potential benefits of participating in the study  23. Patients who are unlikely to comply with the study protocol, or who are likely to be moving and lost to follow‐up in the study period  24. Known contraindication, adverse reaction, or hypersensitivity to any constituents of this food supplement  25. Patients who have participated in any clinical investigation within the last 30 days or who are currently participating in a clinical study  26. Patients who are addicted to alcohol or drugs  27. Patients with neurotic, psychiatric disorders or suicidal tendencies  28. Patients who plan to start a diet or to change their diet during the course of the study Equivalence of baseline characteristics? (Y/N): not reported
Interventions	Intervention #1: Medilar™: oral supplementation with 855 mg of omega‐3 and 15 mg of omega‐6, vitamins (C, E, B6, B12), and zinc per day (3 capsules per day) Intervention #2 (control): placebo (medium‐chain triglycerides), 3 capsules per day Length of follow‐up: 3 months Notes: none
Outcomes	Primary outcome(s): percentage of conjunctival epithelial cells expressing human leukocyte antigen DR‐1 (HLA‐DR) inflammatory markers in the worst eye, measured at baseline and at month 3 Secondary outcome(s): efficacy (in worst eye) at baseline, week 6, and month 3  1. Global subjective dry eye score (foreign body sensation, dryness, burning, stinging, photophobia)  2. Subjective dry eye score for each symptom  3. Objective dry eye score for each test (fluorescein staining of the cornea, van Bijsterveld test, tear break‐up time [TBUT] test, Schirmer I)  4. Fluorescence intensity of conjunctival cells expressing HLA‐DR inflammatory marker  5. Quality of life questionnaire for ocular surface disease Safety outcome: adverse or unexpected events Adverse events reported? (Y/N): not reported Measurement time points (specify intervals at which outcomes were assessed): not reported Other issues with outcome assessment (eg, quality control for outcomes, if any): none
Starting date	November 22, 2005
Contact information	Prof. Catherine Creuzot‐Garcher Hôpital Général  Service d'Ophtalmologie  3 Rue du Faubourg Raines  BP 1519, Dijon 21034, France.
Notes	Notes: retrospectively registered Overall trial end date: January 18, 2007 Other notes: industry sponsor (Laboratoire Chauvin, Bausch & Lomb Inc., France)

Trial name or title	A placebo controlled double masked clinical assessment study of essential fatty acid supplement and its effect on patients with apparent aqueous deficient dry eye syndrome
Methods	Study design: randomized, parallel‐group, controlled trial Study site(s): single‐center Number randomized (total and per group): 42 participants Unit of randomization (individual or eye): not reported Exclusions after randomization: not reported Losses to follow‐up: not reported Number analyzed (total and per group): not reported Unit of analysis (individual or eye): not reported Reported power calculation? (Y/N): N Reported subgroup analysis? (Y/N): N
Participants	Participant characteristics Country: United States Age (mean ± SD, range): not reported Gender: not reported Inclusion criteria: 1. Patient over 18 years of age 2. Patient willing and able to comply with the protocol; no planned changes in diet, topical or systemic drugs during course of study 3. Ocular symptoms consistent with dry eye of insidious onset and greater than 3 months' duration 4. Ocular surface vital staining consistent with aqueous deficient dry eyes with less than +1 conjunctival injection and no more than minimal lid inflammation Exclusion criteria: 1. Patients who use topical eye drops other than artificial tears 2. Patients with punctal occlusion or punctal plugs 3. Patients with active ocular infection or inflammatory disease 4. History of herpetic keratitis 5. History of retinal detachment 6. Concurrent contact lens use during the trial period 7. Ocular surgery within the past 6 months 8. Patients with glaucoma, anterior membrane dystrophy, active trichiasis, or any eyelid globe malposition abnormality (eg, entropion, ectropion) 9. Patients with epiphora (excessive tearing) 10. Patients taking medications known to affect aqueous tear production or meibomian secretions 11. Patient must not have participated in (or be currently participating in) any investigational therapeutic drug or device trial within the previous 30 days before the start date for this trial 12. Patients suffering from organic brain syndromes or major psychiatric disorder that would interfere with compliance or subjective reporting Equivalence of baseline characteristics? (Y/N): not reported
