Efficacy of Once-Nightly Sodium Oxybate in Patients with Narcolepsy: Post Hoc Analyses of Sensitivity, Effect Size, and Numbers Needed to Treat from the Phase 3 REST-ON Trial.

IF 7.4 2区 医学 Q1 CLINICAL NEUROLOGY
CNS drugs Pub Date : 2025-03-01 Epub Date: 2025-03-20 DOI:10.1007/s40263-025-01160-0
Thomas Roth, Michael J Thorpy, Clete A Kushida, Jennifer Gudeman
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引用次数: 0

Abstract

Background: Once-nightly sodium oxybate (ON-SXB; LUMRYZ™; FT218) treatment significantly improved the coprimary endpoints of mean sleep latency on the Maintenance of Wakefulness Test (MWT), Clinical Global Impression of Improvement (CGI-I) rating, and number of weekly cataplexy episodes versus placebo in a randomized, placebo-controlled trial (REST-ON). The objective of these post hoc sensitivity analyses was to evaluate the robustness of treatment with ON-SXB, while accounting for missing participant data. Number needed to treat (NNT) and effect size analyses were conducted to quantify the treatment benefits.

Methods: Participants ≥ 16 years of age with narcolepsy type 1 or 2 were randomized 1:1 to receive ON-SXB (4.5 g [week 1]; 6 g [weeks 2-3]; 7.5 g [weeks 4-8]; or 9 g [weeks 9-13]) or placebo. Sensitivity analyses included completer population, placebo-based multiple imputation (MI) with a missing-not-at-random assumption, analysis of covariance (ANCOVA), and tipping-point-based MI of worsening values until P > 0.05. Mean differences and P-values were calculated for the MWT and number of cataplexy episodes. For CGI-I, odds ratios and P-values were calculated for completers; mean differences (1-7 points; lower values indicate greater improvement) and P-values were calculated using ANCOVA. Effect sizes were calculated using Cohen's d; NNTs were calculated as the inverse of the absolute risk reduction.

Results: In the completer population (ON-SXB, n = 69; placebo, n = 79), all ON-SXB doses demonstrated significant improvements versus placebo for all coprimary endpoints (P < 0.001). All ON-SXB doses demonstrated significant improvements (P < 0.001) versus placebo for all coprimary endpoints when missing values in both treatment arms were imputed from observed values in the placebo arm (i.e., missing data were replaced with placebo data) and when analyzed using ANCOVA. Tipping-point-based analysis on the change from baseline in mean sleep latency on the MWT demonstrated that implausible or nearly implausible baseline MWT assumptions were needed to render the differences between ON-SXB and placebo no longer statistically significant. All doses of ON-SXB had NNTs of three and effect sizes of 0.7-0.9 for MWT response. For the response in terms of number of cataplexy episodes, NNT was six for the 6 g dose and three for the 7.5 g and 9 g doses; the effect sizes were between -0.7 and -0.8. For the Epworth Sleepiness Scale (ESS) response, NNTs ranged from three to six, with a dose-response effect. Effect sizes were between -0.5 and -0.7 for all doses.

Conclusions: These post hoc results demonstrate the robustness of the REST-ON clinical trial efficacy data.

Clinical trial id: NCT02720744.

每晚一次羟酸钠对发作性睡患者的疗效:敏感性、效应大小和3期REST-ON试验所需治疗人数的事后分析
背景:每晚一次的氧酸钠(ON-SXB;LUMRYZ™;在一项随机、安慰剂对照试验(REST-ON)中,与安慰剂相比,FT218治疗显著改善了清醒维持测试(MWT)的平均睡眠潜伏期、临床总体改善印象(CGI-I)评分和每周发作次数的主要终点。这些事后敏感性分析的目的是评估ON-SXB治疗的稳健性,同时考虑缺失的参与者数据。需要治疗的数量(NNT)和效应量分析进行量化治疗效益。方法:年龄≥16岁的1型或2型发作性睡病患者以1:1的比例随机分配,接受ON-SXB治疗(4.5 g[第1周];6 g[2-3周];7.5 g[周4-8];或9克[9-13周])或安慰剂。敏感性分析包括完整总体、缺失非随机假设的基于安慰剂的多重imputation (MI)、协方差分析(ANCOVA)和基于恶化值的临界点MI,直到P < 0.05。计算MWT和猝倒发作次数的平均差异和p值。对于CGI-I,计算完井的优势比和p值;平均差值(1-7分;值越低表明改善越大),p值使用ANCOVA计算。效应量采用Cohen’s d计算;nnt计算为绝对风险降低的倒数。结果:在完全性人群(ON-SXB, n = 69;与安慰剂相比,所有ON-SXB剂量在所有主要终点均表现出显著改善(P < 0.001)。当两个治疗组的缺失值均来自安慰剂组的观察值(即缺失数据被安慰剂数据替代),并使用ANCOVA进行分析时,所有ON-SXB剂量与安慰剂相比,在所有主要终点均显示出显著改善(P < 0.001)。基于引爆点的MWT平均睡眠潜伏期基线变化分析表明,需要不可信或几乎不可信的基线MWT假设,才能使on - sxb和安慰剂之间的差异不再具有统计学意义。所有剂量的ON-SXB的nnt均为3,MWT反应的效应量为0.7-0.9。对于猝倒发作次数的反应,6g剂量的NNT为6次,7.5 g和9g剂量的NNT为3次;效应量在-0.7到-0.8之间。对于Epworth嗜睡量表(ESS)反应,nnt的范围从3到6,具有剂量反应效应。所有剂量的效应值在-0.5到-0.7之间。结论:这些事后结果证明了REST-ON临床试验疗效数据的稳健性。临床试验编号:NCT02720744。
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来源期刊
CNS drugs
CNS drugs 医学-精神病学
CiteScore
12.00
自引率
3.30%
发文量
82
审稿时长
6-12 weeks
期刊介绍: CNS Drugs promotes rational pharmacotherapy within the disciplines of clinical psychiatry and neurology. The Journal includes: - Overviews of contentious or emerging issues. - Comprehensive narrative reviews that provide an authoritative source of information on pharmacological approaches to managing neurological and psychiatric illnesses. - Systematic reviews that collate empirical evidence to answer a specific research question, using explicit, systematic methods as outlined by the PRISMA statement. - Adis Drug Reviews of the properties and place in therapy of both newer and established drugs in neurology and psychiatry. - Original research articles reporting the results of well-designed studies with a strong link to clinical practice, such as clinical pharmacodynamic and pharmacokinetic studies, clinical trials, meta-analyses, outcomes research, and pharmacoeconomic and pharmacoepidemiological studies. Additional digital features (including animated abstracts, video abstracts, slide decks, audio slides, instructional videos, infographics, podcasts and animations) can be published with articles; these are designed to increase the visibility, readership and educational value of the journal’s content. In addition, articles published in CNS Drugs may be accompanied by plain language summaries to assist readers who have some knowledge of, but not in-depth expertise in, the area to understand important medical advances.
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