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

• ClinicalTrials.gov Identifier: NCT06043440
• Recruitment Status: Recruiting
• First Posted: September 21, 2023
• Last Update Posted: February 22, 2024
• Sponsor: Brigham and Women's Hospital
• Collaborators: Children's Hospital Medical Center, Cincinnati; Children's Hospital of Philadelphia; Rainbow Babies and Children's Hospital; University of Michigan; Children's Hospital Los Angeles; Children's Hospital of The King's Daughters; Seattle Children's Hospital; University of Southern California
• Information provided by (Responsible Party): Susan Redline, Brigham and Women's Hospital

Study Description

Brief Summary:

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).

Condition or disease	Intervention/treatment	Phase
Down Syndrome; Obstructive Sleep Apnea	Drug: Oxygen	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 230 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Randomized Control Trial of Oxygen Therapy in Children and Adolescents With Down Syndrome and Obstructive Sleep Apnea
• Actual Study Start Date: October 24, 2023
• Estimated Primary Completion Date: August 31, 2027
• Estimated Study Completion Date: December 27, 2027

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

1. Stanford-Binet Intelligence Scales, 5th edition (SB-5) Working Memory Total raw score [ Time Frame: Baseline and 6 Months ]
   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.
2. Stanford-Binet Intelligence Scales, 5th edition (SB-5) Working Memory Verbal raw score [ Time Frame: Baseline and 6 Months ]
   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.
3. Stanford-Binet Intelligence Scales, 5th edition (SB-5) Working Memory Non Verbal raw score [ Time Frame: Baseline and 6 Months ]
   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.
4. Differential Ability Scales-2 (DAS-II) Recall of Digits Forward raw score [ Time Frame: Baseline and 6 Months ]
   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.
5. Cambridge Neuropsychological Test Automated Battery (CANTAB) Paired Associates Learning (PAL) adjusted total errors based on stages completed [ Time Frame: Baseline and 6 Months ]
   Change from baseline in Cambridge Neuropsychological Test Automated Battery (CANTAB) Paired Associates Learning (PAL) adjusted total errors based on stages completed
6. Cambridge Neuropsychological Test Automated Battery (CANTAB) Reaction Time (RTI) [ Time Frame: Baseline and 6 Months ]
   Change from baseline in Cambridge Neuropsychological Test Automated Battery (CANTAB) Reaction Time (RTI)
7. Developmental Neuropsychological Assessment 2nd Edition (NEPSY-II) verbal fluency test raw score [ Time Frame: Baseline and 6 Months ]
   Change from baseline in Developmental Neuropsychological Assessment 2nd Edition (NEPSY-II) verbal fluency test raw score. Range-N/A
8. Observer Memory Questionnaire - Parent Form (OMQ-PF) total T-score [ Time Frame: Baseline and 6 Months ]
   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.
9. 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 ]
   Change from baseline in Behavior Rating Inventory of Executive Function 2 (BRIEF2) T-scores for subscales (Inhibit, Self-Monitor, Shift, Emotional Control, Initiate).
10. Child Behavior Checklist (CBCL) T-scores for domains (Internalizing, Externalizing, Total Problems). [ Time Frame: Baseline and 6 Months ]
    Change from baseline in Child Behavior Checklist (CBCL) T-scores for domains (Internalizing, Externalizing, Total Problems).
11. Child Behavior Checklist (CBCL) T-scores for subscales (Attention Problems, Thought Problems, Rule-Breaking Behaviors, Aggressive Behaviors) [ Time Frame: Baseline and 6 Months ]
    Change from baseline in Child Behavior Checklist (CBCL) T-scores for subscales (Attention Problems, Thought Problems, Rule-Breaking Behaviors, Aggressive Behaviors)
12. KIDSCREEN-27 T-score [ Time Frame: Baseline and 6 Months ]
    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
13. Patient-Reported Outcomes Measurement Information System (PROMIS) sleep disturbance T-score [ Time Frame: Baseline and 6 Months ]
    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.
14. Patient-Reported Outcomes Measurement Information System (PROMIS) sleep-related impairment T-score [ Time Frame: Baseline and 6 Months ]
    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.
15. Presence of right ventricular hypertension [ Time Frame: Baseline and 6 Months ]
    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)
16. Wechsler Intelligence Scale (WISC) for Children 5th edition (WISC-5) Cancellation raw score [ Time Frame: Baseline and 6 Months ]
    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.
17. Wechsler Preschool and Primary Scale of Intelligence 4th edition (WPPSI-4) Cancellation task raw score [ Time Frame: Baseline and 6 Months ]
