Outcomes of Patients Who Survived Treatment on an Intensive Care Unit for COVID-19 in England and Wales: a Comparative Retrospective Cohort Study (OPTIC-19)
Conditions: Covid19, Myocardial Infarction, Stroke, Critical Illness, Heart Failure, Deep Vein Thrombosis, Pulmonary Embolism, Renal Failure
Sponsor: University of Oxford

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Study Title:  Outcomes of Patients who survived Treatment on an Intensive Care unit for COVID-19 in 
England and Wales: a comparative retrospective cohort study 
Internal Reference Number / Short title: OPTIC-19 
Version No and Date: Version 5 – 17/06/2022 
Ethics Ref: 21/SC/0021 
CAG Ref: 21/CAG/0017 
IRAS Project ID: 291887 
Joint Research Office Ref: PID15456 
NHS Digital Ref: DARS-NIC-419335-H5P8T-v0.0 
ClinicalTrials.gov: NCT04838106 
 
Chief Investigator: 
Peter Watkinson 
 
 
Investigators:  
Oliver C Redfern, University of Oxford 
Stephen Gerry, University of Oxford 
Robert Hatch, University of Oxford 
Kathryn Rowan, Intensive Care National Audit and Research Centre 
(ICNARC) 
David Harrison, ICNARC 
James Doidge, ICNARC  
Doug Gould, ICNARC 
Sponsor:  
University of Oxford  
Clinical Trials & Research Governance,  
Boundary Brook House,   
Oxford,  
OX3 7GB,  
United Kingdom 
Funder: 
University of Oxford’s COVID-19 Research Response Fund (Ref: 
0009471) 

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Chief Investigator Signature:   
 
Statistician Signature:   
 
Conflicts of interes 
The applicants have no relevant conflicts of interest to declare 
 
Confidentiality Statement 
This document contains confidential information that must not be disclosed to anyone other than the 
Sponsor, the Investigator Team, HRA, host organisation, and members of the Research Ethics Committee, 
unless authorised to do so. 
 

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TABLE OF CONTENTS 
 
1. 
KEY CONTACTS ................................................................................................................................... 6 
2. 
LAY SUMMARY................................................................................................................................... 6 
3. 
SYNOPSIS ........................................................................................................................................... 7 
4. 
ABBREVIATIONS ................................................................................................................................. 8 
5. 
BACKGROUND AND RATIONALE ........................................................................................................ 9 
Background ............................................................................................................................................ 9 
Aim ....................................................................................................................................................... 10 
6. 
OBJECTIVES AND OUTCOME MEASURES ......................................................................................... 10 
7. 
STUDY DESIGN ................................................................................................................................. 11 
7.1. 
Design ...................................................................................................................................... 11 
7.2. 
Setting ...................................................................................................................................... 11 
7.3. 
Data collection ......................................................................................................................... 12 
8. 
PARTICIPANT IDENTIFICATION ........................................................................................................ 13 
8.1. 
Study Participants .................................................................................................................... 13 
8.2. 
Inclusion Criteria ...................................................................................................................... 13 
8.3. 
Exclusion Criteria ..................................................................................................................... 13 
9. 
PROTOCOL PROCEDURES ................................................................................................................ 13 
9.1. 
Recruitment ............................................................................................................................. 13 
9.2. 
Screening and Eligibility Assessment ....................................................................................... 13 
9.3. 
Informed Consent .................................................................................................................... 13 
Patient Notification Strategy ............................................................................................................... 13 
Opt-out ................................................................................................................................................ 14 
Your data matters ................................................................................................................................ 14 
9.4. 
Enrolment ................................................................................................................................ 14 
9.5. 
Blinding and code-breaking ..................................................................................................... 15 
9.6. 
Description of study intervention(s), comparators and study procedures (clinical) ............... 15 
9.7. 
Baseline Assessments .............................................................................................................. 15 
9.8. 
Subsequent Visits .................................................................................................................... 15 
9.9. 
Sample Handling ...................................................................................................................... 15 
No additional samples will be taken during this observational study. ................................................ 15 
9.10. 
Early Discontinuation/Withdrawal of Participants .................................................................. 15 

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9.11. 
Definition of End of Study ....................................................................................................... 15 
10. 
SAFETY REPORTING ......................................................................................................................... 15 
11. 
STATISTICS AND ANALYSIS ............................................................................................................... 15 
11.1. 
Statistical Analysis Plan (SAP) .................................................................................................. 15 
11.2. 
Description of the Statistical Methods .................................................................................... 15 
Primary outcome ................................................................................................................................. 16 
Secondary outcomes ........................................................................................................................... 16 
Statistical methods .............................................................................................................................. 16 
11.3. 
Sample Size Determination ..................................................................................................... 17 
11.4. 
Analysis populations ................................................................................................................ 17 
Primary group ...................................................................................................................................... 17 
Comparator groups ............................................................................................................................. 17 
Pregnant patients ................................................................................................................................ 17 
11.5. 
Decision points ........................................................................................................................ 17 
11.6. 
Stopping rules .......................................................................................................................... 18 
11.7. 
The Level of Statistical Significance ......................................................................................... 18 
11.8. 
Procedure for Accounting for Missing, Unused, and Spurious Data. ...................................... 18 
11.9. 
Procedures for Reporting any Deviation(s) from the Original Statistical Plan ........................ 18 
12. 
DATA MANAGEMENT ...................................................................................................................... 18 
12.1. 
Source Data ............................................................................................................................. 18 
Data linkage ......................................................................................................................................... 18 
Data sources ........................................................................................................................................ 19 
Data timeframes .................................................................................................................................. 19 
Data storage for analysis ..................................................................................................................... 19 
12.2. 
Access to Data ......................................................................................................................... 19 
12.3. 
Data Recording and Record Keeping ....................................................................................... 20 
13. 
QUALITY ASSURANCE PROCEDURES ............................................................................................... 20 
13.1. 
Risk assessment ....................................................................................................................... 20 
13.2. 
Study monitoring ..................................................................................................................... 20 
13.3. 
Study Committees ................................................................................................................... 21 
Study management group ................................................................................................................... 21 
14. 
PROTOCOL DEVIATIONS .................................................................................................................. 21 
15. 
SERIOUS BREACHES ......................................................................................................................... 21 
16. 
ETHICAL AND REGULATORY CONSIDERATIONS ............................................................................... 21 

