AmblyopiaPhase 1/2VARANCT07226141
Valproate for the Treatment of Residual Amblyopia
A Phase 1/2 study testing Valproate and Patch in people with Amblyopia and Amblyopia Unilateral, run by Boston Children's Hospital at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 8 to 17 years
- Conditions the study is for
- Amblyopia, Amblyopia Unilateral, Amblyopia, Anisometropic
- What is being tested?
- Valproate and Patch
- Type of treatment
- Pill or oral medicine, Lifestyle or therapy programme
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 28 participants
- Where
- 1 siteUnited States
- Study dates
- 1 Jul 2026to 30 Sep 2027
- Phase
- Phase 1/2
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 8 to 17 years
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- 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
Show all 71Show fewer
- 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
Who cannot join
None listed.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
Peter Casey-Caplan, BA contact
United States1 site, 1 recruiting
- Recruiting
Boston Children's Hospital
Boston, Massachusetts, 02115
Eric Gaier, MD, 617-355-6401, Eric.Gaier@childrens.harvard.edu
Peter Casey-Caplan, BA, Peter.Casey-Caplan@childrens.harvard.edu
About this study
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.
Read the 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.
- Being tested
- Valproate, Placebo, Patch
- Keywords
- Amblyopia, valproate, valproic acid, pediatric, lazy eye, Histone deacetylase Inhibitor, HDAC, patching, eye patch, visual acuity, visual impairment, critical period, children, ophthalmology
- Medical subject headings
- Amblyopia, Vision Disorders
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ValproateDrug
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.
PlaceboDrug
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.
PatchBehavioural
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.
| Study group | Role | What they receive |
|---|---|---|
| Arm 1 - Placebo first | Placebo comparator | 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. Receives: Drug: Valproate; Drug: Placebo; Behavioral: Patch |
| Arm 2 - Valproate first | Experimental | 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. Receives: Drug: Valproate; Drug: Placebo; Behavioral: Patch |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: The comparison will be made between the randomized groups at the 8-week visit, prior to cross-over.
Secondary outcomes (5)
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.
Measured: 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.
Measured: 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.
Measured: 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).
Measured: 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.
Measured: Assessed throughout the study duration at 1,2, 4, 6, 8, 9, 10, 12, 14 and 16 weeks.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted10 Nov 2025
- Study start1 Jul 2026
- Primary completion30 Sep 2027 (estimated)
- Study completion30 Sep 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (54)Papers the sponsor has linked to this study.
- Other trials for AmblyopiaStudies of the same condition, open and under way.
- More trials run by Boston Children's HospitalThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Model description
- This is a prospective, randomized, double-blind, placebo-controlled interventional study with a cross-over-like design. Participants (ages 8-17) are randomized 1:1 to receive either valproate plus patching followed by placebo plus patching, or placebo plus patching followed by valproate plus patching. Each phase lasts 8 weeks (16 weeks total). The model ensures all participants are exposed to valproate, increases efficiency in a small pilot sample, and allows assessment of durability of response after discontinuation. Randomization is stratified by amblyopia severity, and both participants and investigators are masked to treatment assignment.
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 28 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Boston Children's Hospital
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Eric Gaier, Boston Children's Hospital
- Investigators
- Eric D Gaier, MD, PhD, Principal investigator, Boston Children's Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07226141
- Sponsor's protocol ID
- IRB-P00051999
- Acronym
- VARA
- Status last verified
- Jul 2026
- First submitted
- 26 Sep 2025
- Last updated
- 30 Jul 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: 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.
Publications
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.
PubMed 16123414Woodruff 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.
PubMed 7867817Holmes JM, Levi DM. Treatment of amblyopia as a function of age. Vis Neurosci. 2018 Jan;35:E015. doi: 10.1017/S0952523817000220.
PubMed 29905125Ashrafi 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.
PubMed 16120482Mattson 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.
PubMed 350128Tomson 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.
PubMed 25851171Hiilesmaa 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.
PubMed 6103246Nau 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.
PubMed 1803343Cotariu D, Zaidman JL. Developmental toxicity of valproic acid. Life Sci. 1991;48(14):1341-50. doi: 10.1016/0024-3205(91)90430-j.
