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

ABSTRACT: 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.To determine whether high-dose docosahexaenoic acid (DHA), an ?-3 polyunsaturated fatty acid, slows progression of X-linked retinitis pigmentosa measured by cone electroretinography (ERG).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).All participants received a multivitamin and were randomly assigned to oral DHA (30 mg/kg/d) or placebo.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.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?

SUBMITTER: Hoffman DR

PROVIDER: S-EPMC4795002 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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

Hoffman Dennis R DR Hughbanks-Wheaton Dianna K DK Pearson N Shirlene NS Fish Gary E GE Spencer Rand R Takacs Alison A Klein Martin M Locke Kirsten G KG Birch David G DG

JAMA ophthalmology 20140701 7

<h4>Importance</h4>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.<h4>Objective</h4>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).<h4 ...[more]

PMID: 24805262

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Project description:ImportanceThere are no approved drug treatments for autosomal dominant retinitis pigmentosa, a relentlessly progressive cause of adult and childhood blindness.ObjectivesTo evaluate the potential efficacy and assess the safety of orally administered valproic acid (VPA) in the treatment of autosomal dominant retinitis pigmentosa.Design, setting, and participantsMulticenter, phase 2, prospective, interventional, placebo-controlled, double-masked randomized clinical trial. The study took place in 6 US academic retinal degeneration centers. Individuals with genetically characterized autosomal dominant retinitis pigmentosa were randomly assigned to receive treatment or placebo for 12 months. Analyses were intention-to-treat.InterventionsOral VPA 500 mg to 1000 mg daily for 12 months or placebo.Main outcomes and measuresThe primary outcome measure was determined prior to study initiation as the change in visual field area (assessed by the III4e isopter, semiautomated kinetic perimetry) between baseline and month 12.ResultsThe mean (SD) age of the 90 participants was 50.4 (11.6) years. Forty-four (48.9%) were women, 87 (96.7%) were white, and 79 (87.8%) were non-Hispanic. Seventy-nine participants (87.8%) completed the study (42 [95.5%] received placebo and 37 [80.4%] received VPA). Forty-two (46.7%) had a rhodopsin mutation. Most adverse events were mild, although 7 serious adverse events unrelated to VPA were reported. The difference between the VPA and placebo arms for mean change in the primary outcome was -150.43 degree2 (95% CI, -290.5 to -10.03; P = .035).Conclusions and relevanceThis negative value indicates that the VPA arm had worse outcomes than the placebo group. This study brings to light the key methodological considerations that should be applied to the rigorous evaluation of treatments for these conditions. This study does not provide support for the use of VPA in the treatment of autosomal dominant retinitis pigmentosa.Trial registrationClinicalTrials.gov Identifier: NCT01233609.

Project description:BackgroundPast clinical trials of docosahexaenoic Acid (DHA) supplements for the prevention of Alzheimer's disease (AD) dementia have used lower doses and have been largely negative. We hypothesized that larger doses of DHA are needed for adequate brain bioavailability and that APOE4 is associated with reduced delivery of DHA and eicosapentaenoic acid (EPA) to the brain before the onset of cognitive impairment.Methods33 individuals were provided with a vitamin B complex (1 mg vitamin B12, 100 mg of vitamin B6 and 800 mcg of folic acid per day) and randomized to 2,152 mg of DHA per day or placebo over 6 months. 26 individuals completed both lumbar punctures and MRIs, and 29 completed cognitive assessments at baseline and 6 months. The primary outcome was the change in CSF DHA. Secondary outcomes included changes in CSF EPA levels, MRI hippocampal volume and entorhinal thickness; exploratory outcomes were measures of cognition.FindingsA 28% increase in CSF DHA and 43% increase in CSF EPA were observed in the DHA treatment arm compared to placebo (mean difference for DHA (95% CI): 0.08 µg/mL (0.05, 0.10), p<0.0001; mean difference for EPA: 0.008 µg/mL (0.004, 0.011), p<0.0001). The increase in CSF EPA in non-APOE4 carriers after supplementation was three times greater than APOE4 carriers. The change in brain volumes and cognitive scores did not differ between groups.InterpretationDementia prevention trials using omega-3 supplementation doses equal or lower to 1 g per day may have reduced brain effects, particularly in APOE4 carriers.Trial registrationNCT02541929.FundingHNY was supported by R01AG055770, R01AG054434, R01AG067063 from the National Institute of Aging and NIRG-15-361854 from the Alzheimer's Association, and MGH by the L. K. Whittier Foundation. This work was also supported by P50AG05142 (HCC) from the National Institutes of Health. Funders had no role in study design, data collection, data analysis, interpretation, or writing of the report.

Project description:There is no generally accepted medical or surgical treatment to stop the progressive course of retinitis pigmentosa. Previous studies have suggested lutein as a potential treatment with positive effects on macular pigment density. The objective of this study was to examine the effect of lutein supplementation on preservation of visual function in patients with retinitis pigmentosa (RP) METHODS: In a double-masked randomized placebo-controlled phase I/II clinical trial with a cross-over design, 34 adult patients with RP were randomized to two groups. One group, consisted of 16 participants, received lutein supplementation (10 mg/d for 12 wks followed by 30 mg/d) for the first 24 weeks and then placebo for the following 24 weeks, while the other group included 18 participants for whom placebo (24 weeks) was administered prior to lutein. Visual acuity, contrast sensitivity, and central visual field were measured at different illumination levels at baseline and every week using a PC-based test at home.For visual acuity (VA) at normal illumination level, treatment with lutein reduced logMAR, i.e. improved VA, but this effect was not statistically significant. The changes in normal (100%), low (4%), and very low (0.1%) illumination log CS were not statistically significant (p-values: 0.34, 0.23, and 0.32, respectively). Lutein had a statistically significant effect on visual field (p-value: 0.038) and this effect increased in the model assuming a 6-week delay in effect of lutein. Comparing the development of vision measures against the natural loss expected to occur over the course of 48 weeks, most measures showed reduced decline, and these reductions were significant for normal illumination VA and CS.These results suggest that lutein supplementation improves visual field and also might improve visual acuity slightly, although these results should be interpreted cautiously. As a combined phase I and II clinical trial, this study demonstrated the efficacy and safety of lutein supplementation.

Dataset Information

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

Publications

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

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