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CompletedNCT01233609VPAUpdated Dec 2, 2017Results posted

Trial of Oral Valproic Acid for Retinitis Pigmentosa

A Phase 2 interventional study of Valproic Acid and Placebo in Retinitis Pigmentosa, sponsored by Foundation Fighting Blindness. Completed at 6 sites in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2017-12-02.

Sponsored by Foundation Fighting Blindness · Phase 2, Interventional, and Treatment

Phase
Phase 2
Study type
Interventional
Enrollment
90
Allocation
Randomized
Ages
18 Years and older
Sex
All
01

Study 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.

Read the detailed description

Retinitis Pigmentosa (RP) is an incurable and untreatable group of heterogeneous retinal degenerative diseases that cause severe visual loss. There is currently no therapeutic that substantially slows the progression of this disease, and certainly none that can restore vision in RP patients. The Valproic Acid (VPA) study is designed as a six-site, interventional, prospective, randomized, placebo controlled, double-blinded study of 90 participants to evaluate the efficacy of oral Valproic Acid to both slow the progression of visual function loss and/or to restore visual function in patients with an Autosomal Dominant RP genetic mutation and to collect safety and tolerability information. Patients that participate in the study will be randomized to either placebo or VPA in a 1:1 ratio.

02

Conditions studied

  • Retinitis Pigmentosa

Keywords

  • retinitis pigmentosa
  • valproic acid
  • visual field
03

Who can participate

Ages eligible
18 Years and older
Sexes eligible
All
Accepts healthy volunteers
No

Inclusion criteria

  1. Understand/sign the IRB-approved study informed consent document.
  2. Age greater than or equal to 18 years, no upper age limit
  3. 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.
  4. Diagnosis of Retinitis Pigmentosa (RP).
  5. 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).
  6. Genotyped as autosomal dominant form of RP.
  7. 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.
  8. Female subjects of childbearing potential must have a negative urine pregnancy test at study entry and throughout the duration of the study.
  9. Willingness to comply with the protocol.

Exclusion criteria

Exclusion Criteria:

  1. 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.
  2. Other retinal diseases: Glaucoma, retinal inflammatory disease (CME is allowable), cataract worse than +2 NS, or herpes simplex virus of the eye.
  3. Intact visual field of 5⁰ or less.
  4. Subject unable to provide reliable perimetry measurements in both eyes for both static and kinetic visual field, as determined by the Reading Center.
  5. Diabetes.
  6. History of cancer (other than non-melanoma skin cancer) diagnosed, or requiring treatment within the past 2 years.
  7. A hemoglobin concentration, a platelet count or an absolute neutrophil count below the lower limit of normal at study entry.
  8. Suspected liver dysfunction determined by having liver function values elevated above the upper limit of normal.
  9. History of pancreatitis by clinical features and/or laboratory abnormalities in the last 12 months.
  10. Renal dysfunction based on serum creatinine,(MDRD) equation.
  11. Urea cycle disorders.
  12. History of neurological conditions including epilepsy, history of brain injury, encephalitis, or any organic brain syndrome.
  13. History of schizophrenia, schizoaffective disorder, bipolar disorder, suicidality or organic mental disorders.
  14. Currently receiving valproic acid or other anti-convulsants.
  15. Sensitive to or have ever had an allergic reaction to valproic Acid.
  16. Sensitive to or have ever had an allergic reaction to peanuts as peanut oil is an inactive ingredient in valproic acid capsules and the placebo.
  17. Has taken one of the disallowed drugs at least 2 weeks prior to randomization.
  18. Pregnant women.
  19. Lactating mothers who are breast feeding their babies.
  20. RP patients involved in other clinical trials within the last 3 months.
  21. Require enrollment by consent of a legally authorized representative.
  22. Persons who are unable to read are not allowed to consent for themselves or others to participate in this study.
  23. The potential participant lives in the same household as a current participant in this protocol.
04

Study design

Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
Quadruple (Participant, Care provider, Investigator, Outcomes assessor)
Enrollment
90 participants (actual)

Study arms

  • Active comparator
    Valproic Acid

    Subjects who receive valproic acid

    Drug: Valproic Acid

  • Placebo comparator
    Placebo

    Subjects who receive placebo

    Drug: Placebo

Interventions

  • DrugValproic Acid

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

    Also known as: Valproate

  • DrugPlacebo

    Dosage per subject weight- same schedule as the active comparator

05

What researchers measure

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

    Time frame: baseline to week 52

Secondary outcomes

  1. Mean Change in Visual Field Area From Baseline to 52 Weeks--I4e 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 I4e 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

    Time frame: baseline to week 52

  2. Static Perimetry by Treatment Arm--Full Field Hill of Vision

    Mean change from baseline at week 52 for Full field Hill of Vision (Static perimetry)

    Time frame: baseline to week 52

  3. Static Perimetry Volume--30 Degree Hill of Vision

    Mean Change from baseline to week 52 for Static Perimetry Volume --30 Degree Hill of Vision. Full field static perimetry protocol was followed using the Octopus 900 (Haag-Streit) for a single session for each eye.

