Efficacy of Supporting Play Exploration and Early Development Intervention in the First Months of Life for Infants Born Very Preterm: 3-Arm Randomized Clinical Trial Protocol

Abstract

Objective

The aim of this project is to study the effect of a physical therapist intervention provided in the first months of life on developmental outcomes of infants born very preterm. Secondary aims are to investigate the impact of intervention timing on the efficacy and impact of the intervention on infants with and without cerebral palsy.

Methods

This study is a multisite longitudinal controlled trial comparing developmental outcomes from infants in the Supporting Play, Exploration, and Early Development Intervention (SPEEDI)_Late or SPEEDI_Early group to a usual care group.

Settings are urban

Urban and rural areas surrounding 2 academic medical centers. There will be 90 preterm infants enrolled in this study born at <29 weeks of gestation. SPEEDI is a developmental intervention provided by collaboration between a physical therapist and parent to support a child’s motor and cognitive development. The primary outcome measure is the Bayley Scale of Infant and Toddler Development Cognitive and Gross Motor Scaled Scores. Secondary measures include behavioral coding of early problem solving skills, the Gross Motor Function Measure, and Test of Infant Motor Performance.

Impact

More than 270,000 infants are born very preterm in the United States each year, 50% of whom will have neurological dysfunction that limits their ability to keep pace with peers who are typically developing. This study is a step toward understanding the impact that intensive developmental intervention could have in this population in the first months of life.

More than 275,000 infants are born very preterm (<29 weeks of gestation) in the United States each year.¹ Fifty percent of infants born very preterm will have some degree of neurological dysfunction, limiting their ability to keep up with their typically developing peers.² Nineteen percent of infants born very preterm and 40% of those with neonatal white matter injury will be diagnosed with cerebral palsy (CP), a static neurological injury that impairs movement and limits activity and participation throughout the lifespan.^2,3 While medical advances continue to improve neonatal care, clinical rehabilitation for these high-risk infants has not kept pace with advances in basic science or developmental theory.^3–6

The mandate under the Individuals with Disabilities Education Improvement Act^7,8 is to provide early intervention (EI) to infants with disabilities. However, typical EI services are not designed to provide high-intensity, high-dose intervention during the time of maximum neuroplasticity in the first months of life.^9,10 Families of infants born preterm want information on how to support their infant’s development.^11,12 National data suggest 16 to 20% of infants under 3 years have unmet therapy needs for EI therapy with significant racial and socioeconomic disparities.^13–15 While there are federal guidelines for the timeline to complete enrollment in EI, data from multiple states^9,16 suggest that the majority of infants born preterm are not enrolled in EI by 3 months of adjusted age.^16–19 This delay means that the vast majority of infants do not receive intervention during a critical window for altering neural pathways. Additionally, children without a specific diagnosis receive fewer services than children with a diagnosis. This suggests that very preterm infants are likely to be among the 1 out of 3 enrolled children receiving less than 1 hour per month of EI until a significant delay is documented or diagnosis such as CP is made.¹³

Given the high risk of developmental disabilities, motor learning and coordination impairment, as well as the need for high repetitions to enhance learning in infants born preterm, interventions must engage parents to achieve a high dose of early experience (Fig. 1).^5,20–23 The proposed study will assess the efficacy of a program coined Supporting Play, Exploration, and Early Development Intervention (SPEEDI). At the core of the protocol, a parent/therapist collaborative is started by building confidence and supporting the parent to enhance parent-child interactions and develop daily routines that provide developmentally supportive activities earlier than traditional models of EI services (Fig. 1).

Figure 1.

Theoretical Model for Supporting Play Exploration and Developmental Intervention (SPEEDI).

