Conditions: COVID19
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 23
Healthy volunteers: no

Brief summary:
The rationale in severe COVID19 infection is to undertake PEX to aid reduction of the hyperinflammation and reduce the morbidity and mortality to the lungs, but also systemically, such as the heart, kidneys and brain. A feasibility study of PEX therapy has been undertaken and confirmed a reduction in the inflammatory markers, no VTE/arterial events and normalisation of the renal function and cardiac function throughout the period of therapy. As plasma exchange is an intensive treatment modality, blocks of 5 daily PEX will be undertaken. Further blocks of PEX treatment can be initiated as dictated by the clinical and laboratory parameters. Unlike many therapeutic schedules, there is no immunosuppression associated with PEX; indeed, the resulting decrease in inflammatory markers were shown to be associated with an increase and sustained lymphocytes count.

Detailed description:
COVID19 is a viral pandemic associated with primarily respiratory pathology, in the form of microvascular and macrovascular thrombosis. In patients requiring hospital admission, there is severe disease, requiring respiratory support, from high dose oxygen therapy or ventilatory assistance, which may be invasive or non invasive. The pathology of COVID19 is poorly understood, but it is accepted there is an inflammatory-thrombotic basis. Despite current therapeutic platforms, there is no consensus on a specific therapy within a trial setting that has proven benefit in severe COVID 19.

Thrombotic microangiopathies, such as TTP, are a different disease, but have a comparable prothrombotic phenotype, and similar or higher inflammatory parameters, including D Dimers, ferritin, LDH and IL-6 at acute presentation and resolve with plasma exchange (PEX). The rationale in severe COVID19 infection is to undertake PEX to aid reduction of the hyperinflammation and reduce the morbidity and mortality to the lungs, but also systemically, such as the heart, kidneys and brain. A feasibility study of PEX therapy has been undertaken and confirmed a reduction in the inflammatory markers, no VTE/arterial events and normalisation of the renal function and cardiac function throughout the period of therapy. As plasma exchange is an intensive treatment modality, blocks of 5 daily PEX will be undertaken. Further blocks of PEX treatment can be initiated as dictated by the clinical and laboratory parameters. Unlike many therapeutic schedules, there is no immunosuppression associated with PEX; indeed, the resulting decrease in inflammatory markers were shown to be associated with an increase and sustained lymphocytes count. Therefore, as patients with COVID-19 have elevated procoagulant factors including VWF and factor VIII secondary to direct endothelial activation. This is associated with an exaggerated pro-inflammatory immune response and microvascular thrombosis; resulting in multi-organ dysfunction and eventually death. PEX will improve coagulopathy, as measured by VWF:ADAMTS 13 ratio and D Dimers, with an associated reduction in inflammation, organ-related microthrombosis, and ventilatory support.

Arms:
arm 1: Standard patient care for severe COVID-19 arm 2: Standard patient care for severe COVID-19 with. plasma exchange daily for 5 days x 3 courses as required

Interventions: intervention 1: OCTAPLAS
Intervention descriptions: intervention 1: plasma exchange

Protocol document:
Prot_SAP_000.pdf: 
Short title: PEX in severe COVID19   Sponsor code: 132796 
UCL protocol template V03, 20/03/15 
 
 
 
 
 
Page 1 of 53 
Protocol Version V1.1        18th June 2020        
 
 
 
 
 
Full title of trial 
 
A Randomised Controlled Trial of plasma 
exchange with standard of care compared to 
standard of care alone in the treatment of 
severe COVID19        infection (COVIPLEX) 
 
Short title 
 
PEX in severe COVID19 
Version and date of protocol 
 
Version 1.1 18th June 2020 
  
Sponsor: 
University College London (UCL) 
Sponsor protocol number 
132796 
Funder (s): 
 
EudraCT no  
IRAS Project ID: 
2020-002668-29 
284554 
 
ISRCTN / Clinicaltrials.gov no:  
 
 
 
ACTIVE IMP(s): 
Octaplas via plasma exchange  
Phase of trial 
Phase II 
Sites(s) 
[Single site]  
Chief investigator: 
Professor Marie Scully 
250 Euston Road, 
London NW12PG 
 
Sponsor Representative: 
Nikkayla Dixon 
Joint Research Office, UCL, 1st Floor Maple House, 
149 Tottenham Court Road, 
London W1T 7NF 
Postal address: 
Joint Research Office, UCL 
Gower Street,  
London WC1E 6BT 
 
 
 
 
 
 
 
 
 
 


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Protocol Version V1.1        18th June 2020        
 
Protocol Version History 
Version 
Number 
Date 
Protocol Update Finalised By (insert 
name of person):  
Reasons for 
Update 
1.1 
18/06/2020 MScully 
Ethics, HRA 
and MHRA 
changes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Protocol Version V1.1        18th June 2020        
Signatures 
The Chief Investigator and the JRO have discussed this protocol. The investigator agrees to perform the 
investigations and to abide by this protocol  
The investigator agrees to conduct the trial in compliance with the approved protocol, EU GCP and UK 
Regulations for CTIMPs (SI 2004/1031; as amended), the UK Data Protection Act (1998), the Trust 
Information Governance Policy (or other local equivalent), the current Research Governance Framework, 
the GMO (Contained Use) Regulations 2000 (and subsequent amendments), the Sponsor’s SOPs, and 
other regulatory requirements as amended. 
 
Chief investigator 
Professor Marie Scully 
 
 
 
Signature 
Date 
Sponsor  
Dr Nick McNally  
 
 
UCL 
Signature 
Date 
 
 
 
 
 


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Protocol Version V1.1        18th June 2020        
Contents 
Table of contents should be updated once the protocol is final 
Protocol Version History ...............................................................................................2 
Signatures ...........................................................................................................................3 
Contents ..............................................................................................................................4 
Table of contents should be updated once the protocol is final .........................................4 
List of abbreviations ...........................................................................................................8 
1 
Trial personnel ....................................................................................................... 10 
2 
Summary ................................................................................................................. 12 
3 
Background and Rationale..................................................................................... 15 
3.1 
Assessment and management of risk .......................................................... 19 
4 
Objectives ................................................................................................................ 21 
5 
Trial design ............................................................................................................. 22 
5.1 
Overall design ................................................................................................ 22 
6 
Investigational Medicinal Products and Non-Investigational 
Medicinal Products .......................................................................................................... 22 
6.1 
Name and description of IMP(s) .................................................................. 22 
6.2 
Source of IMP, Manufacture, Distribution and Storage.............................. 22 
6.3 
Name and description of each NIMP (if applicable) ................................... 16 
6.4 
Storage and handling of IMP(s) at site ........................................................ 17 
6.5 
Accountability of IMP(s) ............................................................................... 17 
6.6 
Concomitant medication .............................................................................. 23 
6.7 
Post-trial IMP arrangements ........................................................................ 23 
7 
Selection of Participants ........................................................................................ 23 
7.1 
Eligibility of trial participants ...................................................................... 23 
7.2 
Recruitment ................................................................................................... 24 
7.3 
Informed consent procedure ....................................................................... 24 
8 
Trial procedures ..................................................................................................... 26 
8.1 
Pre-treatment Assessments ......................................................................... 26 
8.2 
Registration / Randomisation Procedures (delete as appropriate) ......... 27 
8.3 
Treatment Schedule ...................................................................................... 27 
8.3.1 
Dose Modifications ....................................................................................... 28 


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8.4 
Subsequent assessments and procedures .................................................. 28 
8.4.1 
Visit schedule and assessments .................................................................... 28 
8.5 
Laboratory Assessments and Procedures ..................................................... 30 
Translational Research Samples (delete if not applicable) ............................................... 31 
8.6 
Clinical Procedures and Data Collection ....................................................... 31 
8.7 
Assessment of IMP/NIMP compliance ........................................................ 31 
8.8 
Discontinuation/withdrawal of participants.............................................. 31 
8.9 
Replacements ................................................................................................ 32 
8.10 
Stopping rules................................................................................................ 33 
8.11 
Definition of End of Trial .............................................................................. 33 
9 
Recording and reporting of adverse events and reactions ................................. 33 
9.1 
Definitions ..................................................................................................... 33 
9.2 
Recording adverse events ............................................................................ 34 
9.3 
Assessments of Adverse Events ................................................................... 35 
9.3.1 
Severity ........................................................................................................ 35 
9.3.2 
Causality ...................................................................................................... 35 
9.3.3 
Expectedness ............................................................................................... 35 
9.3.4 
Seriousness .................................................................................................. 36 
9.3.5 
Other Notifiable Adverse Events (if applicable) ............................................ 32 
9.4 
Procedures for recording and reporting Serious Adverse Events ............ 36 
9.5 
Serious Adverse Events which do not require immediate reporting (if applicable and 
in liaison with JRO) .......................................................................................................... 38 
9.6 
Notification of Deaths (if applicable) ............................................................ 38 
9.7 
Reporting SUSARs ........................................................................................ 38 
9.8 
Unblinding (if applicable) ............................................................................. 36 
9.9 
Emergency Unblinding ................................................................................. 36 
9.10 
Unblinding for the submission of SUSAR reports .......................................... 37 
9.11 
Development Safety Update Reports........................................................... 39 
9.12 
Pregnancy (If applicable) ............................................................................. 39 
9.13 
Overdose ........................................................................................................ 38 
9.14 
Reporting Urgent Safety Measures and other safety events ..................... 40 
9.15 
Notification of Serious Breaches to GCP and/or the protocol (SPON/S15)40 
9.16 
Reporting incidents involving a medical device(s) (if applicable) ........... 40 


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Protocol Version V1.1        18th June 2020        
10 
Data management and quality assurance ............................................................ 41 
10.1 
Confidentiality ............................................................................................... 41 
10.2 
Data collection tools and source document identification ........................ 41 
10.3 
Completing Case Report Forms ................................................................... 41 
10.4 
Data handling and analysis........................................................................... 42 
11 
Statistical Considerations ...................................................................................... 42 
11.1 
Outcomes ....................................................................................................... 42 
11.1.1 
Primary outcomes ........................................................................................ 42 
11.1.2 
Secondary outcomes .................................................................................... 42 
11.2 
Sample size and recruitment........................................................................ 43 
11.2.1 
Sample size calculation ................................................................................ 43 
11.2.2 
Planned recruitment rate ............................................................................. 43 
11.3 
Randomisation methods............................................................................... 43 
11.4 
Statistical analysis plan................................................................................. 43 
11.4.1 
Summary of baseline data and flow of participants ...................................... 43 
11.4.2 
Primary outcome analysis ............................................................................ 44 
11.4.3 
Secondary outcome analysis ........................................................................ 44 
11.4.4 
Sensitivity and other planned analyses ........................................................ 44 
11.5 
Interim analysis ............................................................................................. 44 
11.6 
Other statistical considerations ................................................................... 44 
12 
Record keeping and archiving ............................................................................... 44 
13 
Oversight Committees ............................................................................................ 45 
13.1 
Trial Management Group (TMG) ................................................................. 45 
13.2 
Trial Steering Committee (TSC) ................................................................... 45 
13.3 
Independent Data Monitoring Committee (IDMC) or Data Monitoring Committee 
(DMC) 
45 
14 
Direct Access to Source Data/Documents ............................................................ 45 
15 
Ethics and regulatory requirements ..................................................................... 45 
16 
Monitoring requirement for the trial .................................................................... 46 
17 
Finance .................................................................................................................... 46 
18 
Insurance ................................................................................................................. 46 
19 
Publication policy ................................................................................................... 46 
20 
References ............................................................................................................... 47 


