SPEctacle Correction for the TReatment of Amblyopia (SPECTRA): study protocol for a prospective non-randomised interventional trial in adults with anisometropic/mixed mechanism amblyopia

Abstract

Introduction

Amblyopia is a neurodevelopmental vision disorder typically affecting one eye, resulting in compromised binocular function. While evidence-based treatments exist for children, there are no widely accepted treatments for adults. This trial aims to assess the efficacy of appropriate optical treatment in improving vision and visual functions in adults with amblyopia. This is hypothesised to significantly improve visual acuity of the amblyopic eye and other visual functions.

Methods and analysis

SPEctacle Correction for the TReatment of Amblyopia is a prospective non-randomised interventional trial. The following criteria for amblyopia will be used: best corrected visual acuity (BCVA) in the amblyopic eye of 0.3 to 1.0 (inclusive) logMAR VA and in the fellow eye, 0.1 logMAR or better, with an interocular VA difference of ≥2 logMAR lines. Eligible participants aged 18–39 will receive full/near-full optical treatment requiring wear for at least half their waking hours for the trial duration. A difference of ≥1.00D spherical equivalent between a participant’s current refractive correction and the study prescription is required for eligibility. Primary outcome is the change in amblyopic eye BCVA from baseline to 24-week postenrolment. Secondary outcomes include distance and near VA of both eyes, stereoacuity, contrast sensitivity, interocular suppression, angle of strabismus and fixation stability measured at monthly intervals. Visual evoked potentials will also be measured at baseline, week 12 and week 24. Treatment compliance and quality of life for all participants will be monitored.

Analyses comparing baseline and week 24 will utilise pairwise comparisons. Linear mixed models will be fitted to the data for measures taken monthly. This allows estimates and inferences to be drawn from the coefficients of the model, while handling missing data.

Ethics and dissemination

Human ethics approval was obtained from the respective ethics board of the Hong Kong Polytechnic University (HSEARS20210915002) and the University of Waterloo (#44235). The study protocol will conform to the principles of the Declaration of Helsinki. Results will be disseminated through peer-reviewed journals and conferences.

Trial registration number

NCT05394987; clinicaltrials.org.

STRENGTHS AND LIMITATIONS OF THIS STUDY.

• SPEctacle Correction for the TReatment of Amblyopia is a prospective study into the long-term efficacy of optical correction for the treatment of adults with anisometropic/mixed mechanism amblyopia.

• Electrophysiological and psychophysical outcome measures will help characterise neuroplasticity mechanisms in the adult human visual cortex.

• The study adopts a longitudinal design, allowing for the examination of changes over time and providing insights into a wide range of outcome measures of various visual functions.

• Treatment effects that last longer than 24 weeks will not be captured.

• It is not possible to design a placebo control for the refractive correction intervention.

Introduction

Background and rationale

Amblyopia is a developmental disorder that causes reduced vision and can significantly reduce quality of life (QoL).¹ The condition results from abnormal visual experiences in early life due to strabismus (turned eye), anisometropia (unequal refractive error between the eyes), visual deprivation or a combination of these factors.^{2 3} The abnormal visual experience alters neurodevelopment of visual brain areas, which results in visual impairment. The primary clinical indicator of amblyopia is reduced visual acuity (VA) in the affected eye that cannot be explained by pathology. However, other visual functions such as contrast sensitivity,⁴ spatial localisation,⁵ fixation stability⁶ and asymmetries in pursuits⁷ might also be impaired in individuals with amblyopia. Worldwide, the estimated total number of people with amblyopia was 99.2 million in 2019 and the total number of people with amblyopia is estimated to increase to 175.2 million in 2030.⁸

Conventional amblyopia treatment modalities for children include occlusion or penalisation of the non-amblyopic fellow eye using an eye patch, atropine or optical penalisation.^{9 10} Appropriate optical correction alone can also improve vision in children with amblyopia (mean VA improvement of approximately three lines)^{9 11–13} and is recommended as the first step in treatment.

While effective in children, current treatments are typically not offered to youths or adults because it is assumed that no substantial improvement in visual functions are possible beyond the ‘critical period’ of visual development.^{3 14 15} Clinicians often consider the upper age limit for successful treatment to be around 9 or 10 years of age, and there is evidence for a slightly reduced response to treatment after the age of 6 or 7.^{14 16} However, standard amblyopia therapy is still effective in older children and teenagers (up to 17 years old) with amblyopia¹⁷ and adults can also benefit from strategies like monocular perceptual learning to improve their visual function (for review, see Levi and Li¹⁸). Furthermore, vision in adults with amblyopia can improve with optical correction alone,¹⁹ with the BRAVO clinical trial²⁰ reporting a 13% improvement in VA from optical correction alone in their adult participants with amblyopia during a 16-week prerandomisation spectacle adaptation period. Despite this, clinical trial evidence for adult amblyopia treatment is lacking and high-quality evidence is needed to guide clinical decisions for evidence-based practice.

