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DREAM study reflects ‘real-world’ dry eye disease patients
The design of the trial included real-world, symptomatic patients to better understand the impact of omega-3 treatment.
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The 1-year Dry Eye Assessment and Management study was designed to include “real-world” dry eye disease patients and determine if omega-3 oral supplementation affected their dry eye symptoms.
The study design, the decision to allow all participants to remain on their current dry eye therapies and the use of olive oil as the trial placebo have been questioned by some ophthalmologists after the results of the trial were released in April.
Typical real-world patients
The majority of patients with symptomatic dry eye disease are treated for their disease before trying omega-3 supplementation. By the time omega-3 supplementation is used, patients have typically tried artificial tears, Restasis (cyclosporine ophthalmic emulsion 0.05%, Allergan), and/or any number of other therapies to control their symptoms, OSN Cornea/External Disease Board Member Penny A. Asbell, MD, FACS, MBA, FARVO, study chair of the DREAM trial, told Ocular Surgery News.
“My question, my real goal, was to take patients who were symptomatic on their current treatment and to see if adding omega-3 in a high dose was effective in alleviating their symptoms. That’s what the trial was all about. I have no financial interest in omega-3 products. I was interested in the typical dry eye patient who walks in, who has tried other treatments and who wants to try something additional for his/her symptoms. These are the patients who most of us see in our offices every day,” Asbell said.
Insufficient evidence supporting omega-3
The results of the DREAM study found insufficient evidence to support recommending the use of oral omega-3 supplements to reduce signs and symptoms of dry eye disease after 1 year. The trial allowed participants in both the active supplementation group and placebo group to remain on their current dry eye treatment therapies.
The active supplement group, two-thirds of the 535 total patient cohort, received a daily dose of 3,000 mg of marine-derived omega-3 fatty acid in triglyceride form, 2,000 mg of eicosapentaenoic acid and 1,000 mg of docosahexaenoic acid. The placebo group, one-third of the patient cohort, received 5,000 mg of refined olive oil.
The decision to include just omega-3 supplementation instead of other omega supplements such as gamma linolenic acid was due to several factors, Asbell said.
“We specifically wanted to look at omega-3. When you look at the past data of essential fatty acids, most say it’s the omega-3 that is missing from the modern diet. That’s what we concentrated on. You can do any combination of anything, but we screened almost 1,000 people, randomized over 500, so you can imagine the size of the trial if we had three different varieties of treatment,” she said.
Both study groups ultimately experienced improved symptoms after 1 year. Patients who received omega-3 experienced a 13.9-point mean reduction in Ocular Surface Disease Index score at 12 months compared with a 12.5-point mean reduction in OSDI score in patients who received placebo, a statistically insignificant difference between the groups.
Criticism of the study design
Mitchell A. Jackson, MD, an OSN Refractive Surgery Board Member, said the trial was “not well controlled” due to patients being allowed to stay on their current dry eye medications and olive oil being used as a placebo.
“The participants in both arms, active supplement and placebo, were able to remain on existing dry eye therapies, which adds a lot of co-variables in my opinion. I would have had people on the omega or the proper control and nothing else. You don’t know how much Restasis or Xiidra (lifitegrast ophthalmic solution 5%, Shire) or warm compresses or steroids are helping these people. Some patients might be more compliant than others. There are too many variables. For me, having all these other dry eye therapies allowed is not a good control for this study in general,” Jackson said.
Typically, in FDA trials designed to lead to drug approval, participants take no other treatment except for the investigational treatment or a placebo, Asbell said.
“I wanted our trial to be what people actually do, to have the kind of patients people actually see and the kind of patients who are asking, what else can you do for me? That is very rarely someone who does nothing for their dry eye,” Asbell said.
Also, a placebo is usually the active treatment minus the active ingredient. For example, in testing a new eye drop, the active treatment is taken out of the drop and whatever is left over is used as the placebo, Asbell explained.
For omega-3, the only way to package the supplement is in a capsule. The placebo had to be similar in size, shape and color as the omega-3 capsule. Water cannot be used in a capsule since it will cause the capsule to melt, so an oil had to be selected, she said.
