Down Syndrome Obstructive Sleep Apnea

Official title

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

Overview

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

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).

Interventions

• Drug Oxygen
  Active nocturnal oxygen concentrator

Primary outcome measures

• Behavior Rating Inventory of Executive Function 2 (BRIEF2) working memory score [Time frame: Baseline and 6 months]
• Differential Ability Scales - 2nd Edition (DAS-II) T-score. [Time frame: Baseline and 6 months]

Secondary outcome measures (12)

• Stanford-Binet Intelligence Scales, 5th edition (SB-5) Working Memory Total raw score [Time frame: Baseline and 6 Months]
• Stanford-Binet Intelligence Scales, 5th edition (SB-5) Working Memory Verbal raw score [Time frame: Baseline and 6 Months]
• Stanford-Binet Intelligence Scales, 5th edition (SB-5) Working Memory Non Verbal raw score [Time frame: Baseline and 6 Months]
• Differential Ability Scales-2 (DAS-II) Recall of Digits Forward raw score [Time frame: Baseline and 6 Months]
• Cambridge Neuropsychological Test Automated Battery (CANTAB) Paired Associates Learning (PAL) adjusted total errors based on stages completed [Time frame: Baseline and 6 Months]
• Cambridge Neuropsychological Test Automated Battery (CANTAB) Reaction Time (RTI) [Time frame: Baseline and 6 Months]
• Developmental Neuropsychological Assessment 2nd Edition (NEPSY-II) verbal fluency test raw score [Time frame: Baseline and 6 Months]
• Observer Memory Questionnaire - Parent Form (OMQ-PF) total T-score [Time frame: Baseline and 6 Months]
• Behavior Rating Inventory of Executive Function 2 (BRIEF2) T-scores for subscales (Inhibit, Self-Monitor, Shift, Emotional Control, Initiate) [Time frame: Baseline and 6 Months]
• Child Behavior Checklist (CBCL) T-scores for domains (Internalizing, Externalizing, Total Problems). [Time frame: Baseline and 6 Months]
• Child Behavior Checklist (CBCL) T-scores for subscales (Attention Problems, Thought Problems, Rule-Breaking Behaviors, Aggressive Behaviors) [Time frame: Baseline and 6 Months]
• KIDSCREEN-27 T-score [Time frame: Baseline and 6 Months]

Eligibility criteria

Inclusion criteria

• Ages 5.0 to 17.9 years at the time of screening
• Children with OSA and obstructive apnea hypopnea index (OAHI) ≥5/hour.
• 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.
• 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 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.
• Oxygen flow required does not exceed 3.0 LPM and does not exceed a FiO2 > 40 %.
• Willingness to comply with all study procedures and available for 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Triple blind

Primary purpose

Treatment

Study locations

United States · 7 centers

• Children's Hospital of Los Angeles — Los Angeles
• University of Michigan, Ann Arbor Hospital — Ann Arbor
• Cincinnati Children's Hospital Medical Center — Cincinnati
• Rainbow Babies and Children's Hospital, Case Medical Center — Cleveland
• Children's Hospital of Philadelphia — Philadelphia
• East Virginia Medical Center — Norfolk
• Seattle Children's Hospital — Seattle

Publications

• Das D, Medina B, Baktir MA, Mojabi FS, Fahimi A, Ponnusamy R, Salehi A. Increased incidence of intermittent hypoxemia in the Ts65Dn mouse model of Down syndrome. Neurosci Lett. 2015 Sep 14;604:91-6. doi: 10.1016/j.neulet.2015.07.040. Epub 2015 Aug 1. PMID 26240993
• Schloo BL, Vawter GF, Reid LM. Down syndrome: patterns of disturbed lung growth. Hum Pathol. 1991 Sep;22(9):919-23. doi: 10.1016/0046-8177(91)90183-p. PMID 1833304
• Bush D, Galambos C, Ivy DD, Abman SH, Wolter-Warmerdam K, Hickey F. Clinical Characteristics and Risk Factors for Developing Pulmonary Hypertension in Children with Down Syndrome. J Pediatr. 2018 Nov;202:212-219.e2. doi: 10.1016/j.jpeds.2018.06.031. Epub 2018 Jul 17. PMID 30025669
• Cooney TP, Wentworth PJ, Thurlbeck WM. Diminished radial count is found only postnatally in Down's syndrome. Pediatr Pulmonol. 1988;5(4):204-9. doi: 10.1002/ppul.1950050405. PMID 2976929
• Gonzalez OR, Gomez IG, Recalde AL, Landing BH. Postnatal development of the cystic lung lesion of Down syndrome: suggestion that the cause is reduced formation of peripheral air spaces. Pediatr Pathol. 1991 Jul-Aug;11(4):623-33. doi: 10.3109/15513819109064794. PMID 1835001
• O'Neill AC, Richter GT. Pharyngeal dysphagia in children with Down syndrome. Otolaryngol Head Neck Surg. 2013 Jul;149(1):146-50. doi: 10.1177/0194599813483445. Epub 2013 Mar 22. PMID 23525851
• Jackson A, Maybee J, Moran MK, Wolter-Warmerdam K, Hickey F. Clinical Characteristics of Dysphagia in Children with Down Syndrome. Dysphagia. 2016 Oct;31(5):663-71. doi: 10.1007/s00455-016-9725-7. Epub 2016 Jul 12. PMID 27405422
• Khoo MCK, Hu WH, Amin R. Effects of Ventilation-Perfusion Mismatch on Severity of Obstructive Sleep Apnea: A Modeling Study. Annu Int Conf IEEE Eng Med Biol Soc. 2020 Jul;2020:2792-2795. doi: 10.1109/EMBC44109.2020.9175297. PMID 33018586

Identifiers

NCT: NCT06043440 · 2023P000062

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