Safety assessment of docosahexaenoic acid in X-linked retinitis pigmentosa: the 4-year DHAX trial

Abstract

Purpose: Docosahexaenoic acid (DHA) continues to be evaluated and recommended as treatment and prophylaxis for various diseases. We recently assessed efficacy of high-dose DHA supplementation to slow vision loss in patients with X-linked retinitis pigmentosa (XLRP) in a randomized clinical trial. Because DHA is a highly unsaturated fatty acid, it could serve as a target for free-radical induced oxidation, resulting in increased oxidative stress. Biosafety was monitored during the 4-year trial to determine whether DHA supplementation was associated with identifiable risks.

Methods: Males (n = 78; 7-31 years) meeting entry criteria were enrolled. The modified intent-to-treat cohort (DHA = 33; placebo = 27) adhered to the protocol ≥ 1 year. Participants were randomized to an oral dose of 30 mg/kg/d DHA or placebo plus a daily multivitamin. Comprehensive metabolic analyses were assessed for group differences. Treatment-emergent adverse events including blood chemistry metabolites were recorded.

Results: By year 4, supplementation elevated plasma and red blood cell-DHA 4.4- and 3.6-fold, respectively, compared with the placebo group (P < 0.00001). Over the trial duration, no significant differences between DHA and placebo groups were found for vitamin A, vitamin E, platelet aggregation, antioxidant activity, lipoprotein cholesterol, or oxidized LDL levels (all P > 0.14). Adverse events were transient and not considered severe (e.g., gastrointestinal [GI] irritability, blood chemistry alterations). One participant was unable to tolerate persistent GI discomfort.

Conclusions: 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. (ClinicalTrials.gov number, NCT00100230.).

Keywords: adverse events; biosafety; fatty acids.

Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.

Figures

Figure 1

Docosahexaenoic acid and ARA levels in plasma lipids as a function of treatment intervention. Mean ± SE plasma levels of DHA (□, ▪) and ARA (▵, ▴) in participants of the high-dose DHA-supplementation arm (filled symbols) or the placebo arm (open symbols), respectively. Gray dashed lines are average plasma DHA (lower section of plot; 1.42% ± 0.1%) and average plasma ARA (upper section of plot; 9.60% ± 0.27%) from 29 age-matched individuals with normal visual function; grayed area demarks 95% CI (DHA range, 1.22%–1.62%; ARA range, 9.1%–10.1%).

Figure 2

Docosahexaenoic acid and ARA levels in RBC lipids as a function of treatment intervention. Mean ± SE RBC levels of DHA (□, ▪) and ARA (▵, ▴) in participants of the high-dose DHA-supplementation arm (filled symbols) or the placebo arm (open symbols), respectively. Gray dashed lines are average RBC-DHA (lower section of plot; 2.9% ± 0.3%) and average RBC-ARA (upper section of plot; 16.8% ± 0.4%) from 29 age-matched individuals with normal visual function; grayed area demarks 95% CI (DHA range, 2.3%–3.5%; ARA range, 16.0%–17.6%).