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Protocol Version V1.1        18th June 2020        
Appendix 1 - Schedule of assessments .......................................................................... 50 
 
 


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Protocol Version V1.1        18th June 2020        
List of abbreviations 
AE 
Adverse Event 
AR 
Adverse Reaction 
CA 
Competent Authority 
CI 
Chief Investigator 
CRF 
Case Report Form 
CRO 
Contract Research Organisation 
CTA 
Clinical Trial Authorisation 
CTIMP 
Clinical Trial of Investigational Medicinal Product 
 
DI 
Designated Individual 
DMC 
Data Monitoring Committee 
DSUR 
Development Safety Update Report 
DVT 
Deep vein thrombosis 
EC 
European Commission 
EMEA 
European Medicines Agency 
EU 
European Union 
EUCTD 
European Clinical Trials Directive 
EudraCT 
European Clinical Trials Database 
EudraVigilance 
European database for Pharmacovigilance 
GAfREC 
Governance Arrangements for NHS Research Ethics 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice  
GMO 
Genetically Modified Organisms 
HTA 
Human Tissue Authority 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
IDMC 
Independent Data Monitoring Committee 
IMP 
Investigational Medicinal Product 
IMPD 
Investigational Medicinal Product Dossier 
ISF 
Investigator Site File 
ISRCTN 
International Standard Randomised   
MA 
Marketing Authorisation 


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MHRA 
Medicines and Healthcare products Regulatory Agency 
MS 
Member State 
NHS R&D 
National Health Service Research & Development 
PE   
Pulmonary Embolism 
PEX 
Plasma exchange 
PI 
Principal Investigator 
PIS 
Participant Information Sheet 
PL 
Product License 
QA 
Quality Assurance 
QC 
Quality Control 
QP 
Qualified Person (for release of trial drug) 
RCT 
Randomised Controlled Trial 
REC 
Research Ethics Committee 
RSI 
Reference Safety Information 
SAR 
Serious Adverse Reaction 
SAE 
Serious Adverse Event 
SDV 
Source Document Verification 
SOC 
Standard of Care 
SOP 
Standard Operating Procedure  
SPC 
Summary of Product Characteristics  
SSA 
Site Specific Assessment 
SUSAR 
Suspected Unexpected Serious Adverse Reaction  
TMA 
Thrombotic Microangiopathy 
TMG 
Trial Management Group 
TSC 
Trial Steering Committee 
TTP 
Thrombotic Thrombocytopenic Purpura 
VWF 
Von Willebrand Factor 


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Protocol Version V1.1        18th June 2020        
1 
Trial personnel 
See protocol cover page for Chief Investigator and Sponsor contact details. 
Dr Mari Thomas 
Department of Haematology 
UCLH 
mari.thomas@nhs.net 
 
Dr Nish Arulkumaran 
ICU Consultant 
UCLH 
Nish.arulkumaran@nhs.net 
 
Professor Mervyn Singer 
Professor of ICU 
UCL/UCLH 
m.singer@ucl.ac.uk 
 
Dr Dave Brealey 
ICU Consultant 
UCLH 
d.brealey@nhs.net 
 
 
Mrs Ingrid Obu, 
Senior Clinical Trial Coordinator 
UCLH 
Ingrid.obu@nhs.net 
 
Mr Deepak Singh 
Senior BMS-Special Coagulation laboratory 
HSL/UCLH 
60 Whitfield Street, London W1T4EU 
Deepak.singh@tdlapthology.com 
 
Trial Statistican 
 
Dr Gareth Ambler 
Associate Professor in Medical Statistics 


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Protocol Version V1.1        18th June 2020        
UCL Statistical Science and JRO 
g.ambler@ucl.ac.uk 
020 8395 1325 
 
 
 


Short title: PEX in severe COVID19   Sponsor code: 132796 
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Protocol Version V1.1        18th June 2020        
2 
Summary 
 COVID19 is a viral pandemic associated with primarily respiratory pathology, in the form of microvascular 
and macrovascular thrombosis. In patients requiring hospital admission, there is severe disease, requiring 
respiratory support, from high dose oxygen therapy or ventilatory assistance, which may be invasive or non 
invasive. The pathology of COVID19 is poorly understood, but it is accepted there is an inflammatory-
thrombotic basis. Despite current therapeutic platforms, there is no consensus on a specific therapy within 
a trial setting that has proven benefit in severe COVID 19. 
Thrombotic microangiopathies, such as TTP, are a different disease, but have a comparable prothrombotic 
phenotype, and similar or higher inflammatory parameters, including D Dimers, ferritin, LDH and IL-6 at 
acute presentation and resolve with plasma exchange (PEX). The rationale in severe COVID19 infection is 
to undertake PEX to aid reduction of the hyperinflammation and reduce the morbidity and mortality to the 
lungs, but also systemically, such as the heart, kidneys and brain. A feasibility study of PEX therapy has 
been undertaken and confirmed a reduction in the inflammatory markers, no VTE/arterial events and 
normalisation of the renal function and cardiac function throughout the period of therapy. As plasma 
exchange is an intensive treatment modality, blocks of 5 daily PEX will be undertaken. Further blocks of 
PEX treatment can be initiated as dictated by the clinical and laboratory parameters. Unlike many 
therapeutic schedules, there is no immunosuppression associated with PEX; indeed, the resulting decrease 
in inflammatory markers were shown to be associated with an increase and sustained lymphocytes count. 
Therefore,  as patients with COVID-19 have elevated procoagulant factors including VWF and factor VIII 
secondary to direct endothelial activation. This is associated with an exaggerated pro-inflammatory immune 
response and microvascular thrombosis; resulting in multi-organ dysfunction and eventually death. PEX 
will improve coagulopathy, as measured by VWF:ADAMTS 13 ratio and D Dimers, with an associated 
reduction in inflammation, organ-related microthrombosis, and ventilatory support. 
 
 
 
Objectives: 
Primary: To compare the  reduction in inflammatory markers 
between Plasma Exchange (PEX) and the control group in patients 
with severe COVID 
Secondary:  
To compare rates of mechanical ventilation between Plasma 
Exchange (PEX) and control groups in patients with severe COVID 
requiring CPAP/ NIV at treatment onset 
 
To compare rates of clinical thrombotic events either venous (deep 
vein thrombosis DVT or pulmonary embolism PE) or arterial 
thrombus (cardiac, neurological and peripheral vascular) between 


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Protocol Version V1.1        18th June 2020        
Plasma Exchange (PEX) and control groups in patients with severe 
COVID  
 
To compare reduction in the inflammatory-thrombotic response by 
monitoring von Willebrand factor VWFA antigen/ADAMTS 13 
activity ratio  between Plasma Exchange (PEX) and control groups 
in patients with severe COVID 
 
To compare the stability of cardiac function based on 
echocardiogram/troponin/BNP measurements  cardiac function 
between Plasma Exchange (PEX) and control groups in patients 
with severe COVID 
 
To compare incidence of acute kidney injury as defined by KDIGO 
criteria between Plasma Exchange (PEX) and control groups in 
patients with severe COVID 
 
To compare mortality at day 28 between the PEX and control 
groups 
 
Type of trial: 
A Phase II, Parallel-group, unblinded, randomised controlled trial 
in COVID 19 
Trial 
design 
and 
methods: 
Patients will receive  standard of care (SOC), or SOC and PEX. 
Single volume PEX capped at 3 litres if <100Kg and 4 litres if 
>100Kg. PEX will be given once a day for a minimum of 5 days. 
The course can be repeated at the discretion of the treating clinician, 
depending on patient’s response based on a reassessment on D5-7, 
where there is clinical and biochemical improvement following 
initial 5-day block but persistent pro-thrombotic phenotype ie 5 
days initial block plus reassess.  
Data collection includes routine laboratory parameters, FBC, renal 
function and liver function; inflammatory markers (D Dimers, 
LDH, CRP) and pre and post PEX samples to measure von 
Willebrand factor  (VWF) and ADAMTS13 activity levels. The 
latter samples will be stored for further investigation related to 
COVID, for example, COVID19 viral analysis, cytokines. 
The control patients will have citrate and serum samples taken 
daily. Following the initial 5 day period. If patients have more than 
one 5 block of PEX, comparable daily samples will be taken. 
Thereafter, weekly to day 28.  


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Protocol Version V1.1        18th June 2020        
Trial 
duration 
per 
participant: 
 From consent to 28 days 
Estimated 
total 
trial 
duration: 
From when first participant enrolled to last participant follow-up. 
Planned trial sites: 
Single-site  
Total 
number 
of 
participants planned: 
Minimum 20, maximum 40 
Main inclusion/exclusion 
criteria: 
Inclusion Criteria:  
• 
Age 18-70 
• 
Proven COVID-19/high clinical suspicion of COVID-19 
• 
Hypoxia/respiratory compromise defined as requiring 
respiratory support of >2L/min of oxygen by nasal 
cannulae to maintain SpO2<96%.  
• 
Raised inflammatory parameters: at least 2 of the 
following:  
a. Raised LDH  (> 2 x ULN) 
b. Raised D Dimers (> 2X ULN) 
c. Raised CRP (>2X ULN) 
• 
Females of childbearing potential have a negative 
pregnancy test within 7 days prior to being randomised.  
Participants are considered not of child bearing potential if 
they are surgically sterile (i.e. they have undergone a 
hysterectomy, bilateral tubal ligation, or bilateral 
oophorectomy) or they are postmenopausal 
 
Exclusion Criteria: 
• 
Significant co-morbid illness with treatment escalation 
limited to CPAP 
• 
Active bleeding 
• 
PF ratio < 100 on mechanical ventilation OR 
noradrenaline  requirement > 0.5mcg/kg/min to maintain 
MAP > 65mmHg (suggests futility) 
• 
Known allergies to Octaplas or excipients 
• 
Females who are pregnant 
 
 
Statistical 
methodology 
and analysis: 
The primary analysis will involve a comparison of the binary 
outcome ‘50% reduction in at least two inflammation markers’ 
between the PEX+SOC and SOC trial arms using a chi-squared test. 
The risk difference (and ratio) will be estimated with a 95% 
confidence interval. All analyses will be performed on an intention 
to treat basis. 
Patient characteristics will be summarised by trial arm and 
inspected for balance. Patient flow throughout the trial will be 
summarised using a CONSORT diagram.  
Secondary outcomes will be summarised and compared using 
suitable statistical methods. For example, binary outcomes may be 


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Protocol Version V1.1        18th June 2020        
compared using chi-squared tests and numerical outcomes may be 
compared using t-tests. P-values from tests of secondary outcomes 
may be adjusted to account for multiple testing. Appropriate 
regression methods will be used to perform adjusted analyses or to 
account for repeated measures. 
The level of missing data will be reported and sensitivity and/or 
adjusted analyses performed to account for missing data. 
 
