Randomized single-blind, placebo-controlled intervention study (RCT), embedded within standard clinical care.
The study will be executed at the Neonatology department of an academic medical center, in collaboration with the department of Pediatric Ophthalmology and with four regional centers of a center of expertise for blind and partially sighted people that provides visual diagnostics and (re)habilitation.
Participant characteristics & timeline
It is expected that 25-50% of the very preterm population is at risk of VPD at 1 year CA(15, 16). Therefore, all infants who have been born before 30 weeks gestational age and who participate in the clinical follow-up program of the dept. Neonatology, will be available for inclusion around 1 year CA. We aim to include:
- N=100 children from 1 year CA, born < 30 weeks of gestation. About 50% are expected to be at risk of VPD (and eligible for the intervention)
- N=100 children born at term without VPD from 1 year of age, to add to an existing database of typically developing children (healthy control group).
The study population can be divided in 3 groups:
Group 1: children born very preterm from 1 year CA, without a risk of VPD
Group 2: children born very preterm from 1 year CA, with a risk of VPD
Group 2A: 50% will receive direct visual intervention (intervention group)
Group 2B: 50% will receive postponed visual intervention (control group)
Group 3: children born at term without a risk of VPD
- Born <30 weeks gestational age
- Age at inclusion of 1 year CA (+/- 2 months)
- Visual acuity below 0.05 (Snellen equivalent)
The visual screening (i.e. eye tracking-based exam) is designed to be visible with a visual acuity of 0.05 or higher.
- High chance of epileptic activity during assessment
More than 2 attacks in the previous year or when using the anti-epileptic Vigabatrin (which may lead to visual dysfunctions).
- Retinopathy of prematurity (ROP) of grade 3 or higher, assessed by a pediatric ophthalmologist, as this will account for their visual dysfunctions.
Figure 1 outlines the general time schedule of the study. The separate components are:
Participant inclusion and baseline screening
Children born < 30 weeks GA will be recruited around the corrected age (CA) of 1 year at the department of Neonatology of an academic medical center. After obtaining written informed consent (see Additional file 2), a visual screening is performed to identify the prevalence and nature of VPD (for details see ‘Data collection methods’). The first part of the screening consists of an eye tracking-based assessment of visual attention and processing . The visual assessment results are compared to normative references to identify the children with a risk of visual processing dysfunctions (VPD). The second part of the screening is a checklist to identify common neurological risk factors for VPD, and that is completed by the neonatologists.
The children who are identified as being at risk of VPD will first undergo an orthoptic and ophthalmic exam at dept. Pediatric Ophthalmology (including refraction, ocular alignment). Next, they will be referred to a visual advisory and rehabilitation center in order to receive standard care, consisting of a visual function assessment (VFA) and a visual intervention program. The VFA is used to evaluate visual sensory functions (e.g., visual acuity, visual field, contrast sensitivity, ocular motility), and to observe the functional visual behavior of the child. This assessment is performed by experienced orthoptists, optometrists and behavioral therapists, and together they will determine the visual level of the child(5, 29):
- Profound visual dysfunction/ legally blind (mainly responding to light)
- Severe visual dysfunction, passive attentional system (reactions to stimuli do not reach normative levels, child does not actively search for visual stimulation, low recognition)
- Moderate visual dysfunction/ basic perception (active visual attention system and basic visual recognition)
- Mild visual dysfunction, subnormal visual function (functioning at the lower bound of normal)
For a detailed outline of the visual rehabilitation protocol we refer to the section ‘Intervention: a visual habilitation protocol’ and to Additional file 3; template visual intervention protocol. To reliably examine the effectiveness of the visual intervention program with an RCT, children who are at risk of VPD will be randomly allocated to one of two groups:
- Intervention group (direct)
This group consists of very preterm children who are at risk of VPD and who will start the visual intervention program upon referral to the visual rehabilitation center (i.e. around 1 year CA). The program consists of a general protocol (standardized across participants) and a supplement protocol (tailored to the child’s specific VPD), and lasts ~1 year.