PubMed 2008152Shoshany TN, Michalak S, Staffa SJ, Chinn RN, Bishop K, Hunter DG. Effect of Primary Occlusion Therapy in Asymmetric, Bilateral Amblyopia. Am J Ophthalmol. 2020 Mar;211:87-93. doi: 10.1016/j.ajo.2019.10.030. Epub 2019 Nov 9.
PubMed 31712066Chinn RN, Wilkinson CL, Staffa SJ, Michalak SM, Shoshany TN, Bishop K, Hunter DG, Gaier ED. Amblyopia treatment outcomes in patients with neurodevelopmental disorders. J AAPOS. 2023 Oct;27(5):276.e1-276.e8. doi: 10.1016/j.jaapos.2023.07.014. Epub 2023 Sep 21.
PubMed 37739211Morrison DG, Heidary G, Chang MY, Binenbaum G, Cavuoto KM, Galvin J, Trivedi R, Kim SJ, Pineles SL. Levodopa/Carbidopa to Augment the Treatment of Amblyopia: A Report by the American Academy of Ophthalmology. Ophthalmology. 2023 Nov;130(11):1221-1227. doi: 10.1016/j.ophtha.2023.07.008. Epub 2023 Aug 29.
PubMed 37642618Sharif MH, Talebnejad MR, Rastegar K, Khalili MR, Nowroozzadeh MH. Oral fluoxetine in the management of amblyopic patients aged between 10 and 40 years old: a randomized clinical trial. Eye (Lond). 2019 Jul;33(7):1060-1067. doi: 10.1038/s41433-019-0360-z. Epub 2019 Feb 19.
PubMed 30783259Huttunen HJ, Palva JM, Lindberg L, Palva S, Saarela V, Karvonen E, Latvala ML, Liinamaa J, Booms S, Castren E, Uusitalo H. Fluoxetine does not enhance the effect of perceptual learning on visual function in adults with amblyopia. Sci Rep. 2018 Aug 27;8(1):12830. doi: 10.1038/s41598-018-31169-z.
PubMed 30150750Chung STL, Li RW, Silver MA, Levi DM. Donepezil Does Not Enhance Perceptual Learning in Adults with Amblyopia: A Pilot Study. Front Neurosci. 2017 Aug 7;11:448. doi: 10.3389/fnins.2017.00448. eCollection 2017.
PubMed 28824369
Study at a glance
From the registry record, last updated by the sponsor on 30 Jul 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Valproate for the Treatment of Residual Amblyopia
- ClinicalTrials.gov ID
- NCT07226141
- Acronym / sponsor ID
- VARA / IRB-P00051999
- Keywords
- Amblyopia, valproate, valproic acid, pediatric, lazy eye, Histone deacetylase Inhibitor, HDAC, patching
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 28 participants (estimated)
- Lead sponsor
- Boston Children's HospitalUniversity, hospital or other
- Study start
- 1 Jul 2026 (actual)
- Primary completion
- 30 Sep 2027 (estimated)
- Study completion
- 30 Sep 2027 (estimated)
- First posted
- 10 Nov 2025 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Double blind (participant, investigator)
- Number of arms
- 2
- Model description
- This is a prospective, randomized, double-blind, placebo-controlled interventional study with a cross-over-like design. Participants (ages 8-17) are randomized 1:1 to receive either valproate plus patching followed by placebo plus patching, or placebo plus patching followed by valproate plus patching. Each phase lasts 8 weeks (16 weeks total). The model ensures all participants are exposed to valproate, increases efficiency in a small pilot sample, and allows assessment of durability of response after discontinuation. Randomization is stratified by amblyopia severity, and both participants and investigators are masked to treatment assignment.