SPEEDI acknowledges and is supported by a body of evidence suggesting a strong association between motor activity and early cognition.^24–27 Motor experience provides typically developing infants an opportunity to learn about object affordances and social interaction, which leads to enhancements in learning that support development across multiple domains.^27,28–30 The perception action model of development is governed by the theory that motor activity contributes to the infant’s attempts to attend to the environment, allowing the infant to receive and interpret important information and solve problems by linking the mind and body in a cycle that supports development.³¹ Children with motor impairments or delays have limited ability to interact with and interpret the environment, restricting their opportunities to learn through action.²⁶ Children born preterm with motor coordination disorders or CP score lower at school age on problem-solving tasks than those without motor disabilities.^24,25 SPEEDI is designed to alter this developmental trajectory through early experiences provided by parents, with the support of a therapist, that aid the infant’s development of perceptual and motor action pathways that promote global development (Fig. 1).

Reduced movement variability and a lack of adaptive postural control strategies are associated with delayed reaching, kicking coordination, and sitting in the first year of life.^32–35 Early movement quality (motor repertoire) is an early predictor of motor disability in children with CP and neurological dysfunction.^36,37 These persistent postural control deficits and lack of adaptive postural control in preterm infants provide theoretical support for SPEEDI’s focus on posture and self-directed movement. However, there is debate in the field of early infant development as to how early motor repertoires and neuronal connections can be modified and if so at what ages they are most adaptive.^4,30,38–42 Evaluating the efficacy and timing of delivering SPEEDI will begin to evaluate if the parent and child are more responsive to the intervention prior to or after 3 months of adjusted age. Three months of age was selected as it is when infants are often seen in developmental follow-up clinics, prompting referral to therapy services if not already started (Fig. 2).⁴³

Figure 2.

Assessment and intervention timeline. CP = cerebral palsy; EI = early intervention; EPSI = Early Problem Solving Indicator; GMFM = Gross Motor Function Measure; NICU = neonatal intensive care unit; V = visit.

The primary purpose of this study is to evaluate the effect of SPEEDI on developmental outcomes measured on the Bayley Scales of Infant and Toddler Development, 3rd edition for infants born very preterm compared with infants in usual care. The primary hypothesis is that infants who receive SPEEDI (either early or late) will have higher scores on Bayley motor and cognitive tests at visit 3, 7 months post baseline, compared with the usual care group. The secondary purposes are to begin to investigate longer term outcomes at 24 months, the impact of intervention timing on the efficacy of intervention, and compare the efficacy of the intervention in children who are later diagnosed with CP.

Methods

Participants

Ninety infants born very preterm (˂29 weeks of gestation) and cared for in level IV neonatal intensive care units (NICUs) associated with an academic medical center will participate in this study. Infants must be medically stable, off ventilator support by 42 weeks of gestation, and live within 60 miles of a participating hospital. All infants who meet these inclusion criteria are considered to be at high risk of developmental disability and meet eligibility criteria for EI services in Virginia.⁴⁴ Exclusion criteria include diagnosis of a genetic syndrome and parents who cannot consent to participation in English. Participating NICUs discharge infants to urban, suburban, and rural locations.

Recruitment and Randomization

All infants admitted to the participating NICUs will be screened for inclusion in the study. Once a family consents to participation, a full medical record review will be completed to gain medical information needed for randomization. Following a baseline assessment, each infant will be randomized into 1 of 3 groups: usual care, SPEEDI_Early, or SPEEDI_Later. Blocked and stratified randomization will be completed by the statistician for each site of this randomized clinical trial. Blocks of 9, 3 per group, will be used to ensure equal balance between groups and throughout the enrollment period. Strata will be based on the presence/absence of a high risk for neurological impairment at baseline.^45,46 Any infants with abnormal writhing movements on the Prechtl General Movement Assessment at the baseline assessment, intraventricular hemorrhage grade III/IV, or periventricular leukomalacia identified in the medical record prior to or at baseline will be placed in the high-risk strata to increase the likelihood the 3 groups will have a similar number of infants who are later diagnosed with CP. Computer-generated random numbers will be used by the study statistician to make the randomization sequence separately for each site. Allocation will be concealed using a numbered opaque envelope provided to each site’s study coordinator prior to enrollment initiation. Following the baseline assessment and stratification of each participant, the study coordinator will open the next envelope in the sequence to determine group assignment.

