Participation of children with obstructive sleep apnea in clinical trials: A systematic review of barriers and interventions

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Despite this, children with OSA remain underrepresented in research, setting the standards for clinical diagnoses and treatments. Consequently, most evidence on treatment is based on adult data. This review focuses on studies assessing the barriers to clinical trial participation for children with OSA and discusses the intervention studies and efforts to overcome these barriers. Method We retrieved articles from Scopus, Embase, PubMed, and the Cochrane Library without date restrictions until May 2024. The language was restricted to English. The Joanna Briggs Institute (JBI) tool was used to assess methodological quality. Results From 25 studies included, 14 barrier subcategories were identified, which were classified as an objective factor, provider, and patient/caregiver. Conclusions Our findings emphasize the multifaceted barriers to enrolling children with OSA in clinical trials. Furthermore, we provide several underutilized solutions to facilitate children's participation in clinical trials. However, formal targeted strategies are still needed in the future because these recommendations alone might not solve the evidence gap in children. Registration: Registered in PROSPERO with ID: CRD42024533326. children obstructive sleep apnea clinical trials patient participation barrier Figures Figure 1 Introduction Obstructive sleep apnea (OSA) is a common sleep breathing disorder. OSA is a major global health problem that can lead to various adverse health outcomes[ 1 ]. OSA in children is a condition that differs from that in adults regarding etiology, clinical presentation, and consequences[ 2 ]. Studies suggested OSA prevalence in children of 1–5%[ 3 , 4 ] with most affected children aged 2–8 years[ 5 , 6 ]. Evidence shows that if untreated, pediatric OSA may lead to serious complications[ 7 ], such as dentofacial deformities (adenoid face), decreased attention, decreased academic performance, neurobehavioral problems, disturbed emotional regulation, impaired growth, endocrine disorders, pulmonary hypertension, and systemic hypertension[ 8 – 10 ]. However, children are vastly underrepresented in clinical trials setting the standards for diagnosis and intervention, leading to a lack of uniform standards for the OSA diagnosis and treatment guidelines in children[ 11 ]. Even when children are enrolled in clinical trials, they typically receive less attention than the general population treated in clinical practice, i.e., adults. Consequently, most evidence about the benefits and risks of OSA therapeutics was extrapolated from adults, subsequently leading to significant restriction disparities in clinical diagnosis and treatment strategies in children with OSA. Although children's participation in clinical trials has been the subject of frequent inquiries, the issue remains unresolved[ 12 , 13 ]. Several studies described the barriers as multifaceted, often involving a combination of caregiver, patient, and provider factors[ 14 – 16 ]. On the one hand, the diagnostic methods, including polysomnography (PSG), regarded as the gold standard, have several important limitations, such as stressfulness to children and parents, difficult-to-wear sensors, the need for hospitalization, and expensiveness[ 17 ]. Besides, there was no unity standard defining the minimum respiratory disturbance index of pediatric OSA[ 18 ]. On the other hand, treatment can cause adverse reactions reducing adherence, which can be particularly challenging in children[ 19 ]. Specific efforts to improve clinical trial enrollment of children with OSA included the unity standard, the attention of parents/caregivers, and the development of a limited number of trials dedicated to children[ 20 , 21 ]. However, no relevant studies to date have synthesized this research. This review focuses on studies that assessed the barriers to the participation of children with OSA in clinical trials and discusses the intervention studies and efforts to overcome these barriers. Evidence from such qualitative analysis will provide effective strategies on the barriers to clinical trial enrollment and interventions to facilitate the inclusion of children in OSA clinical trials. Methods Search strategy This systematic research was conducted and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines[ 22 ] and was registered with the International Prospective Register of Systematic Reviews database (PROSPERO, CRD42024533326). The search of Embase, Scopus, PubMed, and Cochrane Library identified relevant studies published up to May 2024. The search strategy was developed with relevant Population, Intervention, Comparison, and Outcomes terms linked using the AND operator: (ⅰ) children (pediatrics, etc.); (ⅱ) obstructive sleep apnea (sleep disorder breathing, apneic, etc.); (ⅲ) clinical trials (therapeutic research, human experimentation, etc.); (ⅳ) participation (eligibility, patient selection, etc.). A manual search of reference lists in articles retrieved online was conducted to identify other studies that might have been missed. Supplementary Table S1 displays the search strategy. Literature inclusion and exclusion criteria Included studies were independently screened for eligibility by two authors (ZD and XW). Disagreements were resolved through discussion or judged by a third reviewer (LW). Studies were included if they (ⅰ) were full-text articles of empirical, peer-reviewed experimental, quasi-experimental, or observational studies published in English and (ⅱ) focused on patients with OSA aged < 18. Studies were excluded if they (ⅰ) had no available data to extract and (ⅱ) described the situation but did not state the reasons for the low enrollment of children with OSA. Two independent authors (LW and XL) extracted data indicating the year of publication, geographic location, author, study type, sample size, age, interventions, and study duration according to a standardized template of Cochrane Collaboration and resolved disagreements through discussion. Quality and risk assessment The Joanna Briggs Institute (JBI)[ 23 ], a set of tailored quality assessment tools specific to certain study designs and tested for potential flaws in study methods or implementation, was used to evaluate the quality of included studies. Figure 1 Prisma flow diagram. Results Identification of relevant studies A total of 12561 studies were identified, and 1528 duplicates were removed. Furthermore, 10781 records were removed during the evaluation of titles and abstracts as they were irrelevant based on the review question. Full texts of 252 reports were retrieved and evaluated, and 25 were qualified for the systematic review (Fig. 1). Since quantitative synthesis (meta-analysis) was not impossible due to the diverse nature of data across studies, a qualitative synthesis was performed. Characteristics of included studies Table 1 summarizes the study characteristics of each study. Of the included studies, 8 were observational studies (4 cross-sectional[ 24 – 27 ] and 4 cohort studies[ 28 – 31 ]) and 17 were controlled intervention studies (2 quasi-experimental studies[ 32 , 33 ] and 15 randomized controlled trials[ 34 – 48 ]). Most studies were based in the USA (n = 10) [ 27 , 33 , 35 , 42 – 48 ] and Australia (n = 5) [ 29 , 30 , 32 , 37 , 39 ], followed by Vietnam (n = 1) [ 24 ], Brazil (n = 1) [ 36 ], Israel (n = 1) [ 34 ], Canada (n = 4) [ 25 , 26 , 31 , 40 ], Sweden (n = 1) [ 41 ], Finland (n = 1) [ 28 ], and China (n = 1) [ 38 ]. These studies were published between 1996 and 2023. The main influencing factors were summarized as parent/caregiver, patient, and physician factors. Table 1 Characteristics of the 25 studies included in this review Author Year Country Study type Age Sample size Study duration Sample source Baker et al. [ 39 ] 2023 Australia randomized controlled trial 3–12 2,142 6 weeks multiple institutions Dien et al. [ 24 ] 2022 Vietnam cross-sectional 2–12 195 NA single institution Dos et al. [ 36 ] 2021 Brazil randomized controlled trial 2–6 98 NA single institution Au et al. [ 38 ] 2021 China randomized controlled trial 6–11 521 9 months single institution Naara et al. [ 34 ] 2020 Israel randomized controlled trial 1.2–15 200 NA single institution Dalesio et al. [ 33 ] 2020 America quasi-experimental study 5–12 331 NA single institution Tsampalieros et al. [ 25 ] 2019 Canada cross-sectional 6–18 62 NA single institution Lynch et al. [ 31 ] 2019 Canada