Topical cyclosporine A therapy for dry eye syndrome

Cintia S de Paiva; Stephen C Pflugfelder; Sueko M Ng; Esen K Akpek

doi:10.1002/14651858.CD010051.pub2

. 2019 Sep 13;2019(9):CD010051. doi: 10.1002/14651858.CD010051.pub2

Topical cyclosporine A therapy for dry eye syndrome

Cintia S de Paiva ^1,^✉, Stephen C Pflugfelder ¹, Sueko M Ng ², Esen K Akpek ³

Editor: Cochrane Eyes and Vision Group

PMCID: PMC6743670 PMID: 31517988

Abstract

Background

Topical cyclosporine A (also known as ciclosporin A) (CsA) is an anti‐inflammatory that has been widely used to treat inflammatory ocular surface diseases. Two CsA eyedrops have been approved by US Food and Drug Administration for managing dry eye: Restasis (CsA 0.05%, Allergan Inc, Irvine, CA, USA), approved in 2002, and Cequa (CsA 0.09%, Sun Pharma, Cranbury, NJ, USA), approved in 2018. Numerous clinical trials have been performed to assess the effectiveness and safety of CsA for dry eye; however, there is no universal consensus with regard to its effect.

Objectives

To assess the effectiveness and safety of topical CsA in the treatment of dry eye.

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2018, Issue 2); Ovid MEDLINE; Embase.com; PubMed; Latin American and Caribbean Health Sciences Literature Database (LILACS); ClinicalTrials.gov; and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). We did not use any date or language restrictions in the electronic search for trials. We last searched the electronic databases on 16 February 2018.

Selection criteria

We included randomized controlled trials (RCTs) of people with dry eye regardless of age, sex, severity, etiology, or classification of dry eye. We included RCTs in which different concentrations of topical CsA were compared with one another or with artificial tears, placebo, or vehicle. We also included RCTs in which CsA in combination with artificial tears was compared to artificial tears alone.

Data collection and analysis

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

Main results

We included 30 RCTs (4009 participants) with follow‐up periods ranging from 6 weeks to 12 months. We studied dry eye of various severity and underlying causes. The interventions investigated also varied across RCTs: CsA versus artificial tears; CsA with artificial tears versus artificial tears alone; and in some studies, more than one concentration of CsA. Artificial tears were used as adjunctive to study medication in all but five trials. Almost all trials had deficiencies in the reporting of results (e.g. reporting P values or direction only), precluding the calculation of between‐group estimates of effect or meta‐analysis.

Eighteen trials compared topical CsA 0.05% plus artificial tears versus vehicle plus artificial tears or artificial tears alone. One trial reported subjective symptoms of dry eye at 6 months and the results were in favor of CsA (mean difference (MD) ‐4.80, 95% confidence interval (CI) ‐6.41 to ‐3.19; low‐certainty evidence). Two trials reported MD in ocular surface dye staining at 6 months, but the results were inconsistent in these two trials (MD −0.35, 95% CI −0.69 to −0.01 in one and MD 0.58, 95% CI 0.06 to 1.10 in the other; low‐certainty evidence). Four trials reported MD in Schirmer test scores at 6 months and the estimates ranged from ‐4.05 (95% CI ‐6.67 to ‐1.73) to 3.26 (95% CI ‐1.52 to 5.00) (low‐certainty evidence). Three trials reported risk ratio (RR) of improved Schirmer test scores at 6 months; estimates ranged from 0.98 (95% CI 0.83 to 1.17) to 3.50 (95% CI 2.09 to 5.85) (low‐certainty evidence). Four trials reported MD in tear film stability measured by tear break‐up time at 6 months and the estimates ranged from ‐1.98 (95% CI ‐3.59 to ‐0.37) to 1.90 (95% CI 1.44 to 2.36) (low‐certainty evidence). Three trials reported RR of improved tear break‐up time at 6 months and the estimates ranged from 0.90 (95% CI 0.77 to 1.04) to 4.00 (95% CI 2.25 to 7.12) (low‐certainty evidence). Three trials reported frequency of artificial tear usage at 6 months without providing any estimates of effect; the direction of effect seem to be in favor of CsA (low‐certainty evidence). Because of incomplete reporting of the results data or considerable statistical heterogeneity, we were only able to perform a meta‐analysis on mean conjunctival goblet cell density. Mean conjunctival goblet cell density in the CsA treated group may be greater than that in the control group at the end of follow‐up at four and 12 months (MD 22.5 cells per unit, 95% CI 16.3 to 28.8; low‐certainty evidence). All but two trials reported adverse events that included burning and stinging. Participants treated with CsA may be more likely to have treatment‐related adverse events than those who treated with vehicle (RR 1.33, 95% CI 1.00 to 1.78; low‐certainty evidence).

Other comparisons evaluated were CsA 0.05% plus artificial tears versus higher concentrations of CsA plus artificial tears (4 trials); CsA 0.05% versus placebo or vehicle (4 trials); CsA 0.1% plus artificial tears versus placebo or vehicle plus artificial tears (2 trials);  CsA 0.1% cationic emulsion plus artificial tears versus vehicle plus artificial tears (2 trials); CsA 1% plus artificial tears versus placebo plus artificial tears (3 trials); and CsA 2% plus artificial tears versus placebo plus artificial tears (3 trials). Almost all of these trials reported P value or direction of effect only (mostly in favor of CsA), precluding calculation of between‐group effect estimates or meta‐analyses.

Authors' conclusions

Despite the widespread use of topical CsA to treat dry eye, we found that evidence on the effect of CsA on ocular discomfort and ocular surface and tear film parameters such as corneal fluorescein staining, Schirmer's test, and TBUT is inconsistent and sometimes may not be different from vehicle or artificial tears for the time periods reported in the trials. There may be an increase in non‐serious, treatment‐related adverse effects (particularly burning) in the CsA group. Topical CsA may increase the number of conjunctival goblet cells. However, current evidence does not support that improvements in conjunctival mucus production (through increased conjunctival goblet cells) translate to improved symptoms or ocular surface and tear film parameters. All published trials were short term and did not assess whether CsA has longer‐term disease‐modifying effects. Well‐planned, long‐term, large clinical trials are needed to better assess CsA on long‐term dry eye‐modifying effects. A core outcome set, which ideally includes both biomarkers and patient‐reported outcomes in the field of dry eye, is needed.

Plain language summary

Cyclosporine A eye drops for the treatment of dry eye

What is the aim of this review?  The aim of this Cochrane Review was to find out if cyclosporine A (CsA) eye drops are helpful in the treatment of dry eye. Cochrane researchers collected and analyzed all relevant studies to answer this question and found 30 studies.

What is the key message of this review?  It is unclear whether CsA eyedrops reduce the symptoms and signs of dry eye. People using CsA drops may experience adverse effects, such as burning or stinging.

What was studied in the review?  The surface of the eye is moist and covered with a thin layer of tears. When there are problems with this layer of tears, people can develop a common condition called dry eye. People with dry eye may feel discomfort, as though they have something in their eye, they may have burning sensations, or be sensitive to light. They can also have blurred vision and fluctuating vision which can affect driving and reading.

Dry eye may develop because of underlying health problems, eye treatment or for no apparent reason. One potential underlying cause of dry eye may be inflammation. CsA drops (marketed as Restasis or Cequa) aim to improve tear production by treating this inflammation.

What are the main results of the review?  Cochrane researchers found 30 relevant studies. These studies took place in many different countries (Austria, Belgium, Brazil, China, Czech Republic, France, Germany, Italy, South Korea, Spain, Sweden, Thailand, Turkey, the United Kingdom, and the United States). Twelve studies were funded by the manufacturer, one was funded by a government agency, and the remaining studies did not report funding.

Eighteen studies compared CsA combined with artificial tears versus artificial tears alone. At 6 months:

⇨ There was only low‐certainty evidence on whether or not CsA combined with artificial tears may help to reduce the symptoms and signs of dry eye compared with artificial tears alone.  ⇨ There was inconsistent low‐certainty evidence as to whether or not CsA provides any benefit for tear production and stability.  ⇨ People using CsA may have more conjunctival goblet cells (low‐certainty evidence). Conjunctival goblet cells may have a role in protecting the eye by secreting mucus (a lubricant).  ⇨ People using CsA drops may have more treatment‐related adverse events, in particular, "burning and stinging" eyes (low‐certainty evidence).

The remaining studies made several other comparisons of CsA in different concentrations with either placebo or artificial tears. The reporting of these studies did not allow us to understand the magnitude of effect.

How up‐to‐date is this review?  Cochrane researchers searched for studies that had been published up to 16 February 2018.

Summary of findings

Background

Description of the condition

Dry eye, more broadly defined as tear dysfunction, occurs when the lacrimal functional unit (comprised of the lacrimal glands, ocular surface and lids, and the sensory and motor nerves connecting them) is no longer able to maintain a stable precorneal tear layer. Dry eye may develop from dysfunction or disease of one or more components of the lacrimal functional unit due to ageing, inflammation, secondary to refractive or cataract surgery, secondary to a local ocular disease such as glaucoma, or systemic diseases such as Sjögren syndrome or diabetes. This review considered all types of dry eye.