- Control group (postponed & placebo)
This group consists of very preterm children who are also at risk of VPD, but for whom the visual intervention program will be postponed for the duration of 1 year. These children will be placed on a waiting list for the duration of the direct visual intervention (i.e. ~1 year). During this first year they will receive a placebo intervention: general developmental support that is aimed at monitoring the child’s developmental progress without providing specific visual habilitation. As soon as the follow-up assessments of the direct intervention group are completed, children in the control group will start visual intervention (i.e. around 2 years CA).
Importantly, this study design ensures that all children at risk of VPD will receive visual intervention at an earlier age than is the case in current standard care (i.e. where only a small number of young will be referred based on obvious ocular disorders, and others will not receive interventions before four to six of age)), while the RCT design enables a reliable and controlled comparison of the effectiveness of visual intervention within this group.
Follow-up after one year
One year after inclusion, the children at risk of VPD will repeat the visual function assessments, and all included children (with and without VPD risk) will repeat the eye tracking-based visual screening and undergo a neurodevelopmental assessment (that is standard care at most Neonatology departments, from 2 years CA). That way, the specific effects of early visual intervention on visual processing and neurocognitive development are compared and evaluated.
After the first follow-up, the children in the postponed intervention group will start their visual intervention program, which will also be evaluated one year later. In addition, the results of the visual screening are again evaluated for all children, to identify new cases with a risk of VPD who will then also qualify to start visual intervention. Differences in effectiveness of direct and postponed early visual intervention are assessed. The intervention study will have a duration of either one year or two years, depending on the visual intervention group.
Data collection methods
Medical and demographic information will be extracted from the medical records available at the academic medical center.
Visual screening – A0
All included children will be screened for a risk of VPD, which consists of 1) an eye tracking-based assessment, and 2) a neurological checklist.
The eye tracking-based assessment is used to measure visual attention and processing functions. The assessment will be combined with an existing appointment for standard outpatient visits at the Neonatology department when the child is ~ 1 year CA (T0) and 2 years CA (T1). During this assessment, children sit in front of the eye tracker monitor at a distance of approximately 60 cm, either independently, on the lap of their parent or in a pram. They do not receive verbal instructions and their body and head position is not restricted. The assessments are conducted in a quiet room with ambient light conditions. Visual stimuli (images and movies) are presented on the monitor to engage reflexive orienting eye movements of the child, while simultaneously the eye positions are recorded over time using infrared cornea reflection [Tobii T60 XL or Tobii X3, Tobii Corporation, Danderyd, Sweden]. That way, the child’s eye movement responses to various types of visual information (i.e. contrast, color, motion and form) are automatically recorded. These viewing behavior responses indicate whether and how fast a specific stimulus was detected and looked at. From these responses, the number of detected stimuli and the reaction time to fixation (RTF) of a stimulus are calculated. RTF is a measure for the timing of detecting and processing visual information and is the main study parameter(12, 13, 30, 31). Total test duration is approximately 15 minutes. The child’s viewing behavior parameters per visual stimulus are analyzed and compared with normative data, i.e. developmental trajectories of an existing database of healthy control children, born at term to identify abnormal detection and timing of processing of the visual stimuli. This results in a classification of normal and abnormal visual attention and processing functions.
Second, medical specialists examine the child’s medical history for the presence of neurological risk factors for VPD in the context of prematurity (32-35), i.e.,
- moderate-severe damage on neonatal MRI scans;
- cerebral palsy; unilateral, bilateral, hemiplegia, diplegia
- infantile esotropia/ convergent strabismus or nystagmus
- deviating head circumference (>1 SD in 12 months)
Inventories for daily life visual functioning – B0
The PAI-CY 0-2 questionnaire(36) will be filled in by parents upon inclusion. This questionnaire assesses daily visual functioning in seven domains. Originally developed as a list to identify participation and activity needs, it can also be used to investigate and monitor intervention needs of visually impaired young children. It is the only available patient-reported visual outcome measure for young children and has satisfactory psychometric properties (37).
