# Long-term (180-Day) Outcomes in Critically Ill Patients with COVID-19 in the REMAP-CAP Randomized Clinical Trial

Alisa M. Higgins, Lindsay R. Berry, Elizabeth Lorenzi, Srinivas Murthy, Zoe

K. Mcquilten, Paul R. Mouncey, Farah Al-Beidh, Djillali Annane, Yaseen M.

Arabi, Abigail Beane, et al.

► To cite this version:

Alisa M. Higgins, Lindsay R. Berry, Elizabeth Lorenzi, Srinivas Murthy, Zoe K. Mcquilten, et al. Long-term (180-Day) Outcomes in Critically Ill Patients with COVID-19 in the REMAP-CAP Randomized Clinical Trial. Journal of the American Medical Association, 2023, 329 (1), pp.39-51. 10.1001/jama.2022.23257. hal-03949589

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# Long-term (180-day) outcomes in critically ill patients with COVID-19 in the REMAP-CAP randomized clinical trial

The REMAP-CAP Investigators*

*Author and Group Information

The members of the writing committee appear at the end of the main text and the full list of investigators and collaborators in the Supplementary Appendix.

## Running Head

180-Day Outcomes in the REMAP-CAP COVID-19 RCT

## Key words

Adaptive platform trial; randomized controlled trial; intensive care, pneumonia; COVID-19; antiplatelet; immunoglobulin; antiviral; corticosteroid; immune modulation; anticoagulation

Word count 4170

Date of Revision 25 November 2022

## Corresponding Author

Dr Alisa M Higgins

Email: lisa.higgins@monash.edu; Tel: +61 400658694

Address: ANZIC-RC, School of Public Health and Preventive Medicine, Monash University, 553 St Kilda

Rd, Melbourne 3004, Australia
# Key points

## Question

What is the effect of treatment for critically ill patients with COVID-19 on longer-term mortality, disability and health-related quality of life (HRQoL)?

## Findings

In this Bayesian adaptive randomized clinical platform trial that included 4869 critically ill patients with COVID-19, the probability was high that interleukin-6 receptor antagonists and antiplatelet agents improved survival at 6 months (posterior probabilities of superiority >99.9% and 95.0%). Long-term outcomes were not improved with therapeutic anticoagulation (11.5%), convalescent plasma (54.7%), or lopinavir-ritonavir (31.9%), and were worsened with hydroxychloroquine (posterior probability of harm 96.8%). Corticosteroids did not improve long-term outcomes, although enrollment had been terminated early in response to external evidence.

## Meaning

Among critically ill patients with COVID-19 randomized to receive one or more therapeutic interventions, there was a high likelihood of improved 180-day mortality among patients treated with IL-6 receptor antagonists and antiplatelets.
# Abstract

**IMPORTANCE** The longer-term effects of therapies for the management of critically ill patients with COVID-19 are unknown.

**OBJECTIVE** To determine the effect of multiple interventions for critically ill adults with COVID-19 on longer-term outcomes.

**DESIGN, SETTING AND PARTICIPANTS** Pre-specified secondary analysis of an ongoing adaptive platform trial (REMAP-CAP) testing interventions within multiple therapeutic domains, in which 4869 critically ill adult patients with COVID-19 were enrolled between 9 March 2020 and 22 June 2021 from 197 sites in 14 countries. The final day-180 follow up was completed on 2 March 2022.

**INTERVENTIONS** Patients were randomized to one or more interventions within six treatment domains – immune modulators (n=2274), convalescent plasma (n=2011), antiplatelet therapy (n=1557), anticoagulation (n=1033), antivirals (n=726), and corticosteroids (n=401).

**MAIN OUTCOMES AND MEASURES** The main outcome was survival through day 180, analyzed using a Bayesian piecewise exponential model. A hazard ratio (HR)<1 represented improved survival (superiority), while a HR>1 represented worsened survival (harm); futility was represented by a <20% relative improvement in outcome shown by a HR>0.83 (1/1.2).

**RESULTS** Among 4869 patients who were randomized (mean age, 59.3 years; 1537 (32.1%) females), 4107 (84.3%) had known day 180 vital status and 2590 (63.1%) were alive. Interleukin-6 receptor antagonists and antiplatelet agents had a >99.9% and 95.0% probability of improving 6-month survival compared with control (adjusted hazard ratios [HR]
0.74 [95% CrI 0.61-0.90] and 0.85 [0.71-1.03]), while the probability of trial-defined statistical futility (HR >0.83) was high for therapeutic anticoagulation (99.9%, HR 1.13 [95% CrI 0.93-1.42], convalescent plasma (99.2%, HR 0.99 [95% CrI 0.86-1.14]), and lopinavir-ritonavir (96.6%, HR 1.06 [95% CrI 0.82-1.38]), and the probability of harm from hydroxychloroquine and the combination of lopinavir-ritonavir and hydroxychloroquine was high (96.9% and 96.8%, HR 1.51 [95% CrI 0.98-2.29] and 1.61 [95% CrI 0.97-2.67]). The corticosteroid domain was stopped early, prior to reaching a predefined statistical trigger; there was a 57.1% to 61.6% probability of improving 6-month survival across varying hydrocortisone dosing strategies.

**CONCLUSIONS AND RELEVANCE** Among critically ill patients with COVID-19 randomized to receive one or more therapeutic interventions, treatment with an IL-6 receptor antagonist had a >99.9% probability of improved 180-day mortality compared with patients randomized to control, and treatment with an antiplatelet had a 95.0% probability of improved 180-day mortality compared with patients randomized to control. Overall, when considered with previously reported short-term results, the findings indicate that initial in-hospital treatment effects were consistent for most therapies through 6 months.
# Introduction

Randomized clinical trials in critically ill patients, including those with COVID-19, typically assess short-term outcomes such as organ failure or 28-day mortality, with fewer published trials assessing whether treatments affect long-term survival and patient-centered outcomes such as disability and health-related quality of life (HRQoL). Longer-term survival free of major disability and with an acceptable HRQoL may be more important to patients than short-term survival.¹,² The World Health Organization and others have called for additional research on the effect of initial therapeutic interventions on longer-term outcomes.³

The Randomized Embedded Multifactorial Adaptive Platform for Community Acquired Pneumonia (REMAP-CAP) trial is an ongoing international, multicenter, randomized platform trial evaluating multiple treatments for patients with severe pneumonia in both pandemic and non-pandemic settings (NCT02735707) (Supplement 1).⁴ To date, the trial has reported results for six treatment domains for patients with COVID-19—corticosteroids, antivirals, immune modulators, immunoglobulin, anticoagulation and antiplatelet therapy.⁵⁻¹⁰ The trial primary outcome for patients with COVID-19 is the composite of hospital survival and organ support provision up to 21 days. The trial reported benefit on this primary outcome for interleukin-6 receptor antagonists (immune modulators), but not for antivirals, anakinra (immune modulator), convalescent plasma (immunoglobulin), therapeutic anticoagulation (in critically ill patients), or antiplatelet therapies.⁶⁻¹⁰ The corticosteroid domain was closed early on the basis of external evidence but a moderate probability of benefit was observed.⁵

Whether these initial treatment effects translate into effects on longer-term survival, disability and HRQoL is unknown. The objective of this study was to report on the effects of these treatments on pre-specified longer-term outcomes including mortality, disability and
HRQoL at 6 months for patients randomized to one or more of the reported domains in the trial.

# Methods

## Trial Design and Oversight

The design of REMAP-CAP has been reported previously.<sup>4-10</sup> In brief, patients are assessed for eligibility and potentially randomized to one or more interventions across multiple treatment domains. Domains encompass therapeutic areas and contain two or more interventions (including control). The trial enrolls both critically ill and non-critically ill patients in separate severity states, and distinct group-specific effects are estimated. This report includes only critically ill patients as follow up beyond 90 days does not include non-critically ill patients.

The trial was approved by relevant regional ethics committees and conducted in accordance with Good Clinical Practice guidelines and the principles of the Declaration of Helsinki.

Written or verbal informed consent, in accordance with local legislation, was obtained from patients or their substitute decision maker.

## Participants

Adult patients (aged ≥18 years) admitted to an ICU with clinically suspected or microbiologically confirmed COVID-19, and receiving respiratory or cardiovascular organ support, were eligible for enrollment. Patients had to be enrolled within 48 hours of admission to ICU. Exclusion criteria along with additional inclusion and exclusion criteria for each domain are shown in Table S1.<sup>5-10</sup> Patients were enrolled from 197 sites in 14 countries
(Table S2). In view of racial and ethnic differences in outcomes during the pandemic, this trial collected self-reported race and ethnicity from either the participants or their surrogates via fixed categories appropriate to their region, where ethical approval allowed. Collection of race and ethnicity data was not approved in Asia, Canada, and continental Europe.

## Treatment Allocation

Patients were randomized via a centralized computer program with allocation ratios dependent on response adaptive randomization and the number of interventions available at each site. The interventions within each domain, including timing and doses, are reported previously.⁵⁻¹⁰ In brief, patients in the corticosteroid domain were randomized to receive a fixed 7-day course of intravenous hydrocortisone, a shock-dependent course, or no corticosteroid; patients in the immune modulation domain were randomized to receive tocilizumab, sarilumab (both interleukin-6 receptor antagonists [IL-6 RAs]), anakinra (an interleukin-1 receptor antagonist), interferon-β1a, or no immune modulator; patients in the antiviral domain were randomized to receive lopinavir-ritonavir, hydroxychloroquine, the combination of both therapies, or no antiviral; patients in the immunoglobulin domain were randomized to receive 2 units of high-titer, ABO-compatible convalescent plasma, delayed convalescent plasma (given if clinical deterioration, only available in the US), or no convalescent plasma; patients in the anticoagulation domain were randomized to receive therapeutic-dose anticoagulation with heparin or pharmacologic thromboprophylaxis in accordance with local usual care; and patients in the antiplatelet domain were randomized to receive aspirin, a P2Y12 inhibitor (clopidogrel, prasugrel, orticagrelor), or no antiplatelet therapy. Patients could be randomized to additional interventions within other domains, depending on domains active at the site, patient eligibility, and consent (see
www.remapcap.org).⁴ Other aspects of care were provided as per each site's standard of care.

## Outcome Measures

The main outcome for this prespecified secondary analysis of longer-term outcomes was all-cause mortality within 6 months (day 180 after randomization), a prespecified secondary outcome in the REMAP-CAP core protocol. This was modelled as a time to event outcome for this analysis. Additional secondary outcomes were prespecified in the Core Protocol and included day 90 mortality, HRQoL at day 180 measured using the EQ-5D-5L utility score and visual analogue score (VAS), and disability at day 180, measured using the 12-item World Health Organization Disability Assessment Schedule (WHODAS) 2.0. The EQ-5D-5L is a preference-based HRQoL instrument comprised of five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The EQ-5D-5L utility score is calculated from the individual response to each item and ranges from -0.593 (where a score of 0 is equivalent to death, negative values representing values as worse than dead) to 1.00 (the value of full health), with higher values indicating better health states.¹¹ An EQ-5D-5L utility score of 0 was imputed for all patients known or imputed to be deceased at Day 180. For the EQ VAS, respondents are asked to indicate their present health state on a visual analogue scale ranging from the worst imaginable health state ("0") to the best imaginable health state ("100").¹²,¹³ The EQ-5D-5L utility score and EQ VAS have no established minimal clinically important difference among critically ill patients. The WHODAS 2.0 covers six domains of functioning with scores for each item from 0 (no difficulty) to 4 (extreme difficulty) and a total score ranging from 0 to 48, with higher scores representing greater disability.¹⁴ The total score is divided by 48 and multiplied by 100 to convert it to a percentage of maximum
disability, with the percent score used to determine five mutually exclusive disability
categories, from no disability to complete disability. ¹⁵ The MCID for the WHODAS in critically
ill patients is 10%. ¹⁶

Day 90 mortality was collected at all sites, whereas day 180 outcomes were collected only by a subset (174/197, 88.3%) of sites. The decision to participate in the collection of longer-term outcomes was made regionally or locally reflecting funding, regulatory approval, and site resource availability. In the UK, the large numbers of recruited participants from 5 January 2021 to 25 February 2021 exceeded the capacity for extended follow-up of all patients within the required time window. Accordingly, at the time, a subset of participants was randomly selected not to be followed-up. Overall, 587/787 (74.6%) survivors enrolled during this period were followed through 6 months.

Survival status was assessed at days 90 and 180 and determined using medical records, or
contact with the participant, their next of kin, or other healthcare professional. Where a
participant was deceased, the date of death was recorded. Day 180 HRQoL and disability in
survivors were collected by central trial staff or site staff by telephone, with the patient or a
proxy where the patient was not available. EQ-5D-5L utility scores were calculated using the
crosswalk link function and the individual responses to the EQ-5D-5L descriptive system,
using the UK time trade off (TTO) value set.¹¹ EQ-5D-5L and WHODAS scores were only
included when the questionnaire was completed within the 12 weeks following day 180
(additional details in Supplemental Methods).

**Statistical Analysis**
This study reports the analysis of longer-term secondary outcomes prespecified in the REMAP-CAP trial Core Protocol (Supplement 1). The analysis plan for evaluating these outcomes was finalized in a Statistical Analysis Plan (Supplement 1) on 10th March 2022, prior to unblinding the day 180 outcomes. All patients were analyzed in the groups to which they were originally randomized. The full analysis set included all critically ill patients with suspected or proven COVID-19 randomized to an intervention in one or more of the six domains which have been closed and reported, excluding patients who had withdrawn consent. For consistency with the original analyses,⁵⁻¹⁰ the P2Y12 inhibitor and aspirin groups are reported as a pooled antiplatelet group, and the tocilizumab and sarilumab groups as a pooled IL-6 RA group, given that both sets of interventions reached the prespecified definition of equivalence on organ support-free days in the original analysis. Due to the low number of patients randomized, the interferon-beta-1a group within the immune modulation domain and the delayed convalescent plasma intervention within the immunoglobulin domain were not analyzed.

The primary analysis was performed using a Bayesian piecewise exponential model. The underlying hazard rate was piecewise constant for each 15-day period up to day 90 and the 90-day period from day 90 to 180. The prior distribution for each hazard rate was a gamma distribution with 1 day of exposure and a mean equal to the total exposure (in days) divided by the total number of events. The primary model estimated treatment effects (log HRs) for each intervention relative to control within each domain with standard normal priors. The primary model included variables for each domain with each domain treatment as a category (with control interventions from each domain set as the referent) and was adjusted for location (site nested within country), patient age (categorized into 6 groups), sex, and time-
period (2-week epochs). The posterior distributions of the interventions' hazard ratios (HR)
was summarized with medians, 95% credible intervals (CrIs) and the probability that an
intervention was superior to the control for that domain (i.e. a HR less than 1.0). Harm was
defined as the probability the HR was greater than 1. Futility was defined as the probability
that there was not more than a 20% relative improvement in outcome (HR>0.83 or 1/1.2). A
pre-specified interaction was modelled between antiplatelet therapy (pooled P2Y12 inhibitor
and aspirin group) in the antiplatelet domain and therapeutic-dose heparin in the
anticoagulation domain. Statistical thresholds based on posterior probabilities for superiority
and harm were used for the primary outcome to determine trial stopping rules but not used
to guide interpretation of other findings; rather, effect sizes along with posterior probabilities
are presented for all analyses.

Day 90 mortality was analyzed with a Bayesian logistic regression model. The EQ-5D-5L utility
score was analyzed with a two-part/mixture model including two components: 1) a
continuous distribution of EQ-5D-5L utility scores for patients who survived to day 180, and
2) a point mass at 0 for patients who died before day 180. The posterior distributions of the
mean difference between treatment and control for EQ-5D-5L utility scores were
summarized with medians, 95% CrIs and the probability that an intervention was superior to
the control for that domain (i.e. a mean difference less than 0). Treatment effects were
estimated for all patients, along with estimates for survivors only. The EQ VAS was reported
using descriptive statistics only. The WHODAS disability category was analyzed with a two-
part/mixture model including two components: 1) an ordinal model of disability category for
patients that survived to day 180, and 2) the worst category of "death" for patients that died
before day 180. Similarly, the posterior distributions of the interventions' odds ratio (OR) for
WHODAS disability category for survivors were summarized with medians, 95% CrIs and the probability that an intervention was superior to the control for that domain (i.e. an OR less than 1). The EQ-5D-5L utility score and WHODAS category were multiply imputed as a function of the patient's covariates for patients censored alive before day 180 or missing the HRQoL outcome. Sampling was from all patients enrolled in the timeframe and the sampling probability was independent of treatment assignment. The relationship between shorter- and longer-term endpoints was assessed by plotting the OSF D OR versus Day 180 mortality HR for each intervention and reporting the coefficient of determination (R²).

Sensitivity analyses for the main outcome included, 1) excluding patients with negative SARS-CoV-2 testing, 2) removing adjustments for assignments in other domains and 3) estimating independent effects of the two interleukin-6 receptor antagonist interventions and the two antiplatelet interventions. For secondary outcomes, sensitivity analyses included no imputation of missing EQ-5D-5L utility and WHODAS scores. Post hoc sensitivity analyses were conducted to evaluate the main outcome model and robustness to model assumptions, including 1) the assumption of proportional hazards for treatment effects; 2) the assumption of a parametric distribution of survival times (piecewise exponential); and 3) the use of prior distributions in the Bayesian framework (Supplemental Methods).

Two subgroup analyses were performed stratifying treatment effects on day 180 mortality based on the binary categories of receipt of invasive mechanical ventilation at baseline and pre-existing immunosuppression. Further details of all analyses are provided in the Statistical Analysis Plan in Supplement 1. Data management and summaries were created using R version 3.6.0, with the primary analysis computed in R version 4.1.2 using the rstan package
version 2.21.1. Additional data management and analyses were performed in SQL 2016, and
Stata version 17.0.

## Results

### Enrollment and Participant Characteristics

A total of 4869 patients were enrolled from 9 March 2020 through 24 June 2021 to one or more of the six reported domains in the trial. Seventy-eight patients withdrew consent, resulting in 4791 patients included in the analysis of longer-term outcomes (Figure 1). Of these, 473 were randomized at 19 sites that only participated in the 90-day follow-up, including all sites in Nepal, India, and the United States. Details of recruitment and follow up by country of enrollment are shown in Table S2. The final day 180 follow up was completed on 2 March 2022. The baseline characteristics of the included patients are shown in Table 1. Baseline characteristics by intervention within each domain are shown in Tables S3 to S8.

### Main Outcome

Of the 4318 patients randomized at sites participating in day 180 follow-up, day 180 mortality status was available for 4107 (95.1%) patients. Patients with known day 180 mortality status differed from those with unknown status; patients with unknown status were younger, had higher frequencies of non-invasive ventilation receipt at baseline, lower frequencies of invasive mechanical ventilation and vasopressor use at baseline, lower APACHE II scores, and were less likely to have prevalent asthma or COPD, immunosuppressive disease, or to be receiving chronic immunosuppressive therapy (Table
S9). Of patients with known day 180 mortality status, 1517 (36.9%) patients had died. (Table 2 and Figure 2) Of patients who died by day 180, 6.0% (91/1516) of deaths occurred between hospital discharge and day 180. The pooled interleukin-6 receptor antagonists and anti-platelet treatment groups each had a high probability of benefit (>99.9% and 95.0% respectively) compared with their control groups. The probability of benefit for fixed dose corticosteroids and shock-dependent corticosteroids compared to no corticosteroids was 61.6% and 57.1%, respectively. The probability of trial-defined statistical futility was high for therapeutic anticoagulation in the critically ill (99.9%, HR 1.13 [95% CrI 0.93-1.42]), convalescent plasma (99.2%, HR 0.99 [95% CrI 0.86-1.14]), and lopinavir-ritonavir (96.6%, HR 1.06 [95% CrI 0.82-1.38]). Hydroxychloroquine and its combination with lopinavir-ritonavir had a high probability of harm (96.9% and 99.5%, HR 1.51 [95% CrI 0.98-2.29] and 1.61 [95% CrI 0.97-2.67] respectively) (Table 2 and Figure S1). Results of the sensitivity analyses for non-negative COVID patients and in domain-specific populations were consistent with the primary analysis (see Tables S10 to S12 and Figure S2). Post hoc sensitivity analyses found the results were robust to model assumptions including the proportional hazards assumption (Figures S3-S4 and Model Evaluation Report in the supplement). Across interventions there was a strong association (R² = 0.84) between the ORs for the composite of in-hospital mortality and organ support free days to day 21 (primary outcome in the trial) and the reciprocals of day 180 mortality hazard ratios (Figure S5).

## Secondary Outcomes

The ORs for day 90 mortality are shown in Table S13 and Figure S6. Results were consistent with the day 180 mortality analysis.
Of the 2589 survivors at sites participating in follow up, the EQVAS was available in 1009 patients (39.0%), the EQ-5D-5L utility score in 989 patients (38.2%), and the WHODAS in 720 patients (27.8%) (Figure 1). Patients without EQ-5D-5L utility and WHODAS scores differed from those with scores - patients missing scores were younger; received less high-flow nasal oxygen and more non-invasive and invasive ventilation, and were less likely to have immunosuppressive disease or be receiving chronic immunosuppressive therapy (Tables S14 and S15).

In the overall cohort, the median (IQR) EQ-5D-5L utility score in survivors was 0.74 (0.55 to 0.88; n=989). The median (IQR) EQ VAS score was 75 (50 to 85; n=1009). The proportion of patients reporting problems in each domain and the EQ VAS scores are shown in Tables S16 and S17. Among survivors, the adjusted mean difference (95% CrI) in the EQ-5D-5L utility score in the pooled antiplatelet group was 0.08 (0.00 to 0.15) higher compared with control, with a posterior probability of superiority of 97.4%, while among all patients (survivors and non-survivors) the adjusted mean difference (95% CrI) was 0.08 (0.02 to 0.13) with a probability of superiority of 99.6% (Table 3). Among all patients, the adjusted mean difference in the pooled IL-R RAs was 0.08 (0.02 to 0.13) higher compared with control, with a posterior probability of 99.5%. The mean EQ-5D-5L utility score in the lopinavir-ritonavir group was lower than the control group, with a posterior probability of harm of 98.7% among survivors, and 98.4% among all patients. The mean difference in EQ-5D-5L utility scores between each remaining intervention and their control group are shown in Table 3 and Figure S7.

Disability in survivors is shown in Tables S18 and S19. 37.9% (273/720) of survivors had moderate, severe, or complete disability at day 180. The 95% CrIs for the ORs for WHODAS
disability category were wide, with intervals crossing 1 for all interventions (Figure S8).

Among these interventions, pooled interleukin-6 receptor antagonists and anakinra had a
92.6% and 90.8% probability of reducing disability and lopinavir-ritonavir had a 91.7%
probability of worsening disability.

Results for the sensitivity analyses of the EQ-5D-5L utility score and WHODAS without imputation for missing scores were consistent with the imputed analysis (Tables S20-S21).

## Subgroup Analyses

Treatment effects on day 180 mortality did not meaningfully vary by invasive mechanical ventilation status at baseline (Tables S22-S23 and Figure S9). In patients with immunodeficiency at baseline, therapeutic anticoagulation and antiplatelet therapy had posterior probabilities of worsened day 180 mortality of 98.8% and 92.4% (Table S24-S25 and Figure S10).

## Discussion

In this prespecified secondary analysis of a Bayesian adaptive randomized clinical platform trial that included 4791 critically ill patients with COVID-19, there was a >99.9% and 95.0% probability that interleukin-6 receptor antagonists and antiplatelet agents improved survival through 6 months respectively. In contrast, survival was not improved with therapeutic anticoagulation, convalescent plasma, or lopinavir-ritonavir, and the probability that survival was worsened with hydroxychloroquine alone or in combination with lopinavir-ritonavir was 96.8%. Corticosteroids did not confer a high probability of improved longer-term survival, but enrollment into this domain was closed early in response to external evidence which may
limit statistical power to detect any potential effect. Although the majority of deaths occurred early, 6% of all deaths occurred between hospital discharge and day 180.

Interventions are delivered in critically ill patients with the goal of increasing long-term survival as well as improving HRQoL and functional status in survivors. However most clinical trials in critically ill patients have evaluated shorter-term outcomes, many of which may not be patient-centered.¹⁷ Longer-term trajectories after critical illness, including acute respiratory distress syndrome (ARDS) and sepsis, are characterized by frequent rehospitalization, sustained impairments in HRQoL and functional status, an excess hazard of mortality, and exacerbation of chronic comorbidities which may persist for years after initial hospitalization.¹⁸⁻²³ Patients who initially survive face later mortality and morbidity hazards that may offset potential benefits of treatment. Accordingly, the effect of many treatments administered in the ICU on long-term outcomes after critical illness—including COVID-19—remain uncertain. Although the REMAP-CAP trial evaluated a hospital-based primary outcome reflecting survival to discharge and, in survivors, receipt of ICU-level organ support, the protocol included the collection of longer-term (6-month) outcomes reflecting survival, HRQoL and disability. Overall, there was a strong correlation between the trial primary outcome and 6-month outcomes.

There was broad variation in 6-month HRQoL and disability scores. The majority of survivors reported favorable HRQoL and functional status, although approximately 1 in 3 patients had at least moderate disability that persisted through 6 months (although participants' baseline disability was not known). Interleukin-6 receptor antagonists, which improved organ support-free days, also had a >99.9% probability of improving survival over 6 months compared to no immune modulator. Furthermore, among survivors, there was an 87.0% probability of
improved HRQoL and 92.6% probability of reduced disability, suggesting that improvement in survival was not occurring at the expense of poor-quality survival. Although antiplatelet agents did not improve the organ support-free days outcome, they had a 92.3% and 95.0% probability of improved day 90 and day 180 survival, and a 97.4% probability of improved HRQoL in survivors at 6 months. When death and HRQoL were evaluated as a composite, the probability of superiority was 99.6%.

Although there was a 93% probability that fixed dose hydrocortisone improved organ support-free days, no early or late effect on survival was observed. Other treatments that did not improve organ support-free days, including therapeutic anticoagulation, convalescent plasma, lopinavir-ritonavir, and hydroxychloroquine, were similarly ineffective in improving longer-term outcomes. Overall, there was a strong correlation between organ support-free days and longer-term outcomes in critically ill patients with COVID-19.

To the best of our knowledge this is the largest trial that has reported on the effect of treatments for COVID-19 on longer-term mortality, HRQoL and disability in critically ill patients. The HRQoL and disability outcomes in this trial are similar to observational cohort reports of critically ill survivors of COVID-19,²⁴⁻²⁶ and similar to both observational and trial cohorts of critically ill patients prior to the pandemic.²⁴,²⁷,²⁸ Although there do not appear to be large effects of ICU-based treatments on either HRQoL or disability, it is encouraging that overall increases in longer-term survival are not accompanied by a decrement in HRQoL or increased disability. There is a theoretical risk that a treatment that saves lives amongst critically ill patients may convert non-survivors into survivors who have poor quality of survival. A recent systematic review evaluating HRQoL in randomized trials reporting a survival benefit in critically ill patients found only 2.9% of studies reporting a significant
reduction in mortality also reported on HRQoL.²⁹ Of those trials reporting HRQoL, results were inconsistent, with 2 studies reporting improvements in both survival and HRQoL, 3 reporting no difference in HRQoL in survivors, and 2 reporting lower HRQoL in survivors.²⁹

The present study demonstrates that the improved survival associated with interleukin-6 receptor antagonists and antiplatelet agents does not result in a lower HRQoL in survivors.

Given the global effect of COVID-19, small differences in mortality or other patient-centred outcomes such as HRQoL and disability can result in important clinical and health economic benefits at the population level, particularly in a global pandemic.