Epidemiology

Dry eye is one of the most prevalent eye conditions. Epidemiologic studies performed worldwide have reported a prevalence of dry eye ranging from 5% to 50% depending on the study population and diagnostic criteria (Stapleton 2017). These prevalence data translate to between 6 and 43.2 million people living with dry eye in the United States. A number of risk factors for dry eye have been identified. Age is the strongest risk factor, with prevalence increasing in both men and women with every decade of life over the age of 40. A greater proportion of women have dry eye for every age group compared with men (Altinors 2006; Karakus 2018; Larson 2011; Mathews 2017; Moss 2000; Moss 2004; Schaumberg 2003; Schaumberg 2009; Sun 2017; Uchino 2011; Uchiyama 2007; van Landingham 2014; Schaumberg 2009). Other potential risk factors include wearing contact lenses (Uchino 2011), diabetes mellitus (Moss 2000; Moss 2004), cigarette smoking (Altinors 2006; Moss 2000), prolonged video display viewing (Uchino 2011), and low‐humidity environments (Uchiyama 2007). People with dry eye typically report irritation symptoms such as foreign body sensation, burning, photophobia, and dryness, as well as vision‐related symptoms such as blurred and/or fluctuating vision and inability to read or drive. These symptoms may decrease the quality of life of those afflicted. In some cases, in particular the vision‐related consequences of dry eye, can be devastating and result in functional and occupational disability (Karakus 2018; Mathews 2017; Sun 2017; van Landingham 2014).

Description of the intervention

In 2002 the US Food and Drug Administration (FDA) approved Restasis (0.05% cyclosporine A (CsA) ophthalmic emulsion, Allergan Inc, Irvine, CA, USA) with the indication to increase tear production in people whose tear production is presumed to be suppressed due to ocular inflammation associated with keratoconjunctivitis sicca (chronic dry eye). The FDA also approved Cequa (0.09% CsA drops, Sun Pharma, Cranbury, NJ, USA) based on increase in tear production in 2018.

How the intervention might work

CsA has been widely used as an immunomodulatory therapy to prevent or control rejection of solid organ transplants and to treat autoimmune diseases including uveitis by inhibiting the activation and function of T lymphocytes (Larson 2011). The immunomodulation activity of CsA is relevant to dry eye because activated CD4⁺ T cells have been found to infiltrate the conjunctiva (the transparent membrane covering the outer surface of the eyeball, except the cornea, and the inner surface of the eyelids) of people with both Sjögren syndrome (a chronic autoimmune disease characterized by dry eye and dry mouth) and non‐Sjögren syndrome‐associated dry eye. CsA, by binding to cyclophilin D, is thought to be primarily responsible for its inhibition of apoptosis, or programmed cell death (Waldmeier 2003). The CsA‐cyclophilin D complex binds to and prevents opening of the mitochondrial permeability transition (MPT) pore (Li 2004). Opening of this pore in response to cellular stress or damage is an early step in the apoptosis cascade. Increased apoptosis in the ocular surface epithelium, particularly the conjunctiva, has also been found in dry eye. CsA significantly reduced apoptosis of conjunctival epithelial cells, as assessed by DNA fragmentation and levels of activated caspase‐3, and a decrease in interferon‐gamma and interleukin‐17 production in an experimental murine model of dry eye (De Paiva 2011; Galatoire 2003; Kunert 2000; Strong 2005).

Why it is important to do this review

In targeting the underlying inflammatory mechanisms associated with dry eye, CsA is thought to mitigate symptoms associated with these pathways. However, dry eye is multifactorial, and patients are diagnosed at various chronicity or severity levels. It is unknown whether CsA can help all individuals with dry eye. This systematic review aimed to evaluate the evidence from randomized controlled trials (RCTs) for CsA therapy for people with dry eye.

Objectives

To assess the effectiveness and safety of topical CsA in the treatment of dry eye.

Methods

Criteria for considering studies for this review

Types of studies

We included only RCTs in this review.

Types of participants

We included trials of participants with dry eye, defined as evidence of tear dysfunction based on irritation symptoms, presence of unstable tear film or ocular surface disease. We included trials of participants of any age, sex, chronicity, severity, or classification of dry eye, such as Sjögren or non‐Sjögren associated dry eye.

Types of interventions

We considered trials in which topical formulations of CsA were compared with one another (head‐to‐head comparison) or with artificial tears, placebo, or vehicle. We also considered trials in which CsA in combination with artificial tears was compared to artificial tears alone.

Types of outcome measures

Primary outcomes

Our primary outcome was improvement of dry eye symptoms such as dryness, scratchiness, foreign body sensation, and burning at six months follow‐up, measured by patient questionnaires or clinician‐based assessments.

Secondary outcomes

Our secondary outcomes, also analyzed at six months follow‐up, included the following.

Ocular surface dye staining, as measured by the mean change in corneal fluorescein or conjunctival lissamine green or rose bengal score.
Aqueous tear production, as measured by the mean change in Schirmer test scores (millimeters) performed with or without anesthesia.
Tear film stability, as measured by the mean change in tear film break‐up time (seconds).
Frequency of artificial tear usage, as defined by the included trials.
Conjunctival goblet cell density.
Blurred vision symptoms.
Inflammatory biomarkers, including human leukocyte antigen (HLA)‐DR isotype and T‐cell infiltration.

Adverse events

We documented and compared adverse events reported by treatment groups.

Follow‐up

As treatment duration, dose, and frequency vary depending on severity (mild, moderate, or severe) and type (aqueous deficient or evaporative) of dry eye, we used the time points for outcome assessments as reported by the included studies in addition to our primary endpoint of six months. We considered a follow‐up period from 2 to 12 months as long‐term follow‐up.

Search methods for identification of studies

Electronic searches

The Cochrane Eyes and Vision Information Specialist searched the following electronic databases for RCTs and controlled clinical trials. There were no restrictions on language or year of publication. We last searched the electronic databases on 16 February 2018.

Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 2) (which contains the Cochrane Eyes and Vision Trials Register) in the Cochrane Library (searched 16 February 2018) (Appendix 1).
MEDLINE Ovid (1946 to 16 February 2018) (Appendix 2).
Embase.com (1947 to 16 February 2018) (Appendix 3).
PubMed (1948 to 16 February 2018) (Appendix 4).
Latin American and Caribbean Health Sciences Literature Database (LILACS) (1982 to 16 February 2018) (Appendix 5).
US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (clinicaltrials.gov/; searched 16 February 2018) (Appendix 6).
World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/en/; searched 16 February 2018) (Appendix 7).

Searching other resources

We searched the reference lists of reports from identified trials for additional trials. We did not conduct manual searches of conference proceedings or abstracts specifically for this review.

Data collection and analysis

Selection of studies

Two methodologists from Cochrane Eyes and Vision United States (CEV@US) independently assessed the titles and abstracts of records identified by the search. Each methodologist classified each record as (1) relevant, (2) possibly relevant or unclear, or (3) definitely not relevant (see Criteria for considering studies for this review). For all records classified as (1) or (2) after adjudication, we obtained the full‐text reports, and two methodologists independently assessed each full‐text report for inclusion in the review. We assessed each full‐text report as (1) include, (2) unclear, or (3) definitely exclude. We contacted primary investigators of studies classified as (2) for clarification. We documented the reasons for exclusion of studies excluded after review of the full‐text report. Any discrepancies were resolved by discussion.

Data extraction and management

Two methodologists from CEV@US independently extracted data for each included trial using forms developed by CEV. We extracted data relevant to study methods, participants, interventions, and outcomes. Any discrepancies were resolved by consensus. One review author (SN) entered data into Review Manager 5 (Review Manager 2014), and a second review author (CSDP) verified the data entry.

Assessment of risk of bias in included studies

Two methodologists from CEV@US independently assessed the risk of bias for each included study according to Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We assessed the following 'Risk of bias' domains:

selection bias (sequence generation and allocation concealment);
performance bias (masking of participants and study personnel);
detection bias (masking of outcome assessors);
attrition bias (loss to follow‐up and intention‐to‐treat analysis);
reporting bias (selective outcome reporting); and
other potential sources of bias such as funding source.

We judged each parameter as low risk, unclear risk, or high risk. We contacted the primary investigators of studies for which 'Risk of bias' information was unclear or not reported. When no response was received within six weeks, we made assessments based on the information available. Any discrepancies were resolved by consensus.

Measures of treatment effect

We reported dichotomous outcomes as risk ratios (RRs) with 95% confidence intervals (CIs). We considered the following as dichotomous outcomes: proportion of participants with improved subjective symptoms and/or objective signs of dry eye, and proportion of participants with adverse events.

We reported continuous outcomes as mean differences (MDs) with 95% CIs. We considered the following as continuous outcomes: mean change in subjective improvement of dry eye symptoms, mean change in corneal fluorescein or conjunctival lissamine green or rose bengal score, mean change in Schirmer test scores, mean change in tear film break‐up time, mean change in conjunctival goblet cell density, and mean change in inflammatory biomarkers. If data were not available for continuous outcomes as mean changes from baseline, we used the difference in mean values at specified time points for the data analysis.