Interventions	Intervention #1: omega‐3 fatty acid supplement, containing a daily dose of EPA (eicosapentaenoic acid) 450 mg, DHA (docosahexaenoic acid) 300 mg, and flaxseed oil (organic) 1000 mg Intervention #2 (control): placebo supplements, containing wheat germ oil but not essential fatty acids Length of follow‐up: not reported Notes: patient's topical therapy will be standardized after identification exam, so that all patients will use TheraTears™ 4 times daily
Outcomes	Primary outcome(s): meibomian gland secretion lipid biochemistry changes (before and after treatment) Secondary outcome(s): tear evaporation rate and tear fluorophometry (both measured before and after treatment) Adverse events reported? (Y/N): N Measurement time points (specify intervals at which outcomes were assessed): not reported Other issues with outcome assessment (eg, quality control for outcomes, if any): none
Starting date	September 2004
Contact information	James McCulley University of Texas, Southwestern Medical Center at Dallas, USA
Notes	Recruitment status: completed Actual completion date: October 2008 Last update posted: May 2018

Trial name or title	Evaluation of the efficacy of T1675, a per os omega 3 and omega 6 polyunsaturated essential fatty acid dietary formulation versus placebo in patients with bilateral treated moderate dry eye syndrome
Methods	Study design: randomized, parallel‐group, controlled trial Study site(s): single‐center Number randomized (total and per group): not reported Unit of randomization (individual or eye): not reported Exclusions after randomization: not reported Losses to follow‐up: not reported Number analyzed (total and per group): not reported Unit of analysis (individual or eye): individual (right eye) Reported power calculation? (Y/N): N Reported subgroup analysis? (Y/N): N
Participants	Participant characteristics Country: France Age (mean ± SD, range): not reported Gender: not reported Inclusion criteria: 1. Signed and dated informed consent 2. Male or female from 18 to 90 years old 3. Known treated bilateral dry eye 4. Dry eye syndrome confirmed by ocular examination with fluorescein and/or lissamine green staining, TBUT, and Schirmer, performed within the last 12 months before the inclusion visit, for both eyes 5. Bilateral symptoms suggestive of dry eye defined by at least 1 of the following ocular symptoms suggestive of dry eye (burning, stinging, dryness feeling, sandy and/or gritty sensation, light sensitivity, reflex tearing, ocular fatigue) and questioning on patient’s feeling (score ≥ 3) 6. Fulfilling the following criteria of dry eye syndrome in both eyes defined by keratoconjunctivitis defined by a lissamine green score ≥ 4 (van Bijsterveld score) and Schirmer test ≤ 10 mm in 5 min or TBUT < 10 s Exclusion criteria: 1. Severe dry eye symptoms 2. Eyelid dysfunction 3. Severe progressive rosacea 4. Any relevant ocular anomaly interfering with ocular surface 5. Best‐corrected far visual acuity ≤ 1/10 6. History of ocular allergy 7. Trauma, infection, inflammation within last 3 months 8. Ocular surgery and laser within last 3 months 9. LASIK, laser, PRK within last 12 months 10. Contact lenses 11. Any concomitant nutritive supplementation, vitamins 12. Any topical concomitant treatment Equivalence of baseline characteristics? (Y/N): not reported
Interventions	Intervention #1: omega‐3 and omega‐6 polyunsaturated essential fatty acid (T1675) supplements Intervention #2 (control): placebo supplements Length of follow‐up: 6 months Notes: none
Outcomes	Primary outcome(s): total score of lissamine green staining in the right eye Secondary outcome(s): global efficacy; tolerance Adverse events reported? (Y/N): N Measurement time points (specify intervals at which outcomes were assessed): baseline, months 1, 3, 12, 18, 24, 30, and 36 Other issues with outcome assessment (eg, quality control for outcomes, if any): none