Intervention

All infants will receive standard care in the NICU and community (Fig. 2). Typical services in the NICU include routine medical care that may include physical, occupational, or speech therapy assessments or intervention as ordered by the medical team and referral to the infant’s local EI program at NICU discharge. All infants will be referred to an NICU follow-up program per the NICU’s usual protocols. Services will not be withheld from any group as this is deemed unethical; however, it is unusual for infants to receive direct therapy services prior to 6 to 7 months of adjusted age.¹⁰ The use of community services will be assessed via parent report at each assessment visit. The 2 groups who will receive the SPEEDI intervention are divided into SPEEDI_Early and SPEEDI_Late based on their randomization. Both SPEEDI groups will receive the same intervention, at the same dose, but at different developmental periods (Fig. 2). Infants in either SPEEDI intervention group will receive 10 therapist visits plus 3 months of daily parent-provided intervention. Each of the 10 intervention sessions is provided through collaboration between a physical therapist with experience treating neonates and a parent, addressing key principles or theoretical tenets of the SPEEDI intervention. The therapists providing the intervention and the parents of the participants in the intervention cannot be blinded due to the nature of this intervention requiring interaction between the 2 parties and discussion of the key principles. The intervention will be discontinued if requested by the parent for any reason.

The key principles of SPEEDI are directly related to the deficits commonly seen in infants born preterm. The theoretical model of SPEEDI highlights the proposed direct and indirect (parent interaction) pathways to support motor and cognitive development through targeted environmental enrichment, sensory motor learning opportunities, and collaboration between the parent, therapist, and infant to determine the best time and way to interact to provide opportunities to advance motor and cognitive skills.

SPEEDI intervention is provided using specific intervention strategies that address the key principles. The intervention is delivered in 2 phases with a focus on parent learning and interaction in phase 1 and direct intervention in phase 2. Infants born preterm often have unclear behavioral cues, autonomic instability, unstable behavioral state, and motor-based stress signs that can be difficult to interpret for parents and providers who are not skilled in working with this population during the first months of life. The first 5 sessions (phase 1) occur over 3 weeks in which the therapist uses a guided participation approach to help parents learn to identify ideal times for interaction as well as positive and negative behavioral interaction cues and how to adjust the environment to enhance interaction with the infant in response to the infant’s changing abilities.⁴⁷ Parents are also provided with an iPad that includes a video demonstration of various examples of stress signs, calming strategies, and environmental modifications. The therapist reviews the short video clips with the parent at the initial visit, and the videos remain accessible to the parent throughout phase 1. These videos can be used by the therapist as needed during phase 1 to help the parent identify behaviors and visualize strategies in other parent child dyads rather than trying to elicit them in their own baby. Guiding a parent through identifying stressors and successes as well as problem-solving strategies to reduce infant stress encourages the parent to use their knowledge for future opportunities to enhance interaction. In pilot work, 5 visits plus use of videos the parent could watch between sessions was adequate to engage parents as well as build their confidence and skills during interaction with their infant.

In SPEEDI phase 2, parents are taught a series of daily activities to complete with the infant. The parent uses what they learned in phase 1 to determine the best time, necessary environmental modifications, and engagement strategies to allow the infant to be as successful as possible with the activities each day. While providing opportunities to practice skills like head control, early reaching, kicking, and tummy time, the parent is trained to encourage the infant’s self-directed movement, movement variability, visual and manual object interaction, and social interaction. Parents are taught to encourage infant movements through environmental enrichment rather than to impose passive movement experiences. Key strategies or therapeutic intervention approaches are used to address the key principles and enrich the infant’s opportunities for movement. The strategies used through our the SPEEDI intervention include:

• 1) Providing graded postural support;

• 2) observing spontaneous movement in response to support;

• 3) varying postural support to encourage different opportunities and sensory-motor exploration;

• 4) varying positions with minimal support to encourage variable, infant-directed movement; and

• 5) providing opportunities to visualize, track, and manipulate objects. Towards the end of phase 1, the parent is provided a printed activity booklet that reviews suggested activities.