Unit of analysis issues

When one eye per individual was randomized, the unit of analysis was straightforward (i.e. individual or eye). When both eyes were randomized, either to the same intervention or different interventions, the analysis had to account for the correlation between two eyes within the same individual (i.e. intraperson correlation). We assessed whether trials (including paired‐eye design, crossover design, and cluster‐randomized design) had properly accounted for the intraperson or intracluster correlation following the recommendations in the Handbook (Deeks 2011). We analyzed CsA by dose when multiple doses were examined.

Dealing with missing data

We contacted primary investigators for missing data related to study characteristics, 'Risk of bias' assessment, and/or outcome data. We allowed six weeks for a response, after which time we used the available information. We did not impute data for the purposes of this review.

Assessment of heterogeneity

We assessed clinical and methodological heterogeneity by comparing the design, populations, interventions and comparisons, outcomes, and risk of bias across trials. We assessed statistical heterogeneity using the I² statistic, considering an I² value greater than 50% as indicative of significant statistical heterogeneity.

Assessment of reporting biases

We assessed selective reporting of outcomes as part of the 'Risk of bias' assessment. We did not assess publication bias by using a funnel plot because there was an insufficient number of trials included in meta‐analysis.

Data synthesis

When data were sufficient (e.g. an estimate of effect and its precision) and no concerning heterogeneity was detected, we combined study results in a meta‐analysis using Review Manager 5 (Review Manager 2014). We used a random‐effects model when there were three or more trials and a fixed‐effect model when there were fewer than three trials. When we detected substantial heterogeneity, we did not combine results, instead presenting a narrative summary of results.

Subgroup analysis and investigation of heterogeneity

Because only a small number of trials provided sufficient data for any meta‐analysis, we did not perform any subgroup analysis.

Sensitivity analysis

For the same reason, we did not conduct sensitivity analyses to investigate the impact of excluding studies with high risk of bias, industry funding, or unpublished status.

'Summary of findings' table

We prepared a 'Summary of findings' table for main outcomes of this review for the comparison most relevant to decision making. Two review authors (CSDP, SN) independently graded the quality of evidence for each outcome using the GRADE classification (www.gradeworkinggroup.org/). Any discrepancies were resolved by discussion and consensus within the review team. For each outcome, we graded the quality of evidence as high, moderate, low, or very low using the following criteria to downgrade the assessment.

High risk of bias among included trials
Indirectness of evidence
Unexplained heterogeneity or inconsistency of results
Imprecision of results (i.e. wide confidence intervals)
High probability of publication bias

Results

Description of studies

Results of the search

The electronic searches yielded a total of 4357 titles and abstracts as of 16 February 2018, of which we identified 85 relevant reports for full‐text review. We included 30 RCTs (reported in 55 references) and excluded 19 studies (reported in 25 references). We assessed one study as awaiting classification and four studies as ongoing (see Characteristics of studies awaiting classification and Characteristics of ongoing studies). A study flow chart is shown in Figure 7.

Included studies

The 30 included RCTs are described in the Characteristics of included studies table. A summary of interventions and comparisons, study design, participant characteristics, and follow‐up periods is shown in Table 2. Four trials were published in abstract form only (Foulks 1996; Helms 1996; Lankaranian 2006; Lopez 2006). Two trials were published in Chinese (Ma 2015; Wu 2009), one in German (Schrell 2012), and one in Portuguese (Barreto 2009). The included trials were published between 1996 and 2017. Of the 30 included trials, 19 used a parallel‐group design, two used a cross‐over design, one used an intraperson comparative design, and four used a cluster‐randomized design because participants were randomized to interventions and the unit of analysis was individual eye. The design for the remaining four trials was not specified. Overall, 4009 participants were randomized in the included trials, the numbers of participants in individual studies ranging from 21 to 877. Follow‐up periods ranged from 6 weeks to 12 months. The included trials were conducted across broad geographic regions internationally: Austria, Belgium, Brazil, China, Czech Republic, France, Germany, Italy, South Korea, Spain, Sweden, Thailand, Turkey, the United Kingdom, and the United States (12 trials did not report this information). The conditions studied were dry eye of varying severity and underlying causes.

1. Summary of included studies.

	Intervention	Comparison	Study ID Study design	Condition(s) included	Number of randomized participants	Follow‐up period(s)
CsA 0.05% + AT versus vehicle + AT or AT only	CsA 0.05% (Restasis) + AT (Refresh Tears)	AT (Refresh Tears)	Altiparmak 2010 Cluster‐randomized controlled trial	People with thyroid orbitopathy	45 participants	6 months
	CsA 0.05% in Sophisen vehicle + AT (methylcellulose 0.5%)	Vehicle + AT (methylcellulose 0.5%)	Baiza‐Durán 2010 Parallel‐group randomized controlled trial	People with dry eye	183 participants (including another arm)	16, 21, 42, 70, and 98 days
	CsA 0.05% + AT (sodium carboxymethylcellulose 0.5%)	AT (sodium carboxymethylcellulose)	Barreto 2009 Parallel‐group randomized controlled trial	People with moderate dry eye secondary to HIV infection	20 participants	6 months
	CsA 0.05% + AT	Vehicle + AT	Brignole 2001 Parallel‐group randomized controlled trial	People with moderate‐to‐severe KCS	169 participants (including another arm)	3 and 6 months
	CsA 0.05% + AT	Vehicle + AT	Chen 2010 Parallel‐group randomized controlled trial	People with moderate‐to‐severe dry eye	233 participants	2, 4, and 8 weeks
	CsA 0.05% (Restasis) + AT (Tears Naturale Free)	AT (Tears Naturale Free)	Demiryay 2011 Parallel‐group randomized controlled trial	People with dysfunctional tear	42 participants	4 months
	CsA 0.05% (Restasis) + AT (Tears Naturale Free)	Vehicle + AT (Tears Naturale Free)	Guzey 2009 Parallel‐group randomized controlled trial	People with severe trachomatous dry eye	64 participants	1, 3, and 6 months
	CsA 0.05% (Restasis) + AT (Refresh Plus)	AT (Refresh Plus)	Kim 2009 Parallel‐group randomized controlled trial	People with dry eye	150 participants	1, 2, and 3 months
	CsA 0.05% (Restasis) + AT (Visine Pure Tears)	Vehicle + AT (Visine Pure Tears)	Liew 2012 Parallel‐group randomized controlled trial	People with dry eye	327 participants	8 weeks
	CsA 0.05% + AT	Vehicle + AT	Ma 2015 Parallel‐group randomized controlled trial	People with moderate‐to‐severe dry eye	40 participants	1, 4, 8, and 12 weeks, and 2 weeks after withdrawal
	CsA 0.05% (Restasis) + AT	AT	Prabhasawat 2012 Parallel‐group randomized controlled trial	People with symptomatic Meibomian gland dysfunction	70 participants	1, 2, and 3 months
	CsA 0.05% (Restasis) + AT (Refresh Endura)	AT (Refresh Endura)	Rao 2010 Parallel‐group randomized controlled trial	People with dry eye	74 participants	4, 8, and 12 months
	CsA 0.05% (Restasis) + AT	AT (Refresh)	Salib 2006 Cluster‐randomized controlled trial	People with dry eye syndrome undergoing laser in situ keratomileusis (LASIK)	21 participants	1 week, and 1, 3, 6, and 12 months after surgery
	CsA 0.05% + AT (Refresh)	Vehivle + AT (Refresh)	Sall 2000 Parallel‐group randomized controlled trial	People with moderate‐to‐severe dry eye	877 participants (including another arm)	1, 3, 4, and 6 months
	CsA 0.05% (Restasis) + AT (Refresh Tears); CsA 0.05% (Restasis) + AT (Systane)	AT (Systane)	Sall 2006 Cluster‐randomized controlled trial	People with aqueous deficient dry eye	61 participants	7, 14, 28, and 42 days and 4 and 6 months
	CsA 0.05% + AT	AT	Schrell 2012 Randomized controlled trial	People with dry eye	62 participants	3 months
	CsA 0.05% + AT (Refresh)	AT (Refresh)	Stevenson 2000 Parallel‐group randomized controlled trial	People with moderate‐to‐severe dry eye	162 participants (including other arms)	4, 8, and 12 weeks and post‐treatment 2 and 4 weeks
	CsA 0.05% + AT	AT	Wu 2009 Cluster‐randomized controlled trial	People with dry eye	52 participants	1, 2, 3, 4, 6, 8, and 12 weeks
CsA 0.05% + AT versus CsA 0.1%, 0.2%, 0.4% + AT	CsA 0.05% in Sophisen vehicle + AT (methylcellulose 0.5%)	CsA 0.1% in Sophisen vehicle + AT (methylcellulose 0.5%)	Baiza‐Durán 2010 Parallel‐group randomized controlled trial	People with dry eye	183 participants (including another arm)	16, 21, 42, 70, and 98 days
	CsA 0.05% + AT	CsA 0.1% + AT	Brignole 2001 Parallel‐group randomized controlled trial	People with moderate‐to‐severe KCS	169 participants (including another arm)	3 and 6 months
	CsA 0.05% + AT (Refresh)	CsA 0.1% + AT (Refresh)	Sall 2000 Parallel‐group randomized controlled trial	People with moderate‐to‐severe dry eye	877 participants (including another arm)	1, 3, 4, and 6 months
	CsA 0.05% + AT (Refresh)	CsA 0.1% + AT (Refresh); CsA 0.2% + AT (Refresh); CsA 0.4% + AT (Refresh)	Stevenson 2000 Parallel‐group randomized controlled trial	People with moderate‐to‐severe dry eye	162 participants (including another arm)	1, 3, 4, and 6 months
CsA 0.05% versus placebo, vehicle, or AT	CsA 0.05% (Restasis)	Saline	Chung 2013 Intra‐individual comparative randomized controlled trial	People with dry eye syndrome after cataract surgery	32 participants	2 weeks, 1 month, 2 and 3 months postoperatively
	CsA 0.05% (Restasis)	AT	Lankaranian 2006 Parallel‐group randomized controlled trial	People with dry eye syndrome undergoing glaucoma filtering surgery	44 participants	6 months
	CsA 0.05% (Restasis)	Vehicle (Endura)	Lopez 2006 Randomized controlled trial	People with dry eye	56 participants	1, 2, and 3 months
	CsA 0.05% (Restasis)	AT (Refresh)	Willen 2008 Parallel‐group randomized controlled trial	People with dry eye syndrome associated with contact lens wear	44 participants	3 months
CsA 0.1% + AT versus vehicle + AT	CsA 0.1% + AT	Vehicle + AT	Fan 2003 Non‐parallel‐group randomized controlled trial	People with Sjögren syndrome associated with KCS	50 participants	14, 30, 60, and 90 days
CsA 0.1% + AT versus vehicle + AT	CsA 0.1% + AT (Refresh)	Vehicle + AT (Refresh)	Stevenson 2000 Parallel‐group randomized controlled trial	People with moderate‐to‐severe dry eye	162 participants (including other arms)	4, 8, and 12 weeks and post‐treatment 2 and 4 weeks
CsA 0.1% cationic emulsion + AT versus vehicle + AT	CsA 0.1% cationic emulsion (Ikervis) + AT (saline solution)	Vehicle + AT (saline solution)	Baudouin 2017 Parallel‐group randomized controlled trial	People with moderate‐to‐severe dry eye	495 participants	6 months
CsA 0.1% cationic emulsion + AT versus vehicle + AT	CsA 0.1% unpreserved single‐dose cationic emulsion (Ikervis) + AT (saline solution)	Vehicle + AT (saline solution)	Leonardi 2016 Parallel‐group randomized controlled trial	People with severe dry eye disease	261 participants	1 month, 3, 6, 9, and 12 months (9 and 12 months safety only)
CsA 1% + AT versus placebo or vehicle + AT	CsA 1% + AT (Refresh)	Placebo + AT (Refresh)	Foulks 1996 Parallel‐group randomized controlled trial	People with Sjögren syndrome associated with KCS	33 participants	2, 4, 6, and 8 weeks
	CsA 1% + AT (Refresh)	Placebo + AT (Refresh)	Helms 1996 Randomized controlled trial	People with KCS	256 participants (including other arms)	2 and 4 weeks during treatment, and 2 and 4 weeks post‐treatment
	CsA 1% + AT (Refresh)	Vehicle + AT (Refresh)	Laibovitz 1993 Cross‐over‐design randomized controlled trial	People with KCS	26 participants	6 weeks in each phase
CsA 2% + AT versus placebo or vehicle + AT	CsA 2% + AT (carboxypolymethylene gel tear)	Vehicle + AT (carboxypolymethylene gel tear)	Gündüz 1994 Parallel‐group randomized controlled trial	People with secondary Sjögren syndrome	30 participants	2 months
	CsA 2% + AT (Refresh)	Placebo + AT (Refresh)	Helms 1996 Randomized controlled trial	People with KCS	256 participants (including other arms)	2 and 4 weeks during treatment, and 2 and 4 weeks post‐treatment
	CsA 2%	Placebo	Jain 2007 Cross‐over‐design randomized controlled trial	People with acquired primary lachrymal disease and Sjögren syndrome	30 participants	2 months
CsA 2% + AT versus CsA 0.5% or 1% + AT	CsA 2% + AT (Refresh)	CsA 0.5% + AT (Refresh); CsA 1% + AT (Refresh)	Helms 1996 Randomized controlled trial	People with KCS	256 participants (including other arms)	2 and 4 weeks during treatment, and 2 and 4 weeks post‐treatment

