Valproate for the Treatment of Residual Amblyopia

Обзор

The goal of this clinical trial is to determine the efficacy of valproate as an adjunct therapy to treat amblyopia beyond the critical period in children aged 8-17 years who have amblyopia of ≥3 lines of interocular best-corrected (with glasses) visual acuity difference. The main questions it aims to answer are: * Does valproate enable clinically meaningful and durable visual recovery from amblyopia? * Do valproate-treated patients show a change in amblyopic eye visual acuity (lines)? Participants will undergo daily patching for 2 hours (standard of care) plus the addition of valproate or placebo for a total of 16 weeks.

Подробное описание

This pilot randomized, double-blind, placebo-controlled clinical trial is designed to evaluate the efficacy and safety of valproate as an adjunctive therapy for residual amblyopia in children and adolescents aged 8-17 years. Amblyopia, the leading cause of monocular visual impairment in children, is responsive to early interventions such as patching and pharmacologic penalization; however, many patients remain with residual visual deficits despite treatment. Current approaches are limited by age-dependent declines in cortical plasticity after closure of the visual system's "critical period."

Valproate (valproic acid), a widely used antiepileptic and mood-stabilizing agent, is also a histone deacetylase (HDAC) inhibitor that promotes synaptic plasticity through chromatin remodeling. Preclinical studies in rodents have demonstrated that HDAC inhibition with valproate restores ocular dominance plasticity and enables recovery of visual function even in adulthood. Translational work has further shown that valproate can reopen critical periods in humans, as evidenced by acquisition of absolute pitch in adult subjects. Together, these data provide strong proof-of-concept support for repurposing valproate as a treatment for amblyopia by reactivating plasticity mechanisms rather than targeting neuromodulatory pathways alone.

In this study, 28 subjects with residual amblyopia (best-corrected amblyopic eye visual acuity 20/40-20/400, stable over ≥8 weeks) will be randomized 1:1 to receive either oral valproate (15 mg/kg/day, divided BID) plus two hours of prescribed daily patching, or oral placebo plus patching, for 8 weeks. After the initial phase, subjects will cross over to the alternate treatment arm for an additional 8 weeks. This cross-over-like design ensures all participants receive valproate, allows assessment of treatment durability, and has precedent in both amblyopia and valproate neuroplasticity studies. Dose escalation up to 30 mg/kg/day will be permitted at interim visits if insufficient visual improvement is observed without adverse effects.

The primary endpoint is change in visual acuity in the amblyopic eye after 8 weeks of treatment. Secondary endpoints include the proportion of patients achieving resolution of amblyopia, change in stereoacuity, durability of treatment response after cross-over, visual acuity in the fellow eye, and prospective evaluation of the valproate safety profile in this population.

Subjects will be monitored closely through a structured schedule of phone calls and in-person visits over 16 weeks. Safety assessments include symptom surveys, liver function tests, complete blood counts, and pregnancy testing as indicated. Standardized visual acuity and stereoacuity testing will be performed at each visit. Compliance will be tracked using patient logs, capsule counts, and investigator assessments.

Potential risks include known adverse effects of valproate, ranging from common but generally mild gastrointestinal and neurological symptoms to rare severe outcomes such as hepatotoxicity, pancreatitis, teratogenicity, and hematologic abnormalities. Subjects will be carefully screened for contraindications, including liver disease, mitochondrial disorders, and pregnancy risk. A Data and Safety Monitoring Committee will oversee adverse event reporting and trial safety.

This trial is intended as a proof-of-concept study to establish feasibility, safety, and preliminary efficacy of valproate for residual amblyopia. Results will inform the design of a larger multicenter randomized trial and provide essential data on effect size, tolerability, and durability of response. If successful, this work could represent a paradigm shift in amblyopia treatment by introducing an epigenetic, plasticity-enhancing approach with the potential for durable recovery of vision in older children and adolescents who currently have limited therapeutic options.

