Valproate for the Treatment of Residual Amblyopia (VARA)

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Amblyopia; Amblyopia, Anisometropic; Amblyopia Strabismic; Amblyopia Unilateral
• Intervention / Treatment: Drug: Valproate; Drug: Placebo; Behavioral: Patch

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.

• Study Type: Interventional
• Enrollment (Estimated): 28
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Eric D Gaier, MD, PhD; Phone Number: 617-355-6401; Email: Eric.Gaier@childrens.harvard.edu
• Study Contact Backup: Name: Peter Casey-Caplan, BA; Email: Peter.Casey-Caplan@childrens.harvard.edu

Study Locations

• United States
  • Massachusetts
    • Waltham, Massachusetts, United States, 02453
      • Boston Children's Waltham
      • Contact: Peter Casey-Caplan, BA; Email: Peter.Casey-Caplan@childrens.harvard.edu
      • Contact: Eric Gaier, MD; Phone Number: 617-355-6401; Email: Eric.Gaier@childrens.harvard.edu
      • Principal Investigator: Eric Gaier, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age 8-17 years

2. 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

3. 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.

4. 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

5. 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
6. Eye examination within 6 months prior to enrollment
7. 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
8. 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

1. Myopia > -6.00 D spherical equivalent

2. Presence of associated findings that could cause reduced visual acuity

   • Nystagmus does not exclude the subject if the above visual acuity criteria are met

3. Previous intraocular or refractive surgery
4. Strabismus surgery planned within 16 weeks
5. Current vision therapy or orthoptics
6. Known past or present liver or kidney disease
7. Known past or present mitochondrial/metabolic disorder
8. Known past or present psychological problems
9. Known allergies or contraindications to the use of valproate or anti-epileptic medication
10. 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.
11. Prior valproate use
12. Known skin reaction to patch or bandage adhesives
13. Treatment with topical atropine within the past 12 weeks

14. 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Arm 1 - Placebo first; Participants randomized to Arm 1 will receive oral placebo (250 mg twice daily) in combination with 2 hours of prescribed daily patching for 8 weeks. At the 8-week visit, participants will cross over to oral valproate at an initial dose of 15 mg/kg/day divided twice daily, while continuing the prescribed 2 hours of daily patching for an additional 8 weeks. Dose escalation of valproate up to 30 mg/kg/day (or placebo to 500 mg mice daily) will be permitted at interim visits if visual acuity has not improved and no adverse effects are present. All study medication will be discontinued after 16 weeks, with patching also discontinued at that time.	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.
Experimental: Arm 2 - Valproate first; Participants randomized to Arm 2 will receive oral valproate at an initial dose of 15 mg/kg/day divided twice daily, together with 2 hours of prescribed daily patching for 8 weeks. At the 8-week visit, participants will cross over to oral placebo (250 mg twice daily) while continuing 2 hours of daily patching for an additional 8 weeks. If visual acuity has not improved at interim visits and no adverse effects are observed, the valproate dose may be escalated up to 30 mg/kg/day during the initial treatment phase, or placebo increased to 500 mg twice daily during the cross-over phase. After 16 weeks, both study medication and patching will be discontinued.	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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Amblyopic Eye Best-Corrected Visual Acuity (BCVA)	Change in visual acuity of the amblyopic eye after 8 weeks of treatment with valproate plus patching versus placebo plus patching.	The comparison will be made between the randomized groups at the 8-week visit, prior to cross-over.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patients with resolved amblyopia	Proportion of participants achieving resolution of amblyopia, defined as visual acuity in the amblyopic eye of 20/25 or better, following 8 weeks of treatment.	8 weeks
Durability of amblyopic eye visual acuity response	Among those in the study arm receiving valproate followed by placebo, the visual acuity in the amblyopic eye will be compared between the 8 week visit (when valproate is discontinued) to the 16 week visit (after completion of placebo). This difference reflects the maintenance of visual acuity and will be analyzed and interpreted in the context of change at an individual level in response to valproate between weeks 0 and 8. The proportion of subjects from the valproate then placebo group maintaining a ≥ 10 letters (2 lines) improvement in the amblyopic eye visual acuity will be calculated and a 95% confidence interval on overall change will be computed.	8 weeks
Change in stereoacuity	Change in log arcsec in stereoacuity assessed with the Randot Preschool Stereoacuity Test. The change in log arcseconds will be compared between groups. Aggregated results will inform how overall stereoacuity has changed, and the difference from baseline will be compared across treatment groups and timepoints.	8 weeks and 16 weeks
Quality of life measures using the Pediatric Eye Questionnaire (PedEyeQ)	This measure assesses the quality of life deficits across four domains: functional vision, bothered by eyes/vision, social, and frustration/worry. It uses a 3-point frequency scale and Rasch-calibrated domain scores (0-100).	Change from baseline at 8 weeks and 16 weeks.
Tolerability and Safety of Valproate	This measure evaluates the tolerability and safety of valproate, assessing the proportion of patients reporting mild, moderate, and severe adverse events, and comparing the proportion of participants requiring dose tapering or de-escalation.	Assessed throughout the study duration at 1,2, 4, 6, 8, 9, 10, 12, 14 and 16 weeks.