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16.1. 
Declaration of Helsinki............................................................................................................. 21 
16.2. 
Guidelines for Good Clinical Practice ...................................................................................... 21 
16.3. 
Approvals ................................................................................................................................. 21 
16.4. 
Other Ethical Considerations ................................................................................................... 22 
16.5. 
Reporting ................................................................................................................................. 22 
16.6. 
Transparency in Research ........................................................................................................ 22 
16.7. 
Participant Confidentiality ....................................................................................................... 22 
16.8. 
Expenses and Benefits ............................................................................................................. 22 
17. 
FINANCE AND INSURANCE .............................................................................................................. 22 
17.1. 
Funding .................................................................................................................................... 22 
17.2. 
Insurance ................................................................................................................................. 22 
17.3. 
Contractual arrangements ...................................................................................................... 22 
18. 
PUBLICATION POLICY ....................................................................................................................... 22 
19. DEVELOPMENT OF A NEW PRODUCT/ PROCESS OR THE GENERATION OF INTELLECTUAL PROPERTY 23 
19. 
ARCHIVING....................................................................................................................................... 23 
20. 
REFERENCES .................................................................................................................................... 23 
21. 
APPENDIX A:  DATA FLOW DIAGRAM .............................................................................................. 24 
22. 
APPENDIX C:  AMENDMENT HISTORY ............................................................................................. 24 
 
 
 

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1. KEY CONTACTS 
 
Chief Investigator 
Dr Peter Watkinson 
Kadoorie Centre, University of Oxford, Level 3, John Radcliffe Hospital, 
Headley Way, Oxford, OX3 9DU 
01865 857613 
peter.watkinson@ndcn.ox.ac.uk 
Sponsor 
University of Oxford 
Clinical Trials & Research Governance,  
Boundary Brook House,   
Oxford,  
OX3 7GB,  
United Kingdom 
Telephone: +44 1865 616480 
Email: ctrg@admin.ox.ac.uk 
   
Funder(s) 
The study is funded by the University of Oxford’s COVID-19 Research 
Response Fund (Ref: 0009471). 
Clinical Trials Unit 
N/A 
 
Statistician 
Mr Stephen Gerry 
Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, 
Rheumatology and Musculoskeletal sciences 
01865 223463 
stephen.gerry@csm.ox.ac.uk 
Committees 
Study management group. Chair: Peter Watkinson 
 
2. LAY SUMMARY  

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Across England and Wales, over 10,000 patients have been treated for severe coronavirus disease 2019 
(COVID-19) on an intensive care unit. Around 60% survived to leave hospital. We do not know how 
survivors’ severe COVID-19 infection, or the treatment they received on the intensive care unit, will 
affect their long-term health. Understanding what happens to these patients can help us make sure they 
receive suitable care from their GP and other NHS services after they leave hospital. 
This study will follow up survivors for 1 year after discharge from hospital. We will use data collected by 
the Intensive Care National Audit and Research Centre (ICNARC) to identify patients who were treated 
on an ICU for COVID-19. We will then use NHS data to see whether these patients were readmitted to 
hospital and why. Information from the Office of National Statistics will allow us to know whether these 
patients died. By linking different sources of patient data, we will be able to estimate the health risks 
faced by survivors of severe COVID-19. We will compare these risks to patients treated on an ICU for 
other conditions. 
3. SYNOPSIS 
 
Study Title 
Outcomes of Patients who survived Treatment on an Intensive Care unit for 
COVID-19 in England and Wales: a comparative retrospective cohort study 
Internal ref. no. / short 
title 
OPTIC-19 
Study registration 
ClinicalTrials.gov:  
Sponsor  
University of Oxford  
Clinical Trials & Research Governance,  
Boundary Brook House,   
Oxford,  
OX3 7GB,  
United Kingdom 
Funder  
The study is funded by the University of Oxford’s COVID-19 Research 
Response Fund (Ref: 0009471). 
Study Design 
Retrospective cohort study 
Study Participants 
Patients aged 16 or over admitted as an emergency to an intensive care unit 
in England or Wales and discharged alive from hospital, and treated for 
either COVID-19 or another acute condition. 
Sample Size 
319,600 
Planned Study Period 
Project length: 36 months 
Follow up period: 1 year after discharge from an intensive care unit 
 
Planned Recruitment 
period 
January 2016 to July 2020 
 
Objectives 
Outcome Measures 
Timepoint(s) 
Primary 
 
To estimate the risk 
of death for 
patients who 
Mortality 
1 year 

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survived to hospital 
discharge after 
treatment on an 
ICU for COVID-19 
and compare these 
risks to patients 
treated on ICU as 
an emergency for 
other conditions 
Secondary 
 