Topical cyclosporine A 0.05% + artificial tears versus vehicle + artificial tears or artificial tears alone for dry eye syndrome
Patient or population: People with dry eye syndrome Intervention: Topical CsA 0.05% + artificial tears Comparison: Vehicle + artificial tears, or artificial tears alone Setting: Outpatient
Outcomes	Outcomes		No. of participants  (studies)	Certainty of the evidence  (GRADE)	Comments
Outcomes	Definition of outcome	MD (95% CI, or P value); RR (95% CI)	No. of participants  (studies)	Certainty of the evidence  (GRADE)	Comments
Subjective symptoms of dry eye at 6 months	Mean change from baseline or final mean score or number of participants with improved symptoms	Only 1 trial reported sufficient data to permit calculation of a between‐group difference (MD −4.80, 95% CI −6.41 to −3.19) (Rao 2010); this difference was in favor of CsA 0.05%.	56 (1 RCT)	⊕⊕⊝⊝  Low‐certainty^1,2	The remaining 12 trials had deficiencies in reporting (e.g. reporting P value or direction only), precluding the calculation of between‐group estimates of effect or meta‐analysis.
Ocular surface dye staining at 6 months	Mean change from baseline or final mean score	Only 2 trials reported sufficient data to permit calculation of a between‐group difference (MD −0.35, 95% CI −0.69 to −0.01 in Chen 2010; MD 0.58, 95% CI 0.06 to 1.10 in Rao 2010).	291 (2 RCTs)	⊕⊕⊝⊝  Low‐certainty^1,3	The estimates of effect were inconsistent in these 2 trials, precluding any meta‐analysis. The remaining 11 trials had deficiencies in reporting (e.g. reporting P value or direction only).
Aqueous tear production measured by Schirmer test scores (mm/5 minutes) at 6 months	Mean change from baseline or final mean scores	The final mean difference scores in 4 of the trials ranged from ‐4.05 (‐6.67 to ‐1.73), to 3.26 (‐1.52 to 5.00). RR scores for the proportion of participants with improved scores ranged from RR 0.98 (0.83 to 1.17) to RR 3.50 (2.09 to 5.85).	406 (4 RCTs) 267 (3 RCTs)	⊕⊕⊝⊝  Low‐certainty^1,3 ⊕⊕⊝⊝  Low‐certainty^1,3	We were able to present the results using the final mean scores in 4 trials (Analysis 1.1; Figure 1) or proportion of participants with improved scores in 3 trials (Analysis 1.2; Figure 2). We did not combine these data in meta‐analyses due to considerable clinical, methodological, and statistical heterogeneity among trials (the I² statistic was more than 90% in both analyses). Reporting of this outcome in the remaining trials was insufficient or incomplete.
Tear film stability measured by tear break‐up time (seconds) at 6 months	Final mean scores or proportion of participants with improved scores	Mean Difference scores for the TBUT ranged from ‐1.98 (‐3.59 to ‐0.37) to 1.90 (1.44 to 2.36). RR scores for the proportion of participants with improved TBUT score ranged from 0.90 (0.77 to 1.04) to 4.00 (2.25 to 7.12).	676 (5 RCTs) 262 (3 RCTs)	⊕⊕⊝⊝  Low‐certainty^1,3 ⊕⊕⊝⊝  Low‐certainty^1,3	We were able to present the results as a continuous outcome in 5 trials (Analysis 1.3; Figure 3) or as a dichotomous outcome in 3 trials (Analysis 1.4; Figure 4). We did not combine these data in meta‐analyses due to considerable methodological and statistical heterogeneity (I² = 96%) across trials. Reporting in the remaining trials was insufficient or incomplete.
Frequency of artificial tear usage at 6 months	Proportion of participants who used artificial tears	The direction of effect seem to be in favor of CsA.	910 (3 trials)	⊕⊕⊝⊝  Low‐certainty^1,3	All 3 trials reported P values or direction only, precluding the calculation of between‐group estimates of effect or meta‐analysis.
Conjunctival goblet cell density (cells per unit) at 6 months	Final mean score	Summary estimate of 2 trials (100 participants) shows that mean conjunctival goblet cell density in the CsA group was greater than that in the control group at the end of follow‐up visit (MD 22.5, 95% CI 16.3 to 28.8; I² = 40%) (Analysis 1.5; Figure 5).	100 (2 trials)	⊕⊕⊝⊝  Low‐certainty^1,2	We were unable to include 4 trials in the meta‐analysis due to lack of data or insufficient reporting.
Treatment related adverse events, follow up at 2 to 6 months	Proportion of participants who experienced adverse events	Participants treated with CsA were more likely to have treatment‐related adverse events (RR 1.33, 95% CI 1.00 to 1.78) (Analysis 1.6; Figure 6). Corresponding risk: 225 per 1,000 (169 to 301)	743 (3 trials)	⊕⊕⊝⊝  Low‐certainty^1,2	RR 2.12 (95% CI 1.28 to 3.50) for burning eye; RR 0.41 (95% CI 0.15 to 1.09) for visual disturbance; and RR 0.64 (95% CI 0.17 to 2.44) for eye pain (Analysis 1.6; Figure 6)
CI: confidence interval; CsA: cyclosporine A; MD: mean difference; NS: no significant between‐group difference; RR: risk ratio
GRADE Working Group grades of evidence  High‐certainty: We are very confident that the true effect lies close to that of the estimate of the effect  Moderate‐certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different  Low‐certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect  Very low‐certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mean Schirmer test score	4		Mean Difference (IV, Random, 95% CI)	Subtotals only
2 Proportion of participants with improved Schirmer test score	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
3 Mean TBUT score	5		Mean Difference (IV, Random, 95% CI)	Subtotals only
4 Proportion of participants with improved TBUT score	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
5 Mean goblet cell density	2	100	Mean Difference (IV, Fixed, 95% CI)	22.54 [16.30, 28.79]
6 Adverse events	6		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
6.1 Treatment‐related adverse events	3	743	Risk Ratio (M‐H, Fixed, 95% CI)	1.33 [1.00, 1.78]
6.2 Burning eye	2	649	Risk Ratio (M‐H, Fixed, 95% CI)	2.12 [1.28, 3.50]
6.3 Foreign body sensation	2	649	Risk Ratio (M‐H, Fixed, 95% CI)	1.49 [0.54, 4.15]
6.4 Conjunctival hyperemia	2	649	Risk Ratio (M‐H, Fixed, 95% CI)	2.99 [0.61, 14.69]
6.5 Visual disturbance	2	649	Risk Ratio (M‐H, Fixed, 95% CI)	0.41 [0.15, 1.09]
6.6 Eye pain	2	649	Risk Ratio (M‐H, Fixed, 95% CI)	0.64 [0.17, 2.44]
6.7 Discontinuation of study due to adverse events	4	837	Risk Ratio (M‐H, Fixed, 95% CI)	2.94 [1.66, 5.19]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Adverse events	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
1.1 Treatment‐related adverse events	2	648	Risk Ratio (M‐H, Fixed, 95% CI)	0.87 [0.67, 1.13]
1.2 Burning eye	2	648	Risk Ratio (M‐H, Fixed, 95% CI)	0.91 [0.62, 1.33]
1.3 Foreign body sensation	2	648	Risk Ratio (M‐H, Fixed, 95% CI)	2.99 [0.82, 10.93]
1.4 Conjunctival hyperemia	2	648	Risk Ratio (M‐H, Fixed, 95% CI)	0.66 [0.24, 1.84]
1.5 Visual disturbance	2	648	Risk Ratio (M‐H, Fixed, 95% CI)	0.55 [0.19, 1.63]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mean change from baseline in global ocular discomfort	2	679	Mean Difference (IV, Fixed, 95% CI)	‐1.96 [‐4.94, 1.02]
2 Mean change from baseline in TBUT	2	695	Mean Difference (IV, Fixed, 95% CI)	0.16 [‐0.14, 0.46]
3 Adverse events	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
3.1 Any treatment‐related ocular adverse events	2	736	Risk Ratio (M‐H, Fixed, 95% CI)	2.15 [1.65, 2.80]
3.2 Any treatment‐related ocular adverse events leading to study discontinuation	2	736	Risk Ratio (M‐H, Fixed, 95% CI)	1.49 [0.91, 2.43]
3.3 Instillation site pain/irritation	2	736	Risk Ratio (M‐H, Fixed, 95% CI)	3.96 [2.21, 7.08]

