抗呼吸道合胞病毒（Clesrovimab）单克隆抗体在婴儿和儿童中的评价：晚期临床试验的综合理论基础和研究设计

IF 1.9 3区医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL

Contemporary clinical trials Pub Date : 2025-06-30 DOI:10.1016/j.cct.2025.107995

Anushua Sinha , Radha A. Railkar , Luis Castagnini , Andrea Guerra , Andrea Likos , Jeannine Lutkiewicz , Brian M. Maas , Xiaowei Zang , Brad A. Roadcap , Yoonyoung Choi , Georges J. Nahhas , Carmen S. Arriola , Louis Bont , Paolo Manzoni , Octavio Ramilo , Flor M. Muñoz , Lyn Finelli , Andrew W. Lee

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引用次数: 0

摘要

背景：呼吸道合胞病毒（RSV）是婴儿发病和死亡的主要原因。Clesrovimab是一种半衰期延长的RSV中和单克隆抗体，用于预防婴儿RSV疾病。本文描述了加速两项关键后期临床试验的方法，CLEVER (MK-1654-004；NCT04767373)和SMART (MK-1654-007；NCT04938830)，用于评价clesrovimab。方法：CLEVER是一项在健康早产儿和足月婴儿中进行的安慰剂对照2b/3期研究，评估clesrovimab预防rsv相关医疗护理下呼吸道感染（RSV-MALRI）和rsv相关住院治疗的有效性和安全性。SMART是一项3期帕利珠单抗对照研究，评估了与帕利珠单抗相比，clesrovimab在预防RSV相关MALRI和RSV相关住院治疗中严重RSV疾病风险增加的婴儿和儿童的安全性、耐受性和有效性。这些研究的剂量选择使用基于模型的荟萃分析，分析了1期和2期clesrovimab试验数据。通过巧妙的无缝设计，程序加速得以实现，从2b阶段快速推进到3阶段。此外，根据SMART和SMART之间的药代动力学桥接，对SMART人群的疗效进行了推断。结论：加速clesrovimab后期开发的方法，包括模型知情剂量选择方法、CLEVER 3期部分的无缝入组，以及从CLEVER人群到SMART人群的疗效外推，可用于为未来需要加速以解决未满足医疗需求的试验设计提供信息。

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Evaluation of a monoclonal antibody against respiratory syncytial virus, clesrovimab, in infants and children: Comprehensive rationale and study design for the late-stage clinical trials

Background

Respiratory syncytial virus (RSV) is a leading cause of infant morbidity and mortality. Clesrovimab is a half-life–extended, RSV neutralizing monoclonal antibody for the prevention of RSV disease in infants. This article describes the methodology that enabled the acceleration of two pivotal late-stage clinical trials, CLEVER (MK-1654-004; NCT04767373) and SMART (MK-1654-007; NCT04938830), for the evaluation of clesrovimab.

Methods

CLEVER is a placebo-controlled phase 2b/3 study in healthy preterm and full-term infants, evaluating the efficacy and safety of clesrovimab for the prevention of RSV-associated medically attended lower respiratory tract infection (RSV-MALRI) and RSV-associated hospitalization. SMART is a phase 3 palivizumab-controlled study evaluating the safety, tolerability, and efficacy of clesrovimab, compared with palivizumab, for the prevention of RSV-associated MALRI and RSV-associated hospitalization in infants and children at increased risk of severe RSV disease. Dose selection in these studies was informed using a model-based meta-analysis of phase 1 and 2 clesrovimab trial data. Program acceleration was enabled by designing CLEVER seamlessly, to rapidly progress from phase 2b to phase 3. Additionally, efficacy was extrapolated to the SMART population, based on pharmacokinetic bridging between CLEVER and SMART.

Conclusion

The methodology of the accelerated late-stage development of clesrovimab, including the model-informed dose selection approach, the seamless enrollment in the phase 3 portion of CLEVER, and the extrapolation of efficacy from the population in CLEVER to the population in SMART, may be used to inform future trial designs where acceleration is needed to address an unmet medical need.

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来源期刊

Contemporary clinical trials 医学-药学

CiteScore

3.70

自引率

4.50%

发文量

281

审稿时长

44 days

期刊介绍： Contemporary Clinical Trials is an international peer reviewed journal that publishes manuscripts pertaining to all aspects of clinical trials, including, but not limited to, design, conduct, analysis, regulation and ethics. Manuscripts submitted should appeal to a readership drawn from disciplines including medicine, biostatistics, epidemiology, computer science, management science, behavioural science, pharmaceutical science, and bioethics. Full-length papers and short communications not exceeding 1,500 words, as well as systemic reviews of clinical trials and methodologies will be published. Perspectives/commentaries on current issues and the impact of clinical trials on the practice of medicine and health policy are also welcome.