Randomised Multi-arm Trial of Ruxolitinib (RUX) and Fostamatinib (FOS) for COVID-19 Pneumonia
Phase: PHASE1
Conditions: Coronavirus, Covid19, Pneumonia
Sponsor: Imperial College London

 
 
 
 
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Multi-arm trial of Inflammatory Signal Inhibitors 
for COVID-19 (MATIS) 
 
 
 
Sponsor:  
 
 
 
Imperial College London 
Funder: 
 
 
 
Imperial Biomedical Research Centre 
 
 
Sponsor Protocol Number: 
20HH5926 
IRAS ID: 
 
 
 
282552 
EudraCT: 
 
 
 
2020-001750-22 
IRAS Project ID: 
 
 
282552                           
REC reference:  
20/HRA/2618 
Protocol Version:  
 
4.0 
Protocol Date 
 
 
2nd November 2022  
Study Product 
 
 
ruxolitinib (RUX); fostamatinib (FOS) 
Key Words:   
 
 
coronavirus, COVID-19, pneumonia, ruxolitinib, fostamatinib 
 
 
 
PROTOCOL AUTHORISED BY 
 
Name:  
Dr Nichola Cooper   
 
Role:  Chief Investigator 
 
 
Signature: ___________________ 
 
Date:  ___________________  
 

 
 
 
 
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ROLES AND RESPONSIBILITIES 
These membership lists are correct at the time of writing; please see terms of reference documentation in the 
Trial Master File (TMF) for current lists. 
 
TRIAL TEAM 
Name 
Affiliation 
Role 
Contact details 
Dr Nichola 
Cooper 
 
Imperial College 
Healthcare NHS Trust, 
Hammersmith Hospital, 
London UK 
Chief 
Investigator 
n.cooper@imperial.ac.uk 
Tel: 07766546432 
Dr Nikhil Vergis 
Imperial College 
Healthcare NHS Trust, St 
Mary’s Hospital (SMH), 
London UK 
Principal 
Investigator 
SMH 
n.vergis@imperial.uk 
Dr Anna Daunt 
Imperial College 
Healthcare NHS Trust, St 
Mary’s Hospital, London 
UK 
Co-Investigator 
a.daunt@nhs.net 
Dr Richard 
Turner 
Imperial College 
Healthcare NHS Trust, 
Charing Cross Hospital 
(CXH), London UK 
Principal 
Investigator 
CXH 
richard.turner17@nhs.net 
Dr Andrew 
Innes 
Imperial College 
Healthcare NHS Trust, 
Hammersmith Hospital, 
London UK 
Co-Investigator 
a.innes@imperial.ac.uk 
Prof Dragana 
Milojkovic 
Imperial College 
Healthcare NHS Trust, 
Hammersmith Hospital, 
London UK 
Co-Investigator 
d.milojkovic@imperial.ac.uk 
Dr Lucy Cook 
Imperial College 
Healthcare NHS Trust, 
Hammersmith Hospital, 
London UK 
Co-Investigator 
l.cook@imperial.ac.uk 
Dr Taryn 
Youngstein 
Imperial College 
Healthcare NHS Trust, 
Hammersmith Hospital, 
London UK 
Co-Investigator 
t.youngstein@imperial.ac.uk 

 
 
 
 
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Prof Mark 
Thursz 
Imperial College London, 
St Mary’s Campus, London 
UK 
Co-Investigator 
m.thursz@imperial.ac.uk 
Prof Graham 
Cooke 
Imperial College London, 
St Mary’s Campus, London 
UK 
Co-Investigator 
g.cooke@imperial.ac.uk 
Prof Onn Min 
Kon 
National Heart & Lung 
Institute, St Mary’s 
Campus, London UK 
Co-Investigator 
onn.kon@imperial.ac.uk 
Prof James 
Wason 
Newcastle University,  
Newcastle upon Tyne UK 
Statistician 
james.wason@ncl.ac.uk 
Dr Asad 
Charania  
Imperial College 
Healthcare NHS Trust, 
Hammersmith Hospital, 
London UK 
Co-Investigator 
asad.charania@nhs.net 
Dr Ashley 
Whittington 
London Northwest 
University Healthcare NHS 
Trust, Northwick Park 
Hospital, London.  
Principle 
Investigator 
a.whittington@nhs.net 
Dr Pratap 
Neelakantan 
Royal Berkshire NHS 
Foundation Trust, Royal 
Berkshire Hospital, 
Reading. 
Principle 
Investigator 
pratap.neelakantan@royalberkshire.nhs.uk 
 
TRIAL MANAGEMENT GROUP 
Name 
Affiliation 
Role 
Contact details 
Dr Nichola 
Cooper 
 
Imperial College Healthcare 
NHS Trust, Hammersmith 
Hospital, London UK 
Chief Investigator 
n.cooper@imperial.ac.uk 
Tel: 07766546432 
Dr Nikhil Vergis 
Imperial College Healthcare 
NHS Trust, St Mary’s Hospital 
(SMH), London UK 
Principal Investigator 
SMH 
n.vergis@imperial.uk 
Dr Victoria 
Cornelius 
Imperial College London, 
White City Campus, London 
UK 
Statistician 
v.cornelius@imperial.ac.uk 
Dr Rachel 
Phillips 
Imperial College London, 
White City Campus, London 
UK 
Statistician 
r.phillips@imperial.ac.uk 

 
 
 
 
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Donna 
Copeland 
Imperial College Healthcare 
NHS Trust, London UK 
Divisional Research 
Manager 
donna.copeland@nhs.net 
Maria Martinez 
Imperial College 
London/Imperial College 
Healthcare NHS Trust, CHART, 
Cancer & Haematology 
Academic Research Team, 
London UK 
Operations Manager 
m.martinez@imperial.ac.uk 
 
TRIAL STEERING COMMITTEE 
Name 
Affiliation 
Role 
Contact details 
Dr Nichola 
Cooper 
 
Imperial College Healthcare 
NHS Trust, Hammersmith 
Hospital, London UK 
Chief Investigator 
n.cooper@imperial.ac.uk 
Tel: 07766546432 
Dr Pratima 
Chowdary 
Royal Free Hospital, London UK 
Chair 
p.chowdary@nhs.net 
Dr Fred Tam 
Imperial College London, 
London UK 
Non-independent 
member 
f.tam@imperial.ac.uk 
Dr Sarah Brown 
Leeds University, Leeds UK 
Independent member, 
Statistician 
medsbro@leeds.ac.uk 
 
DATA MONITORING COMMITTEE 
Name 
Affiliation 
Role 
Contact details 
Dr James 
Galloway 
King’s College, London UK 
Chair 
James.galloway@nhs.net 
Dr Arian 
Laurence 
University College London 
Hospital, London UK 
Independent Member 
arian.laurence@nhs.net 
Sam Norton 
King’s College, London UK 
Independent member, 
Statistician 
sam.norton@kcl.ac.uk 
 
STUDY COORDINATION CENTRE 
For general queries, supply of trial documentation, and collection of data, please contact: 
CHART – Cancer & Haematology Academic Research Team 
Oncology Project Manager: Maria Martinez 
Address: Garry Weston Centre, 3rd floor,  Hammersmith Hospital, Du Cane Road, W12 0HS  

 
 
 
 
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Tel: 020 3313 1362 
Fax: n/a 
Email: m.martinez@imperial.ac.uk  
 
RANDOMISATION 
Sealed Envelope  
 
  
 
Email: contact@sealedenvelope.com  
Web address: https://www.sealedenvelope.com/help/access/access/ 
 
CLINICAL QUERIES 
Clinical queries should be directed to Dr Nichola Cooper or Dr Nikhil Vergis who will direct the query to the 
appropriate person. 
 
 
 
SPONSOR 
Imperial College London is the main research Sponsor for this study.  For further information regarding the 
sponsorship conditions, please contact the Head of Regulatory Compliance at: 
 
Joint Research Compliance Office 
 
Imperial College London and Imperial College Healthcare NHS Trust 
 
Room 215, Level 2, Medical School Building 
 
Norfolk Place 
 
London, W2 1PG 
 
Tel: 0207 594 9480 
 
http://www3.imperial.ac.uk/clinicalresearchgovernanceoffice  
 
This protocol describes the MATIS study and provides information about procedures for entering participants. 
The protocol should not be used as a guide for the treatment of other participants; every care was taken in its 
drafting, but corrections or amendments may be necessary. These will be circulated to investigators in the 
study, but centres entering participants for the first time are advised to contact the trials centre to confirm they 
have the most recent version. Problems relating to this trial should be referred, in the first instance, to the study 
coordination centre. This trial will adhere to the principles outlined in the Medicines for Human Use (Clinical 
Trials) Regulations 2004 (SI 2004/1031), amended regulations (SI 2006/1928) and the International Conference 
on Harmonisation Good Clinical Practice (ICH GCP) guidelines. It will be conducted in compliance with the 
protocol, the Data Protection Act and other regulatory requirements as appropriate. 
 
AMENDMENTS 

 
 
 
 
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The following amendments and/or administrative changes have been made to this protocol since the 
implementation of the first approved version: 
 
Amendment 
Number 
Date of 
Amendment 
Protocol 
Version 
Number 
Type of 
Amendment 
Summary of Amendment 
1 
14.08.2020 
1.8 
Substantial 
Amendment 
The opening site will be Imperial College 
Healthcare NHS Trust in the United Kingdom. 
Additional UK based sites for the trial will 
include Hillingdon, Royal Free Hospital, 
Northwick Park and Chelsea and Westminster 
added according to trial progress. 171  (57 per 
arm) patients with COVID-19 pneumonia will be 
recruited to Stage 1, if the trial progresses to 
Stage 2 an additional maximum of 285 (95 per 
arm) will be recruited, resulting in a potential 
sample size of 456 if three trial arms continue 
for the whole trial ( 152 per arm). These 
numbers have been chosen to provide a power 
of 90% with a maximum 5% chance of an 
intervention arm being recommended when it 
provides no improvement over control (5% one-
sided family-wise error rate). 
 
2 
29.10.2020 
1.9 
Substantial 
Amendment 
Additional UK sites Leeds and Leicester. 
Inclusion criteria: CRP now less than or equal to 
30 mg/L. Exclusion criteria: removed end stage 
renal failure, clarified patients on home 
NIV/CPAP now eligible. Dialysis patients 
randomised to Ruxolitinib (RUX), will receive 
only 20mg on dialysis days Week 1, then 10mg 
on dialysis days Week 2. Pharmacokinetics will 
be assessed at Baseline, before each dialysis and 
Day 28. RUX dose for these patients will be 
assessed after 10 dialysis patients complete Day 
14. Research samples will be processed and 
analysed at Immunology of Infection lab at 
Imperial College London, St Mary’s Campus. 
Added location of research lab. Updated PIS. 
Updated early discharge. Trial Team and 
oversight committees updated. Updated 
unblinding. 
3 
24/02/2021 
2.0 
Non- 
Substantial 
Amendment 
Correcting the name of sites from Northwick 
Park Hospital to London North West University 
Healthcare NHS Trust (Northwick Park Hospital 
and Ealing Hospital) 

 
 
 
 
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2 
31/03/2021 
2.1 
Non-
Substantial 
Amendment 
Addition of UK site: Sheffield Teaching Hospitals 
NHS Foundation Trust  
3 
04/05/20221 
2.2 
Substantial 
Amendment 
Secondary objective added, to determine the 
efficacy of RUX or FOS to reduce the level of 
serum creatinine. Clarification of exclusion 
criteria, requiring CPAP or high flow nasal 
oxygen at any point ‘after hospital admission’ 
and before baseline not due to a pre-existing 
condition (e.g. obstructive sleep apnoea). Under 
Serious Adverse Events, added section 8.3 on 
Severity Grading. Minor document changes: 
date of last amendment added, clarified 
abbreviations for ADL and SAE, updated table of 
contents to reflect addition of 8.3 SAE grading. 
Under Schedule of Events in section 9.2, 
specified labs to be taken at baseline, Days 1, 7, 
14 and 28: Coagulation, Chemistry, Ferritin, 
Troponin, Procalcitonin; added abbreviation for 
full blood count (FBC); changed follow-up visit 
windows from +/-1 day to +/-3 days for Days 7, 
14 and 28; changed to +1 day for Day 1 and 
added -2 days for Day 0. Addition of research 
samples to be taken on day 14 and patient 
information sheet updated to reflect this 
change. Under consent in section 12.3, 
specification of who can take consent to any 
competent health care professional as delegated 
by the CI including doctor, nurse or research 
practitioner.  
 
