key: cord-0814767-49xgcxgb
authors: Mølgaard Nielsen, Frederik; Lass Klitgaard, Thomas; Crescioli, Elena; Rosborg Aagaard, Søren; Andreasen, Anne Sofie; Musaeus Poulsen, Lone; Siegemund, Martin; Craveiro Brøchner, Anne; Bestle, Morten H.; Andi Iversen, Susanne; Brand, Björn A.; Laake, Jon Henrik; Grøfte, Thorbjørn; Hildebrandt, Thomas; Lange, Theis; Perner, Anders; Lilleholt Schjørring, Olav; Steen Rasmussen, Bodil
title: Handling oxygenation targets in ICU patients with COVID‐19—Protocol and statistical analysis plan in the HOT‐COVID trial
date: 2021-08-12
journal: Acta Anaesthesiol Scand
DOI: 10.1111/aas.13956
sha: 70b7169a343ed740fbe9cbbcf420c458704dbf2f
doc_id: 814767
cord_uid: 49xgcxgb

BACKGROUND: Coronavirus disease (COVID‐19) primarily affects the lungs and lower airways and may present as hypoxaemic respiratory failure requiring admission to an intensive care unit (ICU) for supportive treatment. Here, supplemental oxygen remains essential for COVID‐19 patient management, but the optimal dosage is not defined. We hypothesize that targeting an arterial partial pressure of oxygen of 8 kPa throughout ICU admission is superior to targeting 12 kPa. METHODS: The Handling Oxygenation Targets in ICU patients with COVID‐19 (HOT‐COVID) trial, is an investigator‐initiated, pragmatic, multicentre, randomized, parallel‐group trial comparing a lower oxygenation target versus a higher oxygenation target in adult ICU patients with COVID‐19. The primary outcome is days alive without life‐support (use of mechanical ventilation, renal replacement therapy or vasoactive therapy) at day 90. Secondary outcomes are 90‐day and 1‐year mortality, serious adverse events in the ICU and days alive and out of hospital in the 90‐day period, health‐related quality‐of‐life at 1 year, and health economic analyses. One‐year follow‐up of cognitive and pulmonary function is planned in a subgroup of Danish patients. We will include 780 patients to detect or reject an absolute increase in days alive without life‐support of 7 days with an α of 5% and a β of 20%. An interim analysis is planned after 90‐day follow‐up of 390 patients. CONCLUSIONS: The HOT‐COVID trial will provide patient‐important data on the effect of two oxygenation targets in ICU patients with COVID‐19 and hypoxia. This protocol paper describes the background, design and statistical analysis plan for the trial.

Since its emergence in November 2019, the severe acute respiratory syndrome corona-virus-2 (SARS-CoV-2) has spread across the globe and caused an on-going pandemic. 1 Currently, more than 181,000,000 confirmed cases of infection have been recorded and more than 3,900,000 people have died. 2 The disease caused by SARS-CoV-2 has been named coronavirus disease 2019 (COVID-19)-in its most severe form it is characterized by pneumonia leading to profound hypoxia and a clinical presentation resembling acute respiratory distress syndrome (ARDS). 3, 7, 8 Admission to an intensive care unit (ICU) is required in 1-16% of cases 4-6 and the reported a mortality rate for the most severely affected ranges from 35 to 46%. 3, 9, 10, 11 Administration of supplemental oxygen therapy is essential for management of severe COVID-19. 12 Whereas supplementary oxygen therapy is categorized as a medical drug in most of the world, its correct dosage remains a much-contested issue. [13] [14] [15] Current treatment strategies aim to avoid life-threatening hypoxaemia and tend to apply a large margin of safety [16] [17] [18] and evidence for systematic strategies of oxygenation titrating is limited. 19 This is important as hyperoxaemia has potential deleterious effects through systemic vasoconstriction, 20 pulmonary absorption atelectasis 21 and production of free radicals causing oxidative stress. 22 The global health crisis caused by SARS-CoV-2 combined with the essential role of supplemental oxygen for managing the disease makes optimization of oxygen dosage pertinent. 8 

This publication represents the protocol and detailed statistical analysis plan for the Handling Oxygenation Targets in COVID-19 (HOT-COVID) trial. The HOT-COVID trial is an amendment to the HOT-ICU trial. [23] [24] [25] The main HOT-ICU protocol applies to all patients included in the HOT-COVID trial except in respect to any protocol alterations described in this publication. 23,24

The HOT-COVID trial is an investigator-initiated, pragmatic, international, multicentre, randomized, outcome-assessor blinded, parallel-group trial. Adult ICU patients with confirmed COVID-19 and hypoxaemic respiratory failure will be allocated 1:1 to a lower oxygenation target (PaO 2 of 8 kPa) or a higher oxygenation target (PaO 2 of 12 kPa). All screening and randomization procedures are conducted as in the Handling Oxygenation Targets in the ICU (HOT-ICU) trial. [23] [24] [25] Randomization is centralized and web-based according to concealed computer-generated allocation sequence lists stratified for trial site and with permuted varying block sizes.

