Trial of Oral Valproic Acid for Retinitis Pigmentosa

Retinitis Pigmentosa Clinical Trial

— VPA  

Official title:

A Phase II Multiple Site, Randomized, Placebo-Controlled Trial of Oral Valproic Acid for Autosomal Dominant Retinitis Pigmentosa

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01233609
• Other study ID #: H-13371
• Status: Completed
• Phase: Phase 2
• First received: November 1, 2010
• Last updated: October 24, 2017
• Start date: November 2010
• Est. completion date: December 2015

Study information

• Verified date: October 2017
• Source: Foundation Fighting Blindness Clinical Research Institute
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 90
• Est. completion date: December 2015
• Est. primary completion date: December 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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:

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 5° 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.

Related Conditions & MeSH terms

• Retinitis
• Retinitis Pigmentosa

Intervention

Drug:
• Valproic Acid
One to four 250mg softgels by mouth daily (dose determined by body weight)
• Placebo
Dosage per subject weight- same schedule as the active comparator

Locations

Country	Name	City	State
United States	University of Michigan, Ann Arbor	Ann Arbor	Michigan
United States	Retina Foundation of the Southwest	Dallas	Texas
United States	University of Tennessee, Hamilton Eye Institute	Memphis	Tennessee
United States	University of Miami, Bascom Palmer Eye Institute	Miami	Florida
United States	Oregon Health & Science University	Portland	Oregon
United States	University of Utah School of Medicine, Moran Eye Center	Salt Lake City	Utah

Sponsors (2)

Lead Sponsor	Collaborator
Foundation Fighting Blindness Clinical Research Institute	United States Department of Defense

Country where clinical trial is conducted

United States, 

References & Publications (19)

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. — View Citation

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. — View Citation

Bryant AE 3rd, Dreifuss FE. Valproic acid hepatic fatalities. III. U.S. experience since 1986. Neurology. 1996 Feb;46(2):465-9. — View Citation

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. Epub 2007 Jul 28. — View Citation

Delyfer MN, Léveillard T, Mohand-Saïd S, Hicks D, Picaud S, Sahel JA. Inherited retinal degenerations: therapeutic prospects. Biol Cell. 2004 May;96(4):261-9. Review. — View Citation

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. — View Citation

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

Göttlicher M, Minucci S, Zhu P, Krämer 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. — View Citation

Hartong DT, Berson EL, Dryja TP. Retinitis pigmentosa. Lancet. 2006 Nov 18;368(9549):1795-809. Review. — View Citation

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

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. — View Citation

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. — View Citation

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. Epub 2007 Mar 19. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Peterson GM, Naunton M. Valproate: a simple chemical with so much to offer. J Clin Pharm Ther. 2005 Oct;30(5):417-21. Review. — View Citation

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. — View Citation

* Note: There are 19 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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	baseline to week 52
Secondary	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)	baseline to week 52
Secondary	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.	baseline to week 52
Secondary	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	baseline to week 52

External Links

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