5 
18/05/2022 
3.0 
Substantial 
Amendment 
Addition of long term follow up sub-study 
assessing the impact of inflammatory signal 
inhibitors on the development of PACS. Removal 
of nasosorption biomarkers at baseline, day 14, 
day 28 and exploratory endpoints. 
6 
26/10/2022 
4.0 
Substantial 
Amendment 
Created a new telephone information and 
consent process for the long term follow up 
substudy 
 
 
 
 
 

 
 
 
 
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ABBREVIATIONS 
ADL 
Activities of Daily Living 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
ARDS 
Adult Respiratory Distress Syndrome 
AST 
Aspartate Aminotransferase 
βhCG 
β human chorionic gonadotropin 
BP 
Blood Pressure 
CCO 
Central Coordinating Office 
CLR 
C-type lectin receptors 
CPAP 
Continuous positive airway pressure 
CRF 
Case Report Form 
CRP 
C-Reactive Protein 
CXR 
Chest X-Ray 
DNA 
Deoxyribonucleic Acid 
FOS 
Fostamatinib 
ECMO 
Extracoporeal membrane oxygenation 
EDTA 
Ethylene Diamine Tetra-acetic Acid 
EoS 
End of Study 
eGFR 
Estimated Glomerula Filtration Rate 
FBC 
Full Blood Count 
FcR 
Fc receptors 
GI 
Gastrointestinal 
Hb 
Haemoglobin 
ICH GCP 
International Conference on Harmonisation of Good Clinical Practice 
ICL 
Imperial College London 
ITT 
Intention to treat 
JAK 
Janus kinase 
LCC 
Local Coordinating Centre 
LDH 
Lactate dehydrogenase 
LFTs 
Liver Function Tests 
LC 
Lymphocyte Count 
MSU 
Mid-Stream Urine 
PACs 
Post-acute COVID-19 syndrome 
PCR 
Polymerase chain reaction 
PI 
Principal Investigator 
PIS-ICF 
Patient Information Sheet-Informed Consent Forms 
PT 
Prothrombin time 
QA 
Quality assurance 
QC 
Quality control 
R&D 
Research and Development 
RNA 
Ribonucleic acid 
RR 
Risk Ratio 
RRT 
Renal Replacement Therapy 

 
 
 
 
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RUX 
Ruxolitinib 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SOC 
Standard of care 
STAT 
Signal transducer and activator of transcription proteins 
TMG 
Trial Management Group 
TSC 
Trial Steering Committee 
USS 
Ultrasound Scan 
VTE 
Venous Thromboembolism 
WCC 
White Cell Count 
WHO 
World Health Organisation 
 
 
 
 

 
 
 
 
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TABLE OF CONTENTS 
1 
Introduction ............................................................................................................................ 17 
1.1 
Background .................................................................................................................................. 17 
1.2 
Purpose of the study .................................................................................................................... 18 
1.3 
Rationale for the study population ............................................................................................... 19 
1.4 
Rationale for the long covid sub-study .......................................................................................... 19 
2 
Study objectives ...................................................................................................................... 20 
2.1 
Primary objective ......................................................................................................................... 20 
2.2 
Secondary Objectives ................................................................................................................... 21 
3 
Study Design ........................................................................................................................... 22 
3.1 
Sample size .................................................................................................................................. 23 
3.2 
Study sites.................................................................................................................................... 23 
3.3 
Study endpoints ........................................................................................................................... 23 
3.4 
long covid follow up sub-study ..................................................................................................... 25 
4 
Statistics and data analysis ...................................................................................................... 26 
4.1 
Data analysis ................................................................................................................................ 26 
4.2 
Statistical analysis plan ................................................................................................................. 27 
4.3 
Data management and retention .................................................................................................. 29 
5 
Participant entry ..................................................................................................................... 29 
5.1 
Patient selection .......................................................................................................................... 29 
5.2 
Inclusion criteria ........................................................................................................................... 30 
5.3 
Exclusion criteria .......................................................................................................................... 30 
6 
Randomisation and enrolment ................................................................................................ 31 
6.1 
Enrolment Procedures for Patients ............................................................................................... 31 
6.2 
Randomisation ............................................................................................................................. 31 
6.3 
Unblinding ................................................................................................................................... 32 
6.4 
Case Report Form and Patient Numbers ........................................................................................ 32 
6.5 
Specimens and Laboratory handling .............................................................................................. 32 
7 
Treatment ............................................................................................................................... 32 
7.1 
Interim analysis to guide dosing regimen ...................................................................................... 33 
7.2 
Future changes to Standard of Care .............................................................................................. 33 

 
 
 
 
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 ........................................................................................................... 33 
7.4 
Administration of Fostamatinib .................................................................................................... 34 
7.5 
Dose modifications for Fostamatinib ............................................................................................. 34 
7.6 
Rationale for Ruxolitinib ............................................................................................................... 36 
7.7 
Dose modifications for Ruxolitinib ................................................................................................ 36 
7.8 
Treatment recommendations for other adverse events ................................................................. 38 
7.9 
Treatment compliance .................................................................................................................. 38 
7.10 
Best supportive therapy ............................................................................................................... 38 
7.11 
Permitted concomitant therapy requiring caution and/or action ................................................... 38 
7.12 
Strong CYP3A4 inhibitors or dual CYP3A4/CYP2C9 inhibitors ......................................................... 38 
7.13 
Prohibited medication .................................................................................................................. 39 
7.14 
Concomitant medication .............................................................................................................. 39 
7.15 
Supply of study treatment ............................................................................................................ 39 
7.16 
Treatment duration ...................................................................................................................... 40 
8 
Pharmacovigilance .................................................................................................................. 40 
8.1 
Definitions ................................................................................................................................... 40 
8.2 
Causality ...................................................................................................................................... 41 
8.3 
SAE GRADING ............................................................................................................................... 42 
8.4 
Reporting procedures ................................................................................................................... 42 
8.5 
COVID-19 considerations .............................................................................................................. 43 
9 
Assessment and Follow-up ....................................................................................................... 46 
9.1 
Collecting follow-up information .................................................................................................. 46 
9.2 
Duration and mode of follow-up ................................................................................................... 46 
9.3 
Follow up schedule – long covid Sub-study .................................................................................... 48 
1 .............................................................................................................................................................. 48 
9.4 Incidental findings ............................................................................................................................. 49 
9.5 
Lost to follow-up .......................................................................................................................... 49 
9.6 
End of trial ................................................................................................................................... 49 
10 
Trial management ............................................................................................................... 49 
10.1 
Trial Management Group .............................................................................................................. 49 
10.2 
Trial Steering Committee (TSC) ..................................................................................................... 49 
10.3 
Data Monitoring Committee ......................................................................................................... 50 

 
 
 
 
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11 
Monitoring .......................................................................................................................... 50 
11.1 
Risks and benefits ........................................................................................................................ 50 
11.2 
Monitoring at study coordination centre ....................................................................................... 51 
11.3 
Monitoring at local sites ............................................................................................................... 51 
11.4 
Data and Safety Monitoring .......................................................................................................... 51 
12 
Ethical considerations and Regulatory Compliance ............................................................... 52 
12.1 
CTA .............................................................................................................................................. 52 
12.2 
Ethics approval ............................................................................................................................. 52 
12.3 
Consent........................................................................................................................................ 52 
12.4 
Withdrawal of Consent ................................................................................................................. 53 
12.5 
Confidentiality ............................................................................................................................. 53 
12.6 
Indemnity .................................................................................................................................... 54 
12.7 
Sponsor ........................................................................................................................................ 54 
12.8 
Funding ........................................................................................................................................ 54 
12.9 
Audits and inspections.................................................................................................................. 54 
13 
Publications and reports ...................................................................................................... 54 
14 
References ........................................................................................................................... 55 
 
TABLE OF FIGURES 
Figure 1. Classification of COVID-19 Disease States and Potential Therapeutic Targets ........................................ 17 
Figure 2. Schematic of study design ........................................................................................................................ 22 
Figure 3. Safety Reporting Overview ....................................................................................................................... 45 
 
TABLE OF TABLES 
Table 1. Modified WHO COVID-19 Severity Scale, from the WHO R&D Blueprint ................................................. 20 
Table 2. Ruxolitinib (RUX) ........................................................................................................................................ 32 
Table 3. Fostamatinib (FOS)..................................................................................................................................... 32 
Table 4. Dose Adjustments for Fostamatinib .......................................................................................................... 34 
Table 5. Management of decline in haematologic parameters .............................................................................. 37 
Table 6. Defining causality ....................................................................................................................................... 41 

 
 
 
 
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Table 7. Schedule of events ..................................................................................................................................... 47 
 

 
 
 
 
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SYNOPSIS 
TITLE 
Randomised multi-arm trial of ruxolitinib (RUX) and fostamatinib (FOS) for 
COVID-19 pneumonia 
AIM 
To evaluate efficacy of RUX and FOS compared to standard of care (SOC) in the 
treatment of COVID-19 pneumonia   
PRIMARY OBJECTIVE 
To determine the efficacy of RUX and FOS compared to standard of care (SOC) 
to reduce the proportion of hospitalised patients progressing from mild or 
moderate to severe COVID-19 pneumonia  
SECONDARY OBJECTIVES 
• 
Determine the efficacy of RUX or FOS to reduce mortality  
• 
Determine the efficacy of RUX or FOS to reduce the need for invasive 
ventilation or ECMO 
• 
Determine the efficacy of RUX or FOS to reduce the need for non-
invasive ventilation  
• 
Determine the efficacy of RUX or FOS to reduce the proportion of 
patients suffering significant oxygen desaturation 
• 
Determine the efficacy of RUX or FOS to reduce the need for renal 
replacement therapy  
• 
Determine the efficacy of RUX and FOS to reduce the incidence of 
venous thromboembolism COVID-19 pneumonia   
• 
Determine the efficacy of RUX and FOS to reduce the severity on 
COVID-19 pneumonia [graded by a modified WHO Ordinal Scale] 
• 
Determine the efficacy of RUX or FOS to reduce the level of 
inflammatory biomarkers  
• 
Determine the efficacy of RUX or FOS to reduce blood ferritin, CRP, 
LDH, and D-dimer 
• 
Determine the efficacy of RUX or FOS to reduce the level of serum 
creatinine  
• 
Determine the efficacy of RUX or FOS to reduce duration of hospital 
admission 
• 
Evaluate the safety of RUX and FOS for COVID-19 pneumonia 
• 
Determine the impact of RUX or FOS on long term (12-24 months) 
survival 
• 
Determine the ability of RUX or FOS to reduce the development of the 
post-acute COVID-19 syndrome in patients who presented with mild-
moderate COVID-19 pneumonia 
• 
Assess impact of signal inhibitors (RUX or FOS) on health related quality 
of life at 6, 12 and 18 months post COVID-19 
DESIGN 
Multi-site, Two stage, open label, randomized (1:1:1) controlled trial  
STUDY DURATION 
Treatment is for 14 day from baseline. Patients will receive follow-up 
assessment at 7, 14 and 28 days after the first study dose. 
Screen Period: up to 7 days 
Treatment Period: 14 days 

 
 
 
 
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Follow-up period: Day 14 to 28 
Follow-up period of sub-study: Up to 24 months  
SAMPLE SIZE 
171 in Stage 1 (57 per arm) and up to an additional 285 in Stage 2 (additional 95 
per included arm), to allow for 5% dropout. Patients with mild or moderate 
COVID-19 pneumonia will be recruited. Patients will be enrolled into RUX, FOS 
or SOC groups, as shown in the flow chart.  
STUDY SITES 
The opening site will be Imperial College Healthcare NHS Trust in the United 
Kingdom. Additional UK based sites for the trial will include Reading, London 
North West University Healthcare NHS Trust (Northwick Park Hospital and 
Ealing Hospital, Leeds and Sheffield Teaching Hospitals NHS Foundation Trust. 
 
