Trial of Oral Valproic Acid for Retinitis Pigmentosa

NCT01233609 | Completed Phase 2 Results DMC

• 1 other identifier: H-13371
• Study Type: interventional
• Target: 90
• Locations: 1 country
• Sites: 6

Brief Summary

The objectives of this study are to evaluate the efficacy of Valproic Acid (VPA) to both slow the progression of visual function loss and/or to restore visual function in patients with Autosomal Dominant Retinitis Pigmentosa (RP) and to collect safety and tolerability information.

Conditions

Retinitis Pigmentosa

Keywords

retinitis pigmentosa; valproic acid; visual field

Outcome Measures

Primary Outcomes (1)

• Mean Change in Visual Field Area From Baseline to 52 Weeks--III4e Isopter

  Mean change in visual field area from baseline to 52 weeks. Visual field area is measured with semi-automated kinetic perimetry (SKP) using the Octopus 900 (Haag-Streit) with the III4e target size for each eye and done at least twice to ensure reliable sessions; the visual field area measurements are averaged over the two sessions. Analysis performed with linear mixed model

  baseline to week 52

Secondary Outcomes (4)

• Mean Change in Visual Field Area From Baseline to 52 Weeks--I4e Isopter

  baseline to week 52

• Static Perimetry by Treatment Arm--Full Field Hill of Vision

  baseline to week 52

• Static Perimetry Volume--30 Degree Hill of Vision

  baseline to week 52

• Mean Change From Baseline in Best Corrected Visual Acuity

  baseline to week 52

Study Arms (2)

Valproic Acid

ACTIVE COMPARATOR

Subjects who receive valproic acid

Drug: Valproic Acid

Placebo

PLACEBO COMPARATOR

Subjects who receive placebo

Drug: Placebo

Interventions

Valproic Acid DRUG

One to four 250mg softgels by mouth daily (dose determined by body weight)

Also known as: Valproate

Valproic Acid

Placebo DRUG

Dosage per subject weight- same schedule as the active comparator

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Understand/sign the IRB-approved study informed consent document.
• Age greater than or equal to 18 years, no upper age limit
• Males and non-child bearing females must weigh ≥40 Kg and ≤158.9 Kg; Females of child bearing potential must weigh ≥40 Kg and ≤74.9 Kg.
• Diagnosis of Retinitis Pigmentosa (RP).
• Visual acuity of greater than or equal to 35 letters in at least one eye as measured by the EVA-ETDRS (equivalent to 20/200 on a Snellen chart).
• Genotyped as autosomal dominant form of RP.
• Female subjects of childbearing potential and male subjects able to father children must have (or have a partner who has) had a hysterectomy or vasectomy, be completely abstinent from intercourse or must commit to practice at least two acceptable methods of contraception to minimize the chance of pregnancy during the study and for the 13 week period after stopping the study drug.
• Female subjects of childbearing potential must have a negative urine pregnancy test at study entry and throughout the duration of the study.
• Willingness to comply with the protocol.

You may not qualify if:

• Medical problems that make consistent follow-up over the treatment period unlikely (e.g. stroke, severe MI, end stage malignancy), or in general a poor medical risk because of other systemic diseases or active uncontrolled infections.
• Other retinal diseases: Glaucoma, retinal inflammatory disease (CME is allowable), cataract worse than +2 NS, or herpes simplex virus of the eye.
• Intact visual field of 5⁰ or less.
• Subject unable to provide reliable perimetry measurements in both eyes for both static and kinetic visual field, as determined by the Reading Center.
• Diabetes.
• History of cancer (other than non-melanoma skin cancer) diagnosed, or requiring treatment within the past 2 years.
• A hemoglobin concentration, a platelet count or an absolute neutrophil count below the lower limit of normal at study entry.
• Suspected liver dysfunction determined by having liver function values elevated above the upper limit of normal.
• History of pancreatitis by clinical features and/or laboratory abnormalities in the last 12 months.
• Renal dysfunction based on serum creatinine,(MDRD) equation.
• Urea cycle disorders.
• History of neurological conditions including epilepsy, history of brain injury, encephalitis, or any organic brain syndrome.
• History of schizophrenia, schizoaffective disorder, bipolar disorder, suicidality or organic mental disorders.
• Currently receiving valproic acid or other anti-convulsants.
• Sensitive to or have ever had an allergic reaction to valproic Acid.

