Conditions: Severe Acute Respiratory Syndrome
Keywords: COVID-19 Otilimab Ordinal scale Coronavirus GSK3196165
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1156
Healthy volunteers: no

Brief summary:
OSCAR (Otilimab in Severe COVID-19 Related Disease) is a multi-center, double-blind, randomized, placebo-controlled trial to assess the efficacy and safety of otilimab for the treatment of severe pulmonary COVID-19 related disease. The study is being conducted in 2 parts (Part 1 and Part 2). Otilimab is a human monoclonal anti-granulocyte macrophage colony stimulating factor (GM-CSF) antibody that has not previously been tested in participants with severe pulmonary COVID-19 related disease in Part 1. The aim of this study is to evaluate the benefit-risk of a single infusion of otilimab in the treatment of hospitalized participants with severe COVID-19 related pulmonary disease with new onset hypoxia requiring significant oxygen support or requiring early invasive mechanical ventilation (less than or equal to \[\<=\] 48 hours before dosing). Participants will be randomized to receive a single intravenous (IV) infusion of otilimab or placebo, in addition to standard of care.

Detailed description:

Arms:
arm 1: Participants (age \>=18 years and \<=79 years) will receive a single dose of otilimab administered as an IV infusion in addition to standard of care in Part 1. arm 2: Participants (age \>=18 years and \<=79 years) will receive a single dose of matching placebo administered as an IV infusion in addition to standard of care in Part 1. arm 3: Participants (age 70 years or above) will receive a single dose of otilimab administered as an IV infusion in addition to standard of care in Part 2. arm 4: Participants (age 70 years or above) will receive a single dose of matching placebo administered as an IV infusion in addition to standard of care in Part 2.

Interventions: intervention 1: Otilimab intervention 2: Placebo 1 intervention 3: Placebo 2 intervention 4: Standard of care
Intervention descriptions: intervention 1: Otilimab will be administered once via IV route. intervention 2: Placebo 1 will consist of sterile 0.9 percent (%) sodium chloride solution administered once via IV route. intervention 3: Placebo 2 will consist of sterile 5% dextrose or 5% glucose solution administered once via IV route. intervention 4: All participants will receive standard of care as per institutional protocol.

Protocol document:
Prot_002.pdf: 
TMF-11795607 
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GlaxoSmithKline group of companies 
 
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TITLE PAGE 
Protocol Title: A randomized, double-blind, placebo-controlled, study evaluating the 
efficacy and safety of otilimab IV in patients with severe pulmonary COVID-19 related 
disease. 
Protocol Number: 214094/Amendment 03 
Compound Number 
or Name: 
GSK3196165 (otilimab) 
 
Study Name: OSCAR (Otilimab in Severe COVID-19 Related Disease). 
Brief Title: Investigating otilimab in patients with severe pulmonary COVID-19 related 
disease. 
Study Phase: Phase 2 (Part 1), Phase 3 (Part 2) 
Sponsor Name and Legal Registered Address: 
GlaxoSmithKline Research & Development Limited 
980 Great West Road 
Brentford 
Middlesex, TW8 9GS 
UK 
Regulatory Agency Identifying Number(s): 
IND: 149754 
EudraCT: 2020-001759-42 
 
 
Approval Date: 25-JAN-2021 
 
 
 
Copyright 2021 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorized copying or use of this information is prohibited. 


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SPONSOR SIGNATORY 
Protocol Title: A randomized, double-blind, placebo-controlled, study evaluating the 
efficacy and safety of otilimab IV in patients with severe pulmonary COVID-19 related 
disease. 
Protocol Number: 214094/Amendment 03 
Compound Number 
or Name: 
GSK3196165 (otilimab) 
 
 
 
 
 
 
 
 
 
 
Dr. Jatin Patel 
Clinical Development Leader 
Clinical Science (II and Fibrosis) 
 
Date 
The signed page is a separate document. 
 
 
 
Medical Monitor Name and Contact Information can be found in the Study Reference 
Manual 
 


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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date 
DNG Number 
Amendment 3 
25-JAN-2021 
TMF-11795607 
Amendment 2 
02-JUL-2020 
2020N436091_02 
Amendment 1 
18-MAY-2020 
2020N436091_01 
Original Protocol 
30-APR-2020 
2020N436091_00 
 
Amendment 3: 25-JAN-2021 
This amendment is considered substantial, based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European 
Union. 
Overall Rationale for the Amendment to add an additional cohort in the study.  
Before the last of 806 participants completed the study (Last Subject Last Visit, Day 60), 
an interim analysis of the primary endpoint and all-cause mortality data at Day 28 
showed that substantial clinical benefit was evident in one of the pre-defined stratification 
subgroups “Age 70 to <80 years”, with no safety concerns in any subgroup.  Given the 
ongoing pandemic and particularly high mortality of COVID-19 disease in patients over 
70 years old, together with recent publications that support the hypothesis that the 
severity of the disease is driven by a maladaptive innate immune response in which GM-
CSF plays a key role and which is more commonly elevated in older patients. GSK has 
therefore determined to urgently confirm these subgroup findings by amending the 
protocol to allow the enrolment of an additional cohort of patients aged 70 years and 
above with no upper age limit.  GSK has reviewed the results from what is now 
considered as the first part of the study (Part 1) and decided that a second part will be 
added to the study (Part 2) which has less frequent assessments to decrease the burden on 
sites.  The following changes have been made in Amendment 3 for Part 2. 
Section # and Name 
Description of Change 
Brief Rationale 
Title Page. Study 
Phase 
Added that Part 2 is Phase 3. 
Part 2 of the study is confirmatory 
and therefore, considered Phase 3. 
1.1. Synopsis, Brief 
Summary, Number of 
Participants 
Added Part 2. 
Additional cohort required to confirm 
efficacy and safety in Part 1. 
1.1. and 3.2. 
Objectives and 
Endpoints - Part 2 
Added objectives and endpoints for 
Part 2 based on objectives and 
endpoints in Part 1, added a 
secondary endpoint “All-cause 
mortality” at Day 28, and deleted 
exploratory endpoints “Improvement 
of at least 2 points relative to baseline 
of Sequential Organ Failure 
Assessment (SOFA) score” and 
“Improvement relative to baseline in 
SpO2, FiO2, and SpO2/FiO2 ratio”. 
A pre-specified endpoint is a key 
value driver in the cost-effectiveness 
model, and the exploratory endpoints 
will not be reported. 


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Section # and Name 
Description of Change 
Brief Rationale 
1.1 and 3.2. Objectives 
and Endpoints - Part 2 
Removed ‘high-dose vasopressor’ 
from the Category 7 description for 
Part 2. 
Based on complexity to define / 
record ‘high-dose’ in Part 1. 
1.4. Schedule of 
Activities (SoA) – Part 
2 
Added SoA for Part 2. Reduced 
frequency of: COVID-19 signs and 
symptom score, vital signs, SpO2, 
FiO2 and local lab testing.  Removed 
SOFA score (except at Screening).  
Removed Day 1 ECG.  Added height 
and participant baseline and 
discharge location information.  
Revised guidance notes. 
Assessments considered non-
essential in Part 1 removed to reduce 
site burden.  Height collected for Part 
2 to allow BMI estimates to be 
calculated.  Guidance given in the 
SRM for Part 1 moved to the protocol. 
2. Introduction, 2.1. 
Study Rationale, 2.2.2. 
Scientific rationale to 
inhibit GM-CSF in 
COVID-19 patients, 
2.2.3. Timing of GM-
CSF inhibition in 
COVID patients 
Added recent and relevant changes in 
the increased understanding of the 
pathophysiology of COVID-19, 
immunosenescence, epidemiology 
and mortality risk. 
Supports the rationale for the 
additional cohort of participants 
70 years or older required to confirm 
efficacy and safety in Part 1. 
2.3.1. Risk 
Assessment 
Updated Sections on Serious 
hypersensitivity reactions (TENS 
case) and Infections (additional 
immunosuppressant therapies). 
Risk Assessment updated with 
preliminary safety data from Part 1. 
2.3.2. Benefit 
Assessment 
Added statement for Part 2. 
Supports the rationale for the 
additional cohort of participants 
70 years or older required to confirm 
efficacy in Part 1, with no safety 
concerns. 
2.3.3. Overall Benefit: 
Risk Conclusion 
Added statement for Part 2. 
Supports the rationale for the 
additional cohort of participants 
70 years or older required to confirm 
efficacy in Part 1, with no safety 
concerns. 
4.1.2. Main Cohort, 
4.1.2..2 Stratification in 
Part 2 
Added Part 2 stratification information 
and additional guidance. 
Stratification added for Part 2 to 
obtain a balanced population across 
the treatment arms with respect to the 
severity of the disease and gender, 
which are both associated with 
mortality. 
Additional guidance to increase site 
understanding. 
4.4. End of Study 
Definition 
Revised definition of End of Study for 
Part 2, and any future cohorts. 
To facilitate adding at least one extra 
cohort required to confirm efficacy 
and safety in Part 1. 


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Section # and Name 
Description of Change 
Brief Rationale 
5.2. Inclusion Criteria – 
Part 2 
Added Inclusion Criteria for Part 2 
based on Inclusion Criteria for Part 1.  
Revised age range to 70 years or 
above (#1); added footnote to indicate 
that guidance on ‘high-flow oxygen or 
equivalent’ is provided in the SRM; 
and removed text on requirement for 
contraceptive guidance for females 
(#4 Part 1). 
Additional cohort of participants 70 
years or older required to confirm 
efficacy and safety in Part 1. Upper 
age limit removed to assess potential 
benefit in an even older population.  
Contraception criterion removed 
based on age range for Part 2 (70 
years and over). 
Additional guidance to increase site 
understanding. 
5.4. Exclusion Criteria 
– Part 2 
Added Exclusion Criteria for Part 2 
based on Exclusion Criteria for Part 1: 
clarified that SOFA score is used for 
intubated ICU patients (#2), removed 
reference to ‘high-dose 
vasopressors/inotropes’ (#3), added 
the following additional medical 
conditions: severe renal dysfunction, 
severe dementia, severe disability 
(#4), clarified that patients 
demonstrating a sustained virologic 
response (SVR) for HCV are not 
excluded from participation (#8), 
clarified chemotherapy treatments 
(hormone based therapies are 
permitted) (#9), added more examples 
of immunosuppressant therapies 
(#11), reduced ANC threshold from 
<1.5 x 109/L (neutropenia  Grade 2) 
to <1.0 x 109/L (neutropenia  Grade 
3) (#19). 
Exclusion criteria modified based on 
experience in Part 1, and additional 
medical conditions added to reflect 
the recruitment of a population 70 
years and older. 
5.5. Screen Failures 
Added that participants who are 
randomized but not subsequently 
dosed, are not screen failures. 
Clarification on guidance regarding 
screen failures. 
6.1. Study 
Intervention(s) 
Administered 
Switched from sterile 0.9% (w/v) 
sodium chloride solution for placebo 
infusion in Part 1 to sterile 5% (w/v) 
dextrose solution in Part 2. 
Added text from the SRM that an in-
line filter must be used and added a 
statement that the Study Intervention 
preparation must be conducted in 
accordance with the SRM. 
Change in diluent and placebo from 
normal saline to 5% dextrose, based 
on new compatibility information. 
Clarifications of information 
previously in the SRM only. 
6.6. Concomitant 
Therapy 
Added requirement to record COVID-
19 current vaccination status in Part 
2., Removed requirement to monitor 
or caution in respect of CYP3A4 
substrate drugs. 
COVID-19 vaccines were not 
available during Part 1. 
Guidance on the caution of CYP3A4 
substrate drugs considered 
unnecessary for this single dose 
study, so removed for Part 2. 


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Section # and Name 
Description of Change 
Brief Rationale 
6.6.1. Medication NOT 
Permitted During the 
Study 
Clarified that the medications listed in 
Section 6.6.1 cannot be planned to be 
administered during the study. 
Added more examples of 
immunosuppressant therapies. 
Clarification and extra examples 
added to assist site understanding. 
6.6.2. 
Medication/Treatment 
PERMITTED During 
the Study 
Added more examples of COVID-19 
medications and clarified the guidance 
on the permitted use of these 
medications. 
Clarification and extra examples 
added to assist site understanding. 
7.1.1. Demography 
and Medical History 
Clarification added that medical 
history includes COVID-19 signs and 
symptoms on admission, and that 
COVID-19 vaccination status will be 
recorded at Screening. 
Extra guidance provided. 
COVID-19 vaccines were not 
available during Part 1. 
7.2.1.Clinical features 
of COVID-19 
Reduced frequency of collecting 
COVID-19 Signs and Symptoms from 
daily to key timepoints only. 
To reduce site burden. 
7.2.2. SpO2 (for 
participants not on 
invasive mechanical 
ventilation) 
Reduced frequency of assessment 
and clarified guidance. 
To reduce site burden and improve 
guidance. 
7.2.3. Concentration of 
inspired oxygen (FiO2) 
Reduced frequency of assessment 
and clarified guidance. 
To reduce site burden and improve 
guidance. 
7.2.6. Ordinal Scale 
Removed ‘high-dose vasopressor’ 
from the Category 7 description for 
Part 2. 
Based on complexity to define / 
record ‘high-dose’ in Part 1 
7.2.7. Participant 
baseline and discharge 
location information 
Added guidance on collecting 
participant location information (at 
baseline and discharge). 
Guidance given in the SRM for Part 1 
moved to the protocol. 
7.2.8. Sequential 
Organ Failure 
Assessment (SOFA) 
Scores 
Clarified guidance on collecting SOFA 
score. 
Clarified the text. 
To reduce site burden and improve 
guidance. 
7.3.2. Vital Signs 
Added that temperature location 
(rather than method) is collected.  
Added that height will be collected at 
Screening for Part 2. 
To improve guidance. 
Height collected for Part 2 to allow 
BMI estimates to be calculated. 
7.3.5. Pregnancy 
Testing (Part 1 only) 
Removed requirement for pregnancy 
testing in Part 2. 
Based on age range for Part 2 (70 
years and over). 
7.4.5. Pregnancy (Part 
1 only) 
Removed requirement for pregnancy 
testing in Part 2. 
Based on age range for Part 2 (70 
years and over). 
7.4.7. Adverse Events 
of Special Interest 
Clarified that CRS is an AESI if not 
related to COVID-19. 
Added reference to extra guidance in 
the protocol and SRM. 
To improve guidance. 


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Section # and Name 
Description of Change 
Brief Rationale 
7.4.7.1. Cytokine 
Release Syndrome 
Added clarification that CRS (possibly 
related to study drug, rather than 
progression of hyperinflammation in 
COVID-19 disease) is defined as a 
worsening of the CRS Grading 
System within 6 hours after start of 
study drug infusion. 
Added clarification that ‘unexpected 
oxygen requirement΄ in Grades 2 and 
3 equates to FiO2. 
To improve guidance on when to 
report CRS events. 
7.5. Pharmacokinetics 
Added clarification to Part 2 that if 
central laboratory kits are not 
available at a site, participants can be 
randomised and dosed, and the PK 
samples not collected. 
To ensure that the operational 
aspects of an exploratory endpoint 
does not prevent participant 
enrolment. 
7.7. 
Pharmacodynamics 
Added clarification to Part 2 that if 
central laboratory kits are not 
available at a site, participants can be 
randomised and dosed, and the PD 
samples not collected. 
To ensure that the operational 
aspects of an exploratory endpoint 
does not prevent participant 
enrolment. 
8.1. Statistical 
Hypothesis 
Clarification that the null hypothesis 
being tested applies to all parts of the 
study. 
To accommodate addition of Part 2. 
8.2. Sample Size 
Determination 
Added sample size for Part 2. 
Required for Part 2. 
8.4. Statistical 
Analyses 
Added clarification that each part of 
the study will be analysed separately, 
and separate analysis plans will be 
produced. 
Clarification of statistical analysis plan 
with the addition of Part 2. 
8.4.1. General 
Considerations 
Added Part 2 general considerations 
for stratification assignment. 
Required for Part 2. 
8.4.2. Primary 
Endpoint(s) 
Revised text that the primary endpoint 
was analysed when all participants in 
Part 1 had completed Day 28.  
Added text for Part 2, and details of 
how the corresponding difference in 
proportion and confidence interval will 
be calculated from the model. 
Clarification for Part 1 and required 
for Part 2. 
8.5. Interim Analysis 
Added text to confirm no interim 
analyses to assess futility and efficacy 
in Part 2, and that the IDMC will only 
review safety data. 
Information for Part 2. 
9.1.5. Committees 
Structure 
Added text to confirm that the IDMC 
will only review safety data in Part 2. 
Information for Part 2.  IDMC will 
review only safety data, because 
there are no interim analyses planned 
for Part 2. 


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Section # and Name 
Description of Change 
Brief Rationale 
Table 4. Protocol-
Required Safety 
Laboratory Tests – 
Part 2 
Changes in Part 2: removed lactate, 
procalcitonin, pregnancy testing, 
requirement for fasting glucose, and 
ALP fractionation.  Stated that PT or 
INR can be collected. 
Removed the Day 2 timepoint. 
Removed local lab tests from Part 2, 
which were considered unnecessary 
from Part 1 data. 
Removed pregnancy testing based 
on age range for Part 2 (70 years and 
over). 
9.4. Appendix 4: 
Contraceptive and 
Barrier Guidance 
Removed contraception guidance in 
Part 2. 
Based on age range for Part 2 (70 
years and over). 
9.5. Appendix 5: 
Abbreviations and 
Trademarks 
Added new abbreviations. 
Site understanding. 
9.6. Appendix 6: 
Protocol Amendment 
History 
Amendment 2 changes moved from 
the front of the protocol to this 
appendix. 
Because Amendment 3 is the current 
version. 
9.7.Appendix 7: 
Country-Specific 
Protocol Addendums 
Added country-specific protocol 
addendums for The Netherlands, 
South Africa, India and Japan. 
Added country-specific protocol 
addendums that were not included in 
previous versions of the protocol, in 
error. 
9.10. References. 
Added references and deleted 
references not cited in the main body 
of the protocol. 
New references required for the 
recent and relevant changes in the 
increased understanding of the 
pathophysiology of COVID-19, 
immunosenescence, epidemiology 
and mortality risk. 
All sections 
Other minor, grammatical and typographical corrections to improve 
readability. 
 


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TABLE OF CONTENTS 
PAGE 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE .................................... 3 
1. 
PROTOCOL SUMMARY ...................................................................................... 12 
1.1. 
Synopsis .................................................................................................. 12 
1.2. 
Schema .................................................................................................... 16 
1.3. 
Schedule of Activities (SoA) – Part 1 ......................................................... 17 
1.4. 
Schedule of Activities (SoA) – Part 2 ......................................................... 20 
2. 
INTRODUCTION ................................................................................................. 23 
2.1. 
Study Rationale ........................................................................................ 23 
2.2. 
Background .............................................................................................. 25 
2.2.1. 
Role of GM-CSF in inflammation ................................................ 25 
2.2.2. 
Scientific rationale to inhibit GM-CSF in COVID-19 
patients ...................................................................................... 26 
2.2.3. 
Timing of GM-CSF inhibition in COVID patients .......................... 28 
2.3. 
Benefit/Risk Assessment .......................................................................... 31 
2.3.1. 
Risk Assessment........................................................................ 31 
2.3.2. 
Benefit Assessment ................................................................... 36 
2.3.3. 
Overall Benefit: Risk Conclusion ................................................. 36 
3. 
OBJECTIVES AND ENDPOINTS ......................................................................... 37 
3.1. 
Part 1 ....................................................................................................... 37 
3.2. 
Part 2 ....................................................................................................... 38 
4. 
STUDY DESIGN .................................................................................................. 40 
4.1. 
Overall Design .......................................................................................... 40 
4.1.1. 
Initial Safety Cohort (first 20 participants) .................................... 41 
4.1.2. 
Main Cohort (after 20 participants).............................................. 41 
4.1.2.1. 
Stratification in Part 1 ................................................ 42 
4.1.2.2. 
Stratification in Part 2 ................................................ 42 
4.2. 
Scientific Rationale for Study Design ......................................................... 43 
4.3. 
Justification for Dose ................................................................................ 43 
4.3.1. 
Otilimab ..................................................................................... 43 
4.3.2. 
Placebo ..................................................................................... 44 
4.4. 
End of Study Definition ............................................................................. 44 
5. 
STUDY POPULATION ......................................................................................... 45 
5.1. 
Inclusion Criteria – Part 1 .......................................................................... 45 
5.2. 
Inclusion Criteria – Part 2 .......................................................................... 46 
5.3. 
Exclusion Criteria – Part 1......................................................................... 47 
5.4. 
Exclusion Criteria – Part 2......................................................................... 48 
5.5. 
Screen Failures ........................................................................................ 49 
6. 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ............................. 50 
6.1. 
Study Intervention(s) Administered............................................................ 50 
6.2. 
Preparation/Handling/Storage/Accountability ............................................. 51 
6.3. 
Measures to Minimize Bias: Randomization and Blinding........................... 52 
6.4. 
Study Intervention Compliance.................................................................. 53 
6.5. 
Treatment of Overdose ............................................................................. 53 
6.6. 
Concomitant Therapy................................................................................ 53 


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6.6.1. 
Medication NOT Permitted During the Study ............................... 54 
6.6.2. 
Medication/Treatment PERMITTED During the Study ................. 54 
6.7. 
Participant Discontinuation/Withdrawal from the Study .............................. 55 
6.8. 
Lost to Follow Up ...................................................................................... 55 
7. 
STUDY ASSESSMENTS AND PROCEDURES .................................................... 55 
7.1. 
Entry/Screening Assessments................................................................... 56 
7.1.1. 
Demography & Medical History .................................................. 56 
7.1.2. 
Chest X-ray or CT Scan ............................................................. 57 
7.2. 
Efficacy Assessments ............................................................................... 57 
7.2.1. 
Clinical features of COVID-19 ..................................................... 57 
7.2.2. 
SpO2 (for participants not on invasive mechanical 
ventilation) ................................................................................. 57 
7.2.3. 
Concentration of inspired oxygen (FiO2)...................................... 58 
7.2.4. 
Ventilation status........................................................................ 58 
7.2.5. 
ICU Supportive Care .................................................................. 58 
7.2.6. 
Ordinal Scale ............................................................................. 58 
7.2.7. 
Participant baseline and discharge location information............... 59 
7.2.8. 
Sequential Organ Failure Assessment (SOFA) Scores................ 59 
7.3. 
Safety Assessments ................................................................................. 60 
7.3.1. 
Physical Examinations ............................................................... 60 
7.3.2. 
Vital Signs.................................................................................. 60 
7.3.3. 
Electrocardiograms .................................................................... 60 
7.3.4. 
Clinical Safety Laboratory Assessments ..................................... 60 
7.3.5. 
Pregnancy Testing (Part 1 only).................................................. 61 
7.4. 
Adverse Events (AEs), Serious Adverse Events (SAEs) and Other 
Safety Reporting ....................................................................................... 61 
7.4.1. 
Time Period and Frequency for Collecting AE and SAE 
Information................................................................................. 61 
7.4.2. 
Method of Detecting AEs and SAEs............................................ 62 
7.4.3. 
Follow-up of AEs and SAEs........................................................ 62 
7.4.4. 
Regulatory Reporting Requirements for SAEs............................. 62 
7.4.5. 
Pregnancy (Part 1 only) .............................................................. 62 
7.4.6. 
Cardiovascular and Death Events............................................... 63 
7.4.7. 
Adverse Events of Special Interest ............................................. 63 
7.4.7.1. 
Cytokine Release Syndrome ..................................... 64 
7.5. 
Pharmacokinetics ..................................................................................... 65 
7.6. 
Genetics ................................................................................................... 65 
7.7. 
Pharmacodynamics .................................................................................. 66 
7.8. 
Immunogenicity Assessments ................................................................... 66 
7.9. 
Health Economics/Medical Resource Utilization and Health 
Economics................................................................................................ 66 
8. 
STATISTICAL CONSIDERATIONS ...................................................................... 66 
8.1. 
Statistical Hypotheses............................................................................... 66 
8.2. 
Sample Size Determination....................................................................... 67 
8.3. 
Analysis Sets............................................................................................ 67 
8.4. 
Statistical Analyses ................................................................................... 67 
8.4.1. 
General Considerations .............................................................. 68 
8.4.2. 
Primary Endpoint(s).................................................................... 68 
8.4.3. 
Secondary Endpoint(s) ............................................................... 69 
8.4.4. 
Exploratory Endpoint(s) .............................................................. 69 
8.4.5. 
Safety Analysis .......................................................................... 69 
8.5. 
Interim Analysis ........................................................................................ 69 


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9. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS............................................................................................. 71 
9.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ......................................................................................... 71 
9.1.1. 
Regulatory and Ethical Considerations ....................................... 71 
9.1.2. 
Financial Disclosure ................................................................... 71 
9.1.3. 
Informed Consent Process ......................................................... 72 
9.1.4. 
Data Protection .......................................................................... 74 
9.1.5. 
Committees Structure................................................................. 74 
9.1.6. 
Dissemination of Clinical Study Data .......................................... 75 
9.1.7. 
Data Quality Assurance .............................................................. 76 
9.1.8. 
Source Documents..................................................................... 77 
9.1.9. 
Study and Site Start and Closure ................................................ 77 
9.1.10. Publication Policy ....................................................................... 78 
9.2. 
Appendix 2: Clinical Laboratory Tests ....................................................... 79 
9.3. 
Appendix 3: AEs and SAEs: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting ...................................... 81 
9.3.1. 
Definition of AE .......................................................................... 81 
9.3.2. 
Definition of SAE ........................................................................ 82 
9.3.3. 
Definition of Cardiovascular Events ............................................ 83 
9.3.4. 
Recording and Follow-Up of AE and SAE ................................... 83 
9.3.5. 
Reporting of SAE to GSK ........................................................... 85 
9.4. 
Appendix 4: Contraceptive and Barrier Guidance (Part 1 only)................... 86 
9.4.1. 
Definitions: ................................................................................. 86 
9.4.2. 
Contraception Guidance: ............................................................ 86 
9.5. 
Appendix 5: Abbreviations and Trademarks .............................................. 88 
9.6. 
Appendix 6: Protocol Amendment History.................................................. 91 
9.7. 
Appendix 7: Country-Specific Protocol Addendums ................................... 94 
9.7.1. 
The Netherlands (27-MAY-2020) ................................................ 94 
9.7.2. 
South Africa (28-MAY-2020)....................................................... 94 
9.7.3. 
India (31-JUL-2020)_IND_01...................................................... 95 
9.7.4. 
Japan (22-JAN-2021)_JPN_04 ................................................... 96 
10. REFERENCES .................................................................................................. 103 
 


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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
A randomized, double-blind, placebo-controlled, study evaluating the efficacy and safety 
of otilimab IV in patients with severe pulmonary COVID-19 related disease. 
Brief Title: 
Investigating otilimab in patients with severe pulmonary COVID-19 related disease. 
Rationale: 
The aim of this study is to evaluate the benefit-risk of a single infusion of otilimab in the 
treatment of patients with severe pulmonary COVID-19 related disease.  
Objectives and Endpoints - Part 1: 
Objectives 
Endpoints 
Primary 
 To compare the efficacy of otilimab 90 
mg IV versus placebo 
 Participants alive and free of respiratory failure at Day 
28 
Secondary 
 To compare the efficacy of otilimab 90 
mg IV versus placebo 
 All-cause mortality at Day 60 
 Time to all-cause mortality up to Day 60 
 Participants alive and free of respiratory failure at Day 
7, 14, 42, and 60 
 Time to recovery from respiratory failure up to Day 28 
 Participants alive and independent of supplementary 
oxygen at Day 7, 14, 28, 42, and 60 
 Time to last dependence on supplementary oxygen up 
to Day 28 
 Admission to ICU up to Day 28 
 Time to final ICU discharge up to Day 28 
 Time to final hospital discharge up to Day 28 
 To compare the safety and tolerability 
of otilimab 90 mg IV versus placebo 
 Occurrence of adverse events (AEs) [up to Day 60] 
 Occurrence of serious adverse events (SAEs) [up to 
Day 60] 
Exploratory 
 To compare the efficacy of otilimab 
90 mg IV versus placebo 
Other endpoints up to Day 28 
 Invasive mechanical ventilation (if not previously 
initiated) 
 Time to invasive mechanical ventilation (if not 
previously initiated) 
 Alive and not invasively mechanically-ventilated 
 Time to definitive extubation 
 Improvement of at least 2 points relative to baseline of 
Sequential Organ Failure Assessment (SOFA) score 
 Improvement relative to baseline in SpO2, FiO2, and 
SpO2/FiO2 ratio 


T M F -1 1 7 9 5 6 0 7  
C O N FI D E N TI A L  
 
 
 
2 1 4 0 9 4  
1 3  
O bj e cti v e s  
E n d p oi nts  
 Oxy gen -fr ee days 
 Ventilator -fr e e days 
 Ti m e to r es olution of pyr exia (for at least 48h)  
Ot h er e n d p oi nt s u p t o Day 60  
 Clinic al status ass ess ed using an or dinal sc ale 1 
ass ess ed at Days 4, 7, 14, 28, 42, and 60  
 Ti m e to i m pr ov e m ent of at least 2 c ategories r elativ e to 
bas eline on an or dinal sc ale 1 
 Change in C O VI D -19 signs and sy m pto ms  
 T o deter mine the  phar m ac okinetics 
( P K) pr ofile of otili m ab 
P K E n d p oi nt s u p t o Day 14 
 Otili m ab clear anc e ( CL) and other P K par a m eters as 
appr opriate using s pars e P K s a m pling  
 T o deter mine:  
 Ex pos ur e -r es pons e. 
 P har m ac ody na mic ( P D) 
bio m ark ers  
 Changes in k ey m ark ers of 
infla m m atio n 
P D E n d p oi nt s u p t o Day 28 
 Ex pos ur e -r es pons e r elations hi p for k ey effic acy, s afety 
and P D endpoints  
 K ey m ark ers of infla m m ati on including, but not li mited 
to C R P, s er u m ferritin and infla m m atory cytokines as 
appr opriate 
 
1Or di n al S cale ( G S K mo difie d versi o n, a d a pt e d fr o m W H O , 2020 versi o n) 
 
 
O bje cti v e s a n d E n d p oi nts - P art 2  
O bj e cti v e s  
E n d p oi nts  
Pri m ar y  
 T o c o m par e the effic acy of otili m ab 90 
m g I V v ers us plac ebo  
 P articipants aliv e and fr ee of r es pir atory failur e at Day 
28 
Se c o n d ar y  
 T o c o m par e the effic acy of otili m ab 90 
m g I V v ers us plac ebo  
 All -c aus e m ortality at Day 28 
 All -c aus e m ortality at Day 60 
 Ti m e to all -c aus e m ortality up to Day 60 
 P articipants aliv e and fr ee of r es pir atory failur e at Day 
7, 14, 42, and 60 
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e 
pr ot e ct e d b y t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d b y 
t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.


T M F -1 1 7 9 5 6 0 7  
C O N FI D E N TI A L  
 
 
 
2 1 4 0 9 4  
1 4  
O bj e cti v e s  
E n d p oi nts  
 Ti m e to r ec ov ery fr o m r es pir atory failur e up to Day 28  
 P articipants aliv e and independe nt of s upple m entary 
oxy gen at Day 7, 14, 28, 42, and 60  
 Ti m e to last dependenc e  on s upple m entary oxy gen up 
to Day 28 
 Ti m e to final I C U disc har ge up to Day 28 
 Ti m e to first disc h arg e fro m i nvesti g ator site u p to 
D ay 6 0  
 Ti m e to first disc h arg e to n o n -h ospitalise d resi d e nc e 
u p to D ay 6 0  
 T o c o m par e the s afety and toler ability 
of otili m ab 90 m g I V v ers us plac ebo  
 Occ urr enc e of adv ers e ev ents ( A Es) [up to Day 60]  
 Occ urr enc e of s erious adv ers e ev ents ( S A Es) [up to 
Day 60]  
Expl or at or y  
 T o c o m par e the effic acy of otili m ab 
90 m g I V v ers us  plac ebo 
Ot h er e n d p oi nt s u p t o Day 28  
 Inv asiv e m ec hanic al v entilati o n (if not pr eviously 
initiate d) 
 Ti m e to inv asiv e m ec hanic al v entilati on (if not 
pr eviously initiate d)  
 Aliv e and not inv asiv ely m ec hanic ally -v entil ated 
 Ti m e to definitiv e extubatio n  
 Oxy gen -fr ee days 
 Ventilator -fr e e days 
 A d mission to I C U up to Day 28 
Ot h er e n d p oi nt s u p t o Day 60  
 Ti m e to i m pr ov e m ent of at least 2 c ategories r elativ e to 
bas eline on an or dinal sc ale 1 
 Change in C O VI D -19 signs and sy m pto ms  
 T o deter mine the phar m ac okinetics 
( P K) pr ofile of otili m ab 
P K E n d p oi nt s  u p t o Day 14  
 Otili m ab clear anc e ( CL) and other P K par a m eters as 
appr opriate using s pars e P K s a m pling  
 T o deter mine:  
 Ex pos ur e -r es pons e. 
 P har m ac ody na mic ( P D) 
bio m ark ers  
 Changes in k ey m ark ers of 
infla m m atio n 
P D E n d p oi nt s u p t o Day 28 
 Ex pos ur e -r es pons e r elations hi p for k ey effic acy, s afety 
and P D endpoints  
 K ey m ark ers of infla m m ati on including, but not li mited 
to C R P, s er u m ferritin and infla m m atory cytokines as 
appr opriate 
 
1Or di n al S cale ( G S K mo difie d versi o n, a d a pt e d fr o m W H O , 2020 versi o n) 
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d 
b y t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.


T M F -1 1 7 9 5 6 0 7  
C O N FI D E N TI A L  
 
 
 
2 1 4 0 9 4  
1 5  
 
O v e r all D e si g n:  
T his st u d y is a m ulti -c e nter, ra n d o mize d, d o u ble -blin d, pla c e b o -c o ntr olle d trial t o ass ess 
t he effic a c y a n d s afet y of otili ma b f or t he tre at me nt of s e vere p ul m o nar y C OVI D -1 9 
relate d dis e as e.  T he st u d y p o p ulatio n c o nsists of h os pitalize d participa nts wit h ne w o ns et 
h y p o xia re q uirin g sig nific a nt o x y ge n s u p p ort  or re q uirin g in vasive me c ha nic al ve ntilatio n 
(4 8 h o urs  bef ore d osin g ).  All participa nts will re c eive sta n dar d of c are as per 
instit utio nal pr ot oc ols, in a d ditio n t o st u d y tre at me nt. 
B rief S u m m ar y:  
P articipa nts will be re cr uite d fr o m t w o m ut ually -e xcl usive  c ate g ories wit hin t he or dinal 
s c ale: 
 
P art 1  
T he first 2 0 participa nts (initial s afet y c o h ort) will be fr o m c ate g or y 5 a b o ve 
(
).  
Sinc e t his is t he first ti me t hat otili ma b has be e n teste d in participa nts wit h s e vere 
p ul m o nar y C O VI D -1 9 relate d dis e as e, initial d osin g will be sta g gere d, a n d s afet y data 
re vie w e d.  U nless a s af et y sig nal is ide ntifie d d urin g t he o n g oin g s afet y re vie w b y t he 
G S K s afet y re vie w te a m (S R T ) a n d perio dic re vie w b y t he I n de pe n de nt D ata M o nit orin g 
C o m mitte e ( I D M C), e nr ol me nt of t he main c o h ort of participa nts will be initiate d, a n d 
t he e nr ol me nt rate will be c a p pe d t o c o ntr ol ra n d o mizatio n . 
P art 2  
After e valuatio n of t he pri mar y e n d p oint in P art 1, t he ne xt a p pr o xi mately 3 5 0 
participa nts will be a ge 7 0 ye ars o r a b o ve. 
N u m be r of P artici p a nts:  
P art 1  
A ma xi m u m of a p pr o xi mately 8 0 0 participa nts will be ra n d o mly assig ne d t o st u d y 
inter ve ntio n.  A n y participa nt w h o re c eives st u d y inter ve ntio n will be c o nsidere d  
e valua ble.  
P art 2  
A ma xi m u m of a p pr o xi mately 
3 5 0 participa nts will be ra n d o mly assig ne d t o st u d y 
inter ve ntio n.  A n y participa nt w h o re c eives st u d y inter ve ntio n will be c o nsidere d 
e valua ble .  
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e 
pr ot e ct e d b y t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.
C CI
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d 
b y t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.


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Intervention Groups and Duration: 
Participants will be randomized 1:1 by interactive response technology (IRT) in a blinded 
manner to receive either a blinded 1-hour infusion of otilimab 90 mg or placebo IV in 
addition to standard of care.  Participants will be assessed daily until Discharge (or 
Day 28, whichever is sooner), and followed up at Days 42 and 60 after randomization. 
Independent Data Monitoring Committee: Yes 
1.2. 
Schema 
 
 


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1.3. 
Schedule of Activities (SoA) – Part 1 
See Section 7 for further details of study procedures listed in the SoA. 
Assessments 
Screening2 
Day 1 Days 2-7 Day 144 Day 285 
Discharge / 
Early 
Withdrawal7  
Follow-up 
Phone call (D42 & 60 / 
Early Withdrawal)6, 7 
Notes 
Informed consent3 
X 
 
 
 
 
 
 
 
Eligibility assessment 
X 
 
 
 
 
 
 
 
Thoracic CT scan or chest X-ray 
X 
 
 
 
 
 
 
Chest X-ray or CT scan must be available 
at Screening to confirm a diagnosis of 
pneumonia and eligibility.  Record in the 
eCRF if a CT scan or chest X-ray is done 
between Screening and Discharge. 
Demography 
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
At Screening, record the signs and 
symptoms of COVID-19 at admission, as 
detailed in the eCRF. 
Daily clinical features of COVID-19 (for 
non-mechanically ventilated participants) 
 
=============== Daily1 =============== 
X 
Daily review of COVID-19 signs and 
symptoms, as detailed in the eCRF. 
Full physical examination 
X 
 
 
 
 
X 
 
 
12-lead ECG 
X 
X 
 
 
 
X 
 
Day 1 - record before dosing. 
Weight 
X 
 
 
 
 
 
 
 
Vital Signs:  blood pressure, pulse, 
respiratory rate and temperature 
X 
=============== Daily1 =============== 
 
Day 1 – measure pre-infusion and 
approximately 1 hour post-infusion.  
Measure daily AM (at about same time 
daily), as per standard of care (SoC). 
SpO2 (for participants not on invasive 
mechanical ventilation) 
X 
=============== Daily1 =============== 
 
Day 1 - record before dosing.  Measure 
daily AM and PM (at about same times 
daily), as per SoC. 
Concentration of inspired oxygen (FiO2) 
and / or oxygen flow rate (L/min) 
X 
=============== Daily1 =============== 
 
Day 1 - record before dosing.  Measure 
daily AM and PM (at about same times 
daily), as per SoC. 
Ventilation status, ICU admission and 
discharge, and ICU supportive care 
X 
=============== Daily1 ===============
X 
Includes ventilation status (method of non-
invasive ventilation or mechanical 
ventilation).  Record participant admission 
or discharge from the ICU.  Record 
oxygen treatment if used at home. 


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Assessments 
Screening2 
Day 1 Days 2-7 Day 144 Day 285 
Discharge / 
Early 
Withdrawal7  
Follow-up 
Phone call (D42 & 60 / 
Early Withdrawal)6, 7 
Notes 
Ordinal scale 
X 
=============== Daily1 =============== 
X 
Day 1 - record category before 
randomization (for stratification).   
Record daily AM (at about same time 
daily). 
SOFA score (ICU participants ONLY) 
X 
=============== Daily1 =============== 
 
Day 1 - record before dosing.  Record 
daily AM (at about same time daily), as per 
SoC. 
SAE/AE review 
X 
=============== Daily1 =============== 
X 
At Screening, only SAEs related to study 
participation or GSK concomitant 
medication will be recorded. 
Concomitant medication review 
X8 
=============== Daily1 =============== 
X 
 
Survival follow-up 
 
 
 
 
 
X 
X 
 
Laboratory Assessments 
Local Laboratory tests9 
X 
X 
X11 
X 
X 
X 
 
Day 1 - collect before dosing. 
Only if not discharged.  Refer to Table 3 
for the list of laboratory assessments 
required.  Collected at any time during the 
day, as convenient. 
Pregnancy test 
X 
 
 
 
 
X 
(verbal confirmation  
on Day 60) 
Local urine or serum test at Screening and 
Discharge.  Verbal confirmation of 
pregnancy status will be obtained at 
follow-up phone call. 
PD sample (cytokines)9 
X10 
 
X11 
 
 
 
 
Only if not discharged.  Collected at any 
time during the day, as convenient.  
Sample collection time must be recorded. 
PK sample 
 
X12 
X13 
X 
 
 
 
Only if not discharged.  Samples after Day 
1 can be collected at any time during the 
day, as convenient.  Sample collection 
time must be recorded. 


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Assessments 
Screening2 
Day 1 Days 2-7 Day 144 Day 285 
Discharge / 
Early 
Withdrawal7  
Follow-up 
Phone call (D42 & 60 / 
Early Withdrawal)6, 7 
Notes 
Treatment Administration 
Randomization 
 
X 
 
 
 
 
 
 
IV dosing with otilimab or placebo 
 
X 
 
 
 
 
 
1-hour IV infusion.  Record start and end 
times of the infusion.  Randomization and 
Dosing should be as close as possible. 
1. 
Assessment to be conducted every day from Day 1 until Discharge (or until Day 28 if the participant remains hospitalized). 
2. 
Up to 48 h before randomization.  If Screening and Randomization are within 24h, there is no need to repeat Day 1 pre-dose assessments (except Ordinal Scale and pre-infusion 
vital signs). 
3. 
Consent may be collected before the 48h screening window if the investigator considers that the participant is likely to become eligible, and wants to ensure that consent is given 
by the participant (rather than an LAR). 
4. 
If the participant is discharged before Day 13, the Day 14 and Day 28 visits will be replaced with a phone call (±2 days).  If the participant is discharged on Day 13, the Day 14 visit 
is not required, and the Day 28 visit will be a phone call (±2 days).  When visits are replaced with a phone call, complete the same assessments as the Day 42 or 60 phone call. 
5. 
If the participant is discharged between Day 15 and Day 27, the Day 28 visit will be replaced with a phone call (±2 days).  When visits are replaced with a phone call, complete the 
same assessments as the Day 42 or Day 60 phone call. 
6. 
Follow-up phone calls at Day 42 (±2 days) and Day 60 (±2 days).  If the participant has not been discharged, these will be visits. 
7. 
See Section 6.7 for information on Early Withdrawal. 
8. 
At Screening, prior medications will be recorded from the 14 days before Screening. 
9. 
If a cytokine release syndrome (CRS) is suspected (see Section 7.4.7.1), the following samples should be taken as soon as possible after suspected CRS onset and again 24 h 
later: Hematology, CRP, D-dimer, ferritin, PD sample (cytokines). 
10. Sample can be collected anytime from Screening up to start of infusion. 
11. Days 2, 4 and 7 only. 
12. Immediately after infusion. 
13. Days 2 and 7 only. 
 


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1.4. 
Schedule of Activities (SoA) – Part 2 
See Section 7 for further details of study procedures listed in the SoA. 
Assessments 
Screening3 
Day 1 Days 2-7 Day 145 Day 286 
Discharge / 
Early 
Withdrawal8  
Follow-up 
Phone call (D42 & 60 / 
Early Withdrawal)7, 8 
Notes 
Informed consent4 
X 
 
 
 
 
 
 
 
Eligibility assessment 
X 
 
 
 
 
 
 
 
Thoracic CT scan or chest X-ray 
X 
 
 
 
 
 
 
Chest X-ray or CT scan must be available 
at Screening to confirm a diagnosis of 
pneumonia and eligibility. Record in the 
eCRF if a CT scan or chest X-ray is done 
between Screening and Discharge. 
Demography 
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
At Screening, record the signs and 
symptoms of COVID-19 at admission, as 
detailed in the eCRF. 
SOFA score (intubated patients only) 
X 
 
 
 
 
 
 
 
Clinical features of COVID-19 (for non-
mechanically ventilated participants) 
 
X 
X1 
X 
X 
X 
X 
Review of COVID-19 signs and 
symptoms, as detailed in the eCRF. 
Full physical examination 
X 
 
 
 
 
X 
 
 
12-lead ECG 
X 
 
 
 
 
X 
 
Screening ECG can be taken any time 
before dosing to confirm eligibility. 
Weight and height 
X 
 
 
 
 
 
 
Weight and height can be estimated, refer 
to Section 7.3.2. 
Vital Signs: blood pressure, pulse, 
respiratory rate and temperature 
X 
X 
X1 
X 
X 
X 
 
Day 1 – measure pre-infusion and 
approximately 1 hour post-infusion. 
Measure AM (at about same time), as per 
standard of care (SoC). 
SpO2 (for participants not on invasive 
mechanical ventilation) 
X 
=============== Daily2 =============== 
 
Day 1 - record before dosing. Measure 
daily AM (at about same time), as per 
SoC. 
Concentration of inspired oxygen (FiO2) 
and / or oxygen flow rate (L/min) 
X 
=============== Daily2 =============== 
 
Day 1 - record before dosing. Measure 
daily AM (at about same time), as per 
SoC. 
Ventilation status, ICU admission and 
discharge, and ICU supportive care 
X 
=============== Daily2 ===============
X 
Includes ventilation status (method of non-
invasive ventilation or mechanical 


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Assessments 
Screening3 
Day 1 Days 2-7 Day 145 Day 286 
Discharge / 
Early 
Withdrawal8  
Follow-up 
Phone call (D42 & 60 / 
Early Withdrawal)7, 8 
Notes 
ventilation). Record participant admission 
or discharge from the ICU. Record oxygen 
treatment if used at home. 
Ordinal scale 
X 
=============== Daily2 =============== 
X 
Day 1 - record category before 
randomization (for stratification). 
Record daily AM (at about same time). 
SAE/AE review 
X 
=============== Daily2 =============== 
X 
At Screening, only SAEs related to study 
participation or GSK concomitant 
medication will be recorded. 
Concomitant medication review 
X9 
=============== Daily2 =============== 
X 
 
Survival follow-up 
 
 
 
 
 
X 
X 
 
Participant baseline and discharge 
location information 
X 
 
 
 
 
X 
X 
Refer to Section 7.2.7. At baseline, record 
the participant’s residence status before 
contracting COVID-19 and before initial 
hospital admission. 
Laboratory Assessments 
Local Laboratory tests10 
X 
X 
X1 
X 
X 
X 
 
Day 1 - collect before dosing. No need 
to collect after discharge.  Refer to Table 4 
for the list of laboratory assessments 
required. Collected at any time during the 
day, as convenient. 
PD sample (cytokines)10, 15 
X11 
 
X12 
 
 
 
 
No need to collect after discharge. 
Collected at any time during the day, as 
convenient.  Sample collection time must 
be recorded. If participants are discharged 
on a day when a PD sample is scheduled, 
the sample should be collected prior to 
discharge. 
PK sample15 
 
X13 
X14 
X 
 
 
 
No need to collect after discharge. After 
Day 1, samples can be collected at any 
time during the day, as convenient.  
Sample collection time must be recorded. 
If participants are discharged on a day 
when a PK sample is scheduled, the 


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Assessments 
Screening3 
Day 1 Days 2-7 Day 145 Day 286 
Discharge / 
Early 
Withdrawal8  
Follow-up 
Phone call (D42 & 60 / 
Early Withdrawal)7, 8 
Notes 
sample should be collected prior to 
discharge. 
Treatment Administration 
Randomization 
 
X 
 
 
 
 
 
 
IV dosing with otilimab or placebo 
 
X 
 
 
 
 
 
Approximately 1-hour IV infusion. Record 
start and end times of the infusion. 
Randomization and Dosing should be as 
close as possible on the same day. 
1. Assessment to be conducted on Days 4 and 7 (if not discharged). 
2. Assessment to be conducted every day from Day 1 until Discharge (or until Day 28 if the participant remains hospitalized). 
3. Up to 48 h before randomization.  If Screening and Randomization are within 24h, there is no need to repeat Day 1 pre-dose assessments (except Ordinal Scale and pre-infusion 
vital signs). 
4. Consent may be collected before the 48h screening window if the investigator considers that the participant is likely to become eligible, and wants to ensure that consent is given 
by the participant (rather than an LAR). 
5. If the participant is discharged before Day 13, the Day 14 and Day 28 visits will be replaced with a phone call (±2 days).  If the participant is discharged on Day 13, the Day 14 visit 
is not required, and the Day 28 visit will be a phone call (±2 days).  When visits are replaced with a phone call, complete the same assessments as the Day 42 or 60 phone call. 
6. If the participant is discharged between Day 15 and Day 27, the Day 28 visit will be replaced with a phone call (±2 days).  When visits are replaced with a phone call, complete the 
same assessments as the Day 42 or Day 60 phone call. 
7. Follow-up phone calls at Day 42 (±2 days) and Day 60 (±2 days).  If the participant has not been discharged, these will be visits. 
8. See Section 6.7 for information on Early Withdrawal. 
9. At Screening, record COVID-19 current vaccination status, and any other prior medications within 14 days before Screening. 
10. If a cytokine release syndrome (CRS) related to drug is suspected (see Section 7.4.7.1), the following samples should be taken as soon as possible after suspected CRS onset 
and again 24 h later: Hematology, CRP, D-dimer, ferritin, PD sample (cytokines). 
11. Sample can be collected anytime from Screening up to start of infusion. 
12. Days 2, 4 and 7 only. 
13. Immediately after infusion. 
14. Days 2 and 7 only. 
15. If central laboratory kits for PK/PD sampling are not available at a site (for operational reasons), participants can be randomised and dosed, and the PK or PD samples not 
collected (refer to Section 7.5 and Section 7.7. 
  


