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