Sheppard 2013.

Methods	Study design: randomized, parallel‐group, controlled trial Study site(s): multi‐center (2 sites) Number randomized (total and per group): 90 eyes of 45 participants Unit of randomization (individual or eye): individual Exclusions after randomization: 1 participant withdrew because fish consumption exceeded the amount that was allowed; 1 participant enrolled in another study; 1 participant withdrew for health reasons; 1 participant withdrew because a rash developed Losses to follow‐up: 3 participants Number analyzed (total and per group): 38 participants in total; 19 participants in each intervention group Unit of analysis (individual or eye): individual Reported power calculation? (Y/N): Y (80% power) Reported subgroup analysis? (Y/N): N
Participants	Participant characteristics Country: United States Age (mean ± SE, range): 62 ± 1 years, range 52 to 70 years in the fatty acid treatment group; 61 ± 2 years, range 44 to 86 years in the control group Gender: 45 women in total Inclusion criteria: moderate to severe dry eye defined as: 1. TBUT ≤ 8 s in at least 1 eye 2. At least grade 1 fluorescein superficial punctate keratitis in at least 1 corneal quadrant or at least grade 1 conjunctival lissamine green staining in at least 1 eye 3. OSDI score ≥ 16 4. Willing to discontinue use of any current dry eye treatment (except Refresh artificial tears) for 4 weeks before randomization and during the course of the 6‐month study 5. Postmenopausal women aged 40 years and older; postmenopause is defined as the absence of menstrual period for at least 1 year, or surgical hysterectomy with bilateral oophorectomy no less than 6 months previously 6. If using transdermal, vaginal, or systemic estrogen, progesterone, or estrogen derivatives, must be on a stable dose for at least 90 days, and must be planning on staying on the same stable dose for the duration of the study 7. Signature on the written informed consent form 8. Patient motivation and willingness to cooperate with the investigator by following the required medication regimen 9. Patient willingness and ability to return for all visits during the study Exclusion criteria: 1. Concurrent involvement in any other clinical trial involving an investigational drug or device 2. Compromised cognitive ability that may be expected to interfere with study compliance 3. Uncontrolled or poorly controlled systemic disease (eg, hypertension, diabetes) or the presence of any significant illness (eg, serious gastrointestinal, renal, hepatic, endocrine, pulmonary, cardiac, neurological disease, cancer, AIDS, or cerebral dysfunction) that could, in the judgement of the investigator, jeopardize subjects’ safety or interfere with interpretation of study results 4. Known hypersensitivity to any diagnostic components of the study or procedural drops or medications 5. Anticipated contact lens wear during the study 6. History of corneal transplant, active ocular infection, uveitis, or non‐KCS inflammation 7. History of recurrent herpes keratitis or active disease within the past 6 months 8. History of cataract surgery within 3 months before enrollment, history of ocular surface surgery (ie, refractive, laser in situ keratomileusis, pterygium) within 6 months before enrollment 9. Corneal disorder or abnormality that affects corneal sensitivity or normal spreading of the tear film except superficial punctate keratitis 10. Use of systemic cyclosporine within the previous 3 months. Initiation, discontinuation, or change in dosage of antihistamines, cholinergic agents, beta‐blocking agents, tricyclic or selective serotonin reuptake inhibitor antidepressants, phenothiazines, or topical or systemic acne rosacea medications in the 2 months before enrollment, or anticipated change in dosage during course of study 11. Topical ophthalmic medications within the previous 4 weeks or anticipated use of the same during the study (except artificial tears) 12. Use of Coumadin or Plavix within the previous 2 weeks or anticipated use of the same during study. Stable dosing of aspirin 325 or 85 mg/d was permitted 13. Use of supplemental fish, borage, evening primrose, flaxseed, or black current seed oils in the past 3 months. Routine, usual dietary intake of more than 12 ounces of cold water fatty fish (tuna, salmon, mackerel, sea bass, sardines, or herring) per week 14. Occlusion of the lacrimal puncta surgically or with temporary collagen punctal plugs within 1 month before the study, or anticipated use of the same during the study Equivalence of baseline characteristics? (Y/N): Y