Вмешательства

• Препарат Valproate
  Valproate is an anti-epileptic medication used in this study to treat amblyopia. Participants will receive valproate in oral tablet form. The dosage will be determined based on the participant's weight and age, following standard dosing guidelines for valproate. The medication will be administered daily for a duration of 8 weeks. Participants will be monitored for any adverse effects, and dosage adjustments will be made if necessary to ensure safety and tolerability.
• Препарат Placebo
  The placebo intervention consists of an inert substance designed to mimic the appearance and administration of valproate tablets. Participants in the placebo group will receive the placebo tablets daily for the same duration of 8 weeks. This control group will help to assess the efficacy of valproate by comparing outcomes between the valproate and placebo groups. Participants receiving the placebo will also be monitored for any adverse effects to ensure the study's integrity and participant safe
• Поведенческое Patch
  Patching is a standard treatment for amblyopia, involving the occlusion of the fellow eye to stimulate the amblyopic eye. Participants will be required to patch their fellow eye for 2 hours daily throughout the 16-week study period. The patching regimen aims to improve visual acuity in the amblyopic eye by encouraging its use. Compliance with the patching protocol will be monitored, and participants will be provided with instructions and support to ensure proper application and adherence to the

Первичные конечные точки

• Amblyopic Eye Best-Corrected Visual Acuity (BCVA) [Срок оценки: The comparison will be made between the randomized groups at the 8-week visit, prior to cross-over.]

Вторичные конечные точки (5)

• Proportion of patients with resolved amblyopia [Срок оценки: 8 weeks]
• Durability of amblyopic eye visual acuity response [Срок оценки: 8 weeks]
• Change in stereoacuity [Срок оценки: 8 weeks and 16 weeks]
• Quality of life measures using the Pediatric Eye Questionnaire (PedEyeQ) [Срок оценки: Change from baseline at 8 weeks and 16 weeks.]
• Tolerability and Safety of Valproate [Срок оценки: Assessed throughout the study duration at 1,2, 4, 6, 8, 9, 10, 12, 14 and 16 weeks.]

Критерии участия

Критерии включения

• Age 8-17 years
• Amblyopia associated with strabismus and/or anisometropia

• Criteria for strabismus: must meet at least one of the following:

• Heterotropia at distance and/or near with or without spectacle correction
• History of strabismus surgery
• Documented history of strabismus that is no longer present and felt by the investigator could have caused the amblyopia
• Criteria for anisometropia: must meet at least one of the following:

• ≥ 0.50 D difference in spherical equivalent between eyes
• ≥ 1.50 D difference in astigmatism in any meridian between the eyes
• Visual acuity measured in each eye within 7 days prior to enrollment using ETDRS protocol on a study certified visual acuity tester as follows:

• Amblyopic eye visual acuity of 20/40 - 20/400
• Sound eye acuity of ≥ 20/25.
• Current amblyopia treatment (other than spectacle correction)

• Subjects actively patching at the time of enrollment screening should continue patching through enrollment
• Visual acuity in amblyopic eye has not improved ≥ 1 line (5 letters) by the same testing method from a previous visit ≥ 8 weeks earlier while on treatment

• Since this determination is a pre-study examination, the method of visual acuity testing is not mandated
• Atropine treatment at any time during this pre-enrollment period is not allowed
• Any treatment prior to the current patching episode with stable acuity is allowed
• Spectacle correction for measurement of enrollment visual acuity must meet the following criteria and be based on a cycloplegic refraction < 6 months old:

• Requirement for spectacle correction:
• Spherical equivalent must be within 0.50 D of fully correcting anisometropia
• Hyperopia ≥ 3.00 D must be corrected
• Hyperopia may not be undercorrected by > 1.50 D spherical equivalent and must be symmetrically reduced in each eye
• Cylinder power must be within 0.50 D of fully correcting the astigmatism
• Cylinder axis must be within 6 degrees of the axis in the spectacles when the cylinder power is ≥ 1.00 D
• Myopia of the amblyopic eye > 0.50 D spherical equivalent must be corrected

◊ Myopia may not be undercorrected by > 0.25 D or overcorrected by > 0.50D

• Spectacles meeting the above criteria must be worn:
• Until visual acuity in amblyopic eye has not improved ≥ 1 line (5 letters) by the same testing method during 2 consecutive visual acuity measurements at least 4 weeks apart (i.e. minimum of 8 weeks spectacle correction) ◊ Since this determination is a pre-study examination, the method of visual acuity testing is not mandated
• Eye examination within 6 months prior to enrollment
• Subject must be available for at least 6 months of follow-up, have access to a phone, and be willing to be contacted by clinical staff
• By investigator judgment, the subject is likely to comply with prescribed treatment (i.e. no prior history of poor compliance with patching) and unlikely to continue to improve with 2 hours of daily patching alone

2.2.2 Exclusions

• Myopia > -6.00 D spherical equivalent
• Presence of associated findings that could cause reduced visual acuity