Starting date	November 2004
Contact information	Dr. Catherine Creuzot‐Garcher CHU of Dijon, France
Notes	Recruitment status: completed (May 2005) Last post updated: October 2006

Trial name or title	Clinical trial of essential fatty acids for dry eye disease: feasibility study
Methods	Study design: randomized, parallel‐group, controlled trial Study site(s): not reported Number randomized (total and per group): 18 participants in total; 9 in each treatment group Unit of randomization (individual or eye): not reported Exclusions after randomization: 2 participants (due to adverse events), both in the omega‐3 intervention group Losses to follow‐up: none Number analyzed (total and per group): 16 participants in total; 7 in the omega‐3 intervention group; 9 in the placebo group Unit of analysis (individual or eye): not reported Reported power calculation? (Y/N): N Reported subgroup analysis? (Y/N): N
Participants	Participant characteristics Country: United States Age (mean ± SD, range): 56 ± 14 years in total; 55 ± 14 years in the omega‐3 intervention group; 57 ± 15 years in the placebo group Gender: 3 men and 15 women in total; 1 man and 8 women in the omega‐3 intervention group; 2 men and 7 women in the placebo group Inclusion criteria: 1. Signed and dated informed consent form approved by the IRB 2. ≥ 18 years of age 3. Demonstrated at least 2 of the 4 following signs in the same eye at 2 consecutive visits (visit 1: 7 to 21 days before randomization, and visit 2: day of randomization): (a) conjunctival staining present ≥ 1; (b) corneal fluorescein staining present ≥ 1; (c) tear film break‐up time (TBUT) ≤ 7 seconds; (d) Schirmer test ≤ 7 mm/5 min 4. Demonstrated symptoms of dry eye disease (OSDI score of at least 22 at screening visit and at least 15 at randomization visit) 5. Use or desire to use artificial tears on average 2 times per day in the 2 weeks preceding study entry (run‐in period). No newly diagnosed patients can be enrolled, and if a new patient wants to participate, she/he must be put on tears and re‐evaluated in 6 months 6. Intraocular pressure (IOP) ≥ 5 mmHg and ≤ 22 mmHg in each eye 7. Women of child‐bearing potential must agree to use a reliable method of contraception during study participation, and must demonstrate a negative urine pregnancy test at screening visit 8. Must be willing/able to return for all study visits and to follow instructions from the study investigator and his/her staff 9. Must be able to swallow large, soft gel caps Exclusion criteria: 1. Patients who are allergic to ingredients of active or placebo pills (fish, olive oil) 2. Current diagnosis of ocular infection (eg, bacterial, viral, fungal) 3. History of ocular herpetic keratitis 4. Eye surgery (including cataract surgery) within 6 months before randomization 5. Previous LASIK surgery 6. Pregnant or nursing/lactating 7. Participation in a study of an investigational drug or device within the past 30 days 8. Recent (≤ 3 months) initiation of use of systemic corticosteroids or other immunosuppressive agent and/or planning to change treatment during study participation 9. Cognitive or psychiatric deficit that precludes informed consent or ability to perform requirements of the investigation 10. Contact lens wearers 11. Use of glaucoma medication or history of surgery for glaucoma 12. Recent (≤ 3 months) insertion of punctal plugs 13. Use of punctal plugs but unwilling to commit to their use for the duration of the study 14. Unwilling to commit to same brand of artificial tears throughout the study 15. Current use of EPA/DHA supplements in excess of 1 gram/d 16. Recent (≤ 6 months) initiation of use of Restasis 17. Use of Restasis but unwilling to commit to use of Restasis for the duration of the study 18. Discontinued use of Restasis within the last 3 months Equivalence of baseline characteristics? (Y/N): Y