    Time frame: baseline to week 52

  4. Mean Change From Baseline in Best Corrected Visual Acuity

    Mean change in best corrected visual acuity as assessed by ETDRS (Early Treatment Diabetic Retinopathy Study) method from baseline to week 52

    Time frame: baseline to week 52

06

Results

Posted Dec 2, 2017

Participant flow

Participant flow — Overall Study
MilestoneValproic AcidPlacebo
Started4644
Completed3742
Not completed92
Withdrew: Death10
Withdrew: Lost to follow-up31
Withdrew: Adverse event21
Withdrew: Withdrawal by subject30

Outcome measures

PrimaryMean 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

Time frame:
baseline to week 52
Reported as:
Mean · Visual field area (degrees squared)
Mean Change in Visual Field Area From Baseline to 52 Weeks--III4e Isopter
Visual field area (degrees squared)Placebo--Right EyePlacebo--Left EyeValproic Acid--Right EyeValproic Acid--Left Eye
Mean Change in Visual Field Area From Baseline to 52 Weeks--III4e Isopter-122.9 ± 543.60-112.0 ± 584.63-293.7 ± 736.56-237.1 ± 691.76
Statistical analysis
  • Placebo--Right Eye vs Placebo--Left Eye vs Valproic Acid--Right Eye vs Valproic Acid--Left Eye · Mixed Models Analysis · p = 0.035 · Mean difference (net): -150.43Right eye and Left Eye within each of the 2 treatment groups (Placebo and Valproic Acid) were combined to estimate the difference
SecondaryMean Change in Visual Field Area From Baseline to 52 Weeks--I4e 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 I4e 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

Time frame:
baseline to week 52
Reported as:
Mean · Visual field area (degrees squared)
Mean Change in Visual Field Area From Baseline to 52 Weeks--I4e Isopter
Visual field area (degrees squared)Placebo--Right EyePlacebo--Left EyeValproic Acid--Right EyeValproic Acid--Left Eye
Mean Change in Visual Field Area From Baseline to 52 Weeks--I4e Isopter80.9 ± 406.2115.7 ± 696.895.3 ± 759.4619.5 ± 703.83
Statistical analysis
  • Placebo--Right Eye · Mixed Models Analysis · p = 0.581
SecondaryStatic Perimetry by Treatment Arm--Full Field Hill of Vision

Mean change from baseline at week 52 for Full field Hill of Vision (Static perimetry)

Time frame:
baseline to week 52
Reported as:
Mean · db-steridians
Static Perimetry by Treatment Arm--Full Field Hill of Vision
db-steridiansPlacebo--Right EyePlacebo--Left EyeValproic Acid--Right EyeValproic Acid--Left Eye
Static Perimetry by Treatment Arm--Full Field Hill of Vision-0.3 ± 2.55-1.4 ± 3.27-0.2 ± 5.11-0.6 ± 4.68
Statistical analysis
  • Placebo--Right Eye · Wilcoxon (Mann-Whitney) · p = 0.409
SecondaryStatic Perimetry Volume--30 Degree Hill of Vision

Mean Change from baseline to week 52 for Static Perimetry Volume --30 Degree Hill of Vision. Full field static perimetry protocol was followed using the Octopus 900 (Haag-Streit) for a single session for each eye.

Time frame:
baseline to week 52
Reported as:
Mean · db-steridans
Static Perimetry Volume--30 Degree Hill of Vision
db-steridansPlacebo--Right EyePlacebo--Left EyeValproic Acid--Right EyeValproic Acid--Left Eye
Static Perimetry Volume--30 Degree Hill of Vision-0.3 ± 0.61-0.3 ± 0.73-0.2 ± 1.07-0.2 ± 0.96
Statistical analysis
  • Placebo--Right Eye · Wilcoxon (Mann-Whitney) · p = 0.229
SecondaryMean Change From Baseline in Best Corrected Visual Acuity

Mean change in best corrected visual acuity as assessed by ETDRS (Early Treatment Diabetic Retinopathy Study) method from baseline to week 52

Time frame:
baseline to week 52
Reported as:
Mean · letters read correctly
Mean Change From Baseline in Best Corrected Visual Acuity
letters read correctlyValproic Acid -- Right EyeValproic Acid--Left EyePlacebo --Right EyePlacebo --Left Eye
Mean Change From Baseline in Best Corrected Visual Acuity-1.4 ± 5.210.0 ± 3.410.2 ± 4.411.3 ± 5.05

