Down Syndrome Obstructive Sleep Apnea (DOSA)

Randomized Control Trial of Oxygen Therapy in Children and Adolescents With Down Syndrome and Obstructive Sleep Apnea

The purpose of this study is to assess whether oxygen supplementation during sleep improves working memory and other clinical and patient-reported outcomes among children who have Down Syndrome (DS) with moderate to severe Obstructive Sleep Apnea (OSA).

Study Overview

• Status: Recruiting
• Conditions: Obstructive Sleep Apnea; Down Syndrome
• Intervention / Treatment: Drug: Oxygen

Detailed Description

This will be a randomized, single-blind 6-month Phase-2 clinical trial that compares the impact of oxygen therapy during sleep on measures of cognition, behavior, quality of life, cardiac structure and function, and sleep in children with Down Syndrome(DS) with moderate to severe obstructive sleep apnea.

The proposed study will involve participation of children and their caregivers. Children will be recruited from each site's sleep clinics and laboratories, Down syndrome clinics and otolaryngology clinics. Community recruitment will be coordinated with local Down Syndrome Associations.

Children who agree to participate in the study will be screened for eligibility based on history, physical examination, and review of medical records including history of congenital heart disease and Pulmonary Hypertension (PHTN), and use of Continuous Positive Airway Pressure (CPAP). Children eligible for the study are those with persistent obstructive apnea after adenotonsillectomy or children with obstructive sleep apnea without adenotonsillar hypertrophy or in situations when parents refuse adenotonsillectomy.. The enrollment PSG eligibility will be determined by central scoring of either a research Polysomnography (PSG). In addition to an oxygen titration PSG, which determines responsiveness to oxygen, participants will be asked to wear a wrist actigraph and undergo neurocognitive testing, echocardiography, physical examination, anthropometry, and venipuncture. Caregivers will complete questionnaires to assess their child's emotional, physical, social, and school functioning, sleep quality; child's behavior and cognitive function, and will complete a sleep diary that is used concurrently with their child's use of a wrist actigraph. The latter includes caregiver completion of the "Behavior Rating Inventory of Executive Function" (BRIEF2), a co-primary outcome.

At 3 months, caregivers will complete the BRIEF2. At 6 months, all baseline studies and a PSG will be repeated.

At baseline, demographic data will be collected, including information on residential address (for use in geocoding).

• Study Type: Interventional
• Enrollment (Estimated): 230
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Oltion Sina; Phone Number: 8573407909; Email: osina@bwh.harvard.edu
• Study Contact Backup: Name: Suzie Hicks; Phone Number: 5136364944; Email: suzanna.hicks@cchmc.org

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90027
      • Recruiting
      • Children's Hospital of Los Angeles
      • Contact: Danny Del Cid-Linare; Email: ddelcidlinares@chla.usc.edu
      • Principal Investigator: Sally Ward, MD
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • Recruiting
      • University of Michigan, Ann Arbor Hospital
      • Contact: Emily Herreshoff; Email: egalopin@med.umich.edu
      • Principal Investigator: Ronald Chervin, MD
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Recruiting
      • Cincinnati Children's Hospital Medical Center
      • Principal Investigator: Raouf Amin, MD
      • Contact: Suzanna Hicks; Email: suzanna.hicks@cchmc.org
    • Cleveland, Ohio, United States, 44106
      • Recruiting
      • Rainbow Babies and Children's Hospital, Case Medical Center
      • Contact: Alyssa Keller; Email: Alyssa.Keller@Uhhospitals.org
      • Principal Investigator: Sally Ibrahim, MD
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Recruiting
      • Children's Hospital of Philadelphia
      • Contact: Ebereh Uwah; Email: uwahe@chop.edu
      • Principal Investigator: Christopher Cielo, MD
  • Virginia
    • Norfolk, Virginia, United States, 23507
      • Recruiting
      • East Virginia Medical Center
      • Contact: Thomas Boswick; Email: BoswicST@EVMS.edu
      • Principal Investigator: Cristina Baldassari, MD
  • Washington
    • Seattle, Washington, United States, 98105
      • Recruiting
      • Seattle Children's Hospital
      • Contact: Sharon McNamara; Email: sharon.mcnamara@seattlechildrens.org
      • Principal Investigator: Maida Chen, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Ages 5.0 to 17.9 years at the time of screening
2. Children with OSA and obstructive apnea hypopnea index (OAHI) ≥5/hour.
3. Absence of clinically significant hypoxia defined as oxygen saturation <88% for 5 minutes or episodic desaturation to 60% as these levels would otherwise identify children eligible to routinely receive oxygen.