To estimate the risk 
of adverse events 
for patients who 
survived to hospital 
discharge after 
treatment on an 
ICU for COVID-19 
and compare these 
risks to patients 
treated on ICU as 
an emergency for 
other conditions 
• 
Emergency hospital 
admission  
• 
Emergency hospital 
admission 
for respiratory infection 
• 
Emergency hospital 
admission for a major 
adverse cardiac event 
(myocardial infarction, 
stroke, heart failure) 
• 
Emergency hospital 
admission for a venous 
thrombotic event (deep 
vein thrombosis or 
pulmonary embolism) 
• 
Development of end 
stage renal failure 
treated by renal 
replacement therapy 
1 year 
Intervention(s) 
Non-interventional study 
 
4. ABBREVIATIONS 
 
CAG 
Confidentiality Advisory Group 
CCRG 
Critical Care Research Group 
CI 
Chief Investigator 
CMP 
Case Mix Programme 
COVID-19 
COronaVIrus Disease 2019  
CRF 
Case Report Form 
CTRG 
Clinical Trials & Research Governance, University of Oxford 
HES 
Hospital Episode Statistics 
GCP 
Good Clinical Practice 
GP 
General Practitioner 

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HRA 
Health Research Authority 
ICF 
Informed Consent Form 
ICNARC 
Intensive Care National Audit and Research Centre 
ICU 
Intensive Care Unit 
NHS 
National Health Service 
NICOR 
National Institute for Cardiovascular Outcomes Research 
RES 
Research Ethics Service 
OXTREC 
Oxford Tropical Research Ethics Committee 
PEDW 
Patient Episode Database for Wales 
PI 
Principal Investigator 
PIL 
Participant/ Patient Information Leaflet 
R&D 
NHS Trust R&D Department 
REC 
Research Ethics Committee 
SOP 
Standard Operating Procedure 
SSNAP 
Stroke Sentinel National Audit Programme 
UKOSS 
UK Obstetric Surveillance System 
UKRR 
UK Renal Registry 
5. BACKGROUND AND RATIONALE 
Background 
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in late 2019. By mid-July 
2020 14 million people globally had been infected, of which over 600,000 died of coronavirus disease 
2019 (COVID-19) (1). In the UK, nearly 20% of patients hospitalised with COVID-19 were transferred to an 
intensive care unit (ICU) or high dependency ward (2). In total, over 10,000 patients have been treated 
for COVID-19 on an ICU in England and Wales. On average, 50% of these patients survived to hospital 
discharge, although survival rates appear to be increasing (3,4). The long-term impact on the health of 
survivors is unknown.  
Previous studies have shown that critically ill patients who survive ICU treatment are at greater risk of 
death and report lower health-related quality of life when compared with population norms (5–7). While 
pre-existing comorbidities partially account for these differences, organ damage caused by critical illness 
and the impact of intensive organ support given in the ICU likely also play a role (8). Analysis by the 
Intensive Care National Audit and Research Centre (ICNARC) suggests that patients admitted with COVID-
19 receive higher intensity organ support and suffer more complications than observed in other viral 
respiratory infections (4). For example, nearly all COVID-19 patients required respiratory support, with 
nearly 60% receiving mechanical ventilation (compared to 43% with viral pneumonias) (4). Around one 
third of patients also required advanced cardiovascular or renal support (4,9). Cardiac (myocarditis, heart 
failure, arrhythmias, acute coronary syndrome) and venous thrombotic complications (e.g. pulmonary 

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embolism) were not uncommon (10–12). Although rare, some patients developed neurological 
complications such as stroke, encephalitis and Guillain-Barré syndrome (13). 
Aim 
This protocol describes a retrospective cohort study aiming to characterise outcomes for patients treated 
on an ICU with COVID-19 in England and Wales, one year after discharge from hospital. The study will use 
existing national audit data linked to routine healthcare datasets. 
6. OBJECTIVES AND OUTCOME MEASURES 
 
Objectives 
Outcome Measures  
Timepoint(s) 
of 
evaluation of this 
outcome measure 
(if applicable) 
Primary Objective 
To estimate the risk of death for 
patients who survived to hospital 
discharge after treatment on an 
ICU for COVID-19 and compare 
these risks to patients treated on 
ICU as an emergency for other 
conditions 
Primary outcome 
• 
Death as recorded in the Civil 
Registration -- Deaths 
 
1 year after 
discharge from ICU 
 
 
 
 
 
 
 
 
Secondary Objectives 
To estimate the risk of adverse 
events for patients who survived to 
hospital discharge after treatment 
on an ICU for COVID-19 and 
compare these risks to patients 
treated on ICU as an emergency for 
other conditions 
Secondary outcomes 
• 
Emergency hospital admission  
• 
Emergency hospital admission 
for respiratory infection 
• 
Emergency hospital admission for 
a major adverse cardiac event 
(myocardial infarction, stroke, 
heart failure) 
• 
Emergency hospital admission for 
a venous thrombotic event (deep 
180 days after 
discharge from ICU 
AND 1 year after 
discharge from ICU 
 
 
 

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vein thrombosis or pulmonary 
embolism) 
• 
Development of end stage renal 
failure treated by renal 
replacement therapy 
Exploratory Objectives 
To compare the risks in patients 
treated in ICU for COVID-19 to 
patients who survived to hospital 
discharge after treatment on an 
ICU for other bacterial or viral 
respiratory infections during the 
same period (January to June 2020) 
To compare the risks in pregnant 
patients treated in ICU for COVID-
19 with an age-matched control 
group 
Primary outcome 
• 
Death as recorded in the Civil 
Registration -- Deaths 
Secondary outcomes 
• 
Emergency hospital admission  
• 
Emergency hospital admission 
for respiratory infection 
• 
Emergency hospital admission for 
a major adverse cardiac event 
(myocardial infarction, stroke, 
heart failure) 
• 
Emergency hospital admission for 
a venous thrombotic event (deep 
vein thrombosis or pulmonary 
embolism) 
• 
Development of end stage renal 
failure treated by renal 
replacement therapy 
180 days after 
discharge from ICU 
AND 1 year after 
discharge from ICU 
 