Interventions	Intervention #1 (omega‐3 treatment group): total daily dose of eicosapentaenoic acid 2000 mg and docosahexaenoic acid 1000 mg (from 5 capsules) Intervention #2 (control group): placebo (olive oil), 5 capsules daily containing 3000 mg of olive oil Length of follow‐up: 3 months Notes: none
Outcomes	Primary outcome(s): change in OSDI and red blood cell membrane fatty acid content Secondary outcome(s): change in each of Brief Ocular Discomfort Inventory (BODI); Impact of Dry Eye on Everyday Life (IDEEL); Quality of Life Associated With Chronic Pain; ocular surface; Schirmer test; HLA‐DR; MUC 5A; cytokines Adverse events reported? (Y/N): Y Measurement time points (specify intervals at which outcomes were assessed): not reported Other issues with outcome assessment (eg, quality control for outcomes if any): none
Starting date	January 2010
Contact information	Penny Asbell, MD
Notes	Recruitment status: completed Last post updated: August 2012

Trial name or title	SYSTANE family efficacy in meibomian gland functionality for lipid deficient evaporative dry eye subjects
Methods	Study design: randomized, parallel‐group, controlled trial Study site(s): single‐center Number randomized (total and per group): 26 participants in total; 13 participants in each group ("experimental" group and "active comparator" group) Unit of randomization (individual or eye): not reported Exclusions after randomization: none Losses to follow‐up: none Number analyzed (total and per group): 26 participants in total; 13 participants in each group ("experimental" group and "active comparator" group) Unit of analysis (individual or eye): not reported Reported power calculation? (Y/N): N Reported subgroup analysis? (Y/N): N
Participants	Participant characteristics Country: United States Age (mean ± SD, range): 41.7 ± 19.8 years total; 38.1 ± 19.9 years in the experimental group; 45.4 ± 19.8 years in the active comparator group Gender: 5 men and 21 women in total; 2 men and 11 women in the experimental intervention group; 3 men and 10 women in the active comparator group Inclusion criteria: 1. Clinical diagnosis of lipid deficient evaporative dry eye; meibomian gland functionality ‐ not more than 6 glands yielding liquid secretion 2. Willing to discontinue the use of all other meibomian glands 3. Dysfunction management before receiving the study test article at visit 1, up until the end of the study period 4. Best‐corrected visual acuity of 20/40 Snellen or better in each eye 5. Must be able to follow instructions and must be willing to attend required study visits 6. Read, sign, and date an ethics committee reviewed and approved informed consent form 7. Other protocol‐defined inclusion criteria may apply Exclusion criteria: 1. History or evidence of ocular or intraocular surgery or serious ocular trauma in either eye within the past 6 months 2. Current punctal occlusion of any type (eg, collagen plugs, silicone plugs) 3. History of intolerance or hypersensitivity to any component of study medications 4. History or evidence of epithelial herpes simplex keratitis (dendritic keratitis); vaccinia; active or recent varicella viral disease of the cornea and/or conjunctiva; chronic bacterial disease of the cornea and/or conjunctiva and/or eyelids; mycobacterial infection of the eye; and/or fungal disease of the eye 5. Pregnant or lactating at the time of enrollment 6. Not willing to take adequate precautions to avoid becoming pregnant during the study 7. Use of any concomitant topical ocular medications during the study period 8. Use of systemic medications that may contribute to dry eye unless on a stable dosing regimen for a minimum of 30 days before visit 1 9. Ocular conditions that may preclude safe administration of either drop under investigation 10. Unwilling to discontinue contact lens wear during the study period and for at least 1 week before visit 1 11. Participation in an investigational drug or device study within 30 days of entering this study 12. Other protocol‐defined exclusion criteria may apply Equivalence of baseline characteristics? (Y/N): Y
Interventions	Intervention #1 (experimental group): SYSTANE Lid Wipes administered to treated eye(s) once a day; SYSTANE BALANCE Lubricant Eye Drops administered to treated eye(s), 1 drop, 4 times a day; SYSTANE Vitamins, 2 soft gels ingested daily Intervention #2 (active comparator group): microfiber towels as warm compress once daily for 8 minutes Length of follow‐up: 3 months Notes: none