## Limitations

This study has several limitations. First, the trial used an open-label design, although the mortality outcome is at a lower risk for bias. Second, the collection of outcomes beyond day 90 was not mandated although 6-month survival status was available for 85.7% of patients. Not all regions and sites collected HRQoL and disability outcomes and there was a substantial amount of missing data for these outcomes. Bayesian multiple imputation techniques were used to account for missing data and sensitivity analyses without imputation did not meaningfully change the results. Third, HRQoL and disability scores could not be collected at baseline while patients were critically ill, and therefore this trial could not assure balance across randomization groups, nor could this trial evaluate change in score over time. As such, it is possible that differences in HRQoL or disability may have been due to imbalances in these measures at baseline, although randomization and temporal and site adjustment in the models would have been expected to balance these across the treatment arms. Fourth, the results relate to the effectiveness of interventions on prior variants of COVID-19 and prior to
widespread availability of vaccination, and the effectiveness on newer variants and vaccinated patients is unknown. Further study is needed to determine whether the observed impacts are sustained through different waves of the pandemic.

## Conclusions

Among critically ill patients with COVID-19 randomized to receive one or more therapeutic interventions, treatment with an IL-6 receptor antagonist had a >99.9% probability of improved 180-day mortality compared with patients randomized to control, and treatment with an antiplatelet had a 95.0% probability of improved 180-day mortality compared with patients randomized to control. Overall, when considered with previously reported short-term results, the findings indicate that initial in-hospital treatment effects were consistent for most therapies.
**Article Information**

**Authors/Members of the Writing Committee**

Alisa M. Higgins, Ph.D. ¹; Lindsay R. Berry, Ph.D. ²; Elizabeth Lorenzi, Ph.D. ²; Srinivas Murthy, M.D. ³; Zoe McQuilten, Ph.D. ¹,⁴; Paul R. Mouncey, M.Sc. ⁵; Farah Al-Beidh, Ph.D. ⁶; Djillali Annane, M.D., Ph.D. ⁷,⁸; Yaseen M. Arabi, M.D. ⁹; Abi Beane, Ph.D. ¹⁰; Wilma van Bentum-Puijk, M.Sc. ¹¹; Zahra Bhimani, M.P.H. ¹²; Marc J.M. Bonten, M.D., Ph.D. ¹¹; Charlotte A. Bradbury, M.D., Ph.D. ¹³; Frank M. Brunkhorst, M.D., Ph.D. ¹⁴; Aiden Burrell, M.B.B.S., Ph.D. ¹; Adrian Buzgau, M.Sc. ¹; Meredith Buxton ¹⁵; Walton N. Charles, M.B.B.S. ⁵; Matthew Cove, M.B.B.S. ¹⁶; Michelle A. Detry, Ph.D. ²; Lise J. Estcourt, M.B.B.Ch., Ph.D. ¹⁷; Elizabeth O Fagbodun, M.Sc. ⁶; Mark Fitzgerald, Ph.D. ²; Timothy D. Girard M.D. M.S.C.I. ¹⁸; Ewan C. Goligher, M.D. Ph.D. ¹⁹,²⁰; Herman Goossens, Ph.D. ²¹; Rashan Haniffa, Ph.D. ²²,²³; Thomas Hills, M.B.B.S., Ph.D ²⁴,; Christopher M. Horvat, M.D. ²⁵; David T. Huang M.D., M.P.H. ¹⁸; Nao Ichihara, M.D, M.P.H, Ph.D. ²⁶; Francois Lamontagne, M.D. ²⁷; John C. Marshall, M.D. ¹²; Daniel F. McAuley, M.D. ²⁸,²⁹; Anna McGlothlin, Ph.D. ²; Shay P. McGuinness, M.D. ¹,³⁰; Bryan J. McVerry, M.D. ¹⁸; Matthew D. Neal M.D. ¹⁸; Alistair D. Nichol, M.D., Ph.D. ¹,³¹; Rachael L. Parke, Ph.D. ³⁰,³²; Jane C. Parker, B.N. ¹; Karen Parry-Billings, M.Sc. ⁵; Sam E.C. Peters, B.Arch. ⁵; Luis F. Reyes, M.D, Ph.D. ³³,³⁴; Kathryn M. Rowan, Ph.D. ⁵; Hiroki Saito, M.D., M.P.H. ³⁵; Marlene S. Santos, M.D., M.S.H.S. ¹²; Christina T. Saunders, Ph.D. ²; Ary Serpa-Neto Ph.D. M.Sc., M.D. ¹,³⁶; Christopher W. Seymour, M.D., M.Sc. ¹⁸; Manu Shankar-Hari, M.D., Ph.D. ³⁷,³⁸; Lucy M Stronach, B.Sc. ⁶; Alexis F. Turgeon, M.D., M.Sc. ³⁹,⁴⁰; Anne M. Turner, M.P.H. ²⁴; Frank L. van de Veerdonk, M.D., Ph.D. ⁴¹; Ryan Zarychanski, M.D., M.Sc. ⁴²; Cameron Green, M.Sc. ¹; Roger J. Lewis, M.D., Ph.D. ²,⁴³; Derek C. Angus, M.D., M.P.H. ¹⁸; Colin J. McArthur, M.D. ³⁰; Scott Berry, Ph.D. ²; Lennie P.G. Derde, M.D., Ph.D. ¹¹; Anthony C. Gordon, M.B.B.S., M.D. ⁶,⁴⁴*
Steve A. Webb, M.D., Ph.D. ¹,⁴⁵*; and Patrick R. Lawler, M.D., M.P.H. ¹⁹,²⁰* for The REMAP-CAP
Investigators

*Joint last author

**Affiliations of Authors/Members of the Writing Committee**

1. Monash University, Melbourne, Australia

2. Berry Consultants, Austin, Texas, United States

3. University of British Columbia, Vancouver, Canada

4. Monash Health, Melbourne, Australia

5. Intensive Care National Audit & Research Centre (ICNARC), London, United Kingdom

6. Imperial College London, London, United Kingdom

7. Hospital Raymond Poincaré (Assistance Publique Hôpitaux de Paris), Garches, France

8. Université Versailles SQY – Université Paris Saclay, Montigny-le-Bretonneux, France

9. King Saud bin Abdulaziz University for Health Sciences and King Abdullah International
Medical Research Center, Riyadh, Kingdom of Saudi Arabia

10. University of Oxford, Oxford, United Kingdom

11. University Medical Center Utrecht, Utrecht, The Netherlands

12. St. Michael's Hospital Unity Health, Toronto, Canada

13. University of Bristol, Bristol, United Kingdom

14. Jena University Hospital, Jena, Germany

15. Global Coalition for Adaptive Research

16. Yong Loo Lin Scholle of Medicine, National University Singapore, Singapore

17. NHS Blood and Transplant, Oxford, United Kingdom

18. University of Pittsburgh, Pittsburgh, PA, United States

19. Peter Munk Cardiac Centre at University Health Network, Toronto, Canada
20. University of Toronto, Toronto, Canada

21. University of Antwerp, Antwerp, Belgium

22. University of Oxford, Bangkok, Thailand

23. National Intensive Care Surveillance (NICST), Colombo, Sri Lanka

24. Medical Research Institute of New Zealand (MRINZ), Wellington, New Zealand

25. UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, United States

26. University of Tokyo, Japan

27. Université de Sherbrooke, Sherbrooke, Québec, Canada

28. Queen's University Belfast, Belfast, Northern Ireland

29. Royal Victoria Hospital, Belfast, Northern Ireland

30. Auckland City Hospital, Auckland, New Zealand

31. University College Dublin, Dublin, Ireland

32. University of Auckland, Auckland, New Zealand

33. Universidad de La Sabana, Chia, Colombia

34. Clinica Universidad de La Sabana, Chia, Colombia

35. St Marianna University School of Medicine, Yokohama City Seibu Hospital, Yokohama, Japan

36. Hospital Israelita Albert Einstein, Sao Paulo, Brazil

37. King's College London, London, United Kingdom

38. Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom

39. Université Laval, Québec City, Canada

40. CHU de Québec-Université Laval Research Center, Québec City, Canada

41. Radboud University Medical Center, Nijmegen, The Netherlands

42. University of Manitoba, Winnipeg, Canada
43. Harbor-UCLA Medical Center, Torrance, CA, United States

44. Imperial College Healthcare NHS Trust, St. Mary's Hospital, London, United Kingdom

45. St John of God Hospital, Subiaco, Australia

**Author contributions**

Dr Higgins had full access to all the data in the trial and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Drs Lawler, Webb and Gordon are joint last authors.

Concept and design: Higgins, Lawler, Gordon, Webb, L. Berry, Lorenzi, S. Berry

Acquisition, analysis or interpretation of the data: All authors

Drafting of the manuscript: Higgins, Lawler, Gordon, Webb, L. Berry, Lorenzi, Murthy

Critical revision of the manuscript for important intellectual content: All authors

Statistical analysis: Higgins, L. Berry, Lorenzi, S. Berry.

Obtained funding: Higgins, Rowan, Beane, Bhimani, Bonten, Buxton, Cove, Goligher, Goossens, Hills, Marshall, McGuinness, McQuilten, McVerry, Murthy, Nichol, Reyes, Rowan, Turgeon, Zarychanski, Angus, McArthur, Derde, Gordon, Webb, Lawler.

Administrative, technical, or material support: Higgins, Mouncey, Al-Beidh, McQuilten, Rowan, Arabi, Beane, van Bentum-Puijk, Bhimani, Bihari, Brunkhorst, Buzgau, Buxton, Cove, Estcourt, Girard, Horvat, Ichihara, McAuley, McGuinness, Montgomery, McVerry, Nichol,
Parker, Reyes, Santos, Seymour, Shankar-Hari, Turgeon, Turner, Zarychanski, Green, Lewis, Angus, McArthur, Derde, Gordon, Webb, Lawler.

Supervision: Bonten, Buxton, Estcourt, Girard, Lamontagne, Neal, Nichol, Reyes, Rowan, Saito, Shankar-Hari, Lewis, Angus, McArthur, S.Berry, Derde, Gordon, Webb, Lawler

**Conflict of Interest Disclosures**

See submitted ICMJE forms for declared potential conflict of interests.

**Funding/Support:**

The Platform for European Preparedness Against (Re-) emerging Epidemics (PREPARE) consortium by the European Union, FP7-HEALTH-2013-INNOVATION-1 (#602525), the Rapid European COVID-19 Emergency Research response (RECOVER) consortium by the European Union's Horizon 2020 research and innovation programme (#101003589), the Australian National Health and Medical Research Council (#APP1101719), the Australian Medical Research Future Fund (#APP2002132), the Health Research Council of New Zealand (#16/631), the Canadian Institute of Health Research Strategy for Patient-Oriented Research Innovative Clinical Trials Program Grant (#158584) and the Canadian Institute of Health Research COVID-19 Rapid Research Funding (#447335), the UK National Institute for Health Research (NIHR) and the NIHR Imperial Biomedical Research Centre, the Health Research Board of Ireland (CTN 2014-012), the UPMC Learning While Doing Program, the Translational Breast Cancer Research Consortium, the French Ministry of Health (PHRC-20-0147), the Wellcome Trust Innovations Project (215522), the Minderoo Foundation, the EU Programme Emergency Support Instrument, the NHS Blood and Transplant Research and Development Programme, the Translational Breast Cancer Research Consortium, the NSW Office of Health
and Medical Research, Amgen, Eisai, and the Pittsburgh Foundation. Dr Higgins is funded by an NHMRC Emerging Leadership Fellowship (GNT2008447). A/Prof McQuilten is funded by an NHMRC Emerging Leadership Fellowship (APP194811). Prof Gordon is funded by an NIHR Research Professorship (RP-2015-06-18) and Prof Shankar-Hari by an NIHR Clinician Scientist Fellowship (CS-2016-16-011). Prof Turgeon is the Chairholder of the Canada Research Chair in Critical Care Neurology and Trauma. Dr Lawler is supported by a career award from the Heart and Stroke Foundation of Canada.

The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health and Social Care.

## Role of the Funder/Sponsor

The funders had no role in the design and conduct of the trial; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. The platform trial has six regional non-profit sponsors (Monash University, Melbourne, Australia (sponsor for Australia, India, Pakistan, Nepal, Saudi Arabia and Colombia); Medical Research Institute of New Zealand (New Zealand sponsor); Utrecht Medical Center, Utrecht, the Netherlands (European sponsor); Unity Health, Toronto, Canada (Canadian sponsor); Global Coalition for Adaptive Research (GCAR), San Francisco, USA (US sponsor); and St Marianna University Hospital, Japan (Japanese sponsor)). Several authors are employees of these organizations. However, beyond the declared author contributions, the sponsors had no additional role.
**The REMAP-CAP Investigators**

See Supplement 2 'The REMAP-CAP Investigators and Collaborators'.

**Acknowledgements**

We are grateful to the NIHR Clinical Research Network (UK), UPMC Health System Health Services Division (US), and the Direction de la Recherche Clinique et de l'Innovation de l'AP-HP (France) for their support of participant recruitment. We are also very thankful to the patients who have participated in this trial.

Data Sharing Statement: See Supplement 3
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14. Ustun TB, Chatterji S, Kostanjsek N, et al. Developing the World Health Organization Disability Assessment Schedule 2.0. Bulletin of the World Health Organization 2010;88(11):815-23. DOI: 10.2471/BLT.09.067231.

15. Ustun TB, Kostanjsek N, Chatterji S, Rehm J. Measuring Health and Disability: Manual for WHO Disability Assessment Schedule (WHODAS 2.0). Geneva: 2010.
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# Summary of Supplements

## Supplement 1. Protocol Supplement

* Brief introduction to explain the protocol structure given modular nature of ongoing platform trial

* REMAP-CAP Core Protocol (Version 3.0, 10th July 2019, the Original Version - predating any Covid-19 screening and inclusion)

* Pandemic Appendix to Core (PAtC) protocol (Final Version 2.0, 18th May 2020 including summary of changes from version 1.1 and Original Version 1.1, 12th February 2020)

* REMAP-COVID Core Protocol (Version 1.0, 27th March 2020)

* Statistical Analysis Plan for the secondary analysis of long-term survival and disability in relation to randomized treatments in patients with suspected of proven COVID-19 in the REMAP-CAP trial (Version 1.1, 10th March 2022)

## Supplement 2.

* REMAP CAP Investigators and Collaborators

* Supplementary Methods

* Supplemental Tables

Table S1: Platform and domain-specific inclusion and exclusion criteria

Table S2: Patients and follow up by country of enrolment

Table S3: Baseline characteristics of patients in the immune modulation domain

Table S4: Baseline characteristics of patients in the immunoglobulin domain
Table S5: Baseline characteristics of patients in the antiplatelet domain

Table S6: Baseline characteristics of patients in the anticoagulation domain

Table S7: Baseline characteristics of patients in the antiviral domain

Table S8: Baseline characteristics of patients in the corticosteroid domain

Table S9: Baseline characteristics of survivors with and without known day 180 vital status

Table S10: Sensitivity Analysis of Day 180 mortality in non-negative COVID-19 population

Table S11: Sensitivity Analysis of Day 180 mortality with independent effects for interleukin-6 receptor antagonists and antiplatelet interventions

Table S12: Sensitivity Analysis of Day 180 mortality within domain-specific populations

Table S13: Day 90 mortality

Table S14: Baseline characteristics of survivors with and without EQ-5D-5L utility scores

Table S15: Baseline characteristics of survivors with and without WHODAS scores

Table S16: Day 180 EQ-5D-5L results

Table S17: Day 180 EQ VAS results

Table S18: Day 180 Disability Categories

Table S19: Day 180 Disability

Table S20: Sensitivity Analysis of EQ-5D-5L utility score without imputation

Table S21: Sensitivity Analysis of WHODAS disability category without imputation

Table S22: Day 180 mortality in patients mechanically ventilated at baseline

Table S23: Day 180 mortality in patients not mechanically ventilated at baseline

Table S24: Day 180 mortality in immune deficient patients

Table S25: Day 180 mortality in non-immune deficient patients

## Supplemental Figures

Figure S1: Forest plot of Day 180 mortality hazard ratios in unblinded ITT population
Figure S2: Forest plot of Day 180 mortality hazard ratios in sensitivity analyses

Figure S3: Fitted Kaplan-Meier curves for mortality through Day 180 with proportional hazard ratios, adjusting for covariates

Figure S4: Fitted Kaplan-Meier curves for mortality through Day 180 with time-varying hazards, adjusting for covariates

Figure S5: Association between OSFD odds ratios and the reciprocal of day 180 mortality hazard ratios

Figure S6: Forest plot of Day 90 mortality odds ratios in unblinded ITT population

Figure S7: Forest plot of expected effect on EQ-5D-5L utility score in all patients (assuming patients who died within 180 days have a utility score of 0)

Figure S8: Forest plot of the odds ratio on WHODAS disability category in survivors in unblinded ITT analysis

Figure S9: Forest plot of Day 180 mortality hazard ratios in unblinded ITT population comparing mechanical ventilation status at baseline

Figure S10: Forest plot of Day 180 mortality hazard ratios in unblinded ITT population comparing immune deficient status at baseline

## Model Evaluation Report

# Supplement 3. Data Sharing Statement
Figures

Figure 1. Cohort development in an analysis of longer-term follow-up of critically ill participants in the REMAP-CAP COVID-19 Clinical Trial

Figure 2. Kaplan Meier Curves for Mortality through Day 180

Each Kaplan-Meier curve summarizes 180-day all-cause mortality in critically ill patients for each treatment within each domain. The probability of superiority of each active intervention to control for 180-day mortality is reported from the fully adjusted Bayesian model (adjusting for other treatments from other domains, site, time, sex, and age). Censored subjects are indicated on the Kaplan-Meier curve as vertical tick marks.
# Tables

<table><caption>Table 1: Baseline characteristics of patients in one or more domains included in the analysis of mortality at 180 days<sup>a</sup></caption><thead><tr><th>Characteristic</th><th>N=4791</th></tr></thead><tbody><tr><td>Age in years, median (IQR)</td><td>60 (51 - 68) [N=4790]</td></tr><tr><td>Male sex, n/N (%)</td><td>3253/4790 (67.9)</td></tr><tr><td>Female sex, n/N (%)</td><td>1537/4790 (32.1)</td></tr><tr><td>Race/Ethnicity<sup>a</sup>, n/N (%)</td><td></td></tr><tr><td>Asian</td><td>504/3557 (14.2)</td></tr><tr><td>Black</td><td>160/3557 (4.5)</td></tr><tr><td>Mixed</td><td>69/3557 (1.9)</td></tr><tr><td>Other<sup>b</sup></td><td>159/3557 (4.5)</td></tr><tr><td>White</td><td>2665/3557 (74.9)</td></tr><tr><td>Confirmed SARS-CoV2 infection, n/N (%)<sup>c</sup></td><td>4139/4764 (86.9)</td></tr><tr><td>Body mass index, kg/m<sup>2</sup>, median (IQR)</td><td>30.5 (26.6 - 35.8) [N=4317]</td></tr><tr><td>APACHE II score<sup>d</sup>, median (IQR)</td><td>13 (8-19) [N=4673]</td></tr><tr><td>Pre-existing conditions, n/N (%)<sup>e</sup></td><td></td></tr><tr><td>Diabetes mellitus</td><td>1404/4788 (29.3)</td></tr><tr><td>Respiratory disease<sup>a</sup></td><td>1067/4788 (22.3)</td></tr><tr><td>Asthma/COPD</td><td>897/4788 (18.7)</td></tr><tr><td>Other</td><td>218/4788 (4.6)</td></tr><tr><td>Kidney disease</td><td>370/4427 (8.4)</td></tr><tr><td>Severe cardiovascular disease</td><td>376/4703 (8.0)</td></tr><tr><td>Immunosuppressive disease</td><td>190/4788 (4.0)</td></tr><tr><td>Chronic immunosuppressive therapy</td><td>175/4788 (3.7)</td></tr><tr><td>Time to enrolment, median (IQR)</td><td></td></tr><tr><td>From hospital admission, days</td><td>1.7 (0.9 - 3.3)</td></tr><tr><td>From ICU admission, hours</td><td>16.7 (9.1 - 22.5)</td></tr><tr><td>Acute respiratory support, n (%)</td><td></td></tr><tr><td>None/supplemental oxygen only</td><td>7 (0.2)</td></tr><tr><td>High flow nasal cannula</td><td>1198 (25.0)</td></tr><tr><td>Non-invasive ventilation only</td><td>1848 (38.6)</td></tr><tr><td>Invasive mechanical ventilation</td><td>1746 (36.4)</td></tr><tr><td>ECMO, n/N (%)</td><td>4/4729 (0.1)</td></tr><tr><td>Vasopressor support, n (%)</td><td>1005 (21.0)</td></tr><tr><td>Median (IQR) acute physiology and laboratory values<sup>f</sup></td><td></td></tr><tr><td>PaO<sub>2</sub>/FiO<sub>2</sub></td><td>116 (89 - 158) [N=4368]</td></tr><tr><td>C-reactive protein, µg/mL</td><td>117 (65 - 192) [N=3585]</td></tr><tr><td>Creatinine, mg/dL</td><td>0.8 (0.7 - 1.1) [N=4681]</td></tr><tr><td>Lactate, mmol/L</td><td>1.3 (1.0 - 1.8) [N=4205]</td></tr><tr><td>Platelets, x10<sup>9</sup>/L</td><td>245 (183 - 314) [N=4626]</td></tr><tr><td>Bilirubin, mg/dL</td><td>0.5 (0.4 - 0.8) [N=4443]</td></tr></tbody></table>
Percentages may not sum to 100 because of rounding. SD denotes standard deviation; APACHE, Acute Physiology and Chronic Health Evaluation; COPD, chronic obstructive pulmonary disease; IQR, interquartile range; ECMO, extracorporeal membrane oxygenation.

a Baseline characteristics by intervention in each of the six domains can be found in Tables S3-S8

b Self-reported via fixed categories. Data collection was not approved in Asia, Canada, and continental Europe. “Other” includes “other ethnic group” and those who declined to respond or were not asked by registration personnel.

c SARS-CoV2 infection was confirmed by respiratory tract polymerase chain reaction test.

d Measures the severity of illness based on age, medical history, and physiological variables. Scores range from 0 to 71; higher numbers represent greater risk of death. The median score of 12 is typical for patients with COVID-19 admitted to intensive care units (ICUs).

e Kidney disease was determined from the most recent stable serum creatinine level prior to this hospital admission, except in patients who were receiving dialysis. Abnormal kidney function was defined as a creatinine level of 130 µmol/L or greater (1.5 mg/dL) for males or 100 µmol/L or greater (1.1 mg/dL) for females not previously receiving dialysis. Cardiovascular disease was defined as New York Heart Association class IV symptoms. Immunosuppression was defined by the receipt of recent chemotherapy, radiation, high-dose or long-term steroid treatment, or presence of immunosuppressive disease.

f Laboratory results available when captured for clinical care. Although specific laboratory cut-offs may vary, ranges for the following variables are generally considered normal: $P_aO_2/F_iO_2$ ratio ≥400; creatinine <1.2 mg/dL; platelets ≥150 x 10⁹/L; and bilirubin <1.2 mg/dL.
<table><caption>Table 2: Day 180 mortality</caption><thead><tr><th></th><th>N</th><th>Day 180 mortality<sup>a</sup>, n/N (%)</th><th>Adjusted Hazard Ratio<sup>b</sup> (95% CrI)</th><th>Estimated Difference in Day 180 mortality (95% CrI)<sup>c</sup></th><th>Probability of Superiority of Intervention (%)<sup>d</sup></th><th>Probability of Futility of Intervention (%)<sup>d</sup></th><th>Probability of Superiority of Intervention for organ support free days (%)<sup>e</sup></th></tr></thead><tbody><tr><td><strong>Immune Modulation Domain<sup>f</sup></strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>IL-6 receptor antagonists</td><td>1433</td><td>436/1248 (34.9)</td><td>0.74 (0.61 to 0.90)</td><td>-7.9% (-13.2% to -2.7%)</td><td>&gt;99.9%</td><td>12.2%</td><td>&gt;99.9%</td></tr><tr><td>Anakinra</td><td>371</td><td>138/325 (42.5)</td><td>0.96 (0.75 to 1.23)</td><td>-1.3% (-6.9% to 4.5%)</td><td>63.7%</td><td>85.9%</td><td>50.0%</td></tr><tr><td>No immune modulator</td><td>406</td><td>140/350 (40.0)</td><td>1 (referent)</td><td>-</td><td>-</td><td>-</td><td>-</td></tr><tr><td><strong>Immunoglobulin Domain</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Convalescent plasma</td><td>1078</td><td>370/944 (39.2)</td><td>0.99 (0.80 to 1.14)</td><td>-0.3% (-4.1% to 3.5%)</td><td>54.7%</td><td>99.2%</td><td>26.6%</td></tr><tr><td>No convalescent plasma</td><td>911</td><td>324/790 (41.0)</td><td>1 (referent)</td><td>-</td><td>-</td><td>-</td><td>-</td></tr><tr><td><strong>Antiplatelet Domain</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Antiplatelet agent<sup>g</sup></td><td>1019</td><td>274/871 (31.5)</td><td>0.85 (0.71 to 1.03)</td><td>-3.5% (-7.9% to 0.7%)</td><td>95.0%</td><td>57.7%</td><td>62.8%</td></tr><tr><td>No antiplatelet agent</td><td>527</td><td>143/441 (32.4)</td><td>1 (referent)</td><td>-</td><td>-</td><td>-</td><td>-</td></tr><tr><td><strong>Anticoagulation Domain</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Therapeutic anticoagulation<sup>g</sup></td><td>499</td><td>165/403 (40.9)</td><td>1.13 (0.93 to 1.42)</td><td>3.2% (-1.7% to 8.5%)</td><td>11.5%</td><td>99.9%</td><td>10.8%</td></tr><tr><td>Usual care thromboprophylaxis</td><td>511</td><td>147/418 (35.2)</td><td>1 (referent)</td><td>-</td><td>-</td><td>-</td><td>-</td></tr><tr><td><strong>Antiviral Domain</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Lopinavir-ritonavir</td><td>256</td><td>81/226 (35.8)</td><td>1.06 (0.82 to 1.38)</td><td>1.8% (-4.3% to 7.3%)</td><td>31.9%</td><td>96.6%</td><td>11.4%</td></tr><tr><td>Hydroxychloroquine</td><td>50</td><td>16/41 (39.0)</td><td>1.51 (0.98 to 2.29)</td><td>11.6% (1.7% to 21.6%)</td><td>3.2%</td><td>99.6%</td><td>0.4%</td></tr><tr><td>Combination antiviral therapy</td><td>27</td><td>13/26 (50.0)</td><td>1.61 (0.97 to 2.67)</td><td>13.8% (2.6% to 24.7%)</td><td>3.2%</td><td>99.5%</td><td>0.3%</td></tr><tr><td>No antiviral</td><td>362</td><td>107/311 (34.4)</td><td>1 (referent)</td><td>-</td><td>-</td><td>-</td><td>-</td></tr><tr><td><strong>Corticosteroid Domain</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Fixed dose corticosteroids</td><td>137</td><td>34/109 (31.2)</td><td>0.93 (0.61 to 1.47)</td><td>-1.4% (-11.7% to 7.8%)</td><td>61.6%</td><td>69.1%</td><td>94.6%</td></tr><tr><td>Shock-dependent corticosteroids</td><td>147</td><td>39/137 (28.5)</td><td>0.96 (0.61 to 1.50)</td><td>0.0% (-11.5% to 10.4%)</td><td>57.1%</td><td>72.5%</td><td>75.6%</td></tr><tr><td>No corticosteroid</td><td>101</td><td>27/79 (34.2)</td><td>1 (referent)</td><td>-</td><td>-</td><td>-</td><td>-</td></tr></tbody><tfoot><tr><td colspan="8" style="text-align: center;">Favors treatment</td></tr><tr><td colspan="8" style="text-align: center;">Favors usual care</td></tr></tfoot></table>
Crl denotes credible interval; OSFD, organ support free days.