 
7. STUDY DESIGN 
7.1. Design 
This is a retrospective cohort study of outcomes for patients treated on an ICU in England and Wales, 
one year after discharge from hospital. Our primary group will include patients admitted to ICU with 
confirmed COVID-19 between 1st January and 1st July 2020, who were discharged alive from hospital. 
We will use the ICNARC Case Mix Programme (CMP) to identify comparator groups of emergency ICU 
admissions, to which outcomes in the primary group can be compared. Once identified, each cohort will 
be linked to the national data sets to obtain information on subsequent hospitalisations, and longer-term 
mortality, cardiac and renal outcomes.  
The study will be reported using the REporting of studies Conducted using Observational Routinely-
collected health Data (RECORD) (14). 
7.2. Setting 

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This study will use data from patients admitted to general adult ICUs in England and Wales, collected as 
part of the CMP. The CMP is an audit of patients admitted to adult general (and some specialist) ICUs 
that covers England, Wales and Northern Ireland. This study will only use data from ICUs in England and 
Wales, all of which have participated in the CMP programme since 2015. 
7.3. Data collection 
Eligible participants identified from the CMP will be assigned a pseudonymous “study key”. The study key 
will be sent to the other participating organisations for linkage alongside the following direct identifiers: 
• 
Date of birth 
• 
NHS number 
• 
Postcode 
• 
Sex/gender 
Linkage will be performed by each participating organisation, following the principles of the NHS Digital 
matching algorithm. At no point will direct identifiers be sent to the co-ordinating site (Critical Care 
Research Group, University of Oxford).  
Participating organisations performing linkage will be: 
• 
NHS Digital  
• 
Patient Episode Database for Wales (PEDW)  
• 
UK Renal Registry (UKRR) 
• 
National Institute for Cardiovascular Outcomes Research (NICOR) 
• 
Stroke Sentinel National Audit Programme (SSNAP) 
On a per patient level, the study will request 5 years of diagnostic coding data prior to ICU admission (to 
accurately assess prior medical co-morbidities) and 1 year post hospital discharge (to assess the 
outcomes of this study).  
After linkage, only pseudonymous personal data will be securely transferred to the sponsor (Critical Care 
Research Group, University of Oxford), where it will be stored and accessed within a secure computing 
system that conforms to UK government Cyber Essentials Plus and NHS Digital Security Toolkit 
certifications. The study will also link data from the UK Obstetric Surveillance System (UKOSS) to identify 
patients who were pregnant at the time of ICU admission. As UKOSS does not collect direct identifiers, it 
will be linked to the pseudonymous data set using probabilistic matching.  
Data will be combined into the final pseudonymised study dataset by researchers in the Critical Care 
Research Group at the University of Oxford for analysis. Analysis of the study dataset will be conducted 
by researchers at the University of Oxford and ICNARC, following the methods outlined in Section 11. The 
accompanying Data Flow Diagram outlines the exchange of confidential patient information within the 
study. 
 

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8. PARTICIPANT IDENTIFICATION 
 
8.1. Study Participants 
 
8.2. Inclusion Criteria 
• 
Age ≥16 years 
• 
Admitted to an adult, general ICU in England or Wales as an emergency (unplanned) 
• 
Admitted to ICU for either: 
o confirmed COVID-19 between 1st January to 1st July 2020 
o without confirmed COVID-19 between 1st July 2016 and 1st July 2020  
8.3. Exclusion Criteria 
The participant may not enter the study if ANY of the following apply: 
• 
Patients who died in hospital after treatment on an ICU 
 
We chose to exclude ICU admissions after 1st July 2020 to account for a possible three-month delay in 
patient data being registered in HES and national audit databases. Linking data sources in March and 
October 2021 will maximise the chance that complete data will be available for outcomes at 180 and 365 
days respectively. 
9. PROTOCOL PROCEDURES  
9.1. Recruitment 
Participants will be recruited from general adult ICUs across England and Wales who participate in the 
ICNARC CMP audit. All ICUs in England and Wales have participated in the CMP audit since 2015. 
9.2. Screening and Eligibility Assessment 
Changes to inclusion and exclusion criteria will be made by ethical amendment only. 
There will be no exceptions made regarding eligibility. 
9.3. Informed Consent 
We will apply for Health Research Approval (HRA), under advice from the Research Ethics Committee and 
the Confidentiality Advisory Group (CAG) to allow access to confidential medical records without 
informed or written consent (Section 251 support). 
Patient Notification Strategy 