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2. 
INTRODUCTION 
Granulocyte-macrophage colony stimulating factor (GM-CSF) is a hemopoietic growth 
factor and a key mediator of tissue inflammation, that signals through the GM-CSFα/β 
receptor complex.  GM-CSF has multiple cellular sources, including monocytes, 
macrophages, T cells, B cells, neutrophils and tissue resident cells [Wicks, 2016].  GM-
CSF exerts multiple pro-inflammatory effects on myeloid cells including macrophages, 
monocytes and neutrophils.  Pre-clinical models and human clinical trials have 
demonstrated that neutralizing GM-CSF or blocking the GM-CSFRα subunit can be 
efficacious in inflammatory diseases such as rheumatoid arthritis.  Otilimab is a fully 
human anti-GM-CSF monoclonal antibody (mAb) that has been well tolerated by 
subjects and demonstrates anti-inflammatory activity in RA patients (phase 3 clinical 
trials ongoing). 
Emerging data from COVID-19 patients indicate that GM-CSF may play an important 
role in the acute hyper-inflammatory state associated with severe stages of illness.  
Treatment with an anti-GM-CSF receptor (anti-GM-CSFR) mAb (mavrilimumab) was 
well tolerated, reduced fever and improved oxygenation in 6 patients experiencing a steep 
decline of pulmonary status due to COVID-19 pneumonia.  All patients were reported to 
respond to treatment, and 3 out of the 6 patients were discharged within 5 days [Kiniksa, 
2020], further supporting the scientific rationale to evaluate the efficacy of otilimab in 
these patients. 
Update for Part 2 
New literature data has associated raised levels of GM-CSF in the circulation of COVID-
19 patients with age, disease severity and mortality [Hue, 2020; Thwaites, 2020].  
Furthermore, dysregulation of the circulating myeloid cell compartment involving 
inflammatory / dysfunctional / maladapted monocytes and neutrophils is being 
increasingly recognised as a key driver of severe COVID-19 disease.  GM-CSF targets 
monocytes, macrophages and neutrophils and GM-CSF as a key driver of severe COVID-
19 disease has been widely proposed [Bonaventura, 2020; Lang, 2020; Mehta, 2020a].  
The scientific rationale supporting targeting GM-CSF in severe COVID-19 disease is 
also supported by use of an anti-GM-CSF receptor (anti-GM-CSFR) mAb 
(mavrilimumab) in the clinic.  Mavrilimumab was shown to be well tolerated and clinical 
outcomes compared with standard care in 17 non-mechanically ventilated patients with 
severe COVID-19 pneumonia and systemic hyperinflammation (17 patients, single-centre 
prospective cohort study [De Luca, 2020]. 
2.1. 
Study Rationale 
A subset of patients with SARS-CoV-2 infection develop pulmonary complications and 
may transition to a form of acute respiratory distress syndrome (ARDS) and the most 
severe stage of illness, which manifests as an extra-pulmonary, systemic hyper-
inflammation syndrome [Siddiqi, 2020].  Markers of systemic inflammation appear to be 
elevated at this disease stage and have shown that inflammatory cytokines such as IL-2, 
IL-7, G-CSF, MCP-1, MIP-1α and TNFα were significantly elevated, particularly in 
COVID-19 patients requiring ICU treatment compared with those not requiring ICU 


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treatment [Huang, 2020].  Elevated levels of IL-6 have also been detected in COVID-19 
patients and have been correlated with adverse patient outcomes [Coomes, 2020]. 
In healthy subjects, GM-CSF is not detectable in the circulation, however, GM-CSF was 
detectable in plasma of some COVID-19 patients whether they received ICU care or not 
[Huang, 2020].  In a separate study, numbers of GM-CSF-expressing monocytes, T -
cells, B cells and NK cells were found in the blood of COVID-19 ICU and non-ICU 
patients compared with healthy controls.  The COVID-19 ICU patient group also had 
increased numbers of CD4+ T cells co-expressing GM-CSF and IFNγ, as well as 
increased numbers of GM-CSF+ CD8+ T cells compared with non-ICU patients [Zhou, 
2020]. 
GM-CSF is well known to drive monocytes/macrophages into proinflammatory 
phenotypes that are primed to produce inflammatory cytokines including TNFα, IL-1β 
and IL-6 [Hamilton, 2019; Wicks, 2016].  The observation that GM-CSF neutralization 
prevented IL-6, IL-8 and MCP-1 cytokine release by monocytes in a co-culture CAR T-
cell assay [Sachdeva, 2019], and cytokine release in a humanized CAR T-cell xenograft 
mouse model [Sterner, 2019], suggests a role for GM-CSF as a driver of hyper-
inflammation and cytokine release syndrome (CRS). 
Therefore, by blocking GM-CSF signaling, an anti-GM-CSF mAb such as otilimab is 
hypothesized to work “upstream” of IL-6 in the hyper-inflammatory processes triggered 
by SARS-CoV-2 infection and will directly inhibit proinflammatory activities of 
monocytes/macrophages (e.g. by reducing TNFα, IL-1β and IL-6 production) that 
perpetuate inflammation and cause tissue damage. 
Otilimab, an anti-GM-CSF mAb, is currently in phase 3 development (ContRAst 
program) for rheumatoid arthritis (RA) following phase 2 results, which showed a 
positive efficacy and safety profile based on a large clinically-driven response for joint 
improvement and pain. 
In addition, lenzilumab (KB003), another anti-GM-CSF mAb dosed IV over 20 weeks 
was generally well tolerated in a placebo-controlled study in inadequately controlled 
asthma patients, with no safety signals of concern and no increase in infection rate 
[Molfino, 2016].  Moreover, there were no dose limiting toxicities identified and no 
treatment emergent, study drug-related, grade 3 or 4 toxicities reported in a phase 1 study 
of lenzilumab dosed in 15 patients with chronic myelomonocytic leukemia [Patnaik, 
2020]. 
Otilimab has not previously been tested in patients with severe pulmonary COVID-19 
related disease.  This study aims to show that otilimab improves the respiratory status of 
patients with severe pulmonary COVID-19 related disease compared with standard of 
care.  In order to understand risk and benefit in a stepwise fashion, the study has a leading 
cohort with detailed safety assessments to provide early evidence of safety prior to the 
larger cohort of patients to provide further confirmatory efficacy and safety data that may 
facilitate early access to patients. 


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Update for Part 2 
Recent literature data have shown GM-CSF to be particularly elevated in hospitalised 
COVID-19 patients 70 years not requiring oxygen, and in all patient ages with severe 
disease [Thwaites, 2020] and was associated with mortality [Hue, 2020; Thwaites, 2020].  
Age is widely recognised as the most significant risk factor for severe COVID-19 disease 
and immune cell changes in severe COVID-19 disease bear resemblance to those 
observed in the aging immune system [Hazeldine, 2020; Pietrobon, 2020; Salimi, 2020].  
The ageing immune system is characterized by an expansion of inflammatory / 
dysfunctional monocytes, reduced lymphocyte function, reduced naïve T cell numbers 
and dysregulated myeloid cell responses [Aiello, 2019; Hazeldine, 2020; Pietrobon, 
2020; Salimi, 2020].  These changes result in a reduced ability of older individuals to 
respond to novel antigens and increased levels of circulating inflammatory mediators.  
This may predispose older patients to the development of severe COVID-19 disease with 
resultant increased viral load, increasing immune cell accumulation and further 
dysregulating monocytes, macrophage and neutrophil activities (in the circulation and the 
lung) [Pence, 2020; Pietrobon, 2020].  Post-mortem findings in fatal COVID-19 disease 
have shown the inflammatory infiltrate in lungs and other organs consists of high levels 
of macrophages and neutrophils [Carsana 2020; Nienhold, 2020; Schurink, 2020]. 
Therefore, targeting GM-CSF may prove more beneficial in severe COVID-19 patients 
aged 70 years. 
Otilimab has been tested in patients with severe pulmonary COVID-19 related disease in 
Part 1 of this study, with evidence of efficacy in the pre-defined stratification group of 
participants 70 to <80 years old, with no safety concerns.  The second part of this study 
aims to confirm that otilimab improves the recovery of patients 70 years old with severe 
pulmonary COVID-19 related disease. 
2.2. 
Background 
2.2.1. 
Role of GM-CSF in inflammation 
Originally identified as a hematopoietic growth factor, GM-CSF is now recognized as a 
key driver of tissue inflammation that exerts multiple pro-inflammatory effects on 
myeloid cells.  The cellular sources of GM-CSF include T cells, B cells, monocytes, 
macrophages, neutrophils and tissue resident cells [Wicks, 2016] and GM-CSF signals 
via the GM-CSFα/β receptor complex which is expressed on myeloid cells.  GM-CSF 
promotes survival and polarizes monocytes/macrophages into pro-inflammatory 
phenotypes that are primed to produce pro-inflammatory cytokines including TNFα, 
IL-1β and IL-6 [Hamilton, 2019].  GM-CSF also extends neutrophil survival, primes the 
neutrophil oxidative burst, enhances phagocytosis and promotes neutrophil adhesion to 
endothelial cells and promotes neutrophil trafficking to sites of inflammation [Wicks, 
2016]. 
Therapeutic inhibition of GM-CSF signaling by mavrilimumab in RA subjects has been 
shown to reduce circulating serum IL-6 levels and indirectly suppress T-cell activation 
[Guo, 2018].  Efficacy and safety data from clinical trials in rheumatoid arthritis (RA) 


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patients indicate that inhibition of GM-CSF or its receptor is anti-inflammatory and well 
tolerated with long-term dosing [Burmester, 2018; Taylor, 2019]. 
2.2.2. 
Scientific rationale to inhibit GM-CSF in COVID-19 patients 
Some patients with severe acute respiratory syndrome–coronavirus-2 (SARS-CoV-2) 
infection develop pulmonary complications and may transition to acute respiratory 
distress syndrome (ARDS) and the most severe stage of illness, which manifests as an 
extra-pulmonary, systemic hyper-inflammation syndrome.  It is widely proposed that 
intervention with immunomodulatory therapies to reduce this hyper-inflammatory state 
could be beneficial, particularly in the later and more severe stages of COVID-19 disease 
[Mehta, 2020b; Siddiqi, 2020]. 
COVID-19 pneumonia patients have serological markers associated with macrophage 
activation syndrome and the limited COVID-19 post-mortem data available shows 
prominent alveolar edema, hyalinosis (intra-alveolar proteinosis) and fibrin deposition 
with pneumocytes viral cytopathic change and immune cell infiltration [McGonagle, 
2020].  Pulmonary post-mortem findings from 38 COVID-19 cases from Italy have 
shown that inflammatory infiltrate was composed by macrophages in alveolar lumens and 
lymphocytes mainly in the interstice [Carsana, 2020].  Therefore, in later stages of severe 
disease suppressing hyper-inflammatory processes (“cytokine storm syndrome” [Mehta, 
2020b]) with an immunomodulator would be important to limit further lung damage, 
prevent respiratory failure, shock, and multi-organ failure. 
In health, GM-CSF is not detectable in the circulation, however, GM-CSF was detectable 
in plasma of some COVID-19 patients whether they received ICU care or not [Huang, 
2020].  In a separate study, increased numbers of GM-CSF-expressing monocytes, T-
cells, B cells and NK cells were found in the blood of COVID-19 ICU and non-ICU 
patients compared with healthy controls.  The COVID-19 ICU patient group also had 
increased numbers of CD4+ T cells co-expressing GM-CSF and IFNγ, as well as 
increased numbers of GM-CSF+ CD8+ T cells compared with non-ICU patients [Zhou, 
2020]. 
COVID-19 patients have increased numbers of circulating GM-CSF+ monocytes 
compared to healthy controls.  ICU treated patients also have increased numbers of IL-6+ 
monocytes and CD14+CD16+ monocytes compared with non-ICU patients [Zhou, 2020]. 
A small study has also shown that pro-inflammatory monocyte-derived macrophages 
dominate over resident alveolar macrophages in the lungs of patients with severe 
COVID-19, whereas resident alveolar macrophages predominated in the lungs of 
mild/recovering COVID-19 patients [Liao, 2020].  The existence of these monocyte-
derived macrophages suggests that activated monocytes infiltrate the injured lung from 
the blood, release inflammatory cytokines and may differentiate into activated 
macrophages.  It has been proposed that in severe or critical COVID-19 cases, since the 
lung barrier integrity is interrupted, monocytes and neutrophils are chemotactic to the 
infection site to clear exudates with virus particles and infected cells, resulting in 
uncontrolled inflammation.  In this process, because of the substantial reduction and 
dysfunction of lymphocytes, the adaptive immune response cannot be effectively 
initiated, and the uncontrolled virus infection leads to more macrophage infiltration and a 


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further worsening of lung injury [Li, 2020].  GM-CSF is well known to drive 
monocytes/macrophages into proinflammatory phenotypes that are primed to produce 
inflammatory cytokines including IL-6, TNF and IL-1β [Hamilton, 2019; Wicks, 2016]. 
The observation that GM-CSF neutralization prevented IL-6, IL-8 and MCP-1 cytokine 
release by monocytes in a co-culture CAR T-cell assay [Sachdeva, 2019], and that GM-
CSF neutralization prevented human VEGF, IP10 and IL-1R cytokine release and 
murine IP10 and MCP-1 chemokine release in a humanized CAR T-cell xenograft mouse 
model [Sterner, 2019], suggests a role for GM-CSF as a driver of hyper-inflammation 
and cytokine release syndrome (CRS). 
As well as GM-CSF, other markers of systemic inflammation are elevated in hospitalized 
COVID-19 patients [Huang, 2020].  Plasma levels of IL-1β, IL-1Rα, IL-6, IL-8, IL-9, IL-
10, IFNγ, IP-10, MIP-1β, PDGF, and VEGF concentrations were higher in both ICU 
patients and non-ICU COVID-19 patients than in healthy controls.  Plasma levels of IL-2, 
IL-7, G-CSF, MCP-1, MIP-1α and TNFα were significantly elevated in COVID-19 
patients requiring ICU treatment compared with those not requiring ICU treatment 
[Huang, 2020].  Elevated levels of IL-6 are reported in COVID-19 patients and have been 
correlated with adverse patient outcomes [Coomes, 2020]. 
These observations support the hypothesis that hyper-inflammation leads to poor 
outcome in hospitalized patients, transition to ICU/ventilator and death due to cytokine 
storm and organ damage.  In these patients there is a strong rationale that inhibiting 
hyper-inflammatory processes with targeted immunomodulatory approaches would be 
beneficial [Mehta, 2020b; McGonagle, 2020]. 
Update for Part 2 
More recent studies have reported that levels of some inflammatory mediators, including 
IL-6, are elevated in COVID-19 [Kox, 2020; Sinha, 2020], but are typically ten times 
lower than those reported in acute respiratory distress syndrome (ARDS) and sepsis 
[Damas, 1992] suggesting that other factors may play a major role in COVID-19 severity. 
The latest data from the CDC show the increases in risk of death for COVID-19 patients 
were 10x, 30x, 90x, 220x, and 630x higher for patients in the 40-49, 50-64, 65-74, 75-84, 
and 85+ year age groups, respectively, than those in the 18-29 age group [CDC, 2020].  
In addition, it is clear that mortality increases significantly with age for COVID-19 
patients in US intensive care units (ICUs) with 17.1%, 25.5%, 36.3%, 45.1%, and 48.9% 
in the 40-49, 50-59, 60-69, 70-79, and 80+ year old groups dying (GSK analysis, data on 
file).  Similar trends have been reported in the UK, with 17%, 24%, 42%, 55%, and 65% 
of COVID-19 patients in the 40-49, 50-59, 60-69, 70-79, and 80+ year old groups dying 
within 28 days; and patients aged 70 accounted for 27% of all patients recently admitted 
to ICUs [ICNARC, 2021]. 
Emerging analyses of circulating immune cells have revealed that severe COVID-19 is 
marked by a dysregulated myeloid cell compartment involving emergency myelopoiesis 
with both dysfunctional/maladapted and immature monocytes and neutrophils [Mann, 
2020; Schulte-Schrepping, 2020].  Changes in COVID-19 monocyte function and 
phenotype have been proposed to resemble those that occur with age and have been 


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hypothesised to be a potential mechanism predisposing older patients to increased 
morbidity and mortality due to SARS-CoV-2 infection [Pence, 2020; Pietrobon, 2020].  
In addition, single-cell studies of bronchoalveolar lavage samples suggest dysregulated 
pulmonary immune responses, resulting in pro-inflammatory monocyte-derived 
macrophages dominating over resident alveolar macrophages in the lungs of severe 
COVID-19 patients [Liao, 2020].  Moreover, post-mortem findings in fatal COVID-19 
disease have shown the inflammatory infiltrate in lungs and other organs consists of high 
levels of neutrophils and macrophages as well as neutrophilic plugs [Carsana 2020; 
Nienhold, 2020; Schurink, 2020]. 
SARS-CoV-2 infection has been shown to cause increased expression of pulmonary 
epithelial GM-CSF [Blanco-Melo, 2020; Chandrashekar, 2020], and persistent activation 
of GM-CSF has been proposed to contribute to injurious lung inflammation preclinically 
[Halstead, 2015].  Intranasal administration of an anti-GM-CSFRα or anti-GM-CSF 
monoclonal antibody inhibited cell influx and inflammation in the lungs of mice 
challenged with LPS [Alessandris, 2019; Bozinovski, 2002].  Neutralization of GM-CSF 
was shown to dose-dependently suppress neutrophilic inflammation, inhibit TNF mRNA 
expression, reduce macrophage replication and suppress matrix metalloprotease 9 (MMP-
9) levels and activity [Bozinovski, 2002; Bozinovski, 2004].  MMP-9 is a protease that 
degrades extracellular matrix proteins and an early increase in circulating MMP-9 has 
been observed in COVID-19 patients with respiratory failure [Ueland, 2020]. 
Therefore, by blocking GM-CSF signalling, an anti-GM-CSF mAb is hypothesized to 
have beneficial effects on the hyperinflammatory state associated with severe COVID-19 
disease and poor patient outcomes in patients aged 70 for a number of reasons.  Firstly, 
elevated circulating GM-CSF levels have been associated with disease severity and 
mortality in COVID-19 patients [Hue, 2020; Thwaites, 2020] and raised GM-CSF levels 
are already evident in hospitalised 70 year old COVID-19 patients not requiring oxygen 
[Thwaites, 2020].  Secondly, changes in COVID-19 monocyte function and phenotype 
have been proposed to resemble those that occur with age and have been hypothesised to 
be a potential mechanism predisposing older patients to severe COVID-19 disease 
[Pence, 2020].  Thirdly, as the main target for GM-CSF is myeloid cells and 
dysfunctional/inflammatory/maladapted monocytes and macrophages are associated with 
severe COVID-19 disease, blocking GM-CSF may have broad immunomodulatory 
effects.  For example, it could affect monocyte/macrophage production of multiple pro-
inflammatory cytokines, chemokines and other mediators that lead to hyperinflammation, 
tissue damage, end organ failure and drive severe COVID-19 pathogenesis [Bonaventura, 
2020; Lang, 2020; Mehta, 2020a]. 
2.2.3. 
Timing of GM-CSF inhibition in COVID patients 
GM-CSF is not produced in most healthy tissues, but local alveolar production of GM-
CSF is necessary for mature alveolar macrophage differentiation and lung homeostasis 
function over the long term.  Complete genetic or auto-antibody ablation of GM-CSF (or 
its receptor) eventually results in pulmonary alveolar proteinosis (PAP), however this is 
likely not to be a concern in severe pulmonary COVID-19 related disease since PAP 
takes many months/years to develop [Sakagami, 2010; Trapnell, 2019], and has not been 


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observed following long-term inhibition of GM-CSF signaling with an anti-GM-CSF 
mAb (mavrilimumab) treatment in RA patients [Burmester, 2018]. 
Increased levels of GM-CSF in bronchoalveolar lavage (BAL) fluids on Day 1 and 3 of 
diagnosis with ARDS was associated with improved survival [Matute-Bello, 2000], and a 
second study of 29 critically-ill patients within 24 hours of diagnosis with ventilator-
associated pneumonia (VAP) demonstrated that higher GM-CSF/TGFβ1 BAL ratios 
correlated with increased patient survival [Overgaard, 2015].  However, administration of 
recombinant GM-CSF by intravenous (IV) infusion daily for 14 days evaluated in a 
randomized phase II trial in 130 patients with acute lung injury (ALI)/ARDS had no 
effect on ventilator-free days, mortality or organ failure [Paine, 2012]. 
Intranasal administration of an anti-GM-CSFR or anti-GM-CSF monoclonal antibody 
inhibited cell influx and inflammation in the lungs of mice challenged with LPS 
[Alessandris, 2019; Bozinovski, 2002].  Neutralization of GM-CSF was shown to dose-
dependently suppress neutrophilic inflammation, inhibit TNF mRNA expression, 
suppress matrix metalloprotease 9 (MMP9) levels and activity, and reduce macrophage 
replication [Bozinovski, 2002; Bozinovski, 2004]. 
Conversely, preclinical studies assessing influenza A infection in mice deficient in GM-
CSF or its receptor have demonstrated a more severe viral infection in the absence of 
pulmonary GM-CSF signaling; whereas intranasal administration of GM-CSF to 
wildtype mice or GM-CSF overexpression in the airways of GM-CSF knockout mice 
reduced mortality following influenza A infection [Halstead, 2015; Halstead, 2018; 
Huang, 2011].  However, it has been speculated that at high influenza viral titer, 
persistent activation of GM-CSF as induced by highly pathogenic influenza strains, GM-
CSF may contribute to injurious inflammation [Halstead, 2015]. 
Thus, local lung expression of GM-CSF in the early stages of COVID-19 related 
pulmonary disease in patients may help control viral titer and to maintain the epithelial 
lung barrier.  As the disease progresses to hypoxia, controlling the viral load is thought to 
be less important, whereas suppressing the systemic hyper-inflammatory process 
(“cytokine storm syndrome” [Mehta, 2020b]) is much more important to limit further 
lung damage, prevent respiratory failure, shock, and multi-organ failure.  Therefore, once 
hypoxia occurs in COVID-19 patients, it is reasonable to propose that reducing systemic 
hyper-inflammatory processes with targeted immunomodulatory approaches may be most 
beneficial [Mehta, 2020b]. 
To support this, there have been several reports of anti-IL-6 mAbs having some benefit in 
small studies of patients with severe pulmonary COVID-19 related disease where 
beneficial clinical response has been inferred by outcomes such as reduction in fever, 
oxygen requirements, C-reactive protein (CRP), radiological pulmonary abnormalities 
[Roche, 2020; Xu, 2020], or need for ventilation [Hermine, 2020].  Moreover, review of 
interim data from an ongoing large phase 3 study of sarilumab led to a recommendation 
by the IDMC to continue only in the more advanced “critical” group whose outcomes had 
improved and discontinuing the less advanced “severe” group, without any new safety 
findings [Sanofi, 2020].   


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By blocking GM-CSF signaling, an anti-GM-CSF mAb such as otilimab is hypothesized 
to work “upstream” of IL-6 in the hyper-inflammatory processes triggered by SARS-
CoV-2 infection and will directly inhibit proinflammatory activities of 
monocytes/macrophages (e.g. by reducing IL-6, TNF and IL-1 production) that 
perpetuate inflammation and cause tissue damage.  In addition, as described previously, 
early experience in treating COVID-19 patients with severe pulmonary disease with an 
anti-GM-CSF receptor mAb (mavrilimumab) has been well tolerated and demonstrated 
clinical benefit through fever reduction and improved oxygenation. 
Update for Part 2 
As discussed above, recent publications suggest that the severity of COVID-19 disease is 
driven by a maladaptive innate immune response in which GM-CSF plays a key role and 
where an aging immune system may predispose older patients to the worst outcomes.  
Therefore, targeting GM-CSF may prove more beneficial in severe COVID-19 patients 
aged 70 years.  This hypothesis is supported by the preliminary clinical efficacy 
findings with otilimab in Part 1.  The second part of this study aims to confirm that 
otilimab facilitates the recovery of patients 70 years old with severe pulmonary COVID-
19 related disease.   
As of the date of approval of this protocol amendment, no targeted immunomodulatory 
therapy has been demonstrated to improve oxygen requirements, recovery from 
respiratory failure, or reduce mortality in a patient population with severe COVID-19-
related pulmonary disease. 
 


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2.3. 
Benefit/Risk Assessment 
The potential risk assessment and mitigation strategy for the administration of otilimab in this protocol is outlined below. 
2.3.1. 
Risk Assessment 
More detailed information about the known and expected benefits and risks and reasonably expected adverse events of otilimab may be 
found in the Investigator’s Brochure (IB).  The assessment of potential risks and mitigation strategy for the administration of otilimab in 
this protocol is outlined below. 
Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Study Intervention(s) Otilimab 
Cytokine release syndrome (CRS) 
CRS is a systemic inflammatory response caused by 
the release of inflammatory cytokines, such as IL-6, 
tumor necrosis factor alpha (TNFα), by lymphocytes 
(B cells, T cells, and/or natural killer cells) and/or 
myeloid cells (macrophages, dendritic cells, and 
monocytes).  This can lead to a constellation of 
clinical symptoms including fever, flu-like symptoms, 
hypotension, to severe inflammatory syndrome 
leading to widespread organ dysfunction, even 
death.  It is not expected that the inhibition of GM-
CSF signaling, by administration of otilimab, would 
carry the risk of directly inducing CRS. 
Pre-Clinical Data 
GM-CSF neutralization in CAR T-cell assays or in 
vivo models  inhibited cytokine release [Sachdeva, 
2019; Sterner, 2019].  In vitro otilimab showed 
variable results, with evidence of cytokine elevation 
at elevated levels of otilimab (50 and 100 µg/mL). 
Primate toxicology studies demonstrated no 
evidence of CRS with concentrations at Cmax of 
2,690 µg/mL (54x higher than anticipated human 
levels) and substantial safety margin for AUCs. 
Mitigation: 
Part 1:  
 To mitigate the uncertainty around safety and 
tolerability of otilimab IV, dosing will occur in an 
initial safety cohort of 20 non-mechanically 
ventilated participants, and these participants will 
be closely monitored and dosed in a staggered 
manner (see Section 4.1). 
 Unless a safety signal is identified during the 
ongoing safety review by the GSK SRT and 
periodic review by the IDMC, enrolment of the 
main cohort of participants will be initiated. 
Part 1 and Part 2 
 Careful dose selection. 
 Exclusion of participants who do not require 
oxygen therapy, and estimated GFR 
30 mL/min/1.73m2 (Section 5.3 and Section 
5.4, Exclusion Criteria). 
Monitoring: 
Part 1 
 All participants will be hospitalized during 
infusion and will be closely monitored for signs 
and symptoms of CRS (defined as a worsening 


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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Clinical Data: 
There has been no evidence of cytokine release or 
symptoms suggestive of CRS in any human study 
with otilimab or in Part 1 of the study.  PK data from 
IV administration of absolute doses of otilimab 90 
mg or higher is available from a total of 46 HVs and 
patients, with a maximum concentration of 56 µg/mL 
in one HV. 
of the CTCAE CRS Grade, Section 7.4.7.1.  
Cytokine Release Syndrome) within 6 hours of 
infusion. 
 CRS (considered not related to COVID-19) is 
categorized as an AESI. 
 Evidence of CRS that occurs within 6 hours of 
infusion and demonstrated as worsening of CRS. 
 In the event of CRS (considered not related to 
COVID-19), investigators should follow 
institutional guidelines for symptom 
management. 
 In the event that new onset of CRS (considered 
not related to COVID-19) is suspected, the 
medical monitor must be notified immediately 
and under no circumstance can this exceed 
24 hours, and the event must also be reported 
within 24 hours as an AE or an SAE. 
Part 2 
 All participants will be hospitalized during 
infusion and will be closely monitored for signs 
and symptoms of CRS (Section 7.4.7.1) within 
6 hours of the start of infusion. 
 CRS (considered not related to COVID-19) of 
new onset or worsening of CRS grade, and 
occurring within 6 hours from the start of infusion 
is categorized as an AESI and must be reported 
as an AE or SAE. 
 If CRS (considered not related to COVID-19) 
does occur, the medical monitor must be notified 
immediately (within 24 hours). 
Serious hypersensitivity reactions 
There is a potential risk of hypersensitivity reactions, 
including anaphylaxis, during and following the 
administration of protein-based products, such as 
otilimab. 
Mitigation: 
 Exclusion of participants with a history of allergic 
reaction, including anaphylaxis to any previous 
treatment with an anti-GM-CSF therapy (Section 
5.3 and Section 5.4 Exclusion Criteria) 


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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Clinical Data: 
No serious allergic or acute systemic reactions have 
been observed in completed clinical trials with 
otilimab. 
In Part 1 of Study 214094, a participant developed 
toxic epidermal necrolysis 32 days after a single 
dose of otilimab 90 mg administered intravenously 
with a fatal outcome. The participant received 
confounding concomitant medications, including 
sertraline, lansoprazole, piperacillin/tazobactam, 
cefotaxime and rovamycine. 
Monitoring: 
 Serious hypersensitivity reactions are 
categorized as AESIs. 
 Hypersensitivity to be managed appropriately per 
local guidelines/medical judgement 
 All participants hospitalized during infusion and 
will undergo monitoring for hypersensitivity 
reactions 
Infusion site reactions 
Infusions may be associated with local reactions 
(e.g. swelling, induration, pain). 
Non-clinical Data: 
No macroscopic or microscopic changes indicative 
of local injection site reactions were observed 
following SC administration in cynomolgus monkeys. 
Clinical Data: 
Injection/infusion site reactions have been reported 
in completed Phase II studies with otilimab and were 
non-serious and of mild to moderate intensity. 
Monitoring: 
 Infusion site reactions are categorized as AESIs 
 Monitor for infusion site reactions throughout 
study. 
Neutropenia  Grade 3 (<1.0 x 109/L) 
Although there is a perceived theoretical risk that 
GM-CSF blockade may affect maturation of 
leukocytes and their precursors, mice lacking GM-
CSF do not develop neutropenia or show any major 
perturbation of hematopoiesis [Stanley, 1994]. 
Clinical Data: 
Neutropenia has been observed in completed 
studies of otilimab; however, no clinically significant 
cases have been observed. 
Mitigation: 
Part 1  
Exclusion of participants with ANC <1.5 x 109/L 
(neutropenia  Grade 2) (Section 5.3 Exclusion 
Criteria) 
Part 2  
Exclusion of participants with ANC <1.0 x 109/L 
(neutropenia  Grade 3) (Section 5.4 Exclusion 
Criteria) 
Monitoring: 
 Neutropenia Grade 3 (<1.0 x 109/L) is 
categorized as an AESI. 
 Full blood count (with differential) performed 
throughout hospitalization. 


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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Infections 
Immune-modulating biologic drugs are associated 
with an increased risk of serious and opportunistic 
infections.  Because of the role of GM-CSF in anti-
infective immunity, otilimab also has the potential to 
increase the risk of infection.  GM-CSF has been 
noted to play a role in helping the lung fight infection 
and recover from any injury.  Therefore, it is possible 
that otilimab, by blocking GM-CSF, may affect the 
ability of the lungs to fight lung infection or properly 
recover from infection 
Non-clinical Data: 
Studies in knock-out mice showed that GM-CSF 
deficiency affects the ability of mice to control 
infection when infected with M. tuberculosis or 
pulmonary group B streptococcus [Paine, 2001; 
LeVine, 1999]. 
No changes in peripheral blood populations 
(lymphocytes, neutrophils, monocytes, eosinophils 
or basophils), phagocytic activity of peripheral blood 
polymorphonuclear cells (investigational endpoint in 
the 26 week study), T-cell dependent B-cell primary 
or secondary response, or circulating cytokine levels 
(26 week study) were observed. 
Clinical Data: 
Based on the mechanism of action of otilimab an 
increased risk of infection including TB, fungal and 
opportunistic infections could be expected for anti-
GM-CSF treatment, because of the role of GM-CSF 
in anti-infective immunity. 
One healthy subject in study MSC-1000 experienced 
septic shock secondary to pneumonia 29 days after 
receiving a single dose of 1.5 mg/kg but recovered 
after treatment with antibiotics. 
In Phase II completed studies, no significant 
infections or opportunistic infections were reported. 
Eligibility Criteria  
Exclusion of participants with: 
 Untreated systemic bacterial, fungal, viral, or 
other infection (other than SARS-CoV-2). 
 Known active tuberculosis (TB), history of 
untreated or incompletely treated active or latent 
TB, suspected or known extrapulmonary TB 
 Known HIV regardless of immunological status 
 Known HBsAg and/or anti-HCV positive 
 Part 1: Absolute neutrophil count (ANC) <1.5 x 
109/L (neutropenia  Grade 2) 
 Part 2: ANC <1.0 x 109/L (neutropenia  Grade 
3) 
 Received monoclonal antibody therapy (e.g. 
tocilizumab, sarilumab) within the past 3 months 
prior to randomization, including intravenous 
immunoglobulin, or planned to be received 
during the study 
 Part 1: Received immunosuppressant therapy 
including but not limited to cyclosporin, 
azathioprine, tacrolimus, mycophenolate, janus 
kinase (JAK) inhibitors (e.g. baricitinib, tofacitinib, 
upadacitinib) within the last 3 months prior to 
randomization or planned to be received during 
the study. 
 Part 2:  Received immunosuppressant therapy 
including but not limited to cyclosporin, 
azathioprine, tacrolimus, mycophenolate, JAK 
inhibitors (e.g. baricitinib, tofacitinib, 
upadacitinib), nintedanib, disease-modifying 
antirheumatic drugs (DMARDs, e.g. 
methotrexate) within the last 3 months prior to 
randomization or planned to be received during 
the study. 


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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
 Currently receiving chronic oral corticosteroids 
for a non-COVID-19 related condition in a dose 
higher than prednisone 10 mg or equivalent per 
day. 
Monitoring: 
 Serious infections are categorized as AESIs. 
Note: An infection is considered serious if it 
meets any of the regulatory definitions of serious 
which include fatal, life-threatening, prolongation 
of existing hospitalization (since subjects are 
already hospitalized) or re-hospitalization, and if 
in the opinion of the investigator the infection 
meets other serious criteria.  
 Participants will be hospitalized under direct 
medical supervision and closely monitored for 
signs of infection as part of SoC with appropriate 
diagnostic tests and antibiotic treatment, as 
necessary. 
 Routine laboratory assessments will be obtained 
throughout hospitalization. 
AESI=Adverse Event of Special Interest, ANC= Absolute Neutrophil Concentration, AUC=Area Under the Curve, CAR=Chimeric Antigen Receptor, Cmax=Maximum Concentration, 
CRS=Cytokine Release Syndrome, CTCAE=Common Terminology Criteria for Adverse Events, DMARDs=Disease Modifying Antirheumatic Drugs, HV=Healthy Volunteer, 
GFR=Glomerular Filtration Rate, IDMC=Independent Data Monitoring Committee, SC=Subcutaneous. 
 


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2.3.2. 
Benefit Assessment 
Otilimab is currently in Phase 3 clinical development for the treatment of RA, at weekly 
doses of 90 and 150 mg SC for up to 12 months in pivotal studies and thereafter eligible 
for treatment in a long-term extension study. 
In completed studies (IV and SC), cumulatively 447 patients and healthy volunteers (HV) 
have received otilimab (326 RA patients, 25 multiple sclerosis (MS) patients, 22 hand 
osteoarthritis patients, and 74 HVs). 
Although otilimab has not been studied before in this acutely ill population, there is 
biologic rationale which supports the use of otilimab in the treatment of COVID-19 
patients with pulmonary complications. 
GM-CSF can act as a proinflammatory cytokine that promotes myeloid cell survival and 
polarizes monocytes/macrophages into pro-inflammatory phenotypes that are primed to 
produce pro-inflammatory cytokines including TNFα, IL-1β and IL-6.  GM-CSF also 
extends neutrophil survival, primes the oxidative burst, enhances phagocytosis and 
promotes neutrophil adhesion to endothelial cells and neutrophil trafficking to sites of 
inflammation. 
COVID-19 ICU patients have increased circulating numbers of IL-6+ monocytes, 
CD14+CD16+ monocytes and GM-CSF+IFNγ+ helper T cells compared with non-ICU 
COVID-19 patients.  Once hypoxia occurs, stopping the systemic hyper-inflammatory 
processes to limit further damage to lung and other organs would the most important 
therapeutic approach.  Preclinical data suggest that elevated levels of GM-CSF in the 
lung could be more beneficial in the early stages of disease and may play a role in disease 
resolution by helping control viral titer, restore or maintain the lung barrier function, and 
return to tissue homeostasis.  As the disease progresses, suppressing the systemic hyper-
inflammatory processes would be a priority and where otilimab could be beneficial.  
Therefore, a single dose of otilimab in patients with pneumonia and oxygenation 
impairment, would be expected to inhibit inflammation and still allow sufficient GM-
CSF levels in the lung during the recovery phase. 
Update for Part 2 
Otilimab has been tested in patients with severe pulmonary COVID-19 related disease in 
Part 1 of this study, with substantial clinical benefit in the pre-defined stratification group 
of participants 70 to <80 years old, with no safety concerns identified (including all 
AESIs) in either the overall study population or the pre-defined stratification group of 
participants 70 to <80 years old. 
2.3.3. 
Overall Benefit: Risk Conclusion 
The overall benefit-risk assessment takes into account the potential benefit of otilimab 
treatment through GM-CSF blockade and mitigation of the hyper-inflammatory response. 
This hyper-inflammatory response associated with severe SARS-CoV-2 infection can 
result in severe or fatal pulmonary disease and multi-organ failure. 


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With the planned safety monitoring measures around the expected low risk of CRS and 
overall favorable safety profile to date, the overall benefit-risk assessment for the patient 
population proposed for this study is considered positive. 
Part 2 
With the planned safety monitoring measures around the expected very low risk of CRS 
and overall favorable safety profile to date, the overall benefit-risk assessment for the 
patient population included in Part 1 and proposed for Part 2 of this study is considered 
positive. 
3. 
OBJECTIVES AND ENDPOINTS 
3.1. 
Part 1 
Objectives 
Endpoints 
Primary 
 To compare the efficacy of otilimab 90 
mg IV versus placebo 
 Participants alive and free of respiratory failure at Day 
28 
Secondary 
 To compare the efficacy of otilimab 90 
mg IV versus placebo 
 All-cause mortality at Day 60 
 Time to all-cause mortality up to Day 60 
 Participants alive and free of respiratory failure at Day 
7, 14, 42, and 60 
 Time to recovery from respiratory failure up to Day 28 
 Participants alive and independent of supplementary 
oxygen at Day 7, 14, 28, 42, and 60 
 Time to last dependence on supplementary oxygen up 
to Day 28 
 Admission to ICU up to Day 28 
 Time to final ICU discharge up to Day 28 
 Time to final hospital discharge up to Day 28 
 To compare the safety and tolerability 
of otilimab 90 mg IV versus placebo 
 Occurrence of adverse events (AEs) [up to Day 60] 
 Occurrence of serious adverse events (SAEs) [up to 
Day 60] 
Exploratory 
 To compare the efficacy of otilimab 90 
mg IV versus placebo 
Other endpoints up to Day 28 
 Invasive mechanical ventilation (if not previously 
initiated) 
 Time to invasive mechanical ventilation (if not 
previously initiated) 
 Alive and not invasively mechanically-ventilated 
 Time to definitive extubation 
 Improvement of at least 2 points relative to baseline of 
Sequential Organ Failure Assessment (SOFA) score 
 Improvement relative to baseline in SpO2, FiO2, and 
SpO2/FiO2 ratio 
 Oxygen-free days 


T M F -1 1 7 9 5 6 0 7  
C O N FI D E N TI A L  
 
 
 
2 1 4 0 9 4  
 
3 8  
 
O bj e cti v e s  
E n d p oi nts  
 Ventilator -fr e e days 
 Ti m e to r es olution of pyr exia (for at least 48h)  
Ot h er e n d p oi nt s u p t o Day 60  
 Clinic al status ass ess ed using an or dinal sc ale 1 
ass ess ed at Days 4, 7, 14, 28, 42, and 60  
 Ti m e to i m pr ov e m ent of at least 2 c ategories r elativ e to 
bas eline on an or dinal sc ale 1 
 Change  in C O VI D -19 signs and sy m pto ms  
 T o deter mine the phar m ac okinetics 
( P K) pr ofile of otili m ab 
P K E n d p oi nt s u p t o Day 14  
 Otili m ab clear anc e ( CL) and other P K par a m eters as 
appr opriate using s pars e P K s a m pling  
 T o deter mine:  
 Ex pos ur e -r es pons e. 
 P har m ac ody na mic ( P D) 
bio m ark ers  
 Changes in k ey m ark ers of 
infla m m atio n 
P D E n d p oi nt s u p t o Day 28 
 Ex pos ur e -r es pons e r elations hi p for k ey effic acy, s afety 
and P D endpoints  
 K ey m ark ers of infla m m ati on including, but not li mited 
to C R P, s er u m ferritin and infla m m atory cytokines as 
appr opriate 
 
1Or di n al Sc al e ( G S K m o difi e d v er si o n, a d a pte d fr o m  W H O , 2 0 2 0 v er si o n)  
 
T he pri mar y esti ma n d is t he o d ds ratio bet w e e n otili ma b vers us pla c e b o in t he p r o p ortio n 
of participa nts alive a n d fre e of res pirat or y failure  at D a y 2 8 in participa nts wit h s e vere 
p ul m o nar y C O VI D -1 9 relate d dis e as e re gar dless of us e of a d ditio nal 
me dic atio ns or 
c ha n ges t o sta n dar d of c are.  
3. 2.  
P art 2  
O bj e cti v e s  
E n d p oi nts  
Pri m ar y  
 T o c o m par e the effic acy of otili m ab 90 
m g I V v ers us plac ebo  
 P articipants aliv e and fr ee of r es pir atory failur e at Day 
28 
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d b y 
t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d b y 
t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.


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Objectives 
Endpoints 
Secondary 
 To compare the efficacy of otilimab 90 
mg IV versus placebo 
 All-cause mortality at Day 28 
 All-cause mortality at Day 60 
 Time to all-cause mortality up to Day 60 
 Participants alive and free of respiratory failure at Day 
7, 14, 42, and 60 
 Time to recovery from respiratory failure up to Day 28 
 Participants alive and independent of supplementary 
oxygen at Day 7, 14, 28, 42, and 60 
 Time to last dependence on supplementary oxygen up 
to Day 28 
 Time to final ICU discharge up to Day 28 
 Time to first discharge from investigator site up to 
Day 60  
 Time to first discharge to non-hospitalised residence 
up to Day 60 
 To compare the safety and tolerability 
of otilimab 90 mg IV versus placebo 
 Occurrence of adverse events (AEs) [up to Day 60] 
 Occurrence of serious adverse events (SAEs) [up to 
Day 60] 
Exploratory 
 To compare the efficacy of otilimab 
90 mg IV versus placebo 
Other endpoints up to Day 28 
 Invasive mechanical ventilation (if not previously 
initiated) 
 Time to invasive mechanical ventilation (if not 
previously initiated) 
 Alive and not invasively mechanically-ventilated 
 Time to definitive extubation 
 Oxygen-free days 
 Ventilator-free days 
 Admission to ICU up to Day 28 
Other endpoints up to Day 60 
 Time to improvement of at least 2 categories relative to 
baseline on an ordinal scale1 
 Change in COVID-19 signs and symptoms 
 To determine the pharmacokinetics 
(PK) profile of otilimab 
PK Endpoints up to Day 14 
 Otilimab clearance (CL) and other PK parameters as 
appropriate using sparse PK sampling 
 To determine: 
 Exposure-response. 
 Pharmacodynamic (PD) 
biomarkers 
 Changes in key markers of 
inflammation 
PD Endpoints up to Day 28 
 Exposure-response relationship for key efficacy, safety 
and PD endpoints 
 Key markers of inflammation including, but not limited 
to CRP, serum ferritin and inflammatory cytokines as 
appropriate 
 


T M F -1 1 7 9 5 6 0 7  
C O N FI D E N TI A L  
 
 
 
2 1 4 0 9 4  
 
4 0  
 
1Or di n al Sc al e ( G S K m o difi e d v er si o n, a d a pte d fr o m  W H O , 2 0 2 0 v er si o n)  
T he pri mar y esti ma n d is t he o d ds ratio bet w e e n otili ma b vers us pla c e b o in t he p r o p ortio n 
of participa nts alive a n d fre e of res p irat or y failure at D a y 2 8 in participa nts wit h s e vere 
p ul m o nar y C O VI D -1 9 relate d dis e as e re gar dless of us e of a d ditio nal 
me dic atio ns or 
c ha n ges t o sta n dar d of c are.  
4.  
S T U D Y D E SI G N  
4. 1.  
O v er all D e si g n  
T his st u d y is a m ulti -c e nter, ra n d o mize d, d o u ble -blin d,  pla c e b o -c o ntr olle d trial t o ass ess 
t he effic a c y a n d s afet y of otili ma b f or t he tre at me nt of s e vere p ul m o nar y C O VI D-1 9 
relate d dis e as e.  T he st u d y p o p ulatio n c o nsists of h os pitalize d  participa nts  wit h ne w o ns et 
h y p o xia re q uirin g sig nific a nt o x y ge n s u p p ort  or  re q uirin g in vasive me c ha nic al ve ntilatio n 
(4 8 h o urs  bef ore d osin g ).  All participa nts will re c eive sta n dar d of c are as per 
instit utio nal pr ot oc ols, in a d ditio n t o st u d y tre at me nt.  Us e of  dr u gs  or tre at me nts 
s pe cific ally inte n de d f or C O VI D -1 9 relate d dis e as e are per mitte d o nly if a c c or din g t o 
loc al h os pital/instit uti o nal p olicies, a n d if n ot e xclu de d in Se ctio n  5. 3  a n d Se ctio n 5. 4  
E xclusio n C riteria Prior/ C o nc o mita nt t hera pies.  A n y c o nc er ns relate d t o eligibilit y in 
res pe ct of me dic atio ns or tre at me nts ta ke n f or C O VI D-1 9 relate d dis e as e s h o uld be 
dis c uss e d wit h t he G S K me dic al m o nit or (s).  Se e Se ctio n  6. 6 . 
After c o m pletio n of s cre e nin g ass ess me nts, participa nts will be tre ate d wit h a sin gle I V 
d os e of otili ma b 9 0 m g o n D a y 1, ass ess e d daily  w hile in h os pital u ntil D is c har ge ( or 
D a y  2 8, w hic he ver is s o o ner) , a n d f ollo w e d u p at D a y s 4 2  a n d 6 0 after ra n d o mizatio n. 
P articipa nts will be re cr uite d fr o m t w o m ut ually -e xcl usive  c ate g ories  wit hin t he or dinal 
s c ale: 
 
P articipa nts will initially be ra n d o mize d 1:1 b y intera ctive res p o ns e te c h n olo g y (I R T) in a 
blin de d ma n ner t o re c eive eit her a 1-h o ur inf usio n of  otili ma b 9 0 m g or pla c e b o I V  in 
a d ditio n t o sta n dar d of c are . 
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d b y 
t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e 
pr ot e ct e d b y t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d 
b y t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.


T M F -1 1 7 9 5 6 0 7  
C O N FI D E N TI A L  
 
 
 
2 1 4 0 9 4  
 
4 1  
 
4. 1. 1.  
I niti al S af et y C o h ort (fir st 2 0 p arti ci p a nt s)  
P art 1  
 
T he first 2 0 participa nts will be fr o m c ate g or y  5  a b o ve (
 
).  Sinc e t his is t he first ti me t hat 
otili ma b has be e n teste d in participa nts wit h s e vere p ul m o nar y C O VI D -1 9  relate d 
dis e as e , initial d osin g will be sta g gere d, a n d s afet y data re vie w e d as f ollo ws: 
 
T he first t w o participa nts t o be d os e d will be ra n d o mize d 1:1 ( otili ma b: pla c e b o) a n d 
m o nit ore d clos ely.  After a p pr o xi mately 2 4 h o urs, t he clinic al stat us of b ot h 
participa nts will be ass ess e d b y t he in vestigat or(s) a n d t he n dis c uss e d wit h t he G S K 
me dic al m o nit or.  If n o s afet y iss ues are ide ntifie d, a n d t he G S K  me dic al m o nit or 
a n d in vestigat or(s) a gre e, t w o f urt her participa nts will be allo w e d t o be d os e d.  
 
T he t hir d a n d f o urt h participa nts will als o be ra n d o mize d 1:1 ( otili ma b: pla c e b o ) a n d 
m o nit ore d clos ely.  After a p pr o xi mately 2 4 h o urs, t he clinic al stat us of all f o ur 
participa nts will be ass ess e d b y t he in vestigat or(s) a n d t he n dis c uss e d wit h t he G S K 
me dic al m o nit or.  If n o s afet y iss ues are ide ntifie d, a n d t he G S K me dic al m o nit or 
a n d in vestigat or(s) a gre e, re cr uit me nt a n d d osin g of f urt her participa nts will start. 
 
T he G S K Safet y Re vie w Te a m ( S R T) wil l re vie w a vaila ble blin de d s afet y data o n a 
w e e kly basis f or t he a d ditio nal 1 6 participa nts  in t he initial s afet y c o h ort. 
 
S afet y data will  be re vie w e d b y t he I n de pe n de nt D ata M o nit orin g C o m mitte e 
(I D M C), as o utline d in t he I D M C c harter  (refer t o Se ctio n 9. 1. 5  f or m ore 
inf or matio n a b o ut t he I D M C). 
U nless a s afet y sig nal is ide ntifie d d urin g t he o n g oin g s afet y re vie w b y t he G S K S R T  a n d 
e valuatio n b y t he I D M C, e nr ol me nt of t he mai n c o h ort  of participa nts ( b ot h c ate g ories 5 
a n d 6) will be  initiate d. 
4. 1. 2.  
M ai n  C o h ort ( aft er 2 0 p arti ci p a nt s)  
P art 1  
After t he initial s afet y c o h ort, e nr ol me nt rate will initiall y be c a p pe d t o c o ntr ol 
ra n d o mizatio n.  F or t he first 2 0 0 participa nts, a w e e kly ma xi m u m ra n d o mizatio n c a p will 
be s et usin g t he st u d y I R T s yste m, as f ollo ws:  
 
P articipa nt 2 1 t o 1 0 0 –  ra n d o mizati o n c a p of 2 0 participa nts / w e e k  
 
P articipa nt 1 0 1 t o 2 0 0 –  ra n d o mizatio n c a p of 5 0 participa nts / w e e k  
After 2 0 0 participa nts, it is pla n ne d t hat t he ra n d o mi zatio n c a p will be re m o ve d.  T he 
ra n d o mizatio n c a ps will be s u bje ct t o re visio n b y t he I D M C at t he s c he d ule d data re vie w 
me etin gs ( as o utline d in t he I D M C C harter). 
 
P art 2  
After e valuatio n of t he pri mar y e n d p oint  a n d all-c a us e m ortalit y data  at D a y 2 8 in P art 1, 
t he ne xt a p pr o xi mate ly 3 5 0 participa nts will be at le as t 7 0 ye ars old  wit h n o u p per li mit .  
C CI


T M F -1 1 7 9 5 6 0 7  
C O N FI D E N TI A L  
 
 
 
2 1 4 0 9 4  
 
4 2  
 
4. 1. 2. 1.  
Str atifi c ati o n i n P art 1  
B as e d o n t he st u d y eligibilit y criteria, t he clinic al stat us of t he participa nts e nterin g t he 
main c o h ort (i. e. after t he 2 0t h participa nt) of t he st u d y will be wit hin t he t w o or dinal 
s c ale c ate g ories 5 a n d 6  a n d als o a ge gr o u ps, as f ollo ws: 
 
 
.  A ge < 6 0  ye ars  
 
 
  A ge 6 0 t o < 7 0  ye ars  
 
 
.  A ge 7 0 t o < 8 0  ye ars  
 
 A ge < 6 0  ye ars  
 
 A ge 6 0 t o < 7 0  ye ars  
 
 A ge 7 0 t o < 8 0  ye ars  
T he ratio nale f or t h e se  stratific atio n fa ct ors is t o o btain a bala nc e d p o p ulatio n a cr oss t he 
tre at me nt ar ms wit h res pe ct t o t he s e verit y of t he dis e as e a n d a ge gr o u p w hic h are b ot h 
ass ociate d wit h incre as e d m ortalit y [Grass elli , 2 0 2 0 ; W u , 2 0 2 0].  
F urt her , t he tar get perc e nta ge of participa nt s in c ate g or y 6 (
 
) will be n o m ore t ha n 6 0 % of t he st u d y p o p ulatio n .  Ho w e ver , t his 
tar get ma y be re vis e d bas e d o n o n g oin g I D M C re vie ws  (s e e Se ctio n 9. 1. 5 ). 
4. 1. 2. 2.  
Str atifi c ati o n i n P art 2  
B as e d o n t he st u d y eligibilit y criteria, t he clinic al stat us of t he participa nts e nterin g P art 2  
of t he st u d y will be wit hin t he t w o or dinal s c ale c ate g ories 5 a n d 6 a n d als o ge n der , as 
f ollo ws: 
 
 
  Male  
 
 
.  Fe male  
 
 Male  
 
 Fe male  
F urt her, t he tar get perc e nta ge of participa nts in c ate g or y 6 (
 
) will be n o m ore t ha n a p pr o xi mately 4 0 % of t he st u d y p o p ulatio n.  
T he ratio nale f or t hes e stratific atio n fa ct ors is t o o btain a bala nc e d p o p ulatio n a cr oss t he 
tre at me nt ar ms wit h res pe ct t o t he s e verit y of t he dis e as e a n d ge n der  w hic h are ass ociate d 
wit h incre as e d m ortalit y [I C N A R C, 2 0 21 ]. Stratific atio n  t o eit her Cate g or y 5 or 6 will be 
c o n d ucte d at ra n d o mizatio n.   F ollo win g ra n d o mizatio n usin g t he I R T s yste m, it is n ot 
p ossible t o c ha n ge a participa nt’s strata –  t heref ore, e ver y eff ort m ust be ma de t o e nter 
t he strata inf or matio n c orre ctly.   If a participa nt’s stat us c ha n ges bet w e e n ra n d o mizatio n 
a n d d osin g, t he y c a n still be d os e d (if de e me d a p pr o priate b y t he in vestigat or).  F or this 
re as o n, ra n d o mizatio n a n d d osin g s h o uld be as clos e as p ossible o n t he s a me da y . 
C CI
C CI
C CI
C CI
C CI
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a 
c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d b y t hir d p art y 
c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.
C CI
C CI
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a 
c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d b y t hir d p art y 
c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.