The activity booklet has 3 stages of difficulty per activity and information on how to select the ideal time for interaction. During the last 1 or 2 visits of phase 1, these activities are introduced, videos of the activities can be watched, and the parent and therapist may work together to determine what the infants’ abilities are at the end of phase 1.

In phase 2 of SPEEDI, parents provide 20 minutes of the daily activities included in the activity booklet over a 3-month period. Parents are encouraged to reflect on what they learned during phase 1 to provide opportunities during times of positive interaction consistent with the principles of phase 1, such as when the infant is awake, alert, and showing signs of interest in interaction. Throughout phase 2 the therapist and parent collaborate in person during 5 in-home or clinic-based sessions to determine the infant’s “just right challenge” or ideal level of developmental practice that challenges the infant slightly beyond the infant’s current abilities in motor, cognitive, and social domains but without being frustrating. Through the use of guided participation strategies, the therapist empowers the parent and supports the parents’ attempts to enrich the environment and provide daily opportunities for learning consistent with the intervention key principles. Between phase 2 sessions, parents are encouraged to progress the intervention activities independently through use of the guidance in the activity booklet. However, the primary focus of the sessions with the therapist during phase 2 is to help parents evaluate the infant’s readiness to advance the intervention so that the infant is always working at their optimal level of their “just right challenge.” Parents are encouraged to consider the balance between motor, attention, and cognitive challenges throughout each session.⁴⁸ This intervention approach is designed to be adaptable to the abilities of infants under 6 to 8 months of age. As such, a large portion of the intervention is helping parents learn to adapt their interactions with the infant as the infant grows and changes. Thus, the same key principles and strategies apply in both the SPEEDI_Early and SPEEDI_Late groups.

To measure fidelity of the intervention, both the therapist sessions as well as the independent parent sessions at home need to be monitored. During phase 2, parents are asked to document the daily completion of 20 minutes of the recommended activities in either the paper activity book or in an electronic application customized for this study. The completion of this activity log during phase 2 of intervention serves as a fidelity measure and allows for tracking of the number of days the parent reports providing intervention, reasons why an intervention day is missed, and the parent’s interpretation of the infant’s progress on the different stages of the activities. The interventionist reviews parent comments on the activity log and encourages completion at each visit.

In addition to the activity logs, the fidelity of the therapists to the SPEEDI intervention is measured in 2 ways. Two of the 10 sessions, 1 per phase, are videotaped and coded for fidelity to the intervention principles. In addition, after each of the 10 SPEEDI sessions, the therapist completes a checklist documenting the key principles and strategies used or reviewed at each session. In our pilot work, we found very high agreement between the therapists’ self-reflection on the fidelity and the PI scoring of their fidelity videos.

Role of the Funding Source

The funding agency has no role or responsibility in this study. The authors of this paper are the study key personnel and were responsible for developing the study protocol. The Data Safety Monitoring Board (DSMB), including 2 neonatologists and a statistician, had no role in developing the protocols primary outcomes or intervention. However, they did require the addition of safety outcomes that are not included in this protocol paper.

Outcome Measures

Primary outcomes

All infants will participate in the same assessment schedule regardless of group assignment (Fig. 2). An assessor blinded to group assignment and trained to reliability will conduct all assessments. Assessment visits can be split into 2 sessions completed within 24 hours if under 4 months or completed within 7 days if 4 months or over, based on the infant’s energy level. The primary outcome measure is the Bayley Scales of Infant and Toddler Development, 3rd edition (Bayley), Cognitive and Gross Motor Scaled Scores, which will be assessed at visit 2 through 5 with data from visit 3 used to answer the primary study aim. Bayley is a norm-referenced test designed to assess multiple developmental domains, including cognition, language, and motor abilities in infants 3 to 42 months of age.⁴⁹ Bayley provides summary scores on the broad constructs of development and comparison with a sample of typically developing children.

