Atomoxetine + Oxybutynin for Sleep Apnea in Down Syndrome

(MOSAIC Trial)

Age: < 18

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: University of Arizona

Must not be taking: Monoamine oxidase inhibitors

Disqualifiers: Central sleep apnea, Seizure disorder, Congenital heart disease, others

No Placebo Group

Prior Safety Data

Approved in 2 Jurisdictions

Trial Summary

What is the purpose of this trial?

This trial tests a combination of two medications, atomoxetine and oxybutynin, in children with Down syndrome and sleep apnea. The goal is to see if these medications can improve their breathing during sleep over several months. The study will measure changes in sleep quality and overall health. Atomoxetine is a nonstimulant medication used for ADHD and generally has fewer negative effects on sleep compared to other treatments.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are using a monoamine oxidase inhibitor. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug Atomoxetine + Oxybutynin for treating sleep apnea in Down syndrome?

Research shows that the combination of atomoxetine and oxybutynin significantly reduces the severity of obstructive sleep apnea, especially in patients with moderate pharyngeal collapsibility. This suggests potential effectiveness for treating sleep apnea in children with Down syndrome. ^{1 2 3 4 5}

Is the combination of atomoxetine and oxybutynin safe for humans?

Studies have evaluated the safety of atomoxetine and oxybutynin for treating obstructive sleep apnea, and while they show potential benefits, there are concerns about reduced arousal threshold, which might affect sleep quality. Further research is needed to fully understand the safety profile of this combination. ^{1 2 3 4 6}

How is the drug atomoxetine plus oxybutynin unique for treating sleep apnea in Down syndrome?

The combination of atomoxetine and oxybutynin is unique for treating sleep apnea in Down syndrome because it targets the condition's severity by addressing moderate pharyngeal collapsibility, which is a specific trait in some patients. This approach is different from standard treatments, which often have limited effectiveness in this population. ^{1 2 3 4 6}

Research Team

Eligibility Criteria

Children aged 6-17 with Down syndrome and obstructive sleep apnea can join this trial. They must have a confirmed diagnosis of trisomy 21 Down syndrome, not due to translocation or mosaicism. Kids with untreated depression, hypothyroidism, severe prematurity, certain heart diseases without clearance, or those on specific medications like MAO inhibitors cannot participate.

Inclusion Criteria

I am between 6 and 17 years old.

I have been diagnosed with Down syndrome.

Exclusion Criteria

My tonsils are significantly enlarged.

You are pregnant, as confirmed by a urine test.

I have depression that I haven't treated yet.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive ato-oxy for 6 months, with dosing occurring approximately 30 minutes prior to bedtime

6 months

1 visit (in-person) for final night of dosing

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Atomoxetine and Oxybutynin (ato-oxy) (Other)

Trial Overview The study tests a combination medication called ato-oxy (atomoxetine and oxybutynin) given before bedtime for six months to see if it improves sleep apnea and cognition in children with Down syndrome. The effectiveness is measured by changes in the number of breathing pauses during sleep from the start to the end of treatment.

Participant Groups

Group I: Ato-oxy Experimental Treatment 1 Intervention

0.5 mg/kg (max 40 mg) atomoxetine and 5 mg oxybutynin

Who Is Running the Clinical Trial?

University of Arizona

Lead Sponsor

Trials

545

Recruited

161,000+

Dr. Richard Carmona

University of Arizona

Chief Medical Officer since 2021

MD, University of Arizona

Dr. Evan Unger

University of Arizona

Chief Executive Officer since 2021

PhD in Medical Imaging, University of Arizona

National Institutes of Health (NIH)

Collaborator

Trials

2,896

Recruited

8,053,000+

Dr. Jeanne Marrazzo

National Institutes of Health (NIH)

Chief Medical Officer

MD from University of California, Los Angeles

Dr. Jay Bhattacharya

National Institutes of Health (NIH)

Chief Executive Officer

MD, PhD from Stanford University

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

Dr. Gary H. Gibbons

National Heart, Lung, and Blood Institute (NHLBI)

Chief Executive Officer since 2012

MD from Harvard Medical School

Dr. James P. Kiley

National Heart, Lung, and Blood Institute (NHLBI)

Chief Medical Officer since 2011

MD from University of California, San Francisco

Findings from Research

In a clinical trial involving 15 children with Down syndrome and obstructive sleep apnea, the combination of atomoxetine and oxybutynin (ato-oxy) significantly reduced the obstructive apnea-hypopnea index, indicating improved sleep quality.

