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Clinical Trial
. 2018 Aug 1;136(8):849-856.
doi: 10.1001/jamaophthalmol.2018.1171.

Effect of Oral Valproic Acid vs Placebo for Vision Loss in Patients With Autosomal Dominant Retinitis Pigmentosa: A Randomized Phase 2 Multicenter Placebo-Controlled Clinical Trial

David G Birch  1 , Paul S Bernstein  2 , Alessandro Iannacone  3   4 , Mark E Pennesi  5 , Byron L Lam  6 , John Heckenlively  7 , Karl Csaky  1 , Mary Elizabeth Hartnett  2 , Kevin L Winthrop  4 , Thiran Jayasundera  7 , Dianna K Hughbanks-Wheaton  1 , Judith Warner  2 , Paul Yang  5 , Gary Edd Fish  1 , Michael P Teske  2 , Neal L Sklaver  1 , Laura Erker  8 , Elvira Chegarnov  8 , Travis Smith  8 , Aimee Wahle  9 , Paul C VanVeldhuisen  9 , Jennifer McCormack  9 , Robert Lindblad  9 , Steven Bramer  10 , Stephen Rose  10 , Patricia Zilliox  10 , Peter J Francis  10 , Richard G Weleber  5
Affiliations
Clinical Trial

Effect of Oral Valproic Acid vs Placebo for Vision Loss in Patients With Autosomal Dominant Retinitis Pigmentosa: A Randomized Phase 2 Multicenter Placebo-Controlled Clinical Trial

David G Birch et al. JAMA Ophthalmol. .

Erratum in

Abstract

Importance: There are no approved drug treatments for autosomal dominant retinitis pigmentosa, a relentlessly progressive cause of adult and childhood blindness.

Objectives: To 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 participants: Multicenter, 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.

Interventions: Oral VPA 500 mg to 1000 mg daily for 12 months or placebo.

Main outcomes and measures: The 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.

Results: The 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 relevance: This 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 registration: ClinicalTrials.gov Identifier: NCT01233609.

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Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Birch reports grants and personal fees from Foundation Fighting Blindness during the conduct of the study; grants from Nightstar, Applied Genetic Technologies Corporation, Ionis Pharmaceuticals, Regeneron, 4D Molecular Therapeutics, and Second Sight Medical Products outside the submitted work; and personal fees from Nightstar, Applied Genetic Technologies Corporation, Ionis Pharmaceuticals, 4D Molecular Therapeutics, Nacuity Pharmaceuticals, Editas Medicine, and Genentech outside the submitted work. Dr Bernstein reports grants from Foundation Fighting Blindness during the conduct of the study; personal fees from Spark Therapeutics, Acucela, Makindus, and ScienceBased Health outside the submitted work; and grants from the National Institutes of Health outside the submitted work. Dr Iannaccone reports grants from Foundation Fighting Blindness Clinical Research Institute during the conduct of the study; grants from BCM Families Foundation and Foundation Fighting Blindness Clinical Research Institute outside the submitted work; personal fees from Ionis Pharmaceuticals, Advance Medical, EyeCRO, ClearView Healthcare Partners, Gerson Lehrman Group, and Huron Consulting Group outside the submitted work; and other support from Applied Genetic Technologies Corporation, Shire Human Genetic Therapies, and Allergan/RetroSense outside the submitted work. Dr Pennesi reports other support from Foundation Fighting Blindness during the conduct of the study; personal fees from Nacuity Pharmaceuticals outside the submitted work; and other support from Applied Genetic Technologies Corporation, Sanofi, Ionis Pharmaceuticals, Spark Therapeutics, Editas Medicine, Biogen, RegenexBio, Astellas Pharmaceuticals, GenSight Biologics, Ophthotech, and Nightstar Therapeutics outside the submitted work. Dr Lam reports grants from the National Eye Institute and Foundation Fighting Blindness during the conduct of the study; grants from Applied Genetic Technologies Corporation, Nightstar, Astellas Pharmaceuticals, Quark Pharmaceuticals, Second Sight, Sanofi, and Editas Medicine outside the submitted work; and personal fees from Spark Therapeutics, Shire, and Ionis Pharmaceuticals outside the submitted work. Dr Csaky reports personal fees from Applied Genetic Technologies Corporation, Ophthotech, Spark Therapeutics, Acucela, Allergan, Roche Genentech, Regeneron, and Heidelberg Engineering outside the submitted work. Dr Hartnett reports grants from the National Eye Institute and Foundation Fighting Blindness during the conduct of the study; personal fees from SanBio outside the submitted work; and has a patent U-5618 pending. Dr Yang reports grants from Foundation Fighting Blindness and the National Institutes of Health; personal fees from Astellas Pharmaceuticals; and research grants from Sanofi, Applied Genetic Technologies Corporation, Nightstar, and Ophthotech. Dr Fish reports other support from Retina Foundation of the Southwest during the conduct of the study. Dr Erker reports grants from the National Institutes of Health, US Food and Drug Administration, US Department of Defense, and Foundation Fighting Blindness Clinical Research Institute during the conduct of the study and other support from Sanofi, Applied Genetic Technologies Corporation, Meira Gtx, Nightstar Therapeutics, and Novelion Therapeutics outside the submitted work. Ms Chegarnov reports grants from the National Institutes of Health, US Food and Drug Administration, US Department of Defense, and Foundation Fighting Blindness Clinical Research Institute during the conduct of the study and other support from Sanofi, Applied Genetic Technologies Corporation, Meira Gtx, Nightstar Therapeutics, and Novelion Therapeutics outside the submitted work. Dr Smith reports grants from the National Institutes of Health, US Food and Drug Administration, US Department of Defense, and Foundation Fighting Blindness Clinical Research Institute during the conduct of the study; a grant from Medical Research Foundation of Oregon outside the submitted work; and other support from Sanofi outside the submitted work. Ms Wahle reports other support from Foundation Fighting Blindness during the conduct of the study. Dr VanVeldhuisen reports other support from Foundation Fighting Blindness during the conduct of the study and other support from Regeneron and Allergan outside the submitted work. Ms McCormack reports other support from Foundation Fighting Blindness during the conduct of the study. Dr Lindblad reports other support from Foundation Fighting Blindness during the conduct of the study. Dr Rose reports a grant from the US Department of Defense/Telemedicine and Advanced Technology Research Center to the Foundation Fighting Blindness to establish a clinical trial network (National Eye Evaluation Research) for testing potential treatments for inherited orphan retinal degenerations during the conduct of this study; other support was reported from Allergan, Editas Medicine, Nacuity Pharmaceuticals, Shire, and Second Sight outside the submitted work (these companies listed outside the submitted work provided general support to the Foundation Fighting Blindness through donations to VisionWalks and Dining in the Dark and donations to the Foundation Fighting Blindness directly). Dr Zilliox reports personal fees from Foundation Fighting Blindness during the conduct of the study and personal fees from Eyevensys and Nanoscope Technologies outside the submitted work. Dr Francis reports personal fees from Foundation Fighting Blindness during the conduct of the study and personal fees from Foundation Fighting Blindness, 4D Molecular Therapeutics, ReNeuron, Allergan, RetroSense, Sanofi, Gyroscope, Clearside Biomedical, Your Encore, Orion Eye, and Oregon Eye Physicians and Surgeons outside the submitted work. Dr Weleber reports grants, personal fees, and other support from Foundation Fighting Blindness and the US Department of Defense during the conduct of the study; grants from the National Institutes of Health and Applied Genetic Technologies Corporation, and Sanofi outside the submitted work; other support from Applied Genetic Technologies Corporation, the National Institutes of Health, Sanofi, Meira Gtx, and Nightstar Therapeutics; and has a patent (US patent 8 657 446), method, and apparatus for visual field monitoring issued. The other authors reported nothing to disclose.