Secondary Outcomes

Given the high risk of CP in the study population, the Gross Motor Function Measure item set version will be used to assess the infant’s motor function in addition to the Bayley.⁴³ A secondary outcome measure, which is an adaptation of the Early Problem-Solving Indicator, will be used as a measure of play-based problem solving.^50,51 This play-based measure will provide a quantitative score of problem solving during self-directed actions. The Test of Infant Motor Performance will be completed at baseline and at visit 2 to fully describe the sample.^52,53 In addition, the Test of Infant Motor Performance is 1 of the few measures that can be completed both at baseline and visit 2 allowing for the assessment of short-term changes in motor function. No measure of cognitive function is validated for assessment in the NICU, limiting our ability to include a baseline measure of cognition.

Assessment of Cerebral Palsy

Prechtl’s General Movement Assessment (GMs) along with clinical brain imaging will be used during stratification to determine the risk of the infant having CP at baseline.^38,54,55 Writhing movements will be scored as normal or abnormal, including poor repertoire, cramped-synchronized, or chaotic.

To have the data needed to complete a retrospecific analysis of measures of the likelihood of having CP and the diagnosis of CP by 24 months, all infants will have an additional assessment of fidgety GM completed at 12 to 14 weeks. This will be completed at visit 2 or with a video submitted by the parents during this time frame, which will be scored as normal or abnormal (absent or abnormal). In addition, the Hammersmith Infant Neurological Exam, a standardized neurological exam, will be administered to support early identification of cerebral palsy.⁵⁶ At the completion of the study, the GMA, brain imaging, and Hammersmith Infant Neurological Exam score will be used by the study neurologist to indicate if the infant was at high risk of having CP at visit 2 and if the child had a diagnosis of CP by age 24 months. This will allow for a post-hoc assessment of the efficacy of SPEEDI in children with a high risk of CP or later diagnosed as having CP.

Additional Assessment

Given the focus on training parents to provide intervention daily during SPEEDI phase 2, we will assess parent child interaction using behavioral coding of a videotape of a 5-minute natural free play session. These measures will allow us to begin to describe any mediating factors on the efficacy of intervention. Additionally, parents will be asked to complete a series of surveys at each assessment visit. These surveys are an electronic version of the demographic, medical, and services questionnaires including the recommended common data elements for cerebral palsy from the National Institutes of Health. This will include race, ethnicity, socioeconomic status, parental education, infant health, emergency room visits, or hospitalization since the last visit and home access to toys.^57,58 In addition, the short form of the parent stress index⁵⁹ will be used to evaluate the potential change in stress that a parent may perceive while participating in this intervention. A secure web-based data entry system is used for direct data entry for all parent surveys. Data entry errors are screened automatically with data-limited database fields and manually every 6 months when preparing for DSMB reviews.

Data Analysis

To determine the efficacy of SPEEDI, intervention analysis will include a 2-sample t test comparing 3 outcome variables (Bayley Cognitive Standard Score, Bayley Gross Motor Standard Score, and problem solving behaviors) for the control versus combined SPEEDI_Early & SPEEDI_Late at visit 3. Additionally, a repeated-measures analysis of variance (RMANOVA) will be used to analyze each outcome using the longitudinal nature of the data collection. These RMANOVA models will be fit using a mixed linear model (MLM). The MLM will include 1 between-subjects variable (group: control or SPEEDI), 1 within-subject variable (visit: 2, 3, 4, 5), and the interaction between group and visit. If the interaction between group and visit is statistically significant, post-hoc comparisons will be constructed to test for group differences at the visits. The post-hoc comparisons will be tests using an α = .0083 to control the family-wise error rate.