T M F -1 1 7 9 5 6 0 7  
C O N FI D E N TI A L  
 
 
 
2 1 4 0 9 4  
 
4 3  
 
4. 2.  
S ci e ntifi c R ati o n al e f or St u d y D e si g n  
A m ultic e nt er, ra n d o mize d, d o u ble-bli n d, pla c e b o -c o ntr olle d trial is a w ell-esta blis he d 
strate g y t o e valuate effic a c y a n d s afet y of in vestigatio nal 
me dicinal pr o d ucts. 
T he st u d y will utili ze a gr o u p s e q ue ntial desig n wit h interi m a nalys es  t hat inte n ds t o 
ide ntif y e arly sig ns of clinic al effic a c y if res p o ns es are hig her t ha n e x pe cte d a n d t o a v oid 
t he us e of ineffe ctive t hera pe utics in se verely or critic ally ill participa nts wit h s e vere 
p ul m o nar y C O VI D -1 9 relate d dis e as e.  I n a d ditio n, fre q ue nt in-stre a m re vie ws of s afet y 
data will be perf or me d t o ide ntif y e arly sig ns of har m  a n d st o p t he st u d y if t hes e are 
ide ntifie d.  T his desig n allo ws  f or t he ass ess me nt of effic a c y a n d s afet y as w ell as 
e valuatin g t he be nefit:ris k.  
4. 3.  
J u stifi c ati o n f or D o s e  
4. 3. 1.  
Otili m a b  
C CI


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4 4  
 
4. 3. 2.  
Pl a c e b o  
T here is n o esta blis he d tre at me nt f or s e vere p ul m o nar y C O VI D -1 9 relate d dis e as e, he nc e 
a pla c e b o c o ntr ol is re q uire d t o distin g uis h t he s afet y a n d t olera bilit y of otili ma b fr o m t he 
ba c k gr o u n d sig ns a n d s y m pt o ms of s e vere p ul m o nar y C O VI D -1 9 relat e d dis e as e a n d t o 
e valuate its p ote ntial be nefit o n clinic al o utc o mes.  
4. 4.  
E n d of St u d y D efi niti o n  
P art 1  
 
A participa nt is c o nsidere d t o ha ve c o m plete d t he st u d y if he/s he has c o m plete d all visits 
of t he st u d y t hr o u g h t o D a y 6 0  or has die d  pr ior t o D a y 6 0.  T he e n d of t he st u d y is 
define d as t he date of t he last c o nta ct of t he last participa nt in P art 2 of  t he st u d y. 
P art 2  
 
A participa nt is c o nsidere d t o ha ve c o m plete d t he st u d y if he/s he has c o m plete d all visits 
of t he st u d y t hr o u g h t o D a y 6 0 or has die d  prior t o D a y 6 0.  T he e n d of t he st u d y is 
define d as t he date of t he last c o nta ct of t he last participa nt in  t his a d ditio nal c o h ort  in 
P art 2 ( or a n y f ut ure a d ditio nal c o h orts) in t he st u d y. 
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5. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria – Part 1 
Participants are eligible to be included in Part 1 of the study only if all of the following 
criteria apply: 
AGE 
1. Age 18 years and 79 years at the time of obtaining informed consent. 
TYPE OF PARTICIPANT AND DISEASE CHARACTERISTICS 
2. Participants must: 
a. have positive SARS-CoV-2 result (any validated test, e.g. RT-PCR [performed 
on an appropriate specimen; e.g. respiratory tract sample]) 
b. AND be hospitalized due to diagnosis of pneumonia (chest X-ray or 
computerized tomography [CT] scan consistent with COVID-19) 
c. AND be developing new onset of oxygenation impairment requiring any of the 
following: 
1. high-flow oxygen (15L/min) 
2. non-invasive ventilation (e.g. CPAP, BiPAP) 
3. mechanical ventilation 48h prior to dose 
d. AND have increased biological markers of systemic inflammation (either CRP 
>ULN1 or serum ferritin >ULN1). 
1According to local reference range.  Repeat CRP or ferritin tests are permitted. 
 
SEX 
3. No gender restriction. 
4. Female participants must meet and agree to abide by the contraceptive criteria 
detailed in Appendix 4.  Contraceptive use by women should be consistent with 
local regulations regarding the methods of contraception for those participating in 
clinical studies. 
A female participant is eligible to participate if she is not pregnant or breastfeeding, 
and one of the following conditions applies: 
o Is a woman of non-childbearing potential (WONCBP) as defined in Section 
9.4: Contraceptive and Barrier Guidance. 
OR 
o Is a woman of childbearing potential (WOCBP) and using a contraceptive 
method that is highly effective, with a failure rate of <1%, as described in 
Section 9.4 during the study intervention period and for at least 60 days after 
the last dose of study intervention (sexual abstinence is acceptable if it is the 
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o If not consistently on a highly effective method of contraception (Section 
9.4) during hospitalization, the participant must agree to a highly effective 
contraception plan if discharged before Day 60. 
o The investigator should evaluate potential for contraceptive method failure (e.g. 
noncompliance, recently initiated) in relation to the first dose of study 
intervention. 
o A WOCBP must have a negative highly sensitive pregnancy test (urine or 
serum as required by local regulations) at hospital admission or before the first 
dose of study intervention.  See Section 7.3.5 Pregnancy Testing (additional 
requirements for pregnancy testing during and after study intervention). 
o The investigator is responsible for review of medical history, menstrual history, 
and recent sexual activity to decrease the risk for inclusion of a woman with an 
early undetected pregnancy. 
 
INFORMED CONSENT 
5. Capable of giving written informed consent as described in Section 9.1.3.  If 
participants are not capable of giving written informed consent, alternative consent 
procedures will be followed as detailed in Section 9.1.3. 
 
5.2. 
Inclusion Criteria – Part 2 
Participants are eligible to be included in Part 2 of the study only if all of the following 
criteria apply: 
AGE 
1. Age 70 years or above at the time of obtaining informed consent. 
TYPE OF PARTICIPANT AND DISEASE CHARACTERISTICS 
2. Participants must: 
a. have positive SARS-CoV-2 result (any validated test, e.g. RT-PCR [performed 
on an appropriate specimen; e.g. respiratory tract sample]) 
b. AND be hospitalized due to diagnosis of pneumonia (chest X-ray or 
computerized tomography [CT] scan consistent with COVID-19) 
c. AND be developing new onset of oxygenation impairment requiring any of the 
following: 
1. high-flow oxygen (15L/min)1 
2. non-invasive ventilation (e.g. CPAP, BiPAP) 
3. mechanical ventilation 48h prior to dose 
d. AND have increased biological markers of systemic inflammation (either CRP 
>ULN2 or serum ferritin >ULN2). 
1or equivalent as detailed in the study reference manual (SRM). 
2According to local reference range.  Repeat CRP or ferritin tests are permitted. 
 
SEX 
3. No gender restriction. 


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INFORMED CONSENT 
4. Capable of giving written informed consent as described in Section 9.1.3.  If 
participants are not capable of giving written informed consent, alternative consent 
procedures will be followed as detailed in Section 9.1.3. 
 
5.3. 
Exclusion Criteria – Part 1 
Participants are excluded from Part 1 of the study if any of the following criteria apply: 
RELATED TO SEVERE PULMONARY COVID-19 RELATED DISEASE 
1. Progression to death is imminent and inevitable within the next 48 hours, 
irrespective of the provision of treatments, in the opinion of the investigator. 
2. Multiple organ failure according to the investigator’s judgement or a Sequential 
Organ Failure assessment (SOFA score) >10 if in the ICU. 
3. Extracorporeal membrane oxygenation (ECMO) hemofiltration/dialysis, or high-
dose (>0.15g/kg/min) noradrenaline (or equivalent) or more than one vasopressor. 
 
CONCOMITANT MEDICAL CONDITIONS 
4. Current serious or uncontrolled medical condition (e.g. significant pulmonary 
disease [such as severe COPD or pulmonary fibrosis], heart failure [NYHA class 
III or higher], renal dysfunction, acute myocardial infarction or acute 
cerebrovascular accident within the last 3 months), or abnormality of clinical 
laboratory tests that, in the investigator's judgment, precludes the participant's safe 
participation in and completion of the study. 
5. Untreated systemic bacterial, fungal, viral, or other infection (other than SARS-
CoV-2). 
6. Known active tuberculosis (TB), history of untreated or incompletely treated active 
or latent TB, suspected or known extrapulmonary TB. 
7. Known HIV regardless of immunological status. 
8. Known HBsAg and/or anti-HCV positive. 
9. Currently receiving radiotherapy, chemotherapy or immunotherapy for malignancy. 
 
PRIOR MEDICATIONS/TREATMENTS 
10. Received monoclonal antibody therapy (e.g. tocilizumab, sarilumab) within the 
past 3 months prior to randomization, including intravenous immunoglobulin, or 
planned to be received during the study. 
11. Received immunosuppressant therapy including but not limited to cyclosporin, 
azathioprine, tacrolimus, mycophenolate, JAK inhibitors (e.g. baricitinib, 
tofacitinib, upadacitinib) within the last 3 months prior to randomization or planned 
to be received during the study. 
Note: Participants with an organ transplant are therefore excluded (except patients 
with corneal transplants not requiring immunosuppression). 
12. History of allergic reaction, including anaphylaxis to any previous treatment with 
an anti-GM-CSF therapy. 
13. Received COVID-19 convalescent plasma within 48 hours of randomization. 


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Note: Participants who have received COVID-19 convalescent plasma but continue 
to worsen in the 48 hours after infusion of the convalescent plasma, in the opinion 
of the investigator, will become eligible for the study. 
 
PROHIBITED MEDICATIONS 
14. Currently receiving chronic oral corticosteroids for a non-COVID-19 related 
condition in a dose higher than prednisone 10 mg or equivalent per day. 
15. Treatment with an investigational drug within 30 days of randomization. 
 
PRIOR/CONCURRENT CLINICAL STUDY EXPERIENCE 
16. Participating in other drug clinical trials, including for COVID-19. 
 
DIAGNOSTIC ASSESSMENTS 
17. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >5x upper 
limit of normal (ULN). 
18. Platelets <50,000/mm3. 
19. Hemoglobin 9 g/dL. 
20. Absolute neutrophil count (ANC) <1.5 x 109/L (neutropenia  Grade 2). 
21. Estimated GFR 30 mL/min/1.73m2. 
 
OTHER CRITERIA 
22. Pregnant or breastfeeding females.  
 
5.4. 
Exclusion Criteria – Part 2 
Participants are excluded from Part 2 of the study if any of the following criteria apply: 
RELATED TO SEVERE PULMONARY COVID-19 RELATED DISEASE 
1. Progression to death is imminent and inevitable within the next 48 hours, 
irrespective of the provision of treatments, in the opinion of the investigator. 
2. Multiple organ failure according to the investigator’s judgement or a Sequential 
Organ Failure assessment (SOFA score) >10 if intubated in the ICU. 
3. Extracorporeal membrane oxygenation (ECMO) hemofiltration/dialysis, or more 
than one inotrope/vasopressor of any class. 
 
CONCOMITANT MEDICAL CONDITIONS 
4. Current serious or uncontrolled medical condition (e.g. significant pulmonary 
disease [such as severe COPD or pulmonary fibrosis], heart failure [NYHA class 
III or higher], severe renal dysfunction, acute myocardial infarction or acute 
cerebrovascular accident within the last 3 months), severe dementia, severe 
disability, or abnormality of clinical laboratory tests that, in the investigator's 
judgment, precludes the participant's safe participation in and completion of the 
study. 
5. Untreated systemic bacterial, fungal, viral, or other infection (other than SARS-
CoV-2). 
6. Known active tuberculosis (TB), history of untreated or incompletely treated active 
or latent TB, suspected or known extrapulmonary TB. 


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7. Known HIV regardless of immunological status. 
8. Known HBsAg and/or anti-HCV positive (patients demonstrating a sustained 
virologic response (SVR) are not excluded from participation). 
9. Currently receiving radiotherapy, chemotherapy (hormone based therapies are 
permitted) or immunotherapy for malignancy. 
 
PRIOR MEDICATIONS/TREATMENTS 
10. Received monoclonal antibody therapy (e.g. tocilizumab, sarilumab) within the 
past 3 months prior to randomization, including intravenous immunoglobulin, or 
planned to be received during the study. 
11. Received immunosuppressant therapy including but not limited to cyclosporin, 
azathioprine, tacrolimus, mycophenolate, JAK inhibitors (e.g. baricitinib, 
tofacitinib, upadacitinib), nintedanib, DMARDs (e.g. methotrexate) within the last 
3 months prior to randomization or planned to be received during the study. 
Note: Participants with an organ transplant are therefore excluded (except patients 
with corneal transplants not requiring immunosuppression). 
12. History of allergic reaction, including anaphylaxis to any previous treatment with 
an anti-GM-CSF therapy. 
13. Received COVID-19 convalescent plasma within 48 hours of randomization. 
Note: In order to become eligible for the study, participants who have received 
COVID-19 convalescent plasma must, in the opinion of the Investigator, continue 
to worsen clinically for at least 48 hours after infusion of the convalescent plasma.  
 
PROHIBITED MEDICATIONS 
14. Currently receiving chronic oral corticosteroids for a non-COVID-19 related 
condition at a dose higher than prednisone 10 mg or equivalent per day. 
15. Treatment with an investigational drug or substance within 30 days of 
randomization unless approved by the Medical Monitor. 
 
PRIOR/CONCURRENT CLINICAL STUDY EXPERIENCE 
16. Participating in other drug clinical trials, including for COVID-19. 
 
DIAGNOSTIC ASSESSMENTS 
17. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >5x upper 
limit of normal (ULN). 
18. Platelets <50,000/mm3. 
19. Hemoglobin 9 g/dL. 
20. Absolute neutrophil count (ANC) <1.0 x 109/L (neutropenia  Grade 3). 
21. Estimated GFR 30 mL/min/1.73 m2. 
 
5.5. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomized.  Participants who are randomized but not 
subsequently dosed, are not screen failures.  A minimal set of screen failure information 
is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 


T M F -1 1 7 9 5 6 0 7  
C O N FI D E N TI A L  
 
 
 
2 1 4 0 9 4  
 
5 0  
 
res p o n d t o q ueries fr o m re g ulat or y a ut h orities.  Mini mal inf or matio n inclu des 
de m o gra p h y, s cre e n failure details, eligibilit y criteria,  a n y pr ot oc ol de viatio ns  a n d a n y 
pr ot oc ol de viatio ns a n d a n y s erio us a d vers e e ve nts ( S A Es).  
I n divid uals w h o d o n ot me et t he criteria f or participatio n in t his st u d y ma y be res cre e ne d 
o nc e.   Res cre e ne d participa nts s h o uld be assig ne d a ne w participa nt n u m ber f or e a c h 
s cre e nin g/res cre e nin g e ve nt. 
6.  
S T U D Y I N T E R V E N TI O N( S) A N D C O N C O MI T A N T 
T H E R A P Y  
St u d y inter ve ntio n is define d as a ny in vestigatio nal inter ve ntio n(s) or pla c e b o inte n de d t o 
be a d ministere d t o a st u d y participa nt a c c or din g t o t he st u d y pr ot oc ol.  
6. 1.  
St u d y I nt er v e nti o n(s ) A d mi ni st er e d  
C CI


T M F -1 1 7 9 5 6 0 7  
C O N FI D E N TI A L  
 
 
 
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5 1  
 
6. 2.  
Pr e p ar ati o n/ H a n dli n g/ St or a g e/ A c c o u nt a bilit y  
 T he site u n blin de d p har ma cist m ust c o nfir m a p pr o priate te m perat ure c o n ditio ns 
ha ve be e n maintaine d d urin g tra nsit f or all st u d y inter ve ntio n re c eive d a n d a n y 
dis cre pa ncies are re p orte d a n d res olve d bef ore us e of  t he st u d y inter ve ntio n. 
 O nly participa nts e nr olle d in t he st u d y ma y re c eive st u d y inter ve ntio n.  All st u d y 
inter ve ntio ns m ust be st ore d in a s e c ure, e n vir o n me ntally c o ntr olle d, a n d 
m o nit ore d ( ma n ual or a ut o mate d) are a in a c c or da nc e wit h t he la belle d st orage 
c o n ditio ns wit h a c c ess li mite d t o t he in vestigat or a n d a ut h orize d site staff. 
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 The investigator, institution, or the head of the medical institution (where 
applicable) is responsible for study intervention accountability, reconciliation, and 
record maintenance (i.e. receipt, reconciliation, and final disposition records). 
 Further guidance and information for the final disposition of unused study 
intervention are provided in the SRM. 
 Under normal conditions of handling and administration, study intervention is not 
expected to pose significant safety risks to site staff.  Take adequate precautions 
to avoid direct eye or skin contact and the generation of aerosols or mists.  In the 
case of unintentional occupational exposure notify the monitor, Medical Monitor 
and/or GSK study contact. 
 A Material Safety Data Sheet (MSDS)/equivalent document describing 
occupational hazards and recommended handling precautions either will be 
provided to the investigator, where this is required by local laws, or is available 
upon request from GSK. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
All participants will be centrally randomized using IRT.  Before the study is initiated, the 
log in information and directions for the IRT will be provided to each site.  Study 
intervention will be administered at the time-point detailed in the SoA (Section 1.3 and 
Section Returned study intervention must not be re-dispensed. 
The IRT will be programmed with blind-breaking instructions.  In case of an emergency, 
the investigator has the sole responsibility for determining if unblinding of a participant’s 
intervention assignment is warranted.  Participant safety must always be the first 
consideration in making such a determination.  If a participant’s intervention assignment 
is unblinded GSK must be notified within 24 hours after breaking the blind.  The date and 
reason that the blind was broken must be recorded in the source documentation and case 
report form, as applicable. 
Participants will be randomized in a ratio of 1:1 to receive study intervention (Section 
1.2, Section 4.1 and Section 6.1).  Investigators will remain blinded to each participant’s 
assigned study intervention throughout the course of the study.  To maintain this blind, all 
participants will receive a single IV infusion.  An unblinded pharmacist (or unblinded 
designee) will be responsible for the dispensation of the study intervention and will 
endeavor to ensure that there are no differences in time taken to dispense between the 
different intervention arms.  The IV bag should be prepared away from view of the 
blinded site staff and the participant.  Every IV infusion must be labelled to maintain the 
blind (refer to SRM). 
Unblinded monitors and in the event of a Quality Assurance audit, the auditor(s) will be 
allowed access to unblinded study intervention records at the site(s) to verify that 
randomization/dispensing has been done accurately. 
A participant may continue in the study if that participant’s intervention assignment is 
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GSK’s Pharma Safety staff may unblind the intervention assignment for any participant 
with an SAE.  If the SAE requires that an expedited regulatory report be sent to one or 
more regulatory agencies, a copy of the report, identifying the participant’s intervention 
assignment, may be sent to investigators in accordance with local regulations and/or GSK 
policy. 
6.4. 
Study Intervention Compliance 
Participants will receive study intervention directly from the investigator or designee, 
under medical supervision.  The date and time of the dose administered will be recorded 
in the source documents.  The dose of study intervention and study participant 
identification will be confirmed at the time of dosing by a member of the study site staff 
other than the person administering the study intervention. 
6.5. 
Treatment of Overdose 
For this study, any dose of otilimab greater than the 90 mg dose indicated in this study or 
used more frequently than permitted (otilimab 90 mg single IV infusion) will be 
considered an overdose. 
No specific treatment is recommended for an overdose of otilimab, and the investigator 
should treat as clinically indicated. 
In the event of a potential overdose, the investigator should: 
 Contact the Medical Monitor immediately. 
 Closely monitor the participant for adverse event (AE)/serious adverse event 
(SAE) and laboratory abnormalities. 
 Contact the unblinded monitor with the quantity and duration of the overdose to 
be documented. 
6.6. 
Concomitant Therapy 
At Screening, information will be collected on any medications the participant has taken 
in the 14 days before screening.  In Part 2, current COVID-19 vaccination status will also 
be recorded. 
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements) that the participant is receiving at the time of 
enrolment or receives during the study must be recorded along with: 
 reason for use 
 dates of administration including start and end dates 
 dosage information including dose and frequency 
The Medical Monitor should be contacted if there are any questions regarding 
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A participant who has received COVID-19 convalescent plasma will be eligible for the 
study if, in the opinion of the Investigator, they continue to worsen clinically for at least 
48 hours after infusion of the convalescent plasma. 
Part 1 only - Due to the effect of cytokines on the CYP450 enzymes (Section 2.3) 
initiation or discontinuation of study intervention may have a clinically relevant effect for 
CYP substrates with a narrow therapeutic index e.g. warfarin and theophylline should be 
monitored. 
Part 1 only - Investigators should exercise caution when study intervention is co-
administered with CYP3A4 substrate drugs where decrease in effectiveness is 
undesirable, e.g., oral contraceptives, lovastatin, atorvastatin, etc. 
Aside from those medications specified in Exclusion Criteria (Section 5.3 and Section 
5.4) or Section 6.6.1, all regular medications that are required by the participant will be 
allowed.  All concomitant medications (and treatments, such as convalescent plasma) 
should be recorded in the eCRF. 
6.6.1. 
Medication NOT Permitted During the Study 
The following medications cannot be planned to be administered during the study (see 
the note in Section 6.6.2, which provides guidance on the use of treatments for COVID-
19 that might benefit the patient or be considered lifesaving): 
 Any monoclonal antibody therapy (e.g. tocilizumab, sarilumab), including 
intravenous immunoglobulin 
 Immunosuppressant therapy including but not limited to cyclosporin, 
azathioprine, tacrolimus, mycophenolate, JAK inhibitors (e.g. baricitinib, 
tofacitinib, upadacitinib), nintedanib, DMARDs (e.g. methotrexate). 
 Chronic oral corticosteroids (for a non-COVID-19 related condition) in a dose 
higher than prednisone 10 mg or equivalent per day, are not permitted. 
6.6.2. 
Medication/Treatment PERMITTED During the Study 
The following medications are permitted during the study: 
 The participant’s regular medication. 
 Treatment required for standard of care (e.g. analgesia, antipyretic, sedation). 
 Medications/treatments required for ICU care. 
 Additional medications/treatments of COVID-19 related disease (e.g. remdesivir, 
favipiravir, convalescent plasma, tocilizumab, sarilumab) are permitted only if 
according to local hospital/institutional policies, and not part of a clinical trial if it 
is felt that the participant might benefit or it might be considered life-saving.  Any 
concerns regarding the acceptability of potential treatments should be discussed 
with the GSK medical monitor(s). 


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6.7. 
Participant Discontinuation/Withdrawal from the Study 
 A participant may withdraw from the study at any time at his/her own request, at 
the request of their legally authorized representative (LAR) or may be withdrawn 
at any time at the discretion of the investigator for safety, behavioral, or 
compliance reasons.  This is expected to be uncommon. 
 At the time of discontinuing from the study, if possible, a Withdrawal visit (same 
as Discharge visit) should be conducted (for hospitalized participants) or a 
Withdrawal phone call (same as Follow-up phone call) should be conducted (for 
non-hospitalized participants), as shown in the SoA. 
 If the participant withdraws consent or the LAR requests that the participant is 
withdrawn for disclosure of future information, the sponsor may retain and 
continue to use any data collected before such a withdrawal of consent. 
 If a participant withdraws from the study or the LAR requests that the participant 
is withdrawn, he/she may request destruction of any samples taken and not tested, 
and the investigator must document this in the site study records. 
6.8. 
Lost to Follow Up 
A participant will be considered lost to follow-up if he or she is unable to be contacted by 
the study site after discharge from hospital.  Every effort must be made to reduce missing 
data.   
 The site must attempt to contact the participant as soon as possible and counsel 
the participant on the importance of maintaining the assigned study schedule and 
ascertain whether or not the participant wishes to and/or should continue in the 
study. 
 Before a participant is deemed lost to follow up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 
telephone calls and, if necessary, a certified letter to the participant’s last known 
mailing address or local equivalent methods).  These contact attempts should be 
documented in the participant’s medical record. 
 Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study. 
Discontinuation of specific sites or of the study as a whole is described in Section 9.1.9. 
7. 
STUDY ASSESSMENTS AND PROCEDURES 
This section lists the parameters of each planned study assessment.  Participants will 
mainly be evaluated using standard of care investigations.  In addition to standard care, 
data will be collected for the Ordinal Scale and the Clinical Features of COVID-19, and 
blood samples will be collected for PK and PD analysis (collected as detailed in the SoA, 
Section 1.3 and Section 1.4). 


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 Study procedures and their timing are summarized in the SoA (Section 1.3 and 
Section 1.4). 
 As detailed in the SoA (Section 1.3 and Section 1.4), follow-up phone calls must 
be made within ±2 days of the scheduled time-point, but every effort must be 
made to complete the phone call on the scheduled day.  This is particularly 
important if the Day 28 time-point is a phone call, because this is the study 
primary endpoint. 
 Every effort must be made to reduce missing data throughout the study. 
 Protocol waivers or exemptions are not allowed. 
 Urgent study-related safety concerns should be discussed with the GSK medical 
monitor immediately upon occurrence or awareness to determine if the participant 
should continue or in exceptional circumstances withdraw from the study. 
 Adherence to the study design requirements, including those specified in the SoA 
(Section 1.3 and Section 1.4), is essential and required for study conduct. 
 All screening evaluations must be completed and reviewed to confirm that 
potential participants meet all eligibility criteria.  The investigator will maintain a 
screening log to record details of all participants screened and to confirm 
eligibility or record reasons for screening failure, as applicable. 
 Procedures conducted as part of the participant’s routine clinical management 
(e.g., blood count) and taken before obtaining consent may be utilized for 
screening or baseline purposes provided the procedure met the protocol-specified 
criteria and was performed within the time frame defined in the SoA. 
 The maximum amount of blood collected from each participant over the duration 
of the study for the purpose of meeting the objectives will not exceed 200 mL.  
This does not include any standard of care assessments. 
 Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples. 
7.1. 
Entry/Screening Assessments 
7.1.1. 
Demography & Medical History 
The following demographic parameters will be captured: year of birth, gender and 
ethnicity/race.  If it is not possible to collect at Screening, demography can be collected at 
any point during the study. 
We are collecting details of race and ethnicity in this study since there have been reports 
from several counties that ethnic minority groups have been disproportionately affected 
by either the incidence or outcomes of COVID-19 related disease.  In line with ICH E5 
principles, this information is therefore paramount to the assessment of the ethnic 
sensitivity of otilimab in this patient population. 


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To the extent practical given the participant’s condition, a full medical history, including 
cardiovascular risk, will be taken during Screening or as information becomes available 
at any point during the study.  This should record concurrent medical conditions and 
concomitant medications. 
Medical history will include a detailed list of signs and symptoms of COVID-19 recorded 
at admission (see Section 7.2.1) 
Part 1- At Screening, information will be collected on any medications the participant 
has taken in the 14 days before Screening. 
Part 2 - At Screening, COVID-19 vaccination status will be recorded, as well as any 
prior medications within 14 days before Screening. 
7.1.2. 
Chest X-ray or CT Scan 
A chest X-ray or computerized tomography (CT) scan must be available at Screening to 
confirm a diagnosis of pneumonia and eligibility.  If another chest X-ray or CT scan is 
done after Screening and before Discharge, this status should be recorded in the eCRF. 
7.2. 
Efficacy Assessments 
General Note: Research staff are asked to liaise with clinical staff managing the 
participant to ensure that all study relevant data is collected efficiently and accurately and 
that study related assessments are not performed soon after or before those required for 
participant clinical management.  Hence, all study mandated physical examination 
assessments, measurements of vital signs and obtaining blood for laboratory tests / point 
of care tests should be performed in coordination with the clinical staff looking after the 
participant. 
7.2.1. 
Clinical features of COVID-19 
Signs and symptoms of COVID-19 will be collected for non-mechanically ventilated 
participants.  A detailed list of signs and symptoms of COVID-19 at admission will be 
recorded at Screening, and an abbreviated list of signs and symptoms of COVID-19 will 
be recorded at the timepoints defined in the SoA (Section 1.3 and Section 1.4; list of 
signs and symptoms outlined in the eCRF). 
7.2.2. 
SpO2 (for participants not on invasive mechanical ventilation) 
SpO2 should be measured at the timepoints defined in the SoA (Section 1.3 and Section 
1.4).  Where possible, SpO2 should be measured “at rest” i.e. not having undergone a 
procedure for at least 5 minutes.  When a participant is mechanically ventilated, no SpO2 
value is expected in the eCRF. 
Part 2:  SpO2 should be measured once daily in the morning (up to discharge) at 
approximately the same time as the Ordinal Scale categorisation.   


T M F -1 1 7 9 5 6 0 7  
C O N FI D E N TI A L  
 
 
 
2 1 4 0 9 4  
 
5 8  
 
7. 2. 3.  
C o n c e ntr ati o n of i n s pir e d o x y g e n ( Fi O 2 ) 
C o nc e ntratio n of ins pire d o x y ge n ( Fi O 2) a n d/ or o x y ge n flo w rate ( L/ min) s h o uld be 
me as ure d at t he ti me p oints define d in t he S o A ( Se ctio n 1. 3  a n d Se ctio n 1. 4 ). 
P art 2:   Fi O 2 a n d/ or o x y ge n flo w rate s h o uld be me as ure d o nc e daily in t he m or nin g ( u p 
t o dis c har ge) at a p pr o xi mately t he s a me ti me as t he Or dinal Sc ale c ate g oris atio n.  
7. 2. 4.  
V e ntil ati o n st at u s  
V e ntilatio n stat us (in vasive  or n o n -in vasive ve ntilatio n), 
mas k or nas al cat heter  o x y ge n 
will be c olle cte d at ti mes o utline d in t he S o A  ( Se ctio n 1. 3  a n d Se ctio n 1. 4 ).  F or 
me c ha nic ally ve ntilate d participa nts, in dic ate if t he participa nt w as in t he pr o ne or s e mi-
pr o ne p ositio n  at a n y ti me  w hilst me c ha nic ally ve ntilate d .  If t he participa nt is dis c har ge d 
fr o m h os pital wit h o x y ge n s u p p ort, re c or d o x y ge n tre at me nt at s u bs e q ue nt p h o ne c all 
f ollo w-u ps (at ti mes o utline d in t he S o A ( Se ctio n 1. 3  a n d Se ctio n 1. 4 ). 
7. 2. 5.  
I C U S u p p orti v e C ar e  
F or participa nts in I C U, a d ditio nal inf or matio n will be c olle cte d o n t he us e of s u p p ortive 
c are:  in otr o pes/ vas o press ors, re nal re pla c e me nt t hera p y (R R T ) a n d e xtra c or p ore al 
me m bra ne o x y ge natio n ( E C M O ) s h o uld be re c or de d at t he ti me p oints define d in t he S o A 
( Se ctio n 1. 3  a n d Se ctio n  1. 4 ). 
7. 2. 6.  
Or di n al S c al e  
T he m ut ually e xclusive or dinal s c ale pres e nte d in  Ta ble 2 , a da pte d fr o m t he W H O  s c ale 
2 0 2 0, will be us e d t o ass ess clinic al i m pr o ve me nt at t he ti me p oints in dic ate d in t he S o A 
( Se ctio n 1. 3  a n d Se ctio n  1. 4 ). 
T a bl e 2  
Or di n al S c al e ( G S K m o difi e d v er si o n, a d a pt e d fr o m  W H O , 2 0 2 0 
v e r si o n)  
 
 
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e 
pr ot e ct e d b y t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d b y 
t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.


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7.2.7. 
Participant baseline and discharge location information 
At Discharge, the location of where a participant is discharged to must be recorded in the 
eCRF.  There are 2 categories of location (each with sub-categories): 
1. Non-hospitalized residence / facility 
2. Hospitalized residence / facility 
A detailed description is provided in the SRM for the sub-categories for 1 and 2 above. 
In order to relate the above discharge information to the participant’s residence status 
before contracting COVID-19, information must be collected at Screening about the 
participant’s residence before initial hospital admission for COVID-19 (refer to the SRM 
for more information). 
7.2.8. 
Sequential Organ Failure Assessment (SOFA) Scores 
The SOFA score is a tool for grading organ dysfunction in critically ill participants - 
usually those who are in ICU and intubated and mechanically ventilated.  Scores range 
from 0 to 4 for each component and represent the extent of dysfunction or failure 
[Vincent, 1996]. 
The SOFA score is made up of the following components: 
 The Respiratory System component of the SOFA score will be assessed using 
PaO2/FiO2 (mmHg) and will require an arterial blood gas (ABG) measurement.  If 
an ABG is not available, it is acceptable to estimate PaO2/FiO2 (mmHg) from 
SpO2/FiO2. 
 The Nervous System component of the SOFA score will be determined using the 
Glasgow Coma Scale (GCS).  If possible, GCS is assessed  during a sedation 
holiday.  If a participant is intubated and ventilated (and there is no sedation 
holiday in the previous 24 hours), the Glasgow Coma Score (GCS) assessment 
can be omitted, and a score of +4 used. 
 The Cardiovascular System component of the SOFA score can be determined by 
Mean Arterial Pressure (MAP) measurement or administration of vasopressors. 
 The Liver, Renal, and Coagulation components of the SOFA score will be 
determined by measurement of total bilirubin, serum creatinine, and platelet count 
respectively.  The highest score of the last 24-hour period for each measurement 
should be used. 
Part 1:  SOFA scores will be determined at the time points stipulated in SoA (Section 
1.3). 
Part 2:  SOFA score will be used only for eligibility assessment in patients who are 
intubated and mechanically ventilated (Section 1.4). 


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7.3. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA (Section 1.3 and 
Section 1.4) – where possible, these should be aligned with standard of care. 
7.3.1. 
Physical Examinations 
 A full physical examination will include, at a minimum, assessments of the 
Cardiovascular, Respiratory, Gastrointestinal and Neurological systems.  Results 
will not be recorded in the eCRF. 
7.3.2. 
Vital Signs 
 Temperature, pulse rate, respiratory rate, blood pressure will be assessed.  Single 
measurements will be used at all timepoints as detailed in the SoA. 
 The location used to measure temperature will be as per standard of care but must 
be recorded in the eCRF. 
 At Screening only, body weight should either be measured, established from the 
medical records e.g. last 3 months, or reported/estimated at the bedside.   
 Part 2 only: at Screening only, height should be measured, established from the 
medical records, or reported by the participant or LAR. 
7.3.3. 
Electrocardiograms 
 Single 12-lead ECG will be obtained as outlined in the SoA (see Section 1.3 and 
Section 1.4). 
 Each ECG report must be reviewed by the Principal Investigator (PI) or his 
qualified designee.  Each ECG must be initialled and dated by the PI or his/her 
qualified designee reviewing the report. 
7.3.4. 
Clinical Safety Laboratory Assessments 
 See Appendix 2 for the list of clinical laboratory tests to be performed and to the 
SoA for the timing and frequency. 
 The investigator must review the laboratory report, document this review, and 
record any clinically significant changes occurring during the study as an AE.  
The laboratory reports must be filed with the source documents. 
 Abnormal laboratory findings associated with the underlying disease are not 
considered clinically significant, unless judged by the investigator to be more 
severe than expected for the participant's condition. 
 All laboratory tests with values considered clinically significantly abnormal 
(during participation in the study until the follow up visit) should be repeated until 
the values return to normal or baseline or are no longer considered significantly 
abnormal by the investigator or medical monitor.  If clinically significant values 


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do not return to normal/baseline within a period of time judged reasonable by the 
investigator, the etiology should be identified and the sponsor notified. 
 If laboratory values from non-protocol specified laboratory tests are performed 
and require a change in participant management or are considered clinically 
significant by the investigator (e.g. SAE), then the results must be recorded. 
7.3.5. 
Pregnancy Testing (Part 1 only) 
 Pregnancy testing (urine or serum as required by local regulations) should be 
conducted at Screening to confirm eligibility as per Section 5.1. 
 Pregnancy testing (urine or serum as required by local regulations) should be 
conducted at Discharge.  If the participant has been discharged before Day 60, the 
Day 60 phone call will include a verbal confirmation about pregnancy status. 
 Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the 
absence of pregnancy at any time during the participant’s time in the study. 
7.4. 
Adverse Events (AEs), Serious Adverse Events (SAEs) and 
Other Safety Reporting 
The definitions of AEs or SAEs can be found in Section 9.3. 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, 
or the participant's legally authorized representative). 
The investigator and any qualified designees are responsible for detecting, documenting, 
and reporting events that meet the definition of an AE or SAE and remain responsible for 
following up all AEs that are serious, considered related to the study intervention or the 
study, or that caused the participant to discontinue the study. 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 9.3. 
7.4.1. 
Time Period and Frequency for Collecting AE and SAE 
Information 
 All AEs and SAEs will be collected from the start of intervention until the follow-up 
visit at the time points specified in the SoA (Section 1.3 and Section 1.4).  However, 
any SAEs assessed as related to study participation (e.g., study intervention, protocol-
mandated procedures, invasive tests, or change in existing therapy) or related to a 
GSK product will be recorded from the time a participant consents to participate in 
the study. 
 Medical occurrences that begin before the start of study intervention but after 
obtaining informed consent will be recorded as Medical History/Current Medical 
Conditions not as AEs. 


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 All SAEs will be recorded and reported to the sponsor or designee immediately and 
under no circumstance should this exceed 24 hours, as indicated in Appendix 3.  The 
investigator will submit any updated SAE data to the sponsor within 24 hours of it 
being available. 
 Investigators are not obligated to actively seek information on AEs or SAEs after the 
conclusion of the study participation.  However, if the investigator learns of any SAE, 
including a death, at any time after a participant has been discharged from the study, 
and he/she considers the event to be reasonably related to the study intervention or 
study participation, the investigator must promptly notify the sponsor. 
7.4.2. 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AE and/or SAE.  Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence. 
7.4.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts.  All SAEs, and non-serious AEs of special 
interest (as defined in Section 7.4.7), will be followed until the event is resolved, 
stabilized, otherwise explained, or the participant is lost to follow-up (as defined in 
Section 6.8).  Further information on follow-up procedures is given in Appendix 3. 
7.4.4. 
Regulatory Reporting Requirements for SAEs 
 Prompt notification by the investigator to the sponsor of an SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met. 
 The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation.  The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and investigators. 
 An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the sponsor will 
review and then file it along with the Investigator’s Brochure and will notify the 
IRB/IEC, if appropriate according to local requirements. 
7.4.5. 
Pregnancy (Part 1 only) 
 Details of all pregnancies in female participants will be collected after the start of 
study intervention and until follow-up visit (Day 60). 
 If a pregnancy is reported, the investigator will record pregnancy information on the 
appropriate form and submit it to GSK within 24 hours of learning of the pregnancy 
in a female participant.  While pregnancy itself is not considered to be an AE or SAE, 


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any pregnancy complication or elective termination of a pregnancy for medical 
reasons will be reported as an AE or SAE. 
 Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs and will be reported 
as such. 
 The participant will be followed to determine the outcome of the pregnancy.  The 
investigator will collect follow-up information on the participant and the neonate, and 
the information will be forwarded to the sponsor. 
 Any post-study pregnancy-related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in Section 
7.4.4.  While the investigator is not obligated to actively seek this information in 
former study participants, he or she may learn of an SAE through spontaneous 
reporting. 
7.4.6. 
Cardiovascular and Death Events 
For any cardiovascular events detailed in Appendix 3 and all deaths, whether or not they 
are considered SAEs, specific Cardiovascular (CV) and Death sections of the eCRF will 
be required to be completed.  These sections include questions regarding cardiovascular 
(including sudden cardiac death) and non-cardiovascular death. 
The CV eCRFs are presented as queries in response to reporting of certain CV MedDRA 
terms.  The CV information should be recorded in the specific cardiovascular section of 
the eCRF within one week of receipt of a CV Event data query prompting its completion. 
The Death eCRF is provided immediately after the occurrence or outcome of death is 
reported.  Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported. 
7.4.7. 
Adverse Events of Special Interest 
The potential risks of otilimab are discussed in Section 2.3. 
Adverse events of special interest (AESI) include: 
 Cytokine release syndrome (CRS) (not related to COVID-19 [see Section 7.4.7.1]) 
 Serious hypersensitivity reactions 
 Infusion site reactions 
 Neutropenia  Grade 3 (<1.0 x 109/L) 
 Serious infections 
 
AESIs should be reported as AEs or SAEs, as appropriate.  Please refer to Section 9.3 
(Appendix 3) and the SRM.   


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7.4.7.1. 
Cytokine Release Syndrome 
Cytokine-associated toxicity, also known as cytokine release syndrome (CRS), is a non–
antigen-specific toxicity that occurs as a result of strong immune activation.  The 
magnitude of immune activation typically required to mediate clinical benefit using 
modern immunotherapies exceeds levels of immune activation that occurs in more 
natural settings.  As immune-based therapies have become more potent, CRS is becoming 
increasingly recognized. 
Symptomatology associated with CRS and the severity of symptoms varies greatly but 
may be quite mild, and management can be complicated by inter-current conditions in 
these participants.  This may be particularly the case in patients with severe pulmonary 
COVID-19 related disease. 
Potentially life-threatening severe complications of CRS include cardiac dysfunction, 
acute respiratory distress syndrome, neurologic toxicity, renal and/or hepatic failure, and 
disseminated intravascular coagulation.  Of particular concern is cardiac dysfunction, 
which can be rapid onset and severe, but is typically reversible. 
In the event of CRS, investigators should follow institutional guidelines for symptom 
management.  Additional guidance can be found in the published literature [Lee, 2014]. 
 
For this study, CRS (possibly related to study drug, rather than progression of 
hyperinflammation in COVID-19 disease) is defined as a worsening of the CRS Grading 
System (below) within 6 hours after start of study drug infusion. 
 
In the event that CRS is suspected (defined as a worsening of the CRS Grading System 
within 6 hours of drug administration) and is thought to be caused by otilimab by the 
investigator, additional blood samples should be taken (see Section 1.3 and Section 1.4, 
and Section 9.2).  These blood samples should be taken as soon as possible after 
suspected CRS onset and then again 24 hours later.  The following blood samples should 
be taken: 
 PD (cytokine) sample 
 Hematology 
 CRP 
 D-dimer 
 Ferritin 
In the event that new onset of CRS is suspected, the medical monitor must be notified 
immediately and under no circumstance can this exceed 24 hours, and the event must 
also be reported within 24 hours as an AE or an SAE.  The investigator will submit any 
updated data related to the CRS event (including completion of any AE or SAE CRF 
forms) to the sponsor within 24 hours of it being available. Additional CRF forms related 
to the CRS event should then be completed as soon as possible. 


T M F -1 1 7 9 5 6 0 7  
C O N FI D E N TI A L  
 
 
 
2 1 4 0 9 4  
 
6 5  
 
C R S Gr a di n g S yste m 1 
Gr a d e  
T o xi city  
1Ad a pte d fr o m  L e e , 2 0 1 4  
2Gr a d es
r efer to C T C A E v 5. 0 gr a din g 
 
7. 5.  
P h ar m a c o ki n eti c s  
 B lo o d s a m ples (a p pr o xi mately 3. 5  m L ) will be c olle cte d f or me as ure me nt of 
s er u m c o nc e ntratio ns of otili ma b  as s pe cifie d in t he S o A  ( Se ctio n 1. 3  a n d Se ctio n 
1. 4 ). 
 T he a ct ual date a n d ti me  ( 2 4-h o ur cloc k ti me) of e a c h blo o d s a m ple c olle ctio n 
will be re c or de d.  
 C olle ctio n, pr oc essin g, st ora ge a n d s hip pin g pr oc e d ures are pr o vide d in t he 
c e ntral la b orat or y ma n ual.    
 P art 2  - If c e ntral la b orat or y kits are n ot a vaila ble at a site  (f or o peratio nal 
re as o ns), participa nts c a n be ra n d o mis e d a n d d os e d , a n d t he P K s a m ples n ot 
c olle cte d.  I n t his sit uatio n, t he missin g s a m ples w o uld n ot be a pr ot oc ol 
de viatio n.  T his is justifia ble, be c a us e P K s a m plin g is a n e x plorat or y e n d p oint.  
 I nter ve ntio n c o nc e ntratio n inf or matio n t hat ma y/ w o uld u n blin d t he st u d y will n ot 
be re p orte d t o in vestigative sites or blin de d pers o n nel u ntil t he st u d y has be e n 
u n blin de d.  
7. 6.  
G e n eti c s  
Ge net ics are n ot e valuate d in t his st u d y. 
C CI
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d 
b y t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.


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7.7. 
Pharmacodynamics  
 Blood samples will be collected to help understand the disease, otilimab target 
levels and response to otilimab in COVID-19 related  disease, as specified in the 
SoA (Section 1.3 and Section 1.4). 
 Biomarkers may include, but are not limited to: inflammatory cytokines, such as 
IL-6; growth factors, such as GM-CSF; and other molecules that are indicative of 
hyper-inflammation. 
 The actual date and time (24-hour clock time) of each blood sample collection 
will be recorded. 
 Collection, processing, storage and shipping procedures are provided in the 
central laboratory manual. 
 Part 2 - If central laboratory kits are not available at a site (for operational 
reasons), participants can be randomised and dosed, and the PD samples not 
collected.  In this situation, the missing samples would not be a protocol 
deviation.  This is justifiable, because PD sampling is an exploratory endpoint. 
GSK may store samples for up to 15 years after the end of the study to achieve study 
objectives.  Additionally, with participants’ consent, samples may be used for further 
research by GSK or others such as universities or other companies to contribute to the 
understanding of SARS-CoV-2 infection, associated COVID-19 disease or other 
diseases, the development of related or new treatments or research methods. 
7.8. 
Immunogenicity Assessments 
Antibodies to otilimab will not be assessed as part of this study, since this is a single dose 
study. 
7.9. 
Health Economics/Medical Resource Utilization and Health 
Economics 
Health Economics/Medical Resource Utilization and Health Economics parameters will 
not be evaluated in this study. 
8. 
STATISTICAL CONSIDERATIONS 
8.1. 
Statistical Hypotheses 
The primary objective of this study is to compare the efficacy of otilimab 90 mg IV 
versus placebo in participants with severe pulmonary COVID-19 related disease. 
In all parts of the study, the study will test the null hypothesis that the difference between 
otilimab 90 mg and placebo on the proportion of participants alive and free of respiratory 
failure at Day 28 is less than or equal to zero versus the alternative hypothesis that 
otilimab 90 mg increases the proportion of participants alive and free of respiratory 
failure compared with placebo at Day 28. 


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8.2. 
Sample Size Determination 
Otilimab and placebo will be randomized in a 1:1 ratio. 
Part 1 
The study will utilize a group sequential design, using a Lan-DeMets alpha-spending 
function to control the type I error with four interim analyses for futility, two early in the 
study where futility alone will be assessed, using Pocock analogue rules; and two for 
efficacy, at later times in the study and at the same time as futility, using the O’Brien-
Fleming analogue rules [Lan, 1983].  A sample size of 800 participants will provide 
approximately 90% power to detect a difference of 12% in the proportion of participants 
alive and free of respiratory failure at a one-sided 2.5% significance level and an assumed 
placebo response rate of 45%.  The minimal detectable effect for this design is 7%. 
Full details of the decision criteria and interim analysis plan will be given in the IDMC 
charter and analysis plan. 
The assumed placebo response is based on data from recent publications of studies of 
patients with severe pulmonary COVID-19 related disease [Sanofi, 2020]. 
Part 2 
A sample size of 346 participants will provide approximately 80% power to detect a 
difference of 15% in the proportion of participants alive and free of respiratory failure at 
a one-sided 2.5% significance level and an assumed placebo response rate of 45%.  The 
minimal detectable effect for this design is 10.6%. 
8.3. 
Analysis Sets 
Part 1 and Part 2 
The primary population will be the modified intent to treat (MITT) population, defined as 
all participants who were randomized and received study drug.  This population will be 
used for all data summaries and analyses.  Any participant who receives study 
intervention will be considered evaluable. 
Further details of analysis sets will be provided in the Analysis Plan. 
8.4. 
Statistical Analyses 
Full details of all analyses will be described in the Analysis Plan.  Each part of the study 
will be analysed separately, and separate analysis plans will be produced.   
This section is a summary of the planned statistical analyses for the primary endpoint. 


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8.4.1. 
General Considerations 
Part 1 
In the case of a difference between the stratification assigned at the time of randomization 
and the data collected in the eCRF, the analyses will be performed based on the 
calculated stratum at randomization.  All analyses will be adjusted for ordinal scale 
category at baseline (category 5 or 6) and age group (treated as categorical variable 
defined by the levels <60 years, 60 to <70 years, 70 to <80 years).  Confidence intervals 
will use the 95% levels unless otherwise specified. 
Part 2 
In the case of a difference between the stratification assigned at the time of randomization 
and the data collected in the eCRF, the analyses will be performed based on the 
calculated stratum at randomization.  All analyses will be adjusted for ordinal scale 
category at baseline (category 5 or 6) and gender (male or female).  Confidence intervals 
will use the 95% levels unless otherwise specified. 
8.4.2. 
Primary Endpoint(s) 
The primary endpoint is whether or not a participant is alive and free of respiratory 
failure at Day 28. 
The primary endpoint was analysed when all participants in Part 1 had completed Day 
28.  In Part 2, the primary endpoint will be analysed after all participants have completed 
Day 28. The final analysis will be conducted for each part of the study after the last 
participant has completed the study. Participants are considered alive and free of 
respiratory failure if they are in category 1, 2, 3 or 4 from the GlaxoSmithKline (GSK) 
modified version ordinal scale adapted from World Health Organization (WHO) scale 
2020 (Section 7.2.6. Table 2 - Ordinal Scale). 
Part 1 and Part 2 
The primary estimand is the odds ratio between otilimab versus placebo in the proportion 
of participants alive and free of respiratory failure at Day 28 in participants with severe 
pulmonary COVID-19 related disease regardless of use of additional medications or 
changes to standard of care.  No other intercurrent events are expected and the strategy 
for analysis will be to use the treatment policy strategy, with data analyzed as collected.  
It is expected missing data will be minimal and most will be lost to follow up data after 
discharge and this along with intermittent data will be imputed using multiple imputation 
under the missing at random assumption.  Every effort will be made to reduce missing 
data.  Supplemental estimand strategies and missing data sensitivities may be performed 
and further details will be provided in the analysis plan. 
The primary endpoint will be summarized using counts and proportions of the number of 
participants alive and free of respiratory failure and will be analyzed using a logistic 
regression model, adjusting for ordinal scale category at baseline and age group.  The 
outcome of the model is an odds ratio, and a confidence interval for the odds of 
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In addition, the corresponding difference in proportion and confidence interval will be 
calculated from the model [Ge, 2011]. 
The analysis of the primary endpoint at the in-stream interim analyses in Part 1 will be 
the same as that described for the primary endpoint above. 
8.4.3. 
Secondary Endpoint(s) 
Full details of all analysis methods for the secondary endpoints will be provided in the 
analysis plan. 
8.4.4. 
Exploratory Endpoint(s) 
Full details of all analysis methods for the exploratory endpoints will be provided in the 
analysis plan. 
8.4.5. 
Safety Analysis 
For safety data, no formal hypotheses will be tested.  Occurrence of AEs, SAEs, and 
AESIs, including laboratory tests, vital signs, and 12-lead ECGs will be displayed in the 
form of listings, frequencies, summary statistics, graphs, and statistical analyses where 
appropriate.  Interpretation will be aided by clinical expertise.  Full details, including 
example outputs, will be documented in the analysis plan. 
8.5. 
Interim Analysis 
Part 1 
Interim analyses will be used to assess safety, futility and efficacy.  Safety stopping rules 
will be put in place for the IDMC to stop the study if there is an excess risk of mortality.  
Full details of timing of analyses and all stopping criteria will be given in the IDMC 
charter. 
An IDMC will actively monitor in-stream interim unblinded safety and efficacy data to 
make recommendations to GSK as per IDMC charter.  The IDMC members will include 
4-6 physicians with relevant medical specialist training and one statistician.  Details 
regarding the IDMC process will be available in relevant IDMC documents prior to the 
first participant’s visit. 
A GSK Safety Review Team (SRT) will review the blinded safety data of this study at 
regular intervals through both initial safety and main cohort dosing.  Details regarding the 
SRT process will be available in relevant SRT documents.  The SRT will inform the 
IDMC if any safety signals are identified. 
Part 2 
There will be no interim analyses to assess futility and efficacy. 
An IDMC will actively monitor in-stream interim unblinded safety data to make 
recommendations to GSK as per IDMC charter for Part 2.  The IDMC members will 
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Details regarding the IDMC process will be available in relevant IDMC documents prior 
to the first participant’s visit. 
A GSK Safety Review Team (SRT) will review the blinded safety data of this study at 
regular intervals through the study.  Details regarding the SRT process will be available 
in relevant SRT documents. 
 


