Neurotrials Research Inc, Atlanta, Georgia.
Brian Abaluck MD Sleep Medicine, Malvern, Pennsylvania.
J Clin Sleep Med. 2022 Dec 1;18(12):2837-2844. doi: 10.5664/jcsm.10250.
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.
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.
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 ( < .001) and to 7.3[2-12.5] (%min)/h on the low dose ( < .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 ( < .001) and to 7.8[4-13.7] events/h on the low dose ( < .05). AD109 demonstrated a favorable safety profile.
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.
Registry: ClinicalTrials.gov; Name: AD109 Dose Finding in Mild to Moderate OSA; URL: https://clinicaltrials.gov/ct2/show/NCT04631107; Identifier: NCT04631107.
Rosenberg R, Abaluck B, Thein S. Combination of atomoxetine with the novel antimuscarinic aroxybutynin improves mild to moderate OSA. . 2022;18(12):2837-2844.
阻塞性睡眠呼吸暂停是一种常见且严重的睡眠障碍，由于对已批准疗法的依从性差，其治疗仍然具有挑战性。以前针对与睡眠相关的上气道肌肉张力减退的药理学研究表明，托莫西汀和羟丁宁的联合使用可有效治疗阻塞性睡眠呼吸暂停。本研究使用的是阿罗羟丁宁（AD109），它是羟丁宁的一种新对映异构体纯形式，与外消旋羟丁宁相比具有更好的安全性。
这是一项在轻至中度阻塞性睡眠呼吸暂停患者中进行的随机、双盲、安慰剂对照、交叉研究。每位患者在 3 个夜间周期内以随机顺序分别在睡前服用低剂量 AD109（37.5/2.5 mg）、高剂量 AD109（75/2.5 mg）和安慰剂。在每个洗脱期内，通过电话联系参与者收集不良事件。主要终点是缺氧负担的变化，次要终点是呼吸暂停低通气指数。
接受 AD109 高、低剂量治疗的患者与安慰剂相比，缺氧负担有统计学意义和临床意义的差异。安慰剂组参与者的中位[四分位间距]缺氧负担为 13.9[4.5-21.9]（%min）/h，而高剂量组为 2.3[0.1-10.5]（%min）/h（<0.001），低剂量组为 7.3[2-12.5]（%min）/h（<0.01）。呼吸暂停低通气指数从安慰剂组的中位 13.2[8.0-19.1]次/h降至高剂量组的 5.5[2.2-9.6]次/h（<0.001）和低剂量组的 7.8[4-13.7]次/h（<0.05）。AD109 表现出良好的安全性。
这项研究提供了额外的支持，即针对阻塞性睡眠呼吸暂停的药物干预，即托莫西汀和阿罗羟丁宁的联合使用，具有有前景的结果。需要进一步开发这种化合物和其他化合物。
注册号：ClinicalTrials.gov；名称：AD109 在轻度至中度 OSA 中的剂量研究；网址：https://clinicaltrials.gov/ct2/show/NCT04631107；标识符：NCT04631107。
Rosenberg R, Abaluck B, Thein S. 托莫西汀联合新型抗毒蕈碱药物阿罗羟丁宁治疗轻中度 OSA。. 2022;18(12):2837-2844.