Outcomes	Primary outcome(s): number of meibomian glands yielding liquid secretion Secondary outcome(s): Standard Patient Evaluation of Eye Dryness (SPEED) questionnaire; OSDI Adverse events reported? (Y/N): Y Measurement time points (specify intervals at which outcomes were assessed): not reported Other issues with outcome assessment (eg, quality control for outcomes, if any): none
Starting date	February 2013
Contact information	Donald R. Korb, O.D. Korb and Associates
Notes	Recruitment status: completed First posted: November 2012 Last post updated: June 2018

Trial name or title	Dry eye disease in the vitamin D and omega‐3 trial (VITAL)
Methods	Study design: randomized, parallel‐group, controlled trial Study site(s): not reported Number randomized (total and per group): 25,875 participants Unit of randomization (individual or eye): not reported Exclusions after randomization: not reported Losses to follow‐up: not reported Number analyzed (total and per group): not reported Unit of analysis (individual or eye): not reported Reported power calculation? (Y/N): N Reported subgroup analysis? (Y/N): N
Participants	Participant characteristics Country: United States Age (mean ± SD, range): not reported Gender: not reported (males and females) Inclusion criteria: 1. All participants in VITAL (NCT 01169259) are eligible to participate in this ancillary study Exclusion criteria: 1. Not reported Equivalence of baseline characteristics? (Y/N): not reported
Interventions	Intervention #1: vitamin D (cholecalciferol, 2000 IU per day) plus fish oil placebo Intervention #2: vitamin D placebo, plus 1 capsule containing 840 mg of marine omega‐3 fatty acids (eicosapentaenoic acid 465 mg and docosahexaenoic acid 375 mg) Intervention #3: vitamin D placebo plus fish oil placebo Intervention #4: vitamin D (cholecalciferol, 2000 IU per day) plus 1 capsule containing 840 mg of marine omega‐3 fatty acids (eicosapentaenoic acid 465 mg and docosahexaenoic acid 375 mg) Length of follow‐up: 5 years Notes: none
Outcomes	Primary outcome(s): dry eye disease (report of a diagnosis of dry eye disease confirmed by medical record review) Secondary outcome(s): none specified Adverse events reported? (Y/N): not reported Measurement time points (specify intervals at which outcomes were assessed): not reported Other issues with outcome assessment (eg, quality control for outcomes, if any): none
Starting date	July 2010
Contact information	None provided
Notes	Recruitment status: unknown First posted: June 2013 Last post updated: January 2016

Trial name or title	a study to determine the relief of dry eye symptoms with the use of TheraTears® products (DUNLIN)
Methods	Study design: randomized, parallel‐group, controlled trial Study site(s): single‐center Number randomized (total and per group): 33 participants Unit of randomization (individual or eye): not reported Exclusions after randomization: not reported Losses to follow‐up: not reported Number analyzed (total and per group): not reported Unit of analysis (individual or eye): not reported Reported power calculation? (Y/N): N Reported subgroup analysis? (Y/N): N
Participants	Participant characteristics Country: Canada Age (mean ± SD, range): 18 to 65 years (planned) Gender: both (planned) Inclusion criteria: between 18 and 65 years of age and has full legal capacity to volunteer; read and signed an information consent letter; willing and able to follow instructions and maintain the appointment schedule; symptoms of dry eye for at least 3 months; OSDI score of ≥ 23; currently on a non‐omega 3 dry eye treatment regimen that, at the minimum consists of instilling artificial tears at least once a day for the past 3 months; an average non‐invasive tear breakup time ≤ 5.00 seconds in at least one eye. Exclusion criteria: participating in any concurrent clinical or research study; has any known active* ocular disease and/or infection and/or allergies;* For the purposes of study, active ocular disease is defined as infection or inflammation