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9. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
9.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
9.1.1. 
Regulatory and Ethical Considerations 
 This study will be conducted in accordance with the protocol and with: 
o Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
o Applicable International Conference on Harmonisation (ICH) Good Clinical 
Practice (GCP) Guidelines 
o Applicable laws and regulations 
 The protocol, protocol amendments, informed consent form (ICF), IB and other 
relevant documents (e.g., advertisements) must be submitted to an IRB/IEC by the 
investigator and reviewed and approved by the IRB/IEC before the study is 
initiated. 
 Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants. 
 Protocols and any substantial amendments to the protocol will require health 
authority approval prior to initiation except for changes necessary to eliminate an 
immediate hazard to study participants. 
 The investigator will be responsible for the following: 
o Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/EC 
o Notifying the IRB/IEC of SAE or other significant safety findings as required by 
IRB/IEC procedures 
o Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies (if applicable), European Medical Device Regulation 
2017/745 for clinical device research (if applicable), and all other applicable local 
regulations 
9.1.2. 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 


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financial certification or disclosure statements to the appropriate regulatory authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study. 
9.1.3. 
Informed Consent Process 
Given that this trial is being conducted in participants with COVID-19, and given that 
some of the participants will be mechanically ventilated upon enrolment, alternative 
procedures to obtain informed consent will be used.  Participants may be consented in 
three ways, as described below.  The EMA Guidance on the Management of Clinical 
Trials during the COVID-19 (Coronavirus) pandemic (Version 2, 27-Mar-20) [EMA, 
2020] and the FDA Guidance on Conduct of Clinical Trials of Medical Products during 
the COVID-19 Pandemic (updated 16-Apr-20) [FDA, 2020] have been considered. 
 
1.  Participant is enrolled by signing the informed consent. 
If the participant is capable of understanding and signing the informed consent (paper or 
eConsent), the below points will apply: 
 The investigator or his/her representative will explain the nature of the study to 
the participant and answer all questions regarding the study. 
 The medical record must include a statement that written (or electronic) informed 
consent was obtained before the participant was enrolled in the study and the date 
the written consent was obtained.  The authorized person obtaining informed 
consent must also sign the informed consent form (ICF).  If paper consent is used, 
and there is an infection risk to the person obtaining consent, the trial participant 
and the person obtaining consent may sign and date separate ICFs.  All relevant 
records should be archived in the Investigator Site File.  A correctly signed and 
dated ICF should be obtained from the trial participant as soon as possible. 
 Consent may be collected before the 48h screening window if the investigator 
considers that the participant is likely to become eligible, and wants to ensure that 
consent is given by the participant rather than a legally authorized representative 
(LAR). 
 
2. Participant is enrolled by consenting orally. 
If the participant is capable of understanding, but not able to provide written consent 
(paper or eConsent), informed consent can be obtained orally, the below points will 
apply: 
 The investigator or his/her representative will explain the nature of the study to 
the participant and answer all questions regarding the study. 
 Oral consent must be given in the presence of an impartial witness.  In such cases, 
the witness is required to sign and date the ICF (paper or electronic) and the 
investigator is expected to record how the impartial witness was selected.  All 
relevant records should be archived in the Investigator Site File.  A correctly 
signed and dated ICF should be obtained from the trial participant as soon as 
possible. 
 


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3. Participant is enrolled by his/her legally authorized representative (LAR) (written 
or oral). 
If the participant is unable to provide informed consent, the investigator or delegate can 
obtain consent from an LAR.  If consent is obtained from an LAR, the following points 
will apply: 
 The investigator or his/her representative will explain the nature of the study to 
the LAR and answer all questions regarding the study. 
 Best efforts will be undertaken to obtain written consent (paper, email or 
eConsent) from an LAR.  However, if the LAR is not able to provide written or 
electronic consent for logistical reasons, informed consent can be obtained orally 
from the LAR.  As above for oral participant consent, oral LAR consent must be 
given to the investigator in the presence of an impartial witness.  In such cases, 
the witness is required to sign and date the ICF and the investigator is expected to 
record how the impartial witness was selected.  A correctly signed and dated ICF 
should be obtained from the LAR as soon as possible. 
 The investigator has responsibility for applying local laws in the matter of who 
has the capacity to consent and who qualifies as an LAR of a potential participant. 
 An LAR is defined as an individual or juridical or other body authorized under 
applicable law to consent, on behalf of a prospective participant, to the 
participant’s participation in the clinical trial. 
 An LAR can be a member of the participant’s family, next-of-kin or trusted 
person previously designated by the participant. 
 As soon as is practically possible following a participant regaining capacity, 
participants will be asked to provide informed consent to remain in the study.  If 
they decline, then they will be withdrawn from the study.  The participant will 
decide if they want to allow samples already collected to be used or request for 
them to be discarded if not yet analyzed. 
 All relevant records should be archived in the Investigator Site File. 
Documentation of Informed consent process 
 
The management of the informed consent process will be documented in the medical 
source notes.  This will include which process was used to obtain consent.  The following 
should be noted in regard to the informed consent process: 
 
 If consent is provided orally by the participant or LAR in the presence of an 
impartial witness, the witness name, time and date of witnessing must be recorded 
in medical source notes.  The investigator must also document how the impartial 
witness was selected. 
 If consent is provided by LAR, name, time and date of LAR and name of the 
personnel at site that collected this information. 
 Participants/LAR must be informed that their participation is voluntary.  
Participants and/or LAR will be required to sign electronically or on paper (or 
agree orally) to a statement of informed consent that meets the requirements of 21 
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Accountability Act (HIPAA) requirements, where applicable, and the IEC or 
study center. 
A copy of all signed ICF(s) must be provided to the participant or the participant’s LAR. 
GSK (alone or working with others) may use participant’s coded study data and samples 
and other information to carry out this study; understand the results of this study; learn 
more about otilimab or about the study disease; publish the results of these research 
efforts; work with government agencies or insurers to have otilimab approved for medical 
use or approved for payment coverage. 
The ICF contains a separate section that addresses the use of participant data and 
remaining samples for optional further research.  The investigator or authorized designee 
will inform each participant or their LAR of the possibility of further research not related 
to the study/disease.  Participants or their LAR will be told that they are free to refuse to 
participate and may withdraw their consent at any time and for any reason during the 
storage period.  A separate signature (participant or LAR) will be required to document 
agreement to allow any participant data and/or remaining leftover samples to be used for 
further research not related to the study/disease.  Participants or their LAR who decline 
further research will tick the corresponding “No” box. 
9.1.4. 
Data Protection 
 Participants will be assigned a unique identifier by the sponsor.  Any participant 
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred. 
 The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law.  The level of 
disclosure must also be explained to the participant who will be required to give 
consent for their data to be used as described in the informed consent. 
 The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed by 
the sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
9.1.5. 
Committees Structure 
Part 1 
 
An Independent Data Monitoring Committee (IDMC) comprised of clinical experts 
external to GSK will review unblinded data at defined timepoints during the study.  If 
deemed appropriate by the IDMC, or upon request by GSK or investigators, additional 
timepoints for review may be added. 
Details of the structure and function of the IDMC, and analysis plan for IDMC reviews, 
are outlined in the IDMC Charter, which is available upon request. 


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In addition to the IDMC, the GSK SRT will review blinded safety data at a minimum of a 
weekly basis to ensure participant safety, which includes safety signal detection at any 
time during the study.  Details of this are included in Section 8.5. 
In the unlikely event that the IDMC cannot be convened for a scheduled meeting, the 
GSK Independent Safety Review Committee (iSRC) will review the unblinded outputs 
(as outlined in the IDMC Charter). 
Part 2 
 
An IDMC comprised of clinical experts external to GSK will review unblinded safety 
data at defined timepoints during the study.  If deemed appropriate by the IDMC, or upon 
request by GSK or investigators, additional timepoints for review may be added. 
Details of the structure and function of the IDMC, and analysis plan for IDMC reviews, 
are outlined in the IDMC Charter, which is available upon request. 
The GSK SRT will review blinded safety data at a minimum of a monthly basis to ensure 
participant safety, which includes safety signal detection at any time during the study.  
Details of this are included in Section 8.5. 
In the unlikely event that the IDMC cannot be convened for a scheduled meeting, the 
GSK Independent Safety Review Committee (iSRC) will review the unblinded outputs 
(as outlined in the IDMC Charter). 
9.1.6. 
Dissemination of Clinical Study Data 
 Where required by applicable regulatory requirements, an investigator signatory 
will be identified for the approval of the clinical study report.  The investigator 
will be provided reasonable access to statistical tables, figures, and relevant 
reports and will have the opportunity to review the complete study results at a 
GSK site or other mutually-agreeable location. 
 GSK will also provide all investigators who participated in the study with a 
summary of the study results and will tell the investigators what treatment their 
participants received.  The investigator(s) is/are encouraged to share the summary 
results with the study participants, as appropriate. 
 Under the framework of the SHARE initiative, GSK intends to make anonymized 
participant-level data from this trial available to external researchers for scientific 
analyses or to conduct further research that can help advance medical science or 
improve patient care.  This helps ensure the data provided by trial participants are 
used to maximum effect in the creation of knowledge and understanding.  
Requests for access may be made through www.clinicalstudydatarequest.com. 
 GSK will provide the investigator with the randomization codes for their site only 
after completion of the full statistical analysis. 
 The procedures and timing for public disclosure of the protocol and results 
summary and for development of a manuscript for publication for this study will 
be in accordance with GSK Policy. 


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 GSK intends to make anonymized patient-level data from this trial available to 
external researchers for scientific analyses or to conduct further research that can 
help advance medical science or improve patient care.  This helps ensure the data 
provided by trial participants are used to maximum effect in the creation of 
knowledge and understanding 
 A manuscript will be progressed for publication in the scientific literature if the 
results provide important scientific or medical knowledge. 
9.1.7. 
Data Quality Assurance 
 All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (e.g., laboratory 
data).  The investigator is responsible for verifying that data entries are accurate 
and correct by physically or electronically signing the CRF. 
 Guidance on completion of CRFs will be provided in the eCRF Guidelines. 
 Quality tolerance limits (QTLs) will be pre-defined in the QTL Plan to identify 
systematic issues that can impact participant safety and/or reliability of study 
results.  These pre-defined parameters will be monitored during and at the end of 
the study and all deviations from the QTLs and remedial actions taken will be 
summarized in the clinical study report. 
 The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents. 
 Monitoring details describing strategy including definition of study critical data 
items and processes (e.g., risk-based initiatives in operations and quality such as 
Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site 
monitoring) are provided in the Monitoring Plan. 
 The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 
 The sponsor assumes accountability for actions delegated to other individuals 
(e.g., Contract Research Organizations). 
 Records and documents, including signed ICF, pertaining to the conduct of this 
study must be retained by the investigator for 25 years from the issue of the final 
Clinical Study Report (CSR)/ equivalent summary unless local regulations or 
institutional policies require a longer retention period.  No records may be 
destroyed during the retention period without the written approval of the sponsor.  
No records may be transferred to another location or party without written 
notification to the sponsor. 


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9.1.8. 
Source Documents 
 Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected.  Source documents are filed at the 
investigator’s site. 
 Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies 
must be explained.  The investigator may need to request previous medical 
records or transfer records, depending on the study.  Also, current medical records 
must be available. 
 Definition of what constitutes source data and its origin can be found in the 
Source Data Acknowledgment. 
 The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF. 
 Study monitors will perform ongoing monitoring (remote or on-site) as per the 
Monitoring Plan to confirm that data entered into the CRF by authorized site 
personnel are accurate, complete, and verifiable from source documents; that the 
safety and rights of participants are being protected; and that the study is being 
conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 
9.1.9. 
Study and Site Start and Closure 
GSK or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK.  Study sites will be closed upon study 
completion.  A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to: 
For study termination: 
 If the study is prematurely terminated or suspended, the sponsor shall promptly 
inform the investigators, the IECs/IRBs, the regulatory authorities, and any 
contract research organization(s) used in the study of the reason for termination or 
suspension, as specified by the applicable regulatory requirements.  The 
investigator shall promptly inform the participant and should assure appropriate 
participant therapy and/or follow-up 
 Discontinuation of further study intervention development 
 
 


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For site termination: 
 Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines 
 Inadequate or no recruitment of participants (evaluated after a reasonable amount 
of time) by the investigator 
9.1.10. 
Publication Policy 
 The results of this study may be published or presented at scientific meetings.  If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to 
the sponsor before submission.  This allows the sponsor to protect proprietary 
information and to provide comments. 
 The sponsor will comply with the requirements for publication of study results.  
In accordance with standard editorial and ethical practice, the sponsor will 
generally support publication of multicenter studies only in their entirety and not 
as individual site data.  In this case, a coordinating investigator will be designated 
by mutual agreement. 
 Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 


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9.2. 
Appendix 2: Clinical Laboratory Tests  
The tests detailed in Table 3 and Table 4 will be performed by the local laboratory. 
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol. 
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations. 
Table 3 
Protocol-Required Safety Laboratory Tests – Part 1 
Laboratory 
Assessments1 
Parameters 
Hematology 
Hemoglobin 
RBC Indices: 
WBC count (differential) 
absolute and/or %: 
 
Hematocrit 
MCV 
Neutrophils 
 
Platelet Count 
MCH 
Lymphocytes 
 
RBC Count 
%Reticulocytes 
Monocytes 
 
 
 
Eosinophils 
 
 
 
Basophils 
Coagulation 
APTT / APTR 
PT 
INR 
Clinical 
Urea (BUN) 
Phosphate 
AST / SGOT 
Chemistry 
Creatinine 
Troponin I4 
ALT / SGPT 
 
Glucose2 
D-dimer 
Gamma-GT 
 
Potassium 
Ferritin5 
Total bilirubin 
 
Sodium 
CRP 
Direct bilirubin 
 
Calcium   
LDH 
ALP7 
 
Lactate3 
Procalcitonin5, 6  
Total protein 
 
Creatine kinase 
ESR5 
Albumin 
Pregnancy 
Highly sensitive serum or urine human chorionic gonadotropin (hCG) 
pregnancy test (as needed for women of childbearing potential) 
CRS Event 
If CRS is suspected, the following samples should be taken as soon as 
possible after suspected CRS on-set and again 24 h later: Hematology, CRP, 
D-dimer, ferritin, PD (cytokine sample – see Section 1.3) 
1. Hematology, Coagulation and Clinical Chemistry testing at the following time-points (unless 
otherwise indicated below):  Screening, Day 1, Day 2, Day 4, Day 7, Day 14, Day 28 and 
Discharge 
2. Record glucose fasting / non-fasting status 
3. Can be measured from arterial blood gas test 
4. If troponin I is not available locally, troponin T can be reported  
5. To be measured at Screening, Day 7 and Day 14 only 
6. Procalcitonin to be measured if the test is available locally 
7. If alkaline phosphatase is elevated, consider fractionating 
 


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Table 4 
Protocol-Required Safety Laboratory Tests – Part 2 
Laboratory 
Assessments1 
Parameters 
Hematology 
Hemoglobin 
RBC Indices: 
WBC count (differential) 
absolute and/or %: 
 
Hematocrit 
MCV 
Neutrophils 
 
Platelet Count 
MCH 
Lymphocytes 
 
RBC Count 
%Reticulocytes 
Monocytes 
 
 
 
Eosinophils 
 
 
 
Basophils 
Coagulation 
APTT / APTR 
PT or INR 
 
Clinical 
Urea (BUN) 
Phosphate 
AST / SGOT 
Chemistry 
Creatinine 
Troponin I2 
ALT / SGPT 
 
Glucose 
D-dimer 
Gamma-GT 
 
Potassium 
Ferritin3 
Total bilirubin 
 
Sodium 
CRP 
Direct bilirubin 
 
Calcium   
LDH 
ALP 
 
Creatine kinase 
ESR3 
Total protein 
 
 
 
Albumin 
CRS Event 
If CRS (considered possibly drug related – see Section 7.4.7.1) is suspected, 
the following samples should be taken as soon as possible after suspected 
CRS on-set and again 24 h later: Hematology, CRP, D-dimer, ferritin, PD 
(cytokine sample – see Section 1.3 and Section 1.4) 
1. Hematology, Coagulation and Clinical Chemistry testing at the following time-points (unless 
otherwise indicated below):  Screening, Day 1, Day 4, Day 7, Day 14, Day 28 and Discharge 
2. If troponin I is not available locally, troponin T can be reported  
3. To be measured at Screening, Day 7 and Day 14 only 


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9.3. 
Appendix 3: AEs and SAEs: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
9.3.1. 
Definition of AE 
AE Definition 
 An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of a study intervention, whether or not considered related to the 
study intervention. 
 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated 
with the use of a study intervention. 
 
Events Meeting the AE Definition 
 Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (e.g., ECG, radiological scans, vital signs measurements), including 
those that worsen from baseline, considered clinically significant in the medical and scientific 
judgment of the investigator (i.e., not related to progression of underlying disease). 
 Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or intensity of the condition. 
 New conditions detected or diagnosed after study intervention administration even though it 
may have been present before the start of the study. 
 Signs, symptoms, or the clinical sequelae of a suspected intervention- intervention 
interaction. 
 Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.  Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming intent.  
Such overdoses should be reported regardless of sequelae. 
 "Lack of efficacy" or "failure of expected pharmacological action" per se will not be reported 
as an AE or SAE.  Such instances will be captured in the efficacy assessments.  However, 
the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be reported 
as AE or SAE if they fulfil the definition of an AE or SAE. 
 
Events NOT Meeting the AE Definition  
 Any clinically significant abnormal laboratory findings or other abnormal safety assessments 
which are associated with the underlying disease, unless judged by the investigator to be 
more severe than expected for the participant’s condition. 
 The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
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 Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 
 Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital). 
 Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
 
9.3.2. 
Definition of SAE 
An SAE is defined as any serious adverse event that, at any dose: 
a. Results in death 
b. Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the participant 
was at risk of death at the time of the event.  It does not refer to an event, which hypothetically 
might have caused death, if it were more severe. 
c. Requires inpatient hospitalization or prolongation of existing hospitalization 
 In general, hospitalization signifies that the participant has been admitted (usually involving at 
least an overnight stay) at the hospital or emergency ward for observation and/or treatment 
that would not have been appropriate in the physician’s office or outpatient setting.  
Complications that occur during hospitalization are AE.  If a complication prolongs 
hospitalization or fulfils any other serious criteria, the event is serious.  When in doubt as to 
whether “hospitalization” occurred or was necessary, the AE should be considered serious. 
 Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
d. Results in persistent or significant disability/incapacity 
 The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. 
 This definition is not intended to include experiences of relatively minor medical significance 
such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental 
trauma (e.g. sprained ankle) which may interfere with or prevent everyday life functions but 
do not constitute a substantial disruption. 
e. Is a congenital anomaly/birth defect 
f. Other situations: 
 Medical or scientific judgment should be exercised by the investigator in deciding whether 
SAE reporting is appropriate in other situations such as significant medical events that may 
jeopardize the participant or may require medical or surgical intervention to prevent one of 
the other outcomes listed in the above definition.  These events should usually be considered 
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o Examples of such events include invasive or malignant cancers, intensive treatment for 
allergic bronchospasm, blood dyscrasias, convulsions, acute deterioration of liver 
function, or development of intervention dependency or intervention abuse. 
 
9.3.3. 
Definition of Cardiovascular Events 
Cardiovascular Events (CV) Definition: 
Investigators will be required to fill out the specific CV event page of the eCRF for the following 
AEs and SAEs: 
 Myocardial infarction/unstable angina 
 Congestive heart failure 
 Arrhythmias 
 Valvulopathy 
 Pulmonary hypertension 
 Cerebrovascular events/stroke and transient ischemic attack 
 Peripheral arterial thromboembolism 
 Deep venous thrombosis/pulmonary embolism 
 Revascularization 
 
9.3.4. 
Recording and Follow-Up of AE and SAE 
AE and SAE Recording 
 When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g. hospital progress notes, laboratory, and diagnostics reports) related to 
the event. 
 The investigator will then record all relevant AE/SAE information. 
 It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to GSK in lieu of completion of the GSK required form. 
 There may be instances when copies of medical records for certain cases are requested by 
GSK.  In this case, all participant identifiers, with the exception of the participant number, will 
be redacted on the copies of the medical records before submission to GSK. 
 The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information.  Whenever possible, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported during the 
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 Mild: An event that is easily tolerated by the participant, causing minimal discomfort and not 
interfering with everyday activities. 
 Moderate: An event that causes sufficient discomfort and interferes with normal everyday 
activities. 
 Severe: An event that prevents normal everyday activities.  An AE that is assessed as severe 
should not be confused with an SAE.  Severe is a category utilized for rating the intensity of 
an event; and both AE and SAE can be assessed as severe. 
 An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe. 
Assessment of Causality 
 
The investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. 
 A "reasonable possibility" of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
 The investigator will use clinical judgment to determine the relationship. 
 Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention administration 
will be considered and investigated. 
 The investigator will also consult the Investigator’s Brochure (IB) and/or Product Information, 
for marketed products, in his/her assessment. 
 For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
 There may be situations in which an SAE has occurred, and the investigator has minimal 
information to include in the initial report to GSK.  However, it is very important that the 
investigator always make an assessment of causality for every event before the initial 
transmission of the SAE data to GSK. 
 The investigator may change his/her opinion of causality in light of follow-up information and 
send an SAE follow-up report with the updated causality assessment. 
 The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
 
Follow-up of AE and SAE 
 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to elucidate 
the nature and/or causality of the AE or SAE as fully as possible.  This may include additional 
laboratory tests or investigations, histopathological examinations, or consultation with other 
health care professionals. 
 If a participant dies during participation in the study or during a recognized follow-up period, 
the investigator will provide GSK with a copy of any post-mortem findings including 
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 New or updated information will be recorded in the originally submitted documents. 
 The investigator will submit any updated SAE data to GSK within 24 hours of receipt of 
the information. 
 
9.3.5. 
Reporting of SAE to GSK 
SAE Reporting to GSK via Electronic Data Collection Tool 
 
The primary mechanism for reporting SAE to GSK will be the electronic data collection tool. 
 If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) to report the event within 24 hours. 
 The site will enter the SAE data into the electronic system as soon as it becomes available. 
 The investigator or medically-qualified sub-investigator must show evidence within the eCRF 
(e.g., check review box, signature, etc.) of review and verification of the relationship of each 
SAE to investigational product/study participation (causality) within 72 hours of SAE entry into 
the eCRF. 
 After the study is completed at a given site, the electronic data collection tool will be taken 
off-line to prevent the entry of new data or changes to existing data. 
 If a site receives a report of a new SAE from a study participant or receives updated data on 
a previously reported SAE after the electronic data collection tool has been taken off-line, 
then the site can report this information on a paper SAE form (see next section) or to the SAE 
coordinator by telephone. 
 Contacts for SAE reporting can be found in Study Reference Manual. 
 
SAE Reporting to GSK via Paper Data Collection Tool 
 
Facsimile transmission of the SAE paper data collection tool is the preferred method to 
transmit this information to the SAE coordinator. 
 In rare circumstances and in the absence of facsimile equipment, notification by telephone is 
acceptable with a copy of the SAE data collection tool sent by overnight mail or courier 
service. 
 Initial notification via telephone does not replace the need for the investigator to complete 
and sign the SAE data collection tool within the designated reporting time frames. 
 Contacts for SAE reporting can be found in Study Reference Manual. 


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9.4. 
Appendix 4: Contraceptive and Barrier Guidance (Part 1 
only) 
9.4.1. 
Definitions: 
Woman of Childbearing Potential (WOCBP) 
Women in the following categories are considered WOCBP (fertile): 
1. Following menarche 
2. From the time of menarche until becoming post-menopausal unless permanently 
sterile (see below) 
Notes: 
 A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
o Females on HRT and whose menopausal status is in doubt will be required to use 
one of the non-estrogen hormonal highly effective contraception methods if they 
wish to continue their HRT during the study. 
 Permanent sterilization methods (for the purpose of this study) include: 
o Documented hysterectomy 
o Documented bilateral salpingectomy 
o Documented bilateral oophorectomy 
 For individuals with permanent infertility due to an alternate medical cause other than 
the above, (e.g., Mullerian agenesis, androgen insensitivity, gonadal dysgenesis), 
investigator discretion should be applied to determining study entry. 
 
 
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview. 
 
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual 
cycle cannot be confirmed before first dose of study intervention, additional evaluation 
should be considered. 
9.4.2. 
Contraception Guidance: 
 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
 
Highly Effective Methodsb That Have Low User Dependency Failure rate of <1% per 
year when used consistently and correctly. 
 Implantable progestogen-only hormone contraception associated with inhibition of 
ovulationc 
 Intrauterine device (IUD) 
 Intrauterine hormone-releasing system (IUS)c 
 Bilateral tubal occlusion 
 Azoospermic partner (vasectomized or due to a medical cause) 


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 
Azoospermia is a highly effective contraceptive method provided that the partner is the sole 
sexual partner of the woman of childbearing potential and the absence of sperm has been 
confirmed.  If not, an additional highly effective method of contraception should be used.  
Spermatogenesis cycle is approximately 90 days. 
 
 
Note: documentation of azoospermia for a male participant can come from the site personnel’s 
review of the participant’s medical records, medical examination, or medical history interview 
 
Highly Effective Methodsb That Are User Dependent Failure rate of <1% per year when 
used consistently and correctly. 
 Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationc 
o oral 
o intravaginal 
o transdermal 
o injectable 
 Progestogen-only hormone contraception associated with inhibition of ovulationc 
o oral 
o injectable 
 Sexual abstinence 
 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study intervention 
and  is the participant’s normal practice.  The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the study and the preferred and usual lifestyle of the 
participant. 
a. Contraceptive use by men or women should be consistent with local regulations regarding 
the use of contraceptive methods for those participating in clinical studies. 
b. Failure rate of <1% per year when used consistently and correctly.  Typical use failure rates 
differ from those when used consistently and correctly. 
c.  Male condoms must be used in addition to hormonal contraception.  If locally required, in 
accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable 
contraceptive methods are limited to those which inhibit ovulation as the primary mode of 
action. 
 
Note: Periodic abstinence (calendar, sympto-thermal, post-ovulation methods), withdrawal 
(coitus interruptus), spermicides only, and lactational amenorrhea method (LAM) are not 
acceptable methods of contraception.  Male condom and female condom should not be used 
together (due to risk of failure from friction). 
 


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9.5. 
Appendix 5: Abbreviations and Trademarks 
Ab 
Antibody 
ABG 
Arterial Blood Gas 
ADE 
Adverse Device Effect 
AE(s) 
Adverse event(s) 
AESI 
Adverse event of special interest 
ALI 
Acute Lung Injury 
ALP 
Alkaline phosphatase 
ALT 
Alanine transaminase 
ANC 
Absolute Neutrophil Count 
APTT/APTR 
Activated Partial Thromboplastin Time/Activated Partial 
Thromboplastin Time Ratio 
ARDS 
Acute Respiratory Distress Syndrome 
AST 
Aspartate transaminase 
AUC 
Area Under the Curve 
BAL 
Bronchoalveolar Lavage 
BiPAP 
Bilevel Positive Airway Pressure 
BUN 
Blood Urea Nitrogen 
CAR 
Chimeric Antigen Receptor 
CFR 
Code of Federal Regulations 
CIOMS 
Council for International Organizations of Medical Sciences 
CL 
Clearance 
Cmax 
Maximum Concentration 
CONSORT 
Consolidated Standards of Reporting Trials 
COVID-19 
Coronavirus Disease 2019 
CPAP 
Continuous Positive Airway Pressure 
CRF 
Case Report Form 
CRP 
C-reactive protein 
CRS 
Cytokine Release Syndrome 
CSR 
Clinical Study Report 
CT 
Computed Tomography 
CTCAE 
Common terminology criteria for Adverse Events 
CTFG 
Clinical Trial Facilitation Group 
CV 
Cardiovascular 
DMARD 
Disease-modifying antirheumatic drug 
ECG 
Electrocardiogram 
ECMO 
Extracorporeal Membrane Oxygen 
eCRF 
Electronic case report form 
EMA 
European Medicines Agency 
ESR 
Erythrocyte sedimentation rate 
FDA 
Food and Drug Administration 
FiO2 
Concentration of Inspired Oxygen 
FU 
Follow-up 
GCP 
Good Clinical Practice 
GCS 
Glasgow Coma Scale 
GFR 
Glomerular filtration rate 
GM-CSF 
Granulocyte-macrophage colony stimulating factor 


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GM-CSFR 
Granulocyte-macrophage colony stimulating factor receptor 
GSK 
GlaxoSmithKline 
h 
Hour 
HBsAg 
Hepatitis B-surface Antigen 
hCG 
Human chorionic gonadotropin 
HF 
Human Factors 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
HRT 
Hormone replacement therapy 
HV 
Healthy volunteer 
IB 
Investigator’s brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
ICU 
Intensive Care Unit 
IDMC 
Independent Data Monitoring Committee 
IEC 
Institutional ethics committee 
IFN 
Interferon Gamma 
IFU 
Instructions For Use 
IL 
Interleukin 
IMP 
Investigational medicinal product 
INR 
International normalized ratio 
IRB 
Institutional review board 
IRT 
Interactive Response Technology 
iSRC 
Independent Safety Review Committee 
ITT 
Intent to Treat 
IUD 
Intrauterine device 
IUS 
Intrauterine hormone-releasing system 
IV 
Intravenous 
JAK 
Janus Kinase 
L 
Liter 
LAM 
Lactational amenorrhea method 
LAR 
Legally Authorized Representative 
LDH 
Lactate dehydrogenase 
mAb 
Monoclonal antibody 
MAP 
Mean Arterial Pressure 
MCP-1 
Monocyte Chemoattractant Protein-1 Alpha 
MCV 
Mean cell volume 
MCH 
Mean corpuscular hemoglobin 
MedDRA 
Medical dictionary for regulatory activities 
g 
Microgram 
m2 
Square Meters 
mg 
Milligram 
Min 
Minute 
MIP-1 
Macrophage Inflammatory Protein-1 
mL 
Milliliter 
mm3 
Cubic Millimeters 
mmHg 
Millimeters of Mercury 
MS 
Multiple sclerosis 


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MSDS 
Material safety data sheet 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
NOAEL 
No observed adverse effect level 
NYHA 
New York Heart Association 
OR 
Odds Ratio 
PAP 
Pulmonary alveolar proteinosis 
PD 
Pharmacodynamic 
PFS 
Prefilled syringe 
PI 
Principal Investigator 
PT 
Prothrombin Time 
PK 
Pharmacokinetics 
RA 
Rheumatoid arthritis 
RBC 
Red Blood Cell 
RRT 
Renal replacement therapy 
RT-PCR 
Reverse Transcriptase Polymerase Chain Reaction 
SADE 
Serious Adverse Device Effect  
SARS-CoV-2 
Severe Acute Respiratory Syndrome–Coronavirus-2 
SC 
Subcutaneous 
SAE(s) 
Serious adverse event(s) 
SoA 
Schedule of Activities 
SOFA 
Sequential Organ Failure Assessment 
SpO2 
Blood Oxygen Saturation 
SRM 
Study Reference Manual 
SRT 
Safety Review Team 
SSD 
Safety Syringe Device 
TB 
Tuberculosis 
TNFα 
Tumor necrosis factor alpha 
ULN 
Upper limit of normal 
USADE 
Unanticipated Serious Adverse Device Effect 
VAP 
Ventilator-associated Pneumonia 
WBC 
White Blood Cell 
WHO 
World Health Organization 
WOCBP 
Woman of Childbearing Potential 
WONCBP 
Woman of Non-Childbearing Potential 
 
Trademark Information 
Trademarks of the GlaxoSmithKline 
group of companies 
 
Trademarks not owned by the 
GlaxoSmithKline group of companies 
None 
 
MedDRA 


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9.6. 
Appendix 6: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC). 
Amendment 2: 02-JUL-2020 
This amendment is considered to be non-substantial based on the criteria set forth in 
Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
Overall Rationale for the Amendment: modifications to the protocol in response to 
regulatory and ethics committee feedback, and clarifications based on investigator 
feedback.  The main changes are (1) clarification that Day 1 pre-dose assessments do not 
need to be repeated if Screening and Randomization are within 24 hours; (2) expedited 
reporting of cytokine release syndrome (CRS) as an AESI; (3) clarification that organ 
transplant patients are excluded per Exclusion Criteria #11; (4) clarification of conditions 
by which convalescent plasma is permitted or not during the study; (5) removed specific 
mention of chloroquine and hydroxychloroquine; (6) expanded the null hypothesis; (7) 
consent may be collected before the 48h screening window. 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.3. Schedule 
of Activities 
Revised text that if Screening and 
Randomization are within 24 hours rather 
than the same day, there is no need to 
repeat Day 1 pre-dose assessments, 
(except Ordinal Scale and pre-infusion vital 
signs), and that Randomization and Dosing 
should be as close as possible. 
Added note that consent may be collected 
before the 48h screening window. 
Investigator’s feedback. 
Section 2.3.1. Risk 
Assessment and 
Section 7.4.7.1. 
Cytokine Release 
Syndrome 
Added statement that in the event that new 
onset of CRS is suspected, the medical 
monitor should be notified immediately and 
under no circumstance should this exceed 
24 hours, and the event must also be 
reported within 24 hours as an AE or an 
SAE. 
Regulatory request. 
Section 4.4 
Definition of a participant who completes 
the study updated to include participants 
who die prior to Day 60. 
Clarification of definition. 
Section 5.2. 
Exclusion Criteria 
#11 
Added note that participants with an organ 
transplant are excluded. 
Ethics Committee request. 
Section 5.2. 
Exclusion Criteria 
#13 
Added conditions by which convalescent 
plasma is not permitted during the study. 
Investigator’s feedback. 
Section 5.2. 
Exclusion Criteria 
#19 
Hemoglobin 9 g/dL. 
Error in units. 
Section 6.6. 
Concomitant Therapy 
Added conditions by which convalescent 
plasma is permitted. 
Investigator’s feedback. 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 6.6.2. 
Medication/Treatment 
PERMITTED During 
the Study 
Removed specific mention of chloroquine 
and hydroxychloroquine. 
No longer expected to be widely 
used following clinical trials 
results. 
Section 7.2.4. 
Ventilation status 
Added statement to record if the participant 
was in the prone or semi-prone position at 
any time whilst mechanically ventilated. 
Investigator’s feedback. 
Section 7.2.6. Ordinal 
Scale 
Added note for additional organ support. 
Clarification. 
Section 7.3.1. 
Physical 
Examinations 
Clarification that physical exam results will 
not be recorded in the eCRF. 
Investigator’s feedback. 
Section 8.1. 
Statistical 
Hypotheses 
Expanded the null hypothesis. 
Clarification of the null 
hypothesis. 
Section 9.1.3. 
Informed Consent 
Process 
Added note that consent may be collected 
before the 48h screening window. 
Clarification. 
All sections 
Other minor, grammatical and typographical corrections to improve readability. 
 
Amendment 1: 18-MAY-2020 
This amendment is considered to be substantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
Overall Rationale for the Amendment: modifications to the protocol in response to 
regulatory feedback, and clarifications based on investigator feedback.  The key change is 
revision of the primary endpoint (where definition of “free of respiratory failure” is 
participants in categories 1-4 on GSK Ordinal Scale).  Other changes are (1) to revise 
recording of blood pressure and pulse rate; (2) to add details of randomization caps; (3) to 
simplify/clarify some Inclusion and Exclusion Criteria; (4) to clarify medications 
permitted during the study. 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1 and 
Section 3 Objectives 
and Endpoints 
Revised “independent of 
supplementary oxygen” to “free 
of respiratory failure” for 
Primary Endpoint; added or 
revised Secondary Endpoints 
(added Time to all-cause 
mortality, Time to recovery from 
respiratory failure and Time to 
last dependence on 
supplementary oxygen); added 
or revised some Exploratory 
Endpoints (added Change in 
COVID-19 signs and 
symptoms). 
Regulatory feedback, new FDA guidance 
for the development of COVID-19 
treatments, and clarification. 
 
 
 
 
 
 
 
 
 
 
 


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Section # and Name 
Description of Change 
Brief Rationale 
 
Removed details of organ 
support in the Ordinal Scale. 
 
Clarification based on regulatory and 
investigator feedback and to ensure 
alignment with Exclusion Criteria 3 and 
description of categories in the Ordinal 
Scale. 
Section 1.3 Schedule 
of Activities 
Revised recording of blood 
pressure and pulse rate to daily 
up to Day 28 or discharge. 
Regulatory request. 
Section 4.1.2. Main 
Cohort (after 20 
Participants) 
Acknowledgment that 
randomization caps will be 
used. 
Text added in line with the IDMC Charter 
for transparency purposes. 
Section 5.1. Inclusion 
Criteria 
Inclusion 2: Removal of SpO2 
93% on room air. 
 
Inclusion 4: Clarification of 
sexual abstinence. 
#2 Feedback from investigators based on 
clinical practice to identify participants with 
oxygenation impairment. 
#4 Regulatory feedback. 
Section 5.2. Exclusion 
Criteria 
Exclusion 3: Added use of high-
dose or multiple vasopressors 
as an exclusion. 
Clarification of Exclusion Criteria related to 
organ support. 
Section 6.6.2. 
Medication/Treatment 
Permitted During the 
Study 
Added statement that all 
treatments for participants in 
the ICU are permitted, and 
clarification of additional 
treatments of COVID-19 related 
disease. 
Clarification based on regulatory and 
investigator feedback and to ensure 
alignment with Exclusion Criteria 3 and 
description of categories on the ordinal 
scale. 
Section 7.2.6, Ordinal 
Scale 
Removed details of organ 
support in the Ordinal Scale. 
Clarification based on regulatory and 
investigator feedback and to ensure 
alignment with Exclusion Criteria 3 and 
description of categories in the Ordinal 
Scale. 
Section 8.1. Statistical 
Hypotheses 
Revised null hypothesis for 
consistency with changes to the 
Primary Endpoint and added 
alternative to the null 
hypothesis. 
Regulatory feedback for Primary Endpoint 
and clarification for alternative to null 
hypothesis. 
Section 8.4.2. Primary 
Endpoint(s) 
Revised “independent of 
supplementary oxygen” to “free 
of respiratory failure” for 
Primary Endpoint. 
Regulatory feedback. 
8.5. Interim Analysis 
Safety stopping rules have 
been put in place for the IDMC 
to stop the study if there is an 
excess risk of mortality. 
Regulatory request. 
Section 9.4.2. 
Contraception 
Guidance: 
Clarification of situations when 
sexual abstinence is 
acceptable. 
Regulatory request. 
All sections 
Other minor, grammatical and typographical corrections to improve 
readability. 


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9.7. 
Appendix 7: Country-Specific Protocol Addendums 
The addition of Part 2 has changed the section numbering of the document, which means 
that the numbering of the Country-Specific Protocol Addendums will have changed.  
This will be documented at a local level (if the impacted countries are approved for 
Part 2).  Therefore, all investigators in countries with a Country-Specific Protocol 
Addendum should refer to the locally provided Country-Specific Protocol Addendum and 
any associated documentation.  
9.7.1. 
The Netherlands (27-MAY-2020) 
A country specific addendum for the Netherlands was made to the Global Protocol (dated 
30-APR-2020) and all future versions.   
The addendum requires that in the Netherlands (hydroxy)chloroquine as a concomitant 
medication is prohibited. 
The following section of the Global Protocol was amended: 
6.6.1. Medication NOT Permitted During the Study 
…… Chloroquine and hydroxychloroquine. 
 
9.7.2. 
South Africa (28-MAY-2020) 
A country specific addendum for South Africa was made to the Global Protocol (dated 
30-APR-2020) and all future versions.   
The addendum requires that in South Africa HIV testing should be conducted at 
Screening. 
The following sections of the Global Protocol were amended: 
1.3. Schedule of Activities 
HIV test added at Screening (if HIV status unknown). 
5.2. Exclusion Criteria 
HIV positive added as an exclusion criterion – as below: 
CONCOMITANT MEDICAL CONDITIONS 
4. Current serious or uncontrolled medical condition (e.g. significant pulmonary 
disease [such as severe COPD or pulmonary fibrosis], heart failure [NYHA class 
III or higher], significant renal dysfunction, acute myocardial infarction or acute 
cerebrovascular accident within the last 3 months) or abnormality of clinical 
laboratory tests that, in the investigator’s judgment, precludes the participant’s safe 
participation in and completion of the study. 
5. Untreated systemic bacterial, fungal, viral, or other infection (other than SARS-
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6. Known active tuberculosis (TB), history of untreated or incompletely treated active 
or latent TB, suspected or known extrapulmonary TB. 
7. Known HIV positive regardless of immunological status. 
8. Known HBsAg and/or anti-HCV positive. 
9. Currently receiving radiotherapy, chemotherapy or immunotherapy for malignancy. 
 
9.7.3. 
India (31-JUL-2020)_IND_01 
A country specific addendum for India was made to the Global Protocol (Amendment 2, 
dated 02-JUL-2020) and all future versions.   
If India participate in Part 2 of the study, the country specific addendum for India (dated 
31-Jul-20) will be updated to reflect the changes in Protocol Amendment 3 (country 
specific addendum update not completed at the point of Protocol Amendment 3 sign off).   
A global Protocol Amendment will not be issued when the second version of the India 
country specific addendum is released.  Therefore, all investigators in India should refer 
to the locally provided country specific addendum for India. 
The addendum was made based on a recommendation from the SEC for patients with 
severe pulmonary COVID-19 related disease (29-Jul-2020). 
The following section of the Global Protocol was amended (text in bold and underlined 
indicates new text): 
5.1. Inclusion Criteria 
AGE 
1. Age 18 years and 79 years at the time of obtaining informed consent. 
TYPE OF PARTICIPANT AND DISEASE CHARACTERISTICS 
2. Participants must: 
a. have positive SARS-CoV-2 result (any validated test, e.g. RT-PCR [performed 
on an appropriate specimen; e.g. respiratory tract sample]) 
b. AND be hospitalized due to diagnosis of pneumonia (chest X-ray or 
computerized tomography [CT] scan consistent with COVID-19) 
c. AND be developing new onset of oxygenation impairment defined as SpO2 
90% on room air 
d. AND requiring any of the following: 
1. high-flow oxygen (15L/min) 
2. non-invasive ventilation (e.g. CPAP, BiPAP) 
3. mechanical ventilation 48h prior to dose 
e. AND have increased biological markers of systemic inflammation (either CRP 
>ULN1 or serum ferritin >ULN1). 
1According to local reference range.  Repeat CRP or ferritin tests are permitted. 
 


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9.7.4. 
Japan (22-JAN-2021)_JPN_04 
If minor changes are made to the Country Specific Requirements for Japan (e.g. the 
Study Period dates are amended), the global protocol will not be updated, and the 
changes will be recorded in the local document only.  Therefore, all investigators in Japan 
should refer to the locally provided Country Specific Requirements Document for Japan. 
The following country specific requirements apply for Japan: 
1. Study Conduct Considerations 
1.1 Regulatory and Ethical Considerations 
The study will be conducted in accordance with “the Ministerial Ordinance on the 
Standards for the Conduct of Clinical Trials of Medicinal Products (MHW Notification 
No.28 dated 27th March, 1997)” and Pharmaceuticals and Medical Devices Act. 
The statement “I acknowledge that I am responsible for overall the study conduct.” on the 
Investigator Protocol Agreement Page means the investigator’s responsibility defined by 
Japanese GCP. 
GSK will submit the CTN to the regulatory authorities in accordance with 
Pharmaceuticals and Medical Devices Act before conclusion of any contract for the 
conduct of the study with study sites. 
1.2 Informed Consent 
Prior to participation in the study, the investigator should fully inform the potential 
participant and/or the participant's legally acceptable representative of the study including 
the written information. The investigator should provide the participant and/or the 
participant's legally acceptable representative ample time and opportunity to inquire 
about details of the study. The participant and/or the participant’s legally acceptable 
representative should sign and personally date the consent form. If the participant is 
capable of understanding but not able to provide written consent, or if the legally 
authorized representative is not able to provide written consent, informed consent can be 
obtained orally in the presence of an impartial witness (Protocol Section 9.1.3). The 
person, who conducted the informed consent discussion and the study collaborator giving 
supplementary explanation, where applicable, should sign and personally date the consent 
form. If an impartial witness is required, the witness should sign and personally date the 
consent form. The investigator should retain this signed and dated form (and other written 
information) together with the source medical records, such as clinical charts (in 
accordance with the rules for records retention, if any, at each medical institution) and 
give a copy to the participant and/or the participant’s legally acceptable representative. If 
the participant is a minor, document informed consent will be obtained from both the 
participant and his/her legally acceptable representative. In addition, if a minor 
participant reaches an adult during the treatment period, the participant's consent to 
participate in the clinical trial will be obtained again. 
Regarding informed consent process of this study, the following is added according to 
GCP 7.3. 


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 
The study population consists of hospitalized participants with new onset hypoxia 
requiring significant oxygen support or requiring early invasive mechanical 
ventilation (48 hours before dosing). The consent by participants themselves is 
obtained whenever possible, but the study population includes participants who may 
have difficulty in giving their own consent under Article 50, Paragraphs 1 and 2. An 
application for marketing approval of otilimab is intended to be submitted so that 
otilimab will be used for emergency treatment to save lives of patients in a life-
threatening condition. 
 
There is no approved drug specifically targeting severe pulmonary COVID-19 
related disease in Japan as of 3 June 2020, although remdesivir has been approved in 
Japan for SARS-CoV-2 infection. Currently it is unknown if available treatments are 
likely to achieve sufficient therapeutic effects on severe pulmonary COVID-19 
related disease in the prospective participants. 
 
Otilimab is expected to inhibit inflammation due to SARS-CoV-2 infection. There is 
a sufficient possibility of preventing further aggravation and saving the life of the 
prospective participants by using otilimab for patients with severe COVID-19 related 
pulmonary disease (protocol Section 2). 
 
An Independent Data Monitoring Committee (IDMC) has been established for this 
study, and interim analyses will be used to assess safety, futility and efficacy 
(protocol Section 9.1.5).  
 
If the participant is unable to provide informed consent and consent is obtained from 
his/her legally authorized representative (LAR), participants will be asked to provide 
informed consent to remain in the study as soon as practically possible following the 
participant regaining capacity. If they decline, then they will be withdrawn from the 
study. Unidentified persons are excluded from the study because of the consent 
process in that consent is obtained from a his/her LAR before the study start if the 
participant is unable to provide informed consent (protocol Section 9.2.3). 
1.3 Study Period 
JUL/2020 – SEP/2021  
1.4 Study Administrative Structure 
Sponsor information is included in Exhibit 1. List of Medical Institutions and 
Investigators is included in Exhibit 2. 
2 MODIFICATION TO THE GLOBAL PROTOCOL 
2.1 Exclusion Criteria – Part 1 (Protocol Section 5.3) 
The following underlined texts are added in the relevant part of the protocol. 
No.6 of the exclusion criteria 
Known active tuberculosis (TB), history of untreated or incompletely treated active or 
latent TB, suspected or known extrapulmonary TB. 


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In addition, conduct QuantiFERON-TB Gold plus test or T-SPOT test at screening, if 
either of tests was not conducted within 4 weeks before Day 1. If either of test results is 
obtained during screening and show positive result, the participants are ineligible. If any 
test results can’t be obtained during screening because of result availability, check either 
of test results after IP dosing once the result is obtained. If it is found that either of tests 
shows positive result after IP dosing, the participants should be managed appropriately 
per local guidelines/medical judgement.  
No.8 of the exclusion criteria 
Known HBsAg and/or anti-HCV positive 
In addition, hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), 
hepatitis B surface antibody (HBsAb) and HBV deoxyribonucleic acid (DNA) are tested 
about all participants in Japan at screening. Based on all results obtained during 
screening, check the below about all participants in principle.  
 
positive for hepatitis B surface antigen (HBsAg) or  
 
positive for hepatitis B core antibody (HBcAb) and positive for HBV 
deoxyribonucleic acid (DNA) or  
 
positive for hepatitis B surface antibody (HBsAb) and positive for HBV 
deoxyribonucleic acid (DNA) 
If any of the above can’t be judged during screening because of result availability, check 
the tests after IP dosing once the remaining results are obtained. If it is found that 
participants are applied any of the above after IP dosing, the participant should be 
managed appropriately per local guidelines/medical judgement. If it is found that 
participants are positive for HBcAb and/or HBsAb and negative for HBV DNA, the 
participants should be checked for HBV DNA again at Day 28 (or at Discharge if before 
Day 28).  
2.2 Exclusion Criteria – Part 2 (Protocol Section 5.4) 
The following underlined texts are added in the relevant part of the protocol. 
No.6 of the exclusion criteria 
Known active tuberculosis (TB), history of untreated or incompletely treated active or 
latent TB, suspected or known extrapulmonary TB. 
In addition, conduct QuantiFERON-TB Gold plus test or T-SPOT test at screening, if 
either of tests was not conducted within 4 weeks before Day 1. If either of test results is 
obtained during screening and show positive result, the participants are ineligible. If any 
test results can’t be obtained during screening because of result availability, check either 
of test results after IP dosing once the result is obtained. If it is found that either of tests 
shows positive result after IP dosing, the participants should be managed appropriately 
per local guidelines/medical judgement.  


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No.8 of the exclusion criteria 
Known HBsAg and/or anti-HCV positive (patients demonstrating a sustained virologic 
response (SVR) are not excluded from participation). 
In addition, hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), 
hepatitis B surface antibody (HBsAb) and HBV deoxyribonucleic acid (DNA) are tested 
about all participants in Japan at screening. Based on all results obtained during 
screening, check the below about all participants in principle.  
 
positive for hepatitis B surface antigen (HBsAg) or  
 
positive for hepatitis B core antibody (HBcAb) and positive for HBV 
deoxyribonucleic acid (DNA) or  
 
positive for hepatitis B surface antibody (HBsAb) and positive for HBV 
deoxyribonucleic acid (DNA) 
If any of the above can’t be judged during screening because of result availability, check 
the tests after IP dosing once the remaining results are obtained. If it is found that 
participants are applied any of the above after IP dosing, the participant should be 
managed appropriately per local guidelines/medical judgement. If it is found that 
participants are positive for HBcAb and/or HBsAb and negative for HBV DNA, the 
participants should be checked for HBV DNA again at Day 28 (or at Discharge if before 
Day 28). 
2.3 Study Intervention(s) Administered (Protocol Section 6.1) 
The following supplementary explanation is added. 
 
In this study, only single-use vials will be used. 
 
2.4 STUDY ASSESSMENTS AND PROCEDURES (Protocol Section 7) 
The following texts are updated in the relevant part of the protocol according to the tests 
for TB and HBV. 
 
The maximum amount of blood collected from each participant over the duration of 
the study for the purpose of meeting the objectives will not exceed 200 mL 230 mL.  
This does not include any standard of care assessments. 
 
2.5 Clinical Laboratory Tests (Protocol Appendix 2) 
The following underlined texts are added in the relevant part of the protocol. 


