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Trial registered on ANZCTR


Registration number
ACTRN12613001004752
Ethics application status
Approved
Date submitted
4/09/2013
Date registered
10/09/2013
Date last updated
7/06/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
A randomized clinical trial of a new binocular treatment for amblyopia (lazy eye)
Scientific title
For older children and adult patients with amblyopia, will six weeks of binocular treatment with a modified videogame be more effective than a placebo game in improving amblyopic eye visual acuity?
Secondary ID [1] 283135 0
Nil
Universal Trial Number (UTN)
Nil
Trial acronym
BRAVO
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Amblyopia 289986 0
Condition category
Condition code
Eye 290368 290368 0 0
Diseases / disorders of the eye

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants will be provided with an iPod touch device loaded with a modified version of the videogame Tetris and will be asked to play for 1 to 2 hours per day for a total of 6 weeks while wearing red/green anaglyphic glasses. The Tetris blocks will be presented so that some blocks are seen by the amblyopic eye and other blocks are seen by the fellow (non-amblyopic) eye by means of red/green anaglyphic glasses. Tetris blocks will be presented to the amblyopic eye at 100% contrast and to the fellow eye at a contrast determined by a random dot kinematogram measure of suppression at the start of training. The contrast of the blocks presented to the fellow eye will be increased if patients play the game successfully. Specifically, if the patient successfully completes 3 or more levels of the game within 24 hours the contrast to the fellow eye will be increased by 10% for the next 24 period of play. If the game is attempted and 3 or more levels are not successfully completed the contrast presented to the fellow eye will be reduced by 5%. The time participants spend playing the game will be automatically recorded on the iPod device.
Intervention code [1] 287860 0
Treatment: Devices
Comparator / control treatment
The control (placebo) device will be an iPod touch running identical videogame software to the real treatment device, except that both eyes will see the same images with no contrast offset. Participants will be instructed to play the placebo videogame for 1-2 hours every day for 6 weeks while wearing red/green anaglyphic glasses and their normal refractive correction where applicable.
Control group
Placebo

Outcomes
Primary outcome [1] 290397 0
Change in best-corrected distance visual acuity in the amblyopic eye from baseline to 6 weeks post-randomisation, measured using the highly standardised E-ETDRS protocol EVA testing system
Timepoint [1] 290397 0
From baseline to 6 weeks post-randomisation
Secondary outcome [1] 304412 0
Change from baseline in stereopsis at 3, 6, 12 and 24 weeks post-randomisation measured using Randot Preschool Stereotest
Timepoint [1] 304412 0
Baseline measurements upon participant recruitment and 3, 6, 12 and 24 weeks after randomization to treatment or placebo.
Secondary outcome [2] 304413 0
Change in interocular suppression measured using the dichoptic motion coherence test and Worth 4-dot tests at near and distance.
Timepoint [2] 304413 0
Baseline measurements upon participant recruitment and 3, 6, 12 and 24 weeks after randomization to treatment or placebo.
Secondary outcome [3] 304414 0
Change in angle of strabismus (where applicable) measured using the simultaneous prism cover test.
Timepoint [3] 304414 0
Baseline measurements upon participant recruitment and 3, 6, 12 and 24 weeks after randomization to treatment or placebo.
Secondary outcome [4] 304415 0
Treatment compliance at 3 and 6 weeks post-randomisation. Participants’ compliance will be recorded in two ways: through data stored on the iPod device and through a diary provided to participants. Compliance will be defined as = 25% of the prescribed dose (i.e. playing the game for at least 5 hours 15 minutes at 3 weeks and for at least 10 hours 30 minutes at 6 weeks post-randomisation)
Timepoint [4] 304415 0
3 weeks and 6 weeks after randomization to treatment or placebo.
Secondary outcome [5] 304416 0
Change in quality of life measured in adult patients (>17 years) using the World Health Organization Quality of Life (WHOQOL) – BREF. This outcome will not be measured in child participants (17 years or under).
Timepoint [5] 304416 0
Baseline measurements upon participant recruitment and 24 weeks after randomization to treatment or placebo.
Secondary outcome [6] 304417 0
Serious adverse events reported by the participants or identified via eye exams during follow-up visits.
Timepoint [6] 304417 0
3, 6, 12 and 24 weeks after randomization to treatment to placebo.
Secondary outcome [7] 308691 0
Treatment acceptability questionnaire for adults and children assessed using a modified version of the Amblyopia Treatment Index, which is 5 point Likert Scales for a series of 20 questions for parents of child participants and 19 questions for adult participants.
Timepoint [7] 308691 0
3 and 6 weeks after randomization to treatment or placebo.
Secondary outcome [8] 325291 0
Change from baseline in best-corrected distance visual acuity in the amblyopic eye, fellow eye and both eyes at 3, 6, 12 and 24 weeks post-randomisation
Timepoint [8] 325291 0
From baseline to 3, 6, 12 and 24 weeks post-randomisation
Secondary outcome [9] 325292 0
Change from baseline in best-corrected near visual acuity in the amblyopic eye, fellow eye and both eyes at 3, 6, 12 and 24 weeks post-randomisation measured using the Lighthouse ETDRS near visual acuity chart.
Timepoint [9] 325292 0
From baseline to 3, 6, 12 and 24 weeks post-randomisation
Secondary outcome [10] 325293 0
Change from baseline in interocular contrast at 3 and 6 weeks post-randomisation based on the log file extracted from the iPod.
Timepoint [10] 325293 0
3 and 6 weeks post-randomisation