cohort study 8–16 42 3 months single institution Blake et al. [ 45 ] 2019 America randomized controlled trial 3–17 75 14 days single institution Diercks et al. [ 35 ] 2019 America randomized controlled trial 2–18 1,832 NA multiple institutions Liu et al. [ 37 ] 2018 Australia randomized controlled trial 5-9.9 453 7 months multiple institutions Gudnadottir et al. [ 41 ] 2018 Sweden randomized controlled trial 4–10 134 6 weeks single institution Vlahandonis et al. [ 30 ] 2014 Australia cohort study 7–13 155 4 years population-based Massicotte et al. [ 26 ] 2014 Canada cross-sectional 4–18 45 NA single institution Kheirandish et al. [ 27 ] 2014 America cross-sectional 6-7.6 176 NA multiple institutions Vlahandonis et al. [ 29 ] 2013 Australia cohort study 7–11 155 4 years single institution Friedman et al. [ 43 ] 2012 America randomized controlled trial 2–18 150 6 months single institution Kohler et al. [ 32 ] 2009 Australia quasi-experimental study 3–12 226 6 months single institution Kheirandish et al. [ 42 ] 2008 America randomized controlled trial 6–12 71 6 weeks single institution Khalil et al. [ 48 ] 2008 America randomized controlled trial 2.5–12 72 NA single institution Chang et al. [ 46 ] 2005 America randomized controlled trial 2–16 128 NA single institution Goldstein et al. [ 47 ] 2004 America randomized controlled trial 2–14 78 6 months multiple institutions Nieminen et al. [ 28 ] 2002 Finland cohort study 2.4–10.5 78 6 months single institution Brouillette et al. [ 40 ] 2001 Canada randomized controlled trial 2–6 278 6 weeks single institution Helfaer et al. [ 44 ] 1996 America randomized controlled trial 1–18 18 NA single institution TABLE 2 Identified barriers to clinical trial participation of children with obstructive sleep apnea Quality of the studies Supplementary Figure S1 -4 demonstrates the quality and risk of bias analyses of included studies. Of them, twelve were rated as having low quality for ≥ 2 questions on their appraisals. Studies assessing barriers to the participation of children with OSA in clinical trials We identified 14 subcategories of barriers across the studies, which were classified as objective, provider, and patient/caregiver factors. Most studies (92%) reported objective barriers. Twenty studies reported stringent eligibility criteria as a major barrier[ 24 – 26 , 28 , 32 – 47 ]. Other causes included language barriers[ 32 , 35 , 39 , 43 , 45 ], duration [ 30 , 33 ], technical inadequacies[ 25 , 26 , 28 – 30 , 33 , 37 , 44 ], and the need for emergency/other treatment[ 24 , 31 , 32 , 36 , 40 , 41 , 43 , 45 ]. Details are given in Table 2 . Five studies reported provider barriers[ 35 , 39 , 45 , 46 , 48 ]. One found that surgeon consensus was in favor of surgery rather than medicine during the follow-up, possibly changing the treatment[ 39 ]. Four studies reported other barriers[ 35 , 45 , 46 , 48 ], such as another surgical method during the study[ 45 ], not timely prepared medication[ 48 ], late contact[ 46 ], and medication misuse[ 35 ]. Twenty-three studies reported patient/caregiver barriers[ 24 – 28 , 31 – 48 ], including disagreement on or rejection of the treatment[ 24 , 25 , 27 , 28 , 32 – 36 , 41 – 43 , 47 ], preferences for another treatment[24,27,45–47), and refusion to follow-up[ 25 , 27 , 28 , 32 , 34 , 35 , 37 , 38 , 41 – 43 , 47 ]. Other identified barriers were transportation issues[ 28 – 31 ], PSG tolerability[ 26 , 43 , 47 ], and congenital diseases or cognitive disorders[ 24 – 27 , 31 , 32 , 38 – 45 , 47 , 48 ]. Discussion Key findings To our knowledge, this study is the first systematic review of the barriers and interventions related to children with OSA, which identified 25 relevant studies examining barriers hindering the participation of children with OSA in clinical trials. Our findings generally define the barriers as subjective and objective causes. However, the research on interventions in this population is limited. Consequently, effective strategies to improve the participation of children with OSA in clinical trials are still underdeveloped. Our study underscores the complex system impediments that effectively exclude children and their parents from clinical trials and offers some solutions to expand clinical trials. Broaden eligibility criteria Our findings highlight the rigid eligibility criteria as a major structural barrier to children’s access to available trials. Efforts to address this problem and particular measures are needed. Specific inclusion criteria should be adopted according to experimental design rather than based on the subjective preferences of the investigators. Moreover, ensuring which comorbidity can be accepted by clinical trial criteria is essential to guide investigators. Providers should cooperate with pediatricians and caregivers to better understand the requirements of children when designing trials. Another factor also known to influence trial participation is language[ 49 ]. A proportion of children with parents cannot understand the study protocol. Additionally, organizing translators is often difficult, and even if they are present, patients or their guardians may have difficulty comprehending the information they were given. Thus, researchers may be unwilling to spend time explaining the study protocol, leading to the exclusion of this eligible group. Thus far, there is no perfect solution for this issue. Senior doctors and translators might need to approach those patients, but it could increase the financial and time burden. Addressing subject barriers Besides structure barriers, attention should also be directed to subject barriers. Our findings highlight the practical impediments, such as time constraints, inadequate transportation, lack of interest, and cost, which limit the participation of children and their families in clinical trials. Hence, practical strategies to overcome these barriers are needed. The government or trial unit should cooperate with transportation companies to provide financial and transportation support for long-distance patients, which may help facilitate participation. Besides, telemedicine may assist people with inconvenient transportation[ 50 ]. Moreover, nonpractical psychosocial barriers cannot be ignored. Efforts to identify patient’s preferences may help individuals be better prepared for participation. In pediatric clinical trials, legal guardians usually have strong demands for the results[ 51 ]. On the one hand, misunderstanding the content of the subject recruitment may affect the authenticity and objectivity of the intention to participate. On the other hand, high expectations for the experimental method determine their concern about the efficacy of the method and about being placed in an unwanted group, such as the placebo group[ 52 ]. Strategies need tailoring to specific obstacles to prevent subjects from blindly worrying about rejection because of insufficient understanding of clinical trials. The national governing bodies can develop "sunny" official clinical trial public videos to promote and introduce clinical trials through websites, podcasts, and other channels to alleviate blind rejection[ 53 ]. Meanwhile, medical and allied health professionals can promote clinical trials in the communities to help the public establish a correct understanding of clinical trials. Expanding the reach of clinical trials Many children have health defects or other limitations that prevent their enrollment in some trials. Evidence shows that OSA occurs at higher rates and greater severity in children with Down syndrome[ 54 ]. Some studies indicated that children with cleft palate have a higher risk of OSA compared with children without cleft palate[ 55 ]. Thus, increasing the enrollment of exceptional children in current trials by broadening studies to include an exceptional population is a promising solution[ 56 ]. Virtually, exceptional children-specific trials could examine whether those new treatments apply to a more clinically diverse patient population or can be broadly implemented[ 57 ]. To promote the implementation of these trials, suitable ways facilitating the cooperation between experimenters and guardians should be founded to ensure that these studies are amenable to the participation of frail or disabled children with consequences meeting their needs[ 58 ]. According to our findings, government and financial support are vital[ 59 ]. Assistance from policy and financial aid for the special children population could promote their participation. One example is surgical assistance and subsidy work for OSA in preschool