Magnitude and Predictors of the Placebo Effects in the Dry Eye Assessment and Management Study.

PURPOSE

To determine the magnitude and predictors of placebo effects on dry eye symptoms and signs in the Dry Eye Assessment and Management (DREAM) study.

DESIGN

Secondary analysis of data from the DREAM study, a large-scale multicenter randomized clinical trial of patients with moderate to severe dry eye disease (DED).

PARTICIPANTS

One hundred sixty-four participants who were randomized to the placebo group (daily oral 1000 mg refined olive oil) and completed a 12-month follow-up in 27 United States centers.

METHODS

At baseline, 3, 6, and 12 months, DED symptoms were evaluated using the Ocular Surface Disease Index (OSDI), and signs were assessed using conjunctival staining, corneal staining, tear break-up time (TBUT), Schirmer test, and meibomian gland dysfunction (MGD). Placebo effects were calculated as changes from baseline in DED symptoms and signs over 12 months. Univariable and multivariable models determined predictors for placebo effects.

MAIN OUTCOME MEASURES

Changes from baseline in DED symptoms and signs over 12 months after administration of the placebo.

RESULTS

Among 164 participants (mean age 58 years, 82% female, 74% White) randomized to the placebo group, there were significant placebo effects that were evident by 3 months and remained until 12 months with improvement in OSDI total score (mean decline 10.4 points,  < 0.001), conjunctival staining score (mean decrease 0.5 points,  < 0.001), corneal staining score (mean decrease 0.9 points,  < 0.001), TBUT (mean increase 0.7 seconds,  < 0.001), and MGD score (mean decrease 0.3 points,  = 0.01). In multivariable analysis, a higher baseline OSDI total score ( < 0.001) and absence of rheumatoid arthritis ( = 0.01) predicted more improvement in OSDI total score (  = 0.25). More severe DED in OSDI ( = 0.005), conjunctival staining ( = 0.04), and MGD ( < 0.001) at baseline predicted more improvement in MGD score (  = 0.25).

CONCLUSIONS

The DREAM study revealed significant placebo effects on DED symptoms and signs, with more severe DED predicting larger placebo effects. Future DED trials should consider placebo effects in the trial design, statistical analysis, and result interpretation.

FINANCIAL DISCLOSURES

Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.