Eligibility
Key inclusion criteria
* Amblyopia associated with the presence or history of strabismus, anisometropia or both (mixed mechanism).
* Unilateral amblyopia, defined as best corrected visual acuity (VA) in the amblyopic eye of 0.3-1.0 logMAR inclusive, measured using the E-ETDRS protocol from the Electronic Visual Acuity (EVA) testers, VA in the fellow eye equal to or less than 0.1 logMAR and an interocular VA difference equal to or greater than 0.2 log units
* Strabismic amblyopia, defined as amblyopia in the presence of heterotropia distance and/or near fixation, a history of strabismus surgery, or resolution of misalignment following hyperopic spectacle correction, with a spherical equivalent difference < 1.00D between the eyes and a difference in astigmatism in any meridian < 1.50D between the eyes
* Anisometropic amblyopia, defined as amblyopia in the presence of a spherical equivalent difference equal to or greater than 0.50D between the eyes, or a difference of astigmatism in any meridian equal to or greater than 1.50D
* Mixed mechanism amblyopia, defined as amblyopia in the presence of a heterotropia at distance and/or near fixation, a history of strabismus surgery, or a history of resolution of misalignment following a hyperopic spectacle correction and a spherical equivalent difference equal to or greater than 1.00D between the eyes or a difference in astigmatism in any meridian equal to or greater than 1.50D between the eyes
* An ability to align the images shown to each eye on the iPod device under normal binocular viewing conditions in order to successfully play the game as part of their treatment
* Refractive corrections meet the following criteria and are based on a cycloplegic refraction that is not more than six months old (a new cycloplegic refraction will be provided if necessary): 1) Hypermetropia will not be under-corrected by more than +1.50D spherical equivalent and the reduction in plus sphere must be identical between the two eyes. 2) Spherical equivalent power will be equal to or less than +/-0.50D of fully correcting the anisometropia. 3) Cylinder power in each eye will be equal to or less than +/-0.50D of fully correcting the astigmatism for each eye. 4) Cylinder axis in the spectacle lenses in both eyes must be equal to or less than +/-6 degrees of the axis of the cycloplegic refraction when cylinder power is equal to or greater than 1.00 D. Spectacles meeting the above criteria will have been worn either for 16 weeks prior to the baseline visit or until visual acuity is stable (a change equal to or less than 0.1 log units over two measurements made at least four weeks apart) through the refractive adaptation period in this study
* Willing and being able to provide written informed consent for participation in the study
Minimum age
7 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Myopia > 6.00D, previous intraocular surgery, any co-existent ocular pathology, known neurological anomalies and an inability to align the images shown to each eye on the iPod device.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Participants will be recruited from the University of Auckland Optometry Clinics, ophthalmology practices in Auckland and in Melbourne and the Department of Ophthalmology Clinics at McGill University in Canada. Potential participants will be identified through a search of current records and during the course of routine clinical appointments. Initial contact will be made via an invitation letter which will include a patient information sheet and a parent/guardian information sheet where appropriate. This initial contact will either be by mail or in person at the end of a clinic visit. A follow-up telephone call will be made by a researcher who will answer any questions about the trial.

Allocation concealment: Participants will be randomized to the placebo or treatment group after they have been judged to be eligible for the trial. Randomization will be conducted using an internet-based system that accesses a computer that is remote from the test sites. Allocation to each group will be made using a 1:1 ratio.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Immediately after baseline data have been recorded, participants will be randomised by computer (using an internet-based system) in a 1:1 ratio. Stratified minimisation will be carried out by age (7-12 years, 13-17 years and >17 years), severity of amblyopia (better or worse than 6/24 visual acuity in the amblyopic eye) and presence or absence of strabismus (a squint), to ensure a balance in these key prognostic indicators between the intervention and control groups.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint(s)
Efficacy
Statistical methods / analysis
A sample size of 108 patients (54 per arm) will provide 90% power at p=0.05 to detect a minimal clinically important difference of 0.2 log units improvement in visual acuity at six weeks, assuming a standard deviation of 0.17. This sample size allows for an overall loss-to-follow-up of 10% and each of the three age-groups is powered (90%) separately (36 in each group). This sample size also allows for the consistency of effects for pre-specified subgroups, namely severity of amblyopia, and presence or absence of strabismus, to be assessed.