    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.
18. Behavior Rating Inventory of Executive Function 2 (BRIEF2) T-scores for Behavior Regulation Index (BRI) domain. [ Time Frame: Baseline and 6 Months ]
    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.
19. Behavior Rating Inventory of Executive Function 2 (BRIEF2) T-scores for Emotional Recognition Index (ERI) domain. [ Time Frame: Baseline and 6 Months ]
    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.
20. Behavior Rating Inventory of Executive Function 2 (BRIEF2) T-scores for Cognitive Regulation Index (CRI) domain. [ Time Frame: Baseline and 6 Months ]
    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.
21. 7-day actigraphy measurement of sleep efficiency [ Time Frame: Baseline and 6 Months ]
    Change from baseline in 7-day actigraphy measurement of sleep efficiency
22. 7-day actigraphy measurement of time wake after sleep onset [ Time Frame: Baseline and 6 Months ]
    Change from baseline in 7-day actigraphy measurement of time wake after sleep onset
23. 7-day actigraphy measurement of sleep fragmentation [ Time Frame: Baseline and 6 Months ]
    Change from baseline in 7-day actigraphy measurement of sleep fragmentation
24. 7-day actigraphy measurement of total sleep duration [ Time Frame: Baseline and 6 Months ]
    Change from baseline in 7-day actigraphy measurement of total sleep duration
25. Polysomnography (PSG) AHI parameter [ Time Frame: Baseline and 6 Months ]
    Change from baseline in Polysomnography (PSG) AHI parameter. The score ranges from 0- >40. A higher score is a worse outcome.
26. Polysomnography (PSG) percentage time of O2 <90 % parameter [ Time Frame: Baseline and 6 Months ]
    Change from baseline in Polysomnography (PSG) percentage time of O2 <90 % parameter
27. Polysomnography (PSG) sleep apnea associated hypoxic burden parameter [ Time Frame: Baseline and 6 Months ]
    Change from baseline in Polysomnography (PSG) sleep apnea associated hypoxic burden, parameter
28. Polysomnography (PSG) end-tidal CO2 level, parameter [ Time Frame: Baseline and 6 Months ]
    Change from baseline in Polysomnography (PSG) end-tidal CO2 parameter.
29. Polysomnography (PSG) -based measure of sleep stages [ Time Frame: Baseline and 6 Months ]
    Change from baseline in Polysomnography (PSG) -based measure of sleep stages. Range- N/A
30. Polysomnography (PSG) -based measure of EEG power bands [ Time Frame: Baseline and 6 Months ]
    Change from baseline in Polysomnography (PSG) -based measure of EEG power bands
31. Polysomnography (PSG) -based measure of spindle morphology [ Time Frame: Baseline and 6 Months ]
    Change from baseline in Polysomnography (PSG) -based measure of spindle morphology
32. Polysomnography (PSG) -based measure of spindle numbers [ Time Frame: Baseline and 6 Months ]
    Change from baseline in Polysomnography (PSG) -based measure of spindle numbers
33. Polysomnography (PSG) -based measure of spindle density [ Time Frame: Baseline and 6 Months ]
    Change from baseline in Polysomnography (PSG) -based measure of spindle density
34. Polysomnography (PSG) -based measure of slow wave oscillations [ Time Frame: Baseline and 6 Months ]
    Change from baseline in Polysomnography (PSG) -based measure of slow wave oscillations
35. Left ventricular diastolic function as measured by Mitral E and A wave (E:A ratio) [ Time Frame: Baseline and 6 Months ]
    Change from baseline in left ventricular diastolic function as measured by Mitral E and A wave (E:A ratio)
36. Left ventricular diastolic function as measured by E wave deceleration time [ Time Frame: Baseline and 6 Months ]
    Change from baseline in left ventricular diastolic function as measured by E wave deceleration time
37. Left ventricular diastolic function as measured by Mitral septal and lateral e' and a' (E/e') [ Time Frame: Baseline and 6 Months ]
    Change from baseline in left ventricular diastolic function as measured by Mitral septal and lateral e' and a' (E/e')
38. Left ventricular diastolic function as measured by Mitral lateral tissue Doppler isovolumic relaxation time [ Time Frame: Baseline and 6 Months ]
    Change from baseline in left ventricular diastolic function as measured by Mitral lateral tissue Doppler isovolumic relaxation time
39. Left ventricular diastolic function as measured by Pulmonary vein A wave reversal duration [ Time Frame: Baseline and 6 Months ]
    Change from baseline in left ventricular diastolic function as measured by Pulmonary vein A wave reversal duration
40. Left ventricular diastolic function as measured by Left atrial volume [ Time Frame: Baseline and 6 Months ]
    Change from baseline in left ventricular diastolic function as measured by Left atrial volume