• Nystagmus does not exclude the subject if the above visual acuity criteria are met
• Previous intraocular or refractive surgery
• Strabismus surgery planned within 16 weeks
• Current vision therapy or orthoptics
• Known past or present liver or kidney disease
• Known past or present mitochondrial/metabolic disorder
• Known past or present psychological problems
• Known allergies or contraindications to the use of valproate or anti-epileptic medication
• Current use of medication for the treatment of seizures, bipolar disorder, or migraine, or any medication on the appended list of medications that interact with valproate/valproate acid and its derivatives which can be found here.
• Prior valproate use
• Known skin reaction to patch or bandage adhesives
• Treatment with topical atropine within the past 12 weeks
• Individuals capable of pregnancy who are pregnant, lactating, or may become pregnant within the next 6 months

• A negative urine pregnancy test will be required for all participants who have experienced menarche at the time of enrollment
• Individuals capable of pregnancy must convey an active suitable plan to avoid pregnancy that includes at least one of the following:
• Hormonal Contraceptives:

• Combined oral contraceptives (the pill)
• Contraceptive patch
• Vaginal contraceptive ring
• Progestin-only pills
• Hormonal injections (e.g., Depo-Provera)
• Hormonal implants (e.g., Nexplanon)
• Intrauterine Devices (IUDs):

• Copper IUD (e.g., ParaGard)
• Hormonal IUDs (e.g., Mirena, Skyla, Liletta)
• Barrier Methods with Spermicide (less commonly used alone but may be used in combination with other methods for added protection):

• Male condoms
• Female condoms
• Diaphragms with spermicide
• Cervical caps with spermicide
• Sterilization:

• Tubal ligation (for females)
• Vasectomy (Having a partner who has undergone a vasectomy, confirmed by semen analysis)
• Abstinence or True Sexual Abstinence:

o Refraining from heterosexual intercourse

• Requirements regarding the establishment of pregnancy status and monitoring for pregnancy over the course of the study may be further defined by the IRB

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Перекрёстный дизайн

Маскирование

Двойное слепое

Основная цель

Лечение

Центры проведения

США · 1 центр

• Boston Children's Hospital — Boston

Публикации

• Stewart CE, Fielder AR, Stephens DA, Moseley MJ. Treatment of unilateral amblyopia: factors influencing visual outcome. Invest Ophthalmol Vis Sci. 2005 Sep;46(9):3152-60. doi: 10.1167/iovs.05-0357. PMID 16123414
• Woodruff G, Hiscox F, Thompson JR, Smith LK. Factors affecting the outcome of children treated for amblyopia. Eye (Lond). 1994;8 ( Pt 6):627-31. doi: 10.1038/eye.1994.157. PMID 7867817
• Holmes JM, Levi DM. Treatment of amblyopia as a function of age. Vis Neurosci. 2018 Jan;35:E015. doi: 10.1017/S0952523817000220. PMID 29905125
• Ashrafi MR, Shabanian R, Zamani GR, Mahfelati F. Sodium Valproate versus Propranolol in paediatric migraine prophylaxis. Eur J Paediatr Neurol. 2005;9(5):333-8. doi: 10.1016/j.ejpn.2005.05.004. Epub 2005 Aug 24. PMID 16120482
• Mattson RH, Cramer JA, Williamson PD, Novelly RA. Valproic acid in epilepsy: clinical and pharmacological effects. Ann Neurol. 1978 Jan;3(1):20-5. doi: 10.1002/ana.410030105. PMID 350128
• Tomson T, Marson A, Boon P, Canevini MP, Covanis A, Gaily E, Kalviainen R, Trinka E. Valproate in the treatment of epilepsy in girls and women of childbearing potential. Epilepsia. 2015 Jul;56(7):1006-19. doi: 10.1111/epi.13021. Epub 2015 May 16. PMID 25851171
• Hiilesmaa VK, Bardy AH, Granstrom ML, Teramo KA. Valproic acid during pregnancy. Lancet. 1980 Apr 19;1(8173):883. doi: 10.1016/s0140-6736(80)91387-2. No abstract available. PMID 6103246
• Nau H, Hauck RS, Ehlers K. Valproic acid-induced neural tube defects in mouse and human: aspects of chirality, alternative drug development, pharmacokinetics and possible mechanisms. Pharmacol Toxicol. 1991 Nov;69(5):310-21. doi: 10.1111/j.1600-0773.1991.tb01303.x. PMID 1803343

Идентификаторы

NCT: NCT07226141 · IRB-P00051999

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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