Statistical analyses will be performed using SAS version 9.4 (SAS Institute Inc. Cary NC). All statistical tests will be two-sided at 5% significance level. Treatment evaluations will be carried out on an intention-to-treat (ITT) basis, using data collected from all randomised participants. Missing data on the primary outcome will be imputed using the last value carry forward method. Sensitivity analyses may be conducted to test the robustness of trial results under different assumptions on the missing data. This may include complete case analysis and multiple imputations methods. Per protocol analysis will also be conducted on those randomised participants who have no major protocol violations.
Baseline demographics, visual acuity, stereopsis, suppression, and quality of life will be summarised using descriptive statistics by treatment arms. Regression models appropriate to continuous and categorical outcome variables will be used to assess the overall treatment effect, adjusting for baseline outcome value and by age groups (stratification factor). Repeated measures analyses will be conducted on those outcomes measured repeatedly over time. For binary outcomes simple incidence rates, relative risks, and adjusted odds ratios will be calculated with 95% CI. For continuous outcomes simple mean/SDs, and adjusted mean differences will be calculated with 95% CI.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 6088 0
The Royal Victorian Eye and Ear Hospital - East Melbourne
Recruitment outside Australia
Country [1] 5378 0
New Zealand
State/province [1] 5378 0
Auckland
Country [2] 5379 0
Canada
State/province [2] 5379 0
Ontario
Country [3] 5380 0
Canada
State/province [3] 5380 0
Quebec
Country [4] 5381 0
China
State/province [4] 5381 0
Hong Kong

Funding & Sponsors
Funding source category [1] 287886 0
Government body
Name [1] 287886 0
Health Research Council of New Zealand
Address [1] 287886 0
Level 3 - ProCARE Building, Grafton Mews, at 110 Stanley Street, Auckland 1141
Country [1] 287886 0
New Zealand
Primary sponsor type
University
Name
The University of Auckland
Address
Private Bag 90210
Auckland 1142
Country
New Zealand
Secondary sponsor category [1] 286612 0
None
Name [1] 286612 0
Address [1] 286612 0
Country [1] 286612 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 289827 0
University of Auckland Human Participants Ethics Committee
Ethics committee address [1] 289827 0
Level 10, 49 Symonds Street, Auckland 1010
Ethics committee country [1] 289827 0
New Zealand
Date submitted for ethics approval [1] 289827 0
Approval date [1] 289827 0
14/08/2013
Ethics approval number [1] 289827 0
Ref. 10122

Summary
Brief summary
Amblyopia, also known as lazy eye, is a developmental disorder of vision whereby the brain ignores the information from one eye. This leads to a reduction in the vision of that eye. Also, the two eyes fail to work together resulting in a lack of binocular vision. This study is designed to test a new treatment for amblyopia implemented as a videogame on an iPod touch device that aims to strengthen binocular vision. The treatment is expected to establish stereopsis (3D vision) and to improve monocular acuity in participants with lazy eye. Participants will be given real or placebo treatment for 6 weeks and standard clinical tests of monocular and binocular vision will be used to assess treatment outcomes.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 42630 0
Dr Benjamin Thompson
Address 42630 0
Department of Optometry and Vision Science University of Auckland
Private Bag 92019 Auckland 1142
Country 42630 0
New Zealand
Phone 42630 0
+64 9 923 6020
Fax 42630 0
Email 42630 0
b.thompson@auckland.ac.nz
Contact person for public queries
Name 42631 0
Dr Benjamin Thompson
Address 42631 0
Department of Optometry and Vision Science University of Auckland
Private Bag 92019 Auckland 1142
Country 42631 0
New Zealand
Phone 42631 0
+64 9 923 6020
Fax 42631 0
Email 42631 0
b.thompson@auckland.ac.nz
Contact person for scientific queries
Name 42632 0
Dr Benjamin Thompson
Address 42632 0
Department of Optometry and Vision Science University of Auckland
Private Bag 92019 Auckland 1142
Country 42632 0
New Zealand
Phone 42632 0
+64 9 923 6020
Fax 42632 0
Email 42632 0
b.thompson@auckland.ac.nz

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Yes
Other publications
Have study results been made publicly available in another format?
No
Results – basic reporting
Results – plain English summary