Conditions: COVID-19
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 115
Healthy volunteers: no

Brief summary:
The primary objective of the study is to evaluate the efficacy of bemcentinib as an add-on therapies to standard of care (SoC) in participants hospitalized with coronavirus disease 2019 (COVID-19).

Detailed description:

Arms:
arm 1: Bemcentinib will be administered for up to 15 days, or until discharge from hospital, whichever comes sooner. SoC will be administered based on local guidelines. arm 2: The SoC will be administered based on local guidelines in place at the time of treatment during the study.

Interventions: intervention 1: Bemcentinib intervention 2: SoC
Intervention descriptions: intervention 1: Bemcentinib capsules will be administered orally. intervention 2: The SoC will be administered based on local guidelines.

Protocol document:
Prot_000.pdf: 
CONFIDENTIAL  
 
Protocol BGBC020 – Amendment 2 Final 
Final, 08 October 2020  
1  
TITLE PAGE 
Protocol Title: A Multicentre, Phase 2, Randomised Study to Assess the Efficacy and Safety of 
Bemcentinib for the Treatment of COVID-19 in Hospitalised Patients 
 
Protocol Number: BGBC020 
Amendment Number: Amendment 2 
Product: Bemcentinib 
Study Phase: 2 
Sponsor Name: BerGenBio ASA 
Legal Registered Address: 
Jonas Lies vei 91 
5009 Bergen 
NORWAY 
 
Date of Protocol:  08 October 2020 
Version: Amendment 2, Final 
 
 
 


CONFIDENTIAL  
 
Protocol BGBC020 – Amendment 2 Final 
Final, 08 October 2020  
2  
Sponsor Signatory: 
 
 
I have read this protocol in its entirety and agree to conduct the study accordingly: 
 
  
  
  
  
  
  
  
 
 
BSc MB ChB MSc PhD FRCPE FRCP 
 
Date 
 BerGenBio ASA   
Medical Monitor name and contact information can be found in Appendix 2.
PPD
PPD


CONFIDENTIAL  
 
Protocol BGBC020 – Amendment 2 Final 
Final, 08 October 2020  
3  
VERSION HISTORY 
Name 
Date 
Summary of Changes 
Original Protocol 
05Aug2020 
Creation 
Original Protocol 
26Aug2020 
Modification of Inclusion/Exclusion criteria: 
exclusion patient with planned or current HIV and/or 
TB treatment, exclusion of Hep B and C positive 
patients, addition of Hep B and C viral serology at 
screening. 
Amendment 2 
08Oct2020 
Addition and clarification on Steering committee, 
addition of IDMC (section 9.7.2 
 
Independent Data and Safety 
Monitoring Committee), addition of stopping 
criteria (section 6.9 
Stopping Rules), 
typographical corrections, addition of country-
specific grade eligibility criteria (India – section 5.1 
 
Inclusion Criteria and 5.2  
Exclusion 
Criteria), addition of country target enrolment 
numbers, addition of procedures for handling 
protocol violations (section 7.4  Protocol Violation), 
addition of details on central laboratory assessments 
(section 8.2.3  Clinical Safety Laboratory 
Assessments), clarification of wording regarding 
adverse event of special interest (section 8.3.6 
 
Adverse Events of Special Interest), 
addition of section on known adverse event serious 
adverse events (section 8.3.8 
Adverse events 
reported in non-COVID studies and 8.3.9
 
Expected Serious Adverse Events), 
addition of details on study monitoring (section 10.0 
 
 
STUDY 
MONITORING) 
 
 
 


CONFIDENTIAL  
 
Protocol BGBC020 – Amendment 2 Final 
Final, 08 October 2020  
4  
TABLE OF CONTENTS 
 
TITLE PAGE .............................................................................................................................................. 1 
TABLE OF CONTENTS ........................................................................................................................... 4 
TABLE OF TABLES .................................................................................................................................. 8 
TABLE OF FIGURES ................................................................................................................................ 9 
1.0 PROTOCOL SUMMARY ................................................................................................................. 10 
1.1  
Synopsis ...................................................................................................................................... 10 
1.2  
Schema ....................................................................................................................................... 16 
1.3  
Schedule of Activities ................................................................................................................ 17 
2.0 INTRODUCTION ............................................................................................................................... 21 
2.1  
Study Rationale ......................................................................................................................... 21 
2.2  
Background ............................................................................................................................... 21 
2.3  
Benefit/Risk Assessment ........................................................................................................... 22 
2.3.1 
Background/Rationale in Support of Bemcentinib for COVID-19 .............................. 22 
2.3.2 
Preliminary Efficacy Data vs With SARS-CoV-2 in Vitro ............................................ 23 
2.3.3 
Cardiac Safety ................................................................................................................... 25 
3.0 OBJECTIVES AND ENDPOINTS ................................................................................................... 27 
4.0 STUDY DESIGN ................................................................................................................................. 30 
4.1  
Overall Design ........................................................................................................................... 30 
4.2  
Scientific Rationale for Study Design ...................................................................................... 31 
4.3  
Justification for Dose ................................................................................................................ 31 
4.4 
Human Experience from Trials in Cancer Patients ............................................................... 33 
4.5  
End of Study Definition ............................................................................................................ 33 
5.0 STUDY POPULATION ..................................................................................................................... 34 
5.1  
Inclusion Criteria ...................................................................................................................... 34 
5.2  
Exclusion Criteria ..................................................................................................................... 35 
5.3  
Lifestyle Considerations ........................................................................................................... 36 
5.4  
Screen Failures .......................................................................................................................... 36 
6.0 STUDY TREATMENT ...................................................................................................................... 37 
6.1  
Study Treatment(s) Administered ........................................................................................... 37 


CONFIDENTIAL  
 
Protocol BGBC020 – Amendment 2 Final 
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5  
6.2  
Dose Modifications and Toxicity Management ...................................................................... 37 
6.3  
Preparation/Handling/Storage/Accountability....................................................................... 38 
6.3.1 
Bemcentinib Storage, Dispensing, and Destruction ....................................................... 38 
6.4  
Measures to Minimise Bias: Randomisation and Blinding ................................................... 38 
6.5  
Study Treatment Compliance .................................................................................................. 39 
6.6  
Concomitant Therapy ............................................................................................................... 39 
6.6.1 
Citalopram – Specific Guidance for Use ......................................................................... 40 
6.6.2 
Dosing with Remdesivir .................................................................................................... 40 
6.7  
Dose Modification ..................................................................................................................... 40 
6.8  
 Treatment after the End of the Study .................................................................................... 40 
6.9 
Stopping Rules ........................................................................................................................... 41 
7.0 DISCONTINUATION OF STUDY TREATMENT AND PATIENT 
DISCONTINUATION/WITHDRAWAL ............................................................................................... 42 
7.1  
Discontinuation of Study Treatment ....................................................................................... 42 
7.2  
Patient Discontinuation/Withdrawal from the Study ............................................................ 42 
7.3  
Lost to Follow-up ...................................................................................................................... 43 
7.4  
Protocol Violation ..................................................................................................................... 43 
8.0 STUDY ASSESSMENTS AND PROCEDURES ............................................................................. 44 
8.1  
Efficacy Assessments................................................................................................................. 44 
8.1.1  
Improvement on the 9-Point Scale .................................................................................. 44 
8.1.2  
Other Efficacy Assessments ............................................................................................. 46 
8.2  
Safety Assessments .................................................................................................................... 46 
8.2.1  
Physical Examinations ...................................................................................................... 47 
8.2.2  
Vital Signs and Blood Gases ............................................................................................. 47 
8.2.3  
Clinical Safety Laboratory Assessments ......................................................................... 47 
8.3  
Adverse Events .......................................................................................................................... 48 
8.3.1 
Time Period and Frequency for Collecting AE and SAE Information ........................ 48 
8.3.2  
Method of Detecting AEs and SAEs ................................................................................ 48 
8.3.3  
Follow-up of AEs and SAEs ............................................................................................. 49 
8.3.4  
Regulatory Reporting Requirements for SAEs .............................................................. 49 
8.3.5  
Pregnancy .......................................................................................................................... 49 
8.3.6  
Adverse Events of Special Interest .................................................................................. 49 


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Protocol BGBC020 – Amendment 2 Final 
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6  
8.3.7  
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as Adverse 
Events or Serious Adverse Events ................................................................................................... 50 
8.3.8 
Adverse events reported in non-COVID studies ............................................................ 50 
8.3.9 
Expected Serious Adverse Events .................................................................................... 50 
8.4  
Treatment of Overdose ............................................................................................................. 50 
8.5  
Pharmacokinetics ...................................................................................................................... 50 
8.6  
Pharmacodynamics ................................................................................................................... 51 
8.7  
Virologic Load ........................................................................................................................... 51 
8.8  
Immunology ............................................................................................................................... 51 
8.9 Serology Research ........................................................................................................................... 52 
9.0 STATISTICAL CONSIDERATIONS .............................................................................................. 53 
9.1  
Design Overview ........................................................................................................................ 53 
9.2  
Statistical Hypotheses ............................................................................................................... 53 
9.3  
Sample Size Determination ...................................................................................................... 53 
9.3.1 
Sample Size Calculations .................................................................................................. 53 
9.4  
Populations for Analyses .......................................................................................................... 54 
9.5  
Statistical Analyses .................................................................................................................... 55 
9.5.1 
Efficacy Analyses............................................................................................................... 55 
9.5.2  
Safety Analyses .................................................................................................................. 56 
9.5.3  
Other Analyses .................................................................................................................. 57 
9.5.4  
Missing Data ...................................................................................................................... 58 
9.6  
Interim Analyses ....................................................................................................................... 58 
9.7  
Review Committees ................................................................................................................... 59 
9.7.1  
Steering Committee (Scientific Review Committee) ...................................................... 59 
9.7.2  
Independent Data and Safety Monitoring Committee................................................... 59 
10.0  
 STUDY MONITORING.......................................................................................................... 60 
10.1  
 Monitoring of the Study ...................................................................................................... 60 
10.2  
Monitoring plan..................................................................................................................... 61 
11.0 REFERENCES .................................................................................................................................. 62 
12.0 APPENDICES ................................................................................................................................... 64 
Appendix 1  Abbreviations ................................................................................................................ 65 
Appendix 2  Regulatory, Ethical, and Study Oversight Considerations ....................................... 66 
Protocol Compliance ......................................................................................................................... 66 


CONFIDENTIAL  
 
Protocol BGBC020 – Amendment 2 Final 
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7  
Regulatory and Ethical Considerations .......................................................................................... 66 
Financial Disclosure .......................................................................................................................... 67 
Indemnity ........................................................................................................................................... 67 
Informed Consent Process................................................................................................................ 67 
Data Protection .................................................................................................................................. 68 
Administrative Structure ................................................................................................................. 69 
Dissemination of Clinical Study Data .............................................................................................. 69 
Data Quality Assurance .................................................................................................................... 69 
Source Documents ............................................................................................................................. 69 
Study and Study Centre Closure ..................................................................................................... 70 
Publication Policy .............................................................................................................................. 70 
Appendix 3  Clinical Laboratory Tests ............................................................................................. 72 
Appendix 4  Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-up, 
and Reporting ........................................................................................................................................ 74 
Appendix 5  Contraceptive Guidance and Collection of Pregnancy Information ........................ 79 
Definitions: ......................................................................................................................................... 79 
Contraception Guidance................................................................................................................... 79 
Collection of Pregnancy Information .............................................................................................. 81 
Appendix 6  Avoidance of Concomitant Medication with QT Prolongation Risk or CYP3A4 
Interaction with Narrow Therapeutic Index ...................................................................................... 83 
Appendix 7 
The NEWS2 Scoring System ........................................................................................ 85 
Appendix 8 
Study Procedures During Special Circumstances ...................................................... 86 
Appendix 9  Signature of Investigator .............................................................................................. 87 
 
 
 


CONFIDENTIAL  
 
Protocol BGBC020 – Amendment 2 Final 
Final, 08 October 2020  
8  
TABLE OF TABLES 
Table 1 Schedule of Activities ................................................................................................................. 17 
Table 2 Study Objectives and Endpoints ................................................................................................. 27 
Table 3 Sample Size for 80% and 90% Power for Time to Improvement, Discharge from Hospital, or 
Fit for Discharge Using Log-rank Test for a Hazard Ratio of 1.6 in Treatment Arm to Standard of Care 54 
Table 4 Analysis Sets ............................................................................................................................... 55 
Table 5 Efficacy Analyses ....................................................................................................................... 56 
Table 6 Protocol-required Safety Laboratory Assessments ..................................................................... 73 


CONFIDENTIAL  
 
Protocol BGBC020 – Amendment 2 Final 
Final, 08 October 2020  
9  
TABLE OF FIGURES 
Figure 1 
Study Schema .......................................................................................................................... 16 
Figure 2 
Bemcentinib Potently Inhibits Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-
CoV-2) Infection of Vero E6 Cells ............................................................................................................. 24 
Figure 3 
Complete Inhibition of AXL Kinase Activation (p-AXL) in Two Acute Myeloid Leukaemia 
Patients Treated with Bemcentinib at the Recommended Phase 2 Dose (200 mg Maintenance Daily 
Dosing) 
................................................................................................................................................. 32 
Figure 4 
Bemcentinib Plasma Pharmacokinetics in Acute Myeloid Leukaemia Patients ..................... 32 
  
 


CONFIDENTIAL  
 
Protocol BGBC020 – Amendment 2 Final 
Final, 08 October 2020  
10  
1.0 PROTOCOL SUMMARY 
1.1  
Synopsis 
Protocol Title: A Multicentre, Phase 2, Randomised Study to Assess the Efficacy and Safety of 
Bemcentinib for the Treatment of COVID-19 in Hospitalised Patients 
Rationale: 
There are currently only 2 approved therapeutic agents available to treat coronavirus disease 2019 
(COVID-19) in patients whose disease severity warrants treatment in hospital with supplementary oxygen 
(with or without ventilatory support). 
• 
Remdesivir is an adenosine nucleotide prodrug indicated for the treatment of adults and 
adolescent patients hospitalised with severe acute respiratory syndrome coronavirus 2 
(SARS-CoV-2) infection and severe disease. 
• 
In the RECOVERY trial in the UK, dexamethasone reduced deaths by one-third in ventilated 
patients and by one-fifth in other patients receiving oxygen only. This has formed the basis for its 
inclusion in the SoC management of severe COVID-19 worldwide since June 2020, given its 
prior authorised posology for a broad range of non-endocrine corticosteroid responsive 
conditions. 
Despite these advances in the therapeutic options for coronaviruses such as SARS-CoV-2 (causative 
agent of COVID-19), there is an urgent public health need for rapid development of additional 
interventions. The aim of this study is to rapidly assess bemcentinib as a treatment for COVID-19, in 
order to provide evidence of efficacy in this preliminary evaluation and to help with the design 
considerations of a later confirmatory stage. Hospitalised patients that may require either supplemental 
oxygen, non-invasive ventilation or high-flow oxygen devices would be considered for enrolment in the 
study. Patients in the need of intubation and invasive ventilation at the time of enrolment, would not be 
considered for this study. 
 


CONFIDENTIAL  
 
Protocol BGBC020 – Amendment 2 Final 
Final, 08 October 2020  
11  
Objectives and Endpoints 
Objectives  
Endpoints  
Primary  
  
• 
To evaluate the efficacy of bemcentinib as 
add-on therapy to standard of care (SoC) in 
patients hospitalised with coronavirus disease 2019 
(COVID-19).  
• 
Time to sustained clinical improvement of at 
least 2 points (from randomisation) on a 9-point 
category ordinal scale, live discharge from the 
hospital, or considered fit for discharge (a score of 
0, 1, or 2 on the ordinal scale), whichever comes 
first, by Day 29 (this will also define the 
“responder” for the response rate analyses). 
9-point category ordinal scale: 
0. Uninfected, no clinical or virological evidence 
of infection 
1. Ambulatory, no limitation of activities 
2. Ambulatory, limitation of activities 
3. Hospitalised – mild disease, no oxygen therapy 
4. Hospitalised – mild disease, oxygen by mask or 
nasal prongs 
5. Hospitalised – severe disease, non-invasive 
ventilation or high-flow oxygen 
6. Hospitalised – severe disease, intubation and 
mechanical ventilation 
7. Hospitalised – severe disease, ventilation and 
additional organ support – vasopressors, renal 
replacement therapy, extracorporeal membrane 
oxygenation 
8. Death  
 
Key Secondary  
 
• 
To evaluate the ability to prevent deterioration 
according to the ordinal scale by 1, 2, or 3 points  
• 
The proportion of patients not deteriorating 
according to the ordinal scale by 1, 2, or 3 points on 
Days 2, 8, 15, and 29 
• 
To evaluate the number of oxygen-free days  
• 
Duration (days) of oxygen use and oxygen-free 
days  
 
 


CONFIDENTIAL  
 
Protocol BGBC020 – Amendment 2 Final 
Final, 08 October 2020  
12  
• 
To evaluate severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2) viral load  
• 
Qualitative and/or quantitative polymerase chain 
reaction (PCR) determination of severe acute 
respiratory syndrome coronavirus 2 (SARS-CoV-2) in 
oropharyngeal/nasal swab while hospitalised on Days 
1, 3, 5, 8, 11, 15, and 29  
Other Secondary  
 
• 
To evaluate ventilator-free days and incidence 
and duration of any form of new ventilation use 
• 
Duration (days) of ventilation and ventilation-
free days 
• 
Incidence of any form of new ventilation use and 
duration (days) of new ventilation use 
• 
To evaluate duration of organ support (eg, 
including respiratory, renal, and cardiac support) 
• 
Duration (days) of organ support 
• 
To evaluate response rate (see primary 
endpoint for definition of responder) 
• 
Response rate (number and %) by treatment arm 
at Days 2, 8, 15, and 29 
• 
To evaluate time to discharge  
• 
Time to live discharge from the hospital 
• 
To evaluate overall mortality  
• 
Mortality at Days 15, 29, and 60 
• 
Time from treatment start date to death 
• 
Change in the ratio of the oxygen saturation to 
fraction of inspired oxygen concentration 
(SpO2/FiO2) 
• 
SpO2/FiO2, measured daily from randomisation 
to Day 15, hospital discharge, or death  
• 
To evaluate the safety of bemcentinib as 
add-on therapy to SoC in patients with COVID-19 
• 
Physical examination. 
• 
Clinical laboratory examinations. 
• 
Vital signs (blood pressure/heart 
rate/temperature/respiratory rate). 
• 
Adverse events  
• 
To evaluate intensive care unit (ICU) and 
hospitalisation length  
• 
Duration (days) of ICU and hospitalisation  
• 
To evaluate National Early Warning Score 2 
(NEWS2) 
• 
NEWS2 assessed daily while hospitalised and on 
Days 15 and 29. 
• 
Time to a NEWS2 of ≤2, maintained for at least 
24 hours  
• 
To evaluate improvement taking into account 
worsening and death  
• 
Ranked trajectory over 29 days, with trajectory 
ranked in the following order of the ordinal scale: 
o 
[ascending order] The worst score 
o 
[ascending order] The last recorded 
score 
o 
[ascending order] The number of days at 
worst score 
o 
[ascending order] The best score that 
occurs after the worst score (this will 
equal the worst score if the worst score 
is the last score) 
o 
[descending order] The number of days 


CONFIDENTIAL  
 
Protocol BGBC020 – Amendment 2 Final 
Final, 08 October 2020  
13  
the patient is at 4), counting only days 
after the last occurrence of the worst 
score (the number of days for this item 
will be 0 if the worst score is the last 
score)  
Exploratory  
 
• 
To evaluate PK of bemcentinib 
• 
PK concentration and parameters 
• 
To evaluate SARS-CoV-2 viral load  
• 
Qualitative and/or quantitative PCR 
determination of SARS-CoV-2 in blood (on Day 1) 
and saliva (while hospitalised) on Days 1, 3, 5, 8, 11, 
15, and 29 (may be become a secondary endpoint 
once the assays are available)  
• 
To collect samples for serology research, viral 
genomics, serum antibody production, and 
COVID-19 diagnostics  
• 
Analysis of samples collected at baseline prior to 
treatment and at specific time points  
 
Overall Design: 
BGBC020 is a study designed to rapidly seek and determine the nature of signals of efficacy and safety of 
bemcentinib in the treatment of hospitalised patients with SARS-CoV2. The study design is analogous to 
the first stage of the ACCORD-2 platform protocol, a national study protocol in the United Kingdom in 
which bemcentinib is being evaluated. 
 
BGBC020 (referred to henceforth as “the current study”) will include hospitalised adult patients 
(≥18 years) who have infection with SARS-CoV-2 (the virus that causes COVID-19), as confirmed by 
laboratory tests and/or point of care tests. For inclusion, patients will need to have clinical status of 
Grade 3 (hospitalised – mild disease, no oxygen therapy) to Grade 5 (hospitalised – severe disease, non-
invasive ventilation or high-flow oxygen), as defined by a 9-point ordinal scale.  
Participating sites in India will enrol only patients categorised as Grades 4 or 5 (hospitalised with 
moderate disease requiring oxygen supplementation, but not intubation). The reason for this is that, in 
accordance with India national COVID-19 management guidelines, patients who do not require 
supplementary oxygen therapy, would not generally be admitted to hospital. The effect of this is that 
Grade 3 patients in India, would only constitute a group of patients who had improved from more severe 
categories and were being prepared for discharge from hospital. 
First dose of bemcentinib must take place within 72 hours of Investigator receipt of laboratory or 
validated point of care test confirmation of SARS-CoV-2 infection. If a patient has a confirmed result 
prior to hospital admission which is more than 72 hours old, first dose of bemcentinib should take place 
within a calendar day of admission to hospital, where in the opinion of the Investigator, the reason for 
admission is relevant to ongoing COVID-19 infection. Any exceptions to this must be authorised by the 
Medical monitor and/or Sponsor medical team. 
 
Patients will be randomised (1:1) to treatment arm to receive bemcentinib (as an add-on to standard of 
care [SoC]) or to control arm where only SoC will be administered. 
 
Number of Investigators and Study Centres: 
Study centres will be located in South Africa and India. 


CONFIDENTIAL  
 
Protocol BGBC020 – Amendment 2 Final 
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14  
 
Number of Patients: 
The expected number of patients for each treatment arm will be 60; for a total of 120 patients in this 
study. For each country, South Africa and India, an enrolment target of 60 patients (randomised 1:1) is in 
place. 
 
Treatment Arms and Duration: 
There will be 2 treatment arms- 
- 
Patients receiving bemcentinib as an add-on to the SoC 
- 
 Patients receiving only SoC 
 
The total study duration would be approximately 90 days.  
 
Statistical Methods: 
Sample size determination: 
Note: the sample size calculation may re-evaluated as the treatment of COVID-19 evolves. 
 
Approximately 60 patients will be randomised into each arm of the study, whereby patients will 
receive either bemcentinib (with SoC) or SoC alone. The chosen endpoint to compare treatments will 
be the time to a sustained 2-point improvement on a 9-point category ordinal scale, discharge from 
hospital, or considered fit for discharge. 
 
It is expected that 54 patients are needed per arm, which will provide 80% power to detect a hazard 
ratio of 1.6 for the occurrence of the event, when comparing bemcentinib with SoC. This calculation is 
based on a 1-sided test and a 10% significance level, and assumes 85.5% of patients will improve, be 
discharged from hospital, or considered fit for discharge at Day 29 for bemcentinib versus 70% of 
patients for the SoC. To allow for uncertainty in the recruitment rates, 60 patients are planned to be 
randomised to each treatment arm in order to achieve the required number of events for this analysis. 
 
Analysis sets: 
• 
Intention to Treat (ITT) Set: All patients who are randomised and match the inclusion/exclusion 
criteria of the protocol will be included in the ITT. 
• 
Safety Analysis Set: All patients who are randomised and receive study intervention (bemcentinib 
or SoC) will be included in the Safety Analysis Set. 
• 
Pharmacokinetic Analysis Set (PKS): All patients who are randomised and take at least 1 dose of 
bemcentinib and have bemcentinib concentrations postdose without protocol deviations or events 
affecting the pharmacokinetic (PK) results will be included in the PKS. 
• 
Pharmacodynamic Analysis Set (PDS): All patients who are randomised and receive study 
intervention (bemcentinib or SoC) and have evaluable results for at least 1 pharmacodynamic 
(PD) endpoint postdose. All analyses of the PDS will be based on each patient’s randomised 
assigned treatment (not actual treatment received). 
Efficacy, safety, pharmacokinetic, and pharmacodynamic results will be listed and summarised by stage, 
dose, and scheduled time for the respective analysis sets, where appropriate. Bemcentinib concentration 
versus response variables may be graphically displayed for selected endpoints. 


CONFIDENTIAL  
 
Protocol BGBC020 – Amendment 2 Final 
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15  
Exposure-response data obtained from this study may be combined with data from other studies and used 
for modelling and simulations. 
 
Internal Sponsor Steering Committee: Yes 
 
.  
 


CONFIDENTIAL  
 
Protocol BGBC020 – Amendment 2 Final 
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16  
1.2  
Schema 
Figure 1 
Study Schema 
 
Abbreviation: COVID-19 = coronavirus disease 2019, EOS = end of study, SOC= Standard of care 
 


CONFIDENTIAL  
 
 
Protocol BGBC020 – Amendment 2 Final 
 
Final 08 October 2020 
17  
1.3  
Schedule of Activities 
Table 1 
Schedule of Activities 
 
Screening 
Visit 
Baseline 
Visit 
Inpatient Visit 
Follow-
up Visit 
End of 
Study 
Visit 
Day (± Window) 
Day-1 or 
Day 0 
Day 1 
Day 2 
Day 3 
Day 
4 
Daily 
Until 
Hospital 
Discharge 
Day 15a 
(±2 days) 
Day 29a 
(±3 days) 
Day 60a 
(±4 days) 
Day 90a 
(±6 days) 
ELIGIBILITY 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Relevant medical historyb 
X 
 
 
 
 
 
 
 
 
 
Review SARS-CoV-2 diagnostic tests 
X 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
STUDY INTERVENTION 
 
 
 
 
 
 
 
 
 
 
Randomisation 
 
X 
 
 
 
 
 
 
 
 
Administration of bemcentinibc 
 
X 
X 
X 
X 
X 
X 
 
 
 
Treatment with SoC 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
STUDY PROCEDURES 
 
 
 
 
 
 
 
 
 
 
Clinical frailty score 
X 
 
 
 
 
 
 
 
 
 
Diagnostic imaging (chest X-ray and/or 
computed tomography)d 
X 
 
 
 
 
 
 
 
 
 
Physical examination (including presenting 
signs, height, weight) 
X 
 
 
 
 
 
 
 
 
 
Targeted physical examination (To be 
performed as clinically indicated) 
 
 
X 
X 
X 
X 
 
 
 
 
Vital signs, including temperature, pulse 
rate, blood pressure, respiratory rate, SpO2 
 
Xe 
X 
X 
X 
X 
X 
X 
 
 
Clinical assessmentsf 
 
Xe 
X 
X 
X 
X 
X 
X 
 
 
Targeted medication review (including use 
of vasopressors) 
 
Xe 
X 
X 
X 
X 
X 
X 
 
 
Adverse event evaluation (including 
adverse events of special interest) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Disease-related co-infection evaluation 
(including microbiologic/infectious agent 
assessment/results; bacteria, viral, fungi) 
 
X 
X 
X 
X 
X 
 
 
 
 


CONFIDENTIAL  
 
 
Protocol BGBC020 – Amendment 2 Final 
 
Final 08 October 2020 
18  
 
Screening 
Visit 
Baseline 
Visit 
Inpatient Visit 
Follow-
up Visit 
End of 
Study 
Visit 
Day (± Window) 
Day-1 or 
Day 0 
Day 1 
Day 2 
Day 3 
Day 
4 
Daily 
Until 
Hospital 
Discharge 
Day 15a 
(±2 days) 
Day 29a 
(±3 days) 
Day 60a 
(±4 days) 
Day 90a 
(±6 days) 
Survival status 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood gases and FiO2 at worst PO2g 
 
X 
X 
X 
X 
X 
X 
 
 
 
12-lead ECGh 
X 
X 
 
 
X 
Xh 
X 
 
 
 
LOCAL SAFETY LABORATORYi 
 
 
 
 
 
 
 
 
 
 
Haematology, chemistry, liver function 
tests, coagulationi 
Xe,j,k 
 
 
X 
 
Days  5, 
8, 11 (all 
±1 day)  
X l 
X l 
 
 
Hepatitis B and C virus serology 
Xr 
 
 
 
 
 
 
 
 
 
Pregnancy test for females of childbearing 
potentialm 
Xj 
 
 
 
 
 
 
 
 
 
CENTRAL LABORATORY 
 
 
 
 
 
 
 
 
 
 
Blood (SST) for exploratory soluble factors 
analysis 
 
X 
 
X 
 
Days  5, 
8, 11 (all 
±1 day) 
X 
X 
 
 
Blood (sodium heparin tube) for PBMC 
cellular immunity assays (optional)n 
 
X 
 
X 
 
Day 8 
X 
 
 
 
Blood (EDTA) for SARS-CoV-2 PCR 
(qualitative and/or quantitative) 
 
X 
 
X 
 
 
 
 
 
 
Oropharyngeal/nasal swab for SARS-CoV-
2 PCR (qualitative and/or quantitative) 
 
X 
 
X 
 
Days 5, 
8, 11 (all 
±1 day) 
X 
X 
 
 
Saliva for SARS-CoV-2 PCR (qualitative 
and/or quantitative) 
 
X 
 
X 
 
Days 5, 
8, 11 (all 
±1 day) 
X 
X 
 
 
Blood (SST) for SARS-CoV-2 serology 
researcho  
 
X 
 
 
 
Day 8 
X 
X 
X 
 
Mid-turbinate nasal swab viral genomep 
 
X 
 
 
 
 
 
 
 
 
Blood samples for PDq 
 
X 
 
 
X 
Day 8 
X 
X 
X 
 
PK samplingq 
 
X 
 
 
X 
Day 8  
X 
 
 
 
ECG=electrocardiogram; EDTA=ethylenediaminetetraacetic acid; FiO2=fraction of inspired oxygen; PBMC=peripheral blood mononuclear cell; 
PCR=polymerase chain reaction; PD=pharmacodynamic; PK=pharmacokinetic; PO2=partial pressure of oxygen; RT PCR=reverse transcription polymerase 
chain reaction; SARS-CoV-2=severe acute respiratory syndrome coronavirus 2; SoC=standard of care; SpO2=oxygen saturation; SST=serum separator tube. 


