title: Four-year placebo-controlled trial of docosahexaenoic acid in X-linked retinitis pigmentosa (DHAX trial): a randomized clinical trial.
abstract: OBJECTIVE
  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).
  
  
  METHODS
  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).
  
  
  METHODS
  All participants received a multivitamin and were randomly assigned to oral DHA (30 mg/kg/d) or placebo.
  
  
  METHODS
  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
  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.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT00100230.
authors.affiliation: Retina Foundation of the Southwest, Dallas, Texas2Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas.
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Hoffman
authors.affiliation: Retina Foundation of the Southwest, Dallas, Texas2Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas.
authors.forename: Dianna K
authors.initials: DK
authors.lastname: Hughbanks-Wheaton
authors.affiliation: Pearson Statistical Consulting and Expert Witness Testimony, Richardson, Texas.
authors.forename: N Shirlene
authors.initials: NS
authors.lastname: Pearson
authors.affiliation: Texas Retina Associates, Dallas.
authors.forename: Gary E
authors.initials: GE
authors.lastname: Fish
authors.affiliation: Texas Retina Associates, Dallas.
authors.forename: Rand
authors.initials: R
authors.lastname: Spencer
authors.affiliation: Retina Foundation of the Southwest, Dallas, Texas.
authors.forename: Alison
authors.initials: A
authors.lastname: Takacs
authors.affiliation: Retina Foundation of the Southwest, Dallas, Texas.
authors.forename: Martin
authors.initials: M
authors.lastname: Klein
authors.affiliation: Retina Foundation of the Southwest, Dallas, Texas.
authors.forename: Kirsten G
authors.initials: KG
authors.lastname: Locke
authors.affiliation: Retina Foundation of the Southwest, Dallas, Texas2Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas.
authors.forename: David G
authors.initials: DG
authors.lastname: Birch
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D002214:Capsules; D002648:Child; D002849:Chromatography, Gas; D018450:Disease Progression; D004281:Docosahexaenoic Acids / Q000008:administration & dosage* / Q000097:blood / Q000627:therapeutic use; D004311:Double-Blind Method; D004596:Electroretinography; D004910:Erythrocyte Membrane / Q000378:metabolism; D040181:Genetic Diseases, X-Linked / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D008297:Male; D017949:Retinal Cone Photoreceptor Cells / Q000502:physiology; D017948:Retinal Rod Photoreceptor Cells / Q000502:physiology; D012174:Retinitis Pigmentosa / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D002214:Capsules; D004281:Docosahexaenoic Acids