children with cleft palate, funded by the Civil Affairs Department to reduce surgical costs. We hope that a more inclusive medical environment will improve the evidence for diagnosing and treating OSA in children, including children with special needs and comorbidities. Strengthening provider’s training The success of children's participation in the clinical trials also depends on providers. Strategies for providers to improve trial methods and follow-up are required. The technical inadequacies in trials include incomplete data, missing or poor signal in PSG, and pharmacy or study personnel error. Some studies mentioned the barriers to obtaining PSG due to the lack of tolerability of PSG equipment in children[ 26 , 43 , 47 ]. Some studies emphasized aborted follow-ups by researchers. Equipment control and data management should be performed by specialists or professionally trained recorders to avoid data loss caused by improper operation[ 44 ]. Due to poor children’s compliance, the application of wearable devices faces special challenges. The design of data inspection equipment or children's interest and compliance should be improved through play interactions. The follow-up is the process of exchanging information with and helping patients as much as possible[ 60 ]. Therefore, researchers not only need to collect data but also to understand the patient’s needs. Building trust quickly is the first step and foundation for high-quality follow-up. Hence, paying attention to communication skills and enhancing the trust of the interviewees are necessary for good compliance. During the follow-up, disturbing the rest of the patients should be avoided. In the case of relatively sufficient resource allocation, strategies, models, and tools can be constantly updated and improved, and intelligent follow-up systems, such as mobile apps, can be developed to provide remote consultation services in conjunction with data collection. Leveraging cloud database Researchers should use cloud databases including a large number of children with OSA to fill the evidence gap due to the deficiencies in the trials[ 61 ]. Databases provide vast amounts of crowd-based and multiple-source data, which can be retrospectively analyzed. For example, data from Electronic Health Records (EHRs) or other health management systems that combine data from multiple visualization platforms may help obtain the evidence[ 62 ]. Thus, researchers and other related technicists should work together to develop a multi-participation value co-creation platform for ensuring the safe sharing and circulation of data to realize optimal resource allocation and collaborative services. Strengths and limitations The present study has several strengths. First, this is the first systematic review to synthesize the literature on barriers to the participation of children with OSA in clinical trials and discuss strategies to overcome them. Second, this study combined these barriers and classified them to propose more targeted measures for each subcategory. Third, this study extends previous knowledge, assessing and reporting the findings according to PRISMA guidelines. Moreover, this study has several limitations. First, a meta-analysis could not be conducted owing to the diverse nature of data across studies. Thus, our analysis was limited to a qualitative synthesis of data. Second, we investigated trials purposely designed for children rather than for the general population, possibly leading the focus on the evidence base per se but not the strategies aimed at improving clinical trial enrollment. Finally, we discussed the barriers to participation but did not analyze the potential causes of these issues. Conclusion Our findings emphasize that promoting the participation of children with OSA in clinical trials is relevant to all providers, patients themselves, and parents or caregivers. Therefore, we propose that providers should pay attention to promoting and encouraging their pediatric patients and their families to participate in clinical trials. Additionally, they should develop formal, targeted strategies to provide data and technical support for the development of diagnosis and treatment standards specific to children with OSA, ensuring that all children receive specific, evidence-based, and high-quality therapy. Abbreviations OSA: Obstructive sleep apnea EHRs: Electronic Health Records PRISMA: Systematic Reviews and Meta-Analysis JBI: Joanna Briggs Institute PSG: Polysomnography Declarations Author Contributions ZD, XW, LW and XL conducted the search and data extraction. The draft was written by LW. XLZ and ZJL reviewed and edited the manuscript extensively. All authors contributed to the article and approved the final manuscript. Funding None Data availability The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author. Ethical approval and consent to participate Not applicable. Consent for publication Not applicable. Competing interests The authors declare no competing interests. References Au CT, Chan KCC, Lee DLY, et al. Effect of surgical intervention for mild childhood obstructive sleep apnoea on attention and behavioural outcomes: A randomized controlled study. Respirol Carlton Vic. 2021;26(7):690-699. Baker A, Grobler A, Davies K, et al. Effectiveness of Intranasal Mometasone Furoate vs Saline for Sleep-Disordered Breathing in Children: A Randomized Clinical Trial. JAMA Pediatr. 2023;177(3):240-247. Baker CN, Arnold DH, Meagher S. Enrollment and attendance in a parent training prevention program for conduct problems. Prev Sci Off J Soc Prev Res. 2011;12(2):126-138. Bitners AC, Arens R. 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Efficacy of obstructive sleep apnea treatment by antileukotriene receptor and surgery therapy in children with adenotonsillar hypertrophy: A descriptive and cohort study. Front Neurol. 2022;13:1008310. Tsampalieros A, Blinder H, Hoey L, et al. Obstructive sleep apnea and hypertension in pediatric chronic kidney disease. Pediatr Nephrol Berl Ger. 2019;34(11):2361-2370. Vlahandonis A, Nixon GM, Davey MJ, Walter LM, Horne RSC. Improvement of sleep-disordered breathing in children is associated with a reduction in overnight blood pressure. Sleep Med. 2013;14(12):1295-1303. Vlahandonis A, Yiallourou SR, Sands SA, et al. Long-term changes in heart rate variability in elementary school-aged children with sleep-disordered breathing. Sleep Med. 2014;15(1):76-82. Wendler D, Jenkins T. Children’s and their parents’ views on facing research risks for the benefit of others. Arch Pediatr Adolesc Med. 2008;162(1):9-14. Zaffanello M, Piacentini G, La Grutta S. Beyond the growth delay in children with sleep-related breathing disorders: a systematic review. Panminerva Med. 2020;62(3):164-175. Zaffanello M, Piacentini G, La Grutta S. The cardiovascular risk in paediatrics: the paradigm of the obstructive sleep apnoea syndrome. Blood Transfus Trasfus Sangue. 2020;18(3):217-225. Additional Declarations No competing interests reported. Supplementary Files supplementarymaterialFigureS14.docx supplementarymaterialTableS1.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4640956","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":323643954,"identity":"b1e9fcc9-0710-44e7-ba47-eb10631a091f","order_by":0,"name":"Lan Wu","email":"","orcid":"","institution":"Shenyang Children’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"Lan","middleName":"","lastName":"Wu","suffix":""},{"id":323643955,"identity":"86f40b0e-e0fe-4718-bf8e-d6d724c84351","order_by":1,"name":"Xin Li","email":"","orcid":"","institution":"the Fourth Affiliated Hospital of China Medical University","correspondingAuthor":false,"prefix":"","firstName":"Xin","middleName":"","lastName":"Li","suffix":""},{"id":323643957,"identity":"f7ffd3c4-ef22-4d3e-b3e3-4dac55a9114a","order_by":2,"name":"Xin Wang","email":"","orcid":"","institution":"Shenyang Children’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"Xin","middleName":"","lastName":"Wang","suffix":""},{"id":323643959,"identity":"5da90c2b-c177-41a9-bf11-d574e1a0ff76","order_by":3,"name":"Zhuo Du","email":"","orcid":"","institution":"Shenyang Children’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"Zhuo","middleName":"","lastName":"Du","suffix":""},{"id":323643961,"identity":"10b99058-0c16-4f37-8417-92ffee108f10","order_by":4,"name":"Xinli Zhang","email":"","orcid":"","institution":"Shenyang Children’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"Xinli","middleName":"","lastName":"Zhang","suffix":""},{"id":323643962,"identity":"6775b67f-90fc-4337-a760-464d0a5346a0","order_by":5,"name":"Zhijian Liu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAxElEQVRIiWNgGAWjYBACfvb2gw8+GEjI8ROtRbLnTLLhjAobY8kGYrUY3Egwk+Y5k5a44QDR1hxISJPgbTvMuPl48gaGHxXbCOtgbDh42EKy7TCz2ZlnBYw9Z24T1sLM2JB4w7DtMJvZjRwDZsY2IrSwMTMYSCS2HeYxnkGsFh42BiOJA2fSJAwkiNUiwcOTbNhQYWMgAfTLQaL8Yn//+cHHfwwk6vvbkzc++FFBhBYkkGBwgCT1YC2k6hgFo2AUjIIRAgATtUAk1IdHwQAAAABJRU5ErkJggg==","orcid":"","institution":"Shenyang Children’s Hospital","correspondingAuthor":true,"prefix":"","firstName":"Zhijian","middleName":"","lastName":"Liu","suffix":""}],"badges":[],"createdAt":"2024-06-26 08:04:13","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4640956/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4640956/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":60943843,"identity":"c7383b71-d157-4398-8a07-d012135536b2","added_by":"auto","created_at":"2024-07-23 22:04:35","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":560964,"visible":true,"origin":"","legend":"\u003cp\u003ePrisma flow diagram.