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a These visits will be performed even if a patient has already been discharged. If discharged prior to scheduled visit, in-person visits are preferred, but recognising 
that quarantine and other factors may limit the patient’s ability to return to the clinic, these visits may be conducted by telephone or with a home visit by study 
staff (blood samples scheduled for Days 15 and 29 will only be collected if the visit is conducted at the clinic). For visits conducted by telephone, it will not 
be possible to perform some scheduled assessments (eg, vital signs). The Day 29 assessments will also be performed, where possible, for patients who 
discontinue the study prematurely. 
b Medical history includes estimated date and time of first signs and symptoms and number of co-morbidities (eg, respiratory, cardiovascular, metabolic, 
malignancy, endocrine, gastrointestinal, immunologic, renal). 
c First dose of bemcentinib must take place within 72 hours of Investigator receipt of laboratory or validated point of care test confirmation of SARS-CoV-2 
infection. Any exceptions to this must be authorised by the Medical monitor and/or Sponsor medical team. If a patient has a confirmed result prior to hospital 
admission which is more than 72 hours old, first dose of bemcentinib should take place within a calendar day of admission to hospital, where in the opinion of 
the Investigator, the reason for admission is relevant to ongoing COVID-19 infection. Up to 15 days of bemcentinib treatment can be administered or until 
hospital discharge if less than 15 days. Bemcentinib should be taken once per day, in the morning, on an empty stomach or more than 2 hours after a light 
meal, with water. Patients should not consume anything other than water for at least 1 hour after taking study drug. 
 
Patients will receive 400 mg loading doses on Days 1, 2, and 3 and 200 mg maintenance doses daily from Day 4 till the discharge or Day 15, whichever 
occurs earlier. 
d Results obtained outside of the screening window are acceptable. If multiple assessments are performed during this time, the assessment closest to dosing will 
be regarded as the formal baseline assessment. 
e Baseline assessments should be performed prior to study drug administration. 
f Includes ordinal score, National Early Warning Score 2 (NEWS2), oxygen requirement, organ support, non-invasive or invasive ventilator requirement, 
including start and stop of low- or high-flow oxygen supply or of any form of ventilation etc. 
g If done as part of SoC, blood gases results to be fully recorded with date and time. 
h ECG to coincide with selected PK and PD sampling time points, ie, pre-loading dose (Day 1); then pre-maintenance dose and 6 hours postdose (Day 4). 
Subsequently predose on Days, 8 and 15. If QTcF is calculated from any ECG to be greater than or equal to 501 msec, then the ECG should be repeated after 
an interval of more than 10 minutes, to confirm this finding on a second ECG. If QTcF confirmed to be 501 msec or greater, bemcentinib should be 
permanently discontinued (see Section 7.0) by Investigator  
i Please see Appendix 3. 
j Laboratory tests performed in the 48 hours prior to first dose of study treatment will be accepted for determination of eligibility. If multiple tests are performed 
during this time, the test closest to dosing will be regarded as the formal baseline sample. 
k Any laboratory tests performed as part of routine clinical care within the specified visit window can be used for safety laboratory testing. 
l Additional safety laboratory evaluations to be performed on Days 15 and 29 only if patient is still hospitalised. 
m Serum or urine pregnancy test. 
n Samples collected for immediate laboratory processing and frozen storage. 
o Samples collected on Day 1, Day 8 (if still an inpatient or at day of discharge, whichever comes first), Day 15 (if still an inpatient or at day of discharge, 
whichever comes first), Day 29 (if still an inpatient or at day of discharge, whichever comes first), and Day 60. 
p Samples collected dependent on capacity of study centre, need for reduced study burden on staff, and potentially limited access to patients. 


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q Procedures for the collection, processing, storage and shipment of the PK and PD samples will be provided in the Study Laboratory Manual. When PK/PD 
sample is on the same day as ECGs, sample collection to coincide with the ECGs, ie, pre-loading dose (Day 1); then pre-maintenance dose and 6 hours 
postdose (Day 4). Subsequently predose on Days 8 and 15. 
r Hepatitis B surface antigen and either Hepatitis C virus RNA PCR or Hepatitis C core antigen test as per standard screening by local laboratory. 
 
 


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2.0 INTRODUCTION 
2.1  
Study Rationale 
There are currently only 2 approved therapeutic agents available to treat coronavirus disease 
2019 (COVID-19) in patients whose disease severity warrants treatment in hospital with 
supplementary oxygen (with or without ventilatory support). 
• Remdesivir is an adenosine nucleotide prodrug indicated for the treatment of adults and 
adolescent patients hospitalised with severe acute respiratory syndrome coronavirus 2 
(SARS-CoV-2) infection and severe disease. 
• In the RECOVERY trial in the UK, dexamethasone reduced deaths by one-third in 
ventilated patients and by one-fifth in other patients receiving oxygen only. This has 
formed the basis for its inclusion in the SoC management of severe COVID-19 
worldwide since June 2020, given its prior authorised posology for a broad range of non-
endocrine corticosteroid responsive conditions. 
Despite these advancements in the therapeutic options for coronaviruses such as SARS-CoV-2 
(the causative agent of COVID-19 disease), there is an urgent public health need for rapid 
development of additional interventions. The aim of this study is to rapidly assess bemcentinib as 
a treatment for COVID-19, in order to provide evidence for its efficacy in this preliminary 
evaluation and to help with design considerations of a later confirmatory stage.  Hospitalised 
patients that may require either supplemental oxygen, non-invasive ventilation or high-flow 
oxygen devices would be considered for enrolment in the study. Patients in the need of 
intubation and invasive ventilation at the time of enrolment, would not be considered for this 
study. 
2.2  
Background 
Coronaviruses are single-stranded RNA viruses, capable of causing life-threatening disease in 
humans and animals. The novel coronavirus SARS-CoV-2 was initially identified during an 
outbreak of viral pneumonia cases of unknown cause in China. Most of the initial infections 
outside of China were travel associated (ie, from people who had travelled from the infected 
regions of China to other countries), although person-to-person transmission in other countries 
was quickly established. The disease caused by the SARS-CoV-2 virus has been designated 
COVID-19. 
SARS-CoV-2 binds via an angiotensin converting enzyme (ACE) receptor located on alveolar 
cells and intestinal epithelia.1 The virus is mutating and showing diversity in critical surface 
protein; indicating that virulence and transmission will shift over time. New evidence suggests 
there are 2 groups of SARS-CoV-2; L-type and S-type.1 S-type is the less aggressive (30%); the 


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L-type is now the most prevalent version (70%) and is more aggressive. Additionally, 
individuals appear to be affected to a different degree with varying symptoms and outcomes. 
These findings strongly support an urgent need for immediate comprehensive studies and robust 
validation of testing methods that combine genomic data, chart records, and clinical symptoms to 
help better understand the disease, enable risk assessment, and triage and support public health 
resource planning. 
Due to the rapid global widespread increase in SARS-CoV-2 and COVID-19, there is an urgent 
need to develop efficacious treatments for the disease. Current clinical studies involve the use of 
already approved medications for other indications (repurposing) where it is thought that they 
might also be effective in the treatment of COVID-19 disease, as well as development of 
antibody-based therapies against the virus. 
The current study will test bemcentinib with the aim of identifying potentially efficacious 
treatment in the shortest timeframe possible. In addition, it will support secondary research 
objectives that are critical for understanding the disease, spread of infection, and robust tests to 
diagnose it. 
2.3  
Benefit/Risk Assessment 
2.3.1 
Background/Rationale in Support of Bemcentinib for COVID-19 
Bemcentinib is a clinical-stage, oral, selective small molecule AXL kinase inhibitor with well 
documented anti-viral effects in several systems. Bemcentinib is reported to block dengue, 
Ebola, and Zika virus infections in several cell types including epithelial, fibroblast, endothelial, 
neuronal and myeloid cell types in in vitro cell culture and organoid systems. Bemcentinib 
treatment is associated with increased interferon (IFN) signalling and reduced viral 
replication.6,7,8 
During the 2013/2014 Ebola virus (EBOV) outbreak, bemcentinib was 1 of 60 compounds 
evaluated by Public Health England as an experimental therapy for EBOV, using its Biosafety 
Containment Level 4 facilities at Porton Down. Bemcentinib 200 mg/kg/day starting 6 hours post 
viral challenge protected 1/6 EBOV infected guinea pigs from weight loss and early mortality in 
an 18-day in vivo mortality study7, compared with 1/6 untreated animals surviving to Day 18 but 
exhibiting weight loss during the observation period. The authors concluded that bemcentinib 
may have had some protective effect in this model. 
Nonclinical in vitro and in vivo data suggest that bemcentinib might be useful for the treatment 
of early SARS-CoV-2 infection for which a few medical counter measures are currently 
approved. These data support testing the efficacy of bemcentinib treatment among hospitalised 
adults with COVID-19. 


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The AXL receptor tyrosine kinase promotes the infection of a wide range of enveloped viruses 
including pox-, retro-, flavi-, arena-, filo-, and alpha-viruses.3,4,5,6,7 AXL increases viral infection 
through two mechanisms: 1) enhanced viral entry through “apoptotic mimicry”; and 
2) suppression of anti-viral type I IFN responses. 
The AXL receptor and related receptors (Tyro3 and MerTK, collectively TAM) are important for 
the clearance of apoptotic cells (efferocytosis) by macrophages.8 Enveloped viruses co-opt this 
mechanism to expand tropism and enhance viral entry. Gas arrest-specific 6 (GAS6), the AXL 
ligand, binds PS exposed on the surface of the viral envelope, tethering the viral particle to the 
AXL receptor and promoting uptake by phagocytosis. This mechanism of viral entry, based on 
phosphatidylserine exposure, is common to most enveloped viruses and is termed viral 
“apoptotic mimicry”.10,11 
Binding of the viral particle to GAS6-AXL potently activates signal transduction through its 
tyrosine kinase domain to suppress type I IFN signalling and facilitate viral replication.6,11 The 
AXL expression is induced by inflammation and serves as an innate immune checkpoint. AXL 
signalling suppresses viral-induced IFN responses via induction of protein synthesis suppressor 
of cytokine signalling 1 and 3 (SOCS1, SOCS3) leading to increased viral replication in infected 
cells and decreased anti-viral defences of neighbouring cells.12,13,8 Consequently, AXL-null mice 
are resistant to Zika pathogenesis likely due to a combination of reduced virus entry and 
enhanced IFN responses 14, indicating a potential role for AXL inhibitors as therapeutics during 
viral infection. 
Therapeutic AXL receptor inhibition ameliorated pulmonary pathology resulting from primary 
viral infection in experimental models, indicating an important role for AXL within the lung.15 
During primary respiratory syncytial virus infection, AXL inhibition increased the number of 
IFNg–producing T cells and natural killer cells, suppressed respiratory syncytial virus replication 
and whole lung levels of interleukin (IL)-4 and IL-13. Also, the lethal effect of intrapulmonary 
H1N1 infection inflammation was reduced by AXL inhibition. AXL inhibition in infected mice 
increased the number of IFN-b–producing macrophages and dendritic cells and suppressed 
neutrophil infiltration. 
2.3.2 
Preliminary Efficacy Data vs With SARS-CoV-2 in Vitro 
Professor Wendy Maury, University of Iowa, conducted a preliminary analysis of the anti-viral 
effects of bemcentinib on SARS-CoV-2 in a Vero E6 cell line. As shown in Figure 2, 
bemcentinib incubation starting 1 hour prior to virus inoculation potently inhibited SARS-CoV-2 
infection of Vero E6 cells in a dose-dependent manner. Other studies using vesicular stomatitis 
virus pseudotyped with SARS-CoV spike protein and a mouse betacoronavirus (mouse hepatitis 
virus [MHV]) showed that bemcentinib may both inhibit uptake and activate the IFN-mediated 
antiviral gene, ISG15, to control viral infection. SARS-CoV-2 cell tropism is likely to include PS 
dependent viral uptake and may target critical immune cell populations (eg, macrophages, 


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dendritic cells) that produce IFN and mobilise antiviral immunity. Importantly, delayed IFN 
signalling is characteristic of pathogenic human betacoronaviruses and correlates with disease 
severity in animal models, suggesting that early intervention with IFN-activating treatment may 
provide therapeutic benefit.16 Thus, AXL targeting is expected to attenuate SARS-CoV-2 
pathogenesis both by limiting viral uptake and promoting innate antiviral immunity. 
Figure 2 
Bemcentinib Potently Inhibits Severe Acute Respiratory Syndrome 
Coronavirus 2 (SARS-CoV-2) Infection of Vero E6 Cells 
 
Vero E6 cells (60,000) in a 48-well format were incubated (1 hour) with bemcentinib prior to addition of severe 
acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (MOI 0.0005). Cells were lysed at 24 hours and viral 
load was analysed by quantitative reverse transcription polymerase chain reaction (RT PCR) for spike protein 
gene expression as normalised to the housekeeping gene Cyclophilin. W. Maury et al., unpublished results 
Recent data that differentiate SARS-CoV-2 from severe acute respiratory syndrome (SARS) 
have emerged that support the hypothesis that AXL may have a more dominant role in 
SARS-CoV-2 infection, and therefore that bemcentinib may have specifically a more important 
role to play in inhibiting this viral infection: 
SARS-CoV-2 has similar replication kinetics to SARS-CoV but demonstrates differential 
sensitivity to type I IFN treatment (1 of 2 mechanisms of action of bemcentinib through AXL 
inhibition).17 
Structural analysis of the spike (S) protein of SARS-CoV-2 showed that its S protein has weaker 
binding to ACE2 receptor on human cells compared with strong affinity of human SARS 
coronavirus18 – supporting the large magnitude effect observed for inhibition of viral replication 
using clinically appropriate doses of bemcentinib in ACE2 receptor +ve cells. 
The currently approved therapeutic agents available (ie, dexamethasone and remdesivir) to treat 
coronaviruses such as SARS-CoV-2 and the severe disease manifestations in hospitalised 


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COVID-19 patients, have demonstrated benefits in reduced mortality risk and duration of 
hospitalisation. Despite the advances in available therapeutic interventions, there remains an 
unmet need in terms of mortality and morbidity due to SARS-CoV-2. Thus, while there may not 
be benefits for an individual patient participating in this study, there may be benefits to society if 
a safe and efficacious therapeutic agent can be identified during the global COVID-19 outbreak. 
2.3.3 
Cardiac Safety 
Bemcentinib has shown in vitro evidence of antiviral effect against SARS-CoV-2 infection at 
concentrations below those achieved at the proposed dose regimen for use in this trial. This dose 
matches the recommended Phase 2 dose (RP2D) derived from multiple studies in various cancer 
populations. Treatment at this dose in 286 patients with cancer over a range of 6 weeks up to 
2 years demonstrates that monotherapy or combination is largely well tolerated. Therefore, short 
term administration (15 days) in the context of hospitalised patients with SARS-CoV-2 infection 
is anticipated to be well tolerated. A non-severe, asymptomatic effect on QTc interval has been 
noted with bemcentinib treatment. 
BerGenBio have amended the QTcF interval limit suggested in ICH E14, after taking specialist 
advice on pharmacometric characteristics and nonclinical toxicology of bemcentinib, and 
consultation with a clinical cardiac electrophysiology expert. 
In order to mitigate the risk of drug-induced Torsades de Pointes (TdP) and drug-induced sudden 
cardiac death the following steps are enacted: 
• Patients with a baseline QTcF interval >470 msec are excluded from the protocol. 
• The cut off of 470 msec has been selected because this represents the estimated 99th 
percentile QTc values derived from otherwise healthy individuals (≤470 msec in men, 
and ≤480 msec in women).19,20. These QTc values are recommended by the American 
Heart Association consensus group for assessment of asymptomatic individuals for the 
presence of congenital long QT syndrome. In the absence of any exogenous 
QTc-aggravating factors, individuals with a QTc interval >470 msec have a higher 
probability of congenital long QT syndrome and therefore are at higher risk of QT-related 
ventricular arrhythmias if QT prolonging agents are administered;21 for this reason, these 
patients are excluded from the study. 
Additional risk mitigation steps will be in place: 
• Regular electrocardiogram (ECG) monitoring is included in the clinical trial enabling 
early identification of prolonged QTc and early stopping rules (Appendix 6 ). 
• Bemcentinib treatment will be withdrawn if QTcF interval prolongs to ≥501 msec. This is 
because population studies show that patients with a QTcF interval >500 msec are at 
increased risk of mortality.22,23 


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• Medication will be administered to participants while they are in hospital under medical 
supervision. Treatment is administered for a relatively short duration (maximum 
15 days), ie, a relatively short exposure to any QTc prolonging effect of the medication. 
• Bemcentinib treatment after stopping medication with potential for QT prolongation or 
concomitant with such medication which cannot be immediately discontinued, may be 
managed by increased frequency of QT evaluation and application of existing individual 
stopping rules. Coadministration of 2 medications with QT prolonging potential is not 
necessarily additive.24 
Given the high morbidity and potential mortality of SARS-CoV-2 in hospitalised patients, there 
is a favourable balance of potential benefit: risk in the proposed clinical investigation of 
bemcentinib treatment for COVID-19 within the context of this clinical study. The QTcF cut-off 
criterion has been extended so that it represents the upper limit of normal values for otherwise 
healthy individuals. This will increase the number of patients who are eligible to take part in the 
study, while mitigating the risk of adverse effects due to potential QT prolonging effects of the 
treatment. 
.  
 


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3.0 OBJECTIVES AND ENDPOINTS 
Table 2 
Study Objectives and Endpoints  
 
Objectives  
Endpoints  
Primary  
  
• 
To evaluate the efficacy of bemcentinib as 
add-on therapies to standard of care (SoC) in 
patients hospitalised with coronavirus disease 2019 
(COVID-19).  
• 
Time to sustained clinical improvement of at 
least 2 points (from randomisation) on a 9-point 
category ordinal scale, live discharge from the 
hospital, or considered fit for discharge (a score of 
0, 1, or 2 on the ordinal scale), whichever comes 
first, by Day 29 (this will also define the 
“responder” for the response rate analyses). 
9-point category ordinal scale: 
0. Uninfected, no clinical or virological evidence 
of infection 
1. Ambulatory, no limitation of activities 
2. Ambulatory, limitation of activities 
3. Hospitalised – mild disease, no oxygen therapy 
4. Hospitalised – mild disease, oxygen by mask or 
nasal prongs 
5. Hospitalised – severe disease, non-invasive 
ventilation or high-flow oxygen 
6. Hospitalised – severe disease, intubation and 
mechanical ventilation 
7. Hospitalised – severe disease, ventilation and 
additional organ support – vasopressors, renal 
replacement therapy, extracorporeal membrane 
oxygenation 
8. Death  
 
Key Secondary  
 
• 
To evaluate the ability to prevent deterioration 
according to the ordinal scale by 1, 2, or 3 points  
• 
The proportion of patients not deteriorating 
according to the ordinal scale by 1, 2, or 3 points on 
Days 2, 8, 15, and 29 
• 
To evaluate the number of oxygen-free days  
• 
Duration (days) of oxygen use and oxygen-free 
days  
• 
To evaluate severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2) viral load  
• 
Qualitative and/or quantitative polymerase chain 
reaction (PCR) determination of severe acute 
respiratory syndrome coronavirus 2 (SARS-CoV-2) in 
oropharyngeal/nasal swab while hospitalised on Days 
1, 3, 5, 8, 11, 15, and 29  
Other Secondary  
 


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• 
To evaluate ventilator-free days and incidence 
and duration of any form of new ventilation use 
• 
Duration (days) of ventilation and ventilation-
free days 
• 
Incidence of any form of new ventilation use and 
duration (days) of new ventilation use 
• 
To evaluate duration of organ support (eg, 
including respiratory, renal, and cardiac support) 
• 
Duration (days) of organ support 
• 
To evaluate response rate (see primary 
endpoint for definition of responder) 
• 
Response rate (number and %) by treatment arm 
at Days 2, 8, 15, and 29 
• 
To evaluate time to discharge  
• 
Time to live discharge from the hospital 
• 
To evaluate overall mortality  
• 
Mortality at Days 15, 29, and 60 
• 
Time from treatment start date to death 
• 
Change in the ratio of the oxygen saturation to 
fraction of inspired oxygen concentration 
(SpO2/FiO2) 
• 
SpO2/FiO2, measured daily from randomisation to 
Day 15, hospital discharge, or death  
• 
To evaluate the safety of bemcentinib as 
add-on therapy to SoC in patients with COVID-19 
• 
Physical examination. 
• 
Clinical laboratory examinations. 
• 
Vital signs (blood pressure/heart 
rate/temperature/respiratory rate). 
• 
Adverse events  
• 
To evaluate intensive care unit (ICU) and 
hospitalisation length  
• 
Duration (days) of ICU and hospitalisation  
• 
To evaluate National Early Warning Score 2 
(NEWS2) 
• 
NEWS2 assessed daily while hospitalised and on 
Days 15 and 29. 
• 
Time to a NEWS2 of ≤2, maintained for at least 
24 hours  
• 
To evaluate improvement taking into account 
worsening and death  
• 
Ranked trajectory over 29 days, with trajectory 
ranked in the following order of the ordinal scale: 
o 
[ascending order] The worst score 
o 
[ascending order] The last recorded score 
o 
[ascending order] The number of days at 
worst score 
o 
[ascending order] The best score that 
occurs after the worst score (this will 
equal the worst score if the worst score is 
the last score) 
o 
[descending order] The number of days 
the patient is at 4), counting only days 
after the last occurrence of the worst 
score (the number of days for this item 
will be 0 if the worst score is the last 
score)  
Exploratory  
 
• 
To evaluate PK of bemcentinib 
• 
PK concentration and parameters 


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• 
To evaluate SARS-CoV-2 viral load  
• 
Qualitative and/or quantitative PCR determination 
of SARS-CoV-2 in blood (on Day 1) and saliva (while 
hospitalised) on Days 1, 3, 5, 8, 11, 15, and 29 (may 
be become a secondary endpoint once the assays are 
available)  
• 
To collect samples for serology research, viral 
genomics, serum antibody production, and COVID-
19 diagnostics 
• 
Analysis of samples collected at baseline prior to 
treatment and at specific time points  
 
 


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4.0 STUDY DESIGN 
4.1  
Overall Design 
BGBC020 is a study designed to rapidly seek and determine the nature of signals of efficacy and 
safety of bemcentinib in the treatment of hospitalised patients with SARS-CoV2. The study 
design is analogous to the first stage of the ACCORD-2 platform protocol, a multicentre national 
UK government sponsored protocol in the United Kingdom in which bemcentinib is being 
evaluated. BGBC020 (this protocol) is therefore analogous to ACCORD-2, a seamless, Phase 2, 
adaptive, randomised platform study, designed to rapidly test candidate agents in the treatment of 
COVID-19 disease. Bemcentinib was the first agent to be adopted to ACCORD-2 platform. 
BGBC020 (referred to henceforth as “the current study”) will include hospitalised adult patients 
(≥18 years) who have infection with SARS-CoV-2, the virus that causes COVID-19, as 
confirmed by laboratory tests and/or validated point of care tests. For inclusion, patients will 
need to have clinical status of Grade 3 (hospitalised - mild disease, no oxygen therapy) to Grade 
5 (hospitalised – severe disease, non-invasive ventilation or high-flow oxygen), as defined by a 
9-point ordinal scale, which was detailed in the World Health Organization R&D Blueprint 
“Novel Coronavirus - COVID-19 Therapeutic Trial Synopsis” (February 2020). In India, only 
patients with Grade 4 or Grade 5 disease severity at screening, will be enrolled (per local 
guidelines Grade 3 patients would not typically be hospitalised). Medical history will record the 
estimated date and time of first symptoms. 
This study will aim to evaluate the safety and efficacy of bemcentinib for treatment of 
COVID-19 disease. 
First dose of bemcentinib must take place within 72 hours of Investigator receipt of laboratory or 
validated point of care test confirmation of SARS-CoV-2 infection. If a patient has a confirmed 
result prior to hospital admission which is more than 72 hours old, first dose of bemcentinib 
should take place within a calendar day of admission to hospital, where in the opinion of the 
Investigator, the reason for admission is relevant to ongoing COVID-19 infection. Any 
exceptions to this must be authorised by the Medical monitor and/or Sponsor medical team. 
Patients will be randomised to the treatment arm to receive bemcentinib (as an add-on to 
standard of care [SoC]) or to control arm where only SoC will be administered. 
Patients will be screened on Day -1 or Day 1 and will remain in the hospital from Day 1 until fit 
for discharge. Dosing with bemcentinib (as an add-on to SoC) will commence on Day 1 until 
Day 15 or discharge. The last day of assessments while hospitalised will be on Day 29. An 
outpatient visit will be conducted on Day 60 (±4 days), with an end of study visit conducted on 
Day 90 (±6 days). Please refer to Figure 1 for further details. 
Please refer to Appendix 8 for details of study procedures during special circumstances. 


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4.2  
Scientific Rationale for Study Design 
Bemcentinib is being assessed as a potential treatment for SARS-CoV 2 infection in this study, 
as there is an urgent public health need for rapid development of additional interventions. The 
study is randomised to minimise any kind of bias that could affect the study outcome. 
4.3  
Justification for Dose 
Bemcentinib’s antiviral action stems from a cellular effect, inhibiting AXL kinase to prevent 
viral attachment and intracellular viral replication (through maximisation of the early type I 
interferon rather than a direct antiviral action). The target is AXL kinase inhibition rather than 
viral IC50, nevertheless, from estimates of pooled data, the half maximal inhibitory 
concentration (IC50) at 24 hours for bemcentinib inhibition of viral load is approximately 140 nM 
and the approximate concentration required for 90% of maximum inhibition (IC90) is 650 nM. 
This broadly corresponds to cancer cell data demonstrating high potency of bemcentinib to 
inhibit AXL. This high potency is reflected in translational data from clinical trials that 
demonstrate that at the RP2D steady state, AXL kinase is completely inhibited in myeloblasts 
from acute myeloid leukaemia (AML) patients on bemcentinib (Figure 3). 
At RP2D, AXL kinase target demonstrates complete kinase inhibition (Figure 3), thus the 
maximal possible antiviral effect with this mechanism of action is accessed at the current clinical 
dose. 
Frequent monotherapy complete responses are observed in AML at RP2D (Figure 3). 
Bemcentinib pharmacokinetic (PK) exhibits a prolonged enteral absorptive phase which overlaps 
with prolonged elimination kinetics after the second dose, to proportionately reduce peak to 
trough difference in plasma concentration-time profile, over a 24-hour dose interval, resulting in 
smooth steady state without noticeable peak to trough variation (Figure 4). Thus, at the clinical 
RP2D it is predicted that bemcentinib would be a highly potent antiviral against SARS-CoV-2, 
and potentially as efficacious as its main use an anticancer therapeutic. 


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Figure 3 
Complete Inhibition of AXL Kinase Activation (p-AXL) in Two Acute 
Myeloid Leukaemia Patients Treated with Bemcentinib at the Recommended 
Phase 2 Dose (200 mg Maintenance Daily Dosing) 
 
C=cycle; D=day; Pat=patient 
 
Figure 4 
Bemcentinib Plasma Pharmacokinetics in Acute Myeloid Leukaemia Patients 
 
Bemcentinib is given orally as 100-mg capsules. Early clinical development in oncology patients 
identified the RP2D for that population; dose administration of bemcentinib in this study will 
utilise the same dosing regimen, ie, a loading dose (400 mg) given once daily for 3 days 
followed by a maintenance dose of 200 mg once daily. Planned duration of bemcentinib 
treatment is for a total of 15 days. 
In preclinical and Phase 1 clinical studies, it was shown that systemic exposure to bemcentinib 
increased dose proportionately. The terminal half-life was 45.6 to 88.7 hours in man. Modelling 
of the PK data from this study indicated that the most effective approach to rapidly achieving 
steady state is to administer 3 daily loading doses followed by a lower daily maintenance dose. 