While the treatment showed promise in reducing apnea events, it did not significantly improve health-related quality of life scores or sleep architecture, and the most common side effects were mild irritability and fatigue.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The combination of atomoxetine and oxybutynin for the treatment of obstructive sleep apnea in children with Down syndrome. Combs, D., Edgin, J., Hsu, CH., et al.[2023]

In a phase 2 trial involving 62 patients with obstructive sleep apnea (OSA), the combination treatment AD036 (atomoxetine 80 mg and oxybutynin 5 mg) significantly reduced the apnea-hypopnea index (AHI) from a median of 14.2 events/hour on placebo to 6.2 events/hour, indicating a marked improvement in OSA severity.

AD036 not only improved OSA severity but also reduced the oxygen desaturation index and hypoxic burden, while atomoxetine alone showed some benefits but was associated with more sleep disruption, suggesting that oxybutynin may help mitigate these effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of atomoxetine plus oxybutynin in the treatment of obstructive sleep apnea with moderate pharyngeal collapsibility. Schweitzer, PK., Maynard, JP., Wylie, PE., et al.[2023]

In a study involving 17 Japanese patients with obstructive sleep apnea (OSA), combination therapy with atomoxetine (ATO) and oxybutynin (OXY) did not significantly reduce the apnoea-hypopnoea index (AHI) compared to no medication, indicating limited overall efficacy.

However, a subset of five patients did show a notable decrease in AHI, suggesting that ATO-OXY therapy may benefit certain individuals, although the treatment did alter sleep architecture by increasing light sleep (N1) and decreasing deeper sleep stages.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of the combination of atomoxetine and oxybutynin in Japanese patients with obstructive sleep apnoea: A randomized controlled crossover trial. Kinouchi, T., Terada, J., Sakao, S., et al.[2023]

The combination of atomoxetine and trazodone (Ato-Trazo) significantly reduced the apnea-hypopnea index in patients with obstructive sleep apnea (OSA), indicating improved severity of the condition, with a reduction from 18.2 to 7.4 events per hour (P = .024).

Unlike previous treatments, Ato-Trazo did not lower the arousal threshold, suggesting it may be better tolerated by patients, although it worsened self-reported sleep quality and further studies are needed to optimize dosage and identify the best patient subgroups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of atomoxetine plus a hypnotic on obstructive sleep apnea severity in patients with a moderately collapsible pharyngeal airway. Corser, B., Eves, E., Warren-McCormick, J., et al.[2023]

In a randomized, double-blind, placebo-controlled study involving patients with mild to moderate obstructive sleep apnea, the new drug aroxybutynin (AD109) significantly reduced hypoxic burden and apnea-hypopnea index compared to placebo, indicating its efficacy in treating this condition.

AD109 demonstrated a favorable safety profile, suggesting it may be a promising pharmacological option for patients who struggle with adherence to traditional therapies for obstructive sleep apnea.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination of atomoxetine with the novel antimuscarinic aroxybutynin improves mild to moderate OSA. Rosenberg, R., Abaluck, B., Thein, S.[2023]

A study using Taiwan's National Health Insurance Research Database found that long-term use of the atomoxetine-oxybutynin combination (AOC) is associated with a significantly reduced risk of developing obstructive sleep apnea (OSA), with an adjusted hazard ratio of 0.299 for those using AOC for over a year.

The incidence of OSA was lower in patients using AOC (21.92 per 100,000 person-years) compared to those not using it (22.93 per 100,000 person-years), suggesting that this combination therapy may effectively lower OSA risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term atomoxetine-oxybutynin combination use may be beneficial for the prevention of obstructive sleep apnea. Chen, TY., Chung, CH., Chang, HA., et al.[2021]

References

1. United States pubmed.ncbi.nlm.nih.gov

The combination of atomoxetine and oxybutynin for the treatment of obstructive sleep apnea in children with Down syndrome. [2023]

2. Germany pubmed.ncbi.nlm.nih.gov

Efficacy of atomoxetine plus oxybutynin in the treatment of obstructive sleep apnea with moderate pharyngeal collapsibility. [2023]

3. Australia pubmed.ncbi.nlm.nih.gov

Effects of the combination of atomoxetine and oxybutynin in Japanese patients with obstructive sleep apnoea: A randomized controlled crossover trial. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

Effects of atomoxetine plus a hypnotic on obstructive sleep apnea severity in patients with a moderately collapsible pharyngeal airway. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

Combination of atomoxetine with the novel antimuscarinic aroxybutynin improves mild to moderate OSA. [2023]

6. England pubmed.ncbi.nlm.nih.gov

Long-term atomoxetine-oxybutynin combination use may be beneficial for the prevention of obstructive sleep apnea. [2021]