<sup>a</sup> Due to censoring, reported day 180 mortality rates are restricted to patients at sites participating in day 180 follow-up with known day 180 vital status. The Kaplan Meier curves in Figure 2 include additional exposure and events from patients that were censored before day 180 or enrolled at sites that did not participate in day 180 follow-up.

<sup>b</sup> Hazard ratios <1 indicate improved survival while hazard ratios >1 indicate worsened survival

<sup>c</sup> The difference in Day 180 mortality is determined from the Day 180 mortality rates which are estimated from the primary analysis model. For each domain, day 180 mortality rates are estimated for the population of patients randomized within that domain based on their baseline covariates and the estimated model parameters. For each patient within the domain population, separate survival curves are predicted assuming the patient received each intervention within the domain. The survival curves are averaged across patients to summarize the average survival for each intervention within the domain population.

<sup>d</sup> The probability of superiority (HR<1) and futility (HR>1/1.2) is computed from a Bayesian piecewise exponential model using the posterior distribution.

<sup>e</sup> OSFD are a composite ordinal scale consisting of survival to hospital discharge and days free of organ support to day 21. Probabilities may differ from those presented in the original manuscript for each domain due to changes in patient consent.

<sup>f</sup> Domains are ordered based on the total number of patients enrolled in the domain from largest to smallest

<sup>g</sup> 35 patients within the antiplatelet and anticoagulation domains were randomized to the prespecified combination of therapeutic anticoagulation and an antiplatelet agent. The combination effect provides the effect of giving both therapeutic anticoagulation and antiplatelet interventions together in combination (relative to giving control in both domains). This is estimated by multiplying the hazard ratio for antiplatelet, therapeutic anticoagulation and the interaction effect for antiplatelet and therapeutic anticoagulation. The HR for the combination effect is 1.34 (0.82 to 2.23) with a probability of superiority of 11.6%. The HR for the therapeutic anticoagulation/antiplatelet interaction is 1.39 (0.87 to 2.19).
<table><caption>Table 3: Day 180 HRQoL<sup>a</sup></caption><thead><tr><th></th><th>EQ-5D-5L utility score, mean (SD) [N]</th><th>Adjusted Mean Difference in Survivors (95% CrI)<sup>b</sup></th><th>Probability of Superiority of Intervention in Survivors (%)<sup>a</sup></th><th>Adjusted Mean Difference in Survivors and Non-Survivors (95% CrI)<sup>b</sup></th><th>Probability of Superiority of Intervention in Survivors and Non-Survivors (%)<sup>a</sup></th></tr></thead><tbody><tr><td><strong>Immune Modulation Domain <sup>c</sup></strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>IL-6 receptor antagonists</td><td>0.66 (0.29) [N=302]</td><td>0.04 (-0.03 to 0.12)</td><td>87.0%</td><td>0.08 (0.02 to 0.13)</td><td>99.5%</td></tr><tr><td>Anakinra</td><td>0.72 (0.28) [N=78]</td><td>0.07 (-0.03 to 0.18)</td><td>91.5%</td><td>0.05 (-0.03 to 0.13)</td><td>89.6%</td></tr><tr><td>Control</td><td>0.64 (0.29) [N=92]</td><td>0 (referent)</td><td>-</td><td>0 (referent)</td><td>-</td></tr><tr><td><strong>Immunoglobulin Domain</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Convalescent plasma</td><td>0.62 (0.32) [N=216]</td><td>-0.03 (-0.09 to 0.03)</td><td>18.8%</td><td>-0.02 (-0.06 to 0.03)</td><td>25.2%</td></tr><tr><td>Control</td><td>0.64 (0.29) [N=174]</td><td>0 (referent)</td><td>-</td><td>0 (referent)</td><td>-</td></tr><tr><td><strong>Antiplatelet Domain</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Antiplatelet</td><td>0.69 (0.27) [N=163]</td><td>0.08 (0.00 to 0.15)</td><td>97.4%</td><td>0.08 (0.02 to 0.13)</td><td>99.6%</td></tr><tr><td>Control</td><td>0.63 (0.30) [N=95]</td><td>0 (referent)</td><td>-</td><td>0 (referent)</td><td>-</td></tr><tr><td><strong>Anticoagulation Domain</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Therapeutic anticoagulation</td><td>0.67 (0.28) [N=116]</td><td>0.01 (-0.07 to 0.09)</td><td>59.2%</td><td>-0.02 (-0.07 to 0.04)</td><td>28.8%</td></tr><tr><td>Thromboprophylaxis</td><td>0.67 (0.30) [N=124]</td><td>0 (referent)</td><td>-</td><td>0 (referent)</td><td>-</td></tr><tr><td><strong>Antiviral Domain</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Lopinavir-ritonavir</td><td>0.62 (0.3) [N=74]</td><td>-0.10 (-0.19 to -0.01)</td><td>1.3%</td><td>-0.08 (-0.15 to -0.01)</td><td>1.6%</td></tr><tr><td>Hydroxychloroquine</td><td>1.00 (NA) [N=1]</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td></tr><tr><td>Combination antiviral therapy</td><td>0.58 (0.19) [N=2]</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td></tr><tr><td>Control</td><td>0.71 (0.27) [N=101]</td><td>0 (referent)</td><td>-</td><td>0 (referent)</td><td>-</td></tr><tr><td><strong>Corticosteroid Domain</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Fixed dose corticosteroids</td><td>0.79 (0.20) [N=27]</td><td>-0.01 (-0.18 to 0.16)</td><td>45.9%</td><td>0.006 (-0.13 to 0.14)</td><td>53.1%</td></tr><tr><td>Shock-dependent corticosteroids</td><td>0.77 (0.17) [N=34]</td><td>-0.02 (-0.18 to 0.14)</td><td>41.0%</td><td>-0.006 (-0.13 to 0.12)</td><td>46.7%</td></tr><tr><td>Control</td><td>0.75 (0.28) [N=21]</td><td>0 (referent)</td><td>-</td><td>0 (referent)</td><td>-</td></tr></tbody></table>

SD denotes standard deviation; IQR, interquartile range; NA, not available; CrI, credible interval.

<figure><img src="image_2.png" /></figure>
<footnote>ᵃ Results for the EQ VAS and the WHODAS are available in Supplement Tables S17 to S19</footnote>

<footnote>ᵇ The probability of superiority and adjusted mean difference are computed from the posterior distribution of a Bayesian two-part/mixture model that multiply imputes EQ-5D-5L utility scores using patients' baseline covariates for 1) patients censored alive before 6 months and 2) patients known to be alive at 6 months with unknown HRQoL. For patients that are censored before 6 months, first 6-month mortality outcomes are multiply imputed from the piecewise exponential component of the Bayesian two-part/mixture model. For patients that are known or imputed to be alive at 6 months, a value of EQ-5D-5L is multiply imputed from the continuous component of the two-part/mixture model. For patients that are imputed as dead by 6 months, EQ-5D-5L is set to 0 and they do not contribute to the analysis of EQ-5D-5L in survivors. In this analysis, 4307 of 4791 patients (90%) have known survival status at 6 months and a mortality outcome is multiply imputed for the remaining 484 (10%) of patients. Of the 2590 patients known to be alive at 6 months, 852 (33%) have known EQ-5D-5L utility score and the remaining 1738 (67%) are imputed.</footnote>

<footnote>ᶜ Domains are ordered based on the total number of patients enrolled in the domain from largest to smallest</footnote>
A) Immune Modulation Domain

Cumulative mortality

<figure><img src="image_3.png" /></figure>

No. at risk

<table><tr><td>406</td><td>2%</td><td>248</td><td>215</td><td>210</td></tr><tr><td>371</td><td>2%</td><td>215</td><td>190</td><td>187</td></tr><tr><td>1433</td><td>9%</td><td>928</td><td>825</td><td>812</td></tr></table>

C) Antiplatelet Domain

Cumulative mortality

<figure><img src="image_4.png" /></figure>

<table><tr><td>527</td><td>362</td><td>351</td><td>308</td><td>298</td></tr><tr><td>No. at risk</td><td>1019</td><td>722</td><td>704</td><td>597</td></tr></table>

E) Antiviral Domain

Cumulative mortality

<figure><img src="image_5.png" /></figure>

No. at risk

<table><tr><td>362</td><td>252</td><td>245</td><td>207</td><td>204</td></tr><tr><td>256</td><td>165</td><td>160</td><td>147</td><td>145</td></tr><tr><td>50</td><td>34</td><td>32</td><td>26</td><td>25</td></tr><tr><td>27</td><td>15</td><td>13</td><td>13</td><td>13</td></tr></table>

B) Immunoglobulin Domain

<figure><img src="image_6.png" /></figure>

No. at risk

<table><tr><td>911</td><td>5%</td><td>543</td><td>473</td><td>466</td></tr><tr><td>1078</td><td>6%</td><td>659</td><td>582</td><td>574</td></tr></table>

D) Anticoagulation Domain

<figure><img src="image_7.png" /></figure>

<table><tr><td>511</td><td>337</td><td>323</td><td>277</td><td>271</td></tr><tr><td>No. at risk</td><td>499</td><td>309</td><td>299</td><td>240</td><td>238</td></tr></table>

F) Corticosteroid Domain

<figure><img src="image_8.png" /></figure>

No. at risk

<table><tr><td>101</td><td>64</td><td>63</td><td>53</td><td>52</td></tr><tr><td>137</td><td>95</td><td>94</td><td>76</td><td>75</td></tr><tr><td>147</td><td>113</td><td>110</td><td>100</td><td>98</td></tr></table>
Supplement to:

# 180-Day Outcomes in Critically Ill Patients with COVID-19 in the REMAP-CAP Randomized Clinical Trial.

## The REMAP-CAP Investigators

### Table of Contents

<table><tbody><tr><td>1.</td><td><strong>REMAP-CAP Investigators and Collaborators</strong></td><td>3</td></tr><tr><td></td><td>International Trial Steering Committee</td><td>3</td></tr><tr><td></td><td>Regional Management Committees</td><td>3</td></tr><tr><td></td><td>Regional Coordinating Centers</td><td>4</td></tr><tr><td></td><td>Domain-Specific Working Groups</td><td>4</td></tr><tr><td></td><td>Statistical Analysis Committee</td><td>7</td></tr><tr><td></td><td>Statistical Design Team</td><td>7</td></tr><tr><td></td><td>Data Coordinating Team</td><td>7</td></tr><tr><td></td><td>Project Management</td><td>7</td></tr><tr><td></td><td>Database Providers</td><td>7</td></tr><tr><td></td><td>Clinical Trials Groups</td><td>8</td></tr><tr><td></td><td>Site Investigators and Research Coordinators</td><td>9</td></tr><tr><td>2.</td><td><strong>Supplementary methods</strong></td><td>25</td></tr><tr><td></td><td>2.1 Outcomes</td><td>25</td></tr><tr><td>3.</td><td><strong>Supplemental Results Tables</strong></td><td>26</td></tr><tr><td></td><td>Table S1: Platform and domain-specific inclusion and exclusion criteria</td><td>27</td></tr><tr><td></td><td>Table S2: Patients and follow up by country of enrolment</td><td>31</td></tr><tr><td></td><td>Table S3: Baseline characteristics of patients in the immune modulation domain</td><td>32</td></tr><tr><td></td><td>Table S4: Baseline characteristics of patients in the immunoglobulin domain</td><td>33</td></tr><tr><td></td><td>Table S5: Baseline characteristics of patients in the antiplatelet domain</td><td>34</td></tr><tr><td></td><td>Table S6: Baseline characteristics of patients in the anticoagulation domain</td><td>35</td></tr><tr><td></td><td>Table S7: Baseline characteristics of patients in the antiviral domain</td><td>36</td></tr><tr><td></td><td>Table S8: Baseline characteristics of patients in the corticosteroid domain</td><td>37</td></tr><tr><td></td><td>Table S9: Baseline characteristics of survivors with and without known day 180 vital status</td><td>38</td></tr><tr><td></td><td>Table S10: Sensitivity Analysis of Day 180 mortality in non-negative COVID-19 population</td><td>39</td></tr><tr><td></td><td>Table S11: Sensitivity Analysis of Day 180 mortality with independent effects for interleukin-6 receptor antagonists and antiplatelet interventions</td><td>40</td></tr><tr><td></td><td>Table S12: Sensitivity Analysis of Day 180 mortality within domain-specific populations</td><td>41</td></tr><tr><td></td><td>Table S13: Day 90 mortality</td><td>42</td></tr></tbody></table>
<table><tbody><tr><td>Table S14: Baseline characteristics of survivors with and without EQ-5D-5L utility scores</td><td>43</td></tr><tr><td>Table S15: Baseline characteristics of survivors with and without WHODAS scores</td><td>45</td></tr><tr><td>Table S16: Day 180 EQ-5D-5L results</td><td>47</td></tr><tr><td>Table S17: Day 180 EQ VAS results</td><td>48</td></tr><tr><td>Table S18: Day 180 Disability Categories</td><td>49</td></tr><tr><td>Table S19: Day 180 Disability</td><td>50</td></tr><tr><td>Table S20: Sensitivity Analysis of EQ-5D-5L utility score without imputation</td><td>51</td></tr><tr><td>Table S21: Sensitivity Analysis of WHODAS disability category without imputation</td><td>52</td></tr><tr><td>Table S22: Day 180 mortality in patients mechanically ventilated at baseline</td><td>53</td></tr><tr><td>Table S23: Day 180 mortality in patients not mechanically ventilated at baseline</td><td>54</td></tr><tr><td>Table S24: Day 180 mortality in immune deficient patients<sup>a</sup></td><td>55</td></tr><tr><td>Table S25: Day 180 mortality in non-immune deficient patients</td><td>56</td></tr><tr><td>4. Supplemental Results Figures</td><td>57</td></tr><tr><td>Figure S1: Forest plot of Day 180 mortality hazard ratios in unblinded ITT population</td><td>57</td></tr><tr><td>Figure S2: Forest plot of Day 180 mortality hazard ratios in sensitivity analyses</td><td>58</td></tr><tr><td>Figure S3: Fitted Kaplan-Meier curves for mortality through Day 180 with proportional hazard ratios, adjusting for covariates</td><td>59</td></tr><tr><td>Figure S4: Fitted Kaplan-Meier curves for mortality through Day 180 with time-varying hazards, adjusting for covariates</td><td>60</td></tr><tr><td>Figure S5: Association between OSFD odds ratios and the reciprocal of day 180 mortality hazard ratios</td><td>61</td></tr><tr><td>Figure S6: Forest plot of Day 90 mortality odds ratios in unblinded ITT population</td><td>61</td></tr><tr><td>Figure S7: Forest plot of expected effect on EQ-5D-5L utility score in all patients (assuming patients who died within 180 days have a utility score of 0)</td><td>62</td></tr><tr><td>Figure S8: Forest plot of the odds ratio on WHODAS disability category in survivors in unblinded ITT analysis</td><td>62</td></tr><tr><td>Figure S9: Forest plot of Day 180 mortality hazard ratios in unblinded ITT population comparing mechanical ventilation status at baseline</td><td>63</td></tr><tr><td>Figure S10: Forest plot of Day 180 mortality hazard ratios in unblinded ITT population comparing immune deficient status at baseline</td><td>64</td></tr><tr><td>5. Model Evaluation Report</td><td>65</td></tr></tbody></table>
# 1. REMAP-CAP Investigators and Collaborators

**International Trial Steering Committee:**

Farah Al-Beidh, Derek Angus, Djillali Annane, Yaseen Arabi, Abigail Beane, Wilma van Bentum-Puijk, Scott Berry, Zahra Bhimani, Marc Bonten, Charlotte Bradbury, Frank Brunkhorst, Aidan Burrell, Meredith Buxton, Allen Cheng, Matthew Cove, Lennie Derde (Chair), Lise Estcourt, Herman Goossens, Anthony Gordon, Cameron Green, Rashan Haniffa, David Huang, Nao Ichihara, Francois Lamontagne, Patrick Lawler, John Marshall, Colin McArthur, Daniel McAuley, Shay McGuinness, Bryan McVerry, Stephanie Montgomery, Paul Mouncey, Srinivas Murthy, Alistair Nichol, Rachael Parke, Jane Parker, Luis Felipe Reyes, Kathryn Rowan, Hiroki Saito, Marlene Santos, Christopher Seymour, Manu Shankar-Hari, Alexis Turgeon, Anne Turner, Frank van de Veerdonk, Steve Webb, Ryan Zarychanski

**Regional Management Committees**

**Australia and New Zealand**

Yaseen Arabi, Aidan Burrell, Lewis Campbell, Allen Cheng, Lennie Derde, Andrew Forbes, David Gattas, Cameron Green, Stephane Heritier, Thomas Hills, Peter Kruger, Colin McArthur (Deputy Executive Director), Shay McGuinness (Chair), Zoe McQuilten, Alistair Nichol, Rachael Parke, Jane Parker, Sandra Peake, Jeffrey Presneill, Manoj Saxena, Ian Seppelt, Vanessa Singh, Tony Trapani, Anne Turner, Steve Webb (Executive Director), Paul Young

**Canadian Regional Management Committee**

Zahra Bhimani, Brian Cuthbertson, Rob Fowler, Francois Lamontagne, John Marshall (Executive Director), Venika Manoharan, Srinivas Murthy (Deputy Executive Director), Marlene Santos, Alexis Turgeon, Ryan Zarychanski

**Critical Care Asia (CCA) Regional Management Committee**

Diptesh Aryal, Abigail Beane (Chair), Arjen M Dondrop, Cameron Green, Rashan Haniffa (Executive Director), Madiha Hashmi, Deva Jayakumar, John Marshall, Colin McArthur, Srinivas Murthy, Sumayyah Rashan, Timo Tolppa, Vanessa Singh, Steve Webb

**European Regional Management Committee**

Farah Al-Beidh, Derek Angus, Djillali Annane, Wilma van Bentum-Puijk, Scott Berry, Marc Bonten (Co-Executive Director), Frank Brunkhorst, Maurizio Cecconi, Lennie Derde (Co-Executive Director and Chair), Stephan Ehrmann, Bruno Francois, Herman Goossens, Anthony Gordon, Cameron Green, Sebastiaan
Hullegie, Colin McArthur, Paul Mouncey, Alistair Nichol, Mathias Pletz, Pedro Povoa, Gernot Rohde, Kathryn Rowan, Lorraine Parker, Irma Scheepstra-Beukers, Steve Webb

**United States Regional Management Committee**

Brian Alexander, Derek Angus (Executive Director), Kim Basile, Meredith Buxton (Chair), Timothy Girard, Christopher Horvat, David Huang, Kelsey Linstrum, Florian Mayr, Bryan McVerry, Stephanie Montgomery, Christopher Seymour, Renee Wunderley, Tracey Roberts

**<u>Regional Coordinating Centers</u>**

**Australia, CCA region, and Saudi Arabia:** The Australia and New Zealand Intensive Care Research Centre (ANZIC-RC), Monash University

**Canada:** St. Michael's Hospital, Unity Health Toronto

**Europe:** University Medical Center Utrecht (UMCU)

**New Zealand:** The Medical Research Institute of New Zealand (MRINZ)

**United States:** Global Coalition for Adaptive Research (GCAR), and University of Pittsburgh

**CRIT Care Asia (CCA):** NICS MORU.

**<u>Domain-Specific Working Groups</u>**

**Antibiotic and Macrolide Duration Domain-Specific Working Group**

Richard Beasley, Marc Bonten, Allen Cheng (Chair), Nick Daneman, Lennie Derde, Robert Fowler, David Gattas, Anthony Gordon, Cameron Green, Peter Kruger, Colin McArthur, Steve McGloughlin, Susan Morpeth, Srinivas Murthy, Alistair Nichol, David Paterson, Mathias Pletz, Gernot Rohde, Steve Webb

**Corticosteroid Domain-Specific Working Group**

Derek Angus (Chair), Wilma van Bentum-Puijk, Lennie Derde, Anthony Gordon, Sebastiaan Hullegie, Peter Kruger, Edward Litton, John Marshall, Colin McArthur, Srinivas Murthy, Alistair Nichol, Bala Venkatesh, Steve Webb

**Influenza Antiviral Domain-Specific Working Group**

Derek Angus, Scott Berry, Marc Bonten, Allen Cheng, Lennie Derde, Herman Goossens, Sebastiaan Hullegie, Menno de Jong, John Marshall, Colin McArthur, Srinivas Murthy (Chair), Tim Uyeki, Steve Webb
**COVID-19 Antiviral Domain-Specific Working Group**

Derek Angus, Yaseen Arabi (Chair), Diptesh Aryal, Kenneth Baillie, Richard Beasley, Scott Berry, Marc Bonten, Frank Brunkhorst, Aidan Burrell, Allen Cheng, Menno de Jong, Lennie Derde, Eamon Duffy, Rob Fowler, Herman Goossens, Anthony Gordon, Cameron Green, Rashan Haniffa, Madhia Hashmi, Thomas Hills, David Huang, Sabin Koirala, Edward Litton, John Marshall, Colin McArthur, Susan Morpeth, Srinivas Murthy, Mihai Netea, Alistair Nichol, Katrina Orr, Rachael Parke, Jane Parker, Asad Patanwala, Kathryn Rowan, Steve Tong, Tim Uyeki, Frank van de Veerdonk, Steve Webb

**COVID-19 Immune Modulation Domain-Specific Working Group**

Derek Angus, Yaseen Arabi, Kenneth Baillie, Richard Beasley, Scott Berry, Marc Bonten, Frank Brunkhorst, Allen Cheng, Nichola Cooper, Olaf Cremer, Menno de Jong, Lennie Derde (Chair), Eamon Duffy, James Galea, Herman Goossens, Anthony Gordon, Cameron Green, Thomas Hills, Andrew King, Helen Leavis, John Marshall, Florian Mayr, Colin McArthur, Bryan McVerry, Susan Morpeth, Srinivas Murthy, Mihai Netea, Alistair Nichol, Kayode Ogungbenro, Katrina Orr, Jane Parker, Asad Patawala, Ville Pettilä (Deputy Chair), Emma Rademaker, Kathryn Rowan, Manoj Saxena, Christopher Seymour, Wendy Sligl, Steven Tong, Tim Uyeki, Frank van de Veerdonk, Steve Webb, Taryn Youngstein

**COVID-19 Immune Modulation -2 Domain-Specific Working Group**

Derek Angus, Scott Berry, Lennie Derde, Cameron Green, David Huang, Nao Ichihara, Florian Mayr, Colin McArthur, Bryan McVerry, Stephanie Montgomery, Hiroki Saito, Christopher W. Seymour (Chair), Steve Webb

**Therapeutic Anticoagulation Domain-Specific Working Group**

Derek Angus, Diptesh Aryal, Scott Berry, Shailesh Bihari, Charlotte Bradbury, Marc Carrier, Dean Fergusson, Robert Fowler, Ewan Goligher (Deputy Chair), Anthony Gordon, Christopher Horvat, David Huang, Beverley Hunt, Devachandran Jayakumar, Anand Kumar, Mike Laffan, Patrick Lawler, Sylvain Lother, John Marshall, Colin McArthur, Zoe McQuilten, Bryan McVerry, Saskia Middeldorp, Matthew Neal, Alistair Nichol, Asad Patanwala, Roger Schutgens, Christopher Seymour, Simon Stanworth, Alexis Turgeon, Steve Webb, Ryan Zarychanski (Chair)

**Vitamin C Domain-Specific Working Group**

Neill Adhikari (Chair), Derek Angus, Djillali Annane, Matthew Anstey, Yaseen Arabi, Scott Berry, Emily Brant, Angelique de Man, Lennie Derde, Anthony Gordon, Cameron Green, David Huang, Francois Lamontagne (Chair), Edward Litton, John Marshall, Marie-Helene Masse, Colin McArthur, Shay McGuinness, Paul Mouncey, Srinivas Murthy, Rachael Parke, Alistair Nichol, Tony Trapani, Andrew Udy, Steve Webb
**COVID-19 Immunoglobulin Domain-Specific Working Group**

Jacinta Abraham, Derek Angus, Donald Arnold, Phillipe Begin, Scott Berry, Richard Charlewood, Michael Chasse, Jamie Cooper, Mark Coyne, James Daly, Lise Estcourt (Chair, UK lead), Dean Fergusson, Anthony Gordon, Iain Gosbell, Heli Harvala-Simmonds, Tom Hills (New Zealand lead), Christopher Horvat, David Huang, Sheila MacLennan, John Marshall, John McDyer, Colin McArthur (New Zealand lead), Zoe McQuilten (Australian lead), Bryan McVerry (USA lead), David Menon, Susan Morpeth, Paul Mouncey, Srinivas Murthy, Alistair Nichol (Ireland lead), Nicole Pridee, David Roberts, Kathryn Rowan, Christopher Seymour, Manu Shankar-Hari (UK lead), Helen Thomas, Alan Tinmouth, Darrell Triulzi, Alexis Surgeon (Canada lead), Tim Walsh, Steve Webb, Erica Wood, Ryan Zarychanski (Canada lead)

**Simvastatin Domain-Specific Working Group**

Derek Angus, Yaseen Arabi, Abigail Beane, Carolyn Calfee, Anthony Gordon, Cameron Green, Rashan Haniffa, Deva Jayakumar, Peter Kruger, Patrick Lawler, Edward Litton, Colin McArthur, Daniel McAuley (Chair), Bryan McVerry, Matthew Neal, Alistair Nichol, Cecilia O'Kane, Murali Shyamsundar, Pratik Sinha, Taylor Thompson, Steve Webb, Ian Young

**Antiplatelet Domain-Specific Working Group**

Derek Angus, Scott Berry, Shailesh Bihari, Charlotte Bradbury (Chair), Marc Carrier, Timothy Girard, Ewan Goligher, Anthony Gordon, Ghady Haidar, Christopher Horvat, David Huang, Beverley Hunt, Anand Kumar, Patrick Lawler, John Marshall, Colin McArthur, Zoe McQuilten, Bryan McVerry, Matthew Neal, Alistair Nichol, Christopher Seymour, Simon Stanworth, Steve Webb, Alexandra Weissman, Ryan Zarychanski

**Mechanical Ventilation Domain**

Derek Angus, Wilma van Bentum-Puijk, Aidan Burrell, Lewis Campbell, Lennie Derde, Niall Ferguson, Timothy Girard, Ewan Goligher, Anthony Gordon, Cameron Green, Carol Hodgson, Peter Kruger, John Laffey, Edward Litton, John Marshall, Colin McArthur, Daniel McAuley, Shay McGuinness, Ary Neto, Alistair Nichol (Chair), Neil Orford, Jason Phua, Kathryn Rowan, Ian Seppelt, Steve Webb

**ACE-2 RAAS Domain**

Rebecca Baron, Lennie Derde, Slava Epelman, Claudia Frankfurter, David Gattas, Frank Gommans, Anthony Gordon, Rashan Haniffa, David Huang, Edy Kim, Francois Lamontagne, Patrick Lawler (Chair), David Leaf, John Marshall, Colin McArthur, Daniel McAuley, Bryan McVerry, Muthiah Vaduganathan, Roland van Kimmenade, Frank van de Veerdonk, Steve Webb
**Statistical Analysis Committee**

Michelle Detry, Mark Fitzgerald, Roger Lewis (Chair), Anna McGlothlin, Christina Saunders

**Statistical Design Team**

Lindsay Berry, Scott Berry, Elizabeth Lorenzi

**Data Coordinating Team**

Adrian Buzgau, Cameron Green, Alisa Higgins

**Project Management**

**Australia and Saudi Arabia:** Jane Parker, Rebecca McEldrew, Claire Reynolds

**Canada:** Zahra Bhimani, Marlene Santos

**CCA:** Vanessa Singh, Abigail Beane, Rashan Haniffa, Timo Tolppa, Sumayyah Rashan

**Europe:** Nora Azergui, Sara Bari, Mercedes Beltran, Wilma van Bentum-Puijk, Curt Brugman, Erika Groeneveld, Mina Jafarzadeh, Nicole Keijzer-Timmers, Esmee Kester, Maaike Koelink, Marion Kwakkenbos-Craanen, Clementina Okundaye, Lorraine Parker, Svenja Peters, Sophie Post, Ilse Rietveld, Irma Scheepstra-Beukers, Gerwin Schreuder Albertine Smit

**Germany:** Nicole Brillinger, René Markgraf, Fred Christian Eichinger

**Global:** Cameron Green

**Ireland:** Kate Ainscough, Kathy Brickell, Peter Doran

**New Zealand:** Anne Turner

**United Kingdom:** Farah Al-Beidh, Aisha Anjum, Janis-Best Lane, Walton Charles, Elizabeth Fagbodun, Frances Barton, Lorna Miller, Paul Mouncey, Karen Parry-Billings, Sam Peters, Alvin Richards-Belle, Michelle Saull, Stefan Sprinckmoller, Daisy Wiley, Robert Darnell, Carly Au, Lucy Stronach

**United States of America:** Kim Basile, Meredith Buxton, Kelsey Linstrum, Stephanie Montgomery, Tracey Roberts, Renee Wunderley

**Database Providers**

**Research Online:** Marloes van Beurden, Evelien Effelaar, Joost Schotsman,

**Spinnaker Software:** Craig Boyd, Cain Harland, Audrey Shearer, Jess Wren

**University of Pittsburgh Medical Center:** Giles Clermont, William Garrard, Christopher Horvat, Kyle Kalchthaler, Andrew King, Daniel Ricketts, Salim Malakouti, Oscar Marroquin, Edvin Music, Kevin Quinn
**NICS MORU:** on behalf of CCA: Udara Attanayaka, Abigail Beane, Sri Darshana, Rashan Haniffa, Pramodya Ishani, Sumayyah Rashan, Timo Tolppa, Ishara Udayanga.