Eligibility Criteria

• Ages Eligible for Study: 5 Years to 215 Months (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Ages 5.0 to 17.9 years at the time of screening
2. Children with Obstructive Sleep Apnea (OSA) and obstructive apnea hypopnea index (OAHI) 5-40/hour. :
3. Absence of clinically significant hypoxia defined as oxygen saturation <88% for 5 minutes or episodic desaturation to 60%.

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 without hypoventilation.
   4. Oxygen flow required does not exceed 3.0 liter/minute or Fraction of Inspired Oxygen (FiO2) >40%.
5. Willingness to comply with all study procedures and be available for the 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.

Contacts and Locations

Contacts

Contact: Oltion Sina; 8573407909; osina@bwh.harvard.edu

Contact: Suzie Hicks; 5136364944; suzanna.hicks@cchmc.org

Locations

United States, California

Children's Hospital of Los Angeles; Recruiting

Los Angeles, California, United States, 90027

Contact: Danny Del Cid-Linare ddelcidlinares@chla.usc.edu

Principal Investigator: Sally Ward, MD

United States, Michigan

University of Michigan, Ann Arbor Hospital; Recruiting

Ann Arbor, Michigan, United States, 48109

Contact: Emily Herreshoff egalopin@med.umich.edu

Principal Investigator: Ronald Chervin, MD

United States, Ohio

Cincinnati Children's Hospital Medical Center; Recruiting

Cincinnati, Ohio, United States, 45229

Contact: Suzanna Hicks suzanna.hicks@cchmc.org

Principal Investigator: Raouf Amin, MD

Rainbow Babies and Children's Hospital, Case Medical Center; Recruiting

Cleveland, Ohio, United States, 44106

Contact: Alyssa Keller Alyssa.Keller@Uhhospitals.org

Principal Investigator: Sally Ibrahim, MD

United States, Pennsylvania

Children's Hospital of Philadelphia; Recruiting

Philadelphia, Pennsylvania, United States, 19104

Contact: Ebereh Uwah uwahe@chop.edu

Principal Investigator: Christopher Cielo, MD

United States, Virginia

East Virginia Medical Center; Recruiting

Norfolk, Virginia, United States, 23507

Contact: Thomas Boswick BoswicST@EVMS.edu

Principal Investigator: Cristina Baldassari, MD

United States, Washington

Seattle Children's Hospital; Recruiting

Seattle, Washington, United States, 98105

Contact: Sharon McNamara sharon.mcnamara@seattlechildrens.org

Principal Investigator: Maida Chen, MD

Sponsors and Collaborators

Brigham and Women's Hospital

Children's Hospital Medical Center, Cincinnati

Children's Hospital of Philadelphia

Rainbow Babies and Children's Hospital

University of Michigan

Children's Hospital Los Angeles

Children's Hospital of The King's Daughters

Seattle Children's Hospital

University of Southern California

Investigators

• Principal Investigator: Susan Redline; Brigham and Women's Hospital
• Principal Investigator: Raouf Amin; Children's Hospital Medical Center, Cincinnati

More Information

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.

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.

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.

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.

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.

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.

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.

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.