Methods	Study design: cluster randomized controlled trial Number randomized: total: 90 eyes; CsA group: 40 eyes, control group: 50 eyes Exclusions after randomization: 9 eyes discontinued topical CsA treatment due to intense burning sensation Losses to follow‐up: 6 eyes lost to follow‐up in CsA group; 2 eyes lost to follow‐up in control group Number analyzed (total and per group): 73 eyes in total, 25 eyes in CsA group; 48 eyes in the control group Unit of analysis: eye How were the missing data handled?: excluded from the analyses Power calculation: not reported
Participants	Country: Turkey Age: range: 23 to 66; mean: 41 years Sex: men: 12 (16%); women: 61 (84%) Inclusion criteria: "The diagnosis of thyroid orbitopathy was made, when two of the following three signs of the disease were present: (1) Concurrent or recently treated immune‐related thyroid dysfunction: Graves hyperthyroidism, hashimoto's thyroiditis, and the presence of circulating thyroid antibodies without a coexisting dysthyroid state; (2) typical orbital signs (one or more of the following): unilateral or bilateral eyelid retraction with typical temporal flare (with/or without lagophthalmos), bilateral proptosis (as evidenced by comparison with patient's old photos), restrictive strabismus in a typical pattern compressive optic neuropathy, fluctuating eyelid oedema/erythema, chemosis/caruncular oedema; and (3) radiographic evidence of thyroid orbitopathy including unilateral/bilateral fusiform enlargement of one or more of the following: medial rectus muscle, inferior rectus muscle, superior rectus levator complex." Exclusion criteria: "Patients with a Clinical Activity Score of 4 and above (presence of clinically active thyroid orbitopathy) were left out of the study, to avoid interference with thyroid orbitopathy symptoms. For all patients, presence of conjunctival tumours, corneal diseases that may influence conjunctival vascularization, glaucoma, a history of previous ocular surgery, as well as persistent meibomian gland dysfunction were other criteria for exclusion. Patients enrolled were not using any topical medication before the study." Equivalence of baseline characteristics: yes
Interventions	Intervention 1: topical CsA 0.05% eye drop (Restasis, Allergan) twice daily plus artificial tear drops (Refresh Tears, Allergan) 4 times daily for 6 months Intervention 2: artificial tear drops (Refresh Tears, Allergan) 4 times daily for 6 months Length of follow‐up: 6 months
Outcomes	Primary outcomes, as defined: no primary outcome defined Secondary outcomes: Aqueous tear production, as measured by the mean change in Schirmer test scores (millimeters) 6 months from baseline Tear film stability, as measured by the mean change in TBUT (seconds) 6 months from baseline Impression cytology, as measured by the proportion with improvement 6 months from baseline Adverse events reported: 9 participants had intense burning sensation and discontinued the treatment for topical CsA 0.05% Intervals at which outcomes were assessed: 6 months
Notes	Study period: May 2005 to December 2007 Funding sources: not reported Declarations of interest: reported explicitly that none of the authors has any financial relationship Reported subgroup analyses: not reported Trial registration: not available
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	The method of random sequence generation is not adequately reported.
Allocation concealment (selection bias)	Unclear risk	The method of allocation concealment is not adequately reported.
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	The method of masking of participants and personnel is not adequately reported.
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	"Patients were seen 6 months later by a masked observer to the treatments and the same measurements (including impression cytology specimens) were obtained."
Incomplete outcome data (attrition bias)   All outcomes	High risk	9/40 (22.5%) eyes discontinued topical CsA treatment due to intense burning sensation; 6/40 (15%) eyes of 3 participants lost to follow‐up in CsA group and 1/50 (2%) participant lost to follow‐up in control group; 17 eyes that discontinued the study were not included in the analysis.
Selective reporting (reporting bias)	Unclear risk	Protocol was not available.
Other bias	High risk	Unit of analysis error: unit of randomization was the individual, but unit of analysis was the eye.

Methods	Study design: parallel‐group randomized controlled trial Number randomized: total: 183 participants; per group not reported Exclusions after randomization: not reported Losses to follow‐up: not reported Number analyzed (total and per group): total 183 participants, per group not reported Unit of analysis: participant How were the missing data handled?: not reported Power calculation: not reported
Participants	Country: Turkey Age: mean ± SD = 57 ± 13 years Sex: men: 71 (39%); women: 112 (61%) Inclusion criteria: age 18 years and older; male or female with dry eye defined as Schirmer 1 test (with anesthesia) of < 5 mm/5 min in at least 1 eye; mild superficial punctate keratitis (fluorescein staining score of > 3 out of 15 in either eye); 1 or more dry eye symptoms (dryness, burning, photophobia, tearing, ocular fatigue, and foreign body sensation) Exclusion criteria: contact lens user; history of hypersensitivity or any medical condition that contraindicates the use of the study drug or any of its compounds, or derivatives; individuals with any other ocular disorder: ocular injury, infection, non‐dry eye ocular inflammation, trauma, or surgery within the previous 6 months; individuals with history of active stage of any other concomitant ocular disease Equivalence of baseline characteristics: not reported
Interventions	Intervention 1: CsA 0.1% in Sophisen vehicle twice daily for 98 days Intervention 2: CsA 0.05% in Sophisen vehicle twice daily for 98 days Intervention 3: vehicle (Sophisen) twice per day for 98 days Length of follow‐up: 98 days Notes: all interventions along with a lubricant (benzalkonium chloride preserved methylcellulose 0.5%) at least 8 times daily; wash‐out with methylcellulose 0.5% at least 8 times a day for 2 weeks
Outcomes	Primary outcomes, as defined: Improvement in symptoms (tearing, dryness, foreign body sensation, ocular fatigue, photophobia, red eye) at 98 days of follow‐up Secondary outcomes: Ocular staining with fluorescein, measured 1 min after instillation of a drop of topical anesthetic Tear film stability, as measured by the mean change in TBUT (seconds) Aqueous tear production, as measured by the mean change in Schirmer test scores (millimeters) Adverse events reported: "No serious adverse effects were reported in any of the groups during follow‐up" Intervals at which outcomes were assessed: days 16, 21, 42, 70, and 98
Notes	Study period: not reported Funding sources: not reported Declarations of interest: Two authors are employees of the Clinical Research Department of Laboratorios Sophia, S.A. de C.V., which manufactures and distributes the cyclosporine aqueous solution. The other authors have no competing interests. Reported subgroup analyses: not reported Trial registration: not available
*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	This study was "double‐masked," but details of masking were not reported.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	This study was "double‐masked," but details of masking were not reported.
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Participants excluded or lost to follow‐up were not reported.
Selective reporting (reporting bias)	Unclear risk	Protocol was not available.
Other bias	High risk	2 authors were affiliated with a pharmaceutical firm; baseline equivalence was not reported.