3 
Background and Rationale 
Mortality in COVID-19 is primarily associated with severe hypoxaemic respiratory 
failure and histological features of pulmonary thromboses. The proportion of all 
hospitalised patients requiring ICU admission varies from 7.3% to 32% 1-3, majority of 
who require respiratory support. Whilst the overall outcome of patients who are admitted 
to ICU is high, outcomes of patients who require mechanical ventilation are particularly 
poor; with 86% of ventilated patients dead by 28 days 3 or only a third of patients 
extubated by 14 days 4 (Table 1). 
 
 
  
Author, 
Journal 
Country 
Cases 
admitted 
to ICU 
% 
Mechanic
ally 
ventilated 
Mortality in 
mechanicall
y ventilated 
group 
Ove
Mort
Xiaobo Yang 
Lancet Resp 3 
Jin Yin-tan 
hospital 
(Wuhan, 
China)  
 n=52 
42% 
(n=22) 
86.4%  
(19 of 22) 
61.
(n=
Dawei Wang 
JAMA 2 
Zhongnan 
Hospital 
(Wuhan, 
China) 
 n=36 
47% 
(n=17) 
(Not 
reported) 
17
(n=
Huang 
Chaolin 
Lancet 1 
Jin Yintan 
Hospital 
(Wuhan, 
China) 
n=13 
15% 
(n=2) 
(Not 
reported) 
38
(n=
Arentz 
Matthew 
JAMA 5 
Evergreen 
Hospital 
(Washingto
n, USA) 
n=21 
 
71% 
(n=15) 
(Not 
reported) 
67
(n=
Bhatraju 
Pavan NEJM 4 
Multi-
Centre (9) 
Seattle area 
hospitals, 
USA 
n=24 
 
75% 
(n=18) 
50% 
(n=9)  
50
(n=
Grasselli 
Giacomo 
JAMA 6 
Multi-centre 
(72 
hospitals, 
Lombardy), 
Italy  
n=1591 
 
88% 
(1150 of 
1300 
patients) 
(Not 
reported) 
26
(n=4


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Table 1: Clinical features and outcomes of patients with COVID-19  admitted to 
intensive care units 
 
Routine laboratory parameters of inflammation including ferritin, CRP, and D-dimers are 
elevated in these patients 7. Levels of inflammatory markers are significantly higher in 
non-survivors compared to survivors 7, which may represent  an exaggerated host immune 
response to the viral infection, leading to organ dysfunction and death.  The proportion 
of coagulopathy is much greater among non-survivors compared to survivors, with an 
elevated D-dimer (1microg/ml) independently predicting mortality 7 (Table 2). Patients 
with COVID-19 have elevated levels of factor VIII and virtually all patients have 
detectable lupus anticoagulant 8.  
 
 
Non survivor (n=54) 
Survivor (n=137) 
p-value 
Lymphocytes < 0.8x109/L 
41 (76%) 
36 (26%) 
<0.0001 
Platelet count <100x109/L 
10 (20%) 
2 (1%) 
<0.0001 
LDH (IU) 
521 (98%) 
253 (54%) 
<0.0001 
Troponin I (> 28 pg/ml) 
46% 
1% 
<0.0001 
Prothrombin time (>16s) 
13% 
3% 
- 
Serum ferritin ug/L 
1435 (96%) 
503 (71%) 
0.0008 
IL-6 pg/ml 
11 (7-14.5) 
6.3 (5.0-7.9) 
<0.0001 
D Dimer >1 ug/ml 
81% 
24% 
<0.0001 
 
Table 2: Biochemical features of critically ill patients with COVID-19 (Adapted from 
(Zhou et al, Lancet March 28th 2020; 395:1054-62) 7) 
 
Unlike ‘typical’ ARDS, patients with COVID-19 ARDS have good pulmonary 
compliance but are significantly hypoxemic early in the disease 9. This suggests a 
significant shunt fraction which may be explained by impaired pulmonary 
microcirculation. Histological data suggests that this may be a result of microthrombi. In 
a series of 12 COVID-19 patients, autopsy revealed deep venous thrombosis in 7 of 12 
patients (58%) in whom venous thromboembolism was not suspected before death; 
pulmonary embolism was the direct cause of death in 4 patients 10. The primary cause of 
death was respiratory failure with exudative diffuse alveolar damage with massive 
capillary congestion often accompanied by microthrombi despite anticoagulation 11.  


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Consistent with histopathological data, the incidence of thromboembolic complications 
in critically ill patients with COVID-19 is high 12-14 (Table 3). The incidence of 
thromboembolic complications despite the use of thromboprophylaxis occurs in 17% to 
31% of critically ill COVID-19 patients 12-14. This is greater than matched patients with 
non- COVID-19 ARDS 13. Similarly, the reported incidence of thromboembolic 
complications general ICU patients is also significantly lower, with a propensity for deep 
vein thrombosis (DVT) rather than pulmonary embolism ( PE) 15.  
The striking increased risk in thromboembolic complications in critically ill patients with 
COVID-19 is associated with pulmonary thromboembolic disease rather than deep vein 
thromboses 13. This may relate to the underlying pathophysiology of COVID-19, which 
uses ACE2 receptor expressed by pneumocytes in the epithelial alveolar lining to infect 
the host, thereby causing lung injury 16. Endothelial activation in patients with systemic 
inflammation is associated with activation and degranulation of endothelium in vascular 
beds leading to an increased plasma levels of VWF 17.  
 
 
Total population 
Use 
of 
systemic 
thromboprophylaxis 
All 
thrombotic 
complications 
DVT alone 
PE ± DVT 
CVA 
Helms J 13 
150 COVID-19 on 
ICU 
 
 
233 Non- COVID-19 
ARDS 
n=150 (100%) 
Prophylaxis 
n=105 
Therapeutic 
n=45 
 
n=233 (100%) 
Prophylaxis 
n=188 
Therapeutic 
n=45 
n=27 
                (18%) 
 
 
n=14 
(6%) 
n=3 
(2%) 
 
 
n=3 
(1.3%) 
n=25 
               (17%) 
 
 
n=3 
              (1.3%) 
n=
             (1.3%)
 
 
n=1 
(0.4%) 
Klok FA 14 
184 on 
ICU 
184 (100%) 
57 
(31%) 
n=3 
(1.6%) 
n=25 
(13.6%) 
n
(1.6%) 
Lodigiani C 12 
Ward: 
326 
(84%) 
 
ICU: 62 
(16%) 
75% of ward 
patients 
 
 
100% of ICU 
patients 
n=20 
(6.4%) 
 
n=8 
(16.7%) 
n=4 
(1.3%) 
 
n=1 
(2.1%) 
n=2 
(4.2%) 
 
n=8 
(2.5%) 
n
(1.9%) 
n
(6.3%) 
Zhang 
15 
Non 
COVID-
19 
281 ICU 
patients 
               (9.6%) 
n=24 
n=1 


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Table 3: Thromboembolic complications in patients with COVID-19 
  
The UK already adopts a policy of thromboprophylaxis (after VTE risk assessment) in all 
hospital inpatients to prevent thrombosis. The risk of thrombosis is compounded in sick 
patients in HDU/ICU settings by immobility, co-morbidities, (arterial disease, diabetes) 
body weight, acute inflammatory response and associated therapies e.g. steroids. 
 
UCLH has the largest international cohort of patients with thrombotic thrombocytopenic 
purpura (TTP) and other thrombotic microangiopathies. Their presentation is acute, 
associated with anaemia, thrombocytopenia and end organ damage, primarily, the heart, 
brain and kidney. The respiratory system is not affected in TTP. Other thrombotic 
microangiopathies (TMA) have variable organ involvement eg HUS does have 
pulmonary disease. The diagnosis of TMA is primarily clinical, but may be defined by 
histology.  The mainstay of treatment is plasma exchange, using octaplas. The rationale 
for Octaplas is its safety profile and reduced high molecular weight forms of von 
Willebrand factor. The role of plasma exchange (PEX) is delivery of high volumes of 
plasma, 
replenishing 
deficient 
factors 
e.g. 
ADAMTS 
13, 
natural 
anticoagulants/coagulation factors, and complement proteins, leading to normalization of 
routine laboratory parameters, in particular, FBC, renal function, and LDH. Furthermore 
PEX has been demonstrated to reduce inflammatory markers, which are extremely high 
at presentation in TMAs (comparable to levels seen in COVID19) and subsequently 
ameliorated following PEX. PEX is standard of care for thrombotic microangiopathies, 
which severe COVID-19 infection appears to mimic. 
 
 
 
3.1 
Hypothesis: 
 
Patients with COVID-19 have elevated procoagulant factors including VWF and factor VIII 
secondary to direct endothelial activation. This is associated with an exaggerated pro-
inflammatory immune response and microvascular thrombosis; resulting in multi-organ 
dysfunction and eventually death. PEX will improve coagulopathy, as measured by 
VWF:ADAMTS 13 ratio and D Dimers, with an associated reduction in inflammation, organ-
related microthrombosis, and ventilatory support. 


