Trial Population

From October 2014 through July 2016, a total of 923 patients completed a screening visit at 27 clinical centers in the United States (Fig. S1 in the Supplementary Appendix, available with the full text of this article at NEJM.org). At the screening visit, 678 patients (73.5%) met none of the exclusion criteria; these patients were provided with run-in supplements (placebo capsules) and were scheduled to attend an eligibility-confirmation visit approximately 2 weeks later. Of the 615 patients who returned for the eligibility-confirmation visit, 535 (87.0%) were eligible for inclusion in the trial.

The trial was designed to include a broad spectrum of patients with symptomatic moderate-to-severe dry eye disease. Eligibility criteria were an age of 18 years or older, the presence of ocular symptoms related to dry eye disease for at least 6 months, the use of or a desire to use artificial tears an average of at least two times per day during the 2 weeks before the screening visit, and a score on the Ocular Surface Disease Index (OSDI) of 25 to 80 at the screening visit and of 21 to 80 at the eligibility-confirmation visit. Scores on the 12-item OSDI range from 0 to 100, with a score of 0 indicating no ocular discomfort and higher scores indicating greater symptom severity. The minimal clinically meaningful change in score is 10 points.8,9 Scores on three subscales of the OSDI (ocular symptoms, vision-related function, and environmental triggers) also range from 0 to 100, with higher scores indicating greater symptom severity.

In addition, patients had to have at least two of the following four signs in at least one eye: a conjunctival lissamine-green staining score of 1 or more (on a scale ranging from 0 to 6, with higher scores indicating greater abnormality), a corneal fluorescein staining score of 4 or more (on a scale ranging from 0 to 15, with higher scores indicating greater abnormality), a tear break-up time (the time from a blink to the appearance of gaps in the tear film, with shorter times indicating greater abnormality) of 7 seconds or less, and a result on Schirmer’s test with anesthesia (the length of wetting of paper strips placed in the inferior cul de sac of the lower eyelid, with shorter lengths indicating greater abnormality) of 1 to 7 mm in 5 minutes. The same qualifying signs had to be present in the same eye at both the screening visit and the eligibility-confirmation visit.

Patients were excluded from the trial if they did not take at least 90% of the run-in supplements (five per day) or if they had worn contact lenses during the 30 days before the screening visit, had undergone laser-assisted in situ keratomileusis or recent ocular surgery (within the past 6 months), or had a history of ocular infection or contraindications to treatment with high-dose n−3 fatty acid supplementation (see the Supplementary Appendix and the protocol, available at NEJM.org). Patients who were regularly using treatments for dry eye disease (including n−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.

The DREAM Study Research Group had control of the design and conduct of the trial and the interpretation of the data. The protocol was approved by the institutional review board at each center, and the trial was carried out under a Food and Drug Administration Investigational New Drug application. The first four members of the writing committee vouch for the accuracy and completeness of the data and the fidelity of the trial to the protocol. All the patients provided written informed consent.

Trial Groups

Patients were randomly assigned, in a 2:1 ratio, to receive active or placebo supplements for 12 months. 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. Personnel at the Investigational Drug Service, University of Pennsylvania, mailed the supplements directly to the patients.

In both trial groups, the regimen was five soft-gelatin capsules per day. Each active capsule contained 400 mg of EPA and 200 mg of DHA, for a total daily dose of 2000 mg of EPA and 1000 mg of DHA. Each placebo capsule contained 1000 mg of refined olive oil; each capsule was 68% oleic acid, 13% palmitic acid, and 11% linoleic acid. The active and placebo capsules contained 3 mg of vitamin E (alpha-tocopherol), as an antioxidant, as well as masking flavor and lemon flavor. The Access Business Group manufactured and donated the capsules. The fish oil concentrate in triglyceride form that was included in the active supplements was donated by Epax. The contents of the active and placebo capsules were verified by an independent laboratory (Nutrasource Diagnostics). The regimen was reduced or suspended when the patient reported gastrointestinal symptoms or when a contraindication to treatment with the full dose of active supplements developed. With resolution of symptoms or contraindications, the patient could restart or increase the regimen.

Outcome Measures

The primary outcome was the mean change from baseline in the OSDI score. The following measures were prespecified secondary outcomes: the proportion of patients with a decrease from baseline in the OSDI score of 10 points or more, 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 staining score, corneal staining score, tear break-up time, and the result on Schirmer’s test), changes in the scores on the 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 the 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), and the incidence of adverse events. Coordinators asked patients about adverse events during each visit (at 3, 6, and 12 months) and by telephone (at 9 months) and coded these events according to the Medical Dictionary for Regulatory Activities (MedDRA) system; a medical monitor reviewed serious adverse events and their codes. All patients, clinical staff, and laboratory personnel were unaware of the trial-group assignments.

RPS Diagnostics provided their InflammaDry Detector test kits, TearLab provided materials for their TearLab Osmolarity System, and TearScience provided their Meibomian Gland Evaluators at a discounted cost. Results of these tests were used to define subgroups for analyses shown in the Supplementary Appendix.

Statistical Analysis

For the primary and secondary outcomes, baseline values were the means of values obtained during the screening and eligibility-confirmation visits, except for values obtained only during the eligibility-confirmation visit (e.g., visual acuity and results of impression cytology). The values used for assessing change were the means of values obtained during the 6-month and 12-month visits; if a value from only one of these visits was available, that value was used. The 97.5 percentile for the mean change from baseline in the EPA level at 6 months in the placebo group (0.32 percentage points) was used as a threshold for adherence to treatment in the active supplement group. Analyses were performed according to the intention-to-treat principle.

Comparisons of the mean change in continuous measures between trial groups and associated 95% confidence intervals were based on linear regression with a robust variance estimator. Generalized estimating equations were used for ocular measures to accommodate the correlation between eyes in the same person.10 Propensity scores and the regression method of multiple imputation were used for missing OSDI scores at month 6 or 12.11 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). Comparisons of categorical outcomes were based on chi-square tests, and 95% confidence intervals for the difference in proportions were calculated with the Wilson method.12 Differences between trial groups in the cumulative proportion of patients with an adverse event were evaluated with the log-rank test; Fisher’s exact test was used when the number of patients in a group with a given adverse event was 5 or fewer. The significance of differences between trial groups for 18 secondary outcomes, measures of adherence to the trial regimen, and safety measures were evaluated with post hoc application of the Benjamini–Hochberg adjustment.

Prespecified subgroups were defined according to baseline severity of symptoms (OSDI score ≥40 vs. <40), severity of signs (severe [conjunctival staining score, ≥2; corneal staining score, ≥4; tear break-up time, <5 seconds; and the result on Schirmer’s test, ≤7 mm in 5 minutes] vs. not severe), EPA and DHA levels in red cells (both levels above vs. one or both levels equal to or below the mean levels in the reference population of the central laboratory [DHA, 3.7%; EPA, 0.6%]), and ocular inflammation (0 vs. 1 vs. 2 eyes with a percentage of HLA-DR+ epithelial cells on impression cytology that was greater than the median percentage among all patients in the trial [5%]). Tests of interaction were used to evaluate whether the effect of supplementation with n−3 fatty acids differed among subgroups.

We determined that a sample of 505 patients would provide the trial with 90% statistical power to detect a 6-point mean difference between trial groups in the mean change in the OSDI score, assuming a standard deviation of 18 points and missing data for 15% of patients. This report includes data that were available by October 24, 2017. Statistical computations were performed with SAS software, version 9.4 (SAS Institute).