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Dianna K H Wheaton, David G Birch, Gary E Fish, Rand Spencer, N Shirlene Pearson, Alison Takacs, Robbie Baker, Dennis R Hoffman; Safety Assessment of High Dose Docosahexaenoic Acid (DHA) Supplementation in a 4-Year Randomized Clinical Trial in X-linked Retinitis Pigmentosa (XLRP). Invest. Ophthalmol. Vis. Sci. 2014;55(13):1391.
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DHA (22:6ω3), a highly unsaturated long-chain fatty acid, is concentrated in photoreceptor outer segment membranes. High dose DHA intake could serve as a potential target for free-radical induced oxidation and thereby lead to an increase in oxidative stress. In a Phase II, placebo-controlled, randomized trial to elevate blood-DHA levels in patients with XLRP, the goal was to determine efficacy of high dose DHA supplementation in slowing progressive vision loss. Here we assess biological safety and adverse events at the conclusion of the 4-year supplementation trial.
Male participants with XLRP (7-31 yrs) were randomized to 30 mg DHA/kg bodyweight/day or placebo; all received a daily multivitamin. Safety assays and adverse events were recorded for all enrolled participants, reported are data for a modified Intent-To-Treat cohort of 60 participants (33 DHA, 27 Placebo) who completed at least one year on the trial. Blood samples were collected every six months during the trial. Biological safety analysis included blood fatty acids, plasma vitamin A & E, whole blood platelet aggregation, total plasma antioxidant capacity, lipoprotein cholesterol, and oxidized LDL. Treatment-emergent adverse events (TEAE) were categorized and tabulated.
By year 4, supplementation elevated plasma DHA by 4.4-fold to 5.8±0.3% total fatty acids (mean±SE) compared to 1.3±0.1% in the placebo group (p<0.00005). Over the trial duration, no significant differences between DHA and placebo groups were found for vitamin A (p=0.30), vitamin E (p=0.46), platelet aggregation (p=0.81), plasma antioxidant activity (p=0.26), total cholesterol (p=0.82), LDL cholesterol (p=0.83), HDL cholesterol (p=0.70), triglycerides (p=0.18), and oxidized LDL levels (p=0.14). TEAEs were transient and not considered severe (e.g., gastrointestinal [GI] irritability, blood chemistry alterations, cholesterol/lipid panel deviations). However, one participant with a family history of inflammatory bowel disease (Crohn’s) was unable to tolerate persistent GI discomfort and withdrew from the study.
The long-term, high dose DHA supplementation to patients with XLRP was associated with limited safety risks in this 4-year trial. Nevertheless, GI symptoms should be monitored in all patients taking high dose DHA especially those with personal or family history of GI disturbances.
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