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4.4 
Human Experience from Trials in Cancer Patients 
Experience has been gained in the use of bemcentinib in the treatment of many types of cancer 
(including over 286 patients with AML, lung cancer, breast cancer, melanoma, and pancreatic 
cancer) in Phase 2 clinical studies. This has helped to define the safety profile, recommended 
dose and schedule as a monotherapy.25 The safety profile of bemcentinib, initially ascertained in 
healthy human volunteers is tolerable and allows monotherapy approaches as well as 
combinations with chemotherapy (low dose cytosine arabinoside or with docetaxel), targeted 
therapy (epidermal growth factor receptor inhibitors) and immunotherapy (pembrolizumab). 
Bemcentinib is given as 2 oral capsules once daily (200 mg) following 3 daily 400 mg loading 
doses, to achieve steady state. Its principal significant AEs are a low incidence of diarrhoea 
(28%, with 6% Grade 3/4), asymptomatic QT prolongation (6% Grade 3/4), asthenia, and nausea 
at the RP2D.25 Many patients have received bemcentinib without untoward effects for over 
2 years at full dose. In particular, there were no QT prolongation related cardiac sequelae 
observed with either monotherapy or combination therapy in over 286 cancer patients, including 
elderly multimorbid patients (as presented in the Investigator’s Brochure). Evidence of 
monotherapy efficacy has been documented in heavily pre-treated patients with AML. Complete 
response rates of approximately 40% have been observed in AXL expressing AML patients25, 
indicating on target potency and specificity of bemcentinib as a monotherapy, through complete 
inhibition of the AXL kinase target. Treatment was well tolerated by most subjects, including the 
frail elderly. Bemcentinib was well tolerated when combined with pembrolizumab, 
demonstrating synergy with programmed cell death-1 antagonists through targeting 
of -AXLdependent immune suppressive mechanisms (M2 macrophages, suppressor dendritic 
cells, regulatory T cells, and myeloid derived suppressor cells). Collectively, 
bemcentinib- -mediated activation of innate immunity within the tumour microenvironment 
synergises with immune checkpoint therapy.26 
4.5  
End of Study Definition 
The end of the study is defined as the date on which the last patient completes the last visit. 
Once a patient has completed this study, there are no restrictions on them entering another study, 
subject to the eligibility criteria of that subsequent study, however, there will be ongoing 
requirement to adhere to the contraceptive conditions for 120 days after cessation of bemcentinib 
dosing.  
 


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5.0 STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
In order to enrol, a patient or legally authorised representative must sign an informed consent 
form (ICF) and meet all entry criteria for the protocol. 
Concurrent participation in another clinical study of an investigational medicinal product while 
taking part in the current study (BGBC020) is not permitted, unless co-enrolment in the other 
study has been pre-approved by the Sponsor. 
5.1  
Inclusion Criteria 
Patients are eligible to be included in the study only if all of the following criteria are met: 
1. Adults (≥18 years) with SARS-CoV-2 infection confirmed by laboratory tests and/or 
point of care tests (which may include results from a test that was performed prior to 
hospital admission if, in the opinion of the Investigator, it is relevant to ongoing 
COVID-19). 
2. Patients with symptoms and/or signs consistent with COVID-19, requiring treatment. 
3. A score of Grade 3 to 5 on the 9-point ordinal scale (Section 8.1.1). 
In India; only patients with a score of Grade 4 or 5 will be enrolled. 
4. a) Male patients: 
• A male patient must agree to use contraception as detailed in Appendix 5 during the 
treatment period and for at least 120 days after the last dose of study treatment and refrain 
from donating sperm during this period. 
b) Female patients: 
• A female patient is eligible to participate if she is not pregnant, not breastfeeding, and at 
least 1 of the following conditions applies: 
i 
Not a woman of childbearing potential as defined in Appendix 5 
OR 
ii 
A woman of childbearing potential who agrees to follow the contraceptive 
guidance in Appendix 5 during the treatment period and for at least 120 days after 
the last dose of study treatment. 


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5. Women who are lactating who agree not to breastfeed their child during the study and for 
at least 120 days after termination of study therapy (they may continue to express milk 
away from the child during this period, but this milk must be discarded). 
6. Ability to provide informed consent signed by the study patient or legally authorised 
representative. 
5.2  
Exclusion Criteria 
Patients are excluded from the study if any of the following criteria apply: 
1. Patients who have previously had a score of 6 or 7 on the 9-point ordinal scale. 
2. Inability to swallow capsules (administration via nasogastric tube is permitted in patients 
who become unable to swallow after starting the study drug) 
3. History of the following cardiac conditions: 
a) Myocardial infarction within 3 months prior to the first dose 
b) Unstable angina 
c) History of clinically significant dysrhythmias (long QT features on ECG, 
sustained bradycardia [≤55 bpm]), left bundle branch block, or ventricular 
arrhythmia) or history of familial long QT. 
Patients with an implantable cardioverter defibrillator device in place, will be 
allowed to enrol. Atrial fibrillation will not be a reason for exclusion. 
4. Screening 12-lead ECG with a measurable QT interval according to Fridericia correction 
(QTcF) >470 msec.  
In the presence of a cardiac pacemaker, QTcF will need to be calculated from an ECG 
which has been recorded during a period where ventricular (QRS) complexes without 
pacing are present. If no unpaced ventricular complexes are present to allow calculation 
of QTcF, the patient should not be enrolled in this protocol 
5. Clinically significant hypokalaemia: Individuals who do not meet this criterion may be 
rescreened once, after correction of electrolyte abnormality. 
6. Therapeutic anticoagulation with vitamin K antagonists. Note: Patients receiving low 
doses prescribed to maintain the patency of venous access devices may be included. 
7. Previous bowel resection that would interfere with drug absorption. 
8. Any patient whose interests are not best served by study participation, as determined by a 
senior attending clinician. 
9. Alanine aminotransferase/aspartate aminotransferase >5 × the upper limit of normal. 


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10. Current treatment (or planned initiation of treatment during the first 15 days of the study) 
for human immunodeficiency virus (HIV) or tuberculosis (TB). 
11. Positive serologic assay at screening for hepatitis B virus (Hep B surface antigen) or 
hepatitis C virus (hepatitis C PCR or hepatitis C core antigen) at local laboratory. 
12. Stage 4 severe chronic kidney disease. 
13. Anticipated transfer to another hospital that is not a study centre within 72 hours. 
14. Allergy to any study treatment. 
15. Experimental off-label usage of medicinal products as treatments for COVID-19 (except 
where the product has either been given a positive opinion under the Early Access to 
Medicines Scheme [EAMS] or is a SARS-CoV-2 vaccine) at the time of enrolment. 
16. Patients participating in another clinical study of an investigational medicinal product. 
17. Current or planned treatment for tuberculosis. 
5.3  Lifestyle Considerations 
Female patients are advised to avoid becoming pregnant during the study. 
5.4  
Screen Failures 
Screen failures are defined as patients who consent to participate in the clinical study but are not 
subsequently randomly assigned to study treatment. A minimal set of screen failure information 
is required to ensure transparent reporting of screen failure subjects to meet the Consolidated 
Standards of Reporting Trials publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility criteria, 
and any serious adverse event (SAE).  


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6.0 STUDY TREATMENT 
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo, or 
medical device(s) intended to be administered to a patient according to the study protocol. 
6.1 Study Treatment(s) Administered 
Bemcentinib will be administered as a 400 mg oral loading dose on Days 1, 2, and 3, followed 
by 200 mg once daily oral maintenance dose from Day 4, for a total of 15 days. 
Bemcentinib should be taken once per day, in the morning, on an empty stomach or more than 
2 hours after a light meal, with water. The first dose on Day 1 may be taken at any time before 
1800 hours, with a subsequent loading dose on day 2 administered in the morning. Patients 
should not consume anything other than water for at least 1 hour after taking study drug. 
The SoC will be based on appropriate local guidelines in place at the time of treatment during the 
study. The SoC may change during the course of the study as new information becomes available 
about treating COVID-19. 
Where a patient is being treated with a product that has received a positive opinion under 
relevant local or global emergency use authorisation (eg, dexamethasone or remdesivir), 
appropriate clinical monitoring for that product should be adhered to (eg, daily renal or hepatic 
function testing). 
6.2 Dose Modifications and Toxicity Management 
 
Note: this modified guidance has been added to the Investigators’ Brochure under relevant 
section of treatment of COVID-19. 
 
Event 
Recommended Bemcentinib Dose Modification 
Estimated creatinine clearance decreases 
by more than ≥50% from baseline 
Study medication should be withheld until estimated creatinine 
clearance returns to baseline 
ALT or AST increases to >5 ULN 
Study medication should be withheld until ALT and AST returns to 
baseline 
Dose Modification of Bemcentinib Daily Dose for QTc Prolongation 
QTcF 
Recommended Bemcentinib Dose Modification 
>501 msec 
1st occurrence 
Discontinue permanently 
Ventricular arrhythmia 
1st occurrence 
Discontinue permanently 
ALT=alanine aminotransferase; AST=aspartate aminotransferase; QTcF= QTc interval according to Fridericia correction; ULN=upper 
limit of normal 
Note: Serum calcium, magnesium and potassium should be measured regularly whilst receiving bemcentinib; all abnormal results should 
be corrected; check for use of concomitant medication that are associated with QT prolongation. 


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6.3 Preparation/Handling/Storage/Accountability 
6.3.1 
Bemcentinib Storage, Dispensing, and Destruction 
Bemcentinib will be shipped to the participating site and must be stored at the site in a secure 
location under ambient temperature conditions (<25°C).  
Site level accountability for study treatment is the responsibility of the Principal Investigator. 
The Investigator/designee must ensure that the bemcentinib will only be dispensed to patients in 
accordance with the dosing instructions in this protocol. Study staff should refer to the 
Bemcentinib Pharmacy Manual for specific instructions regarding the handling, storage, 
dispensing and destruction of bemcentinib. 
The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for study treatment received and any discrepancies are reported and 
resolved before its use. 
Only patients enrolled in the study may receive bemcentinib and only authorised study centre 
staff may supply or administer study drug. Study drug must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labelled storage conditions (see Bemcentinib Pharmacy Manual) with access limited to the 
Investigator and authorised study centre staff. 
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for bemcentinib accountability, reconciliation, and record maintenance (ie, receipt, 
reconciliation, and final disposition records). 
Further guidance and information for the final disposition of unused bemcentinib are provided in 
the Pharmacy Manual. 
The Investigator, a member of the study centre staff, or a hospital pharmacist must maintain an 
adequate record of the receipt and distribution of bemcentinib the Drug Accountability Form. 
These forms must be available for inspection at any time. 
6.4 Measures to Minimise Bias: Randomisation and Blinding 
No blinding will be used in this study. 
The study will randomise participants to receive either bemcentinib as an add-on to SoC or to 
receive SoC alone. Randomisation will be stratified by baseline severity grade and by current use 
of approved agents in SoC. 


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6.5 Study Treatment Compliance 
The prescribed dosage, timing, and mode of administration may not be changed, except as 
defined in Section 6.6. Any departures from the intended regimen must be recorded in the 
electronic case report forms (eCRFs). 
Each dose of bemcentinib will be administered by a member of the clinical research team that is 
qualified and licensed to administer the study medication. Administration and date, time, and 
route will be entered into the eCRF. 
6.6  
Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the patient is receiving at the time of enrolment (including 
screening) or receives during the study must be recorded in the eCRF 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 concomitant or 
prior therapy. 
Administration of bemcentinib is not recommended in patients requiring treatment with 
concomitant medications known to prolong QTc interval and promote TdP listed in Appendix 6. 
Patients already in receipt of such medications, where possible, should have these medications 
discontinued or replaced prior to starting bemcentinib; concomitant administration of 2 
medications with potential for QT prolongation does not necessarily result in an additive effect 
on QTc.24 If it is not clinically feasible to discontinue a specific medication, requiring its 
simultaneous short term use with bemcentinib, then patients may enrol as long as their baseline 
QTcF is not >470 msec. The Investigator should have a low threshold for initiating additional 
daily ECG monitoring, managing in accordance with the individual stopping rules (Section 6.2) 
Medicines with both cytochrome P450 3A4 and TdP liabilities are particularly hazardous and 
their concomitant use should be subject to heightened caution, with a low threshold for 
additional ECG monitoring and discontinuation in line with individual stopping rules 
(Section 6.2). 
Concomitant medications that are cytochrome P450 3A4 substrates are not reasons for exclusion 
of patients, however they should be discontinued, where possible, or used with caution. 
Treatment with histamine receptor 2 inhibitors (cimetidine, ranitidine) or protein pump inhibitors 
(omeprazole) is permitted provided that administration is in the evening. 


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6.6.1 
Citalopram – Specific Guidance for Use 
Citalopram is a commonly prescribed medication, among the cohort of patients admitted to 
hospital for treatment of COVID-19. The product labels for citalopram, both European Summary 
of Product Characteristics 2019 and American product label (Celexa Proposed Labelling Text 
2009), identify a specific risk of dose-dependent QT prolongation and TdP with contraindication 
against coadministration with other medicines with a potential for QT prolongation. 
Following post-marketing reports of QT interval prolongation and TdP associated with 
citalopram, the Food and Drug Administration in 2012 evaluated formal thorough QT studies of 
citalopram and escitalopram in adults. These studies show that citalopram causes dose-dependent 
QT interval prolongation that is clinically significant with the 60 mg daily dose. In addition, 
clinical trials do not show any added effectiveness of citalopram at 60 mg/day compared with 
40 mg/day. Therefore, citalopram should not be used at doses above 40 mg per day. Important 
safety information about the potential for QT interval prolongation and TdP with updated drug 
dosage and usage recommendations have been added to the citalopram drug label. Given that 
these findings were not observed with escitalopram, there are no changes planned for 
escitalopram at this time. 
In accordance with the European Medicines Agency citalopram label, the maximum citalopram 
dose in patients over 60 years of age is limited to 20 mg daily. 
Patients on citalopram, whose QTcF is not raised above 470 msec at screening, may continue on 
citalopram while on short term coadministration of study drug, but Investigators should have a 
low threshold for initiating additional ECG monitoring, managing in accordance with the 
individual stopping rules (Section 6.2). 
6.6.2 
Dosing with Remdesivir 
No change in bemcentinib dose is recommended for patients taking both bemcentinib and 
remdesivir. Safety monitoring under current approval within each study region will apply and 
must be followed when remdesivir is used as standard of care; for example, the EAMS guidance 
in the UK, or any subsequent authorisation for its use, which supersedes this. 
6.7  
Dose Modification 
The Sponsor will actively monitor interim data throughout the duration of the study to make 
recommendations about early study closure or changes to the study treatment arms. 
6.8  
 Treatment after the End of the Study 
This is a study in an acute severe respiratory disease and study treatment will not be 
continued/required following hospital discharge. 


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6.9 
Stopping Rules 
The stopping rules for this study pertain to assessments of the safety of bemcentinib use in the 
context of the protocol defined procedures for the treatment of patients hospitalised due to 
COVID-19. At this stage of development (exploratory clinical proof-of-concept in this 
indication) there is insufficient evidence on which to base a statistically robust futility analysis, 
therefore there are no defined stopping rules based on efficacy. 
If any of the following events occur, the study enrolment will be paused with an urgent, ad hoc 
meeting of the IDMC convened in order to review the study data and make their 
recommendations (see IDMC charter): 
• 
An unexpected Grade 5 event reported either with a possible or probable relationship to 
bemcentinib or reported as due to a study-related procedure 
• 
Greater than 20% incidence of Grade 4 cardiac events (include ventricular arrhythmias 
and Torsade de pointes) reported in the bemcentinib treatment arm; a minimum 
enrolment of 1/3 of target patient number to the bemcentinib arm would be required to 
assess incidence rate. 
• 
Incidence of QTcF ≥501 msec leading to discontinuation in the study of ≥ 25% in the 
bemcentinib treatment arm; a minimum enrolment of 1/3 of target patient number to the 
bemcentinib arm required to assess incidence rate. 
If any of the above criteria were met, the IDMC will carefully review the totality of the data 
available at the time. 
 
  
 


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7.0 DISCONTINUATION OF STUDY TREATMENT AND 
PATIENT DISCONTINUATION/WITHDRAWAL 
7.1 Discontinuation of Study Treatment 
A patient in this study may discontinue from treatment for any of the following reasons: 
1. Patient requests to discontinue study drug. 
2. Occurrence of any medical condition or circumstance that does not allow the 
patient to adhere to the requirements of the protocol or patient fails to comply 
with protocol requirements or study-related procedures. 
3. Any SAE, clinically significant AE, severe laboratory abnormality (including 
abnormal liver function test results), intercurrent illness, or other medical 
condition that indicates to the Investigator that continued participation is not in 
the best interest of the patient. 
4. Pregnancy recognised post start and prior to end of study treatment. 
Unless the patient withdraws consent, those who discontinue study drug early should remain in 
the study for further acquisition of endpoint measurements. The reason for patient 
discontinuation of study drug should be documented in the eCRF. 
7.2 Patient Discontinuation/Withdrawal from the Study 
1. A patient may withdraw from study treatment or the study at any time at his/her 
own request or may be withdrawn from study treatment or the study at any time at 
the discretion of the Investigator for safety, behavioural, compliance, or 
administrative reasons. 
2. If the patient withdraws consent for disclosure of future information, the Sponsor 
may retain and continue to use any data collected before such a withdrawal of 
consent. 
3. If a patient withdraws from the study, he/she may request destruction of any 
residual remaining samples taken and not tested, and the Investigator must 
document this in the study centre study records. However, any laboratory or test 
data generated from samples that have already been processed and included in any 
secondary research may not be recalled. 
4. See Schedule of Activities (SoA, Section 1.3) for data to be collected at the time 
of study discontinuation and follow-up and for any further evaluations that need 
to be completed. 


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7.3 Lost to Follow-up 
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study centre. 
The following actions must be taken if a patient fails to return to the study centre for a required 
study visit: 
5. All efforts should be made to ascertain the vital status of the patient. 
6. The study centre must attempt to contact the patient and reschedule the missed 
visit as soon as possible and counsel the patient on the importance of maintaining 
the assigned visit schedule and ascertain whether or not the patient wishes to 
and/or should continue in the study. Recognising that quarantine and other factors 
may limit the patient’s ability to return to the clinic, post-discharge visits may be 
conducted by telephone or with a home visit by study staff although patient visits 
to the site are preferred. 
7. Before a patient is deemed lost to follow-up, the Investigator or designee must 
make every effort to regain contact with the patient (where possible, 3 telephone 
calls and, if necessary, a certified letter to the patient’s last known mailing address 
or local equivalent methods). These contact attempts should be documented in the 
patient’s medical record. 
8. Should the patient continue to be unreachable, he/she will be considered to have 
withdrawn from the study.  
 
7.4 Protocol Violation 
The investigator is accountable for protocol violations resulting from failure to adequately 
supervise the conduct of the clinical study.  
All protocol violations will be recorded in CTMS and will be managed according to the Clinical 
Monitoring Plan and the Protocol Deviation Plan developed for the study. Protocol violations 
taken to guarantee subjects safety or other significant protocol violations will be reported 
according to local requirement. All violations will be reported in the clinical study report. 
 
 


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8.0 STUDY ASSESSMENTS AND PROCEDURES 
Note: Given the nature of the disease and the condition of the patients, it may not always be 
possible to perform all planned assessments at all time points; however, all efforts should be 
made to perform assessments as long as it considered clinically safe to do so. 
The SoA is presented in Section 1.3. 
Protocol waivers or exemptions are not allowed. 
Immediate safety concerns should be discussed with the Sponsor immediately upon occurrence 
or awareness to determine if the patient should continue or discontinue study treatment. 
Adherence to the study design requirements is essential and required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential patients 
meet all eligibility criteria. The Investigator will maintain a screening log to record details of all 
patients screened and to confirm eligibility or record reasons for screening failure, as applicable. 
Procedures conducted as part of the patient’s routine clinical management (eg, blood count) and 
obtained before signing of the ICF may be utilised for screening or baseline purposes provided 
the procedures met the protocol-specified criteria and were performed within the timeframe 
defined in the SoA. 
The maximum amount of blood collected from each patient over the duration of the study, 
including any extra assessments that may be required, will not exceed 350 mL. Repeat or 
unscheduled samples may be taken for safety reasons or for technical issues with the samples. 
All biological samples collected will be stored in a secure storage space in line with 
recommended guidelines for infectious substance handling, and with adequate measures to 
protect confidentiality. The samples will be retained while research on COVID-19 continues but 
no longer than 10 years or other period as per local requirements. For patients who withdraw 
consent to have their data analysed, samples will be destroyed. 
8.1 Efficacy Assessments 
8.1.1  
Improvement on the 9-Point Scale 
For the purposes of this study, the condition of each potential participant in the study will be 
assessed using a 9-point category ordinal scale: 
0. Uninfected, no clinical or virological evidence of infection 
1. Ambulatory, no limitation of activities 
2. Ambulatory, limitation of activities 


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3. Hospitalised – mild disease, no oxygen therapy 
4. Hospitalised – mild disease, oxygen by mask or nasal prongs 
5. Hospitalised – severe disease, non-invasive ventilation or high-flow oxygen 
6. Hospitalised – severe disease, intubation and mechanical ventilation 
7. Hospitalised – severe disease, ventilation and additional organ support – vasopressors, 
renal replacement therapy, extracorporeal membrane oxygenation 
8. Death 
For Grade 5, ‘high-flow oxygen’ consists of a heated, humidified high-flow nasal cannula 
delivering up to 100% heated and humidified oxygen at a maximum flow of 60 L/minute via 
nasal prongs or cannula to a patient at rates of flow higher than traditional low-flow therapy. In 
high-flow oxygen, the fraction of inspired oxygen (FiO2) can be titrated from 21% to 100% 
independent of the flow rate. 
Note: If initial data suggest that there are too few patients in certain categories, the decision may 
be made to combine parts of the ordinal scale, leading to a smaller number of categories. 
To be considered for inclusion in the study, patients must be Grade 3 to 5 on this scale. 
To be considered a “responder” to treatment with bemcentinib, a patient needs to show an 
improvement of at least 2 points (from randomisation) on this scale. For example, a patient who 
is Grade 5 (hospitalised - severe disease, non-invasive ventilation or high-flow oxygen) at 
randomisation but improves to Grade 3 (hospitalised - mild disease, no oxygen therapy) would 
be considered to be a responder. A patient with a live discharge from hospital or who is 
considered fit for discharge (a score of 0, 1, or 2 on the ordinal scale) will also be considered to 
be a responder. 
The primary endpoint will be time to sustained clinical improvement of at least 2 points (from 
randomisation) by Day 29. Sustained clinical improvement is defined as improvement without 
subsequent worsening. The response rate (number and percentage of patients) will be determined 
for each treatment arm (bemcentinib) on Days 2, 8, 15, and 29 as a secondary endpoint. 
In addition, a secondary endpoint will be proportion of patients not deteriorating according to the 
ordinal scale by 1, 2, or 3 points on Days 2, 8, 15, and 29. 
Ranked trajectory over 29 days will be calculated, with trajectory ranked in the following order 
of the ordinal scale: 
1. [ascending order] The worst score 
2. [ascending order] The last recorded score 


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3. [ascending order] The number of days at worst score 
4. [ascending order] The best score that occurs after the worst score (this will equal the 
worst score if the worst score is the last score) 
5. [descending order] The number of days the patient is at 4), counting only days after the 
last occurrence of the worst score (the number of days for this item will be 0 if the worst 
score is the last score) 
8.1.2  
Other Efficacy Assessments 
Overall mortality will be assessed on Days 15, 29, and 60, and, where applicable, time from 
treatment (bemcentinib) start date to death will be calculated. 
The duration (days) of oxygen use and oxygen-free days (to Day 29) will be a secondary 
endpoint.  
The duration of ventilator-free days (to Day 29) will be a secondary endpoint, as will be the 
incidence and duration (days) of new ventilation use. 
The duration of overall organ support (eg, including respiratory, renal, and cardiac support) will 
be calculated. 
The duration (days) of intensive care unit (ICU) and hospitalisation will also be a secondary 
endpoint. 
The National Early Warning Score 2 (NEWS2 in Appendix 7) has demonstrated an ability to 
discriminate patients at risk of poor outcomes.27 This score is based on 6 physiological 
measurements (respiration rate, oxygen saturation [SpO2], systolic blood pressure, pulse rate, 
level of consciousness or new confusion, and temperature), and the overall score is uplifted by 2 
points for patients requiring supplemental oxygen to maintain their recommended SpO2. For 
patients confirmed to have hypercapnic respiratory failure on blood gas analysis, on either a prior 
or their current hospital admission, and requiring supplemental oxygen, the following are 
recommended: (i) a prescribed SpO2 target range of 88% to 92%, and (ii) that the dedicated SpO2 
scoring scale (Scale 2) on the NEWS2 chart should be used to record and score the SpO2 for the 
NEWS2. 
NEWS2 will be assessed daily while hospitalised and on Days 15 and 29. This should be 
evaluated at the first assessment of a given study day. 
8.2 Safety Assessments 
Planned time points for all safety assessments are provided in the SoA (Section 1.3). 


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8.2.1  
Physical Examinations 
A general physical examination will be performed at screening, including assessment of 
presenting signs, height and weight. 
As clinically indicated, a symptom-directed (targeted) physical examination will be performed 
from Day 2 through to hospital discharge. 
8.2.2  
Vital Signs and Blood Gases 
Temperature, pulse rate, blood pressure, and respiratory rate will be assessed. Blood pressure and 
pulse measurements will be assessed with a completely automated device. SpO2 will also be 
assessed. Manual techniques will be used only if an automated device is not available. 
Blood gases (oxygen and carbon dioxide) and respiratory support will be recorded. FiO2, the 
assumed percentage of oxygen concentration participating in gas exchange in the alveoli, will 
also be recorded. 
Measurements will be taken in line with standard practices for the study centre. 
Vital signs measurements will contribute to the NEWS2 score (see Section 8.1.2). 
8.2.3  
Clinical Safety Laboratory Assessments 
Fasting is not required before collection of laboratory samples. See Appendix 3 for the list of 
clinical laboratory tests to be performed and to the SoA (Section 1.3) for the timing and 
frequency. 
Local laboratories will be performing the test according to Appendix 3. These laboratories will 
be managed by the respective clinical trial site, reference ranges, accreditations and laboratory 
head Curriculum Vitae will be collected and filed in the site files accordingly. 
The central laboratory will analyse the samples for the following: 
Exploratory soluble factors, PBMC cellular immunity assays (optional test), blood for SARS 
CoV 2 PCR (qualitative and/or quantitative), oropharyngeal/nasal swab for SARS CoV-2 PCR 
(qualitative and/or quantitative),  saliva for SARS¬ CoV 2 PCR (qualitative and/or quantitative), 
SARS-CoV-2 serology research, nasal swab viral genome, pharmaco-dynamics and 
pharmacological kinetics. 
The involved central laboratories will be: 
1. Q Squared Solutions301-A, Leela Business Park,  M V Road, Andheri (East)  Mumbai 
400059, India 
2. Q Squared Solutions Valencia 27027, Tourney Road, Suite 2EValencia, CA, 91000, USA 


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3. Myriad RBM 3300 Duval Td, Austin,  Texas 78759 
4. Alderly Analytical, UK, Alderly Park,  Macclesfield, Cheshire, SK 10 4TG 
5. Q Squared Solutions, Europe Alba Campus, Rosebank Livingston, West Lothian 
Scotland, EH54 7EG, UK 
6. Expression Analysis, Q Squared Solutions 5927 South Miami, Blvd.Suite 100Morrisville, 
. NC, 27560, USA 
7. CyteSpace 121 Amkor Road, Lyttelton Manor, Centurion, Gauteng, 0157, South Africa 
8.3 Adverse Events 
The definitions of an adverse event (AE) or SAE can be found in Appendix 4. 
AEs will be reported by the patient (or, when appropriate, by a caregiver, surrogate, or the 
participant’s legally authorised representative). 
The Investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE and remain responsible for following up AEs 
that are serious, considered related to the study treatment or study procedures, or that caused the 
patient to discontinue the study treatment or the study (see Section 7.0). 
8.3.1 
Time Period and Frequency for Collecting AE and SAE Information 
All AEs will be collected from provision of informed consent until the final follow-up visit, at 
the time points specified in the SoA (Section 1.3). 
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours, as indicated 
in Appendix 4. 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 AEs or SAEs after conclusion of the study 
participation. However, if the Investigator learns of any SAE, including a death, at any time after 
a patient has been discharged from the study, and he/she considers the event to be reasonably 
related to the study treatment or study participation, the Investigator must promptly notify the 
Sponsor. 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 4. 
8.3.2  
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the patient is the preferred method to inquire about AE 
occurrences. 