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As part of a similar study (the C3 study), we developed a patient notification strategy with input from the 
Oxford REC B ethics committee and members of the Oxford ICU Forum (a group of previous ICU patients, 
families, and lay members).  
In common with C3, the current study: 
• 
Uses retrospective patient data.  
• 
At no point will any attempt be made to contact or otherwise influence the future care of any 
the participants. 
• 
The data set compiled for analysis will be pseudonymised and therefore stripped of all direct 
identifiers. 
• 
The study will fully implement the National Data Opt-out (DCB3058) and will therefore exclude 
any records related to patients who have notified the NHS of their wish for their data not to be 
used in research. 
For the C3 study, we were advised by the ethics committee that placing posters in the relative rooms or 
waiting areas of the participating ICUs to notify patients of the study, “was not practical and should not 
therefore be used”.  All members of the PPI panel agreed with the ethics committee that displaying 
posters would not be appropriate. However, the PPI group advised that information should be available 
on a study website. The group advised that the website summary should be brief and accessible, with 
links to the detail (such as formal privacy policy) available.   
Members of the Oxford ICU patient forum were also consulted for this study (OPTIC-19) and were 
supportive of its approach and aims. 
Opt-out 
The study will fully support and implement the NHS National Opt-out.  We will utilise our link to NHS 
Digital asking them to inform us (by pseudonymous study ID) which patients have opted out and that will 
be a continuous process from enrolment until the study ends.  Records that are already flagged within 
each site as meeting the opt-out will not be extracted. 
If we are informed by NHS Digital of patients completing the Opt-out after data extraction, these data 
will be purged and future records relating to these patients will not be extracted. 
We will also purge records from the study (in the same manner) if patients contact the study directly. 
We will clearly display on the website links to register for the opt-out, as well as contact details for the 
study team. 
Your data matters 
The study will openly support the ICO “Your data matters campaign” (https://ico.org.uk/your-data-
matters/). The aim is to increase the public's trust and confidence in how their data is used and made 
available.  We will also support the NHS implementation of this campaign that has direct relevance to the 
study using data for patient benefit (https://digital.nhs.uk/services/national-data-opt-out/supporting-
patients-information-and-resources). 
9.4. Enrolment 

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This is a non-randomised observational study. Enrolment of participants will occur through their data 
being present within the ICNARC CMP. 
9.5. Blinding and code-breaking  
There is no blinding or code-breaking in this observational study. 
9.6. Description of study intervention(s), comparators and study procedures (clinical) 
This is a non-interventional study.  
9.7. Baseline Assessments 
Not applicable 
9.8. Subsequent Visits 
Not applicable 
9.9. Sample Handling  
No additional samples will be taken during this observational study. 
9.10. 
Early Discontinuation/Withdrawal of Participants 
This is an observational study. Participants can request their data to be deleted at any time in accordance 
with GPDR and the trial privacy policy. 
9.11. 
Definition of End of Study 
The end of the study will be 31st July 2023. 
10. SAFETY REPORTING  
This is an observational study using routinely-collected retrospective data, so safety reporting is not 
applicable 
11. STATISTICS AND ANALYSIS 
11.1. 
Statistical Analysis Plan (SAP) 
The statistical aspects of the study are summarised here with details fully described in a statistical 
analysis plan that will be available from the time that the last participant is recruited. The SAP will be 
finalised before any analysis takes place.  
11.2. 
Description of the Statistical Methods  

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Primary outcome 
The primary outcome will be all-cause mortality at 1 year after discharge from ICU. For patients 
transferred between ICUs, this will be the time of discharge from the last ICU. Dates of death will be 
extracted from Civil Registration (deaths). 
Secondary outcomes 
Secondary outcomes will be: 
• 
All-cause mortality at 30, 60, 90 and 180 days 
• 
Any emergency (non-elective) hospital admission 
• 
Emergency hospital admissions for respiratory infection 
• 
Emergency hospital admission for a venous thrombotic event (deep vein thrombosis or 
pulmonary embolism) 
• 
Emergency hospital admission for a major adverse cardiac event (myocardial infarction, stroke, 
heart failure) 
• 
Development of end stage renal failure treated by renal replacement therapy 
Reasons for hospital admission (i.e. primary diagnosis) will be identified using the International 
Classification of Diseases 10th Edition (ICD- 10) codes obtained by linkage to the HES/PEDW. Where 
required, ICD-10 codes will be assigned to broader diagnostic groups (e.g. respiratory infections) as per 
the UK Summary Hospital-level Mortality Indicator (SHMI) (16). 
Statistical methods 
For patients treated on ICU for COVID-19 and comparator groups, we will report the unadjusted 
proportions/incidence of primary and secondary outcomes, along with cumulative incidence function 
estimates over the 1 year follow-up period. When considering secondary outcomes (and where 
appropriate), the cumulative incidence estimates will account for the competing risk of death. For the 
COVID-19 group, we will also investigate the effect of ICU admission time (i.e. early epidemic, late 
epidemic) as this may impact their outcomes, as treatments changed over time. 
We will compare the risk of the primary and secondary outcomes between the COVID-19 and 
comparator groups using survival models, such as Cox proportional hazards regression models or Fine 
and Gray models (when death is a competing risk). We will fit both univariable models (i.e. just including 
the COVID-19 vs comparator group variable) and multivariable models including potential confounders. 
We will also analyse the data using propensity score matching as an alternative method to account for 
any potential confounding associated with the COVID-19 and comparator populations. A logistic 
propensity score will be used to create a matched population. The following variables will be considered 
for inclusion in the propensity score: 
• 
Age at discharge from hospital 
• 
Charlson/Elixhauser comorbidity index 
• 
Ethnicity 
• 
Illness severity (APACHE-II or ICNARC severity score) on admission to ICU 
• 
Days of mechanical ventilation 
• 
Week of the year of ICU admission (to account for potential increased survival over the course of 
the pandemic) 

