Background

Solriamfetol, a dopamine/norepinephrine reuptake inhibitor, improved wakefulness and reduced excessive daytime sleepiness (EDS) in studies of participants with narcolepsy with and without cataplexy.

Objective

Prespecified subgroup analyses of data from a 12-week randomized, double-blind, placebo-controlled, phase III trial of solriamfetol for EDS in narcolepsy evaluated the efficacy and safety of solriamfetol by cataplexy status.

Methods

Participants with narcolepsy received solriamfetol (75, 150, or 300 mg/day) or placebo and were stratified by cataplexy status. Coprimary endpoints were change from baseline on Maintenance of Wakefulness Test (MWT) and Epworth Sleepiness Scale (ESS); Patient Global Impression of Change (PGI-C) was the key secondary endpoint. Change in frequency of cataplexy attacks was evaluated in participants reporting cataplexy at baseline. Safety was evaluated. No adjustments were made for multiple comparisons; therefore p values are nominal.

Results

There were 117 participants in the cataplexy subgroup and 114 in the non-cataplexy subgroup. At week 12, least-squares (LS) mean (95% confidence interval [CI]) differences from placebo on change from baseline in MWT for solriamfetol 75, 150, and 300 mg in the cataplexy subgroup were 1.6 (− 3.6 to 6.9), 6.1 (0.7–11.4), and 8.9 (3.5–14.2) minutes, respectively (p < 0.05; 150 and 300 mg), and in the non-cataplexy subgroup were 3.4 (− 1.9 to 8.7), 9.1 (3.8–14.3), and 11.2 (5.8–16.6) minutes, respectively (p < 0.001; 150 and 300 mg). At week 12, LS mean (95% CI) differences from placebo on ESS change from baseline for solriamfetol 75, 150, and 300 mg in the cataplexy subgroup were − 1.3 (− 3.9 to 1.3), − 3.7 (− 6.4 to − 1.1), and − 4.5 (− 7.1 to − 1.9), respectively (p < 0.01; 150 and 300 mg), and in the non-cataplexy subgroup were − 3.0 (− 5.6 to − 0.4), − 3.7 (− 6.3 to − 1.2), and − 4.9 (− 7.6 to − 2.2), respectively (p < 0.05; all doses). For PGI-C at week 12, the mean percentage difference from placebo (95% CI) for solriamfetol 75, 150, and 300 mg in the cataplexy subgroup was 10% (− 15 to 35), 33% (9–57), and 39% (16–61), respectively (p < 0.05; 150 and 300 mg), and in the non-cataplexy subgroup was 48% (25–70), 44% (21–67), and 52% (30–73), respectively (p < 0.001; all doses), with somewhat differential treatment effects for 75 mg by cataplexy status. No changes in the number of cataplexy attacks were observed for solriamfetol compared with placebo (mean ± standard deviation changes: − 3.6 ± 13.3 [combined solriamfetol] and − 3.5 ± 9.8 [placebo]). Common adverse events (headache, nausea, decreased appetite, and nasopharyngitis) were similar between cataplexy subgroups.

Conclusions

These data strongly indicate that solriamfetol was effective in treating EDS in participants with narcolepsy with or without cataplexy, as indicated by robust effects on MWT, ESS, and PGI-C. The safety profile was similar regardless of cataplexy status.

Trial Registration and Date

ClinicalTrials.gov NCT02348593. 28 January 2015.

中文翻译：

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Solriamfetol 用于治疗伴有和不伴有猝倒的发作性睡病参与者的白天过度嗜睡：随机对照试验中猝倒状态的疗效和安全性数据的亚组分析。

背景

Solriamfetol 是一种多巴胺/去甲肾上腺素再摄取抑制剂，在对伴有和不伴有猝倒的发作性睡病参与者的研究中改善了清醒并减少了白天过度嗜睡 (EDS)。

目标

对 solriamfetol 治疗发作性睡病 EDS 的 12 周随机、双盲、安慰剂对照、III 期试验数据的预设亚组分析通过猝倒状态评估了 solriamfetol 的疗效和安全性。

方法

发作性睡病参与者接受 solriamfetol（75、150 或 300 毫克/天）或安慰剂，并根据猝倒状态进行分层。共同主要终点是维持清醒测试 (MWT) 和 Epworth 嗜睡量表 (ESS) 相对于基线的变化；患者总体印象变化 (PGI-C) 是关键的次要终点。在基线时报告猝倒的参与者中评估猝倒发作频率的变化。评估了安全性。未对多重比较进行调整；因此p值是名义上的。

结果

猝倒亚组有 117 名参与者，非猝倒亚组有 114 名参与者。在第 12 周时，在猝倒亚组中，solriamfetol 75、150 和 300 mg 的 MWT 从基线变化与安慰剂的最小二乘 (LS) 均值（95% 置信区间 [CI]）差异为 1.6（- 3.6 至 6.9） 、6.1 (0.7–11.4) 和 8.9 (3.5–14.2) 分钟（p  < 0.05；150 和 300 毫克），在非猝倒亚组中分别为 3.4 (- 1.9 到 8.7)、9.1 (3.8–14.3) ) 和 11.2 (5.8–16.6) 分钟（p  < 0.001；150 和 300 毫克）。在第 12 周时，在猝倒亚组中，solriamfetol 75、150 和 300 mg 的 ESS 变化与安慰剂的 LS 平均 (95% CI) 差异为 - 1.3 (- 3.9 至 - 1.1)，- 3.7 (- 6.4 至 - 1.1) ), 和 − 4.5 (− 7.1 to − 1.9), 分别 ( p < 0.01; 150 和 300 毫克），在非猝倒亚组中分别为 - 3.0（- 5.6 至 - 0.4）、- 3.7（- 6.3 至 - 1.2）和 - 4.9（- 7.6 至 - 2.2）（p  < 0.05 ；所有剂量）。对于第 12 周的 PGI-C，在猝倒亚组中，solriamfetol 75、150 和 300 mg 与安慰剂（95% CI）的平均百分比差异为 10%（- 15 至 35）、33%（9-57）、和 39% (16–61) ( p  < 0.05；150 和 300 mg)，在非猝倒亚组中分别为 48% (25–70)、44% (21–67) 和 52% (30 –73), 分别 ( p < 0.001; 所有剂量），根据猝倒状态，75 mg 的治疗效果略有不同。与安慰剂相比，solriamfetol 的猝倒发作次数没有变化（平均值 ± 标准偏差变化：- 3.6 ± 13.3 [联合 solriamfetol] 和 - 3.5 ± 9.8 [安慰剂]）。猝倒亚组的常见不良事件（头痛、恶心、食欲下降和鼻咽炎）相似。

结论

这些数据强烈表明 solriamfetol 可有效治疗伴有或不伴有猝倒的发作性睡病参与者的 EDS，如对 MWT、ESS 和 PGI-C 的强大影响所表明的。无论猝倒状态如何，安全性都是相似的。

试用注册和日期

ClinicalTrials.gov NCT02348593。2015 年 1 月 28 日。