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8.3.3  
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each patient at 
subsequent visits/contacts. All SAEs, and nonserious AESIs (see Section 8.3.6), will be followed 
until resolution, stabilisation, the event is otherwise explained, or the patient is lost to follow-up 
(as defined in Section 7.3). Further information on follow-up procedures is given in Appendix 4.  
8.3.4  
Regulatory Reporting Requirements for SAEs 
Prompt notification by the Investigator to the Sponsor of an SAE (within 24 hours of becoming 
aware) is essential so that legal obligations and ethical responsibilities towards the safety of 
patients and the safety of a study treatment 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 treatment under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority, main research ethics committee (REC), and Investigators. 
Investigator safety reports must be prepared for suspected unexpected serious adverse reactions 
according to local regulatory requirements and Sponsor policy and forwarded to Investigators as 
necessary. 
An Investigator who receives an Investigator safety report describing an SAE or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will review and then file it 
along with the Investigator’s Brochure and will notify the REC, if appropriate according to local 
requirements. 
8.3.5  
Pregnancy 
Details of all pregnancies in female patients will be collected after the start of study treatment 
and until a time period that is at least 5 terminal half-lives after the last dose of the bemcentinib. 
1. If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours 
of learning of the pregnancy and should follow the procedures outlined in Appendix 5. 
2. Abnormal pregnancy outcomes (eg, spontaneous abortion, foetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs. 
8.3.6  
Adverse Events of Special Interest 
There are no adverse events of special interest (AESI) in this study. Respiratory failure and QTc 
related AEs are not considered as AESI with bemcentinib treatment as respiratory failure is a 
sequelae of disease progression in Covid-19. QTc prolongation is minimised in this study 
through study inclusion/ exclusion criteria and as per Section 2.3.3 Cardiac Safety and Section 
6.2 Dose Modifications and Toxicity Management.  


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8.3.7  
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as 
Adverse Events or Serious Adverse Events 
Events that are typically associated with the disease under study will not be reported according to 
the standard process for expedited reporting of SAEs even though the event may meet the 
definition of an SAE. 
8.3.8 
Adverse events reported in non-COVID studies 
Investigators may refer to the current versions of the Investigator brochure (Section 6 – 
Summary of Data and Guidance for Investigators) for detailed information on adverse events. 
Summary information on adverse events for patients and/or legal representatives is provided in 
the relevant information sheets. 
8.3.9 
Expected Serious Adverse Events 
The reference safety information is detailed in the current versions of the investigator brochure. 
Of those listed in the RSI, only serious adverse events due to gastrointestinal disorders 
(diarrhoea, nausea or vomiting) or infections and infestations (pneumonia) with a severity of 
Grade 3 and lower would be considered  expected among patients with Covid-19. 
8.4 Treatment of Overdose 
In the event of an overdose of bemcentinib, the Investigator/treating physician should: 
1. Contact the Medical Monitor immediately. 
2. Closely monitor the patient for any AEs/SAEs and laboratory abnormalities until 
bemcentinib can no longer be detected systemically. 
3. Obtain a plasma sample for PK analysis if requested by the Medical Monitor (determined 
on a case-by-case basis). 
4. Document the quantity of the excess dose as well as the duration of the overdose in the 
eCRF. 
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the patient. 
8.5 Pharmacokinetics 
Venous blood samples for PK analysis will be collected according to the SoA (Section 1.3). The 
samples will be analysed for plasma concentrations of bemcentinib and bemcentinib metabolites. 
Detailed procedures for the collection, processing, storage and shipment of the samples will be 
provided in the Study Laboratory Manual. 


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Plasma samples for determination of bemcentinib concentration will be analysed by 
BerGenBio’s Bioanalytical Services vendor using the validated liquid chromatography with 
tandem mass spectrometry method. 
If a patient refuses blood collection for PK analysis or Investigator’s judgement resolves that this 
blood collection is unsafe (eg, clinically significant anaemia), this will not be considered a 
protocol deviation as the PK is an exploratory endpoint in this study.  
8.6 Pharmacodynamics 
Blood samples for pharmacodynamic (PD) analysis will be collected according to the SoA 
(Section 1.3) and stored for future analysis in both the bemcentinib arm and the control arm. The 
samples will be analysed for soluble AXL, GAS6 (which could be predictive, PD, and 
mechanism biomarkers and hence require comparison with control arm not receiving 
bemcentinib), and other blood proteins. Detailed procedures for the collection, processing, 
storage and shipment of the samples will be provided in the Study Laboratory Manual. 
If a patient refuses blood collection for pharmacodynamic analysis or Investigator’s judgement 
resolves that this blood collection is unsafe (eg, clinically significant anaemia), this will not be 
considered a protocol deviation as the pharmacodynamic analysis is an exploratory endpoint in 
this study. 
8.7 Virologic Load 
Qualitative and/or quantitative polymerase chain reaction (PCR) determination of SARS-CoV-2 
in oropharyngeal/nasal swab and in saliva (while hospitalised) on Days 1, 3, 5, 8, 11, 15, and 29 
will be performed. A blood sample for PCR will be collected at baseline. 
8.8 Immunology 
Details regarding the type of sample and the specific soluble factors to be analysed and the 
analytical methods will be presented in the laboratory manual. 
At time points indicated in the SoA (Section 1.3), an optional blood sample may be collected in a 
sodium heparin tube for immediate shipping to a central laboratory. Samples will be analysed for 
peripheral blood mononuclear cell cellular immunity assays. 
If a patient refuses blood collection for immunology analysis or Investigator’s judgement 
resolves that this blood collection is unsafe (eg, clinically significant anaemia), this will not be 
considered a protocol deviation as the immunology analysis is not a primary or secondary 
objective of the protocol. 


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8.9 Serology Research  
At time points indicated in the SoA (Section 1.3), a whole blood sample will be collected in a 
serum separator tube to be processed to serum (within 48 hours) to be used in different antibody 
analysis methods for understanding immunity, antibody repertoire, and for validation of 
appropriate testing methods. 
If a patient refuses blood for serology analysis, or Investigator’s judgement resolves that this 
blood collection is unsafe (eg, clinically significant anaemia), this will not be considered a 
protocol deviation as the serology analysis are not a primary or secondary objective of the 
protocol. 


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9.0 STATISTICAL CONSIDERATIONS 
9.1 Design Overview 
Note: the sample size calculation may be re-evaluated as the treatment of COVID-19 evolves. 
9.2 Statistical Hypotheses 
The primary hypothesis is time to response (2-point improvement in the 9-point ordinal scale, 
live discharge from hospital, or considered fit for discharge, as analysed at Day 29) of the 
bemcentinib arm is shorter than the SoC. 
As the events are 2-point improvement in 9-point ordinal scale, live discharge, or considered fit 
for discharge, a hazard ratio (HR) larger than 1 is favourable to the test treatment, with the HR 
comparing the test treatment with the control. 
𝐻𝐻0:𝐻𝐻R ≤1 𝑣𝑣s 𝐻𝐻𝐴𝐴:𝐻𝐻R >1 
9.3 Sample Size Determination 
Approximately 60 patients will be randomised into each arm of the study, whereby patients will 
receive either bemcentinib (with SoC) or SoC alone. The chosen endpoint to compare treatments 
will be the time to a sustained 2-point improvement on a 9-point category ordinal scale, 
discharge from hospital, or considered fit for discharge. 
It is expected that 54 patients are needed per arm, which will provide 80% power to detect a 
hazard ratio of 1.6 for the occurrence of the event, when comparing bemcentinib with SoC. This 
calculation is based on a 1-sided test and a 10% significance level, and assumes 85.5% of 
patients will improve, be discharged from hospital, or considered fit for discharge at Day 29 for 
bemcentinib versus 70% of patients for the SoC (the estimate of SoC was taken from Cao 
202028). To allow for uncertainty in the recruitment rates, it is expected that up to 60 patients 
(rather than 54 patients) will be randomised to each arm in order to achieve the required number 
of events for the preliminary analysis. 
Safety data will also be assessed. 
9.3.1 
Sample Size Calculations 
The calculations below (Table 3) are associated with time to improvement, discharge from 
hospital, or fit for discharge, and are associated with 80% and 90% power. The sample sizes are 
derived from a log-rank test, using a hazard ratio of 1.6 for the occurrence of the event, when 
comparing a bemcentinib with SoC. 


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Table 3 
Sample Size for 80% and 90% Power for Time to Improvement, Discharge 
from Hospital, or Fit for Discharge Using Log-rank Test for a Hazard Ratio 
of 1.6 in Treatment Arm to Standard of Care 
2-Point Improvement, Discharge from Hospital, or Fit 
for Discharge at Day 29  
Patients/Arm [Total Events]  
SoC  
Experimental 
Arm  
Relative 
Improvement 
to SoC  
Hazard 
Ratio  
One-sided 
Alpha  
Power  
80%  
90%  
0.7  
0.855  
15.5%  
1.6  
0.1  
54 [81]  
79 [118]  
0.9  
20%  
1.9  
0.1  
29 [43]  
42 [63]  
0.7  
0.855  
15.5%  
1.6  
0.025  
94 [141]  
126 [188]  
0.9  
20%  
1.9  
0.025  
50 [75]  
67 [100]  
SoC=standard of care 
9.4 Populations for Analyses 
For purposes of analysis, the analysis sets are defined in Table 4. 


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Table 4 
Analysis Sets 
Analysis Set  
Description  
Intention to Treat (ITT)  
All patients who are randomised and match the inclusion/exclusion criteria of 
the protocol.  
Safety Set  
All patients who are randomised and receive study intervention (bemcentinib 
or SoC).  
Pharmacokinetic Analysis Set 
(PKS)  
All patients who are randomised and take at least 1 dose of bemcentinib and 
have quantifiable bemcentinib concentrations postdose without protocol 
deviations or events affecting the pharmacokinetic results.  
Pharmacodynamic Analysis Set 
(PDS)  
All patients who are randomised and receive study intervention (bemcentinib 
or standard of care) and have evaluable results for at least 1 pharmacodynamic 
endpoint postdose. All analyses of the PDS will be based on each patient’s 
randomised assigned treatment (not actual treatment received).  
9.5 Statistical Analyses 
The Statistical Analysis Plan (SAP) will describe the patient analysis sets to be included in the 
analyses and procedures for accounting for missing, unused, and spurious data. 
Efficacy, safety, PK, and pharmacodynamic results will be listed and summarised by, dose, and 
scheduled time for the respective analysis sets, where appropriate. Bemcentinib concentration 
versus response variables may be graphically displayed for selected endpoints. Exposure-
response data obtained from this study may be combined with data from other studies and used 
for modelling and simulations. 
9.5.1 
Efficacy Analyses 
Please see Table 5. 


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Table 5 
Efficacy Analyses 
Endpoint  
Statistical Analysis Methods  
Primary  
Time to 2-point sustained improvement on the 9-point ordinal scale, live discharge, 
or fit for discharge (as analysed at Day 29), whichever comes first, will be 
compared with each treatment arm with standard of care (SoC) using log-rank test 
at the one-sided 0.1 alpha level. Intention to Treat (ITT) set will be used for the 
primary endpoint analysis. 
 
The time to 2-point sustained improvement on the 9-point ordinal scale, live 
discharge, or fit for discharge (as analysed at Day 29), whichever comes first, 
analyses will be conducted between the selected treatments plus SoC and SoC 
alone. 
 
The time to 2-point sustained improvement on 9-point ordinal scale, live discharge, 
or fit for discharge at Day 29 will be conducted between each selected treatment 
arm and control using the log-rank statistic, stratifying baseline severity grade, and 
the p-value associated with the log-rank statistic will be compared at the 2-sided 
0.05 alpha level. The hazard ratio between treatment arm and SoC will be estimated 
using Cox regression, including treatment, age category (age <70 years vs 
≥70 years), baseline severity, age category and treatment interaction, baseline 
severity and treatment interaction as fixed effect, and study centre as random effect.  
Secondary  
2-point sustained improvement on a 9-point ordinal scale will be analysed using 
CMH test, with stratification factors as covariates. 
Time to live discharge. 
 
Binary endpoints, including response rates at Days 2, 8, 15, and 29, and mortality 
rates at Days 15, 29, and 60, will be analysed using the same CMH test and logistic 
regression model as in the primary endpoint. 
Time-to-event endpoints, including time to sustained clinical improvement, time to 
worsening, time to death, and time to live discharge, from treatment start date will 
be plotted with Kaplan-Meier curves and will be tested with the log-rank test. 
Difference between treatment arms in the rank endpoints will be tested using the 
stratified Wilcoxon (van Elteren) test stratified by baseline ordinal score. 
Other continuous endpoints will be summarised with descriptive statistics such as 
mean, standard deviation, median, minimum, and maximum.  
Exploratory  
It will be described in the Statistical Analysis Plan finalised before database lock.  
 9.5.2  
Safety Analyses 
Analysis of Adverse Events 
All AEs reported in this study will be coded using the currently available version of the Medical 
Dictionary for Regulatory Activities. Coding will be to lowest level terms. The preferred term 
(PT), and the primary system organ class will be listed. 


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Summaries of all treatment-emergent adverse events (TEAEs) by treatment arm will include: 
• The number (n) and percentage (%) of patients with at least 1 TEAE by system organ 
class and PT 
• TEAEs by severity, presented by system organ class and PT 
• TEAEs by relationship to treatment (related, not related), presented by system organ class 
and PT 
• Deaths and other SAEs will be listed and summarised by treatment arm. 
• TEAEs leading to permanent treatment discontinuation will be listed and summarised by 
treatment arm. 
Analysis of Clinical Laboratory Evaluations 
The number and proportion of patients with normal/abnormal laboratory tests or different grades 
on Days 3, 5, 8, and 11 (or day of discharge) will be presented as shift tables by the baseline 
status (Day 1). 
Analysis of Vital Signs 
Potentially clinically significant abnormality values are defined as abnormal values considered 
medically important by the Sponsor according to predefined criteria/thresholds based on 
literature review. The incidence of potentially clinically significant abnormality vital signs on 
Days 8, 15, and 29 (or day of discharge) will be summarised overall and by their baseline 
normality status (normal/abnormal). 
9.5.3  
Other Analyses 
Where appropriate (if data collected), PK, pharmacodynamic, and biomarker exploratory 
analyses will be described in the SAP finalised before database lock. Drug concentration versus 
response variables may be graphically displayed for select endpoints. Exposure-response data 
may be obtained from this study and may be modelled and/or combined with data from other 
studies and used for modelling and simulations. If modelling and/or simulations are performed, 
these will be presented separately from the main clinical study report. 
Subgroup analyses will be performed, and will include a repeat of the primary analysis by 
o Severity at intervention; 
o Comorbidity (cardiovascular; diabetes; any of chronic respiratory disease, 
hypertension or cancer; none of the above); 
o Age group (up to 69 years of age; more than 69 years of age); 


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o Days from onset (less than 12 days; 12 or more days). 
9.5.4  
Missing Data 
Missing data will be minimised, with outcomes collected after premature withdrawal of 
treatment. The estimand will therefore be a “treatment policy” one. 
All patients recruited into the study will be accounted for, including those who did not complete 
the study along with the reasons for withdrawal from study and from study treatment. Patients 
who withdraw from the study and/or from the treatment will have the reasons of withdrawal 
collected in the eCRF. More details will be described in the SAP before database lock. 
9.6 Interim Analyses 
There is no plan for an interim efficacy analysis for this study. An Independent data and Safety 
monitoring committee will be established for this study (Section 9.7.2  
Independent Data 
and Safety Monitoring Committee). 
 
 


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9.7 Review Committees 
9.7.1  
Steering Committee (Scientific Review Committee) 
A Steering Committee has been assembled for the executive oversight and supervision of this 
study. The Steering Committee will serve this role through regular scheduled meetings or 
teleconferences and, if necessary, additional ad hoc meetings.  
The Steering Committee will be expected to:  
• Provide guidance, advice, and recommendations to the BGBC020 study on relevant clinical 
issues related to the strategy, implementation, and conduct of the study. This may include, 
but not necessarily be limited to:  
- 
Advice on the strategy and design of the protocol and any subsequent 
amendments or revisions.  
- 
Advice on issues of study enrolment including patient accrual, number and 
location of investigator sites, recruitment goals, and patient eligibility/ineligibility 
issues.  
- 
Advice on issues relating to the clinical conduct of the protocol including protocol 
violations/deviations and investigative site or Ethics Committee/Institutional 
Review Board concerns/issues, and regulatory engagement.  
- 
Advice on safety issues. 
9.7.2  
Independent Data and Safety Monitoring Committee 
An independent IDMC will be established for this study to assess safety on an ongoing basis 
throughout the study. The committee will be established for the purpose of objectively 
monitoring the safety data and will not include any assessment of efficacy data. The IDMC 
members will perform ongoing safety surveillance and provide recommendations to the Sponsor 
Steering Committee regarding study conduct. 
The IDMC will consist of at least 4 independent experts appointed by the study Sponsor based 
on their expertise. IDMC members will not be Investigators in the study, nor will they have any 
conflict of interest with the Sponsor or its designees.  
Further details (eg, frequency of data reviews and study committee composition and 
membership) will be provided in the IDMC charter. The charters will define the criteria, 
frequency of reviews, data, and source documentation required to adjudicate all events. 


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10.0   
STUDY MONITORING 
10.1  
Monitoring of the Study 
Study Monitors will be responsible for the monitoring of the study.  The Study Monitor will 
review the progress of the study on a regular basis to ensure adequate and accurate data 
collections.  Monitoring visits to review eCRF, patient case notes, administrative documentation, 
including the Investigator Site File will be performed throughout the study. 
Due to the current COVID-19 pandemic, any site training or monitoring methods may be 
conducted remotely (involving remote source data verification) with sites (via video calls and 
redacted source notes transferred to IQVIA via a secure file transfer method, or phone calls). 
Depending on the situation at each site over time, it is possible that the monitoring visits may be 
on-site visits at a later stage.  
Before or during study initiation, representatives of the Sponsor or its designee(s) will review the 
protocol and eCRF with the investigators and their staff and perform study-specific training.  
During the study, the IQVIA Biotech monitor and other IQVIA Biotech project team members, 
will check site specific documentation, either remotely or on-site, to confirm and ensure the 
following: completeness of records, accuracy of source data entries in the eCRFs, adherence to 
the protocol and ICH GCP, enrolment progress, and confirmation study drug supply/logistics.  
Key study personnel must be available to assist the study monitor during remote or on-site visits. 
The investigator must maintain source documents for each subject in the study, which may 
consist of reports and visit notes (hospital or clinic medical records). All information on eCRFs 
must be traceable to these source documents in the subject's file.  
For any on-site visits, the investigator must give the study monitor direct access to any relevant 
source documents to confirm their consistency with the eCRF entries, and compliance to the 
protocol. The investigator must also keep records documenting the informed consent process.  
Information in source documents that could identify the subjects (such as the subjects’ names) 
will not be forwarded to the Sponsor, IQVIA Biotech (or its designee(s)). 
Once COVID-19 restrictions are lifted, the Sponsor or its representative(s) may visit the study 
facilities in order to maintain current knowledge of the study through review of the records, 
comparison with source documents, check of IP accountability, observation and discussion of the 
conduct and progress of the study. The clinical site will permit any trial related monitoring, 
audits, IRB/IEC review, and regulatory Clinical Trial Application inspection(s) by providing 
direct access to source data/documents. 


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10.2  
Monitoring plan 
For the current protocol, the study design and protocol details are strongly supportive of utilizing 
a 100% remote monitoring strategy, by managing or eliminating the unintended COVID 19 risk 
exposure to clinical monitoring staff.  
From the monitor´s perspective, monitors will be conducting remote monitoring visits with sites 
and will be conducting Source data review over identified data points (detailed in the Clinical 
Monitoring Plan) including Informed consent review, inclusion/exclusion criteria, primary and 
secondary endpoints, contraception, pregnancy/lactation, COVID-19 testing, reasons for early 
discontinuation and AE/SAE review. Source documentation will be reviewed depending on the 
nature and capacities of each sites.  
The use and access to validated electronic source documentation systems will be the preferred 
method if this exists at the site. Alternatively, sites will be able to upload source documentation 
to a secure platform/portal where monitors will review the mentioned data remotely. 
Additionally, monitor may be reviewing IP and reconciliation via teleconferencing as per study 
specifications, but this may change to be done at on-site visits when this is possible.  
Remote monitoring includes subject safety, data quality, protocol compliance, endpoints and 
other reviews as identified during upfront risk assessment exercise. Detailed guidelines on 
monitoring activities are captured in the Clinical Monitoring Plan. 
 
 


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Covid-19. N Engl J Med. 2020;382(19):1787‐1799. 
 
 


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12.0 APPENDICES  
 


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Appendix 1  
Abbreviations 
Abbreviation  
Definition  
ACE 
Angiotensin-converting enzyme 
AE 
Adverse event 
AESI 
Adverse event of special interest 
AML 
Acute myeloid leukaemia 
COVID-19 
Coronavirus disease 2019 
EAMS 
Early Access to Medicines Scheme 
EBOV 
Ebola virus 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
FiO2 
Fraction of inspired oxygen 
GAS6 
Gas arrest-specific 6 
ICF 
Informed consent form 
IFN 
Interferon 
IL 
Interleukin 
NEWS2 
National Early Warning Score 2 
PCR 
Polymerase chain reaction 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PT 
Preferred term 
REC 
Research ethics committee 
RP2D 
Recommended phase 2 dose 
SAE 
Serious adverse evet 
SAP 
Statistical analysis plan 
SARS 
Severe acute respiratory syndrome 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SoA 
Schedule of Activities  
SoC 
Standard of care  
SpO2 
Oxygen saturation 
TEAE 
Treatment-emergent adverse event 
TdP 
Torsades de Pointes 
  
 
 


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Appendix 2  
Regulatory, Ethical, and Study Oversight Considerations 
Protocol Compliance 
The Investigator agrees to comply with the requirements of the Protocol and Good Clinical 
Practice. Prospective, planned deviations or waivers to the protocol are not allowed under 
applicable regulations on Clinical Trials and must not be used; eg, it is not acceptable to enrol a 
patient if they do not meet the eligibility criteria or restrictions specified in the protocol. 
Accidental protocol deviations can happen at any time. They must be adequately documented on 
the relevant forms and reported to the Medical monitor and Sponsor immediately. 
Deviations from the protocol, which are found to frequently recur, are not acceptable and will 
require immediate action by the Sponsor. Frequent non-compliances could potentially be 
classified as a serious breach. 
Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the Protocol: 
- 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines. 
- 
Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines. 
- 
Applicable local laws and regulations. 
• The Protocol, protocol amendments, ICF, Investigator Brochures, and other relevant 
documents (eg, advertisements) must be approved by the appropriate regulatory body, local 
regulations, and REC before the study, or a new study arm introducing  bemcentinib, is 
initiated. 
• Any substantial amendments to the protocol will not be implemented until local regulations 
and REC have provided the relevant authorisations, except for changes necessary to 
eliminate an immediate hazard to patients. 
• All correspondence with the local regulatory and the REC will be retained in the Trial Master 
File and the Investigator Site File (maintained by the site). 
• An annual progress report will be submitted to the REC within 30 days of the anniversary 
date on which the favourable opinion was given, and annually until the study is declared 
ended. 
• Within 90 days after the end of the study (as defined in Section 4.4), the Medical monitor 
and/or Sponsor medical team will ensure that the local regulatory and the main REC are 
notified that the study has finished. If the study is terminated prematurely, those reports will 
be made within 15 days after the end of the study. 
• The Medical Monitor will supply the Sponsor with a summary report of the study, which will 
then be submitted to the main REC within 1 year after the end of the study. 


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• All results will be published on a publicly accessible database. 
• After reading the protocol, each Investigator will sign the protocol signature page and send a 
copy of the signed page to the Sponsor or representative (Appendix 9). The study will not 
start at any study centre at which the Investigator has not signed the protocol. 
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 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. 
Indemnity 
The Sponsor of the study is BerGenBio ASA. Insurance certificate will be provided. 
Informed Consent Process 
Note: Informed consent from a patient will be obtained on paper and then scanned/photographed 
to retain an electronical copy, the original will be destroyed at site. 
By consenting to participate in the study participants also consent to all the secondary research 
endpoints. 
Some patients will be unable to give consent themselves and therefore consent can be given on 
their behalf by a legally authorised representative. If legally authorised representatives are unable 
to visit the patient in person due to COVID-19 restrictions, it may not be possible to obtain 
legally authorised consent in person; in these circumstances a legally authorised representative 
can give consent via a remote process. The legally authorised representative will be contacted by 
telephone to discuss the patient’s condition and the consent documents; they will then be sent an 
e-mail invitation about the study, and they can sign the ICF remotely. Study staff will be 
available by telephone to answer questions. 
The Investigator or his/her representative will explain the nature of the study to the patient or 
his/her legally authorised representative and answer all questions regarding the study. 
Patients must be informed that their participation is voluntary. Where they are able, patients or 
their legally authorised representative will be required to sign the ICF. If the patient is not able to 
read the text and/or sign the ICF for themselves but has capacity to give consent, an independent 
witness can witness the consent process and sign the ICF to confirm this. Where a legal 
representative is not able to sign the ICF but can provide verbal consent over the telephone, an 
independent witness can witness the consent process and sign the ICF to confirm this. In these 
instances, the patient or legally authorised representative must also sign the ICF within a 
reasonably practicable time frame. 


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The patient’s medical record must include a statement that informed consent was obtained before 
the patient was entered in the study and the date the consent was obtained. The authorised person 
obtaining the informed consent must also sign the ICF. 
If there are changes to the ICF, patients must be re-consented to the most current version of the 
ICF(s) during their participation in the study. The above-mentioned electronic processes will also 
apply in these instances if needed. 
A copy of the signed ICF(s) must be provided to the patient or the patient’s legally authorised 
representative. 
Data Protection 
• 
Patients will be assigned a unique identifier by the Sponsor. Any patient records or datasets 
that are transferred to the Sponsor will contain the identifier only; patient names or any 
information which would make the patient identifiable will not be transferred. 
• 
The patient 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 patient. 
• 
The patient must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorised personnel appointed by the Sponsor, by 
appropriate REC members, and by inspectors from regulatory authorities. 
• 
The ICF will incorporate (or, in some cases, be accompanied by a separate document 
incorporating) wording that complies with relevant data protection and privacy legislation, 
that also explains that his/her medical records (past and future) may be linked to their study 
data and accessed and examined for healthcare research, and that participant data may be 
stored and processed in the cloud or outside the country. 
• 
The ICF will explain that the individual genotype results will not be returned to patients, 
provided to any insurance company, to any employer, their family members, general 
physician, or any other third party, unless required to do so by law. 
• 
Participants will not receive any financial benefit from the use of their samples or data in 
research. Samples and data may be processed and used by commercial entities as well as 
government or academic entities. 
• 
Extra precautions are taken to preserve confidentiality and prevent genetic data being linked 
to the identity of the patient. In exceptional circumstances, however, certain individuals 
might see both the genetic data and the personal identifiers of a patient. For example, in the 
case of a medical emergency, the Sponsor or representative physician or an Investigator 
might know a patient’s identity and also have access to his or her genetic data. Also, 
regulatory authorities may require access to the relevant files. 


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Administrative Structure 
The IQVIA Therapeutic Medical Advisor (Medical Monitor) is available for 24 hours a 
day/7 days a week urgent contact. If the IQVIA Therapeutic Medical Advisor is not able to 
provide 24/7 services for a period longer than 2 hours (eg, for international business travel) or 
during vacations, adequate back-up will be arranged and communicated. 
The administrative structure will be documented in more detail in the Trial Master File. 
Dissemination of Clinical Study Data 
The results of the study should be reported within 1 year from the end of the clinical study. 
Irrespective of the outcome, the Sponsor will submit to the European Union database a summary 
of the results of the clinical study within 1 year from the end of the clinical study. It shall be 
accompanied by a summary written in a manner that is understandable to laypersons. 
Data Quality Assurance 
• 
All patient data relating to the study will be recorded on eCRFs unless transmitted to the 
Sponsor or designee electronically (eg, laboratory data). The Investigator is responsible for 
verifying that data entries are accurate and correct by physically or electronically signing the 
eCRF. 
• 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
• 
The Investigator must permit study-related monitoring, audits, REC review, and regulatory 
agency inspections and provide direct access to source data documents. 
• 
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
• 
Study monitors will perform ongoing source data review to confirm that data entered into the 
eCRF by authorised study centre personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of patients 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. 
• 
Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the Investigator for 25 years after study completion 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. 
Source Documents 
The Investigator/institution should maintain adequate and accurate source documents and study 
records that include all pertinent observations on each of the study centre’s patients. Source data 
should be attributable, legible, contemporaneous, original, accurate, and complete. Changes to 


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source data should be traceable, should not obscure the original entry, and should be explained if 
necessary (eg, via an audit trail). 
• 
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s study centre. 
• 
Data reported on the eCRF 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 can be found in the eCRF completion guidelines. 
Study and Study Centre Closure 
The Sponsor designee reserves the right to close the study centre or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study centres will be closed upon study 
completion. A study centre is considered closed when all required documents and study supplies 
have been collected and a study centre closure visit has been performed. 
The Investigator may initiate study centre 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 centre by the Sponsor or Investigator may include but 
are not limited to: 
• 
Failure of the Investigator to comply with the protocol, the requirements of the REC or local 
health authorities, the Sponsor’s procedures, or GCP guidelines. 
• 
Inadequate recruitment of patients by the Investigator. 
• 
Discontinuation of further study treatment development. 
Publication Policy 
The data generated by this study are confidential information of the Sponsor. The Sponsor will 
make the results of the study publicly available. 
The publication policy with respect to the Investigator and study centre will be set forth in the 
Clinical Trial Agreement. 
• 
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 multicentre studies only in their entirety and not as individual study centre 
data. In this case, a Coordinating Investigator will be designated by mutual agreement. 


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• 
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements. 