INCLUSION CRITERIA 
• 
Patients age ≥ 18 years at screening 
• 
Patients with mild or moderate C19 pneumonia, defined as Grade 3 or 
4 severity by the WHO COVID-19 Ordinal Scale  
• 
Patients meeting criteria: 
o Hospitalization AND 
o  SARS-CoV2 infection (clinically suspected* or laboratory 
confirmed) AND  
o Radiological change consistent with COVID-19 disease 
• 
CRP  30mg/L at any time point 
• 
Informed consent from patient or personal or professional 
representative 
• 
Agreement to abstain from sexual intercourse or use contraception 
that is >99% effective for all participants of childbearing potential for 42 
days after the last dose of study drug. For male participants, agreement 
to abstain from sperm donation for 42 days after the last dose of study 
drug. 
• 
Non-English speakers will be able to join the study. If patients are 
unable to understand verbal or written information in English - hospital 
translation services will be requested at the participating site for the 
participant where possible. 
• 
Patients normally on non-invasive ventilation such as continuous 
positive airway pressure (CPAP) at home are eligible 
EXCLUSION CRITERIA 
• 
Requiring either invasive or non-invasive ventilation including CPAP or 
high flow nasal oxygen at any point after hospital admission and before 
baseline not due to a pre-existing condition (e.g. obstructive sleep 
apnoea) 
• 
Grade  5 severity on the modified WHO COVID-19 Ordinal Scale, viz. 
O2 saturation < 90% on  60% inspired oxygen at baseline; non-invasive 
ventilation; or invasive mechanical ventilation  
• 
In the opinion of the investigator, progression to death is inevitable 
within the next 24 hours, irrespective of the provision of therapy  
• 
Known severe allergic reactions to the investigational agents 

 
 
 
 
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• 
Child Pugh B or C grade hepatic dysfunction 
• 
Use of drugs within the preceding 14 days that are known to interact 
with any study treatment (FOS or RUX), as listed in the Summary of 
Product Characteristics  
• 
Pregnant or breast feeding 
• 
Any medical condition or concomitant medication that in the opinion of 
the investigator would compromise subjects’ safety or compliance with 
study procedures. 
• 
Any medical condition which in the opinion of the principal investigator 
would compromise the scientific integrity of the study 
MAIN STUDY PROCEDURES 
Specific assessments occur at: 
Day 14: death, ventilation status, oxygenation status, renal status  
Day 28: death, ventilation status, oxygenation status, renal status  
PRIMARY ENDPOINTS 
• 
Pairwise comparison of the proportion of patients diagnosed with 
severe COVID-19 pneumonia within 14 days.  
• 
Severe COVID-19 pneumonia is defined by a modified WHO COVID-19 
Ordinal Score  5, comprising the following indicators of disease 
severity: 
o Death OR 
o Requirement for invasive ventilation OR 
o Requirement for non-invasive ventilation including CPAP or 
high flow oxygen OR 
o O2 saturation < 90% on 60% inspired oxygen 
 
SECONDARY ENDPOINTS 
• 
Pairwise comparison of the proportion, median or odds ratio of each of 
the parameters below at 14 and 28 days between RUX or FOS versus 
SOC: 
o Mortality  
o Invasive ventilation or ECMO 
o Non-invasive ventilation including CPAP or high flow nasal 
oxygen 
o Renal replacement therapy 
o Venous thromboembolism 
Length of stay 
o Serious adverse events and discontinuations of study arms 
o Inflammatory markers 
o Change in pneumonia severity on the modified WHO COVID-19 
Ordinal Scale 
 
• 
Mortality at 3, 6, 12 & 18 months. 
• 
Venous thromboembolism rate at 3, 6, 12 and 18 months 
• 
Renal replacement therapy at 3, 6, 12 and 18 months 

 
 
 
 
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• 
Number of re-admissions within 12 months 
• 
Occurrence of lung fibrosis  
• 
Number of re-infections of COVID-19 
• 
Additional co-morbidities developed during long-term follow up period 
 
 
EXPLORATORY ENDPOINTS 
• 
Biomarkers of disease including plasma, PBMC and RNA/DNA changes 
• 
Changes in health related quality of life  
 
Further secondary and exploratory objectives are not the focus of this study but 
maybe adopted using routine healthcare records (e.g. NHS Digital or equivalent 
international databases) and relevant research studies (e.g. UK Biobank or 
equivalent international resources). This will allow subsidiary analyses of the 
effect of the study treatments on particular non-fatal events (e.g. ascertained 
through linkage to Hospital Episode Statistics), the influence of pre-existing 
major co-morbidity (e.g. chronic heart disease and use of immunosuppressive 
drugs) and longer-term outcomes (e.g. 6 month survival) as well as in particular 
sub-categories of patient (e.g. by genotype). 
 
1 INTRODUCTION  
1.1 
BACKGROUND 
COVID-19 pneumonia is characterised by respiratory and multi-organ failure in the context of marked systemic 
inflammation. It is caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARSCoV2) infection. The 
hallmark of severe disease is hypoxia and a radiological pattern of acute lung injury that shares features with 
Acute Respiratory Distress Syndrome (ARDS). Early features of COVID-19 result from host viral response and 
typically include symptoms such as fever and dry cough. Later features, typically occurring beyond 7 days, are 
characterised by marked and progressive systemic inflammation, identified by elevations in a plethora of 
inflammatory molecules such as C-reactive protein, ferritin and IL6. In a subset of patients, hyperinflammatory 
responses drive acute lung injury and may result in catastrophic multi-organ failure and death (Huang et al., 
2020).  
 
Figure 1. Classification of COVID-19 Disease States and Potential Therapeutic Targets 
 

 
 
 
 
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(Siddiqi & Mehra, 2020) 
The aetiology of COVID-19 induced ARDS is incompletely understood but appears to be associated with lung 
inflammation effected by a monocytic and neutrophilic infiltration, elevated cytokine levels and tissue damage 
(Siddiqi & Mehra, 2020). Elevations in circulating inflammatory molecules are associated with poor prognosis. In 
particular, the COVID-19 hyperinflammatory response syndrome is associated thrombotic complications which 
are postulated to drive cardiac dysfunction and microvascular thrombi, suggested by elevations in troponin and 
D-dimer, respectively (Ruan et al., 2020). Similar hyperinflammatory responses are also seen in macrophage 
activation syndromes such as haemophagocytic lymphohistiocytosis, or in the cytokine release syndrome 
associated with chimeric antigen receptor T cell therapy (Singanayagam et al., 2018). Further, preliminary data 
from China and Italy have shown immediate resolution of symptoms using anti-IL6 therapy and JAK/STAT 
inhibitors in patients with severe disease (Richardson et al., 2020; Wu & Yang, 2020). There may be an early 
window of opportunity to treat the COVID-19 hyperinflammatory syndrome before acute lung injury leads to 
organ failure. 
1.2 
 PURPOSE OF THE STUDY 
A number of therapeutic interventions targeting inflammatory signalling might reduce the severity of the 
inflammatory response phase resulting in amelioration of the lung damage thereby averting respiratory failure 

 
 
 
 
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and the need for mechanical ventilation. This trial aims to evaluate the efficacy of two inhibitors of key signalling 
pathways using drugs which are already licensed for use in other clinical indications. 
 
1.3 
RATIONALE FOR THE STUDY POPULATION 
Patients with COVID-19 infection in the community may be asymptomatic or experience only mild transient 
symptoms which do not merit experimental therapeutic intervention. Patients who are admitted to hospital due 
to the severity of their symptoms are invariably in the inflammatory phase of the disease with dyspnoea and/or 
hypoxia indicating involvement of the lower respiratory tract. Data from our own hospital as well as Chinese and 
Italian experiences indicate that around 30% of hospitalised patients will deteriorate during their admission 
resulting in the need for ventilatory support. The study population is therefore selected to evaluate whether the 
experimental treatments are effective in prevention of clinical deterioration in a hospitalised population. 
 
1.4 
RATIONALE FOR THE LONG COVID SUB-STUDY 
With the global impact of the COVID-19 pandemic our understanding of the SARS-COV2 pathogen is continually 
evolving.  COVID-19 is well recognized as a respiratory and multi-organ disease, caused by marked systemic 
inflammation. Despite the advances in the acute management of COVID-19, our understanding of the post-
acute COVID-19 syndrome (PACS) is poorly understood.  
 
Post-acute COVID-19 syndrome is defined as persistent symptoms of COVID-19 which have developed during or 
after infection, that continue for more than 12 weeks and are not explained by an alternative diagnosis. COVID-
19 is well recognised as a multi-organ disease (Gupta et al., 2020), with severe disease being characterised with 
marked and progressive systemic inflammation (Qin et al., 2020). Similarly, the range of symptoms of PACS 
represents the multi-organ impact of the syndrome and include; fatigue, myalgia, autonomic dysfunction, 
gastrointestinal manifestations, anxiety/depression and altered concentration (Nalbandian et al., 2021).  
 
The underlying pathophysiology of PACS is not known, but suggested mechanisms include chronic dysregulation 
of the immune system subsequent to the acute infection. Studies have identified immunological dysfunction in 
patients with ‘long covid’ at 8 months from acute infection with highly activated innate immune cells. This is 
reflected by 4 cytokines which were most associated with symptomatic long covid-19 patients; IL-6, interferon 
gamma, MCP-19 and VCAM-1.  
 

 
 
 
 
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Immune exhaustion has also been suggested as a mechanism for ‘long covid’. Immune exhaustion has been 
observed in other chronic infections as a result persistent inflammatory signal exposure, including chronic 
hepatitis and HIV (Ramakrishnan et al., 2021). This leads to impairment in functionality of CD4 and CD8 T-cells.  
 
Immune exhaustion has also been seen in patients with COVID-19 with increased levels of PD-1 and Tim-3 being 
shown in patients with severe COVID-19 (Diao et al., 2020), (Ueland et al., 2021). Similar results have been seen 
at 8 months in patients with ‘long covid’ with raised levels of sTIM3 and PD-1, as well as raised level of T-cell 
activation proteins, IFN 1 and 3, as well as their downsteam chemokines CXCL9 and CXCL10 (Phetsouphanh et 
al., 2021). 
 
We will therefore explore the impact of RUX or FOS on the long term outcome from COVID-19 infection 
including overall survival and other co-morbidities such as VTE, diabetes, hypertension and long-COVID. 
 
2 STUDY OBJECTIVES 
2.1 
PRIMARY OBJECTIVE 
The primary objective is to determine the efficacy of RUX and FOS to reduce the proportion of hospitalised 
patients progressing from mild/moderate to severe COVID-19 pneumonia. A modified WHO COVID-19 Severity 
Ordinal Scale (COVID-19 Therapeutic Trial Synopsis published 18th February 2020) will be used to grade clinical 
deterioration from Hospitalised Mild Disease (<5) to Hospitalised Severe Disease ( 5). The modification includes 
an additional grade for Hospitalised Severe Disease that allows the capture of clinical deterioration in patients 
for whom escalation in organ support is not offered. Patients are eligible for recruitment to MATIS at grades 3 or 
4. These patients stand to gain the greatest benefit from inflammatory signal inhibitors that may ameliorate the 
cytokine storm and prevent organ failure. 
 
Table 1. Modified WHO COVID-19 Severity Scale, from the WHO R&D Blueprint 
Patient state 
Descriptor 
Grade 
Uninfected 
No clinical or virological evidence of infection 
0 
Ambulatory 
No limitation of activities 
1 

 
 
 
 
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Limitation of activities 
2 
Hospitalised mild disease 
Hospitalised, no oxygen therapy 
3 
Oxygen by mask or nasal prongs 
4 
Hospitalised severe disease 
SpO2< 90% on FiO2  60% by face mask 
5 
Non-invasive ventilation, CPAP or high-flow oxygen 
6 
Intubation and mechanical ventilation 
7 
Ventilation + additional organ support (vasopressors, 
RRT, ECMO) 
8 
Dead 
Death 
9 
Published in the COVID Therapeutic Trial Synopsis, February 18th 2020 
2.2 
SECONDARY OBJECTIVES  
• 
Determine the efficacy of RUX or FOS to reduce mortality  
• 
Determine the efficacy of RUX or FOS to reduce the need for invasive ventilation and/or ECMO  
• 
Determine the efficacy of RUX or FOS to reduce the need for non-invasive ventilation including CPAP or 
high flow nasal oxygen  
• 
Determine the efficacy of RUX or FOS to reduce the proportion of patients suffering clinically significant 
oxygen desaturation 
• 
Determine the efficacy of RUX or FOS to reduce the need for renal replacement therapy  
• 
Determine the efficacy of RUX and FOS to reduce the incidence of venous thromboembolism COVID-19 
pneumonia   
• 
Determine the efficacy of RUX and FOS to improve the severity of COVID19 pneumonia on a modified 
WHO COVID19 Ordinal Scale  
• 
Determine the efficacy of RUX or FOS to reduce the level of inflammatory biomarkers 
• 
Determine the efficacy of RUX or FOS to reduce blood ferritin, CRP, LDH and D-dimer 
• 
Determine the efficacy of RUX or FOS to reduce the level of serum creatinine.  
• 
Determine the efficacy of RUX or FOS to reduce duration of hospital admission  
• 
Evaluate the safety of RUX and FOS for COVID19 pneumonia 
 

 
 
 
 
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• 
Determine the impact of RUX or FOS to reduce the development of the post-acute COVID-19 syndrome 
in patients who presented with mild-moderate COVID-19 pneumonia 
• 
Determine the impact of RUX or FOS on long term (12-18 months) survival 
• 
Determine the ability of RUX or FOS to reduce the development of the post-acute COVID-19 syndrome 
in patients who presented with mild-moderate COVID-19 pneumonia 
• 
Assess impact of signal inhibitors (RUX or FOS) on health related quality of life at 6 and 12, 18 months 
post COVID-19 
 
3 STUDY DESIGN 
This is a multi-site, two stage, open label, randomized (1:1:1) controlled trial. 
Figure 2. Schematic of study design 
 