The SPECTRA study aims to assess changes in the best-corrected VA (BCVA) and other monocular and binocular visual functions before and after 24 weeks of wearing appropriate optical treatment in adults with amblyopia. The SPECTRA study is the first prospective interventional trial of optical treatment of amblyopia in adults, which aims to enhance VA in the amblyopic eye beyond the level achieved through immediate optical correction of refractive error. Optical treatment differs from optical correction in that for optical correction, vision is improved immediately following correction of the refractive error with appropriate lenses. In the case of optical treatment, the improvement in vision requires neuroplastic changes to occur within the visual cortex and is a gradual process that ultimately enables improved processing of visual information from the amblyopic eye, thereby improving vision. Evidence from existing studies^{12 13} lend support to this premise with data showing optical treatments generally taking effect within the first 16–18 weeks but with some continuing to show improvements up to 45 weeks. These studies, however, were completed in populations of children with amblyopia, which assumes a relatively early (childhood) detection of the condition. If detected late, amblyopia in adults is often left untreated due to the belief that the brain no longer has the capacity to alter cortical processing in response to corrected visual input.^{21 22} 24 weeks was selected on the basis that a previous clinical trial¹⁷ observed that this duration was sufficient for 23%–25% of 7–17-year-old patients with mixed treatment history to show a significant improvement in VA following optical correction. The results of this trial will provide valuable evidence on the efficacy of optical correction for the treatment of amblyopia in adults. If successful, this treatment could provide a simple, non-invasive and cost-effective option for improving the vision of adults with amblyopia. The study’s findings may also lead to a better understanding of the neuroplasticity of the adult brain and its potential for improvement in response to changes in sensory input.

Methods and analysis

Aim and hypothesis

The primary aim of this trial is to investigate whether prolonged wear of optical treatment alone is sufficient to enhance the BCVA of the amblyopic eye in adults with amblyopia. Secondary aims include assessment of changes in the BCVA of the fellow eye and binocular, contrast sensitivity, stereopsis, ocular alignment, fixation stability, interocular suppression and QoL measures. It is hypothesised that prolonged wear of optical treatment will lead to improvements in BCVA of the amblyopic eye.

Study design and recruitment

The trial follows a within-subject, pre–post interventional design. Data will be collected in both clinical and psychophysical laboratory settings.

The definition for amblyopia used by this trial follows the criteria set by the BRAVO study²³ which in turn is adapted from the Amblyopia Preferred Practice Pattern²⁴ guidelines and are as follows:

• Amblyopia: BCVA in the amblyopic eye of 0.3 logMAR to 1.0 logMAR (inclusive), VA in the fellow eye of 0.1 logMAR or better, and an interocular VA difference of 2 logMAR lines or more.

• Anisometropia: ≥0.50 dioptre (D) difference between the eyes in spherical equivalent or ≥1.50D difference between the eyes in astigmatism in any meridian.

• Strabismus: heterotropia at near or distance on examination with or without spectacles or history of strabismus that was corrected.

Potential participants will be identified through a database of known individuals with amblyopia, established by the BRAVO study team (Hong Kong site).²⁵ Following this first pass, participants will be recruited through advertisements within The Hong Kong Polytechnic University campus, The Hong Kong Polytechnic Optometry Clinic, Hong Kong Science Park and public advertisements. Interested participants will be invited to register interest via an online link. If eligible, participants will complete a telephone screening followed by a visit to the Centre for Eye and Vision Research for an in-person eligibility screening if appropriate. All participants will provide written consent for participation. Recruitment began on 13 June 2022 and is estimated to be completed by 31 May 2027. A secondary site in Canada was set up at the University of Waterloo (UW) in 2023. Recruitment will be through the patient database at the School of Optometry clinic at UW and by disseminating information to different departments at UW. Registration of interest and eligibility screenings will then be conducted in a similar manner to the HK site.

Eligibility

Inclusion/exclusion criteria:

Inclusion:

• Age: 18–39 (inclusive).

• Amblyopia associated with anisometropia or both strabismus and anisometropia (mixed mechanism).

• Difference between current refractive correction and study prescription by 1.00D spherical equivalent or more.

• Currently not under any amblyopia treatment/therapy.

• Good general health.

Exclusion:

• Other pathological ocular anomalies known to cause reduced VA.

• Presbyopia (determined by the average of the push-up, push-down measurements to estimate monocular and binocular amplitudes of accommodation).

• Inability to tolerate prescribed refractive correction in spectacles (eg, due to aniseikonia).

• >-6.00DS of myopia in either eye with spectacles.

• Being at risk of adverse reactions towards cycloplegic eye drops.

• Eccentric fixation (determined by the 4-prism dioptre base-out test and visuoscopy assessment).