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Appendix 3  
Clinical Laboratory Tests 
• 
The minimum tests to be performed are detailed in Table 6. Clinical laboratory tests will be 
performed at a local laboratory. 
• 
Protocol-specific requirements for inclusion or exclusion of patients are detailed in 
Section 5.0 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. 
• 
Changes to some laboratory parameters are anticipated for any patients moving on to ECMO 
therapy. 
• 
Investigators must document their review of each laboratory safety report. 


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Table 6 
Protocol-required Safety Laboratory Assessments 
Laboratory Assessments  
Parameters  
Haematology  
Platelet Count 
Haemoglobin 
White blood cell count with differential: 
  Neutrophils 
  Lymphocytes 
  Monocytes 
  Eosinophils 
  Basophils  
Coagulation  
D-dimer test 
Fibrinogen 
Activated partial thromboplastin time (aPTT) 
Prothrombin time 
International Normalised Ratio (INR)  
Clinical Chemistry  
Potassium 
Sodium 
Calcium 
Magnesium 
Phosphate 
Alkaline phosphatase 
Bicarbonate 
Creatinine 
Creatine kinase (including MB fraction if available) 
Glucose 
Total bilirubin 
Aspartate aminotransferase (AST) 
Alanine aminotransferase (ALT) 
Gamma-glutamyl transferase (GGT) 
C-reactive protein 
Ferritin 
Triglycerides 
Lactate dehydrogenase (LDH) 
Troponin  
Additional laboratory serology 
Hepatitis B and Hepatitis C 
 


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Appendix 4  
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
Definition of AE 
AE Definition  
• 
An adverse event (AE) is any untoward medical occurrence in a patient or patient, temporally 
associated with the use of study treatment, whether or not considered related to the study treatment. 
• 
NOTE: An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of 
study treatment.  
 
Events Meeting the AE Definition  
• 
Any abnormal laboratory test results (haematology, clinical chemistry, or urinalysis) or other safety 
assessments (eg, electrocardiogram, radiological scans, vital signs measurements), including those that 
worsen from baseline, considered clinically significant in the medical and scientific judgement of the 
Investigator (ie, 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 treatment administration even though it may have 
been present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study treatment or a 
concomitant medication. Overdose per se will not be reported as an AE/serious adverse event (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 patient’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 patient’s condition. 
• 
Medical or surgical procedure (eg, 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.  


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Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (eg, hospitalisation for signs/symptoms of the disease under study, death due to 
progression of disease). 
An SAE is defined as any untoward medical occurrence 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 patient 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 hospitalisation or prolongation of existing hospitalisation 
In general, hospitalisation signifies that the patient has been detained (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 
hospitalisation are AEs. If a complication prolongs hospitalisation or fulfils any other serious criteria, the 
event is serious. When in doubt as to whether “hospitalisation” occurred or was necessary, the AE should 
be considered serious. 
Hospitalisation for elective treatment of a pre-existing condition that did not worsen from baseline is not 
considered an AE.  
d) Results in persistent 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, diarrhoea, influenza, and accidental trauma (eg, 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 judgement should be exercised in deciding whether SAE reporting is appropriate 
in other situations such as important medical events that may not be immediately life-threatening or 
result in death or hospitalisation but may jeopardise the patient or may require medical or surgical 
intervention to prevent 1 of the other outcomes listed in the above definition. These events should 
usually be considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias, or convulsions that do not result in 
hospitalisation, or development of drug dependency or drug abuse.  
 
 
 


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Recording and Follow-up of AE and/or SAE  
AE and SAE Recording  
• 
When an AE/SAE occurs, it is the responsibility of the Investigator to review all documentation (eg, 
hospital progress notes, laboratory reports, and diagnostics reports) related to the event. 
• 
The Investigator will then record all relevant AE/SAE information in the eCRF. Each event must be 
recorded separately. 
• 
It is not acceptable for the Investigator to send photocopies of the patient’s medical records to the 
CRO/Sponsor in lieu of completion of the AE/SAE eCRF page. 
• 
There may be instances when copies of medical records for certain cases are requested by the 
CRO/Sponsor. In this case, all patient identifiers, with the exception of the patient number, will be 
redacted on the copies of the medical records before submission to the CRO/Sponsor. 
• 
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 study and 
assign it to 1 of the following Common Terminology Criteria for Adverse Events (CTCAE) grades: 
• 
Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention 
not indicated. 
• 
Grade 2 Moderate; minimal, local or non-invasive intervention indicated; limiting age appropriate 
instrumental activities of daily living (preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc). 
• 
Grade 3 Severe or medically significant but not immediately life-threatening; hospitalisation or 
prolongation of hospitalisation indicated; disabling; limiting selfcare activities of daily living (bathing, 
dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden). 
• 
Grade 4 Life-threatening consequences; urgent intervention indicated. 
• 
Grade 5 Death related to AE. 
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 (Grade 3 and higher).  
 
 
 


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Assessment of Causality  
• 
The Investigator is obligated to assess the relationship between study treatment and each occurrence of 
each AE/SAE. The AE must be characterised as related or unrelated. 
o 
“Related” conveys that there are facts, evidence, and/or arguments to suggest a causal 
relationship for the individual case. 
o 
“Unrelated” is used if there is not a reasonable possibility that the study treatment caused the 
AE. 
• 
The Investigator will use clinical judgement 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 treatment 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 the CRO/Sponsor. 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 the CRO/Sponsor.  
•  
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 AEs and SAEs  
• 
The Investigator is obligated to perform or arrange for the conduct of supplemental measurements 
and/or evaluations as medically indicated or as requested by the CRO/Sponsor 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 patient dies during participation in the study or during a recognised follow-up period, the 
Investigator will provide the CRO/Sponsor with a copy of any postmortem findings including 
histopathology. 
• 
New or updated information will be recorded in the originally completed eCRF. 
• 
The Investigator will submit any updated SAE data to the Sponsor within 24 hours of receipt of the 
information.  
 
 
 


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Reporting of SAEs 
SAE Reporting to the CRO/Sponsor via an Electronic Data Collection Tool  
• 
The primary mechanism for reporting an SAE to the CRO/Sponsor will be the electronic data collection 
tool. 
• 
If the electronic system is unavailable for more than 24 hours, then the study centre will use the paper 
SAE data collection tool (see next section). 
• 
The study centre will enter the SAE data into the electronic system as soon as it becomes available. 
• 
After the study is completed at a given study centre, the electronic data collection tool will be taken off-
line to prevent the entry of new data or changes to existing data. 
• 
If a study centre receives a report of a new SAE from a patient or receives updated data on a previously 
reported SAE after the electronic data collection tool has been taken off-line, then the study centre can 
report this information on a paper SAE form (see next section) or to the Medical Monitor/SAE 
coordinator by telephone.  
 
SAE Reporting to CRO/Sponsor via Paper Case Report Form  
• 
Facsimile transmission of the SAE paper case report form is the preferred method to transmit this 
information to the Medical Monitor or 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 eCRF pages within the designated reporting time frames.  
 


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Appendix 5  
Contraceptive Guidance and Collection of Pregnancy 
Information 
Definitions: 
Fertile Male 
A man is considered fertile after puberty unless permanently sterile by bilateral orchidectomy. 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below). 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
a) Documented hysterectomy. 
b) Documented bilateral salpingectomy. 
c) Documented bilateral oophorectomy. 
Note: Documentation can come from the study centre personnel’s: review of the patient’s 
medical records, medical examination, or medical history interview. 
3. Postmenopausal female: 
a) A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) level in the 
postmenopausal range may be used to confirm a postmenopausal state in women not 
using hormonal contraception or hormonal replacement therapy (HRT). However, in 
the absence of 12 months of amenorrhea, a single FSH measurement is insufficient. 
b) Females on HRT and whose menopausal status is in doubt will be required to use 1 of 
the non-oestrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrolment. 
Contraception Guidance 
Male patients 
• 
Male patients with female partners of childbearing potential are eligible to participate if they 
agree to ONE of the following: 
− Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent. 


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− Agree to use a male condom plus partner use of a contraceptive method with a failure 
rate of <1% per year as described in the table below when having penile-vaginal 
intercourse with a woman of childbearing potential who is not currently pregnant. 
• 
In addition, male patients must refrain from donating sperm for the duration of the study and 
for at least 120 days after the last dose of study treatment. 
• 
Male patients with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile-vaginal intercourse or use a male condom during each episode of penile penetration 
for the duration of the study and for at least 120 days after the last dose of study treatment. 
Female patients 
Female patients of childbearing potential are eligible to participate if they agree to use a highly 
effective method of contraception consistently and correctly as described in the table below. 
 
Highly Effective Contraceptive Methods 
Highly Effective Contraceptive Methods That are User Dependent a Failure 
Rate of <1% Per Year When Used Consistently and correctly.  
Combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulationb 
Oral 
Intravaginal. 
Transdermal.  
Progestogen only hormonal contraception associated with inhibition of ovulationb 
Oral. 
Injectable  
Highly Effective Methods That Are User Independent a  
Implantable progestogen only hormonal contraception associated with inhibition of ovulationb 
Intrauterine device (IUD). 
Intrauterine hormone-releasing system (IUS). 
Bilateral tubal occlusion.  
Vasectomised Partner 
A vasectomised partner is a highly effective birth control method provided that the partner is the sole male sexual 
partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method 
of contraception should be used.  
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 treatment. 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 patient.  


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NOTES: 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with 
local regulations regarding the use of contraceptive methods for patients participating in clinical studies. 
b Hormonal contraception may be susceptible to interaction with the study treatment, which may reduce the efficacy 
of the contraceptive method. In this case, 2 highly effective methods of contraception should be utilised during the 
treatment period and for at least 120 days after the last dose of study treatment.  
Pregnancy Testing: 
• WOCBP should only be included after a negative highly sensitive pregnancy test. 
• Pregnancy testing will also be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected. 
Collection of Pregnancy Information 
Male subjects with partners who become pregnant (if required as per local country regulations). 
• The Investigator will attempt to collect pregnancy information on any male subject’s female 
partner who becomes pregnant while the male subject is in this study. This applies only to 
male subjects who receive bemcentinib. 
• After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. The female 
partner will also be followed to determine the outcome of the pregnancy. Information on the 
status of the mother and child will be forwarded to the Sponsor. Generally, the follow-up will 
be no longer than 6 to 8 weeks following the estimated delivery date. Any termination of the 
pregnancy will be reported regardless of foetal status (presence or absence of anomalies) or 
indication for the procedure.  
Female Subjects who become pregnant 
Please refer to Section 8.3.5. 
• The Investigator will collect pregnancy information on any female patient who becomes 
pregnant while participating in this study. Information will be recorded on the appropriate 
form and submitted to the Sponsor within 24 hours of learning of a patient’s pregnancy. The 
patient will be followed to determine the outcome of the pregnancy. The Investigator will 
collect follow-up information on the patient and the neonate and the information will be 
forwarded to the Sponsor. Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date. Any termination of pregnancy will be reported, 
regardless of foetal status (presence or absence of anomalies) or indication for the procedure. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy will be reported as an AE or SAE. A spontaneous 
abortion is always considered to be an SAE and will be reported as such. 


CONFIDENTIAL  
 
Protocol BGBC020 – Amendment 2 Final 
Final 08 October 2020 
82  
• Any poststudy pregnancy-related SAE considered reasonably related to bemcentinib by the 
Investigator will be reported to the Sponsor as described in Section 8.3.4. While the 
Investigator is not obligated to actively seek this information in former patients, he or she 
may learn of an SAE through spontaneous reporting. 
Continuation of study treatment may be allowed, as COVID-19 is a high mortality disease. 


CONFIDENTIAL  
 
Protocol BGBC020 – Amendment 2 Final 
Final 08 October 2020 
83  
Appendix 6  Avoidance of Concomitant Medication with QT Prolongation 
Risk or CYP3A4 Interaction with Narrow Therapeutic 
Index 
For any concomitant medication, please check the following website for the drug’s Torsades de 
Pointes (TdP) risk: https://crediblemeds.org/oncosupport/. 
If a medication can be discontinued, the 3-day bemcentinib loading regime may be started as 
long as the QTcF on prior therapy is not prolonged above that required for eligibility (470 msec). 
While it is desirable to discontinue concomitant medications with QT prolonging liability prior 
to trial entry, and replace where indicated with non-QT prolonging medications, where it is not 
clinically feasible to immediately discontinue, concomitant administration will not exclude the 
patient, but Investigators should have a low threshold for applying additional ECG monitoring 
(daily) in this setting as clinically indicated, and discontinue bemcentinib permanently if QTcF 
becomes ≥501 msec. 
For drugs with a conditional risk, please review the product label and correct any abnormalities, 
eg, hypokalaemia. 
Sensitive Cytochrome P450 3A4 Substrates With A Narrow Therapeutic Margin 
THESE MEDICATIONS SHOULD BE DISCONTINUED BEFORE ENROLMENT 
Alfentanyl 90-111 minutes 
Dihydroergotamine & ergotamine 
2 hours 
Quinidine 6 hours 
Astemizole 7 – 9 hours 
Fentanyl 8 – 10 hours 
Sirolimus 63 hours 
Cisapride 12 hours 
Fluticasonea 3 – 8 hours 
Tacrolimus (FK506) 12 hours 
Cyclosporine 8.4 hours 
Pimozide 55 hours 
Terfenadine 3.5 hours 
a Fluticasone, administered either nasally or inhaled, has limited systemic exposure and may continue without 
interruption. 
 


CONFIDENTIAL  
 
Protocol BGBC020 – Amendment 2 Final 
Final 08 October 2020 
84  
Common medication Associated with a Risk of QT Prolongation and TdP – 
USE NOT RECOMMENDED AS CONCOMITANT MEDICATION 
Amiodarone 50 days$ 
Erythromycin 2 hours$ 
Pimozide 55 hours ** 
Astemizole 24 hours ** 
Escitalopram 30 hours$a 
Procainamide 2.5-4.75 hours$ 
Azithromycin 2-4 days$ 
Fluconazole 30 hours$ 
Quinidine 6 hours **$ 
Chloroquine 1-2 months$ 
Haloperidol 15 – 27 hours$ 
Sotalol 10 – 20 hours$ 
Citalopram 35 hours$a 
Ketoconazole 3 – 10 hours$ 
Terfenadine 3.5 hours** 
Clarithromycin 3-4 hours$ 
Methadone 25 – 55 hours$ 
Thioridazine 21 – 24 hours$ 
Cocaine 0.6 – 1.3 hours$ 
Moxifloxacin 12 hours$ 
Voriconazole 6 hours$ 
Disopyramide 6.7 hours$ 
Ondansetron 3 hours$ 
 
Droperidol 2 hours$ 
Petamidine 10 – 14 days$ 
 
**also CYP3A4 substrates 
$ also TdP risk 
 
RECOMMENDED ACTION 
 
 
1. QTcF >470 msec (on above medication)  patient is not eligible for enrolment in the subprotocol 
2. QTcF ≤470 msec (on above medication): 
a) Stop drug, if possible, for duration of study dosing and consider alternatives 
 
3-day bemcentinib loading regime may be initiated and consider enhanced frequency of ECG monitoring 
b) If drug cannot be stopped, may be continued with enhanced ECG monitoring frequency (daily) 
In either case bemcentinib must be discontinued permanently if QTcF is calculated at ≥501 msec (see 
Section 6.2) 
For specific advice on citalopram or escitalopram, see Section 6.5.1. 
Woosley RL, Heise CW, Gallo T, Tate J, Woosley D and Romero KA, www.CredibleMeds.org, QTdrugs List, 
[14Apr2020], AZCERT, Inc. 1822 Innovation Park Dr., Oro Valley, AZ 85755 
a Citalopram/escitalopram may be continued with short term coadministration of bemcentinib, in accordance with 
guidance in Section 6.5.1. 
Guidance on other concomitant medication 
Use of gastric acid-reducing agents 
Treatment with histamine receptor 2 inhibitors (cimetidine, ranitidine) 
or protein pump inhibitors (omeprazole) is permitted provided that 
administration is once daily, in the evening, 
Anti-diarrhoeal 
Loperamide use is permitted at up to a maximum dose of 16 mg in a 
24-hour period 
Nausea/anti-emetic 
No evidence for specific restrictions on coadministration of anti-emetic 
medication, but Investigators should note QT prolongation potential 
associated with ondansetron and should not be newly initiated 
 
 
 
 


CONFIDENTIAL  
 
Protocol BGBC020 – Amendment 2 Final 
Final 08 October 2020 
85  
Appendix 7 
The NEWS2 Scoring System 
 
 
 


CONFIDENTIAL  
 
Protocol BGBC020 – Amendment 2 Final 
Final 08 October 2020 
86  
Appendix 8 
Study Procedures During Special Circumstances 
During special circumstances (eg, COVID-19 pandemic), the specific guidance from local public 
health and other competent authorities regarding the protection of individuals’ welfare must be 
applied. For the duration of such special circumstances, the following measures may be 
implemented for enrolled subjects: 
• 
Safety follow-up may be made by a telephone call, other means of virtual contact, or 
home visit, if appropriate.  
• 
Diary cards may be transmitted from and to the site by electronic means and/or 
conventional mail.  
• 
Biological samples may be collected at a different location* other than the study site or at 
subject’s home. Biological samples should not be collected if they cannot be processed in 
a timely manner or appropriately stored until the intended use.  
• 
If despite best efforts it is not possible to collect blood samples within the interval 
predefined in the protocol, then the interval for blood sampling may be extended up to a 
maximum length of 30 days before the next blood sampling. Impact on the per protocol 
set for analysis of immunogenicity will be determined on a case-by-case basis.  
• 
A limited number of subjects may be recruited in the active arms, should there be a high 
rate of missed visit and/or visit outside of planned interval and/or withdrawal due to the 
current exceptional and unpredictable circumstances.  
*It is the Investigator’s responsibility to identify an alternate location. The Investigator should 
ensure that this alternate location meets International Council for Harmonisation Good Clinical 
Practice requirements, such as adequate facilities to perform study procedures, appropriate 
training of the staff and documented delegation of responsibilities in this location. This alternate 
location should be covered by proper insurance for the conduct of study on subjects by 
Investigator and staff at a site other than the designated study site. 
  
 


CONFIDENTIAL  
 
Protocol BGBC020 – Amendment 2 Final 
Final 08 October 2020 
87  
Appendix 9  
Signature of Investigator 
PROTOCOL TITLE:   
A Multicentre, Phase 2, Randomised Study to Assess the Efficacy 
and Safety of Bemcentinib for the Treatment of COVID-19 in Hospitalised Patients 
PROTOCOL NO:  
BGBC020 
VERSION:  
  
Original Protocol 
This protocol is a confidential communication of the Sponsor. I confirm that I have read this 
protocol, I understand it, and I will work according to this protocol. I will also work consistently 
with the ethical principles that have their origin in the Declaration of Helsinki and that are 
consistent with Good Clinical Practices and the applicable laws and regulations. Acceptance of 
this document constitutes my agreement that no unpublished information contained herein will 
be published or disclosed without prior written approval from the Sponsor. 
Instructions to the Investigator: Please SIGN and DATE this signature page. PRINT your name, title, and the name of the study 
centre in which the study will be conducted. Return the signed copy to the CRO/Sponsor. 
 
I have read this protocol in its entirety and agree to conduct the study accordingly: 
 
Signature of Investigator:  
__________________________Date: ________  
Printed Name:  
___________________________  
Investigator Title: 
 
___________________________  
Name/Address of Centre:  
___________________________  
 
  
  
  
  
___________________________  
 
  
  
  
  
___________________________  
 

SAP_001.pdf: 
BerGenBio ASA 
Protocol Number: BGBC020 
Statistical Analysis Plan 
Page 1 of 48 
Author: 
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Version Date:  
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STATISTICAL ANALYSIS PLAN
BGBC020 
A Multicentre, Phase 2, Randomised Study to Assess the Efficacy and Safety of 
Bemcentinib for the Treatment of COVID-19 in Hospitalised Patients 
AUTHOR: 
VERSION NUMBER AND DATE: V1.0, November 17th, 2020 
PPD
PPD
NCT04890509


BerGenBio ASA  
Protocol Number: BGBC020 
Statistical Analysis Plan 
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Author: 
 
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proprietary to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE 
Statistical Analysis Plan V1.0 (Dated 17NOV2020) for BGBC020 
 
 
Name 
Signature 
Date (DDMMYYYY) 
Author: 
 
 
 
Position: 
 
Company: 
IQVIA Biotech 
 
 
Upon review of this document, the undersigned approves this version of the Statistical Analysis Plan, authorising 
that the content is acceptable for the reporting of this study. 
 
Name 
Signature 
Date (DDMMYYYY) 
Approved By: 
 
 
 
Position: 
 
Company: 
BerGenBio ASA   
PPD
PPD
PPD
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BerGenBio ASA  
Protocol Number: BGBC020 
Statistical Analysis Plan 
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Author: 
 
Version Number: 
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Version Date:  
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proprietary to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
MODIFICATION HISTORY 
 
Unique 
Identifier for 
this Version 
Date of the 
Document 
Version 
Author 
Significant Changes from  
Previous Authorised Version 
0.1 
26Oct2020 
 
Not Applicable – Prepared based on Protocol 
Amendment 2.0 
0.2 
11Nov2020 
 
• 
Accept Sponsor’s updates 
• 
Remove Adverse Events of Special 
Interest 
1.0 
17Nov2020 
 
• 
Finalize 
 
 
PPD
PPD
PPD
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BerGenBio ASA  
Protocol Number: BGBC020 
Statistical Analysis Plan 
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Author: 
 
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Version Date:  
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proprietary to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
TABLE OF CONTENTS 
1. 
INTRODUCTION............................................................................................................... 8 
2. 
STUDY OBJECTIVES AND END POINTS .................................................................... 8 
2.1. 
Primary Objectives and End Points ............................................................................................................... 8 
2.2. 
Key Secondary Objectives and End Points ................................................................................................... 8 
2.3. 
Other Secondary Objectives and End Points ................................................................................................ 9 
2.4. 
Exploratory Objectives and End Points ...................................................................................................... 10 
3. 
STUDY DESIGN ............................................................................................................... 10 
3.1. 
General Description ....................................................................................................................................... 10 
3.2. 
Schedule of Events ......................................................................................................................................... 11 
3.3. 
Changes to Analysis from Protocol .............................................................................................................. 11 
4. 
PLANNED ANALYSES ................................................................................................... 11 
4.1. 
Review Committees ....................................................................................................................................... 11 
4.1.1. 
Steering Committee (Scientific Review Committee) ............................................................................... 11 
4.1.2. 
Independent Data Monitoring Committee (IDMC) ................................................................................. 12 
4.2. 
IDMC Data Review........................................................................................................................................ 12 
4.3. 
Final Analysis ................................................................................................................................................. 13 
5. 
ANALYSIS SETS.............................................................................................................. 13 
5.1. 
Intention to Treat Analysis Set ..................................................................................................................... 13 
5.2. 
Safety Analysis Set ......................................................................................................................................... 13 
5.3. 
Pharmacokinetic Analysis Set ....................................................................................................................... 14 
5.4. 
Pharmacodynamic Analysis Set ................................................................................................................... 14 
5.5. 
Process for Analysis Set Assignment ............................................................................................................ 14 
6. 
GENERAL CONSIDERATIONS ................................................................................... 14 
6.1. 
Reference Start Date and Study Day ........................................................................................................... 14 
6.2. 
Baseline ........................................................................................................................................................... 14 
6.3. 
Retests, Unscheduled Visits and Early Termination Data ......................................................................... 15 
6.4. 
Windowing Conventions ............................................................................................................................... 15 
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6.5. 
Common Calculations ................................................................................................................................... 15 
7. 
STATISTICAL CONSIDERATIONS ............................................................................ 15 
7.1. 
Sample Size Considerations .......................................................................................................................... 15 
7.2. 
Missing Data ................................................................................................................................................... 16 
7.3. 
Statistical Tests .............................................................................................................................................. 16 
7.4. 
Multiple Comparisons/ Multiplicity ............................................................................................................. 16 
7.5. 
Multicentre Study .......................................................................................................................................... 16 
7.6. 
Adjustments for Covariates and Factors to be Included in Analyses ....................................................... 16 
7.7. 
Examination of Subgroups ............................................................................................................................ 17 
7.8. 
Handling Model Convergence or Estimation Issues ................................................................................... 18 
7.9. 
Software Version ............................................................................................................................................ 18 
8. 
OUTPUT PRESENTATIONS ......................................................................................... 18 
9. 
DISPOSITION AND WITHDRAWALS ........................................................................ 18 
9.1. 
Disposition ...................................................................................................................................................... 18 
9.2. 
Protocol Deviations ........................................................................................................................................ 19 
10. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ....................... 20 
10.1. Derivations ..................................................................................................................................................... 20 
11. 
COVID-19 CO-MORBIDITIES AND MEDICAL HISTORY..................................... 20 
12. 
DISEASE HISTORY ........................................................................................................ 21 
12.1. Derivations ..................................................................................................................................................... 22 
13. 
MEDICATIONS ............................................................................................................... 23 
14. 
EXPOSURE TO STUDY TREATMENT ....................................................................... 23 
14.1. Derivations ..................................................................................................................................................... 23 
15. 
STUDY MEDICATION COMPLIANCE ...................................................................... 23 
15.1. Derivations ..................................................................................................................................................... 23 
16. 
EFFICACY OUTCOMES................................................................................................ 24 
16.1. Primary Efficacy ............................................................................................................................................ 24 
16.1.1. 
Primary Efficacy Variable & Derivation ................................................................................................. 24 
16.1.2. 
Missing Data Methods for Primary Efficacy Variable(s) ........................................................................ 25 
16.1.3. 
Primary Analysis of Primary Efficacy Variable ...................................................................................... 25 
16.1.4. 
Sensitivity Analysis of Primary Efficacy Variable .................................................................................. 26 
16.1.5. 
Supplementary Analysis of Primary Efficacy Variable ........................................................................... 26 
16.2. Secondary Efficacy ........................................................................................................................................ 27 
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16.2.1. 
Key Secondary Efficacy Variables & Derivations................................................................................... 27 
16.2.1.1. 
The proportion of patients not deteriorating according to the ordinal scale by 1, 2, or 3 points on 
Days 2, 8, 15, 22, and 29 ..................................................................................................................................... 27 
16.2.1.2. 
Duration (days) of oxygen use and oxygen-free days ...................................................................... 27 
16.2.1.3. 
Qualitative and quantitative PCR determination of SARS-CoV-2 in oropharyngeal/nasal swab on 
Days 1, 3, 5, 8, 11, 15, and Day 29 ...................................................................................................................... 27 
16.2.2. 
Missing Data Methods for Key Secondary Efficacy Variables ............................................................... 28 
16.2.3. 
Analysis of Key Secondary Efficacy Variables ....................................................................................... 28 
16.2.3.1. 
Analysis of the proportion of patients not deteriorating according to the ordinal scale by 1, 2, or 3 
points on Days 2, 8, 15, 22, and 29 ...................................................................................................................... 28 
16.2.3.2. 
Analysis of duration (days) of oxygen use and oxygen-free days ................................................... 28 
16.2.3.3. 
Analysis of qualitative and quantitative PCR determination of SARS-CoV-2 ................................ 28 
16.2.4. 
Other Secondary Efficacy Variables & Derivations ................................................................................ 29 
16.2.4.1. 
Duration (days) of ventilation and ventilation-free days ................................................................. 29 
16.2.4.2. 
Incidence of any form of new ventilation use and duration (days) of new ventilation use .............. 29 
16.2.4.3. 
Duration (days) of organ support ..................................................................................................... 29 
16.2.4.4. 
Response rate at Days 2, 8, 15, 22 and 29........................................................................................ 29 
16.2.4.5. 
Time to live discharge from the hospital by Day 29 ........................................................................ 30 
16.2.4.6. 
Mortality at Days 15, 29, and 60 ...................................................................................................... 30 
16.2.4.7. 
Time from randomisation to death ................................................................................................... 30 
16.2.4.8. 
SpO2/FiO2 from randomisation to Day 15, hospital discharge, or death .......................................... 30 
16.2.4.9. 
Duration (days) of ICU and hospitalisation ..................................................................................... 30 
16.2.4.10. NEWS2 assessed daily while hospitalised and on Days 15 and 29 ................................................. 31 
16.2.4.11. Time to a NEWS2 of ≤2, maintained for at least 24 hours .............................................................. 31 
16.2.4.12. Ranked trajectory over 29 days ........................................................................................................ 31 
16.2.5. 
Analysis of Other Secondary Efficacy Variables..................................................................................... 32 
16.2.5.1. 
Analysis of duration (days) of ventilation and ventilation-free days ............................................... 32 
16.2.5.2. 
Analysis of Incidence of any form of new ventilation use and duration (days) of new ventilation 
use 
32 
16.2.5.3. 
Analysis of duration (days) of organ support ................................................................................... 32 
16.2.5.4. 
Analysis of response rate at Days 2, 8, 15, 22 and 29 ...................................................................... 33 
16.2.5.5. 
Analysis of time to live discharge from the hospital by Day 29 ...................................................... 33 
16.2.5.6. 
Analysis of mortality at Days 15, 29, and 60 ................................................................................... 33 
16.2.5.7. 
Analysis of time from randomisation to death ................................................................................. 33 
16.2.5.8. 
Analysis of SpO2/FiO2 from randomisation to Day 15, hospital discharge, or death ...................... 33 
16.2.5.9. 
Analysis of duration of ICU and hospitalisation .............................................................................. 33 
16.2.5.10. Analysis of NEWS2 assessed daily while hospitalised and on Days 15 and 29 .............................. 33 
16.2.5.11. Analysis of time to a NEWS2 of ≤2, maintained for at least 24 hours ............................................ 33 
16.2.5.12. Analysis of Ranked trajectory over 29 days .................................................................................... 34 
17. 
SAFETY OUTCOMES .................................................................................................... 34 
17.1. Adverse Events ............................................................................................................................................... 34 
17.1.1. 
All TEAEs ............................................................................................................................................... 35 
17.1.1.1. 
Severity ............................................................................................................................................ 35 
17.1.1.2. 
Relationship to Study Treatment ..................................................................................................... 35 
17.1.1.3. 
Relationship to Non-Study Drug...................................................................................................... 35 
17.1.1.4. 
Relationship to Study Procedure ...................................................................................................... 35 
17.1.2. 
Adverse Events with an Outcome of Death ............................................................................................. 35 
17.1.3. 
Serious Adverse Events ........................................................................................................................... 35 
17.1.4. 
TEAEs Leading to Discontinuation of Study Treatment ......................................................................... 36 
17.1.5. 
Adverse Events of Special Interest (AESIs) ............................................................................................ 36 
17.2. There are no adverse events of special interest (AESI) in this study. Deaths ........................................... 36 
PPD