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As an exploratory analysis, we will examine potential prognostic factors (such as patient or ICU 
treatment characteristics) for the primary and secondary outcomes. We will further investigate whether 
some of the secondary outcomes are time-varying predictors of mortality. Latent class analysis may also 
be used to identify any clustering of the secondary outcomes and their severity and/or timing. 
Where common patient data items are available from multiple data sources (e.g. age, gender ethnicity), 
we will develop a standard protocol to resolve inconsistencies. Should substantial differences remain, we 
will explore any effect on our results through a sensitivity analysis.  
11.3. 
Sample Size Determination  
The study size will be determined by the number of ICU survivors available from the CMP. The CMP 
currently holds around 10,000 patients admitted with confirmed COVID-19, of which ≈5,000 survived to 
hospital discharge. Of the survivors, we expected 90% (4,600) to have been admitted to an ICU in 
England or Wales.   
Prior to the COVID-19 pandemic, there were around 130,000 emergency ICU admissions per annum in 
the CMP. Of these, around 100,000 survived to hospital discharge. We expect ≈90,000 to have been 
admitted to an ICU in England or Wales.   
Study participants will include around 3.5 years of pre-pandemic admissions (90,000 x 3.5 = 315,000) and 
4,600 COVID admission during the pandemic giving a total sample size of 319,600. 
11.4. 
Analysis populations 
Primary group 
Our primary group will be patients admitted with confirmed COVID-19 between 1st January to 1st July 
2020. 
Comparator groups 
The primary comparator group will be patients admitted to ICU with viral or bacterial pneumonia 
between 1st July 2016 and 1st July 2019.  
Secondary comparator groups will include: 
• 
All emergency ICU admissions between 1st July 2016 and 1st July 2019 
• 
All emergency ICU admissions between 1st July 2016 and 1st January 2020 where the primary 
diagnosis was not COVID-19  
• 
All emergency ICU admissions between 1st January and 1st July 2020 where the primary 
diagnosis was not COVID-19 
Pregnant patients 
We will undertake a sub-group analysis in patients who were pregnant when treated for COVID-19 on 
ICU between 1st January and 1st July 2020. 
11.5. 
Decision points  

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• 
March 2021: We will undertake data linkage and extraction from participating organisations. An 
interim analysis of outcomes at 180 days follow-up will be undertaken. 
• 
October 2021: We will undertake data linkage and extraction from participating organisations. A 
final analysis of outcomes at 365 days follow-up will be undertaken. 
11.6. 
Stopping rules 
Not applicable 
11.7. 
The Level of Statistical Significance 
The level of statistical significance will be set at p<0.05. 
11.8. 
Procedure for Accounting for Missing, Unused, and Spurious Data. 
For multivariate models, we will impute missing covariates using fully conditional specification 
implemented using the Multivariate Imputation by Chained Equations (MICE) algorithm (17). The 
multiple imputation model will include all covariates, alongside the relevant outcome. 
11.9. 
Procedures for Reporting any Deviation(s) from the Original Statistical Plan 
Any deviation from the statistical analysis plan will be described and justified in all study publications. 
12. DATA MANAGEMENT 
The plan for the data management of the study are outlined below. There is not a separate Data 
Management document in use for the study.  
12.1. 
Source Data 
This study requires accessing and linking confidential health care records. Access to these data will be 
subject to approval from a REC and Section 251 support from the CAG. 
Data linkage 
Eligible participants will be identified by ICNARC from the CMP audit. Each eligible participant will be 
assigned a pseudonymous “study key”. The study key will be sent to the other participating organisations 
for linkage alongside the following direct identifiers: 
• 
Date of birth 
• 
NHS number 
• 
Postcode 
• 
Sex/gender 
Linkage will be performed by each participating organisation, following the principles of the NHS Digital 
matching algorithm, after which all direct identifiers will be removed. Only pseudonymised data (including 
the study key) will be securely transferred to the Sponsor (Critical Care Research Group, University of 

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Oxford), where researchers will assemble these data sources for analysis. At no point will direct identifiers 
be sent to the Sponsor.  
Data sources 
The following data sources will be linked to the CMP audit: 
• 
NHS Digital 
o Hospital Episode Statistics (HES) 
▪ 
Admitted Patient Care 
▪ 
Outpatients 
o Maternity Services Data Set (MSDS) 
o Civil Registration (deaths) 
o Emergency Care Data Set (ECDS) 
o Hospital Episode Statistics Accident and Emergency 
o GPES Data for Pandemic Planning and Research (COVID-19) 
• 
Patient Episode Database for Wales (PEDW)  
• 
UK Renal Registry (UKRR) 
• 
National Institute for Cardiovascular Outcomes Research (NICOR) 
• 
Stroke Sentinel National Audit Programme (SSNAP) 
The study will also link data from the UK Obstetric Surveillance System (UKOSS) to identify patients who 
were pregnant at the time of ICU admission. As UKOSS does not collect direct identifiers, it will be linked 
to the pseudonymous data set using probabilistic matching.  
Data timeframes 
On a per patient level, the study will request 5 years of diagnostic coding data prior to ICU admission (to 
accurately assess prior medical co-morbidities) and 1 year post hospital discharge (to assess the 
outcomes of this study). The use of a 5 year window of prior diagnostic coding data is based on previous 
literature that has shown this enhances data accuracy (14). This is preferable to relying solely on the 
diagnostic coding relating to the hospital admission, as complications cannot be differentiated from prior 
co-morbidities (15). 
Data storage for analysis 
The Sponsor will hold pseudonymised data within a secure “Data Safe Haven”, which is owned and 
maintained by the group. The “Data Safe Haven” is a computing environment which has been designed 
to store and analyse large datasets in a manner that is safe and secure. It conforms to NHS Digital 
Security Toolkit and Cyber Essentials Plus accreditation. The environment is designed to prevent patient 
level data leaving this environment. 
ICNARC will hold data within a secure environment, which conforms to the NHS Digital Security Toolkit. 
12.2. 
Access to Data 