4. Favorable response to oxygen therapy (allowing randomization) will be defined as follows:

   1. Oxygen saturation nadir >92% and
   2. Decrease in obstructive index < 5 / hour or by > 50% from screening PSG
   3. Reaching an optimum oxygen flow which is defined as the flow that achieves the lowest level of AHI with maximum CO2 level less than 65 mmHg observed for 5 consecutive minutes and or an increase in CO2 by less than 15 points above baseline. The above criteria are observed while the patient spends a minimal of 30 minutes in the supine position and at least one cycle of rapid eye movement (REM) sleep.
   4. Oxygen flow required does not exceed 3.0 LPM and does not exceed a FiO2 > 40 %.
5. Willingness to comply with all study procedures and available for duration of study.
6. At baseline the participant attempts to perform the neuropsychological tests

Exclusion Criteria:

1. Current CPAP use with documented compliance(> 4 hrs/ night; > 70% of nights).
2. Oxygen saturation < 90% at rest during wakefulness.
3. Chronic daytime or nighttime use of supplemental oxygen.
4. Smoker in the child's bedroom.
5. Unrepaired congenital heart disease.
6. Moderate to severe pulmonary hypertension requiring treatment with oxygen and or pulmonary vasodilator.
7. Unable to participate in a PSG.
8. Individuals who develop alveolar hypoventilation with oxygen as previously defined.
9. Other severe chronic diseases determined by their provider as making them poor study candidates.
10. Enrolled or planning to enroll in another study that may conflict with protocol requirements or confound results in this trial.
11. Documented clinically significant untreated hypothyroidism
12. Children with adenotonsillar hypertrophy who are candidates for adenotonsillectomy and parents agree to the surgery.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Oxygen plus supportive care (OXT); Nocturnal oxygen therapy plus providing patient with healthy sleep habits materials, healthy diet materials and nasal dilators.	Drug: Oxygen; Active nocturnal oxygen concentrator
No Intervention: Supportive care (SC); Providing patient with healthy sleep habits materials, healthy diet materials and nasal dilators.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Behavior Rating Inventory of Executive Function 2 (BRIEF2) working memory score	Change from baseline in the Behavior Rating Inventory of Executive Function 2 (BRIEF2) working memory score (BRIEF2wm). The score ranges from 35-90. A higher score is a worse outcome.	Baseline and 6 months
Differential Ability Scales - 2nd Edition (DAS-II) T-score.	Change from baseline in the Differential Ability Scales - 2nd Edition (DAS-II) recognition of pictures (DAS2RoP) T-score. The score ranges from 10-90. A higher score is a better outcome.	Baseline and 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cambridge Neuropsychological Test Automated Battery (CANTAB) Paired Associates Learning (PAL) adjusted total errors based on stages completed	Change from baseline in Cambridge Neuropsychological Test Automated Battery (CANTAB) Paired Associates Learning (PAL) adjusted total errors based on stages completed	Baseline and 6 Months
Cambridge Neuropsychological Test Automated Battery (CANTAB) Reaction Time (RTI)	Change from baseline in Cambridge Neuropsychological Test Automated Battery (CANTAB) Reaction Time (RTI)	Baseline and 6 Months
Child Behavior Checklist (CBCL) T-scores for domains (Internalizing, Externalizing, Total Problems).	Change from baseline in Child Behavior Checklist (CBCL) T-scores for domains (Internalizing, Externalizing, Total Problems).	Baseline and 6 Months
Child Behavior Checklist (CBCL) T-scores for subscales (Attention Problems, Thought Problems, Rule-Breaking Behaviors, Aggressive Behaviors)	Change from baseline in Child Behavior Checklist (CBCL) T-scores for subscales (Attention Problems, Thought Problems, Rule-Breaking Behaviors, Aggressive Behaviors)	Baseline and 6 Months
Presence of right ventricular hypertension	Presence of right ventricular hypertension as measured by tricuspid regurgitation continuous wave peak velocity (defined as a ratio of pulmonary artery pressure / systolic arterial pressure (PAP/SAP) >1/3); interventricular septal flattening as measured by eccentricity index (defined as systolic ratio of >1.25)	Baseline and 6 Months
7-day actigraphy measurement of sleep efficiency	Change from baseline in 7-day actigraphy measurement of sleep efficiency	Baseline and 6 Months
7-day actigraphy measurement of time wake after sleep onset	Change from baseline in 7-day actigraphy measurement of time wake after sleep onset	Baseline and 6 Months
7-day actigraphy measurement of sleep fragmentation	Change from baseline in 7-day actigraphy measurement of sleep fragmentation	Baseline and 6 Months
7-day actigraphy measurement of total sleep duration	Change from baseline in 7-day actigraphy measurement of total sleep duration	Baseline and 6 Months
Polysomnography (PSG) percentage time of O2 <90 % parameter	Change from baseline in Polysomnography (PSG) percentage time of O2 <90 % parameter	Baseline and 6 Months
Polysomnography (PSG) sleep apnea associated hypoxic burden parameter	Change from baseline in Polysomnography (PSG) sleep apnea associated hypoxic burden, parameter	Baseline and 6 Months
Polysomnography (PSG) -based measure of EEG power bands	Change from baseline in Polysomnography (PSG) -based measure of EEG power bands	Baseline and 6 Months
Polysomnography (PSG) -based measure of spindle morphology	Change from baseline in Polysomnography (PSG) -based measure of spindle morphology	Baseline and 6 Months
Polysomnography (PSG) -based measure of spindle numbers	Change from baseline in Polysomnography (PSG) -based measure of spindle numbers	Baseline and 6 Months
Polysomnography (PSG) -based measure of spindle density	Change from baseline in Polysomnography (PSG) -based measure of spindle density	Baseline and 6 Months
Polysomnography (PSG) -based measure of slow wave oscillations	Change from baseline in Polysomnography (PSG) -based measure of slow wave oscillations	Baseline and 6 Months