Similarly, analysis will include a 2-sample t test (SPEEDI_Early vs SPEEDI_Late) on 3 outcome measures (Bayley Cognitive Standard Score, Bayley Gross Motor Standard Score, and a problem solving measure to test for differences between the 2 groups at visit 3). To control for multiple comparisons, a Bonferroni adjustment–corrected α = .0167 will be used for these t tests. Similar to the RMANOVA models described above, a RMANOVA model will be used to analyze each of the 3 outcomes using the longitudinal nature of the data.

Additionally, a 2-sample t test (SPEEDI vs usual) will be performed in both the high risk CP group and again in the low risk CP group on the outcome measure (Bayley Gross Motor and Cognitive Standard Score) to test the efficacy of SPEEDI separately for the 2 risk groups. To control for multiple comparisons, a Bonferroni adjustment (corrected α = .025) will be used for these t tests. The same analysis will be repeated using the children classification as no CP or CP at visit 5. Additionally, a RMANOVA model will be used to analyze the outcomes using the longitudinal nature of the data collection. All analysis will be completed using intent to treat analysis. All available data points will be included for each participant in the analysis, a strength of the RMANOVA model fit via a MLM. The impact of missing data will be assessed using a sensitivity analysis assuming the data missing is not missing at random using multiple imputation based on a pattern-mixture model. Multiple imputations create multiple copies of the original dataset with the same values for nonmissing observations but different values for the missing observations based on their pattern of messiness. Then, each of these imputed data sets, containing no missing values, will be analyzed using the RMANOVA model, after which all results will be combined for overall inference and compared with the original analysis with missing data. The sensitivity analysis tests the assumption that data are missing at random. We plan to use 100 imputed data sets for this sensitivity analysis.

Previous studies completed by this team have demonstrated retention of 80% to 90% as parents often enjoy observing the assessments and are provided a small stipend for their time, a toy for their infant, and, if requested, videos of the assessments. Sample size estimates were calculated for aim 1 using pilot data at 3 months post SPEEDI_Early Intervention or the equivalent of visit 3 in the proposed study.⁴⁸ For hypothesis 1a and 1b, we will be comparing any SPEEDI intervention (SPEEDI_Early + SPEEDI_Later) with the usual care group, and there will be a 2/1 ratio of SPEEDI intervention patients to usual care patients. To control for multiple comparisons for the 3 outcome measures, we used a Bonferroni correction and rather than an α = .05 significance level we used an α = .0167 significance level. Effect sizes of 0.84 for the Bayley Cognitive Standard Score and 1.44 for the Bayley Gross Motor Standard Score were used to calculate sample size. For a 2-sided, 2-group t test with equal variances, 48 pre-term infants in the combined SPEEDI intervention group and 24 pre-term infants in the usual care group will minimally have 80% power to detect group differences at visit 3. We have calculated the power at 12 months based on an analyzable sample of 72 pre-term infants (48 in the combined SPEEDI intervention group and 24 in the usual care group). These calculations are based on 12-month effects size of 0.963 for the Bayley Cognitive Standard Score and 0.779 for the Bayley Gross Motor Standard Score derived from our preliminary data, assuming a Bonferroni corrected α = .0167, and a 2-sided 2-group t test assuming equal variances between the groups. These power calculations show that at 12 months, we will have a power of 91% to detect the expected effect size for the Bayley Cognitive Standard Score and power of 74% for the Bayley Gross Motor Standard Score. Thus, we will plan to recruit 90 pre-term infants (30 per group), which will allow for a 20% drop-out rate and result in an analyzable sample of 72 pre-term infants. It should be noted that these sample size and power calculations do not consider the longitudinal nature of our data collection and thus are likely to be conservative. For our secondary aims 2 and 3, we have limited information regarding the difference between the proposed SPEEDI_Early and SPEEDI_Later and the high and low risk CP groups from our preliminary data. While approximations have been used to estimate power and detectable effect sizes, the study was powered for the primary aim.