Treatment is for 14 days from baseline. Patients will receive follow-up assessment at 7, 14 and 28 days after the 
first dose.  
The time allowed for screening assessments allows time for eligibility assessments to be included. 
- 
Screening Period: up to 7 days to the day randomisation  
- 
Treatment Period: 14 days 
Randomise
57 patients
57 patients
57 patients
171 patients
Hospitalised with 
mild/moderate 
C19 pneumonia
Stage 1 
Primary 
endpoint: 
% severe 
pneumonia
RR 0.6
alpha 0.25 
(one-sided)
Power 92%
Stage 2 
Primary 
endpoint: 
% severe 
pneumonia
RR 0.6
alpha 0.027 
(one-sided)
Power 90%
95 patients
95 patients
Overall MATIS power 90% with family-wise error rate 0.05 (one-sided) for RR 0.6
Stage 1
Stage 2
95 patients
Ruxolitinib (RUX)
Standard of care 
(SOC)
Fostamatinib (FOS)
RUX or STOP
SOC
FOS or STOP

 
 
 
 
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- 
Follow-up period: Day 14 to 28 
Patients who have recovered and are fit for discharged from hospital during the treatment period, will be 
discharged home with trial medication to complete a fixed 14 day course. Such patients will be followed up 
weekly with telephone monitoring until day 28 and additional blood test monitoring where practically possible. 
3.1 
SAMPLE SIZE 
171  (57 per arm) patients with COVID-19 pneumonia will be recruited to Stage 1, if the trial progresses to Stage 
2 an additional maximum of 285 (95 per arm) will be recruited, resulting in a potential sample size of 456 if 
three trial arms continue for the whole trial (152 per arm). These numbers have been chosen to provide a power 
of 90% with a maximum 5% chance of an intervention arm being recommended when it provides no 
improvement over control (5% one-sided family-wise error rate). 
Patients will be enrolled into RUX, FOS or SOC groups, as shown in the flow chart.  
3.2 
STUDY SITES 
The trial will commence at one site, Imperial College Healthcare NHS Trust in the UK, with further UK based sites 
that will include Reading, Hillingdon, London North West University Healthcare NHS Trust (Northwick Park 
Hospital and Ealing Hospital), Leeds and Sheffield Teaching Hospitals NHS Foundation Trust. 
3.3 
STUDY ENDPOINTS 
Primary endpoints 
The primary endpoint is progression from mild to severe COVID-19 pneumonia within 14 days in hospitalised 
patients. Patients are recruited at a WHO COVID-19 Severity Score of 3 and 4 and the primary endpoint is the 
comparison of patients whose COVID-19 pneumonia progresses to a severity score  5 on the modified WHO 
Ordinal Scale. Specifically, the primary endpoint is met when the following are recorded within 14 days: 
• 
Death 
• 
Requirement for invasive ventilation 
• 
Requirement for non-invasive ventilation including CPAP and high flow nasal oxygen 
• 
O2 saturation < 90% on 60% inspired oxygen 
 
Secondary endpoints 
Comparison of the incidence, time-to-event, median or odds ratio of each of the parameters below at 14 and 28 
days between RUX or FOS versus SOC: 

 
 
 
 
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• 
Mortality  
• 
Invasive ventilation 
• 
Non-invasive ventilation including CPAP and high flow nasal oxygen 
• 
Renal replacement therapy 
• 
Venous thromboembolism 
• 
Inflammatory markers CRP, LDH, ferritin, D-dimer 
• 
Serum creatinine 
• 
Length of stay 
• 
SSARs and discontinuations of study arms 
• 
Change in severity on the modified WHO COVID-19 Ordinal Scale 
 
Comparison of the incidence, time-to-event, median or odds ratio of each of the parameters below: 
• 
Mortality at 3, 6, 12 & long term outcome 
• 
Venous thromboembolism rate at 6, 12 and 18 months 
• 
Renal replacement therapy at 6, 12 and 18 months 
• 
Occurrence of new hypertension diagnosis  
• 
Occurrence of new diabetes diagnosis  
• 
Number of re-admissions within 12 months 
• 
Causes of re-admissions in the last 12 months 
• 
Occurrence of lung fibrosis  
• 
Co-morbidities developed within 18 months post-discharge from hospital 
 
Further secondary and exploratory objectives are not the focus of this study but maybe adopted using routine 
healthcare records (e.g. NHS Digital) and relevant research studies (e.g. UK Biobank and Genomics England). This 
will allow subsidiary analyses of the effect of the study treatments on particular non-fatal events (e.g. 
ascertained through linkage to Hospital Episode Statistics), the influence of pre-existing major co-morbidity (e.g. 
chronic heart, lung, kidney, liver disease, diabetes and use of immunosuppressive drugs) and longer-term 
outcomes (e.g. 6 month survival) as well as in particular sub-categories of patient (e.g. by genotype).  
 
Exploratory endpoints 

 
 
 
 
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Blood samples will be taken as per protocol schedule to evaluate changes in immune cells and platelets over 
time to look for biomarkers to predict response. This will include fresh blood analysis, and collecting DNA, 
plasma, serum and PBMCs for freezing and future analysis. Samples will be stored under Imperial College Tissue 
Bank. 
 
3.4 
LONG COVID FOLLOW UP SUB-STUDY 
The LONG COVID sub-study is a prospective cohort study. The aim of the study is to assess the long term effects 
of COVID-19 infection in patients who were mild-moderately affected and hospitalised due to a COVID-19 
infection and to assess the impact of signal inhibitors on the development of PACS. Patients with PACS are 
defined as those who have had the following symptoms >12 weeks post COVID-19 infection with no alternative 
diagnosis: 
- 
Persistent fatigue 
- 
Shortness of breath 
- 
Decline in Quality of Life 
- 
Persistent cough 
- 
Cognitive disturbance (brain fog) 
- 
Thromboembolism (spontaneous)  
- 
Chronic kidney disease (post covid-19) 
 
 
Participants approached and randomised for the study will also be approached to participate in the sub-study. 
All participants enrolled into the main study will be eligible for the PACs sub-study. This study is covered in a 
separate patient information sheet and informed consent form.  
 
Data will be collected up to 18 months post-consent of the main study will be collection  from participants, and, 
where appropriate, legal representatives who have provided informed consent (where relevant). Participant’s 
general practitioners and local health authorities may also be contacted in order to obtain further data 
regarding the participant’s health during the 18 month follow up period. Data will include clinical and treatment 
data regarding the long term effect of COVID-19 on participants’ health; and other data of relevance to their 
health will be collected from participants via phone and electronic medical records.  

 
 
 
 
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Participants will be asked to either consent via telephone with their local PI or person delegated within the 
study team or in person on site. 
For telephone consenting, the PIS will be sent to already recruited participants in the main study 
before following up with a call explaining the substudy and asking for consent.  We will request 
confirmation of who they are (full name and date of birth), explain that the call is regarding MATIS 
study and ask that they clarify this in order to ensure correct person identification whilst not revealing 
any personal information. 
When all confirmed the study will be explained according to the PIS previously sent to them. 
Telephone consent will be obtained in which on the consent form it is clearly stated that a 
conversation is had with the patient and the researcher initials the boxes that the patient has verbally 
declared participation. 
 
 
4 STATISTICS AND DATA ANALYSIS  
4.1 
DATA ANALYSIS 
The aim of the trial (stage 1 and 2) is to test whether RUX and FOS (separately) provide significant improvement 
in primary outcome compared to SOC. To do this we will test the two null hypotheses and provide estimated 
treatment effect (ORs) with 95% confidence intervals (CIs). 
 
Interim analysis (Stage 1) 
The aim of the Stage 1 interim analysis is to provide an opportunity to stop enrolling patients to an intervention 
arm that is not showing sufficient promise of efficacy. The Stage 1 review will be undertaken by a statistician 
that is independent of ICTU and overseen by the data monitoring committee who will advise on whether the 
trial should continue with both intervention arms, with one intervention arm, or stop at this stage. This decision 
will be based on a suggested one-sided p<0.25 although interpretation of the p-value will be on the continuous 
scale as strength against the null hypotheses and will not be restricted to a single binary threshold. Our sample 
size calculations for both stages ensure we have a good prospect of these achieving these aims. 

 
 
 
 
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Current rate of severe pneumonia in the standard of care is 50%. In the case that an experimental arm reduces 
this to 30% (relative risk, RR, 0.6), then the design provides a 92% chance (one sided alpha 0.25) of it being 
recommended to continue to stage 2.  
  
 
Full trial (Stage 2) 
If the trial is recommended to continue at Stage 2 based on DMC interim review the full trial will need to recruit 
an additional 95 for each arm that continues (152 per arm in total; 456 to the complete trial). This will provide 
90% power to detect a change of RR of 0.6 (50% to 30%), with one-sided alpha of 0.027 (5% FWER) and has been 
inflated for 5% for missing outcome data.  Here the power is the chance of an effective treatment passing stage 
1 and being recommended after stage 2. The design recommends stopping an intervention arm at stage 1 if the 
one-sided p-value is >0.25. The above power assumes this rule is always followed and the FWER assumes it is 
not followed (hence the actual FWER will be lower if the rule is always followed). 
 
4.2 
STATISTICAL ANALYSIS PLAN 
Analysis will be on an intention to treat (ITT) population including all randomized patients, multiple imputation 
will be used to include participants who have missing outcome data. Comparisons for efficacy will be made 
between all participants randomised to the different treatment arms, irrespective of whether they received 
their allocated treatment (“ITT” analyses). Comparisons for safety will be made between all participants 
randomised to the different treatment arms who have received at least one dose of study medication. Multiple 
imputation makes a missing at random assumption and a sensitivity analysis around the assumptions made will 
be performed using controlled multiple imputation that permits exploration of a not missing at random 
assumption. A complete case analysis will also be performed. The primary outcome will be analysed as binary 
with participants categorised WHO COVID-19 Ordinal Score <5/  5 by 14 days.  
 
For Stage 1 analysis (after a target recruitment of 171 participants) we will calculate the Wald test statistics from 
separate logistic regression models for RUX vs SOC and FOS vs SOC, adjusted for stratification variables, with 
95% confidence intervals and p-values. P-values will be one-sided and judged at the 0.25 level.  
 
If at least one intervention arm shows promise, then stage 2 will recruit a further 95 per arm (the maximum 
combined sample size of stages 1 and 2 is 456 patients). The stage 2 analysis will use a one-sided p-value 

 
 
 
 
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threshold of 0.027. This has been chosen to control the maximum chance of recommending an ineffective 
treatment at 0.05.  
 
Contamination is a potential threat in many C19 trials, as standard of care is continuously evolving, and co-
enrolment to ongoing trials present a real challenge if unequal enrolment occurs across arms. For participants 
who were co-enrolled to a trial at the same time, or prior to the randomisation to this trial, we will adjust the 
final analysis though covariate adjustment. For participants who were subsequently co-enrolled after 
randomisation, we treat this as a post-randomisation variable and undertake a supplementary analysis to adjust 
for this variable along with the receipt of post-randomisation rescue medication. 
 
In Stage 2 a logistic regression model will be used to assess the treatment effect of RUX and FOS compared to 
SOC. The model will include the treatment arms, baseline modified WHO Severity Score, trial co-enrolment at 
baseline, and randomisation stratification variables viz. site and age (<65 vs ≥65). As well as reporting OR and 
95% CIs, the model will be used to estimate the difference in proportion of participants with modified WHO 
COVID-19 Ordinal Score 5. The treatment effect in the absence of post-randomisation co-enrolment and 
receipt of rescue medication will be estimated in a supplementary analysis where participants’ outcomes after 
either will be treated as missing and a controlled multiple imputation using a delta based approach will be used.  
 
 For the primary outcome, progression to severe COVID-19 disease within 14 days, discharge alive from the 
admitting hospital before 14 days will assume safety from the event (in the absence of additional data 
confirming otherwise). An additional sensitivity analysis will be performed if there is a change of dose after 
review of the first thirty patients. 
 
For time-to-event analyses required for secondary endpoints such as time to discharge, each treatment group 
will be compared with SOC and modelled using a proportional hazards time-to-event model adjusted for 
randomisation stratification variables. Kaplan-Meier estimates for the time to event will also be plotted (with 
confidence intervals). The log-rank ‘observed minus expected’ statistic (and its variance) will be used to estimate 
the average event rate ratio (and its confidence interval) for those allocated to each treatment group versus the 
no additional treatment group.  
 
Pre-specified subgroup analysis will be conducted for the primary outcome using the statistical test for 
interaction (or test for trend where appropriate) for the following: disease severity as graded by the WHO 

 
 
 
 
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COVID-19 Ordinal Severity Scale; time since onset of symptoms; sex; age; and comorbidities obesity, chronic 
heart, lung, kidney and liver disease,  diabetes, immunocompromised  and smoking status. Pre-specified 
subgroup analyses will also be conducted for the primary outcome using the statistical test for interaction (or 
test for trend where appropriate) for patients with admission CRP >200mg/L and/or D-dimer 2500ng/mL. 
 