Left ventricular diastolic function as measured by Mitral E and A wave (E:A ratio)	Change from baseline in left ventricular diastolic function as measured by Mitral E and A wave (E:A ratio)	Baseline and 6 Months
Left ventricular diastolic function as measured by E wave deceleration time	Change from baseline in left ventricular diastolic function as measured by E wave deceleration time	Baseline and 6 Months
Left ventricular diastolic function as measured by Mitral septal and lateral e' and a' (E/e')	Change from baseline in left ventricular diastolic function as measured by Mitral septal and lateral e' and a' (E/e')	Baseline and 6 Months
Left ventricular diastolic function as measured by Mitral lateral tissue Doppler isovolumic relaxation time	Change from baseline in left ventricular diastolic function as measured by Mitral lateral tissue Doppler isovolumic relaxation time	Baseline and 6 Months
Left ventricular diastolic function as measured by Pulmonary vein A wave reversal duration	Change from baseline in left ventricular diastolic function as measured by Pulmonary vein A wave reversal duration	Baseline and 6 Months
Left ventricular diastolic function as measured by Left atrial volume	Change from baseline in left ventricular diastolic function as measured by Left atrial volume	Baseline and 6 Months
Stanford-Binet Intelligence Scales, 5th edition (SB-5) Working Memory Total raw score	Change from baseline of Stanford-Binet Intelligence Scales, 5th edition (SB-5) Working Memory Total raw score. The score ranges from 0-64. A higher score is a better outcome.	Baseline and 6 Months
Stanford-Binet Intelligence Scales, 5th edition (SB-5) Working Memory Verbal raw score	Change from baseline of Stanford-Binet Intelligence Scales, 5th edition (SB-5) Working Memory Verbal raw score. The score ranges from 0-30. A higher score is a better outcome.	Baseline and 6 Months
Stanford-Binet Intelligence Scales, 5th edition (SB-5) Working Memory Non Verbal raw score	Change from baseline of Stanford-Binet Intelligence Scales, 5th edition (SB-5) Working Memory Non Verbal raw score. The score ranges from 0-34. A higher score is a better outcome.	Baseline and 6 Months
Differential Ability Scales-2 (DAS-II) Recall of Digits Forward raw score	Change from baseline in Differential Ability Scales-2 (DAS-II) Recall of Digits Forward raw score. The score ranges from 0-38. A higher score is a better outcome.	Baseline and 6 Months
Developmental Neuropsychological Assessment 2nd Edition (NEPSY-II) verbal fluency test raw score	Change from baseline in Developmental Neuropsychological Assessment 2nd Edition (NEPSY-II) verbal fluency test raw score. Range-N/A	Baseline and 6 Months
Observer Memory Questionnaire - Parent Form (OMQ-PF) total T-score	Change from baseline in Observer Memory Questionnaire - Parent Form (OMQ-PF) total T-score. The score ranges from 0-135. A higher score is a better outcome.	Baseline and 6 Months
Behavior Rating Inventory of Executive Function 2 (BRIEF2) T-scores for subscales (Inhibit, Self-Monitor, Shift, Emotional Control, Initiate)	Change from baseline in Behavior Rating Inventory of Executive Function 2 (BRIEF2) T-scores for subscales (Inhibit, Self-Monitor, Shift, Emotional Control, Initiate).	Baseline and 6 Months
KIDSCREEN-27 T-score	Change from baseline in KIDSCREEN-27 T-score, including domains of: physical well-being; psychological well-being; autonomy and parent relations; social support and peers; school environment. Range-N/A	Baseline and 6 Months
Patient-Reported Outcomes Measurement Information System (PROMIS) sleep disturbance T-score	Change from baseline in Patient-Reported Outcomes Measurement Information System (PROMIS) sleep disturbance T-score. The score ranges from 28.7-85.6. A higher score is a worse outcome.	Baseline and 6 Months
Patient-Reported Outcomes Measurement Information System (PROMIS) sleep-related impairment T-score	Change from baseline in Patient-Reported Outcomes Measurement Information System (PROMIS) sleep-related impairment T-score. The score ranges from 37.9-86.6. A higher score is a worse outcome.	Baseline and 6 Months
Wechsler Intelligence Scale (WISC) for Children 5th edition (WISC-5) Cancellation raw score	Change from baseline of Wechsler Intelligence Scale (WISC) for Children 5th edition (WISC-5) Cancellation raw score. The score ranges from 0-128. A higher score is a better outcome.	Baseline and 6 Months
Wechsler Preschool and Primary Scale of Intelligence 4th edition (WPPSI-4) Cancellation task raw score	Change from baseline in Wechsler Preschool and Primary Scale of Intelligence 4th edition (WPPSI-4) Cancellation task raw score (if unable to complete Wechsler Intelligence Scale 5th edition Cancellation test). The score ranges from 0-96. A higher score is a better outcome.	Baseline and 6 Months
Behavior Rating Inventory of Executive Function 2 (BRIEF2) T-scores for Behavior Regulation Index (BRI) domain.	Change from baseline in Behavior Rating Inventory of Executive Function 2 (BRIEF2) T-scores for Behavior Regulation Index (BRI) domain. The score ranges from 35-90. A higher score is a worse outcome.	Baseline and 6 Months
Behavior Rating Inventory of Executive Function 2 (BRIEF2) T-scores for Emotional Recognition Index (ERI) domain.	Change from baseline in Behavior Rating Inventory of Executive Function 2 (BRIEF2) T-scores for Emotional Recognition Index (ERI) domain. The score ranges from 35-90. A higher score is a worse outcome.	Baseline and 6 Months
Behavior Rating Inventory of Executive Function 2 (BRIEF2) T-scores for Cognitive Regulation Index (CRI) domain.	Change from baseline in Behavior Rating Inventory of Executive Function 2 (BRIEF2) T-scores for Cognitive Regulation Index (CRI) domain. The score ranges from 35-90. A higher score is a worse outcome.	Baseline and 6 Months
Polysomnography (PSG) AHI parameter	Change from baseline in Polysomnography (PSG) AHI parameter. The score ranges from 0- >40. A higher score is a worse outcome.	Baseline and 6 Months
Polysomnography (PSG) end-tidal CO2 level, parameter	Change from baseline in Polysomnography (PSG) end-tidal CO2 parameter.	Baseline and 6 Months
Polysomnography (PSG) -based measure of sleep stages	Change from baseline in Polysomnography (PSG) -based measure of sleep stages. Range- N/A	Baseline and 6 Months

