Endotype DIrected Treatment for OSA in Down Syndrome

NCT ID: NCT07280468

Last Updated: 2025-12-12

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Clinical Phase: PHASE4
• Total Enrollment: 200 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2026-02-01
• Study Completion Date: 2030-01-31

Brief Summary

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.

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.

Conditions

Obstructive Sleep Apnea (OSA); Down Syndrome

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Uniform therapy (ato-oxy)

All participants receive the combination of atomoxetine and oxybutynin (ato-oxy) once nightly

Group Type: ACTIVE_COMPARATOR

ato-oxy

Intervention Type: DRUG

0.5 mg/kg (max 40 mg) of atomoxetine and 5mg oxybutynin taken nightly.

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).

Group Type: EXPERIMENTAL

ato-oxy

Intervention Type: DRUG

0.5 mg/kg (max 40 mg) of atomoxetine and 5mg oxybutynin taken nightly.

Oxygen

Intervention Type: DRUG

Oxygen via nasal cannula used nightly

Interventions

ato-oxy

0.5 mg/kg (max 40 mg) of atomoxetine and 5mg oxybutynin taken nightly.

Intervention Type: DRUG

Oxygen

Oxygen via nasal cannula used nightly

Intervention Type: DRUG

Other Intervention Names

atomoxetine and oxybutynin

Eligibility Criteria

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)

• Minimum Eligible Age: 6 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Patient-Centered Outcomes Research Institute

OTHER

Sponsor Role: collaborator

University of Arizona

OTHER

Sponsor Role: lead

Responsible Party

Daniel A. Combs

Associate Professor of Pediatrics and Medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Daniel Combs, MD

Role: PRINCIPAL_INVESTIGATOR

University of Arizona

Locations

University of Arizona

Tucson, Arizona, United States

University of Miami

Miami, Florida, United States

Advocate Medical Group Adult Down Syndrome Center

Park Ridge, Illinois, United States

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

Countries

United States

Central Contacts

Natalie Provencio-Dean

Role: CONTACT

nataliep@arizona.edu

520-403-6165

Facility Contacts

Natalie Provencio-Dean

Role: primary

nataliep@arizona.edu

520-403-6165

Ignacio Tapia

Role: primary

itapia@miami.edu

305-243-6162

Alex Albers

Role: primary

alexander.albers@aah.org

920-288-3129

Ruth Bradford

Role: primary

BRADFORD@chop.edu

267-426-5747

References

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.

Reference Type: BACKGROUND

PMID: 37555595 (View on PubMed)

Other Identifiers

IDD-2024C1-37111

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

STUDY00007297

Identifier Type: -

Identifier Source: org_study_id