CLOVER: A Phase 3 Randomized Trial Investigating the Efficacy and Safety of a Detoxified Toxin A/B Vaccine in Adults 50 Years and Older at Increased Risk of Clostridioides difficile Infection.

IF 8.2 1区医学 Q1 IMMUNOLOGY Clinical Infectious Diseases Pub Date : 2024-08-24 DOI:10.1093/cid/ciae410

Curtis J Donskey, Erik R Dubberke, Nicola P Klein, Elizabeth G Liles, Katarzyna Szymkowiak, Mark H Wilcox, Jody Lawrence, Salim Bouguermouh, Haiying Zhang, Kenneth Koury, Ruth Bailey, Helen M Smith, Stephen Lockhart, Erik Lamberth, Warren V Kalina, Michael W Pride, Chris Webber, Annaliesa S Anderson, Kathrin U Jansen, William C Gruber, Nicholas Kitchin

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Abstract

Background: Clostridioides difficile infection (CDI) causes substantial mortality and healthcare burden. We assessed the detoxified toxin-A/B PF-06425090 vaccine for primary CDI prevention.

Methods: This phase 3 observer-blinded study randomized (1:1) ≥50-year-olds at increased CDI risk (N=17,535) to receive 3 PF-06425090 or placebo doses (0,1,6-months). Primary endpoints were first CDI episode (≥3 unformed stools within 24 hours; central laboratory-confirmed toxin A/B positive) ≥14 days post-dose 3 (PD3; first primary) and post-dose 2 (PD2; second primary). CDI duration, need for CDI-related medical attention (secondary endpoints), and antibiotic use (post hoc analysis) PD3 were evaluated. Tolerability/safety was assessed.

Results: The primary endpoint was not met (17 PF-06425090 and 25 placebo recipients had first CDI episode ≥14 days PD3 [vaccine efficacy (VE)=31.0% (96.4%CI: -38.7%-66.6%)]; 24 PF-06425090 and 34 placebo recipients had first CDI episode ≥14 days PD2 [VE=28.6% (-28.4%-61.0%)]). Median CDI duration was lower with PF-06425090 (1 day) versus placebo (4 days; 2-sided nominal P=0.02). Of participants with first CDI episode, 0 PF-06425090 and 11 placebo recipients sought CDI-related medical attention (post hoc analysis estimated VE=100% [95%CI: 59.6%-100.0%]) and 0 PF-06425090 and 10 placebo recipients required antibiotic treatment (VE=100% [54.8%-100.0%]). Local reactions were more frequent in PF-06425090 recipients and systemic events were generally similar between groups; most were mild-to-moderate. AE rates were similar between groups.

Conclusions: Three PF-06425090 doses were safe and well-tolerated. Although the primary endpoint was not met, PF-06425090 reduced symptom duration, CDI requiring medical attention, and CDI-directed antibiotic treatment, highlighting its potential to reduce CDI-associated healthcare burden. NCT03090191.

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CLOVER：一项第 3 期随机试验，研究解毒毒素 A/B 疫苗对 50 岁及以上艰难梭菌感染风险较高的成人的疗效和安全性。

背景：艰难梭菌感染（CDI）会造成大量死亡和医疗负担。我们对解毒毒素-A/B PF-06425090 疫苗用于初级 CDI 预防进行了评估：这项 3 期观察者盲法研究随机（1:1）让 CDI 风险较高的≥50 岁人群（N=17,535）接种 3 次 PF-06425090 或安慰剂（0、1、6 个月）。主要终点为剂量 3（PD3；第一主要终点）和剂量 2（PD2；第二主要终点）后≥14 天的首次 CDI 发作（24 小时内≥3 次不成形大便；中心实验室证实毒素 A/B 阳性）。评估了 CDI 持续时间、CDI 相关医疗护理需求（次要终点）和抗生素使用（事后分析）PD3。对耐受性/安全性进行了评估：主要终点未达到（17例PF-06425090和25例安慰剂受试者首次CDI发作≥14天，PD3[疫苗疗效（VE）=31.0%（96.4%CI：-38.7%-66.6%）]；24例PF-06425090和34例安慰剂受试者首次CDI发作≥14天，PD2[VE=28.6%（-28.4%-61.0%）]）。PF-06425090的中位CDI持续时间（1天）低于安慰剂（4天；双侧名义P=0.02）。在首次出现 CDI 的参与者中，0 名 PF-06425090 受试者和 11 名安慰剂受试者寻求 CDI 相关的医疗护理（事后分析估计 VE=100% [95%CI: 59.6%-100.0%] ），0 名 PF-06425090 受试者和 10 名安慰剂受试者需要抗生素治疗（VE=100% [54.8%-100.0%] ）。PF-06425090受试者的局部反应更为频繁，而各组之间的全身反应基本相似；大多数为轻度至中度反应。各组的 AE 发生率相似：结论：三种剂量的 PF-06425090 安全且耐受性良好。尽管未达到主要终点，但PF-06425090缩短了症状持续时间、减少了需要就医的CDI和CDI导向的抗生素治疗，凸显了其减少CDI相关医疗负担的潜力。NCT03090191。

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来源期刊

Clinical Infectious Diseases 医学-传染病学

CiteScore

25.00

自引率

2.50%

发文量

900

审稿时长

3 months

期刊介绍： Clinical Infectious Diseases (CID) is dedicated to publishing original research, reviews, guidelines, and perspectives with the potential to reshape clinical practice, providing clinicians with valuable insights for patient care. CID comprehensively addresses the clinical presentation, diagnosis, treatment, and prevention of a wide spectrum of infectious diseases. The journal places a high priority on the assessment of current and innovative treatments, microbiology, immunology, and policies, ensuring relevance to patient care in its commitment to advancing the field of infectious diseases.