Methods	Study design: intra‐individual comparative randomized controlled trial Number randomized: total: 32 participants; 32 eyes in each group (paired‐eye design) Exclusions after randomization: none Losses to follow‐up: none Number analyzed (total and per group): 32 participants in total, 32 eyes in each group (paired‐eye design) Unit of analysis: eye How were the missing data handled?: not applicable Power calculation: not reported
Participants	Country: South Korea Age: mean ± SD: 68.3 ± 6 years, range: 60 to 84 years Sex: not reported Inclusion criteria: "age > 50 years bilateral phacoemulsification with completed implantation of posterior chamber intraocular lens, and a visual potential of 20/25 or better." Exclusion criteria: "Exclusion criteria included history of a primary condition that could cause dry eye such as a pterygium, dellen, previous refractive surgery, and systemic connective tissue disease. Exclusion criteria also included active ocular disease, uncontrolled systemic disease, a history of ocular allergic disease, prior refractive surgery, ocular surgery, or prior use of topical CsA. We also excluded any patient who had been diagnosed with dry eye disease by Schirmer test I (ST‐I), <10 mm or TBUT <10 seconds, or those with meibomian gland disease." Equivalence of baseline characteristics: yes
Interventions	Intervention 1: topical CsA 0.05% eye drops (Restasis, Allergan) twice daily for 3 months Intervention 2: saline eye drops twice daily for 3 months Length of follow‐up: 3 months Notes: participants applied gatifloxacin (Gatiflo; Handok, Seoul, Korea) and remexolone (Vexol; Alcon, Fort Worth, TX, USA) 4 times daily after surgery
Outcomes	Primary outcomes, as defined: no primary outcome defined Secondary outcomes: Aqueous tear production, as measured by Schirmer test at 2 weeks, 1 month, 2 months, and 3 months of follow‐up Tear film stability by the mean change in tear break‐up time (seconds) at 2 weeks, 1 month, 2 months, and 3 months of follow‐up Improvement in dry eye symptoms measured by OSDI at 2 weeks, 1 month, 2 months, and 3 months of follow‐up Adverse events reported: not reported Intervals at which outcomes were assessed: 2 weeks, 1 month, 2 months, and 3 months postoperatively
Notes	Study period: April 2010 to November 2010 Funding sources: "This work was supported by research grants from Samil Allergan Korea Ltd." Declarations of interest: explicitly reported that none of the authors has any financial relationship Reported subgroup analyses: not reported Trial registration: not available
*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	It is unclear if study personnel were masked; participants were masked: "We explained to the patients that the difference was for preventing confusion (for example, vials for right eye and bottles for left eye). We cut and removed tips of vials which had the Restasis logo, in order to disguise the liquid."
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	"A blinded examiner measured ST‐I, TBUT, corneal temperature and administered the dry eye symptom questionnaire at 2 weeks, 1 month, 2 months and 3 months"
Incomplete outcome data (attrition bias)   All outcomes	Low risk	No missing outcome data
Selective reporting (reporting bias)	Unclear risk	Protocol was not available.
Other bias	High risk	Industry funding: "This work was supported by research grants from Samil Allergan Korea Ltd." In this intra‐individual comparative study, the results were reported mean and SD in each treatment group without taking into account non‐independence of eyes.

Methods	Study design: non‐parallel‐group randomized controlled trial Number randomized: total 50 participants; topical CsA: 30 participants, vehicle only: 20 participants Exclusions after randomization: none Losses to follow‐up: topical CsA: 6 participants withdrew due to severe irritation with applied drops; vehicle only: 4 participants lost to follow‐up, reasons unspecified Number analyzed (total and per group): total 40 participants; topical CsA: 24 participants, vehicle only: 16 participants Unit of analysis: participant, both eyes included and 1 eye selected for analysis or both eyes averaged How were the missing data handled?: excluded from analyses Power calculation: not reported
Participants	Country: not reported Age: topical CsA 1%: mean ± SD: 50.8 ± 10.7; range: 32 to 68 years vehicle only: mean ± SD: 53.5 ± 11.5; range: 33 to 74 years Sex: men: 3 (7.5%), women: 37 (92.5%) Inclusion criteria: diagnosed with Sjogren syndrome: 5‐minute Schirmer test with anesthesia less than or equal to 5‐millimeter strip wetting, interpalpebral conjunctival and corneal rose bengal staining, presence of 1 or more serum autoantibodies (rheumatoid autoantibody [rheumatoid factor] > 1:160, antinuclear antibodies > 1:160, anti‐Sjögren's syndrome‐A, anti‐Sjögren's syndrome‐B), xerostomia, and absence of a connective tissue disease Exclusion criteria: active ocular infection or inflammatory disease not related to dry eye, ocular surgery, trauma, Meibomian gland dysfunction or punctal occlusion Equivalence of baseline characteristics: yes
Interventions	Intervention 1: topical CsA 1% eye drops twice daily for 90 days Intervention 2: vehicle‐only eye drops twice daily for 90 days Length of follow‐up: 90 days Notes: participants were allowed to use artificial tears as needed
Outcomes	Primary outcomes, as defined: the primary outcome for comparison of interventions was subjective improvement of dry eye symptoms at 30 and 90 days follow‐up. Subjective improvement of symptoms may have been measured by patient questionnaires, scales (such as visual analogue scales or global improvement scales), or by patient‐reported or clinician‐based assessments. Secondary outcomes: Ocular surface dye staining, as defined by the mean change in rose bengal score from baseline to 30 and 90 days follow‐up Aqueous tear production, as measured by the mean change in Schirmer test scores (millimeters) from baseline to 30 and 90 days follow‐up Adverse events reported: severe stinging sensations in topical CsA 1% group Intervals at which outcomes were assessed: days 14, 30, 60, and 90
Notes	Study period: started from February 2000 Funding sources: not reported Declarations of interest: not reported Reported subgroup analyses: not reported Trial registration: not available
*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	This is a double‐masked study; "The masked medication was instilled twice daily"
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	This is a double‐masked study, but details of masking of outcome assessors were not reported.
Incomplete outcome data (attrition bias)   All outcomes	High risk	10/50 (20%) participants were either excluded or lost to follow‐up, and they were not included in the analyses.
Selective reporting (reporting bias)	Unclear risk	Protocol was not available.
Other bias	Unclear risk	Funding source is not specified.

Methods	Study design: randomized controlled trial, details of study design not reported Number randomized: total 256 participants; topical CsA 0.5%: 64 participants, topical CsA 1%: 64 participants, topical CsA 2%: 64 participants, placebo eye drops: 64 participants Exclusions after randomization: not reported Losses to follow‐up: not reported Number analyzed (total and per group): not reported Unit of analysis: not reported How were the missing data handled?: not reported Power calculation: not reported
Participants	Country: not reported Age: not reported Sex: not reported Inclusion criteria: not reported Exclusion criteria: not reported Equivalence of baseline characteristics: not reported
Interventions	Intervention 1: topical CsA 0.5% eye drops 4 times daily for 4 months Intervention 2: topical CsA 1% eye drops 4 times daily for 4 months Intervention 3: topical CsA 2% eye drops 4 times daily for 4 months Intervention 4: placebo eye drops 4 times daily for 4 months Length of follow‐up: 4 weeks Notes: artificial tears (Refresh) were applied 4 times daily concurrently with the study medication
Outcomes	Primary outcomes, as defined: the primary outcome for comparison of interventions was subjective improvement of DES symptoms (conjunctival redness) at 2 and 4 weeks during treatment, 2 and 4 weeks post‐treatment Secondary outcomes: aqueous tear production, as measured by the mean change in Schirmer test scores (millimeters) at 2 and 4 weeks during treatment, 2 and 4 weeks post‐treatment Adverse events reported: "No serious adverse events were reported" Intervals at which outcomes were assessed: 2 and 4 weeks during treatment, and 2 and 4 weeks post‐treatment
Notes	Study period: not reported Funding sources: not reported Declarations of interest: not reported Reported subgroup analyses: not reported Notes: this study is only available in abstract Trial registration: not available
*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	This is a double‐masked study, but details of masking were not reported.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	This is a double‐masked study, but details of masking were not reported.
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Not reported if participants were lost to follow‐up or excluded or if intention‐to‐treat was followed
Selective reporting (reporting bias)	Unclear risk	Protocol was not available.
Other bias	Unclear risk	Baseline equivalence was not reported; funding source was not specified.