Determining the risk of VPD
The risk of VPD is determined based on the baseline screening: abnormal viewing behavior, indicated by abnormal RTF values on one or more visual stimuli AND/OR the presence of at least one neurological risk factor for VPD. The children at risk of VPD are referred to standard care for children with suspected visual dysfunctions, i.e.:
- They will undergo an ophthalmic exam to evaluate eye and orthoptic function,
- They will become clients of the visual advisory and rehabilitation center where they undergo a visual function assessment and are enrolled in the visual intervention program.
Ophthalmic exam (standard care; group 2A and 2B) – C0
All children at risk of VPD will be referred to the Pediatric Ophthalmology department to evaluate visual acuity, refractive error and ocular alignment. This evaluation is performed by ophthalmologists and/or research orthoptists. Total time of the exam is approximately an hour.
Visual function assessment (VFA; standard care; group 2A and 2B) – D0
All children at risk of VPD will undergo an extensive VFA. This assessment is part of standard care and will be done by an experienced orthoptist or optometrist. All assessments will be performed according to a standardized protocol that ensures similar assessments, choice of tests and scoring by the various examiners. The following functions will be assessed: ocular alignment and fixation preference, binocular vision, presence of nystagmus, oculomotor function (fixation, saccades, pursuit, motility), convergence, visual acuity, visual field, contrast sensitivity and color vision. Performance per function is classified as normal or abnormal for the child’s age.
First follow-up (T1):
Starting one year after inclusion, i.e., from 2 years CA, the following assessments are repeated:
Visual screening (study-specific; all groups) – A1
The visual assessment (eye tracking-based exams) will be repeated in all included children, and will be combined with an existing appointment for standard outpatient visits at the Neonatology department.
Inventory for daily life visual functioning (study-specific) – B1
Parents are asked to complete the inventory again around the time of first follow-up.
Visual function assessments (VFA; standard care) – D1
The VFAs will be repeated in the children at risk of VPD (independent of the visual intervention group they are in), as part of standard care at the visual advisory center.
Neurodevelopmental assessment (standard care) – E
From 2 years CA, all children will receive a neurodevelopmental assessment at the NICU as part of the standard follow-up program of the dept. Neonatology. This assessment consists of the Bayley Scales of Infant and Toddler Development (Bayley-III-NL) and is performed by experienced (neuro)psychologists.
Second Follow-up (T2):
Two years after inclusion, i.e. from 3 years CA, all included children will repeat the eye tracking-based visual screening (A2) and the inventories for daily life visual functioning (B2). Since at 3 years CA there is no regular follow-up within clinical care, study-specific appointments will be made at the academic hospital or in the form of home visits. In addition, the children at risk of VPD who have been referred to the visual advisory center will undergo the VFA again (D2), as part of standard care.
By embedding the majority of this study within standard clinical care, by closely collaborating with involved medical and visual (re)habilitation specialists, and by planning participation together with regular appointments or in the form of home visits, we expect to maximize participants’ completion of the follow-up measurements.
Intervention: visual habilitation protocol (Additional file 3)
We developed a structured visual intervention protocol using a two-stepped approach: 1) dissecting available scientific knowledge about visual interventions in young children, and 2) establishing other, clinically relevant, factors in close collaboration with experienced behavioral therapists and neuropsychologists.
