Treatment of Obstructive Sleep Apnea With Personalized Surgery in Children With Down Syndrome (TOPS-DS) (TOPS-DS)

The overall objective of this randomized clinical trial is to test the effectiveness of a personalized approach to the surgical treatment of OSA in children with Down syndrome (DS).The estimated prevalence of obstructive sleep apnea (OSA) in children with DS ranges from 45-83%, compared to 1-6% in the general pediatric population. Untreated OSA in children has been associated with daytime sleepiness, cognitive or behavioral problems, and cardiovascular complications, all which are common in children with DS. Adenotonsillectomy (AT) is the first line treatment for OSA in children, however, most large studies of AT outcomes have excluded children with DS. Available evidence demonstrates that AT is far less effective in children with DS than in the general pediatric population, with 48 to 95% of children with DS having persistent OSA after AT. Medical treatments such as positive airway pressure (PAP) therapy are frequently inadequate or poorly tolerated in this population, so many children with DS and OSA remain untreated. Drug-induced sleep endoscopy (DISE) enables direct observation of the sites and patterns of obstruction during sedated sleep using a flexible endoscope passed through the nose into the pharynx. DISE was developed to guide surgical decisions in adult OSA, and in recent years has also been used to design personalized surgical interventions in children. Using this DISE Rating Scale, the investigators have demonstrated that children with DS are more prone to tongue base and supraglottic obstruction than non-DS children, suggesting the need for more personalized surgical treatments that are tailored to the common sources of obstruction in this population. Several small case series demonstrate that DISE-directed surgery can be effective in treating OSA in children with DS. However, because there have been few prospective studies and no randomized trials comparing different treatment options in this population, there remains uncertainty about whether such a personalized approach leads to superior outcomes compared to the first line AT.

It is the investigators' hypothesis that personalized DISE-directed surgery that uses existing procedures to address specific fixed and dynamic anatomic features causing obstruction in each child with DS will be superior to the current first line approach of AT. This novel approach may improve OSA outcomes and reduce the burden of unnecessary AT or secondary surgery for persistent OSA after an ineffective AT.

Study Overview

• Status: Enrolling by invitation
• Conditions: Obstructive Sleep Apnea; Down Syndrome
• Intervention / Treatment: Procedure: DISE-Directed Surgery; Procedure: Adenotonsillectomy

Detailed Description

The overall objective of this randomized clinical trial is to test the effectiveness of a novel personalized approach to the surgical treatment of OSA in children with Down syndrome (DS). DS is a common disorder, affecting 1 in 691 births. The estimated prevalence of obstructive sleep apnea (OSA) in children with DS ranges from 45-83%, compared to 1-6% in the general pediatric population. Untreated OSA in children has been associated with daytime sleepiness, cognitive and behavioral problems, and cardiovascular complications, all of which are common in children with DS. Adenotonsillectomy (AT) is the first line treatment for OSA in children, however, most large studies of AT outcomes have excluded children with DS. Available evidence demonstrates that AT is far less effective in children with DS than in the general pediatric population, with 48 to 95% of children with DS having persistent OSA after AT. Medical treatments such as positive airway pressure (PAP) therapy are frequently inadequate or poorly tolerated in this population, so many children with DS and OSA remain untreated.

Pharyngeal hypotonia, unfavorable craniofacial anatomy, and obesity are commonly cited risk factors for OSA and failure of AT in children with DS, however, there have been few attempts to characterize the pharyngeal anatomy or mechanisms of obstruction in this population. Drug-induced sleep endoscopy (DISE) enables direct observation of the sites and patterns of pharyngeal obstruction during sedated sleep using a flexible endoscope passed through the nose into the pharynx. DISE was developed to guide surgical decisions in adult OSA, and in recent years has also been used to design personalized surgical interventions in children. To help standardize DISE assessments, the investigators previously developed and validated the DISE Rating Scale in children based on ordinal ratings of maximal airway obstruction (none, partial, complete) at six anatomic sites from the nose to the larynx. Using this DISE Rating Scale, the investigators have demonstrated that children with DS are more prone to tongue base and supraglottic obstruction than non-DS children, suggesting the need for more personalized surgical treatments that are tailored to the common sources of obstruction in this population. Several small case series demonstrate that DISE-directed surgery can be effective in treating OSA in children with DS. However, because there have been few prospective studies and no randomized trials comparing different treatment options in this population, there remains uncertainty about whether such a personalized approach leads to superior outcomes compared to the first line AT.