The protocol has been written according to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 Statement. 26 The SPIRIT checklist is presented in the Supplement.

The HOT-COVID trial is approved as an amendment to the HOT- The trial is externally events in the ICU and days alive and out of hospital in the 90-day period, healthrelated quality-of-life at 1 year, and health economic analyses. One-year follow-up of cognitive and pulmonary function is planned in a subgroup of Danish patients. We will include 780 patients to detect or reject an absolute increase in days alive without life-support of 7 days with an α of 5% and a β of 20%. An interim analysis is planned after 90-day follow-up of 390 patients.

The HOT-COVID trial will provide patient-important data on the effect of two oxygenation targets in ICU patients with COVID-19 and hypoxia. This protocol paper describes the background, design and statistical analysis plan for the trial.

COVID-19, hypoxia, intensive care units, oxygen monitored according to the Good Clinical Practice (GCP) standards, it will adhere to the Helsinki Declaration, 27 and patients will be enrolled after consent to participate has been obtained as according to national regulations. 

Patients will be withdrawn from the trial if informed consent is retracted or not given in accordance with national regulations.

Furthermore, patients are withdrawn from the trial if they encounter a suspected unexpected serious adverse reaction (SUSAR). Of note, no SUSARs were reported in the HOT-ICU trial. 25 In case of withdrawal, data collection will be continued if consent for this is given.

The primary outcome in the HOT-COVID trial is the absolute number of days alive without life support, that is, mechanical ventilation, circulatory support or renal replacement therapy in 90 days after randomization. Mechanical ventilation is defined as either invasive mechanical ventilation, NIV or CPAP. Intermittent CPAP is not con- 

Based on available data on mortality and the clinical experience available in spring 2020 for patients with severe COVID-19, it was assumed that 40% of patients die while on life-support in the ICU. 28 These patients will have 0 days alive without life-support. 

The registered variables at baseline, daily during ICU-stay, at 90-day follow-up, and at 1-year follow-up in the HOT-COVID trial are similar to registrations in the HOT-ICU trial. 24 They are available in the Supplement. Data will be collected in an electronic data form.

All analyses will be conducted according to the intention-to-treat principle 29 with the exception of the per-protocol sensitivity analyses. The intention-to-treat population includes all randomized patients except those where follow-up data cannot be obtained due to withdrawal of consent according to national regulations. [30] [31] [32] All results will be presented with 95% confidence intervals (CIs) unless specified otherwise. All tests for significance will be two-sided, a p-value below .05 will be considered statistically significant unless specified otherwise. CIs adjusted for the multiple secondary outcomes not including the null effect will be considered statistically significant. We will adopt the five step procedure as described by 

A complete case analysis without imputation of missing values will be performed if less than 5% of the data are missing in any primary or secondary outcome analysis. If missing data exceed 5%, the need of imputation will be evaluated, and multiple imputation of missing data will be conducted, in similar way as specified for the HOT-ICU trial. 24 Further details are available in the Supplement.

The primary outcome in the HOT-COVID trial is the absolute number of days alive without life support in the 90-day period. It will be compared between the intervention groups using a generalized linear model or a semi-parametric test, adjusted for the stratification variable site. We will use Poisson distribution or alternately negative binomial distribution for the generalized linear model. 35 If assumptions are not met for these distributions, we will use the nonparametric van Elteren test to analyse the data. 36 Evaluation of significance of the result will be based on the p-value from the generalized linear model or the van Elteren test. We will also report unadjusted absolute differences with 95% CIs based on bootstrap procedures.

An adjusted secondary analysis will be conducted, adjusting for the stratification variable site as well as for important prognostic baseline factors being age, active haematological malignancy, known chronic obstructive pulmonary disease (COPD), active metastatic cancer and Sequential Organ Failure (SOFA) score, analysed using a generalized linear model similar to the primary analysis if assumptions for this is met. If data does not fulfil the assumptions for the parametric models, we will apply a linear model for the, mean regardless of the non-parametric data distributions to allow for the multiple adjustments required. Furthermore, differences between each of the individual components of the primary outcome, that is, days without mechanical ventilation, circulatory support or renal replacement therapy, will be investigated in explorative analyses using a generalized linear model or nonparametric test, adjusted for the stratification variable site.

Sensitivity analyses of the primary outcome measure will be conducted in per-protocol populations as described for the HOT-ICU trial. 23 The primary sensitivity analysis in the HOT-COVID trial will be all randomized patients, except patients with a major protocol violation (MPV) 23 in two or more consecutive 12-h intervals, corresponding to the patient being at least 24 h off target; only consecutive MPVs that deviate to the same side (either above or below the allocated oxygenation target) will exclude the participant.

