Tests performed at baseline and each follow-up visit
After obtaining consent and assent, health-related quality of life (HRQOL) will first be assessed using the Intermittent Exotropia Questionnaire (IXTQ); these will be completed by each participant and their guardians in separate and quiet rooms. Then, each participant will undergo comprehensive ophthalmic examinations, including best corrected visual acuity (BCVA), subjective refraction, slit-lamp biomicroscopy, and fundus examination. Then, strabismic and binocular visual examinations will be performed, including stereopsis, the amplitude of fusional vergence at far and near, monocular and binocular accommodative amplitude, monocular and binocular accommodative facility, near point of convergence, the prism and alternate cover test (PACT) and simultaneous prism and cover test (SPCT). The principal inspection sequence is first binocular then monocular without breaking fusion. If this principle is broken, for example, the monocular items are performed first, then before testing the binocular items, at least 15 minutes of rest for steady binocular fusion will be provided. The present study included a baseline visit and 6-, 12-, 18-, and 24-month follow-up visits. Each examination is completed on the same day. The 4 follow-up visits will fall into a ± 2-week range. The HRQOL was designed to be completed at the first examination time and at the last examination time. To ensure the quality and repeatability of data acquisition, all procedures will be performed by two experienced clinicians (MX and YW), and the procedures have been unified and standardized. The standard process regarding the important test items is as follows:
Health-related quality of life questionnaire
We will use the Intermittent Exotropia Questionnaire (IXTQ) to assess the participants’ and their guardians’ health-related quality of life (HRQOL). The IXTQ consists of 3 components:
- Child questionnaire: This will be used to assess the feelings of the child about his or her eye condition. Because the children enrolled in our study will be over 7 years old and have been attending primary school, they already have a certain level of understanding. We uniformly use the child questionnaire as the version for children aged 8 years and older, which consists of 12 items and a five-level response scale (never, almost never, sometimes, often, and almost always) and is self-administered as far as possible. Of course, if the child cannot understand the question by her or himself, there will be staff nearby to provide oral guidance and help.
- Parent proxy questionnaire: This will be used to assess how parents think their child's eye condition affects their child. The questionnaire consists of 12 items, and a 5-level response scale, similar to the child questionnaire, is used.
- Parental questionnaire: This will be used to assess the parents’ feelings about their child’s eye condition. This component of the questionnaire consists of 17 items and the 5-level response scale.
All questionnaires about the parents are completed by the parents themselves; if there is a part that they do not understand, the assistant staff can help to explain it. Parents and children are separated into two different rooms during the completion of the questionnaire to avoid interfering with each other.
Exodeviation control at distance and near
We will assess the exodeviation control at each follow-up period using the Office Control Score. This assessment will be conducted before all other examinations. The investigator looks at the participant’s eyes when he or she focuses at an accommodative target at distance (6 m) or near (40 cm) and determines a score based on the following scoring principle:
5 is constant exotropia
4 is exotropia > 50% of the 30-second period before dissociation
3 is exotropia < 50% of the 30-second period before dissociation
2 is no exotropia unless dissociated; recovers in > 5 seconds
1 is no exotropia unless dissociated; recovers in 1–5 seconds
0 is no exotropia unless dissociated; recovers in < 1 second (phoria).
Near and distance stereoacuity will be assessed using the Titmus circles test and TNO at 40 cm and the Distance Randot Stereotest at 3 m, respectively. Stereoacuity will be assessed with the participant’s refractive correction. The Titmus circles measure from 40 to 800 seconds of arc (arcsec). The TNO test (Laméris Ootech B.V., Nieuwegein, the Netherlands) ranges from 15 to 480 arcsec. The Distance Randot Stereotest (DRS, American Stereo Optical Company U.S.A.) ranges from 63 to 400 arcsec. Testing starts with the largest disparity, and the inability to correctly identify the target with the largest disparity will be recorded as nil stereo. Nil stereoacuity will be assigned the next highest log level (near 1600 seconds of arc for Titmus; 960 seconds of arc for TNO; distance 800 seconds of arc for DRS) for the purpose of data analysis.
The Worth 4 Dot test will be conducted at a 40-cm and 5-m fixation to assess near and far sensory fusion, respectively. The participants will wear red-and-green spectacles and view the Worth 4 Dot flashlight at near and at distance. If participants report 2 red or 3 green lights, it will be taken to represent “suppression” of the left eye or right eye. If they report 4 lights at distance or at near, it means they have “normal” peripheral or central fusion. If 5 lights are reported, it will represent “diplopia”.
The amplitude of fusional vergence will be assessed by a 1 to 40 PD prism bar for both near and far fixation. Each participant will fixate on a single letter (20/40 Snellen level) at 33 cm or 5 m and will be asked to report when the fixated letter appears to double (this will be recorded as the break point) as the prism strength gradually increases. Then, the prism power will be gradually decreased, and the point at which the patient regains single vision will be recorded as the recovery point. Participants will be reminded to keep the target single as long as possible. Both the divergence (BI) and convergence (BO) of the break point and recovery point are recorded at near and at distance. If the subject reports suppression, which will be assessed by the Worth 4 Dot test, then this part will be omitted and recorded as 0/0. For subjects who still retain fusion at 45 PD, the break point will be recorded as 45 PD, and the recovery point will be recorded as “-” and excluded from the recovery analysis. The testing order for fusional vergence is distance first and then near, divergence first and then convergence. The PD values of break points are defined as the amplitude of the vergence, which is defined as convergence reserve in our study.