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Protocol Number: BGBC020 
Statistical Analysis Plan 
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proprietary to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
17.3. Laboratory Evaluations ................................................................................................................................ 36 
17.3.1. 
Laboratory Normal Ranges ...................................................................................................................... 37 
17.4. Vital Signs ....................................................................................................................................................... 37 
17.4.1. 
Vital Signs Potentially Clinically Significant Abnormality (PCSA) Criteria .......................................... 38 
17.5. ECG Evaluations ........................................................................................................................................... 38 
17.5.1. 
ECG Markedly Abnormal Criteria........................................................................................................... 39 
17.6. Other Safety Data .......................................................................................................................................... 39 
17.6.1. 
General Physical Examination ................................................................................................................. 39 
17.6.2. 
Diagnostic Imaging .................................................................................................................................. 39 
17.6.3. 
Disease-related co-infection evaluation ................................................................................................... 40 
18. 
PHARMACOKINETICS ................................................................................................. 40 
18.1. Deviations or Events Affecting PK Results ................................................................................................. 40 
18.2. Plasma Concentration Data .......................................................................................................................... 40 
19. 
PHARMACODYNAMICS............................................................................................... 41 
19.1. Exploratory PD Analysis ............................................................................................................................... 41 
19.2. Exploratory PK/PD Analysis ........................................................................................................................ 41 
20. 
REFERENCES .................................................................................................................. 43 
APPENDIX 1. PARTIAL DATE CONVENTIONS ............................................................. 44 
Algorithm for Treatment Emergence of Adverse Events ....................................................................................... 44 
Algorithm for Prior / Concomitant Medications .................................................................................................... 45 
APPENDIX 2. NEWS2 SCORING SYSTEM ....................................................................... 46 
APPENDIX 3. LABORATORY ASSESSMENTS ................................................................ 47 
 
 
PPD


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Protocol Number: BGBC020 
Statistical Analysis Plan 
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proprietary to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
1. INTRODUCTION 
This statistical analysis plan (SAP) describes the rules and conventions to be used in the presentation and analysis of 
efficacy, safety, pharmacokinetic (PK) and pharmacodynamic (PD) data for BGBC020, “A Multicentre, Phase 2, 
Randomised Study to Assess the Efficacy and Safety of Bemcentinib for the Treatment of COVID-19 in 
Hospitalised Patients”.  It describes the data to be summarised and analysed, including specifics of the statistical 
analyses to be performed.  
This SAP is based on the protocol amendment 2.0, dated 08 October 2020. 
2. STUDY OBJECTIVES AND END POINTS 
2.1. PRIMARY OBJECTIVES AND END POINTS 
Objectives  
Endpoints  
To evaluate the efficacy of bemcentinib as add-on 
therapies to standard of care (SoC) in patients 
hospitalised with coronavirus disease 2019 (COVID-
19).  
Time to sustained clinical improvement of at least 2 
points (from randomisation) on a 9-point category 
ordinal scale, live discharge from the hospital, or 
considered fit for discharge (a score of 0, 1, or 2 on the 
ordinal scale), whichever comes first, by Day 29 (this 
will also define the “responder” for the response rate 
analyses).  
2.2. KEY SECONDARY OBJECTIVES AND END POINTS 
Objectives  
Endpoints  
To evaluate the ability to prevent deterioration 
according to the ordinal scale by 1, 2, or 3 points  
The proportion of patients not deteriorating according to 
the ordinal scale by 1, 2, or 3 points on Days 2, 8, 15, and 
29 
To evaluate the number of oxygen-free days  
Duration (days) of oxygen use and oxygen-free days  
To evaluate severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2) viral load  
Qualitative and/or quantitative polymerase chain reaction 
(PCR) determination of severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2) in oropharyngeal/nasal 
swab while hospitalised on Days 1, 3, 5, 8, 11, 15, and 29  
PPD