Sponsors & Collaborators

• Foundation Fighting Blindness: lead
• United States Department of Defense: collaborator

Study Sites (6)

University of Miami, Bascom Palmer Eye Institute

Miami, Florida, 33136, United States

Location

University of Michigan, Ann Arbor

Ann Arbor, Michigan, 48105, United States

Location

Oregon Health & Science University

Portland, Oregon, 97239, United States

Location

University of Tennessee, Hamilton Eye Institute

Memphis, Tennessee, 38163, United States

Location

Retina Foundation of the Southwest

Dallas, Texas, 75231, United States

Location

University of Utah School of Medicine, Moran Eye Center

Salt Lake City, Utah, 84132, United States

Location

Related Publications (20)

• Berson EL, Rosner B, Weigel-DiFranco C, Dryja TP, Sandberg MA. Disease progression in patients with dominant retinitis pigmentosa and rhodopsin mutations. Invest Ophthalmol Vis Sci. 2002 Sep;43(9):3027-36.

  PMID: 12202526 BACKGROUND

• Bryant AE 3rd, Dreifuss FE. Valproic acid hepatic fatalities. III. U.S. experience since 1986. Neurology. 1996 Feb;46(2):465-9. doi: 10.1212/wnl.46.2.465.

  PMID: 8614514 BACKGROUND

• Berson EL, Sandberg MA, Rosner B, Birch DG, Hanson AH. Natural course of retinitis pigmentosa over a three-year interval. Am J Ophthalmol. 1985 Mar 15;99(3):240-51. doi: 10.1016/0002-9394(85)90351-4.

  PMID: 3976802 BACKGROUND

• Chen PS, Wang CC, Bortner CD, Peng GS, Wu X, Pang H, Lu RB, Gean PW, Chuang DM, Hong JS. Valproic acid and other histone deacetylase inhibitors induce microglial apoptosis and attenuate lipopolysaccharide-induced dopaminergic neurotoxicity. Neuroscience. 2007 Oct 12;149(1):203-12. doi: 10.1016/j.neuroscience.2007.06.053. Epub 2007 Jul 28.

  PMID: 17850978 BACKGROUND

• Delyfer MN, Leveillard T, Mohand-Said S, Hicks D, Picaud S, Sahel JA. Inherited retinal degenerations: therapeutic prospects. Biol Cell. 2004 May;96(4):261-9. doi: 10.1016/j.biolcel.2004.01.006.

  PMID: 15145530 BACKGROUND

• Dragunow M, Greenwood JM, Cameron RE, Narayan PJ, O'Carroll SJ, Pearson AG, Gibbons HM. Valproic acid induces caspase 3-mediated apoptosis in microglial cells. Neuroscience. 2006 Jul 21;140(4):1149-56. doi: 10.1016/j.neuroscience.2006.02.065.

  PMID: 16600518 BACKGROUND

• Gaby AR. Nutritional therapies for ocular disorders: Part Three. Altern Med Rev. 2008 Sep;13(3):191-204.

  PMID: 18950246 BACKGROUND

• Gottlicher M, Minucci S, Zhu P, Kramer OH, Schimpf A, Giavara S, Sleeman JP, Lo Coco F, Nervi C, Pelicci PG, Heinzel T. Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J. 2001 Dec 17;20(24):6969-78. doi: 10.1093/emboj/20.24.6969.

  PMID: 11742974 BACKGROUND

• Hartong DT, Berson EL, Dryja TP. Retinitis pigmentosa. Lancet. 2006 Nov 18;368(9549):1795-809. doi: 10.1016/S0140-6736(06)69740-7.

  PMID: 17113430 BACKGROUND

• Henry TR. The history of valproate in clinical neuroscience. Psychopharmacol Bull. 2003;37 Suppl 2:5-16.

  PMID: 14624229 BACKGROUND

• Hoffman DR, Locke KG, Wheaton DH, Fish GE, Spencer R, Birch DG. A randomized, placebo-controlled clinical trial of docosahexaenoic acid supplementation for X-linked retinitis pigmentosa. Am J Ophthalmol. 2004 Apr;137(4):704-18. doi: 10.1016/j.ajo.2003.10.045.

  PMID: 15059710 BACKGROUND

• Jacobson SG, Cideciyan AV, Huang Y, Hanna DB, Freund CL, Affatigato LM, Carr RE, Zack DJ, Stone EM, McInnes RR. Retinal degenerations with truncation mutations in the cone-rod homeobox (CRX) gene. Invest Ophthalmol Vis Sci. 1998 Nov;39(12):2417-26.