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3.2 
Pilot data  
Levels of protein S, protein C, antithrombin, Factor VIII, vWf, platelet counts, and ADAMTS-13 
activity were measured in patients admitted to the ICU for respiratory support. Levels of protein 
S, protein C, antithrombin, and ADAMTS-13 activity were within the normal range. In contrast, 
levels of factor VIII and VWF were significantly elevated among critically ill patients with 
COVID-19.  
A total of 6 patients at UCLH with COVID-19 requiring advanced respiratory support with 
features of TMA were consented to undergo PEX. A total of 5 days single volume PEX was 
conducted, and patients clinical and biochemical data compared to matched controls.  Matched 
controls included patients who were eligible for PEX but did not consent (n=1) or did not receive 
PEX due to limitations on staff resource (n=7).  
There were no reported adverse events associated with PEX.  
The pertinent findings were : 
• no thrombotic events during the duration of PEX 
• decrease in the VWF/ADAMTS 13 ratio throughout the period of treatment 
• decrease in inflammatory markers, in particular, D Dimers, ferritin and LDH  
• increase in lymphocyte count in all patients which was sustained after the PEX 
course was completed  
• increase in median PaO2:FiO2 ratio from the beginning to the end of the PEX 
period  
• No deterioration to acute kidney injury:    
• Stable cardiac function as assessed by echocardiography  
 
 
 
4 
Assessment and management of risk  
 
1.Central vascath insertion:  
There is a risk of pain, infection and bleeding or thrombosis with central vascath 
insertion. All the central lines are put in by a defined trained group within the trust i.e. 
ICU/anaesthetics or interventional radiology. Patients with severe COVID-19 
infection are likely to need central line access e.g. PICC/Central line. While these 
lines are not suitable for PEX, central venous access is common in COVID-19 
patients in ICU. Patients will be monitored frequently for infections, bleeding or 
thrombosis 
 


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2: PEX 
A. Reaction to plasma: There is a risk of infusional and allergic reactions and 
rarely anaphylaxis with the use of Octaplas. This is considerably reduced with 
the use of Octaplas compared to standard fresh frozen plasma (FFP) Reactions 
grade 1-3 are amenable to standard therapy  including antihistamine, 
hydrocortisone and paracetamol. If a patient experiences symptoms of 
anaphylaxis, treatment would be stopped immediately. 
 
B. Citrate reactions: Some patients treated with PEX present with features of 
hypocalcaemia (fatigue, paraesthesia, tremor, and hypocalcemia). This is 
treated with calcium boluses, but offset by a calcium infusion throughout 
PEX. 
 
C. Risk of viral transmission:  Standard measures to prevent infections resulting 
from the use of medical products prepared from human blood or plasma 
include selection of donors, screening of individual donations and plasma pool 
for specific markers of infection and the inclusion of effective manufacturing 
steps for the inactivation/removal of viruses. When medicinal products 
prepared from human blood or plasma are administered, the possibility of 
transmitting infective agents cannot be totally excluded. However Octaplas 
LG undergoes a number of additional pathogen inactivation steps and is 
considered very safe.  
 
The table below summarises the risks, frequencies and mitigations of the IMP(s) and NIMP(s) (delete 
NIMP if it is not applicable) 
Name of 
IMP(s) / NIMP  
Octaplas 
Potential risk 
 
-Reactions to plasma 
- 
 
 
-Pathogen 
transmission 
 
 
Risk Frequency 
 
-Severe reactions-
grade 4-
anaphylaxis <1% 
 
-Due to 
nanofiltration and 
S/D processing, 
this is the safest 
and most 
effective plasma 
available 
Risk Management 
 
-Any reactions treated with 
antihistamine, paracetamol and /or 
hydrocortisone 
-PEX would be stopped if any severe 
reaction/anaphylaxis  
 
-routine viruses are checked pre PEX.  
PEX 
procedure 
Citrate 
toxicity 
10-20% of 
procedures 
IV calcium is run during PEX and added 
boluses given if required 


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Vascath 
insertion 
Infection, 
bleeding, 
thrombosis 
Approx. 10% 
Lines are changed weekly to reduce 
infection, intermediate LMWH given, 
reducing thrombosis. Bleeding rare as 
lines inserted by USS 
 
 
 
Type A = No higher than the risk of standard medical care  
 
 
5 
Objectives 
The rationale of this study is to compare outcomes of patients receiving PEX to those 
who do not. We hope to ascertain if PEX provides a clinical benefit to expand its use 
nationally and internationally, as there is currently no treatment which improves the 
morbidity and mortality of patients with severe COVID-19. 
 
 
Primary objectives:  
To compare reduction in inflammatory markers between Plasma Exchange (PEX) and 
control groups in patients with severe COVID 
 
Secondary objectives:  
To compare rates of mechanical ventilation between Plasma Exchange (PEX) and 
control groups in patients with severe COVID requiring CPAP/ NIV at treatment onset 
 
To compare rates of clinical thrombotic events either venous (deep vein thrombosis 
DVT or pulmonary embolism PE) or arterial thrombus (cardiac, neurological and 
peripheral vascular) between Plasma Exchange (PEX) and control groups in patients 
with severe COVID 
 
 
To compare reduction in the inflammatory-thrombotic response by monitoring von 
Willebrand factor VWF antigen/ADAMTS 13 activity ratio  between Plasma Exchange 
(PEX) and control groups in patients with severe COVID 
 
To compare the stability of cardiac function based on echocardiogram/troponin/BNP 
measurements between Plasma Exchange (PEX) and control groups in patients with 
severe COVID  
 
To compare incidence of acute kidney injury as defined by KDIGO criteria between 
Plasma Exchange (PEX) and control groups in patients with severe COVID 
 
To compare mortality at day 28 between the PEX and control groups 
 


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6 
Trial design 
6.1 
Overall design 
This a parallel-group randomised controlled trial, which will be unblinded to the investigators 
and patients . 
Patients will be randomised in a 1:1 ratio to either PEX+SOC or SOC.  PEX will be delivered in 
conjunction with standard of care in all patients as dictated by the treating clinicians. 
PEX will be given for a minimum of 5 days, but the course can be repeated depending on 
patient’s response, based on a reassessment on D5-7.  The 5 day PEX will be repeated at the 
discretion of the treating clinician  in patients showing clinical and biochemical improvement but 
a persistent pro-thrombotic phenotype following the initial 5-day block . 
Patients will be followed up until 28 days post treatment.  
1.2. 
  TRIAL SETTING 
The study will be undertaken within the COVID wards in hospital.  Trial site 
feasibility will be undertaken to ensure that sites participating in the trial are able to 
undertake the plasma exchange procedure 
 
7 
Investigational Medicinal Products and Non-Investigational Medicinal 
Products 
 
7.1 
Name and description of IMP(s) 
OctaplasLG solution for infusion 
7.2 
Source of IMP, Manufacture, Distribution and Storage 
OctaplasLG solution for infusion is a UK licensed product. The MA holder is 
Octapharma Limited with PL 10673/0009. It is licensed for therapeutic plasma exchange  
OctaplasLG will be sourced from hospital stock  
(Appendix 1) 
Drug storage and supply   
Octaplas LG will be sourced via hospital pharmacy and stored at ≤ -18°C in the Blood 
Transfusion Laboratory).  
 
Preparation and labelling of Investigational Medicinal Product 


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On request for Octaplas LG, an order is made via Blood transfusion. Either AB plasma 
or group specific product is made available for the patient and information for patients 
will be tagged to each unit, as per standard trust protocol for blood products. Each bag 
consists of 200mls of plasma. The label on the IMP bag will be as per requirements of 
Annex 13 (EudraLex Volume 4), and approved by relevant regulatory authority (MHRA). 
 
Plasma is defrosted within blood bank as per standard SOP in a plasma thawer. 
Octaplas LG will be couriered to the back up fridges.  
Octaplas LG must be used within 24 hours or will be returned to the blood transfusion 
laboratory and destroyed. All blood products require a fate on the BT IT system. 
 
 
7.3 
Concomitant medication 
Concomitant medications will be recorded in the Participant’s medical records/CRF. 
7.4 
Post-trial IMP arrangements 
No arrangements for IMP to be provided to trial participants post trial participation 
 
8 
Selection of Participants 
Patients meeting the inclusion/exclusion criteria only will be approached and inclusion requires 
they meet these parameters. 
Patients who have already consented to a COVID19 study involving an IMP or another research 
study relating to an IMP will not be eligible. 
 
8.1 
Eligibility of trial participants 
8.1.1 Trial participant inclusion criteria 
1. 
Age > 18 years 
2. 
Proven COVID-19/high clinical suspicion of COVID-19* 
3. 
Hypoxia/respiratory compromise defined as requiring respiratory support of >2L/min of 
oxygen by nasal cannulae to maintain SpO2<96%.  
4. 
Raised inflammatory parameters: at least 2 of the following:  
Raised LDH  (> 2 x ULN) 
Raised D Dimers (> 2X ULN) 
Raised CRP (>2X ULN) 
5. Females of childbearing potential have a negative pregnancy test within 7 days prior to 
being randomised.  Participants are considered not of child bearing potential if they are 


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surgically sterile (i.e. they have undergone a hysterectomy, bilateral tubal ligation, or 
bilateral oophorectomy) or they are postmenopausal 
 
*In light of a 20% false negative rate with PCR swab tests, patients confirmed as having the  
clinical phenotype, in conjunction with raised inflammatory parameters and exclusion of any 
other precipitant, as judged by 2 consultants. 
 
8.1.2 Trial participant exclusion criteria 
1. Significant co-morbid illness with treatment escalation limited to CPAP such as, but not 
limited to,  active cancer, severe cardiac or renal disease, history of organ 
transplantation, active inflammatory disease 
2. Active bleeding 
3. PF ratio < 100 on mechanical ventilation OR noradrenaline requirement > 0.5mcg/kg/min to 
maintain MAP > 65mmHg (suggests futility) 
4. Known allergies to Octaplas or excipients 
5. Females who are pregnant or breastfeeding 
 
8.2 
     Recruitment 
Participant recruitment at a site will only commence when the trial has  
1. Been initiated by the Sponsor (or its delegated representative), and  
2. Issued with the ‘Open to Recruitment’ letter. 
 
Patients will be recruited following admission to hospital for supportive care relating to presumed 
or confirmed COVID19. Those deemed appropriate for inclusion, meeting the above criteria, will 
be discussed by 2 senior clinicians and approached about the study. In conjunction, this will be 
discussed with the next of kin. Currently a pathway exists for COVID patients between ED/AMU, 
ICU and dedicated areas within the hospital. 
 