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Table 3 
Protocol-Required Safety Laboratory Tests – Part 1  
Laboratory 
Assessments1 
Parameters 
Hematology 
Hemoglobin 
RBC Indices: 
WBC count (differential) 
absolute and/or %: 
 
Hematocrit 
MCV 
Neutrophils 
 
Platelet Count 
MCH 
Lymphocytes 
 
RBC Count 
%Reticulocytes 
Monocytes 
 
 
 
Eosinophils 
 
 
 
Basophils 
Coagulation 
APTT / APTR 
PT 
INR 
Clinical 
Urea (BUN) 
Phosphate 
AST / SGOT 
Chemistry 
Creatinine 
Troponin I4 
ALT / SGPT 
 
Glucose2 
D-dimer 
Gamma-GT 
 
Potassium 
Ferritin5 
Total bilirubin 
 
Sodium 
CRP 
Direct bilirubin 
 
Calcium   
LDH 
ALP7 
 
Lactate3 
Procalcitonin5, 6  
Total protein 
 
Creatine kinase 
ESR5 
Albumin 
Pregnancy 
Highly sensitive serum or urine human chorionic gonadotropin (hCG) 
pregnancy test (as needed for women of childbearing potential) 
CRS Event 
If CRS is suspected, the following samples should be taken as soon as 
possible after suspected CRS on-set and again 24 h later: Hematology, CRP, 
D-dimer, ferritin, PD (cytokine sample – see Section 1.3) 
Other Tests8 
Serology [hepatitis B surface antigen (HBsAg), hepatitis B core antibody 
(HBcAb), hepatitis B surface antibody (HBsAb), HBV DNA], tuberculosis 
(QuantiFERON-TB Gold plus test or T-Spot TB test) 
1. Hematology, Coagulation and Clinical Chemistry testing at the following time-points (unless 
otherwise indicated below):  Screening, Day 1, Day 2, Day 4, Day 7, Day 14, Day 28 and 
Discharge 
2. Record glucose fasting / non-fasting status 
3. Can be measured from arterial blood gas test 
4. If troponin I is not available locally, troponin T can be reported  
5. To be measured at Screening, Day 7 and Day 14 only 
6. Procalcitonin to be measured if the test is available locally 
7. If alkaline phosphatase is elevated, consider fractionating 
8. Test at screening. In addition, the participants with positive HBcAb and/or HBsAb and 
negative HBV DNA should be checked for HBV DNA again at Day 28 (or at Discharge if 
before Day 28).  
 


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Table 4 
Protocol-Required Safety Laboratory Tests – Part 2 
Laboratory 
Assessments1 
Parameters 
Hematology 
Hemoglobin 
RBC Indices: 
WBC count (differential) 
absolute and/or %: 
 
Hematocrit 
MCV 
Neutrophils 
 
Platelet Count 
MCH 
Lymphocytes 
 
RBC Count 
%Reticulocytes 
Monocytes 
 
 
 
Eosinophils 
 
 
 
Basophils 
Coagulation 
APTT / APTR 
PT or INR 
 
Clinical 
Urea (BUN) 
Phosphate 
AST / SGOT 
Chemistry 
Creatinine 
Troponin I2 
ALT / SGPT 
 
Glucose 
D-dimer 
Gamma-GT 
 
Potassium 
Ferritin3 
Total bilirubin 
 
Sodium 
CRP 
Direct bilirubin 
 
Calcium   
LDH 
ALP 
 
 
 
Total protein 
 
Creatine kinase 
ESR 3 
Albumin 
CRS Event 
If CRS (considered possibly drug related – see Section 7.4.7.1) is suspected, 
the following samples should be taken as soon as possible after suspected 
CRS on-set and again 24 h later: Hematology, CRP, D-dimer, ferritin, PD 
(cytokine sample – see Sections 1.3 and 1.4) 
Other Tests4 
Serology [hepatitis B surface antigen (HBsAg), hepatitis B core antibody 
(HBcAb), hepatitis B surface antibody (HBsAb), HBV DNA], tuberculosis 
(QuantiFERON-TB Gold plus test or T-Spot TB test) 
1. Hematology, Coagulation and Clinical Chemistry testing at the following time-points (unless 
otherwise indicated below):  Screening, Day 1, Day 4, Day 7, Day 14, Day 28 and Discharge 
2. If troponin I is not available locally, troponin T can be reported  
3. To be measured at Screening, Day 7 and Day 14 only 
4. Test at screening. In addition, the participants with positive HBcAb and/or HBsAb and 
negative HBV DNA should be checked for HBV DNA again at Day 28 (or at Discharge if 
before Day 28). 
 
2.6 CONTRACEPTIVES ALLOWED DURING THE STUDY – Part 1 only 
(Appendix 4) 
Of contraceptive methods defined in the protocol Appendix 4, Contraceptive Methods 
Approved in this Study, the following are not approved in Japan as contraceptive 
methods. 
Highly Effective Methods That Have Low User Dependency 
 
Implantable progestogen-only hormone contraception associated with inhibition of 
ovulation 


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Highly Effective Methods That Are User Dependent 
 
Combined (estrogen- and progestogen-containing) hormonal contraception 
associated with inhibition of ovulation  
 
intravaginal 
 
transdermal 
 
injectable 
 
Progestogen-only hormonal contraception associated with inhibition of ovulation 
 
oral 
 
injectable 
 
 


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10. 
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Zhou Y, Fu B, Zheng X, et al. Aberrant pathogenic GM-CSF+ T cells and inflammatory 
CD14+CD16+ monocytes in severe pulmonary syndrome patients of a new coronavirus. 
2020; bioRxiv preprint doi: https://doi.org/10.1101/2020.02.12.945576. 
 

SAP_003.pdf: 
 
 
 
Statistical Analysis Plan 
 
Study ID:  214094 
 
Official Title of Study: A randomized, double-blind, placebo-controlled, study evaluating 
the efficacy and safety of otilimab IV in patients with severe pulmonary COVID-19 
related disease. 
 
Date of Document: 03-JUN-2021 
 


 
CONFIDENTIAL 
 
The GlaxoSmithKline group of companies 
 
214094 
1 
 
Division 
: Worldwide Development 
Information Type 
: Statistical Analysis Plan (SAP) 
TITLE PAGE 
Protocol Title: A randomized, double-blind, placebo-controlled, study evaluating the 
efficacy and safety of otilimab IV in patients with severe pulmonary COVID-19 related 
disease. 
Protocol Number: 214094 
Compound Number: GSK3196165 (otilimab) 
Short Title: Investigating otilimab in patients with severe pulmonary COVID-19 related 
disease. 
Sponsor Name: 
GlaxoSmithKline Research & Development Limited 
980 Great West Road 
Brentford 
Middlesex, TW8 9GS 
UK 
Regulatory Agency Identifier Number(s) 
Registry 
ID 
IND 
149754 
EudraCT 
2020-001759-42 
 
 
 
 
 
 
Copyright 2021 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.


 
CONFIDENTIAL 
 
 
 
214094 
2 
 
TABLE OF CONTENTS 
PAGE 
1. 
INTRODUCTION ...................................................................................................... 6 
1.1. 
Objectives, Endpoints and Estimands ........................................................... 6 
1.1.1. 
Objectives and Endpoints .............................................................. 6 
1.1.2. 
Estimands ...................................................................................... 8 
1.2. 
Study Design .............................................................................................. 12 
2. 
STATISTICAL HYPOTHESES / SUCCESS CRITERIA .......................................... 14 
2.1. 
Multiple Comparisons and Multiplicity ......................................................... 14 
3. 
ANALYSIS SETS ................................................................................................... 15 
3.1. 
Protocol Deviations ..................................................................................... 15 
4. 
STATISTICAL ANALYSES ..................................................................................... 16 
4.1. 
General Considerations .............................................................................. 16 
4.1.1. 
General Methodology .................................................................. 16 
4.1.2. 
Baseline Definition ....................................................................... 16 
4.1.3. 
Multicenter Studies ...................................................................... 17 
4.1.4. 
Intercurrent Events ...................................................................... 17 
4.1.5. 
Missing Data Handling Rules ....................................................... 17 
4.1.6. 
Examination of Covariates, Other Strata and Subgroups ............. 18 
4.1.6.1. 
Covariates and Other Strata ....................................... 18 
4.1.6.2. 
Examination of Subgroups .......................................... 18 
4.2. 
Primary Endpoint(s) Analyses ..................................................................... 19 
4.2.1. 
Definition of Endpoint(s) ............................................................... 19 
4.2.2. 
Main Analytical Approach ............................................................ 20 
4.2.3. 
Sensitivity Analyses ..................................................................... 20 
4.2.3.1. 
Tipping Point Analyses ............................................... 20 
4.2.4. 
Supplementary Analyses ............................................................. 21 
4.2.4.1. 
Treatment policy estimand when correct 
treatment administered ............................................... 21 
4.2.4.2. 
Composite estimand for COVID-19 
medications ................................................................ 21 
4.2.5. 
Subgroup Analyses ...................................................................... 21 
4.3. 
Secondary Endpoint(s) Analyses ................................................................ 21 
4.3.1. 
Endpoint Definition ....................................................................... 22 
4.3.1.1. 
All-cause Mortality at Day 28 and 60 .......................... 22 
4.3.1.2. 
Time to All-cause Mortality up to Day 60 .................... 22 
4.3.1.3. 
Participants Alive and Free of Respiratory 
Failure at Day 7, 14, 42, and 60.................................. 22 
4.3.1.4. 
Time to Recovery from Respiratory Failure up 
to Day 28 .................................................................... 22 
4.3.1.5. 
Participants Alive and Independent of 
Supplementary Oxygen at Day 7, 14, 28, 42, 
and 60 ........................................................................ 22 
4.3.1.6. 
Time to Last Dependence on Supplementary 
Oxygen up to Day 28 .................................................. 22 
4.3.1.7. 
Time to Final ICU Discharge up to Day 28 .................. 23 


 
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4.3.1.8. 
Time to First Discharge from Investigator Site 
up to Day 60 ............................................................... 23 
4.3.1.9. 
Time to First Discharge to Non-Hospitalized 
Residence up to Day 60 ............................................. 23 
4.3.2. 
Main Analytical Approach ............................................................ 23 
4.3.2.1. 
Binary Endpoints ........................................................ 23 
4.3.2.2. 
Time to Event Endpoints ............................................ 24 
4.3.3. 
Sensitivity Analyses ..................................................................... 25 
4.3.3.1. 
Binary Endpoints ........................................................ 25 
4.3.3.2. 
Time to Event Endpoints ............................................ 25 
4.3.4. 
Supplementary Analyses ............................................................. 25 
4.3.5. 
Subgroup Analyses ...................................................................... 25 
4.4. 
Exploratory Endpoint(s) Analyses ............................................................... 25 
4.4.1. 
Definition of Endpoint(s) ............................................................... 25 
4.4.1.1. 
Invasive Mechanical Ventilation (if not 
previously initiated) up to Day 28 ................................ 25 
4.4.1.2. 
Invasive Mechanical Ventilation (if not 
previously initiated) at Day 4, 7, 14, 28 ....................... 26 
4.4.1.3. 
Time to Invasive Mechanical Ventilation (if not 
previously initiated) up to Day 28 ................................ 26 
4.4.1.4. 
Alive and Not Invasively Mechanically 
Ventilated ................................................................... 26 
4.4.1.5. 
Time to Definitive Extubation up to Day 28 ................. 26 
4.4.1.6. 
Oxygen-free Days up to Day 28.................................. 26 
4.4.1.7. 
Ventilator-free Days up to Day 28 ............................... 27 
4.4.1.8. 
Admission to ICU up to Day 28 ................................... 27 
4.4.1.9. 
Change from Baseline in Inspired Oxygen 
(FiO2) up to Day 28 .................................................... 27 
4.4.1.10. Oxygen Use Following Discharge to Non-
hospitalized Residence ............................................... 27 
4.4.1.11. Time to Improvement of at Least 2 Categories 
Relative to Baseline in Clinical Status up to 
Day 60 ........................................................................ 28 
4.4.1.12. Number of Days in Each Category of Clinical 
Status up to Day 60 .................................................... 28 
4.4.1.13. Change in COVID-19 Signs and Symptoms up 
to Day 60 .................................................................... 28 
4.4.1.14. Post-Baseline Glucocorticoid Use up to Day 60 .......... 29 
4.4.2. 
Main Analytical Approach ............................................................ 29 
4.4.2.1. 
Time to Event Endpoints ............................................ 29 
4.4.2.2. 
Binary Endpoints ........................................................ 29 
4.4.2.3. 
Count Endpoints ......................................................... 30 
4.4.2.4. 
Continuous Endpoints ................................................ 30 
4.4.3. 
Sensitivity Analyses ..................................................................... 30 
4.4.4. 
Supplementary Analyses ............................................................. 30 
4.4.5. 
Subgroup Analyses ...................................................................... 30 
4.5. 
Safety Analyses .......................................................................................... 31 
4.5.1. 
Extent of Exposure ...................................................................... 31 
4.5.2. 
Adverse Events............................................................................ 31 
4.5.2.1. 
Adverse Events of Special Interest ............................. 32 
4.5.2.2. 
Adverse Event Groups of Interest ............................... 32 
4.5.2.3. 
Subgroup Analyses .................................................... 33 


 
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4.5.3. 
Additional Safety Assessments .................................................... 33 
4.5.3.1. 
Deaths ........................................................................ 33 
4.5.3.2. 
Laboratory Data .......................................................... 33 
4.5.3.3. 
Vital Signs .................................................................. 38 
4.5.3.4. 
ECG ........................................................................... 39 
4.6. 
Other Analyses ........................................................................................... 39 
4.6.1. 
Pharmacokinetics (PK) ................................................................ 39 
4.6.2. 
Population Pharmacokinetics ....................................................... 39 
4.6.3. 
Pharmacodynamics ..................................................................... 39 
4.6.4. 
Pharmacokinetics/Pharmacodynamics ........................................ 39 
4.7. 
Interim Analyses ......................................................................................... 39 
4.8. 
Changes to Protocol Defined Analyses ....................................................... 40 
5. 
SAMPLE SIZE DETERMINATION ......................................................................... 41 
6. 
SUPPORTING DOCUMENTATION ....................................................................... 42 
6.1. 
Appendix 1 Abbreviations and Trademarks ................................................. 42 
6.1.1. 
List of Abbreviations .................................................................... 42 
6.1.2. 
Trademarks ................................................................................. 43 
6.2. 
Appendix 2: Statistical Modelling ................................................................ 44 
6.2.1. 
Multiple Imputation ....................................................................... 44 
6.2.2. 
Tipping Point ................................................................................ 45 
6.2.3. 
Time to Event Model Checking .................................................... 46 
6.2.4. 
Count Data Model Checking ........................................................ 46 
6.3. 
Appendix 3: Selected Considerations for Data Analyses and Data 
Handling ..................................................................................................... 47 
6.3.1. 
Assessment Windows .................................................................. 47 
6.3.2. 
Derived and Transformed Efficacy Data ...................................... 47 
6.3.2.1. 
Ventilation Status ....................................................... 47 
6.3.2.2. 
Clinical Status Ordinal Scale ...................................... 48 
6.3.2.3. 
Fraction of Inspired Oxygen (FiO2) ............................. 50 
6.3.2.4. 
Vital Signs Temperature Standardisation .................... 50 
6.4. 
Appendix 4: Study Population Analysis ....................................................... 51 
6.4.1. 
Overview of Planned Study Population Analyses ......................... 51 
6.4.2. 
Subject Disposition ...................................................................... 51 
6.4.3. 
Demographic and Baseline Characteristics .................................. 51 
6.4.4. 
Medical Conditions ...................................................................... 52 
6.4.5. 
COVID-19 Signs and Symptoms .................................................. 52 
6.4.6. 
Protocol Deviations ...................................................................... 52 
6.4.7. 
Pre-Treatment Hospitalization and Time in ICU ........................... 52 
6.4.8. 
Subject Residence Prior to Hospital Admission............................ 52 
6.4.9. 
Prior and Concomitant Medication ............................................... 52 
6.4.10. 
Treatment Exposure .................................................................... 53 
6.5. 
Appendix 5 SAP Amendments .................................................................... 53 
7. 
REFERENCES ....................................................................................................... 55 
 


 
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VERSION HISTORY 
This Statistical Analysis Plan (SAP) for study 214094 is based on the protocol 
amendment 3 (GSK Document Number TMF-11795607) dated 25-Jan-2021.  This SAP 
is for Part 2 of study 214094 only. 
SAP Version History Summary 
SAP 
Version 
Approval 
Date 
Change 
Rationale 
Amendment 
1 
 
See Section 6.5 
Update to the SAP in 
response to regulatory 
feedback for testing 
hierarchy, addition of 
subgroups based on 
clinical feedback, see 
Table 3 for changes 
based on the protocol-
defined analysis. 
Original 
SAP 
25-JAN-2021 Not Applicable 
Original version 


 
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1. 
INTRODUCTION 
The purpose of this SAP is to describe the planned analyses to be included in the Clinical 
Study Report for Part 2 of Study 214094.  Details of the planned final analyses are 
provided. 
Additional detail with regards to data handling conventions and the specification of data 
displays will be provided in the Output and Programming Specification (OPS) document. 
1.1. 
Objectives, Endpoints and Estimands 
The following Objectives, Endpoints and Estimands are specific to Part 2 of this study. 
1.1.1. 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
• To compare the efficacy of otilimab 
90mg IV versus placebo. 
• Participants alive and free of respiratory failure at 
Day 28. 
Secondary 
• To compare the efficacy of otilimab 
90mg IV versus placebo. 
• All-cause mortality at Day 28 
• All-cause mortality at Day 60 
• Time to all-cause mortality at Day 60 
• Participants alive and free of respiratory failure at 
Day 7, 14, 42, and 60 
• Time to recovery from respiratory failure up to Day 
28 
• Participants alive and independent of 
supplementary oxygen at Day 7, 14, 28, 42, and 60 
• Time to last dependence on supplementary oxygen 
up to Day 28 
• Time to final ICU discharge up to Day 28 
• Time to first discharge from investigator site up to 
Day 60 
• Time to first discharge to non-hospitalized 
residence up to Day 60 
• To compare the safety and 
tolerability of otilimab 90mg IV 
versus placebo. 
• Occurrence of adverse events (AEs) [up to Day 60] 
• Occurrence of serious adverse events (SAEs) [up 
to Day 60] 
 


 
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214094 
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• To determine the pharmacokinetics 
(PK) profile of otilimab. 
PK Endpoints up to Day 14 
• Otilimab apparent clearance (CL/F) and other PK 
parameters as appropriate using sparse PK 
sampling 
• To determine: 
o Exposure-response. 
o Pharmacodynamic (PD) 
biomarkers. 
o Changes in key markers of 
inflammation 
PD Endpoints up to Day 28 
• Exposure-response relationship for key efficacy, 
safety and PD endpoints. 
• Key markers of inflammation including, but not 
limited to CRP, serum ferritin and inflammatory 
cytokines as appropriate. 
Objectives 
Endpoints 
Exploratory 
• To compare the efficacy of 
otilimab 90mg IV versus 
placebo. 
Other endpoints up to Day 28 
• 
Invasive mechanical ventilation (if not previously 
initiated) 
• 
Time to invasive mechanical ventilation (if not 
previously initiated) 
• 
Alive and not invasively mechanically-ventilated 
• 
Time to definitive extubation 
• 
Oxygen-free days 
• 
Ventilator-free days 
• 
Admission to ICU up to Day 28 
• 
Change from Baseline in Concentration of Inspired 
Oxygen (FiO2) 
Other endpoints up to Day 60 
• 
Time to improvement of at least 2 categories 
relative to baseline on an ordinal scale 
• 
Change in COVID-19 signs and symptoms  
• 
Number of Days in Each Category of Clinical Status 
up to Day 60 
• 
Oxygen Use following Discharge to Non-
Hospitalized Residence 
• 
Post-Baseline Glucocorticoid Use up to Day 60 


 
C O N FI D E N TI A L  
 
 
 
2 1 4 0 9 4  
8  
 
1. 1. 2.  
E sti m a n d s  
E ac h st u d y o bjecti ve is prese nte d b el o w wit h a d diti o nal i nf or mati o n , i ncl u di n g p res p ecifie d esti ma n ds wit h relate d attri b utes. 
T a bl e  1  
E sti m a n d s  
E sti m a n d 
C at e g or y  
E sti m a n d  
V ari a ble/ E n d p oi nt  
P o p ul ati o n  
I nt er c urr e nt Ev e nt Str at e gy 
S u m m ar y 
M e a s ur e a n d 
Tr e at m e nt 
C o m p ari s o n  
Pri m ary O bj e cti ve : T o co m p ar e th e effic acy of otili m a b 9 0 m g I V v ers us pl ace b o  
Pri m ary  
P artici p a nts aliv e a n d fr e e of 
r es pir at ory f ail ur e at Day 2 8  
P articip a nts i n Part 2 of th e 
tri al r a n d o mis ed a n d 
r ec eive d  tr eat m ent ( MI T T) 
D at a a n alys ed as coll ect e d (tr e at m e nt p olicy 
str at e gy) 
O d ds r atio  an d 
diff er e nce i n 
pr o p orti ons  
S e c o n d ary O bje cti ve:  T o co m p ar e th e effic acy of otili m a b 9 0 m g I V v ers us pl ac e b o.  
S ec o nd ary 1  
All -c a us e m ort ality at D ay 28 
P articip a nts i n Part 2 of th e 
tri al r a n d o mis ed a n d 
r ec eive d  tr eat m ent ( MI T T) 
D at a a n alys ed as coll ect e d (tr e at m e nt p olicy 
str at e gy) 
O d ds r atio an d 
diff er e nce i n 
pr o p orti ons  
S ec o nd ary 2   
All -c a us e m ort ality at D ay 60 
P articip a nts i n Part 2 of th e 
tri al r a n d o mis ed a n d 
r ec eive d  tr eat m ent ( MI T T) 
D at a a n alys ed as coll ect e d (tr e at m e nt p olicy 
str at e gy) 
O d ds r atio an d 
diff er e nce i n 
pr o p orti ons  
S ec o nd ary 3  
Ti me t o all -c a use m ort ality u p 
t o D ay 6 0 
P articip a nts i n Part 2 of th e 
tri al r a n d o mis ed a n d 
r ec eive d  tr eat m ent ( MI T T) 
D at a a n alys ed as coll ect e d (tr e at m e nt p olicy 
str at e gy) 
H az ar d r ati o  
S ec o nd ary 4  
P artici p a nts aliv e a n d fr e e of 
r es pir at ory f ail ur e at Day 7, 1 4, 
4 2, a n d 6 0  
P articip a nts i n Part 2 of th e 
tri al r a n d o mis ed a n d 
r ec eive d  tr eat m ent ( MI T T) 
D at a a n alys ed as coll ect e d (tr e at m e nt p olicy 
str at e gy) 
O d ds r atio  an d 
diff er e nce i n 
pr o p orti ons  


 
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214094 
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Estimand 
Category  
Estimand 
Variable/Endpoint 
Population  
Intercurrent Event Strategy 
Summary 
Measure and 
Treatment 
Comparison 
Secondary 5 
Time to recovery from 
respiratory failure up to Day 28 
Participants in Part 2 of the 
trial randomised and 
received treatment (MITT) 
Participants who die will be censored at end of 
follow-up (composite strategy) 
 
For all other intercurrent events, the data 
analysed as collected (treatment policy strategy) 
Hazard ratio 
Secondary 6 
Participants alive and 
independent of supplementary 
oxygen at Day 7, 14, 28, 42 
and 60 
Participants in Part 2 of the 
trial randomised and 
received treatment (MITT) 
Data analysed as collected (treatment policy 
strategy) 
Odds ratio and 
difference in 
proportions 
Secondary 7 
Time to last dependence on 
supplementary oxygen up to 
Day 28 
Participants in Part 2 of the 
trial randomised and 
received treatment (MITT) 
Participants who die will be censored at end of 
follow-up (composite strategy) 
 
For all other intercurrent events, the data will be 
analysed as collected (treatment policy strategy) 
Hazard ratio  
Secondary 8 
Time to final ICU discharge up 
to Day 28 
Participants in Part 2 of the 
trial randomised and 
received treatment (MITT) 
Participants who die will be censored at end of 
follow-up (composite strategy) 
 
All other intercurrent events the data will be 
analysed as collected (treatment policy strategy) 
Hazard ratio 


 
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Estimand 
Category  
Estimand 
Variable/Endpoint 
Population  
Intercurrent Event Strategy 
Summary 
Measure and 
Treatment 
Comparison 
Secondary 9 
Time to first discharge from 
investigator site up to Day 60 
Participants in Part 2 of the 
trial randomised and 
received treatment (MITT) 
Participants who die will be censored at end of 
follow-up (composite strategy) 
 
All other intercurrent events the data will be 
analysed as collected (treatment policy strategy) 
Hazard ratio 
Secondary 10 
Time to first discharge to non-
hospitalized residence up to 
Day 60 
Participants in Part 2 of the 
trial randomised and 
received treatment (MITT) 
Participants who die will be censored at end of 
follow-up (composite strategy) 
 
All other intercurrent events the data will be 
analysed as collected (treatment policy strategy) 
Hazard ratio 
Secondary 11 
Occurrence of adverse events 
(AEs) [up to Day 60] 
 
Participants in Part 2 of the 
trial received treatment 
(Safety) 
Data analysed as collected (treatment policy 
strategy) 
Frequency & 
Percentage of 
Participants 
Secondary 12 
Occurrence of serious adverse 
events (SAEs) [up to Day 60] 
Participants in Part 2 of the 
trial received treatment 
(Safety) 
Data analysed as collected (treatment policy 
strategy) 
Frequency & 
Percentage of 
Participants 
 
The rationale for all estimands with the treatment policy intercurrent event strategy is that interest lies in the consequences of a single 
dose treatment in addition to standard of care, no interventions are restricted by the protocol and all relevant assessment outcomes or 
events are captured as part of relevant endpoints. 


 
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214094 
11 
 
For time-to-event estimands, where the endpoint represents an improvement in participant status, the event of death is incorporated into 
the estimand in a composite strategy, with censoring occurring at the end of the period in question with a treatment policy strategy for 
other inter current events.  The rationale for this strategy is that these estimands assess positive outcomes for patients so death should be 
treated unfavorably.     
 


 
C O N FI D E N TI A L  
 
 
 
2 1 4 0 9 4  
1 2  
 
1. 2.  
St u d y D e si g n  
O ver vie w of St u d y D esi g n a n d Ke y Feat ures  
 
 
D esi g n F e at ur es  T his st u dy is a m ulti -c e nter, r a n d o miz e d, do u ble-bli n d, pl ac e b o -c ontr oll e d 
tri al t o assess t he effic acy a n d s af ety of otili m a b f or th e tr e at m e nt of s ev er e 
p ul m o n ary C O VI D -1 9 r elat e d dis eas e.  Th e st u dy p op ulati o n co nsists of 
h os pitaliz e d p articip a nts with n e w o nset hyp oxi a re q uirin g si gnific a nt oxy ge n 
s u p port or r e quiri n g e arly i nv asiv e m ec ha nic al v e ntil ati on ( ≤4 8 h ours b efor e 
d osi n g).  All p articipa nts will r ec eiv e sta n dar d of c ar e as p er i nstituti o nal 
pr ot oc ols, i n a d diti on t o st udy tr e at m ent.  
St u dy 
i nt erv e ntio n 
Otili m a b 9 0 m g or Pl ace b o, si n gl e i ntr ave no us i nfusi o n  
St u dy 
i nt erv e ntio n 
Assi g n m e nt  
P artici p a nts will b e r an d o miz e d 1: 1 by i nt eractiv e r esp ons e tec h nol o gy (I R T) 
i n a bli nd e d m a nn er t o r ec eiv e eit her a bli n d ed 1-ho ur i nf usi o n of otili m a b 
9 0 m g or pl ac e b o I V i n a dditi o n to st an d ard of c ar e.  P artici p a nts will b e 
ass ess e d d aily u ntil d isc harg e fr o m i nvesti g at or sit e (or D ay 2 8, w hic h ever is 
s o o ner), a nd f oll o w ed u p at D ays 4 2 a nd 6 0 after r a nd o miz ati o n.  
 
Str atifi c ati o n i n P art 1  –  bas e d o n t h e st u dy eli gi bility crit eria, t h e cli nical 
st at us of th e p articip ants ent erin g th e m ai n c o hort ( i. e. aft er t he 2 0t h 
p artici p a nt) of th e st u dy will b e wit hi n or di nal sc al e cat e g ories  ( 5 or 6) a nd 
als o ag e gr o u ps, as sh o w n b el o w. 
•  
 
  A g e < 6 0 y e ars 
•  
 
.  A g e 6 0 t o <7 0 ye ars 
•  
 
.  A g e 7 0 t o <8 0 ye ars 
•  
.  Age < 6 0 y e ars 
•  
.  Age 6 0 t o <7 0 
y e ars 
•  
  Age 7 0 t o <8 0 
y e ars 
 
 
C CI
C CI
C CI
C CI
C CI
C CI


 
C O N FI D E N TI A L  
 
 
 
2 1 4 0 9 4  
1 3  
 
Str atifi c ati o n i n P art 2  –  Bas e d o n t h e st u dy eli gi bility crit eria, t h e cli nical 
st at us of th e p articip ants ent erin g Part 2 of th e st u dy will b e wit hi n t h e t w o 
or di n al sc ale c ate g ories 5 an d 6 a nd als o s ex, as foll o ws: 
•  
 
.  M ale  
•  
 
.  Fe m al e  
•  
  M al e  
•  
  F e m al e  
C CI
C CI
C CI


 
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214094 
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2. 
STATISTICAL HYPOTHESES / SUCCESS CRITERIA 
The primary objective of Part 2 of this study is to compare the efficacy of otilimab 90 mg 
IV versus placebo in age 70 and above years old participants with severe pulmonary 
COVID-19 related disease. 
Part 2 of the study will test the null hypothesis that there is no difference (odds ratio = 1) 
between otilimab 90 mg and placebo on the proportion of participants alive and free of 
respiratory failure at Day 28 versus the alternative hypothesis that there is a difference 
(odds ratio ≠ 1).  The primary endpoint and all secondary and exploratory endpoints will 
be conducted using a two-sided test at the 5% significance level.  
2.1. 
Multiple Comparisons and Multiplicity 
The testing of secondary endpoints will be carried out sequentially according to the 
following hierarchy, significance can only be claimed only if the current test and all prior 
tests are significant.   
1. Participants alive and free of respiratory failure at Day 60 
2. All-cause mortality at Day 28 
3. All-cause mortality at Day 60 
4. Time to recovery from respiratory failure up to Day 28 
5. Time to final ICU discharge up to Day 28 


 
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3. 
ANALYSIS SETS 
Analysis Set 
Definition / Criteria 
Analyses Evaluated 
Screened  
• 
All participants who were screened for 
eligibility 
• 
Study Population 
Enrolled 
• 
All participants who entered the study. 
• 
Data should be reported according to the 
randomised treatment 
• 
Note: screening failures are excluded from 
the enrolled analysis set as they did not 
enter the study. 
• 
Study Population 
Safety 
• 
All participants who received study 
intervention. 
• 
Data should be reported according to the 
actual treatment received 
o If participants receive any Otilimab 
then they will be summarised 
according to “Otilimab 90mg”, 
including interrupted/incomplete 
infusion. 
• 
Safety 
• 
Study Population 
Modified Intent-
To-Treat (MITT) 
• 
All randomized participants who received 
study intervention 
• 
Data should be reported according to the 
randomised treatment 
• 
Efficacy 
Pharmacokinetic 
(PK) 
• 
All participants in the Safety analysis set 
who had at least 1 non-missing PK 
assessment (Non-quantifiable [NQ] values 
will be considered as non-missing values). 
• 
Data should be reported according to the 
actual treatment 
o 
If participants receive any Otilimab 
then they will be summarised 
according to “Otilimab 90mg”, 
including interrupted/incomplete 
infusion. 
• 
PK 
 
3.1. 
Protocol Deviations 
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, patient management or patient assessment) will be 
summarised. 
Protocol deviations will be tracked by the study team throughout the conduct of the 
study.  These protocol deviations will be reviewed to identify those considered as 
important as follows: 


 
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o Data will be reviewed prior to freezing the database to ensure all important 
deviations are captured and categorised in the protocol deviations SDTM 
dataset. 
o This dataset will be the basis for the summaries of important protocol 
deviations. 
A separate listing of all inclusion/exclusion criteria deviations will also be provided.  This 
listing will be based on data as recorded on the inclusion/exclusion page of the eCRF. 
4. 
STATISTICAL ANALYSES 
4.1. 
General Considerations 
4.1.1. 
General Methodology 
The study population analyses will be based on the “Enrolled”, “Screened” or “Safety” 
populations.  The MITT Analysis Set will be used for all Efficacy analyses, and Safety 
Analysis Set will be used for all safety analyses, unless otherwise specified. 
In the case of a difference between the stratification assigned at the time of randomization 
and the data collected in the eCRF: 
• subgroups will be summarised based on the actual subgroup to which the 
participant belongs 
• covariate adjustment will be based on the randomised strata 
In general, all analyses will be adjusted for treatment, clinical status at Baseline, sex 
(male or female), age (as a continuous variable), baseline of the variable of interest (if 
appropriate) unless otherwise stated.  If the number of participants is small within a 
category of a covariate, then the covariate categories may be refined.  If the category 
cannot be refined further, then the covariate may be included as a continuous measure. If 
a covariate is highly or perfectly correlated with a subgroup/population, e.g. ICU Status 
and clinical status at Baseline, then covariates may be removed. Confidence intervals will 
use the 95% levels unless otherwise specified. 
Unless otherwise specified, continuous data will be summarized using descriptive 
statistics: n, mean, standard deviation, median, minimum and maximum.  Categorical 
data will be summarized as the number and percentage of participants in each category. 
Visit windows will be applied to the analysis days, where data within the window of the 
target day may be used if data is not recorded on the actual day. See Section 6.3.1 for 
assessment windows. 
4.1.2. 
Baseline Definition 
For all treated participants, for all endpoints and measurements the baseline value will be 
the latest pre-dose assessment with a non-missing value, including those from 
unscheduled visits.  If time is not collected, Day 1 assessments that were noted to be pre-


 
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dose per the Schedule of Activities are assumed to be taken prior to first dose and used as 
baseline. 
For all participants randomized but not dosed, for all endpoints and measurements the 
baseline value will be the latest assessment on or prior to the date of randomization with a 
non-missing value, including those from unscheduled visits. 
For ventilation status, baseline ventilation status will be derived as the ventilation at the 
time of dosing, and if there are multiple ventilation types being used the worst case will 
be assumed. 
Unless otherwise stated, if baseline data is missing no derivation will be performed and 
baseline will be set to missing. 
4.1.3. 
Multicenter Studies 
It is anticipated that patient accrual will be spread thinly across centers and summaries of 
data by center would unlikely be informative and will not, therefore, be provided. 
4.1.4. 
Intercurrent Events 
In general, the following may be considered intercurrent events (ICEs) if not part of the 
endpoint definition: 
• Interruption or infusion stopped early and not completed 
• Incorrect study treatment administered 
• Use of additional medications or changes to standard of care 
• Death 
• Initiation of Invasive Mechanical Ventilation 
• Extubation following Invasive Mechanical Ventilation 
• Independence from supplementary oxygen 
• Discharge from investigator site 
The applicable intercurrent events for each endpoint will be highlighted within in the 
endpoint definition along with the strategy for handling them. 
In general, unless otherwise specified, the handling strategy for all these intercurrent 
events will be based on a treatment policy approach; specifically, the effects estimated 
will be based on initial randomized treatment arm regardless of whether the participant 
had experienced an intercurrent event.  If possible, data will continue to be collected after 
the occurrence of the intercurrent event, until the participant either completes the study or 
withdraws from the study before completion. 
4.1.5. 
Missing Data Handling Rules 
Unless otherwise stated the following rules will be applied to all Primary and Secondary 
endpoints: 


 
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• Missing data can occur due to study withdrawal or participants lost to follow-up 
before the completion of the study or due to intermittent missing values (i.e. data 
between two non-missing assessments). 
• Missing data will be imputed under a missing at random (MAR) assumption using 
a multiple imputation (MI) model, unless otherwise specified.  The MI model will 
include covariates; treatment, clinical status at baseline, sex and age group and 
baseline of the variable of interest (if appropriate).  More details will be provided 
in Appendix 2. 
4.1.6. 
Examination of Covariates, Other Strata and Subgroups 
4.1.6.1. 
Covariates and Other Strata 
The list of covariates and other strata may be used in descriptive summaries and 
statistical analyses, some of which may also be used for subgroup analyses.  Additional 
covariates and other strata of clinical interest may also be considered. 
• 
If the number of participants is small within a category of a covariate, then the 
covariate categories may be refined prior to unblinding the trial. 
• 
If the category cannot be refined further, then the covariate may be included as a 
continuous measure. 
Category 
Details 
Strata 
Clinical status at baseline, Sex (Male or Female) 
Covariates 
Treatment, Clinical Status at Baseline, Sex, Age (as continuous), baseline of the 
variable of interest (if appropriate). 
 
4.1.6.2. 
Examination of Subgroups 
The list of subgroups may be used in descriptive summaries and statistical analyses. 
Additional subgroups of clinical interest may also be considered. 
• 
If there are less than 10 participants within a subgroup, then the subgroup categories 
may be refined prior to unblinding the trial. 
• 
If the category cannot be refined further, then descriptive rather than statistical 
comparisons may be performed for the subgroup. 


 
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Subgroup 
Categories  
Sex 
• 
Male 
• 
Female 
Clinical status at baseline 
• 
5 (Hospitalized, high-flow oxygen (≥15L/min), CPAP, 
BiPAP, non-invasive ventilation) 
• 
6 (Hospitalized, intubation and mechanical ventilation) 
Strata at baseline 
• 
Clinical Status 5 (Hospitalized, high-flow oxygen 
(≥15L/min), CPAP, BiPAP, non-invasive ventilation) and 
Male 
• 
Clinical Status 5 (Hospitalized, high-flow oxygen 
(≥15L/min), CPAP, BiPAP, non-invasive ventilation) and 
Female 
• 
Clinical Status 6 (Hospitalized, intubation and mechanical 
ventilation) and Male 
• 
Clinical Status 6 (Hospitalized, intubation and mechanical 
ventilation) and Female 
Age Group 
• 
70 - < 80 years 
• 
>= 80 years 
ICU Status at Baseline 
• 
In ICU on IMV1 
• 
In ICU not on IMV 
• 
Not in ICU and Not on IMV 
1. Subjects on Invasive Mechanical Ventilation (IMV) but not in ICU will be classified as in ICU 
on MV 
 
4.2. 
Primary Endpoint(s) Analyses 
4.2.1. 
Definition of Endpoint(s) 
Participants are free of respiratory failure if they are in category 1, 2, 3 or 4 from the 
GlaxoSmithKline (GSK) modified ordinal scale adapted from World Health Organization 
(WHO, 2020) scale 2020 (See Table 2 - Clinical Status using Ordinal Scale). Missing 
data prior to study withdrawal will be derived using ventilation data as described in 
Section 6.3.2. 
Participants will meet the endpoint if they are alive and free of respiratory failure at Day 
28.  As participants may be discharged from the investigator site prior to Day 28, analysis 
windows will be used to define the endpoint as described in Section 6.3.1. 


 
C O N FI D E N TI A L  
 
 
 
2 1 4 0 9 4  
2 0  
 
T a bl e 2  
Cli ni c al St at u s u si n g Or di n al S c al e  
Or di n al Sc ale ( G S K m o difie d v ersi o n, a d a pt e d fr o m  W H O , 2 0 20 ver si o n) 
4. 2. 2.  
M ai n A n al yti c al A p pr o a c h  
T he pri mar y e n d p oi nt will be s u m marize d usi n g c o u nts a n d pr o p orti o ns of t he n u m ber of 
partici pa nts ali ve a n d free of res pir at or y fail ure a n d will be a nal yse d usi n g a l o gistic 
re gressi o n m o del, a dj usti n g f or treat me nt, cli nical stat us  at baseli ne, se x a n d age as a 
c o nti n u o us varia ble .  T he o utc o me of t he m o del is a n o d ds rati o f or t he treat me nt effect, a 
c o nfi de nce i nter val a n d p -val ue f or t h e o d ds of a differe n ce  i n t he pr o p orti o n of 
partici pa nts ali ve a n d free of res pir at or y fail ure at Da y 2 8 , w here a n o d ds rati o > 1 
i n dicates i m pr o ve me nt.  T he c orres p o n di n g differe nce i n pr o p orti o n a n d c o nfi de nce 
i nter val will be calc ul ate d [Ge , 2 0 1 1 ]. 
I n a d diti o n, u na dj uste d relati ve ris ks a n d ris k differe nces will be calc ulat e d i n a d diti o n t o 
t he a dj uste d o d ds rati os .  T hese will be pres e nte d wit h 9 5 % Wal d c o nfi de nce i nter vals .  
A n y e n d p oi nt w here a n o d ds rati o/ hazar d rati o a b o ve 1 i n dicates i m pr o ve m e nt of 
otili ma b o ver place b o, t h e i n verse o d d s rati o/ hazar d rati o/relati ve ris k will als o be 
prese nte d . 
I n a d diti o n, t he f oll o wi n g will be pr o d uce d: 
•  
A ta ble a n d stac k e d bar c hart of t he pr o p orti o n of partici pa nts i n eac h cate g or y of t he 
cli nical stat us  at eac h visit.  
•  
a s hift ta ble fr o m bas eli ne t o t h e cli nical stat us at Da y 4, 7, 1 4, 2 8, 4 2 a n d 6 0 
i ncl u di n g a r o w f or i m pr o ve me nt ( defi n e d as m o vi n g fr o m a hi g h er cate g or y t o a 
l o wer cat e g or y).  
4. 2. 3.  
S e n siti vit y A n al y s e s  
As a se nsiti vit y t o t he missi n g data, t he f oll o wi n g se nsiti vit y a nal yses will  be  perf or me d . 
4. 2. 3. 1.  
Ti p pi n g P oi nt A n al y s e s  
F or t he ti p pi n g p oi nt a n al ys es, t he u n d erl yi n g res p o nse rate a m o n g t h ose p artici pa nt s wit h 
missi n g res p o nse stat us i n eac h ar m will be teste d ra n gi n g b et wee n 0 a n d 1 .  T his a nal ysis 
will be t w o -di me nsi o nal, i.e. will all ow f or ass u m pti o ns a b o ut t he ass u me d res p o nse rate 
(a n d t h us missi n g o utc o mes) i n t he t w o ar ms t o v ar y i n de pe n d e ntl y, f urt her m ore t he y will 
C C C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e 
pr ot e ct e d b y t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.


 
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include scenarios where dropouts on otilimab have worse outcomes than dropouts on 
placebo.  For combinations of the assumed response rates in the two arms, the number of 
additional responders among participants with missing response will be imputed multiple 
times by drawing from a binomial distribution.  The log-odds ratio and associated 
standard error for each imputed dataset will be calculated using a logistic regression with 
treatment as the only covariate and results combined using Rubin’s rules to calculate the 
test statistic and the corresponding p-value.  Results will be presented via a heatmap. 
4.2.4. 
Supplementary Analyses 
The following supplementary analyses may be conducted. 
4.2.4.1. 
Treatment policy estimand when correct treatment administered 
Supplementary analyses to assess the impact of incorrect treatment administration may be 
performed using an estimand for the primary and key secondary endpoints which will 
analyse data as collected when the correct treatment has been administered (with a 
treatment policy strategy for all other ICEs).  These supplementary analyses will use the 
same analytical approach as the main estimands and will differ only in the way that the 
intercurrent event of “Incorrect study treatment administered” is handled.  
4.2.4.2. 
Composite estimand for COVID-19 medications 
As a supplementary strategy to help understand the impact of some concomitant 
medications, a composite estimand may be considered for the handling of the intercurrent 
event of use of specific COVID-19 medications. A participant is considered to have an 
assessment of an intercurrent event if they start or increase dose of any of the known 
COVID-19 medications on Day 1 or later. This will be determined by a blinded review of 
the concomitant medications to determine whether a patient has had a new use. A 
participant may be considered as a non-responder if they have taken specific COVID-19 
medications post-baseline. See Section 6.4.9 for a list of COVID-19 medications.  
4.2.5. 
Subgroup Analyses 
Subgroup analyses using the subgroups listed in Section 4.1.6.2 will be performed using 
the same methodology as the primary endpoint with the addition of a treatment by 
subgroup interaction.  A joint test of the interaction term will be provided in the summary 
table.  Results will be presented as per primary analyses and, in addition a forest plot of 
the difference in proportions will be generated. 
For subgroup analyses, if there are <10 events in a subgroup then only a summary will be 
produced.  
4.3. 
Secondary Endpoint(s) Analyses 
The estimands are described in Table 1. 


 
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4.3.1. 
Endpoint Definition 
4.3.1.1. 
All-cause Mortality at Day 28 and 60 
Participants will meet the endpoint if they have died due to any cause prior to Day 28 and  
60. All-cause mortality will be based on the clinical status as defined in Section 6.3.2. 
4.3.1.2. 
Time to All-cause Mortality up to Day 60 
Defined as the time (days) from dosing to death, due to any cause, up to (and including) 
Day 60. 
4.3.1.3. 
Participants Alive and Free of Respiratory Failure at Day 7, 14, 42, and 
60 
Defined as per primary endpoint, see Section 4.2.1. 
4.3.1.4. 
Time to Recovery from Respiratory Failure up to Day 28 
Defined as the time (days) from dosing to last recovery from respiratory failure up to 
(and including) Day 28.  Participants are in respiratory failure if they are in category 5 or 
above from the GlaxoSmithKline (GSK) modified ordinal scale adapted from World 
Health Organization (WHO, 2020) scale 2020 (Table 2).  
Note: if a participant has recovered from respiratory failure but then progresses back into 
respiratory failure on or prior to the end of follow up (Day 28) the participant has not had 
their last recovery from respiratory failure. 
This endpoint will use a composite approach for death such that if the intercurrent event 
of death occurs (on or prior to Day 28), then time will be censored at end of follow up 
(Day 28). 
4.3.1.5. 
Participants Alive and Independent of Supplementary Oxygen at Day 7, 
14, 28, 42, and 60 
Participants are independent of supplementary oxygen if they are in category 1, 2 or 3 
from the GlaxoSmithKline (GSK) modified ordinal scale adapted from World Health 
Organization (WHO, 2020) scale 2020 (See Table 2- Ordinal Scale).  Missing data prior 
to study withdrawal will be derived using ventilation data as described in Section 6.3.2 
Participants will meet the endpoints if they are alive and independent of supplementary 
oxygen at Day 7, 14, 28, 42, and 60 respectively.  As participants may be discharged 
from investigator site, analysis windows will be used to define the endpoint as described 
in Section 6.3.1. 
4.3.1.6. 
Time to Last Dependence on Supplementary Oxygen up to Day 28 
Defined as the time (days) from dosing to last dependence on supplementary oxygen up 
to (and including) Day 28.  Participants are dependent on supplementary oxygen if they 
are in category 4 or above from the GlaxoSmithKline (GSK) modified ordinal scale 
adapted from World Health Organization (WHO, 2020) scale 2020 (Table 2).  


 
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Alternatively, if the clinical status is unknown but ventilation or oxygen status is 
available, then the endpoint is defined as the last day up to (and including) Day 28 where 
oxygen support is required.  
Note: if a participant is independent of supplementary oxygen but then progresses back 
into dependence of supplementary oxygen on or prior to the end of follow up (Day 28) 
the participant has not had their last dependence on supplementary oxygen. 
This endpoint will use a composite approach such that if the intercurrent event of death 
occurs (on or prior to Day 28), then time will be censored at end of follow up (Day 28). 
4.3.1.7. 
Time to Final ICU Discharge up to Day 28 
This is defined as the time (days) from dosing to the participants final ICU discharge up 
to (and including) Day 28.  It will only be evaluated for participants in the ICU at 
baseline. 
This endpoint will use a composite approach such that if the intercurrent event of death 
occurs (on or prior to Day 28), then time will be censored at the end of follow-up (Day 
28), including those that were discharged from ICU prior to death. 
4.3.1.8. 
Time to First Discharge from Investigator Site up to Day 60 
This is defined as the time (days) from dosing to when the participant is first discharged 
from investigator site up to (and including) Day 60. 
This endpoint will use a composite approach such that if the event has not occurred prior 
to the intercurrent event of death (on or prior to Day 60), then time will be censored at the 
end of follow-up (Day 60). 
4.3.1.9. 
Time to First Discharge to Non-Hospitalized Residence up to Day 60 
This is defined as the time (days) from dosing to when the participant is discharged to a 
non-hospitalized residence for the first time up to (and including) Day 60. 
This endpoint will use a composite approach such that if the event has not occurred prior 
to the intercurrent event of death occurred (on or prior to Day 60), then time will be 
censored at the end of follow-up (Day 60). 
4.3.2. 
Main Analytical Approach 
4.3.2.1. 
Binary Endpoints 
The binary endpoints: 
• All-cause mortality at Day 28 and Day 60 
• Participants alive and free of respiratory failure at Day 7, 14, 42, and 60 
• Participants alive and independent of supplementary oxygen at Day 7, 14, 28, 42, 
and 60 
Binary secondary endpoints will be analysed as per Section 4.2.2. 


 
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4.3.2.2. 
Time to Event Endpoints 
The following endpoints will be analysed using time to event analyses with a follow-up 
to Day 60: 
• Time to all-cause mortality 
• Time to first discharge from investigator site 
• Time to first discharge to non-hospitalized residence 
The following exploratory endpoints will be analysed using time to event analyses with a 
follow-up to Day 28: 
• Time to recovery from respiratory failure 
• Time to last dependence on supplementary oxygen 
• Time to final ICU discharge 
For time to event endpoints where the event is a worsening participant status, participants 
with missing data due to study withdrawal prior to occurrence of the event will be 
censored at the time of study withdrawal, participants alive at the end of follow-up will 
be censored at the time of end of follow-up (i.e. Day 28/60). 
For time to event endpoints where the event is an improvement participant status, 
participants with missing data due to study withdrawal prior to first occurrence of the 
event will be censored at the time of end of follow-up.  The end of follow up will be the 
earliest of the nominal timepoint (i.e. Day 28/60) and their actual study day of visit.  If a 
participant meets the endpoint at the point of withdrawal, then the participant will be 
assumed to have achieved the event. 
The endpoint will be analysed using a Cox proportional hazards model adjusted for 
covariates per Section 4.1.1.  Ties will be broken using Efron’s method.  The hazard ratio 
of the treatment group and corresponding confidence interval and p-value will be 
reported.  For any endpoint where a hazard ratio above 1 indicates improvement of 
otilimab over placebo, the inverse hazard ratio will also be presented.  For model checks 
refer to Section 6.2.3. 
Kaplan-Meier plots will be presented by treatment group.  Estimates of the median time-
to-event and other relevant percentiles will be derived from the unadjusted Kaplan-Meier 
plots and reported in a table.  If 50% of participant do not meet the event definition 
during the study, alternative percentiles may be produced. 
These time to event endpoints may also be derived using additional follow-up times to 
support future sensitivity analyses. 
Additionally, for time to ICU discharge, the following summaries will be produced: 
• For participants who are in the ICU at any point during the trial, the duration of 
ICU stay will be summarised overall and separately for participants that have died 
and those that complete the study, it will be further split by participants ICU 
status (in ICU at dosing or entered ICU post-dose). 


 
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• Additionally, for all participants a count and proportion of participants with stays 
in the ICU of 0 days, 1-<7 days, 7-<14 days and ≥14 days will be produced. 
For hospitalization: 
• The duration of hospitalization will be summarized overall and separately for 
participants that have died and those that complete the study. A count and 
proportion of participants with hospitalization stays of  1-<7 days, 7-<14 days and 
≥14 days will be produced.  
• A separate summary of discharge location will also be provided. 
4.3.3. 
Sensitivity Analyses 
4.3.3.1. 
Binary Endpoints 
Sensitivity analyses as per Section 4.2.3 will be performed on the binary endpoints in the 
hierarchy specified in Section 2.1. 
4.3.3.2. 
Time to Event Endpoints 
As a sensitivity to the proportional hazards assumption, and time of censoring, for the 
time to event endpoints where the event is an improvement participant status with a 
follow up time of 28 days, the endpoints will be calculated for an extended follow-up 
time up to Day 60 and analysis may be performed as per Section 4.3.2.2. 
4.3.4. 
Supplementary Analyses 
Supplementary estimands as described in Section 4.2.4 may be performed on all-cause 
mortality endpoints (Day 28 and Day 60). 
4.3.5. 
Subgroup Analyses 
Subgroup analyses for the endpoints listed in the testing hierarchy in Section 2.1 may be 
performed as per Section 4.2.5 and will use the methods described above. 
4.4. 
Exploratory Endpoint(s) Analyses 
Exploratory endpoints may be analysed at the final analysis only. 
4.4.1. 
Definition of Endpoint(s) 
4.4.1.1. 
Invasive Mechanical Ventilation (if not previously initiated) up to Day 28 
Participants will meet the endpoint if they have had invasive mechanical ventilation 
initiated up to (and including) Day 4, 7, 14, 28.  This will only be evaluated for 
participants who are not supported using invasive mechanical ventilation at baseline. This 
will be derived from the worst-case ventilation record as detailed in Section 6.3.2.1. 
Participants who die on or prior to Day 28 without the initiation of invasive mechanical 
ventilation will be considered to have met the endpoint (composite estimands strategy). 


