Valproate for the Treatment of Residual Amblyopia (VARA)

Boston Children's Hospital

Status and phase: Not yet enrolling; Phase 2; Phase 1

Conditions: Amblyopia Unilateral; Amblyopia; Amblyopia Strabismic; Amblyopia, Anisometropic

Treatments: Drug: Valproate; Behavioral: Patch; Drug: Placebo

Study type: Interventional

Funder types: Other

Identifiers

NCT07226141

IRB-P00051999

Details and patient eligibility

About

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.

Full 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.

Enrollment: 28 estimated patients

Sex: All

Ages: 8 to 17 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: Double Blind

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28 participants in 2 patient groups, including a placebo group

Arm 1 - Placebo first

Placebo Comparator group

Description:

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.

Treatment:

Drug: Placebo

Behavioral: Patch

Drug: Valproate

Arm 2 - Valproate first

Experimental group

Description:

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.

Treatment:

Drug: Placebo

Behavioral: Patch

Drug: Valproate