which requires therapeutic treatment. Lid abnormalities (blepharitis, meibomian gland dysfunction, papillae), corneal and conjunctival staining and dry eye are typical findings and are not considered active ocular disease. Neovascularization and corneal scars are the result of previous hypoxia, infection or inflammation and are therefore not active; a systemic condition that in the opinion of the investigator may affect a study outcome variable; Is using any systemic or topical medications that in the opinion of the investigator may affect a study outcome variable; known sensitivity to the diagnostic pharmaceuticals to be used in the study; pregnant, lactating or planning a pregnancy at the time of enrollment, as determined verbally; aphakic; undergone refractive error surgery; take part in another (pharmaceutical) research study within the last 30 days; worn contact lenses within the past 5 years; currently using or have used omega 3 supplements in the past 3 months. Equivalence of baseline characteristics? (Y/N): not reported
Interventions	Intervention #1: TheraTears® lubricant eye drop, TheraTears® preservative‐free single‐use containers, TheraTears® Nutrition, and TheraTears® TheraLid® eyelid cleanser Intervention #2 (control): no treatment Length of follow‐up: 3 months Notes: none
Outcomes	Primary outcome(s): OSDI; visual analogue scores; tear osmolarity; TBUT; corneal staining Secondary outcome(s): lid wiper epitheliopathy; meibomian gland expressibility; meibum quality; tear film lipid layer thickness; tear meniscus height, Schirmer test Adverse events reported? (Y/N): N Measurement time points (specify intervals at which outcomes were assessed): baseline, 1 month and 3 months Other issues with outcome assessment (eg, quality control for outcomes, if any): none
Starting date	December 2013
Contact information	Centre for Contact Lens Research, University of Waterloo School of Optometry & Vision Science, Waterloo, Ontario, Canada, N2L3G1
Notes	Recruitment status: completed Actual completion date: November 2014 Last update posted: March 11, 2015

Trial name or title	The effect of oral Zanthoxylum Schinifolium seed oil in individuals with dry eye disease
Methods	Study design: randomized, parallel‐group, controlled trial Study site(s): single‐center Number randomized (total and per group): 20 participants (planned) Unit of randomization (individual or eye): not reported Exclusions after randomization: not reported Losses to follow‐up: not reported Number analyzed (total and per group): not reported Unit of analysis (individual or eye): not reported Reported power calculation? (Y/N): N Reported subgroup analysis? (Y/N): N
Participants	Participant characteristics Country: South Korea Age (mean ± SD, range): 20 to 70 years (planned) Gender: both (planned) Inclusion criteria: men and women; 20 to 70 years with dry eye disease low tear break‐up time (TBUT) (<10 seconds) or low Schirmer score (with application of local anesthetic) (<10mm for 5 min) or presence of corneal and conjunctival damage at the time of screening; blood level of triglyceride higher than 150 mg/dL or HDL‐cholesterol less than 40 and 50 mg/dL for men and women, respectively. Exclusion criteria: under the anti‐inflammatory eye drops for dry eye (topical steroid and topical cyclosporin); hypolipidemic medication within 3 months of study entry; history of chronic disease; any clinical trial using an investigative medicinal product within 2 months before the first dose of the present study allergic or hypersensitive to any of the ingredients in the test products; women who were pregnant or breast feeding; a history of alcoholism or drug abuse or medical or psychological conditions Equivalence of baseline characteristics? (Y/N): not reported
Interventions	Intervention #1: Zanthoxylum Schinifolium Seed Oil(4g/day) Intervention #2 (control): placebo/soy bean oil(4g/day) Length of follow‐up: 10 weeks Notes: none