Further details will be fully described in the Statistical Analysis Plan (SAP). 
4.3 
DATA MANAGEMENT AND RETENTION 
Clinical research teams will use the bespoke study web-based applications for study management and to record 
participant data (including case report forms) in accordance with the protocol. Data will be held in central 
databases located at the CCO or on secure cloud servers. In some circumstances (e.g. where there is difficulty 
accessing the internet or necessary IT equipment), paper case report forms may be required with subsequent 
data entry by either LCC or CCO staff. Although data entry should be mindful of the desire to maintain integrity 
and audit trails, in the circumstances of this epidemic, the priority is on the timely entry of data that is sufficient 
to support reliable analysis and interpretation about treatment effects. CCO staff will be responsible for 
provision of the relevant web-based applications and for generation of data extracts for analyses.  
All data access will be controlled by unique usernames and passwords, and any changes to data will require the 
user to enter their username and password as an electronic signature in accordance with regulatory 
requirements. Staff will have access restricted to the functionality and data that are appropriate for their role in 
the study. 
 
Data retention 
Data and all appropriate documentation will be securely archived for a minimum of 10 years after the 
completion of the study, including the follow-up period in accordance with College policy 
 
5 PARTICIPANT ENTRY  
5.1 
PATIENT SELECTION  
In hospital, potential participants will be identified through hospital workers upon presentation at recruiting 
sites and through public health agencies 

 
 
 
 
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5.2 
INCLUSION CRITERIA 
• 
Patients age ≥ 18 years at screening 
• 
Patients meeting criteria of: 
o Hospitalization AND 
o  SARS-CoV2 infection (clinically suspected* or laboratory confirmed) AND 
o Radiological change consistent with COVID-19 disease 
• 
Mild or moderate (Grade 3 or 4 severity by modified WHO COVID-19 Ordinal Scale) C19 pneumonia 
• 
CRP  30mg/L at any time point 
• 
Informed consent from patient or personal or professional representative 
• 
No medical history that might, in the opinion of the responsible clinician, put the patient at significant risk 
if he/she were to participate in the trial 
• 
Agreement to abstain from sexual intercourse or use contraception that is >99% effective for all 
participants of childbearing potential for 42 days† 
• 
For male participants, agreement to abstain from sperm donation for 42 days after the last dose of study 
drug ‡ 
• 
Non-English speakers will be able to join the study. If patients are unable to understand verbal or written 
information in English - hospital translation services will be requested at the participating site for the 
participant where possible 
• 
Patients normally on non-invasive ventilation such as continuous positive airway pressure (CPAP) at home 
are eligible 
 
5.3 
EXCLUSION CRITERIA 
• 
Requiring either invasive or non-invasive ventilation including CPAP or high flow nasal oxygen at any point 
 
* Clinical suspicion of COVID-19 pneumonia will be confirmed by two independent clinicians.  
† Females must be either post-menopausal for at least 1 year or surgically sterile; or if female of child-bearing potential, 
must not be pregnant or lactating and must agree to use an acceptable method of birth control throughout the duration of 
the trial and for 30 days following the last dose. Acceptable methods of birth control are defined as: hormonal 
contraception (pill, injection or implant) used consistently for at least 30 days prior to enrolment, intrauterine device (IUD), 
double-barrier (ie, condom and spermicide, or condom and diaphragm), or true abstinence (when this is in line with the 
preferred and usual lifestyle of the subject).  
‡ Male subject with a partner of childbearing potential must agree to use an appropriate double-barrier method of 
contraception during the time interval between administration of the first dose of study drug and 30 days following the last 
dose, or must agree to true abstinence (when this is in line with the preferred and usual lifestyle of the subject). 

 
 
 
 
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after hospital admission and before baseline not related to a pre-existing condition (e.g. obstructive sleep 
apnoea) 
• 
Grade  5 severity on the WHO COVID-19 Ordinal Scale 
• 
O2 saturation < 90% on  60% inspired oxygen at baseline 
• 
In the opinion of the investigator, progression to death is inevitable within the next 24 hours, irrespective 
of the provision of therapy  
• 
Any medical condition or concomitant medication that in the opinion of the investigator would 
compromise subjects’ safety or compliance with study procedures. 
• 
Any medical condition which in the opinion of the principal investigator would compromise the scientific 
integrity of the study 
• 
Known severe allergic reactions to the investigational agents 
• 
Use of drugs within the preceding 14 days that are known to interact with any study treatment (FOS or 
RUX), as listed in the Summary of Product Characteristics 
• 
Child Pugh B or C grade hepatic dysfunction 
• 
Pregnant or breast feeding 
 
6 RANDOMISATION AND ENROLMENT 
6.1 
ENROLMENT PROCEDURES FOR PATIENTS 
Eligible patients who have given informed consent to participate will be enrolled to the study. With due 
consideration to the circumstances of possible admission to a high-level isolation unit a full study information 
sheet will be given subsequent to the consent discussion. All patients will have clinical information collected 
either directly through examination including a review of medical, contact and travel history, or from available 
medical notes. Information will be recorded in the case report form. 
6.2 
RANDOMISATION 
Patients will be randomized to one of three actively recruiting trial arms, RUX, FOS or SOC.  Eligible patients will 
be allocated using a central web-based randomisation service that uses randomisation sequences with random 
block sizes that are stratified by age (<65 vs ≥65) and site. If stage 2 occurs with one intervention arm stopped 
then the randomisation ratio will be 1:1. 

 
 
 
 
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6.3 
UNBLINDING  
Analysis will be undertaken primarily by the trial statistician who will be blinded to treatment assignment. Any 
analysis of primary efficacy outcomes or data with the potential to unblind the trial statistician (e.g. adherence 
to allocated intervention) will be undertaken by an independent statistician from Newcastle University. An 
independent statistician based in Imperial Clinical Trials Unit will hold the information to unblind the data for 
closed DMC discussions. 
 
6.4 
CASE REPORT FORM AND PATIENT NUMBERS 
Case Report Forms (CRFs) will be used to collect data at enrolment to this study. Patient numbers will be 
assigned a 2-digit site code and a 3-digit patient number sequentially beginning with 001.  
6.5 
SPECIMENS AND LABORATORY HANDLING 
All samples will be analysed at Imperial College Healthcare NHS Trust laboratories (operating as North West 
London Pathology). Research samples will be processed and analysed at the Immunology of Infection lab at 
Imperial College London, St Mary’s Campus.  
 
7 TREATMENT 
It is accepted that SOC may change during a rapidly evolving pandemic. Co-enrolment to other trials and rescue 
therapy, either pre- or post-randomisation, is permitted and will be accounted for in the statistical analysis. 
 
Table 2. Ruxolitinib (RUX) 
Period 
Dose 
Frequency 
Day 1-7 
10mg 
Twice daily 
Day 8-14 
5mg 
Twice daily 
 
Table 3. Fostamatinib (FOS) 
Period 
Dose 
Frequency 
Day 1-7 
150mg 
Twice daily 

 
 
 
 
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Day 8-14 
100mg 
Twice daily 
7.1 
INTERIM ANALYSIS TO GUIDE DOSING REGIMEN 
There is no prior evidence with which to base particular dosing regimens for RUX or FOS for the treatment of 
COVID-19 pneumonia. After the first 10 patients have been recruited in each arm, an interim analysis will 
therefore be conducted to test whether a mean 25% decrease in CRP (an inflammatory biomarker) has been 
achieved in each of the treatment arms compared to SOC at day 14. This analysis will inform a recommendation 
by the DMC to consider dose escalation for subsequent patients. In the event of that the dosing regimen is 
changed for subsequent patients, all patients will be included in the final analysis of the primary outcome, but a 
sensitivity analysis will be performed that excludes patients treated with the prior dosing.  
7.2 
FUTURE CHANGES TO STANDARD OF CARE 
The study team will remain cognisant of the prevailing global literature during the current pandemic on effective 
therapies for COVID-19 pneumonia. If a treatment emerges with efficacy and safety profile that is superior to 
SOC then options for adoption of the new therapy as SOC will be discussed with the DMC. Specifically, the 
impact that the new SOC might have on original trial statistical parameters and outcomes measures will be 
considered. 
 
 

 
 
 
 
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7.4 
ADMINISTRATION OF FOSTAMATINIB 
Administration 
For subjects who become unable to receive fostamatinib treatment orally (e.g, intubated subjects), tablets can 
be crushed until granular with an approximate particle size <2 mm (based on the diameter of an NG tube), 
added to approximately 10 mL of water (or suitable volume for administration through a feeding tube), and 
stirred to mix before administration through an enteral feeding tube.  The tablet is not expected to be fully 
dissolved prior to administration. 
  
Caveats 
The safety and efficacy of fostamatinib was evaluated using intact tablets only, so we do not have specific safety 
or efficacy data to support crushing tablets and administering through an NG tube.  However, we have internal 
data on file that supports the stability of the crushed tablet for approximately 24 hours in a slightly basic pH (e.g. 
sterile water). 
  
Crushing tablets 
Based on findings from animal studies and the mechanism of action, fostamatinib can cause fetal harm when 
administered to a pregnant woman.  Therefore, it is recommended that appropriate precautions should be 
followed during preparation of the crushed tablets: the tablets should be crushed and solubilized in water 
within a hood, and the individual preparing the crushed tablet wear gloves and a particle mask. 
  
7.5 
DOSE MODIFICATIONS FOR FOSTAMATINIB 
Table 4. Dose Adjustments for Fostamatinib 
Hypertension 
Recommended Action 
 
Stage 1: systolic between 
130-139 or diastolic 
between 80-89 mmHg 
- 
Monitor, or initiate or increase dosage of antihypertensive 
medication for subjects with increased cardiovascular risk and 
adjust as needed until BP is controlled, in accordance with local 
standards. 
Stage 2: systolic at 
least 140 or diastolic 
at least 90 mmHg 
- 
Initiate or increase dosage of antihypertensive medication and 
adjust as needed until BP is controlled. 

 
 
 
 
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Hypertensive crisis: systolic 
over 180 and/or diastolic 
over 120 mmHg 
- 
Interrupt or discontinue study drug. 
- 
Initiate or increase dosage of antihypertensive medication and 
adjust as needed until BP is controlled. If BP returns to less than 
the target BP, resume study drug at same daily dose. 
 
Toxicity 
Recommended Action 
 
AST/ALT is 5 x ULN or 
higher and total BL is less 
than 2 x ULN 
- 
Interrupt study drug. 
- 
Recheck LFTs every 72 hours: 
- 
If AST and ALT decrease, recheck until ALT and AST are no 
longer elevated (below 1.5xULN) and total BL remains less than 
2xULN; resume study drug at next lower daily dose. 
- 
If AST/ALT persist at 5xULN or higher for 2 weeks or more, 
discontinue study drug. 
AST/ALT is 3 x ULN or 
higher and less than 5 x 
ULN 
If patient is symptomatic (e.g., nausea, vomiting, abdominal pain): 
- 
Interrupt study drug. 
- 
Recheck LFTs every 72 hours until ALT/AST values are no longer 
elevated (below 1.5 x ULN) and total BL remains less than 2 x 
ULN. 
- 
Resume study drug at next lower daily dose. 
 
  If patient is asymptomatic: 
- 
Recheck LFTs every 72 hours until ALT/AST <1.5 x ULN) and 
total BL remains less than 2xULN. 
- 
Consider interruption or dose reduction of study drug if 
ALT/AST and TBL remain in this category (AST/ALT is   3 to 5 x 
ULN; and total BL remains less than 2 x ULN). 
- 
If interrupted, resume study drug at next lower daily dose when 
ALT/AST are no longer elevated (<1.5xULN) and total BL 
remains <2 x ULN. 
- 
If AST/ALT persist at 5 x ULN or higher for 2 weeks or more, 
discontinue study drug. 
AST/ALT is 3 x ULN or 
higher and total BL >2 
x ULN 
- 
Check direct and indirect BL levels. If direct BL is >2x ULN then 
discontinue study drug, if only indirect BL is >2x ULN then 
monitor as above. 
Elevated unconjugated 
(indirect) BL in absence of 
other LFT abnormalities 
 
- 
Continue study drug with frequent monitoring since isolated 
increase in unconjugated (indirect) BL may be due to UGT1A1 
inhibition or the underlying disease. 
Diarrhoea 
- 
Manage diarrhoea using supportive measures (e.g., dietary 
changes, hydration and/or antidiarrheal medication) early 
after the onset until symptom(s) have resolved. 
- 
If symptom(s) become severe (Grade 3 or above), temporarily 
interrupt study drug. 