Interventions	Intervention #1 (fatty acid treatment group): oral capsule containing γ‐linolenic acid and omega‐3 polyunsaturated fatty acids twice daily, 2 capsules at a time. Daily dose linoleic acid 710 mg, γ‐linolenic acid 240 mg, arachidonic acid < 3 mg, EPA 126 mg, DHA 99 mg, and DPA 39 mg Intervention #2 (control group): placebo capsule containing sunflower oil (dose not reported), twice daily, 2 capsules at a time Length of follow‐up: 6 months Notes: participants were provided with Refresh artificial tears (Allergan, Inc., Irvine, CA, USA) to use as needed for the duration of the study. No other topical medications were allowed
Outcomes	Primary and secondary outcome measures were not clearly distinguished Specified outcome(s): OSDI; Schirmer test; TBUT; corneal fluorescein staining; conjunctival lissamine green staining; topographic corneal smoothness indexes; CD11c staining; HLA‐DR expression; frequency of artificial tear usage; facial expression discomfort scale; surface regularity and surface asymmetry corneal topography smoothness indexes; logMAR visual acuity, all reported at study endpoint Adverse events reported? (Y/N): Y Measurement time points (specify intervals at which outcomes were assessed): baseline, months 1, 3, and 6 Other issues with outcome assessment (eg, quality control for outcomes, if any): none
Notes	Study dates: enrollment between September 2008 and December 2010 Funding source(s): "supported by an unrestricted research grant from ScienceBased Health and the Virginia Eye Foundation" Conflicts of interest: "J. D. Sheppard is a scientific advisor with Alcon (Fort Worth, TX), Allergan, Bausch + Lomb (Rochester, NY), Lux Biosciences (New Jersey), Merck (New Jersey), ScienceBased Health, and Vistakon (Jacksonville, FL). S. C. Pflugfelder is a consultant for Allergan, Alcon, Bausch & Lomb, GlaxoSmithKline, Mimetogen, and ScienceBased Health. He receives research funding from Allergan and GlaxoSmithKline. R. Singh, A. J. McClellan, M. P. Weikert, S. V. Scoper, T. J. Joly, W. O. Whitley, and E. Kakkar have no financial interests related to the current study" Publication language: English Registered on clinical trials registry? (Y/N): Y ‐ clinical trial registry (clinicaltrials.gov ‐ NCT00883649)
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Eligible patients were randomized 1:1 using a computer generated randomization procedure"; "Patients were randomized using a permuted‐block randomization design with a block size of 4 for each center"
Allocation concealment (selection bias)	Low risk	"An independent statistician, who was also masked to the identity of the subjects until after the analyses were complete, generated these allocation sequences" "Codes linking the randomization number for each subject to the actual treatment were secured in a sealed opaque envelope and were maintained in a locked drawer in each research center"
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"Double‐masked" study "Investigators, subjects, and staff were masked to the identity of the supplement and placebo" "The placebo was identical in appearance to the test supplement and contained sunflower oil as the main ingredient along with beeswax, lecithin, and calcium carbonate" "All subjects and research staff were masked to the identity of the subject treatment group until the end of the study. Supplements and placebo tablets were packaged uniformly. Codes linking the randomization number for each subject to the actual treatment were secured in a sealed opaque envelope and were maintained in a locked drawer in each research center"
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"Double‐masked" study "Investigators, subjects, and staff were masked to the identity of the supplement and placebo" "All subjects and research staff were masked to the identity of the subject treatment group until the end of the study. Supplements and placebo tablets were packaged uniformly. Codes linking the randomization number for each subject to the actual treatment were secured in a sealed opaque envelope and were maintained in a locked drawer in each research center"
Incomplete outcome data (attrition bias) All outcomes	High risk	7/45 (15.6%) participants discontinued the study (3 participants were lost to follow‐up; 1 participant due to deviation from the protocol; 1 participant entered another study; 1 participant for health reasons; 1 participant due to an adverse event), and these participants were not included in the analysis
Selective reporting (reporting bias)	Low risk	All prespecified outcomes in the trial registry were reported
Other bias	High risk	One author is a scientific advisor to pharmaceutical firms; one author is a consultant for pharmaceutical firms and receives research funding from a company