Methods	Study design: cross‐over‐design randomized controlled trial Number randomized: total 30 eyes of 30 participants, including 15 participants with acquired primary lachrymal disease (APLD) and 15 with Sjögren syndrome; topical CsA treatment then olive oil eye drops: 15 participants; olive oil eye drops then topical CsA: 15 participants Exclusions after randomization: none Losses to follow‐up: none Number analyzed (total and per group): total 30 eyes of 30 participants, including 15 participants with APLD and 15 with Sjögren syndrome; topical CsA treatment then olive oil eye drops: 15 participants; olive oil eye drops then topical CsA: 15 participants Unit of analysis: participant, both eyes included and 1 eye selected for analysis or both eyes averaged How were the missing data handled?: not reported Power calculation: not reported
Participants	Country: not reported Age: mean 56.7 years in APLD group; 47.5 years in Sjögren syndrome group Sex: men: 3 (10%), women: 27 (90%) Inclusion criteria: presence of functional symptoms of dry eye with a total symptom score of 6 or higher, and an OSDI score of 22 or higher; positive rose bengal test in the interpalpebral area, with a score of 4 or more; Schirmer test (after topical anesthesia) showing 5 mm or less of strip wetting in 5 min; TBUT showing a value of 5 seconds or less; presence of squamous metaplasia in the conjunctival impression cytology samples with a total cytological score of 9 or higher; diagnosis with Sjögren syndrome; presence of bilateral trachomatous scarring Exclusion criteria: hypersensitivity to any component of the study Equivalence of baseline characteristics: yes
Interventions	Intervention 1: topical CsA 2% eye drops 3 times daily for 8 weeks in each phase Intervention 2: placebo (olive oil) eye drops 3 times daily for 8 weeks in each phase Length of follow‐up: 8 weeks cross‐over, 16 weeks total
Outcomes	Primary outcomes, as defined: the primary outcome for comparison of interventions was subjective improvement of dry eye symptoms (dryness, scratchiness, foreign body sensation, burning) at 6 months follow‐up. Secondary outcomes: Ocular surface dye staining, as defined by the mean change in corneal fluorescein from baseline to 8 weeks follow‐up Ocular surface dye staining, as defined by the mean change in rose bengal score from baseline to 8 weeks follow‐up Aqueous tear production, as measured by the mean change in Schirmer test scores (millimeters) from baseline to 8 weeks follow‐up Tear film stability, as measured by the mean change in TBUT (seconds) from baseline to 8 weeks follow‐up Adverse events reported: no adverse effects in the form of infection or allergic reaction were reported in any participant Intervals at which outcomes were assessed: week 8 in each phase
Notes	Study period: not reported Funding sources: not reported Declarations of interest: explicitly reported that none of the authors has any financial relationship; the authors have stated that they do not have a significant financial interest or other relationship with any product manufacturer or provider of services discussed in this article Reported subgroup analyses: yes, subgroup (effectiveness) analysis for patient‐reported outcomes: Sjögren‐associated or non‐Sjögren‐associated Trial registration: not available
*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	This is a single‐masked study, but details of masking were not reported.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	This is a single‐masked study, but details of masking were not reported.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	There were no missing outcome data.
Selective reporting (reporting bias)	Unclear risk	Protocol was not available.
Other bias	Unclear risk	This was a cross‐over study without a wash‐out, and results were not reported separately for each phase.

Methods	Study design: cluster‐randomized controlled trial Number randomized: 21 participants, per group not reported Exclusions after randomization: none Losses to follow‐up: none Number analyzed (total and per group): total 42 eyes of 21 participants, per group not reported Unit of analysis: cluster, unit of randomization was individual, but unit of analysis was eye except for OSDI scores How were the missing data handled?: not available Power calculation: not reported
Participants	Country: not reported Age: mean: 47 years, range: 40 to 59 years Sex: men: 2 (10%), women: 19 (90%) Inclusion criteria: age 40 years or older; dry eyes, defined by having all of the following: (1) symptoms of dry eyes, (2) a previous history of dry eyes, (3) history of artificial tear use at least 6 times a day, (7) at least 6 spots of superficial punctate keratitis found with fluorescein staining at the slit lamp during the examination before contact studies were performed, and (8) Schirmer testing (with topical anesthesia) greater than 0 but less than 10 mm at 5 minutes; post‐LASIK; a good LASIK candidate (as determined at the pre‐treatment examination), myopia between 0.75 diopters and 15.00 diopters spherical equivalent scheduled correction at the corneal plane Exclusion criteria: use of contact lens; significant ocular pathology other than dry eyes Equivalence of baseline characteristics: not reported
Interventions	Intervention 1: topical CsA 0.05% eye drops (Restasis, Allergan Inc) twice daily for 3 months Intervention 2: artificial tear eye drops (Refresh) twice daily for 3 months Length of follow‐up: 12 months Notes: participants were not permitted to use ocular medications other than those designated in the study protocol during the trial; additional preservative‐free artificial tears were allowed to use as needed; participants also instilled ofloxacin 0.3% (Ocuflox) 4 times daily during the first 7 days after surgery
Outcomes	Primary outcomes, as defined: the primary outcome for comparison of interventions was subjective improvement of DES symptoms change from baseline to 3 months follow‐up Secondary outcomes: aqueous tear production, as measured by the mean change in Schirmer test scores (millimeters) to 3 months follow‐up Adverse events reported: during follow‐up of 3 to 12 months, a loss of 2 lines of visual acuity occurred in both treatment groups Intervals at which outcomes were assessed: week 1, and months 1, 3, 6, and 12 after surgery
Notes	Study period: not reported Funding sources: not reported Declarations of interest: explicitly reported that none of the authors has any financial relationship Reported subgroup analyses: not reported Trial registration: not available
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"After a pretreatment (baseline) examination, patients were randomly assigned (using a random table of numbers) a masked medication, unpreserved artificial tears (Refresh) or CsA 0.05% (Restasis) to be instilled twice daily"
Allocation concealment (selection bias)	Unclear risk	Allocation concealment was not reported.
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	This is a double‐masked study: "After a pretreatment (baseline) examination, patients were randomly assigned (using a random table of numbers) a masked medication, unpreserved artificial tears (Refresh) or CsA 0.05% (Restasis) to be instilled twice daily"
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	"Double‐masked" study, but details of masking were not reported
Incomplete outcome data (attrition bias)   All outcomes	Low risk	There were no missing outcome data.
Selective reporting (reporting bias)	Unclear risk	Protocol was not available.
Other bias	High risk	Unit of analysis error: unit of randomization was individual, but unit of analysis was eye except for OSDI scores; baseline equivalence was not reported

Study	Reason for exclusion
Arman 2015	Not interventions of interest
Boynton 2015	Not interventions of interest
Brown 2009	Not randomized: cost‐utility analysis of multiple CsA for DES studies
Deveci 2014	Not randomized
Donnenfeld 2007	Not participants of interest: in people with multifocal intraocular lens implantation
Donnenfeld 2010	Not participants of interest: in people undergoing cataract surgery
Hessert 2013	Not participants of interest: in people undergoing photorefractive keratectomy and laser in situ keratomileusis
Hom 2006	Not participants of interest: in people with contact lens intolerance
Lee 2014	Not study design of interest
Lee 2016	Not interventions of interest
Lin 2015	Not interventions of interest
Moon 2007	Not interventions of interest
Roberts 2007a	Not interventions of interest
Roberts 2007b	Not participants of interest: in people undergoing cataract surgery
Schechter 2006	Not participants of interest: used in the prevention of ocular surface inflammation secondary to pterygia
Su 2011	De‐escalation study: people with DES and treated with topical CsA twice daily for 1 year randomized to maintain twice daily dosing or decrease to once daily dosing for 6 months
Wan 2012	Not interventions of interest
Wang 2008	Not randomized: "This was a prospective comparative study and not randomized or vehicle control study. We assigned the patients for topical Cys treatment group and control group alternatively depending on patients’ consent to use topical Cys eye drops."
Wittpenn 2005	Not participants of interest: in people with ocular rosacea

