title: Safety assessment of docosahexaenoic acid in X-linked retinitis pigmentosa: the 4-year DHAX trial.
abstract: OBJECTIVE
  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.).
authors.affiliation: Retina Foundation of the Southwest, Dallas, Texas, United States Department of Ophthalmology, UT Southwestern Medical Center, Dallas, Texas, United States.
authors.forename: Dianna K
authors.initials: DK
authors.lastname: Hughbanks-Wheaton
authors.affiliation: Retina Foundation of the Southwest, Dallas, Texas, United States Department of Ophthalmology, UT Southwestern Medical Center, Dallas, Texas, United States.
authors.forename: David G
authors.initials: DG
authors.lastname: Birch
authors.affiliation: Texas Retina Associates, Dallas, Texas, United States.
authors.forename: Gary E
authors.initials: GE
authors.lastname: Fish
authors.affiliation: Texas Retina Associates, Dallas, Texas, United States.
authors.forename: Rand
authors.initials: R
authors.lastname: Spencer
authors.affiliation: Pearson Statistical Consulting & Expert Testimony, Richardson, Texas, United States.
authors.forename: N Shirlene
authors.initials: NS
authors.lastname: Pearson
authors.affiliation: Retina Foundation of the Southwest, Dallas, Texas, United States.
authors.forename: Alison
authors.initials: A
authors.lastname: Takacs
authors.affiliation: Retina Foundation of the Southwest, Dallas, Texas, United States Department of Ophthalmology, UT Southwestern Medical Center, Dallas, Texas, United States.
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Hoffman
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D002648:Child; D002851:Chromatography, High Pressure Liquid; D019587:Dietary Supplements; D004281:Docosahexaenoic Acids / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004596:Electroretinography; D005500:Follow-Up Studies; D040181:Genetic Diseases, X-Linked / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects*; D012174:Retinitis Pigmentosa / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D004281:Docosahexaenoic Acids
keywords: adverse events; biosafety; fatty acids