First, based on available (visual) intervention literature we extracted several key features for the intervention, i.e. we made a protocol that:
- starts well before school age to maximize experience-dependent neuroplasticity(38, 39)
- involves the total spectrum of visual development, not restricted to only a few visual functions(40) or general neurodevelopment(41)
- has quantitative and functional outcomes(23, 28)
- employs two intervention strategies that have complementary value(20, 27):
- Passive (bottom-up-feedforward) visual stimulation that is purposeful and specific(42-44)
- Active (top-down-modulated) visual perceptual training that is contingent on children’s abilities(28, 43, 45)
- can be individually-tailored by adapting materials and activities to children’s preferences and capabilities(25)
- incorporates children’s systems through active caregiver involvement(38, 46)
Second, we examined the clinical and practical requirements for an intervention protocol by consulting professionals about, e.g., which types of habilitation, in which (developmental) domains, which elements, materials and objects, minimum duration and frequency, and how to handle parental motivational and resistance issues. The answers to these questions were grouped and analyzed in order to extract common themes and select the most important clinical features the protocol should contain.
The result of this two-step process is a visual intervention program that consists of:
- A general protocol that is identical for all children
- A supplement protocol that is tailored to the specific VPD of the child.
Both parts are designed to adhere to the child’s basic visual skills and to their cognitive, motor and socio-emotional developmental level. Importantly, the parent-child relationship will be taken into account in order to support, involve and stimulate the parents in executing the intervention program at home.
The general visual protocol is adapted to the child’s age and developmental level and consists of exercises focused on the following functions: fixation, pursuit, visual attention, enhancing visual experiences and knowledge, perception of details and combining vision with motor action (visuomotor skills). The intervention program consists of several steps that can be applied to all functions:
- Enhancing the diversity of training with different visual materials
- Enhancing the duration of visual training
- Developing increasingly complex visual skills and behavior that are ecologically valid, i.e. related to the child’s activities and daily environment(20).
Visual input is provided in the form of different visual materials of different visual modalities (colors, black-white, moving and static objects, light and dark). The nature of visual input will be adapted to the preferences and abilities of the child, and successful responses and behavior will be rewarded (based on operant conditioning). Visual training of more complex skills and behavior is done by teaching the child to use a specific visual skill, to expand its use to other tasks and to integrate it in everyday life.
The supplement visual protocol is designed around the specific VPD that are determined based on results of the visual screening and assessments (VFA and observation) performed at baseline. For example, children with abnormal processing of form and motion information, but with normal processing of contrast and color information, will get additional training for the processing of form and motion-related visual information that is integrated within the visual intervention program itself, in order to comprehensively support the child.
- Focus moments. These therapy sessions with video feedback, evaluation with the parents and reports of behavioral observations, are done three times throughout the intervention period to determine whether the program suffices or needs adaptations.
- Stepping cards (per therapy session). An instruction for the daily practice sessions of parents that contains a specific goal, instruction, observational points, and evaluation..
- Logbook for therapists (per session) and parents (to be completed weekly). The logbooks are used to keep track of the frequency, intensity and content of the therapy sessions and the daily practice sessions by parents.
- Protocol for Activities & Materials to be used, based on chapter 5(29)
Criteria for discontinuing or modifying interventions
Modifying the intensity of intervention: after the second focus moment (around week 16), it is determined whether the child still benefits from sessions every week or every two weeks. If this intervention intensity is no longer needed, the intensity is brought down to once every four or six weeks, to keep monitoring (visual) development, and to enable another frequency adaptation when needed. This will be done until the end of the program.
Modifying the content or focus of rehabilitation: this is based on the evaluations with parents and the observations after each therapy session. If a modification is warranted, only the supplement protocol will be modified, the standard protocol will not change.
Improving and monitoring intervention adherence
All intervention activities are demonstrated and explained to the parents by the therapists. The goal is to have them understand the content of activities and the underlying motivation, to stimulate parents to practice daily with their child. Parents will participate in all therapy sessions: they do not only receive practice instructions but will also be educated on the visual development of their child. The parents are asked to log their daily practice session in order to evaluate them in the therapy sessions. These evaluations will give insights in improvements and/or changes in visual performance of the child, which is known to motivate parents and enhance intervention adherence.
