The Combination of Aroxybutynin and Atomoxetine in the Treatment of Obstructive Sleep Apnea (MARIPOSA): A Randomized Controlled Trial.

Rationale: Obstructive sleep apnea (OSA) is a common sleep disorder for which the principal treatment option, continuous positive airway pressure, is often poorly tolerated. There is currently no approved pharmacotherapy for OSA. However, recent studies have demonstrated improvement in OSA with combined antimuscarinic and noradrenergic drugs. Objectives: The aim of this study was to evaluate the efficacy and safety of AD109, a combination of the novel antimuscarinic agent aroxybutynin and the norepinephrine reuptake inhibitor atomoxetine, in the treatment of OSA. Methods: Phase II randomized, double-blind, placebo-controlled, parallel-group, 4-week trial comparing AD109 2.5/75 mg, AD109 5/75 mg, atomoxetine 75 mg alone, and placebo (www.clinicaltrials.gov identifier NCT05071612). Measurements and Main Results: Of 211 randomized patients, 181 were included in the prespecified efficacy analyses. Sleep was assessed by two baseline and two treatment polysomnograms. Apnea-hypopnea index with a 4% desaturation criterion (primary outcome) was reduced from a median (IQR) of 20.5 (12.3-27.2) to 10.8 (5.6-18.5) in the AD109 2.5/75 mg arm (-47.1%), from 19.4 (13.7-26.4) to 9.5 (6.1-19.3) in the AD109 5/75 mg arm (-42.9%; both P < 0.0001 vs. placebo), and from 19.0 (11.8-28.8) to 11.8 (5.5-21.5) with atomoxetine alone (-38.8%; P < 0.01 vs. placebo). Apnea-hypopnea index with a 4% desaturation criterion decreased from 20.1 (11.9-25.9) to 16.3 (11.1-28.9) in the placebo arm. Subjectively, there was improvement in fatigue with AD109 2.5/75 mg (P < 0.05 vs. placebo and atomoxetine). Atomoxetine taken alone decreased total sleep time (P < 0.05 vs. AD109 and placebo). The most common adverse events were dry mouth, insomnia, and urinary hesitancy. Conclusions: AD109 showed clinically meaningful improvement in OSA, suggesting that further development of the compound is warranted. Clinical trial registered with www.clinicaltrials.gov (NCT05071612).

RESTORE: Once-nightly oxybate dosing preference and nocturnal experience with twice-nightly oxybates.

Objective/Background: Preference for extended-release, once-nightly sodium oxybate (ON-SXB, FT218) vs twice-nightly immediate-release (IR) oxybate was assessed in participants switching from IR oxybate to ON-SXB in an open-label/switch study, RESTORE (NCT04451668). Patients/Methods: Participants aged ≥16 years with narcolepsy who completed the phase 3 REST-ON trial, were oxybate-naive, or were on a stable IR oxybate dose (≥1 month) were eligible for RESTORE. For participants who switched from twice-nightly dosing to ON-SXB, initial doses were closest or equivalent to their previous nightly IR oxybate dose. These participants completed a questionnaire at baseline about nocturnal adverse events associated with the middle-of-the-night IR oxybate dose in the preceding 3 months, a preference questionnaire after 3 months of stable-dose ON-SXB, and an end-of-study (EOS) questionnaire. Results: There were 130 switch participants; 92/98 (93.9 %) who completed the preference questionnaire preferred ON-SXB. At baseline, 69.2 % reported missing their second IR oxybate dose at least once; in these cases, 80 % felt worse the next day. Approximately 39 % reported taking a second nightly IR oxybate dose >4 h after the first dose, 51 % of whom felt somewhat to extremely groggy/unsteady the next morning; 120 participants (92 %) reported getting out of bed after their second oxybate dose. Of those, 9 (8 %) reported falls and 5 (4 %) reported injuries. Of the switch participants who completed the EOS questionnaire, 91.2 % felt better able to follow the recommended ON-SXB dosing schedule. Conclusions: The second nightly IR oxybate dose presents significant treatment burdens and adherence concerns. Participants overwhelmingly preferred the once-nightly dosing regimen of ON-SXB.

