Medical Research Institute of New Zealand, Private Bag 7902, Newtown, Wellington, 6242, New Zealand.
University College Dublin - Clinical Research Centre at St. Vincent's University Hospital, Dublin, Ireland.
Trials. 2022 Jun 27;23(1):534. doi: 10.1186/s13063-022-06402-w.
Coronavirus disease 2019 (COVID-19) has exposed the disproportionate effects of pandemics on frontline workers and the ethical imperative to provide effective prophylaxis. We present a model for a pragmatic randomised controlled trial (RCT) that utilises Bayesian methods to rapidly determine the efficacy or futility of a prophylactic agent.
We initially planned to undertake a multicentre, phase III, parallel-group, open-label RCT, to determine if hydroxychloroquine (HCQ) taken once a week was effective in preventing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in healthcare workers (HCW) aged ≥ 18 years in New Zealand (NZ) and Ireland. Participants were to be randomised 2:1 to either HCQ (800 mg stat then 400 mg weekly) or no prophylaxis. The primary endpoint was time to Nucleic Acid Amplification Test-proven SARS-CoV-2 infection. Secondary outcome variables included mortality, hospitalisation, intensive care unit admissions and length of mechanical ventilation. The trial had no fixed sample size or duration of intervention. Bayesian adaptive analyses were planned to occur fortnightly, commencing with a weakly informative prior for the no prophylaxis group hazard rate and a moderately informative prior on the intervention log hazard ratio centred on 'no effect'. Stopping for expected success would be executed if the intervention had a greater than 0.975 posterior probability of reducing the risk of SARS-CoV-2 infection by more than 10%. Final success would be declared if, after completion of 8 weeks of follow-up (reflecting the long half-life of HCQ), the prophylaxis had at least a 0.95 posterior probability of reducing the risk of SARS-CoV-2 infection by more than 10%. Futility would be declared if HCQ was shown to have less than a 0.10 posterior probability of reducing acquisition of SARS-CoV-2 infection by more than 20%.
This study did not begin recruitment due to the marked reduction in COVID-19 cases in NZ and concerns regarding the efficacy and risks of HCQ treatment in COVID-19. Nonetheless, the model presented can be easily adapted for other potential prophylactic agents and pathogens, and pre-established collaborative models like this should be shared and incorporated into future pandemic preparedness planning.
The decision not to proceed with the study was made before trial registration occurred.
2019 年冠状病毒病（COVID-19）暴露了大流行对一线工作人员的影响，并凸显了提供有效预防措施的道德必要性。我们提出了一种实用的随机对照试验（RCT）模型，该模型利用贝叶斯方法快速确定预防剂的疗效或无效性。
我们最初计划进行一项多中心、三期、平行组、开放性 RCT，以确定每周一次服用羟氯喹（HCQ）是否能有效预防≥18 岁的新西兰（NZ）和爱尔兰医护人员（HCW）中严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）感染。参与者按 2:1 随机分为 HCQ（800mg 一次，然后每周 400mg）或无预防组。主要终点是核酸扩增试验（NAA）证实的 SARS-CoV-2 感染时间。次要结局变量包括死亡率、住院率、重症监护病房（ICU）入院率和机械通气时间。该试验没有固定的样本量或干预持续时间。计划每两周进行一次贝叶斯适应性分析，从对无预防组危险率的弱信息先验和对干预对数危险比的适度信息先验开始，该先验以“无效果”为中心。如果干预措施有超过 0.975 的后验概率降低 SARS-CoV-2 感染风险超过 10%，则将进行预期成功的停止。如果在完成 8 周的随访后（反映了 HCQ 的半衰期较长），预防措施至少有 0.95 的后验概率降低 SARS-CoV-2 感染风险超过 10%，则将宣布最终成功。如果 HCQ 降低 SARS-CoV-2 感染风险的可能性小于 0.10，则将宣布无效。
由于 NZ COVID-19 病例的显著减少以及对 HCQ 治疗 COVID-19 的疗效和风险的担忧，该研究没有开始招募。尽管如此，提出的模型可以很容易地适用于其他潜在的预防剂和病原体，并且应该共享和纳入这种预先建立的合作模型，以纳入未来的大流行准备计划。
在试验注册之前，就做出了不进行研究的决定。