“Why olive oil vs. any other oil? We spent quite a bit of time on both the active and the placebo, picking the products and their concentrations. Almost all the other clinical trials on omega-3, whether cardiac disease, rheumatoid arthritis, asthma, etc, used olive oil as their placebo. Nobody ever objected, said it’s an active ingredient, you shouldn’t use it. I don’t recall ever seeing an article suggesting that,” Asbell said.
Trial vetted by experts
Experts vetted the use of olive oil as a placebo, including Artemis Simopoulos, MD, FACN, founder and president of the Center for Genetics, Nutrition and Health, whose recommendation noted that olive oil was an appropriate placebo, Asbell said.
The trial was funded by the National Eye Institute and went through several review committees made up of experts, and nobody objected to olive oil as the placebo. Additionally, an independent committee with expertise in clinical trials, picked by the NEI, reviewed the trial protocol for efficacy and safety prior to the start of the trial, she said.
“None of them had any objection. Among them were several worldwide experts in nutrition, and not one of them objected to using olive oil either. There were a large number of experts who looked at this before any patient was entered in the clinical trial,” Asbell said.
No member of the placebo group experienced elevated levels of oleic acid or alpha-linolenic acid, two components of olive oil, at baseline, 6 months or 1 year, Asbell said.
Additionally, other dry eye disease randomized clinical trials, even other omega-3 trials, have experienced symptom improvements in the placebo and treatment groups, she said.
“That is an incredibly common event in dry eye trials. Is it a placebo effect? Who knows? They all improved. This wasn’t the only trial where the placebo group showed substantial improvement. It happened with cyclosporine, lifitegrast and many other trials that never were published where both the active and placebo groups improved. In our trial, the placebo group received only one teaspoon of olive oil a day, probably less than is typically used in a salad dressing. It’s a small amount, far less than what is considered typical of a Mediterranean diet, which is at least 12 times that. It’s not plausible that the placebo had any active impact on dry eye disease,” Asbell said.
Jackson said he would continue to prescribe omega supplements to his dry eye disease patients despite the results of the DREAM trial.
“There is a lot of confusion with this trial and a lot of different interpretations of the results. The placebo could have been chosen better, the covariables eliminated, and all the omegas could have been looked at (such as omega GLA) and not just certain omegas, which would have been helpful to stratify the results of which omega was useful vs. a true placebo,” he said. – by Robert Linnehan
- References:
- Asbell P. Featured lecture: Role of nutritional supplements in dry eye disease. Presented at: American Society of Cataract and Refractive Surgery annual meeting; April 13-17, 2018; Washington.
- Dry Eye Assessment and Management Study Research Group, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1709691.
- Jackson MA. Should premium surgeons consider DREAMing when optimizing the ocular surface? www.healio.com/ophthalmology/practice-management/news/print/ocular-surgery-news/%7B450e653a-09fd-4a45-943a-a6b1cb5b0e7b%7D/should-premium-surgeons-consider-dreaming-when-optimizing-the-ocular-surface. Published July 10, 2018. Accessed July 11, 2018.
- For more information:
- Penny A. Asbell, MD, FACS, MBA, FARVO, can be reached at the Hamilton Eye Institute, 930 Madison Avenue, Memphis, TN 38163; email: pasbell@uthsc.edu.
- Mitchell A. Jackson, MD, can be reached at Jacksoneye, 300 N. Milwaukee Ave., Suite L, Lake Villa, IL 60046; email: mjlaserdoc@msn.com.
Disclosures: Asbell reports she receives grants from National Eye Institute and Office of Dietary Supplements, NIH, during the conduct of the study; personal fees from Santen, Shire, Medscape, Allergan, ScientiaCME, Oculus and Vindico; grants and personal fees from Novartis, MC2 Therapeutics, Rtech and Miotech; grants, personal fees, and nonfinancial support from Valeant and Bausch + Lomb; and personal fees and nonfinancial support from Shire, Santen and CLAO outside the submitted work. Jackson reports he is a consultant for ScienceBased Health and Shire and a speaker for Allergan.