 
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4.4.1.2. 
Invasive Mechanical Ventilation (if not previously initiated) at Day 4, 7, 
14, 28 
Participants will meet the endpoint if they had invasive mechanical ventilation on the 
specified day.  This will only be evaluated for participants who are not supported using 
invasive mechanical ventilation at baseline. This will be derived from the worst-case 
ventilation record as detailed in Section 6.3.2.1. 
Participants who die on or prior to the specified day will be considered to have met the 
endpoint (composite estimands strategy). 
4.4.1.3. 
Time to Invasive Mechanical Ventilation (if not previously initiated) up 
to Day 28 
Time from dosing (days) to first use of invasive mechanical ventilation or death up to 
(and including) Day 28 as defined in Section 4.4.1.1.  This will only be evaluated for 
participants who are not supported using invasive mechanical ventilation at baseline. This 
will be derived from the worst-case ventilation record as detailed in Section 6.3.2.1. 
This endpoint will use a composite approach for death such that for participants who die 
on or prior to Day 28 without the initiation of invasive mechanical ventilation, the time to 
invasive mechanical ventilation will be set as the time of death. 
4.4.1.4. 
Alive and Not Invasively Mechanically Ventilated  
Participants will meet the endpoint if they are alive and not requiring invasive mechanical 
ventilation at Day 7, 14, 28, 42 and 60.  This will be evaluated only for participants 
supported using invasive mechanical ventilation at baseline. This will be derived from the 
worst-case ventilation record as detailed in Section 6.3.2.1. 
4.4.1.5. 
Time to Definitive Extubation up to Day 28 
For participants supported using invasive mechanical ventilation at baseline this is 
defined as the time from dosing (days) to final extubation from invasive mechanical 
ventilation up to (and including) Day 28. This will be derived from the worst-case 
ventilation record as detailed in Section 6.3.2.1. 
This endpoint will use a composite approach for death such that if the event intercurrent 
event of death (on or prior to Day 28) occurs, then time will be censored at the end of 
follow-up (Day 28), including those that were extubated prior to death. 
4.4.1.6. 
Oxygen-free Days up to Day 28 
A participant is considered oxygen free on a day if they are not using oxygen 
(Ventilation=None) as derived from the worst case ventilation record on a day as detailed 
in Section 6.3.2.1.  
 
Intermittent data is expected after discharge from investigator site, therefore if 
participants have discontinued oxygen and have been discharged to a non-hospitalized 
residence, they will be considered to be oxygen-free during the intermittent timepoints. 


 
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4.4.1.7. 
Ventilator-free Days up to Day 28 
A participant is considered ventilator-free on a day if they are not using invasive 
mechanical ventilation as derived from the worst case ventilation record on a day as 
detailed in Section 6.3.2.1. 
 
Intermittent data is expected after discharge from investigator site, therefore if 
participants have discontinued ventilation and have been discharged to a non-hospitalized 
residence, they will be considered to be ventilation-free during the intermittent 
timepoints. 
4.4.1.8. 
Admission to ICU up to Day 28 
Participants will meet the endpoint if they have been admitted to the ICU at any point up 
to (and including) Day 28, only evaluated for participants not in ICU at time of dosing. 
Participants who die prior to Day 28 without being admitted ICU will be considered to 
have met the endpoint (composite estimands strategy). 
4.4.1.9. 
Change from Baseline in Inspired Oxygen (FiO2) up to Day 28 
Change from baseline in FiO2 will be calculated, for participants up to Day 28. FiO2 will 
be summarized as a fraction rather than a percentage for observed data and using a 
trimmed means approach as specified in the Section 4.4.2.4.  
For the trimmed means, if >50% of the participants experience the intercurrent events 
listed below at any timepoint, then the data will be summarized up to that timepoint only.  
If a participant experiences multiple intercurrent events, then the worst response status 
will be assumed. 
If FiO2 is not recorded but Oxygen Flow Rate is, the FiO2 will be calculated.   
Intercurrent event 
Response Status 
Death 
Non-responder 
Discharge from investigator site to advanced facilitated care 
Non-responder 
Discharge from Investigator Site for any other reason other than 
advanced facilitated care  
Responder 
Independence from supplementary oxygen and missing FiO2 
Responder 
 
4.4.1.10. 
Oxygen Use Following Discharge to Non-hospitalized Residence 
The number of participants will be presented for the following categories:  
• Not discharged to non-hospitalized residence or death  
• Discharged to non-hospitalized residence and used oxygen post-discharge 


 
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• Discharged to non-hospitalized residence and did not use oxygen post-discharge. 
 In addition, for participants discharged to a non-hospitalized residence and for oxygen 
usage post-discharge, the number of days on oxygen will be summarized for each 
participant for the following: 
• 1-< 7 days 
• 7- <14 days 
•  ≥ 14 days.  
Summary statistics for the number of days of oxygen use, including mean, median (IQR), 
min and max will also be provided.  
4.4.1.11. 
Time to Improvement of at Least 2 Categories Relative to Baseline in 
Clinical Status up to Day 60 
Time from dosing (days) to final improvement of at least 2 categories relative to baseline 
in clinical status (see Table 2) up to (and including) Day 60.  Evaluated for all 
participants with clinical status greater than 2 at baseline. 
Note: if a participant has an improvement of at least 2 categories relative to baseline but 
then progresses back to a less than 2 category improvement the participant has not had 
their final improvement of at least 2 categories. 
This endpoint will use a composite approach such that if the event has not occurred prior 
to the intercurrent event of death (on or prior to Day 60), then time will be censored at the 
end of follow-up (Day 60). 
4.4.1.12. 
Number of Days in Each Category of Clinical Status up to Day 60 
For each participant, the number of days in each clinical status (see Table 2) or missing 
will be calculated up to (and including) Day 60.  
The median number of days in each category will be presented overall. a participant’s 
final outcome (Alive vs Dead or Withdrawn) 
4.4.1.13. 
Change in COVID-19 Signs and Symptoms up to Day 60 
Participants change in COVID-19 signs and symptoms at Day 4, 7, 14, 28, 42 and 60 
relative to baseline will be analysed. Participants will be absent of a symptom if they had 
a symptom at baseline and the symptom was not present at the timepoint of interest.  This 
endpoint will use a composite approach for death or initiation of invasive mechanical 
ventilation, such that participants who die prior to or are using invasive mechanical 
ventilation on the day of interest (and so cannot have symptoms recorded), will be 
considered to still have the symptom. 
 
Unadjusted relative risks, risk differences and odds ratios will be calculated and 
presented with 95% confidence intervals.  For odds ratios, if the proportions are below 
2% in any treatment group then exact 95% confidence interval will be calculated by 
inverting two one-sided (equal tail) exact tests that are based on the noncentral 


 
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hypergeometric distribution.  All other confidence intervals will use the Wald method.  A 
2-sided Fisher's Exact Test will be performed, and p-values will be presented. 
4.4.1.14. 
Post-Baseline Glucocorticoid Use up to Day 60 
Post-Baseline glucocorticoid use is defined such that participants who required 
glucocorticoid use on a day if their concomitant medications include glucocorticoids on 
that day, where glucocorticoids for COVID-19 were defined prior to DBF. A missing 
stop date for any glucocorticoids has been assumed to be the minimum of last contact, 
end of study and Day 60.  
Summaries up to Day 60 will be provided on the duration of post-Baseline glucocorticoid 
use, overall and separately for participants that have died or withdrew, and those that 
completed the study. This will include counts and proportions of participants with post-
Baseline glucocorticoid use of 0 days, 1-<7 days, 7-<14 days and ≥14 days 
4.4.2. 
Main Analytical Approach 
4.4.2.1. 
Time to Event Endpoints 
The following exploratory endpoints will be analysed using time to event analyses with a 
follow-up to Day 28: 
• Time to invasive mechanical ventilation (if not previously initiated) 
• Time to definitive extubation 
The following exploratory endpoints will be analysed using time to event analyses with a 
follow-up to Day 60: 
• Time to improvement of at least 2 categories relative to baseline on an ordinal 
scale 
The endpoints will be analysed as per Section 4.3.2.2 
These time to event endpoints may also be derived using additional follow-up times to 
support future sensitivity analyses. 
4.4.2.2. 
Binary Endpoints 
The following exploratory endpoints will be analysed as binary endpoints: 
• Invasive mechanical ventilation (if not previously initiated) 
• Alive and not invasively mechanically ventilated 
Binary secondary endpoints will be analysed as per Section 4.2.2. 
In addition, the following will be produced: 
• 
A table and stacked bar chart of the counts and proportion of participants in each 
ventilation status at each visit. 


 
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• 
A summary of duration of invasive mechanical ventilation will be produced, using 
descriptive statistics and counts and proportion of participants who have 1- < 7 days, 
7- < 14 days, ≥ 14 days use. 
 
4.4.2.3. 
Count Endpoints 
The following exploratory endpoints will be analysed as count data 
• Oxygen-free days 
• Ventilator-free days 
Summary statistics of the number of days will be presented and the data will be analysed 
using negative binomial regression adjusting for covariates as per Section 4.1.1.  
4.4.2.4. 
Continuous Endpoints 
The following exploratory endpoints will be analysed as continuous endpoints: 
• Change from Baseline in FiO2 
Continuous endpoints will be summarised using the trimmed means approach (Permutt, 
2017) where the proportion of data to be trimmed will be determined by the amount of 
missing data due to intercurrent events as defined in Section 4.1.4. 
Study withdrawal will be treated as a negative event if it occurs prior to one of the listed 
intercurrent events. If the subject has recovered (has one of the intercurrent events listed 
within the endpoint definition) prior to withdrawal then they will be considered to be 
recovered post-withdrawal. 
Missing data without reason (no accompanying intercurrent event or withdrawal) will be 
treated as missing at random and will not count towards the trimmed sample. 
A plot of the change from baseline using the trimmed sample will be generated. 
4.4.3. 
Sensitivity Analyses 
As a sensitivity to the proportional hazards assumption, and time of censoring, for the 
time to event endpoints with a follow up time of 28 days the endpoints will be calculated 
for an extended follow-up time up to Day 60 and analysis may be performed as per 
Section 4.3.2.2. 
4.4.4. 
Supplementary Analyses 
No supplementary analyses planned. 
4.4.5. 
Subgroup Analyses 
No subgroup analyses are planned. 


 
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4.5. 
Safety Analyses 
4.5.1. 
Extent of Exposure 
As this is a single dose study, summaries of exposure will be limited to the number of 
participants exposed and the number of participants with interruptions or infusion 
stopped early and not completed.  This will be presented with participant disposition. 
4.5.2. 
Adverse Events 
Adverse events analyses including the analysis of adverse events (AEs) and Serious AEs 
(SAEs) will be based on GSK Core Data Standards.  All adverse events reported will be 
treatment emergent adverse events. 
A summary of the number and percentage of subjects with any adverse event, AEs 
related to study treatment, AEs leading to permanent discontinuation of study treatment, 
AE leading to dose reduction, AE leading to dose interruption/delay, any serious adverse 
events (SAE), SAEs related to study treatment, fatal SAEs, fatal SAEs related to study 
treatment will be produced. 
Adverse events will be coded using the standard Medical Dictionary for Regulatory 
Affairs (MedDRA dictionary). 
A summary of number and percentage of participants with any adverse events overall and 
by maximum intensity will be produced.  AEs will be sorted by Preferred term (PT) in 
descending order. These summaries will be also provided for common (>=5% in either 
treatment group) AEs and non-serious AEs. The summary will use the following 
algorithms for counting the participant: 
• 
Preferred term row: Participants experiencing the same AE preferred term several 
times with different intensities will only be counted once with the maximum grade. 
• 
Any event row: Each participant with at least one adverse event will be counted 
only once at the maximum intensity no matter how many events they have. 
The frequency and percentage of AEs (all intensities) will be summarized and displayed 
in two ways: 1) in descending order by PT only and 2) in descending order by System 
Organ Class (SOC) and PT.  In the SOC row, the number of participants with multiple 
events under the same SOC will be counted once. 
A separate summary of  all non-serious and common (>=5% in either treatment group) 
AEs will be provided for study intervention-related AEs.  A study intervention-related 
AE is defined as an AE for which the investigator classifies the possible relationship to 
study intervention as “Yes”.  A worst-case scenario approach will be taken to handle 
missing relatedness data, i.e. the summary table will include events with the relationship 
to study intervention as ‘Yes’ or missing.  The summary table will be displayed by PT 
only. All SAEs will be tabulated based on the number and percentage of participants who 
experienced the event as well as number of occurrences.  Separate summaries will also be 
provided for study intervention-related SAEs and common (>=5% in either treatment 
group) SAEs.  The summary tables will be displayed by PT. 


 
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A study intervention-related SAE is defined as an SAE for which the investigator 
classifies the relationship to study intervention as “Yes”.  A worst-case scenario approach 
will be taken to handle missing data, i.e. the summary table will include events with the 
relationship to study intervention as ‘Yes’ or missing. 
In addition the following summaries will be produced: 
• Non-fatal AEs and SAEs by PT and SOC. 
• Fatal AEs  
• Fatal study intervention-related AEs 
• AEs leading to Discontinuation  
• AEs leading to Dose Interruptions 
Unadjusted Relative risks with Wald confidence intervals based on observed frequencies, 
for the proportions of participants with common (>=5% in either treatment group) AEs 
will be calculated for otilimab versus placebo. 
Relative risks will not be calculated if there are no events in either of the two treatment 
arms being compared.  The relative risks and exact confidence interval will be plotted on 
log base 10 scale. 
The adverse events with calculated relative risks will be presented in decreasing order as 
per the IDSL standard. 
4.5.2.1. 
Adverse Events of Special Interest 
The following will be considered adverse events of special interest (AESI) for the 
purpose of analyses: 
• Cytokine release syndrome (CRS) 
• Serious hypersensitivity reactions 
Note: these will be adjudicated by the SRT. 
• Infusion site reactions 
• Neutropenia ≥ Grade 3 (<1.0 x 109/L) 
• Serious infections 
Listings of event characteristics will be provided for each AESI respectively.  For AESIs 
with more than 8 events a summary of event characteristics will be provided for each 
AESI respectively, including number and percentage of participants with any event, 
number and percentage of events, maximum intensity, outcomes and the action taken for 
the event.  The worst-case approach will be applied at participant level for the maximum 
intensity, i.e. a participant will only be counted once as the worst case from all the events 
experienced by the participant. 
4.5.2.2. 
Adverse Event Groups of Interest 
Standardized MedDRA Queries (SMQ) will be used, if available, to identify all AEs in 
the following Adverse Event groups of interest: 


 
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• Pneumonia  
• Sepsis 
• Opportunistic Infections  
• Thromboembolic Events 
• Pulmonary Embolism 
An SMQ is not available for pulmonary embolism, therefore a grouping for pulmonary 
embolism will be created by review of AE PTs reported for the study and PT will be 
identified that are indicative of PE.  
Summaries of All AEs and SAEs by PT group and PT will be presented.  These will also 
be produced for each of the clinical statuses at baseline.  Analysis of the PT groups of 
interest will follow the approach for the analysis of AEs in PTs (including that if a subject 
has more than one event in each PT group of interest, they will be counted once). 
4.5.2.3. 
Subgroup Analyses 
The following subgroups will be included in the safety subgroup analyses: sex, clinical 
status at Baseline, and age as defined in Section 4.1.6.2. 
For the Safety population and all subgroups defined above, summaries of common AEs, 
common SAEs (see Section 4.5.2), AESIs, and all AEs and SAEs by PT group (see 
Section 4.5.2.2) and PT will be presented. 
4.5.3. 
Additional Safety Assessments 
4.5.3.1. 
Deaths 
Deaths will be summarized and a table of Subject Numbers for Specific Causes of Deaths 
will be produced. The summary of deaths will include n (number of subjects) and percent 
of subject status, primary cause of death and whether COVID-19 contributed to death. 
The table of Subject Numbers will include primary cause of death, details, whether 
COVID-19 contributed to death, treatment, and the number of subjects with their subject 
identifiers. 
4.5.3.2. 
Laboratory Data 
Summaries of worst-case grade increase from baseline grade will be provided for all the 
lab tests that are gradable by a modified CTCAE v5.  These summaries will display the 
number and percentage of participants with a maximum post-baseline grade increasing 
from their baseline grade.  Any increase in grade from baseline will be summarized along 
with any increase to a maximum grade of 3 and any increase to a maximum grade of 4.  
Missing baseline grade will be assumed as grade 0.  For laboratory tests that are graded 
for both low and high values, summaries will be done separately and labelled by 
direction, e.g., sodium will be summarized as hyponatremia and hypernatremia 
separately. 


 
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The CTCAE v5 grades were modified to remove grading criteria that cannot be derived 
programmatically with the data collected (see footnotes).  The modified CTCAE v5 
grades are defined as follows: 


 
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Laboratory 
parameters of 
interest1 
Grade 
1 
2 
3 
4 
HEMOGLOBIN 
decreased  
(CTCAE term is 
Anemia)2 
<LLN - 10.0 
g/dL;  
<LLN - 6.2 
mmol/L;  
<LLN - 100 g/L 
<10.0 - 8.0 g/dL;  
<6.2 - 4.9 
mmol/L;  
<100 - 80 g/L 
<8.0 g/dL;  
<4.9 mmol/L;  
<80 g/L 
- 
HEMOGLOBIN 
increased 
>0 - 2 g/dL 
>2 - 4 g/dL 
>4 g/dL 
- 
LEUKOCYTE 
(White blood 
cell) decreased 
<LLN - 
3000/mm3; 
<LLN - 3.0 x 
10e9 /L 
<3000-
2000/mm3; <3.0 
- 2.0 x 10e9 /L 
<2000-
1000/mm3; <2.0 
- 1.0 x 10e9 /L 
<1000/mm3; 
<1.0 x 10e9 /L 
LYMPHOCYTE 
COUNT 
decreased 
<LLN - 800 
/mm3;  
<LLN - 0.8 x 
10e9/L 
<800 - 500 
/mm3;  
<0.8 - 0.5 x 
10e9/L 
<500 - 200 
/mm3;  
<0.5 - 0.2 x 
10e9/L 
<200/mm3;  
<0.2 x 10e9/L 
LYMPHOCYTE 
COUNT 
increased 
 - 
>4,000 - 20,000 
/mm3;  
>4 - 20 x 10e9/L 
>20,000 /mm3;  
>20 x 10e9/L 
 - 
NEUTROPHIL 
COUNT 
decreased 
<LLN - 1,500 
/mm3;  
<LLN - 1.5 x 
10e9/L 
<1,500 - 1,000 
/mm3;  
<1.5 - 1.0 x 
10e9/L 
<1,000 - 500 
/mm3;  
<1.0 - 0.5 x 
10e9/L 
<500 /mm3;  
<0.5 x 10e9/L 
PLATELET 
COUNT 
decreased 
<LLN - 75,000 
/mm3;  
<LLN - 75.0 x 
10e9/L 
<75,000 - 50,000 
/mm3;  
<75.0 - 50.0 x 
10e9/L 
<50,000 - 25,000 
/mm3;  
<50.0 - 25.0 x 
10e9/L 
<25,000 /mm3;  
<25.0 x 10e9/L 
AST (SGOT) 
>ULN - 3.0 x 
ULN if baseline 
was normal; 1.5 - 
3.0 x baseline if 
baseline was 
abnormal 
>3.0 - 5.0 x ULN 
if baseline was 
normal; >3.0 - 
5.0 x baseline if 
baseline was 
abnormal 
>5.0 - 20.0 x 
ULN if baseline 
was normal; >5.0 
- 20.0 x baseline 
if baseline was 
abnormal 
>20.0 x ULN if 
baseline was 
normal; >20.0 x 
baseline if 
baseline was 
abnormal 
ALP 
>ULN - 2.5 x 
ULN if baseline 
was normal; 2.0 - 
2.5 x baseline if 
baseline was 
abnormal 
>2.5 - 5.0 x ULN 
if baseline was 
normal; >2.5 - 
5.0 x baseline if 
baseline was 
abnormal 
>5.0 - 20.0 x 
ULN if baseline 
was normal; >5.0 
- 20.0 x baseline 
if baseline was 
abnormal 
>20.0 x ULN if 
baseline was 
normal; >20.0 x 
baseline if 
baseline was 
abnormal 


 
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Laboratory 
parameters of 
interest1 
Grade 
1 
2 
3 
4 
ALT (SGPT) 
>ULN - 3.0 x 
ULN if baseline 
was normal; 1.5 - 
3.0 x baseline if 
baseline was 
abnormal 
>3.0 - 5.0 x ULN 
if baseline was 
normal; >3.0 - 
5.0 x baseline if 
baseline was 
abnormal 
>5.0 - 20.0 x 
ULN if baseline 
was normal; >5.0 
- 20.0 x baseline 
if baseline was 
abnormal 
>20.0 x ULN if 
baseline was 
normal; >20.0 x 
baseline if 
baseline was 
abnormal 
BLOOD 
BILIRUBIN 
increased 
>ULN - 1.5 x 
ULN if baseline 
was normal; > 
1.0 - 1.5 x 
baseline if 
baseline was 
abnormal 
>1.5 - 3.0 x ULN 
if baseline was 
normal; >1.5 - 
3.0 x baseline if 
baseline was 
abnormal 
>3.0 - 10.0 x 
ULN if baseline 
was normal; >3.0 
- 10.0 x baseline 
if baseline was 
abnormal 
>10.0 x ULN if 
baseline was 
normal; >10.0 x 
baseline if 
baseline was 
abnormal 
ALBUMIN 
(Hypo-
albuminemia) 
<LLN - 3 g/dL; 
<LLN - 30 g/L 
<3 - 2 g/dL; <30 
- 20 g/L 
<2 g/dL; <20 g/L 
- 
APTT Activated 
partial 
thromboplastin 
time prolonged 
>ULN - 1.5 x 
ULN 
>1.5 - 2.5 x ULN 
>2.5 x ULN 
- 
CALCIUM 
(Hypercalcemia) 
Corrected serum 
calcium of >ULN 
- 11.5 mg/dL; 
>ULN - 2.9 
mmol/L; Ionized 
calcium >ULN - 
1.5 mmol/L 
Corrected serum 
calcium of >11.5 
- 12.5 mg/dL; 
>2.9 - 3.1 
mmol/L; Ionized 
calcium >1.5 - 
1.6 mmol/L 
Corrected serum 
calcium of >12.5 
- 13.5 mg/dL; 
>3.1 - 3.4 
mmol/L; Ionized 
calcium >1.6 - 
1.8 mmol/L 
Corrected serum 
calcium of >13.5 
mg/dL; >3.4 
mmol/L; Ionized 
calcium >1.8 
mmol/L 
CALCIUM 
(Hypocalcemia) 
Corrected serum 
calcium of <LLN 
- 8.0 mg/dL; 
<LLN - 2.0 
mmol/L; Ionized 
calcium <LLN - 
1.0 mmol/L 
Corrected serum 
calcium of <8.0 - 
7.0 mg/dL; <2.0 - 
1.75 mmol/L; 
Ionized calcium 
<1.0 - 0.9 
mmol/L 
Corrected serum 
calcium of <7.0 - 
6.0 mg/dL; <1.75 
- 1.5 mmol/L; 
Ionized calcium 
<0.9 - 0.8 
mmol/L 
Corrected serum 
calcium of <6.0 
mg/dL; <1.5 
mmol/L; Ionized 
calcium <0.8 
mmol/L 
CPK increased 
>ULN - 2.5 x 
ULN 
>2.5 x ULN - 5 x 
ULN 
>5 x ULN - 10 x 
ULN 
>10 x ULN 
CREATININE 
increased 
>ULN - 1.5 x 
ULN 
>1.5 - 3.0 x 
baseline;  
>1.5 - 3.0 x ULN 
>3.0 x baseline;  
>3.0 - 6.0 x ULN 
>6.0 x ULN 


 
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Laboratory 
parameters of 
interest1 
Grade 
1 
2 
3 
4 
GGT increased 
>ULN - 2.5 x 
ULN if baseline 
was normal; 2.0 - 
2.5 x baseline if 
baseline was 
abnormal 
>2.5 - 5.0 x ULN 
if baseline was 
normal; >2.5 - 
5.0 x baseline if 
baseline was 
abnormal 
>5.0 - 20.0 x 
ULN if baseline 
was normal; >5.0 
- 20.0 x baseline 
if baseline was 
abnormal 
>20.0 x ULN if 
baseline was 
normal; >20.0 x 
baseline if 
baseline was 
abnormal 
GLUCOSE 
(Hypoglycemia) 
<LLN - 55 
mg/dL; <LLN - 
3.0 mmol/L 
<55 - 40 mg/dL; 
<3.0 - 2.2 
mmol/L 
<40 - 30 mg/dL; 
<2.2 - 1.7 
mmol/L 
<30 mg/dL; <1.7 
mmol/L 
LDH (Blood 
lactate 
dehydrogenase 
increased) 
>ULN 
- 
- 
- 
POTASSIUM 
(Hyperkalemia) 
>ULN – 5.5 
mmol/L 
>5.5 – 6.0 
mmol/L;  
>6.0 – 7.0 
mmol/L 
>7.0 mmol/L 
POTASSIUM 
(Hypokalemia)3 
<LLN – 3.0 
mmol/L 
 
<3.0 – 2.5 
mmol/L 
<2.5 mmol/L 
SODIUM 
(Hypernatremia) 
>ULN – 150 
mmol/L 
>150 - 155 
mmol/L 
>155 - 160 
mmol/L 
>160 mmol/L 
SODIUM 
(Hyponatremia)4 
<LLN - 130 
mmol/L 
- 
120-129 mmol/L 
<120 mmol/L 
INR increased5 
>1.2 – 1.5 
>1.5 – 2.5  
>2.5 
- 
Eosinophils6 
>ULN and 
>Baseline 
- 
- 
- 
1. 
Removal of cardiac troponin I or T increased gradings.  Specifically Grade 1 indicated by levels above the 
upper limit of normal and below the level of myocardial infarction as defined by the manufacturer and 
Grade 3 indicated by levels consistent with myocardial infarction as defined by the manufacturer 
2. 
Removal of Grade 3 defined as transfusion indicated by transfusion and grade 4 indicated by Life-
threatening consequences or urgent intervention indicated 
3. 
Removal of Grade 2 defined as symptomatic with <LLL – 3.0 mmol/L 
4. 
Removal of Grade 2 defined as 125-129 mmol/L and asymptomatic, Grade 3 is re-defined as 120-129 
mmol/L i.e . conservatively including the grade 2 criteria of “125-129 mmol/L and asymptomatic” into the 
Grade 3 criteria of “120-124 mmol/L regardless of symptoms; 125-129 mmol/L symptomatic” as 
asymptomatic/symptomatic is not collected. 
5. 
Removal of Grade 1 indicated by >1 – 1.5 x baseline if on anticoagulation; Grade 2 indicated by >1.5 – 
2.5 x baseline if on anticoagulation; and Grade 3 indicated by >2.5 x baseline if on anticoagulation. 
6. 
Removal of Grade 3 defined as steroids initiated 
Note: The grading will be rederived for any laboratory parameters with modifications from the CTCAE V5 
 
For lab tests that are not gradable by modified CTCAE v5, summaries of worst-case 
changes from baseline with respect to normal range will be generated.  Decreases to low, 
changes to normal or no changes from baseline, and increases to high will be summarized 
for the worst-case post-baseline.  If a participant has a decrease to low and an increase to 


 
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high during the same time interval, then the participant is counted in both the “Decrease 
to Low” categories and the “Increase to High” categories. 
Separate summary tables for haematology, and chemistry laboratory tests will be 
produced.  Liver function laboratory tests will be included with chemistry lab tests. 
In addition, if any AE of CRS is reported a summary table of hematology, CRP, D-dimer 
and ferritin will be produced. 
Summaries of hepatobiliary laboratory events will be provided in addition to what has 
been described above.  Possible Hy’s law cases defined as any elevated alanine 
aminotransferase (ALT) ≥ 3 × upper limit of normal (ULN) and total bilirubin ≥ 2 × ULN 
(>35% direct bilirubin) or ALT ≥ 3 × ULN and INR > 1.5 will be presented in a plot of 
maximum ALT vs maximum total bilirubin. 
4.5.3.3. 
Vital Signs 
Summaries of worst-case systolic blood pressure (SBP), diastolic blood pressure (DBP) 
and heart rate relative to Potential Clinical Importance (PCI) post-baseline relative to 
baseline will be provided.  This will include all post-baseline assessments. 
Potential Clinical Importance ranges are defined as follows: 
Vital Sign 
Parameter 
Units 
Clinical Concern Range 
Lower 
Upper 
Absolute 
Systolic blood pressure 
mmHg 
<80 
>170 
Diastolic blood pressure 
mmHg 
<45 
>110 
Heart Rate 
bpm 
<40 
>100 
Change from Baseline 
Systolic blood pressure 
mmHg 
≥30↓ 
≥30↑ 
Diastolic blood pressure 
mmHg 
≥20↓ 
≥20↑ 
 
Worst case summaries will display the number and percentage of participants with 
changes in the absolute values “To Low”, “To w/in Range or No Change” or “To High” 
post baseline relative to baseline.  Participants will be reported in both the "To Low" and 
"To High" categories if both of these changes are observed post-baseline.  Participants 
will only be reported in the “To w/in Range or No Change” category if they experience 
no “To Low” or “To High” changes post-baseline.  The summaries will also display the 
number and percentage of participants with “PCI Increase from Baseline”, “PCI Decrease 
from Baseline” or “No PCI Change from Baseline”.  Participants will be reported in the 
"PCI Increase from Baseline" (/"PCI Increase from Baseline") categories if the upper 
(/lower) change from baseline clinical concern range value is observed, respectively.  
Participants will be reported in both the “PCI Increase from Baseline” and “PCI Decrease 
from Baseline” categories if both of these changes are observed post-baseline.  
Participants will only be reported in the “No PCI Change from Baseline” category if they 


 
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experience no “PCI Increase from Baseline” or “PCI Decrease from Baseline” changes 
post-baseline. 
In addition, summaries of change from baseline in systolic blood pressure (SBP), 
diastolic blood pressure (DBP), respiratory rate and temperature over Days 1 to 28 will 
be provided. 
4.5.3.4. 
ECG 
A summary of the number and percentage of participants with ECG findings will be 
summarized by treatment.  The ECG findings to be summarized are the ECG 
interpretation and clinical significance of abnormal ECGs.  Participants with missing 
baseline values will be excluded from this summary. 
4.6. 
Other Analyses 
4.6.1. 
Pharmacokinetics (PK) 
Pharmacokinetic concentrations will be listed and summarised by visit. 
4.6.2. 
Population Pharmacokinetics 
Sparse PK samples will be analysed using population PK approach.  Otilimab PK data 
from this study will be combined with PK data after IV administration from 4 studies in 
healthy volunteers, RA and MS adult participants.  The PK parameters reported will be 
clearance, volume of distribution and AUC. 
Further details will be provided in a supplemental analyses plan. 
4.6.3. 
Pharmacodynamics 
Pharmacodynamic biomarkers measures including free GM-CSF, key markers of 
inflammation including, but not limited to CRP, serum ferritin and inflammatory cytokines 
as appropriate will be listed and summarised by visit. 
Further details will be provided in a supplemental analyses plan. 
4.6.4. 
Pharmacokinetics/Pharmacodynamics 
Exposure-response relationship for key efficacy, safety and PD endpoints will be 
explored graphically and if data permits (range of otilimab concentrations observed in 
this study is wide enough) will be followed by model-based analysis. 
Further details will be provided in a supplemental analyses plan. 
4.7. 
Interim Analyses 
Primary Completion of the study will follow the last subject’s last assessment at the time 
point of the primary endpoint (Day 28), unblinded analysis of the primary endpoint will 


 
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be conducted by the main biostatistics group and will not be considered an interim 
analysis. 
There will be no interim analyses to assess futility and efficacy.  However, an IDMC will 
actively monitor in-stream interim unblinded safety data to make recommendations to 
GSK as per IDMC charter for Part 2. 
Details regarding the IDMC process and analysis will be available in relevant IDMC 
documents prior to the first participant’s visit. 
4.8. 
Changes to Protocol Defined Analyses 
The following clarifications, detailed in Table 3 are made from the originally planned 
statistical analysis specified in the protocol (Amendment 3, GSK Document Number 
TMF-11795607, Dated: 25- JAN-2021). 
Table 3 
Changes and Clarifications to Protocol Defined Analysis Plan 
Protocol Defined Analysis 
SAP Defined Analysis 
Rationale for Changes or 
Clarifications 
• 
Stratified by gender 
• 
Stratified by sex 
• 
The stratification factor of 
gender (male/female) was 
unintendedly used 
interchangeably for the sex 
characteristics that are 
biologically defined. To avoid 
confusion sex will be used 
from this point forward. 
• 
N/A 
• 
Additional exploratory 
endpoints added (Change 
from Baseline in 
Concentration of Inspired 
Oxygen (FiO2), Oxygen Use 
following Discharge to Non-
Hospitalized Residence, 
Number of Days in Each 
Category of Clinical Status up 
to Day 60, Post-Baseline 
Glucocorticoid Use up to Day 
60)) 
• 
Additional exploratory 
analyses were requested to 
quantify resource, specifically 
around oxygen and 
glucocorticoid use  
• 
N/A 
• 
Clarification of SAP text 
regarding safety summaries 
and the addition of 
summaries of non-fatal 
adverse events 
• 
Most safety summaries were 
produced already just not well 
described 
• 
8.2 Sample Size Section refers to 
a one-sided test and 2.5% 
significance level. 
• 
The SAP clarifies that all 
analyses in part 2 will use 
two-sided significance tests 
at the 5% level (Section 2)  
• 
Using two-sided tests will 
simplify interpretation of the 
results.  This is a clarification 
rather than a change to the 
pre-specified analysis. 
• 
8.4.1 General Considerations (for 
Statistical Analysis) description of 
covariates does not include age 
• 
The SAP states that age will 
be included as a continuous 
covariate in the primary 
analysis in Section 4.2.2 Main 
• 
Clarification: While ‘age 
group’ was specified in part 1, 
part 2 does not use age 
group, including age as a 


 
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Protocol Defined Analysis 
SAP Defined Analysis 
Rationale for Changes or 
Clarifications 
• 
8.4.2 Primary Endpoint (Statistical 
Analysis) description of covariates 
includes ‘age group’ 
Analytical Approach and 
Section 4.1.6.1 Covariates 
continuous covariate is 
expected to increase the 
precision of estimates. 
 
5. 
SAMPLE SIZE DETERMINATION 
For Part 2: 
A sample size of 346 participants will provide approximately 80% power to detect a 
difference of 15% in the proportion of participants alive and free of respiratory failure at 
a one-sided 2.5% significance level and an assumed placebo response rate of 45%.  The 
minimal detectable effect for this design this design is 10.6%. 
 


 
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6. 
SUPPORTING DOCUMENTATION 
6.1. 
Appendix 1 Abbreviations and Trademarks 
6.1.1. 
List of Abbreviations 
Abbreviation 
Description 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ANCOVA 
Analyses of Covariance 
AUC 
Area Under the Curve 
BIPAP 
Bilevel Positive Airway Pressure 
CL 
Clearance 
COVID-19 
Corona Virus Disease 2019 
CPAP 
Continuous Positive Airway Pressure 
CRP 
C-Reactive Protein 
CRS 
Cytokine Release Syndrome 
CTCAE 
Common Terminology Criteria for Adverse Events 
DBP 
Diastolic Blood Pressure 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Record Form 
FCS 
Fully Conditional Specification 
FiO2 
Concentration of Inspired Oxygen 
FU 
Follow-up 
GM-CSF 
Granulocyte-macrophage colony-stimulating factor 
GSK 
GlaxoSmithKline 
ICE 
Inter-Current Events 
ICH 
International Conference on Harmonization 
ICU 
Intensive Care Unit 
IDMC 
Independent Data Monitoring Committee  
IDSL 
Integrated Data Standards Library 
IND 
Investigational New Drug 
IRT 
Interactive Response Technology 
IV 
Intravenous 
MAR 
Missing at random 
MCMC 
Markov Chain Monte Carlo 
MI 
Multiple imputation 
MITT 
Modified Intent-To-Treat 
MS 
Multiple Sclerosis 
OPS 
Output and Programming Specification  
PCI 
Potential Clinical Importance 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PT 
Preferred Term 
RA 
Rheumatoid Arthritis 
RMST 
Restricted Mean Survival Time 


 
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Abbreviation 
Description 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SDTM 
Study Data Tabulation Model 
SOC 
System Organ Class 
SOFA 
Sequential Organ Failure Assessment 
SpO2 
Blood Oxygen Saturation 
SRT 
Safety Review Team 
ULN 
Upper Limit of Normal 
WHO 
World Health Organisation 
6.1.2. 
Trademarks 
Trademarks of the GlaxoSmithKline 
Group of Companies 
 
Trademarks not owned by the 
GlaxoSmithKline Group of Companies 
None 
 
None 
 
 
 


 
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6.2. 
Appendix 2: Statistical Modelling 
6.2.1. 
Multiple Imputation 
Multiple imputation will be utilized to impute data that is missing following intercurrent 
events as detailed in the endpoint derivations. 
For endpoints that are derived from the clinical status ordinal scale, as shown below, 
missing data will first be imputed on the ordinal scale prior to deriving the binary 
endpoints: 
• All-cause Mortality 
• Alive and Free of Respiratory Failure 
• Alive and Independent of Supplementary Oxygen 
For other endpoints, missing data will be imputed directly on the binary endpoint. 
A monotone logistic regression imputation will be performed on both binary and ordinal 
endpoints adjusting for treatment and the analyses covariates.  
This will be performed in a stepwise fashion, where each visit will be imputed from the 
selected visits preceding it, such that intermediate missing data (data that is between two 
non-missing values) will be imputed based only on the data that precedes it. 
Death will always be considered a permanent event, such that if a subject is imputed to 
have died, missing data succeeding it will always be assigned the state of ‘died’. 
As it is expected that the data may have either a complete separation pattern or a quasi-
complete separation pattern, observations will be added to each response group and then 
this augmented data will be used to fit a weighted logistic regression as proposed by 
White (2010) 
If the logistic regression step fails to converge despite augmenting the likelihood, then a 
discriminant function [Brand, 1999] may be used in place of the logistic function. 
A sufficient number of imputations will be performed to ensure the stability of the 
estimates, 10,000 imputation will be used.  The results of analysis from each complete 
imputed dataset will be combined using Rubin’s rule.  Table 4 details the models, 
covariates and the seed to be used for the analyses. 
For subgroup analyses the multiple imputation model will be identical to the main 
endpoint analyses and the interaction term will be added into the analysis step.  The chi-
squared test statistic of the interaction term will be pooled using the procedure of Rubin  
(1987) and Li (1991). 


 
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Table 4 
Multiple Imputation Specifications  
Endpoint  
Covariates 
Post-Baseline 
Timepoints Included in 
Prediction Model 
Initial 
Seed 
Participants alive and free of respiratory 
failure at Day 7, 14, 28, 42, and 60. 
 
All-cause mortality at Day 28, 60. 
 
Participants alive and independent of 
supplementary oxygen at Day 7, 14, 28, 42, 
and 60 
See 
Section 
4.1.6.1 
Days 7,14,28,42 and 60 
122 
If the number of participants is small within a category of a covariate, then the covariate 
categories may be refined.  If the category cannot be refined further, then the covariate may be 
included as a continuous measure.   
 
The seeds were generated using the following code: 
DATA seeds; 
  DO i=1 to 1; 
    seed=int(10000*ranuni(21409402)); 
    OUTPUT; 
  END; 
RUN; 
 
If additional seeds are required, then the initial seed as specified will be incremented by 
one. 
6.2.2. 
Tipping Point 
The following seeds will be used for the tipping point analyses: 
Endpoint  
Initial Seed 
Participants alive and free of respiratory failure at Day 28 
1227 
Participants alive and free of respiratory failure at Day 60 
28903 
All-cause mortality at Day 28 
29843 
All-cause mortality at Day 60 
87712 
 
The seeds were generated using the following code: 
DATA seeds; 
  DO i=1 to 4; 


 
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    seed=int(100000*ranuni(21409402)); 
    OUTPUT; 
  END; 
RUN; 
 
6.2.3. 
Time to Event Model Checking 
For the Cox proportional hazards model, the proportional hazards assumption will be 
assessed prior to model fitting using the following methods: 
• Plot of log(-log(survival)) versus log(time) by treatment group: A non-parallel 
pattern is an indication of violation of the proportional hazard assumption. 
• Plot of weighted Schoenfeld residuals versus time: A non-zero slope is an 
indication of a violation of the proportional hazard assumption. 
• Evaluation of time-dependency of treatment effect by adding an interaction term 
of treatment and time in the Cox model.  If the interaction term is significant (p< 
0.05), it is considered that the proportional hazards assumption is violated. 
If one or more of the procedures above demonstrates clear violation of the proportional 
hazards assumption, it will be considered the proportional hazards assumption does not 
hold. 
6.2.4. 
Count Data Model Checking 
Distributional assumptions underlying the model used for analysis will be checked.  If 
there are any departures from the distributional assumptions, alternative models may be 
explored as sensitivity analyses. 
 
 


 
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6.3. 
Appendix 3: Selected Considerations for Data Analyses and 
Data Handling 
6.3.1. 
Assessment Windows 
All data, except efficacy data, laboratory assessments, and vital signs assessments will be 
reported according to the nominal time of clinic visits and assessments as specified in the 
protocol.  Laboratory and vital signs assessments will be analyzed based on the visit 
information recorded in the eCRF.  Data for unscheduled visits will be assigned to a 
scheduled visit if the visit date falls within the corresponding visit window as specified 
below. For statistical analysis it is important to keep the intermediate data, so for efficacy 
data, visit slotting will be conducted in addition to the actual timepoint.  Lab, vital signs, 
and efficacy data will be slotted according to the windows specified below.  Where data 
is collected daily, this will be analyzed based on the data recorded in the eCRF.   
In case of multiple assessments slotting to the same visit, nominal visit will take 
precedence.  If two assessments slot to the same visit and does not include the nominal 
visit, then the one closest to the nominal visit will take precedence with the last 
assessment taking precedence it they are equidistant from the nominal visit. 
Analysis 
Set / 
Domain 
Parameter (if applicable) 
Target  
Analysis Window 
Analysis 
Timepoint 
Beginning 
Timepoint 
Ending 
Timepoint 
LAB 
 
All 
 
Day 4 
Day 3 
Day 5 
4 
Day 7 
Day 6 
Day 8 
7 
Day 14 
Day 13 
Day 15 
14 
Day 28 
Day 27 
Day 29 
28 
Vital Signs 
 
Blood pressure, pulse, 
respiratory rate and temperature 
Day 4 
Day 3 
Day 5 
4 
Day 7 
Day 6 
Day 8 
7 
Day 14 
Day 13 
Day 15 
14 
Day 28 
Day 27 
Day 29 
28 
Efficacy 
 
Ventilation Status, Clinical Status, 
signs and symptoms of COVID-19 
 
Day 4 
Day 3 
Day 5 
4 
Day 7 
Day 6 
Day 8 
7 
Day 14 
Day 12 
Day 16 
14 
Day 28 
Day 26 
Day 30 
28 
Day 42 
Day 40 
Day 44 
42 
Day 60 
Day 53 
Day 67 
60 
 
 
6.3.2. 
Derived and Transformed Efficacy Data 
6.3.2.1. 
Ventilation Status 
Ventilation status as shown below, will be derived for Days 1-60 based on the log-based 
collection (start and end dates/time).  


 
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Code 
Decode 
1 
None 
2 
Low flow oxygen therapy 
3 
High-flow oxygen therapy (>= 15 L/min) 
4 
Non-invasive mechanical ventilation 
5 
Invasive mechanical ventilation 
6 
Death 
99 
Other 
 
Ventilation status at baseline is defined as the ventilation status at the time of dosing, if 
no ventilation is recorded then the last ventilation use will be assigned to baseline. If 
multiple ventilation types are being used at the start of baseline the worst case is 
assumed.  
For post-baseline the worst-case ventilation on a day will be used, Other will only be 
considered worst-case if no other ventilation is recorded. 
Ventilation statuses with missing end-dates will be assumed ongoing. 
Ventilation status will only be missing after last contact for subjects who have withdrawn 
from the trial, such that participants with no open ventilation logs will be assumed to 
have Ventilation=None. 
Other will not be included in figures 
6.3.2.2. 
Clinical Status Ordinal Scale 
Additional derivation of clinical status will be performed. If subject dies then their 
clinical status will be recorded as 8-Death from date of death to Day 60 inclusive, this 
will override any collected clinical status. 
Otherwise if clinical status is missing and the assessment day is prior to last contact with 
participant, then the following rules will apply: 
 
Category 
Rule 
8 - DEATH 
Date of death <= date of assessment 
7 - HOSPITALIZED, 
MECHANICAL 
VENTILATION+ADDITIONAL 
ORGAN SUPPORT 
Ventilation = “INVASIVE MECHANICAL VENTILATION”  
and additional support includes: 
“EXTRACORPOREAL MEMBRANE OXYGENATION“ 
“RENAL REPLACEMENT THERAPY (RRT)/DIALYSIS” 
“INOTROPES/VASOPRESSORS”  
6 - HOSPITALIZED, 
INTUBATION AND 
MECHANICAL VENTILATION 
Ventilation = “INVASIVE MECHANICAL VENTILATION”  
and does not meet the classification for additional organ support 


 
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Category 
Rule 
5 - HOSPITALIZED, HIGH-
FLOW OXYGEN(>=15L/MIN), 
CPAP, BIPAP, NIV 
Ventilation is: 
“NON-INVASIVE MECHANICAL VENTILATION” or 
“HIGH-FLOW OXYGEN THERAPY (>=15 L/MIN)” 
4 - HOSPITALIZED, LOW-FLOW 
OXYGEN BY MASK OR NASAL 
PRONGS 
Ventilation = “LOW-FLOW OXYGEN THERAPY”  
and date of discharge to non-hospitalized residence is missing or 
greater than date of assessment 
3 - HOSPITALIZED, NO 
OXYGEN THERAPY 
Date of assessment < date of discharge to non-hospitalized residence 
and 
Date of assessment > date of last oxygen usage 
2 - NON-HOSPITALIZED, 
LIMITATION OF ACTIVITY  
Date of assessment > date of discharge to non-hospitalized residence  
and participant has not been re-hospitalized  
and date of assessment > date of last oxygen usage  
and does not meet the classification for group 1. 
1 - NON-HOSPITALIZED, NO 
LIMITATION OF ACTIVITY 
Date of assessment > date of discharge to non-hospitalized residence  
and participant has not been re-hospitalized  
and date of assessment > date of last oxygen usage  
and last and subsequent recorded assessment is “1 - NON-
HOSPITALIZED, NO LIMITATION OF ACTIVITY”. 
 
All non-Death derived values will be flagged in the dataset. 
 
 


 
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6.3.2.3. 
Fraction of Inspired Oxygen (FiO2) 
FiO2 may be derived from oxygen flow rate. For participants not yet discharged from 
investigator site, if a participant has missing FiO2 who have reported any of the following 
ventilation procedures on that day: 
• HIGH-FLOW OXYGEN THERAPY 
• LOW-FLOW OXYGEN THERAPY  
 
Then FiO2 will be derived from Oxygen flow rate using the formula:  
 
FiO2=min(24+(Oxygen flow rate-1)*4, 100) 
 
This is consistent with the reference that for 1 L/min (Oxygen flow rate) the FiO2 is 24% 
then thereafter the FiO2 increases by 4% for every 1 L/min increase of oxygen flow rate, 
(or 2% for every 0.5 L/min) up to a maximum of 100%. 
 
FiO2 will not be derived if participants are using non-invasive or invasive mechanical 
ventilation 
6.3.2.4. 
Vital Signs Temperature Standardisation 
Temperatures will be converted to core temperature (Rectum or Tympanic 
membrane/Pulmonary artery branch/Bladder/Esophagus/Nasopharynx/Brain) using the 
ratio of pyrexia threshold.  
Location 
Pyrexia Threshold 
Core Temperature 
Equivalent 
Skin 
>36.3°C 
>37.8°C 
Axilla 
>36.6°C 
>37.8°C 
Sublingual region 
>37.2°C 
>37.8°C 
Tympanic membrane 
>37.8°C 
>37.8°C 
Core (brain, bladder, 
esophagus, nasopharynx, 
pulmonary artery branch, 
rectum) 
>37.8°C 
>37.8°C 
Unknown 
>36.3°C (Minimum Pyrexia 
Threshold) 
>37.8°C 
 
For example, to convert Axilla temperature to core temperature equivalent, divide the 
Axilla temperature by the Axilla pyrexia threshold (36.6) then multiply by the core 
temperature pyrexia threshold (37.8). 
 


 
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6.4. 
Appendix 4: Study Population Analysis 
6.4.1. 
Overview of Planned Study Population Analyses 
The study population analyses will be based on the “Enrolled”, “Screened” or “Safety” 
populations.  
Study population analyses including analyses of subject’s disposition, protocol 
deviations, demographic and baseline characteristics, prior and concomitant medications, 
and study intervention compliance will be based on GSK Core Data Standards. 
6.4.2. 
Subject Disposition 
A summary of the number of subjects in each of the analysis sets described in Section 3 
Analysis Sets will be provided. In addition, the “Modified Intent-To-Treat” (MITT) 
population will be further subset into: 
• MITT ICU (admitted to ICU at baseline),  
• MITT Not ICU (not admitted to ICU at baseline),  
• MITT IMV (invasively mechanically ventilated at baseline),  
• MITT Not IMV (not invasively mechanically ventilated at baseline)  
A summary of subject status and reason for study withdrawal will be provided. This 
display will show the number and percentage of subjects who completed the study and 
who withdrew from the study, including primary reason for study withdrawal.  
The number of subjects enrolled by site will be summarized. 
A listing of study withdrawal discontinuation will be generated. The listing will include 
primary reasons for study withdrawal.  
6.4.3. 
Demographic and Baseline Characteristics 
The demographic characteristics  baseline disease characteristics, and randomization 
stratification will be summarized. Demographic characteristics include age, age group, 
age subgroup, race, ethnicity, sex, baseline body weight, height, and BMI. An additional 
summary of race (American Indian or Alaskan Native, Asian, Black or African 
American, Native Hawaiian or Other Pacific Islander, White, and Mixed Race) and racial 
combinations will be provided.  
Baseline disease characteristics include ICU status, ventilation status and clinical status at 
baseline. Randomization strata include sex, clinical status at baseline, and combination of 
sex and clinical status at baseline.  
An additional summary of age ranges using the EMA clinical trial results disclosure 
requirement categories will be produced. 