Outcomes	Primary outcome(s): Schirmer test; TBUT; corneal staining; OSDI Secondary outcome(s): interleukin‐13; interferon‐gamma; interleukin‐1β; interleukin‐17; malondialdehyde; low‐density lipoprotein; total cholesterol; triglyceride; high‐density lipoprotein cholesterol; low‐density lipoprotein cholesterol Adverse events reported? (Y/N): N Measurement time points (specify intervals at which outcomes were assessed): baseline, 5 weeks and 10 weeks Other issues with outcome assessment (eg, quality control for outcomes, if any): none
Starting date	February 2015
Contact information	Clinical Trial Center for Functional Foods; Chonbuk National University Hospital, Jeonju, Jeollabuk‐do, Korea, Republic of, 560‐822
Notes	Recruitment status: completed Actual completion date: February 2016 Last update posted: June 16, 2016

Trial name or title	Public title: a two comparator, controlled phase 3 study in patients with and without evaporative dry eye Scientific title: a two comparator, controlled phase 3 Study of OM3 tear formulation versus OPTIVE ADVANCED unit dose and OPTIVE unit dose eye drops in patients with and without evaporative dry eye
Methods	Study design: randomized, cross‐over, controlled trial Study site(s): not reported Number randomized (total and per group): 57 participants Unit of randomization (individual or eye): not reported Exclusions after randomization: not reported Losses to follow‐up: not reported Number analyzed (total and per group): not reported Unit of analysis (individual or eye): not reported Reported power calculation? (Y/N): N Reported subgroup analysis? (Y/N): N
Participants	Participant characteristics Country: Australia Age (mean ± SD, range): not reported Gender: both sexes eligible to participate Inclusion criteria: 1. Able to read and comprehend English and give informed consent as demonstrated by signing a record of informed consent 2. Over 18 years of age 3. Not wearing contact lenses in the past 3 months before enrolling 4. Willing to use eye drops and comply with the study visit schedule as directed by the investigator 5. Habitual (corrected or uncorrected) visual acuity of 6/9.5 or better in each eye 6. At the screening visit (day ‐14), patients must have Ocular Surface Disease Index (OSDI) score > 18 (0 to 100 scale). At baseline (day 1) visits, patients must have OSDI score > 12 to continue in the study 8. TBUT≤ 10 s in at least 1 eye at screening visit and at baseline visit 9. Corneal fluorescein staining score ≥ 1 and < 4 (Oxford scheme) at screening and baseline visits Exclusion criteria: 1. Schirmer test (with anesthesia) ≤ 2 mm in either eye at screening 2. Patients who are currently using topical ocular medication or have used topical ocular medication within 2 weeks of the screening visit. Patients who are being treated bilaterally with a marketed artificial tear for dry eye can be considered, provided they discontinue use at the screening visit 3. Any active anterior segment disease excluding blepharitis 4. Any systemic disease that may affect ocular health (eg, Graves' disease, autoimmune diseases such as ankylosing spondylitis, multiple sclerosis, and systemic lupus erythematosus) 5. History of epilepsy or migraines exacerbated by flashing, strobe‐like lights 6. Rigid or soft contact lens wearer, including orthokeratology 7. History of eye surgery within 6 months before enrollment in the study 8. Previous corneal refractive surgery Equivalence of baseline characteristics? (Y/N): not reported
Interventions	Intervention #1: omega‐3 eye drop Intervention #2: Optive Advanced eye drop Intervention #3: Optive eye drop Length of follow‐up: 4 weeks Notes: topical omega‐3 intervention
Outcomes	Primary outcome(s): tear evaporation rate, measured by a vapometer (g ‐ 2 h) Secondary outcome(s): TBUT and subjective ocular comfort (measured using visual analogue scales from 0 to 100) Adverse events reported? (Y/N): N Measurement time points (specify intervals at which outcomes were assessed): baseline, up to 4 weeks Other issues with outcome assessment (eg, quality control for outcomes, if any): none
Starting date	September 19, 2016
Contact information	Jacqueline Tan‐Showyin The University of New South Wales, Australia
Notes	Actual study completion date: September 18, 2017 Last update posted: August 2, 2018 Other notes: single‐masked (investigator only) Study undertaken in collaboration with Allergan (industry)