1. The DRy Eye Assessment and Management (DREAM) Study NCT02128763 Penny Asbell 1, Maureen Maguire 2, Ellen Peskin 1, Neha Gadaria 1, Kathy McWilliams 2, Nataliya Antonova 1, Rubinee Simmasalam 1, Brendan Barry 1 for the DREAM Research Group 1 Department of Ophthalmology Mount Sinai Hospital, New York, NY, 2 University of Pennsylvania, Philadelphia, PA. Contact e-mail: penny.asbell@mssm.edu Introduction Dry Eye Disease (DED) is characterized by ocular surface changes and tear film instability. The chief complaints of patients are chronic pain or irritation and associated visual disturbance. Inflammation is considered a core mechanism in the pathogenesis of DED, although the pathogenesis of DED is likely multifactorial,. Inflammation in turn leads to ocular surface damage and further exacerbation of DED, thus creating a self-perpetuating vicious cycle of chronic DED. 1,2,3,4,5,6,7,8 Clinical evidence indicates that anti-inflammatory therapies may be able to break this cycle of DED and inflammation. Rationale for DREAM STUDY: Though there has been some success with use of anti-inflammatory treatments for DED, most of the current options are limited by risks or side-effects, leaving many DED patients with continued signs and symptoms. An anti-inflammatory nutritional supplement such as Omega-3 fatty acids is an appealing alternative for many patients. While RCT studies support the use of Omega-3 for other inflammatory diseases, such as rheumatoid arthritis and asthma, the data on its use in DED is limited and with varying outcomes and success rates. Most studies concerning Omega-3 and DED are small with data recorded from a single site, with different outcome measures and using varying combinations of Omega-3 and other fatty acids with short study duration and contrasting results. 9 The NIH has called for increased evidence on efficacy and safety of supplements for chronic disease, including randomized clinical trials. The U.S. Department of Health & Human services has also noted that few trials have established the efficacy of supplements in chronic disease (http://www.ahrq.gov/clinic/tp/multivittp.htm).http://www.ahrq.gov/clinic/tp/multivittp.htm The DREAM study will be the first large scale, multicenter, double masked randomized controlled trial(RCT) using Omega-3 for DED. Work done in our NEI planning grant, which included a small scale clinical trial with Omega-3 supplements (DREAM: Feasibility study), extensive review of current literature and collaboration with experts in various fields, helped us identify criteria for the DREAM protocol, including standardized outcome measures, biomarkers of inflammation, and compliance measures (blood tests). The DREAM study design of a twelve-month primary RCT trial followed by a twelve-month extension study, enables us to have a longitudinal assessment of DED on a cohort of well characterized subjects. The results obtained from DREAM will help us better understand and describe DED itself and specifically determine the efficacy and safety of the use of Omega-3 in treatment of DED. Objective 1- To test the effectiveness of Omega-3 supplementation for Dry Eye Disease (DED) in a Primary Clinical Trial. 2- To better understand DED features by observation of a well-characterized group of patients treated with either Omega-3 or placebo over twelve months. 3- To determine the effects of extended use and discontinuation of Omega-3 through an Extension Trial. Methods Primary Trial: multi-center, double-masked, placebo-controlled, prospective randomized clinical trial with 600 patients at 20 sites. Active oral supplement (Omega-3) or placebo will be taken for a year. Extension Trial: Randomized Withdrawal trial will evaluate whether Omega-3 taken over another year will have an additional effect or if one year is enough to break up the chain of inflammation in DED. Subjects recruited from patients on active supplements in the Primary Trial. Dose: 2000 mg EPA and 1000 mg DHA per day. Inclusion Criteria: Greater than or equal to 2 of the following 4 signs in the same eye repeated at 2 visits: Conjunctival staining present and greater than or equal to 1 (out of possible score of 6 per eye) Corneal