High Dose Docosahexaenoic Acid (DHA) Supplementation in X-Linked Retinitis Pigmentosa (XLRP): A 4-Year Randomized, Controlled Clinical Trial

Abstract

Purpose: The ω3, polyunsaturated fatty acid, DHA, is highly enriched in photoreceptor membranes where its biophysical properties modify fluidity and enzymatic reactions to facilitate phototransduction. DHA and/or its metabolites also exhibit anti-apoptotic activity and modify gene expression. A previous Phase I trial of 400 mg DHA/day showed a non-statistically significant trend toward slowing disease progression as measured by cone ERG function in XLRP patients (Hoffman et al. 2004). Herein, we report results of a single-site, randomized, double-masked Phase II clinical trial where we assessed efficacy of high dose DHA in slowing progression of XLRP.

Methods: Male patients diagnosed with early stage XLRP who completed at least one year on the trial comprised a modified Intent-To-Treat cohort (mITT; mean age=15.6 yr; range=7-31 yr). Participants were randomized to receive 30 mg DHA/kg/day (n=33) or placebo (n=27). The level of DHA in red blood cells (RBC) was determined every 6 months to monitor adherence. A repeated measures mixed model with maximum likelihood estimation was used to assess efficacy of visual function measures collected annually.

Results: The drop-out rate for the mITT cohort was 13%. Participants in the DHA group completing the 4-year intervention (n=30) had 3.6-fold higher RBC-DHA compared to the placebo group (n=22; p<0.00001). No significant difference was found between high dose DHA and placebo in the rate of loss of cone ERG function, defined as the log fundamental amplitude of the 30-Hz flicker ERG derived from a fast Fourier transform, which was the primary outcome measure (0.022 vs. 0.028 log µV/yr; p=0.30). Changes in rod ERG function (p=0.27), visual acuity (p=0.12) and fundus appearance (pigment disturbances and vessel attenuation; p=0.70) were similar in the two groups. Compared to placebo, DHA supplementation slowed the annual rates of loss in foveal (0.24 vs. 0.15 dB; p=0.07), macular (3.4 vs. 1.7 dB; p=0.03) and peripheral visual field sensitivity (113 vs. 50 dB; p<0.00001).

Conclusions: Long-term, high dose DHA supplementation was not effective in slowing the loss of visual function as measured by cone flicker ERG or visual acuity, both of which primarily reflect macular function in XLRP. Field sensitivity loss was slowed compared to placebo in DHA-supplemented trial participants.

Keywords: 466 clinical (human) or epidemiologic studies: treatment/prevention assessment/controlled clinical trials • 696 retinal degenerations: hereditary • 583 lipids