Endotype DIrected Treatment for OSA in Down Syndrome (EDIT OSA)

Down syndrome is the most common genetic cause of intellectual disability. People with Down syndrome often have obstructive sleep apnea (OSA), a condition where people have difficulties with breathing while asleep. OSA can lead to poor sleep, worse quality of life, behavior problems and more difficulties with thinking ("cognitive impairment"). Current treatments for OSA in people with Down syndrome are not very effective or require surgery. The combination of 2 medications, atomoxetine and oxybutynin ("ato-oxy") is a promising treatment for OSA in people with Down syndrome, but ato-oxy does not work for everyone with Down syndrome. Similarly, oxygen is effective for OSA in some people, but does not work for everyone. This study will evaluate the use a precision medicine approach to increase the effectiveness of OSA treatment in people with Down syndrome. The study will compare two groups. In the first group, everyone will be treated with ato-oxy. In the second group, a precision medicine approach will be used to assign participants to either ato-oxy or oxygen therapy, based on the specific reasons they have OSA.

The research team will enroll 200 children (age 6-17 years old) and adults with Down syndrome and OSA from five sites across the country. Half of participants will randomly receive ato-oxy while the other will receive either oxygen or ato-oxy dependent upon which treatment would be expected to work better for them. The research team will measure OSA severity, quality of life, behavior and cognition at the start of the study and after 12 months of treatment for every participant. The study will also track any treatment side effects for each treatment group.

Study Overview

• Status: Recruiting
• Conditions: Down Syndrome; Obstructive Sleep Apnea (OSA)
• Intervention / Treatment: Drug: ato-oxy; Drug: Oxygen

Detailed Description

Background and Significance: Obstructive sleep apnea (OSA) is one of the most common comorbidities present in individuals with Down syndrome. In children without Down syndrome, OSA has a prevalence of 2-5%2 whereas the prevalence of OSA in children with Down syndrome has been estimated at 50-79%. Similarly, OSA occurs in 12% of adults without Down syndrome, but occurs in 80-100% of adults with Down syndrome. In studies by our group and others, OSA has been associated with neurocognitive impairment and impaired health-related quality of life (HRQOL) in children and adults with Down syndrome. Cognition and HRQOL have been shown to improve with effective treatment of OSA in people with Down syndrome. However, current treatments for OSA have limited effectiveness in people with Down syndrome. Adenotonsillectomy has been shown to have limited efficacy, as 65-73% of children with Down syndrome have residual OSA after adenotonsillectomy. Similarly, positive airway pressure (PAP) effectiveness is limited by poor adherence. Hypoglossal nerve stimulation has emerged as a new treatment but is an invasive procedure that involves a surgically placed implant that many individuals may prefer to avoid. Additionally, surgical complications are more common in people with DS compared to people without Down syndrome. Use is also limited in younger children with significant growth remaining. Given this, there is a great need for effective alternative therapies. The combination of atomoxetine and oxybutynin (ato-oxy) is a promising alternative therapy but is not effective in all individuals with Down syndrome. Similarly, oxygen therapy is often considered as an alternative treatment for OSA but is not effective in all patients. Underlying physiologic patient characteristics (OSA endotype) have predicted treatment response for OSA with both ato-oxy and oxygen. OSA endotype-directed treatment appears to be a means to identify the right treatment for the right patient, which may have greater effectiveness compared to the same treatment for all individuals.

Study Aims: The goal of this study is to determine if a precision medicine approach, endotype-directed treatment, is more effective than a one-size fits all treatment approach (ato-oxy) for OSA in people with Down syndrome. Specific aims of the study include: Aim 1: To compare the effectiveness of ato-oxy therapy versus precision medicine (endotype-directed) treatment for OSA in people with Down syndrome over 12 months; Aim 2: To compare the effectiveness of ato-oxy versus precision medicine (endotype-directed) treatment approach for key patient-centered outcomes (PCOs), including health-related quality of life, behavior and cognition over 12 months; Aim #3: To compare the adverse effects of ato-oxy versus precision medicine (endotype-directed) treatment.