8.3 
     Informed consent procedure 
 
The Principal Investigator (PI) has overall responsibility for the informed consent of participants 
at their site and will ensure that any person delegated responsibility to participate in the informed 
consent process is duly authorised, trained, and competent to participate according to the ethically 
approved protocol, principles of Good Clinical Practice (GCP), and Declaration of Helsinki. If 
delegation of consent occurs then details will be provided in the site delegation log. 
The right of a participant to refuse participation without giving reasons will be respected. The 
participant will remain free to withdraw at any time from the study without giving reasons and 


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without prejudicing his / her further treatment, and will be provided with a contact point where 
he / she may obtain further information about the study.  
Participants will be severely ill at the time of eligibility (non-invasive ventilation or intubated on 
mechanical ventilation and sedation), such that the Medicines for Human Use (Clinical Trials) 
Regulations provides guidance. Those who are not sedated and intubated will have been through 
a psychologically anxiety provoking event and will often be extremely distressed due to severe 
difficulty breathing and hypoxia. As such they may be unable to fully comprehend an important 
consideration when the intervention under investigation is time sensitive.  The PI is responsible 
for ensuring that all vulnerable participants are protected and participate voluntarily in an 
environment free from coercion or undue influence. 
A legal representative can be asked to give consent on behalf of an adult lacking capacity to do so 
themselves. 
Those who are able to act as a legal representative in Clinical Trials of Investigational Medicinal Products 
(CTIMPs), in England and Wales are: 
• 
Personal legal representative i.e. a person not connected with the conduct of the trial who is suitable 
to act as the legal representative by virtue of their relationship with the adult, and is available and willing 
to do so. If one is not available: 
• 
Professional legal representative i.e. a doctor responsible for the medical treatment of the adult if 
they are independent of the study, or a person nominated by the healthcare provider. 
Additional consent provisions for collection and use of participant data and biological 
specimens in ancillary studies: 
All data and samples collected as part of this trial will be available for COVID19 related research, 
to improve the understanding of the condition. This may be within the team/trust or in 
collaboration with external researchers. All data/samples in the latter situation will be 
anonymised. 
Patients with COVID19, provided, or high clinical suspicion, on HDU/ICU,  will have their 
information reviewed by the trial team. If they forfill the inclusion criteria, as confirmed 
by 2 members of the trial team, they will be offered the opportunity to participate in the 
study. This will be discussed with their primary admitting clinician. The study will be 
discussed with the patient and they will be given an opportunity to read the PIS. Once 
permission is sort, the patients NOK will be contacted to explain the study and ensure they 
are happy for inclusion. Patients will be given 24 hours to confirm their participation and 
consent. 
 
In patients who unable to consent, but for whom would fit the inclusion criteria, their 
NOK will be contacted. Consent would be required within 24 hours. This can be signing 
the form by email. If this is not possible, email confirmation they understand the study 
and confirm consent on behalf of the patient. 
 


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Finally, in patients who are eligible, but there is no NOK a legal representative can be 
contacted on behalf of the patient and give consent. 
 
Limitation to recruitment will be the number of patients already receiving PEX. Therefore, all 
patients admitted with COVID19 may not be approached. 
9 
Trial procedures  
9.1 
Pre-treatment Assessments  
 
   
All cases screened for the study will be captured and reason for not being recruited documented. 
The following trial specific procedures will be carried out after consent:  
1.Demographics recorded including gender, age, height, weight, race 
2. Medical History recorded to exclude underlying pre morbid conditions, VTE history, Smoking 
history 
3. General physical examination 
4. Concomitant Medication recorded: Primarily antibiotics, noradrenaline use 
5. Blood tests 
-Serum pregnancy test (for women of child bearing potential) in last 7 days  
-Baseline inflammatory parameters and routine bloods (FBC, renal, liver function and coagulation 
screen with fibrinogen,  LDH, CRP, D dimer, ferritin) 
-Hepatitis A, B, C and HIV pre PEX (result does not need to be available before PEX) 
-Troponin T/BNP (result does not need to be available before PEX) 
-C3/4 (result does not need to be available before PEX) 
-Autoimmune screen (ANA, ENA) (result does not need to be available before PEX) 
-Factor VIII, VWF, ADAMTS-13 activity (result does not need to be available pre PEX 
-IgG and IgM to COVID-19 (result does not need to be available before PEX) 
-PCR result for COVID-19 (result does not need to be available before PEX, see inclusion criteria 
for definition of probable COVID)) 
 
6. Respiratory parameters: SaO2,RR  
-PaO2, FiO2 
-Method of assisted ventilation eg HDNOHFNO, CPAP 
-P:F ratio 
CXR/ CT/HRCT : if undertaken as part of routine clinical care  
 
7.Cardiac investigations 
- ECG (result does not need to be available before PEX) 


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- Echocardiography (if available within 48 hours of enrolment to study) 
 
The results from the following routine procedures may be used:   
Blood test results within 48 hours of enrolment 
PCR result for COVID-19 within past 14 days (result does not need to be available before PEX, 
see inclusion criteria for definition of probable COVID) 
Pregnancy test within 7 days 
Where routine results are not available, the procedure(s) will be carried out at screening after 
consent. 
 
All pre-treatment procedures will be carried out as specified in the schedule of assessments 
(appendix 2). 
 
9.2 
    Registration / Randomisation Procedures  
 
Participant randomisation will be undertaken remotely at sites using central randomisation system 
developed by Sealed Envelope. 
Following participant consent, and confirmation of eligibility (see section 8.1 for pre-treatment 
assessments) the registration/randomisation procedure described below will be carried out.  
Participants are considered to be enrolled into the trial following: consent, pre-treatment 
assessments 
(see 
section 
8.1), 
confirmation 
of 
eligibility, 
completion 
of 
the 
registration/randomisation process, allocation of the participant trial number and treatment by the 
central coordinating team/remote system.  
Patients will be randomized to either PEX+SOC or SOC in a 1:1 ratio using block randomization 
with varying blocks sizes.  
 
Randomisation will be carried out by the online randomisation system provided by commercial 
company Sealed Envelope . This will be accessed by a designated member of staff who will 
communicate the treatment allocation to the clinical team. 
 
9.3 
    Treatment Schedule 
 
IMP = OctaplasLG, Octapharma, Limited UK: 40mls/Kg intravenously via plasmapheresis  
Licensed for therapeutic plasma exchange 
 
OctaplasLG via plasmapheresis  


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Intravenous infusion of Octaplas to the nearest litre (which in the majority of patients will be 3 
litres) through a Cobe Spectra apheresis machine over 2-3 hour, with removal of a comparable 
volume of plasma once daily  for 5 days.  
Single volume PEX capped at 3 litres if <100Kg and 4 litres if >100Kg.  
PEX will be given for a minimum of once a day for 5 days, but the course can be repeated 
depending on patient’s response, based on a reassessment on D5 to D7.  The 5 day PEX will be 
repeated in patients showing clinical and biochemical improvement but persistent pro-thrombotic 
phenotype following the initial 5-day block 
The Cobe Spectra is the preferred technology for plasma exchange, but plasma exchange may be 
performed on haemofilters. 
 
The following drugs are considered to be non-investigational medicinal products (NIMPs) in 
this Trial: 
Medications used during plasma exchange (NIMPs) 
The following drugs are standard adjunctive treatment during plasma exchange which may be 
given during PEX 
• 
Calcium replacement either oral or iv 
• 
Hydrocortisone 100mg intravenously  
• 
Chlorpheniramine 10mg intravenously (or 4mg orally)  
• 
Paracetamol 1g orally.  
All medications need to be documented on the CRF and source document. 
These are NIMPS as they are not treating the disease but are used to potentially reduce any 
infusional side effects of plasma exchange. 
Intermediate dose LMWH for all patients within the study: <100Kg 40mg BD enoxaparin (or 
equivalent LMWH), > 100Kg, 60mg BD Enoxaparin 
 
9.3.1 Dose Modifications 
3 litre PEX if < 100Kg and 4 litre PEX if >100Kg 
. 
 
9.4 
    Subsequent assessments and procedures 
9.4.1 Visit schedule and assessments 
 
A schedule of all trial assessments and procedures is set-out in Appendix 3. 


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Day 1- 5  
• 
eligibility check pre PEX if randomised to PEX 
• 
Vitals pre and post PEX  (temperature, blood pressure, pulse, respiratory rate and oxygen 
saturation level) or once daily 
• 
Plasma exchange if randomised to PEX 
• 
assessment of compliance with PEX 
• 
general physical examination  
• 
recording of relevant concomitant medications eg start stop dates of antibiotics, 
noradrenaline 
• 
Daily routine bloods (FBC, renal, liver function and coagulation screen with fibrinogen )   
• 
Inflammatory markers  on D1,D3 &D5 (LDH, CRP, D dimer, ferritin) 
• 
Citrated plasma and serum samples pre and post PEX, or daily for those randomised to 
SOC to save for VWD screen, ADAMTS13 activity, COVID-19 serology, and multiplex 
inflammatory markers related to ILs cytokines, interferons, and vascular markers of endothelial 
injury. Spare samples can be used for COVID-19 related research as authorised by the trial team 
• 
Respiratory parameters: Oxygen requirement, respiratory rate, type of ventilator support-
as pat of standard of care assessment 
• 
Echocardiogram on D1 
• 
Troponin and BNP on D1 
• 
adverse event collection 
• 
Reactions to Plasma exchange: graded 1-4 
• 
Complications related to central vascath 
• 
Need for antibiotics 
• 
Deterioration requiring  ventilation 
• 
Arterial or venous thrombotic event 
 
Reassessment (Day 5-7) 
Review of clinical and laboratory parameters by trial team. Consideration of further 5 day block 
of PEX if clinical and biochemical improvement following initial 5-day block but persistent pro-
thrombotic phenotype 
*If a patient has a second 5 days of PEX started-follow instructions for  day 1-5 above 
 
Follow up Day 6 - 28* 


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• 
Vitals (temperature, blood pressure, pulse, respiratory rate)  
• 
general physical examination-weekly  
• 
recording of concomitant medications-related to antibiotics, new cardiac medication, but 
not all the routine medicines re SOC and not including PRN medications. 
• 
Daily routine bloods (FBC, renal, liver function and coagulation screen with fibrinogen )   
• 
Inflammatory markers, at least 3 x/week (LDH, CRP, D dimer, ferritin) 
• 
Citrated plasma and serum samples taken at least weekly to 28 days to save for VWD 
screen, ADAMTS 13 activity, COVID-19 serology, and multiplex inflammatory markers related 
to ILs cytokines, interferons, and vascular markers of endothelial injury. Spare samples can be 
used for COVID-19 related research as authorised by the trial team 
• 
Respiratory parameters 
• 
Echocardiography D7  
• 
Troponin/BNP weekly D7, D14, D21, D28 
• 
Adverse event collection  
• 
Need for antibiotics 
• 
Deterioration requiring  ventilation 
• 
Arterial or venous thrombotic event 
 
End of study Day 28 
• 
28 day mortality and outcomes 
• 
Echocardiogram, if available, D28 
 
 
9.5 
     Laboratory Assessments and Procedures 
Local laboratories  
 
The following tests will be carried out at Local Laboratories:  
 
Laboratory test 
Parameters 
BLOOD 
Haematology 
 
leukocytes, erythrocytes, haemoglobin, haematocrit, mean 
corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), 
platelets, neutrophils, eosinophils, basophils, lymphocytes, 
monocytes;  
 


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Serum chemistry 
 
alanine transaminase ( ALT), alkaline phosphatase,  total bilirubin, 
creatinine, urea, potassium, sodium, albumin 
 
Clotting screen 
Prothrombin time, activated partial thromboplastin time, clauss 
fibrinogen,  
Inflammatory markers 
C reactive protein ( CRP), lactate dehydrogenase (LDH), D dimer, 
ferritin 
Pregnancy test 
Serum bhCG 
Virology test 
 
Covid 19 PCR, Covid 19 IgM and IgG, 
Hepatitis-B-virus surface antigen (HBsAg), anti-hepatitis C virus 
(anti-HCV) antibodies, immunodeficiency virus 1 and 2 (anti-
HIV1/2) antibodies,  
 
Cardiac markers 
Troponin, BNP 
Procoagulant markers 
Factor VIII, VWF, ADAMTS-13 activity 
Autoimmune screen 
C3/C4   ANA ENA 
Multiplex inflammatory 
markers 
cytokines including interleukins, interferons, and vascular markers 
of endothelial injury  ‘cytokine storm’ 
 
Central laboratories  
No central laboratory 
 
 Translational Research Samples  
Citrated plasma and serum samples can be used for COVID-19 related translational research as 
authorised by the trial team. All data and samples will be available for COVID19 related research, 
to improve the understanding of the condition. This may be within the team/trust or in 
collaboration with external researchers. All data/samples in the latter situation will be 
anonymised. 
The samples will be spun and stored in Special Coagulation Laboratory, 60 Whitfield street, 
London W1T4EU 
Any analysis of samples needs a formal risk assessment re aerosol risk when spinning or as part 
of analysis and will only be undertaken following health and safety sign off within 
HSL/UCLH/UCL. 
 
