X-Linked Retinitis Pigmentosa (XLRP) is one of the most severe forms of hereditary retinal degeneration and has a prevalence in the U.S. population of approximately 1 in 100,000 making it truly an orphan disease. The purpose of this proposal is to enable continuation of a placebo-controlled, randomized Phase 2 clinical trial designed to definitively determine if nutritional supplementation with the long-chain omega-3 polyunsaturated fatty acid, docosahexaenoic acid (DHA), is of benefit in slowing the progressive loss of visual function associated with early stage XLRP (ages 7 to 32 yr). XLRP has an onset in early childhood and is characterized by nightblindness, decreased acuity, and tunnel vision/legal blindness due to a very slow degeneration of rod and cone photoreceptors. There is no cure for XLRP and treatment of symptoms is limited. Although the disease has distinct genetic origins, nutrition may ultimately influence the rate of progression. The high level (>30%) of DHA in photoreceptors is suggestive of a role in maintaining the integrity of retinal membranes surrounding the enzymes responsible for phototransduction. Based on results of the applicant's Phase 1 clinical trial, they have initiated a 4-year placebo-controlled Phase 2 clinical trial with a goal of testing the hypothesis that 'high dose DHA supplementation is beneficial in retarding progressive degeneration of electroretinogram (ERG) function in patients with XLRP'. Sample size calculations confirm that 33 patients in each arm of the trial should attain statistical significance with 4 years of supplementation. A high dose of DHA based on bodyweight should sufficiently elevate blood DHA to a level estimated to slow the loss of cone photoreceptor function. Capsule intake is 30 mg DHA/kg/day so as to target an RBC-DHA level of 130 g/ml RBC (~12-to-13% of total fatty acids). A 'per protocol' data analysis will reduce outcome variables due to patient non-compliance. Annual vision tests are: full-field cone ERG responses to 31-Hz flicker as the primary functional outcome, rod ERGs, a-wave rod and cone ERG photoreceptor assessment, visual acuity, visual fields, fundus photography, dark-adapted thresholds, and comprehensive eye exams. Blood DHA analysis (every 6 months) and biosafety measures (annually) assess red blood cell (RBC) fatty acids, vitamins A and E, plasma antioxidant capacity, lipoprotein lipids, oxidized LDL, lipoxygenation aldehydes, platelet aggregation, and comprehensive metabolic blood chemistry. Limitations such as the orphan nature of the disease and wide media advocacy of potential benefits derived from omega-3 fatty acids have slowed the recruitment process; however, full enrollment of trial participants is anticipated by the summer of 2007. Based on Phase 1 clinical trial results, a high dose of DHA shows promise in retarding progression of this blinding eye disease.

National Institute of Health (NIH)
Food and Drug Administration (FDA)
Research Project (R01)
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Special Emphasis Panel (ZFD1-OPD-L (01))
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Needleman, Katherine
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Retina Foundation of the Southwest
United States
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Hoffman, Dennis R; Hughbanks-Wheaton, Dianna K; Spencer, Rand et al. (2015) Docosahexaenoic Acid Slows Visual Field Progression in X-Linked Retinitis Pigmentosa: Ancillary Outcomes of the DHAX Trial. Invest Ophthalmol Vis Sci 56:6646-53
Birch, David G; Locke, Kirsten G; Felius, Joost et al. (2015) Rates of decline in regions of the visual field defined by frequency-domain optical coherence tomography in patients with RPGR-mediated X-linked retinitis pigmentosa. Ophthalmology 122:833-9
Hughbanks-Wheaton, Dianna K; Birch, David G; Fish, Gary E et al. (2014) Safety assessment of docosahexaenoic acid in X-linked retinitis pigmentosa: the 4-year DHAX trial. Invest Ophthalmol Vis Sci 55:4958-66
Hoffman, Dennis R; Hughbanks-Wheaton, Dianna K; Pearson, N Shirlene et al. (2014) Four-year placebo-controlled trial of docosahexaenoic acid in X-linked retinitis pigmentosa (DHAX trial): a randomized clinical trial. JAMA Ophthalmol 132:866-73
Birch, David G; Locke, Kirsten G; Wen, Yuquan et al. (2013) Spectral-domain optical coherence tomography measures of outer segment layer progression in patients with X-linked retinitis pigmentosa. JAMA Ophthalmol 131:1143-50