Near point of convergence
For this test, participants will fixate at a single Snellen 6/12 letter as an accommodation target at 40 cm in front of their eyes. The investigator will move the target closer to the subject and observe the subject's eyes until he or she reports diplopia or one eye drifts outward. This point will be recorded, and the distance from the point to the canthus or the plane of the subject's glasses will be measured.
The accommodative function we measure here will include accommodative amplitude and facility. We will separately measure binocular and monocular function in both examinations. Generally, we will measure accommodative facility first and then amplitude, and we will measure binocular function first then monocular function. When measuring binocular function, we will always observe the subjects' eye position and remind them to maintain binocular single vision. The test will be stopped if the patient has diplopia or appears to have an outward deviation.
We will use standard test methods (±2.00 D flipper lenses) to test this facility. The subjects will be asked to read one line above the best visual acuity at 40 cm with their corrected lenses. Then, the + 2.00 D lenses will be placed in front of the subjects’ eyes, and when the letters are reported to be clear, the flipper (-2.00 D lens) will be quickly flipped in front of the eyes; 1 cycle is achieved when clear is reported again. This will be continued while alternating sides of the flipper lenses for 1 minute, and the cycles achieved will be recorded.
We will use “Minus lens” to test the amplitude. A near target will be set at 40 cm, minus lenses will be gradually added in front of the subjects’ eyes until they report sustained blur. The summation of the number of minus lenses and 2.50 D for working distance will provide the total accommodative amplitude.
Ocular alignment testing
Ocular alignment will be assessed by SPCT and PACT both at near (33 cm) and at distance (5 m). The deviation will be recorded as constant or intermittent if a manifest exodeviation is present in at least 3 cover and uncover tests. The amount of manifest exodeviations will be recorded by the values of SPCT, and the total amount of exodeviations will be recorded by the measurement of PACT. If no deviation is present at any time, it will be recorded as “no deviation”.
After a subject completes all of the examinations, the checklist is handed to the research assistant. Subjects will be randomly divided into Group A (orthoptic therapy group) and Group B (control group) based on the order provided in the random table.
Intervention for the orthoptic therapy group
All participants in the orthoptic therapy group will receive at least 8 weeks of hospital-based orthoptic therapy combined with home reinforcement administered by an orthoptic therapist based on their baseline binocular visual status. The therapy protocol in the present study is based on participants’ binocular vision status and modified on the basis of the Convergence Insufficiency Treatment Trial randomized clinical trial24,25. Hospital-based training will mainly include methods that are not easy to master, the operation is more complex, and the training equipment is not suitable for home use. Furthermore, some participants with poor visual function will need to complete this training under the guidance of a therapist. To enhance the treatment confidence of participants and parents, the therapeutic procedures will be arranged from easiest to most difficult. At the same time, therapists will often verbally motivate the participants to perform the more difficult tasks.
The participants will receive hospital-based therapy 1–2 times per week, 60 minutes each time, combined with practice at home for 15–30 minutes, 5 days per week. Therapists will also instruct parents to complete the training log and maintain communication through WeChat in an attempt to enhance compliance and improve the therapeutic effect. The overall treatment program will consist of 3 phases. In each phase there are a number of subcategories. The detailed therapeutic program is summarized in Table 2. The participants in our study will have normal binocular visual acuity and basic binocular visual function, which may be different from other patients with abnormal visual function. Each procedure has a designated endpoint that should be obtained before moving on to the next level or phase.
Before the start of each training, some simple binocular function tests will be performed, and the training program will be adjusted based on those test results. The patients can stop training in the hospital and maintain home training (15 minutes each day) to maintain efficiency if the test results showed that performance had reached or even exceeded the normal level. However, if a decrease in the test results is observed during the follow-up, the appropriate therapeutic treatment will be reinitiated. For the results and purpose of our study, parents are required to record the training in detail, including time, frequency, experience, etc.
Control group therapy
For the participants in the control group, all binocular visual function tests will also be completely performed at each follow-up visit. If refractive status changes, appropriate prescription will be provided and used in a pair of new glasses.
If only binocular visual function deterioration occurs, it is proposed that they continue to be observed; if accompanied by a small angle of exodeviation but not meeting the criteria of suboptimal surgical outcome or if participants ask for visual function therapy, they will have deviated from the study protocol and will be considered to be out of group. If eye position regression is obvious and the definition of recurrence is reached, he or she will be classified as having a suboptimal surgical outcome. They will be offered a reoperation to align the eye position or start orthoptic therapy during the study.
Before the beginning of the study, we demonstrated the feasibility of the project, the reliability of the research methods and the evaluation of the research results. Stereopsis will be checked by the assistant medical staff of the department, and the other binocular vision items and the amount of exodeviation will all be checked by the same senior doctor.