 
 
 
 
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- 
If diarrhoea improves to mild (Grade 1), resume study drug at 
the next lower daily dose. 
  Neutropenia 
- 
If absolute neutrophil count decreases (ANC <1.0 x 109/L) (or is 
low at baseline) give G-CSF support to ensure NP> 1.0 x 109/L  
 
7.6 
RATIONALE FOR RUXOLITINIB 
JAK and STAT molecules are proteins that transduce extracellular stimulation into intracellular signalling, leading 
to expression of a host of inflammatory cytokines in a variety of immune cells (Elli et al., 2019). Ruxolitinib is a 
JAK1/JAK2 inhibitor approved for clinical use in the treatment of splenomegaly, myelofibrosis, polycythaemia 
vera and graft-versus-host disease. It is an oral agent with a rapid mode of action. Inhibition of STAT3 activation 
occurs within 2 hours of RUX administration and downregulates IL-6 and IL-23 signalling important for the pro-
inflammatory effects of Th17 cells. Further, RUX administration leads to in reductions in serum levels TNFa and 
CRP. In addition, JAK2 inhibitors have been shown to block receptor-mediated endocytosis, thereby preventing 
viral cellular entry and assembly (Jagasia et al., 2020). 
 
7.7 
DOSE MODIFICATIONS FOR RUXOLITINIB 
End stage renal failure patients 
Patients with glomerular filtration rate (GFR) <15 ml/min (dialysis and non-dialysis patients) will receive 20mg 
three times a week the first week and for the second week 10 mg three times a week (taken at the end of dialysis 
if on dialysis). 
Patients with GFR ≥15 ml/min to < 30 ml/min, 5 mg twice a day for 1 week, then 5 mg once a day for 1 week. 
 For dialysis patients, pharmacokinetic (PK) levels will be assessed before each dialysis and at Day 14 and Day 28. 
Ruxolitinib dose for these patients will be assessed after 10 dialysis patients complete these doses to Day 14. 
 
Dose reductions  
Dose reductions or interruptions for non-haematological toxicity attributed to ruxolitinib are permitted in order 
to allow the patient to continue on the study. For haematological toxicity, the counts should be supported with 
blood product support ensuring that the platelet count remains > 50 x 109/L. The dose of ruxolitinib may be 
reduced in response to certain toxicities as detailed below. Doses of supportive medications should be adjusted 

 
 
 
 
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according to standard practice. If absolute neutrophil count decreases (ANC <1.0 x 109/L) (or is low at baseline) 
give G-CSF support to ensure NP> 1.0 x 109/L 
 
Table 5. Management of decline in haematologic parameters 
 Parameter(s) at Time of Decline 
 Action 
PLT < 50 x 109/L 
Transfuse platelets to ensure >50 x 109/L 
ANC < 1.0 x 109/L 
Support with G-CSF to ensure NP> 1.0 x 109/L 
 
In response to a decline in renal function (eGFR < 30ml/min) OR hepatic function (AST/ALT > 1.5 x ULN), the 
dose should be reduced by 50%, to be administered twice daily and patients should be carefully monitored. The 
dose can be re-escalated if eGFR subsequently increases above 30ml/min OR AST/ALT decreases to < 1.5 x ULN 
as applicable. 
 
Potential for Ruxolitinib-induced liver injury  
Participants with transaminase increase combined with total bilirubin increase may be indicative of potentially 
severe ruxolitinib-induced liver injury and should be considered as clinically important events and assessed 
appropriately to establish the diagnosis. The required clinical information, as detailed below, should be sought 
to obtain the medical diagnosis of the most likely cause of the observed laboratory abnormalities.  
The threshold for potential ruxolitinib-induced liver injury may depend on the participant’s baseline AST/ALT 
and total bilirubin value; participants meeting any of the following will require further follow-up:  
• 
For participants with normal ALT and AST and total bilirubin value at baseline: AST or ALT > 3.0 x ULN 
combined with total bilirubin > 2.0 x ULN 
• 
For participants with elevated AST or ALT or total bilirubin value at baseline: (AST or ALT > 2 x baseline 
or AST or ALT >300 U/L) whichever occurs first combined with (total bilirubin > 2 x baseline AND > 2.0 x 
ULN) 
Other causes of abnormal liver tests should also be considered, and their role clarified before ruxolitinib is 
assumed as the cause of liver injury. A detailed history, including relevant information such as review of ethanol 
consumption, concomitant medications, herbal remedies, supplement consumption, history of any pre-existing 
liver conditions or risk factors, should be collected. Laboratory tests to be done include ALT, AST, total bilirubin, 
direct and indirect bilirubin, GGT, LDH, prothrombin time (PT)/INR, alkaline phosphatase, albumin, and creatine 
kinase. 

 
 
 
 
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7.8 
TREATMENT RECOMMENDATIONS FOR OTHER ADVERSE EVENTS 
Grade 1 or 2: maintain dose level  
Grade 3: Reduce dose level 50% until resolved to ≤ Grade 2  
Grade 4: Hold dose and then discontinue from study  
7.9 
TREATMENT COMPLIANCE 
The local trial pharmacist will be responsible for maintaining and updating the drug accountability log in the 
study pharmacy file, which will be used to monitor compliance. All unfinished packs will be returned to the trial 
pharmacist who will count and document any unused medication. All IMP can then be destroyed in accordance 
with local pharmacy practice and this will be documented on the drug destruction log in the hospital pharmacy 
file.  
7.10 BEST SUPPORTIVE THERAPY 
All patients will receive best supportive therapy for COVID-19 as per physician’s discretion.  
7.11 PERMITTED CONCOMITANT THERAPY REQUIRING CAUTION AND/OR ACTION  
Patients may receive anti-emetics, calcineurin inhibitors, azole fungal prophylaxis or broad-spectrum antibiotics 
(either semi-synthetic penicillin or third generation cephalosporin with vancomycin, gentamycin or equivalent). 
Use of sedatives should be closely monitored for potential drug-drug interaction effects. Use of oral, injected or 
implanted hormonal methods of contraception are allowed while on ruxolitinib. Ruxolitinib dose adjustments 
may be required, particularly in patients treated with CYP450 modulators.  
7.12 STRONG CYP3A4 INHIBITORS OR DUAL CYP3A4/CYP2C9 INHIBITORS 
Upon initiation of a strong CYP3A4 inhibitor, including clarithromycin or a dual CYP3A4/CYP2C9 inhibitor 
including fluconazole up to a dose of 200 mg, suggest change antibiotic to azithromycin or doxycycline. If patient 
must remain on a strong CYP3A4 inhibitor or dual CYP3A4/CYP2C9 inhibitor, then the dose of ruxolitinib should 
be reduced (e.g. by 50%) with daily monitoring of haematology parameters and clinical signs and symptoms of 
ruxolitinib related adverse events. In the event of suspected study drug related toxicity or overdose; 
administration of ruxolitinib should be dose reduced or held according to the treating physician’s judgement. 
Ideally an alternative therapy should be sourced rather than reduce the dose of ruxolitinib. For additional 
information, please refer to the ruxolitinib summary of product characteristics (SmPC). 

 
 
 
 
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7.13 PROHIBITED MEDICATION 
The following medications are prohibited until treatment discontinuation: 
- 
Concomitant use of another JAK inhibitor 
For additional information, please refer to the ruxolitinib SmPC.  
7.14 CONCOMITANT MEDICATION 
The metabolism of ruxolitinib is affected by CYP3A4 inducers and inhibitors and dual inhibitors of CYP2C9 and 
CYP3A4 enzymes. Strict attention to this detail is required; please refer to permitted and prohibited 
concomitant medication as detailed in the SmPC. Patients should not receive any other JAK2 inhibitor whilst on 
the trial. 
 
All medications, procedures, and significant non-drug therapies (including physical therapy and blood product 
support) administered after the participant was enrolled into the study must be recorded on the Case Report 
Forms. Each concomitant drug must be individually assessed against all exclusion criteria/prohibited medication. 
7.15 SUPPLY OF STUDY TREATMENT  
Ruxolitinib will be provided free of charge by Novartis at the following strengths: 5 mg, 10 mg, and 20 mg. Each 
tablet contains 5 mg, 10mg, or 20mg ruxolitinib (as phosphate). The tablets should not be stored above 300C.  
PVC/PCTFE/Aluminium blister packs containing 14 or 56 tablets or multipacks containing 168 (3 packs of 56) 
tablets.  
 
Fostamatinib will be provided free of charge by Rigel at the following strengths: 100 mg and 150 mg. Each film-
coated tablet contains either 126.2 mg or 189.3mg of fostamatinib disodium hexahydrate equivalent to 100 mg 
and 150mg of fostamatinib respectively. This medicinal product does not require any special temperature 
storage conditions. It should be stored in the original package to protect from moisture and keep the bottle 
tightly closed. 
 
The local trial pharmacist will be responsible for maintaining and updating the drug accountability log in the 
MATIS pharmacy file which will be used to monitor compliance. All unfinished bottles will be returned to the 
trial pharmacist who will count and document any unused medication. All IMPs can then be destroyed in 
accordance with local pharmacy practice and this will be documented on the drug destruction log in the hospital 
pharmacy file 

 
 
 
 
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7.16 TREATMENT DURATION  
The planned duration of treatment is 14 days. Participants may be discontinued from treatment earlier due to 
unacceptable toxicity or disease progression which will be recorded as Serious Adverse Event (SAE). If 
participant is being discharged prior to day 14 they will go home and continue with the treatment plan.  
 
8 PHARMACOVIGILANCE  
8.1 
DEFINITIONS 
Adverse Event (AE): any untoward medical occurrence in a patient or clinical trial subject administered a 
medicinal product and which does not necessarily have a causal relationship with this treatment.  An AE can 
therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of an investigational medicinal product (IMP), whether or not 
considered related to the IMP. 
Adverse Reaction (AR): all untoward and unintended responses to an IMP related to any dose administered.  All 
AEs judged by either the reporting investigator or the sponsor as having reasonable causal relationship to a 
medicinal product qualify as adverse reactions.  The expression reasonable causal relationship means to convey in 
general that there is evidence or argument to suggest a causal relationship. 
Unexpected Adverse Reaction: an AR, the nature or severity of which is not consistent with the applicable product 
information (e.g. investigator’s brochure for an unapproved investigational product or SmPC for an authorised 
product).  When the outcome of the adverse reaction is not consistent with the applicable product information this 
adverse reaction should be considered as unexpected.  Side effects documented in the SmPC which occur in a more 
severe form than anticipated are also considered to be unexpected. 
Serious Adverse Event (SAE) or Serious Adverse Reaction (SAR): any untoward medical occurrence or effect that 
at any dose: 
• 
Results in death. 
• 
Is life-threatening – refers to an event in which the subject 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. 
• 
Requires hospitalisation, or prolongation of existing inpatients’ hospitalisation. 
• 
Results in persistent or significant disability or incapacity. 
• 
Is a congenital anomaly or birth defect. 

 
 
 
 
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Medical judgement should be exercised in deciding whether an AE/AR is serious in other situations.  Important 
AE/ARs that are not immediately life-threatening or do not result in death or hospitalisation but may jeopardise 
the subject or may require intervention to prevent one of the other outcomes listed in the definition above, 
should also be considered serious. 
Suspected Unexpected Serious Adverse Reaction (SUSAR): any suspected adverse reaction related to an IMP 
that is both unexpected and serious.   
8.2 
CAUSALITY  
Most adverse events and adverse drug reactions that occur in this study, whether they are serious or not, will be 
expected treatment-related toxicities due to the drugs used in this study.  The assignment of the causality 
should be made by the investigator responsible for the care of the participant using the definitions in the table 
below. If any doubt about the causality exists, the local investigator should inform the study coordination centre 
who will notify the Chief Investigators.  The pharmaceutical companies and/or other clinicians may be asked to 
advise in some cases. In the case of discrepant views on causality between the investigator and others, all 
parties will discuss the case.  In the event that no agreement is made, the MHRA will be informed of both points 
of view.  
 
Table 6. Defining causality 
Relationship  
Description 
Unrelated  
There is no evidence of any causal relationship  
Unlikely  
There is little evidence to suggest there is a causal relationship (e.g. the event did not 
occur within a reasonable time after administration of the trial medication). There is 
another reasonable explanation for the event (e.g. the participant’s clinical condition, 
other concomitant treatment).  
Possible 
There is some evidence to suggest a causal relationship (e.g. because the event occurs 
within a reasonable time after administration of the trial medication). However, the 
influence of other factors may have contributed to the event (e.g. the participant’s 
clinical condition, other concomitant treatments). 
Probable 
There is evidence to suggest a causal relationship and the influence of other factors is 
unlikely. 
Definitely 
There is clear evidence to suggest a causal relationship and other possible contributing 
factors can be ruled out. 
Not 
assessable 
There is insufficient or incomplete evidence to make a clinical judgement of the causal 
relationship. 
 

 
 
 
 
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8.3 
SAE GRADING 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not 
indicated. 
Grade 2: Moderate; Minimal, local, or non-invasive intervention indicated; limiting age appropriate instrumental 
activities of daily living (ADL). 
Grade 3: Severe or medically-significant but not immediately life-threatening; hospitalisation or prolongation of 
hospitalisation indicated; disabling; limiting self-care ADL. 
Grade 4: Life-threatening consequences; urgent intervention indicated. 
Grade 5: Death related to AE. 
 