Alex RM, Panza GS, Hakim H, Badr MS, Edwards BA, Sands SA, Mateika JH. Exposure to mild intermittent hypoxia increases loop gain and the arousal threshold in participants with obstructive sleep apnoea. J Physiol. 2019 Jul;597(14):3697-3711. doi: 10.1113/JP277711. Epub 2019 May 9.

Vetrano DL, Carfi A, Brandi V, L'Angiocola PD, Di Tella S, Cipriani MC, Antocicco M, Zuccala G, Palmieri V, Silveri MC, Bernabei R, Onder G. Left ventricle diastolic function and cognitive performance in adults with Down syndrome. Int J Cardiol. 2016 Jan 15;203:816-8. doi: 10.1016/j.ijcard.2015.11.041. Epub 2015 Nov 6. No abstract available.

Mann DM, Esiri MM. The pattern of acquisition of plaques and tangles in the brains of patients under 50 years of age with Down's syndrome. J Neurol Sci. 1989 Feb;89(2-3):169-79. doi: 10.1016/0022-510x(89)90019-1.

Bauer J, Strauss S, Schreiter-Gasser U, Ganter U, Schlegel P, Witt I, Yolk B, Berger M. Interleukin-6 and alpha-2-macroglobulin indicate an acute-phase state in Alzheimer's disease cortices. FEBS Lett. 1991 Jul 8;285(1):111-4. doi: 10.1016/0014-5793(91)80737-n.

Di Domenico F, Tramutola A, Butterfield DA. Role of 4-hydroxy-2-nonenal (HNE) in the pathogenesis of alzheimer disease and other selected age-related neurodegenerative disorders. Free Radic Biol Med. 2017 Oct;111:253-261. doi: 10.1016/j.freeradbiomed.2016.10.490. Epub 2016 Oct 24.

Lyman M, Lloyd DG, Ji X, Vizcaychipi MP, Ma D. Neuroinflammation: the role and consequences. Neurosci Res. 2014 Feb;79:1-12. doi: 10.1016/j.neures.2013.10.004. Epub 2013 Oct 19.

Rueda N, Vidal V, Garcia-Cerro S, Narcis JO, Llorens-Martin M, Corrales A, Lantigua S, Iglesias M, Merino J, Merino R, Martinez-Cue C. Anti-IL17 treatment ameliorates Down syndrome phenotypes in mice. Brain Behav Immun. 2018 Oct;73:235-251. doi: 10.1016/j.bbi.2018.05.008. Epub 2018 May 31.

Rueda Revilla N, Martinez-Cue C. Antioxidants in Down Syndrome: From Preclinical Studies to Clinical Trials. Antioxidants (Basel). 2020 Aug 3;9(8):692. doi: 10.3390/antiox9080692.

Zhang P, Wang Y, Wang H, Cao J. Sesamol alleviates chronic intermittent hypoxia-induced cognitive deficits via inhibiting oxidative stress and inflammation in rats. Neuroreport. 2021 Jan 13;32(2):105-111. doi: 10.1097/WNR.0000000000001564.

Sapin E, Peyron C, Roche F, Gay N, Carcenac C, Savasta M, Levy P, Dematteis M. Chronic Intermittent Hypoxia Induces Chronic Low-Grade Neuroinflammation in the Dorsal Hippocampus of Mice. Sleep. 2015 Oct 1;38(10):1537-46. doi: 10.5665/sleep.5042.

Schmidt-Kastner R. Genomic approach to selective vulnerability of the hippocampus in brain ischemia-hypoxia. Neuroscience. 2015 Nov 19;309:259-79. doi: 10.1016/j.neuroscience.2015.08.034. Epub 2015 Sep 14.

Tietze AL, Blankenburg M, Hechler T, Michel E, Koh M, Schluter B, Zernikow B. Sleep disturbances in children with multiple disabilities. Sleep Med Rev. 2012 Apr;16(2):117-27. doi: 10.1016/j.smrv.2011.03.006. Epub 2011 May 26.

Churchill SS, Kieckhefer GM, Bjornson KF, Herting JR. Relationship between sleep disturbance and functional outcomes in daily life habits of children with Down syndrome. Sleep. 2015 Jan 1;38(1):61-71. doi: 10.5665/sleep.4326.