Collaborators and Investigators

• Sponsor: Boston Children's Hospital
• Investigators: Principal Investigator: Eric D Gaier, MD, PhD, Boston Children's Hospital

Publications and helpful links

General Publications

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• Pediatric Eye Disease Investigator Group Writing Committee; Rutstein RP, Quinn GE, Lazar EL, Beck RW, Bonsall DJ, Cotter SA, Crouch ER, Holmes JM, Hoover DL, Leske DA, Lorenzana IJ, Repka MX, Suh DW. A randomized trial comparing Bangerter filters and patching for the treatment of moderate amblyopia in children. Ophthalmology. 2010 May;117(5):998-1004.e6. doi: 10.1016/j.ophtha.2009.10.014. Epub 2010 Feb 16.
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Study record dates

Study Major Dates

• Study Start (Estimated): January 1, 2026
• Primary Completion (Estimated): September 30, 2027
• Study Completion (Estimated): September 30, 2027

Study Registration Dates

• First Submitted: September 26, 2025
• First Submitted That Met QC Criteria: November 5, 2025
• First Posted (Actual): November 10, 2025

Study Record Updates

• Last Update Posted (Actual): November 10, 2025
• Last Update Submitted That Met QC Criteria: November 5, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: pediatric; children; Amblyopia; visual impairment; valproic acid; visual acuity; HDAC; ophthalmology; Histone deacetylase Inhibitor; valproate; patching; lazy eye; eye patch; critical period
• Additional Relevant MeSH Terms: Neurologic Manifestations; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Eye Diseases; Sensation Disorders; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Amblyopia; Vision Disorders; Organic Chemicals; Fatty Acids; Lipids; Acids, Acyclic; Carboxylic Acids; Equipment and Supplies; Pentanoic Acids; Valerates; Fatty Acids, Volatile; Valproic Acid; Transdermal Patch
• Other Study ID Numbers: IRB-P00051999

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

We plan to share individual participant data (IPD) with qualified researchers to promote transparency and further research. Data will be de-identified to ensure privacy and confidentiality. Researchers must submit a formal request outlining their study purpose and intended use of the data. Requests will be reviewed by our study team for ethical and scientific alignment.

Data will be shared through a secure online repository, accessible to approved researchers. Shared data will include demographic information, clinical outcomes, visual acuity measurements, stereoacuity results, quality of life assessments, and adverse event reports. Researchers must agree to use the data solely for approved purposes and not share it with third parties without consent.

Researchers are encouraged to publish their findings in peer-reviewed journals and acknowledge the original study and investigators.

• IPD Sharing Time Frame: The individual participant data (IPD) and supporting information will be available to qualified researchers starting 6 months after the publication of the primary study results. The data will remain accessible for 5 years from the start date. Researchers must submit a formal request, which will be reviewed for ethical and scientific alignment. This plan ensures valuable data contributes to advancements in amblyopia treatment while maintaining confidentiality.

IPD Sharing Access Criteria

Who Will Be Able to Access:

Qualified researchers from academic institutions, research organizations, and healthcare institutions will be able to access the IPD and supporting information. Access will be granted based on the submission and approval of a formal request.

What They Will Be Able to Access:

Researchers will have access to de-identified individual participant data, including:

Demographic information Clinical outcomes Visual acuity measurements Stereoacuity results Quality of life assessments Adverse event reports

How They Will Be Able to Access:

Researchers must submit a formal request detailing their study purpose and intended use of the data. The request will be reviewed by our study team for ethical and scientific alignment. Approved researchers will be granted access to the data through a secure online repository that complies with data protection regulations. Access will be restricted to the approved research purposes, and data sharing with third parties will require

• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No