fluorescein staining present and greater than or equal to 4 (out of a possible score of 15 per eye) Tear film break-up time (TBUT) less than or equal to 7 seconds Schirmer's test greater than or equal to 1 and less than or equal to 7 mm in 5 minutes. OSDI score: 25-80 at screening, 21-80 at baseline. Symptoms of DED for greater than or equal to 6 months. Use of or desire to use artificial tears at least 2 times per day in preceding 2 weeks Ability to swallow large, soft gelcaps Exclusion Criteria: Allergic to ingredients in supplements or placebo Wears contact lenses Pregnant, nursing, or lactating Current ocular infection, inflammation, or acute allergic conjunctivitis History of: ocular herpetic keratitis, ocular surgery in past 6 months, LASIK surgery, use of glaucoma medicine or surgery for glaucoma, liver disease, atrial fibrillation, hemophilia or bleeding tendencies In the process of any anticoagulation therapy Eyelid abnormalities or extensive ocular scarring Use of EPA/DHA supplements in excess of 1200 mg per day Current use, insufficient washout period, or intent to change specific treatments for dry eye disease Results This is the first NEI-funded randomized placebo controlled clinical trial on DED. Results will answer the question of the efficacy and safety of use of Omega-3 in treating dry eye disease. The primary outcomes, secondary outcomes and exploratory outcomes- including biomarkers of inflammation of the ocular surface will provide a expanded “face “ for dry eye disease. Studying a well-characterized cohort will improve our ability to diagnose and treat patients with dry eye disease and may provide new targets for treatment. Results are expected in 2015-2016. Conclusions DED is a multifactorial disease and the DREAM study will provide significant insights in understanding the role of Omega-3 in treating dry eye, as well as, the impact of DED on quality of life. Furthermore, studying biomarkers may shed new light on the mechanisms of action that lead to DED. Supported Grants: NEI U10EY022881 & U10EY022879 Financial Disclosure: Active and placebo supplements have been donated by the Access Business Group with fish oil oil donated by EPAX Norway AS. Commercial Relations: None Outcome Measures: Primary: Change in OSDI score Secondary: Compliance with the study treatment protocol as measured by changes in blood levels of essential fatty acids and pill counts. Incidence of adverse events Change in Signs of DED (conjunctival and corneal staining, TBUT, Shirmer’s test) Frequency of administration of artificial tears and other dry eye treatments Contrast sensitivity Quality of life as measured by the SF-36 Change in Brief Ocular Discomfort Index (BODI) score. Cost-effectiveness of using Omega-3 Exploratory: Signs measured by keratography: TBUT, TMH, redness, meibography Meibomian gland secretion evaluation Tear osmolarity Biomarker levels: MMP-9, tear cytokine levels, HLA-DR expression. 1. Lam H, Bleiden L, De paiva CS, Farley W, Stern ME, Pflugfelder SC. Tear cytokine profiles in dysfunctional tear syndrome. Am J Ophthalmol. 2009;147(2):198-205. 2. Enríquez-de-Salamanca A, Calder V, Gao J, et al. Cytokine responses by conjunctival epithelial cells: an in vitro model of ocular inflammation. 2008 Oct;44(1):160-7. 3. Paiva CS, Pflugfelder SC. Rationale for anti-inflammatory therapy in dry eye syndrome. Arq Bras Oftalmol. 2008 Nov-Dec;71(6 Suppl):89-95. Review. 4. Lemp MA. Advances in understanding and managing dry eye disease. Am J Ophthalmol. 2008 Sep;146(3):350-356. 5. Dry Eye Workshop (DEWS) Committee. 2007 Report of the Dry Eye Workshop (DEWS). Ocul Surf. April 2007;5(2):65-204. 6. Nichols KK, Foulks GN, Bron AJ, et al. The international workshop on meibomian gland dysfunction: Executive summary. Invest Ophthalmol Vis Sci2011;52(4):1922-29. 7. Stevenson W, Chauhan SK, Dana R. Dry eye disease: an immune-mediated ocular surface disorder. Arch Ophthalmol. 2012 Jan;130(1):90-100. 8. Stern ME, Schaumburg CS, Pflugfelder SC. ( 2013) Dry eye as a mucosal autoimmune disease. International reviews of immunology 2013;32:19-41. 9. Rosenberg ES, Asbell PA. Essential fatty acids in the treatment of dry eye. Ocul Surf. 2010;8(1):18–28.