Study Description: This is a randomized clinical trial comparing ato-oxy versus endotype-directed treatment for OSA in children and adults with DS. We will enroll 200 participants with Down syndrome and OSA (100 children age 6-17 years, 100 adults age 18+ years). Participants will be recruited from five clinical sites from across the country as well as via outreach. Participants will be randomized 1:1 at an individual level to either ato-oxy or endotype-directed treatment, which would be either oxygen or ato-oxy dependent upon the individual's OSA endotype. The study primary outcome is obstructive apnea-hypopnea index, the primary measure of OSA severity. Secondary study outcomes include measures of HRQOL, behavior, cognition and adverse effects. Participants will receive treatment and be followed for a total of 12 months during the study.

• Study Type: Interventional
• Enrollment (Estimated): 200
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Natalie Provencio-Dean; Phone Number: 520-403-6165; Email: nataliep@arizona.edu

Study Locations

• United States
  • Arizona
    • Tucson, Arizona, United States, 85724
      • Recruiting
      • University of Arizona
      • Contact: Natalie Provencio-Dean; Phone Number: 520-403-6165; Email: nataliep@arizona.edu
  • California
    • San Diego, California, United States, 92123
      • Not yet recruiting
      • University of California San Diego
      • Contact: Jasmine Tinoco; Phone Number: 224604 858-576-1700; Email: j1tinoco@health.ucsd.edu
      • Principal Investigator: Rakesh Bhattacharjee
  • Florida
    • Miami, Florida, United States, 33136
      • Not yet recruiting
      • University of Miami
      • Contact: Ignacio Tapia; Phone Number: 305-243-6162; Email: itapia@miami.edu
      • Principal Investigator: Ignacio Tapia
  • Illinois
    • Park Ridge, Illinois, United States, 60068
      • Not yet recruiting
      • Advocate Medical Group Adult Down Syndrome Center
      • Contact: Alex Albers; Phone Number: 920-288-3129; Email: alexander.albers@aah.org
      • Principal Investigator: Brian Chicoine
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Recruiting
      • Children's Hospital of Philadelphia
      • Contact: Ruth Bradford; Phone Number: 267-426-5747; Email: BRADFORD@chop.edu
      • Principal Investigator: Chris Cielo

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Age 6 years or older
2. Down syndrome diagnosis
3. Any gender or ethnicity
4. Adults without a legally authorized representative must have a caregiver/support person that can co-sign consent and complete study questionnaires.

Exclusion Criteria:

1. Currently using and adherent to PAP therapy (>4 hours per night for 70% of nights in the past 30 days based on device download or parent/caregiver report)
2. MAO inhibitor use
3. Urinary retention
4. Seizure disorder
5. Untreated or inadequately treated hypothyroidism
6. Significant traumatic brain injury
7. Not cleared to participate in the study by their cardiologist for individuals with congenital heart disease requiring follow up with cardiology at least once in the past year
8. History of current, untreated depression
9. History of liver disease (not including metabolic dysfunction-associated steatotic liver disease)
10. 3+ or greater tonsillar hypertrophy (for children only, no restriction for adults)

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: Uniform therapy (ato-oxy); All participants receive the combination of atomoxetine and oxybutynin (ato-oxy) once nightly	Drug: ato-oxy; 0.5 mg/kg (max 40 mg) of atomoxetine and 5mg oxybutynin taken nightly.; Other Names: atomoxetine and oxybutynin
Experimental: Endotype Directed Treatment; Participants receive either atomoxetine and oxybutynin (ato-oxy) or oxygen nightly. Participants receive the treatment expected to be most beneficial to them based on their baseline sleep study and OSA characteristics (OSA endotype).	Drug: ato-oxy; 0.5 mg/kg (max 40 mg) of atomoxetine and 5mg oxybutynin taken nightly.; Other Names: atomoxetine and oxybutynin; Drug: Oxygen; Oxygen via nasal cannula used nightly