## Clinical Trials Groups

The REMAP-CAP platform is supported by the Australian and New Zealand Intensive Care Society Clinical Trials Group, the Canadian Critical Care Clinical Trials Group, the Irish Critical Care Clinical Trials Network, the UK Critical Care Research Group and the International Forum of Acute Care Trialists.

REMAP-CAP was supported in the UK by the NIHR Clinical Research Network and we acknowledge the contribution of Kate Gilmour, Karen Pearson, Chris Siewerski, Sally-Anne Hurford, Emma Marsh, Debbie Campbell, Penny Williams, Kim Shirley, Meg Logan, Jane Hanson, Anne Oliver, Mihaela Sutu, Sheenagh Murphy, Latha Aravindan, Joanne Collins, Holly Monaghan, Adam Unsworth, Seonaid Beddows, Laura Ann Dawson, Sarah Dyas, Adeeba Asghar, Kate Donaldson, Tabitha Skinner, Nhlanhla Mguni, Natasha Muzengi, Ji Luo, Joanna O'Reilly, Chris Levett, Alison Potter, David Porter, Teresa Lockett, Jazz Bartholomew, Clare Rook, Hannah Williams, Alistair S Hall, Hilary Campbell, Holly Speight, Sandra Halden, Susan Harrison, Mobeena Naz, Charles Rounds, Kaatje Lomme, Johnathan Sheffield, William Van't Hoff, James D Williamson, Catherine Birch, Morwenna Brend, Emma Chambers, Sarah Crawshaw, Chelsea Drake, Heather Harper, Stephen Lock, Eleanor OKell, Amber Hayes, Susan Walker, Jayne Goodwin, Helen Hodgson, Yvette Ellis, Dawn Williamson, Madeleine Bayne, Shane Jackson, Rahim Byrne, Sonia McKenna, Alison Clinton, NIHR Urgent Public Health Group: https://www.nihr.ac.uk/documents/urgent-public-health-group-members/24638#Members

REMAP-CAP was supported in France by the CRICS-TRIGGERSEP network

REMAP-CAP was supported in Ireland by the Irish Critical Care Clinical Trials Network and we acknowledge the contribution of Kate Ainscough, Kathy Brickell and Peter Doran.

REMAP-CAP was supported in the Netherlands by the Research Collaboration Critical Care the Netherlands (RCC-Net).

REMAP-CAP was supported in Canada by the Canadian Institutes of Health Research, St. Michael's Unity Health, and the Canadian Critical Care Trials Group

REMAP-CAP was supported in the United States by the Translational Breast Cancer Research Consortium, the UPMC Learning While Doing Program, and the Global Coalition for Adaptive Research
## Site Investigators and Research Coordinators

### Australia:

**The Alfred Hospital:** Andrew Udy, Phoebe McCracken, Meredith Young, Jasmin Board, Emma Martin;

**Ballarat Health Services:** Khaled El-Khawas, Angus Richardson, Dianne Hill, Robert J Commons, Hussam Abdelkharim;

**Bankstown Hospital:** Manoj Saxena, Margaret Muteithia, Kelsey Dobell-Brown;

**Bendigo Hospital:** Cameron Knott, Julie Smith, Catherine Boschert;

**Blacktown Hospital:** Latesh Poojara, Treena Sara, Kiran Nand;

**Caboolture Hospital:** Julia Affleck, Arif Shaikh, Andrew Murray, Thuy Frakking, Mahesh Ramanan;

**Campbelltown Hospital:** Ritesh Sanghavi, Deepak Bhonagiri, Kelsey Dobell-Brown, Megan Ford;

**Canberra Hospital:** Harshel G. Parikh, Bronwyn Avard, Mary Nourse, Bree McDonald, Natasha Edmunds;

**Concord Repatriation General Hospital:** Winston Cheung, Helen Wong;

**Eastern Health (Box Hill, Maroondah & Angliss Hospitals):** Joanna Simpson, Graeme Duke, Peter Chan, Brittney Carter, Stephanie Hunter;

**Fiona Stanley Hospital:** Edward Litton, Adrian Regli, Susan Pellicano, Annamaria Palermo, Ege Eroglu;

**Flinders Medical Centre:** Shailesh Bihari, Russell D Laver, Xia Jin, Julia Brown, Joanne McIntyre;

**Footscray Hospital:** Craig French, Samantha Bates, Miriam Towns, Yang Yang, Forbes McGain;

**Gold Coast University Hospital:** James McCullough, Mandy Tallott;

**John Hunter Hospital:** Nikhil Kumar, Rakshit Panwar, Amber-Louise Poulter, Krishna Sunkara;

**Launceston General Hospital:** Matthew Brain, Sarah Mineall;

**Liverpool Hospital:** Anders Aneman, Jennene Miller, Kelsey Dobell-Brown;

**Logan Hospital:** Hayden White, Kristen Estensen, Lynette Morrison, Joanne Sutton, Melanie Cooper;

**Lyell McEwin Hospital:** Roy Fischer, Vishwanath Biradar, Natalie Soar;

**Mater Hospital Brisbane:** Anne Leditschke, Mackenzie Finnis, Katherine Jongebloed;

**Monash Health (Monash Medical Centre, Dandenong Hospital & Casey Hospital):** Yahya Shehabi, Wisam Al-Bassam, Amanda Hulley, Umesh Kadam, Kushaharan Sathianathan;

**Nepean Hospital:** Ian Seppelt, Christina Whitehead, Julie Lowrey, Rebecca Gresham, Kristy Masters;

**Northern Beaches Hospital:** Matt Phillips, Lenae Terrill;

**Princess Alexandra Hospital:** Peter Kruger, James Walsham, Jason Meyer, Meg Harward, Cassie Jones;

**The Prince Charles Hospital:** Kara Brady, Cassandra Vale, Kiran Shekar, Jayshree Lavana, Dinesh Parmar;

**Prince of Wales:** Gordon Flynn, Claire Harrington;

**The Queen Elizabeth Hospital:** Sandra Peake, Patricia Williams, Catherine Kurenda;

**Redcliffe Hospital:** Stuart Baker, Maree Duroux, Megan Ratcliffe;

**Rockhampton Hospital:** Helen Miles, Antony Attokaran;

**Royal Adelaide Hospital:** Marianne Chapman, Stephanie O'Connor, Kathleen Glasby, Justine Rivett, Nerissa Brown;
Royal Darwin Hospital: Lewis Campbell, Kirsty Smyth;

Royal Melbourne Hospital: Jeffrey Presneill, Deborah Barge, Kathleen Byrne;

Royal North Shore Hospital: Pierre Janin, Elizabeth Yarad, Frances Bass, Naomi Hammond, Anne O'Connor;

Royal Perth Hospital: Sharon Waterson, Steve Webb, Robert McNamara, Melanie Boardman;

Royal Prince Alfred Hospital: David Gattas, Heidi Buhr, Jennifer Coles;

Sir Charles Gairdner Hospital: Sacha Schweikert, Bradley Wibrow, Matthew Anstey, Rashmi Rauniyar;

St George Hospital: Kush Deshpande, Frank van Haren, Pam Konecny, Raymond Tung, Deborah Inskip;

St. John of God Midland Public and Private Hospitals: Ed Fysh, Ashish Davda, Bhaumik Mevavala;

St. John of God Hospital, Murdoch: Annamaria Palermo, Adrian Regli, Bart De Keulenaer;

St. John of God Hospital, Subiaco: Ed Litton, Janet Ferrier;

St. Vincent's Hospital (NSW): Priya Nair, Hergen Buscher, Claire Reynolds, Sally Newman;

St. Vincent's Hospital (VIC): John Santamaria, Leanne Barbazza, Jennifer Homes, Roger Smith;

Sunshine Coast University Hospital: Peter Garrett, Lauren Murray, Jane Brailsford;

Sunshine Hospital: Craig French, Gerard Fennessy, John Mulder, Rebecca Morgan;

The Sutherland Hospital: Anas Naeem, Laura Fagan, Emily Ryan;

Toowoomba Hospital: Vasanth Mariappa, Judith Smith;

University Hospital Geelong: Scott Simpson, Matthew Maiden, Michelle Horton, Jemma Trickey;

Werribee Mercy Hospital: Umesh Kadam, Marlene Gojanovic;

Westmead Hospital: Vineet Nayyar, David Bowen, Jing Kong, Jenyfer Joy;

Wollongong Hospital: Martin Sterba, Wenli Geng;

## Belgium:

Ghent University Hospital: Pieter Depuydt, Jan De Waele, Liesbet De Bus, Jan Fierens, Stephanie Bracke, Joris Vermassen, Daisy Vermeiren;

## Canada:

Brantford General Hospital: Brenda Reeve, William Dechert;

Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec: Francois Lellouche, Patricia Lizotte;

Centre Hospitalier de l'Universite de Montreal: Michaël Chassé, François Martin Carrier, Dounia Boumahni, Fatna Benettaib, Ali Ghamraoui;

CHU de Québec - Université Laval: Alexis Turgeon, David Bellemare, Ève Cloutier, Rana Daher, Olivier Costerousse, Marie-Claude Boulanger, Émilie Couillard-Chénard, François Lauzier, Charles Francoeur;

Centre Hospitalier Universitaire de Sherbrooke: François Lamontagne, Frédérick D'Aragon, Elaine Carbonneau, Julie Leblond;

Grace Hospital: Gloria Vazquez-Grande, Nicole Marten;
Grand River Hospital (Kitchener): Theresa Liu, Atif Siddiqui;

Health Sciences Centre, Winnipeg: Ryan Zarychanski, Gloria Vazquez-Grande, Nicole Marten, Maggie Wilson;

Hôpital du Sacré Coeur de Montréal: Martin Albert, Karim Serri, Alexandros Cavayas, Mathilde Duplaix, Virginie Williams;

Juravinski Hospital: Bram Rochwerg, Tim Karachi, Simon Oczkowski, John Centofanti, Tina Millen

McGill University Health Centre: Kosar Khwaja, Josie Campisi;

Niagara Health (St. Catherine's Hospital): Erick Duan, Jennifer Tsang, Lisa Patterson;

Regina General Hospital: Eric Sy, Jonathan Mailman, Stephen Lee, Chiraag Gupta, Sandy Kassir;

Royal Alexandra Hospital: Demetrios Kutsogiannis, Patricia Thompson;

St. Boniface General Hospital: Ryan Zarychanski, Nicole Marten;

St. Joseph's Healthcare Hamilton: Deborah Cook, Frances Clarke;

St. Mary's General Hospital (Kitchener): Rebecca Kruisselbrink, Atif Siddiqui;

St. Michael's Hospital: John Marshall, Laurent Brochard, Karen Burns, Gyan Sandhu, Imrana Khalid;

Sunnybrook Health Sciences Centre: Rob Fowler, Neill Adhikari, Maneesha Kamra, Nicole Marinoff;

The Ottawa Hospital: Shane English, Irene Watpool, Rebecca Porteous, Sydney Miezitis, Lauralyn McIntyre;

University Health Network: Elizabeth Wilcox, Lorenzo del Sorbo, Hesham Abdelhady, Tina Romagnuolo;

University of Alberta: Wendy Sligl, Nadia Baig, Oleksa Rewa, Sean Bagshaw;

William Osler Health System: Alexandra Binnie, Elizabeth Powell, Alexandra McMillan, Tracy Luk, Noah Aref;

## Critical Care Asia:

### India

Apollo Speciality Hospital - OMR, Chennai: Devachandran Jayakumar, Ramachandran Pratheema, Suresh Babu;

Apollo Main Hospital, Chennai: C Vignesh, Bharath Kumar TV, N Ramakrishnan, Augustian James, Evangeline Elvira;

Apollo Speciality: Vanagaram, Chennai: R Ebenezer, S Krishnaoorthy, Lakshmi Ranganathan, Manisha Ganesan, Madhu Shree;

Apollo First Med Hospital, Chennai: Ashwin Kumar Mani, Meghena Mathew, Revathi Kandeepan;

### Nepal

Chitwan Medical College: Basanta Gauli, Sirjana Bastola;

Grande International Hospital: Sushil Khanal, Sameena Amatya;

HAMS Hospital: Hem Raj Paneru, Sabin Koirala, Pratibha Paudel;

Nepal Mediciti Hospital: Diptesh Aryal, Kanchan Koirala, Namrata Rai, Subekshya Luitel;

Tribhuvan University Teaching Hospital: Hem Raj Paneru, Binita Bhattarai;
## Pakistan

**Abbasi Shaheed Hospital:** Aneela Kidwai, Sobia Masood;

**National Institute of Cardiovascular Diseases Pakistan:** Nawal Salahuddin, Sobia Masood;

**South City Hospital Karachi:** Nasir Khoso, Namra Asif, Huda Taqdees;

**Ziauddin Hospital Clifton Campus:** Madiha Hashmi, Maryam Ali, Noor Hassan, Ashok Panjwani, Zulfiqar Ali Umrani, Mohiuddin Shaikh, Ayesha Siddiqui;

**Ziauddin Hospital North Nazimabad Campus:** Quratul Ain, Darakhshan Kanwal;

## Croatia:

**General Hospital Pozega:** Zdravko Andric, Sabina Cviljevic, Renata Đimoti, Marija Zapalac, Gordan Mirković;

**University Hospital of Infectious Diseases "Fran Milhajevid":** Vladimir Krajinovic, Marko Kutleša, Viktor Kotarski;

**University Hospital of Zagreb:** Ana Vujaklija Brajković, Jakša Babel, Helena Sever, Lidija Dragija, Ira Kušan;

## Estonia:

**Tartu University Hospital:** Kadri Tamme, Veronika Reinhard, Anneli Ellervee, Liisi Põldots, Pille Rennit, Nikolai Svitškar;

## Finland:

**Helsinki University Hospital:** Suvi Vaara, Leena Pettilä, Jonna Heinonen, Ville Pettilä;

**Tampere University Hospital:** Anne Kuitunen, Sari Karlsson, Annukka Vahtera, Heikki Kiiski, Sanna Ristimäki;

## France:

**Ambroise Pare Hospital:** Amine Azaiz, Cyril Charron, Mathieu Godement, Guillaume Geri, Antoine Vieillard-Baron;

**Centre Hospitalier de Dieppe:** Pierre Louis Declerq, Marchalot Antoine, Saladin EP Lafosse Cecile, Gelinotte Stephanie, Eraldi Jean-Pierre, Bourgerol François, Beuzelin Marion, Rigaud Jean Philippe;

**Centre Hospitalier de Melun:** Franck Pourcine, Mehran Monchi;

**Centre Hospitalier Simone Veil, Beauvais:** David Luis, Romain Mercier, Anne Sagnier, Nathalie Verrier, Cecile Caplin, Jack Richecoeu, Daniele Combaux;

**Centre Hospitalier Sud Essonne:** Shidasp Siami, Christelle Aparicio, Sarah Vautier, Asma Jeblaoui, Delphine Lemaire-Brunel;

**Centre Hospitalier Tenon:** Muriel Fartoukh, Laura Courtin, Vincent Labbe, Guillaume Voiriot, Sara Nesrine Salhi;

**Centre Hospitalier Victor Dupouy:** Gaetan Plantefeve, Cécile Leparco, Damien Contou;
**CH de Mont de Marsan:** Arnaud Sement, Alexandre Gachet, Alexis Hanisch, Abdelmagid Haffiane, Anne-Hélène Boivin, Amelie Barreau, Elodie Guerineau, Séverine Poupblanc;

**CH des pays de Morlaix:** Pierre Yves Egreteau, Montaine Lefevre, Simon Bocher, Guillaume Le Loup, Lenaïg Le Guen, Vanessa Carn, Melanie Bertel;

**CHR d'Orleans:** Grégoire Muller, Mai-Anh Nay, Toufik Kamel, Dalila Benzekri, Sophie Jacquier, Isabelle Runge, Armelle Mathonnet, François Barbier, Anne Bretagnol;

**CHRU Tours Hopital Bretonneau:** Emmanuelle Mercier, Delphine Chartier, Charlotte Salmon, Pierre-François Dequin, Denis Garot;

**CHU de Limoges (Dupuytren):** Bruno Francois, Alexandra Gay, Anne-Laure Fedou;

**Hôpital Civil, Hôpitaux Universitaires de Strasbourg:** Ferhat Meziani, Hayat Allam, Jessy Cattelan, Raphael Clere-Jehl, Julie Helms, Christine Kummerlen, Hamid Merdji, Alexandra Monnier, Hassene Rahmani, Antoine Studer;

**Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg:** Francis Schneider, Vincent Castelain, Guillaume Morel, Sylvie L'Hotellier;

**Hôpital Simon Veil, Eaubonne:** Evelina Ochin, Christian Vanjak, Patrick Rouge, Lynda Bendjemar;

**Hospital Nord Franche-Comté:** Julio Badie, Fernando Daniel Berdaguer, Sylvain Malfroy, Chaouki Mezher, Charlotte Bourgoin, Guy Moneger, Elodie Bouvier;

**Lariboisière Hospital:** Bruno Megarbane, Sebastian Voicu, Nicolas Deye, Isabelle Malissin, Laetitia Sutterlin, Aymen Mrad, Adrien Pépin, Lehalleur, Giulia Naim, Philippe Nguyen, Jean-Michel Ekhérian, Yvonnick Boué, Georgios Sidéris, Dominique Vodovar, Emmanuelle Guérin, Caroline Grant;

**Raymond Poincaré Hospital:** Djillali Annane, Pierre Moine, Nicholas Heming, Virginie Maxime, Isabelle Bossard, Tiphaine Barbarin, Nicholier, Bernard Clair, David Orlikowski, Rania Bounab, Lilia Abdeladim

**Vendee Hospital:** Gwenhael Colin, Vanessa Zinzoni, Natacha Maquigneau, Matthieu Henri-Lagarrigue, Caroline Pouplet;

## Germany:

**Carl-Thiem-Klinikum Cottbus gGmbH:** Jens Soukup, Richard Wetzold, Madlen Löbel, Lisa Starke, Patrick Grimm;

**Charité - Universitätsmedizin Berlin:** André Finn, Gabriele Kreß, Uwe Hoff, Carl Friedrich Hinrichs, Jens Nee;

**Elisabeth Krankenhaus Essen:** Ingo Voigt, Robert Schueler, Elisabeth Blank, Vanessa Hüning, Melanie Steffen, Patricia Goralski;

**Jena University Hospital:** Mathias W. Pletz, Stefan Hagel, Juliane Ankert, Steffi Kolanos, Frank Bloos;

**Klinikum Dortmund gGmbH:** Daniela Nickoleit-Bitzenberger, Bernhard Schaaf, Werner Meermeier, Katharina Prebeg, Harun Said Azzaui, Martin Hower, Klaus-Gerd Brieger, Corinna Elender, Timo Sabelhaus, Ansgar Riepe, Ceren Akamp, Julius Kremling, Daniela Klein, Elke Landsiedel-Mechenbier;

**Universitätsklinikum Hamburg-Eppendorf:** Stefan Kluge, Axel Nierhaus, Dominik Jarczak, Kevin Roedl;
**Universitätsklinikum Köln:** Matthias Kochanek, Giusi Rueß-Patrono, Josette McKenzie, Dennis Eichenauer, Alexander Shimabukuro-Vornhagen;

**University Hospital of Frankfurt:** Gernot Gerhard Ulrich Rohde, Achim Grünewaldt, Jörg Bojunga;

**University Hospital of Leipzig:** Sirak Petros, Kevin Kunz, Bianka Schütze;

**University Hospital of Würzburg:** Dirk Weismann, Anna Frey, Maria Drayss, M.E. Goebeler, Thomas Flor, Gertrud Fragner, Nadine Wahl, Juliane Totzke, Cyrus Sayehli;

**Vivantes Klinikum Neukölln:** Lorenz Reill, Michael Distler, Astrid Maselli;

**Hungary:**

**Almási Balogh Pál Hospital, Ózd:** János Bélteczki, István Magyar, Ágnes Fazekas, Sándor Kovács, Viktória Szőke;

**Jósa András County Hospital, Nyíregyháza:** Gábor Szigligeti, János Leszkoven;

**Ireland:**

**Beacon Hospital Dublin:** Daniel Collins, Kathy Brickell, Liadain Reid, Michelle Smyth, Patrick Breen, Sandra Spain;

**Beaumont Hospital:** Gerard Curley, Natalie McEvoy, Pierce Geoghegan, Jennifer Clarke;

**Cork University Hospital:** Dr Patrick Seigne, Joe Eustace, Ann-Marie O'Callaghan, Fionnuala O'Brien;

**Galway University Hospitals:** John Laffey, Bairbre McNicholas, Michael Scully, Siobhan Casey, Maeve Kernan, Aoife Brennan, Ritika Rangan, Riona Tully, Sarah Corbett, Aine McCarthy, Oscar Duffy, David Burke;

**St Vincent's University Hospital, Dublin:** Alistair Nichol, Kathy Brickell, Michelle Smyth, Leanne Hayes, Liadain Reid, Lorna Murphy, Andy Neill, Bryan Reidy, Michael O'Dwyer, Donal Ryan, Kate Ainscough;

**University Hospital Waterford:** Sheeba Hakak, Wahid Altaf, Mike O'Sullivan, Aisling Murphy, Antonio Rega La Valle, Leo Walsh;

**Italy:**

**Humanitas Research Hospital:** Romina Aceto, Alessio Aghemo, Salvatore Badalamenti, Enrico Brunetta, Maurizio Cecconi, Michele Ciccarelli, Elena Constantini, Massimiliano Greco, Marco Folci, Carlo Selmi, Antonio Voza;

**Netherlands:**

**Bernhoven Ziekenhuis Uden:** Kitty Slieker, Esther Ewalds, Arnate Sanders, Wendy Wittenberg, Heidi Peters Geurts;

**Canisius Wilhelmina Ziekenhuis:** Oscar Hoiting, Marco Peters, Els Rengers, Mirjam Evers, Anton Prinssen;

**Deventer Hospital:** Huub L.A. van den Oever, Arriette Kruisdijk-Gerritsen;
**Hagaziekenhuis Den Haag:** Kees van Nieuwkoop, Thomas Ottens, Yorik Visser, Lettie van den Berg, Annemarie van der Kraan-Donker;

**Jeroen Bosch Ziekenhuis:** Koen Simons, Tamara van Zuylen, Angela Bouman;

**MCL Leeuwarden:** Marit van Vonderen, Mario Pietersma, Loes Vrolijk, Linda Kampschreur;

**Meander Medisch Centrum:** Laura van Gulik;

**OLVG Amsterdam:** Nicole Juffermans, Matty Koopmans, Romein Dujardin, Bashar Alderink;

**Radboud University Medical Center Nijmegen:** Jeroen Schouten, Peter Pickkers, Noortje Roovers, Margreet Klop-Riehl, Hetty van der Eng, Frank van de Veerdonk, Sonja Sloots-Cuppen, Lieke Preijers, Nienke van Oosten;

**Rijnstate Ziekenhuis Arnhem:** Robert Jan Hassing, Frances Greven, Danique Huijbens, Harald Roebers;

**UMC Leiden:** Evert de Jonge, Jeanette Wigbers, Michael del Prado;

**UMC Utrecht:** Marc Bonten, Olaf Cremer, Lennie Derde, Jelle Haitsma Mulier, Anna Linda Peters, Birgit Romberg, Helen Leavis, Roger Schutgens, Darren Troeman, Marjolein van Opdorp, Henny Ophorst-den Besten, Karen Brakké;

**Ziekenhuis Gelderse Vallei Ede:** Sjoerd van Bree, Marianne Bouw-Ruiter, Margreet Osinga, Arthur van Zanten;

**New Zealand:**

**Auckland City Hospital, Cardiothoracic and Vascular ICU:** Shay McGuinness, Rachael Parke, Eileen Guilder, Magdalena Butler, Keri-Anne Cowdrey, Melissa Robertson, Farisha Ali, Ellie McMahon;

**Auckland City Hospital, DCCM:** Colin McArthur, Thomas Hills, Eamon Duffy, Yan Chen, Catherine Simmonds, Rachael McConnochie, Caroline O'Connor;

**Christchurch Hospital:** Jay Ritzema Carter, Kymbalee Van Der Heyden, Jan Mehrtens, Anna Morris, Stacey Morgan, Tara Burke;

**Middlemore Hospital:** Tony Williams, Susan Morpeth, Rima Song, Vivian Lai, Hannah Habraken;

**North Shore Hospital:** Robert Everitt, Danielle Hacking;

**Rotorua Hospital:** Ulrike Buehner, Erin Williams;

**Taranaki Base Hospital:** Jonathan Albrett, Carolyn Jackson, Simon Kirkham;

**Tauranga Hospital:** Troy Browne, Kate Grimwade, Jennifer Goodson, Owen Keet, Owen Callender;

**Waikato Hospital:** Robert Martynoga, Kara Trask, Amelia Butler;

**Wellington Regional Hospital:** Paul Young, Chelsea Young, Eden Lesona, Leanlove Navarra, Raulle Sol Cruz, Kirsha Delaney, Rhoze Sol Cruz, April Aguilar-Dano;

**Whangarei Hospital:** Ralph Fuchs, Bridget Lambert;
**Portugal:**

**Hospital de Abrantes:** Nuno José Teodoro Amaro dos Santos Catorze, Tiago Nuno Alfaro Lima Pereira, Ricardo Manuel Castro Ferreira, Joana Margarida Pereira Sousa Bastos, Teresa Margarida Oliveira Batista;

**Romania:**

"Dr. Victor Babes" Clinical Hospital of Infectious and Tropical Diseases Bucharest: Simin Aysel Florescu, Delia Stanciu, Mihaela Florentina Zaharia, Alma Gabriela Kosa, Daniel Codreanu;