The dichotomous secondary endpoints of all-cause mortality at day 90 and 1 year after randomization, and one or more SAEs during ICU admission will be compared using a generalized linear model with a log-link and binomial error distribution adjusted for site for the relative risk; and using a generalized linear model with an identity-link and binomial error distribution for the absolute difference. Absolute differences and risk ratios with multiplicity adjusted CIs will be reported. The crude all-cause mortality will be illustrated using Kaplan-Meier plots and difference between groups will be assessed using a Cox proportional hazards model adjusted for site. In all secondary outcomes, adjustments of the CIs due to multiplicity will be performed according to the procedure specified by Jakobsen et al. 37 With six separate secondary outcomes (the 90-day and 1-year mortalities are considered one outcome in the adjustments, as they are highly mutually dependent), the multiplicity adjusted p-values will be below .014 to preserve a family wise error rate below 5%, equivalent of an adjusted CI of 98.6%. Thus, if the adjusted 98.6% CIs for the multiple secondary outcomes does not include the null effect, the results will be considered statistically significant. p-values below .014 will be considered definitely significant and p-values above .014 will be considered definitely nonsignificant. p-values below .05 but above .014 will be considered possibly significant but not confirmative.

The proportions of patients with the separate SAEs during ICU stay from the composite SAE endpoint will be reported as supplementary outcomes, analysed using a generalized linear model with a log-link and binomial error distribution with adjustment for the stratification variable site and reported as exploratory results.

The EQ-5D-5L scores from level 1 (best) to level 5 (worst) in each of the five dimensions will be compared using a generalized linear model or a non-parametric test with adjustment for stratification variable site and will be reported as exploratory results.

Non-survivors will be assigned the worst possible score of 5 in all EQ-5D-5L dimensions. Exploratory supplementary analyses omitting non-survivors of the EQ visual analogue scale score and of scores in each of the five EQ-5L-5L dimensions will be conducted.

All exploratory results will be reported with 95% CIs.

We will assess the heterogeneity of intervention effects of the primary outcome in the HOT-COVID trial in five pre-planned sub- Comparisons will be conducted using a generalized linear model or a nonparametric test as specified for the primary analysis, adjusted for the stratification variable site. We will apply tests of interaction for all subgroups in the analyses, if data are non-parametric, a general linear model for the mean will be applied for this.

In the HOT-COVID trial, the baseline variables, the conducted ICU treatment, and the oxygenation target separation in the intervention groups will be reported in similar manner as specified for the HOT-ICU trial. 24 

The trial will be monitored by an independent DMSC during the entire trial period. The DMSC will adhere to the predefined Charter for the DMSC (Supplement) and will operate comparably to the DMSC in the HOT-ICU trial. 23, 25 An interim analysis applying the Lan DeMets' stopping criteria 38 is planned to be conducted when the initial 390 patients, corresponding to 50% of the study population, have completed their 90-day follow-up. The DMSC can request unplanned interim analyses at any time during the trial period.

SARS-CoV-2 has caused a strain on health care systems and especially ICUs worldwide. Patients with COVID-19 admitted to the ICU are primarily affected by lung tissue injury leading to hypoxia, and treatment is presently limited to supportive care with administration of supplemental oxygen therapy being of critical significance for patient survival. Furthermore, reported pathophysiological differences between COVID-19 related lung injury and ARDS complicates using available data on oxygenation strategies for the critically ill to optimize COVID-19 treatment. 8 Presently no evidence-based recommendations are available for oxygen dosage when treating patients with severe COVID-19, while the Surviving Sepsis Guidelines recommends targeting a SpO2 of 92-96% based on expert opinions. 39 As of yet unpublished data concerning a sub-group analysis of 110 patients with COVID-19 in the HOT-ICU trial indicated that targeting an arterial partial pressure of oxygen (PaO 2 ) of 8 kPa compared with targeting a PaO 2 of 12 kPa throughout ICU admission increased the percentage of days alive without life-support. This result however is inconclusive due to the limited size of the subpopulation and furthermore, other clinical outcomes including mortality were not different between groups. The present study seeks to expand on these initial findings with the feasibility of the study design and the safety of the clinical intervention validated by the results from the completed HOT-ICU trial and its COVID-19 subpopulation. 23, 24 To ensure the validity of the obtained results, the trial will utilize a pragmatic, randomized, parallel-group design with patient inclusion and treatment performed at multiple sites. Further, the trial is externally monitored by GCP units to certify that national and international regulations are met.

The complete trial protocol and statistical analysis plan will be submitted and preferably published before the 90-day follow-up of the 390th patient to ensure methodical transparency and safety, also for the interim analysis.