Monitoring

Data are managed by an blinded data entry and management team. The study DSMB, including 2 neonatologists and a statistician who are independent of the study, has reviewed the study protocol and analysis plan. DSMB meetings every 6 months will review the safety with a single assessment of efficacy on the primary aims planned and compared with predetermined stop rules outlined in the DSMB charter. No formal audit is scheduled for this trial. Human participant approval will be maintained using a central system at the lead institution, and all needed amendments will be documented in the manual of procedures with corresponding updates to relevant parties.

Ethics and Dissemination

Approval and consent

Approval of both the protocol and the consent form were obtained before any participant was enrolled. Only 1 parent will be required to sign the consent form; however, space will be provided for 2 parents to sign the consent agreeing to their own participation.

Confidentiality

The study participants’ contact information will be securely stored at each clinical site for internal use during the study. All data will be disseminated in aggregate form without identifying any individual. Any photos or video included in the dissemination will have consent for use in education by the parent. At the conclusion of this study, data will be available in an aggregate form from the investigator and on clinicaltrials.gov.

Discussion

This is 1 of the first large-scale studies designed to assess the efficacy of targeted intervention provided collaboratively between an interventionist and parent focusing on both motor and cognitive development in the first months of life. The theoretically grounded intervention brings together concepts from parent-child interaction, and motor and cognitive development, that, if effective, could be implemented in NICUs and EI programs around the world. The parent engagement model limits the cost of providing care and increases the feasibility of implementation.

While this study has great potential, it is possible that it will not be adequately powered to answer all the secondary questions that are likely to come from the analysis. In addition, this study will not evaluate evidence for NICU-based therapy services in the first weeks after preterm birth since infants will not begin the study until they are at least 35 weeks and medically stable.

Conclusions

This study has the potential to provide information on the best timing of when intervention should begin for infants born preterm at high and low risk of CP. This would allow EI programs to provide parents with evidence-based information on why or why not and when to begin intervention services. Dissemination will target rehabilitation professionals, parents and policy makers.

Author Contributions

Concept/idea/research design: J. Burnsed; S. Brown; S. Dusing; A. Harper; K. Hendricks-Munoz; R. Stevenson; L. Thacker

Writing: S. Dusing; K. Hendricks-Munoz; S. Khurana; L. Thacker; R. Molinini

Data collection: S. Brown; A. Harper; A. Kane; S. Khurana

Data analysis: S. Dusing; L. Thacker; A. Kane

Project management: S. Dusing; K. Hendricks-Munoz; R. Stevenson; R. Stevenson

Fund procurement: S. Dusing

Providing subjects: S. Brown; K. Hendricks-Munoz

Providing facilities/equipment: S. Dusing; R. Stevenson

Providing institutional liaisons: S. Dusing

Consultation (including review of manuscript before submitting): A. Harper; K. Hendricks-Munoz; S. Khurana; R. Stevenson; L. Thacker

Funding

Primary Funding Source: Eunice Kennedy Shriver National Institute of Child Health & Human Development (award number: 1R01HD093624-01A1). Principal Investigator: Stacey Dusing, PT, PhD. Project Period 08/01/2018–07/31/2023.

The funding agency has no role in the design or interpretation of the data. Progress reports and data safety reports will be provided annually to the sponsor, to the funding agency, and Human Subjects Board.

Clinical Trial Registration

National Clinical Trial (NCT) Identified Number: NCT03518736. Clinical Trial registry: US National Library of Medicine. ClinicalTrials.gov, registered on May 8, 2018. Protocol Version 1.1. (approved by DSMB on December 13, 2018).

A Data Safety Monitoring Board (DSMB) is in place and has the responsibility of reviewing safety data every 6 months. Efficacy data will be reviewed 1 time when 50% of the sample has been enrolled. The DSMB will enforce the study stop rules included in the DSMB charter and study protocol. The DSMB will only influence the trial if there is a safety concern or efficacy confirmed with 50% of the sample and it is deemed unethical to continue with the study. The data management team is not involved in study design or stop rules others than to provide an overview of the data to the DSMB before each meeting.

Disclosures

The authors completed the ICMJE Form for Disclosure of Potential Conflicts of Interest and reported no conflicts of interest.