**Saudi Arabia:**

**King Abdulaziz Medical City-Riyadh:** Yaseen M Arabi, Eman Al Qasim, Lolowa Alswaidan, Mohamed M Hegazy, Hatim Arishi, Ali Al Amri, Samah Y AlQahtani, Brintha Naidu, Haytham Tlayjeh, Sajid Hussain, Farhan Al Enezi, Sheryl Ann Abdukahil;

**Spain:**

**Hospital del Mar:** Rosana Muñoz-Bermúdez, Judith Marin-Corral, Anna Salazar Degracia, Francisco Parrilla Gómez, Maria Isabel Mateo López;

**Reina Sofía University Hospital:** Rafael León López, Jorge Rodríguez-Gómez, Sheila Cárcel, Rosario Carmona, Carmen de la Fuente, Marina Rodriguez;

**United Kingdom:**

**Aberdeen Royal Infirmary:** Callum Kaye, Amanda Coutts, Lynn MacKay;

**Addenbrooke's Hospital:** Charlotte Summers, Petra Polgarova, Neda Farahi, Eleonore Fox;

**Alder Hey Children's NHS Foundation Trust:** Stephen J McWilliam, Daniel B Hawcutt, Laura Rad, Laura O'Malley, Jennifer Whitbread, Dawn Jones, Rachael Dore, Paula Saunderson;

**Alexandra Hospital Redditch:** Olivia Kelsall, Nicholas Cowley, Laura Wild, Jessica Thrush, Hannah Wood, Karen Austin;

**Altnagelvin Hospital:** Adrian Donnelly, Martin Kelly, Naoise Smyth, Sinéad O'Kane, Declan McClintock, Majella Warnock, Ryan Campbell, Edmund McCallion;

**Antrim Area Hospital:** Paul Johnson, Shirley McKenna, Joanne Hanley, Andrew Currie, Barbara Allen, Clare McGoldrick, Moyra McMaster;

**Barnet Hospital:** Rajeev Jha, Michael Kalogirou, Christine Ellis, Vinodh Krishnamurthy, Aibhilin O'Connor, Saranya Thurairatnam;

**Basildon University Hospital:** Dipak Mukherjee, Agilan Kaliappan, Mark Vertue, Anne Nicholson, Joanne Riches, Gracie Maloney, Lauren Kittridge, Amanda Solesbury, Angelo Ramos;
**Belfast Health and Social Care Trust (Belfast City Hospital, Mater Infirmorum, Royal Victoria Hospital):** Jon Silversides, Peter McGuigan, Kathryn Ward, Aisling O'Neill, Stephanie Finn, Chris Wright, Jackie Green, Érin Collins;

**Brighton and Sussex University Hospitals Trust:** Barbara Phillips, Laura Oritz-Ruiz de Gordoa;

**Calderdale and Huddersfield Foundation Trust:** Jez Pinnell, Matt Robinson, Lisa Gledhill, Tracy Wood;

**Cardiff and Vale University Health Board:** Matt Morgan, Jade Cole, Helen Hill, Michelle Davies, Angharad Williams, Emma Thomas, Rhys Davies, Matt Wise;

**Charing Cross Hospital:** David Antcliffe, Maie Templeton, Roceld Rojo, Phoebe Coghlan, Joanna Smee, Gareth Barker;

**Chesterfield Royal Hospital:** Euan Mackay, Jon Cort, Amanda Whileman, Thomas Spencer, Nick Spittle, Sarah Beavis, Anand Padmakumar, Katie Dale, Joanne Hawes, Emma Moakes, Rachel Gascoyne, Kelly Pritchard, Lesley Stevenson, Justin Cooke, Karolina Nemeth-Roszpopa;

**The Christie NHS Foundation Trust:** Vidya Kasipandian, Amit Patel, Suzanne Allibone, Roman Mary-Genetu;

**Colchester Hospital:** Mohamed Ramali, Ooi HC, Alison Ghosh, Rawlings Osagie, Malka Jayasinghe Arachchige, Melissa Hartley;

**Countess of Chester Hospital:** Peter Bamford, Andrew Reid, Kathryn Cawley, Maria Faulkner, Charlotte Pickering;

**Croydon University Hospital:** Ashok Sundar Raj, Georgios Tsinaslanidis, Reena Nair Khade, Gloria Nwajei Agha, Rose Nalumansi Sekiwala;

**Cumberland Infirmary:** Tim Smith, Chris Brewer, Jane Gregory;

**Darlington Memorial Hospital:** James Limb, Amanda Cowton, Julie O'Brien, Kelly Postlethwaite;

**Derriford Hospital:** Nikitas Nikitas, Colin Wells, Liana Lankester, Helen McMillan;

**Dorset County Hospital:** Mark Pulletz, Patricia Williams, Jenny Birch, Sophie Wiseman, Sarah Horton;

**East Kent Hospitals (Queen Elizabeth the Queen Mother Hospital):** Ana Alegria, Salah Turki, Tarek Elsefi, Nikki Crisp, Louise Allen;

**East Lancashire Hospitals NHS Trust (Royal Blackburn Hospital):** Nicholas Truman, Matthew Smith, Sri Chukkambotla, Wendy Goddard, Stephen Duberley, Meherunnisa Khan, Aayesha Kazi;

**Freeman Hospital and Royal Victoria Infirmary, Newcastle upon Tyne:** Iain J McCullagh, Tom Cairns, Helen Hanson, Bijal Patel, Ian Clement;

**Frimley Health NHS Foundation Trust:** George Evetts, Omar Touma, Susan Holland, Christopher Hodge, Holly Taylor, Meera Alderman, Nicky Barnes, Joana Da Rocha, Catherine Smith, Nicole Brooks, Thanuja Weerasinghe, Julie-Ann Sinclair, Yousuf Abusamra, Ronan Doherty, Joanna Cudlipp, Rajeev Singh, Haili Yu, Admad Daebis, Christopher Ng, Sara Kendrick, Anita Saran, Ahmed Makky, Danni Greener, Louise Rowe-Leete, Alexandra Edwards, Yvonne Bland, Rozzie Dolman, Tracy Foster;

**Gateshead Health NHS Trust:** Vanessa Linnett, Amanda Sanderson, Jenny Ritzema, Helen Wild, Rachael Lucas, Yvonne Marriott;
**George Eliot Hospital:** Divya Khare, Meredith Pinder, Amitha Gopinath, Thogulava Kannan, Steven Dean, Piyush Vanmali;

**Glan Clwyd Hospital:** Richard Pugh, Richard Lean, Xinyi Qiu, Jeremy Scanlan, Andrew Evans, Gwyneth Davies, Joanne Lewis;

**Glangwili General Hospital:** Yvonna Plesnikova, Ahmed Ben Khoud, Samantha Coetzee;

**Glasgow Royal Infirmary:** Kathryn Puxty, Susanne Cathcart, Dominic Rimmer, Catherine Bagot, Kathryn Scott, Laila Martin;

**Glenfield Hospital Leicester:** Hakeem Yusuff, Graziella Isgro, Chris Brightling, Michelle Bourne, Michelle Craner, Rebecca Boyles;

**Grange University Hospital:** Tamas Szakmany, Shiney Cherian, Gemma Williams, Christie James, Abby Waters;

**Great Western Hospitals NHS Foundation Trust:** Rachel Prout, Roger Stedman, Louisa Davies, Suzannah Pegler, Lynsey Kyeremeh, Louise Moorhouse;

**Guy's & St Thomas' NHS Foundation Trust:** Manu Shankar-Hari, Gill Arbane, Marina Marotti, Aneta Bociek, Sara Campos;

**Hammersmith Hospital:** Stephen Brett, Sonia Sousa Arias, Rebecca Elin Hall;

**Homerton University Hospital NHS Foundation Trust:** Susan Jain, Abhinav Gupta, Catherine Holbrook, Pierre Antoine;

**James Cook University Hospital:** Jeremy Henning, Stephen Bonner, Keith Hugill, Emanuel Cirstea, Dean Wilkinson, Jessica Jones, Mohammed Nagy Tawfik Altomy;

**James Paget University Hospitals:** Michal Karlikowski, Helen Sutherland, Elva Wilhelmsen, Jane Woods, Julie North;

**Kettering General Hospital:** Dhinesh Sundaran, Laszlo Hollos, Anna Williams, Margaret Turns, Joanne Walsh;

**King's College Hospital (Denmark Hill site):** Phil Hopkins, John Smith, Harriet Noble, Kevin O'Reilly, Reena Mehta, Onyee Wong, Esther Makanju, Deepak Rao, Nyma Sikondari, Sian Saha, Ele Corcoran, Evita Pappa, Maeve Cockrell, Clare Donegan, Morteza Balaie;

**Lancashire Teaching Hospitals NHS Foundation Trust:** Shondipon Laha, Mark Verlander, Alexandra Williams, Avinash Kumar Jha;

**Leeds Teaching Hospitals Trust:** Elankumaran Paramasivam, Elizabeth Wilby, Bethan Ogg, Clare Howcroft, Angelique Aspinwall, Sam Charlton, Richard Gould, Deena Mistry, Sidra Awan, Caroline Bedford, Joanne Carr-Wilkinson;

**Leicester General Hospital:** Andrew Hall, Jill Cooke, Caroline Gardiner-Hill, Carolyn Maloney, Nigel Brunskill, Olivia Watchorn, Chloe Hardy;

**Leicester Royal Infirmary:** Hafiz R Qureshi, Neil Flint, Sarah Nicholson, Sara Southin, Andrew Nicholson, Amardeep Ghattaoraya;
**Lewisham and Greenwich NHS Trust:** Daniel Harding, Sinead O'Halloran, Amy Collins, Emma Smith, Estefania Trues;

**Liverpool Foundation Trust Aintree:** Barbara Borgatta, Ian Turner-Bone, Amie Reddy, Laura Wilding;

**Liverpool Heart and Chest Hospital:** Craig Wilson, Zuhra Surti;

**Luton and Dunstable University Hospital:** Loku Chamara Warnapura, Ronan Agno, Prasannakumari Sathianathan, Deborah Shaw, Nazia Ijaz, Adam Spong, Suganya Sabaretnam, Dean Burns, Eva Lang, Margaret Louise Tate;

**Maidstone and Tunbridge Wells NHS Trust:** David Golden, Miriam Davey, Rebecca Seaman, Alexander Osborne;

**Manchester Royal Infirmary:** Jonathan Bannard-Smith, Richard Clark, Kathrine Birchall, Joanne Henry, Fiona Pomeroy, Rachael Quayle, Katharine Wylie, Anila Sukuraman, Maya John, Sindhu Sibin;

**Medway Maritime Hospital:** Arystarch Makowski, Beata Misztal, Syeda Haider, Angela Liao, Rebecca Squires;

**Mid & South Essex NHS Foundation Trust:** Aneta Oborska, Abdul Kayani, Selver Kalchko-Veyssal, Rajalakshmi Orath Prabakaran, Bernard Hadebe, Selver Kalchko-Veyssal;

**Milton Keynes University Hospital:** Richard Stewart, Esther Mwaura, Louise Mew, Lynn Wren, Felicity Williams, Sara-Beth Sutherland, Rashmi Rebello;

**Musgrove Park Hospital:** Richard Innes, Patricia Doble, Libby Graham, Charmaine Shovelton, Tessa Dean;

**Nevill Hall Hospital:** Vincent Hamlyn, Nancy Hawkins, Anna Roynon-Reed, Sean Cutler, Sarah Lewis;

**Newham University Hospital:** Juan Martin Lazaro, Tabitha Newman;

**Ninewells Hospital:** Pauline Austin, Susan Chapman, Louise Cabrelli;

**Norfolk and Norwich University Hospital:** Simon Fletcher, Jurgens Nortje, Deirdre Fottrell-Gould, Georgina Randell, Katie Stammers, Gail Healey, Marta Goncalves Pinto;

**North Manchester General Hospital:** Zoe Borrill, Tracy Duncan, Andrew Ustianowski, Alison Uriel, Ayaa Eltayeb, Jordan Alfonso, Samuel Hey, Joanne Shaw, Claire Fox, Gabriella Lindergard, Bethan Charles, Bethany Blackledge, Karen Connolly, Jade Harris;

**North Middlesex University Hospital:** Jeronimo Moreno Cuesta, Kugan Xavier, Dharam Purohit, Munzir Elhassan, Anne Haldeos, Rachel Vincent, Marwa Abdelrazik, Samuel Jenkins, Arunkumar Ganesan, Rohit Kumar, David Carter, Dhanalakshmi Bakthavatsalam, Alasdair Frater, Malik Tahir Saleem;

**Northampton General Hospital:** Mohsin Zaman, Einas Elmahi, Andrea Jones, Kathryn Hall;

**Northern General Hospital, Sheffield:** Gary H Mills, Ajay Raithatha, Kris Bauchmuller, Kim Ryalls, Kate Harrington, Helen Bowler, Jas Sall, Richard Bourne;

**Northwick Park Hospital NHS Trust:** Jamie Gross, Natalie Massey, Olumide Adebambo, Matilda Long, Kiran Tony;

**Oxford University Hospitals:** Matthew Rowland, Paula Hutton, Archana Bashyal, Neil Davidson, Clare Hird;
**Pilgrim Hospital Boston:** Manish Chhablani, Gunjan Phalod, Amy Kirkby, Simon Archer, Kimberley Netherton;

**Poole Hospital:** Henrik Reschreiter, Julie Camsooksai, Sarah Patch, Sarah Jenkins, Charlotte Humphrey;

**Princess Royal Hospital:** Denise Skinner, Jane Gaylard, Julie Newman;

**Princess of Wales Hospital:** Sonia Sathe, Lisa Roche, Ellie Davies;

**Queen Alexandra Hospital Portsmouth:** David Pogson, Steve Rose, Zoe Daly, Lutece Brimfield, Angie Nown;

**Queen Elizabeth Hospital, Birmingham:** Dhruv Parekh, Colin Bergin, Michelle Bates, Christopher McGhee, Daniella Lynch, Khushpreet Bhandal, Kyriaki Tsakiridou, Amy Bamford, Lauren Cooper, Tony Whitehouse, Tonny Veenith, Elliot Forster, Martin O'Connell;

**Queen Elizabeth University Hospital, Glasgow:** Malcolm A.B. Sim, Sophie Kennedy Hay, Steven Henderson, Maria Nygren, Eliza Valentine;

**Queen's Hospital, Burton:** Amro Katary, Gillian Bell, Louise Wilcox, Michail Mataliotakis, Paul Smith, Murtaza Asif Ali, Agah Isguzar;

**Queen's Hospital, Romford:** Mandeep-Kaur Phull, Abbas Zaidi, Tatiana Pogreban, Lace Paulyn Rosaroso;

**Queen's Medical Centre and Nottingham City Hospital:** Daniel Harvey, Benjamin Lowe, Megan Meredith, Lucy Ryan, DREEAM Research Team;

**The Rotherham NHS Foundation Trust:** Anil Hormis, Rachel Walker, Dawn Collier, Sarah Kimpton, Susan Oakley;

**Royal Alexandra Hospital:** Kevin Rooney, Natalie Rodden, Nicola Thomson, Deborah McGlynn, Lynn Abel, Lisa Gemmell, Radha Sundaram, James Hornsby;

**Royal Berkshire Hospital:** Andrew Walden, Liza Keating, Matthew Frise, Sabi Gurung Rai, Shauna Bartley;

**Royal Bournemouth and Christchurch Hospitals:** Martin Schuster-Bruce, Sally Pitts, Rebecca Miln, Laura Purandare, Luke Vamplew;

**Royal Brompton Hospital:** Brijesh Patel, Debra Dempster, Mahitha Gummadi, Natalie Dormand, Shu Fang Wang;

**Royal Cornwall NHS Trust:** Michael Spivey, Sarah Bean, Karen Burt, Lorraine Moore, Fiona Hammonds, Carol Richards;

**Royal Devon and Exeter NHS Foundation Trust:** Christopher Day, Letizia Zitter, Sarah Benyon;

**Royal Glamorgan Hospital:** Jayaprakash Singh, Ceri Lynch, Lisa Roche, Justyna Mikusek, Bethan Deacon, Keri Turner;

**Royal Gwent Hospital:** Evelyn Baker, John Hickey, Shreekant Champanerkar, Lindianne Aitken, Lorraine LewisProsser, Christie James;

**Royal Hallamshire Hospital, Sheffield:** Gary H Mills, Norfaizan Ahmad, Matt Wiles, Jayne Willson;

**Royal Hampshire Hospitals:** Irina Grecu, Jane Martin, Caroline Wrey Brown, Ana-Marie Arias, Emily Bevan, Samantha Westlake;
**Royal Infirmary of Edinburgh:** Thomas H Craven, David Hope, Jo Singleton, Sarah Clark, Corrienne McCulloch, Simon Biddie;

**Royal Liverpool University Hospital:** Ingeborg D Welters, David Oliver Hamilton, Karen Williams, Victoria Waugh, David Shaw, Suleman Mulla, Alicia Waite, Jaime Fernandez Roman, Maria Lopez Martinez, Brian Johnston;

**The Royal Free Hospital:** Sanjay Bhagani, Mark De Neef, Sara Mingo Garcia, Amitaa Maharajh, Aarti Nandani, Jade Dobson, Gloria Fernando, Christine Eastgate, Keith Gomez, Zakee Abdi;

**Royal London Hospital:** Zudin Puthucheary, Timothy Martin, Filipa Santos, Ruzena Uddin, Maria Fernandez, Fatima Seidu, Alastair Somerville, Mari-Liis Pakats, Salma Begum, Tasnin Shahid;

**The Royal Marsden NHS Foundation Trust:** Kate Colette Tatham, Shaman Jhanji, Ethel Black, Arnold Dela Rosa, Ryan Howle, Ravishankar Rao Baikady;

**The Royal Oldham Hospital:** Redmond P Tully, Andrew Drummond, Joy Dearden, Jennifer E Philbin, Sheila Munt;

**Royal Papworth Hospital:** Alain Vuylsteke, Charles Chan, Saji Victor, COVID Research Team, Papworth Hospital;

**Royal Stoke Hospital:** Ramprasad Matsa, Minerva Gellamucho, Michelle Davies;

**Royal Surrey County Hospital:** Ben Creagh-Brown, Cheryl Marriot, Armorel Salberg, Louisa Zouita, Sarah Stone, Natalia Michalak, Sinead Donlon, Shelia Mtuwa, Irving Mayangao, Jerik Verula, Dorota Burda, Celia Harris, Emily Jones, Paul Bradley, Esther Tarr, Lesley Harden, Charlie Piercy;

**Royal United Hospital Bath:** Jerry Nolan, Ian Kerslake, Tim Cook, Tom Simpson, James Dalton, Carrie Demetriou, Sarah Mitchard, Lidia Ramos, Katie White, Toby Johnson, William Headdon, Stephen Spencer, Alison White, Lucy Howie;

**The Royal Wolverhampton NHS Trust:** Shameer Gopal, Jagtar- Singh Pooni, Saibal Ganguly, Andrew Smallwood, Stella Metherell;

**Russells Hall Hospital:** Michael Reay, Steve Jenkins, Angela Watts, Eleanor Traverse, Stacey Jennings, Vikram Anumakonda, Caroline Tuckwell, Karen Pearson, Kath Harrow, Julie Matthews, Karen McGarry, Vanessa Moore, Lucie Smith, Anna Summerfield;

**Salford Royal NHS Foundation Trust:** Paul Dark, Alice Harvey, Reece Doonan, Liam McMorrow, Karen Knowles, Jessica Pendlebury, Stephanie Lee, Jane Perez, Bethan Charles, Tracy Marsden, Melanie Taylor, Angiy Michael, Matthew Collis, Andrew Claxton, Wadih Habeichi, Dan Horner, Melanie Slaughter, Vicky Thomas, Nicola Proudfoot, Claire Keatley;

**Salisbury NHS Foundation Trust:** Phil Donnison, Ruth Casey, Ben Irving, Wadzanai Matimba-Mupaya, Catherine Reed, Alpha Anthony, Fiona Trim, Lenka Cambalova, Debra Robertson, Anna Wilson;

**Sandwell and West Birmingham NHS Trust:** Jonathan Hulme, Santhana Kannan, Fiona Kinney, Ho Jan Senya, Anne Hayes;

**Sherwood Forest Hospitals NHS Foundation Trust:** Valli Ratnam, Mandy Gill, Jill Kirk, Sarah Shelton;
**South Tyneside District Hospital:** Christian Frey, Riccardo Scano, Madeleine McKee, Peter Murphy;

**Southmead Hospital:** Matt Thomas, Ruth Worner, Beverley Faulkner, Emma Gendall, Kati Hayes, Hayley Blakemore, Borislava Borislavova;

**St. Bartholomew's Hospital:** Colin Hamilton-Davies, Carmen Chan, Celina Mfuko, Hakam Abbass, Vineela Mandadapu;

**St. George's Hospital:** Susannah Leaver, Kamal Patel, Sarah Farnell-Ward, Romina Pepermans Saluzzio, Sam Rawlins, Christine Sicat;

**St. Mary's Hospital:** Anthony Gordon; Dorota Banach, Ziortza Fernández de Pinedo Artaraz, Leilani Cabreros, Victoria Latham;

**St. Peter's Hospital, Chertsey:** Ian White, Maria Croft, Nicky Holland, Rita Pereira;

**Stepping Hill Hospital, Stockport:** Ahmed Zaki, David Johnson, Hywel Garrard, Vera Juhaz, Louise Brown, Abigail Pemberton;

**Sunderland Royal Hospital:** Alistair Roy, Anthony Rostron, Lindsey Woods, Sarah Cornell;

**Swansea Bay University Health Board:** Suresh Pillai, Rachel Harford, Helen Ivatt, Debra Evans, Suzanne Richards, Eilir Roberts, James Bowen, James Ainsworth;

**Torbay and South Devon NHS Foundation Trust:** Angela Foulds, Adam Revill;

**United Lincolnshire NHS Trust:** Russell Barber, Anette Hildrith, Gunjan Phalod;

**University Hospitals Bristol & Weston NHS Foundation Trust:** Jeremy Bewley, Katie Sweet, Lisa Grimmer, Rebekah Johnson, Rachel Wyatt, Karen Morgan, Siby Varghese, Charlotte Bradbury, Joanna Willis, Emma Stratton, Laura Kyle, Daniel Putensen, Kay Drury, Agnieszka Skorko;

**University Hospitals Coventry & Warwickshire NHS Trust:** Pamela Bremmer, Geraldine Ward, Christopher Bassford;

**University Hospital of North Tees:** Farooq Brohi, Vijay Jagannathan, Michele Clark, Sarah Purvis, Bill Wetherill;

**University Hospital Southampton NHS Foundation Trust:** Ahilanandan Dushianthan, Rebecca Cusack, Kim de Courcy-Golder, Karen Salmon, Rachel Burnish, Simon Smith, Susan Jackson, Winningtom Ruiz, Zoe Duke, Magaret Johns, Michelle Male, Kirsty Gladas, Satwinder Virdee, Jacqueline Swabe, Helen Tomlinson;

**Warwick Hospital:** Ben Attwood, Penny Parsons, Bridget Campbell, Alex Smith;

**Watford General Hospital:** Valerie J Page, Xiao Bei Zhao, Deepali Oza, Gail Abrahamson, Ben Sheath, Chiara Ellis;

**Western General Hospital, Edinburgh:** Jonathan Rhodes, Thomas Anderson, Sheila Morris;

**Whipps Cross Hospital:** Charlotte Xia Le Tai, Amy Thomas, Alexandra Keen, Carey Tierney, Nimca Omer, Gina Bacon;

**Whiston Hospital:** Ascanio Tridente, Karen Shuker, Jeanette Anders, Sandra Greer, Paula Scott, Amy Millington, Philip Buchanan, Jodie Kirk;
**Wirral University Teaching Hospital NHSFT:** Craig Denmade, Girendra Sadera, Reni Jacob, Cathy Jones, Debbie Hughes;

**Worcester Royal Hospital:** Stephen Digby, Nicholas Cowley, Laura Wild, Jessica Thrush, Hannah Wood, Karen Austin;

**Wrexham Maelor Betsi Cadwaladr University Hospital:** David Southern, Harsha Reddy, Sarah Hulse, Andrew Campbell, Mark Garton, Claire Watkins, Sara Smuts;

**Wrightington, Wigan and Leigh Teaching Hospitals NHS Foundation Trust:** Alison Quinn, Benjamin Simpson, Catherine McMillan, Cheryl Finch, Claire Hill, Josh Cooper;

**Wye Valley NHS Trust:** Joanna Budd, Charlotte Small, Ryan O'Leary, Janine Birch, Emma Collins, Andrew Holland;

**Wythenshawe Hospital:** Peter D G Alexander, Tim Felton, Susan Ferguson, Katharine Sellers, Luke Ward;

**York Teaching Hospital:** David Yates, Isobel Birkinshaw, Kay Kell, Zoe Scott, Harriet Pearson;

## United States of America:

**University of Pittsburgh Research Staff:** CRISMA Center—Kelsey Linstrum, Stephanie Montgomery, Kim Basile, Dara Stavor, Dylan Burbee, Amanda McNamara, Renee Wunderley, Nicole Bensen, Aaron Richardson; MACRO Center—Peter Adams, Tina Vita, Megan Buhay, Denise Scholl, Matthew Gilliam, James Winters, Kaleigh Doherty, Emily Berryman;

**UPMC Hospital Champions:** UPMC Altoona—Mehrdad Ghaffari, UPMC East—Meghan Fitzpatrick; UPMC Jameson and Horizon—Kavitha Bagavathy, Debra Drapola; UPMC Mercy—Mahwish Hussain, Chenell Donadee; UPMC Williamsport—Emily Brant; UPMC McKeesport—Kayla Bryan-Morris, John Arnold and Bob Reynolds; UPMC Hamot—Gregory Beard; UPMC Presbyterian—David Huang, David McAdams, Bryan McVerry, Gena Walker; UPMC Pinnacle—Janice Dunsavage, Salim Saiyed, Erik Hernandez, John Goldman, Cynthia Brown, Susan Comp, James Raczek, Jenny Lynne Morris, Jesus Vargas Jr., Daniel Weiss, Joseph W. Hensley, Erik Kochert, Chris Wnuk, Christopher Nemeth, Brent Mowery, Christina Hutchinson, Lauren Winters

**UPMC Covid-19 Therapeutics Committee:** Erin McCreary, Elise Martin, Ryan Bariola, Alex Viehman, Jessica Daley, Alyssa Lopus, Mark Schmidhofer, UPMC Directors of Pharmacy;

**UPMC ICU Service Center:** Rachel Sackrowitz, Chenell Donadee, Aimee Skrtich;

**UPMC Wolff Center:** Tami Minnier, Mary Kay Wisniewski, Katelyn Mayak;

**UPMC eRecord Team:** Richard Ambrosino, Sherbrina Keen, Sue Della Toffalo, Martha Stambaugh, Ken Trimmer, Reno Perri, Sherry Casali, Rebecca Medva, Brent Massar, Ashley Beyerl, Jason Burkey, Sheryl Keeler, Maryalyce Lowery, Lynne Oncea, Jason Daugherty, Chanthou Sevilla, Amy Woelke, Julie Dice, Lisa Weber, Jason Roth, Cindy Ferringer, Deborah Beer, Jessica Fesz, Lillian Carpio;
**Data Collection/Curation Team:** Salim Malakouti (Computer Science, University of Pittsburgh), Edvin Music and Dan Ricketts (CRISMA Center), Andrew King (Biomedical Informatics, University of Pittsburgh), Gilles Clermont (Critical Care Medicine), Robert Bart (UPMC Health Services Division);

**UPMC Clinical Analytics:** Oscar Marroquin, Kevin Quinn, William Garrard, Kyle Kalchthaler

**UPMC Office of Healthcare Innovation:** Derek Angus, Christopher Seymour, Kelsey Linstrum, Stephanie Montgomery;

**Department of Emergency Medicine:** Alexandra Weissman, Donald Yealy, David Barton, Nadine Talia;

**Department of Critical Care Medicine:** David Huang, Florian Mayr, Andrew Schoenling, Mark Andreae, Varun Shetty, Emily Brant, Brian Malley, Chenell Donadee, Derek Angus, Christopher Horvat, Christopher Seymour, Timothy Girard, Gilles Clermont, Rachel Sackrowitz, Robert Bart;

**Division of Infectious Diseases:** Ghady Haidar;

**Division of Pulmonary, Allergy, and Critical Care Medicine:** William Bain, Ian Barbash, Meghan Fitzpatrick, Christopher Franz, Georgios Kitsios, Bryan McVerry, Kaveh Moghbeli, Brian Rosborough, Faraaz Shah, Tomeka Suber;

**Global Coalition for Adaptive Research (GCAR):** Meredith Buxton, Brian Alexander, Tracey Roberts, Apoorva Nelli, Rachel Rosenstein-Sisson, Rebecca Speyer, Yadira Pech;

**UPMC Laboratory Services:** Alan H. Wells;
## 2. Supplementary methods

### 2.1 Outcomes:

#### EQ-5D-5L

The EQ-5D-5L is a preference-based QoL instrument comprised of five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Respondents are asked to choose the most appropriate option from five alternatives (no, slight, moderate, severe or extreme problems). In addition, respondents were asked to indicate their present health state on a visual analogue scale (EQ VAS) ranging from the worst imaginable health state ("0") to the best imaginable health state ("100"). EQ-5D-5L utility scores were calculated where a valid response (1 to 5) was available for each of the 5 EQ-5D-5L domains, and the EQ-5D-5L was conducted within the 12 weeks following day 180. Scores were calculated using the crosswalk link function and the individual responses to the EQ-5D-5L descriptive system, using the UK time trade off (TTO) value set, with values between -0.594 and 1.00.