 
9.7 
Assessment of IMP/NIMP compliance 
PEX and NIMP will be administered as an inpatient IMP by trained apheresis staff as per Trust 
protocol so there will be no compliance issues. 
 
9.8.   Discontinuation/withdrawal of participants 
Discontinuation of Trial Treatment for clinical reasons 


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A participant may be withdrawn from trial treatment whenever continued participation is no longer 
in the participant’s best interests, but the reasons for doing so must be recorded.  Reasons for 
discontinuing treatment may include  
 
disease progression whilst on therapy 
 
unacceptable toxicity: anaphylaxis to plasma 
 
intercurrent illness which prevents further treatment 
 
patients withdrawing consent to further trial treatment 
 
Any alterations in the participant’s condition which justifies the discontinuation of 
treatment in the site investigator’s opinion 
 
Persistent non-compliance to protocol requirements 
The decision to withdraw a participant from treatment must be recorded in the CRF and medical 
notes, and the sponsor when required should be notified in writing. 
In these cases participants remain within the trial for the purposes of follow-up for safety and or 
data analysis according to the treatment option to which they have been allocated  
Participant withdrawal from trial treatment 
If a participant expresses their wish to withdraw from trial treatment, sites should explain the 
importance of remaining on trial follow-up and seek permission to allow use of routine follow-up 
data to be used for trial purposes.    The importance of safety follow-up should be emphasised to 
the participant in the Participant Information Sheet. 
The decision of the participant to withdraw from treatment must be recorded in the CRF and 
medical notes. 
The participant may withhold their reason for withdrawal however, if the participant gives a reason 
for their withdrawal, this should be recorded. 
Withdrawal of Consent to Data Collection  
If a participant explicitly states they do not wish to contribute further data to the trial their decision 
must be respected and recorded in the CRF and medical notes.  
Loss to follow-up 
If a participant moves from the area, every effort should be made for the participant to be followed 
up at another participating trial site and for this new site to take over the responsibility for the 
participant.   
 
9.8 
    Replacements 
Withdrawn participants would not be replaced 


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9.9 
   Stopping rules  
The trial may be stopped before completion for the following reasons: 
Anaphylaxis to plasma during PEX 
              On the recommendation of the TMG 
              On the recommendation of the sponsor and CI 
 
9.10 
Definition of End of Trial 
The end of trial is day 28 of the last participant.  
10 
    Recording and reporting of adverse events and reactions 
 
Collection, recording and reporting of adverse events (including serious and non-serious events and 
reactions) to the sponsor will be completed according to the sponsor’s SOP (INV/S05). 
10.1 
Definitions 
 
Term 
Definition 
Adverse Event (AE) 
Any untoward medical occurrence in a patient or clinical trial 
participant administered a medicinal product and which does not 
necessarily have a causal relationship with this treatment.  
Therefore an AE can be any unfavourable or unintended change in the 
structure (signs), function (symptoms) or chemistry (laboratory data) in 
a participant to whom an IMP or procedural intervention has been 
administered, including occurrences which are not necessarily caused 
by or related to that product. 
Adverse Reaction (AR) 
Any untoward and unintended response in a participant to an 
investigational medicinal product which is related to any dose 
administered to that participant.  
This includes medication errors, uses outside of protocol (including 
misuse and abuse of product) 
Serious Adverse Event 
(SAE), Serious Adverse 
Reaction (SAR) or 
Unexpected Serious 
Adverse Reaction  
Any adverse event, adverse reaction or unexpected adverse reaction, 
respectively, that: 
• 
results in death, 
• 
is life-threatening*, 
• 
requires 
hospitalisation 
or 
prolongation 
of 
existing 
hospitalisation**, 


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• 
results in persistent or significant disability or incapacity, or 
• 
consists of a congenital anomaly or birth defect 
*A life- threatening event, this refers to an event in which the 
participant was at risk of death at the time of the event; it does not 
refer to an event which hypothetically might have caused death if it 
were more severe. 
** Hospitalisation is defined as an in-patient admission, regardless of 
length of stay. Hospitalisation for pre-existing conditions, including 
elective procedures do not constitute an SAE. 
Some medical events may jeopardise the subject or may require an 
intervention 
to 
prevent 
one 
of 
the 
above 
characteristics/consequences. Such important medical events should 
also be considered as serious. 
The term “severe” is often used to describe the intensity of an event or 
reaction (mild, moderate or severe) and should not be confused or 
interchanged with the term “serious”. 
Suspected Unexpected 
Serious Adverse 
Reaction (SUSAR) 
A serious adverse reaction, the nature, severity or outcome of which is 
not consistent with the Reference Safety Information. 
Reference Safety 
Information (RSI) 
A list of medical events that defines which reactions are expected for 
the IMP being administered to clinical trial subjects, and so do not 
require expedited reporting to the Competent Authority. It is contained 
in a specific section in the Summary of product characteristics (SmPC) 
or the Investigator Brochure (IB). 
 
10.2 
Recording adverse events 
All adverse events will be recorded in the medical records in the first instance. All adverse events will be 
recorded from consent to the end of trial. 
All adverse events will be recorded with clinical symptoms and accompanied with a simple, brief 
description of the event, including dates as appropriate. 
Non-serious Adverse Events (AEs) and Serious Adverse Events (SAEs) associated with COVID-19 infection 
will not be collected in the CRFs or reported to Sponsor for this trial. Refer to ‘Serious Adverse Events 
which do not require immediate reporting’ section for further details. 
 


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10.3 
Assessments of Adverse Events 
Each adverse event will be assessed for severity, causality, seriousness and expectedness as described 
below. 
10.3.1 Severity  
 
Category 
Definition 
Mild 
The adverse event does not interfere with the participant’s daily routine, and 
does not require intervention; it causes slight discomfort 
Moderate 
The adverse event interferes with some aspects of the participant’s routine, or 
requires intervention, but is not damaging to health; it causes moderate 
discomfort 
Severe 
The adverse event results in alteration, discomfort or disability which is clearly 
damaging to health 
 
10.3.2 Causality 
The assessment of relationship of adverse events to the administration of IMP is a clinical decision based 
on all available information at the time of the completion of the case report form.   
The causality assessments will be captured in the trial specific CRF, SAE Log or SAE Reporting Form.  
The following categories will be used to define the causality of the adverse event: 
 
Category 
Definition 
Related 
A causal relationship between an IMP/investigational treatment and an 
adverse event is at least a reasonable possibility, i.e., the relationship cannot 
be ruled out. 
Not related 
There is no reasonable possibility of a causal relationship between an 
IMP/investigational treatment and an adverse event. 
 
10.3.3 Expectedness 
 
Category 
Definition 
Expected 
An adverse event which is consistent with the information about the IMP listed in 
the current approved Reference Safety Information (RSI) for the trial.  


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Unexpected 
An adverse event which is not consistent with the information about the IMP 
listed in the current approved Reference Safety Information (RSI) for the trial.  
* this includes listed events that are more frequently reported or more severe than 
previously reported 
The RSI to be used to assess expectedness is section 4.8 of the SmPC for octaplasLG (human plasma 
proteins). 
 
10.3.4 Seriousness 
All events are assessed for seriousness as defined for an SAE in section 10.1.  
 
10.4 
Procedures for recording and reporting Serious Adverse Events 
All serious adverse events (SAEs/SARs/SUSARs) will be recorded in the medical records in the 
first instance. Serious Adverse Events (SAEs) related to COVID-19 will not be collected in the 
CRFs or reported to Sponsor for this trial. Refer to ‘Serious Adverse Events which do not require 
immediate reporting’ section for further details. 
All other SAEs will be recorded in the CRF, the Sponsor’s SAE Recording Log and SAE 
Reporting Form.  
All SAEs will be recorded from randomisation until the end of the trial (i.e. 28 days after 
enrolment).    
All SAEs (except COVID-19 related SAEs) must be recorded on a SAE Reporting Form. The 
CI/PI or designated individual will complete the sponsor’s SAE form email to the Sponsor at 
SAE@ucl.ac.uk, within 24 h of his / her becoming aware of the event. The Chief or Principal 
Investigator will respond to any SAE queries raised by the sponsor as soon as possible.  
 
 
 
 
Managing serious adverse events in a multi-site trial 
• 
SAEs from all sites must be reported to Sponsor as detailed above. The SAE Reporting Forms 
should be emailed to the CI at the same time as forwarding to the Sponsor. The CI will 
perform an assessment of the SAE in collaboration with the Sponsor. It should be noted that 
the CI cannot overrule the causality assessment provided by the PI.  
• 
SAE Recording Logs should be sent to UCLH data manager as per the data management 
plan, and to the Sponsor upon request. 
Completed SAE forms must be sent within 24 hours of becoming 
aware of the event to the Sponsor  
Email forms to SAE@ucl.ac.uk  


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Flow Chart for SAE Reporting


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10.5 
Serious Adverse Events which do not require immediate reporting  
SAEs associated with COVID-19 disease do not require recording in the CRF, SAE Recording Log 
or SAE Reporting Form. However, if the relationship between the IMP and an SAE cannot be 
ruled out the SAE must be recorded and reported to Sponsor as detailed above.  
 
