Macsai 2008.

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