This application is being submitted to PA-18-591 in accordance with NOT-OD-18-194, addressing Component 3: Inclusive clinical research for individuals with Down syndrome (DS).
We aim to leverage the existing infrastructure of the NHLBI-funded randomized clinical trial, ?Impact of treatment of mild sleepdisordered breathing on children?s health (PATS)? (1U01 HL125295; UO1 HL125307) to identify the key design features needed to successfully conduct a future randomized controlled trial of sleep apnea treatment as an intervention to improve neurobehavioral, health outcomes, and quality of life of children with DS. Down syndrome (DS) is associated with a wide range of neurobehavioral and physical morbidities. Sleep apnea and sleep disturbances are highly prevalent in children with DS, exposing these children to chronically disturbed sleep, increased work of breathing, and intermittent hypoxemia-mechanisms that may exacerbate neurobehavioral and cardiac morbidities. Improving sleep health thus provides a modifiable intervention target for improving behavior, cognition, quality of life, and physical health of children with DS. However, there are critical knowledge gaps that limit the adoption and implementation of effective sleep apnea intervention strategies, resulting in variability in practice and likely suboptimal treatment of sleep apnea across the spectrum of DS. In particular, it is in unclear how to optimally select candidates likely to benefit from adenotonsillectomy and which polysomnographic, clinical, and demographic parameters are useful predictors of children most likely to benefit from adenotonsillectomy compared to alternative treatments or to watchful waiting. It is also unclear how to integrate alternatives to adenotonsillectomy (CPAP, hypoglossal nerve stimulation) in treatment care paths. The overall goal of this supplemental grant is to collect the necessary data to plan and execute a future pivotal randomized controlled trial (RCT) of the role of OSA treatment in the care of children with DS. Successful conduct of a future RCT requires further knowledge of the technical and logistical approaches for conducting such a trial, as well as an improved understanding of polysomnographic and clinical characteristics of subgroups of children most likely to benefit from OSA interventions. To meet these goals, we will build on the NHLBI-funded PATS study, leveraging expertise in pediatric sleep medicine, clinical trials and neuropsychology, and the infrastructure for recruitment and follow-up examinations. PATS currently studies children ages 3 to 12 years with mild sleep disordered breathing without other significant co-morbidities, comparing neurobehavioral, quality of life, and health care utilization outcomes in relationship to adenotonsillectomy vs. watchful waiting. Thus, children with DS, who have a very high prevalence of OSA and may be particularly susceptible to the adverse effects of nightly disruptions of sleep and intermittent hypoxemia, are not included in PATS. We now propose to recruit 50 children with DS, ages 3 to 12 years, who present to local specialty and primary care practices of the 7 PATS clinical sites for evaluation and treatment of SDB and are referred for adenotonsillectomy. At enrollment and 6 months following adenotonsillectomy, participants will undergo systematic assessments of sleep, behavior, cognition, daytime functioning, quality of life, and have measurements made to characterize key clinical features and health care utilization. Data will be analyzed to address several critical foundational questions needed for designing a pivotal RCT: a) estimate recruitment yields and retention rates across recruitment sources; b) characterize the feasibility of assessing outcomes across clinically relevant domains and across a wide age and morbidity range to inform approaches for optimizing the testing protocols to be most appropriate for this patient population; c) estimate responsiveness of outcome measurements to intervention (e.g., effect size estimation); and d) identify the clinical characteristics of children in whom there is uncertainty (equipoise) regarding OSA interventions and thus would be good candidates for future RCTs. Additionally, we will conduct mixed methods research, soliciting caregiver input on values, concerns and outcomes of greatest priority, and engage national DS organizations to better understand caregiver priorities and equipoise to inform future RCTs. This application is to support the PATS Clinical Coordinating Center role in developing and implementing the DS-Sleep Apnea protocol, coordinating the clinical activities across the 7 PATS sites, interface with a central IRB and assist with regulatory functions.
Adenotonsillectomy is one of the commonest surgical procedures performed in children, usually for symptoms of obstructed breathing during sleep and snoring, but often without actual obstructive sleep apnea (i.e., those with mild sleep-disordered breathing [MSDB]). However, the effects of surgery on MSDB is not known. This study will evaluate the effects of adenotonsillectomy on behavior, attention and health care utilization in children with MSDB, as well as identify subgroups who are most likely to benefit, thus informing future management approaches of this common pediatric condition and helping to direct resources to those children most likely to benefit.