 
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6.4.4. 
Medical Conditions 
Medical conditions will be summarized using counts and percentages by past and current 
conditions for the following categories: any condition, any cardiovascular risk factors, 
any COVID-19 prognostic factors, and other conditions. 
6.4.5. 
COVID-19 Signs and Symptoms 
COVID-19 Signs and Symptoms (e.g. cough, sore throat, rhinorrhea) will be summarized 
at admission and baseline.  
6.4.6. 
Protocol Deviations 
Important protocol deviations will be summarized using counts and percentages by the 
following categories: any important protocol deviations, informed consent, eligibility 
criteria not met, not withdrawn after developing withdrawal criteria, excluded medication 
(vaccine or device), and assessment or time point completion.  
6.4.7. 
Pre-Treatment Hospitalization and Time in ICU 
The number of days in the hospital up to dosing will be summarized as counts and 
percentages for the following: mean, median (IQR), min, and max. The counts and 
percentages for the days in hospital will also be provided for the following subcategories: 
0 days, 1- < 7 days, 7 - < 14 days, and ≥ 14 days.  
In addition, the number of subjects in the ICU at baseline will be summarized as counts 
and percentages for the following: mean, median (IQR), min, and max. The counts and 
percentages for the subjects in the ICU at baseline will also be provided for the following 
subcategories: 0 days, 1- < 7 days, 7 - < 14 days, and ≥ 14 days.  
6.4.8. 
Subject Residence Prior to Hospital Admission 
Subject residence prior to hospital admission will be summarized by counts and 
percentages for the following categories: independent or community dwelling, long-term 
care facility, and other. 
6.4.9. 
Prior and Concomitant Medication 
Concomitant medications will be coded using both the GSK Drug and WHO Drug coding 
dictionaries.  However, they will only be summarized using the GSK Drug dictionary.  In 
the summary of concomitant medications, the ingredients will be summarized by the 
Anatomical Therapeutic Chemical (ATC) level 1 classification and ingredient.  
A summary of the number of patients with Pre-Treatment Use and Post-treatment Use of 
known COVID-19 medications will be produced where the known COVID-19 
medications are as listed below: 
• Glucocorticoids (including Dexamethasone) 
• COVID-19 anti-viral drugs (Remdesivir & Favipiravir) 


 
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• Immunosuppressants (including aIL-6 therapies) 
In addition to the categories above, Remdesivir, Dexamethasone and aIL-6 therapies will 
be summarized alone. A review of the list of unique terms will be performed prior to 
unblinding the main study to confirm the list is inclusive. 
First initiations of Remdesivir and Dexamethasone at baseline by treatment and clinical 
status will be graphically summarized by percentage in the following categories (none, 
pre-only, pre and continued post, Day 1-Day 4, and > Day 5). 
6.4.10. 
Treatment Exposure 
The duration of administration of study treatment (mins) will be calculated and listed.  
Adjustments from planned treatment and underlying reasons will be summarized 
categorically. 
6.5. 
Appendix 5 SAP Amendments 
Overall 
Changes to the protocol defined analysis as described in Table 3  
Overall 
Other minor, grammatical and typographical corrections to improve readability 
Section 1.1.2 
Clarification of secondary endpoint Intercurrent event strategy (per regulatory 
feedback) 
Section 2.1 
Prioritization of the listed binary endpoints over the listed time-to-event endpoints in 
the testing hierarchy 
Section 4.1.6.2 
Addition of ICU Status at Baseline as a subgroup 
Section 4.1.6.2 
Addition of age as a subgroup 
Section 4.2.4.2 
Clarifications of the supplementary estimand for COVID-19 Medications 


 
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Section 4.3.3.2 
Addition of sensitivity analyses for follow-up window for time-to-event analyses with 
28 days follow-up 
Section 4.5.2.3 
Additional safety summaries will be produced for the following: Non-fatal AEs and 
SAEs by PT and SOC, Fatal AEs, Fatal study intervention-related AEs, AEs leading to 
Discontinuation, AEs leading to Dose Interruptions 
Section 4.5.3.1 
Additional summaries of deaths 
Section 6.2.2 
Clarifications regarding tipping point analyses 
 


 
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7. 
REFERENCES 
Brand JPL. Development, Implementation, and Evaluation of Multiple Imputation 
Strategies for the Statistical Analysis of Incomplete Data Sets. Ph.D. thesis, Erasmus 
University 1999. 
Carpenter JR, Kenward MG. Multiple Imputation and its Applications. Wiley 2012. 
Ge, Murray, Meyer, et al. Covariate-adjusted difference in proportions from clinical trials 
using logistic regression and weighted risk differences. Drug Information Journal 
2011;45:481-93. 
Lan KKG, DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika 
1983;70:659-63. 
Li K-H, Meng X-L, Raghunathan TE, Rubin DB. Significance levels from repeated p-
values with multiply-imputed data. Statistica Sinica 1991;1:65-92. 
Permutt T, Li F. Trimmed means for symptom trials with dropouts. Pharm Stat 
2017;16:20-8. 
Rubin D.B. Multiple Imputation for Nonresponse in Surveys. John Wiley and Sons 1987. 
TMF-11795607 A randomized, double-blind, placebo-controlled, study evaluating the 
efficacy and safety of otilimab IV in patients with severe pulmonary COVID-19 related 
disease. Effective Date 25-JAN-2021 
Van Buuren, S. Multiple Imputation of Discrete and Continuous Data by Fully 
Conditional Specification. Statistical Methods in Medical Research 2007;16:219–242. 
White, I. R., Daniel, R., and Royston, P. (2010). “Avoiding Bias Due to Perfect 
Prediction in Multiple Imputation of Incomplete Categorical Variables.” Computational 
Statistics and Data Analysis 54:2267–2275 
WHO. https://www.who. int/blueprint/priority-diseases/key-action/COVID-
19_Treatment_Trial_Design_Master_Protocol_synopsis_Final_18022020.pdf, 2020. 
 


 
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The GlaxoSmithKline group of companies 
 
214094 
1 
 
Division 
: Worldwide Development 
Information Type 
: Statistical Analysis Plan (SAP) 
TITLE PAGE 
Protocol Title: A randomized, double-blind, placebo-controlled, study evaluating the 
efficacy and safety of otilimab IV in patients with severe pulmonary COVID-19 related 
disease. 
Protocol Number: 214094 
Compound Number: GSK3196165 (otilimab) 
Short Title: Investigating otilimab in patients with severe pulmonary COVID-19 related 
disease. 
Sponsor Name: 
GlaxoSmithKline Research & Development Limited 
980 Great West Road 
Brentford 
Middlesex, TW8 9GS 
UK 
Regulatory Agency Identifier Number(s) 
Registry 
ID 
IND 
149754 
EudraCT 
2020-001759-42 
 
 
 
 
 
 
Copyright 2020 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.


 
C O N FI D E N TI A L  
 
 
 
2 1 4 0 9 4  
2  
 
S A P  A ut h or(s):  
A ut h or  
Pri nci pal Statisticia n, Bi ostatistics  
 
S A P  Te a m Re vie w C o nfir m ati o ns  ( E-m ail C o nfir m ati o n) : 
A p pr o ver  
Date of E -m ail C o nfir mati o n  
0 7 -Dec -2 0 2 0  
De vel o p me nt Scie ntist  
0 8 -Dec -2 0 2 0  
P h ysicia n, Disc o v er y Me dici nes  
0 7 -Dec -2 0 2 0  
 P har m a Safet y 
0 4 -Dec -2 0 2 0  
Pri nci pal  Pr o gra m mer  
 
Cli nic al St atistics Li ne A p pr o v al  (e Si g n at ure): 
A p pr o ver  
 Bi ost atistics 
 
 
 
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


 
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TABLE OF CONTENTS 
PAGE 
1. 
INTRODUCTION ...................................................................................................... 8 
1.1. 
Changes to the Protocol Defined Statistical Analysis Plan ............................ 8 
1.2. 
Objectives, Endpoints and Estimands ......................................................... 10 
1.2.1. 
Objectives and Endpoints ............................................................ 10 
1.2.2. 
Estimands .................................................................................... 12 
1.3. 
Study Design .............................................................................................. 15 
2. 
STATISTICAL HYPOTHESES / SUCCESS CRITERIA .......................................... 17 
2.1. 
Multiple Comparisons and Multiplicity ......................................................... 17 
3. 
SAMPLE SIZE DETERMINATION ......................................................................... 18 
4. 
ANALYSIS SETS ................................................................................................... 19 
4.1. 
Protocol Deviations ..................................................................................... 19 
5. 
STATISTICAL ANALYSES ..................................................................................... 20 
5.1. 
General Considerations .............................................................................. 20 
5.1.1. 
General Methodology .................................................................. 20 
5.1.2. 
Baseline Definition ....................................................................... 21 
5.1.3. 
Multicenter Studies ...................................................................... 21 
5.1.4. 
Intercurrent Events ...................................................................... 21 
5.1.5. 
Missing Data Handling Rules ....................................................... 22 
5.1.6. 
Examination of Covariates, Other Strata and Subgroups ............. 22 
5.1.6.1. 
Covariates and Other Strata ....................................... 22 
5.1.6.2. 
Examination of Subgroups .......................................... 22 
5.2. 
Primary Endpoint(s) Analyses ..................................................................... 23 
5.2.1. 
Definition of Endpoint(s) ............................................................... 23 
5.2.2. 
Main Analytical Approach ............................................................ 24 
5.2.2.1. 
Decision Criteria ......................................................... 24 
5.2.3. 
Sensitivity Analyses ..................................................................... 25 
5.2.3.1. 
Tipping Point Analyses ............................................... 26 
5.2.4. 
Supplementary Analyses ............................................................. 26 
5.2.5. 
Subgroup Analyses ...................................................................... 26 
5.3. 
Secondary Endpoint(s) Analyses ................................................................ 26 
5.3.1. 
Endpoint Definition ....................................................................... 26 
5.3.1.1. 
All-cause Mortality at Day 60 ...................................... 26 
5.3.1.2. 
Time to All-cause Mortality up to Day 60 .................... 27 
5.3.1.3. 
Participants Alive and Free of Respiratory 
Failure at Day 7, 14, 42, and 60.................................. 27 
5.3.1.4. 
Time to Recovery from Respiratory Failure up 
to Day 28 .................................................................... 27 
5.3.1.5. 
Participants Alive and Independent of 
Supplementary Oxygen at Day 7, 14, 28, 42, 
and 60 ........................................................................ 27 
5.3.1.6. 
Time to Last Dependence on Supplementary 
Oxygen up to Day 28 .................................................. 27 
5.3.1.7. 
ICU Admission up to Day 28 ....................................... 28 
5.3.1.8. 
Time to Final ICU Discharge up to Day 28 .................. 28 


 
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5.3.1.9. 
Time to First Discharge from Investigator Site 
up to Day 60 ............................................................... 28 
5.3.1.10. Time to First Discharge to Non-Hospitalised 
Residence up to Day 60 ............................................. 28 
5.3.2. 
Main Analytical Approach ............................................................ 28 
5.3.2.1. 
Binary Endpoints ........................................................ 28 
5.3.2.2. 
Time to Event Endpoints ............................................ 29 
5.3.3. 
Sensitivity Analyses ..................................................................... 30 
5.3.3.1. 
Binary Endpoints ........................................................ 30 
5.3.3.2. 
Time to Event Endpoints ............................................ 30 
5.3.4. 
Supplementary Analyses ............................................................. 30 
5.3.5. 
Subgroup Analyses ...................................................................... 30 
5.4. 
Exploratory Endpoint(s) Analyses ............................................................... 31 
5.4.1. 
Definition of Endpoint(s) ............................................................... 31 
5.4.1.1. 
Invasive Mechanical Ventilation (if not 
previously initiated) up to Day 28 ................................ 31 
5.4.1.2. 
Time to Invasive Mechanical Ventilation (if not 
previously initiated) up to Day 28 ................................ 31 
5.4.1.3. 
Alive and Not Invasively Mechanically 
Ventilated up to Day 28 .............................................. 31 
5.4.1.4. 
Time to Definitive Extubation up to Day 28 ................. 31 
5.4.1.5. 
Recovery or Improvement of at Least 2 Points 
Relative to Baseline of Sequential Organ 
Failure Assessment (SOFA) score up to Day 
28 ............................................................................... 31 
5.4.1.6. 
Recovery or Improvement Relative to Baseline 
in Blood Oxygen Saturation (SpO2) ............................ 32 
5.4.1.7. 
Recovery or Improvement Relative to Baseline 
in Concentration of Inspired Oxygen (FiO2) ................ 33 
5.4.1.8. 
Recovery or Improvement Relative to Baseline 
in SpO2/FiO2 Ratio ...................................................... 33 
5.4.1.9. 
Oxygen-free Days up to Day 28.................................. 34 
5.4.1.10. Ventilator-free Days up to Day 28 ............................... 34 
5.4.1.11. Time to Resolution of Pyrexia (>48h) up to Day 
28 ............................................................................... 34 
5.4.1.12. Clinical Status Assessed Using an Ordinal 
Scale Assessed at Days 4, 7, 14, 28, 42, and 
60 ............................................................................... 35 
5.4.1.13. Time to Improvement of at Least 2 Categories 
Relative to Baseline in Clinical Status up to 
Day 60 ........................................................................ 35 
5.4.1.14. Change in COVID-19 Signs and Symptoms up 
to Day 60 .................................................................... 35 
5.4.2. 
Main Analytical Approach ............................................................ 35 
5.4.2.1. 
Time to Event Endpoints ............................................ 35 
5.4.2.2. 
Binary Endpoints ........................................................ 36 
5.4.2.3. 
Ordinal Endpoints ....................................................... 36 
5.4.2.4. 
Continuous Endpoints ................................................ 36 
5.4.2.5. 
Count Endpoints ......................................................... 37 
5.4.3. 
Sensitivity Analyses ..................................................................... 37 
5.4.4. 
Supplementary Analyses ............................................................. 37 
5.4.5. 
Subgroup Analyses ...................................................................... 37 


 
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5.5. 
Safety Analyses .......................................................................................... 37 
5.5.1. 
Extent of Exposure ...................................................................... 37 
5.5.2. 
Adverse Events............................................................................ 37 
5.5.2.1. 
Adverse Events of Special Interest ............................. 39 
5.5.3. 
Additional Safety Assessments .................................................... 39 
5.5.3.1. 
Laboratory Data .......................................................... 39 
5.5.3.2. 
Vital Signs .................................................................. 43 
5.5.3.3. 
ECG ........................................................................... 44 
5.6. 
Other Analyses ........................................................................................... 44 
5.6.1. 
Pharmacokinetics (PK) ................................................................ 44 
5.6.2. 
Population Pharmacokinetics ....................................................... 44 
5.6.3. 
Pharmacodynamics ..................................................................... 45 
5.6.4. 
Pharmacokinetics/Pharmacodynamics ........................................ 45 
5.7. 
Interim Analyses ......................................................................................... 45 
6. 
SUPPORTING DOCUMENTATION ....................................................................... 46 
6.1. 
Appendix 1 Abbreviations and Trademarks ................................................. 46 
6.1.1. 
List of Abbreviations .................................................................... 46 
6.1.2. 
Trademarks ................................................................................. 47 
6.2. 
Appendix 2: Changes to Protocol-Planned Analyses .................................. 48 
6.3. 
Appendix 3: Statistical Modelling ................................................................ 49 
6.3.1. 
Multiple Imputation ....................................................................... 49 
6.3.1.1. 
Adaptive Rounding ..................................................... 51 
6.3.2. 
Proportional Odds Regression Model Checking ........................... 51 
6.3.3. 
Time to Event Model Checking .................................................... 51 
6.3.4. 
Count Data Model Checking ........................................................ 51 
7. 
REFERENCES ....................................................................................................... 52 
 


 
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VERSION HISTORY 
This Statistical Analysis Plan (SAP) for study 214094 is based on the protocol 
amendment 2 (GSK Document Number 2020N436091_02) dated 02-JUL-2020. 
Table 1 
SAP Version History Summary 
SAP Version 
Approval Date 
Change 
Rationale 
Amendment 
3 
Current Version The key changes include: 
• Removal of the ~600 
participant interim analysis 
• Inclusion of interim primary 
endpoint analysis of all 
participants 
• Clarification on exploratory 
endpoints 
• Other minor, grammatical 
and typographical 
corrections to improve 
readability 
Update to the SAP in 
response to regulatory 
feedback, removal of the 
~600 participant interim 
analysis, Inclusion of 
interim primary endpoint 
analysis of all 
participants and 
clarifications.   
Amendment 
2 
30-Sep-2020 
The key changes include: 
• Inclusion of additional 
endpoints related to 
discharge from 
investigational site and 
discharge to non-
hospitalized residence  
• Inclusion of the heart rate 
potential clinical 
importance (PCI) ranges 
• Other minor, grammatical 
and typographical 
corrections to improve 
readability 
Update to the SAP in 
response to regulatory 
feedback, and 
clarifications.   
Amendment 
1 
05-Jun-2020 
The key changes include: 
• revision of the primary 
endpoint (where definition 
of “free of respiratory 
failure” is participants in 
categories 1-4 on GSK 
Ordinal Scale) in line with 
the protocol amendment 
• Inclusion of a hierarchy 
strategy for secondary 
endpoints 
• Other minor, grammatical 
Update to the SAP 
following protocol 
amendment in response 
to regulatory feedback, 
and clarifications based 
on investigator feedback.   


 
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SAP Version 
Approval Date 
Change 
Rationale 
and typographical 
corrections to improve 
readability 
Original SAP 
13-May-2020 
Not Applicable 
Original version 


 
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1. 
INTRODUCTION 
The purpose of this SAP is to describe the planned analyses to be included in the Clinical 
Study Report for Study 214094.  Details of the planned interim analyses, in addition to 
the final analyses, are provided. 
Additional detail with regards to data handling conventions and the specification of data 
displays will be provided in the Output and Programming Specification (OPS) document. 
1.1. 
Changes to the Protocol Defined Statistical Analysis Plan 
Changes from the originally planned statistical analysis specified in the protocol (GSK 
Document Number 2020N436091_02) [(Dated: 02- JUL-2020)] are outlined in Table 2. 
 
Table 2 
Changes to Protocol Defined Analysis Plan 
Protocol 
Reporting & Analysis Plan 
Statistical Analysis Plan 
Statistical Analysis Plan 
Rationale for Changes 
The study will utilize a group 
sequential design, using a Lan-
DeMets alpha-spending function 
to control the type I error with four 
interim analyses for futility, two 
early in the study where futility 
alone will be assessed, using 
Pocock analogue rules; and two 
for efficacy, at later times in the 
study and at the same time as 
futility, using the O’Brien-Fleming 
analogue rules [Lan, 1983].   
 
The study will utilize a group 
sequential design, using a 
Lan-DeMets alpha-spending 
function to control the type I 
error with three interim 
analyses for futility, two 
early in the study where 
futility alone will be 
assessed, using Pocock 
analogue rules; and one for 
efficacy, at a later time in 
the study and at the same 
time as futility, using the 
O’Brien-Fleming analogue 
rules [Lan, 1983]. 
As recruitment has completed 
prior to formal interim analyses 
number 4 (on approximately 
600 participants), it was 
decided to remove the formal 
analyses on approximately 600 
participants and continue to 
the final analyses only.  
Note: The final analyses 
boundary has been adjusted to 
carry over the alpha that would 
have been spent on the 600-
participant analysis. Hierarchy 
has been updated accordingly 
but previous boundaries were 
not amended. 
N/A 
For the primary endpoint, 
clarification has been added 
to detail that the final 
analyses will be conducted 
once all participants have 
been randomised and 
completed to Day 28 or 
withdrawn. 
Given the ongoing pandemic 
situation and the urgent unmet 
need for COVID-19 
treatments, to ensure this is 
met as soon as possible final 
analyses on the primary 
endpoint (assessed at Day 28) 
will be conducted once all 
participants have been 
randomised and completed to 
Day 28 or withdrawn. 


 
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Protocol 
Reporting & Analysis Plan 
Statistical Analysis Plan 
Statistical Analysis Plan 
Rationale for Changes 
N/A 
Included text on the 
proposed hierarchy for 
testing secondary 
endpoints, refer to Section 2 
for full details. 
To account for multiplicity a 
hierarchy has been proposed 
for testing secondary 
endpoints. 
The secondary endpoint: “Time to 
final hospital discharge up to Day 
28” 
Updated secondary 
endpoints to include:  
• Time to first discharge 
from investigational site 
up to Day 60  
• Time to first discharge 
to non-hospitalised 
residence up to Day 60 
Final hospital discharge is not 
being collected. Participants 
may be discharged to an 
intermediator hospital 
residence hence we cannot 
assume discharge from the 
investigator site is equivalent 
to discharge from hospital. 
A post go live change was 
created to capture discharge to 
a non-hospitalised residence. 
eCRF guidelines were updated 
to clarify re-hospitalisation 
refers to the investigator site. 
For exploratory endpoints on 
improvement in SOFA, Blood 
Oxygen Saturation (SpO2), 
Concentration of Inspired Oxygen 
(FiO2) and SpO2/FiO2 ratio 
Clarified exploratory 
endpoints to include 
recovery as part of 
composite strategy, i.e.: 
• Recovery or 
Improvement of at Least 
2 Points Relative to 
Baseline of Sequential 
Organ Failure 
Assessment (Sofa) 
Score up to Day 28 
• Recovery or 
Improvement Relative 
to Baseline in Blood 
Oxygen Saturation 
(SpO2), 
• Recovery or 
Improvement Relative 
to Baseline in 
Concentration of 
Inspired Oxygen (FiO2)  
• Recovery or 
Improvement Relative 
to Baseline in 
SpO2/FiO2 ratio 
Clarified exploratory endpoints 
to include recovery as part of 
composite strategy. 


 
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Protocol 
Reporting & Analysis Plan 
Statistical Analysis Plan 
Statistical Analysis Plan 
Rationale for Changes 
For exploratory endpoints on 
Time to Improvement of at Least 
2 Categories Relative to Baseline 
on an Ordinal Scale up to Day 60 
For exploratory endpoints 
on Time to Improvement of 
at Least 2 Categories 
Relative to Baseline in 
Clinical Status up to Day 60 
Clarified exploratory endpoints 
to use clinical status rather 
than ordinal scale for 
consistency 
 
1.2. 
Objectives, Endpoints and Estimands 
1.2.1. 
Objectives and Endpoints 
 
 
 
 
Objectives 
Endpoints 
Primary 
• To compare the efficacy of otilimab 
90mg IV versus placebo. 
• Participants alive and free of respiratory failure at 
Day 28. 
Secondary 
• To compare the efficacy of otilimab 
90mg IV versus placebo. 
• All-cause mortality at Day 60 
• Time to all-cause mortality at Day 60 
• Participants alive and free of respiratory failure at 
Day 7, 14, 42, and 60 
• Time to recovery from respiratory failure up to Day 
28 
• Participants alive and independent of supplementary 
oxygen at Day 7, 14, 28, 42, and 60 
• Time to last dependence on supplementary oxygen 
up to Day 28 
• Admission to ICU up to Day 28 
• Time to final ICU discharge up to Day 28 
• Time to first discharge from investigational site up to 
Day 60  
• Time to first discharge to non-hospitalised residence 
up to Day 60 
• To compare the safety and 
tolerability of otilimab 90mg IV 
versus placebo. 
• Occurrence of adverse events (AEs) [up to Day 60] 
• Occurrence of serious adverse events (SAEs) [up to 
Day 60] 


 
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Objectives 
Endpoints 
Exploratory 
• To compare the efficacy of otilimab 
90mg IV versus placebo. 
Other endpoints up to Day 28 
• 
Invasive mechanical ventilation (if not previously 
initiated) 
• 
Time to invasive mechanical ventilation (if not 
previously initiated) 
• 
Alive and not invasively mechanically-ventilated 
• 
Time to definitive extubation 
• 
Improvement of at least 2 points relative to baseline 
of Sequential Organ Failure Assessment (SOFA) 
score 
• 
Improvement relative to baseline in SpO2, FiO2, and 
SpO2/FiO2 ratio 
• 
Oxygen-free days 
• 
Ventilator-free days 
• 
Time to resolution of pyrexia (for at least 48h) 
 
Other endpoints up to Day 60 
• 
Clinical status assessed using an ordinal scale 
assessed at  
• 
Days 4, 7, 14, 28, 42, and 60 
• 
Time to improvement of at least 2 categories relative 
to baseline on an ordinal scale 
• 
Change in COVID-19 signs and symptoms 
• To determine the pharmacokinetics 
(PK) profile of otilimab. 
PK Endpoints up to Day 14 
Otilimab apparent clearance (CL/F) and other PK 
parameters as appropriate using sparse PK 
sampling 
• To determine: 
o Exposure-response. 
o Pharmacodynamic (PD) 
biomarkers. 
o Changes in key markers of 
inflammation 
PD Endpoints up to Day 28 
• Exposure-response relationship for key efficacy, 
safety and PD endpoints. 
• Key markers of inflammation including, but not limited 
to CRP, serum ferritin and inflammatory cytokines as 
appropriate. 


 
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1.2.2. 
Estimands 
Each study objective is presented below with additional information, including prespecified estimands with related attributes. 
Table 3 
Estimands 
Estimand 
Category  
Estimand 
Variable/Endpoint 
Population  
Intercurrent Event Strategy 
Treatment 
Comparison 
Primary Objective: To compare the efficacy of otilimab 90 mg IV versus placebo 
Primary  
Participants alive and free of 
respiratory failure at Day 28 
Entire trial population 
randomised and receiving 
treatment (MITT) 
Data analysed as collected (treatment policy 
strategy) 
Odds ratio and 
difference in 
proportions 
Secondary Objective: To compare the efficacy of otilimab 90 mg IV versus placebo. 
Secondary 1  All-cause mortality at Day 60 
 
Entire trial population 
randomised and receiving 
treatment (MITT) 
Data analysed as collected (treatment policy 
strategy) 
Odds ratio and 
difference in 
proportions 
Secondary 2 Time to all-cause mortality up to 
Day 60 
Entire trial population 
randomised and receiving 
treatment (MITT) 
Data analysed as collected (treatment policy 
strategy) 
Hazard ratio 
Secondary 3 Participants alive and free of 
respiratory failure at Day 7, 14, 
42, and 60 
Entire trial population 
randomised and receiving 
treatment (MITT) 
Data analysed as collected (treatment policy 
strategy) 
Odds ratio and 
difference in 
proportions 
Secondary 4 Time to recovery from 
respiratory failure up to Day 28 
 
Entire trial population 
randomised and receiving 
treatment (MITT) 
Participants who die will be censored at end of 
follow-up (composite strategy) 
 
For all other intercurrent events, the data will be 
analysed as collected (treatment policy strategy) 
Hazard ratio 


 
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Estimand 
Category  
Estimand 
Variable/Endpoint 
Population  
Intercurrent Event Strategy 
Treatment 
Comparison 
Secondary 5 Participants alive and 
independent of supplementary 
oxygen at Day 7, 14, 28, 42, and 
60 
Entire trial population 
randomised and receiving 
treatment (MITT) 
Data analysed as collected (treatment policy 
strategy) 
Odds ratio and 
difference in 
proportions 
Secondary 6 Time to last dependence on 
supplementary oxygen up to Day 
28 
Entire trial population 
randomised and receiving 
treatment (MITT) 
Participants who die will be censored at end of 
follow-up (composite strategy) 
 
For all other intercurrent events, the data will be 
analysed as collected (treatment policy strategy) 
Hazard ratio  
Secondary 7 Admission to ICU up to Day 28 
Entire trial population 
randomised and receiving 
treatment (MITT) who are not 
in ICU at time of dosing 
Participants who die will be considered to have 
been admitted to ICU (negative outcome) 
(composite strategy) 
 
For all other intercurrent events the data will be 
analysed as collected (treatment policy strategy) 
Odds ratio and 
difference in 
proportions 
Secondary 8 Time to final ICU discharge up to 
Day 28 
Entire trial population 
randomised and receiving 
treatment (MITT) who are in 
ICU at time of dosing 
 
Participants who die will be censored at end of 
follow-up (composite strategy) 
 
All other intercurrent events the data will be 
analysed as collected (treatment policy strategy) 
Hazard ratio 


 
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Estimand 
Category  
Estimand 
Variable/Endpoint 
Population  
Intercurrent Event Strategy 
Treatment 
Comparison 
Secondary 
9 
Time to first discharge 
from investigational site up 
to Day 60 
Entire trial population 
randomised and receiving 
treatment (MITT) 
Participants who die will be censored at end of follow-up 
(composite strategy) 
 
All other intercurrent events the data will be analysed as 
collected (treatment policy strategy) 
Hazard ratio 
Secondary 
10 
Time to first discharge to 
non-hospitalised residence 
up to Day 60 
Entire trial population 
randomised and receiving 
treatment (MITT) 
Participants who die will be censored at end of follow-up 
(composite strategy) 
 
All other intercurrent events the data will be analysed as 
collected (treatment policy strategy) 
Hazard ratio 
Secondary Objective: To compare the safety and tolerability of otilimab 90 mg IV versus placebo 
Secondary 
11 
Occurrence of adverse 
events (AEs) [up to Day 
60] 
 
Entire trial population 
receiving treatment 
(Safety) 
Data analysed as collected (treatment policy strategy) 
Frequency & 
Percentage of 
Participants 
Secondary 
12 
Occurrence of serious 
adverse events (SAEs) [up 
to Day 60] 
Entire trial population 
receiving treatment 
(Safety) 
Data analysed as collected (treatment policy strategy) 
Frequency & 
Percentage of 
Participants 


 
C O N FI D E N TI A L  
 
 
 
2 1 4 0 9 4  
1 5  
 
1. 3.  
St u d y D e si g n  
O ver vie w of St u d y D esi g n a n d Ke y Feat ures  
 
 
 
D esi g n F e at ur es  
T his st u dy is a m ulti -c e nter, r a n d o miz e d, do u ble-bli n d, pl ac e b o -c ontr oll e d tri al 
t o assess t he effic acy a n d saf ety of otili m a b f or th e tr e at m e nt of s ev er e 
p ul m o n ary C O VI D -1 9 r elat e d dis eas e.  Th e st u dy p op ulati o n co nsists of 
h os pitaliz e d p articip a nts with n e w o nset hyp oxi a re q uirin g si gnific a nt oxy ge n 
s u p port or r e quiri n g e arly inv asiv e m ec ha nic al v e ntil ati on ( ≤4 8 h ours b efor e 
d osi n g).  All p articipa nts will r ec eiv e sta n dar d of c ar e as p er i nstituti o nal 
pr ot oc ols, i n a d diti on t o st udy tr e at m ent.  
St u dy 
i nt erv e ntio n 
Otili m a b 9 0 m g or Pl ace b o, si n gl e i ntr ave no us i nfusi o n  
St u dy 
i nt erv e ntio n 
Assi g n m e nt  
P artici p a nts will b e r an d o miz e d 1: 1 by i nt eractiv e r esp ons e tec h nol o gy (I R T) i n 
a bli n de d m an ner t o r eceiv e eit h er a bli nd e d 1 -h our i nf usi o n of otili m a b 9 0 m g 
or pl ac e b o I V i n a d ditio n to st a n dar d of c ar e.  Particip ants will b e asses s ed 
d aily u ntil d isc h ar ge fr o m i nv esti g ator sit e ( or D ay 2 8, whic h ev er is so o ner), 
a n d f oll o w ed u p at Days 4 2 a n d 6 0 after r a n do miz ati o n.  
 
Str atific ati on –  b ase d o n th e st u dy eli gi bility crit eria, th e cli nic al st at us of th e 
p artici p a nts ent eri n g t he m ai n c o hort ( i. e. aft er th e 2 0th p articip a nt) of th e st u dy 
will b e wit hi n or din al sc al e cat e gories  ( 5 or 6) a nd also a g e gr o ups, as s h o wn 
b el o w.  
•  
 
.  A g e < 6 0 y e ars 
•  
 
.  A g e 6 0 t o <7 0 ye ars 
•  
 
.  A g e 7 0 t o <8 0 ye ars 
•  
  Age < 6 0 y e ars 
•  
  Age 6 0 t o <7 0 ye ars 
•  
  Age 7 0 t o <8 0 ye ars 
I nt eri m & Fi nal 
A n alys es  
I niti al S af ety Co h ort (first 2 0 p articip ants) 
•  
T h e first 20 p articip a nts will b e fr o m  (
 
).  Si nc e this is t h e 
C CI
C CI
C CI
C CI
C CI


 
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214094 
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first time that otilimab has been tested in participants with severe 
pulmonary COVID-19 related disease, initial dosing will be staggered, and 
safety data reviewed as follows: 
• 
The first two participants to be dosed will be randomized 1:1 
(otilimab:placebo) and monitored closely.  After approximately 24 hours, 
the clinical status of both participants will be assessed by the 
investigator(s) and then discussed with the GSK medical monitor.  If no 
safety issues are identified, and the GSK medical monitor and 
investigator(s) agree, two further participants will be allowed to be dosed. 
• 
The third and fourth participants will also be randomized 1:1 
(otilimab:placebo) and monitored closely.  After approximately 24 hours, 
the clinical status of all four participants will be assessed by the 
investigator(s) and then discussed with the GSK medical monitor.  If no 
safety issues are identified, and the GSK medical monitor and 
investigator(s) agree, recruitment and dosing of further participants will 
start. 
• 
The GSK Safety Review Team (SRT) will review available blinded safety 
data on an ongoing basis for the additional 16 participants in the initial 
safety cohort. 
• 
Safety data will be reviewed by the Independent Data Monitoring 
Committee (IDMC), as outlined in the IDMC charter. 
 
Interim Analyses 
• 
Interim analyses will be used to assess futility and efficacy.  Full details of 
timing of analyses and stopping criteria will be given in the IDMC charter. 
• 
An IDMC will actively monitor in-stream interim unblinded safety and 
efficacy data to make recommendations to GSK as per IDMC charter.  
The IDMC members will include 4-6 physicians with relevant medical 
specialist training and one statistician.  Details regarding the IDMC 
process will be available in relevant IDMC documents prior to the first 
participant’s visit. 
• 
A GSK Safety Review Team (SRT) will review the blinded safety data of 
this study at regular intervals through both initial safety and main cohort 
dosing.  Details regarding the SRT process will be available in relevant 
SRT documents.  The SRT will inform the IDMC if any safety signals are 
identified. 
 
Primary Analyses 
• 
The final analyses will be conducted once all participants have been 
randomised and completed to Day 28 or withdrawn. 
 
Final Analyses 
• 
The final analyses will be conducted once all participants have been 
randomised and completed the trial or withdrawn; or all participants 
randomised at the time at which success is declared following an interim 
analysis complete or withdrawn from the trial whichever occurs first. 
 


 
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2. 
STATISTICAL HYPOTHESES / SUCCESS CRITERIA 
The primary objective of this study is to compare the efficacy of otilimab 90 mg IV 
versus placebo in participants with severe pulmonary COVID-19 related disease. 
The study will test the null hypothesis that the difference between otilimab 90 mg and 
placebo on the proportion of participants alive and free of respiratory failure at Day 28 is 
less than or equal to zero versus the alternative hypothesis that otilimab 90 mg increases 
the proportion of participants alive and free of respiratory failure compared with placebo 
at Day 28. 
2.1. 
Multiple Comparisons and Multiplicity 
The study will utilize a group sequential design, using a Lan-DeMets alpha-spending 
function to control the type I error with three interim analyses for futility, two early in the 
study where futility alone will be assessed, using Pocock analogue rules; and one for 
efficacy, at a later time in the study and at the same time as futility, using the O’Brien-
Fleming analogue rules [Lan, 1983]. 
The testing of secondary endpoints is adjusted for multiplicity by using the following 
hierarchy: 
                
 
*The boundaries are based on the estimated amount of information at each interim.  If the 
amount included in the interim analysis differs from these values, the actual boundaries 


 
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will be determined based on the exact amount of information at the time of the interim 
analyses.  
†This boundary is based on the estimated amount of information per the planned sample 
size of N=800, it will not be updated based on the actual sample size.  
Note: The hypothesis on participants alive and free of respiratory failure at Day 14 will 
only be tested if the null hypothesis on participants alive and free of respiratory failure at 
Day 28 is rejected (i.e. primary endpoint is met).  As such the full alpha of 0.025 is 
transferred down between each endpoint/hypothesis. 
3. 
SAMPLE SIZE DETERMINATION 
A sample size of 800 participants will provide approximately 90% power to detect a 
difference of 12% in the proportion of participants alive and free of respiratory failure at 
a one-sided 2.5% significance level and an assumed placebo response rate of 45%.  The 
minimal detectable effect for this design is 7%. 
The assumed placebo response is based on data from recent publications of studies of 
patients with severe pulmonary COVID-19 related disease [Sanofi, 2020]. 


 
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4. 
ANALYSIS SETS 
Analysis Set 
Definition / Criteria 
Analyses Evaluated 
Screened  
• All participants who were screened for 
eligibility 
• 
Study Population 
Enrolled 
• 
All participants who entered the study.  
• 
Data should be reported according to the 
randomised treatment 
• 
Note: screening failures are excluded from 
the enrolled analysis set as they did not 
enter the study. 
• 
Study Population 
Safety 
• 
All participants who received study 
intervention. 
• 
Data should be reported according to the 
actual treatment received 
o If participants receive any Otilimab then 
they will be summarised according to 
“Otilimab 90mg”, including 
interrupted/incomplete infusion.   
• 
Safety  
• 
Study Population 
Modified Intent-
To-Treat (MITT) 
• 
All randomized participants who received 
study intervention 
• 
Data should be reported according to the 
randomised treatment 
• 
Efficacy 
Pharmacokinetic 
(PK) 
• 
All participants in the Safety analysis set 
who had at least 1 non-missing PK 
assessment (Non-quantifiable [NQ] values 
will be considered as non-missing values). 
• 
Data should be reported according to the 
actual treatment  
o If participants receive any Otilimab then 
they will be summarised according to 
“Otilimab 90mg”, including 
interrupted/incomplete infusion. 
• 
PK 
 
4.1. 
Protocol Deviations 
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, patient management or patient assessment) will be 
summarised. 
Protocol deviations will be tracked by the study team throughout the conduct of the 
study.  These protocol deviations will be reviewed to identify those considered as 
important as follows: 


 
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o Data will be reviewed prior to freezing the database to ensure all important 
deviations are captured and categorised in the protocol deviations SDTM 
dataset. 
o This dataset will be the basis for the summaries of important protocol 
deviations. 
A separate listing of all inclusion/exclusion criteria deviations will also be provided.  This 
listing will be based on data as recorded on the inclusion/exclusion page of the eCRF. 
 
5. 
STATISTICAL ANALYSES 
5.1. 
General Considerations 
5.1.1. 
General Methodology 
The study population analyses will be based on the “Enrolled”, “Screened” or “Safety” 
populations. The MITT Analysis Set will be used for all Efficacy analyses, and Safety 
Analysis Set will be used for all safety analyses, unless otherwise specified. 
In the case of a difference between the stratification assigned at the time of randomization 
and the data collected in the eCRF: 
• subgroups will be summarised based on the actual subgroup to which the 
participant belongs 
• covariate adjustment will be based on the randomised strata. For participants in 
the Safety Cohort First Sentinel Pair, Safety Cohort Second Sentinel Pair or 
Safety Cohort Main the randomised strata will be derived as the calculated 
stratum at dosing.   
All analyses will be adjusted for ordinal scale category at baseline (category 5 or 6 per 
randomised strata) and age group (treated as categorical variable defined by the levels 
<60 years, 60 to <70 years, 70 to <80 years per randomised strata). If the number of 
participants is small within a category of a covariate, then the covariate categories may be 
refined. If the category cannot be refined further, then the covariate may be included as a 
continuous measure.  Confidence intervals will use the 95% levels unless otherwise 
specified. 
Unless otherwise specified, continuous data will be summarized using descriptive 
statistics: n, mean, standard deviation, median, minimum and maximum.  Categorical 
data will be summarized as the number and percentage of participants in each category. 
Visit windows will be applied to Day 14, Day 28, Day 42 and Day 60, where data within 
±2 days of the target day may be used if data is not recorded on the actual day. 


 
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5.1.2. 
Baseline Definition 
For all treated participants, for all endpoints and measurements the baseline value will be 
the latest pre-dose assessment with a non-missing value, including those from 
unscheduled visits.  If time is not collected, Day 1 assessments that were noted to be pre-
dose per the Schedule of Activities are assumed to be taken prior to first dose and used as 
baseline. 
For all participants randomised but not dosed, for all endpoints and measurements the 
baseline value will be the latest assessment on or prior to the date of randomisation with a 
non-missing value, including those from unscheduled visits.   
For ventilation status, baseline ventilation status will be derived as the ventilation at the 
time of dosing, and if there are multiple ventilation types being used the worst case will 
be assumed. 
Unless otherwise stated, if baseline data is missing no derivation will be performed and 
baseline will be set to missing. 
5.1.3. 
Multicenter Studies 
It is anticipated that patient accrual will be spread thinly across centers and summaries of 
data by center would unlikely be informative and will not, therefore, be provided.   
5.1.4. 
Intercurrent Events 
In general, the following may be considered intercurrent events if not part of the endpoint 
definition: 
• Interruption or infusion stopped early and not completed 
• Use of additional medications or changes to standard or care 
• Death 
• Discharge from ICU 
• Admittance to ICU 
• Start of Ventilation 
• Termination of Ventilation 
• Independence from supplementary oxygen  
• Discharge from investigator site 
The applicable intercurrent events for each endpoint will be highlighted within in the 
endpoint definition along with the strategy for handling them. 
In general, unless otherwise specified, the handling strategy for all these intercurrent 
events will be based on a treatment policy approach; specifically, the effects estimated 
will be based on initial randomized treatment arm regardless of whether the participant 
had experienced an intercurrent event.  If possible, data will continue to be collected after 
the occurrence of the intercurrent event, until the participant either completes the study or 
withdraws from the study before completion. 


 
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5.1.5. 
Missing Data Handling Rules 
Unless otherwise stated the following rules will be applied to all Primary and Secondary 
endpoints: 
• Missing data can occur due to study withdrawal or participants lost to follow-up 
before the completion of the study or due to intermittent missing values (i.e. data 
between two non-missing assessments). 
• Missing data will be imputed under a missing at random (MAR) assumption using 
a multiple imputation (MI) model, unless otherwise specified.  The MI model will 
include covariates; treatment, ordinal scale category at baseline, age group and 
baseline of the variable of interest (if appropriate).  More details will be provided 
in Appendix 3. 
• For the interim analyses, participant data will only be imputed up to their 
estimated current point in the trial based on the date of the data cut 
5.1.6. 
Examination of Covariates, Other Strata and Subgroups 
5.1.6.1. 
Covariates and Other Strata 
The list of covariates and other strata may be used in descriptive summaries and 
statistical analyses, some of which may also be used for subgroup analyses. Additional 
covariates and other strata of clinical interest may also be considered. 
• 
If the number of participants is small within a category of a covariate, then the 
covariate categories may be refined prior to unblinding the trial. 
• 
If the category cannot be refined further, then the covariate may be included as a 
continuous measure. 
Category 
Details 
Strata 
Clinical status at baseline, age group (<60 years, 60 to <70 years, 70 to <80 years) 
Covariates 
Treatment, Clinical Status at Baseline, Age Group at Baseline, and baseline of the 
variable of interest (if appropriate).   
 
5.1.6.2. 
Examination of Subgroups 
The list of subgroups may be used in descriptive summaries and statistical analyses. 
Additional subgroups of clinical interest may also be considered. 
• 
If there are less than 10 participants within a subgroup, then the subgroup categories 
may be refined prior to unblinding the trial. 
• 
If the category cannot be refined further, then descriptive rather than statistical 
comparisons may be performed for the particular subgroup. 


 
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Subgroup 
Categories  
Age Group 
1. <60 years 
2. 60 to <70 years 
3. >=70 years 
Clinical status at baseline 
1. Group 5 (Hospitalized, high-flow oxygen (≥15L/min), CPAP, 
BiPAP, non-invasive ventilation) 
2. Group 6 (Hospitalized, intubation and mechanical ventilation) 
Strata at baseline 
1. Clinical Status 5 (Hospitalized, high-flow oxygen (≥15L/min), 
CPAP, BiPAP, non-invasive ventilation) and age <60 years 
2. Clinical Status 5 (Hospitalized, high-flow oxygen (≥15L/min), 
CPAP, BiPAP, non-invasive ventilation) and age 60 to <70 
years 
3. Clinical Status 5 (Hospitalized, high-flow oxygen (≥15L/min), 
CPAP, BiPAP, non-invasive ventilation) and age >=70 years 
4. Clinical Status 6 (Hospitalized, intubation and mechanical 
ventilation) and age <60 years 
5. Clinical Status 6 (Hospitalized, intubation and mechanical 
ventilation) and age 60 to <70 years 
6. Clinical Status 6 (Hospitalized, intubation and mechanical 
ventilation) and age >=70 years 
 
5.2. 
Primary Endpoint(s) Analyses 
5.2.1. 
Definition of Endpoint(s) 
Participants are free of respiratory failure if they are in category 1, 2, 3 or 4 from the 
GlaxoSmithKline (GSK) modified ordinal scale adapted from World Health Organization 
(WHO) scale 2020 (See Table 4 - Clinical Status using Ordinal Scale). 
Participants will meet the endpoint if they are alive and free of respiratory failure at Day 
28.  As participants may be discharged from the investigator site prior to Day 28, analysis 
windows will be used to define the endpoint, further details on analysis windows will be 
provided in the Output and Programming Specification (OPS). 


 
C O N FI D E N TI A L  
 
 
 
2 1 4 0 9 4  
2 4  
 
T a bl e 4  
Cli ni c al St at u s u si n g Or di n al S c al e  
Or di n al Sc ale ( G S K m o difie d v ersi o n, a d a pt e d fr o m  W H O , 2 0 20 ver si o n) 
5. 2. 2.  
M ai n A n al yti c al A p pr o a c h  
T he pri mar y e n d p oi nt will be s u m marize d usi n g c o u nts a n d pr o p orti o ns of t he n u m ber of 
partici pa nts ali ve a n d free of res pir at or y fail ure a n d will be a nal yse d usi n g a l o gistic 
re gressi o n m o del, a dj usti n g f or treat me nt, cli nical stat us  cate g or y at b aseli n e a n d a ge 
gr o u p.  T h e o utc o me of t he m o del is a n o d ds rati o  f or t he treat me nt effect, a c o nfi de n ce 
i nter val a n d p-v al ue f or t he o d ds of i m pr o ve me nt i n pr o p orti o n of partici pa nts ali ve a n d 
free of res pir at or y fail ure at Da y 2 8, w here a n o d ds rati o > 1 i n dicates i m pr o ve me nt.  T he 
c orres p o n di n g differe nce i n pr o p orti o n a n d c o nfi d e nce i nter val will be cal c ulate d [Ge , 
2 0 1 1 ].  
I n a d diti o n, u na dj uste d relati ve ris ks a n d ris k differe nces will be calc ulat e d i n a d diti o n t o 
t he a dj uste d o d ds rati os. T hese will be pres e nte d wit h 9 5 % Wal d c o nfi de nce i nter vals. 
A n y e n d p oi nt w here a n o d ds rati o/ hazar d rati o a b o ve 1 i n dicates i m pr o ve m e nt of 
otili ma b o ver place b o, t h e i n verse o d ds rati o/ hazar d rati o/relati ve ris k will als o be 
prese nte d . 
I n a d diti o n, a detaile d s u m mar y of partici pa nt v e ntilati o n stat us ( partici pa nt die d, 
i n vasi ve mec ha nic al ve ntilati o n, BI P A P, C P A P, hi g h-fl o w o x y ge n t hera p y, l o w-fl o w 
nasal ca n n ula/ pr o n gs, l o w -fl o w o xy ge n face mas k, ot her, n o ne) will be s u m marise d f or 
eac h d a y usi n g a stac k e d bar c hart.  
5. 2. 2. 1.  
D e ci si o n Crit eri a  
G ui deli nes f or st o p pi n g t he st u d y f or f utilit y ( e. g. lac k of efficac y) or o v erall s uccess (e. g. 
e vi de nce of efficac y) bas e d o n t he pri mar y e n d p oi nt ar e detaile d bel o w.  
F utilit y will f or mall y be assesse d 2 8 da ys after a p pr o xi matel y 1 6 0 p artici p a nts ha ve bee n 
ra n d o mise d a n d will t he n be assesse d 2 8 d a ys after a p pr o xi matel y 2 8 0 , 4 0 0 a n d 6 0 0 
partici pa nts ha ve b ee n ra n d o mise d.  St u d y s u ccess will be assesse d  2 8 da ys after 
a p pr o xi matel y 4 0 0 a n d 6 0 0 partici pa nts ha ve b ee n ra n d o mise d.  
St u d y st o p pi n g criteria h a ve bee n defi ne d usi n g gr o u p se q ue ntial desi g n m et h o d ol o g y, 
usi n g a La n -D e Mets al p h a -s pe n di n g f u ncti o n t o c o ntr ol t he t y pe I err or t o 2. 5 % o ne-
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d b y 
t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.


 
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sided, with four interim analyses for futility, using Pocock analogue rules with a beta-
spend of 10%; and two for efficacy, using the O’Brien-Fleming analogue rules [Lan, 
1983]. 
Table 5 gives the stopping boundaries based on p-values (one-sided) from the analysis 
and also on the Z score scale.   The p-values or Z scores at each interim analysis will be 
plotted against the boundaries and if either the futility or efficacy success boundary is 
crossed the study should be recommended to stop. 
The boundaries are based on the estimated amount of information at each interim.  If the 
amount included in interim analyses 1-4 differs from these values, the actual boundaries 
will be determined based on the exact amount of information at the time of the interim 
analyses. Note: The boundary at interim 5 is based on the estimated amount of 
information per the planned sample size of N=800, it will not be updated based on the 
actual sample size. 
Table 5 
Formal Stopping Boundaries for Futility and Efficacy Success 
Stage / Formal 
Analysis 
Target Sample 
Size 
Efficacy Success Boundaries Futility Boundaries 
p-value 
Z-Score 
p-value 
Z-Score 
1 
160 
 
 
>0.6005 
<-0.2548 
2 
280 
 
 
>0.3938 
<0.2693 
3 
400 
<0.0015 
>2.9626 
>0.2308 
<0.7363 
4 
600 
<0.0092 
>2.3590 
>0.0744 
<1.4441 
5 – Final 
Analysis 
800 
<0.0220 
>2.0141 
>0.0220 
<2.0141 
As recruitment has completed prior to formal interim analysis number 4 (on 
approximately 600 participants), it was decided to remove this formal pre-specified 
analysis on approximately 600 participants and continue to the final analyses only. The 
final analysis boundary has been adjusted to carry over the alpha that would have been 
spent on the 600-participant analysis as per Table 6. Previous boundaries were not 
amended. 
Table 6  
Final Analysis Stopping Boundaries for Futility and Efficacy 
Success 
 
Stage / Formal 
Analysis 
Target Sample 
Size 
Efficacy Success Boundaries Futility Boundaries 
p-value 
Z-Score 
p-value 
Z-Score 
Final Analysis 
800 
<0.0244 
>1.9697 
>0.0244 
<1.9697 
 
5.2.3. 
Sensitivity Analyses 
As a sensitivity to the missing data, the following sensitivity analyses will be performed.  


 
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5.2.3.1. 
Tipping Point Analyses 
For the tipping point analyses, the underlying response rate among those participants with 
missing response status in each arm will be tested ranging between 0 and 1. This analysis 
will be two-dimensional, i.e. will allow for assumptions about the assumed response rate 
(and thus missing outcomes) in the two arms to vary independently, furthermore they will 
include scenarios where dropouts on otilimab have worse outcomes than dropouts on 
placebo. For combinations of the assumed response rates in the two arms, the number of 
additional responders among participants with missing response will be imputed multiple 
times by drawing from a binomial distribution. The log-odds ratio and associated 
standard error for each imputed dataset will be calculated using a logistic regression with 
treatment as the only covariate and results combined using Rubin’s rules to calculate the 
test statistic and the corresponding p-value. Results will be presented via a heatmap. 
5.2.4. 
Supplementary Analyses 
As a supplementary strategy, a composite estimand may be considered for the handling of 
the intercurrent event of use of specific COVID-19 medications. Specifically, a 
participant may be considered to be a non-responder if they have taken specific COVID-
19 medications post-baseline, further details will be provided in a separate technical 
document.  
5.2.5. 
Subgroup Analyses 
Subgroup analyses of the age group and clinical status at baseline will be performed 
using the same methodology as the primary endpoint with the addition of a treatment by 
subgroup interaction. A joint test of the interaction term will be provided in the summary 
table.  Results will be presented as per primary analyses and, in addition a forest plot of 
the difference in proportions will be generated. 
For subgroup analyses, if there are <10 events in a subgroup then only a summary will be 
produced.  
Additional subgroup analyses may be performed and will be described in a separate 
technical document. 
5.3. 
Secondary Endpoint(s) Analyses 
Secondary endpoints will be analysed at the final analysis only.  The estimands are 
described in Table 3 
5.3.1. 
Endpoint Definition 
5.3.1.1. 
All-cause Mortality at Day 60 
Participants will meet the endpoint if they have died due to any cause prior to Day 60. 
If the date of death is unknown refer to Section 5.1.5 for missing data handling rules. 


