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Randomized Controlled Trial
. 2023 Dec 1;19(12):2065-2073.
doi: 10.5664/jcsm.10764.

The combination of atomoxetine and oxybutynin for the treatment of obstructive sleep apnea in children with Down syndrome

Daniel Combs  1   2 , Jamie Edgin  3 , Chiu-Hsieh Hsu  4 , Kenneth Bottrill  3 , Hailey Van Vorce  3 , Blake Gerken  1 , Daniel Matloff  1 , Sicily La Rue  1 , Sairam Parthasarathy  1   5
Affiliations
Randomized Controlled Trial

The combination of atomoxetine and oxybutynin for the treatment of obstructive sleep apnea in children with Down syndrome

Daniel Combs et al. J Clin Sleep Med. .

Abstract

Study objectives: Children with Down syndrome (DS) are at very high risk for obstructive sleep apnea (OSA). Current OSA treatments have limited effectiveness in this population. We evaluated the effectiveness of atomoxetine and oxybutynin (ato-oxy) to treat OSA in children with Down syndrome.

Methods: Children ages 6-7 years old with Down syndrome and OSA participated in a double-blind crossover clinical trial evaluating two dose regimens of ato-oxy. Participants received low-dose ato-oxy (0.5 mg/kg atomoxetine and 5 mg oxybutynin) and high-dose ato-oxy (1.2 mg/kg atomoxetine and 5 mg oxybutynin) for 1 month in random order. The primary study outcome was change in obstructive apnea-hypopnea index. Health-related quality of life as measured by the OSA-18 as well as changes in sleep architecture were secondary outcomes.

Results: Fifteen participants qualified for randomization and 11 participants had complete data at all points. Baseline obstructive apnea-hypopnea index was 7.4 ± 3.7 (mean ± standard deviation), obstructive apnea-hypopnea index with low-dose ato-oxy was 3.6 ± 3.3 (P = .001 vs baseline), and obstructive apnea-hypopnea index with high-dose ato-oxy was 3.9 ± 2.8 (P = .003 vs baseline). No significant sleep architecture differences were present with ato-oxy. No significant difference in OSA-18 score was present. OSA-18 total score was 51 ± 19 at baseline, 45 ± 17 (P = .09) at the end of 4 weeks of low-dose ato-oxy, and 45 ± 16 (P = .37) at the end of high-dose ato-oxy therapy. The most common adverse effects were irritability and fatigue, and these were generally mild.

Conclusions: Ato-oxy is a promising treatment for OSA in children with Down syndrome.

Clinical trial registration: Registry: Clinicaltrials.gov; Name: Medications for Obstructive Sleep Apnea In Children With Down Syndrome (MOSAIC); URL: https://clinicaltrials.gov/ct2/show/NCT04115878; Identifier: NCT04115878.

Citation: Combs D, Edgin J, Hsu C-H, et al. The combination of atomoxetine and oxybutynin for the treatment of obstructive sleep apnea in children with Down syndrome. J Clin Sleep Med. 2023;19(12):2065-2073.

Keywords: Down syndrome; obstructive sleep apnea.

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Conflict of interest statement

All authors have seen and approved the manuscript. Funding provided by the National Institutes of Health Include (INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndrome) project: HL151254 and HD109777, as well as the Lumind-IDSC foundation. D.C. reports a grant from the American Heart Association. J.E. reports grants from the Lejeune Foundation, the LuMind Foundation, and the National Institutes of Health. S.P. reports grants from the National Institutes of Health, American Academy of Sleep Medicine Foundation, Patient Centered Outcomes Research Institute, personal royalty fees from UpToDate Inc, and consultant fees from Jazz pharmaceuticals. Outside the submitted work, S.P. has a patent US20160213879A1 (home breathing device) that is licensed to SaiOx, Inc. C.-H.H., K.B., H.V.V., S.L.R., B.G., and D.M. have no relationships to disclose.

Figures

Figure 1
Figure 1. Study design.
Participants were randomized to either high- (5 mg oxybutynin and 1.2 mg/kg/d [max 80 mg]) or low-dose ato-oxy (5 mg oxybutynin and 0.5 mg/kg/d [max 40 mg] at baseline. For high-dose ato-oxy, participants took low-dose ato-oxy for the first week prior to increasing to the high ato-oxy dose for the remaining 3 weeks. Polysomnography and a health-related quality of life assessment were performed after 2 weeks of ato-oxy. Participants then took no drug for 2 weeks, then took the alternate ato-oxy dose for 4 weeks with repeat polysomnography and health-related quality of life assessment at the end of therapy. Participants who agreed to participate in the neurocognitive assessment completed the Conners at the same timepoints as polysomnography and the health-related quality of life assessment. ato-oxy = atomoxetine and oxybutynin.
Figure 2
Figure 2. Clinical trial enrollment.
One participant did not have sufficient data recorded on their third polysomnogram; therefore complete data were available from 11 participants. Among individuals who declined participation, 2 reported this was due to study burden being too high, 2 reported this was due to concern about taking medication, and the remaining individuals did not provide a specific reason for declining. Individuals were considered unable to be contacted if they were unreachable after at least two attempts to contact following the initial contact where they initially expressed interest in the study. AHI = apnea-hypopnea index, CPAP = continuous positive airway pressure, SAE = severe adverse event.
Figure 3
Figure 3. Participant-level changes in obstructive AHI (events/h) with low-dose and high-dose ato-oxy.
AHI = apnea-hypopnea index, ato-oxy = atomoxetine and oxybutynin.
See this image and copyright information in PMC

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