Study to assess precision medicine in Down syndrome, OSA

Key takeaways:

• People with Down syndrome also frequently have OSA.
• An upcoming study in this patient population is using a precision medicine approach.
• Atomoxetine plus oxybutynin is a possible treatment option in this study.

There is a lack of effective and simple treatment options for patients with Down syndrome and obstructive sleep apnea, but researchers at the University of Arizona Health Sciences hope to change that, according to a press release.

In a study, expected to start enrollment in February 2026, the release said researchers will analyze 200 children and adults with Down syndrome and OSA to uncover the impact of a combination of atomoxetine plus oxybutynin, as well as a precision medicine approach involving receipt of either oxygen or the combination medication on OSA severity, quality of life, behavior and cognition after 12 months.

As Healio previously reported, a combination of atomoxetine and oxybutynin taken for 30 days was found to lower baseline OSA severity in a randomized, placebo-controlled trial.

Healio spoke with Daniel Combs, MD, research lead and associate professor of pediatrics at the University of Arizona College of Medicine in Tucson, to learn more about current treatment options for this patient population, the study’s design and the expected impact findings will have on clinicians.

Healio: What are the current treatment options for patients with OSA and Down syndrome? Do these options differ for adults and children?

Combs: OSA is super common in people with Down syndrome. If you look at studies (Shott SR, et al; Maris M, et al; Hill CM, et al; Dyken ME, et al; Cornacchia M, et al; and Landete P, et al), basically half of kids and 80% to 100% of adults with Down syndrome will have OSA compared with about 2% of kids without Down syndrome and 10% to 15% of adults. Further, since OSA is associated with cognitive impairment, worse quality of life and poorer school performance, anything you can do to improve that is hugely impactful for families.

Current treatment options for this patient population do somewhat differ between adults and children. CPAP is the most effective therapy for kids and adults. For adults with Down syndrome, this is the standard of care. For children, you can do tonsillectomy as initial treatment, but then CPAP would be next. Studies (Thottam PJ, et al and Shete MM, et al) have found that OSA will get about 50% better on average after tonsillectomy for kids. However, there is significant variation in treatment response. Some kids don’t get better at all, and some kids essentially are totally fine afterwards. The reality is that probably 80% to 90% of kids still have sleep apnea post-tonsillectomy. From there, CPAP is the main standard therapy.

The big issue with CPAP is that if you don’t use it, it doesn’t work. CPAP that is on your face works beautifully, and if you’re using CPAP, you don’t need to worry. If you don’t use CPAP, it’s not doing much for you. Also, if you’re only using CPAP for an hour or two a night and sleeping 6 to 8 hours, you’re not getting much benefit.

On average, CPAP adherence is about 47% of people meeting the criteria of essentially half the night for more than 70% of nights in the month. That number is probably lower in people with Down syndrome. A few studies have found it’s high, but others have shown it’s fairly low. The ones that showed it was relatively high were generally follow-ups from patients who have been coming to clinic for years and are coming to clinic because they’re using their CPAP, so that was probably a bit of selection bias.

I think it’s safe to say that probably less than half of people with Down syndrome and OSA actually use CPAP and potentially a lot less.

Healio: Why are additional treatment options needed in this patient population?

Combs: The alternate treatment option studied and approved specifically for adolescents with Down syndrome is the Inspire Upper Airway Stimulator system (Inspire Medical System Inc.). It has also been studied and approved in adults in general, so if you’re an adult, you could get Inspire.

The issue with this system is it’s a surgical implant, and there’s some evidence that the adolescents with Down syndrome had a slightly higher rate of side effects compared with the studies in adults without Down syndrome. Additionally, since it’s a surgical implant, you need to have surgery every 10 years or so to replace the battery.

The other big issue is that it stimulates your upper airway muscles to treat the sleep apnea, which pushes your tongue forward out of your airway. That can be a strange sensation, and for people with Down syndrome, who might not have the greatest verbal abilities, that can be an issue because they can have this weird discomfort that they can’t explain. Even though the Inspire system is a reasonable option, it’s not without downsides.

In our study, we are really focused on people who might not be great Inspire candidates, don’t want to use Inspire because they don’t want to go through surgery or who aren’t using CPAP.