 
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5.3.1.2. 
Time to All-cause Mortality up to Day 60 
Defined as the time (days) from dosing to death, due to any cause, up to (and including) 
Day 60.   
5.3.1.3. 
Participants Alive and Free of Respiratory Failure at Day 7, 14, 42, and 
60 
Defined as per primary endpoint, see Section 5.2.1. 
5.3.1.4. 
Time to Recovery from Respiratory Failure up to Day 28 
Defined as the time (days) from dosing to last recovery from respiratory failure up to 
(and including) Day 28.  Participants are in respiratory failure if they are in category 5 or 
above from the GlaxoSmithKline (GSK) modified ordinal scale adapted from World 
Health Organization (WHO) scale 2020 (Table 4).  
Note: if a participant has recovered from respiratory failure but then progresses back into 
respiratory failure on or prior to the end of follow up (Day 28) the participant has not had 
their last recovery from respiratory failure. 
This endpoint will use a composite approach for death such that if the intercurrent event 
of death occurs (on or prior to Day 28), then time will be censored at end of follow up 
(Day 28).  
5.3.1.5. 
Participants Alive and Independent of Supplementary Oxygen at Day 7, 
14, 28, 42, and 60 
Participants are independent of supplementary oxygen if they are in category 1, 2 or 3 
from the GlaxoSmithKline (GSK) modified ordinal scale adapted from World Health 
Organization (WHO) scale 2020 (See Table 4- Ordinal Scale). Alternatively, if the 
ordinal scale is unknown but ventilation or oxygen status is available, then the endpoint is 
defined as the first full day where oxygen support is not required. 
Participants will meet the endpoints if they are alive and independent of supplementary 
oxygen at Day 7, 14, 28, 42, and 60 respectively.  As participants may be discharged 
from investigator site prior to Day 28, analysis windows will be used to define the 
endpoint, further details on analysis windows will be provided in the Output and 
Programming Specification (OPS). 
5.3.1.6. 
Time to Last Dependence on Supplementary Oxygen up to Day 28 
Defined as the time (days) from dosing to last dependence on supplementary oxygen up 
to (and including) Day 28.   Participants are dependent on supplementary oxygen if they 
are in category 4 or above from the GlaxoSmithKline (GSK) modified ordinal scale 
adapted from World Health Organization (WHO) scale 2020 (Table 4). Alternatively, If 
the ordinal scale is unknown but ventilation or oxygen status is available, then the 
endpoint is defined as the last day up to (and including) Day 28 where oxygen support is 
required.  
Note: if a participant is independent of supplementary oxygen but then progresses back 


 
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into dependence of supplementary oxygen on or prior to the end of follow up (Day 28) 
the participant has not had their last dependence on supplementary oxygen. 
This endpoint will use a composite approach such that if the intercurrent event of death 
occurs (on or prior to Day 28), then time will be censored at end of follow up (Day 28).  
5.3.1.7. 
ICU Admission up to Day 28 
Participants will meet the endpoint if they have been admitted to the ICU up to (and 
including) Day 28, only evaluated for participants not in ICU at time of dosing. 
Participants who die prior to Day 28 without being admitted ICU will be considered to 
have met the endpoint (composite estimands strategy). 
5.3.1.8. 
Time to Final ICU Discharge up to Day 28 
This is defined as the time (days) from dosing to when the participant is discharged from 
the ICU for the last time up to (and including) Day 28.  It will only be evaluated for 
participants in the ICU at baseline.  
This endpoint will use a composite approach such that if the intercurrent event of death 
occurs (on or prior to Day 28), then time will be censored at the end of follow-up (Day 
28), including those that were discharged from ICU prior to death. 
5.3.1.9. 
Time to First Discharge from Investigator Site up to Day 60 
This is defined as the time (days) from dosing to when the participant is first discharged 
from investigator site up to (and including) Day 60. 
This endpoint will use a composite approach such that if the event has not occurred prior 
to the intercurrent event of death (on or prior to Day 60), then time will be censored at the 
end of follow-up (Day 60). 
5.3.1.10. 
Time to First Discharge to Non-Hospitalised Residence up to Day 60 
This is defined as the time (days) from dosing to when the participant is discharged to a 
non-hospitalised residence for the first time up to (and including) Day 60. 
This endpoint will use a composite approach such that if the event has not occurred prior 
to the intercurrent event of death occurred (on or prior to Day 60), then time will be 
censored at the end of follow-up (Day 60).  
5.3.2. 
Main Analytical Approach 
5.3.2.1. 
Binary Endpoints 
The binary endpoints: 
• All-cause mortality at Day 60 
• Participants alive and free of respiratory failure at Day 7, 14, 42, and 60 


 
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• Participants alive and independent of supplementary oxygen at Day 7, 14, 28, 42, 
and 60 
• ICU admission up to Day 28 
Binary secondary endpoints will be analysed as per Section 5.2.2. 
Additionally, for ICU admission, the counts and proportion of participants in ICU at 
baseline, entered ICU post-baseline and those that never entered ICU will be produced. In 
addition, the counts and proportion of participants who die prior to and post ICU 
admission will be produced. Note: In ICU at Baseline, Entered ICU Post Baseline and 
Never entered ICU are mutually exclusive, participants may only enter ICU post Baseline 
if they were not in ICU at Baseline. 
5.3.2.2. 
Time to Event Endpoints 
The following endpoints will be analysed using time to event analyses with a follow-up 
to Day 60: 
• Time to all-cause mortality  
• Time to first discharge from investigator site 
• Time to first discharge to non-hospitalised residence 
The following exploratory endpoints will be analysed using time to event analyses with a 
follow-up to Day 28: 
• Time to recovery from respiratory failure 
• Time to last dependence on supplementary oxygen 
• Time to final ICU discharge 
For time to event endpoints where the event is a worsening participant status, participants 
with missing data due to study withdrawal prior to occurrence of the event will be 
censored at the time of study withdrawal, participants alive at the end of follow-up will 
be censored at the time of end of follow-up (i.e. Day 28/60).  
For time to event endpoints where the event is an improvement participant status, 
participants with missing data due to study withdrawal prior to first occurrence of the 
event will be censored at the time of end of follow-up. The end of follow up will be the 
earliest of the nominal timepoint (i.e. Day 28/60) and their actual study day of visit. If a 
participant meets the endpoint at the point of withdrawal, then the participant will be 
assumed to have achieved the event. 
The endpoint will be analysed using a Cox proportional hazards model adjusted by 
treatment, clinical status and age group at baseline.  Ties will be broken using Efron’s 
method.  The hazard ratio of the treatment group and corresponding confidence interval 
and p-value will be reported. For any endpoint where a hazard ratio above 1 indicates 
improvement of otilimab over placebo, the inverse hazard ratio will also be presented. 
For model checks refer to Section 6.3.3. 


 
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Kaplan-Meier plots will be presented by treatment group.  Estimates of the median time-
to-event and other relevant percentiles will be derived from the unadjusted Kaplan-Meier 
plots and reported in a table.  If 50% of participant do not meet the event definition 
during the study, alternative percentiles may be produced. 
Kaplan-Meier plots will be presented by treatment group. 
Additionally, for time to ICU discharge, the following summaries will be produced: 
• For participants who are in the ICU at any point during the trial, the duration of 
ICU stay will be summarised separately for participants that have died and those 
that complete the study, it will be further split by participants ICU status (in ICU 
at dosing or entered ICU post-dose). 
• Additionally, for all participants a count and proportion of participants with stays 
in the ICU of 0 days, 1-<7 days, 7-<14 days and ≥14 days will be produced. 
5.3.3. 
Sensitivity Analyses 
5.3.3.1. 
Binary Endpoints 
Sensitivity analyses as per Section 5.2.3 will be performed on the binary endpoints in the 
hierarchy specified in Section 2.1 (Participants alive and free of respiratory failure at Day 
14, All-cause mortality at Day 60). Sensitivity analyses on additional endpoints may be 
investigated, further details will be provided in a separate technical document.  
5.3.3.2. 
Time to Event Endpoints 
As a sensitivity to the competing risk of death an alternative model will be investigated to 
analyse the time to event endpoints in the hierarchy specified in Section 2.1 (time to 
recovery from respiratory failure up to Day 28). Analysis will be performed as follows: 
• Competing risks via Fine-Gray method will be conducted. The competing risk for 
time to recovery from respiratory failure will be death. The model will be adjusted 
for clinical status and age group. In this case, the hazard ratio of the treatment 
group and corresponding confidence interval and p-value will be reported.  
Sensitivity analyses on additional endpoints may be investigated, further details will be 
provided in a separate technical document.  
5.3.4. 
Supplementary Analyses 
Supplementary estimands as described in Section 5.2.4 may be performed. 
5.3.5. 
Subgroup Analyses 
Subgroup analyses may be performed as per Section 5.2.5 and will use the methods 
described above. 


 
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5.4. 
Exploratory Endpoint(s) Analyses 
Exploratory endpoints may be analysed at the final analysis only. 
5.4.1. 
Definition of Endpoint(s) 
5.4.1.1. 
Invasive Mechanical Ventilation (if not previously initiated) up to Day 28 
Participants will meet the endpoint if they have had invasive mechanical ventilation 
initiated up to (and including) Day 28.  This will only be evaluated for participants who 
are not supported using invasive mechanical ventilation at baseline. 
Participants who die on or prior to Day 28 without the initiation of invasive mechanical 
ventilation will be considered to have met the endpoint (composite estimands strategy). 
5.4.1.2. 
Time to Invasive Mechanical Ventilation (if not previously initiated) up 
to Day 28 
Time from dosing (days) to first use of invasive mechanical ventilation or death up to 
(and including) Day 28 as defined in Section 5.4.1.1. This will only be evaluated for 
participants who are not supported using invasive mechanical ventilation at baseline. 
This endpoint will use a composite approach for death such that for participants who die 
on or prior to Day 28 without the initiation of invasive mechanical ventilation, the time to 
invasive mechanical ventilation will be set as the time of death. 
5.4.1.3. 
Alive and Not Invasively Mechanically Ventilated up to Day 28 
Participants will meet the endpoint if they are alive and not requiring invasive mechanical 
ventilation at Day 28.  This will be evaluated only for participants supported using 
invasive mechanical ventilation at baseline 
5.4.1.4. 
Time to Definitive Extubation up to Day 28 
For participants supported using invasive mechanical ventilation at baseline this is 
defined as the time from dosing (days) to final extubation from invasive mechanical 
ventilation up to (and including) Day 28.  
This endpoint will use a composite approach for death such that if the event has not 
occurred prior to the intercurrent event of death (on or prior to Day 28), then time will be 
censored at the end of follow-up (Day 28), including those that were extubated prior to 
death. 
5.4.1.5. 
Recovery or Improvement of at Least 2 Points Relative to Baseline of 
Sequential Organ Failure Assessment (SOFA) score up to Day 28 
The SOFA score will be evaluated for participants in ICU with a SOFA score greater 
than 2 at baseline and analysed using a composite strategy to handle the intercurrent 
events as below. 


 
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Participants will meet the endpoint if they have an improvement of at least 2 points 
relative to baseline in SOFA score (derived where lower values indicate improvement) or 
they have recovered (discharged from ICU or investigator site for any other reason other 
than advanced facilitated care). 
Intercurrent event 
Response Status 
Death 
Non-responder 
Discharge from ICU or Investigator Site to Advanced 
facilitated care 
Non-responder 
Discharge from ICU or Investigator Site for any other reason 
other than advanced facilitated care 
Responder 
In addition, change from baseline in SOFA score will be summarized for participants in 
ICU at baseline up to Day 28. This will be summarised using the trimmed means 
approach given in Section 5.4.2.4.  
For the trimmed means, if >50% of the participants in ICU at baseline experience the 
intercurrent events listed above at any timepoint, then the data will be summarised up to 
that timepoint only. 
If a participant experiences multiple intercurrent events, then the worst response status 
will be assumed. 
5.4.1.6. 
Recovery or Improvement Relative to Baseline in Blood Oxygen 
Saturation (SpO2) 
Change from Baseline in SpO2, calculated as daily average of all assessments, for 
participants who are not invasively mechanically ventilated at baseline.  SpO2 will be 
analysed using a composite strategy to handle the intercurrent events as below. 
Participants will meet the endpoint if they have an improvement relative to baseline in 
SpO2 (derived where higher values indicate improvement) or they have recovered 
(participant is discharged from investigator site for any other reason other than advanced 
facilitated care or participant is independent from supplementary oxygen and SpO2 is 
missing).  
 
Intercurrent event 
Response Status 
Death 
Non-responder 
Discharge from investigator site to advanced facilitated care 
Non-responder 
Use of Invasive Mechanical Ventilation 
Non-responder 
Discharge from Investigator Site for any other reason other than 
advanced facilitated care  
Responder 
Independence from supplementary oxygen and missing SpO2  
Responder 


 
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In addition, change from baseline in SpO2 will be summarized for participants not 
invasively mechanically ventilated at baseline up to Day 28. Participants who have SpO2 
recorded whilst on invasive mechanical ventilation will be set to missing. SpO2 will be 
summarized for observed data and using a trimmed means approach as specified in the 
Section 5.4.2.4.  
For the trimmed means, if >50% of the participants not invasively mechanically 
ventilated at baseline experience the intercurrent events listed above at any timepoint, 
then the data will be summarised up to that timepoint only. 
If a participant experiences multiple intercurrent events, then the worst response status 
will be assumed. 
5.4.1.7. 
Recovery or Improvement Relative to Baseline in Concentration of 
Inspired Oxygen (FiO2) 
Change from Baseline in FiO2, calculated as daily average of all assessments.  FiO2 will 
be analysed using a composite strategy to handle the intercurrent events as below. 
Participants will meet the endpoint if they have an improvement relative to baseline in 
FiO2 (derived where lower values indicate improvement) or they have recovered 
(participant is discharged from investigator site for any other reason other than advanced 
facilitated care or participant is independent from supplementary oxygen and SpO2 is 
missing). If FiO2 is not recorded but Oxygen Flow Rate is, the FiO2 will be calculated.   
 
Intercurrent event 
Response Status 
Death 
Non-responder 
Discharge from investigator site to advanced facilitated care 
Non-responder 
Discharge from Investigator Site for any other reason other than 
advanced facilitated care  
Responder 
Independence from supplementary oxygen and missing SpO2  
Responder 
In addition, change from baseline in FiO2 will be summarized for participants up to Day 
28. FiO2 will be summarized for observed data and using a trimmed means approach as 
specified in the Section 5.4.2.4.  
For the trimmed means, if >50% of the participants experience the intercurrent events 
listed above at any timepoint, then the data will be summarised up to that timepoint only.  
If a participant experiences multiple intercurrent events, then the worst response status 
will be assumed. 
5.4.1.8. 
Recovery or Improvement Relative to Baseline in SpO2/FiO2 Ratio 
The ratio of SpO2/FiO2 will be calculated for each day using date-time matched values. 
Change from baseline in SpO2/FiO2 will be calculated as average of the daily 


 
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assessments, for participants who are not invasively mechanically ventilated.  It will be 
analysed using a composite strategy to handle the intercurrent events as described in the 
individual endpoint sections. If a participant is a non-responder due to an intercurrent 
event for either SpO2 or FiO2 then they will be a non-responder for the ratio. 
Participants will meet the endpoint if they have an improvement relative to baseline in 
SpO2/FiO2 ratio (derived where higher values indicate improvement) or they have 
recovered (the participant is discharged from investigator site for any other reason other 
than advanced facilitated care or the participant is independent from supplementary 
oxygen and SpO2 is missing).  
5.4.1.9. 
Oxygen-free Days up to Day 28 
A participant is considered oxygen free on a day if they meet the definition in Section 
5.3.1.5. 
Intermittent data is expected after discharge from investigator site, therefore if 
participants have discontinued oxygen and have been discharged to a non hospitalised 
residence, they will be considered to be oxygen-free during the intermittent timepoints. 
5.4.1.10. 
Ventilator-free Days up to Day 28 
A participant is considered ventilator-free on a day if they meet the definition for being 
alive and not invasively mechanically ventilated in Section 5.4.1.3.  
Intermittent data is expected after discharge from investigator site, therefore if 
participants have discontinued ventilation and have been discharged to a non hospitalised 
residence, they will be considered to be ventilation-free during the intermittent timepoints. 
5.4.1.11. 
Time to Resolution of Pyrexia (>48h) up to Day 28 
Time from dosing (days) to first resolution of pyrexia (defined as the first day of a >48-
hour period with temperature below thresholds below) up to (and including) Day 28: 
Location 
Pyrexia Threshold 
Core Temperature 
Equivalent 
Forehead 
>36.3°C 
>37.8°C 
Axilla 
>36.6°C 
>37.8°C 
Sublingual region 
>37.2°C 
>37.8°C 
Rectum or Tympanic membrane 
>37.8°C 
>37.8°C 
Pulmonary artery branch 
>37.8°C 
>37.8°C 
Bladder 
>37.8°C 
>37.8°C 
Esophagus 
>37.8°C 
>37.8°C 
Nasopharynx 
>37.8°C 
>37.8°C 
Brain 
>37.8°C 
>37.8°C 
Other 
>36.3°C (Minimum Pyrexia 
Threshold) 
>37.8°C 


 
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Evaluated for all participants with pyrexia at baseline. 
This endpoint will use a composite approach such that if the intercurrent event of death 
occurs (on or prior to Day 28), then time will be censored at the end of follow-up (Day 
28), including those that had resolution of pyrexia prior to death. 
5.4.1.12. 
Clinical Status Assessed Using an Ordinal Scale Assessed at Days 4, 7, 
14, 28, 42, and 60 
Clinical status assessed using an ordinal scale assessed at Days 4, 7, 14, 28, 42 and 60 see 
Table 4. 
5.4.1.13. 
Time to Improvement of at Least 2 Categories Relative to Baseline in 
Clinical Status up to Day 60 
Time from dosing (days) to final improvement of at least 2 categories relative to baseline 
in clinical status (see Table 4) up to (and including) Day 60. Evaluated for all participants 
with clinical status greater than 2 at baseline. 
Note: if a participant has an improvement of at least 2 categories relative to baseline but 
then progresses back to a less than 2 category improvement the participant has not had 
their final improvement of at least 2 categories. 
This endpoint will use a composite approach such that if the event has not occurred prior 
to the intercurrent event of death (on or prior to Day 60), then time will be censored at the 
end of follow-up (Day 60).  
5.4.1.14. 
Change in COVID-19 Signs and Symptoms up to Day 60 
Participants change in COVID-19 signs and symptoms up to Day 60 relative to dosing 
will be analysed. 
 
Unadjusted relative risks, risk differences and odds ratios will be calculated and 
presented with 95% confidence intervals. For odds ratios, if the proportions are below 2% 
in any treatment group then exact 95% confidence interval will be calculated by inverting 
two one-sided (equal-tail) exact tests that are based on the noncentral hypergeometric 
distribution. All other confidence intervals will use the Wald method. A 2-sided Fisher's 
Exact Test will be performed, and p-values will be presented. 
5.4.2. 
Main Analytical Approach 
5.4.2.1. 
Time to Event Endpoints 
The following exploratory endpoints will be analysed using time to event analyses with a 
follow-up to Day 28: 
• Time to invasive mechanical ventilation (if not previously initiated) 
• Time to definitive extubation 
• Time to resolution of pyrexia (for at least 48h) 


 
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The following exploratory endpoints will be analysed using time to event analyses with a 
follow-up to Day 60: 
• Time to improvement of at least 2 categories relative to baseline in clinical status 
The endpoints will be analysed as per Section 5.3.2.2 
5.4.2.2. 
Binary Endpoints 
The following exploratory endpoints will be analysed as binary endpoints: 
• Invasive mechanical ventilation (if not previously initiated) 
• Alive and not invasively mechanically-ventilated 
• Improvement relative to baseline in SpO2, FiO2 and SpO2/FiO2 ratio 
• Improvement of at least 2 points relative to baseline on SOFA score 
Binary secondary endpoints will be analysed as per Section 5.2.2. 
Additionally, for Invasive mechanical ventilation, the counts and proportion of 
participants for whom prone position was, and was not, used will be produced. 
5.4.2.3. 
Ordinal Endpoints 
The clinical status assessed using an ordinal scale assessed at Days 4, 7, 14, 28, 42, and 
60 will be summarized using counts and proportions of the number of participants in each 
category of the ordinal scale and will be analysed using a proportional odds logistic 
regression model, adjusting for treatment, ordinal scale category at baseline and age 
group.  The outcome of the model is an odds ratio, a confidence interval and p-value for 
the odds of improvement on the ordinal scale, where an odds ratio >1 indicates 
improvement in clinical status. 
In addition a shift table from baseline to the clinical status at Day 4, 7, 14, 28, 42 and 60 
including a row for improvement (defined as moving from a higher category to a lower 
category) will be produced and the proportion of participants in each category of the 
ordinal scale will be summarised at each visit using a stacked bar chart. 
 
5.4.2.4. 
Continuous Endpoints 
The following exploratory endpoints will be analysed as continuous endpoints: 
• Change of Sequential Organ Failure Assessment (SOFA) score 
• Change in SpO2, FiO2, and SpO2/FiO2 ratio 
Continuous endpoints will be summarised using the trimmed means approach (Permutt, 
2017) where the proportion of data to be trimmed will be determined by the amount of 
missing data due to intercurrent events as defined in Section 5.1.4. 
Study withdrawal will be treated as a negative event if it occurs prior to one of the listed 
intercurrent events. If the subject has recovered (has one of the intercurrent events listed 


 
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within the endpoint definition) prior to withdrawal then they will be considered to be 
recovered post-withdrawal. 
Missing data without reason (no accompanying intercurrent event or withdrawal) will be 
treated as missing at random and will not count towards the trimmed sample. 
5.4.2.5. 
Count Endpoints 
The following exploratory endpoints will be analysed as count data 
• Oxygen-free days 
• Ventilator-free days 
Summary statistics of the number of days will be presented and the data will be analysed 
using negative binomial regression adjusting for clinical status at baseline and age group. 
5.4.3. 
Sensitivity Analyses 
No sensitivity analyses planned. 
5.4.4. 
Supplementary Analyses 
No supplementary analyses planned. 
5.4.5. 
Subgroup Analyses 
No subgroup analyses are planned. 
5.5. 
Safety Analyses 
5.5.1. 
Extent of Exposure 
As this is a single dose study, summaries of exposure will be limited to the number of 
participants exposed and the number of participants with interruptions or infusion 
stopped early and not completed. This will be presented with participant disposition. 
5.5.2. 
Adverse Events 
Adverse events analyses including the analysis of adverse events (AEs) and Serious AEs 
(SAEs) will be based on GSK Core Data Standards.  All adverse events reported will be 
treatment emergent adverse events. 
An overview summary of AEs, including counts and percentages of participants with 
• any AE 
• AEs related to study intervention 
• AEs leading to permanent discontinuation of study intervention, 
• study intervention related AEs leading to permanent discontinuation of study 
intervention, 


 
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• AEs leading to dose interruption, 
• Common AEs, with common AE defined as any AE with an incidence of at least 
5% in any of the treatment group 
• SAEs, 
• SAEs related to study intervention, 
• fatal SAEs 
• fatal SAEs related to study intervention 
Adverse events will be coded using the standard Medical Dictionary for Regulatory 
Affairs (MedDRA dictionary). 
A summary of number and percentage of participants with any adverse events by 
maximum intensity will be produced.  AEs will be sorted by Preferred term (PT) in 
descending order.  The summary will use the following algorithms for counting the 
participant: 
• 
Preferred term row: Participants experiencing the same AE preferred term several 
times with different intensities will only be counted once with the maximum grade. 
• 
Any event row: Each participant with at least one adverse event will be counted 
only once at the maximum intensity no matter how many events they have. 
The frequency and percentage of AEs (all intensities) will be summarized and displayed 
in two ways: 1) in descending order by PT only and 2) in descending order by SOC and 
PT.  In the SOC row, the number of participants with multiple events under the same 
SOC will be counted once. 
A separate summary will be provided for study intervention-related AEs.  A study 
intervention-related AE is defined as an AE for which the investigator classifies the 
possible relationship to study intervention as “Yes”.  A worst-case scenario approach will 
be taken to handle missing relatedness data, i.e. the summary table will include events 
with the relationship to study intervention as ‘Yes’ or missing.  The summary table will 
be displayed by PT only. 
All SAEs will be tabulated based on the number and percentage of participants who 
experienced the event.  Separate summaries will also be provided for study intervention-
related SAEs.  The summary tables will be displayed by PT. 
A study intervention-related SAE is defined as an SAE for which the investigator 
classifies the relationship to study intervention as “Yes”.  A worst-case scenario approach 
will be taken to handle missing data, i.e. the summary table will include events with the 
relationship to study intervention as ‘Yes’ or missing. 
Unadjusted Relative risks with Wald confidence intervals based on observed frequencies, 
for the proportions of participants with common (>=5% in either treatment group) AEs 
will be calculated for otilimab versus placebo. 


 
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Relative risks will not be calculated if there are no events in either of the two treatment 
arms being compared.  The relative risks and exact confidence interval will be plotted on 
log base 10 scale. 
The adverse events with calculated relative risks will be presented in decreasing order as 
per the IDSL standard. 
5.5.2.1. 
Adverse Events of Special Interest 
The following will be considered adverse events of special interest (AESI) for the 
purpose of analyses: 
• Cytokine release syndrome (CRS) 
• Serious hypersensitivity reactions 
Note: these will be adjudicated by the SRT. 
• Infusion site reactions 
• Neutropenia ≥ Grade 3 (<1.0 x 109/L) 
• Serious infections 
Listings of event characteristics will be provided for each AESI respectively. For AESIs 
with more than 8 events a summary of event characteristics will be provided for each 
AESI respectively, including number and percentage of participants with any event, 
number and percentage of events, maximum intensity, outcomes and the action taken for 
the event.  The worst-case approach will be applied at participant level for the maximum 
intensity, i.e. a participant will only be counted once as the worst case from all the events 
experienced by the participant. 
5.5.3. 
Additional Safety Assessments 
5.5.3.1. 
Laboratory Data 
Summaries of worst-case grade increase from baseline grade will be provided for all the 
lab tests that are gradable by a modified CTCAE v5.  These summaries will display the 
number and percentage of participants with a maximum post-baseline grade increasing 
from their baseline grade.  Any increase in grade from baseline will be summarized along 
with any increase to a maximum grade of 3 and any increase to a maximum grade of 4.  
Missing baseline grade will be assumed as grade 0.  For laboratory tests that are graded 
for both low and high values, summaries will be done separately and labelled by 
direction, e.g., sodium will be summarized as hyponatremia and hypernatremia 
separately. 
The CTCAE v5 grades were modified to remove grading criteria that cannot be derived 
programmatically with the data collected (see footnotes). The modified CTCAE v5 
grades are defined as follows: 
 


 
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Laboratory 
parameters of 
interest1 
Grade 
1 
2 
3 
4 
HEMOGLOBI
N decreased  
(CTCAE term 
is Anemia)2 
<LLN - 10.0 g/dL;  
<LLN - 6.2 
mmol/L;  
<LLN - 100 g/L   
<10.0 - 8.0 g/dL;  
<6.2 - 4.9 mmol/L;  
<100 - 80 g/L   
<8.0 g/dL;  
<4.9 mmol/L;  
<80 g/L 
- 
HEMOGLOBI
N increased 
>0 - 2 g/dL 
>2 - 4 g/dL 
>4 g/dL 
- 
LEUKOCYTE 
(White blood 
cell) 
decreased 
<LLN - 
3000/mm3; <LLN 
- 3.0 x 10e9 /L 
<3000-2000/mm3; 
<3.0 - 2.0 x 10e9 
/L 
<2000-1000/mm3; 
<2.0 - 1.0 x 10e9 
/L 
<1000/mm3; 
<1.0 x 10e9 /L 
LYMPHOCYT
E COUNT 
decreased 
<LLN - 800 /mm3;  
<LLN - 0.8 x 
10e9/L   
<800 - 500 /mm3;  
<0.8 - 0.5 x 
10e9/L   
<500 - 200 /mm3;  
<0.5 - 0.2 x 
10e9/L   
<200/mm3;  
<0.2 x 10e9/L   
LYMPHOCYT
E COUNT 
increased 
 - 
>4,000 - 20,000 
/mm3;  
>4 - 20 x 10e9/L   
>20,000 /mm3;  
>20 x 10e9/L   
 - 
NEUTROPHIL 
COUNT 
decreased 
<LLN - 1,500 
/mm3;  
<LLN - 1.5 x 
10e9/L   
<1,500 - 1,000 
/mm3;  
<1.5 - 1.0 x 
10e9/L   
<1,000 - 500 
/mm3;  
<1.0 - 0.5 x 
10e9/L   
<500 /mm3;  
<0.5 x 10e9/L   
PLATELET 
COUNT 
decreased 
<LLN - 75,000 
/mm3;  
<LLN - 75.0 x 
10e9/L   
<75,000 - 50,000 
/mm3;  
<75.0 - 50.0 x 
10e9/L   
<50,000 - 25,000 
/mm3;  
<50.0 - 25.0 x 
10e9/L   
<25,000 /mm3;  
<25.0 x 10e9/L 
AST (SGOT) 
>ULN - 3.0 x ULN 
if baseline was 
normal; 1.5 - 3.0 x 
baseline if 
baseline was 
abnormal 
>3.0 - 5.0 x ULN if 
baseline was 
normal; >3.0 - 5.0 
x baseline if 
baseline was 
abnormal 
>5.0 - 20.0 x ULN 
if baseline was 
normal; >5.0 - 
20.0 x baseline if 
baseline was 
abnormal 
>20.0 x ULN if 
baseline was 
normal; >20.0 x 
baseline if 
baseline was 
abnormal 
ALP 
>ULN - 2.5 x ULN 
if baseline was 
normal; 2.0 - 2.5 x 
baseline if 
baseline was 
abnormal 
>2.5 - 5.0 x ULN if 
baseline was 
normal; >2.5 - 5.0 
x baseline if 
baseline was 
abnormal 
>5.0 - 20.0 x ULN 
if baseline was 
normal; >5.0 - 
20.0 x baseline if 
baseline was 
abnormal 
>20.0 x ULN if 
baseline was 
normal; >20.0 x 
baseline if 
baseline was 
abnormal 


 
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Laboratory 
parameters of 
interest1 
Grade 
1 
2 
3 
4 
ALT (SGPT) 
>ULN - 3.0 x ULN 
if baseline was 
normal; 1.5 - 3.0 x 
baseline if 
baseline was 
abnormal 
>3.0 - 5.0 x ULN if 
baseline was 
normal; >3.0 - 5.0 
x baseline if 
baseline was 
abnormal 
>5.0 - 20.0 x ULN 
if baseline was 
normal; >5.0 - 
20.0 x baseline if 
baseline was 
abnormal 
>20.0 x ULN if 
baseline was 
normal; >20.0 x 
baseline if 
baseline was 
abnormal 
BLOOD 
BILIRUBIN 
increased 
>ULN - 1.5 x ULN 
if baseline was 
normal; > 1.0 - 1.5 
x baseline if 
baseline was 
abnormal 
>1.5 - 3.0 x ULN if 
baseline was 
normal; >1.5 - 3.0 
x baseline if 
baseline was 
abnormal 
>3.0 - 10.0 x ULN 
if baseline was 
normal; >3.0 - 
10.0 x baseline if 
baseline was 
abnormal 
>10.0 x ULN if 
baseline was 
normal; >10.0 x 
baseline if 
baseline was 
abnormal 
ALBUMIN 
(Hypo-
albuminemia) 
<LLN - 3 g/dL; 
<LLN - 30 g/L 
<3 - 2 g/dL; <30 - 
20 g/L 
<2 g/dL; <20 g/L 
- 
APTT 
Activated 
partial 
thromboplastin 
time prolonged 
>ULN - 1.5 x ULN 
>1.5 - 2.5 x ULN 
>2.5 x ULN 
- 
CALCIUM 
(Hypercalcemi
a) 
Corrected serum 
calcium of >ULN - 
11.5 mg/dL; >ULN 
- 2.9 mmol/L; 
Ionized calcium 
>ULN - 1.5 
mmol/L 
Corrected serum 
calcium of >11.5 - 
12.5 mg/dL; >2.9 - 
3.1 mmol/L; 
Ionized calcium 
>1.5 - 1.6 mmol/L 
Corrected serum 
calcium of >12.5 - 
13.5 mg/dL; >3.1 - 
3.4 mmol/L; 
Ionized calcium 
>1.6 - 1.8 mmol/L 
Corrected serum 
calcium of >13.5 
mg/dL; >3.4 
mmol/L; Ionized 
calcium >1.8 
mmol/L 
CALCIUM 
(Hypocalcemia
) 
Corrected serum 
calcium of <LLN - 
8.0 mg/dL; <LLN - 
2.0 mmol/L; 
Ionized calcium 
<LLN - 1.0 
mmol/L 
Corrected serum 
calcium of <8.0 - 
7.0 mg/dL; <2.0 - 
1.75 mmol/L; 
Ionized calcium 
<1.0 - 0.9 mmol/L 
Corrected serum 
calcium of <7.0 - 
6.0 mg/dL; <1.75 - 
1.5 mmol/L; 
Ionized calcium 
<0.9 - 0.8 mmol/L 
Corrected serum 
calcium of <6.0 
mg/dL; <1.5 
mmol/L; Ionized 
calcium <0.8 
mmol/L 
CPK increased >ULN - 2.5 x ULN 
>2.5 x ULN - 5 x 
ULN 
>5 x ULN - 10 x 
ULN 
>10 x ULN 
CREATININE 
increased 
>ULN - 1.5 x ULN 
>1.5 - 3.0 x 
baseline;  
>1.5 - 3.0 x ULN 
>3.0 x baseline;  
>3.0 - 6.0 x ULN 
>6.0 x ULN 


 
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Laboratory 
parameters of 
interest1 
Grade 
1 
2 
3 
4 
GGT 
increased 
>ULN - 2.5 x ULN 
if baseline was 
normal; 2.0 - 2.5 x 
baseline if 
baseline was 
abnormal 
>2.5 - 5.0 x ULN if 
baseline was 
normal; >2.5 - 5.0 
x baseline if 
baseline was 
abnormal 
>5.0 - 20.0 x ULN 
if baseline was 
normal; >5.0 - 
20.0 x baseline if 
baseline was 
abnormal 
>20.0 x ULN if 
baseline was 
normal; >20.0 x 
baseline if 
baseline was 
abnormal 
GLUCOSE 
(Hypoglycemia
) 
<LLN - 55 mg/dL; 
<LLN - 3.0 
mmol/L 
<55 - 40 mg/dL; 
<3.0 - 2.2 mmol/L 
<40 - 30 mg/dL; 
<2.2 - 1.7 mmol/L 
<30 mg/dL; <1.7 
mmol/L 
LDH (Blood 
lactate 
dehydrogenas
e increased) 
>ULN 
- 
- 
- 
POTASSIUM 
(Hyperkalemia
) 
>ULN – 5.5 
mmol/L 
>5.5 – 6.0 
mmol/L;  
>6.0 – 7.0 mmol/L 
>7.0 mmol/L 
POTASSIUM 
(Hypokalemia)
3 
<LLN – 3.0 
mmol/L 
 
<3.0 – 2.5 mmol/L 
<2.5 mmol/L 
SODIUM 
(Hypernatremi
a) 
>ULN – 150 
mmol/L 
>150 - 155 
mmol/L 
>155 - 160 
mmol/L 
>160 mmol/L 
SODIUM 
(Hyponatremia
)4 
<LLN - 130 
mmol/L 
- 
120-129 mmol/L 
<120 mmol/L 
INR increased5 >1.2 – 1.5 
>1.5 – 2.5  
>2.5 
- 
Eosinophils6 
>ULN and 
>Baseline 
- 
- 
- 
 


 
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1. Removal of cardiac troponin I or T increased gradings. Specifically Grade 1 indicated by 
levels above the upper limit of normal and below the level of myocardial infarction as 
defined by the manufacturer and Grade 3 indicated by levels consistent with myocardial 
infarction as defined by the manufacturer 
2. Removal of Grade 3 defined as transfusion indicated by transfusion and grade 4 indicated 
by Life-threatening consequences or urgent intervention indicated   
3. Removal of Grade 2 defined as symptomatic with <LLL – 3.0 mmol/L 
4. Removal of Grade 2 defined as 125-129 mmol/L and asymptomatic, Grade 3 is re-defined 
as 120-129 mmol/L i.e. conservatively including the grade 2 criteria of “125-129 mmol/L 
and asymptomatic” into the Grade 3 criteria of “120-124 mmol/L regardless of symptoms; 
125-129 mmol/L symptomatic” as asymptomatic/symptomatic is not collected. 
5. Removal of Grade 1 indicated by >1 – 1.5 x baseline if on anticoagulation; Grade 2 
indicated by >1.5 – 2.5 x baseline if on anticoagulation; and Grade 3 indicated by >2.5 x 
baseline if on anticoagulation. 
6. Removal of Grade 3 defined as steroids initiated 
Note: The grading will be rederived for any laboratory parameters with modifications from the 
CTCAE V5 
For lab tests that are not gradable by modified CTCAE v5, summaries of worst-case 
changes from baseline with respect to normal range will be generated.  Decreases to low, 
changes to normal or no changes from baseline, and increases to high will be summarized 
for the worst-case post-baseline.  If a participant has a decrease to low and an increase to 
high during the same time interval, then the participant is counted in both the “Decrease 
to Low” categories and the “Increase to High” categories. 
Separate summary tables for haematology, and chemistry laboratory tests will be 
produced.  Liver function laboratory tests will be included with chemistry lab tests. 
In addition, if any AE of CRS symptoms is reported a summary table of hematology, 
CRP, D-dimer and ferritin will be produced. 
Summaries of hepatobiliary laboratory events will be provided in addition to what has 
been described above.  Possible Hy’s law cases defined as any elevated alanine 
aminotransferase (ALT) ≥ 3 × upper limit of normal (ULN) and total bilirubin ≥ 2 × ULN 
(>35% direct bilirubin) or ALT ≥ 3 × ULN and INR > 1.5 will be presented in a plot of 
maximum ALT vs maximum total bilirubin. 
 
5.5.3.2. 
Vital Signs 
Summaries of worst-case systolic blood pressure (SBP), diastolic blood pressure (DBP) 
and heart rate relative to Potential Clinical Importance (PCI) post-baseline relative to 
baseline will be provided. This will include all post-baseline assessments. 
Potential Clinical Importance ranges are defined as follows: 
 


 
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Vital Sign Parameter 
 
Units 
 
Clinical Concern Range 
Lower 
Upper 
Absolute 
Systolic blood pressure 
mmHg 
<80 
>170 
Diastolic blood pressure 
mmHg 
<45 
>110 
Heart Rate 
bpm 
<40 
>100 
Change from Baseline 
Systolic blood pressure 
mmHg 
≥30↓ 
≥30↑ 
Diastolic blood pressure 
mmHg 
≥20↓ 
≥20↑ 
Worst case summaries will display the number and percentage of participants with 
changes in the absolute values “To Low”, “To w/in Range or No Change” or “To High” 
post baseline relative to baseline.  Participants will be reported in both the "To Low" and 
"To High" categories if both of these changes are observed post-baseline.  Participants 
will only be reported in the “To w/in Range or No Change” category if they experience 
no “To Low” or “To High” changes post-baseline. The summaries will also display the 
number and percentage of participants with “PCI Increase from Baseline”, “PCI Decrease 
from Baseline” or “No PCI Change from Baseline”.  Participants will be reported in the 
"PCI Increase from Baseline" (/"PCI Increase from Baseline") categories if the upper 
(/lower) change from baseline clinical concern range value is observed, respectively. 
Participants will be reported in both the “PCI Increase from Baseline” and “PCI Decrease 
from Baseline” categories if both of these changes are observed post-baseline.  
Participants will only be reported in the “No PCI Change from Baseline” category if they 
experience no “PCI Increase from Baseline” or “PCI Decrease from Baseline” changes 
post-baseline. 
In addition, summaries of change from baseline in systolic blood pressure (SBP), 
diastolic blood pressure (DBP), respiratory rate and temperature over Days 1 to 28 will 
be provided. 
5.5.3.3. 
ECG 
A summary of the number and percentage of participants with ECG findings will be 
summarized by treatment.  The ECG findings to be summarized are the ECG 
interpretation and clinical significance of abnormal ECGs.  Participants with missing 
baseline values will be excluded from this summary. 
5.6. 
Other Analyses 
5.6.1. 
Pharmacokinetics (PK) 
Pharmacokinetic concentrations will be listed and summarised by visit. 
5.6.2. 
Population Pharmacokinetics 
Sparse PK samples will be analysed using population PK approach.  Otilimab PK data 
from this study will be combined with PK data after IV administration from 4 studies in 


 
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healthy volunteers, RA and MS adult participants.  The PK parameters reported will be 
clearance, steady-state volume of distribution and AUC. 
Further details will be provided in a supplemental analyses plan. 
5.6.3. 
Pharmacodynamics 
Pharmacodynamic biomarkers measures including free GM-CSF, key markers of 
inflammation including, but not limited to CRP, serum ferritin and inflammatory 
cytokines as appropriate will be listed and summarised by visit. 
Further details will be provided in a supplemental analyses plan. 
5.6.4. 
Pharmacokinetics/Pharmacodynamics 
Exposure-response relationship for key efficacy, safety and PD endpoints will be 
explored graphically and if data permits (range of otilimab concentrations observed in 
this study is wide enough) will be followed by model-based analysis. 
Further details will be provided in a supplemental analyses plan. 
 
5.7. 
Interim Analyses 
Details of the interim analyses and required outputs are provided in the IDMC Charter 
and IDMC Statistical Analyses Plan. 


 
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6. 
SUPPORTING DOCUMENTATION 
6.1. 
Appendix 1 Abbreviations and Trademarks 
6.1.1. 
List of Abbreviations 
Abbreviation 
Description 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ANCOVA 
Analyses of Covariance 
AUC 
Area Under the Curve 
BIPAP 
Bilevel Positive Airway Pressure 
CL 
Clearance 
COVID-19 
Corona Virus Disease 2019 
CPAP 
Continuous Positive Airway Pressure 
CRP 
C-Reactive Protein 
CRS 
Cytokine Release Syndrome 
CTCAE 
Common Terminology Criteria for Adverse Events 
DBP 
Diastolic Blood Pressure 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Record Form 
FCS 
Fully Conditional Specification 
FiO2 
Concentration of Inspired Oxygen 
FU 
Follow-up 
GM-CSF 
Granulocyte-macrophage colony-stimulating factor 
GSK 
GlaxoSmithKline 
ICH 
International Conference on Harmonization 
ICU 
Intensive Care Unit 
IDMC 
Independent Data Monitoring Committee  
IDSL 
Integrated Data Standards Library 
IND 
Investigational New Drug 
IRT 
Interactive Response Technology 
IV 
Intravenous 
MAR 
Missing at random 
MCMC 
Markov Chain Monte Carlo 
MI 
Multiple imputation 
MITT 
Modified Intent-To-Treat 
MS 
Multiple Sclerosis 
OPS 
Output and Programming Specification  
PCI 
Potential Clinical Importance 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PT 
Preferred Term 
RA 
Rheumatoid Arthritis 
RMST 
Restricted Mean Survival Time 
SAE 
Serious Adverse Event 


 
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Abbreviation 
Description 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SDTM 
Study Data Tabulation Model 
SOC 
System Organ Class 
SOFA 
Sequential Organ Failure Assessment 
SpO2 
Blood Oxygen Saturation 
SRT 
Safety Review Team 
ULN 
Upper Limit of Normal 
WHO 
World Health Organisation 
6.1.2. 
Trademarks 
Trademarks of the GlaxoSmithKline 
Group of Companies 
 
Trademarks not owned by the 
GlaxoSmithKline Group of Companies 
None 
 
None 
 
 
 


 
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6.2. 
Appendix 2: Changes to Protocol-Planned Analyses 
Changes to protocol-planned analyses include: 
• The number of interim analyses in the group sequential design has been reduced 
to three interims for futility and one for efficacy. This is due to recruitment being 
completed prior to formal interim analyses number 4 (on approximately 600 
participants), hence it was decided to remove this formal analysis on 
approximately 600 participants and continue to the final analyses only. The final 
analyses boundary has been adjusted to carry over the alpha that would have been 
spent on the 600-participant analysis. The hierarchy has been updated accordingly 
but previous boundaries were not amended. 
• The study design has been updated such that the final analyses on the primary 
endpoint will be conducted once all participants have been randomised and 
completed to Day 28 or withdrawn. 
• The proposed hierarchy for testing secondary endpoints, refer to Section 2 for full 
details. 
• Updates to secondary endpoint related to hospital discharge, refer to Section 
5.3.1.9 and Section 5.3.1.10 for full details. 
• For exploratory endpoints on improvement in SOFA, Blood Oxygen Saturation 
(SpO2), Concentration of Inspired Oxygen (FiO2) and SpO2/FiO2 ratio, the 
endpoints have been clarified to include recovery as part of composite strategy. 
• The exploratory endpoint “Time to Improvement of at Least 2 Categories Relative 
to Baseline on an Ordinal Scale up to Day 60” has been updated to “Time to 
Improvement of at Least 2 Categories Relative to Baseline in Clinical Status up to 
Day 60” for consistency over the use of clinical status rather than ordinal scale. 
 


 
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6.3. 
Appendix 3: Statistical Modelling 
6.3.1. 
Multiple Imputation 
Multiple imputation will be utilized to impute data that is missing following withdrawal 
of the participant from the study.  Each data type will use one set of imputations with all 
endpoints that depend on that data type being derived from the intermediate dataset. 
The statistical model used for the multiple imputation data generation will use one of two 
approaches depending on data type: 
• Continuous endpoints will use the Markov Chain Monte Carlo (MCMC) method 
with adjustment for covariates. 
• Binary and ordinal endpoints will use a two-stage approach: 
1. First intermittent missing data will be imputed using MCMC followed by 
adaptive rounding [Carpenter, 2012] step to create a monotone structure. 
2. Second a monotone logistic regression imputation will be performed to 
impute data post-study withdrawal, this model will include the analyses 
covariates. If logistic regression step fails to converge the following back-
up options including: 
i. 
A discriminant function [Brand, 1999] may be used in place of 
logistic. 
ii. 
MCMC with adaptive rounding. 
A sufficient number of imputations will be performed to ensure the stability of the 
estimates, the current plan is 10,000 imputation.  The results of analysis from each 
complete imputed dataset will be combined using Rubin’s rule.  Table 7 details the 
models, covariates and the seed to be used for the analyses. 
For subgroup analyses the multiple imputation model will be identical to the main 
endpoint analyses and the interaction term will be added into the analysis step. The chi-
squared test statistic of the interaction term will be pooled using the procedure of Rubin  
(1987) and Li (1991).  


 
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Table 7 
Multiple Imputation Specifications  
Endpoint  
Model 
Covariates 
Post Baseline 
Timepoints 
Included in 
Prediction Model 
Initial 
Seed 
Participants alive and 
free of respiratory failure 
at Day 7, 14, 28, 42, and 
60. 
 
Monotone 
Binary Logistic 
Regression 
Treatment, Clinical 
Status at Baseline, 
Age Group at 
Baseline 
Days 7,14,28,42 
and 60 
3764 
 
All-cause mortality at 
Day 60. 
 
Monotone 
Binary Logistic 
Regression 
Treatment, Clinical 
Status at Baseline, 
Age Group at 
Baseline 
Days 7,14,28,42 
and 60 
1734 
Participants alive and 
independent of 
supplementary oxygen 
at Day 7, 14, 28, 42, and 
60 
Monotone 
Binary Logistic 
Regression 
Treatment, Clinical 
Status at Baseline, 
Age Group at 
Baseline 
Days 7,14,28,42 
and 60 
9849 
Admission to ICU up to 
Day 28 
 
Monotone 
Binary Logistic 
Regression 
Treatment, Clinical 
Status at Baseline, 
Age Group at 
Baseline 
Days 4, 7, 10, 14 
and 28 
6935 
If the number of participants is small within a category of a covariate, then the covariate categories 
may be refined. If the category cannot be refined further, then the covariate may be included as a 
continuous measure.   
The seeds were generated using the following code: 
DATA seeds; 
  DO i=1 to 4; 
    seed=int(10000*ranuni(214094)); 
    OUTPUT; 
  END; 
RUN; 
If additional seeds are required, then the initial seed as specified will be incremented by 1. 


 
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6.3.1.1. 
Adaptive Rounding 
The adaptive rounding algorithm [Carpenter, 2012] is: 
1. For binary variable  in imputed dataset 
, let 
 denote the mean of 
the observed (binary) and imputed (continuous) values. 
2. Construct the threshold 
 
3. In imputed data set , re-code continuous imputed values of the binary variable  
according to the following rule: 
 becomes 
, and  
 
becomes 
. 
6.3.2. 
Proportional Odds Regression Model Checking 
To assess the assumption of proportional odds for the clinical status logistic regressions 
will be performed for each binary grouping: 
7 
and for each covariate separately (treatment, clinical status and age group at baseline). 
The coefficients of a given covariate will be tested for equality across the binary logistic 
regressions using a Wald test.  This test being anti-conservative, the proportionality of the 
odds will be also be assessed graphically. 
6.3.3. 
Time to Event Model Checking 
For the Cox proportional hazards model, the proportional hazards assumption will be 
assessed prior to model fitting using the following methods: 
• Plot of log(-log(survival)) versus log(time) by treatment group: A non-parallel 
pattern is an indication of violation of the proportional hazard assumption. 
• Plot of Schoenfeld residuals versus time for continuous covariates: A non-zero 
slope is an indication of a violation of the proportional hazard assumption. 
• Evaluation of time-dependency of treatment effect by adding an interaction term 
of treatment and time in the Cox model.  If the interaction term is significant (p< 
0.05), it is considered that the proportional hazards assumption is violated. 
If one or more of the procedures above demonstrates clear violation of the proportional 
hazards assumption, it will be considered the proportional hazards assumption does not 
hold.  
6.3.4. 
Count Data Model Checking 
Distributional assumptions underlying the model used for analysis will be checked.  If 
there are any departures from the distributional assumptions, alternative models may be 
explored as sensitivity analyses. 


 
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7. 
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Strategies for the Statistical Analysis of Incomplete Data Sets. Ph.D. thesis, Erasmus 
University 1999. 
Carpenter JR, Kenward MG. Multiple Imputation and its Applications. Wiley 2012. 
Ge, Murray, Meyer, et al. Covariate-adjusted difference in proportions from clinical trials 
using logistic regression and weighted risk differences. Drug Information Journal 
2011;45:481-93 
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blind, placebo-controlled, study evaluating the efficacy and safety of otilimab IV in 
patients with severe pulmonary COVID-19 related disease. Effective Date 02-JUL-2020. 
Lan KKG, DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika 
1983;70:659-63. 
Li, K.-H., Meng, X.-L., Raghunathan, T.E., and Rubin, D.B. Significance levels from 
repeated p-values with multiply-imputed data. Statistica Sinica, 1991;1:65-92 
Permutt T, Li F. Trimmed means for symptom trials with dropouts. Pharm Stat 
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Rubin D.B. Multiple Imputation for Nonresponse in Surveys. John Wiley and Sons 1987. 
Sanofi. Press release. https://www.sanofi.com/en/media-room/press-releases/2020/2020-
04-27-12-58-00. 
Van Buuren, S. Multiple Imputation of Discrete and Continuous Data by Fully 
Conditional Specification. Statistical Methods in Medical Research 2007;16:219–242. 
WHO. https://www.who. int/blueprint/priority-diseases/key-action/COVID-
19_Treatment_Trial_Design_Master_Protocol_synopsis_Final_18022020.pdf, 2020.