| Arm | Type | Receives |
|---|---|---|
| Arm 1 - Placebo first | Placebo comparator | Drug: Valproate, Drug: Placebo, Behavioral: PatchParticipants 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 | Experimental | Drug: Valproate, Drug: Placebo, Behavioral: PatchParticipants 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. |
Who may qualify
- Ages
- 8 to 17 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (71 listed)
- Age 8-17 years
- Amblyopia associated with strabismus and/or anisometropia
- Visual acuity measured in each eye within 7 days prior to enrollment using ETDRS protocol on a study certified visual acuity tester as follows:
- Current amblyopia treatment (other than spectacle correction)
- Spectacle correction for measurement of enrollment visual acuity must meet the following criteria and be based on a cycloplegic refraction < 6 months old:
Key exclusion criteria (0 listed)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| ValproateValproate 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 | Arm 1 - Placebo first, Arm 2 - Valproate first |
| PlaceboThe 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. | Drug | Arm 1 - Placebo first, Arm 2 - Valproate first |
| PatchPatching 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. | Behavioural | Arm 1 - Placebo first, Arm 2 - Valproate first |
Primary outcome
Amblyopic Eye Best-Corrected Visual Acuity (BCVA)
Time frame: 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.
5 secondary outcomes
Proportion of patients with resolved amblyopia
Time frame: 8 weeks
Durability of amblyopic eye visual acuity response
Time frame: 8 weeks
Change in stereoacuity
Time frame: 8 weeks and 16 weeks
Quality of life measures using the Pediatric Eye Questionnaire (PedEyeQ)
Time frame: Change from baseline at 8 weeks and 16 weeks.
Tolerability and Safety of Valproate
Time frame: Assessed throughout the study duration at 1,2, 4, 6, 8, 9, 10, 12, 14 and 16 weeks.
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 30 Jul 2026.
- Background: PubMed 16123414Stewart 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.
- Background: PubMed 7867817Woodruff 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.
- Background: PubMed 29905125Holmes JM, Levi DM. Treatment of amblyopia as a function of age. Vis Neurosci. 2018 Jan;35:E015. doi: 10.1017/S0952523817000220.
- Background: PubMed 16120482Ashrafi 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.
- Background: PubMed 350128Mattson 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.
- Background: PubMed 25851171Tomson 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.
- Background: PubMed 6103246Hiilesmaa 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.
- Background: PubMed 1803343Nau 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.
- Background: PubMed 2008152Cotariu D, Zaidman JL. Developmental toxicity of valproic acid. Life Sci. 1991;48(14):1341-50. doi: 10.1016/0024-3205(91)90430-j.
- Background: PubMed 31712066Shoshany TN, Michalak S, Staffa SJ, Chinn RN, Bishop K, Hunter DG. Effect of Primary Occlusion Therapy in Asymmetric, Bilateral Amblyopia. Am J Ophthalmol. 2020 Mar;211:87-93. doi: 10.1016/j.ajo.2019.10.030. Epub 2019 Nov 9.
- Background: PubMed 37739211Chinn RN, Wilkinson CL, Staffa SJ, Michalak SM, Shoshany TN, Bishop K, Hunter DG, Gaier ED. Amblyopia treatment outcomes in patients with neurodevelopmental disorders. J AAPOS. 2023 Oct;27(5):276.e1-276.e8. doi: 10.1016/j.jaapos.2023.07.014. Epub 2023 Sep 21.
- Background: PubMed 37642618Morrison DG, Heidary G, Chang MY, Binenbaum G, Cavuoto KM, Galvin J, Trivedi R, Kim SJ, Pineles SL. Levodopa/Carbidopa to Augment the Treatment of Amblyopia: A Report by the American Academy of Ophthalmology. Ophthalmology. 2023 Nov;130(11):1221-1227. doi: 10.1016/j.ophtha.2023.07.008. Epub 2023 Aug 29.
- Individual participant dataSharing planned: Yes. 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Peter Casey-Caplan, BA contact
Eric D Gaier, MD, PhD principal investigator
Boston Children's Hospital
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Valproate and Patch in people with Amblyopia and Amblyopia Unilateral, run by Boston Children's Hospital at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 71 inclusion and 0 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 30 Jul 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Eric D Gaier, MD, PhD (617-355-6401, Eric.Gaier@childrens.harvard.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Amblyopic Eye Best-Corrected Visual Acuity (BCVA) (time frame: The comparison will be made between the randomized groups at the 8-week visit, prior to cross-over.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT07226141, which also lists 54 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 30 Jul 2026.