Laibovitz 1993.

Methods	Study design: cross‐over‐design randomized controlled trial Number randomized: total 26 participants; topical CsA: 13 participants, vehicle only: 13 participants; second phase: total 8 participants; topical CsA: 5 participants, vehicle only: 3 participants Exclusions after randomization: 17 participants were excluded for not meeting inclusion criteria Losses to follow‐up: 1 participant dropped out for personal reasons Number analyzed (total and per group): total 8 participants; topical CsA: 5 participants, vehicle only: 3 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: not reported Sex: not reported Inclusion criteria: more than 18 years of age; keratoconjunctivitis sicca defined as a syndrome of ocular surface changed with moderate‐to‐severe symptoms of dry eye based on the following criteria: positive rose bengal staining with a score of > 3 in at least 1 eye using the van Bijsterveld method; 1 or more of the following symptoms present despite conventional management for dry eye, graded at least moderate in severity: itching, tearing, blurred vision, burning, foreign body sensation, redness, sensitivity to light, or mucus production; both symptoms and objective signs must have been present despite conventional management for dry eye Exclusion criteria: concomitant use of contact lenses; serious coexistent ocular disease such as optic atrophy or active retinopathy; subepithelial corneal scarring; active blepharitis; persistent active intraocular inflammation or infection; evidence of ocular herpes simplex virus infection Equivalence of baseline characteristics: not reported
Interventions	Intervention 1: topical CsA 1% (period 1: topical CsA 1%; period 2: vehicle only) eye drops 4 times daily for 6 weeks Intervention 2: vehicle only (period 1: vehicle only; period 2: topical CsA 1%) eye drops 4 times daily for 6 weeks Length of follow‐up: 6 weeks in each phase; 2‐week intertreatment wash‐out period; 14 weeks total Notes: artificial tears (Refresh) 4 times daily were administered concurrently with the study medications; there was a 5‐day run‐in period with unpreserved artificial tears 4 times daily, and 2‐week intertreatment washout with unpreserved artificial tears; periocular cosmetics were not permitted during the study period; the use of concomitant medications that could affect tear production or interfere with the metabolism of CsA was prohibited throughout the trial
Outcomes	Primary outcomes, as defined: the primary outcome for comparison of interventions was subjective improvement of DES symptoms (foreign body sensation) at 4 and 6 weeks follow‐up Secondary outcomes: Ocular surface dye staining, as defined by the mean change in corneal fluorescein from baseline to 6 weeks follow‐up Aqueous tear production, as measured by the mean change in Schirmer test scores (millimeters) at 6 weeks follow‐up from baseline Tear film stability, as measured by the mean change in TBUT (seconds) at 6 weeks follow‐up from baseline Adverse events reported: blurred vision, ocular burning, ocular itching, eyes running, ocular discomfort were reported in both groups Intervals at which outcomes were assessed: 6 weeks in each phase
Notes	Study period: not reported Funding sources: this study is funded by Sandoz Pharmaceuticals Corporation 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, 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	High risk	Intention‐to‐treat was not followed; 1/26 (3.8%) participants dropped out during the first phase, and 17/26 (65.4%) were not qualified for the second phase.
Selective reporting (reporting bias)	High risk	"Of the many parameters studied, only a few showed measurable change or treatment effect, and this discussion is limited to those parameters" "Efficacy data were analyzed for period 1 only"
Other bias	High risk	This study had a cross‐over design, although the efficacy data included results for the first phase only; this study was funded by a pharmaceutical firm; baseline equivalence was not reported.