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

STUDY OBJECTIVE: Obstructive sleep apnea is a common and serious sleep disorder for which treatment remains challenging due to lack of adherence to approved therapies. Previous pharmacological studies addressing sleep-related upper airway muscle hypotonia suggested that the combination of atomoxetine and oxybutynin is effective in treating obstructive sleep apnea. The current study is with aroxybutynin (AD109), a new enantiomerically pure form of oxybutynin with better safety profile compared to racemic oxybutynin. METHODS: This was a randomized, double-blind, placebo-controlled, crossover study in patients with mild to moderate obstructive sleep apnea. Each received low-dose AD109 (37.5/2.5 mg), high-dose AD109 (75/2.5 mg), and placebo at bedtime across 3 overnight periods in a randomized order. Adverse events were collected by telephone contact with participants during each washout period. The primary endpoint was change in hypoxic burden and secondary endpoint was apnea-hypopnea index. RESULTS: Patients treated with both the high and low doses of AD109 had a statistically significant and clinically meaningful difference from placebo in hypoxic burden. Median [interquartile range] hypoxic burden for participants on placebo was 13.9[4.5-21.9] (%min)/h vs 2.3[0.1-10.5] (%min)/h for patients on the high dose (P < .001) and to 7.3[2-12.5] (%min)/h on the low dose (P < .01). Apnea-hypopnea index went from a median of 13.2[8.0-19.1] events/h on placebo reduced to 5.5[2.2 to 9.6] events/h on the high dose (P < .001) and to 7.8[4-13.7] events/h on the low dose (P < .05). AD109 demonstrated a favorable safety profile. CONCLUSIONS: This study provides additional support that a pharmacological intervention for obstructive sleep apnea, namely the combination of atomoxetine and aroxybutynin, offers promising results. Additional development of this compound and others is warranted. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: AD109 Dose Finding in Mild to Moderate OSA; URL: https://clinicaltrials.gov/ct2/show/NCT04631107; Identifier: NCT04631107. CITATION: Rosenberg R, Abaluck B, Thein S. Combination of atomoxetine with the novel antimuscarinic aroxybutynin improves mild to moderate OSA. J Clin Sleep Med. 2022;18(12):2837-2844.

NightBalance Sleep Position Treatment Device Versus Auto-Adjusting Positive Airway Pressure for Treatment of Positional Obstructive Sleep Apnea.

STUDY OBJECTIVES: Compare treatment efficacy and objective adherence between the NightBalance sleep position treatment (SPT) device and auto-adjusting positive airway pressure (APAP) in patients with exclusive positional obstructive sleep apnea (ePOSA) defined as a supine apnea-hypopnea index (sAHI) ≥ 2 times the nonsupine AHI (nsAHI) and a nsAHI < 10 events/h. METHODS: This prospective multicenter randomized crossover trial enrolled treatment naive participants with ePOSA (AHI ≥ 15 events/h and nsAHI < 10 events/h) or (AHI > 10 and < 15 events/h with daytime sleepiness and nsAH < 5 events/h). Polysomnography and objective adherence determination (device data) were performed at the end of each 6-week treatment. Patient device preference was determined at the end of the study. RESULTS: A total of 117 participants were randomized (58 SPT first, 59 APAP first). Of these, 112 started treatment with the second device (adherence cohort) and 110 completed the study (AHI cohort). The AHI on SPT was higher (mean ± standard deviation, 7.29 ± 6.8 versus 3.71 ± 5.1 events/h, P < .001). The mean AHI difference (SPT-APAP) was 3.58 events/h with a one sided 95% confidence interval upper bound of 4.96 events/h (< the prestudy noninferiority margin of 5 events/h). The average nightly adherence (all nights) was greater on SPT (345.3 ± 111.22 versus 286.98 ± 128.9 minutes, P < .0001). Participants found the SPT to be more comfortable and easier to use and 53% reported a preference for SPT assuming both devices were equally effective. CONCLUSIONS: Treatment with SPT resulted in non-inferior treatment efficacy and greater adherence compared to APAP in ePOSA suggesting that SPT is an effective treatment for this group. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Title: The POSAtive Study: Study for the Treatment of Positional Obstructive Sleep Apnea; Identifier: NCT03061071; URL: https://clinicaltrials.gov/ct2/show/NCT03061071.

Role of computerized physician order entry systems in facilitating medication errors.

CONTEXT: Hospital computerized physician order entry (CPOE) systems are widely regarded as the technical solution to medication ordering errors, the largest identified source of preventable hospital medical error. Published studies report that CPOE reduces medication errors up to 81%. Few researchers, however, have focused on the existence or types of medication errors facilitated by CPOE. OBJECTIVE: To identify and quantify the role of CPOE in facilitating prescription error risks. DESIGN, SETTING, AND PARTICIPANTS: We performed a qualitative and quantitative study of house staff interaction with a CPOE system at a tertiary-care teaching hospital (2002-2004). We surveyed house staff (N = 261; 88% of CPOE users); conducted 5 focus groups and 32 intensive one-on-one interviews with house staff, information technology leaders, pharmacy leaders, attending physicians, and nurses; shadowed house staff and nurses; and observed them using CPOE. Participants included house staff, nurses, and hospital leaders. MAIN OUTCOME MEASURE: Examples of medication errors caused or exacerbated by the CPOE system. RESULTS: We found that a widely used CPOE system facilitated 22 types of medication error risks. Examples include fragmented CPOE displays that prevent a coherent view of patients' medications, pharmacy inventory displays mistaken for dosage guidelines, ignored antibiotic renewal notices placed on paper charts rather than in the CPOE system, separation of functions that facilitate double dosing and incompatible orders, and inflexible ordering formats generating wrong orders. Three quarters of the house staff reported observing each of these error risks, indicating that they occur weekly or more often. Use of multiple qualitative and survey methods identified and quantified error risks not previously considered, offering many opportunities for error reduction. CONCLUSIONS: In this study, we found that a leading CPOE system often facilitated medication error risks, with many reported to occur frequently. As CPOE systems are implemented, clinicians and hospitals must attend to errors that these systems cause in addition to errors that they prevent.