Adverse events

Collected over Treatment emergent adverse events are defined as those that occur between the first dose of study drug and the last dose of study drug plus 7 days.. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Placebo0/44 (0%)2/44 (4.5%)41/44 (93.2%)
Valproic Acid1/46 (2.2%)3/46 (6.5%)45/46 (97.8%)
Most frequent serious events
Most frequent serious events
EventPlaceboValproic Acid
Lens DislocationEye disorders1/440/46
Atrial FibrilationCardiac disorders1/440/46
OsteoarthritisMusculoskeletal and connective tissue disorders0/441/46
Road Traffic AccidentsInjury, poisoning and procedural complications0/441/46
Immunodeficiency common variableImmune system disorders0/441/46
Most frequent other events
Showing 10 of 20
Most frequent other events
EventPlaceboValproic Acid
NasopharyngitisInfections and infestations9/443/46
NauseaGastrointestinal disorders3/448/46
DyspepsiaGastrointestinal disorders0/448/46
HeadacheNervous system disorders4/448/46
InfluenzaInfections and infestations7/441/46
SinusitisInfections and infestations3/447/46
Ammonia IncreasedInvestigations1/447/46
FatigueGeneral disorders3/446/46
Vision BlurredEye disorders5/443/46
DiarrheaGastrointestinal disorders1/444/46

Baseline characteristics

Age, Continuous
Age, Continuous(years)PlaceboValproic AcidTotal
Mean51.6 ± 10.949.3 ± 12.350.4 ± 11.6
Sex: Female, Male
Sex: Female, Male(Participants)PlaceboValproic AcidTotal
Female202444
Male242246
Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)PlaceboValproic AcidTotal
Hispanic or Latino6511
Not Hispanic or Latino384179
Unknown or Not Reported000
Race (NIH/OMB)
Race (NIH/OMB)(Participants)PlaceboValproic AcidTotal
American Indian or Alaska Native000
Asian000
Native Hawaiian or Other Pacific Islander000
Black or African American011
White434487
More than one race011
Unknown or Not Reported101
Genetic Mutations
Genetic Mutations(Participants)PlaceboValproic AcidTotal
RHO221941
PRPF315914
RP14913
PRPF8314
PRPH2224
NR2E3022
RHO and PRPH2202
SNRNP200/ASCC3L1202
TOPORS022
IMPDH1101
KLHL7101
NR2E3 and TOPORS011
RHO and ROM1011
07

Study locations

6 sites
  • University of Miami, Bascom Palmer Eye Institute
    Miami, Florida 33136, United States
  • University of Michigan, Ann Arbor
    Ann Arbor, Michigan 48105, United States
  • Oregon Health & Science University
    Portland, Oregon 97239, United States
  • University of Tennessee, Hamilton Eye Institute
    Memphis, Tennessee 38163, United States
  • Retina Foundation of the Southwest
    Dallas, Texas 75231, United States
  • University of Utah School of Medicine, Moran Eye Center
    Salt Lake City, Utah 84132, United States
08

References and documents

Publications

  • 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. PubMed 12202526 ↗
  • 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. PubMed 8614514 ↗
  • 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. PubMed 3976802 ↗
  • 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. PubMed 17850978 ↗
  • 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. PubMed 15145530 ↗
  • 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. PubMed 16600518 ↗
  • Gaby AR. Nutritional therapies for ocular disorders: Part Three. Altern Med Rev. 2008 Sep;13(3):191-204. PubMed 18950246 ↗
  • 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. PubMed 11742974 ↗
  • Hartong DT, Berson EL, Dryja TP. Retinitis pigmentosa. Lancet. 2006 Nov 18;368(9549):1795-809. doi: 10.1016/S0140-6736(06)69740-7. PubMed 17113430 ↗
  • Henry TR. The history of valproate in clinical neuroscience. Psychopharmacol Bull. 2003;37 Suppl 2:5-16. PubMed 14624229 ↗
  • 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. PubMed 15059710 ↗
  • 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. PubMed 9804150 ↗
  • 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. PubMed 17371805 ↗
  • 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. PubMed 11448327 ↗
  • 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. PubMed 18378578 ↗
  • 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. PubMed 15996734 ↗
  • 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. PubMed 19094165 ↗
  • 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. PubMed 16164485 ↗
  • 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. PubMed 18706104 ↗
  • 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. Erratum In: JAMA Ophthalmol. 2018 Dec 1;136(12):1432. doi: 10.1001/jamaophthalmol.2018.4412. PubMed 29879277 ↗
09

Registry details

Key details

Study ID
NCT01233609
Lead sponsor
Foundation Fighting Blindness
Collaborators
United States Department of Defense
Responsible party
Sponsor
First posted
Nov 3, 2010
Start date
Nov 2010
Primary completion
Dec 2015
Completion
Dec 2015
Results posted
Dec 2, 2017
Last update
Dec 2, 2017

Study contacts

Patricia Zilliox, PhD
study director · Foundation Fighting Blindness

Oversight

Data monitoring committee
Yes
View the source record on ClinicalTrials.gov ↗

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