Valproate for the Treatment of Residual Amblyopia

Not Applicable

Not yet recruiting

• Conditions: Amblyopia; Amblyopia Unilateral; Amblyopia, Anisometropic; Amblyopia Strabismic
• Interventions: Drug: Valproate; Drug: Placebo; Behavioral: Patch

• Registration Number: NCT07226141
• Lead Sponsor: Boston Children's Hospital

Brief 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.

Study Timeline

• Status Verified: 2025-09
• Study First Submitted: 2025-09-26
• Study First Submitted QC: 2025-11-05
• Last Update Submitted: 2025-11-05
• Study First Posted: 2025-11-10
• Last Update Posted: 2025-11-10
• Study Start: 2026-01-01
• Primary Completion: 2027-09-30
• Study Completion: 2027-09-30

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 28

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

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Arm 1 - Placebo first	Valproate	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.
Arm 1 - Placebo first	Placebo	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.
Arm 1 - Placebo first	Patch	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.
Arm 2 - Valproate first	Valproate	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.
Arm 2 - Valproate first	Placebo	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.
Arm 2 - Valproate first	Patch	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.

Primary Outcome Measures

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

Secondary Outcome Measures

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

Trial Locations

Locations (1)

Boston Children's Waltham; 🇺🇸 Waltham, Massachusetts, United States