Healio: What was the reasoning behind studying atomoxetine plus oxybutynin in patients with OSA and Down syndrome?

Combs: A group at Harvard has shown that the combination of atomoxetine and oxybutynin (ato-oxy) increases upper airway muscle tone at night. Similar to Inspire, if you can increase the airway muscle strength and open the airway, then you don’t have sleep apnea.

We have one existing trial that will likely wrap up next year. In our initial pilot trial, we showed about a 55% improvement in OSA severity with ato-oxy in kids with Down syndrome. When you look at individual responders, you can see some people get 90% better, and some people maybe got 10% to 15% better. We could see that, even in a small sample, some people do fantastic, and some really don’t improve.

Healio: How have you designed this trial?

Combs: This is a bit of a tricky trial design. There’s a way to look at someone’s sleep study and figure out what’s causing their OSA called OSA endotypes. People have shown retrospectively that you can basically look at that on someone’s diagnostic sleep study and say you should respond well to the ato-oxy, you should respond well to Inspire or you should respond well to oxygen. What we’re trying to do is take that to the next step.

Our study involves 200 people. Half of them get ato-oxy, and the other half get the precision medicine approach (endotype directed therapy), meaning we look at them and predict, you should respond better to ato-oxy, or you should respond better to oxygen. Conveniently, people who aren’t expected to respond well to ato-oxy may be more likely to respond to oxygen because they have different underlying features.

One of the complexities of our study design is it’s not placebo-controlled, and this is on purpose. Most families of people with Down syndrome aren’t particularly enthusiastic about placebo-controlled trials, so one of the upsides for participation is that you’re getting something we think will help you no matter what. It’s really designed for participants to benefit, and we had advocates and families of people with Down syndrome involved in study design from the ground up.

Healio: What impact are your study findings expected to have on the clinicians who treat these patients?

Combs: This study uses normal sleep study data that clinicians are already getting. We’re using a computer program designed by one of our collaborators, Scott A. Sands, PhD, at Harvard Medical School, that uses data from their sleep study. You could theoretically just implement this program into your sleep study software.

The hope would be that someday you get a printout showing here’s how severe your sleep apnea was, here’s your sleep apnea endotypes and these are potential treatments that might work best for you. This is the ultimate goal. Whether we’ll get there at the end of the study, or in 10 or 15 years, I don’t know.

Notably, we’re studying drugs that already exist. Atomoxetine has been on the market for about 20 years, and oxybutynin is old as dirt, so they’re both generic drugs. This means that if the trial is successful, as a prescriber, you could prescribe them off-label the day after the trial is over.

Healio: When can clinicians expect study results?

Combs: We will enroll people for 3 years from Feb. 1, 2026, to 2029, and then follow everyone out for 12 months after that. We hope to have results toward the end of 2030.

For more information:

Daniel Combs, MD, can be reached at combs89@arizona.edu.

References:

• $10M PCORI funding award will fuel study of sleep apnea in people with Down syndrome. https://healthsciences.arizona.edu/news/releases/10m-pcori-award-fund-study-sleep-apnea-down-syndrome. Published July 16, 2025. Accessed July 18, 2025.
• Combs D, et al. J Clin Sleep Med. 2023;doi:10.5664/jcsm.10764.
• Combs D, et al. Sleep. 2025;doi:10.1093/sleep/zsaf090.0998.
• Cornacchia M, et al. Am J Intellect Dev Disabil. 2019;doi:10.1352/1944-7558-124.1.4.
• Dyken ME, et al. Arch Pediatr Adolesc Med. 2003;doi:10.1001/archpedi.157.7.655.
• Hill CM, et al. Sleep Med. 2016;doi:10.1016/j.sleep.2016.10.001.
• Landete P, et al. Am J Med Genet A. 2020;doi:10.1002/ajmg.a.61853.
• Maris M, et al. Sleep. 2016;doi:10.5665/sleep.5554.
• Shete MM, et al. Int J Pediatr Otorhinolaryngol. 2010;doi:10.1016/j.ijporl.2009.11.006.
• Shott SR, et al. Arch Otolaryngol Head Neck Surg. 2006;doi:10.1001/archotol.132.4.432.
• Thottam PJ, et al. Int J Pediatr Otorhinolaryngol. 2015;doi:10.1016/j.ijporl.2015.04.015.