Figures

Figure 1.
Figure 1.. CONSORT Flow Diagram for the Valproic Acid (VPA) Study
ADRP indicates autosomal dominant retinitis pigmentosa. aParticipants may not have passed more than 1 eligibility criterion. bAll valid data collected at baseline, week 26, and week 52 were included in the analysis regardless of whether the participant was missing data at 1 or more visits.
Figure 2.
Figure 2.. Change in Kinetic Visual Field From Baseline by Treatment Arm
VPA indicates valproic acid.
Figure 3.
Figure 3.. Change in Static Visual Field From Baseline by Treatment Arm
VPA indicates valproic acid.
See this image and copyright information in PMC

Comment in

References

    1. Jones BW, Pfeiffer RL, Ferrell WD, Watt CB, Marmor M, Marc RE. Retinal remodeling in human retinitis pigmentosa. Exp Eye Res. 2016;150:149-165. - PMC - PubMed
    1. Daiger SP, Bowne SJ, Sullivan LS. Genes and mutations causing autosomal dominant retinitis pigmentosa. Cold Spring Harb Perspect Med. 2014;5(10):a017129. - PMC - PubMed
    1. Chizzolini M, Galan A, Milan E, Sebastiani A, Costagliola C, Parmeggiani F. Good epidemiologic practice in retinitis pigmentosa: from phenotyping to biobanking. Curr Genomics. 2011;12(4):260-266. - PMC - PubMed
    1. Birch DG, Locke KG, Wen Y, Locke KI, Hoffman DR, Hood DC. Spectral-domain optical coherence tomography measures of outer segment layer progression in patients with X-linked retinitis pigmentosa. JAMA Ophthalmol. 2013;131(9):1143-1150. - PMC - PubMed
    1. Sandberg MA, Rosner B, Weigel-DiFranco C, Dryja TP, Berson EL. Disease course of patients with X-linked retinitis pigmentosa due to RPGR gene mutations. Invest Ophthalmol Vis Sci. 2007;48(3):1298-1304. - PubMed

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