For researchers involved with sleep disorders, developing a pharmacologic treatment for obstructive sleep apnea (OSA) is a bit like searching for the holy grail. P K Schweitzer and colleagues have published the results of the randomized MARIPOSA study assessing a combination of two medicinal products known as AD109, one of the products having an antimuscarinic effect (aroxybutynin), and the other a noradrenergic effect (atomoxetine), in treating this condition. These molecules increase the activity of the dilator muscles in the upper airways by activating the genioglossus muscle with a synergic effect on the upper respiratory tract during sleep.
MARIPOSA Methodology
The trial included 209 patients, 176 of whom completed the 4-week protocol. The trial was double-blinded according to four parallel arms: participants in the first and second arms received AD109 containing doses of 2.5 mg/75 mg and 5 mg/75 mg of aroxybutynin and atomoxetine, respectively. The third arm received atomoxetine alone (75 mg), and the fourth arm was given a placebo.
Two polysomnograms (PSGs) were carried out at the start and end of the trial, allowing researchers to calculate the apnea-hypopnea index (AHI) and to quantify nocturnal desaturation. The impact of these variables are now being deemed as the primary marker of the risk for cardiovascular complications secondary to OSA. Finally, questionnaires that evaluated excessive daytime sleepiness, fatigue, and sleep quality were completed.
The median age varied from 5 to 57 years, depending on the arm of the study, and body mass index varied between 31.2 and 34.5. Inclusion criteria comprised an AHI between 10 and 45 events per hour, of which, at least 75% were described as obstructive. Where continuous positive airway pressure (CPAP) was used (21%-30% of cases), it was abandoned during the trial (in a time frame that is perhaps too short to consider these patients as treatment-naive).
Combination Brought Improvements
After the 4 weeks of treatment, the AHI measured via follow-up PSG went from a median of 20.5 to 10.8 (in arm one and from 19.4 to 9.5 in arm two (P < .0001 vs placebo in these two arms). For participants in arm three, AHI went from 19.0 to 11.8 (P < .01 vs placebo).
The rate of nocturnal desaturation (in percentage per hour) declined from -12.7 in arm one (P = .03), from -16.6 in arm two (P = .005), and from -5.2 in arm three (P = .003) compared with the placebo. The fatigue score was significantly improved by AD109 2.5 mg/75 mg. The use of atomoxetine alone slightly worsened the sleep disturbance score.
The main side effects were dry mouth sensation (which was markedly more common with AD109 5 mg/75 mg), difficulty passing urine in 7%-22% of cases, tachycardia in all trial arms, and increased diastolic blood pressure at the 2.5-mg/75-mg dose. The authors concluded that AD109, a combination of noradrenergic and antimuscarinic molecules, is effective in correcting mild to severe OSA.
The 2.5-mg/75-mg dose was as effective as the 5-mg/75-mg dose. Atomoxetine alone is less effective, has more side effects, and is associated with lower quality sleep. Finally, it is reported that compliance with oral treatment was not checked, yet the argument of patient noncompliance with CPAP is largely used by the authors in their presentation of their study. A phase 3 trial is underway.
Nevertheless, these results herald important scientific benefits if we consider that Colin Sullivan's original 1981 research paper, which ushered in the CPAP era, presented the results of just five participants.
This article was translated from JIM, which is part of the Medscape professional network.
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