It is the investigators' central hypothesis that a personalized DISE-directed surgical approach that uses existing procedures to address the specific fixed and dynamic anatomic features causing obstruction in each child with DS will be superior to the currently recommended first line approach of AT. This novel approach may improve OSA outcomes and reduce the burden of unnecessary AT or secondary surgery for persistent OSA after an ineffective AT.

To test this hypothesis, the investigators propose to study children with DS and OSA ages 2-17 years with the following specific aims:

Aim 1: Compare the physiological outcomes of DISE-directed surgery vs AT in children with DS and OSA.

Hypothesis 1: DISE-directed surgery will result in a greater improvement in the obstructive apnea-hypopnea index compared to the standard AT intervention (effect size ≥ 0.36) after 6 months.

Aim 2: Compare the clinical outcomes of DISE-directed surgery vs AT in children with DS and OSA.

Hypothesis 2: DISE-directed surgery will result in a clinically significantly greater improvement (≥ 9 point improvement) in OSA-specific quality of life (OSA-18) compared to the standard AT intervention after 6 months. Secondarily, the investigators will test other clinical outcomes such as executive function (BRIEF2).

The investigators propose a randomized single-blind comparative effectiveness trial of AT vs DISE-directed sleep surgery for the treatment of OSA in children with DS (Figure 4). The investigators' primary hypothesis is that a personalized surgical intervention based on DISE findings will be more effective in treating OSA in children with DS than the standard AT. The first aim will compare the change in the obstructive apnea-hypopnea index (oAHI) between these treatment arms, and the second aim will compare the change in subjective measures of sleep apnea related quality of life (OSA-18) and executive function (BRIEF2). Outcomes will be assessed 6 months after surgery. The trial will be conducted at five sites: Oregon Health and Science University, Cincinnati Children's Hospital and Medical Center, University of Michigan, University of Texas-Southwestern, and Eastern Virginia Medical School.

• Study Type: Interventional
• Enrollment (Estimated): 303
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Eleni O'Neill; Phone Number: 5034943569; Email: oneilele@ohsu.edu
• Study Contact Backup: Name: Derek Lam, MD; Phone Number: 503-494-9419; Email: lamde@ohsu.edu

Study Locations

• United States
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 17 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Child has a diagnosis of Down syndrome (Trisomy 21). Child has a diagnosis of moderate to severe OSA diagnosed by PSG (oAHI ≥ 5). Child age is 2.00 to 17.99 years of age. Caregiver can provide signed and dated consent and is 18 years of age or older at the time of consent.

Caregiver can speak, read, and write in English or Spanish. Caregiver is primary caretaker of the child. Child is not pregnant. Child is eligible for surgical treatment

Exclusion Criteria:

Child has history of previous tonsillectomy, tonsillotomy, or partial tonsillectomy.

Child has any contraindication to surgery (e.g. bleeding disorders). Child has significant cardiopulmonary comorbidity besides OSA requiring supplemental oxygen, subglottic or tracheal stenosis, tracheostomy dependence.

Caregiver is unwilling or unable to comply with study procedures. Child is or plans to become pregnant.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Drug-Induced Sleep Endoscopy; DISE will be performed at the time of surgery under the same sedation. The decision on specific surgical approach will be made at that time based on DISE findings. Prior to intubation, patients will be sedated with either a propofol infusion or a combination of ketamine and dexmedetomidine. Once adequate sedation is achieved, endoscopy will be performed using a flexible endoscope advanced through the nose. The nasal airway will be evaluated on both sides, then the endoscope will be advanced into the pharynx. The degree of obstruction is scored on a 3-point rating scale. Participants randomized to DISE-directed surgery will undergo one or more potential procedures in a single surgery. Caregivers will be consented for all possible procedures with the understanding that only those needed based on DISE will be performed. Importantly, these procedures are all established treatments with published outcomes data.	Procedure: DISE-Directed Surgery; Participants randomized to DISE-directed surgery will undergo one or more potential procedures in a single surgery (i.e. DISE and subsequent sleep surgery performed) concurrently under the same general anesthetic), depending on anatomic assessment.
Active Comparator: Adenotonsillectomy; Adenotonsillar hypertrophy is the most common risk factor for OSA in children, and adenotonsillectomy (AT) is the first line treatment. An adenotonsillectomy is an operation to remove both the adenoids and tonsils.	Procedure: Adenotonsillectomy; Tonsil and adenoid removal; Other Names: AT