8.4 
REPORTING PROCEDURES  
All adverse events should be reported. Depending on the nature of the event the reporting procedures below 
should be followed. Any questions concerning adverse event reporting should be directed to the study 
coordination centre in the first instance. A flowchart is given below to aid in the reporting procedures. 
Non serious AR/AEs 
All such toxicities, whether expected or not, should be recorded in the toxicity section of the relevant case 
report form and sent to the study coordination centre within one month of the form being due. 
Serious AR/AEs 
Fatal or life-threatening SAEs and SUSARs should be reported on the day that the local site is aware of the event. 
The SAE form asks for nature of event, date of onset, severity, corrective therapies given, outcome and causality 
(i.e. unrelated, unlikely, possible, probably, definitely). The responsible investigator should sign the causality of 
the event. Additional information should be sent within 5 days if the reaction has not resolved at the time of 
reporting. 
SAEs 
An SAE form should be completed and faxed to the study coordination centre for all SAEs within 24 hours. 
However, relapse and death due to <condition>, and hospitalisations for elective treatment of a pre-existing 
condition do not need reporting as SAEs. 
SUSARs 
In the case of suspected unexpected serious adverse reactions, the staff at the site should:  

 
 
 
 
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Complete the SAE case report form & send it immediately (within 24 hours, preferably by fax), 
signed and dated to the study coordination centre together with relevant treatment forms and 
anonymised copies of all relevant investigations.  
                       Or  
Contact the study coordination centre by phone and then send the completed SAE form to the 
study coordination centre within the following 24 hours as above.  
The study coordination centre will notify the MHRA, REC and the Sponsor of all SUSARs occurring during the 
study according to the following timelines; fatal and life-threatening within 7days of notification and non-life 
threatening within 15 days. All investigators will be informed of all SUSARs occurring throughout the study.  
Local investigators should report any SUSARs and /or SAEs as required by their Local Research Ethics Committee 
and/or Research & Development Office. 
8.5 
COVID-19 CONSIDERATIONS 
Recording Suspected Serious Adverse Reactions  
The focus is on those events that, based on a single case, are highly likely to be related to the study medication. 
Examples include anaphylaxis, Stevens Johnson Syndrome, or bone marrow failure, where there is no other 
plausible explanation.  Any SAE that is believed with a reasonable probability to be due to one of the study 
treatments will be considered a Suspected Serious Adverse Reaction (SSAR). In making this assessment, there 
should be consideration of the probability of an alternative cause (for example, COVID-19 itself or some other 
condition preceding randomisation), the timing of the event with respect to study treatment, the response to 
withdrawal of the study treatment, and (where appropriate) the response to subsequent re-challenge. All SSARs 
should be reported by telephone to the Central Coordinating Office and recorded on the study IT system 
immediately.  
 
Central assessment and onward reporting of SUSARs  
Clinicians at the Central Coordinating Office are responsible for expedited review of reports of SSARs received. 
Additional information (including the reason for considering it both serious and related, and relevant medical 
and medication history) will be sought. The focus of SUSAR reporting will be on those events that, based on a 
single case, are highly likely to be related to the study medication. To this end, anticipated events that are either 
efficacy endpoints, consequences of the underlying disease, or common in the study population will be 
exempted from expedited reporting. Thus, the following events will be exempted from expedited reporting: 
(i) 
Events which are the consequence of COVID-19; and  

 
 
 
 
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(ii) 
Common events which are the consequence of conditions preceding randomisation.  
Any SSARs that are not exempt will be reviewed by a Central Coordinating Office clinician and an assessment 
made of whether the event is “expected” or not (assessed against the relevant Summary of Product 
Characteristics or Investigator Brochure). Any SSARs that are not expected would be considered a Suspected 
Unexpected Serious Adverse Reaction (SUSAR). All confirmed SUSARs will be reported to the Chair of the DMC 
and to relevant regulatory authorities, ethics committees, and investigators in an expedited manner in 
accordance with regulatory requirements. 
 
Recording other Adverse Events  
In addition to recording Suspected Serious Adverse Reactions, information will be collected on all deaths and 
efforts will be made to ascertain the underlying cause. Other non-serious adverse events will not be recorded. It 
is anticipated that for some sub-studies, more detailed information on adverse events (e.g. through linkage to 
medical databases) or on other effects of the treatment (e.g. laboratory or radiological features) will be 
recorded and analysed but this is not a requirement of the core protocol. 
 

 
 
 
 
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Figure 3. Safety Reporting Overview 
 
Contact details for reporting SAEs and SUSARs 
rgit.ctimp.team@imperial.ac.uk 
CI email n.cooper@imperial.ac.uk  
Please send SAE forms to: rgit.ctimp.team@imperial.ac.uk and n.cooper@imperial.ac.uk  
Tel: + 44 (0)20 7594 9480 (Mon to Fri 09.00 – 17.00) 
 
 

 
 
 
 
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9 ASSESSMENT AND FOLLOW-UP 
9.1 
COLLECTING FOLLOW-UP INFORMATION  
The following information will be ascertained at the time of death or discharge or at 28 days after 
randomisation (whichever is sooner): 
- 
Vital status (alive / dead, with date and presumed cause of death, if appropriate)  
- 
Hospitalisation status (inpatient / discharged, with date of discharge, if appropriate)  
- 
Use of ventilation (with days of use and type, if appropriate) 
- 
Use of renal dialysis or haemofiltration  
This information will be obtained and entered into the web-based IT system by a member of the hospital clinical 
or research staff. Follow-up information is to be collected on all study participants, irrespective of whether or 
not they complete the scheduled course of allocated study treatment. Study staff will seek follow-up 
information through various means including medical staff, reviewing information from medical notes, routine 
healthcare systems, and registries.  
9.2 
DURATION AND MODE OF FOLLOW-UP  
All randomised participants are to be followed up until death, discharge from hospital or 28 days after 
randomisation (whichever is sooner). It is recognised that in the setting of this trial, there may be some 
variability in exactly how many days after randomisation, information on disease status is collected. This is 
acceptable and will be taken account of in the analyses and interpretation of results, the principle being that 
some information about post-randomisation disease status is better than none.  
Where discharge occurs before 14 days, study medication will be sent home with patient. The study team will 
send a pre-paid envelope to the patients to return any unused medication and empty bottles if patients are not 
able to attend Day 14 and Day 28 visits in person.  
Where discharge occurs before 28 days, patients will be invited to return weekly for monitoring of blood tests to 
confirm continued recovery from illness. Where this is not possible, monitoring of clinical status will be achieved 
by telephone. 
Longer term (up to 10 years) follow-up will be sought through linkage to electronic healthcare records and 
medical databases including those held by NHS Digital, Public Health England and equivalent bodies, and to 
relevant research databases (e.g. UK Biobank, Genomics England). 
 

 
 
 
 
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Table 7. Schedule of events 
Study Day 
Screening 
Baseline 
 
 
 
Last visit 
-6 to 0 
0 
1+ 
7# 
14# 
28# 
Time window 
 
- 2 days 
+ 1 
day 
± 3 
days 
± 3 
days 
± 3 days 
Informed consent 
x 
 
 
 
 
 
Inclusion/Exclusion criteria 
x 
x 
 
 
 
 
Demographic data 
x 
 
 
 
 
 
Medical history including major comorbidities 
x 
 
 
 
 
 
Physical exam 
x 
 
 
 
 
 
COVID-19 diagnosis, duration and severity  
x 
 
 
 
 
 
Pregnancy test 
x 
 
 
 
 
 
Vital signs 
x 
x 
x 
x 
x 
x 
NEWS score 
x 
x 
x 
x 
x 
x 
Inflammatory markers (CRP, D-dimer, LDH, 
ferritin, full blood count) 
 
x 
x 
x 
x 
x 
PK levels* 
 
 
 
 
x 
x 
Full blood count¶ (FBC) 
 
Daily while on CYP3A4 inhibitor 
 
Coagulation, Chemistry, Ferritin, Troponin, 
Procalcitonin 
x 
x 
x 
x 
x 
x 
FiO2  
x 
x 
x 
x 
x 
x 
SpO2 and/or PaO2 
x 
x 
x 
x 
x 
x 
Randomisation 
 
x 
 
 
 
 
Weight and Estimated height 
 
x 
 
 
 
 
Safety monitoring of liver and renal function 
x 
x 
x 
x 
x 
x 
Length of stay 
 
 
 
 
 
 
Serious Adverse Events 
x 
x 
x 
x 
x 
x 
Concomitant medications 
x 
x 
x 
x 
x 
x 
Serum 
 
x 
 
x 
x 
x 
Plasma 
 
x 
 
x 
x 
x 
RNA in PAXgene tube 
 
x 
 
x 
x 
x 
PBMC 
 
x 
 
x 
x 
x 
+ data that is routinely collected for clinical purposes will be recorded and a visit is not required 
# in the event that the patient recovers from COVID19 and is discharged, these visits will not be mandated. Instead a visit 
should occur on the date of discharge. Where possible, patients will be contacted by telephone at day 7, 14 and 28 and 
invited to attend for blood tests to monitor resolution of illness. 
*Ruxolitinib dose for these patients will be assessed after 10 dialysis patients complete Day 14 through pharmacokinetics 
(PK) levels which will be assessed. 
¶For patients randomized to ruxolitinib and prescribed a strong CYP3A4 inhibitor or dual CYP3A4/CYP2C9 inhibitor. Please 
refer to Section 7.8 for details. 
 

 
 
 
 
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9.3 
FOLLOW UP SCHEDULE – LONG COVID SUB-STUDY  
All participants that agree to take part in the study will either be consented via telephone or in person. The sub-
study only involves existing participants which have already consented to the main study.  
Telephone consent process will be an alternative process in case the existing study participants already 
consented are not able to come back to the clinics anymore.    
Participants who take part in the sub-study will be screened for the following: 
• 
Admissions to hospital  
• 
New co-morbidities 
• 
New thrombosis  
• 
Repeat COVID-19 infection 
• 
Number of COVID-19 Vaccinations 
• 
Any ongoing investigations by primary care for long COVID 
• 
Any current chronic infections/acute infections 
 
Patient be asked to complete the following 12 - 24 months after their randomisation to the primary study: 
• 
Fatigue severity scale (FSS) 
• 
MRC Dyspnoea scale 
• 
EQ-5D-5L 
 
Study Day 
Visit 3 
Follow up visit 1 
Consent to sub-study 
X* 
Medical history including new comorbidities 
and current infection 
x 
Concomitant medications 
x 
Confirmation 
of 
repeated 
COVID-19 
diagnosis, duration and severity  
x 
New thrombosis 
x 
Fatigue Severity Scale 
x 
MRC Dyspnoea scale 
x 
EQ-5D-5L 
x 
1 Last follow up visit may be up to 24 months post randomisation 
* Participants will be asked to consent either via telephone call or in person on site by the local PI or the delegated person 
within the study team, please refer to section 3.4 
  

 
 
 
 
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9.4 INCIDENTAL FINDINGS 
If there are any incidental findings of any relevance to the participants at any time during their participation in 
the study, then these will be explained to them. Any incidental findings will be recorded in the clinical notes and 
will be documented in GP and discharge letters. 
9.5 
LOST TO FOLLOW-UP  
The study team will make every reasonable effort to contact participants who have been discharged while on 
the study to complete the necessary protocol assessments. If any participants are lost to follow-up then the 
entire data set will be analysed as per the ITT method. 
9.6 
END OF TRIAL 
The end of the scheduled treatment phase is defined as the date of the last Follow-up visit of the last 
participant. The end of the study is the date of the final data extraction from NHS Digital (anticipated to be 10 
years after the last patient is enrolled).  
 
10 TRIAL MANAGEMENT 
The trial will be coordinated by a Central Coordinating Office within the Department of Haematology staffed by 
members of the Non-malignant Haematology Clinical Trials Unit. 
10.1 TRIAL MANAGEMENT GROUP 
A Trial Management Group (TMG) will be established, and will include the Chief Investigator Dr Nichola Cooper, 
the trial statistician and the trial coordinator. Key trial personnel will be invited to join the TMG as appropriate 
to ensure representation from a range of professional groups. Notwithstanding the legal obligations of the 
Sponsor and Chief Investigator, the TMG will be responsible for the day-to-day running and management of the 
trial and will meet by teleconference or in-person as required. Please refer to the TMG Charter for details.  
10.2 TRIAL STEERING COMMITTEE (TSC) 
The Trial Management Group will also serve as the Trial Steering Committee (TSC) and will provide overall trial 
supervision and provide advice. The ultimate decision for the continuation of the trial lies with the TSC. The TSC 
will meet at least once a year or more often if required. Please refer to the TSC Charter for details. 