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Protocol Number: BGBC020 
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2.3. OTHER SECONDARY OBJECTIVES AND END POINTS 
Objectives  
Endpoints  
To evaluate ventilator-free days and incidence and 
duration of any form of new ventilation use 
Duration (days) of ventilation and ventilation-free days 
Incidence of any form of new ventilation use and 
duration (days) of new ventilation use 
To evaluate duration of organ support (eg, including 
respiratory, renal, and cardiac support) 
Duration (days) of organ support 
To evaluate response rate (see primary endpoint for 
definition of responder) 
Response rate (number and %) by treatment arm at Days 
2, 8, 15, and 29 
To evaluate time to discharge  
Time to live discharge from the hospital 
To evaluate overall mortality  
• 
Mortality at Days 15, 29, and 60 
• 
Time from treatment start date to death 
Change in the ratio of the oxygen saturation to fraction 
of inspired oxygen concentration (SpO2/FiO2) 
SpO2/FiO2, measured daily from randomisation to Day 15, 
hospital discharge, or death  
To evaluate the safety of bemcentinib as add-on 
therapy to SoC in patients with COVID-19 
• 
Physical examination. 
• 
Clinical laboratory examinations. 
• 
Vital signs (blood pressure/heartrate/temperature/ 
respiratory rate). 
• 
Adverse events  
To evaluate intensive care unit (ICU) and 
hospitalisation length  
Duration (days) of ICU and hospitalisation  
To evaluate National Early Warning Score 2 (NEWS2) • 
NEWS2 assessed daily while hospitalised and on 
Days 15 and 29. 
• 
Time to a NEWS2 of ≤2, maintained for at least 24 
hours  
To evaluate improvement taking into account 
worsening and death  
Ranked trajectory over 29 days, with trajectory ranked in 
the following order of the ordinal scale: 
• 
[ascending order] The worst score 
• 
[ascending order] The last recorded score 
• 
[ascending order] The number of days at worst score 
• 
[ascending order] The best score that occurs after the 
worst score (this will equal the worst score if the 
worst score is the last score) 
• 
[descending order] The number of days the patient is 
at 4), counting only days after the last occurrence of 
the worst score (the number of days for this item will 
be 0 if the worst score is the last score)  
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2.4. EXPLORATORY OBJECTIVES AND END POINTS 
Objectives  
Endpoints  
To evaluate PK of bemcentinib 
PK concentration and parameters 
To evaluate SARS-CoV-2 viral load  
Qualitative and/or quantitative PCR determination of 
SARS-CoV-2 in blood (on Day 1) and saliva (while 
hospitalised) on Days 1, 3, 5, 8, 11, 15, and 29 (may 
become a secondary endpoint once the assays are 
available)  
To collect samples for serology research, viral 
genomics, serum antibody production, and COVID-
19 diagnostics 
Analysis of samples collected at baseline prior to 
treatment and at specific time points  
3. STUDY DESIGN 
3.1. GENERAL DESCRIPTION 
BGBC020 is a study designed to rapidly seek and determine the nature of signals of efficacy and safety of 
bemcentinib in the treatment of hospitalised patients with SARS-CoV2. The study design is analogous to the first 
stage of the ACCORD-2 platform protocol, a multicentre national UK government sponsored protocol in the United 
Kingdom in which bemcentinib is being evaluated. BGBC020 (this protocol) is therefore analogous to ACCORD-2, 
a seamless, Phase 2, adaptive, randomised platform study, designed to rapidly test candidate agents in the treatment 
of COVID-19 disease. 
BGBC020 (referred to henceforth as “the current study”) will include hospitalised adult patients (≥18 years) who 
have infection with SARS CoV-2, the virus that causes COVID-19, as confirmed by laboratory tests and/or 
validated point of care tests. For inclusion, patients will need to have clinical status of Grade 3 (hospitalised - mild 
disease, no oxygen therapy) to Grade 5 (hospitalised – severe disease, non-invasive ventilation or high-flow 
oxygen), as defined by a 9-point ordinal scale, which was detailed in the World Health Organization R&D Blueprint 
“Novel Coronavirus - COVID-19 Therapeutic Trial Synopsis” (February 2020). Medical history will record the 
estimated date and time of first symptoms. 
This study will aim to evaluate the safety and efficacy of bemcentinib for treatment of COVID 19 disease. 
First dose of bemcentinib must take place within 72 hours of Investigator receipt of laboratory or validated point of 
care test confirmation of SARS-CoV-2 infection. If a patient has a confirmed result prior to hospital admission 
which is more than 72 hours old, first dose of bemcentinib should take place within a calendar day of admission to 
hospital, where in the opinion of the Investigator, the reason for admission is relevant to ongoing COVID-19 
infection. Any exceptions to this must be authorised by the Medical monitor and/or Sponsor medical team. 
Patients will be randomised to the treatment arm to receive bemcentinib (as an add-on to standard of care [SoC]) or 
to control arm where only SoC will be administered. 
Patients will be screened on Day -1 or Day 1 and will remain in the hospital from Day 1 until fit for discharge. 
Dosing with bemcentinib (as an add-on to SoC) will commence on Day 1 until Day 15 or discharge. The last day of 
assessments while hospitalised will be on Day 29. An outpatient visit will be conducted on Day 60 (±4 days), with 
an end of study visit conducted on Day 90 (±6 days).   
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Protocol Appendix 8 for details of study procedures during special circumstances. 
3.2. SCHEDULE OF EVENTS 
Schedule of events can be found in Section 1.3 of the BGBC020 protocol amendment 2.0. 
3.3. CHANGES TO ANALYSIS FROM PROTOCOL 
Additional details for statistical analyses are provided in this SAP.  
4. PLANNED ANALYSES 
The following analyses will be performed for this study: 
• 
Safety analysis by the Independent Data Monitoring Committee (IDMC)  
• 
Final analysis 
4.1. REVIEW COMMITTEES 
4.1.1. 
STEERING COMMITTEE (SCIENTIFIC REVIEW COMMITTEE) 
A Steering Committee has been assembled for the executive oversight and supervision of this study. The Steering 
Committee will serve this role through regular scheduled meetings or teleconferences and, if necessary, additional 
ad hoc meetings.  
The Steering Committee will be expected to provide guidance, advice, and recommendations to the BGBC020 study 
on relevant clinical issues related to the strategy, implementation, and conduct of the study. This may include, but 
not necessarily be limited to:  
• 
Advice on the strategy and design of the protocol and any subsequent amendments or revisions.  
• 
Advice on issues of study enrolment including patient accrual, number and location of investigator sites, 
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recruitment goals, and patient eligibility/ineligibility issues.  
• 
Advice on issues relating to the clinical conduct of the protocol including protocol violations/deviations 
and investigative site or Ethics Committee/Institutional Review Board concerns/issues, and regulatory 
engagement.  
• 
Advice on safety issues. 
4.1.2. 
INDEPENDENT DATA MONITORING COMMITTEE (IDMC)  
An independent IDMC will be established for this study to assess safety on an ongoing basis throughout the study. 
The committee will be established for the purpose of objectively monitoring the safety data and will not include any 
assessment of efficacy data. The IDMC members will perform ongoing safety surveillance and provide 
recommendations to the Sponsor Steering Committee regarding study conduct. 
The IDMC will consist of at least 4 independent experts appointed by the study Sponsor based on their expertise. 
IDMC members will not be Investigators in the study, nor will they have any conflict of interest with the Sponsor or 
its designees.  
Further details (eg, frequency of data reviews and study committee composition and membership) will be provided 
in the IDMC charter. The charters will define the criteria, frequency of reviews, data, and source documentation 
required to adjudicate all events.  
4.2. IDMC DATA REVIEW 
IDMC will review safety information of the participating patients when 40, 80 and 120 patients have completed Day 
15 or discharged before Day 15. The outputs for review will include: 
• 
Tables showing by treatment arm summaries of: 
o 
Treatment Emergent Adverse Events (TEAEs) by System Organ Class (SOC) and Preferred Term (PT)  
o 
Serious AEs (SAEs) by SOC and PT 
o 
Serious Adverse Reactions (SARs) by SOC and PT. SARs are defined as any AEs related to study 
treatment, non-study treatment, or study procedure 
o 
Grade 3 or higher cardiac events (include ventricular arrhythmias and Torsade de pointes) by PT 
o 
QT, QTc, QTcF, and QTcB shift from Baseline to the highest post-Baseline value:  ≤470 msec, >470-
<501 msec and ≥501 msec  
o 
QT, QTc, QTcF, and QTcB change from Baseline to the highest post-Baseline value: >30 msec 
increase from Baseline and >60 msec increase from Baseline 
o 
Shift from Baseline in overall ECG interpretation to the worst post-Baseline interpretation: normal, 
abnormal not clinically significant, abnormal clinically significant 
o 
Change from Baseline in NEWS2 score  
• 
By patient listings of: 
o 
SAEs 
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o 
SARs 
o 
Treatment-emergent adverse events (TEAEs) leading to discontinuation of study treatment 
o 
Deaths 
o 
Cardiac events (include ventricular arrhythmias and Torsade de pointes) of Grade 3 or worse 
o 
Patients with QTcF ≥501 msec leading to discontinuation of study treatment 
o 
ECG results of patients with abnormal ECG interpretation  
o 
Grade 3or higher laboratory assessments [selected parameters: haemoglobin, white blood cell count 
(total), neutrophils, lymphocytes, platelets; sodium, creatinine, potassium, aspartate transaminase 
(AST), alanine transaminase (ALT), gamma glutamyltransferase (GGT), total bilirubin (TBL), 
glucose, creatinine kinase, activated partial thromboplastin time (aPTT)] 
Further outputs may be requested by the IDMC prior to the first meeting. 
4.3. FINAL ANALYSIS  
The final analysis will be performed when at all randomised patients have completed or discontinued by the End of 
Study Visit.  
All final, planned analyses identified in this SAP will be performed by IQVIA Biotech Biostatistics or IQVIA PK 
Biostatistician (PK TFLs) following Sponsor Authorisation of this SAP and Database Lock (DBL). 
5. ANALYSIS SETS 
5.1. INTENTION TO TREAT ANALYSIS SET  
The intention to treat (ITT) analysis set includes all patients who are randomised and match the inclusion/exclusion 
criteria of the protocol. 
For analyses and displays based on the ITT analysis set, patients will be classified according to randomised 
treatment.  
5.2. SAFETY ANALYSIS SET  
The safety analysis set (SS) will contain all patients who are randomised and receive at least one dose of study 
intervention (bemcentinib or SoC). 
For analyses and displays based on the safety analysis set, patients will be classified according to the actual 
treatment received, i.e. in the event of a patient randomised to SoC receiving bemcentinib, the patient will be 
classified under bemcentinib plus SoC arm.  
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5.3. PHARMACOKINETIC ANALYSIS SET  
The PK analysis set (PKS) will contain all patients who are randomised and take at least 1 dose of bemcentinib and 
have quantifiable bemcentinib concentrations post-dose without protocol deviations or events affecting the 
pharmacokinetic results. 
Protocol deviations or events which may have the potential to affect PK results are described in Section 18.1; refer 
to Section 5.5 for a description of the review process for assessing the deviations or events.  
5.4. PHARMACODYNAMIC ANALYSIS SET   
The pharmacodynamic analysis set (PDS) will contain all patients who are randomised and receive study 
intervention (bemcentinib or standard of care) and have evaluable results for at least 1 pharmacodynamic endpoint 
post-dose. All analyses of the PDS will be based on each patient’s actual treatment received.  
5.5. PROCESS FOR ANALYSIS SET ASSIGNMENT 
For the PKS and the PDS, the identification and agreement of protocol deviations or events which affect PK and/or 
PD results will be performed between the PK analyst, biostatistician, and the sponsor, prior to DBL, with sponsor 
authorisation of any excluded patients or their data.   
6. GENERAL CONSIDERATIONS 
6.1. REFERENCE START DATE AND STUDY DAY 
For efficacy and safety analyses, unless otherwise stated, the reference start date will be the date of randomisation. 
Study Day will be calculated from the reference start date to the date of start/stop day of assessments and events. 
Study Day will be derived as follows: 
• 
Study Day = (Date of event –Date of randomisation) + 1 if the date of the event is on or after the date of 
randomisation 
• 
Study Day = (Date of event – Date of randomisation) if the date of the event is prior to the date of 
randomisation. 
In the situation where the event date is partial or missing, Study Day and any corresponding durations will appear 
missing in the listings and dates will be presented as partial or missing. 
6.2. BASELINE 
Unless otherwise specified, Baseline is defined as the last non-missing measurement taken prior to the date and time 
of randomisation (including unscheduled assessments). In the case where the last non-missing measurement and the 
reference start date coincide and time of measurement is not available, that measurement will be 
considered -Baseline unless the assessment was scheduled to be post-randomisation in the protocol.  
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6.3. RETESTS, UNSCHEDULED VISITS AND EARLY TERMINATION 
DATA 
For by-visit summaries, data recorded at the nominal visit will be presented. Unscheduled measurements will not be 
included in by-visit summaries but will contribute to the Baseline timepoint and/or worst-case value where required 
(e.g. shift tables or summaries involving worst-case values at any time post-Baseline).  
Early termination data will be mapped to the next available visit number for by-visit summaries. 
Listings will include scheduled, unscheduled, retest and early discontinuation data. 
6.4. WINDOWING CONVENTIONS  
No visit windowing will be performed for this study, except for early termination data (refer to Section 6.3) 
6.5. COMMON CALCULATIONS 
Change from Baseline will be calculated as: 
• 
Change from Baseline = Test value at post-Baseline visit – Baseline value 
Percent change from Baseline will be calculated as: 
• 
Percent change from Baseline (%) = (Change from Baseline at post-Baseline visit / Baseline value) * 100% 
7. STATISTICAL CONSIDERATIONS 
7.1. SAMPLE SIZE CONSIDERATIONS 
Approximately 60 patients will be randomised into each arm of the study, whereby patients will receive either 
bemcentinib (with SoC) or SoC alone. The chosen endpoint to compare treatments will be the time to a sustained 2-
point improvement on a 9-point category ordinal scale, discharge from hospital, or considered fit for discharge at 
Day 29. 
It is expected that 54 patients are needed per arm, which will provide 80% power to detect a hazard ratio of 1.6 for 
the occurrence of the event, when comparing bemcentinib with SoC. This calculation is based on a 1-sided test and a 
10% significance level, and assumes 85.5% of patients will improve, be discharged from hospital, or considered fit 
for discharge at Day 29 for bemcentinib versus 70% of patients for the SoC (the estimate of SoC was taken from 
Cao (2020)). To allow for uncertainty in the recruitment rates, it is expected that up to 60 patients (rather than 54 
patients) will be randomised to each arm in order to achieve the required number of events for the preliminary 
analysis.  
The sample size calculation may be re-evaluated as the treatment of COVID-19 evolves. 
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7.2. MISSING DATA 
Missing safety data will not be imputed other than if the severity or relationship to study treatment of an AE is 
missing (see Sections 17.1.1.1 and 17.1.1.2).  Partial or completely missing AE and concomitant medication dates 
will be handled as described in APPENDIX 1. 
Missing efficacy data will be handled as described in Sections 16.1.2 and 16.2.2. Missing bioanalytical data (PK 
data) will be handled as described in Section 18.1. 
7.3. STATISTICAL TESTS 
Statistical tests of the primary endpoint will be one-sided at the 10% significance level, with a one-sided p-value 
provided.  
Two-sided p-values will be provided for the secondary efficacy endpoints if applicable and no formal inference will 
be made based on these endpoints.   
No statistical testing will be performed for the safety endpoints. 
All Confidence Intervals (CIs) will be two-sided with 80% coverage or 95% coverage as specified in the relevant 
efficacy analysis sections. 
7.4. MULTIPLE COMPARISONS/ MULTIPLICITY 
No multiplicity adjustments will be made for the fact that multiple endpoints will be analysed at multiple timepoints.  
7.5. MULTICENTRE STUDY 
The study will be conducted at multiple centres in India and South Africa. At sites in India, hospitalised patients will 
only include baseline severity grades 4 or 5, in accordance with national treatment guidelines.  
Randomisation to study treatment is stratified by baseline severity grades (grade 3, 4 and 5). Patients with baseline 
severity grade 4 and 5 will be further stratified by intended steroid use (none vs. dexamethasone or alternative 
steroid).   
In the primary efficacy endpoint, centre or pooled centre will be included as a random factor in sensitivity analyses. 
7.6. ADJUSTMENTS FOR COVARIATES AND FACTORS TO BE 
INCLUDED IN ANALYSES 
The following factors are used in the primary efficacy analyses. For details of their inclusion in the models, see the 
specific analysis sections. 
• 
Study treatment (bemcentinib plus SoC vs SoC alone ) 
• 
Age category (age <70 years vs ≥70 years) 
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• 
Baseline severity grade (ordinal Grades 3, 4, or 5)  
• 
Age category and treatment interaction 
• 
Baseline severity grade and treatment interaction 
• 
Study centre or pooled study centre 
If the use of all 3 levels Baseline severity grade causes sparsity and inestimable model parameters in the primary 
efficacy analysis, the Baseline levels will be pooled as follows for the purpose of inclusion in analyses: 
• 
If Grade 3 has the least patients it will be pooled with Grade 4 
• 
If Grade 5 has the least patients it will be pooled with Grade 4 
• 
If Grade 4 has the least patients it will be pooled with the Grade (3 or 5) with the least patients.  If Grade 3 
and 5 have the same number of patients, Grade 3 will be pooled with Grade 4. 
If the use of all study centres causes sparsity and inestimable model parameters in the primary efficacy analysis, the 
study centres will be pooled according to country for the purpose of inclusion in analyses. A centre with less than 8 
patients will be pooled with its most adjacent centre.   
7.7. EXAMINATION OF SUBGROUPS 
Subgroup analyses will be performed for the primary efficacy analysis (see Section 16.1.3) by:  
• 
Comorbidity 
o 
Heart disease (yes/no)  
o 
Diabetes (yes/no)  
o 
Chronic lung disease (yes/no)  
o 
Chronic liver disease (yes/no) 
o 
Asthma (yes/no) 
o 
HIV (yes/no) 
o 
Tuberculosis (yes/no) 
o 
Hypertension (yes/no)  
o 
Cancer (yes/no) 
o 
Any of comorbidities (yes/no) 
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• 
Age group (<70 years/≥70 years) 
• 
Days from symptoms onset (<12 days/≥12 days) 
• 
Intended steroid use (none/dexamethasone or alternative steroid) at baseline, among patients with baseline 
Grade 4 or 5 only  
Note that a) the study is not powered to detect statistically significant differences between treatment arms within 
subgroups; b) due to sparsity, only the covariates factors described in Section 7.6 will be included in the model. 
7.8. HANDLING MODEL CONVERGENCE OR ESTIMATION ISSUES 
If there are convergence or estimation issues with any statistical models or analyses due to the number of patients at 
baseline severity levels or centre/pooled study centre, then the baseline severity levels will be pooled as described in 
Section 7.6. If there are still issues, the centre/pooled study centre effect will be removed from the model, and if 
there are still issues, then baseline severity levels will also be removed. Additional covariates or factors may be 
removed if there are still issues. 
7.9. SOFTWARE VERSION 
All analyses will be conducted using SAS Enterprise Guide 7.1 (64-bit). 
8. OUTPUT PRESENTATIONS 
The presentation of data in outputs will follow IQVIA Biotech Data Display Standards.  See TFL shells for 
additional information. 
9. DISPOSITION AND WITHDRAWALS 
All patients who were randomised to study treatment in this protocol will be accounted for. 
9.1. DISPOSITION 
Number of patients in intention to treat analysis set, safety analysis set, PK analysis set and PD analysis set will be 
presented by treatment arm and overall. Number and percentages of patients who completed/discontinued early from 
treatment (including reason for withdrawal) and who completed/discontinued early from the study (including reason 
for withdrawal) will be provided by treatment arm and overall based on the ITT analysis set.  
• 
Complete full course of study treatment 
• 
Treatment discontinued early 
o 
Adverse event  
o 
Death 
o 
Lack of efficacy 
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o 
Lost to follow up 
o 
Non-compliance with study drug 
o 
Pregnancy 
o 
Progressive disease 
o 
Protocol deviation 
o 
Physician decision  
o 
Recovery 
o 
Study terminated by sponsor 
o 
Withdrawal by patient 
o 
Other 
• 
Complete study  
• 
Study discontinued early 
o 
Adverse event  
o 
Death 
o 
Lack of efficacy 
o 
Lost to follow up 
o 
Non-compliance with study drug 
o 
Pregnancy 
o 
Progressive disease 
o 
Protocol deviation 
o 
Physician decision  
o 
Recovery 
o 
Study terminated by sponsor 
o 
Withdrawal by patient 
o 
Other 
A listing of patient disposition will be provided. Additionally, a listing showing inclusion and exclusion of each 
patient from each analysis population, including reason for exclusion, will also be provided. 
9.2. PROTOCOL DEVIATIONS 
Number and percentage of patients with important protocol deviations, as identified by the study team, will be 
provided by treatment arm and overall based on the ITT analysis set for each category specified by PK analyst, 
biostatistician, and the sponsor, prior to DBL. 
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A listing of protocol deviations identified by the study team (important or not) will be provided. For protocol 
deviations which may impact the quality of the PK or PD data, see Section 18.1. 
10. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
The following demographic data and baseline characteristics will be presented for the ITT analysis set:   
• 
Age (years) – calculated relative to date of consent, as a continuous variable  
• 
Age categories (age <70 years/≥70 years) 
• 
Sex (male/female/undifferentiated/unknown)  
o 
Childbearing potential for female patients only (yes/no) 
o 
 Reasons if not of childbearing potential (post-menopausal/premenarchal/surgically sterile/other)  
• 
Race 
• 
Ethnicity 
• 
Clinical frailty score (very fit/well/managing well/vulnerable/mildly frail/moderately frail/severely 
frail/very severely frail/terminally ill) 
• 
Height (cm) 
• 
Weight (kg) 
• 
Body Mass Index (BMI) (kg/m2) 
• 
Resident in care home (yes/no) 
• 
Randomisation strata (grades 3/grades 4 and none/grades 4 and intended steroid use/grade 5 and none/ 
grade 5 and intended steroid use) 
• 
Actual strata (grades 3/grades 4 and none/grades 4 and SoC intervention use (Remdesivir vs 
Dexamethasone)/grade 5 and none/ grade 5 and SoC intervention use (Remdesivir vs Dexamethasone)) 
Continuous demographic and baseline characteristics will be summarised using descriptive statistics by treatment 
arm and overall.  Categorical demographic and baseline characteristics using number and percentages of patients in 
each category by treatment arm and overall.  No statistical testing will be carried out for demographic or baseline 
characteristics. 
10.1. DERIVATIONS 
BMI, in kg/m2, will be calculated as BMI (kg/ m2) = weight (kg)/ [height (m)2]. 
11. COVID-19 CO-MORBIDITIES AND MEDICAL HISTORY 
COVID-19 co-morbidities as captured on the Medical History page of the eCRF will be summarised for the ITT 
analysis set by treatment arm and overall, via the number and percentage of patients with each of the following: 
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• 
History of diabetes 
• 
History of heart disease 
• 
History of chronic lung disease 
• 
History of chronic liver disease 
• 
History of asthma 
• 
History of HIV 
• 
History of tuberculosis 
• 
History of hypertension 
• 
History of cancer 
• 
Any of above 
Medical History will be coded using the Medical Dictionary for Regulatory Activities (MedDRA), version 23.0 or 
above. Medical history will be summarised by SOC and PT by treatment arm and overall based on the ITT analysis 
set.  A patient having more than one reported medical diagnosis within the same SOC/PT will be counted only once 
for that SOC or PT. 
All medical history data will be listed. 
12. DISEASE HISTORY 
The following disease history characteristics will be summarised by treatment arm and overall based on the safety 
analysis set:  
• 
Time since symptoms onset (days) – calculated relative to date of randomisation 
• 
Time since symptoms onset (<12 days/≥12 days) 
• 
Time since diagnosis (days) – calculated relative to date of randomisation 
• 
Presence or absence, and severity (mild/moderate/severe/unknown) of each of the following COVID-19 
symptoms at study entry: 
o 
Cough 
o 
Fever 
o 
Myalgia 
o 
Diarrhoea 
o 
Dyspnoea 
o 
Fatigue 
o 
Malaise 
o 
Loss of appetite 
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o 
Loss of smell 
o 
Loss of taste 
• 
Time since hospital admission (days) for patients already hospitalised at study entry – calculated relative to 
date of randomisation 
• 
On supplemental oxygen at study entry (yes/no) 
• 
Type of supplemental oxygen for patients receiving supplemental oxygen at study entry (Non-Invasive 
Mechanical Ventilation/Nasal Cannula/Venturi Mask - 24% FiO2 flow rate/Venturi Mask - 28% FiO2 flow 
rate/Venturi Mask - 35% FiO2 flow rate/Venturi Mask - 40% FiO2 flow rate/Venturi Mask - 60% FiO2 
flow rate/Simple Face Mask/Nonrebreathing Face Mask with Reservoir and One-Way Valve/Reservoir 
Cannulas/Other) 
o 
if on non-invasive mechanical ventilation 
 Continuous positive airway pressure 
 Bilevel positive airway pressure 
• 
Time since start of supplemental oxygen (days) for patients on supplemental oxygen at study entry - 
calculated relative to date of randomisation 
o 
Time since start of non-invasive mechanical ventilation (days) for patients on non-invasive mechanical 
ventilation at study entry - calculated relative to date of randomisation. 
All disease history characteristics will be listed. 
12.1. DERIVATIONS 
Time since endpoints, in days, will be calculated as follows: 
• 
Time since symptoms onset (days) = (Date of randomisation – Date of symptoms onset) 
• 
Time since diagnosis (days) = (Date of randomisation - Date of diagnosis) 
• 
Time since hospital admission (days) = (Date of randomisation – Date of hospitalisation admission) if 
patient is already hospitalised at study entry. Time since hospitalisation admission will not be computed for 
patients who are not hospitalised at study entry 
• 
Time since start of supplemental oxygen (days) = (Date of randomisation – Date of start of supplemental 
oxygen) if patient is already on supplemental oxygen at study entry. Time since start of supplemental 
oxygen will not be computed for patients who are not on supplemental oxygen at study entry 
• 
Time since start non-invasive mechanical ventilation (days) = (Date of randomisation – Date of start of 
ventilation) if patient is already on non-invasive mechanical ventilation at study entry. Time since start of 
non-invasive mechanical ventilation will not be computed for patients who are not on non-invasive 
mechanical ventilation at study entry. 
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13. MEDICATIONS 
All medications will be coded using the World Health Organisation (WHO) Drug Global dictionary, version B3 
March 2020. Prior medications are defined as any medication that stopped before the date of randomisation. 
Concomitant medications are defined as any medication that were ongoing or ended at the date of randomisation, or 
any medication that started on or after the date of randomisation. 
Partially or completely missing medication start and stop dates will be handled as described in APPENDIX 1. 
Prior and concomitant medications will be summarised separately by Anatomical Therapeutic Class (ATC) level 2 
and preferred drug name by treatment arm and overall based on the safety analysis set. A patient having more than 
one medication within the same ATC Level 2 or preferred drug name will be counted only once for that ATC Level 
2 or preferred drug name. 
All medications (prior and concomitant) will be listed. 
14. EXPOSURE TO STUDY TREATMENT 
Duration of bemcentinib exposure (days) will be summarised for the bemcentinib plus SoC arm.  To provide an 
approximate equivalent exposure duration for the SoC arm, the duration of exposure up to Day 15 for SoC arm 
patients will be summarised.  Additionally, treatment duration will also be summarised for the safety analysis set. 
14.1. DERIVATIONS 
Duration of bemcentinib exposure (days) = Date of last bemcentinib dose – Date of first bemcentinib dose + 1 
Duration of exposure to SoC for patients who receive SoC is Minimum of (Date of last treatment – Date of 
randomisation) +1, or 15 
Total duration of exposure to either arm is Date of last treatment – Date of randomisation +1 
Interruptions and dose changes (increases or decreases) will not be considered for duration of exposure. The dates of 
first and last bemcentinib administration will be taken from the eCRF Oral Drug Administration page.  The date of 
last treatment will be taken from the Date of treatment completion/discontinuation on the eCRF End of Study 
Treatment page. 
15. STUDY MEDICATION COMPLIANCE  
Bemcentinib will be administered as a 400 mg oral loading dose on Days 1, 2, and 3, followed by 200 mg once daily 
oral maintenance dose from Day 4, for a total of 15 days.  Compliance with bemcentinib, in percentage, will be 
summarised based on the safety analysis set of bemcentinib plus SoC arm only.  
15.1. DERIVATIONS 
Bemcentinib compliance (%) = (Total dose received/Dose planned to be received) * 100%.  
• 
Total dose received = the sum of “Dose per administration” in mg recorded on the Oral Drug 
Administration eCRF page, across all study days 
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• 
Dose planned to be received = 400 mg × the duration of bemcentinib exposure, if the duration of 
bemcentinib exposure is 3 days or less  
• 
Dose planned to be received = 1200 mg + [(duration of bemcentinib exposure - 3) × 200 mg], if the 
duration of bemcentinib exposure is more than 3 days 
Bemcentinib compliance will be summarised as a continuous variable as well as a categorical variable for the 
categories of <80%, 80% to <90%, 90% to 100% and >100%.  
16. EFFICACY OUTCOMES  
16.1. PRIMARY EFFICACY 
16.1.1. 
PRIMARY EFFICACY VARIABLE & DERIVATION 
The primary efficacy variable is the time to sustained clinical improvement of at least 2 points (from randomisation) 
on a 9-category ordinal scale, or live discharge from the hospital or fit to be discharged (e.g., a score of 0, 1, or 2), 
whichever comes first, by Day 29 (this will also define the “responder” for the rate of 2-point sustained 
improvement response).  
Time to response = (the date of response event – date of randomisation) +1, where the day of randomisation is 
Day 1. 
Sustained clinical improvement is defined as improvement without subsequent worsening, e.g. if a patient improves 
from an ordinal scale grade of 5 at Baseline to a grade of 3, but subsequently has a grade greater than 3 this would 
be considered as subsequent worsening and the patient would be a non-responder at that timepoint. If a patient is a 
responder based on being fit for discharge with a score of 0 or 1, which later increases but is still a score of 2 or less, 
this patient would still be considered as a responder. 
The 9-point category ordinal scale, used to assess patients is as follows: 
0. Uninfected, no clinical or virological evidence of infection 
1. Ambulatory, no limitation of activities 
2. Ambulatory, limitation of activities 
3. Hospitalised – mild disease, no oxygen therapy 
4. Hospitalised – mild disease, oxygen by mask or nasal prongs 
5. Hospitalised – severe disease, noninvasive ventilation or high-flow oxygen 
6. Hospitalised – severe disease, intubation and mechanical ventilation 
7. Hospitalised – severe disease, ventilation and additional organ support – vasopressors, renal replacement 
therapy (RRT), extracorporeal membrane oxygenation (ECMO) 
8. Death 
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Patients who are alive and who have not met the sustained 2-point improvement in the 9-point ordinal scale, or live 
discharge from hospital, or considered fit for discharge at Day 29 will have their time to response censored at the 
study Day that their last ordinal scale assessment was made, i.e. either Day 29 or earlier. 
Patients who die before they meet the criteria for response, will be included in the analysis with a censored time to 
response of Day 29.  
16.1.2. 
MISSING DATA METHODS FOR PRIMARY EFFICACY VARIABLE(S) 
Missing data will be minimised, with outcomes collected after premature withdrawal of treatment. The estimand will 
therefore be a “treatment policy” one.  
For the purpose of a supplementary analysis, for patients who withdraw from treatment and also withdraw from the 
study (i.e. who refuse to have further data collected), their missing ordinal scores after treatment discontinuation will 
be multiply imputed for a visit based on patients who withdrew from treatment but did not withdraw from the study, 
allowing the estimate of post-withdrawal treatment effect to vary by last observed visit on treatment. Thus, for 
example, if post-treatment withdrawal outcomes tend to get steadily worse over time, this proposed model could 
fully reflect this in imputations of post-withdrawal visit outcomes.  For the MI model,100 imputations will be 
generated using PROC MI with the MNAR statement and the MODELOBS option to base the imputation model on 
patients who withdraw from treatment but did not withdraw from the study. Fully Conditional Specification (FCS) 
model using the regression method will be used with the baseline ordinal score, the scores at prior post-baseline 
visits, and the time of treatment discontinuation as covariates. The ROUND and MINIMUM options will be utilized 
to ensure imputed values are non-negative integers. The seed to be used in all MI model is 20201012. 
If this model is not estimable due to the potentially small numbers of patients discontinuing at a visit, the imputation 
will not take account of time of treatment discontinuation in modelling the imputations for a visit, but will base the 
model for imputations for a visit on all outcomes observed at the visit in patients who discontinued treatment, 
irrespective of when they discontinued treatment. This model would reflect post-discontinuation worsening via an 
average post-treatment-discontinuation worsening, applied to all imputed visit outcomes. 
For all patients, intermittent missing data would be imputed assuming that the data are missing at random using the 
Markov Chain Monte Carlo (MCMC) method. 
Note that prior to any imputation, ordinal severity scores will be set to 8 for all visits after a patient died, and for 
patients discharged live from hospital, any missing ordinal score data post-discharge will be set to their most-recent 
score. 
16.1.3. 
PRIMARY ANALYSIS OF PRIMARY EFFICACY VARIABLE 
The primary efficacy analysis will be performed for ITT analysis set. 
The primary hypothesis of this study is time to response (sustained 2-point improvement in the 9-point ordinal scale, 
live discharge from hospital, or considered fit for discharge, as analysed at Day 29) of the bemcentinib plus SoC arm 
is shorter than the SoC.  This endpoint of sustained 2-point improvement in the 9-point ordinal scale or live 
discharge from hospital, or considered fit for discharge at Day 29, are referred to as the response, and patients with 
this response, are referred to be as responders. 
As the events are sustained 2-point improvement in 9-point ordinal scale, live discharge, or considered fit for 
discharge, a hazard ratio (HR) larger than 1 is favourable to the test treatment, with the HR comparing the 
bemcentinib plus SoC arm with the SoC. 
𝐻𝐻0:𝐻𝐻R ≤1 𝑣𝑣s 𝐻𝐻𝐻𝐻:𝐻𝐻R >1 
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No multiplicity adjustment will be made for the fact that bemcentinib plus SoC arm will be compared with the 
control arm (SoC).  
A Kaplan-Meier curve (product-limit estimate) will be provided along with a summary of the associated statistic for 
time to response including the 25th percentile, 50th percentile (median), and 75th percentile and their corresponding 
two-sided 80% CI and two-sided 95% CI.  These CIs will be calculated according to Brookmeyer and Crowley 
(1982).  
One-sided p value and two-sided p value of time to events between the bemcentinib plus SoC arm and the SoC arm 
will be calculated using a log-rank test stratified by age category, baseline severity grade (3, 4 or 5) and study 
centre/pooled study centre.  HR will be estimated based on a Cox regression model.  The analyses will be stratified 
by study treatment, age category, baseline severity grade, age category and treatment interaction, baseline severity 
grade and treatment interaction, and study centre/pooled centre. Ties will be handled using the exact method. 
16.1.4. 
SENSITIVITY ANALYSIS OF PRIMARY EFFICACY VARIABLE 
If the severity at beginning of treatment does not match the baseline severity, the primary analysis will be re-run 
using the severity at beginning of treatment.   
16.1.5. 
SUPPLEMENTARY ANALYSIS OF PRIMARY EFFICACY VARIABLE 
The following supplementary analyses will be performed for the primary efficacy endpoint: 
• 
The same analysis as for the primary analysis of the primary efficacy endpoint (refer to Section 16.1.3) will 
be repeated but with only treatment arm in the models (unadjusted) 
• 
The same analysis as for the primary analysis of the primary efficacy endpoint (refer to Section 16.1.3) will 
be repeated but the following factor (s) will be removed from the models 
o 
Centre/pooled centre 
o 
Age category 
o 
Age category and Centre/pooled centre 
• 
The same analysis as for the primary analysis of the primary efficacy endpoint (refer to Section 16.1.3) will 
be repeated but the model will include factors relating to use of particular concomitant medications. The 
details of identifying and handling concomitant medications likely to affect COVID outcomes in analysis 
will be finalized before database lock. 
• 
The same analysis as for the primary analysis of the primary efficacy endpoint (refer to Section 16.1.3) will 
be repeated but with the derivation of the endpoint involving imputed ordinal severity grade data (see 
Section 16.1.2 for details).  
• 
The same analysis as for the primary analysis of the primary efficacy endpoint (refer to Section 16.1.3) will 
be repeated in each of the subgroups described in Section 7.7 but without centre/pooled centre in the model 
(as described in Section 7.7).  
• 
A forest plot will be produced for the hazard ratio and its 95% CI within each of the subgroups, and for the 
primary analysis. 
On each imputed dataset, the primary efficacy analysis will be repeated, and the log-rank test statistics, hazard ratios 
and standard errors will be combined using Rubin’s rules, to obtain an overall hazard ratio, p-value and derived 80% 
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and 95% confidence intervals for the hazard ratio. A combined Kaplan-Meier (product-limit estimate) will be 
provided from the multiply imputed time to event analysis, along with a summary of the associated statistic for time 
to response including the 25th percentile, 50th percentile (median), and 75th percentile calculated as the median of 
these statistics across the multiply imputed analyses. The Kaplan-Meier curve will be combined across the multiply 
imputed analyses as in Moscovici (2017). The estimate of the standard error (SE) used in combining the multiply 
imputed results will be computed using Greenwood’s formula. 
16.2. SECONDARY EFFICACY 
The secondary efficacy analyses will be performed on the ITT analysis set. 
16.2.1. 
KEY SECONDARY EFFICACY VARIABLES & DERIVATIONS 
16.2.1.1. The proportion of patients not deteriorating according to the ordinal scale by 1, 2, 
or 3 points on Days 2, 8, 15, 22, and 29 
For each patient, deterioration by 1 point at each of these study days will be defined as an increase in ordinal scale 
score of at least 1 point compared to Baseline. Similarly, for each patient, deterioration by each of 2 points or 3 
points at each of these study days will be defined as an increase in ordinal scale score of at least 2 point or 3 points 
respectively compared to Baseline.  
16.2.1.2. Duration (days) of oxygen use and oxygen-free days 
The duration of each occurrence of oxygen use will be derived based on the start date and time, and end date and 
time of the use of any type of supplemental oxygen (including mechanical ventilation) as captured on the 
Supplemental Oxygen and Mechanical Ventilation page of the eCRF. For each patient, the duration in days of 
oxygen use will be derived as the sum of the duration (in minutes) of each occurrence of oxygen use, divided by 
1440 (24*60). 
The number of oxygen-free days will be derived as the number of unique 24-hour days for which no oxygen was 
used while hospitalized. 
To account for the different durations of the study for patients, including those who die and may therefore have less 
oxygen use recorded than other patients, the duration of oxygen use and the number of oxygen-free days will also be 
converted into percentages based on the total time in hospital for a patient, from randomisation to the Stop date of 
admission as captured on the Hospitalization page of the eCRF. If a patient dies and the stop date of admission is 
missing, the date of death will be used instead. 
16.2.1.3. Qualitative and quantitative PCR determination of SARS-CoV-2 in 
oropharyngeal/nasal swab on Days 1, 3, 5, 8, 11, 15, and Day 29 
PCR determination of SARS-CoV-2 in oropharyngeal/nasal swab on Days 1, 3, 5, 8, 11, 15, and Day 29 will be 
performed. 
Results from for determination of SARS-CoV-2 will be available as either Positive, or Negative. 
For quantitative results, change from Baseline will be derived at each visit as per Section 6.5. Quantitative results 
will also be log (base 10)-transformed, and change from Baseline in the log-transformed data will also be derived as 
per Section 6.5. 
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16.2.2. 
MISSING DATA METHODS FOR KEY SECONDARY EFFICACY VARIABLES 
For the analysis of deterioration of 1, 2 or 3 points, patients with no ordinal score measured at Days 2, 8, 15, 22, or 
29, and who have been discharged from hospital prior to that Day will have their ordinal score used from the most 
recent value recorded prior to the relevant Day. 
Patients who have died prior to Day 2, 8, 15, 22 or 29, will have a score of 8 used for all Days after death. 
All other occurrences of patients with missing ordinal score at Days 2, 8, 15, 22 or 29, will result in the patient being 
classified as having deterioration at that Day. 
16.2.3. 
ANALYSIS OF KEY SECONDARY EFFICACY VARIABLES 
16.2.3.1. Analysis of the proportion of patients not deteriorating according to the ordinal 
scale by 1, 2, or 3 points on Days 2, 8, 15, 22, and 29 
For each Day and for each of the three binary variables (non-deterioration of 1, 2 or 3 points), the number and 
percentage of patients with deterioration will be presented and the proportion of patients will be analysed using a 
Cochran-Mantel-Haenszel (CMH) test, with Baseline severity grade and centre/pooled centre.  
The odds ratio (bemcentinib plus SoC vs SoC) for having deterioration and its two-sided 95% Wald CI and 
associated p-value, from a logistic regression model with treatment and the factors used in the CMH test will also be 
presented.   
In addition, the risk difference (difference in proportions) between treatment arms at each Day will be presented 
along with the 95% CI of the risk difference obtained using the Newcombe hybrid score method (Newcombe 1998). 
16.2.3.2. Analysis of duration (days) of oxygen use and oxygen-free days 
The duration in days, the number of days and the percentage of each of these relative to days in hospital will be 
summarised descriptively for each treatment arm using N, mean, standard deviation, median, minimum, maximum 
and 1st and 3rd quartiles. 
For each of these parameters, these summaries will be further broken down by whether patients died in hospital or 
not. 
16.2.3.3. Analysis of qualitative and quantitative PCR determination of SARS-CoV-2 
The number and percentage of patients with a positive and negative result for SARS-CoV-2 based on 
oropharyngeal/nasal swab, blood and saliva will be provided by treatment arm and visit based on the Intention to 
Treat Analysis Set for PCR test results only. 
PCR test quantitative values for SARS-CoV-2 based on oropharyngeal/nasal swab, blood and saliva will be 
summarised at Baseline and each of Days 3, 5, 8, 11, 15 and 29, and their change from Baseline will be summarised 
at each of Days 3, 5, 8, 11, 15, and Day 29. These summaries will include N, arithmetic mean, standard deviation, 
median, minimum, maximum and 1st and 3rd quartiles. Log (base 10)-transformed, and change from Baseline in the 
log-transformed data will be summarised with geometric mean and geometric standard deviation.    
Any SARS-CoV2 data not obtained from oropharyngeal/nasal swab, blood or saliva, or not analysed via PCR will 
be listed only. 
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16.2.4. 
OTHER SECONDARY EFFICACY VARIABLES & DERIVATIONS 
16.2.4.1. Duration (days) of ventilation and ventilation-free days 
The duration of ventilation will be derived based on the start date and time, and end date and time of either Invasive 
Mechanical Ventilation or Non-Invasive Mechanical Ventilation as the Type of Supplemental Oxygen captured on 
the Supplemental Oxygen and Mechanical Ventilation page of the eCRF. 
The number of ventilation-free days will be derived as the number of unique 24-hour days for which no ventilation 
was provided. 
To account for the different durations of the study for patients, including those who die and may therefore have less 
ventilation recorded than other patients, the duration of ventilation and the number of ventilation-free days will also 
be converted into percentages based on the total time in hospital for a patient, from randomisation to the Stop date of 
admission as captured on the Hospitalization page of the eCRF. If a patient dies and the stop date of admission is 
missing, the date of death will be used instead. 
16.2.4.2. Incidence of any form of new ventilation use and duration (days) of new ventilation 
use 
New ventilation use is defined as ventilation other than that occurring at the time of randomisation, i.e. for patients 
who are on ventilation at the time of randomisation, new ventilation use would be ventilation after the end of the 
ventilation at the time of randomisation.  For patients who are not on ventilation at the time of randomisation, any 
ventilation use after randomisation would be considered as new ventilation use. 
The duration in days, of new ventilation use would be derived in a similar manner as for duration of ventilation in 
Section 16.2.4.1 but excluding the initial period of ventilation for patients who were being ventilated at the time of 
randomisation.  
16.2.4.3. Duration (days) of organ support 
Duration of organ support (eg, including respiratory, renal, and cardiac support) will be derived from the duration of 
the AESIs defined in Section 17.1.5.  For each patient the duration of AESIs will be summed, noting that if there are 
any overlapping dates of AESIs, days will only be counted once for a patient. Only AESIs for which Was treatment 
given? = Yes on the Adverse Events page of the CRF, will be included when deriving the durations. 
To account for the different durations of the study for patients, including those who die and may therefore have less 
organ support than other patients, the duration of organ support will also be converted into percentages based on the 
total time in hospital for a patient, from randomisation to the Stop date of admission as captured on the 
Hospitalization page of the eCRF. If a patient dies and the stop date of admission is missing, the date of death will 
be used instead. 
16.2.4.4. Response rate at Days 2, 8, 15, 22 and 29 
The definition of responder is provided in Section 16.1.1. Patients who have not been discharged and who have no 
ordinal scale assessment on a particular study day, (including patients who have died prior to that study day) will be 
considered as non-responders. Patients who have not been discharged on a study day will be considered as 
responders at all subsequent time-points. 
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16.2.4.5. Time to live discharge from the hospital by Day 29 
Time to live discharge from hospital will be defined as the number of days between randomisation and discharge. It 
will be derived as: (date of discharge - date of randomisation) +1. 
Date of discharge will be taken from the Stop date of admission, recorded on the Hospitalization page of the eCRF. 
Patients who are alive and still in hospital at the time of analysis will have their time to discharge censored at the 
data cut-off date for the analysis. Patients who have died at the time of analysis, without having been discharged 
from hospital, will have their time to live discharge censored at Day 29 
16.2.4.6. Mortality at Days 15, 29, and 60 
For patients who have died, date of death will be taken from the Death Details page of the eCRF. Day of death will 
be derived as (Date of death - date of randomisation) +1.  Patients will be counted as having died at each of Days 15, 
29 and 60 if they died on or prior to each of those respective study Days. Patients who died after each of Day 15, 
Day 29 or Day 60 will be counted as alive at each of these respective study Days. 
Patients who are no longer in the study at each of these days and for whom there is not information available to say 
they are alive at that study day, will not be included in the denominator the mortality rates at the timepoints. 
16.2.4.7. Time from randomisation to death 
Date of death will be taken from the Death Details page of the eCRF. Time from randomisation to death will be 
defined as: (date of death – date of randomisation) +1. 
Patients who are not known to have died at the time of analysis will have their time to death censored at the last date 
the patient was known to be alive. The last date the patient was known to be alive will be the latest date from the 
following: 
• 
The Date of completion/discontinuation on the Disposition page of the eCRF 
• 
The Date of Procedures from Related Procedures page of the eCRF 
• 
The Date contact was made from Contact page of the eCRF when Patient Status is Alive 
• 
The last Date of Ordinal Scale for Clinical Severity from the Ordinal Scale for Clinical Severity page of the 
eCRF. 
The last study day known to be alive for such patients will be derived as (date last known to be alive – date of 
randomisation +1). 
16.2.4.8. SpO2/FiO2 from randomisation to Day 15, hospital discharge, or death 
SpO2 (Oxygen Saturation) and FiO2 (Fraction of Inspired Oxygen) will be taken from Blood Gas Measurements 
page of the eCRF.  The ratio SpO2/FiO2 will be derived based on daily measurement.  Change from Baseline in 
SpO2/FiO2 will be derived at each visit as per Section 6.5.   
16.2.4.9. Duration (days) of ICU and hospitalisation  
Duration of ICU and hospitalisation (days) will be derived based on start/stop date of admission and start/stop date 
of ICU/HDU stay in the Hospitalization page of the eCRF. Duration of hospitalization is derived as stop date of 
admission - start date of admission +1.  Duration of ICU is the sum of duration (days) of each episode of ICU/HDU 
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stay. If a patient dies and the stop date of admission is missing, the date of death will be used instead. 
To account for the different durations of the study for patients, including those who die and may therefore have less 
hospitalisation than other patients, the duration of ICU will also be converted into percentages based on the duration 
of hospitalisation for a patient. 
16.2.4.10. NEWS2 assessed daily while hospitalised and on Days 15 and 29 
The NEWS2 is based on 6 physiological measurements (respiration rate, oxygen saturation [SpO2], systolic blood 
pressure, pulse rate, level of consciousness or new confusion, and temperature). Each of these physiological 
parameters is rated using a 4-point Likert scale (0= no risk to 3 = high risk). The NEWS2 score is obtained by 
summing the 6 physiological parameter individual scores, with higher score indicating higher risk of deterioration 
and need for escalation in clinical care, including transfer of the patient to a higher level of care hospital unit.  The 
NEWS2 score is set to missing if at least one physiological parameter individual score is missing, and the overall 
score is uplifted by 2 points for patients requiring supplemental oxygen to maintain their recommended SpO2. The 
range of NEWS2 score, taking into account this potential 2 point uplifting, is 0-20. 
The scoring system for NEWS2 is provided in APPENDIX 2. 
NEWS2 will be assessed daily while hospitalised and on Days 15 and 29. This should be evaluated at the first 
assessment of a given study day. 
NEWS2 score data will be captured on the National Early Warning Score (NEWS2) page of the eCRF. Although the 
NEWS2 score is also captured on this page of the eCRF in addition to the individual 6 physiological parameters 
scores, the NEWS2 score will be re-calculated by IQVIA Biotech Biostatistics and the re-calculated NEWS2 scores 
will be used in the analysis.  Both the captured and re-calculated NEWS2 scores will be listed. 
Change from Baseline in NEWS2 will be derived as per Section 6.5. 
16.2.4.11. Time to a NEWS2 of ≤2, maintained for at least 24 hours 
NEWS2 will be derived as described in Section Error! Reference source not found.. Time to a NEWS2 of ≤2, 
maintained for at least 24 hours will be derived as follows:  
• 
(The date of the first post-Baseline assessment where NEWS2 is ≤ 2 and sustained for at least 24 hours ) – 
date of randomisation +1. 
Note: To be sustained for at least 24 hours, the most recent NEWS2 score after a score of ≤ 2 must also be ≤ 2 AND 
there must also be at least 24 hours between the two NEWS2 assessments. 
Patients who are alive at the time of analysis and have not had the event will have their time to event censored at the 
date of the last non-missing post-Baseline NEWS2 assessment.  Patients who have died without having the event, 
will have their time to event censored at the same day as the maximum known time to event or censored 
observation. 
16.2.4.12. Ranked trajectory over 29 days 
For all patients across both treatment arms combined, trajectory will be ranked in the following order of the ordinal 
scale:  
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1. [ascending order] The worst (highest) score up to and including Day 29 
2. [ascending order] The last recorded score up to and including Day 29 
3. [ascending order] The number of days at worst score up to and including Day 29 
4. [ascending order] The best (lowest) score up to and including Day29 that occurs after the worst score (this 
will equal the worst score if the worst score is the last score) 
5. [descending order] The number of days the patient is at 4), counting only days after the last occurrence of 
the worst score (the number of days for this item will be 0 if the worst score is the last score). 
Each of the orderings performed at steps 2, 3, 4 and 5 above are used to resolve any tied ranks resulting from the 
previous step, and each patient will have one overall rank for their trajectory compared to all other patients (across 
both treatment arms).  Lower ranks will represent a better trajectory. 
The rankings will be performed on each of the 100 imputed datasets obtained using the multiple imputation of 
ordinal scores data described in Section 16.1.2. 
16.2.5. 
ANALYSIS OF OTHER SECONDARY EFFICACY VARIABLES 
16.2.5.1. Analysis of duration (days) of ventilation and ventilation-free days 
The duration of ventilation and ventilation-free days, and the percentage of days relative to days in hospital will be 
summarised descriptively for each treatment arm using N, mean, standard deviation, median, minimum, maximum 
and 1st and 3rd quartiles. 
For each of these parameters, these summaries will be further broken down by whether patients died in hospital or 
not. 
16.2.5.2. Analysis of Incidence of any form of new ventilation use and duration (days) of new 
ventilation use 
The number and percentage of patients with any form of new ventilation use will be presented and the proportion of 
patients will be analysed using the same methodology as described in Section 16.2.3.1. 
The duration of new ventilation use, and the percentage of days relative to days in hospital will be summarised 
descriptively for each treatment arm using N, mean, standard deviation, median, minimum, maximum and 1st and 3rd 
quartiles.  For each of these parameters, these summaries will be further broken down by whether patients died in 
hospital or not. 
At each Day up to Day 29, patients were classified as one of the following: Died; discharged (alive) from hospital; 
in hospital receiving ventilation; in hospital not receiving ventilation. The percentage of each category will be 
plotted with Day. 
16.2.5.3. Analysis of duration (days) of organ support  
The duration of organ support, and the percentage of days relative to days in hospital will be summarised 
descriptively for each treatment arm using N, mean, standard deviation, median, minimum, maximum and 1st and 3rd 
quartiles. 
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16.2.5.4. Analysis of response rate at Days 2, 8, 15, 22 and 29 
Response rate at each of Days 2, 8, 15, 22 and 29 separately will be analysed using the same methodology as 
described in Section 16.2.3.1. 
16.2.5.5. Analysis of time to live discharge from the hospital by Day 29 
The analyses of time to live discharge will be the same as the primary analysis of the primary efficacy endpoint as 
described in Section 16.1.3. 
16.2.5.6. Analysis of mortality at Days 15, 29, and 60 
The number and percentage of patients alive, dead or with unknown mortality status at each of Day 15, 29 and 60 
will be summarised for each treatment arm. 
For each Day separately, the mortality rate will be analysed using the same methodology as described in Section 
16.2.3.1. 
16.2.5.7.  Analysis of time from randomisation to death  
The analyses of time from randomisation to death will be the same as the primary analysis of the primary efficacy 
endpoint as described in Section 16.1.3. 
16.2.5.8. Analysis of SpO2/FiO2 from randomisation to Day 15, hospital discharge, or death  
Ratio of SpO2/FiO2 will be summarised descriptively for each treatment arm using N, mean, standard deviation, 
median, minimum, maximum and 1st and 3rd quartiles. Change from Baseline in SpO2/FiO2 ratio will be summarised 
similarly at each post-Baseline study day at which SpO2/FiO2 ratio was assessed. 
16.2.5.9. Analysis of duration of ICU and hospitalisation 
Duration of ICU, percentage of duration of ICU and duration of hospitalisation will be summarised descriptively for 
each treatment arm using N, mean, standard deviation, median, minimum, maximum and 1st and 3rd quartiles. 
16.2.5.10. Analysis of NEWS2 assessed daily while hospitalised and on Days 15 and 29 
NEWS2 at Baseline and each day from Day 1 to Day 29 at which NEWS2 was assessed will be summarised 
descriptively as a continuous variable using number of observations, mean, standard deviation, median, minimum, 
maximum and 1st and 3rd quartiles. Change from Baseline in NEWS2 will be summarised similarly at each post-
Baseline study day at which NEWS2 was assessed. 
16.2.5.11. Analysis of time to a NEWS2 of ≤2, maintained for at least 24 hours 
The analysis of time to a NEWS2 of ≤2, maintained for at least 24 hours will be the same as the primary analysis of 
the primary efficacy endpoint as described in Section 16.1.3, but with the following additions: 
• 
For the stratified log-rank test, an additional stratum will be included based on whether the baseline 
NEWS2 score is:  
o 
< the 1st quartile Baseline NEWS2 score across all patients 
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o 
≥ the 1st quartile and < the median Baseline NEWS2 score across all patients 
o 
≥ the median and < the 3rd quartile Baseline NEWS2 score across all patients 
o 
≥ the 3rd quartile Baseline NEWS2 score across all patients. 
• 
For the Cox regression, an additional continuous covariate of baseline NEWS2 score will be included in the 
model. 
If there are convergence or estimation issues with either the log-rank test or the Cox regression model, the Baseline 
NEWs score will remain in the model, and the other factors will be removed, as described in Section 7.8.  If 
convergence or estimation issues still remain, then for the log-rank test, a simplified strata based on values being 
<  or ≥ the median baseline NEWs score across all patients will be used.   
16.2.5.12. Analysis of Ranked trajectory over 29 days 
The ranks of all patients will be compared between treatment arms using the stratified Wilcoxon (van Elteren) test 
(using “Row mean scores differ” test in SAS PROC FREQ with the CMH option, with scores=modridit), stratified 
by Baseline severity and centre/pooled centre. 
17. SAFETY OUTCOMES 
All outputs for safety outcomes will be based on the safety analysis set. There will be no statistical comparisons 
between the treatment arms for safety data, unless otherwise specified with the relevant section. 
17.1. ADVERSE EVENTS 
Prior AEs are defined as any AE that started or worsened in severity on or after the date of signed informed consent 
but before randomisation. 
Treatment emergent AEs (TEAEs) are defined as any AE that started or worsened in severity on or after 
randomisation. For AEs with onset on the day of randomisation, if time of onset of the AE is not recorded, or is 
recorded and is on or after the time of randomisation, the AE will be considered TEAEs.  All other AEs with onset 
on the day of randomisation will be considered as prior AEs.  
See APPENDIX 1 for handling of partial dates for AEs.  In the case where it is not possible to define an AE as 
treatment emergent or not, the AE will be classified by the worst case; i.e. treatment emergent.  
If there are any patients randomised to SoC who received bemcentinib, a separate listing of AEs will be provided for 
these patients, denoting whether AE onset was before or after first administration of bemcentinib. 
AEs will be coded using MedDRA version 23.0 or above. 
An overall summary of number and percentage of patients within each of the categories described in the sub--
sections below will be provided by treatment arm and overall based on the safety analysis set.  Should a patient 
experience multiple events within a category, the patient will be counted only once for that category unless 
otherwise stated. 
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17.1.1. 
ALL TEAES 
Incidence of TEAEs will be presented by System Organ Class and Preferred Term and broken down further by 
maximum severity and relationship to study medication. 
17.1.1.1. Severity 
Severity will be classified according to the Common Terminology Criteria for AEs (CTCAE) grades, version 5.  
TEAEs with a missing severity will be classified as Grade 3 (severe) unless the outcome of the AE was Fatal in 
which case the missing severity would be classified as Grade 5 (fatal).   
A patient experience multiple TEAEs within a System Organ Class or PT, only the patient’s worst CTCAE grade 
will be counted for that System Organ Class or PT. 
17.1.1.2. Relationship to Study Treatment 
Relationship to study treatment, as indicated by the Investigator, will be classified as not related or related. 
TEAEs with a missing relationship to study drug will be regarded as related to study drug. A patient experience 
multiple TEAEs within a System Organ Class or PT, only the patient’s worst relationship will be counted for that 
System Organ Class or PT.  
17.1.1.3. Relationship to Non-Study Drug  
Relationship to non-study drug, as indicated by the Investigator, will be classified as not related or related.  
TEAEs with a missing relationship to non-study drug will be regarded as related to non-study drug. A patient 
experience multiple TEAEs within a System Organ Class or PT, only the patient’s worst relationship will be counted 
for that System Organ Class or PT.  
17.1.1.4. Relationship to Study Procedure  
Relationship to study procedure, as indicated by the Investigator, will be classified as not related or related. 
TEAEs with a missing relationship to study procedure will be regarded as related to study procedure. Should a 
patient experienced multiple TEAEs within a System Organ Class or PT, only the patient’s worst relationship will 
be counted for that System Organ Class or PT.  
17.1.2. 
ADVERSE EVENTS WITH AN OUTCOME OF DEATH 
TEAEs with an outcome of death are those events which are recorded as “Fatal” on the Adverse Events page of the 
eCRF. A summary of TEAEs with an outcome of death by System Organ Class and Preferred Term will be 
prepared. 
A listing of all AEs with an outcome of death will be provided. 
17.1.3. 
SERIOUS ADVERSE EVENTS 
Serious AEs (SAEs) are those events recorded as “Serious” on the Adverse Events page of the eCRF.  A summary of 
serious TEAEs by System Organ Class and Preferred Term will be prepared.  Should a patient experience multiple 
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serious TEAEs within a System Organ Class or PT, the patient will be counted only once for that System Organ 
Class or PT. 
A listing of all SAEs will be provided. 
17.1.4. 
TEAES LEADING TO DISCONTINUATION OF STUDY TREATMENT 
TEAEs leading to permanent discontinuation of study drug are those events recorded as “Drug withdrawal” on the 
Adverse Events page of the eCRF. A summary of TEAEs leading to permanent discontinuation of study drug by 
System Organ Class and Preferred Term will be prepared. Should a patient experience multiple events within a 
System Organ Class or Preferred Term, the patient will be counted only once for that System Organ Class or 
Preferred Term. 
A listing of all TEAEs leading to discontinuation of study treatment will be provided. 
17.1.5. 
ADVERSE EVENTS OF SPECIAL INTEREST (AESIS) 
17.2. THERE ARE NO ADVERSE EVENTS OF SPECIAL INTEREST (AESI) 
IN THIS STUDY. DEATHS 
If any patients die during the study as recorded on the Death Details page of the eCRF, the number and percentage 
of patients who died due to COVID-19 as primary cause of death and those who died due to any other primary cause 
will be summarised by treatment arm based on the safety analysis set.  Similarly, the number and percentage of 
patients who died due to COVID-19 as secondary cause of death and those who died due to any other secondary 
cause will be summarised by treatment arm based on the safety analysis set. 
A listing of all deaths will be provided. 
17.3. LABORATORY EVALUATIONS 
A serum or urine pregnancy test will be performed at the screening visit.  Chemistry, haematology, coagulation tests 
and blood gas assessments will be performed as per the schedule of events (refer protocol Section 1.3).  A list of 
laboratory parameters to be included in the outputs is included in APPENDIX 3.  
Quantitative laboratory parameters reported as “< X”, i.e. below the lower limit of quantification (BLQ) or “> X”, 
i.e. above the upper limit of quantification (ULQ), will be converted to X for the purpose of quantitative summaries, 
but will be presented as recorded, i.e. as “< X” or “> X” in the listings.  
The following summary will be provided by treatment arm based on the safety analysis set for blood gas parameters: 
• 
Observed and change from Baseline in Standard International (SI) units by visit 
The following summaries will be provided by treatment arm based on the safety analysis set for chemistry, 
haematology and coagulation parameters: 
• 
Observed and change from Baseline in SI units by visit (for selected quantitative parameters, see 
parameters with an asterisk in APPENDIX 3) 
• 
Shift from Baseline to the worst post-Baseline value according to the CTCAE toxicity grades (CTCAE 
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toxicity grades for applicable quantitative parameters are defined per CTCAE grading system, v5.0: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm  [accessed 12-Oct-2020]) 
• 
Listing of patients with laboratory value meeting a CTCAE toxicity grade ≥ 3  
• 
Shift from Baseline to the minimum post-Baseline value according to normal range criteria (for selected 
quantitative parameters, see parameters with an asterisk in APPENDIX 3) 
• 
Shift from Baseline to the maximum post-Baseline value according to normal range criteria (for selected 
quantitative parameters, see parameters with an asterisk in APPENDIX 3) 
• 
Listing of patients with abnormal laboratory values not meeting the normal range criteria (for selected 
quantitative parameters, see parameters with an asterisk in APPENDIX 3) 
• 
Number and percentage of patients with maximum post-Baseline ALT/AST observed value categorised as 
< 3 x upper limit of normal (ULN), ≥ 3 to < 5 x ULN, ≥ 5 to < 10 x ULN or ≥ 10 ULN by maximum post-
Baseline total bilirubin observed value categorised as < 2 x ULN or ≥ 2 x ULN  
• 
A listing of patients with at least one observed post-Baseline ALT value > 3 x ULN, AST value > 3 x ULN 
or TBL value ≥ 2 x ULN will be provided. 
17.3.1. 
LABORATORY NORMAL RANGES 
Quantitative laboratory parameters will be compared with the relevant laboratory normal ranges in SI units and 
categorised as: 
• 
Low: Below the lower limit of the laboratory normal range.  
• 
Normal: Within the laboratory normal range (upper and lower limit included). 
• 
High: Above the upper limit of the laboratory normal range. 
17.4. VITAL SIGNS 
The following Vital Signs measurements will be reported for this study: 
• 
Systolic Blood Pressure (SBP) (mmHg) 
• 
Diastolic Blood Pressure (DBP) (mmHg) 
• 
Heart Rate (bpm) 
• 
Respiratory Rate (breaths/min) 
• 
Body Temperature (⁰C) 
• 
Oxygen Saturation (SpO2) (%) 
The following summaries will be provided by treatment arm for vital signs data based on the safety analysis set: 
• 
Incidence of potentially clinically significant abnormalities (PCSAs) at Days 8, 15 and 29 (or day of 
discharge), and at any time post-Baseline, overall and by Baseline normality status (low/normal/high) 
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• 
Listing of patients meeting PCSA criteria.  
17.4.1. 
VITAL SIGNS POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITY (PCSA) 
CRITERIA 
PCSA values are defined as abnormal values considered medically important by the Sponsor according to 
predefined criteria/thresholds based on literature review. 
Vital Signs measurements will be identified as normal/abnormal at Baseline, or as PCSA in accordance with the 
following predefined markedly abnormal criteria:  
Variable 
Unit 
Low 
High 
SBP 
mmHg 
Baseline: ≤ 90 
PCSA: ≤ 90 and CFB ≤ -20 
Baseline: ≥ 180 
PCSA: ≥ 180 and CFB ≥ 20 
DBP 
mmHg 
Baseline: ≤ 50 
PCSA:  ≤ 50 and CFB ≤ -15 
Baseline: ≥ 105 
PCSA: ≥ 105 and CFB ≥ 15 
Heart rate 
bpm 
Baseline: ≤ 50 
PCSA: ≤ 50 and CFB ≤ -15 
Baseline: ≥ 120 
PCSA: ≥ 120 and CFB ≥ 15 
Body 
temperature 
˚C 
NA 
Baseline: ≥ 38.3 
PCSA: ≥ 38.3 and CFB ≥ 1.1 
Oxygen 
saturation 
% 
Baseline: < 94 
PCSA: < 94 
NA 
CFB = change from Baseline. 
17.5. ECG EVALUATIONS 
The following electrocardiogram (ECG) parameters will be measured for this study as per the schedule of events 
(refer to protocol Section 1.3): 
• 
Heart rate (bpm) 
• 
PR interval (msec) 
• 
RR interval (msec) 
• 
QRS interval (msec) 
• 
QT interval (msec) 
• 
QTc interval (msec) 
• 
QTcF interval (msec) 
• 
QTcB interval (msec) 
• 
Overall ECG interpretation (Investigator’s judgment): 
o 
Normal 
o 
Abnormal, not clinically significant (NCS) 
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o 
Abnormal, clinically significant (CS). 
The following summaries will be provided by treatment arm based on the safety analysis set for each ECG 
parameter: 
• 
Shift from Baseline to worst-case markedly abnormal result (for quantitative parameters) post-Baseline for 
the observed values markedly abnormal criteria (refer to Section 17.5.1). In these shift tables values, the 
categories will be ≤470 msec, >470-<501 msec and ≥501 msec 
• 
Incidence of any markedly abnormal change from Baseline values (for quantitative parameters) at any time 
post-Baseline. Patients will be counted in all relevant categories based on their highest post-Baseline 
change from Baseline, e.g. a value of > 60 will also be counted as > 30 
• 
Listing of patients meeting markedly abnormal criteria 
• 
Shift from Baseline in overall ECG interpretation to the worst post-Baseline interpretation 
• 
Listing of patients with an abnormal overall ECG interpretation, including the finding(s) for each patient. 
All ECG data will be listed. 
17.5.1. 
ECG MARKEDLY ABNORMAL CRITERIA 
Markedly abnormal quantitative ECG parameters will be identified in accordance with the following predefined 
markedly abnormal criteria: 
• 
Observed values for QT, QTc, QTcF, and QTcB intervals will be classified as: 
o 
> 470 msec 
o 
≥ 501 msec. 
• 
Change from Baseline for QT, QTc, QTcF, and QTcB intervals will be classified as: 
o 
>30 msec increase from Baseline 
o 
>60 msec increase from Baseline. 
17.6. OTHER SAFETY DATA 
17.6.1. 
GENERAL PHYSICAL EXAMINATION 
Physical examinations will be conducted as per the schedule of events (refer to protocol Section 1.3).  At screening a 
general physical examination will be performed, and at post-Baseline visits a targeted physical examination of the 
chest will be performed. 
All physical examination data will be listed only. 
17.6.2. 
DIAGNOSTIC IMAGING 
Diagnostic imaging (chest X-ray and/or computed tomography) will be performed at Screening as per the schedule 
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of events (refer to protocol Section 1.3). 
All diagnostic imaging data, including findings, will be listed only. 
17.6.3. 
DISEASE-RELATED CO-INFECTION EVALUATION 
Disease-related co-infection evaluation data will be listed only. 
18. PHARMACOKINETICS 
Because only sparse blood sample collections are planned for determination of bemcentinib (and metabolite, to be 
defined) concentration in plasma, non-compartmental analysis is not planned.   
Pharmacokinetic data summaries are limited to concentration-time summary statistics. 
18.1. DEVIATIONS OR EVENTS AFFECTING PK RESULTS 
Changes to the procedures or events which may impact the quality of the PK data will be considered important 
protocol deviations or events and will be documented in the PK results.  These changes or events will include any 
circumstances that will alter the evaluation of the PK.  Examples of deviations/events for PK include, but may not be 
limited to, sample processing errors that lead to inaccurate bioanalytical results, inaccurate dosing on or prior to the 
day of PK sampling, and/or predose samples collected after the administered dose (see specifications below). Note 
that vomiting or diarrhoea are generally considered events that would result in exclusions from the Primary PKS set.  
However, the primary analysis set will include data potentially impacted by vomiting or diarrhoea. A secondary PK 
analysis set will exclude data potentially impacted by vomiting or diarrhoea.  
18.2. PLASMA CONCENTRATION DATA 
All bemcentinib (and metabolites, to be defined) plasma concentration data received will be listed by patient, and 
summaries for both the primary and secondary PKS will be presented by nominal time for patients included in the 
respective analysis sets.  
In addition, for the primary PKS only, summaries will be presented based on further stratification by gender and age 
groups.  The descriptive summary will include number of patients/non-missing observations (N/n), arithmetic mean 
(Mean), standard deviation (SD), coefficient of variation (CV%), minimum (Min), median (Median), and maximum 
(Max). In cases with n ≤2, only n, Min, and Max will be reported. Plasma concentrations below the lower limit of 
quantification (LLOQ) will be set to 0 for calculation of the descriptive statistics. Mean and median values falling 
below the LLOQ will be presented as <LLOQ. Missing plasma concentration data will not be imputed, data will be 
treated as missing for descriptive statistics.   
For both the primary and secondary PKS, there will be no exclusion of concentration-time data related to deviations 
from the scheduled sampling time for the 6-hour sample. Trough samples will be included in the concentration 
summary as long as they are collected no later than 30 minutes after dose administration. 
A listing of individual PK blood sample collection times as well as derived sampling time deviations will be 
provided.   
For the primary PKS only, the individual plasma bemcentinib (and metabolites) concentrations will be plotted 
versus actual time as an x-y scatter plot; the arithmetic mean (±SD, if appropriate) plasma candidate agent 
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concentrations will be plotted for each treatment versus nominal (or scheduled) time.  Plots will be included with the 
y-axis presented on both a linear and a log scale.   
Descriptive statistics of PK concentration data will be calculated using values with the same precision as the source 
data and will be rounded for reporting purposes only. The following conventions will be applied when reporting 
descriptive statistics of PK concentration data: 
Mean, Min, Median, Max:  
Same as source data 
SD: 
One more than source data 
CV%  
1 decimal place  
For the metabolite concentration data, individual and summary metabolite concentration-time tables, listings, and 
figures will be generated as described above for parent bemcentinib.  Depending on the metabolite data generated, 
additional tables, listings and figures may be generated.   Also depending on the data, the generated metabolite 
tables, listings, and figures may not be presented in the CSR; however, all metabolite concentration time data will be 
maintained in the applicable SDTM and ADaM datasets. 
19. PHARMACODYNAMICS 
19.1. EXPLORATORY PD ANALYSIS 
Pharmacodynamics analysis will be performed using the PDS.    
A listing of PD sample collection times as well as derived sampling time deviations (as appropriate) will be 
provided.   
Patient listings of all available PD endpoint-time data will be presented for observed values and baseline-corrected 
values. Baseline will be defined as the closest observation prior to the first dose of study medication.  
Concentrations for blood-based PD endpoints which fall below the LLOQ will be set to the LLOQ for any summary 
and/or inferential analyses. 
The following will be listed:   
• 
PBMC Phenotyping 
• 
Cytokine analysis 
• 
Soluble AXL, GAS6, and other blood proteins. 
19.2. EXPLORATORY PK/PD ANALYSIS 
Exploratory PK/PD correlations may be performed as part of the Stage 1 analysis using appropriately paired 
evaluable bemcentinib concentration - PD endpoint data sets for each analysis.  If sufficient data is available, the 
following will be assessed using an appropriate plot or figure and/or regression analysis:   
• 
Concentration - QTcF analysis: Bemcentinib plasma exposure to QT (C-QT) 
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• 
Soluble AXL levels to bemcentinib exposure   
• 
Viral load to bemcentinib plasma concentration 
• 
Log drop of viral load to bemcentinib plasma exposure 
• 
Bemcentinib agent plasma exposure by prior therapy.  
Some modifications may be necessary to the planned design of tables, figures, and listings to accommodate data 
collected during study conduct.  
 
