Medications for Obstructive Sleep Apnea In Children With Down Syndrome (MOSAIC)

Evaluation of Atomoxetine and Oxybutynin for Obstructive Sleep Apnea in Children With Down Syndrome

This is a randomized, double blind, cross-over study of the combination of atomoxetine and oxybutynin (ato-oxy) in children with DS and OSA documented by polysomnography (PSG). Participants will receive high dose ato-oxy for four weeks as well as low dose ato-oxy for four weeks in random order. During the high dose ato-oxy period, participants will take 5 mg oxybutynin and 0.5mg/kg/day (max 40 mg) atomoxetine nightly for one week. Atomoxetine dose will then be increased to 1.2 mg/kg/day (max 80 mg). During the low dose ato-oxy period, participants will take 5 mg oxybutynin and 0.5mg/kg/day (max 40 mg) atomoxetine. Dosing of the study treatment will occur approximately 30 minutes prior to bedtime. Participants who withdraw from the study will not be replaced.

Study participants will undergo eligibility screening that will include an initial screening to determine whether non- PSG enrollment criteria are met, followed by a 1 night in-lab PSG and health-related quality of life assessment for participants who qualify based on non-PSG criteria. For participants who are eligible and enroll in the study, the screening PSG night will serve as the baseline measure for apnea hypopnea index (AHI) and other PSG endpoints. On the final night of dosing for both high dose ato-oxy and low-dose ato-oxy, participants will return for inpatient PSG and health-related quality of life assessment. The primary efficacy endpoint is the change in obstructive AHI from baseline (high dose ato-oxy vs. low dose ato-oxy).

Study Overview

• Status: Completed
• Conditions: Obstructive Sleep Apnea; Down Syndrome
• Intervention / Treatment: Drug: Atomoxetine and oxybutynin (ato-oxy)

• Study Type: Interventional
• Enrollment (Actual): 22
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Tucson, Arizona, United States, 85721
      • University of Arizona

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years to 17 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Male or female participants between 6 to 17 years of age, inclusive, at the Screening Visit. Enrollment will be stratified to ensure equal representation of children age 6-12 and age 13-17. No more than 14 subjects will be randomized for each age group.
2. Known diagnosis of Down syndrome (trisomy 21, but not translocation or mosaicism)

Exclusion Criteria:

1. Hypoxemia independent of respiratory events on polysomnography (≥5 minutes with oxygen saturation <90%)
2. Presence of central sleep apnea on polysomnography (central AHI ≥ 5)
3. 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 report)
4. MAO inhibitor use
5. Urinary retention
6. Prematurity < 37 weeks estimated gestational age
7. Seizure disorder
8. Untreated or inadequately treated hypothyroidism
9. Significant traumatic brain injury
10. Congenital heart disease and not cleared to participate by the patient's cardiologist
11. History of current, untreated depression
12. History of liver disease
13. 3+ or greater tonsillar hypertrophy.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: High dose ato-oxy	Drug: Atomoxetine and oxybutynin (ato-oxy); Low dose ato-oxy will include 0.5 mg/kg/day of atomoxetine (max 40 mg) in combination with 5 mg oxybutynin High dose ato-oxy will include 1.2 mg/kg/day atomoxetine (max 80 mg) and 5 mg oxybutynin
Active Comparator: Low dose ato-oxy	Drug: Atomoxetine and oxybutynin (ato-oxy); Low dose ato-oxy will include 0.5 mg/kg/day of atomoxetine (max 40 mg) in combination with 5 mg oxybutynin High dose ato-oxy will include 1.2 mg/kg/day atomoxetine (max 80 mg) and 5 mg oxybutynin

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 (% change)	four weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Obstructive Sleep Apnea-18 score (OSA-18)	Change in OSA-18 (a measure of health-related quality of life) from baseline. The OSA-18 score ranges from 18 to 136, with lower scores indicating better health-related quality of life.	four weeks
Arousal Index	change in number of arousals per hour on polysomnography from baseline	four weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pediatric Quality of Life Inventory (PedsQL) total score	Change in PedsQL total score (a measure of health-related quality of life) from baseline. The PedsQL score ranges from 0-100, with higher scores indicating better health-related quality of life.	four weeks
Caregiver Global Impression of Change	Change in Caregiver Global Impression of Change from baseline. This will be assessed on a seven point scale answering the question: Since the start of this therapy, my child's overall status is: 1. Very much improved; 2. Much improved; 3. Minimally Improved; 4. No change; 5. Minimally worse; 6. Much worse or 7. Very much worse.	four weeks
N1 sleep percentage	Change in N1 sleep percentage on polysomnography from baseline	four weeks
REM sleep percentage	Change in REM sleep percentage on polysomnography from baseline	four weeks
N3 sleep percentage	Change in N3 sleep percentage on polysomnography from baseline	four weeks

Collaborators and Investigators

• Sponsor: University of Arizona
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Daniel Combs, MD, University of Arizona

Study record dates

Study Major Dates

• Study Start (Actual): October 21, 2020
• Primary Completion (Actual): December 30, 2022
• Study Completion (Actual): December 30, 2022

Study Registration Dates

• First Submitted: October 2, 2019
• First Submitted That Met QC Criteria: October 2, 2019
• First Posted (Actual): October 4, 2019

Study Record Updates

• Last Update Posted (Actual): May 22, 2023
• Last Update Submitted That Met QC Criteria: May 19, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: oxybutynin; atomoxetine
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Respiratory Tract Diseases; Respiration Disorders; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Neurologic Manifestations; Neurobehavioral Manifestations; Disease; Congenital Abnormalities; Genetic Diseases, Inborn; Signs and Symptoms, Respiratory; Intellectual Disability; Abnormalities, Multiple; Chromosome Disorders; Sleep Apnea Syndromes; Sleep Apnea, Obstructive; Syndrome; Apnea; Down Syndrome; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Parasympatholytics; Autonomic Agents; Peripheral Nervous System Agents; Muscarinic Antagonists; Cholinergic Antagonists; Cholinergic Agents; Urological Agents; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Adrenergic Uptake Inhibitors; Oxybutynin; Atomoxetine Hydrochloride
• Other Study ID Numbers: 1908864846; R61HL151254 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

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