 
 
 
 
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10.3 DATA MONITORING COMMITTEE 
During the study, interim analyses of all study data will be supplied in strict confidence to the independent DMC, 
which will comprise an independent statistician. The DMC will request such analyses at a frequency relevant to 
the emerging data from this and other studies.  
The DMC will independently evaluate these analyses and any other information considered relevant. The DMC 
will determine if, in their view, the randomised comparisons in the study have provided evidence on mortality 
that is strong enough (with a range of uncertainty around the results that is narrow enough) to affect national 
and global treatment strategies. In such a circumstance, the DMC will inform the TSC who will make the results 
available to the public and amend the trial arms accordingly. Unless this happens, the Steering Committee, Chief 
Investigator, study staff, investigators, study participants, funders and other partners will remain blind to the 
interim results until 28 days after the last patient has been randomised for a particular intervention arm (at 
which point analyses may be conducted comparing that arm with the SOC arm). 
 
The Data Monitoring Committee (DMC), will give advice on whether the accumulated data from the trial, 
together with the results from other relevant research, justifies the continuing recruitment of further patients. 
Meetings may be called if recruitment is much faster than anticipated and the DMC may, at their discretion, 
request to meet more frequently or continue to meet following completion of recruitment. An emergency 
meeting may also be convened if a safety issue is identified. The findings will be conveyed to the MHRA, 
funders, and/or sponsors as applicable. The DMC may consider recommending the discontinuation of the trial if 
the recruitment rate or data quality are unacceptable or if any issues are identified which may compromise 
patient safety. 
 
Please refer to the DMC Charter for details. 
11 MONITORING 
11.1 RISKS AND BENEFITS 
There is evidence that blockade/inhibition of the JAK/STAT pathway could have a beneficial effect on the CRS 
and the course of severe respiratory disease/ARDS in patients with COVID-19. However, ruxolitinib has not 
previously been studied in patients with COVID-19 pneumonia. Therefore, it is unknown as to whether there will 
be a benefit for patients being treated with ruxolitinib in this disease.  
 

 
 
 
 
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Important identified and potential risks from ruxolitinib clinical development and post authorization experience 
to date include: infections, tuberculosis, use in patients with hepatic impairment and with moderate or severe 
renal failure or end stage renal failure, elevated transaminases, bleeding, progressive multifocal 
leukoencephalopathy, adverse events after discontinuation of ruxolitinib, non-melanoma skin cancer, hepatitis 
B reactivation, and developmental toxicity. 
Potential risks for research participants 
No disadvantages are anticipated for research participants emanating from taking part in the study. 
Potential benefits for research participants 
There is no direct clinical benefit for research participants, but the information generated by this study may 
benefit future patients. 
11.2 MONITORING AT STUDY COORDINATION CENTRE  
Staff at the Non-malignant Haematology Clinical Trials Unit will review Case Report Form (CRF) data for errors and 
missing key data points. The trial database will also be programmed to generate reports on errors and error rates.  
Essential trial issues, events and outputs, including defined key data points, will be detailed in the MATIS trial Data 
Management Plan. 
11.3 MONITORING AT LOCAL SITES 
The frequency, type and intensity of routine and triggered on-site monitoring will be detailed in the MATIS Quality 
Management and Monitoring Plan (QMMP). The QMMP will also detail the procedures for review and sign-off of 
monitoring reports. In the event of a request for a trial site inspection by any regulatory authority the Sponsor 
must be notified as soon as possible. 
11.4 DATA AND SAFETY MONITORING 
Follow-up safety assessment will occur at day 7, 14 and 28 days.  Serious adverse events (SAEs) will be collected 
and reported in an expedited fashion. The requirements for collection of AEs is as follows: 
• 
All SAEs 
• 
All non-serious AEs 
• 
All reports of IMP exposure during pregnancy 
• 
All reports of misuse and abuse of an IMP, other medication errors and uses outside of what is foreseen in 
the protocol (irrespective if a clinical event has occurred 
 

 
 
 
 
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12 ETHICAL CONSIDERATIONS AND REGULATORY COMPLIANCE  
This study will be carried out in compliance with the protocol and the principles of Good Clinical Practice 
(ICHGCP) & the Medicines for Human Use (Clinical Trials) Regulations 2004 and Amendment Regulations 2006 
and is registered under the General Data Protection Regulation. The Investigator should ensure that all persons 
assisting with the study are adequately informed about the protocol-related duties and maintain a list of Sub-
investigators and other appropriately qualified persons to whom he or she has delegated significant study-
related duties. The Investigator is responsible for keeping a record of all subjects who sign an informed consent 
document and are screened for entry into the study. All versions of trial documents will have the relevant 
ethical approvals. 
12.1 CTA  
This study has Clinical Trials Authorisation from the UK Competent Authority; MHRA.  Reference: 
19174/0421/001-0001 
12.2 ETHICS APPROVAL 
The Study Coordination Centre has obtained approval from the Surrey Research Ethics Committee (REC) and 
Health Regulator Authority (HRA). The study must also receive confirmation of capacity and capability from each 
participating NHS Trust before accepting participants into the study or any research activity is carried out. The 
study will be conducted in accordance with the recommendations for physicians involved in research on human 
subjects adopted by the 18th World Medical Assembly, Helsinki 1964 and later revisions. 
 
Protocol Amendments 
All protocol amendments will be approved by the sponsor prior to submission to the Ethics Committee and 
implementation. 
12.3 CONSENT 
Informed consent should be obtained from each patient before enrolment into the study. However, if the 
patient lacks capacity to give consent due to the severity of their medical condition (e.g. acute respiratory failure 
or need for immediate ventilation), then consent may be obtained from a relative acting as the patient’s legally 
designated personal representative. Further consent will then be sought with the patient if they recover 
sufficiently.  
 

 
 
 
 
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Due to the poor outcomes in COVID-19 patients who require ventilation (>90% mortality in one cohort5), 
patients who lack capacity to consent due to their disease, and for whom a relative to act as the legally 
designated representative is not immediately available, randomisation and consequent treatment will proceed 
with consent provided by a treating clinician (independent of the clinician seeking to enrol the patient) who will 
act as the legally designated professional representative. Consent will then be obtained from the patient’s 
personal legally designated representative (or directly from the patient if they recover promptly) at the earliest 
opportunity. 
Informed consent can be taken by any competent health care professional delegated by the chief investigator 
which can include doctors, nurses and research practitioners. If nurses or research practitioners take consent, 
the most up to date Legal Representative Consent Form (LRCF) should be used with the patient’s treating 
clinician, independent of the study team, to sign as Legal Representative and the nurse/research practitioner as 
the person taking consent.  
12.4 WITHDRAWAL OF CONSENT 
A decision by a participant that they no longer wish to continue receiving study treatment should not be 
considered to be a withdrawal of consent for follow-up. However, participants are free to withdraw consent for 
some or all aspects of the study at any time if they wish to do so. In accordance with regulatory guidance, de-
identified data that have already been collected and incorporated in the study database will continue to be used 
(and any identifiable data will be destroyed). 
12.5 CONFIDENTIALITY 
The research team may exchange emails between themselves about the study and its data analysis. Personal 
addresses, postcodes, faxes, emails or telephone numbers may be used to post study documents to potential 
participants. The signed consent forms and completed health questionnaires will be stored safely in the locked 
clinical trials office, in the Hammersmith Hospital. All electronic files created for the study database will be 
stored in a single NHS computer, access to which is limited by a password. All electronic files/records created for 
the study will be password protected. The study team will ensure that the confidentiality of participant data is 
preserved and will only use NHS email accounts (@nhs.net) to communicate for the study. Participant names 
will not be disclosed and will not appear on any reports produced.  
 

 
 
 
 
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The EU General Data Protection Regulation (GDPR) that came into effect on 25 May 2018 defines expanded 
rights for study patients. The study team will inform all participants of these rights. Personal data will be kept in 
line with Imperial College Healthcare NHS Trust policy for ten years.  
 
Representatives of the sponsor will be granted direct access to original medical records for verification of trial 
participation and data without violating the confidentiality of these records to the extent permitted by the 
applicable laws and regulations. Identifiable data will be stored in the patients’ medical records and NHS 
computers. Participants will consent to this access by signing the informed consent form. 
12.6 INDEMNITY  
Imperial College London holds negligent harm and non-negligent harm insurance policies which apply to this 
study. 
12.7 SPONSOR 
Imperial College London will act as the Trial Sponsor.  
12.8 FUNDING  
This study is supported by the NIHR Imperial Biomedical Research Centre. The data will be collected, analysed 
and published independently of the source of funding; however study outcome results will be shared with Novartis 
or Rigel following interim analyses and prior to publication. 
12.9 AUDITS AND INSPECTIONS  
The study may be subject to inspection and audit by Imperial College Healthcare NHS Trust under their remit as 
sponsor to ensure adherence to GCP. The Chief Investigator will be responsible for the conduct and progress 
monitoring of the study.  
 
13 PUBLICATIONS AND REPORTS  
The Steering Committee will be responsible for drafting the main reports from the study and for review of any 
other reports. In general, papers initiated by the Steering Committee (including the primary manuscript) will be 
written in the name of the MATIS Collaborative Group, with individual investigators named personally at the 
end of the report (or, to comply with journal requirements, in web-based material posted with the report).  

 
 
 
 
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The Steering Committee will also establish a process by which proposals for additional publications (including 
from independent external researchers) are considered by the Steering Committee. The Steering Committee will 
facilitate the use of the study data and approval will not be unreasonably withheld. However, the Steering 
Committee will need to be satisfied that any proposed publication is of high quality, honours the commitments 
made to the study participants in the consent documentation and ethical approvals, and is compliant with 
relevant legal and regulatory requirements (e.g. relating to data protection and privacy). The Steering 
Committee will have the right to review and comment on any draft manuscripts prior to publication. 
 
14 REFERENCES 
Elli, E.M., Baratè, C., Mendicino, F., Palandri, F., et al. (2019) Mechanisms Underlying the Anti-inflammatory and 
Immunosuppressive Activity of Ruxolitinib. Frontiers in Oncology. [Online] 9, 1186. Available from: 
doi:10.3389/fonc.2019.01186. 
 
Huang, C., Wang, Y., Li, X., Ren, L., et al. (2020) Clinical features of patients infected with 2019 novel coronavirus 
in Wuhan, China. Lancet (London, England). [Online] 395 (10223), 497–506. Available from: doi:10.1016/S0140-
6736(20)30183-5. 
 
Jagasia, M., Perales, M.-A., Schroeder, M.A., Ali, H., et al. (2020) Ruxolitinib for the treatment of steroid-
refractory acute GVHD (REACH1): a multicenter, open-label phase 2 trial. Blood. [Online] 135 (20), 1739–1749. 
Available from: doi:10.1182/blood.2020004823. 
 
Richardson, P., Griffin, I., Tucker, C., Smith, D., et al. (2020) Baricitinib as potential treatment for 2019-nCoV 
acute respiratory disease. Lancet (London, England). [Online] 395 (10223), e30–e31. Available from: 
doi:10.1016/S0140-6736(20)30304-4. 
 
Ruan, Q., Yang, K., Wang, W., Jiang, L., et al. (2020) Clinical predictors of mortality due to COVID-19 based on an 
analysis of data of 150 patients from Wuhan, China. Intensive Care Medicine. [Online] 46 (5), 846–848. Available 
from: doi:10.1007/s00134-020-05991-x. 
 

 
 
 
 
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Siddiqi, H.K. & Mehra, M.R. (2020) COVID-19 illness in native and immunosuppressed states: A clinical–
therapeutic staging proposal. The Journal of Heart and Lung Transplantation. [Online] 39 (5), 405–407. Available 
from: doi:10.1016/j.healun.2020.03.012. 
 
Singanayagam, A., Glanville, N., Girkin, J.L., Ching, Y.M., et al. (2018) Corticosteroid suppression of antiviral 
immunity increases bacterial loads and mucus production in COPD exacerbations. Nature Communications. 
[Online] 9 (1), 2229. Available from: doi:10.1038/s41467-018-04574-1. 
 
Wu, D. & Yang, X.O. (2020) TH17 responses in cytokine storm of COVID-19: An emerging target of JAK2 inhibitor 
Fedratinib. Journal of Microbiology, Immunology, and Infection. [Online] 53 (3), 368–370. Available from: 
doi:10.1016/j.jmii.2020.03.005. 
 

 
 
 
 
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 PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
 
The signature of the below constitutes agreement of this protocol by the signatory and provides the necessary 
assurance that this study will be conducted at his/her investigational site according to all stipulations of the 
protocol including all statements regarding confidentiality. 
 
 
Study Title: 
 
MATIS: Multi-arm trial of Inflammatory Signal Inhibitors for COVID-19 
 
 
Address of Institution:  ____________________________________________ 
 
 
 
 
 
 
 
 
 
____________________________________________ 
 
 
 
 
 
____________________________________________ 
 
 
 
 
 
Print Name and Title: 
____________________________________________ 
 
 
Signed:  
 
____________________________________________ 
 
 
Date: 
 
 
 
_____________________