Devine Jaime K, Schwartz Lindsay, Hursh Steven, Asin Jerryll, de Vries Nicolaas, Vonk Patty E, Vermeeren Annemiek, Donjacour Claire E H M, Vinckenbosch Frederick, Ramaekers Johannes G, Janssen Hennie, Wang Grace, Chen Dan, Carter Lawrence P, Overeem Sebastiaan, Lammers Gert Jan
Institutes for Behavior Resources, Inc., 2104 Maryland Avenue, Baltimore, MD, 21218, USA.
Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Neurol Ther. 2023 Feb;12(1):249-265. doi: 10.1007/s40120-022-00425-w. Epub 2022 Dec 10.
Excessive daytime sleepiness (EDS) associated with narcolepsy or obstructive sleep apnea (OSA) can impair vigilance/attention. Solriamfetol, a dopamine/norepinephrine reuptake inhibitor, is approved to treat EDS associated with narcolepsy (75-150 mg/day) or OSA (37.5-150 mg/day). The analysis reported here explored the use of the Sleep, Activity, Fatigue, and Task Effectiveness (SAFTE) model (used in transport industries to model performance based on accumulated sleep and circadian variability) as a substitute for healthy controls using psychomotor vigilance task (PVT) data collected during clinical studies.
Data were analyzed from two phase 2 studies of solriamfetol in adults with OSA (NCT02806895, EudraCT 2015-003930-28) or narcolepsy (NCT02806908, EudraCT 2015-003931-36). Participants were randomly assigned 1:1 to solriamfetol 150 mg/day (3 days) followed by 300 mg/day (4 days), or placebo (7 days), then crossed over to the other treatment. Actual task effectiveness scores were calculated from average PVT inverse reaction time (pre-dose; 2 h post-dose; 6 h post-dose). Actigraphy-derived sleep intervals were used in SAFTE to determine modeled healthy control task effectiveness scores.
In participants with OSA (N = 31) on placebo or solriamfetol, actual and modeled healthy control task effectiveness did not differ at any time point. In participants with narcolepsy (N = 20) on placebo, actual task effectiveness at 2 h post-dose was lower than modeled healthy control task effectiveness (nominal P = 0.03), a difference not present with solriamfetol. There was no main effect of solriamfetol on actual or modeled healthy control task effectiveness across time points.
This study represents a novel application of the SAFTE biomathematical model to approximate healthy controls in sleep disorder research and provides valuable lessons that may optimize future research. Future studies should perform a priori power analyses for model-tested outcomes and use sleep measures that capture sleep fragmentation characteristic of sleep disorders for sleep input (e.g., total sleep time rather than time in bed).
NCT02806895, EudraCT 2015-003930-28: A Randomized, Double-Blind, Placebo-Controlled, Crossover On-Road Driving Study Assessing the Effect of JZP-110 on Driving Performance in Subjects With Excessive Sleepiness Due to Obstructive Sleep Apnea. NCT02806908, EudraCT 2015-003931-36: A Randomized, Double-Blind, Placebo-Controlled, Crossover On-Road Driving Study Assessing the Effect of JZP-110 on Driving Performance in Subjects With Excessive Sleepiness Due to Narcolepsy.
与发作性睡病或阻塞性睡眠呼吸暂停（OSA）相关的日间过度嗜睡（EDS）会损害警觉性/注意力。索利那非是一种多巴胺/去甲肾上腺素再摄取抑制剂，已被批准用于治疗与发作性睡病相关的EDS（75 - 150毫克/天）或OSA（37.5 - 150毫克/天）。本文报道的分析探讨了使用睡眠、活动、疲劳和任务有效性（SAFTE）模型（用于运输行业基于累积睡眠和昼夜节律变异性对性能进行建模），以替代使用临床研究期间收集的精神运动警觉任务（PVT）数据的健康对照。
对索利那非在患有OSA（NCT02806895，EudraCT 2015 - 003930 - 28）或发作性睡病（NCT02806908，EudraCT 2015 - 003931 - 36）的成人中的两项2期研究数据进行分析。参与者被随机1:1分配至索利那非150毫克/天（3天），随后300毫克/天（4天），或安慰剂（7天），然后交叉接受另一种治疗。实际任务有效性得分由平均PVT反向反应时间（给药前；给药后2小时；给药后6小时）计算得出。活动记录仪得出的睡眠间隔时间用于SAFTE模型，以确定模拟的健康对照任务有效性得分。
在接受安慰剂或索利那非治疗的OSA患者（N = 31）中，实际和模拟的健康对照任务有效性在任何时间点均无差异。在接受安慰剂治疗的发作性睡病患者（N = 20）中，给药后2小时的实际任务有效性低于模拟健康对照任务有效性（名义P = 0.03），而索利那非治疗组不存在此差异。索利那非在各时间点对实际或模拟健康对照任务有效性均无主要影响。
本研究代表了SAFTE生物数学模型在睡眠障碍研究中近似健康对照的新应用，并提供了可能优化未来研究的宝贵经验教训。未来研究应对模型测试结果进行先验功效分析，并使用能捕捉睡眠障碍特征性睡眠片段化的睡眠测量指标作为睡眠输入（例如，总睡眠时间而非卧床时间）。
NCT02806895，EudraCT 2015 - 003930 - 28：一项随机、双盲、安慰剂对照、交叉道路驾驶研究，评估JZP - 110对阻塞性睡眠呼吸暂停所致过度嗜睡受试者驾驶性能的影响。NCT02806908，EudraCT 2015 - 003931 - 36：一项随机、双盲、安慰剂对照、交叉道路驾驶研究，评估JZP - 110对发作性睡病所致过度嗜睡受试者驾驶性能的影响。