• Bilateral amblyopia.

• Previous psychiatric (severe schizophrenia, bipolar disorder or major depressive disorder requiring hospitalisation or significant medical intervention within the last 12 months), visual (ie, conditions that can lead to reduced vision or impaired visual function, eg, untreated glaucoma, diabetic retinopathy, macular degeneration or other retinal disorders) or neurological disorders.

• Comprehension disorder that does not allow understanding of tests or training (eg, in severe aphasia).

Optical correction/treatment

In-person screening will involve a standard eye examination to determine eligibility and appropriate optical treatment by trained optometrists and/or ophthalmologists. The following guidelines (based on PEDIG amblyopia clinical trial protocols⁹) will be used for the prescription of spectacle correction for the trials and are based on a cycloplegic refraction. For purposes of the study, appropriate optical treatment refers to a full/near full (modified) prescription that adheres to these guidelines. Due to logistical constraints, the current study will only be able to provide spectacle corrections.

• Myopia: full correction of refractive error.

• Astigmatism: cylinder power in each eye should be within ≤±0.50D of fully correcting the astigmatism for each eye. In cases where the cylinder power is ≥1.00D, the cylinder axis in the spectacle lenses in both eyes should be within ≤±6 degrees of the axis of the cycloplegic refraction.

• Hypermetropia: not undercorrected by more than +1.50D spherical equivalent and the reduction in plus sphere must be identical between the two eyes.

• Anisometropia: full correction of the anisometropic difference.

All participants will receive individualised treatment and will be instructed to wear their study prescription full time for the entire duration of the study. Spectacle wear will commence from visit 2.

Adherence to treatment

Adherence to treatment will be defined as spectacle wear more than 50% of participant’s waking hours (minimum 5 hours/day). Participants will be provided with a diary to record the daily duration of their spectacle wear and to bring the diary on every visit. Study staff will record adherence on each visit. Participants will also receive an inconvenience allowance (study payment) to defray costs of attending sessions and to encourage continued participation for the duration of the study.

Outcomes

All outcome measures will be assessed at baseline, week 4, week 8, week 12, week 16, week 20 and week 24, with the exception of QoL and visual evoked potential (VEP) measures (see table 1). All outcome measures taken at visit 2 (baseline) constitute baseline measures, which are performed after a 30 min adaptation period to the study spectacles.

Table 1.

Schedule of assessments

Assessment	Visit 2 (baseline)	Visit 3 (week 4)	Visit 4 (week 8)	Visit 5 (week 12)	Visit 6 (week 16)	Visit 7 (week 20)	Visit 8 (week 24)
Visual acuity (near and distance)	✓	✓	✓	✓	✓	✓	✓
Stereopsis	✓	✓	✓	✓	✓	✓	✓
Contrast sensitivity	✓	✓	✓	✓	✓	✓	✓
Angle of strabismus (if applicable)	✓	✓	✓	✓	✓	✓	✓
Interocular suppression	✓	✓	✓	✓	✓	✓	✓
Fixation stability	✓	✓	✓	✓	✓	✓	✓
Quality of life	✓						✓
VEP measures	✓			✓			✓

VEP, visual evoked potential.

Primary outcome

The primary outcome is the change in BCVA (measured in logMAR) measured at distance (referred herein as distance BCVA) in the amblyopic eye from baseline to week 24. This will be measured using the standardised Electronic-Early Treatment Diabetic Retinopathy Study (E-ETDRS) protocol on the EVA testing system (Model 11-WIN; Jaeb Center for Human Research, Florida).^{26 27}

Secondary outcomes

The secondary outcomes are as follows:

• Change from baseline to week 24 of distance BCVA for the fellow eye and binocular. Measured using a standardised E-ETDRS protocol on the EVA testing system (Model 11-WIN; Jaeb Center for Human Research, Florida).^{26 27}

• Change from baseline to week 24 of BCVA for near VA for the amblyopic eye, fellow eye and binocular. Measured using an ETDRS format Sloan Letters Near Vision Card (Good-Lite, Illinois).

• Changes from visit to visit of distance BCVA for the amblyopic eye, fellow eye and binocular at week 4, 8, 12, 16, 20, 24. Measured using a standardised E-ETDRS protocol on the EVA testing system (Model 11-WIN; Jaeb Center for Human Research, Florida).^{26 27}

• Changes from visit to visit of BCVA measured at near (referred herein as near VA) for the amblyopic eye, fellow eye and binocular at week 4, 8, 12, 16, 20, 24. Measured using an ETDRS format Sloan Letters Near Vision Card (Good-Lite, Illinois).