Permitted concomitant care
Participating children will not be restricted in receiving care as usual. If applicable, they are allowed to engage in additional neurodevelopmental training programs during this study. However, participation in such programs will be carefully registered and monitored to take into account interference with the possible effects of the visual intervention program. In addition, children in the control intervention group will be provided with general developmental support and monitoring that does not include specific visual training components. This program consists of visits by a psychologist-in-training (under supervision of neuropsychologists from the academic hospital and visual advisory center) and aims at monitoring developmental achievements of preterm children from 1 to 2 years of corrected age. That way, we directly involve all parents in the study, and enable a structured and controlled investigation of the effectiveness of specific visual habilitation. After concluding the study, the children who are at risk of VPD and have been referred to the visual rehabilitation center will remain clients there. This means that their treatment does not necessarily stop, but that this depends on the indications and judgement of the therapists and psychologists.
To answer our main research question about the effectiveness of early visual intervention in young preterm children, we will compare visual outcomes between the intervention and control group. We will analyze results from the eye tracking-based visual assessment and the additional VFAs at baseline and at yearly follow-up measurements. Primary outcomes are the changes in visual parameters after the duration of the intervention study (i.e. from baseline to follow-up T1 and/or T2), i.e.:
- Quantitative visual parameters (eye tracking-based visual detection and viewing reaction times)
- Visual function assessment (VFA: visual acuity, contrast sensitivity, visual field, ocular motility)
Endpoints are the changes in these parameters after the visual intervention program. These parameters are chosen since their combination provides quantitative and objective results about functional viewing behavior (the eye tracking-based assessment), and clinically-relevant visual function outcomes (i.e. the VFAs). In addition, we will compare the effectiveness of direct (at 1 year CA) versus postponed visual habilitation (at 2 years CA) by comparing visual outcomes between these groups at T2.
Secondary outcomes are the neurodevelopmental level at the first follow-up (T1) and results from parental questionnaires about daily visual functioning at T1 and/or T2, i.e.:
- Total score, cognitive and motor sub scores of the neurocognitive assessment with Bayley Scales of Infant and Toddler Development (Bayley-III-NL)
- Total score and sub scores per visual domain of the PAI-CY 0-2 Inventory (i.e. attachment, stimulus processing, orientation, play, mobility, communication)
These measures were chosen because Bayley-III-NL is the only available neurocognitive assessment for children at this age, and the PAI-CY 0-2 Inventory is the only available parental questionnaire about daily (visual) behavior at this age.
Sample size calculation
Each year approximately 200 children are born before 30 weeks of gestation and admitted to the Neonatal Intensive Care Unit at the academic medical center in Rotterdam, the Netherlands. Based on previous research with this population we expect an inclusion rate of ~50%. Therefore, we expect to include at least 100 children at 1 year CA. There are no thorough estimates of the prevalence of VPD in preterm children. A previous study using the eye tracking-based assessment in extremely preterm children identified visual processing delays in 48% of preterm children without evidence for brain damage(16), and in 9% to 23% of children in a cross section of the preterm population at 1y CA(15). In addition, between 25% and 33% of children with CVI have prematurity as contributing factor(32). However, the prevalence of risk factors for VPD in our study population (often with brain damage and perinatal events) is much higher than 50%. Therefore, we expect that each year at least 50 newborn preterm children from the Neonatology department (i.e., 50%) are at risk of VPD and thus eligible for inclusion in the intervention study.
Children will be recruited from a medical follow-up program for children born preterm that is ongoing at the department of Neonatology. Children’s eligibility for inclusion will be screened by a multidisciplinary team (project leader and project members from Neonatology). The project leader and/or project members will approach their parents first by telephone, to ask for permission to send an information leaflet about the study. Two weeks after sending the study information, parents will be contacted again to ask for their permission to include their child in the study. The baseline assessment (i.e. the visual screening) and the 1-year follow-up assessment will be scheduled together with an existing appointment at Neonatology, to minimize burden for children and parents. Children in the control group (group 3) will be recruited through daycare centers. The parents will receive study information by mail and are asked to contact the project leader if they are willing to participate. If they give their consent, an appointment for the visual assessment will be made.