\u003c/p\u003e","description":"","filename":"bmcFig1.Prismaflowdiagram.png","url":"https://assets-eu.researchsquare.com/files/rs-4640956/v1/8330b0ca7db8ed215b0c6f1f.png"},{"id":66871520,"identity":"1b42b9cf-fe98-45ad-9a61-21aca20646ec","added_by":"auto","created_at":"2024-10-17 09:48:06","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1196067,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4640956/v1/16d729bb-f874-437e-931d-58b40b1f2e94.pdf"},{"id":60943844,"identity":"7865342a-923a-4c19-b76f-8824f34fe600","added_by":"auto","created_at":"2024-07-23 22:04:35","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":1916087,"visible":true,"origin":"","legend":"","description":"","filename":"supplementarymaterialFigureS14.docx","url":"https://assets-eu.researchsquare.com/files/rs-4640956/v1/fdd58a93b22a862bc6977279.docx"},{"id":60943845,"identity":"725b01e7-1655-4ab6-8308-fad7c188cb2e","added_by":"auto","created_at":"2024-07-23 22:04:35","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":17824,"visible":true,"origin":"","legend":"","description":"","filename":"supplementarymaterialTableS1.docx","url":"https://assets-eu.researchsquare.com/files/rs-4640956/v1/1db979d579620caa4f5eada0.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Participation of children with obstructive sleep apnea in clinical trials: A systematic review of barriers and interventions","fulltext":[{"header":"Introduction","content":"\u003cp\u003eObstructive sleep apnea (OSA) is a common sleep breathing disorder. OSA is a major global health problem that can lead to various adverse health outcomes[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. OSA in children is a condition that differs from that in adults regarding etiology, clinical presentation, and consequences[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Studies suggested OSA prevalence in children of 1\u0026ndash;5%[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] with most affected children aged 2\u0026ndash;8 years[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Evidence shows that if untreated, pediatric OSA may lead to serious complications[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], such as dentofacial deformities (adenoid face), decreased attention, decreased academic performance, neurobehavioral problems, disturbed emotional regulation, impaired growth, endocrine disorders, pulmonary hypertension, and systemic hypertension[\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHowever, children are vastly underrepresented in clinical trials setting the standards for diagnosis and intervention, leading to a lack of uniform standards for the OSA diagnosis and treatment guidelines in children[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Even when children are enrolled in clinical trials, they typically receive less attention than the general population treated in clinical practice, i.e., adults. Consequently, most evidence about the benefits and risks of OSA therapeutics was extrapolated from adults, subsequently leading to significant restriction disparities in clinical diagnosis and treatment strategies in children with OSA.\u003c/p\u003e \u003cp\u003eAlthough children's participation in clinical trials has been the subject of frequent inquiries, the issue remains unresolved[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Several studies described the barriers as multifaceted, often involving a combination of caregiver, patient, and provider factors[\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. On the one hand, the diagnostic methods, including polysomnography (PSG), regarded as the gold standard, have several important limitations, such as stressfulness to children and parents, difficult-to-wear sensors, the need for hospitalization, and expensiveness[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Besides, there was no unity standard defining the minimum respiratory disturbance index of pediatric OSA[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. On the other hand, treatment can cause adverse reactions reducing adherence, which can be particularly challenging in children[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSpecific efforts to improve clinical trial enrollment of children with OSA included the unity standard, the attention of parents/caregivers, and the development of a limited number of trials dedicated to children[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. However, no relevant studies to date have synthesized this research. This review focuses on studies that assessed the barriers to the participation of children with OSA in clinical trials and discusses the intervention studies and efforts to overcome these barriers. Evidence from such qualitative analysis will provide effective strategies on the barriers to clinical trial enrollment and interventions to facilitate the inclusion of children in OSA clinical trials.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eSearch strategy\u003c/h2\u003e \u003cp\u003eThis systematic research was conducted and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] and was registered with the International Prospective Register of Systematic Reviews database (PROSPERO, CRD42024533326). The search of Embase, Scopus, PubMed, and Cochrane Library identified relevant studies published up to May 2024. The search strategy was developed with relevant Population, Intervention, Comparison, and Outcomes terms linked using the AND operator: (ⅰ) children (pediatrics, etc.); (ⅱ) obstructive sleep apnea (sleep disorder breathing, apneic, etc.); (ⅲ) clinical trials (therapeutic research, human experimentation, etc.); (ⅳ) participation (eligibility, patient selection, etc.). A manual search of reference lists in articles retrieved online was conducted to identify other studies that might have been missed. Supplementary Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e displays the search strategy.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eLiterature inclusion and exclusion criteria\u003c/h2\u003e \u003cp\u003eIncluded studies were independently screened for eligibility by two authors (ZD and XW). Disagreements were resolved through discussion or judged by a third reviewer (LW). Studies were included if they (ⅰ) were full-text articles of empirical, peer-reviewed experimental, quasi-experimental, or observational studies published in English and (ⅱ) focused on patients with OSA aged\u0026thinsp;\u0026lt;\u0026thinsp;18. Studies were excluded if they (ⅰ) had no available data to extract and (ⅱ) described the situation but did not state the reasons for the low enrollment of children with OSA. Two independent authors (LW and XL) extracted data indicating the year of publication, geographic location, author, study type, sample size, age, interventions, and study duration according to a standardized template of Cochrane Collaboration and resolved disagreements through discussion.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eQuality and risk assessment\u003c/h2\u003e \u003cp\u003eThe Joanna Briggs Institute (JBI)[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e], a set of tailored quality assessment tools specific to certain study designs and tested for potential flaws in study methods or implementation, was used to evaluate the quality of included studies.\u003c/p\u003e \u003cp\u003e \u003cb\u003eFigure\u0026nbsp;1\u003c/b\u003e Prisma flow diagram.