The inclusion rate, age and disease severity of patients with COVID-19 admitted to ICUs with hypoxaemic respiratory failure will most likely fluctuate over time due to the introduction of vaccinations, improved treatment protocols and emergence of new virus variants. The potential changes in the study population over time can prolong the study duration and possibly influence the subgroup analyses, but the randomized design of the study will ensure a valid assessment of the primary and secondary outcomes.

Finally, patients randomized into the HOT-COVID trial are available for co-enrolment into other clinical trials provided that the interventions do not conflict. Unpredicted interactions between interventions can in principle occur; these will be addressed through secondary sensitivity analyses. However, co-enrolment ensures that knowledge can be generated more efficiently and prohibiting patients from participating in more than one study infringes on their autonomy and denies them the potential clinical benefit gained from participation.

The HOT-COVID trial is currently the only large randomized clinical trial investigating targeted supplemental oxygen for patients with hypoxia due to COVID-19. The results will be valuable in assessing the optimal dosage of supplemental oxygen for treating severe COVID-19 in an ICU setting.

The first randomization was performed on the 25th of August 2020 and the trial is currently recruiting at 10 active sites. At the 1st of 

The authors thank Dr. Jørn Wetterslev for his large contributions in creating the CRIC network. Furthermore, we thank participating patients, relatives, the clinical staff at all trial sites and DMSC members. 

The clean electronic trial database file will be delivered to the EudraCT Database and Danish Data Archive. All documents, including protocol amendments will be available on the public HOT-COVID trial website (www.cric.nu/hot-covid) and communicated to relevant parties through monthly newsletters. The trial results will be sought 

WHO. WHO Characterizes COVID-19 as a Pandemic

WHO. WHO Coronavirus Disease (COVID-19) Dashboard

Pathophysiology of COVID-19-associated acute respiratory distress syndrome: a multicentre prospective observational study

Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72314 cases from the Chinese center for disease control and prevention

Case-fatality rate and characteristics of patients dying in relation to COVID-19 in Italy

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Prevalence of phenotypes of acute respiratory distress syndrome in critically ill patients with COVID-19: a prospective observational study

Series COVID-19: pathophysiology of acute disease 1 the COVID-19 puzzle: deciphering pathophysiology and phenotypes of a new disease entity

The ALIEN study: incidence and outcome of acute respiratory distress syndrome in the era of lung protective ventilation

Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries

Outcomes from intensive care in patients with COVID-19: a systematic review and meta-analysis of observational studies

Review intensive care management of coronavirus disease 2019 (COVID-19): challenges and recommendations

Higher vs lower oxygenation strategies in acutely Ill adults: a systematic review with meta-analysis and trial sequential analysis

Mortality and morbidity in acutely ill adults treated with liberal versus conservative oxygen therapy (IOTA): a systematic review and meta-analysis

Oxygenation targets in acutely ill patients: still a matter of debate

Current oxygenation practice in ventilated patients-an observational cohort study

Current oxygen management in mechanically ventilated patients: a prospective observational cohort study

Bench-to-bedside review : the effects of hyperoxia during critical illness

Higher vs lower oxygenation strategies in acutely ill adults

Independent cerebral vasoconstrictive effects of hyperoxia and accompanying arterial hypocapnia at 1 ATA

Prevention of atelectasis during general anaesthesia

Perspective oxidative stress and acute lung injury

Handling oxygenation targets in the intensive care unit (HOT-ICU)-protocol for a randomised clinical trial comparing a lower vs a higher oxygenation target in adults with acute hypoxaemic respiratory failure

The handling oxygenation targets in the intensive care unit (HOT-ICU) trial: detailed statistical analysis plan

Lower or higher oxygenation targets for acute hypoxemic respiratory failure

Statement: defining standard protocol items for clinical trials

Ethical Principles for Scientific Requirements and Research Protocols

Characteristics, interventions, and longer term outcomes of COVID-19 ICU patients in Denmark-a nationwide, observational study

Challenges of non-intention-to-treat analyses

International conference on harmonisation; guidance on statistical principles for clinical trials; availability-FDA

Getting the methods right-the foundation of patient-centered outcomes research

The preliminary draft of the methodology report by the Patient-Centered Outcomes Research Institute

The thresholds for statistical and clinical significance-a five-step procedure for evaluation of intervention effects in randomised clinical trials

explanation and elaboration: updated guidelines for reporting parallel group randomised trials

Statistics for Biology and Health: Regression with Linear Predictors. 1st edn

Data analysis in randomised clinical trials

Thresholds for statistical and clinical significance in systematic reviews with meta-analytic methods

Discrete sequential boundaries for clinical trials

Surviving sepsis campaign guidelines on the management of adults with coronavirus disease 2019 (COVID-19) in the ICU: first update

Handling oxygenation targets in ICU patients with COVID-19-Protocol and statistical analysis plan in the HOT-COVID trial