Efficacy and safety of intravenous prasinezumab in individuals with early-stage Parkinson's disease on stable symptomatic monotherapy (PADOVA): a phase 2b, multicentre, randomised, double-blind, placebo-controlled study.

The aim of the PADOVA trial was to evaluate the efficacy and safety of prasinezumab in a broader population of patients receiving stable symptomatic medication.

PADOVA试验的目的是评估普拉西尼珠单抗在更广泛患者群体中的疗效和安全性，这些患者正在接受稳定的症状性药物治疗。

Methods

This phase 2b, multicentre, double-blind, parallel-group, placebo-controlled, randomised, superiority trial recruited participants with early-stage Parkinson's disease (age 50-85 years, 3 months to 3 years from diagnosis, Hoehn and Yahr stage 1 or 2) on stable symptomatic medication from 110 centres in nine countries in Europe and North America.

这项2b期、多中心、双盲、平行组、安慰剂对照、随机、优效试验招募了来自欧洲和北美九个国家110个中心的早期帕金森病患者（年龄50-85岁，诊断后3个月至3年，Hoehn和Yahr分期1或2级），他们在稳定的症状治疗药物下参与研究。

Participants were individually randomly assigned (1:1) via permuted blocks (stratified by symptomatic medication [levodopa or MAO-B inhibitor]) to intravenous prasinezumab (1500 mg) or placebo every 4 weeks for at least 76 weeks and until the target number of motor progression events was reached.

参与者通过随机分层（按症状治疗药物[左旋多巴或MAO-B抑制剂]分层）以1:1的比例通过置换分块随机分配到静脉注射prasinezumab（1500毫克）或安慰剂，每4周一次，至少76周，直到达到运动进展事件的目标数量。

Participants, investigators, and clinical assessors were masked to group assignment.

参与者、研究者和临床评估员对分组分配情况均不知情。

The primary endpoint was time to a confirmed motor progression event (≥5-point increase in MDS-UPDRS Part III off-medication score), assessed in the full analysis set (all randomly assigned participants according to the treatment to which they were assigned).

主要终点是确认运动进展事件的时间（在停药状态下MDS-UPDRS第三部分评分增加≥5分），在全分析集（所有随机分配的参与者按照他们被分配的治疗进行评估）中进行评估。

Safety and tolerability were assessed in all randomly assigned participants who received at least one dose of study drug, with participants grouped according to treatment received.

安全性与耐受性通过评估所有随机分配并至少接受一次研究药物的参与者来确定，参与者根据所接受的治疗进行分组。

The trial is registered with ClinicalTrials.gov (NCT04777331) and EudraCT (2020-004997-23), and is active, not recruiting.

该试验已在ClinicalTrials.gov (NCT04777331)和EudraCT (2020-004997-23)注册，并且目前处于活跃状态，但不接受新参与者。

Results

Between May 5, 2021, and March 22, 2023, 787 individuals were screened. 586 were enrolled and randomly assigned (n=293 per group; mean age 64·2 years [SD 7·3]; 214 [37%] female and 372 [63%] male); 550 completed double-blindtreatment (prasinezumab, n=277; placebo, n=273).

2021年5月5日至2023年3月22日期间，共有787名个体接受了筛查。其中586名被纳入并随机分配（每组n=293；平均年龄64.2岁[标准差7.3]；女性214名[37%]，男性372名[63%]）；550名完成了双盲治疗（prasinezumab组277名，安慰剂组273名）。

The primary endpoint was not met; the primary analysis showed a non-significant delay in motor progression with prasinezumab versus placebo (hazard ratio0·84 [95% CI 0·69-1·01]; p=0·066); median time to confirmed motor progression in the prasinezumab group was 61·1 weeks (95% CI 52·3-71·9), compared with 49·7 weeks (40·1-58·1) in the placebo group.

主要终点未达到；主要分析显示与安慰剂相比，prasinezumab对运动进展的延迟无显著性（风险比0.84 [95% 置信区间0.69-1.01]；p=0.066）；prasinezumab组的运动进展中位时间是61.1周（95% 置信区间52.3-71.9），而安慰剂组为49.7周（40.1-58.1）。

The incidenceof one or more serious adverse events was similar between groups (prasinezumab, 34 [12%] of 292; placebo, 34 [12%] of 290) and three recorded deaths were unrelated to the study drug (prasinezumab, n=1 [<1%]; placebo, n=2 [1%]).

两组中发生一个或多个严重不良事件的发病率相似（prasinezumab组，292人中有34人[12%]；安慰剂组，290人中有34人[12%]），并且记录的三例死亡与研究药物无关（prasinezumab组，n=1[<1%]；安慰剂组，n=2[1%]）。

interpretation

Although PADOVA did not meet the primary endpoint, prespecified exploratory evidence suggests clinical activity of prasinezumab in early-stage Parkinson's disease, supporting continued investigation in the ongoing phase 3 PARAISO trial (NCT07174310).

尽管PADOVA未达到主要终点，但预先设定的探索性证据表明prasinezumab在早期帕金森病中具有临床活性，支持在正在进行的第三阶段PARAISO试验（NCT07174310）中继续进行研究。

funding

F Hoffmann-La Roche.

F Hoffmann-La Roche 公司