Oxygen Therapy in Children and Adolescents With Down Syndrome and Obstructive Sleep Apnea

Study Overview
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Brief Summary
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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).

Detailed Description
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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).

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

Conditions
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Down Syndrome, Obstructive Sleep Apnea

Intervention / Treatment
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* Drug: Oxygen


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ages 5.0 to 17.9 years at the time of screening Children with Obstructive Sleep Apnea (OSA) and obstructive apnea hypopnea index (OAHI) 5-40/hour. : Absence of clinically significant hypoxia defined as oxygen saturation <88% for 5 minutes or episodic desaturation to 60%. Favorable response to oxygen therapy (allowing randomization) will be defined as follows: Oxygen saturation nadir >92% and Decrease in obstructive index < 5 / hour or by > 50% from screening PSG Reaching an optimum oxygen flow, which is defined as the flow that achieves the lowest level of AHI without hypoventilation. Oxygen flow required does not exceed 3.0 liter/minute or Fraction of Inspired Oxygen (FiO2) >40%. Willingness to comply with all study procedures and be available for the duration of study. At baseline, the participant attempts to perform the neuropsychological tests Exclusion Criteria: Current CPAP use with documented compliance(> 4 hrs/ night; > 70% of nights). Oxygen saturation < 90% at rest during wakefulness. Chronic daytime or nighttime use of supplemental oxygen. Smoker in the child's bedroom. Unrepaired congenital heart disease. Moderate to severe pulmonary hypertension requiring treatment with oxygen and or pulmonary vasodilator. Unable to participate in a PSG. Individuals who develop alveolar hypoventilation with oxygen as previously defined. Other severe chronic diseases determined by their provider as making them poor study candidates. Enrolled or planning to enroll in another study that may conflict with protocol requirements or confound results in this trial. Documented clinically significant untreated hypothyroidism Children with adenotonsillar hypertrophy who are candidates for adenotonsillectomy and parents agree to the surgery.

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 215 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

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

What is the study measuring?
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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 |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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) 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) 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) 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 | 
| 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 |