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n \u003ch2\u003eIdentification of relevant studies\u003c/h2\u003e\n \u003cp\u003eA total of 12561 studies were identified, and 1528 duplicates were removed. Furthermore, 10781 records were removed during the evaluation of titles and abstracts as they were irrelevant based on the review question. Full texts of 252 reports were retrieved and evaluated, and 25 were qualified for the systematic review (Fig.\u0026nbsp;1). Since quantitative synthesis (meta-analysis) was not impossible due to the diverse nature of data across studies, a qualitative synthesis was performed.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n \u003ch2\u003eCharacteristics of included studies\u003c/h2\u003e\n \u003cp\u003eTable \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e summarizes the study characteristics of each study. Of the included studies, 8 were observational studies (4 cross-sectional[\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e] and 4 cohort studies[\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e]) and 17 were controlled intervention studies (2 quasi-experimental studies[\u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e33\u003c/span\u003e] and 15 randomized controlled trials[\u003cspan class=\"CitationRef\"\u003e34\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e48\u003c/span\u003e]). Most studies were based in the USA (n\u0026thinsp;=\u0026thinsp;10) [\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e42\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e48\u003c/span\u003e] and Australia (n\u0026thinsp;=\u0026thinsp;5) [\u003cspan class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e39\u003c/span\u003e], followed by Vietnam (n\u0026thinsp;=\u0026thinsp;1) [\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e], Brazil (n\u0026thinsp;=\u0026thinsp;1) [\u003cspan class=\"CitationRef\"\u003e36\u003c/span\u003e], Israel (n\u0026thinsp;=\u0026thinsp;1) [\u003cspan class=\"CitationRef\"\u003e34\u003c/span\u003e], Canada (n\u0026thinsp;=\u0026thinsp;4) [\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e40\u003c/span\u003e], Sweden (n\u0026thinsp;=\u0026thinsp;1) [\u003cspan class=\"CitationRef\"\u003e41\u003c/span\u003e], Finland (n\u0026thinsp;=\u0026thinsp;1) [\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e], and China (n\u0026thinsp;=\u0026thinsp;1) [\u003cspan class=\"CitationRef\"\u003e38\u003c/span\u003e]. These studies were published between 1996 and 2023. The main influencing factors were summarized as parent/caregiver, patient, and physician factors.\u003c/p\u003e\n \u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eCharacteristics of the 25 studies included in this review\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAuthor\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eYear\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCountry\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eStudy type\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSample size\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eStudy duration\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSample source\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBaker et al. [\u003cspan class=\"CitationRef\"\u003e39\u003c/span\u003e]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2023\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAustralia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003erandomized controlled trial\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u0026ndash;12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2,142\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 weeks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003emultiple institutions\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDien et al. [\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVietnam\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ecross-sectional\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u0026ndash;12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e195\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003esingle institution\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDos et al. [\u003cspan class=\"CitationRef\"\u003e36\u003c/span\u003e]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBrazil\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003erandomized controlled trial\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u0026ndash;6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e98\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003esingle institution\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAu et al. [\u003cspan class=\"CitationRef\"\u003e38\u003c/span\u003e]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChina\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003erandomized controlled trial\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6\u0026ndash;11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e521\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003esingle institution\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNaara et al. [\u003cspan class=\"CitationRef\"\u003e34\u003c/span\u003e]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2020\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIsrael\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003erandomized controlled trial\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.2\u0026ndash;15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e200\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003esingle institution\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDalesio et al. [\u003cspan class=\"CitationRef\"\u003e33\u003c/span\u003e]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2020\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAmerica\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003equasi-experimental study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5\u0026ndash;12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e331\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003esingle institution\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTsampalieros et al. [\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2019\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCanada\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ecross-sectional\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6\u0026ndash;18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003esingle institution\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLynch et al. [\u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2019\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCanada\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ecohort study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8\u0026ndash;16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003esingle institution\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBlake et al. [\u003cspan class=\"CitationRef\"\u003e45\u003c/span\u003e]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2019\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAmerica\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003erandomized controlled trial\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u0026ndash;17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14 days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003esingle institution\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDiercks et al. [\u003cspan class=\"CitationRef\"\u003e35\u003c/span\u003e]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2019\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAmerica\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003erandomized controlled trial\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u0026ndash;18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1,832\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003emultiple institutions\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLiu et al. [\u003cspan class=\"CitationRef\"\u003e37\u003c/span\u003e]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2018\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAustralia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003erandomized controlled trial\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5-9.