Safety, tolerability, and efficacy of flexible-dose tavapadon for Parkinson's disease (TEMPO-2): a phase 3, randomised, placebo-controlled, double-blind trial.

Tavapadon is an oral, once-daily, selective D1/D5 agonist that might improve Parkinson's disease motor symptoms.

Tavapadon是一种口服、每日一次的D1/D5选择性激动剂，可能改善帕金森病的运动症状。

We aimed to evaluate the safety, tolerability and efficacy of flexible-dose tavapadon in people with early-stage Parkinson's disease.

我们旨在评估灵活剂量的tavapadon在早期帕金森病患者中的安全性、耐受性和疗效。

Methods

TEMPO-2 was a phase 3, randomised, double-blind, placebo-controlledtrial conducted at 75 clinical sites (both hospital or academic and community settings) across 13 countries.

TEMPO-2是一项在13个国家的75个临床站点（包括医院或学术机构以及社区环境）进行的3期、随机、双盲、安慰剂对照试验。

Adults aged 40-80 years with early-stage Parkinson's disease (<3 years' disease duration) who were treatment-naive or had less than 3 months of previous dopaminergic treatment were eligible.

年龄在40-80岁之间的早期帕金森病患者（病程<3年），无论是治疗前还是之前接受过少于3个月的多巴胺能治疗，均符合入选条件。

Participants were randomly assigned 1:1 to flexible-dose tavapadon (5-15 mg) or placebo orally once daily for 27 weeks.

参与者按1:1的比例随机分配，每天一次口服灵活剂量的tavapadon（5-15毫克）或安慰剂，持续27周。

The primary endpoint was change from baseline to week 26 in the combined score of the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Parts II and III (reflecting activities of daily living and motor performance).

主要终点是从基线到第26周在运动障碍学会统一帕金森病评定量表（MDS-UPDRS）第二部分和第三部分的综合评分的变化（反映了日常生活活动和运动表现）。

Safety endpoints included adverse events, clinical laboratory values, vital signs, and electrocardiograms.

安全性终点包括不良事件、临床实验室值、生命体征和心电图。

The primary endpoint was assessed in the modified intent-to-treat population (participants who received one dose or more of study drug and had both a baseline and one or more post-baseline MDS-UPDRS assessments) and safety was assessed in the safety analysis set (all participants who received one dose or more of tavapadon or placebo).

主要终点是在改良意向治疗人群中评估的（接受一次或多次研究药物剂量，并且有基线和一次或多次基线后MDS-UPDRS评估的参与者），安全性是在安全性分析集中评估的（所有接受一次或多次tavapadon或安慰剂的参与者）。

This study is registered with ClinicalTrials.gov (NCT04223193) and is now complete.

这项研究已在ClinicalTrials.gov上注册（NCT04223193），现在已完成。

Results

Between Jan 6, 2020, and Feb 22, 2024, 473 individuals were screened and 304 were randomly assigned to receive tavapadon 5-15 mg (n=151) or placebo (n=153).

2020年1月6日至2024年2月22日期间，对473名个体进行了筛选，其中304名被随机分配接受tavapadon 5-15 mg（n=151）或安慰剂（n=153）。

The majority of participants were male (169 [56%] of 304 male; 135 [44%] of 304 female), the mean age was 62·9 (SD 9·2) years, and the mean disease duration was 0·86 (0·79) years. 80 (26%) of 304 participants discontinued from the trial (57 [38%] of 151 on tavapadon and 23 [15%] of 153 on placebo), most commonly due to adverse events (42 [14%] of 304; 36 [24%] of 151 on tavapadon and six [4%] of 153 on placebo).

大多数参与者为男性（304名中的169名，占56%；304名中的135名女性，占44%），平均年龄为62.9（标准差9.2）岁，平均病程为0.86（0.79）年。304名参与者中有80名（占26%）退出了试验（tavapadon组151名中的57名，占38%；安慰剂组153名中的23名，占15%），最常见的是由于不良事件（304名中的42名，占14%；tavapadon组151名中的36名，占24%；安慰剂组153名中的6名，占4%）。

The primary endpoint of change from baseline to week 26 in the MDS-UPDRS Parts II and III combined score was significantly improved with tavapadon versus placebo (least squares mean [LSM] decrease of 10·3 [95% CI -12·2 to -8·3] points vs 1·2 [-2·9 to 0·6] points; LSM treatment difference -9·1 [95% CI -11·7 to -6·5]; p<0·0001).

主要终点是从基线到第26周MDS-UPDRS II和III部分综合评分的变化，在tavapadon与安慰剂的比较中显著改善（最小二乘均值[LSM]降低10·3 [95%置信区间-12·2至-8·3]分，而安慰剂为1·2 [-2·9至0·6]分；LSM治疗差异为-9·1 [95%置信区间-11·7至-6·5]；p<0·0001）。

Most adverse events were non-serious and mild to moderate in severity.

大多数不良事件为非严重性，且严重程度为轻度至中度。

More adverse events were observed with tavapadon than with placebo (115 [76%] of 151 participants vs 84 [55%] of 153 participants).

与安慰剂相比，tavapadon 观察到更多的不良事件（151名参与者中有115名[76%]，而153名参与者中有84名[55%]）

The incidenceof adverse events in the tavapadon group was higher during the titration phase (92 [61%] of 151) than during the dose adjustment (44 [37%] of 151) and maintenance (47 [43%] of 151) phases.

tavapadon组在滴定阶段的不良事件发生率（151名中有92名[61%]）高于剂量调整（151名中有44名[37%]）和维持（151名中有47名[43%]）阶段。

The most commonly reported adverse events with tavapadon versus placebo (>10% of participants) were nausea (45 [30%] of 151] vs five [3%] of 153), headache (25 [17%] vs eight [5%]), and dizziness (24 [16%] vs five [3%]).

与安慰剂相比，tavapadon报告的最常见不良事件（>10%的参与者）是恶心（151名参与者中有45名[30%]对比153名参与者中有五名[3%]）、头痛（25名[17%]对比八名[5%]）和头晕（24名[16%]对比五名[3%]）。

interpretation

Tavapadon showed significant and clinically meaningful improvements in Parkinson's disease motor symptoms, with low incidenceof somnolence and impulse control disorders.

Tavapadon在帕金森病运动症状方面显示出显著且具有临床意义的改善，嗜睡和冲动控制障碍的发生率较低。

However, the short observation period limits conclusions about long-term tolerability.

然而，短暂的观察期限制了对长期耐受性的结论。

An ongoing extension study aims to confirm its long-term safety and efficacy.

一项正在进行的扩展研究旨在确认其长期的安全性和有效性。

funding

AbbVie.

艾伯维公司。