Collaborators and Investigators

• Sponsor: Brigham and Women's Hospital
• Collaborators: Children's Hospital of Philadelphia; University of Michigan; University of Southern California; Seattle Children's Hospital; Children's Hospital Medical Center, Cincinnati; Children's Hospital Los Angeles; Children's Hospital of The King's Daughters; Rainbow Babies and Children's Hospital
• Investigators: Principal Investigator: Susan Redline, Brigham and Women's Hospital; Principal Investigator: Raouf Amin, Children's Hospital Medical Center, Cincinnati

Publications and helpful links

General Publications

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Study record dates

Study Major Dates

• Study Start (Actual): October 24, 2023
• Primary Completion (Estimated): November 30, 2027
• Study Completion (Estimated): December 30, 2027

Study Registration Dates

• First Submitted: August 17, 2023
• First Submitted That Met QC Criteria: September 12, 2023
• First Posted (Actual): September 21, 2023

Study Record Updates

• Last Update Posted (Actual): April 20, 2025
• Last Update Submitted That Met QC Criteria: April 18, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neurologic Manifestations; Nervous System Diseases; Pathologic Processes; Genetic Diseases, Inborn; Respiratory Tract Diseases; Disease; Neurobehavioral Manifestations; Respiration Disorders; Sleep Wake Disorders; Congenital Abnormalities; Signs and Symptoms, Respiratory; Abnormalities, Multiple; Sleep Disorders, Intrinsic; Dyssomnias; Intellectual Disability; Chromosome Disorders; Syndrome; Sleep Apnea Syndromes; Sleep Apnea, Obstructive; Apnea; Down Syndrome
• Other Study ID Numbers: 2023P000062

Drug and device information, study documents

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