There is high rate of expected deterioration in this group of patients. Anticipated adverse 
events/interventions associated with COVID-19 infection which are not required to be captured 
as an SAE/AE include: 
-abnormal pathology results from presentation (including inflammatory markers related to a 
hyperinflammatory response) 
-secondary infection 
-renal failure 
-cardiac disease e.g. arrythmias, right heart failure  
-intubation and ventilation 
-VTE/arterial thrombosis  
-end organ damage developing either biochemical e.g. AKI, liver impairment or clinical e.g. 
Intubation, thrombosis (either venous or arterial such as stroke) 
-death from COVID19 
This will be captured within the medical notes. These represent SAEs but are anticipated based 
on the natural history of the COVID-19 disease and so do not require immediate reporting. 
Mortality will be captured as an endpoint. 
 
 
10.6 
Notification of Deaths  
Deaths related to COVID-19 disease is an endpoint of the trial and will be captured in the CRF. 
All other SAEs should be reported to Sponsor as described in the Procedures for recording and 
reporting Serious Adverse Events section above.   
 
10.7 
Reporting SUSARs 
The sponsor will notify the main REC and MHRA of all SUSARs.  SUSARs that are fatal or life-
threatening must be notified to the MHRA and REC within 7 days after the sponsor has learned 


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of them.  Other SUSARs must be reported to the REC and MHRA within 15 days after the sponsor 
has learned of them.   
 
 
10.8 
Development Safety Update Reports 
The sponsor will provide the main REC and the MHRA with Development Safety Update Reports 
(DSUR) which will be written in conjunction with the trial team and the Sponsor’s office. The 
report will be submitted within 60 days of the Developmental International Birth Date (DIBD) of 
the trial each year until the trial is declared ended. 
 
10.9 
Pregnancy  
Pregnancy is considered to be highly unlikely during the study as participants are hospitalised for 
the duration of the trial. 
In the unlikely event that a female participant or the female partner of a male participant becomes 
pregnant at any point during the trial, a completed trial specific Pregnancy Reporting Form will 
be emailed to the Sponsor SAE@ucl.ac.uk, within 24 hours of his / her becoming aware of the 
event in line with the Sponsors SOP (JRO/INV/S05). The Chief or Principal Investigator will 
respond to any queries raised by the sponsor as soon as possible.   
 
 
 
 
 
 
The Sponsor must be kept informed of any new developments involving the pregnancy through 
the completion of a follow-up Pregnancy Reporting Form. Any pregnancy that occurs in a 
female trial subject during a clinical trial should be followed to termination or to term. 
Consent to report information regarding the pregnancy  must be obtained from the pregnant 
participant.  A trial-specific pregnancy monitoring information sheet and informed consent form 
for trial participants and the partners of trial participants must be used for this purpose.   
 
With consent additional information regarding the pregnancy will be collected and reported to 
the Sponsor, the Sponsor will advise on the length of follow up of the pregnancy/ child on a 
case by case basis, 
 
Completed Pregnancy Reporting Forms must be sent within 24 
hours of becoming aware of the event to the Sponsor  
Email forms to SAE@ucl.ac.uk  


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10.10 
Reporting Urgent Safety Measures and other safety events 
If any urgent safety measures are taken the CI/ PI shall immediately and in any event no later than 
3 days from the date the measures are taken, give written notice to the MHRA, the relevant REC 
and Sponsor of the measures taken and the circumstances giving rise to those measures. 
10.11 
Notification of Serious Breaches to GCP and/or the protocol 
(SPON/S15)  
 A “serious breach” is a breach which is likely to effect to a significant degree – 
(a) the safety or physical or mental integrity of the participants of the trial; or 
(b) the scientific value of the trial. 
The sponsor of a clinical trial shall notify the licensing authority in writing of any serious breach 
of – 
(a) the conditions and principles of GCP in connection with that trial; or (b) the protocol relating 
to that trial, as amended from time to time, within 7 days of becoming aware of that breach. 
The sponsor will be notified immediately of any case where the above definition applies during 
the trial conduct phase.  The sponsor’s SOP on the ‘Notification of violations, urgent safety 
measures and serious breaches’ will be followed.  
 
10.12 Reporting incidents involving a medical device(s)  
Any adverse incident involving a medical device should be reported to the manufacturer of the 
device.  
This is especially important where the incident has led to or, was it to occur again could lead to 
an event classified as serious (see section 9.2 for definition of SAE). Other minor safety or 
quality problems should be reported along with incidents that appear to be caused by human 
error.  
Local trust reporting procedures may also need to be followed. It is the responsibility of the PI 
and trial site team to ensure they are aware of any specific local requirements for reporting 
device incidents.  
Sites to report to the manufacturer and an incident form forwarded to the central trial 
coordinator.  
Adverse incidents related to a medical device can be reported directly to the MHRA via the 
online system (www.mhra.gov.uk). Alternative contact details: Medicines & Healthcare 
products Regulatory Agency Adverse Incident Centre (Tel: 020 7084 3080; Fax 020 7084 
3109). 
 


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11 
Data management and quality assurance 
11.1 
Confidentiality 
All data will be handled in accordance with the UK Data Protection Act 1998. 
Case Report Forms (CRFs) for sites will not bear the participant’s name or other personal 
identifiable data.  The participant’s initials, date of birth and trial identification number, will be 
used for identification and this will be clearly explained to the patient in the Patient information 
sheet.  Patient consent for this will be sought. 
 
11.2 
Data collection tools and source document identification 
At UCLH, All data will be available on hospital IT clinical system (EPIC) as source 
documentation and captured on Sealedenvelopes.com. As there may be a number of datapoints 
re observations in a 24 hour period, only those captured within the daily trial update, eg as a 
median will be recorded. 
Data will be collected from sites on Trial specific case report forms (CRFs)  
Source data are contained in source documents and must be accurately transcribed on to the CRF. 
Examples of source documents are medical records which include laboratory and other clinical 
reports etc. 
A source document list will be implemented prior to the start of the trial to identify: 
which data is to be recorded directly onto the CRF;  
which data is recorded firstly into source documents, such as medical notes, and then transcribed 
into the CRF  
It is the responsibility of the investigator to ensure the accuracy of all data entered in the CRFs. 
The delegation log will identify all those personnel with responsibilities for data collection and 
handling, including those who have access to the trial database. 
 
11.3 
Completing Case Report Forms  
CRFs from sites must be completed and signed by staff that are listed on the site staff delegation 
log and authorised by the CI/ PI to perform this duty.  The CI/ PI is responsible for the accuracy of 
all data reported in the CRF. 
Once completed the original CRFs must be sent to HRU, UCLH and a copy kept at site.  The CRFs 
must be returned at least weekly of the participant visit.  Source data verification of a CRF page 
should be completed and all data queries answered prior to submission where possible.  


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11.4 
Data handling and analysis 
All data will be added to an external validated  database hosted by Sealed Envelope.  
Data will be reviewed  by two independent members of the trial team and presented to the TMG 
 
12 
Statistical Considerations  
 
12.1 
Outcomes 
12.1.1 
Primary outcomes 
The (binary) primary outcome is whether a 50% reduction (from baseline) has been observed in 
at least two inflammatory markers (based on CRP, LDH and D dimer) throughout the period of 
PEX or SOC over a comparable time, following initiation of study. 
12.1.2 
Secondary outcomes 
1. 
Number of patients requiring mechanical ventilation who required only supplemental 
O2/CPAP at study entry. This will be captured throughout the period of the study, by review of 
the oxygen requirements and ventilatory support required throughout the study (O2 requirement 
or PaO2:FiO2 (P:F ratio) sequentially) 
2. 
 50% decrease in VWFAg/ADAMTS 13 activity ratio from baseline to end of PEX.  
3. 
Prevent deterioration in myocardial function on ECHO/ cardiac parameters -monitoring of 
cardiac function through echocardiogram and/ or BNP and Troponin levels throughout studty 
period 
4. 
Clinical thrombotic events documented by imaging either venous DVT/PE, or arterial 
thrombus (cardiac, neurological and peripheral vascular) throughout the study period 
5. 
Incidence of acute kidney injury as defined by KDIGO criteria throughout study period 
6. 
Mortality at 28 days 
 
 


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12.2 
Sample size and recruitment 
12.2.1 
Sample size calculation 
 
Mortality of patients on intensive care with COVID-19 has been reported to range from 48% of 
patients no longer on ITU (ICNARC report on COVID-19 in critical care, 27 Mar 2020) to 86% 
of patients who required invasive mechanical ventilation (Yang, Lancet Respiratory Medicine, 
Feb 2020).   
 
We aim to recruit up to 40 patients in total (20 per arm). We will have 80% power to detect a 
statistically significant difference between the treatment groups at the 5% level assuming that 
PEX+SOC will reduce inflammation markers in 80% of patients compared to just 20% for SOC 
if we recruit 20 patients. The power is increased to 99% if 40 patients are recruited. Alternatively, 
if the effect is lower, e.g. PEX+SOC reduces markers in 65% of patients, then the power will be 
85% based on 40 patients. 
 
12.2.2 
Planned recruitment rate 
Subjects will be recruited throughout the COVID19 pandemic 
 
12.3 
Randomisation methods 
 
Patients will be randomized to either PEX+SOC or SOC in a 1:1 ratio using block 
randomization with varying blocks sizes. 
Randomisation will be carried out by the commercial company Sealed Envelope which provides 
online randomisation. This will be accessed by a designated member of staff who will 
communicate the treatment allocation to the clinical team. 
  
 
12.4 
Statistical analysis plan 
12.4.1 
Summary of baseline data and flow of participants 
Patient characteristics will be summarised by trial arm and inspected for balance. Patient flow 
throughout the trial will be summarised using a CONSORT diagram. (APPENDIX 4) 


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12.4.2 
Primary outcome analysis 
The primary analysis will involve a comparison of the binary outcome ‘50% reduction in at least 
two inflammation markers’ between the PEX+SOC and SOC trial arms using a chi-squared test. 
The risk difference (and ratio) will be estimated with a 95% confidence interval. All analyses will 
be performed on an intention to treat basis. 
12.4.3 
Secondary outcome analysis 
Secondary outcomes will be summarised and compared using suitable statistical methods. For 
example, binary outcomes may be compared using chi-squared tests and numerical outcomes may 
be compared using t-tests. P-values from tests of secondary outcomes may be adjusted to account 
for multiple testing. Appropriate regression methods will be used to perform adjusted analyses or 
to account for repeated measures. 
 
12.4.4 
Sensitivity and other planned analyses 
 
The level of missing data will be reported and sensitivity and/or adjusted analyses performed to 
account for missing data. 
 
12.5 
Interim analysis 
No planned interim analysis 
 
13 
     Record keeping and archiving 
At the end of the trial, all essential documentation will be archived securely by the CI and trial 
sites for a minimum of 25 years from the declaration of end of trial.  
Essential documents are those which enable both the conduct of the trial and the quality of the 
data produced to be evaluated and show whether the site complied with the principles of Good 
Clinical Practice and all applicable regulatory requirements.  
The sponsor will notify sites when trial documentation can be archived. All archived documents 
must continue to be available for inspection by appropriate authorities upon request.  
 