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e453\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003emultiple institutions\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGudnadottir et al. [\u003cspan class=\"CitationRef\"\u003e41\u003c/span\u003e]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2018\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSweden\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003erandomized controlled trial\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4\u0026ndash;10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e134\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 weeks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003esingle institution\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVlahandonis et al. [\u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2014\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAustralia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ecohort study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7\u0026ndash;13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e155\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003epopulation-based\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMassicotte et al. [\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2014\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCanada\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ecross-sectional\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4\u0026ndash;18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003esingle institution\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eKheirandish et al. [\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2014\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAmerica\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ecross-sectional\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6-7.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e176\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003emultiple institutions\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVlahandonis et al. [\u003cspan class=\"CitationRef\"\u003e29\u003c/span\u003e]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2013\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAustralia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ecohort study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7\u0026ndash;11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e155\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003esingle institution\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFriedman et al. [\u003cspan class=\"CitationRef\"\u003e43\u003c/span\u003e]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2012\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAmerica\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003erandomized controlled trial\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u0026ndash;18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e150\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003esingle institution\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eKohler et al. [\u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2009\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAustralia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003equasi-experimental study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u0026ndash;12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e226\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003esingle institution\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eKheirandish et al. [\u003cspan class=\"CitationRef\"\u003e42\u003c/span\u003e]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2008\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAmerica\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003erandomized controlled trial\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6\u0026ndash;12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 weeks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003esingle institution\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eKhalil et al. 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[\u003cspan class=\"CitationRef\"\u003e47\u003c/span\u003e]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2004\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAmerica\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003erandomized controlled trial\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u0026ndash;14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003emultiple institutions\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNieminen et al. [\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2002\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFinland\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ecohort study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.4\u0026ndash;10.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003esingle institution\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBrouillette et al. [\u003cspan class=\"CitationRef\"\u003e40\u003c/span\u003e]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCanada\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003erandomized controlled trial\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u0026ndash;6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e278\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 weeks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003esingle institution\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHelfaer et al. [\u003cspan class=\"CitationRef\"\u003e44\u003c/span\u003e]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1996\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAmerica\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003erandomized controlled trial\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u0026ndash;18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003esingle institution\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003cp\u003e\u003c/p\u003e\n\u003c/div\u003e\u003cp\u003eTABLE 2 Identified barriers to clinical trial participation of children with obstructive sleep apnea\u003c/p\u003e\n\u003cp\u003e\u003cimg src=\"https://myfiles.space/user_files/122228_c8a1650c59388082/122228_custom_files/img1721724381.png\"\u003e\u003cbr\u003e\u003c/p\u003e\n\n\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\n \u003ch2\u003eQuality of the studies\u003c/h2\u003e\n \u003cp\u003eSupplementary Figure \u003cspan class=\"InternalRef\"\u003eS1\u003c/span\u003e-4 demonstrates the quality and risk of bias analyses of included studies. Of them, twelve were rated as having low quality for \u0026ge;\u0026thinsp;2 questions on their appraisals.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\n \u003ch2\u003eStudies assessing barriers to the participation of children with OSA in clinical trials\u003c/h2\u003e\n \u003cp\u003eWe identified 14 subcategories of barriers across the studies, which were classified as objective, provider, and patient/caregiver factors. Most studies (92%) reported objective barriers. Twenty studies reported stringent eligibility criteria as a major barrier[\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e47\u003c/span\u003e]. Other causes included language barriers[\u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e43\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e45\u003c/span\u003e], duration [\u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e33\u003c/span\u003e], technical inadequacies[\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e44\u003c/span\u003e], and the need for emergency/other treatment[\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e40\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e41\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e43\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e45\u003c/span\u003e]. Details are given in Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e\n \u003cp\u003eFive studies reported provider barriers[\u003cspan class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e45\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e46\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e48\u003c/span\u003e]. One found that surgeon consensus was in favor of surgery rather than medicine during the follow-up, possibly changing the treatment[\u003cspan class=\"CitationRef\"\u003e39\u003c/span\u003e]. Four studies reported other barriers[\u003cspan class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e45\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e46\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e48\u003c/span\u003e], such as another surgical method during the study[\u003cspan class=\"CitationRef\"\u003e45\u003c/span\u003e], not timely prepared medication[\u003cspan class=\"CitationRef\"\u003e48\u003c/span\u003e], late contact[\u003cspan class=\"CitationRef\"\u003e46\u003c/span\u003e], and medication misuse[\u003cspan class=\"CitationRef\"\u003e35\u003c/span\u003e].