Asbell 2018.

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