NCT07226141

Valproate for the Treatment of Residual Amblyopia

• Status: Not Yet Recruiting
• Phase: Phase 1 / Phase 2
• Study type: Interventional
• Enrollment: 28 (estimated)
• Sponsor: Boston Children's Hospital · Academic / Other
• Sex: All
• Age: 8 Years – 17 Years
• Healthy volunteers: Not accepted

Summary

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.

Detailed description

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.

Conditions

• Amblyopia
• Amblyopia Unilateral
• Amblyopia, Anisometropic
• Amblyopia Strabismic

Interventions

Type	Name	Description
DRUG	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.
DRUG	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 safety.
BEHAVIORAL	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 treatment.

Timeline

• Start date: 2026-01-01
• Primary completion: 2027-09-30
• Completion: 2027-09-30
• First posted: 2025-11-10
• Last updated: 2025-11-10

Locations

1 site across 1 country: United States

Regulatory

• FDA-regulated drug study