\u003c/p\u003e\n \u003cp\u003eTwenty-three studies reported patient/caregiver barriers[\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e48\u003c/span\u003e], including disagreement on or rejection of the treatment[\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e41\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e43\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e47\u003c/span\u003e], preferences for another treatment[24,27,45\u0026ndash;47), and refusion to follow-up[\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e41\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e43\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e47\u003c/span\u003e]. Other identified barriers were transportation issues[\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e], PSG tolerability[\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e43\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e47\u003c/span\u003e], and congenital diseases or cognitive disorders[\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e38\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e45\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e47\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e48\u003c/span\u003e].\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eKey findings\u003c/h2\u003e \u003cp\u003eTo our knowledge, this study is the first systematic review of the barriers and interventions related to children with OSA, which identified 25 relevant studies examining barriers hindering the participation of children with OSA in clinical trials. Our findings generally define the barriers as subjective and objective causes. However, the research on interventions in this population is limited. Consequently, effective strategies to improve the participation of children with OSA in clinical trials are still underdeveloped. Our study underscores the complex system impediments that effectively exclude children and their parents from clinical trials and offers some solutions to expand clinical trials.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eBroaden eligibility criteria\u003c/h2\u003e \u003cp\u003eOur findings highlight the rigid eligibility criteria as a major structural barrier to children\u0026rsquo;s access to available trials. Efforts to address this problem and particular measures are needed. Specific inclusion criteria should be adopted according to experimental design rather than based on the subjective preferences of the investigators. Moreover, ensuring which comorbidity can be accepted by clinical trial criteria is essential to guide investigators. Providers should cooperate with pediatricians and caregivers to better understand the requirements of children when designing trials.\u003c/p\u003e \u003cp\u003eAnother factor also known to influence trial participation is language[\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e]. A proportion of children with parents cannot understand the study protocol. Additionally, organizing translators is often difficult, and even if they are present, patients or their guardians may have difficulty comprehending the information they were given. Thus, researchers may be unwilling to spend time explaining the study protocol, leading to the exclusion of this eligible group. Thus far, there is no perfect solution for this issue. Senior doctors and translators might need to approach those patients, but it could increase the financial and time burden.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eAddressing subject barriers\u003c/h2\u003e \u003cp\u003eBesides structure barriers, attention should also be directed to subject barriers. Our findings highlight the practical impediments, such as time constraints, inadequate transportation, lack of interest, and cost, which limit the participation of children and their families in clinical trials. Hence, practical strategies to overcome these barriers are needed. The government or trial unit should cooperate with transportation companies to provide financial and transportation support for long-distance patients, which may help facilitate participation. Besides, telemedicine may assist people with inconvenient transportation[\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eMoreover, nonpractical psychosocial barriers cannot be ignored. Efforts to identify patient\u0026rsquo;s preferences may help individuals be better prepared for participation. In pediatric clinical trials, legal guardians usually have strong demands for the results[\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e]. On the one hand, misunderstanding the content of the subject recruitment may affect the authenticity and objectivity of the intention to participate. On the other hand, high expectations for the experimental method determine their concern about the efficacy of the method and about being placed in an unwanted group, such as the placebo group[\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e]. Strategies need tailoring to specific obstacles to prevent subjects from blindly worrying about rejection because of insufficient understanding of clinical trials.\u003c/p\u003e \u003cp\u003eThe national governing bodies can develop \"sunny\" official clinical trial public videos to promote and introduce clinical trials through websites, podcasts, and other channels to alleviate blind rejection[\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e]. Meanwhile, medical and allied health professionals can promote clinical trials in the communities to help the public establish a correct understanding of clinical trials.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eExpanding the reach of clinical trials\u003c/h2\u003e \u003cp\u003eMany children have health defects or other limitations that prevent their enrollment in some trials. Evidence shows that OSA occurs at higher rates and greater severity in children with Down syndrome[\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e]. Some studies indicated that children with cleft palate have a higher risk of OSA compared with children without cleft palate[\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e]. Thus, increasing the enrollment of exceptional children in current trials by broadening studies to include an exceptional population is a promising solution[\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e]. Virtually, exceptional children-specific trials could examine whether those new treatments apply to a more clinically diverse patient population or can be broadly implemented[\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTo promote the implementation of these trials, suitable ways facilitating the cooperation between experimenters and guardians should be founded to ensure that these studies are amenable to the participation of frail or disabled children with consequences meeting their needs[\u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e]. According to our findings, government and financial support are vital[\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e]. Assistance from policy and financial aid for the special children population could promote their participation. One example is surgical assistance and subsidy work for OSA in preschool children with cleft palate, funded by the Civil Affairs Department to reduce surgical costs. We hope that a more inclusive medical environment will improve the evidence for diagnosing and treating OSA in children, including children with special needs and comorbidities.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eStrengthening provider\u0026rsquo;s training\u003c/h2\u003e \u003cp\u003eThe success of children's participation in the clinical trials also depends on providers. Strategies for providers to improve trial methods and follow-up are required. The technical inadequacies in trials include incomplete data, missing or poor signal in PSG, and pharmacy or study personnel error. Some studies mentioned the barriers to obtaining PSG due to the lack of tolerability of PSG equipment in children[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e, \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e]. Some studies emphasized aborted follow-ups by researchers.