Four-year placebo-controlled trial of docosahexaenoic acid in X-linked retinitis pigmentosa (DHAX trial): a randomized clinical 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 participants: A 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 measures: The 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.

Conflict of interest statement

Conflict of Interest: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.

Figures

Figure 1

Flowchart and Randomization in Docosahexaenoic Acid in X-Linked Retinitis Pigmentosa (DHAX) Trial The modified intent-to-treat (mITT) cohort (n = 60) included data for trial participants completing at least the first-year annual visit. The per protocol cohort (n = 51) included participants following protocol and completing the 4-year trial. DHA indicates docosahexaenoic acid; XLRP, X-linked retinitis pigmentosa. aOne due to apathy (12 months), 1 due to seeing white circles (6 months), 2 due to lost contact (12 and 10 months), 2 due to parents being too busy to travel to Dallas (12 and 8 months), 1 due to depression from continued vision loss (4 months), and 1 due to floaters and increased sensitivity to light (2 months). bOne had a mutation in the choroideremia gene (CHD; REP-1) and the second had an autosomal recessive retinitis pigmentosa mutation (homozygous CNGB1 mutation). These mutations were identified after trial completion. cOne moved to Iraq, 2 due to apathy (15 and 19.5 months), 1 ran away from home (38 months), and 1 due to being “terribly sick and sore when taking capsules” (35 months). dThree lost to follow-up (0, 4, and 15 months), 1 due to apathy and difficulty in traveling to Dallas (12 months), 1 changed mind about participating and consumed no capsules (0 months), 1 due to apathy (9 months), 1 due to inconsistent bowel movements (8 months), and 1 due to dehydration and fatigue (5 months). eOne lost to follow-up (21 months), 1 due to apathy (21 months), and 1 due to capsules possibly exacerbating inflammatory bowel disease (24 months). fAdmitted in a posttrial interview to not taking capsules for most of the 4-year trial and was confirmed nonadherent by red blood cell DHA levels.

Figure 2

Red Blood Cell (RBC) Docosahexaenoic Acid (DHA) Levels as a Function of Treatment Intervention Mean RBC DHA level as a percentage of total fatty acids vs time receiving placebo or DHA supplementation for participants in the modified intent-to-treat cohort. Error bars indicate standard error; dashed line, mean RBC DHA level (mean [SE], 2.91% [0.15%]) from 29 age-matched individuals with normal visual function; and shaded area, 95% confidence interval.

Figure 3

Fast Fourier Transform (FFT) Cone Electroretinography (ERG) 31-Hz Amplitudes as a Function of Time for Participants in the Modified Intent-to-Treat Cohort Mean log µV values for each trial year in participants receiving placebo or docosahexaenoic acid (DHA) supplementation. For placebo vs DHA groups, P = .58 at year 1; P = .34 at year 2; P = .21 at year 3; and P = .34 at year 4. The lower limit of normal FFT cone amplitudes is 1.43 log µV (27.0 µV). Error bars indicate standard error. aThere was a 14% event rate for the placebo group in the phase 1 X-linked retinitis pigmentosa clinical trial. bThere was an 18% event rate for patients with X-linked retinitis pigmentosa in the natural history study.