#### WHODAS

The 12-item WHODAS 2.0 covers six domains of functioning with scores from 0 (no difficulty) to 4 (extreme difficulty) and a total score ranging from 0 to 48, with higher scores representing greater disability. The total score is divided by 48 and multiplied by 100 to convert it to a percentage of maximum disability. Where a single WHODAS item was missing, the mean value of the remaining 11 items was assigned to the missing item. Scores were only calculated where the WHODAS was conducted within the 12 weeks following day 180. WHODAS percentage scores were used to determine mutually exclusive disability categories: 1) no disability (0-4.5%); 2) mild disability (4.5-24.5%); 3) moderate disability (24.5-49.5%); 4) severe disability (49.5-95.5%); and 5) complete disability (95.5-100%).
<table><caption>Table S1: Platform and domain-specific inclusion and exclusion criteria</caption><thead><tr><th></th><th>Inclusion Criteria</th><th>Exclusion Criteria (including intervention-specific exclusion criteria)</th></tr></thead><tbody><tr><td>Platform</td><td><ul><li>Adult patient admitted to an ICU for acute severe CAP within 48 hours of hospital admission with a. symptoms or signs or both that are consistent with lower respiratory tract infection (for example, acute onset of dyspnea, cough, pleuritic chest pain) AND b. Radiological evidence of new onset infiltrate of infective origin (in patients with preexisting radiological changes, evidence of new infiltrate)</li><li>Up to 48 hours after ICU admission, receiving organ support with one or more of: a. Non-invasive or invasive ventilatory support; b. Receiving infusion of vasopressor or inotropes or both</li></ul></td><td><ul><li>Healthcare-associated pneumonia: a. Prior to this illness, is known to have been an inpatient in any healthcare facility within the last 30 days b. Resident of a nursing home or long-term care facility</li><li>Death is deemed to be imminent and inevitable during the next 24 hours AND one or more of the patient, substitute decision maker or attending physician are not committed to full active treatment</li><li>Previous participation in this REMAP within the last 90 days</li></ul></td></tr><tr><td>Immune modulation</td><td><ul><li>COVID-19 infection is suspected by the treating clinician or has been confirmed by microbiological testing</li><li>Microbiological testing for SARS-CoV-2 infection of upper or lower respiratory tract secretions or both has occurred or is intended to occur</li></ul></td><td><ul><li>More than 24 hours has elapsed since ICU admission</li><li>Patient has already received any dose of one or more of any form of interferon, anakinra, tocilizumab, or sarilumab during this hospitalization or is on long-term therapy with any of these agents prior to this hospital admission</li><li>Known condition or treatment resulting in ongoing immune suppression including neutropenia prior to this hospitalization</li><li>Patient has been randomized in a trial evaluating an immune modulation agent for proven or suspected COVID-19 infection, where the protocol of that trial requires ongoing administration of study drug</li><li>The treating clinician believes that participation in the domain would not be in the best interests of the patient</li><li>Known hypersensitivity to an agent specified as an intervention in this domain will exclude a patient from receiving that agent</li><li>Intention to prescribe systemic corticosteroids for any reason, other than participation in the Corticosteroid Domain of this platform, will result in exclusion from receiving IFN-β1a</li><li>Known hypersensitivity to proteins produced by E. coli will result in exclusion from receiving anakinra</li><li>Known or suspected pregnancy will result in exclusion from the anakinra, IFN-β1a, tocilizumab and sarilumab interventions.</li><li>A baseline alanine aminotransferase or an aspartate aminotransferase that is more than five times the upper limit of normal will result in exclusion from receiving tocilizumab or sarilumab</li><li>A baseline platelet count &lt; 50 x 10<sup>9</sup> / L will result in exclusion from receiving tocilizumab or sarilumab</li></ul></td></tr></tbody></table>
<table><caption>Table S1 continued: Platform and domain-specific inclusion and exclusion criteria</caption><thead><tr><th></th><th>Inclusion Criteria</th><th>Exclusion Criteria (including intervention-specific exclusion criteria)</th></tr></thead><tbody><tr><td>Immunoglobulin</td><td><ul><li>COVID-19 infection is confirmed by microbiological testing</li></ul></td><td><ul><li>More than 48 hours have elapsed since ICU admission</li><li>Patient has already received treatment with any non-trial prescribed antibody therapy (monoclonal antibody, hyperimmune immunoglobulin, or convalescent plasma) intended to be active against COVID-19 during this hospital admission</li><li>More than 14 days have elapsed since hospital admission</li><li>The treating clinician believes that participation in the domain would not be in the best interests of the patient</li><li>Known hypersensitivity to an agent specified as an intervention in this domain</li><li>Known previous history of transfusion-related acute lung injury</li><li>Known objection to receiving plasma products</li></ul></td></tr><tr><td>Antiplatelet</td><td><ul><li>COVID-19 infection is suspected by the treating clinician or has been confirmed by microbiological testing</li><li>Microbiological testing for SARS-CoV-2 infection of upper or lower respiratory tract secretions or both has occurred or is intended to occur</li></ul></td><td><ul><li>More than 48 hours has elapsed since ICU admission (noting that this may be operationalized as more than 48 hours has elapsed since commencement of sustained organ failure support)</li><li>Clinical or laboratory bleeding risk or both that is sufficient to contraindicate antiplatelet therapy</li><li>Patient is already receiving antiplatelet therapy or NSAID (non-steroidal anti-inflammatory drug) or a clinical decision has been made to commence antiplatelet or NSAID therapy</li><li>Enrolment in a trial evaluating anticoagulation or antiplatelet therapy for proven or suspected COVID-19 infection, where the protocol of that trial requires continuation of the treatment assignment specified in that trial</li><li>Patients otherwise eligible for the Therapeutic Anticoagulation Domain will be excluded from the Antiplatelet Domain if age is more than 75 years</li><li>Creatinine Clearance &lt;30ml/min, or receiving renal replacement therapy or ECMO</li><li>The treating clinician believes that participation in the domain would not be in the best interests of the patient</li><li>Known hypersensitivity to an agent specified as an intervention in this domain will exclude a patient from receiving that agent</li><li>Known or suspected pregnancy will result in exclusion from the P2Y12 inhibitor intervention</li><li>Administration or intention to administer lopinavir/ritonavir will result in exclusion from the P2Y12 inhibitor intervention at sites that are using clopidogrel and ticagrelor as the P2Y12 inhibitor</li></ul></td></tr></tbody></table>
<table><caption>Table S1 continued: Platform and domain-specific inclusion and exclusion criteria</caption><thead><tr><th>Domain</th><th>Inclusion Criteria</th><th>Exclusion Criteria (including intervention-specific exclusion criteria)</th></tr></thead><tbody><tr><td>Anticoagulation</td><td><ul><li>COVID-19 infection is suspected by the treating clinician or has been confirmed by microbiological testing</li><li>Microbiological testing for SARS-CoV-2 infection of upper or lower respiratory tract secretions or both has occurred or is intended to occur</li></ul></td><td><ul><li>More than 48 hours has elapsed since ICU admission (noting that this may be operationalized as more than 48 hours has elapsed since commencement of organ failure support)</li><li>Clinical or laboratory bleeding risk or both that is sufficient to contraindicate therapeutic anticoagulation, including intention to continue or commence dual anti-platelet therapy</li><li>Therapeutic anticoagulation is already present due to prior administration of any anticoagulant agent that is known or likely to still be active or a clinical decision has been made to commence therapeutic anticoagulation</li><li>Enrolment in a trial evaluating anticoagulation for proven or suspected COVID-19 infection, where the protocol of that trial requires continuation of the treatment assignment specified in that trial</li><li>Known or suspected previous adverse reaction to UFH or LMWH including heparin induced thrombocytopenia (HIT).</li><li>The treating clinician believes that participation in the domain would not be in the best interests of the patient</li></ul></td></tr><tr><td>Antiviral</td><td><ul><li>COVID-19 infection is suspected by the treating clinician or has been confirmed by microbiological testing</li><li>Microbiological testing for SARS-CoV-2 infection of upper or lower respiratory tract secretions or both has occurred or is intended to occur</li></ul></td><td><ul><li>More than 48 hours has elapsed since ICU admission</li><li>Patient has already received more than 36 hours of treatment with any non-trial prescribed systemic antiviral medication, other than remdesivir, intended to be active against COVID-19 during this hospital admission</li><li>Patient has been randomized in a trial evaluating an antiviral intended to be active against COVID-19, where the protocol of that trial requires ongoing administration of study drug</li><li>In areas where MERS-CoV infection is endemic, the patient has laboratory confirmed MERS-CoV infection</li><li>The treating clinician believes that participation in the domain would not be in the best interests of the patient</li><li>Known hypersensitivity to an agent specified as an intervention in this domain will exclude a patient from receiving that agent</li><li>Receiving an agent that is specified as an intervention in this domain as a usual medication prior to this hospitalization will exclude a patient from receiving that agent</li><li>Known HIV infection will exclude a patient from receiving lopinavir/ritonavir</li><li>Known or suspected pregnancy will result in exclusion from any intervention that includes lopinavir/ritonavir or hydroxychloroquine</li><li>Receiving amiodarone as a usual medication prior to this hospitalization or any administration of amiodarone within the 72 hours prior to assessment of eligibility will exclude a patient from receiving lopinavir/ritonavir</li><li>High clinical risk of sustained ventricular dysrhythmia will exclude a patient from receiving hydroxychloroquine</li></ul></td></tr></tbody></table>
Table S1 continued: Platform and domain-specific inclusion and exclusion criteria

<table><thead><tr><td>Domain</td><td>Inclusion Criteria</td><td>Exclusion Criteria (including intervention-specific exclusion criteria)</td></tr></thead><tbody><tr><td>Corticosteroid</td><td>No domain-specific inclusion criteria</td><td><ul><li>Known hypersensitivity to hydrocortisone</li><li>An indication to prescribe systemic corticosteroids for a reason that is unrelated to the current episode of CAP (or direct complications of CAP), such as chronic corticosteroid use before admission, acute severe asthma, or suspected or proven Pneumocystis jiroveci pneumonia</li><li>More than 24 hours have elapsed since ICU admission; or In France, more than 36 hours have elapsed since ICU admission</li><li>The treating clinician believes that participation in the domain would not be in the best interests of the patient</li></ul></td></tr></tbody></table>
<table><caption>Table S2: Patients and follow up by country of enrolment</caption><thead><tr><th>Country</th><th>Number of sites</th><th>Sites completing Day 180 vital status follow up (n)</th><th>Sites completing HRQoL or disability follow up (n)</th><th>Number of patients randomized <sup>a</sup></th><th>Patients with Day 90 vital status follow up, n/N (%)</th><th>Patients with Day 180 vital status follow up, n/N (%)<sup>b</sup></th><th>Patients with HRQoL or disability follow up, n/N (%)<sup>c</sup></th></tr></thead><tbody><tr><td>Australia</td><td>16</td><td>16</td><td>16</td><td>39</td><td>39/39 (100)</td><td>38/39 (97.4)</td><td>29/34 (85.3)</td></tr><tr><td>Canada</td><td>17</td><td>17</td><td>17</td><td>203</td><td>201/203 (99.0)</td><td>199/203 (98.0)</td><td>116/127 (91.3)</td></tr><tr><td>Finland</td><td>1</td><td>1</td><td>1</td><td>3</td><td>3/3 (100)</td><td>3/3 (100)</td><td>1/1 (100)</td></tr><tr><td>France</td><td>6</td><td>5</td><td>5</td><td>65</td><td>63/65 (96.9)</td><td>58/62 (93.5)</td><td>26/45 (57.8)</td></tr><tr><td>Germany</td><td>1</td><td>1</td><td>1</td><td>7</td><td>6/7 (85.7)</td><td>3/7 (42.9)</td><td>0/3 (0.0)</td></tr><tr><td>India</td><td>4</td><td>0</td><td>0</td><td>62</td><td>55/62 (88.7)</td><td>NA <sup>d</sup></td><td>NA <sup>d</sup></td></tr><tr><td>Ireland</td><td>3</td><td>3</td><td>3</td><td>51</td><td>51/51 (100)</td><td>51/51 (100)</td><td>30/32 (93.8)</td></tr><tr><td>Italy</td><td>1</td><td>1</td><td>0</td><td>13</td><td>13/13 (100)</td><td>12/13 (92.3)</td><td>0/10 (0.0)</td></tr><tr><td>Nepal</td><td>5</td><td>0</td><td>0</td><td>64</td><td>62/64 (96.9)</td><td>NA <sup>d</sup></td><td>NA <sup>d</sup></td></tr><tr><td>Netherlands</td><td>11</td><td>11</td><td>10</td><td>216</td><td>215/216 (99.5)</td><td>208/216 (96.3)</td><td>133/155 (85.8)</td></tr><tr><td>New Zealand</td><td>4</td><td>4</td><td>4</td><td>4</td><td>4/4 (100)</td><td>4/4 (100)</td><td>2/2 (100)</td></tr><tr><td>Saudi Arabia</td><td>1</td><td>1</td><td>1</td><td>111</td><td>111/111 (100)</td><td>108/111 (97.3)</td><td>60/61 (98.4)</td></tr><tr><td>United Kingdom</td><td>126</td><td>117</td><td>112</td><td>3885</td><td>3832/3885 (98.6)</td><td>3423/3609 (94.8)</td><td>579/2119 (27.3)</td></tr><tr><td>United States of America</td><td>1</td><td>0</td><td>0</td><td>68</td><td>64/68 (94.1)</td><td>NA <sup>d</sup></td><td>NA <sup>d</sup></td></tr></tbody></table>

NA denotes Not Applicable

<sup>a</sup>The denominator presented is the number of patients randomized to one or more of the six closed domains who have not withdrawn consent.

<sup>b</sup>The denominator presented is the number of patients randomized to one or more of the six closed domains who have not withdrawn consent and were randomized at a site participating in day 180 vital status follow-up.

<sup>c</sup>The denominator presented is the number of patients randomized to one or more of the six closed domains who have not withdrawn consent, were known to be alive at day 180, and were randomized at a site participating in HRQoL or disability follow-up.

<sup>d</sup>No sites participating in day 180 follow-up
<table><caption>Table S3: Baseline characteristics of patients in the immune modulation domain</caption><thead><tr><th>Characteristic</th><th>Tocilizumab<br>N=948</th><th>Sarilumab<br>N=485</th><th>Anakinra<br>N=371</th><th>No immune modulator<br>N=406</th></tr></thead><tbody><tr><td>Age in years, median (IDR)</td><td>61 (54 - 70)</td><td>59 (51 - 68)</td><td>61 (52-68)</td><td>62 (53-70)</td></tr><tr><td>Male sex, n (%)</td><td>654 (69.0)</td><td>326 (67.2)</td><td>267 (72.0)</td><td>285 (70.2)</td></tr><tr><td>Female sex, n (%)</td><td>294 (31.0)</td><td>159 (32.8)</td><td>104 (28.0)</td><td>121 (29.8)</td></tr><tr><td>Race/Ethnicity <sup>a</sup>, n/N (%)</td><td></td><td></td><td></td><td></td></tr><tr><td>Asian</td><td>124/730 (17.0)</td><td>54/462 (11.7)</td><td>40/254 (15.8)</td><td>53/318 (16.7)</td></tr><tr><td>Black</td><td>37/730 (5.1)</td><td>10/462 (2.2)</td><td>9/254 (3.5)</td><td>10/318 (3.1)</td></tr><tr><td>Mixed</td><td>13/730 (1.8)</td><td>2/462 (0.4)</td><td>6/254 (2.4)</td><td>6/318 (1.9)</td></tr><tr><td>Other <sup>a</sup></td><td>36/730 (4.9)</td><td>22/462 (4.8)</td><td>16/254 (6.3)</td><td>14/318 (4.4)</td></tr><tr><td>White</td><td>520/730 (71.2)</td><td>374/462 (81.0)</td><td>183/254 (72.1)</td><td>235/318 (73.9)</td></tr><tr><td>Confirmed SARS-CoV2 infection, n/N (%)<sup>b</sup></td><td>803/945 (85.0)</td><td>430/485 (88.7)</td><td>321/371 (86.5)</td><td>349/406 (86.0)</td></tr><tr><td>Body mass index, kg/m<sup>2</sup>, median (IQR)</td><td>30.4 (36.6 - 34.9)<br>[N=860]</td><td>31.3 (27.7 - 36.3)<br>[N=419]</td><td>29.7 (26.3 - 35.3)<br>[N=331]</td><td>30.9 (27.1 - 34.9)<br>[N=385]</td></tr><tr><td>APACHE II score <sup>c</sup>, median (IQR)</td><td>13 (8-19) [N=933]</td><td>12 (7-20) [N=477]</td><td>13 (8-19) [N=367]</td><td>12 (8-18) [N=394]</td></tr><tr><td>Pre-existing conditions, n/N (%) <sup>d</sup></td><td></td><td></td><td></td><td></td></tr><tr><td>Diabetes mellitus</td><td>280/946 (29.6)</td><td>108/485 (22.3)</td><td>125/371 (33.7)</td><td>152/406 (37.4)</td></tr><tr><td>Respiratory disease</td><td>217/946 (22.9)</td><td>117/485 (24.1)</td><td>82/371 (22.1)</td><td>100/406 (24.6)</td></tr><tr><td>Asthma/COPD</td><td>182/946 (19.2)</td><td>99/485 (20.4)</td><td>68/371 (18.3)</td><td>89/406 (21.9)</td></tr><tr><td>Other</td><td>40/946 (4.2)</td><td>26/485 (5.4)</td><td>17/371 (4.6)</td><td>17/406 (4.2)</td></tr><tr><td>Kidney disease</td><td>65/863 (7.5)</td><td>30/447 (6.7)</td><td>23/342 (6.7)</td><td>43/377 (11.4)</td></tr><tr><td>Severe cardiovascular disease</td><td>86/927 (9.3)</td><td>33/475 (7.0)</td><td>41/368 (11.1)</td><td>47/401 (11.7)</td></tr><tr><td>Immunosuppressive disease</td><td>20/946 (2.1)</td><td>5/485 (1.0)</td><td>6/371 (1.6)</td><td>15/406 (3.7)</td></tr><tr><td>Chronic immunosuppressive therapy</td><td>10/946 (1.1)</td><td>8/485 (1.7)</td><td>4/371 (1.1)</td><td>7/406 (1.7)</td></tr><tr><td>Time to enrolment, median (IQR)</td><td></td><td></td><td></td><td></td></tr><tr><td>From hospital admission, days</td><td>1.4 (0.9 - 3.3)</td><td>1.6 (0.9 - 3.5)</td><td>1.6 (0.9 - 3.8)</td><td>1.2 (0.8 - 2.8)</td></tr><tr><td>From ICU admission, hours</td><td>13.5 (6.9 - 19.1)</td><td>15.1 (7.8 - 19.9)</td><td>13.6 (7.3 - 19.9)</td><td>14.0 (6.8 - 19.5)</td></tr><tr><td>Acute respiratory support, n (%)</td><td></td><td></td><td></td><td></td></tr><tr><td>None/supplemental oxygen only</td><td>1 (0.1)</td><td>0 (0.0)</td><td>1 (0.3)</td><td>2 (0.5)</td></tr><tr><td>High flow nasal cannula</td><td>225 (23.7)</td><td>96 (19.8)</td><td>101 (27.2)</td><td>110 (27.1)</td></tr><tr><td>Non-invasive ventilation only</td><td>403 (42.5)</td><td>241 (49.7)</td><td>132 (35.6)</td><td>171 (42.1)</td></tr><tr><td>Invasive mechanical ventilation</td><td>319 (33.7)</td><td>148 (30.5)</td><td>137 (36.9)</td><td>123 (30.3)</td></tr><tr><td>ECMO, n/N (%)</td><td>1/936 (0.1)</td><td>0/478 (0.0)</td><td>0/369 (0.0)</td><td>1/396 (0.3)</td></tr><tr><td>Vasopressor support, n (%)</td><td>179 (18.9)</td><td>77 (15.9)</td><td>80 (21.6)</td><td>79 (19.5)</td></tr><tr><td>Median (IQR) acute physiology and laboratory values <sup>e</sup></td><td></td><td></td><td></td><td></td></tr><tr><td>PaO<sub>2</sub>/FiO<sub>2</sub></td><td>111 (86 - 149) [N=872]</td><td>116 (89 - 153) [N=430]</td><td>106 (84 - 147) [N=331]</td><td>118 (89 - 170) [N=359]</td></tr><tr><td>C-reactive protein, µg/mL</td><td>132 (69 - 201) [N=779]</td><td>120 (70 - 199) [N=418]</td><td>112 (70 - 190) [N=324]</td><td>128 (72 - 208) [N=256]</td></tr><tr><td>Creatinine, mg/dL</td><td>0.9 (0.7 - 1.1) [N=940]</td><td>0.8 (0.7 - 1.1) [N=479]</td><td>0.8 (0.7 - 1.1) [N=371]</td><td>0.9 (0.7 - 1.2) [N=404]</td></tr><tr><td>Lactate, mmol/L</td><td>1.3 (1.0 - 1.7) [N=850]</td><td>1.3 (1.0 - 1.7) [N=418]</td><td>1.3 (1.0 - 1.7) [N=335]</td><td>1.4 (1.0 - 1.9) [N=360]</td></tr><tr><td>Platelets, x10<sup>9</sup>/L</td><td>241 (181 - 311)<br>[N=937]</td><td>238 (185 - 308)<br>[N=481]</td><td>252 (193 - 331)<br>[N=371]</td><td>235 (177 - 296)<br>[N=404]</td></tr><tr><td>Bilirubin, mg/dL</td><td>0.5 (0.4 - 0.8) [N=908]</td><td>0.6 (0.4 - 0.8) [N=463]</td><td>0.6 (0.4 - 0.8) [N=365]</td><td>0.5 (0.4 - 0.8) [N=389]</td></tr></tbody></table>

Footnotes for Tables S3 to S9 are at the bottom of Table S9
<table><caption>Table S4: Baseline characteristics of patients in the immunoglobulin domain</caption><thead><tr><th>Characteristic</th><th>Convalescent plasma<br>N=1078</th><th>No Convalescent plasma<br>N=911</th></tr></thead><tbody><tr><td>Age in years, median (IQR)</td><td>61 (52 - 69)</td><td>61 (52 - 70)</td></tr><tr><td>Male sex, n (%)</td><td>727 (67.4)</td><td>619 (68.0)</td></tr><tr><td>Female sex, n (%)</td><td>351 (32.6)</td><td>292 (32.1)</td></tr><tr><td>Race/Ethnicity <sup>a</sup>, n/N (%)</td><td></td><td></td></tr><tr><td>Asian</td><td>146/983 (14.9)</td><td>133/836 (15.9)</td></tr><tr><td>Black</td><td>51/983 (5.2)</td><td>38/836 (4.6)</td></tr><tr><td>Mixed</td><td>16/983 (1.6)</td><td>8/836 (1.0)</td></tr><tr><td>Other <sup>a</sup></td><td>34/983 (3.5)</td><td>34/836 (4.1)</td></tr><tr><td>White</td><td>736/983 (74.9)</td><td>623/836 (74.5)</td></tr><tr><td>Confirmed SARS-CoV2 infection, n (%) <sup>b</sup></td><td>997 (92.5)</td><td>843 (92.5)</td></tr><tr><td>Body mass index, kg/m<sup>2</sup>, median (IQR)</td><td>30.8 (26.9 - 35.6) [N=958]</td><td>31.1 (26.9 - 36.5) [N=818]</td></tr><tr><td>APACHE II score <sup>c</sup>, median (IQR)</td><td>13 (8-19) [N=1056]</td><td>12 (8-19) [N=896]</td></tr><tr><td>Pre-existing conditions, n/N (%) <sup>d</sup></td><td></td><td></td></tr><tr><td>Diabetes mellitus</td><td>338/1078 (31.4)</td><td>269/911 (29.5)</td></tr><tr><td>Respiratory disease</td><td>245/1078 (22.7)</td><td>216/911 (23.7)</td></tr><tr><td>Asthma/COPD</td><td>206/1078 (19.1)</td><td>178/911 (19.5)</td></tr><tr><td>Other</td><td>51/1078 (4.7)</td><td>48/911 (5.3)</td></tr><tr><td>Kidney disease</td><td>106/1000 (10.6)</td><td>83/840 (9.9)</td></tr><tr><td>Severe cardiovascular disease</td><td>96/1053 (9.1)</td><td>67/893 (7.5)</td></tr><tr><td>Immunosuppressive disease</td><td>52/1078 (4.8)</td><td>41/911 (4.5)</td></tr><tr><td>Chronic immunosuppressive therapy</td><td>47/1078 (4.4)</td><td>44/911 (4.8)</td></tr><tr><td>Time to enrolment, median (IQR)</td><td></td><td></td></tr><tr><td>From hospital admission, days</td><td>1.8 (1.0 - 3.3)</td><td>1.7 (0.9 - 3.5)</td></tr><tr><td>From ICU admission, hours</td><td>17.7 (10.1 - 23.5)</td><td>17.2 (10.6 - 23.3)</td></tr><tr><td>Acute respiratory support, n (%)</td><td></td><td></td></tr><tr><td>None/supplemental oxygen only</td><td>2 (0.2)</td><td>1 (0.1)</td></tr><tr><td>High flow nasal cannula</td><td>227 (21.1)</td><td>211 (23.2)</td></tr><tr><td>Non-invasive ventilation only</td><td>494 (45.8)</td><td>408 (44.8)</td></tr><tr><td>Invasive mechanical ventilation</td><td>357 (33.1)</td><td>291 (31.9)</td></tr><tr><td>ECMO, n/N (%)</td><td>2/1060 (0.2)</td><td>1/897 (0.1)</td></tr><tr><td>Vasopressor support, n (%)</td><td>207 (19.2)</td><td>175 (19.2)</td></tr><tr><td>Median (IQR) acute physiology and laboratory values <sup>e</sup></td><td></td><td></td></tr><tr><td>PaO<sub>2</sub>/FiO<sub>2</sub></td><td>118 (92 - 159) [N=971]</td><td>115 (90 - 154) [N=816]</td></tr><tr><td>C-reactive protein, µg/mL</td><td>121 (68 - 195) [N=908]</td><td>125 (72 - 196) [N=759]</td></tr><tr><td>Creatinine, mg/dL</td><td>0.8 (0.7 - 1.1) [N=1070]</td><td>0.8 (0.7 - 1.2) [N=901]</td></tr><tr><td>Lactate, mmol/L</td><td>1.3 (1.0 - 1.7) [N=963]</td><td>1.3 (1.0 - 1.7) [N=811]</td></tr><tr><td>Platelets, x10<sup>9</sup>/L</td><td>235 (177 - 304) [N=1068]</td><td>243 (182 - 307) [N=902]</td></tr><tr><td>Bilirubin, mg/dL</td><td>0.5 (0.4 - 0.8) [N=1028]</td><td>0.5 (0.4 - 0.8) [N=874]</td></tr></tbody></table>