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
obstructive apnea-hypopnea index (oAHI)	change in number of obstructive apneas and hypopneas per hour on polysomnography from baseline. Decreased oAHI indicates better outcome.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in caregiver Pediatric Quality of Life (PedsQL) score from baseline	Change in caregiver reported quality of life as measured by PedsQL, higher scores indicate better outcome.	12 months
Change in Paired Associate Learning test total adjusted errors from baseline	Change in Paired Associate Learning test total errors (a measure of memory) from baseline. Fewer errors indicate better outcome	12 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in processing speed (Arizona Memory Assessment for Preschoolers and Special Populations [A-MAP] task) from baseline.	This is a computerized cognitive assessment. Faster processing speed indicates better outcome.	12 months
Change in total IQ (Kaufman Brief Intelligence Test 2) from baseline	Higher IQ indicates better outcome	12 months
Change in non-verbal IQ (Kaufman Brief Intelligence Test 2) from baseline	Higher IQ indicates better outcome	12 months
Change in verbal IQ (Kaufman Brief Intelligence Test 2) from baseline	Higher IQ indicates better outcome	12 months
Change in Arizona Memory Assessment for Preschoolers and Special Populations (A-MAP) verbal memory task from baseline	This is a computerized assessment of memory, higher scores indicate better outcome.	12 months
Change in expressive language from baseline	This will use the narrative generation task from the Expressive Language Sampling protocol. Narratives will be coded using an established scheme to capture detail generation, narrative length, and semantics. Longer narratives with more details and more correct semantics indicates better outcome.	12 months
Change in Caregiver Global Impression of Change from baseline	This is a single question on overall improvement. Higher reported improvement indicates better outcome.	12 months
Change in N1 sleep (%) from baseline		12 months
Change in REM sleep (%) from baseline		12 months
Change in N3 sleep (%) from baseline		12 months
Change in arousal index (events/hr) from baseline		12 months
Change in Vineland 3 adaptive behavior composite scale from baseline	Higher scores indicate better outcome.	12 months
Change in Conners-3 ADHD Index from baseline	Lower scores indicate better outcome	12 months
Change in self-reported Pediatric Quality of Life Inventory (PedsQL) total score	Change in self-reported quality of life as measured by PedsQL	12 months
Change in caregiver-reported Pediatric Quality of Life Inventory (PedsQL) family impact		12 months
Hypoxic burden	Desaturation area under curve × event frequency, lower burden indicates better outcome.	12 months
Ventilatory burden	The proportion of breaths during sleep with less than 50% of their normal amplitude	12 months
Supine obstructive apnea-hypopnea index (oAHI)	obstructive apnea-hypopnea index while sleeping supine. Lower oAHI indicates better outcome.	12 months
non-supine obstructive apnea-hypopnea index (oAHI)	obstructive apnea-hypopnea index while sleeping in any position other than supine. Lower oAHI indicates better outcome.	12 months
total Apnea Hypopnea Index (AHI)	Lower AHI indicates better outcome	12 months

Collaborators and Investigators

• Sponsor: University of Arizona
• Collaborators: Patient-Centered Outcomes Research Institute
• Investigators: Principal Investigator: Daniel Combs, MD, University of Arizona

Publications and helpful links

General Publications

• Combs D, Edgin J, Hsu CH, Bottrill K, Van Vorce H, Gerken B, Matloff D, La Rue S, Parthasarathy S. The combination of atomoxetine and oxybutynin for the treatment of obstructive sleep apnea in children with Down syndrome. J Clin Sleep Med. 2023 Dec 1;19(12):2065-2073. doi: 10.5664/jcsm.10764.

Study record dates

Study Major Dates

• Study Start (Actual): March 14, 2026
• Primary Completion (Estimated): January 1, 2030
• Study Completion (Estimated): January 1, 2030

Study Registration Dates

• First Submitted: November 23, 2025
• First Submitted That Met QC Criteria: December 3, 2025
• First Posted (Actual): December 12, 2025

Study Record Updates

• Last Update Posted (Actual): April 7, 2026
• Last Update Submitted That Met QC Criteria: April 1, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: oxybutynin; obstructive sleep apnea; atomoxetine; oxygen; Down syndrome; precision medicine; ato-oxy
• Additional Relevant MeSH Terms: Neurologic Manifestations; Nervous System Diseases; Genetic Diseases, Inborn; Respiratory Tract Diseases; Neurobehavioral Manifestations; Respiration Disorders; Sleep Wake Disorders; Congenital Abnormalities; Abnormalities, Multiple; Apnea; Sleep Disorders, Intrinsic; Dyssomnias; Intellectual Disability; Sleep Apnea Syndromes; Chromosome Disorders; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Sleep Apnea, Obstructive; Down Syndrome; Organic Chemicals; Amines; Inorganic Chemicals; Elements; Chalcogens; Gases; Propylamines; Atomoxetine Hydrochloride; Oxygen; oxybutynin
• Other Study ID Numbers: STUDY00007297; IDD-2024C1-37111 (Other Grant/Funding Number: Patient Centered Outcomes Research Institute)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified data will be made available.

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.: No