Division of Infectious Diseases, St. Michael's Hospital, Toronto, Canada.
MAP Centre for Urban Health Solutions, St. Michael's Hospital, Toronto, Canada.
Trials. 2021 Mar 22;22(1):224. doi: 10.1186/s13063-021-05134-7.
Post-exposure prophylaxis (PEP) is a well-established strategy for the prevention of infectious diseases, in which recently exposed people take a short course of medication to prevent infection. The primary objective of the COVID-19 Ring-based Prevention Trial with lopinavir/ritonavir (CORIPREV-LR) is to evaluate the efficacy of a 14-day course of oral lopinavir/ritonavir as PEP against COVID-19 among individuals with a high-risk exposure to a confirmed case.
This is an open-label, multicenter, 1:1 cluster-randomized trial of LPV/r 800/200 mg twice daily for 14 days (intervention arm) versus no intervention (control arm), using an adaptive approach to sample size calculation. Participants will be individuals aged > 6 months with a high-risk exposure to a confirmed COVID-19 case within the past 7 days. A combination of remote and in-person study visits at days 1, 7, 14, 35, and 90 includes comprehensive epidemiological, clinical, microbiologic, and serologic sampling. The primary outcome is microbiologically confirmed COVID-19 infection within 14 days after exposure, defined as a positive respiratory tract specimen for SARS-CoV-2 by polymerase chain reaction. Secondary outcomes include safety, symptomatic COVID-19, seropositivity, hospitalization, respiratory failure requiring ventilator support, mortality, psychological impact, and health-related quality of life. Additional analyses will examine the impact of LPV/r on these outcomes in the subset of participants who test positive for SARS-CoV-2 at baseline. To detect a relative risk reduction of 40% with 80% power at α = 0.05, assuming the secondary attack rate in ring members (p) = 15%, 5 contacts per case and intra-class correlation coefficient (ICC) = 0.05, we require 110 clusters per arm, or 220 clusters overall and approximately 1220 enrollees after accounting for 10% loss-to-follow-up. We will modify the sample size target after 60 clusters, based on preliminary estimates of p, ICC, and cluster size and consider switching to an alternative drug after interim analyses and as new data emerges. The primary analysis will be a generalized linear mixed model with logit link to estimate the effect of LPV/r on the probability of infection. Participants who test positive at baseline will be excluded from the primary analysis but will be maintained for additional analyses to examine the impact of LPV/r on early treatment.
Harnessing safe, existing drugs such as LPV/r as PEP could provide an important tool for control of the COVID-19 pandemic. Novel aspects of our design include the ring-based prevention approach, and the incorporation of remote strategies for conducting study visits and biospecimen collection.
This trial was registered at www.ClinicalTrials.gov ( NCT04321174 ) on March 25, 2020.
暴露后预防（PEP）是预防传染病的一种成熟策略，在这种策略中，最近接触过的人会服用短期疗程的药物来预防感染。以洛匹那韦/利托那韦（LPV/r）为基础的 COVID-19 环式预防试验（CORIPREV-LR）的主要目的是评估在过去 7 天内与确诊病例有高危接触的人群中，使用 14 天疗程的口服洛匹那韦/利托那韦作为 PEP 预防 COVID-19 的疗效。
这是一项开放性、多中心、1:1 集群随机试验，采用适应性方法计算样本量，比较 LPV/r 800/200mg 每日两次（干预组）与无干预（对照组）14 天。参与者为年龄大于 6 个月的人群，在过去 7 天内与 COVID-19 确诊病例有高风险接触。远程和现场研究访问结合，在第 1、7、14、35 和 90 天进行，包括全面的流行病学、临床、微生物学和血清学采样。主要结局是在接触后 14 天内通过聚合酶链反应检测到呼吸道标本中 SARS-CoV-2 阳性的微生物学确诊 COVID-19 感染。次要结局包括安全性、有症状的 COVID-19、血清阳性、住院、需要呼吸机支持的呼吸衰竭、死亡率、心理影响和健康相关的生活质量。额外的分析将检查 LPV/r 在基线时 SARS-CoV-2 检测呈阳性的参与者亚组中对这些结局的影响。为了以 80%的把握度在 α=0.05 时检测到 40%的相对风险降低，假设环成员中的二次攻击率（p）=15%，每个病例 5 个接触者和组内相关系数（ICC）=0.05，则我们需要每个臂 110 个集群，或总共 220 个集群，在考虑到 10%的随访丢失后，大约需要招募 1220 名参与者。我们将在 60 个集群后修改样本量目标，根据 p、ICC 和集群大小的初步估计值，并在中期分析后以及随着新数据的出现，考虑切换到替代药物。主要分析将是广义线性混合模型，采用对数链接来估计 LPV/r 对感染概率的影响。在基线时检测呈阳性的参与者将被排除在主要分析之外，但将保留用于进一步分析，以检查 LPV/r 对早期治疗的影响。
利用 LPV/r 等安全、现有的药物作为 PEP 可能为控制 COVID-19 大流行提供一个重要工具。我们设计的新颖之处包括基于环的预防方法，以及采用远程策略进行研究访问和生物标本采集。
该试验于 2020 年 3 月 25 日在 www.ClinicalTrials.gov（NCT04321174）注册。
