key: cord-0914902-49a22b9h
authors: Fally, Markus; Mathioudakis, Alexander G.; Digby, James Wingfield; Williamson, Paula R.
title: Outcomes assessed in therapeutic randomised controlled trials in hospitalised patients with COVID-19: is the meta Core outcome set (meta-COS) adopted?
date: 2021-11-23
journal: Clin Microbiol Infect
DOI: 10.1016/j.cmi.2021.11.017
sha: ddb8bb24603949bcae96e053062c5d1f8384c502
doc_id: 914902
cord_uid: 49a22b9h

nan

in meta-analyses (MA) and the development of solid treatment recommendations. 2,3 18

To homogenise RCT outcomes, Core Outcome Sets (COS) have previously been developed for many diseases. A COS is 19 a minimum set of outcomes to be measured in all trials in a specific healthcare area. 4 A research collaboration that 20 focussed on COS methodology throughout the past decade is the Core Outcome Measures in Effectiveness Trials 21 (COMET) Initiative. Following a distinct methodology, the COS development comprises: (1) a systematic review to 22 identify outcomes measured in previous trials; (2) qualitative studies to identify outcomes considered important by 23 patients and caregivers; (3) Delphi surveys distributed to patients, caregivers, and other stakeholders, aiming to 24 prioritise the outcomes and (4) consensus meetings involving patients, caregivers, and other stakeholders to finalise 25 the COS. 4 26 From February to March 2020, four COS for trials in patients with COVID-19 were registered in the COMET database 27 and subsequently published. As each of these sets had different scopes, the COMET Initiative sought to define a meta-28 COS covering the most crucial outcome variables across the COS. The overlapping outcomes all authors of the COS 29 agreed upon were mortality and respiratory support and the meta-COS has been published in its final version on 15 30

April 2020 (https://www.comet-initiative.org/assets/downloads/COVID-19 meta COS_Table 1_15th March 2021.pdf). 31

In early COVID-19 RCTs (January to April 2020), the uptake of the meta-COS was 49%. 1 In the present review, we 32 investigated the uptake of the meta-COS in the scientific community by reviewing the protocols for ongoing or planned 33

RCTs registered on clinicaltrials.gov between January and August 2021. We searched the database on 2 September 34 2021 and selected interventional trials, excluding phase 1 and 2 trials. 35

We identified 839 studies which were screened independently for eligibility by three authors. Of these studies, 137 36 (16%) were eligible for this review. Altogether, 702 studies were excluded -104 due to being diagnostic/not 37 interventional, 103 due to targeting outpatients, one due to targeting children, 494 due to not targeting COVID-19 38 (160 not targeting COVID-19 at all, 212 prevention studies, 28 studies on COVID-19 complications, 94 studies on only on mortality and 7 studies (5%) only on respiratory support. Twenty-three (17%) studies report neither mortality 42 nor respiratory support. Of the 98 studies reporting both outcomes, 70 report respiratory support in a complete 43 manner (i.e., all types of support ranging from oxygen by mask/nasal cannula to extra-corporeal membrane 44 oxygenation) and 28 report only selected, often site-specific aspects of respiratory support. 45

Fifty-seven of the 137 eligible studies use an ordinal scale of clinical status to measure the outcomes, ranging from 5-46 point scales to 11-point scales (Table 1) . Thirty-one studies refer specifically to one of the World Health Organization 47 (WHO) scales, four studies use scales published by other societies and 22 use a scale of unspecific origin. 48

Compared to earlier COVID-19 trials, considerably more studies report on the meta-COS outcomes in general. 49

However, there is considerable variation regarding timepoints of outcomes measurement (range 0 days to 365 days, 50 Table 1 ) and the used measurement instruments. This can potentially jeopardise future attempts to perform MA in a 51 reasonable fashion, as both outcomes may vary significantly over time in lower respiratory tract infection, and because 52 the often-used ordinal scales show some variation as well. As MA are often the foundation for solid treatment 53 recommendations, these issues will have impacts on clinical practice guidelines and, ultimately, patient outcomes. 54

The found heterogeneity probably originates in: (1) the quantity of research published for COVID-19, making it difficult 55 for researchers to keep up with the latest recommendations; (2) the unawareness of the existence of COS/meta-COS; 56

(3) and the lack of validated instruments for outcome measurement. Mortality and respiratory support are vague 57 terms if not explained further. Right now, only one of the COS clearly defined mortality to be measured at discharge 58 or day 60. 5 This was also the COS that ultimately defined the latest 10-point ordinal score of disease progression. 5 59

We interpreted the recorded data on clinicaltrials.gov to be the full study protocol. This is probably the main limitation 60 of our review, as it has been shown previously that not all protocol data is registered in this database. Furthermore, 61 we did not incorporate RCTs registered on other platforms. While these studies are missing in our analyses, we still 62 believe that we have captured a globally representative sample of studies. 63

To make it easier to perform MA and systematic reviews for interventions in patients hospitalised with COVID-19 in 64 the future, we strongly recommend using the suggested meta-COS in all planned RCTs. Given the results of our review, 65 we believe that further recommendations are needed on specific timepoints for measuring the prioritised outcomes The present work is a methodological systematic review accessing, processing and analysing data from the publicly 74 accessible database clinicaltrials.gov. Hence, no patient data were processed. Patient consent and/or registration via 75 human research ethics committees were, therefore, not relevant. 76 

Outcomes Evaluated in Controlled Clinical Trials on the 85

Management of COVID-19: A

The authors have nothing to disclose. 72