Randomization & intervention allocation
Prior to recruitment of participants, a randomization scheme has been designed in which the order of visual intervention groups (either direct or postponed) is randomized using an online tool (Sealed Envelope Ltd. 2016; https://www.sealedenvelope.com/simple-randomiser/v1/lists).
Randomization is blocked, to ensure a balance in sample size across groups over time, and stratified, to control and balance the influence of covariates(47). Covariates in the current study are: the presence of brain damage and gestational age (<28 weeks or 28-30 weeks).
After this computer-generated randomization, preterm children who are classified as being at risk of VPD will be assigned a participant number and concurrently be allocated to one of the visual intervention programs. The order of allocation corresponds with the date and order of inclusion. This allocation will be done by the principal investigator and remains concealed to all other investigators, the participating children, and their parents. All participant numbers will be separately placed in opaque envelopes that contain a note with the assigned visual intervention group. Revealing the group allocation to parents will be done by opening the opaque envelopes in their presence.
The study set-up is single-blind. Intervention allocation will be known by the project leader managing the contacts between all involved parties, and by the behavioral therapists of the visual rehabilitation center who will perform the interventions. Parents cannot be blinded to intervention allocation either, as they will actively participate in the intervention programs. However, the allocation will be blinded for the researchers and orthoptists who perform the baseline and follow-up visual assessments, and for the researchers performing data analyses.
Prior to analyzing results of the visual intervention (i.e. analyzing results of the follow-up visual assessments), participant numbers will be converted into a new participant code and visual intervention group will be coded into a new variable (group A or B). That way, group allocation remains concealed and bias during data analysis will be prevented(48).
All data will be handled confidentially and anonymously. Communication about participating children between the various participating departments and organizations will only be done using codes, not names or other personal identifying information. All data will be coded, and a separate coding list will link study data to personal identifying information of a specific subject. The coding list is password-protected and only accessible by the main investigator(s). Data files will be stored on a PC and will be accessible with a password that is only known to the main investigator(s). Paper documents will be stored in a locked cupboard of which only the main investigator(s) will have a key. The investigator(s) will remain blind to the participants’ outcomes during the course of the study. All data will be anonymized prior to analyses and publications. Group allocation and randomization will not be revealed until after the statistical analyses have been finished.
Parents and their children can withdraw from the study at any time for any reason if they wish to do so without any consequences. The investigator can decide to withdraw a subject from the study for urgent medical reasons. When subjects withdraw from the visual intervention program they will not be replaced, to ensure adherence to the randomization protocol for the RCT. Withdrawal of subjects will be taken into account during data analyses, by using intention-to-treat (ITT) analyses. Subjects withdrawn from the visual intervention program will be followed-up with a short questionnaire (assessed by telephone) in which they are asked for their reasons and circumstances of their withdrawal.
Sample size calculation
To answer our primary research question about the effectiveness of early visual intervention programs on visual attention and processing functions in preterm children at risk of VPD, we use a repeated measures ANOVA for the parameter RTF as primary analysis. An a priori power analysis provided a recommended total sample size of 32 children (and an actual power of 0.81 and a critical F of 4.17).
Effectiveness of visual intervention program
In children at risk of VPD who have been allocated to a visual intervention group, differences in viewing behavior parameter RTF between T0 and T1 are analyzed with a Repeated Measures ANOVA. A p-value of 0.05 will be considered statistically significant. Covariates are the medical (perinatal and ophthalmic) and demographic factors and the RM analyses will be done with and without them to obtain their contribution to the main effect. All analyses are done according to the intention-to-treat principle
Other effects of visual intervention on VPD (other parameters)
Secondary study parameters are the differences in other eye tracking-based parameters of viewing behavior and the outcomes of VFAs (e.g., visual acuity, contrast sensitivity, extent of visual field). RM ANOVAs with a p-value of 0.05 will be considered statistically significant. After finding a main effect of group on the viewing behavior parameters, post-hoc comparisons will be done to establish which of the 5 visual stimuli significantly differ from each other in parameter values. For these comparisons, Bonferroni’s correction will be applied to the viewing behavior variables to correct the p-value for the number of comparisons.