Edgin JO, Tooley U, Demara B, Nyhuis C, Anand P, Spano G. Sleep Disturbance and Expressive Language Development in Preschool-Age Children With Down Syndrome. Child Dev. 2015 Nov-Dec;86(6):1984-98. doi: 10.1111/cdev.12443. Epub 2015 Oct 5.

Hoffmire CA, Magyar CI, Connolly HV, Fernandez ID, van Wijngaarden E. High prevalence of sleep disorders and associated comorbidities in a community sample of children with Down syndrome. J Clin Sleep Med. 2014 Apr 15;10(4):411-9. doi: 10.5664/jcsm.3618.

Kuroda H, Sawatari H, Ando S, Ohkusa T, Rahmawati A, Ono J, Nishizaka M, Hashiguchi N, Matsuoka F, Chishaki A. A nationwide, cross-sectional survey on unusual sleep postures and sleep-disordered breathing-related symptoms in people with Down syndrome. J Intellect Disabil Res. 2017 Jul;61(7):656-667. doi: 10.1111/jir.12379. Epub 2017 Apr 5.

Pittaras E, Colas D, Chuluun B, Allocca G, Heller C. Enhancing sleep after training improves memory in down syndrome model mice. Sleep. 2022 Apr 11;45(4):zsab247. doi: 10.1093/sleep/zsab247.

Hawkins A, Langton-Hewer S, Henderson J, Tulloh RM. Management of pulmonary hypertension in Down syndrome. Eur J Pediatr. 2011 Jul;170(7):915-21. doi: 10.1007/s00431-010-1378-1. Epub 2011 Jan 4.

Bush D, Abman SH, Galambos C. Prominent Intrapulmonary Bronchopulmonary Anastomoses and Abnormal Lung Development in Infants and Children with Down Syndrome. J Pediatr. 2017 Jan;180:156-162.e1. doi: 10.1016/j.jpeds.2016.08.063. Epub 2016 Sep 22.

Chi TPL?Krovetz J. The pulmonary vascular bed in children with Down syndrome. J Pediatr. 1975 Apr;86(4):533-8. doi: 10.1016/s0022-3476(75)80142-9.

Iwaya Y, Muneuchi J, Inoue Y, Watanabe M, Okada S, Ochiai Y. Relationship Between Pulmonary Arterial Resistance and Compliance in Patients with Down Syndrome. Pediatr Cardiol. 2019 Apr;40(4):841-847. doi: 10.1007/s00246-019-02080-9. Epub 2019 Mar 4.

Bush D, Galambos C, Dunbar Ivy D. Pulmonary hypertension in children with Down syndrome. Pediatr Pulmonol. 2021 Mar;56(3):621-629. doi: 10.1002/ppul.24687. Epub 2020 Feb 12.

Amin RS, Kimball TR, Kalra M, Jeffries JL, Carroll JL, Bean JA, Witt SA, Glascock BJ, Daniels SR. Left ventricular function in children with sleep-disordered breathing. Am J Cardiol. 2005 Mar 15;95(6):801-4. doi: 10.1016/j.amjcard.2004.11.044.

Domany KA, Huang G, Hossain MM, Schuler CL, Somers VK, Daniels SR, Amin R. Effect of Adenotonsillectomy on Cardiac Function in Children Age 5-13 Years With Obstructive Sleep Apnea. Am J Cardiol. 2021 Feb 15;141:120-126. doi: 10.1016/j.amjcard.2020.11.019. Epub 2020 Nov 19.

Amin RS, Kimball TR, Bean JA, Jeffries JL, Willging JP, Cotton RT, Witt SA, Glascock BJ, Daniels SR. Left ventricular hypertrophy and abnormal ventricular geometry in children and adolescents with obstructive sleep apnea. Am J Respir Crit Care Med. 2002 May 15;165(10):1395-9. doi: 10.1164/rccm.2105118.

Konstantinopoulou S, Tapia IE, Kim JY, Xanthopoulos MS, Radcliffe J, Cohen MS, Hanna BD, Pipan M, Cielo C, Thomas AJ, Zemel B, Amin R, Bradford R, Traylor J, Shults J, Marcus CL. Relationship between obstructive sleep apnea cardiac complications and sleepiness in children with Down syndrome. Sleep Med. 2016 Jan;17:18-24. doi: 10.1016/j.sleep.2015.09.014. Epub 2015 Oct 23.