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from Baseline Polysomnography Measures: oAHI at 6 months	Objective results from sleep studies (polysomnography): Obstructive Apnea-Hypopnea Index (oAHI): 6 months follow up sleep study difference from baseline sleep study	6 month follow up sleep study (after surgery)
Change from Baseline Polysomnography Measures: AHI at 6 months	Objective results from sleep studies (polysomnography): Total Apnea-Hypopnea Index: 6 months follow up sleep study difference from baseline sleep study	6 month follow up sleep study (after surgery)
Change from Baseline Polysomnography Measures: REM AHI at 6 months	Objective results from sleep studies (polysomnography): REM Apnea-Hypopnea Index REM AHI: 6 months follow up sleep study difference from baseline sleep study	6 month follow up sleep study (after surgery)
Change from Baseline Polysomnography Measures: min SpO2 at 6 months	Objective results from sleep studies (polysomnography): Minimum Oxygen Saturation (Min SpO2): 6 months follow up sleep study difference from baseline sleep study	6 month follow up sleep study (after surgery)
Change from Baseline Polysomnography Measures: desat index at 6 months	Oxyhemoglobin desaturation ≥ 3% Index: 6 months follow up sleep study difference from baseline sleep study	6 month follow up sleep study (after surgery)
Change from Baseline Polysomnography Measures: Max End Tidal CO2 (ETCO2) at 6 months	Max End Tidal CO2 (ETCO2): 6 months follow up sleep study difference from baseline sleep study	6 month follow up sleep study (after surgery)
Change from Baseline Polysomnography Measures: % Total Sleep Time with ETCO2 > 50 mmHg at 6 months	% Total Sleep Time with ETCO2 > 50 mmHg: 6 months follow up sleep study difference from baseline sleep study	6 month follow up sleep study (after surgery)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Obstructive Sleep Apnea (OSA)-18 Questionnaire score	Disease specific quality of life measure: 18 questions, scores range from 18-126; higher scores means higher disease burden	6 month follow up
Change in Generic PedsQL (Pediatric Quality of Life) Questionnaire score	Generic quality of life measure: an age specific questionnaire with 23 questions (scores range from 0-100); higher scores indicate better quality of life.	6 month follow up
Total Drug induced sleep endoscopy (DISE) score	Subjective ratings of degree of obstruction at 6 levels of the upper airway, done by surgeon. Scores range from 0 to 12. Higher scores means more breathing obstruction, or more disease burden.	At time of surgery
Adverse Events	Did any adverse events occur in the post-operative time frame? This is a yes/no question, looking at the following outcomes: dehydration and poor oral intake due to post-operative pain, post-tonsillectomy hemorrhage, and respiratory compromise. respiratory compromise.	24 hour period after surgery
Change in Generic PedsQL (Pediatric Quality of Life) Questionnaire answers	Quality of life: questionnaire results by individual question. Adjusted scores range from 0-100; higher scores indicate better quality of life.	6 month follow up
Change in Feeding and Swallowing Impact Survey (FSIS) Questionnaire Answers	Dysphagia specific quality of life measure: 18 questions, scores range from 18-90; higher scores means higher disease burden.	6 month follow up

Collaborators and Investigators

• Sponsor: Oregon Health and Science University
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); University of Michigan; Children's Hospital Medical Center, Cincinnati; University of Texas; Eastern Virginia Medical School
• Investigators: Principal Investigator: Derek Lam, MD, MPH, Oregon Health and Science University

Study record dates

Study Major Dates

• Study Start (Actual): August 23, 2023
• Primary Completion (Estimated): June 30, 2027
• Study Completion (Estimated): June 30, 2027

Study Registration Dates

• First Submitted: August 10, 2022
• First Submitted That Met QC Criteria: August 18, 2022
• First Posted (Actual): August 19, 2022

Study Record Updates

• Last Update Posted (Actual): February 8, 2024
• Last Update Submitted That Met QC Criteria: February 6, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Respiratory Tract Diseases; Respiration Disorders; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Neurologic Manifestations; Neurobehavioral Manifestations; Disease; Congenital Abnormalities; Genetic Diseases, Inborn; Signs and Symptoms, Respiratory; Intellectual Disability; Abnormalities, Multiple; Chromosome Disorders; Sleep Apnea Syndromes; Sleep Apnea, Obstructive; Syndrome; Apnea; Down Syndrome
• Other Study ID Numbers: STUDY00024746; 1R61HL165345 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: IPD will not be made available to researchers who are not primary researchers on this study.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No