Effects of visual intervention on neurodevelopment
At 2 years of age, parameters from Bayley-III-NL are used as indicators of neurocognitive development. First, the relation between the visual assessment parameters and Bayley-III-NL parameters of the cognitive composite score, the language composite score, and the motor composite score will be analyzed using Pearson and Spearman correlation analyses. Next, univariate ANOVA’s are used to analyze differences in Bayley-III-NL scores between preterm children without a risk of VPD and children at risk of VPD, and between preterm children at risk of VPD in the direct versus the postponed intervention group.
Data monitoring & auditing
The risks of our study for patients and for scientific quality have both been judged as negligible, based on the NFU risk classification (Netherlands Federation of University Medical Centers). This risk level implies that monitoring should be done once a year. Monitoring involves:
- Study documents and agreements
- Patient inclusion, consent, compliance and source document verification
- Patient safety
- Study procedures
- Clinical data management system
- Correct saving of raw data, corrected data, and backups
In accordance with section 10, subsection 4 of the WMO, the sponsor will suspend the study if there is sufficient ground that continuation of the study will jeopardize subject health or safety. The sponsor will notify the accredited METC without undue delay of a temporary halt including the reason for such an action. The study will be suspended pending a further positive decision by the accredited METC. The investigator will take care that all subjects are kept informed.
Ethics & dissemination
The present study has been approved by Medical Ethical Testing Committee (METC) of Erasmus Medical Center, Rotterdam (MEC-2016-724) on April 19, 2017. Important protocol modifications have been and will be communicated with the METC (in the form of amendments to the original protocol), project employees/researchers, and participating parents. Written informed consent will be obtained by the researchers before the baseline assessment, based on a comprehensive information document that the potential participants have received. See additional file 2 for a model consent form.
Participant confidentiality will be protected through our data management policy (see section Data Management). The main investigator(s) and the participating medical and clinical specialists will have access to the final trial dataset. There are no contractual agreements that limit such access for investigators. During the course of the study the principal investigator will have no access to patient-identifying data and communication will only be done using participant codes. The involved researchers and sponsors have no financial or other competing interests for the overall trial nor for each study site. No harm is expected from trial participation, in particular since most study components are part of standard clinical care. Therefore ancillary and post-trial care are suspected to be non-applicable.
Nature and extent of the burden, risks and benefits associated with participation
The risks associated with participation are negligible and the burden for the children is minimal. Apart from the visual assessment from 1 year CA onwards, the total program is standard care for children with (suspected) visual problems. Only the age at which this care is applied is advanced for this study, and the visual rehabilitation protocol has been structured in order to enable comparisons between children. There is a general burden for children to perform the study-specific assessments and for parents to accompany their children. A specific burden for parents of children in the intervention groups is the time and effort they are asked to invest in monitoring and logging the child’s daily practices in the home environment. Benefits for all preterm children are earlier visual assessments, general developmental support and, if applicable, earlier habilitation of a risk of VPD than is the case in conventional pediatric care (i.e. from 1-2 years CA instead of ~4 years CA).
Dissemination of the results will include publications in peer-reviewed scientific journals and use of the visual assessments and the intervention protocol in clinical practice. There are no restrictions in the publication policy. The investigators aim to publish all results obtained from the study unreservedly.
Our study adheres to the Research Code of Erasmus MC in which guidelines for publishing and authorships are defined (https://www6.erasmusmc.nl/cs-research/bijlagen/publiceren?reason=404).
Plans for granting public access to full protocol, dataset and statistical code
Public access to the full protocol will be given through this paper. All results will be published open access. The dataset will not be made publicly available given the patient identifying information it contains. Statistical code will be made available upon request.