Four-Year Placebo-Controlled Trial of Docosahexaenoic Acid in X-Linked Retinitis Pigmentosa (DHAX Trial)

Abstract

IMPORTANCE X-linked retinitis pigmentosa is a severe inherited retinal degenerative disease with a frequency of 1 in 100 000 persons. Because no cure is available for this orphan disease and treatment options are limited, slowing of disease progression would be a meaningful outcome.OBJECTIVE To determine whether high-dose docosahexaenoic acid (DHA), an ω-3 polyunsaturated fatty acid, slows progression of X-linked retinitis pigmentosa measured by cone electroretinography (ERG). DESIGN, SETTING, AND PARTICIPANTSA 4-year, single-site, randomized, placebo-controlled, double-masked phase 2 clinical trial at a research center specializing in medical retina. Seventy-eight male patients diagnosed as having X-linked retinitis pigmentosa were randomized to DHA or placebo. Data were omitted for 2 patients with non-X-linked retinitis pigmentosa and 16 patients who were unable to follow protocol during the first year. The remaining participants were tested annually and composed a modified intent-to-treat cohort (DHA group, n = 33; placebo group, n = 27).INTERVENTIONS All participants received a multivitamin and were randomly assigned to oral DHA (30 mg/kg/d) or placebo. MAIN OUTCOMES AND MEASURESThe primary outcome was the rate of loss of cone ERG function. Secondary outcomes were rod and maximal ERG amplitudes and cone ERG implicit times. Capsule counts and red blood cell DHA levels were assessed to monitor adherence.RESULTS Average (6-month to 4-year) red blood cell DHA levels were 4-fold higher in the DHA group than in the placebo group (P < .001). There was no difference between the DHA and placebo groups in the rate of cone ERG functional loss (0.028 vs 0.022 log μV/y, respectively; P = .30). No group differences were evident for change in rod ERG (P = .27), maximal ERG (P = .65), or cone implicit time (no change over 4 years). The rate of cone loss (ie, event rate) was markedly reduced compared with rates in previous studies. No severe treatment-emergent adverse events were found.CONCLUSIONS AND RELEVANCE Long-term DHA supplementation was not effective in slowing the loss of cone or rod ERG function associated with X-linked retinitis pigmentosa. Participant dropout and lower-than-expected disease event rate limited power to detect statistical significance. A larger sample size, longer trial, and attainment of a target blood DHA level (13%) would be desirable. While DHA supplementation at 30 mg/kg/d does not present serious adverse effects, routine monitoring of gastrointestinal tolerance is prudent. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00100230

Effectiveness and safety of nutritional supplements in the treatment of hereditary retinal dystrophies: a systematic review

“…Finally, 8 studies informed in 13 articles were included in the present review. [9][10][11][12][13][14][15][16][17][18][19][20][21] Characteristics of studies…”

“…12 Except Lee et al which studied Best disease, 18 all included studies are on RP. [9][10][11][12][13][14][15][16][17][19][20][21] They assessed supplements based on vitamin A and vitamin E, 12 docosahexaenoic acid (DHA), 9,10,14,16,18 and the carotenoids lutein, 11,13 and β-carotene. 19 We did not identify eligible studies about other HRDs.…”

“…18 In the opposite end we find the RCT with factorial design conducted by Berson et al 12 with 601 randomised participants. Other included studies might be at risk of bias as they present a high rate of dropouts (420%), 9,11 or as in the study conducted by Hoffman et al in 2014 do not inform clearly about patients and researchers blinding procedure. 18 The study by Bahrami et al has an important limitation regarding the method used for data recording, as they were documented by participants on their own using their personal computers.…”

“…In addition, both trials of Hoffman et al did not find any significant mean difference in visual acuity between DHA and placebo groups during a 4 years follow-up period. 9,10,16 Regarding studies on lutein supplementation, Berson et al did not find additional effect of this carotenoid in the annual decline of ETDRS letters in a population supplemented with vitamin A. 13 Bahrami et al found a statistically significant improvement (P = 0.018) of visual acuity related to lutein when measured in very low illumination conditions (0.1%), but not in normal (100%) or low (4%) illumination conditions.…”

“…16 In a subsequent trial by the same group, DHA dose was adapted to each participant's weight and a multivitamins supplementation providing 100% of recommended daily amounts of vitamins A, C, D, E, B6, and B12 was added to both groups. 9 Bahrami et al 11 and Berson et al 13 studied supplementation with lutein in patients with different follow-up periods of 48 weeks and 4 years, respectively. Participants in Berson et al received also vitamin A regardless of the group they were assigned to.…”