Bittles AH, Glasson EJ. Clinical, social, and ethical implications of changing life expectancy in Down syndrome. Dev Med Child Neurol. 2004 Apr;46(4):282-6. doi: 10.1017/s0012162204000441. No abstract available.

Presson AP, Partyka G, Jensen KM, Devine OJ, Rasmussen SA, McCabe LL, McCabe ER. Current estimate of Down Syndrome population prevalence in the United States. J Pediatr. 2013 Oct;163(4):1163-8. doi: 10.1016/j.jpeds.2013.06.013. Epub 2013 Jul 23.

Chamseddin BH, Johnson RF, Mitchell RB. Obstructive Sleep Apnea in Children with Down Syndrome: Demographic, Clinical, and Polysomnographic Features. Otolaryngol Head Neck Surg. 2019 Jan;160(1):150-157. doi: 10.1177/0194599818797308. Epub 2018 Aug 28.

Lee CF, Lee CH, Hsueh WY, Lin MT, Kang KT. Prevalence of Obstructive Sleep Apnea in Children With Down Syndrome: A Meta-Analysis. J Clin Sleep Med. 2018 May 15;14(5):867-875. doi: 10.5664/jcsm.7126.

Cornacchia M, Sethness J, Alapat P, Lin YH, Peacock C. The Prevalence of OSA Among an Adult Population With Down Syndrome Referred to a Medical Clinic. Am J Intellect Dev Disabil. 2019 Jan;124(1):4-10. doi: 10.1352/1944-7558-124.1.4.

Gimenez S, Videla L, Romero S, Benejam B, Clos S, Fernandez S, Martinez M, Carmona-Iragui M, Antonijoan RM, Mayos M, Fortuna A, Penacoba P, Plaza V, Osorio RS, Sharma RA, Bardes I, Rebillat AS, Lleo A, Blesa R, Videla S, Fortea J. Prevalence of Sleep Disorders in Adults With Down Syndrome: A Comparative Study of Self-Reported, Actigraphic, and Polysomnographic Findings. J Clin Sleep Med. 2018 Oct 15;14(10):1725-1733. doi: 10.5664/jcsm.7382.

Gimenez S, Altuna M, Blessing E, Osorio RM, Fortea J. Sleep Disorders in Adults with Down Syndrome. J Clin Med. 2021 Jul 6;10(14):3012. doi: 10.3390/jcm10143012.

Tarasiuk A, Greenberg-Dotan S, Simon-Tuval T, Freidman B, Goldbart AD, Tal A, Reuveni H. Elevated morbidity and health care use in children with obstructive sleep apnea syndrome. Am J Respir Crit Care Med. 2007 Jan 1;175(1):55-61. doi: 10.1164/rccm.200604-577OC. Epub 2006 Oct 12.

Reuveni H, Simon T, Tal A, Elhayany A, Tarasiuk A. Health care services utilization in children with obstructive sleep apnea syndrome. Pediatrics. 2002 Jul;110(1 Pt 1):68-72. doi: 10.1542/peds.110.1.68.

Tarasiuk A, Simon T, Tal A, Reuveni H. Adenotonsillectomy in children with obstructive sleep apnea syndrome reduces health care utilization. Pediatrics. 2004 Feb;113(2):351-6. doi: 10.1542/peds.113.2.351.

Bergeron M, Duggins AL, Cohen AP, Leader BA, Ishman SL. The impact of persistent pediatric obstructive sleep apnea on the Quality of Life of Patients' families. Int J Pediatr Otorhinolaryngol. 2020 Feb;129:109723. doi: 10.1016/j.ijporl.2019.109723. Epub 2019 Oct 12.

Jensen KM, Sevick CJ, Seewald LAS, Halbower AC, Davis MM, McCabe ERB, Kempe A, Abman SH. Greater risk of hospitalization in children with Down syndrome and OSA at higher elevation. Chest. 2015 May;147(5):1344-1351. doi: 10.1378/chest.14-1883.