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The final pseudonymised dataset will be accessed by authorised members of the study team at the 
University of Oxford and ICNARC for analysis purposes. At the University of Oxford, access will be via the 
Data Safe Haven subject to compliance with local information governance policies. Pseudonymised data 
will also be securely transferred to ICNARC and accessed via secure servers managed by ICNARC.  
12.3. 
Data Recording and Record Keeping 
All study records will be electronic -- their generation is detailed above. All records will be subject to 
quality assurance polices both at the University and research group level. These are designed to 
guarantee the accuracy and validity of the study data. 
The participants will be identified by a unique study number (pseudonymous study key). 
13. QUALITY ASSURANCE PROCEDURES 
All research team members will be trained in Information Governance, data protection and 
confidentiality. The study may be monitored, or audited in accordance with the current approved 
protocol, GCP, relevant regulations and standard operating procedures. 
13.1. 
Risk assessment  
This is a retrospective observational study, where researchers will not interact directly with patients or 
intervene in their care. 
This study requires access to confidential patient records. Eligible patient records will be identified by 
ICNARC from the CMP audit and linked with follow-up data held by NHS Digital and three national audit 
projects. Directly identifiable data is only required for record linkage and will not be available to the 
Sponsor. 
To mitigate the risk of reidentification of participants and the risk of data loss we will undertake the 
following: 
• 
All records will be accessed and de-identified at each participating site, using a dedicated 
computer that will conform to NHS information security standards.  
• 
Only pseudonymous personal data will be transferred via secure/encrypted protocols to the 
coordinating centre (Critical Care Research Group (CCRG), Nuffield Department of Clinical 
Neurosciences, Oxford University). 
• 
Only pseudonymous personal data will be held by the CCRG. 
• 
Pseudonymous personal data will be held inside the Sponsors “Data Safe Haven” which conforms 
to the same NHS standards of information security and cyber security. 
13.2. 
Study monitoring  
All research team members will be fully trained in Information Governance, data protection and 
confidentiality. The study may be monitored, or audited in accordance with the current approved 
protocol, GCP, relevant regulations and standard operating procedures. 

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13.3. 
Study Committees  
Study management group 
The study management group will consist of the chief investigator and the named investigators listed 
under Key Contacts. The study management group will be primarily responsible for the running and 
conduct of the study. They will be responsible for ensuring that standard operating procedures are 
followed and that regulations are adhered to. Where appropriate public patient involvement will be 
gained in any changes or amendments that are needed during the study. 
14. PROTOCOL DEVIATIONS  
Any deviations from the protocol will be documented in a protocol deviation form and filed in the study 
master file. 
15. SERIOUS BREACHES 
A “serious breach” is a breach of the protocol or of the conditions or principles of Good Clinical Practice 
which is likely to affect to a significant degree – 
 (a) the safety or physical or mental integrity of the trial subjects; or 
(b) the scientific value of the research. 
In the event that a serious breach is suspected the Sponsor must be contacted within 1 working day. In 
collaboration with the C.I., the serious breach will be reviewed by the Sponsor and, if appropriate, the 
Sponsor will report it to the approving REC committee and the relevant NHS host organisation within 
seven calendar days.  
16. ETHICAL AND REGULATORY CONSIDERATIONS 
16.1. 
Declaration of Helsinki 
The Investigator will ensure that this study is conducted in accordance with the principles of the 
Declaration of Helsinki. 
16.2. 
Guidelines for Good Clinical Practice 
The Investigator will ensure that this study is conducted in accordance with relevant regulations and with 
Good Clinical Practice. 
16.3. 
Approvals 
Following Sponsor approval, the protocol, and any Privacy notification material will be submitted to an 
appropriate Research Ethics Committee (REC), CAG and HRA (where required) and host institutions for 
written approval. 
The Investigator will submit and, where necessary, obtain approval from the above parties for all 
substantial amendments to the original approved documents. 

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16.4. 
Other Ethical Considerations 
16.5. 
Reporting 
The CI shall submit once a year throughout the study, or on request, an Annual Progress report to the 
REC Committee, CAG, HRA (where required) host organisation, Sponsor and funder (where required). In 
addition, an End of Study notification and final report will be submitted to the same parties.  
16.6. 
Transparency in Research  
We will register the study on ClinicalTrails.gov. 
16.7. 
Participant Confidentiality 
The study will comply with the General Data Protection Regulation (GDPR) and Data Protection Act 2018, 
which require data to be de-identified as soon as it is practical to do so. The processing of the personal 
data of participants will be minimised by making use of a unique participant study number only on all 
study documents and any electronic database(sAll documents will be stored securely and only accessible 
by study staff and authorised personnel. The study staff will safeguard the privacy of participants’ 
personal data. 
16.8. 
Expenses and Benefits 
No payments or any other benefits will be provided to participants. 
17. FINANCE AND INSURANCE 
17.1. 
Funding 
The study is funded by the University of Oxford’s COVID-19 Research Response Fund (Ref: 0009471). 
17.2. 
Insurance 
The University has a specialist insurance policy in place which would operate in the event of any 
participant suffering harm as a result of their involvement in the research (Newline Underwriting 
Management Ltd, at Lloyd’s of London).   
17.3. 
Contractual arrangements  
Appropriate contractual arrangements will be put in place with all third parties.  
18. PUBLICATION POLICY 
The Investigators will be involved in reviewing drafts of the manuscripts, abstracts, press releases and 
any other publications arising from the study.  Authors will acknowledge that the study was funded by 
the University of Oxford’s COVID-19 Research Response Fund (Ref: 0009471). Authorship will be 
determined in accordance with the ICMJE guidelines and other contributors will be acknowledged. 