Trial name or title	A multicenter, randomized, partial double blind, active control, parallel clinical trial to evaluate the efficacy, safety and usability of cyclosporin ophthalmic nanoemulsion 0.05% compared with cyclosporin ophthalmic emulsion 0.05% and diquafosol ophthalmic solution 3%
Methods	Study design: parallel‐group randomized controlled trial Target enrollment: 227 participants (actual) Planned study follow‐up: 3 months
Participants	Age: 19 years or older Gender: all Culture: Republic of Korea Inclusion criteria: ≥ 19 years of age; moderate‐to‐severe dry eye syndrome (corneal BFS score (NEI scale) ≥ 4 and ≤ 10 seconds on TBUT); voluntary agreement with signed informed consent Exclusion criteria: cyclosporine or diquafosol use in any form (systemic, topical) within 4 weeks; medical condition or history to be treated within 4 weeks with topical agents besides artifical tears (glaucoma, ocular allergy, ocular inflammation/infectious disease, etc.); new start or medication change within 4 weeks for systemic drugs with probable effect on dry eye condition; Sjögren syndrome; plan to wear contact lens during the study period; current or history of ocular disorders possibly affecting the study results (ocular surgery, trauma, diseases): 1) entropion, blepharelosis, blepharoplegia 2) ocular surgery history within 4 weeks or plan during the study period like punctal plug, punctal closure etc. 3) herpetics keratopathy, conjunctival scarring by cicatricial keratoconjunctivitis, pterygium, congenital lacrimal gland shortage, neurogenic keratitis, keratoconus, corneal transplantation; known hypersensitivity to study medications; pregnancy or lactation; investigator's judge of inappropriateness
Interventions	Intervention 1: nanoemulsion cyclosporine 0.05% ophthalmic solution, 1 drop/time, twice daily for 12 weeks Intervention 2: emulsion cyclosporine 0.05% ophthalmic solution (Restasis) 1 drop/time, twice daily for 12 weeks Intervention 3: diquafosol tetrasodium ophthalmic solution 3% (Diquas), 1 drop/time, 6 times daily for 12 weeks
Outcomes	Primary outcome: changes in corneal conjunctival staining score at week 12 Secondary outcomes: Changes in corneal conjunctival staining score at week 4 Changes in corneal staining score at week 4 and 8 Changes in conjunctival staining score at week 4 and 8 Changes in TBUT at week 4 and 8 Changes in Schirmer I test score at week 4 and 8 Changes in OSDI at week 4, 8, and 12 Patient global evaluation at week 4, 8, and 12 Tear mucin level change (exploratory endpoint) at week 4 Tear cytokine level change (exploratory endpoint) at week 4
Starting date	October 2016 (first enrollment)
Contact information	Hyun‐Seung Kim, MD, The Catholic University of Korea, Yeouido St Mary's Hospital, 10, 63‐ro Yeongdeungpo‐gu, Seoul, Korea
Notes	http://cris.nih.go.kr/cris/en/search/search_result_st01.jsp?seq=10145

Trial name or title	A randomized, multicenter, double‐masked, vehicle‐controlled study of the safety and efficacy of OTX‐101 in the treatment of keratoconjunctivitis sicca
Methods	Study design: parallel‐group randomized controlled trial Target enrollment: 745 participants (actual) Planned study follow‐up: 3 months
Participants	Age: 18 years and older Gender: all Culture: United States Inclusion criteria: history of dry eye syndrome (KCS) for a period of at least 6 months; clinical diagnosis of bilateral KCS; lissamine green conjunctival staining sum score of ≥ 3 to ≤ 9 out of a total possible score of 12 (scoring excludes superior zones 2 and 4) in the same eye at both the screening and baseline visits; global symptom score (Symptom Assessment in Dry Eye) ≥ 40 mm at both the screening and baseline visits; corrected Snellen visual acuity of better than 20/200 in each eye Exclusion criteria: use of cyclosporine ophthalmic emulsion 0.05% (Restasis) within 3 months prior to the screening visit; previous treatment failure (lack of efficacy) with cyclosporine ophthalmic emulsion 0.05% (Restasis); diagnosis of Sjögren's disease > 5 years prior to the screening visits; clinical diagnosis or any history of seasonal and/or perennial allergic conjunctivitis; use of systemic or topical medications within 7 days prior to the screening visit or during the study period that are known to cause dry eye; use of any topical ophthalmic medications, prescription (including antiglaucoma medications) or over the counter (including artificial tears), other than the assigned study medication during the study period; current active eye disease other than dry eye syndrome (i.e. any disease for which topical or systemic ophthalmic medication is necessary); history of herpes keratitis; corneal transplant; corneal refractive surgery within 6 months prior to the screening visit or postoperative refractive surgery symptoms of dryness that have not resolved; cataract surgery within 3 months prior to the screening visit
Interventions	Intervention 1: 0.09% cyclosporine nanomicellar ophthalmic solution (OTX‐101 0.09%) Intervention 2: vehicle of OTX‐101
Outcomes	Primary outcome: proportion of participants with a clinically meaningful increase from baseline in Schirmer's test at week 12 Secondary outcomes: Change from baseline in total conjunctival staining score (lissamine green, modified NEI/FDA scale) at week 12 Change from baseline in central corneal staining score (fluorescein, modified NEI/FDA scale) at week 12 Change from baseline in modified SANDE score at week 12
Starting date	February 2016
Contact information	Tomasz Sablinski, MD, PhD, Ocular Therapeutics SARL
Notes	https://clinicaltrials.gov/ct2/show/study/NCT02688556

Trial name or title	A multicenter, placebo controlled, Restasis referenced, randomized, double blind, Phase II study to evaluate the efficacy and safety of HU00701/HU007 eye drops in patients with dry eye syndrome
Methods	Study design: parallel‐group randomized controlled trial Target enrollment: 114 participants (actual) Planned study follow‐up: 3 months
Participants	Age: 19 years and older Gender: all Culture: Republic of Korea Inclusion criteria: age over 19; corneal staining score (Oxford grading) > 2 or Schirmer test < 10 mm/5 min (if Schirmer test = 0 mm/5 min, nasal stimulation Schirmer test > 3 mm/5 min); volunteer who went through menopause more than 1 year before screening or has surgical menopause; volunteer who has negative result of pregnancy test or use of effective contraception Exclusion criteria: current or recent patients used dry eye syndrome medications (topical or systemic) that could affect the status; patients with systemic or ocular disorders affecting the test result; being treated with systemic steroid; wearing contact lenses within 3 days of screening visit; pregnancy or breastfeeding
Interventions	Intervention 1: topical cyclosporine 0.01% + 3% trehalose 1 drop twice daily at 12‐hour interval for 3 months Intervention 2: topical cyclosporine 0.02% + 3% trehalose 1 drop twice daily at 12‐hour interval for 3 months Intervention 3: topical cyclosporine 0.05% 1 drop twice daily at 12‐hour interval for 3 months Intervention 4: vehicle 1 drop twice daily at 12‐hour interval for 3 months
Outcomes	Primary outcome: change from baseline in corneal staining score at week 12 Secondary outcomes: Change from baseline of corneal staining score ‐ Oxford grading at week 4 and 8 Change from baseline of strip meniscometry assessment at week 4, 8, and 12 Change from baseline of tear film break‐up time at week 4, 8, and 12 Change from baseline of standard patient evaluation of eye dryness questionnaire at week 4, 8, and 12
Starting date	March 2016
Contact information	Seung‐il Baek, Huons Co, Ltd
Notes	https://clinicaltrials.gov/ct2/show/NCT02917512

Trial name or title	CyclASol for the treatment of signs and symptoms of dry eye disease (DED)
Methods	Study design: parallel‐group randomized controlled trial Target enrollment: 328 participants (actual) Planned study follow‐up: 1 month
Participants	Age: 18 years and older Gender: all Culture: United States Inclusion criteria: signed ICF (Informed Consent Form) and HIPAA (Health Insurance Portability and Accountability Act); patient‐reported history of dry eye disease in both eyes; current use of over‐the‐counter and/or artificial tears for dry eye symptoms; ability and willingness to follow instructions, including participation in all study assessments and visits Exclusion criteria: women who are pregnant, nursing, or planning a pregnancy; unwillingness to submit a urine pregnancy test at screening and the last visit (or early termination visit) if of childbearing potential, or unwillingness to use acceptable means of birth control; clinically significant slit‐lamp findings or abnormal lid anatomy at screening; ocular/periocular malignancy; history of herpetic keratitis; active ocular allergies or ocular allergies that may become active during the study period; ongoing ocular or systemic infection at screening or baseline; wear of contact lenses within 3 months prior to screening or anticipated use of contact lenses during the study; history of no response to previous topical cyclosporine A and/or use of topical cyclosporine A or lifitegrast within 2 months prior to screening; intraocular surgery or ocular laser surgery within the previous 6 months, or have any planned ocular and/or lid surgeries over the study period; presence of uncontrolled systemic diseases; presence of known allergy and/or sensitivity to the study drug or its components
Interventions	Intervention 1: cyclosporine A solution in vehicle Intervention 2: vehicle only
Outcomes	Primary outcome: change in total corneal fluorescein staining at month 1, change in OSDI scores at month 1
Starting date	October 2017
Contact information	Sonja Kroesser, PhD, Novaliq GmbH
Notes	https://clinicaltrials.gov/ct2/show/NCT03292809

PERMALINK

Topical cyclosporine A therapy for dry eye syndrome

Cintia S de Paiva

Stephen C Pflugfelder

Sueko M Ng

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

Epidemiology

Description of the intervention

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 events

Follow‐up

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' table

Results

Description of studies

Results of the search

7.

Included studies

1. Summary of included studies.

Excluded studies

Risk of bias in included studies

8.

Allocation

Sequence generation

Allocation concealment

Blinding

Incomplete outcome data

Selective reporting

Other potential sources of bias

Effects of interventions

Summary of findings for the main comparison. Topical cyclosporine A 0.05% + artificial tears versus vehicle + artificial tears or artificial tears alone for dry eye syndrome.

1. Topical CsA 0.05% + artificial tears versus vehicle + artificial tears or artificial tears alone (18 trials)

Primary outcomes (13 trials)

9.

Secondary outcomes

Ocular surface dye staining (13 trials)

Aqueous tear production (16 trials)

1.1. Analysis.

1.

1.2. Analysis.

2.

Tear film stability (12 trials)

1.3. Analysis.

3.