  PMID: 9804150 BACKGROUND

• Kim HJ, Rowe M, Ren M, Hong JS, Chen PS, Chuang DM. Histone deacetylase inhibitors exhibit anti-inflammatory and neuroprotective effects in a rat permanent ischemic model of stroke: multiple mechanisms of action. J Pharmacol Exp Ther. 2007 Jun;321(3):892-901. doi: 10.1124/jpet.107.120188. Epub 2007 Mar 19.

  PMID: 17371805 BACKGROUND

• Mangione CM, Lee PP, Gutierrez PR, Spritzer K, Berry S, Hays RD; National Eye Institute Visual Function Questionnaire Field Test Investigators. Development of the 25-item National Eye Institute Visual Function Questionnaire. Arch Ophthalmol. 2001 Jul;119(7):1050-8. doi: 10.1001/archopht.119.7.1050.

  PMID: 11448327 BACKGROUND

• Noorwez SM, Ostrov DA, McDowell JH, Krebs MP, Kaushal S. A high-throughput screening method for small-molecule pharmacologic chaperones of misfolded rhodopsin. Invest Ophthalmol Vis Sci. 2008 Jul;49(7):3224-30. doi: 10.1167/iovs.07-1539. Epub 2008 Mar 31.

  PMID: 18378578 BACKGROUND

• Nowomiejska K, Vonthein R, Paetzold J, Zagorski Z, Kardon R, Schiefer U. Comparison between semiautomated kinetic perimetry and conventional Goldmann manual kinetic perimetry in advanced visual field loss. Ophthalmology. 2005 Aug;112(8):1343-54. doi: 10.1016/j.ophtha.2004.12.047.

  PMID: 15996734 BACKGROUND

• Nowomiejska K, Vonthein R, Paetzold J, Zagorski Z, Kardon R, Schiefer U. Reaction time during semi-automated kinetic perimetry (SKP) in patients with advanced visual field loss. Acta Ophthalmol. 2010 Feb;88(1):65-9. doi: 10.1111/j.1755-3768.2008.01407.x. Epub 2009 Dec 16.

  PMID: 19094165 BACKGROUND

• Peterson GM, Naunton M. Valproate: a simple chemical with so much to offer. J Clin Pharm Ther. 2005 Oct;30(5):417-21. doi: 10.1111/j.1365-2710.2005.00671.x. No abstract available.

  PMID: 16164485 BACKGROUND

• Wong R, Khan J, Adewoyin T, Sivaprasad S, Arden GB, Chong V. The ChromaTest, a digital color contrast sensitivity analyzer, for diabetic maculopathy: a pilot study. BMC Ophthalmol. 2008 Aug 17;8:15. doi: 10.1186/1471-2415-8-15.

  PMID: 18706104 BACKGROUND

• Birch DG, Bernstein PS, Iannacone A, Pennesi ME, Lam BL, Heckenlively J, Csaky K, Hartnett ME, Winthrop KL, Jayasundera T, Hughbanks-Wheaton DK, Warner J, Yang P, Fish GE, Teske MP, Sklaver NL, Erker L, Chegarnov E, Smith T, Wahle A, VanVeldhuisen PC, McCormack J, Lindblad R, Bramer S, Rose S, Zilliox P, Francis PJ, Weleber RG. 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. JAMA Ophthalmol. 2018 Aug 1;136(8):849-856. doi: 10.1001/jamaophthalmol.2018.1171.

  PMID: 29879277 DERIVED

Related Links

• Click here for more information about this study: Clinical Trial page of the Foundation Fighting Blindness Website.

MeSH Terms

Conditions

Retinitis Pigmentosa

Interventions

Valproic Acid

Condition Hierarchy (Ancestors)

Eye Diseases, Hereditary; Eye Diseases; Retinal Dystrophies; Retinal Degeneration; Retinal Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Pentanoic Acids; Valerates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Fatty Acids, Volatile; Fatty Acids; Lipids

Results Point of Contact

• Title: Chief Drug Development Officer
• Organization: Foundation Fighting Blindness Clinical Research Institute

pzilliox@blindness.org

410 423 0581

Study Officials

• Patricia Zilliox, PhD

  Foundation Fighting Blindness

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 1, 2010
• First Posted: November 3, 2010
• Study Start: November 1, 2010
• Primary Completion: December 1, 2015
• Study Completion: December 1, 2015
• Last Updated: December 2, 2017
• Results First Posted: December 2, 2017

Record last verified: 2017-10

Locations

US (6)