Boulet SL, Molinari NA, Grosse SD, Honein MA, Correa-Villasenor A. Health care expenditures for infants and young children with Down syndrome in a privately insured population. J Pediatr. 2008 Aug;153(2):241-6. doi: 10.1016/j.jpeds.2008.02.046. Epub 2008 Apr 23.

Kong AM, Hurley D, Evans KA, Brixner D, Csoboth C, Visootsak J. A Retrospective, Longitudinal, Claims-Based Comparison of Concomitant Diagnoses Between Individuals with and Without Down Syndrome. J Manag Care Spec Pharm. 2017 Jul;23(7):761-770. doi: 10.18553/jmcp.2017.23.7.761.

Baker AB, Farhood Z, Brandstetter KA, Teufel RJ 2nd, LaRosa A, White DR. Tonsillectomy in Children with Down Syndrome: A National Cohort of Inpatients. Otolaryngol Head Neck Surg. 2017 Sep;157(3):499-503. doi: 10.1177/0194599817711377. Epub 2017 Aug 1.

Nation J, Brigger M. The Efficacy of Adenotonsillectomy for Obstructive Sleep Apnea in Children with Down Syndrome: A Systematic Review. Otolaryngol Head Neck Surg. 2017 Sep;157(3):401-408. doi: 10.1177/0194599817703921. Epub 2017 May 9.

Propst EJ, Amin R, Talwar N, Zaman M, Zweerink A, Blaser S, Zaarour C, Luginbuehl I, Karsli C, Aziza A, Forrest C, Drake J, Narang I. Midline posterior glossectomy and lingual tonsillectomy in obese and nonobese children with down syndrome: Biomarkers for success. Laryngoscope. 2017 Mar;127(3):757-763. doi: 10.1002/lary.26104. Epub 2016 Jun 27.

Merrell JA, Shott SR. OSAS in Down syndrome: T&A versus T&A plus lateral pharyngoplasty. Int J Pediatr Otorhinolaryngol. 2007 Aug;71(8):1197-203. doi: 10.1016/j.ijporl.2007.04.009. Epub 2007 May 29.

Thottam PJ, Trivedi S, Siegel B, Williams K, Mehta D. Comparative outcomes of severe obstructive sleep apnea in pediatric patients with Trisomy 21. Int J Pediatr Otorhinolaryngol. 2015 Jul;79(7):1013-6. doi: 10.1016/j.ijporl.2015.04.015. Epub 2015 Apr 28.

Europe, K.G., The KIDSCREEN Questionnaires. Quality of life Questionnaires for Children and Adolescents. Lengerich. Pabst Science, 2006.

Jennison C and Turnbull GW. 2000. Group Sequential Methods with Applications to Clinical Trials. Boca Raton: Chapman & Hall/CRC.

Wittes J, Brittain E. The role of internal pilot studies in increasing the efficiency of clinical trials. Stat Med. 1990 Jan-Feb;9(1-2):65-71; discussion 71-2. doi: 10.1002/sim.4780090113.

Gould LA, and Shih WJ. 1992. Sample Size Re-Estimation Without Unblinding for Normally Distributed Outcomes with Unknown Variance. Communications in Statistics. Theory and Methods 21 (10): 2833-53.

Friede T and Miller F. 2012. Blinded Continuous Monitoring of Nuisance Parameters in Clinical Trials. Applied Statistics 61 (4): 601-18.

• Responsible Party: Susan Redline, Proffesor, Brigham and Women's Hospital
• ClinicalTrials.gov Identifier: NCT06043440
• Other Study ID Numbers: 2023P000062
• First Posted: September 21, 2023
• Last Update Posted: February 22, 2024
• Last Verified: February 2024

• 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

Additional relevant MeSH terms:

Apnea; Sleep Apnea Syndromes; Sleep Apnea, Obstructive; Down Syndrome; Syndrome; Disease; Pathologic Processes; Respiration Disorders; Respiratory Tract Diseases; Signs and Symptoms, Respiratory; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Nervous System Diseases; Intellectual Disability; Neurobehavioral Manifestations; Neurologic Manifestations; Abnormalities, Multiple; Congenital Abnormalities; Chromosome Disorders; Genetic Diseases, Inborn