• Changes to stereoacuity from baseline to week 24 and changes visit to visit at week 4, 8, 12, 16, 20, 24. Measured using the Randot Preschool test.²⁸

• Changes to contrast sensitivity of the amblyopic eye from baseline to week 24 and changes visit to visit at week 4, 8, 12, 16, 20, 24. Measured using a computer-based Letter Contrast Sensitivity chart in the Thompson Test Chart 2016 (Thomson Software Solutions, Cambridge, UK).

• Changes to the angle of strabismus (if applicable) from baseline to week 24 and changes visit to visit at week 4, 8, 12, 16, 20, 24. Measured using an alternating prism cover test.¹⁷

• Changes to interocular suppression from baseline to week 24 and changes visit to visit at week 4, 8, 12, 16, 20, 24. Measured using a dichoptic letter polarity test similar to that used by Bossi and colleagues.²⁹

• Changes to fixation stability of the amblyopic eye and fellow eye from baseline to week 24 and changes visit to visit at week 4, 8, 12, 16, 20, 24. Measured using a commercially available high-speed eye tracker during fixation as quantified by bivariate contour ellipse area.

• Changes to QoL from baseline to week 24. Measured using the Amblyopia and Strabismus Questionnaire (A&SQ)³⁰ and the WHO QoL-BREF.³¹

Other outcomes

Neurophysiological measures are as follows:

• Changes to VEPs as measured by electroencephalography (VEP amplitude from N75 to P100) when viewing stimuli with the amblyopic eye, fellow eye, and at baseline, week 12 and week 24 for the following conditions:

  • High contrast checkerboard (100% contrast) pattern-reversal VEPs conforming to the International Society for Clinical Electrophysiology of Vision (ISCEV)³² guideline specifications (ie, minimum 15° field size, 1° check size, 500 ms presentation per checkerboard).

  • Low contrast checkerboard (7.7% contrast) pattern-reversal VEPs. Apart from the reduced contrast, all other aspects of this stimulus conformed to ISCEV guidelines.

Sample size

The target number of participants for this study is 36, which will allow for the detection of any within-subject differences at an α of 0.05. This is based on the BRAVO study²⁰ observing a mean improvement in amblyopic eye distance VA of 0.05 (± 0.08) logMAR following spectacle correction in teenagers and adults with amblyopia. Recruitment will cease when the target number is achieved; an attrition rate of approximately 10% is expected.

Patient and public involvement

Patients and/or public were not involved in the intervention design.

Analyses

Throughout the trial, all data collected will be anonymised. Paper copies will be stored in secure filing cabinets and all digitised data will be entered into a secure database.

Statistical analyses will be performed using an appropriate statistical package following a prespecified statistical analysis plan. There will be no interim analyses. Missing data will be classified according to the type of missing data³³ on completion of data collection and dealt with accordingly.

Statistical analysis plan

Primary outcome

Paired samples t-tests (or non-parametric equivalent) will be employed to test the primary outcome, that is, baseline versus week 24 BCVA of the amblyopic eye.

Secondary outcomes

Secondary outcomes comparing baseline vs week 24 will involve paired samples t-tests (or non-parametric equivalent).

For secondary outcomes that involve measures taken over the course of the study at 4-week intervals, a linear mixed model will be fitted to the data. Estimates and inferences can be drawn from the coefficients of the fitted model and will allow for the assessment of observed changes in the visual function measure over time. Additionally, the model can accommodate potential issues that arise from missing data by allowing for variations in number and timing of observations across subjects.

Adherence analysis

The level of adherence to the treatment protocol will be assessed. This includes adherence to (1) the treatment (ie, >50% of waking hours), and (2) attendance of scheduled visits. Adherence can be assessed from the number of hours of daily spectacle wear for each participant and the number of visits attended. The proportion of participants who exceed 5 hours daily of spectacle wear, for the duration of the study and the percentage of attendance for visits can then be used as a measure of adherence. Adherence can then be set as a covariate in outcome models to determine its effect on measured outcomes.

Dropout analysis

In instances of a high dropout rate, the possibility of biases that can impact the validity of any conclusions drawn will be introduced. As such, separate analyses that include the data of all subjects who have dropped out will be performed (in addition to the data from subjects who completed the study). The missing status (ie, dropout or completed) can be modelled as an outcome variable, and relevant covariates can be included in the model. This will provide insights into the potential mechanisms behind dropouts and can help to assess the impact on study findings.

Discussion

This is the first prospective, interventional study investigating the efficacy of optical treatment in adults with amblyopia. This study builds on previous studies that have reported optical correction alone can improve VA in adults who are beyond the critical period of vision development. The study will determine whether aspects of visual function such as interocular suppression, fixation stability and QoL can improve from appropriate spectacle treatment, in addition to measuring improvements in VA.

The SPECTRA trial has the potential to change clinical practice by demonstrating that appropriate optical treatment in adults with amblyopia can improve visual function.

Trial status

Ongoing.

Ethics statements

Patient consent for publication

Not applicable.