Mechanism-Based Therapy With Ampreloxetine for Neurogenic Orthostatic Hypotension in Multiple System Atrophy: A Randomized Withdrawal Trial.

Ampreloxetine, a novel, selective, norepinephrine (NE) reuptake inhibitor, allows once-daily dosing to precisely target residual peripheral autonomic neurons.

Ampreloxetine是一种新型、选择性的去甲肾上腺素（NE）再摄取抑制剂，允许每日一次给药以精确靶向残余的外周自主神经元。

Based on the hypothesis that patients with MSA would be most responsive and the substantial unmet need for symptomatic therapy in this population, an MSA subgroup analysis was prespecified.

基于这样的假设，即多系统萎缩（MSA）患者将最具反应性，且这一人群对症状治疗的需求巨大，因此预先规定了MSA亚组分析。

Methods

We conducted a run-in 4-week, parallel-group, randomized controlled trial(SEQUOIA), followed by a pivotal enriched randomized withdrawal (RW) trial with 16-week open-label treatment and 6 weeks of 1:1 RW (REDWOOD).

我们进行了一项为期4周的启动期、平行组、随机对照试验（SEQUOIA），随后进行了一项关键的富集随机撤回（RW）试验，包括16周的开放标签治疗和6周的1:1 RW（REDWOOD）。

Inclusion criteria for the MSA subgroup included (1) probable or possible MSA, (2) 3-minute orthostatic blood pressure (BP) fall >20/10 mm Hg, and (3) dizziness or lightheadedness score >4 points.

MSA亚组的纳入标准包括：(1) 可能或可能的MSA，(2) 3分钟直立性血压(BP)下降>20/10毫米汞柱，以及(3)头晕或头昏评分>4分。

Outcome measures included self-reported symptom burden captured on the 10-item OH Questionnaire (OHQ).

结果指标包括在10项OH问卷(OHQ)上自我报告的症状负担。

Differences were analyzed using logistic regression and mixed-model repeated measures analysis.

使用逻辑回归和混合模型重复测量分析来分析差异。

Results

Seventy-three patients with MSA entered the program (mean age 63 years old [range: 43-80], 52% male).

共有73名多系统萎缩症（MSA）患者参与了该项目（平均年龄63岁[范围：43-80]，男性占52%）。

Both SEQUOIA and REDWOOD did not meet their primary endpoints.

SEQUOIA 和 REDWOOD 均未达到其主要终点。

In REDWOOD, 40 (61%) fulfilled enrichment criteria and were randomized.

在 REDWOOD 研究中，有 40 名（61%）患者满足富集标准并被随机分组。

After 16-week open-label, OHQ symptom assessment (OHSA) composite domain scores improved 2.6 ± (SD = 2.1) points from pretreatment.

经过16周开放标签的OHQ症状评估(OHSA)综合领域评分从治疗前改善了2.6±（标准差=2.1）分。

The proportion of participants with treatment failure at week 6 of RW treatment period was 40% in the placebo arm and 15% in the ampreloxetine arm (p = 0.11).

在RW治疗期第6周时，安慰剂组中有40%的参与者治疗失败，而在安普洛酮组中这一比例为15%（p = 0.11）。

In secondary endpoints, at week 6 of RW, symptoms remained stable in the ampreloxetine group, but worsened on placebo (mean difference OHSA composite: -1.6 points ± 0.5; p = 0.0056, minimal clinically important worsening = 0.7-1.1 points).

在次要终点中，到 RW 第 6 周时，安普雷洛辛组的症状保持稳定，但在安慰剂组中症状恶化（OHSA 综合评分平均差异：-1.6 分 ± 0.5；p = 0.0056，最小临床重要恶化范围 = 0.7-1.1 分）。

Standing for a short time favored ampreloxetine (-2.0 points ± 0.8; p = 0.015).

站立一小段时间对安普雷洛辛有利（-2.0 分 ± 0.8；p = 0.015）。

Standing BP remained unchanged from open-label in the ampreloxetine group (systolic: 5.6 ± 4.1; diastolic: 3.7 ± 2.9 [SE] mm Hg) but fell after placebo withdrawal (systolic: -10.0 ± 4.5; diastolic: -6.0 ± 3.1 mm Hg).

在安普雷洛特组中，站立血压从开放标签研究中保持不变（收缩压：5.6 ± 4.1；舒张压：3.7 ± 2.9 [SE] 毫米汞柱），但在停用安慰剂后下降（收缩压：-10.0 ± 4.5；舒张压：-6.0 ± 3.1 毫米汞柱）。

The catecholamine profile was consistent with NE transporter inhibition.

儿茶酚胺谱与去甲肾上腺素转运体抑制一致。

There were no observed increases in supine BP.

仰卧位血压未见增加。

Discussion

In a prespecified subgroup analysis of MSA participants in the REDWOOD trial, patients randomized to placebo worsened, whereas those who were randomized to treatment maintained their open-label level of function.

在REDWOOD试验中，对多系统萎缩(MSA)参与者的预先指定的亚组分析显示，被随机分配到安慰剂的患者病情恶化，而那些被随机分配到治疗组的患者则保持了开放标签下的功能水平。

trial_registration_information

REDWOOD trial, NCT03829657; first submitted to registry January 10, 2019; first participant enrolled February 22, 2019.

REDWOOD试验，NCT03829657；首次提交至注册机构为2019年1月10日；首位参与者入组时间为2019年2月22日。

SEQUOIA trial, NCT03750552; first submitted to registry November 20, 2018; first participant enrolled January 24, 2019.

SEQUOIA试验，NCT03750552；首次提交至注册机构为2018年11月20日；首位参与者入组时间为2019年1月24日。

See ClinicalTrials.gov for full-protocol and statistical analysis plan.

请访问ClinicalTrials.gov以获取完整协议和统计分析计划。

classification_of_evidence

This study provides Class III evidence that in patients with MSA who had symptomatic benefit on orthostatic hypotension with ampreloxetine, there was no difference in the odds of treatment failures between those maintained on ampreloxetine and those withdrawn to placebo.

本研究提供了III类证据，表明在多系统萎缩症（MSA）患者中，对于那些在直立性低血压症状上从ampreloxetine中获益的患者，继续使用ampreloxetine与撤药至安慰剂的患者在治疗失败的几率上没有差异。