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20. REFERENCES 
Brookmeyer R, Crowley J. A (1982) Confidence Interval for the Median Survival Time. Biometrics 38:29-41. 
Cao B, Wang Y, Wen D, et al. A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19. N Engl 
J Med. 2020 Mar 18. doi: 10.1056/NEJMoa2001282. [Epub ahead of print]. 
Moscovici J.L, Ratitch B (2017) Combining Survival Analysis Results after Multiple Imputation of Censored Event 
Times, PharmaSUG 2017 – Paper SP05.  
Newcombe, R.G. (1998) Interval Estimation for the Difference between Independent Proportions: Comparison of 
Eleven Methods. Statistics in Medicine 17:873–890. 
 
 
 
 
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BerGenBio ASA  
Protocol Number: BGBC020 
Statistical Analysis Plan 
Page 44 of 48 
 
Author: 
 
Version Number: 
1.0 
 
Version Date:  
[17Nov2020] 
Copyright © 2009, 2010, 2012, 2016, 2018, 2019 IQVIA. All rights reserved. The contents of this document are confidential and 
proprietary to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
APPENDIX 1. PARTIAL DATE CONVENTIONS 
ALGORITHM FOR TREATMENT EMERGENCE OF ADVERSE EVENTS 
START DATE 
END DATE 
ACTION 
Known 
Known/Partial/ 
Missing 
If AE start date < date of randomisation then not a TEAE; 
If AE start date = date of randomisation and time of onset of 
AE is available and is before the time of randomisation then 
not a TEAE; 
Otherwise, TEAE. 
 
 
 
Partial, but known components 
show that AE started before date 
of randomisation 
Known/Partial/ 
Missing 
Not TEAE. 
 
 
 
Partial and known components 
show that AE started on or after 
date of randomisation  
OR  
Missing 
Known 
If AE end date < date of randomisation then not TEAE; 
If AE end date = date of randomisation and time of end of AE 
is available and is before the time of randomisation then not a 
TEAE; 
Otherwise, TEAE 
Partial 
If known components of AE stop date show that AE stopped 
before date of randomisation), then not TEAE; 
Otherwise, TEAE 
Missing 
Assume TEAE. 
Note: If an AE started prior to randomisation but worsened after randomisation, it will be reported as a separate 
adverse event with new AE start date. 
 
 
 
 
 
 
 
 
 
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BerGenBio ASA  
Protocol Number: BGBC020 
Statistical Analysis Plan 
Page 45 of 48 
 
Author: 
 
Version Number: 
1.0 
 
Version Date:  
[17Nov2020] 
Copyright © 2009, 2010, 2012, 2016, 2018, 2019 IQVIA. All rights reserved. The contents of this document are confidential and 
proprietary to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
ALGORITHM FOR PRIOR / CONCOMITANT MEDICATIONS 
START DATE 
STOP DATE 
ACTION 
Known 
Known 
If medication stop date < date of randomisation, assign as prior; 
Otherwise, assign as concomitant  
Partial 
If known components of medication stop date show that medication stopped 
before date of randomisation, assign as prior; 
Otherwise, assign as concomitant 
Missing, or 
ongoing 
Can never be assigned as prior, therefore assign as concomitant. 
 
 
 
Partial 
Known 
If medication stop date < date of randomisation, assign as prior; 
Otherwise, assign as concomitant. 
Partial 
If known components of medication stop date show that medication stopped 
before date of randomisation, assign as prior; 
Otherwise, assign as concomitant. 
Missing, or 
ongoing 
Can never be assigned as prior, therefore assign as concomitant. 
 
 
 
Missing 
Known 
If medication stop date < date of randomisation, assign as prior; 
Otherwise, assign as concomitant 
Partial 
If known components of medication stop date show that medication stopped 
before date of randomisation, assign as prior; 
Otherwise, assign as concomitant; 
Missing, or 
ongoing 
Assign as concomitant. 
 
 
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BerGenBio ASA  
Protocol Number: BGBC020 
Statistical Analysis Plan 
Page 46 of 48 
 
Author: 
 
Version Number: 
1.0 
 
Version Date:  
[17Nov2020] 
Copyright © 2009, 2010, 2012, 2016, 2018, 2019 IQVIA. All rights reserved. The contents of this document are confidential and 
proprietary to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
APPENDIX 2. 
NEWS2 SCORING SYSTEM 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: https://www.rcplondon.ac.uk/file/9434/download [accessed 16 June 2020] 
 
Note: SpO2 Scale 1 corresponds to the eCRF National Early Warning Score (NEWS2) item If Hypercapnic 
respiratory failure is NO. 
SpO2 Scale 2 corresponds to the eCRF National Early Warning Score (NEWS2) item If Hypercapnic respiratory 
failure is YES. 
Air or oxygen corresponds to the eCRF National Early Warning Score (NEWS2) item Room air or Supplemental 
O2? 
CVPU corresponds to eCRF National Early Warning Score (NEWS2) Consciousness item response of New-onset 
confusion (or disorientation/agitation), responds to voice, responds to pain, or unresponsive  
 
 
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BerGenBio ASA  
Protocol Number: BGBC020 
Statistical Analysis Plan 
Page 47 of 48 
 
Author: 
 
Version Number: 
1.0 
 
Version Date:  
[17Nov2020] 
Copyright © 2009, 2010, 2012, 2016, 2018, 2019 IQVIA. All rights reserved. The contents of this document are confidential and 
proprietary to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
APPENDIX 3. 
LABORATORY ASSESSMENTS 
Chemistry (SI unit) 
 
• 
Sodium (mmol/L) * 
• 
Aspartate transaminase (AST) (IU/L) * 
• 
Potassium (mmol/L) * 
• 
Alanine transaminase (ALT) (IU/L) * 
• 
Calcium (mmol/L) 
• 
Carbon dioxide (CO2) (mmol/L) 
• 
Magnesium (mmol/L) 
• 
Albumin (g/L) 
• 
Glucose (mmol/L) * 
• 
C-Reactive protein (CRP) (nmol/L)  
• 
Creatinine (µmol/L) * 
• 
Bicarbonate (mmol/L) 
• 
Creatine kinase (CK) (µkat/L) * 
• 
Triglycerides (mmol/L) 
• 
MB Isoenzyme Fraction of CK (%) 
• 
Ferritin (µg/L) 
• 
Direct bilirubin (µmol/L) 
• 
Lactate dehydrogenase (LDH) (IU/L) 
• 
Indirect bilirubin (µmol/L) 
• 
Phosphate (mmol/L) 
• 
Total bilirubin (µmol/L) * 
• 
Chloride (mmol/L) 
• 
Gamma glutamyl transferase (GGT) 
(µkat/L) * 
• 
Troponin (µg/L) I * and Troponin T 
(µg/L) * 
• 
Alkaline phosphatase (ALP) (IU/L) 
• 
Creatine Clearance Calculation 
(mL/min) 
* Selected parameter to be used in particular laboratory data summaries/analyses : Refer to Section 17.3 for details. 
 
 
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BerGenBio ASA  
Protocol Number: BGBC020 
Statistical Analysis Plan 
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Author: 
 
Version Number: 
1.0 
 
Version Date:  
[17Nov2020] 
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proprietary to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
Haematology (SI unit) 
 
• 
Haemoglobin (g/L) * 
• 
Absolute basophils count (x10E9/L) 
• 
Platelet count (x10E9/L) 
• 
Relative neutrophils count (%) * 
• 
White blood cell (WBC) count total 
(x10E9/L) * 
• 
Relative lymphocyte count (%) 
• 
Absolute neutrophils count (x10E9/L) * 
• 
Relative monocyte count (%) 
• 
Absolute lymphocyte count (x10E9/L) 
• 
Relative eosinophils count (%) 
• 
Absolute monocyte count (x10E9/L) 
• 
Relative basophils count (%) 
• 
Absolute eosinophils count (x10E9/L) 
 
* Selected parameter to be used in particular laboratory data summaries/analyses : Refer to Section 17.3 for details. 
 
Coagulation (SI unit) 
 
• 
International normalised ratio (INR) * 
• 
Fibrinogen (g/L) 
• 
Prothrombin time (PT) (s) * 
• 
D-dimer (µg/L DDU) 
• 
Activated partial thromboplastin time 
(aPTT) (s) * 
 
* Selected parameter to be used in particular laboratory data summaries/analyses : Refer to Section 17.3 for details. 
 
Blood Gas (SIunit) 
 
• 
Arterial pH 
• 
Capillary pH 
• 
Arterial partial pressure of oxygen 
(PaO2) (kPa) 
• 
Capillary PaO2 (kPa) 
• 
Arterial partial pressure of CO2 (PaCO2) 
(kPa) 
• 
Capillary PaCO2 (kPa) 
• 
Arterial base excess/deficit (mEq/L) 
• 
Capillary base excess/deficit (mEq/L) 
• 
Arterial Oxygen Saturation (SpO2, %) 
• 
Capillary Oxygen Saturation (SpO2, %) 
• 
Arterial Fraction of Inspired Oxygen 
(FiO2, %) 
• 
Capillary Fraction of Inspired Oxygen 
(FiO2, %) 
 
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