Design
Population
Hospitalised adult patients with confirmed SARS-CoV-2 infection meeting all the inclusion criteria and none of the exclusion criteria (Table 1).
Study concept and design
The meta-trial employs prospective pooling of individual patient data from ongoing individual clinical trials and early phase studies.[6] The term “meta-trial” has been previously referenced by Li et al,[7] referring to a prospective meta-analysis planned to streamline data collection from multiple individual trials, allowing for faster accumulation of data for major clinical endpoints during the pandemic. This meta-trial is designed as a collaborative prospective individual patient data meta-analysis of investigator-initiated, randomised studies of nebulised UFH in addition to standard care, compared to standard care alone, in hospitalised patients with confirmed COVID-19 infection. The primary outcome of the meta-trial is intubation (or death, for patients who died before intubation) at day 28 after randomisation. Primary outcomes for individual studies may be clinical or biochemical endpoints and are listed in the individual trial protocols.
Study setting
This meta-trial will include hospitalised patients with COVID-19 who do not immediately require invasive mechanical ventilation from participating studies. A full list of participating institutions is available in each individual trial record on respective trial registries. Studies from other institutions and countries may be added to this meta-trial after publication of the meta-trial’s protocol and statistical analysis plan, provided the studies meet the criteria for the meta-trial (patient eligibility criteria, intervention, core set of outcome measures).
Recruitment
Due to the rapidly evolving pandemic situation, we have a strong uncertainty about the pace of enrolment. There is likely to be considerable variation in the number of COVID-19 infections requiring hospital admission in different countries and regions. The pragmatic pre-specified prospective meta-analysis design essentially deals with recruitment difficulties that could occur in the individual trials given the international dynamics of the COVID-19 pandemic.
Randomisation
Each individual study is randomised employing a one-to-one allocation ratio. At randomisation each participant is assigned to nebulised unfractionated heparin or standard care. For analysis, randomisation will be stratified at the individual study level.
Interventions
Participants assigned to “nebulised UFH” will receive nebulised UFH in addition to the standard care required as determined by the treating team. Participants assigned to “standard care” will receive the standard care required as determined by the treating team and willnot be treated with nebulised heparin.
Outcome definitions