Footnotes for Tables S3 to S9 are at the bottom of Table S9
<table><caption>Table S5: Baseline characteristics of patients in the antiplatelet domain</caption><thead><tr><th>Characteristic</th><th>Aspirin<br>N=564</th><th>P2Y12 inhibitor<br>N=455</th><th>No Antiplatelet<br>N=527</th></tr></thead><tbody><tr><td>Age in years, median (IQR)</td><td>57 (48 - 64)</td><td>57 (49 - 65)</td><td>57 (48 - 63)</td></tr><tr><td>Male sex, n (%)</td><td>365 (64.7)</td><td>316 (69.5)</td><td>345 (65.5)</td></tr><tr><td>Female sex, n (%)</td><td>199 (35.3)</td><td>139 (30.6)</td><td>182 (34.5)</td></tr><tr><td>Race/Ethnicity <sup>a</sup>, n/N (%)</td><td></td><td></td><td></td></tr><tr><td>Asian</td><td>46/459 (10.0)</td><td>36/372 (9.7)</td><td>58/419 (13.8)</td></tr><tr><td>Black</td><td>16/459 (3.5)</td><td>9/372 (2.4)</td><td>16/419 (3.8)</td></tr><tr><td>Mixed</td><td>19/459 (4.1)</td><td>5/372 (1.3)</td><td>10/419 (2.4)</td></tr><tr><td>Other <sup>a</sup></td><td>27/459 (5.9)</td><td>15/372 (4.0)</td><td>26/419 (6.2)</td></tr><tr><td>White</td><td>351/459 (76.5)</td><td>307/372 (82.5)</td><td>309/419 (73.8)</td></tr><tr><td>Confirmed SARS-CoV2 infection, n/N (%) <sup>b</sup></td><td>507/564 (89.9)</td><td>406/455 (89.2)</td><td>469/527 (89.0)</td></tr><tr><td>Body mass index, kg/m<sup>2</sup>, median (IQR)</td><td>31.7 (27.2 - 37.6)<br>[N=495]</td><td>31.3 (26.8 - 37.4)<br>[N=384]</td><td>31.0 (26.8 - 35.9)<br>[N=458]</td></tr><tr><td>APACHE II score <sup>c</sup>, median (IQR)</td><td>12 (8-17) [N=562]</td><td>12 (8-18) [N=451]</td><td>12 (8-17) [N=524]</td></tr><tr><td>Pre-existing conditions, n/N (%) <sup>d</sup></td><td></td><td></td><td></td></tr><tr><td>Diabetes mellitus</td><td>135/564 (23.9)</td><td>94/455 (20.7)</td><td>115/527 (21.8)</td></tr><tr><td>Respiratory disease</td><td>112/564 (19.9)</td><td>91/455 (20.0)</td><td>98/527 (18.6)</td></tr><tr><td>Asthma/COPD</td><td>94/564 (16.7)</td><td>78/455 (17.1)</td><td>78/527 (14.8)</td></tr><tr><td>Other</td><td>25/564 (4.4)</td><td>18/455 (4.0)</td><td>27/527 (5.1)</td></tr><tr><td>Kidney disease</td><td>16/529 (3.0)</td><td>19/422 (4.5)</td><td>18/490 (3.7)</td></tr><tr><td>Severe cardiovascular disease</td><td>17/553 (3.1)</td><td>22/441 (5.0)</td><td>24/520 (4.6)</td></tr><tr><td>Immunosuppressive disease</td><td>19/564 (3.4)</td><td>16/455 (3.5)</td><td>15/527 (2.9)</td></tr><tr><td>Chronic immunosuppressive therapy</td><td>14/564 (2.5)</td><td>11/455 (2.4)</td><td>17/527 (3.2)</td></tr><tr><td>Time to enrolment, median (IQR)</td><td></td><td></td><td></td></tr><tr><td>From hospital admission, days</td><td>1.6 (0.9 - 3.0)</td><td>1.8 (1.0 - 3.5)</td><td>1.8 (0.9 - 3.7)</td></tr><tr><td>From ICU admission, hours</td><td>17.2 (9.9 - 22.4)</td><td>17.9 (12 - 23.5)</td><td>18.2 (10.7 - 23.9)</td></tr><tr><td>Acute respiratory support, n (%)</td><td></td><td></td><td></td></tr><tr><td>None/supplemental oxygen only</td><td>0 (0.0)</td><td>0 (0.0)</td><td>1 (0.2)</td></tr><tr><td>High flow nasal cannula</td><td>125 (22.2)</td><td>121 (26.6)</td><td>130 (24.7)</td></tr><tr><td>Non-invasive ventilation only</td><td>227 (40.3)</td><td>173 (38.0)</td><td>202 (38.3)</td></tr><tr><td>Invasive mechanical ventilation</td><td>212 (37.6)</td><td>161 (35.4)</td><td>194 (36.8)</td></tr><tr><td>ECMO, n/N (%)</td><td>0/563 (0.0)</td><td>0/452 (0.0)</td><td>0/525 (0.0)</td></tr><tr><td>Vasopressor support, n (%)</td><td>121 (21.5)</td><td>72 (15.8)</td><td>88 (16.7)</td></tr><tr><td>Median (IQR) acute physiology and laboratory values <sup>e</sup></td><td></td><td></td><td></td></tr><tr><td>PaO<sub>2</sub>/FiO<sub>2</sub></td><td>115 (87-148) [N=539]</td><td>118 (90-163) [N=436]</td><td>113 (89-148) [N=500]</td></tr><tr><td>C-reactive protein, µg/mL</td><td>117 (62-179) [N=488]</td><td>110 (60-178) [N=417]</td><td>114 (60-179) [N=457]</td></tr><tr><td>Creatinine, mg/dL</td><td>0.8 (0.6 - 0.9) [N=547]</td><td>0.8 (0.6 - 1.0) [N=449]</td><td>0.8 (0.6 - 1.0) [N=512]</td></tr><tr><td>Lactate, mmol/L</td><td>1.3 (1.0 - 1.8) [N=516]</td><td>1.3 (1.0 - 1.6) [N=424]</td><td>1.3 (1.0 - 1.7) [N=477]</td></tr><tr><td>Platelets, x10<sup>9</sup>/L</td><td>253 (197 - 315) [N=531]</td><td>240 (184 - 311) [N=447]</td><td>253 (197 - 328) [N=488]</td></tr><tr><td>Bilirubin, mg/dL</td><td>0.5 (0.4 - 0.8) [N=515]</td><td>0.6 (0.4 - 0.8) [N=425]</td><td>0.5 (0.4 - 0.8) [N=491]</td></tr></tbody></table>

Footnotes for Tables S3 to S9 are at the bottom of Table S9
<table><caption>Table S6: Baseline characteristics of patients in the anticoagulation domain</caption><thead><tr><th>Characteristic</th><th>Therapeutic anticoagulation<br>N=499</th><th>Standard thromboprophylaxis<br>N=511</th></tr></thead><tbody><tr><td>Age in years, median (IQR)</td><td>62 (52 - 71) [N=498]</td><td>62 (53 - 70) [N=511]</td></tr><tr><td>Male sex, n/N (%)</td><td>355/498 (71.3)</td><td>348/511 (68.1)</td></tr><tr><td>Female sex, n/N (%)</td><td>143/498 (28.7)</td><td>163/511 (31.9)</td></tr><tr><td>Race/Ethnicity <sup>a</sup>, n/N (%)</td><td></td><td></td></tr><tr><td>Asian</td><td>70/409 (17.1)</td><td>71/430 (16.5)</td></tr><tr><td>Black</td><td>16/409 (3.9)</td><td>6/430 (1.4)</td></tr><tr><td>Mixed</td><td>0/409 (0.0)</td><td>6/430 (1.4)</td></tr><tr><td>Other <sup>a</sup></td><td>11/409 (2.7)</td><td>17/430 (4.0)</td></tr><tr><td>White</td><td>312/409 (76.3)</td><td>330/430 (76.7)</td></tr><tr><td>Confirmed SARS-CoV2 infection, n/N (%) <sup>b</sup></td><td>434/499 (87.0)</td><td>462/511 (90.4)</td></tr><tr><td>Body mass index, kg/m<sup>2</sup>, median (IQR)</td><td>30.2 (26.7 - 35.6) [N=448]</td><td>30.1 (26.5 - 34.6) [N=446]</td></tr><tr><td>APACHE II score <sup>c</sup>, median (IQR)</td><td>14 (8-21) [N=485]</td><td>13 (9-20) [N=496]</td></tr><tr><td>Pre-existing conditions, n/N (%) <sup>d</sup></td><td></td><td></td></tr><tr><td>Diabetes mellitus</td><td>156/498 (31.3)</td><td>164/511 (32.1)</td></tr><tr><td>Respiratory disease</td><td>125/498 (25.1)</td><td>123/511 (24.1)</td></tr><tr><td>Asthma/COPD</td><td>105/498 (21.1)</td><td>107/511 (20.9)</td></tr><tr><td>Other</td><td>24/498 (4.8)</td><td>22/511 (4.3)</td></tr><tr><td>Kidney disease</td><td>47/466 (10.1)</td><td>43/464 (9.3)</td></tr><tr><td>Severe cardiovascular disease</td><td>33/488 (6.8)</td><td>35/504 (6.9)</td></tr><tr><td>Immunosuppressive disease</td><td>21/498 (4.2)</td><td>16/511 (3.1)</td></tr><tr><td>Chronic immunosuppressive therapy</td><td>26/498 (5.2)</td><td>20/511 (3.9)</td></tr><tr><td>Time to enrolment, median (IQR)</td><td></td><td></td></tr><tr><td>From hospital admission, days</td><td>1.7 (1.0 - 3.0)</td><td>1.6 (0.9 - 3.0)</td></tr><tr><td>From ICU admission, hours</td><td>17.6 (10.2 - 23.2)</td><td>16.8 (9.2 - 23.5)</td></tr><tr><td>Acute respiratory support, n (%)</td><td></td><td></td></tr><tr><td>None/supplemental oxygen only</td><td>1 (0.2)</td><td>0 (0.0)</td></tr><tr><td>High flow nasal cannula</td><td>130 (26.1)</td><td>139 (27.2)</td></tr><tr><td>Non-invasive ventilation only</td><td>224 (44.9)</td><td>209 (40.9)</td></tr><tr><td>Invasive mechanical ventilation</td><td>147 (29.5)</td><td>166 (32.5)</td></tr><tr><td>ECMO, n/N (%)</td><td>0/487 (0.0)</td><td>0/498 (0.0)</td></tr><tr><td>Vasopressor support, n (%)</td><td>93 (18.6)</td><td>95 (18.6)</td></tr><tr><td>Median (IQR) acute physiology and laboratory values <sup>e</sup></td><td></td><td></td></tr><tr><td>PaO<sub>2</sub>/FiO<sub>2</sub></td><td>120 (90 - 166) [N=432]</td><td>122 (93 - 164) [N=438]</td></tr><tr><td>C-reactive protein, µg/mL</td><td>121 (67 - 183) [N=347]</td><td>120 (69 - 201) [N=374]</td></tr><tr><td>Creatinine, mg/dL</td><td>0.9 (0.7 - 1.1) [N=497]</td><td>0.8 (0.7 - 1.1) [N=506]</td></tr><tr><td>Lactate, mmol/L</td><td>1.3 (1.0 - 1.8) [N=413]</td><td>1.3 (1.0 - 1.7) [N=430]</td></tr><tr><td>Platelets, x10<sup>9</sup>/L</td><td>248 (190 - 318) [N=491]</td><td>245 (181 - 311) [N=504]</td></tr><tr><td>Bilirubin, mg/dL</td><td>0.5 (0.4 - 0.8) [N=449]</td><td>0.5 (0.4 - 0.8) [N=469]</td></tr></tbody></table>

Footnotes for Tables S3 to S9 are at the bottom of Table S9
<table><caption>Table S7: Baseline characteristics of patients in the antiviral domain</caption><thead><tr><th>Characteristic</th><th>Lopinavir/ritonavir<br>N=256</th><th>Hydroxychloroquine<br>N=50</th><th>Hydroxychloroquine &<br>Lopinavir/ritonavir<br>N=27</th><th>No Antiviral<br>N=362</th></tr></thead><tbody><tr><td>Age in years, median (IQR)</td><td>61 (53 – 71)</td><td>59 (49 – 64)</td><td>61 (54 – 68)</td><td>61 (53 – 72)</td></tr><tr><td>Male sex, n (%)</td><td>183 (71.5)</td><td>35 (70.0)</td><td>19 (70.4)</td><td>252 (69.6)</td></tr><tr><td>Female sex, n (%)</td><td>73 (28.5)</td><td>15 (30.0)</td><td>8 (29.6)</td><td>110 (30.4)</td></tr><tr><td>Race/Ethnicity <sup>a</sup>, n/N (%)</td><td></td><td></td><td></td><td></td></tr><tr><td>Asian</td><td>26/148 (17.6)</td><td>5/32 (15.6)</td><td>1/9 (11.1)</td><td>28/219 (12.8)</td></tr><tr><td>Black</td><td>3/148 (2.0)</td><td>4/32 (12.5)</td><td>1/9 (11.1)</td><td>6/219 (2.7)</td></tr><tr><td>Mixed</td><td>4/148 (2.7)</td><td>2/32 (6.3)</td><td>0/9 (0.0)</td><td>3/219 (1.4)</td></tr><tr><td>Other <sup>a</sup></td><td>6/148 (4.1)</td><td>2/32 (6.3)</td><td>0/9 (0.0)</td><td>11/219 (5.0)</td></tr><tr><td>White</td><td>109/148 (73.7)</td><td>19/32 (59.4)</td><td>7/9 (77.8)</td><td>171/219 (78.1)</td></tr><tr><td>Confirmed SARS-CoV2 infection,<br>n/N (%) <sup>b</sup></td><td>219/256 (85.6)</td><td>43/50 (86.0)</td><td>22/26 (84.6)</td><td>303/362 (83.7)</td></tr><tr><td>Body mass index, kg/m<sup>2</sup>, median (IQR)</td><td>29.5 (25.9 – 34.7)<br>[N=244]</td><td>30.7 (25.6 – 35.5)<br>[N=50]</td><td>29.4 (25.1 – 32.0)<br>[N=25]</td><td>30.2 (26.8 – 35.5)<br>[N=342]</td></tr><tr><td>APACHE II score <sup>c</sup>, median (IQR)</td><td>13 (8-19) [N=250]</td><td>13 (8-20) [N=50]</td><td>14 (10-21) [N=26]</td><td>13 (8-19) [N=354]</td></tr><tr><td>Pre-existing conditions, n/N (%) <sup>d</sup></td><td></td><td></td><td></td><td></td></tr><tr><td>Diabetes mellitus</td><td>91/256 (35.5)</td><td>15/50 (30.0)</td><td>10/26 (38.5)</td><td>123/362 (34.0)</td></tr><tr><td>Respiratory disease</td><td>62/256 (24.2)</td><td>9/50 (18.0)</td><td>6/26 (23.1)</td><td>91/362 (25.1)</td></tr><tr><td>Asthma/COPD</td><td>57/256 (22.3)</td><td>8/50 (16.0)</td><td>6/26 (23.1)</td><td>77/362 (21.3)</td></tr><tr><td>Other</td><td>7/256 (2.7)</td><td>2/50 (4.0)</td><td>0/26 (0.0)</td><td>19/362 (5.3)</td></tr><tr><td>Kidney disease</td><td>31/235 (13.2)</td><td>3/44 (6.8)</td><td>4/24 (16.7)</td><td>37/328 (11.3)</td></tr><tr><td>Severe cardiovascular disease</td><td>40/252 (15.9)</td><td>2/48 (4.2)</td><td>3/26 (11.5)</td><td>37/354 (10.5)</td></tr><tr><td>Immunosuppressive disease</td><td>15/256 (5.9)</td><td>0/50 (0.0)</td><td>1/26 (3.9)</td><td>15/362 (4.1)</td></tr><tr><td>Chronic immunosuppressive<br>therapy</td><td>6/256 (2.3)</td><td>2/50 (4.0)</td><td>1/26 (3.9)</td><td>18/362 (5.0)</td></tr><tr><td>Time to enrolment, median (IQR)</td><td></td><td></td><td></td><td></td></tr><tr><td>From hospital admission, days</td><td>1.1 (0.8 – 2.7)</td><td>1.0 (0.6 – 1.7)</td><td>1.1 (0.7 – 1.5)</td><td>1.1 (0.8 – 2.2)</td></tr><tr><td>From ICU admission, hours</td><td>13.1 (6.7 – 19.0)</td><td>12.6 (4.9 – 20.5)</td><td>14.1 (2.5 – 18.7)</td><td>13.7 (6.3 – 19.4)</td></tr><tr><td>Acute respiratory support, n (%)</td><td></td><td></td><td></td><td></td></tr><tr><td>None/supplemental oxygen only</td><td>0 (0.0)</td><td>0 (0.0)</td><td>0 (0.0)</td><td>4 (1.1)</td></tr><tr><td>High flow nasal cannula</td><td>72 (28.1)</td><td>8 (16.0)</td><td>3 (11.1)</td><td>100 (27.6)</td></tr><tr><td>Non-invasive ventilation only</td><td>111 (43.4)</td><td>16 (32.0)</td><td>11 (40.7)</td><td>144 (39.8)</td></tr><tr><td>Invasive mechanical ventilation</td><td>73 (28.5)</td><td>26 (52.0)</td><td>13 (48.2)</td><td>114 (31.5)</td></tr><tr><td>ECMO, n/N (%)</td><td>0/250 (0.0)</td><td>0/50 (0.0)</td><td>0/26 (0.0)</td><td>0/354 (0.0)</td></tr><tr><td>Vasopressor support, n (%)</td><td>47 (18.4)</td><td>13 (26.0)</td><td>5 (18.5)</td><td>71 (19.6)</td></tr><tr><td>Median (IQR) acute physiology and<br>laboratory values <sup>e</sup></td><td></td><td></td><td></td><td></td></tr><tr><td>PaO<sub>2</sub>/FiO<sub>2</sub></td><td>122 (89 – 174)<br>[N=216]</td><td>115 (86 – 152) [N=46]</td><td>116 (91 – 152) [N=24]</td><td>118 (90 – 169) [N=316]</td></tr><tr><td>C-reactive protein, µg/mL</td><td>157 (83 – 223) [N=130]</td><td>161 (125 – 280) [N=8]</td><td>202 (73 – 380) [N=3]</td><td>158 (91 – 228) [N=193]</td></tr><tr><td>Creatinine, mg/dL</td><td>0.9 (0.7 – 1.2) [N=256]</td><td>1.0 (0.7 – 1.3) [N=50]</td><td>1.0 (0.7 – 1.5) [N=26]</td><td>0.9 (0.7 – 1.2) [N=361]</td></tr><tr><td>Lactate, mmol/L</td><td>1.3 (1.0 – 1.9) [N=218]</td><td>1.1 (1.0 – 1.5) [N=41]</td><td>1.1 (0.9 – 1.6) [N=20]</td><td>1.3 (1.0 – 1.8) [N=312]</td></tr><tr><td>Platelets, x10<sup>9</sup>/L</td><td>245 (180 – 308)<br>[N=255]</td><td>200 (165 – 273) [N=50]</td><td>236 (193 – 378) [N=26]</td><td>247 (188 – 311)<br>[N=359]</td></tr><tr><td>Bilirubin, mg/dL</td><td>0.6 (0.4 – 0.8) [N=233]</td><td>0.6 (0.5 – 0.9) [N=49]</td><td>0.7 (0.5 – 1.0) [N=23]</td><td>0.6 (0.4 – 0.8) [N=346]</td></tr></tbody></table>

Footnotes for Tables S3 to S9 are at the bottom of Table S9
<table><caption>Table S8: Baseline characteristics of patients in the corticosteroid domain</caption><thead><tr><th>Characteristic</th><th>Fixed-dose hydrocortisone<br>N=137</th><th>Shock-dependent<br>hydrocortisone<br>N=147</th><th>No Corticosteroid<br>N=101</th></tr></thead><tbody><tr><td>Age in years, median (IQR)</td><td>60 (53 – 69)</td><td>60 (52 – 69)</td><td>62 (50 – 72)</td></tr><tr><td>Male sex, n/N (%)</td><td>98/137 (71.5)</td><td>105/147 (71.4)</td><td>73/101 (72.3)</td></tr><tr><td>Female sex, n/N (%)</td><td>39/137 (28.5)</td><td>42/147 (28.6)</td><td>28/101 (27.7)</td></tr><tr><td>Race/Ethnicity <sup>a</sup>, n/N (%)</td><td></td><td></td><td></td></tr><tr><td>Asian</td><td>8/55 (14.6)</td><td>7/48 (14.6)</td><td>12/33 (36.4)</td></tr><tr><td>Black</td><td>3/55 (5.5)</td><td>2/48 (4.2)</td><td>3/33 (9.1)</td></tr><tr><td>Mixed</td><td>1/55 (1.8)</td><td>0/48 (0.0)</td><td>1/33 (3.0)</td></tr><tr><td>Other <sup>a</sup></td><td>5/55 (9.1)</td><td>3/48 (6.3)</td><td>2/33 (6.1)</td></tr><tr><td>White</td><td>38/55 (69.1)</td><td>36/48 (75.0)</td><td>15/33 (45.5)</td></tr><tr><td>Confirmed SARS-CoV2 infection, n/N (%) <sup>b</sup></td><td>108/133 (81.2)</td><td>90/128 (70.3)</td><td>78/100 (78.0)</td></tr><tr><td>Body mass index, kg/m<sup>2</sup>, median (IQR)</td><td>29.5 (25.3 – 34.4) [N=133]</td><td>29.3 (25.1 – 33.7) [N=146]</td><td>28.3 (24.7 – 32.5) [N=100]</td></tr><tr><td>APACHE II score <sup>c</sup>, median (IQR)</td><td>15.5 (10-21) [N=118]</td><td>16 (11-23) [N=129]</td><td>14 (11-21) [N=93]</td></tr><tr><td>Pre-existing conditions, n/N (%) <sup>d</sup></td><td></td><td></td><td></td></tr><tr><td>Diabetes mellitus</td><td>51/137 (37.2)</td><td>38/147 (25.9)</td><td>29/101 (28.7)</td></tr><tr><td>Respiratory disease</td><td>27/137 (19.7)</td><td>27/147 (18.4)</td><td>20/101 (19.8)</td></tr><tr><td>Asthma/COPD</td><td>21/137 (15.3)</td><td>24/147 (16.3)</td><td>16/101 (15.8)</td></tr><tr><td>Other</td><td>7/137 (5.1)</td><td>4/147 (2.7)</td><td>4/101 (4.0)</td></tr><tr><td>Kidney disease</td><td>13/128 (10.2)</td><td>11/130 (8.5)</td><td>8/93 (8.6)</td></tr><tr><td>Severe cardiovascular disease</td><td>9/136 (6.6)</td><td>13/142 (9.2)</td><td>6/100 (6.0)</td></tr><tr><td>Immunosuppressive disease</td><td>7/137 (5.1)</td><td>8/147 (5.4)</td><td>2/101 (2.0)</td></tr><tr><td>Chronic immunosuppressive therapy</td><td>8/137 (5.8)</td><td>7/147 (4.8)</td><td>6/101 (5.9)</td></tr><tr><td>Time to enrolment, median (IQR)</td><td></td><td></td><td></td></tr><tr><td>From hospital admission, days</td><td>1.2 (0.8 – 2.8)</td><td>1.0 (0.7 – 2.8)</td><td>1.1 (0.7 – 2.0)</td></tr><tr><td>From ICU admission, hours</td><td>15.1 (7.5 – 19.8)</td><td>12.3 (5.4 – 18.8)</td><td>13.6 (8.1 – 17.9)</td></tr><tr><td>Acute respiratory support, n (%)</td><td></td><td></td><td></td></tr><tr><td>None/supplemental oxygen only</td><td>0 (0.0)</td><td>1 (0.7)</td><td>0 (0.0)</td></tr><tr><td>High flow nasal cannula</td><td>17 (12.4)</td><td>23 (15.7)</td><td>16 (15.8)</td></tr><tr><td>Non-invasive ventilation only</td><td>33 (24.1)</td><td>49 (33.3)</td><td>32 (31.7)</td></tr><tr><td>Invasive mechanical ventilation</td><td>87 (63.5)</td><td>74 (50.3)</td><td>53 (52.5)</td></tr><tr><td>ECMO, n (%)</td><td>1 (0.7)</td><td>0 (0.0)</td><td>2 (2.0)</td></tr><tr><td>Vasopressor support, n (%)</td><td>56 (40.9)</td><td>47 (32.0)</td><td>30 (29.7)</td></tr><tr><td>Median (IQR) acute physiology and laboratory values <sup>e</sup></td><td></td><td></td><td></td></tr><tr><td>PaO<sub>2</sub>/FiO<sub>2</sub></td><td>140 (98 - 200) [N=128]</td><td>136 (104 - 175) [N=138]</td><td>140 (97 - 180) [N=93]</td></tr><tr><td>C-reactive protein, µg/mL</td><td>178 (122 - 316) [N=16]</td><td>160 (127-288) [N=15]</td><td>158 (121 - 221) [N=9]</td></tr><tr><td>Creatinine, mg/dL</td><td>0.9 (0.7 - 1.2) [N=115]</td><td>0.9 (0.7 - 1.2) [N=128]</td><td>0.8 (0.6 - 1.2) [N=91]</td></tr><tr><td>Lactate, mmol/L</td><td>1.2 (0.9 - 1.5) [N=106]</td><td>1.2 (0.9 - 1.7) [N=112]</td><td>1.0 (0.8 - 1.4) [N=83]</td></tr><tr><td>Platelets, x10<sup>9</sup>/L</td><td>236 (181 - 315) [N=115]</td><td>250 (176 - 335) [N=128]</td><td>243 (172 - 320) [N=91]</td></tr><tr><td>Bilirubin, mg/dL</td><td>0.6 (0.5 - 0.9) [N=111]</td><td>0.6 (0.5 - 0.8) [N=120]</td><td>0.6 (0.4 - 0.8) [N=86]</td></tr></tbody></table>