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19. DEVELOPMENT OF A NEW PRODUCT/ PROCESS OR THE GENERATION OF INTELLECTUAL 
PROPERTY  
Ownership of IP generated by employees of the University vests in the University.  The University will 
ensure appropriate arrangements are in place as regards any new IP arising from the study.  
19. ARCHIVING 
The final linked anonymised study dataset will be stored securely within the CCRG data safe haven and 
ICNARC servers. Ethical approval will be sought for ongoing storage of study data as a research database. 
Study data will be available for future research/analysis and access will be governed by the Critical Care 
Research Group (CCRG) Data Access Committee (DAC). Any additional analyses will be restricted to the 
overall purpose of better understanding the epidemiology of and outcomes from, critical illness. All 
outputs will be restricted to aggregate data with small numbers supressed in line with the HES analysis 
guide. 
20. REFERENCES 
1.  
World Health Organization. Coronavirus disease (COVID-19) Situation Report – 183. 2020.  
2.  
Docherty AB, Harrison EM, Green CA, Hardwick HE, Pius R, Norman L, et al. Features of 20 133 UK 
patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: 
prospective observational cohort study. BMJ. 2020 May 22;369(March):m1985.  
3.  
Howdon D, Oke J, Heneghan C. COVID-19: Declining Admissions to Intensive Care Units [Internet]. 
2020 [cited 2020 Jun 29]. Available from: https://www.cebm.net/covid-19/covid-19-declining-
admissions-to-intensive-care-units/ 
4.  
Intensive Care National Audit and Research Centre (ICNARC). ICNARC report on COVID-19 in 
critical care (17th July 2020). 2020;  
5.  
Gerth AMJ, Hatch RA, Young JD, Watkinson PJ. Changes in health-related quality of life after 
discharge from an intensive care unit: a systematic review. Anaesthesia. 2019 Jan;74(1):100–8.  
6.  
Bion J. Long-term survival after intensive care. BMJ. 1990 Dec 8;301(6764):1336–1336.  
7.  
Wright JC, Plenderleith L, Ridley S a. Long-term survival following intensive care: Subgroup 
analysis and comparison with the general population*. Anaesthesia. 2003 Jul;58(7):637–42.  
8.  
Orwelius L, Nordlund A, Nordlund P, Simonsson E, Bäckman C, Samuelsson A, et al. Pre-existing 
disease: the most important factor for health related quality of life long-term after critical illness: 
a prospective, longitudinal, multicentre trial. Crit Care. 2010;14(2):R67.  
9.  
Phua J, Weng L, Ling L, Egi M, Lim C, Divatia JV, et al. Intensive care management of coronavirus 
disease 2019 (COVID-19): challenges and recommendations. Lancet Respir Med. 2020 
Apr;2019(20):1–12.  
10.  
Kunutsor SK, Laukkanen JA. Renal complications in COVID-19: a systematic review and meta-
analysis. Ann Med. 2020 Jul 10;1–9.  
11.  
Bilaloglu S, Aphinyanaphongs Y, Jones S, Iturrate E, Hochman J, Berger JS. Thrombosis in 
Hospitalized Patients With COVID-19 in a New York City Health System. JAMA. 2020 Jul 20;  

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12.  
Klok FA, Kruip MJHA, van der Meer NJM, Arbous MS, Gommers D, Kant KM, et al. Confirmation of 
the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-
19: An updated analysis. Thromb Res. 2020 Jul;191:148–50.  
13.  
Nepal G, Rehrig JH, Shrestha GS, Shing YK, Yadav JK, Ojha R, et al. Neurological manifestations of 
COVID-19: a systematic review. Crit Care. 2020 Dec 13;24(1):421.  
14.  
Bottle A, Gaudoin R, Goudie R, Jones S, Aylin P. Can valid and practical risk-prediction or casemix 
adjustment models, including adjustment for comorbidity, be generated from English hospital 
administrative data (Hospital Episode Statistics)? A national observational study. Heal Serv Deliv 
Res. 2014 Nov;2(40):1–48.  
15.  
Lloyd T, Deeny SR, Steventon A. Weekend admissions may be associated with poorer recording of 
long-term comorbidities: a prospective study of emergency admissions using administrative data. 
BMC Health Serv Res. 2018 Dec 16;18(1):863.  
21. APPENDIX A:  DATA FLOW DIAGRAM 
Please see attached Data Flow Diagram 
22. APPENDIX C:  AMENDMENT HISTORY 
 
Amendment 
No. 
Protocol 
Version 
No. 
Date issued 
Author(s) of changes 
Details of Changes made 
1 
V3 
02/08/2021 
Oliver Redfern, Robert 
Hatch, Peter Watkinson 
• 
Added 5 years of 
prior data for co-
morbidity 
assessment (7.3) 
• 
Updated wording 
around data sources 
and the section this 
applies to (7.3, 12.1) 
2 
V4 
02/12/2021 
Oliver Redfern, Peter 
Watkinson 
• 
Study end date 
changed to 31st July 
2022 
3 
V5 
17/06/2022 
Peter Watkinson and study 
team 
• 
Study end date 
changed to 31st July 
2023. Study length 
updated accordingly 
 
List details of all protocol amendments here whenever a new version of the protocol is produced.   
Protocol amendments must be submitted to the Sponsor for approval prior to submission to the REC 
committee and HRA (where required).