The primary outcomes in our study will be the proportion of participants meeting suboptimal surgical outcomes at any masked follow-up visit examination within 2 years of surgery; these suboptimal outcomes are defined as (1) exodeviation of ≥10 PD at distance or at near using SPCT or (2) loss of 2 octaves or more of stereoacuity from baseline.
The secondary outcomes in our study include the following items: the exodeviation at near and distance tested by PACT, fusional convergence amplitude, stereoacuity, accommodative amplitude and facility.
A total sample size of 136 subjects (68 per group) are required for this study based on the following considerations: the proportion of participants meeting suboptimal surgical outcomes in the PEDIG study was 36.5% in 24 months. Edwin et al.22 confirmed that the successful treatment rate among IXT patients was 83.3% (25/30) in the surgery combined with nonsurgical binocular therapy group. Statistical power was set at 80% with a type 1 error probability (a) of 0.05 based on a 2-tailed t test. The theoretical sample size was 61, with a 1:1 sample ratio. To allow for a maximum drop-out rate of 10% during the 2-year follow-up, the sample size for each group was estimated at 68.
A biostatistician will generate a simple randomized number list at a ratio of 1:1 using SPSS software version 20.0 (IBM Corp., Armonk, NY, USA). Randomization will be conducted on the day that all the enrolment tests are completed. After each subject is enrolled and has completed all of the examinations, he or she will be invited to the principal investigator. The investigator will group the subjects in accordance with the order of the numbers in the randomization table. If the participant is assigned to the blank control group, he or she will be informed to follow the routine clinical follow-up time, that is, 6 months, 12 months, 18 months and 24 months. In addition, an appointment will be made for the next follow-up. If the participant is assigned to the orthoptic therapy group, he or she will be given the detailed therapeutic schedule. If the patient is not satisfied with the group assignment after randomization and does not want to participate in the follow-up study, that patient will be dropped from the study. All procedures will be performed by two investigators (MX and YW), and they will be blinded to the interventions.
Data management and monitoring
To ensure the successful conduct of research and data accuracy, we will conduct detailed training for all project team members before the study starts, and training will include the collection of patient information, examination process and methods, data recording and input, etc. Each patient will have complete case report forms (CRFs), where researchers will record the data. If a mistake is made while recording the data, any changes to a CRF will need to be signed and dated. Because of the possibility of exodrift over the prolonged time after surgery, if patients miss one or two follow-up visits, we will use the last obtained follow-up data instead. Data administrators will enter data into EpiData 3.1. It will be entered and checked by two full-time staff (TP and CW) from our clinical research centre, who will also be blinded to the interventions. The Clinical Trial Centre Office of the Eye Hospital of Wenzhou Medical University is responsible for data monitoring and overseeing the whole study. The original data, including private information, will be kept in the Data Monitoring Committee, which as an important department in Clinical Trial Centre Office. If there is any reasonable request and an agreement with the principal investigator is obtained, the data will be accessible through the research centre. The principal investigator will regularly report the research progress to the co-workers on the study, and the final results will be presented in the form of published articles. Authorship will be determined based on an individual's contribution to the study and in accordance with authorship eligibility guidelines. The ideas and scientificity underlying the research are very important.
To protect the rights and interests of patients, all participants and their guardians will be informed of the potential benefits and possible risks of the trial before they enrol. The whole process will be carried out in a separate and quiet room by a trained professional assistant (JL). After confirming that the patient and guardian understand the relevant content, we will ask both the patient and his or her guardian to sign an informed consent form. If any one of these individuals do not sign the informed consent form, they will not be admitted to the study.
Because the orthoptic therapy being used in our study is a form of functional training, which is a non-invasive operation, the risk of harm to patients is very small. However, we will still inform all individuals of the training process in detail and will give them the researcher's telephone or WeChat to communicate at any time. All participants will be permitted to withdraw or terminate the study for any reason during the study, and the reasons will be recorded. Discontinuation or irregular orthoptic therapy will not be a reason for withdrawal from the study, and participants could complete follow-up visits provided if they are willing.
Statistical analysis will be performed using SPSS software version 20.0 (IBM Corp., Armonk, NY, USA). The parameters to be calculated are the means ± standard deviations for the continuous variables and the rates (proportions) for the categorical variables.
For the primary analysis, the cumulative proportion of participants meeting the criteria for suboptimal surgical outcomes by 2 years will be compared between the 2 groups using the chi-square test. An intergroup difference and a corresponding 95% confidence interval (CI) will also be calculated. Each of the 2 individual components of the specified suboptimal surgical outcome criteria will be assessed as a secondary outcome using the chi-square test.
For all participants who complete the 2-year visit, and after the data entry is completed, the statistician will separate the two groups of data based on the random table. Changes in exodeviation measured by PACT, stereoacuity, accommodative amplitude and facility, and fusional convergence amplitude between baseline and the 2-year time points will be compared between the two groups in linear regression models that will be adjusted for the corresponding baseline values. Additionally, considering that binocular visual function is different in different age, the final data may be divided into two subgroups according to different ages.