Footnotes for Tables S3 to S9 are at the bottom of Table S9
<table><caption>Table S9: Baseline characteristics of survivors with and without known day 180 vital status</caption><thead><tr><th>Characteristic</th><th>Day 180 vital status known<br>N=4107</th><th>Missing day 180 vital status<br>N=684<sup>f</sup></th></tr></thead><tbody><tr><td>Age in years, median (IQR)</td><td>59.6 (12.5) [N=4107]</td><td>57.4 (14.7) [N=683]</td></tr><tr><td>Male sex, n/N (%)</td><td>2791/4107 (68.0)</td><td>462/683 (67.6)</td></tr><tr><td>Female sex, n/N (%)</td><td>1316/4107 (32.0)</td><td>221/683 (32.4)</td></tr><tr><td>Race/Ethnicity <sup>a</sup>, n/N (%)</td><td></td><td></td></tr><tr><td>Asian</td><td>435/3082 (14.1)</td><td>69/475 (14.5)</td></tr><tr><td>Black</td><td>130/3082 (4.2)</td><td>30/475 (6.3)</td></tr><tr><td>Mixed</td><td>56/3082 (1.8)</td><td>13/475 (2.7)</td></tr><tr><td>Other <sup>a</sup></td><td>138/3082 (4.5)</td><td>21/475 (4.4)</td></tr><tr><td>White</td><td>2323/3082 (75.4)</td><td>342/475 (72.0)</td></tr><tr><td>Confirmed SARS-CoV2 infection, n/N (%) <sup>b</sup></td><td>3542/4088 (86.6)</td><td>597/676 (88.3)</td></tr><tr><td>Body mass index, kg/m<sup>2</sup>, median (IQR)</td><td>32.0 (7.8) [N=3777]</td><td>31.9 (7.8) [N=540]</td></tr><tr><td>APACHE II score <sup>c</sup>, median (IQR)</td><td>13 (8-20) [N=4019]</td><td>11 (7-17) [N=654]</td></tr><tr><td>Pre-existing conditions, n/N (%) <sup>d</sup></td><td></td><td></td></tr><tr><td>Diabetes mellitus</td><td>1204/4107 (29.3)</td><td>200/681 (29.4)</td></tr><tr><td>Respiratory disease</td><td>944/4107 (23.0)</td><td>123/681 (18.1)</td></tr><tr><td>Asthma/COPD</td><td>797/4107 (19.4)</td><td>100/681 (14.7)</td></tr><tr><td>Other</td><td>192/4107 (4.7)</td><td>26/681 (3.8)</td></tr><tr><td>Kidney disease</td><td>319/3797 (8.4)</td><td>51/630 (8.1)</td></tr><tr><td>Severe cardiovascular disease</td><td>334/4031 (8.3)</td><td>42/672 (6.3)</td></tr><tr><td>Immunosuppressive disease</td><td>176/4107 (4.3)</td><td>14/681 (2.1)</td></tr><tr><td>Chronic immunosuppressive therapy</td><td>161/4107 (3.9)</td><td>14/681 (2.1)</td></tr><tr><td>Time to enrolment, median (IQR)</td><td></td><td></td></tr><tr><td>From hospital admission, days</td><td>1.7 (0.9 - 3.5)</td><td>1.5 (0.9 - 2.9)</td></tr><tr><td>From ICU admission, hours</td><td>16.6 (8.8 - 22.4)</td><td>17.8 (10.7 - 22.9)</td></tr><tr><td>Acute respiratory support, n (%)</td><td></td><td></td></tr><tr><td>None/supplemental oxygen only</td><td>7 (0.2)</td><td>0 (0.0)</td></tr><tr><td>High flow nasal cannula</td><td>1043 (25.4)</td><td>155 (22.7)</td></tr><tr><td>Non-invasive ventilation only</td><td>1517 (36.9)</td><td>331 (48.4)</td></tr><tr><td>Invasive mechanical ventilation</td><td>1540 (37.5)</td><td>206 (30.1)</td></tr><tr><td>ECMO, n/N (%)</td><td>1/4057 (0.0)</td><td>3/672 (0.5)</td></tr><tr><td>Vasopressor support, n (%)</td><td>912 (22.2)</td><td>93 (13.6)</td></tr><tr><td>Median (IQR) acute physiology and laboratory values <sup>e</sup></td><td></td><td></td></tr><tr><td>PaO<sub>2</sub>/FiO<sub>2</sub></td><td>116 (89 - 157) [N=3878]</td><td>120 (90 - 160) [N=490]</td></tr><tr><td>C-reactive protein, µg/mL</td><td>120 (67 - 195) [N=3128]</td><td>92 (50 - 159) [N=457]</td></tr><tr><td>Creatinine, mg/dL</td><td>0.8 (0.7 - 1.1) [N=4046]</td><td>0.9 (0.7 - 1.2) [N=635]</td></tr><tr><td>Lactate, mmol/L</td><td>1.3 (1.0 - 1.7) [N=3717]</td><td>1.4 (1.1 - 1.9) [N=488]</td></tr><tr><td>Platelets, x10<sup>9</sup>/L</td><td>246 (185 - 315) [N=4038]</td><td>238 (178 - 305) [N=588]</td></tr><tr><td>Bilirubin, mg/dL</td><td>0.5 (0.4 - 0.8) [N=3836]</td><td>0.5 (0.4 - 0.8) [N=607]</td></tr></tbody></table>

Percentages may not sum to 100 because of rounding. SD denotes standard deviation; APACHE, Acute Physiology and Chronic Health Evaluation; COPD, chronic obstructive pulmonary disease; IQR, interquartile range; ECMO, extracorporeal membrane oxygenation.

<sup>a</sup>Self-reported via fixed categories. Data collection was not approved in Asia, Canada, and continental Europe. "Other" includes "other ethnic group" and those who declined to respond or were not asked by registration personnel.

<sup>b</sup>SARS-CoV2 infection was confirmed by respiratory tract polymerase chain reaction test.

<sup>c</sup>Measures the severity of illness based on age, medical history, and physiological variables. Scores range from 0 to 71; higher numbers represent greater risk of death. The median score of 12 is typical for patients with COVID-19 admitted to intensive care units (ICUs).
<sup>d</sup>Kidney disease was determined from the most recent stable serum creatinine level prior to this hospital admission, except in patients who were receiving dialysis. Abnormal kidney function was defined as a creatinine level of 130 µmol/L or greater (1.5mg/dL) for males or 100 µmol/L or greater (1.1 mg/dL) for females not previously receiving dialysis. Cardiovascular disease was defined as New York Heart Association class IV symptoms. Immunosuppression was defined by the receipt of recent chemotherapy, radiation, high-dose or long-term steroid treatment, or presence of immunosuppressive disease.

<sup>e</sup>Laboratory results available when captured for clinical care. Although specific laboratory cut-offs may vary, ranges for the following variables are generally considered normal: $P_3O_2/F_iO_2$ ratio ≥400; creatinine <1.2 mg/dL; platelets ≥150 x10⁹/L; and bilirubin <1.2 mg/dL.

<sup>f</sup>Of the 684 participants with missing day 180 vital status, 512 were randomized at sites not participating in follow up beyond day 90.

<table><caption>Table S10: Sensitivity Analysis of Day 180 mortality in non-negative COVID-19 population</caption><thead><tr><th></th><th>Adjusted Hazard Ratio<br>(95% CrI)</th><th>Probability of<br>Superiority of<br>Intervention (%) <sup>a</sup></th><th>Probability of<br>Futility of<br>Intervention (%) <sup>a</sup></th></tr></thead><tbody><tr><td><strong>Immune Modulation Domain</strong></td><td></td><td></td><td></td></tr><tr><td>IL-6 receptor antagonists</td><td>0.73 (0.59 to 0.90)</td><td>99.7%</td><td>9.6%</td></tr><tr><td>Anakinra</td><td>0.96 (0.73 to 1.23)</td><td>61.5%</td><td>85.1%</td></tr><tr><td>Control</td><td>1 (referent)</td><td>-</td><td>-</td></tr><tr><td><strong>Immunoglobulin Domain</strong></td><td></td><td></td><td></td></tr><tr><td>Convalescent plasma</td><td>0.98 (0.85 to 1.14)</td><td>58.9%</td><td>98.8%</td></tr><tr><td>Control</td><td>1 (referent)</td><td>-</td><td>-</td></tr><tr><td><strong>Antiplatelet Domain</strong></td><td></td><td></td><td></td></tr><tr><td>Antiplatelet</td><td>0.85 (0.70 to 1.04)</td><td>94.5%</td><td>59.7%</td></tr><tr><td>Control</td><td>1 (referent)</td><td>-</td><td>-</td></tr><tr><td><strong>Anticoagulation Domain</strong></td><td></td><td></td><td></td></tr><tr><td>Therapeutic anticoagulation</td><td>1.17 (0.94 to 1.44)</td><td>8.3%</td><td>99.9%</td></tr><tr><td>Thromboprophylaxis</td><td>1 (referent)</td><td>-</td><td>-</td></tr><tr><td><strong>Antiviral Domain</strong></td><td></td><td></td><td></td></tr><tr><td>Lopinavir-ritonavir</td><td>1.09 (0.82 to 1.44)</td><td>27.0%</td><td>96.8%</td></tr><tr><td>Hydroxychloroquine</td><td>1.81 (1.16 to 2.78)</td><td>0.5%</td><td>99.9%</td></tr><tr><td>Combination antiviral therapy</td><td>1.99 (1.15 to 3.32)</td><td>0.6%</td><td>&gt;99.9%</td></tr><tr><td>Control</td><td>1 (referent)</td><td>-</td><td>-</td></tr><tr><td><strong>Corticosteroid Domain</strong></td><td></td><td></td><td></td></tr><tr><td>Fixed dose corticosteroids</td><td>1.01 (0.61 to 1.64)</td><td>48.4%</td><td>78.8%</td></tr><tr><td>Shock-dependent corticosteroids</td><td>0.98 (0.57 to 1.63)</td><td>52.5%</td><td>73.4%</td></tr><tr><td>Control</td><td>1 (referent)</td><td>-</td><td>-</td></tr></tbody></table>

Crl denotes credible interval.

<footnote><sup>a</sup>The probability of superiority and futility is computed from a Bayesian piecewise exponential model using the posterior distribution.</footnote>
<table><caption>Table S11: Sensitivity Analysis of Day 180 mortality with independent effects for interleukin-6 receptor antagonists and antiplatelet interventions</caption><thead><tr><th></th><th>N</th><th>Day 180 mortality <sup>a</sup>, n/N (%)</th><th>Adjusted Hazard Ratio (95% CrI)</th><th>Probability of Superiority of Intervention (%)<sup>b</sup></th><th>Probability of Futility of Intervention (%)<sup>b</sup></th></tr></thead><tbody><tr><td><strong>Immune Modulation Domain</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Tocilizumab</td><td>948</td><td>298/831 (35.9)</td><td>0.76 (0.61 to 0.93)</td><td>99.6%</td><td>17.1%</td></tr><tr><td>Sarilumab</td><td>485</td><td>138/417 (33.1)</td><td>0.72 (0.56 to 0.91)</td><td>99.6%</td><td>10.9%</td></tr><tr><td>Anakinra</td><td>371</td><td>138/325 (42.5)</td><td>0.96 (0.74 to 1.24)</td><td>62.4%</td><td>86.0%</td></tr><tr><td>Control</td><td>406</td><td>140/350 (40.0)</td><td>1 (referent)</td><td>-</td><td>-</td></tr><tr><td><strong>Immunoglobulin Domain</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Convalescent plasma</td><td>1078</td><td>370/944 (39.2)</td><td>0.99 (0.86 to 1.14)</td><td>54.2%</td><td>99.0%</td></tr><tr><td>Control</td><td>911</td><td>324/790 (41.0)</td><td>1 (referent)</td><td>-</td><td>-</td></tr><tr><td><strong>Antiplatelet Domain</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Aspirin</td><td>564</td><td>143/472 (30.3)</td><td>0.83 (0.66 to 1.03)</td><td>95.9%</td><td>47.0%</td></tr><tr><td>P2Y12 inhibitor</td><td>455</td><td>131/399 (32.8)</td><td>0.88 (0.70 to 1.11)</td><td>84.9%</td><td>69.0%</td></tr><tr><td>Control</td><td>527</td><td>143/441 (32.4)</td><td>1 (referent)</td><td>-</td><td>-</td></tr><tr><td><strong>Anticoagulation Domain</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Therapeutic anticoagulation</td><td>499</td><td>165/403 (40.9)</td><td>1.16 (0.93 to 1.41)</td><td>9.6%</td><td>99.8%</td></tr><tr><td>Thromboprophylaxis</td><td>511</td><td>147/418 (35.2)</td><td>1 (referent)</td><td>-</td><td>-</td></tr><tr><td><strong>Antiviral Domain</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Lopinavir-ritonavir</td><td>256</td><td>81/226 (35.8)</td><td>1.07 (0.82 to 1.39)</td><td>31.1%</td><td>96.9%</td></tr><tr><td>Hydroxychloroquine</td><td>50</td><td>16/41 (39.0)</td><td>1.51 (0.96 to 2.29)</td><td>3.7%</td><td>99.6%</td></tr><tr><td>Combination antiviral therapy</td><td>27</td><td>13/26 (50.0)</td><td>1.63 (0.95 to 2.68)</td><td>3.8%</td><td>99.3%</td></tr><tr><td>Control</td><td>362</td><td>107/311 (34.4)</td><td>1 (referent)</td><td>-</td><td>-</td></tr><tr><td><strong>Corticosteroid Domain</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Fixed dose corticosteroids</td><td>137</td><td>34/109 (31.2)</td><td>0.93 (0.59 to 1.45)</td><td>61.2%</td><td>68.2%</td></tr><tr><td>Shock-dependent corticosteroids</td><td>147</td><td>39/137 (28.5)</td><td>0.97 (0.61 to 1.55)</td><td>55.5%</td><td>72.9%</td></tr><tr><td>Control</td><td>101</td><td>27/79 (34.2)</td><td>1 (referent)</td><td>-</td><td>-</td></tr></tbody></table>

Crl denotes credible interval.

<footnote><sup>a</sup>Due to censoring, reported day 180 mortality rates are restricted to patients at sites participating in day 180 follow-up with known day 180 vital status.</footnote>

<footnote><sup>b</sup>The probability of superiority and futility is computed from a Bayesian piecewise exponential model using the posterior distribution.</footnote>
<table><caption>Table S12: Sensitivity Analysis of Day 180 mortality within domain-specific populations</caption><thead><tr><th></th><th>Adjusted Hazard Ratio<br>(95% CrI)</th><th>Probability of Superiority<br>of Intervention (%)<sup>a</sup></th><th>Probability of Futility of<br>Intervention (%)<sup>a</sup></th></tr></thead><tbody><tr><td><strong>Immune Modulation Domain</strong></td><td></td><td></td><td></td></tr><tr><td>IL-6 Receptor Antagonists</td><td>0.72 (0.58 to 0.91)</td><td>99.7%</td><td>10.5%</td></tr><tr><td>Anakinra</td><td>0.92 (0.70 to 1.22)</td><td>72.4%</td><td>76.1%</td></tr><tr><td>Control</td><td>1 (referent)</td><td>-</td><td>-</td></tr><tr><td><strong>Immunoglobulin Domain</strong></td><td></td><td></td><td></td></tr><tr><td>Convalescent plasma</td><td>0.99 (0.85 to 1.14)</td><td>57.0%</td><td>98.9%</td></tr><tr><td>Control</td><td>1 (referent)</td><td>-</td><td>-</td></tr><tr><td><strong>Antiplatelet Domain</strong></td><td></td><td></td><td></td></tr><tr><td>Antiplatelet</td><td>0.91 (0.75 to 1.09)</td><td>84.0%</td><td>80.4%</td></tr><tr><td>Control</td><td>1 (referent)</td><td>-</td><td>-</td></tr><tr><td><strong>Anticoagulation Domain</strong></td><td></td><td></td><td></td></tr><tr><td>Therapeutic anticoagulation</td><td>1.21 (0.99 to 1.49)</td><td>3.3%</td><td>&gt;99.9%</td></tr><tr><td>Thromboprophylaxis</td><td>1 (referent)</td><td>-</td><td>-</td></tr><tr><td><strong>Antiviral Domain</strong></td><td></td><td></td><td></td></tr><tr><td>Lopinavir-ritonavir</td><td>1.11 (0.86 to 1.44)</td><td>21.1%</td><td>98.3%</td></tr><tr><td>Hydroxychloroquine</td><td>1.60 (0.98 to 2.58)</td><td>2.9%</td><td>99.6%</td></tr><tr><td>Combination antiviral<br>therapy</td><td>1.78 (1.03 to 3.09)</td><td>1.9%</td><td>99.7%</td></tr><tr><td>Control</td><td>1 (referent)</td><td>-</td><td>-</td></tr><tr><td><strong>Corticosteroid Domain</strong></td><td></td><td></td><td></td></tr><tr><td>Fixed dose corticosteroids</td><td>1.00 (0.62 to 1.55)</td><td>50.1%</td><td>78.3%</td></tr><tr><td>Shock-dependent<br>corticosteroids</td><td>1.06 (0.68 to 1.74)</td><td>39.7%</td><td>85.0%</td></tr><tr><td>Control</td><td>1 (referent)</td><td>-</td><td>-</td></tr></tbody></table>

Crl, denotes credible interval.

<footnote><sup>a</sup> The probability of superiority and futility is computed from a Bayesian piecewise exponential model using the posterior distribution.</footnote>
Table S13: Day 90 mortality

<table><thead><tr><th></th><th>N</th><th>Day 90 mortality, n/N (%)</th><th>Odds Ratio (95% CrI)</th><th>Probability of Superiority of Intervention (%)<sup>a</sup></th><th>Probability of Futility of Intervention (%)<sup>a</sup></th></tr></thead><tbody><tr><td><strong>Immune Modulation Domain</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>IL-6 receptor antagonists</td><td>1433</td><td>481/1409 (34.1)</td><td>0.71 (0.54 to 0.94)</td><td>99.1%</td><td>12.8%</td></tr><tr><td>Anakinra</td><td>371</td><td>150/365 (41.1)</td><td>1.06 (0.74 to 1.52)</td><td>38.2%</td><td>90.1%</td></tr><tr><td>Control</td><td>406</td><td>151/399 (37.8)</td><td>1 (referent)</td><td>-</td><td>-</td></tr><tr><td><strong>Immunoglobulin Domain</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Convalescent plasma</td><td>1078</td><td>408/1067 (38.2)</td><td>0.97 (0.79 to 1.19)</td><td>60.2%</td><td>93.1%</td></tr><tr><td>Control</td><td>911</td><td>358/901 (39.7)</td><td>1 (referent)</td><td>-</td><td>-</td></tr><tr><td><strong>Antiplatelet Domain</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Antiplatelet</td><td>1019</td><td>298/1001 (29.8)</td><td>0.83 (0.64 to 1.07)</td><td>92.3%</td><td>48.2%</td></tr><tr><td>Control</td><td>527</td><td>171/522 (32.8)</td><td>1 (referent)</td><td>-</td><td>-</td></tr><tr><td><strong>Anticoagulation Domain</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Therapeutic anticoagulation</td><td>499</td><td>191/490 (39.0)</td><td>1.23 (0.92 to 1.63)</td><td>8.1%</td><td>99.7%</td></tr><tr><td>Thromboprophylaxis</td><td>511</td><td>181/504 (35.9)</td><td>1 (referent)</td><td>-</td><td>-</td></tr><tr><td><strong>Antiviral Domain</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Lopinavir-ritonavir</td><td>256</td><td>93/253 (36.8)</td><td>1.29 (0.91 to 1.85)</td><td>7.8%</td><td>99.3%</td></tr><tr><td>Hydroxychloroquine</td><td>50</td><td>17/49 (34.7)</td><td>1.89 (1.06 to 3.37)</td><td>1.7%</td><td>99.7%</td></tr><tr><td>Combination antiviral therapy</td><td>27</td><td>13/26 (50.0)</td><td>2.45 (1.23 to 4.85)</td><td>0.6%</td><td>99.9%</td></tr><tr><td>Control</td><td>362</td><td>116/361 (32.1)</td><td>1 (referent)</td><td>-</td><td>-</td></tr><tr><td><strong>Corticosteroid Domain</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Fixed dose corticosteroids</td><td>137</td><td>41/135 (30.4)</td><td>0.84 (0.48 to 1.54)</td><td>71.1%</td><td>52.0%</td></tr><tr><td>Shock-dependent corticosteroids</td><td>147</td><td>36/146 (24.7)</td><td>0.77 (0.43 to 1.40)</td><td>80.6%</td><td>39.3%</td></tr><tr><td>Control</td><td>101</td><td>34/97 (35.1)</td><td>1 (referent)</td><td>-</td><td>-</td></tr><tr><td><strong>Pre-specified combination c/interaction</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Therapeutic anticoagulation/antiplatelet combination b</td><td>35</td><td>17/35 (48.6)</td><td>1.38 (0.76 to 2.49)</td><td>14.4%</td><td>NA</td></tr><tr><td>Therapeutic anticoagulation/antiplatelet interaction</td><td></td><td></td><td>1.36 (0.80 to 2.26)</td><td></td><td></td></tr></tbody></table>

SD denotes standard deviation; NA, not available; CrI, credible interval.

<footnote>a The probability of superiority and futility is computed from a Bayesian logistic regression model using the posterior distribution.</footnote>

<footnote>b The combination effect provides the effect of giving both therapeutic anticoagulation and antiplatelet interventions together in combination. This is estimated by multiplying the hazard ratio for antiplatelet, therapeutic anticoagulation and the interaction effect for antiplatelet and therapeutic anticoagulation.</footnote>
<table><caption>Table S14: Baseline characteristics of survivors with and without EQ-5D-5L utility scores</caption><thead><tr><th>Characteristic</th><th>EQ-5D-5L utility score available<br>N=989</th><th>Missing EQ-5D-5L utility score<br>N=1601</th></tr></thead><tbody><tr><td>Age in years, median (IQR)</td><td>60 (51 - 67)</td><td>56 (47 - 63)</td></tr><tr><td>Male sex, n (%)</td><td>650 (65.7)</td><td>1064 (66.5)</td></tr><tr><td>Female sex, n (%)</td><td>339 (34.3)</td><td>537 (33.5)</td></tr><tr><td>Race/Ethnicity <sup>a</sup>, n/N (%)</td><td></td><td></td></tr><tr><td>Asian</td><td>53/588 (9.0)</td><td>179/1331 (13.5)</td></tr><tr><td>Black</td><td>24/588 (4.1)</td><td>67/1331 (5.0)</td></tr><tr><td>Mixed</td><td>6/588 (1.0)</td><td>34/1331 (2.6)</td></tr><tr><td>Other <sup>a</sup></td><td>25/588 (4.3)</td><td>76/1331 (5.7)</td></tr><tr><td>White</td><td>480/588 (81.6)</td><td>975/1331 (73.3)</td></tr><tr><td>Confirmed SARS-CoV2 infection, n/N (%) <sup>b</sup></td><td>832/978 (85.1)</td><td>1397/1600 (87.3)</td></tr><tr><td>Body mass index, kg/m<sup>2</sup>, median (IQR)</td><td>30.9 (27.1 - 36.3) [N=926]</td><td>31.5 (27.2 - 36.7) [N=1460]</td></tr><tr><td>APACHE II score <sup>c</sup>, median (IQR)</td><td>12 (8-18) [N=954]</td><td>12 (7-18) [N=1578]</td></tr><tr><td>Pre-existing conditions, n/N (%) <sup>d</sup></td><td></td><td></td></tr><tr><td>Diabetes mellitus</td><td>273/989 (27.6)</td><td>429/1601 (26.8)</td></tr><tr><td>Respiratory disease</td><td>222/989 (22.5)</td><td>325/1601 (20.3)</td></tr><tr><td>Asthma/COPD</td><td>189/989 (19.1)</td><td>280/1601 (17.5)</td></tr><tr><td>Other</td><td>48/989 (4.9)</td><td>59/1601 (3.7)</td></tr><tr><td>Kidney disease</td><td>58/922 (6.3)</td><td>84/1479 (5.7)</td></tr><tr><td>Severe cardiovascular disease</td><td>58/973 (6.0)</td><td>95/1568 (6.1)</td></tr><tr><td>Immunosuppressive disease</td><td>42/989 (4.3)</td><td>38/1601 (2.4)</td></tr><tr><td>Chronic immunosuppressive therapy</td><td>41/989 (4.2)</td><td>34/1601 (2.1)</td></tr><tr><td>Time to enrolment, median (IQR)</td><td></td><td></td></tr><tr><td>From hospital admission, days</td><td>1.6 (0.9 - 3.0)</td><td>1.6 (0.9 - 2.9)</td></tr><tr><td>From ICU admission, hours</td><td>16.1 (7.8 - 21.8)</td><td>16.5 (9.2 - 22.2)</td></tr><tr><td>Acute respiratory support, n (%)</td><td></td><td></td></tr><tr><td>None/supplemental oxygen only</td><td>2 (0.2)</td><td>2 (0.1)</td></tr><tr><td>High flow nasal cannula</td><td>381 (38.5)</td><td>402 (25.1)</td></tr><tr><td>Non-invasive ventilation only</td><td>310 (31.3)</td><td>632 (39.5)</td></tr><tr><td>Invasive mechanical ventilation</td><td>296 (29.9)</td><td>565 (35.3)</td></tr><tr><td>ECMO, n/N (%)</td><td>0/974 (0.0)</td><td>1/1585 (0.1)</td></tr><tr><td>Vasopressor support, n (%)</td><td>183 (18.5)</td><td>304 (19.0)</td></tr><tr><td>Median (IQR) acute physiology and laboratory values <sup>e</sup></td><td></td><td></td></tr><tr><td>PaO<sub>2</sub>/FiO<sub>2</sub></td><td>121 (92 - 165) [N=913]</td><td>121 (94 - 163) [N=1525]</td></tr><tr><td>C-reactive protein, µg/mL</td><td>118 (67 - 183) [N=702]</td><td>119 (65 - 189) [N=1261]</td></tr><tr><td>Creatinine, mg/dL</td><td>0.8 (0.7 - 1.0) [N=961]</td><td>0.8 (0.7 - 1.0) [N=1585]</td></tr><tr><td>Lactate, mmol/L</td><td>1.3 (1.0 - 1.7) [N=886]</td><td>1.2 (1.0 - 1.7) [N=1471]</td></tr><tr><td>Platelets, x10<sup>9</sup>/L</td><td>253 (194 - 320) [N=959]</td><td>253 (198 - 326) [N=1585]</td></tr><tr><td>Bilirubin, mg/dL</td><td>0.5 (0.4 - 0.7) [N=884]</td><td>0.5 (0.4 - 0.8) [N=1532]</td></tr></tbody></table>

Percentages may not sum to 100 because of rounding. SD denotes standard deviation; APACHE, Acute Physiology and Chronic Health Evaluation; COPD, chronic obstructive pulmonary disease; IQR, interquartile range; ECMO, extracorporeal membrane oxygenation.

<sup>a</sup>Self-reported via fixed categories. Data collection was not approved in Asia, Canada, and continental Europe. "Other" includes "other ethnic group" and those who declined to respond or were not asked by registration personnel.

<sup>b</sup>SARS-CoV2 infection was confirmed by respiratory tract polymerase chain reaction test.

<sup>c</sup>Measures the severity of illness based on age, medical history, and physiological variables. Scores range from 0 to 71; higher numbers represent greater risk of death. The median score of 12 is typical for patients with COVID-19 admitted to intensive care units (ICUs).
<sup>d</sup>Kidney disease was determined from the most recent stable serum creatinine level prior to this hospital admission, except in patients who were receiving dialysis. Abnormal kidney function was defined as a creatinine level of 130 µmol/L or greater (1.5mg/dL) for males or 100 µmol/L or greater (1.1 mg/dL) for females not previously receiving dialysis. Cardiovascular disease was defined as New York Heart Association class IV symptoms. Immunosuppression was defined by the receipt of recent chemotherapy, radiation, high-dose or long-term steroid treatment, or presence of immunosuppressive disease.

<sup>e</sup>Laboratory results available when captured for clinical care. Although specific laboratory cut-offs may vary, ranges for the following variables are generally considered normal: $P_3O_2/F_iO_2$ ratio ≥400; creatinine <1.2 mg/dL; platelets ≥150 x10<sup>9</sup>/L; and bilirubin <1.2 mg/dL.