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14 
    Oversight Committees  
.  
14.1 
Trial Management Group (TMG) 
The TMG will include the Chief Investigator and trial staff.  The TMG will be responsible for 
overseeing the trial.  The group will meet regularly monthly and will send updates to PIs. 
The TMG will review recruitment figures, SAEs and substantial amendments to the protocol prior 
to submission to the REC and/or MHRA.  All PIs will be kept informed of substantial amendments 
through their nominated responsible individuals. 
 
15 
     Direct Access to Source Data/Documents 
The investigator(s)/ institution(s) will permit trial-related monitoring, audits, REC review, and 
regulatory inspection(s), providing direct access to source data/documents.  Trial participants are 
informed of this during the informed consent discussion.  Participants will consent to provide 
access to their medical notes. 
 
16 
Ethics and regulatory requirements 
The sponsor will ensure that the trial protocol, participant information sheet, consent form, 
submitted supporting documents have been approved by the appropriate regulatory body (MHRA 
in UK) and an appropriate research ethics committee, prior to any participant recruitment. The 
protocol, all other supporting documents including and agreed amendments, will be documented 
and submitted for ethical and regulatory approval as required. Amendments will not be 
implemented prior to receipt of the required approval(s).  
An annual progress report (APR) will be submitted to the REC within 30 days of the anniversary 
date on which the favourable opinion was given, and annually until the trial is declared ended. 
The chief investigator will prepare the APR. 
Within 90 days after the end of the trial, the CI/Sponsor will ensure that the main REC and the 
MHRA are notified that the trial has finished.  If the trial is terminated prematurely, those reports 
will be made within 15 days after the end of the trial. 
The CI will supply the Sponsor with a  report of the clinical trial which complies with the format 
as defined by the EMA. This will then be  uploaded to EudraCT for availability to the MHRA and 
a copy of the report will be submitted to the main REC, within 1 year after the end of the trial.  


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The study will be reviewed and authorised to proceed through urgent regulatory review by UCLH 
COVID19 Clinical trial group 
 
17 
Monitoring requirement for the trial 
The sponsor will determine the appropriate level and nature of monitoring required for the trial.  
Risk will be assessed on an ongoing basis and adjustments made accordingly. 
The degree of monitoring will be proportionate to the objective, purpose, phase, design, size, 
complexity, blinding, endpoints and risks associated with the trial. 
 
18 
Finance 
No financial interests by CI, PIs or trial management members. 
 
18.1 Insurance 
University College London holds insurance against claims from participants for injury caused by 
their participation in the clinical trial. Participants may be able to claim compensation if they can 
prove that UCL has been negligent. However, as this clinical trial is being carried out in a hospital, 
the hospital continues to have a duty of care to the participant of the clinical trial.  University 
College London does not accept liability for any breach in the hospital’s duty of care, or any 
negligence on the part of hospital employees. This applies whether the hospital is an NHS Trust 
or otherwise.   
Participants may also be able to claim compensation for injury caused by participation in this 
clinical trial without the need to prove negligence on the part of University College London or 
another party.  Participants who sustain injury and wish to make a claim for compensation 
should do so in writing in the first instance to the Chief Investigator, who will pass the claim to 
the Sponsor’s Insurers, via the Sponsor’s office. 
Hospitals selected to participate in this clinical trial shall provide clinical negligence insurance 
cover for harm caused by their employees and a copy of the relevant insurance policy or 
summary shall be provided to University College London, upon request. 
Arrangements must be in place, with the manufacturer, to cover the malfunction and 
breakdown of the apheresis platform. 
 
19 
Publication policy 
 
Access to the final trial dataset 


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• 
All individuals involved in the trial will have access to the full dataset 
 Dissemination policy 
• 
the data arising from the trial will be available to all medical investigators 
• 
that on completion of the trial, the data will be analysed and tabulated and a Final Trial 
Report prepared 
• 
presentation of results at national/international meetings in the future and submission 
for peer reviewed publication 
 
20 
References 
 
1. 
Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in 
Wuhan, China. Lancet. 2020;395(10223):497-506. 
2. 
Wang D, Hu B, Hu C, et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel 
Coronavirus-Infected Pneumonia in Wuhan, China. JAMA. 2020. 
3. 
Yang X, Yu Y, Xu J, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 
pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet 
Respir Med. 2020. 
4. 
Bhatraju PK, Ghassemieh BJ, Nichols M, et al. Covid-19 in Critically Ill Patients in the Seattle 
Region - Case Series. N Engl J Med. 2020. 
5. 
Arentz M, Yim E, Klaff L, et al. Characteristics and Outcomes of 21 Critically Ill Patients With 
COVID-19 in Washington State. JAMA. 2020. 
6. 
Grasselli G, Zangrillo A, Zanella A, et al. Baseline Characteristics and Outcomes of 1591 Patients 
Infected With SARS-CoV-2 Admitted to ICUs of the Lombardy Region, Italy. JAMA. 2020. 
7. 
Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with 
COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054-1062. 
8. 
Bowles L, Platton S, Yartey N, et al. Lupus Anticoagulant and Abnormal Coagulation Tests in 
Patients with Covid-19. N Engl J Med. 2020. 
9. 
Gattinoni L, Coppola S, Cressoni M, Busana M, Rossi S, Chiumello D. Covid-19 Does Not Lead to a 
"Typical" Acute Respiratory Distress Syndrome. Am J Respir Crit Care Med. 2020. 
10. 
Wichmann D, Sperhake JP, Lutgehetmann M, et al. Autopsy Findings and Venous 
Thromboembolism in Patients With COVID-19: A Prospective Cohort Study. Ann Intern Med. 
2020. 
11. 
Menter T, Haslbauer JD, Nienhold R, et al. Post-mortem examination of COVID19 patients 
reveals diffuse alveolar damage with severe capillary congestion and variegated findings of lungs 
and other organs suggesting vascular dysfunction. Histopathology. 2020. 
12. 
Lodigiani C, Iapichino G, Carenzo L, et al. Venous and arterial thromboembolic complications in 
COVID-19 patients admitted to an academic hospital in Milan, Italy. Thromb Res. 2020;191:9-14. 
13. 
Helms J, Tacquard C, Severac F, et al. High risk of thrombosis in patients with severe SARS-CoV-2 
infection: a multicenter prospective cohort study. Intensive Care Med. 2020. 
14. 
Klok FA, Kruip M, van der Meer NJM, et al. Incidence of thrombotic complications in critically ill 
ICU patients with COVID-19. Thromb Res. 2020. 
15. 
Zhang C, Zhang Z, Mi J, et al. The cumulative venous thromboembolism incidence and risk 
factors in intensive care patients receiving the guideline-recommended thromboprophylaxis. 
Medicine (Baltimore). 2019;98(23):e15833. 
16. 
Varga Z, Flammer AJ, Steiger P, et al. Endothelial cell infection and endotheliitis in COVID-19. 
Lancet. 2020;395(10234):1417-1418. 
17. 
McGill SN, Ahmed NA, Christou NV. Increased plasma von Willebrand factor in the systemic 
inflammatory response syndrome is derived from generalized endothelial cell activation. Crit 
Care Med. 1998;26(2):296-300. 
 


Short title: PEX in severe COVID19   Sponsor code: 132796 
UCL protocol template V03, 20/03/15 
 
 
 
 
 
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Appendix 2: Pre study assessments 


Short title: PEX in severe COVID19   Sponsor code: 132796 
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Protocol Version V1.1        18th June 2020        
 
Screening 
(Pre-
treatment 
assessment) 
Treatment Phase  
Day  
Day – 2 to Day 
-1 
 
Day 1 
Day 7 
Day 14 
Day 21 
Day 28 
Window of flexibility for 
timing of visits: 
 
 
e.g.  +/- 2 
days 
e.g.+/- 2 days 
E.g..+/- 3 days 
e.g.+/- 3 days 
Informed Consent 
X 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
Physical Examination 
 
 
 
 
 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
Eligibility confirmation 
X 
X 
 
 
 
 
Add ALL Protocol 
Assessments including 
bloods/urine, ECGs, scans, c 
as applicable both trial 
specific and routine (include 
separate row for each 
assessment) 
X 
X 
X 
X 
X 
X 
Randomisation  
X 
 
 
 
 
 
IMP administration 
 
X 
X 
X 
X 
X 
Adverse Events review 
X 
X 
X 
X 
X 
X 
Concomitant Medication 
review 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 


Short title: PEX in severe COVID19   Sponsor code: 132796 
UCL protocol template V03, 20/03/15 
 
 
 
 
 
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Protocol Version V1.1        18th June 2020        
Appendix 3- Schedule of assessments    


Short title: PEX in severe COVID19   Sponsor code: 132796 
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Protocol Version V1.1        18th June 2020        
 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Day 14 
Day 21 
Day 28 
FBC 
X 
     x 
     X 
x 
x 
x 
x 
x 
x 
     x 
Biochemistry 
      x 
     x 
     X 
x 
x 
x 
x 
x 
x 
      x 
Coagulation 
screen 
including 
fibrinogen 
     x 
      X 
 
x 
 
x 
x 
x 
      x 
Inflammatory 
markers (D 
Dimer, ferritin, 
LDH, CRP) 
      x 
 
     X 
 
        x 
 
x 
x 
x 
     x 
Virology testing 
(Hepatitis A, 
B,C HIV) 
 
       x 
 
 
 
 
 
 
 
 
 
COVID19 
Testing 
       x 
 
 
 
 
 
 
 
 
 


Short title: PEX in severe COVID19   Sponsor code: 132796 
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Protocol Version V1.1        18th June 2020        
Pregnancy test: 
serum bHCG 
      x 
 
 
 
 
 
 
 
 
 
Autoimmune 
screen: ANA, 
ENA 
      x 
 
 
 
 
 
 
 
 
 
Cardiac testing: 
Troponin/BNP 
      x 
 
 
 
x 
 
x 
x 
x 
x
Procoagulant 
samples: Pre 
and post PEX. 
Daily in non PEX 
group/following 
PEX. Including 
cytokine storm 
analysis 
       x 
      x 
      X 
x 
x 
x 
x 
x 
x 
     x 
ECG/Echocardia
gram 
x 
 
 
 
 
 
x 
 
 
      x 
Concomitant 
mediations eg 
antibiotics, 
Noradrenaline 
      x 
      x 
      X 
x 
x 
x 
x 
x 
x 
   x 


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Protocol Version V1.1        18th June 2020        
Change in 
respiratory 
support eg HD 
oxygen/CPAP/I
ntubation 
      x 
      x 
     X 
x 
x 
x 
x 
x 
x 
   x 
haemofiltration      x 
      x 
     X 
x 
x 
x 
x 
x 
x 
     x