\u003c/p\u003e \u003cp\u003eEquipment control and data management should be performed by specialists or professionally trained recorders to avoid data loss caused by improper operation[\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]. Due to poor children\u0026rsquo;s compliance, the application of wearable devices faces special challenges. The design of data inspection equipment or children's interest and compliance should be improved through play interactions.\u003c/p\u003e \u003cp\u003eThe follow-up is the process of exchanging information with and helping patients as much as possible[\u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e]. Therefore, researchers not only need to collect data but also to understand the patient\u0026rsquo;s needs. Building trust quickly is the first step and foundation for high-quality follow-up. Hence, paying attention to communication skills and enhancing the trust of the interviewees are necessary for good compliance. During the follow-up, disturbing the rest of the patients should be avoided. In the case of relatively sufficient resource allocation, strategies, models, and tools can be constantly updated and improved, and intelligent follow-up systems, such as mobile apps, can be developed to provide remote consultation services in conjunction with data collection.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eLeveraging cloud database\u003c/h2\u003e \u003cp\u003eResearchers should use cloud databases including a large number of children with OSA to fill the evidence gap due to the deficiencies in the trials[\u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e]. Databases provide vast amounts of crowd-based and multiple-source data, which can be retrospectively analyzed. For example, data from Electronic Health Records (EHRs) or other health management systems that combine data from multiple visualization platforms may help obtain the evidence[\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e]. Thus, researchers and other related technicists should work together to develop a multi-participation value co-creation platform for ensuring the safe sharing and circulation of data to realize optimal resource allocation and collaborative services.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eStrengths and limitations\u003c/h2\u003e \u003cp\u003eThe present study has several strengths. First, this is the first systematic review to synthesize the literature on barriers to the participation of children with OSA in clinical trials and discuss strategies to overcome them. Second, this study combined these barriers and classified them to propose more targeted measures for each subcategory. Third, this study extends previous knowledge, assessing and reporting the findings according to PRISMA guidelines.\u003c/p\u003e \u003cp\u003eMoreover, this study has several limitations. First, a meta-analysis could not be conducted owing to the diverse nature of data across studies. Thus, our analysis was limited to a qualitative synthesis of data. Second, we investigated trials purposely designed for children rather than for the general population, possibly leading the focus on the evidence base per se but not the strategies aimed at improving clinical trial enrollment. Finally, we discussed the barriers to participation but did not analyze the potential causes of these issues.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eOur findings emphasize that promoting the participation of children with OSA in clinical trials is relevant to all providers, patients themselves, and parents or caregivers. Therefore, we propose that providers should pay attention to promoting and encouraging their pediatric patients and their families to participate in clinical trials. Additionally, they should develop formal, targeted strategies to provide data and technical support for the development of diagnosis and treatment standards specific to children with OSA, ensuring that all children receive specific, evidence-based, and high-quality therapy.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eOSA:\u0026nbsp;Obstructive sleep apnea\u003c/p\u003e\n\u003cp\u003eEHRs:\u0026nbsp;Electronic Health Records\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePRISMA:\u0026nbsp;Systematic Reviews and Meta-Analysis\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eJBI: Joanna\u0026nbsp;Briggs\u0026nbsp;Institute\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePSG: Polysomnography\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eAuthor Contributions\u003c/p\u003e\n\u003cp\u003eZD, XW, LW and XL conducted the search and data extraction. The draft was written by LW. XLZ and ZJL reviewed and edited the manuscript extensively. \u0026nbsp;All authors contributed to the article and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003eFunding\u003c/p\u003e\n\u003cp\u003eNone\u003c/p\u003e\n\u003cp\u003eData availability\u003c/p\u003e\n\u003cp\u003eThe original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eEthical approval and consent to participate\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eAu CT, Chan KCC, Lee DLY, et al. 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Improvement of sleep-disordered breathing in children is associated with a reduction in overnight blood pressure. Sleep Med. 2013;14(12):1295-1303.\u003c/li\u003e\n\u003cli\u003eVlahandonis A, Yiallourou SR, Sands SA, et al. Long-term changes in heart rate variability in elementary school-aged children with sleep-disordered breathing. Sleep Med. 2014;15(1):76-82.\u003c/li\u003e\n\u003cli\u003eWendler D, Jenkins T. Children\u0026rsquo;s and their parents\u0026rsquo; views on facing research risks for the benefit of others. Arch Pediatr Adolesc Med. 2008;162(1):9-14.\u003c/li\u003e\n\u003cli\u003eZaffanello M, Piacentini G, La Grutta S. Beyond the growth delay in children with sleep-related breathing disorders: a systematic review. Panminerva Med. 2020;62(3):164-175.\u003c/li\u003e\n\u003cli\u003eZaffanello M, Piacentini G, La Grutta S. The cardiovascular risk in paediatrics: the paradigm of the obstructive sleep apnoea syndrome. Blood Transfus Trasfus Sangue. 2020;18(3):217-225.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"children, obstructive sleep apnea, clinical trials, patient participation, barrier","lastPublishedDoi":"10.21203/rs.3.rs-4640956/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4640956/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eObstructive sleep apnea (OSA) in children is associated with negative effects on neurocognitive development and metabolic health. Despite this, children with OSA remain underrepresented in research, setting the standards for clinical diagnoses and treatments. Consequently, most evidence on treatment is based on adult data. This review focuses on studies assessing the barriers to clinical trial participation for children with OSA and discusses the intervention studies and efforts to overcome these barriers.\u003c/p\u003e\u003ch2\u003eMethod\u003c/h2\u003e \u003cp\u003eWe retrieved articles from Scopus, Embase, PubMed, and the Cochrane Library without date restrictions until May 2024. The language was restricted to English. The Joanna Briggs Institute (JBI) tool was used to assess methodological quality.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eFrom 25 studies included, 14 barrier subcategories were identified, which were classified as an objective factor, provider, and patient/caregiver.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eOur findings emphasize the multifaceted barriers to enrolling children with OSA in clinical trials. Furthermore, we provide several underutilized solutions to facilitate children's participation in clinical trials. However, formal targeted strategies are still needed in the future because these recommendations alone might not solve the evidence gap in children.\u003c/p\u003e\u003ch2\u003eRegistration:\u003c/h2\u003e \u003cp\u003eRegistered in PROSPERO with ID: CRD42024533326.\u003c/p\u003e","manuscriptTitle":"Participation of children with obstructive sleep apnea in clinical trials: A systematic review of barriers and interventions","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-23 22:04:30","doi":"10.21203/rs.3.rs-4640956/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"48e7fd25-accf-4d11-bc39-0dcf8eaa928b","owner":[],"postedDate":"July 23rd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-10-17T09:39:49+00:00","versionOfRecord":[],"versionCreatedAt":"2024-07-23 22:04:30","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4640956","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4640956","identity":"rs-4640956","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}