A Randomised, Double-blind, Placebo-controlled, Phase III Trial to Determine the Efficacy and Safety of Inhaled SNG001 for the Treatment of Patients Hospitalised Due to Moderate COVID-19
Phase: PHASE3
Conditions: Severe Acute Respiratory Syndrome Coronavirus 2, COVID-19
Sponsor: Synairgen Research Ltd.

Protocol: SG018 
IMP: SNG001 – IFN-β1a nebuliser solution 
Version 5, 09 September 2021 
 
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PROTOCOL  
A randomised, double-blind, placebo-controlled, Phase III trial to 
determine the efficacy and safety of inhaled SNG001 for the treatment of 
patients hospitalised due to moderate COVID-19 
Short Title: 
 
Trial Name: 
Compound: 
SARS-CoV-2: Phase III TRial of Inhaled 
INTERferon-β Therapy 
SPRINTER 
IFN-β1a (for inhalation) 
Compound Name: 
SNG001 
EudraCT Number: 
Protocol Number: 
2020-004743-83 
SG018 
Version and Date: 
5, 09 September 2021 
 
 
Previous Document History: 
Document  
Date 
Version 4 
22 February 2021 
Version 3 
21 December 2020 
Version 2  
20 November 2020 
Version 1 
15 October 2020 
 
This document is the property of Synairgen Research Ltd and may not be used, 
divulged, published, or otherwise disclosed without written consent of Synairgen 
Research Ltd. 
 
 

Protocol: SG018 
IMP: SNG001 – IFN-β1a nebuliser solution 
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SYNAIRGEN RESEARCH LTD 
CLINICAL STUDY PROTOCOL SG018 
 
Study Title: 
A randomised, double-blind, placebo-controlled, Phase III trial to 
determine the efficacy and safety of inhaled SNG001 for the treatment 
of patients hospitalised due to moderate COVID-19 
Protocol Number: 
SG018 
 
Investigational Product: SNG001 (IFN-β1a for inhalation)  
 
Sponsor: 
Synairgen Research Ltd 
Level F (810) South Block, Southampton General Hospital 
Tremona Road, Southampton, SO16 6YD, UK 
 
Development Phase: 
Phase III 
 
Sponsor's Medical 
Monitor: 
 
 
 
Chief Investigator: 
  
 
 
 
 
 
 
 
This document is the property of Synairgen Research Ltd and may not be used, 
divulged, published, or otherwise disclosed without written consent of Synairgen 
Research Ltd. 
 
 
PPD
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SYNAIRGEN RESEARCH LTD 
STUDY PROTOCOL SG018 - PROTOCOL SIGNATURE PAGE 
SPONSOR REPRESENTATIVE 
 
I have reviewed and agreed this protocol and its contents. My signature, in conjunction with 
the signatures of the Sponsor’s Medical Officer, the Chief Investigator, confirms the agreement 
of all parties that the clinical trial will be conducted in accordance with the protocol and all 
applicable laws and regulations including, but not limited to, the International Council on 
Harmonisation Guideline for Good Clinical Practice (ICH GCP), the standards set out by the 
UK Policy Framework for Health and Social Care Research, The UK Medicines for Human 
Use (Clinical Trials) Regulations 2004 and associated amendments, the EU Clinical Trials 
Directive 2001/20/EC, the EU GCP Directive 2005/28/EC, the Clinical Trial Regulation (EU) 
No 536/2014, the US Federal Regulations, including but not limited to 21CFR and the Ethical 
principles that have their origin in the Declaration of Helsinki.  
 
Signature: 
 
 
 
 
 
 
 
 
 
Name (PRINT): 
 
____________________________________ 
 
Title:  
 
 
_________________________________ 
 
Date of signature: 
 
____________________________________
____________________________________ 
 
 
 
 
 
 
 
 
 
 
 
This document is the property of Synairgen Research Ltd and may not be used, 
divulged, published, or otherwise disclosed without written consent of Synairgen 
Research Ltd. 
 
 
PPD
PPD
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SYNAIRGEN RESEARCH LTD  
CLINICAL STUDY PROTOCOL SG018 - PROTOCOL SIGNATURE PAGE  
 
PRINCIPAL INVESTIGATOR 
 
I confirm that I have read and agreed this protocol and its contents. I understand that all 
information concerning SNG001 and this protocol supplied to me by Synairgen Research Ltd 
is confidential. 
 
My signature below confirms that as part of my responsibility as Principal Investigator, I will 
ensure that the clinical trial is conducted in accordance with the protocol and all applicable 
laws and regulations including, but not limited to, the International Council on Harmonisation 
Guideline for Good Clinical Practice (ICH GCP), the standards set out by the UK Policy 
Framework for Health and Social Care Research, The UK Medicines for Human Use (Clinical 
Trials) Regulations 2004 and associated amendments, the EU Clinical Trials Directive 
2001/20/EC, the EU GCP Directive 2005/28/EC, the Clinical Trial Regulation (EU) No 
536/2014, the US Federal Regulations, including but not limited to 21CFR and the Ethical 
principles that have their origin in the Declaration of Helsinki. 
 
 
Signature: 
 
 
 
 
 
 
 
 
 
 
Name (PRINT): 
 
____________________________________ 
 
Title:  
 
 
____________________________________ 
 
Date of signature: 
 
____________________________________ 
 
 
 
This document is the property of Synairgen Research Ltd and may not be used, 
divulged, published, or otherwise disclosed without written consent of Synairgen 
Research Ltd. 
 
 

Protocol: SG018 
IMP: SNG001 – IFN-β1a nebuliser solution 
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PROTOCOL SYNOPSIS 
Study Title:  
A randomised, double-blind, placebo-controlled, Phase III trial to determine the efficacy and 
safety of inhaled SNG001 for the treatment of patients hospitalised due to moderate COVID-19  
Protocol number: SG018 
Study centres: Multi-national and multicentre 
Number of randomised patients:  
At least 610 randomised patients in total, randomised 1:1 to the following arms:  
 
Arm 1: approximately 305 patients - SNG001 - contents of 2 syringes* per dose  
Arm 2: approximately 305 patients - Placebo - contents of 2 syringes+ per dose  
 
*Each syringe contains 
 mL of SNG001 nebuliser solution, containing 
 MIU/mL of 
interferon beta-1a (IFN-β) 
+Each syringe contains 
 mL of formulation buffer 
Study period: 2020 onwards 
Phase of development: Phase III 
Background: 
Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) is a global threat and there 
is a need to assess new treatments which will prevent and effectively treat severe lower 
respiratory tract (LRT) illness caused by the SARS-CoV-2.  
IFN-β has showed antiviral activity against SARS-CoV-2 in cell-based assays (1). IFN-β 
driven anti-viral responses have been shown to be compromised/deficient in older people (2) 
and those with chronic airways diseases (3, 4). These, and other patient groups are at high risk 
of developing severe LRT illness which can be fatal (5). The IFN-β deficiency can be 
overcome through the administration of exogenous IFN-β. This has been shown both in vitro, 
using cells from patients, and in clinical trials using SNG001 (an inhaled IFN-β1a formulation 
for nebulisation). We hypothesise that SNG001 will rectify the deficiency in the lungs in at-
risk patients and prevent severe LRT illness in the context of SARS-CoV-2 infection. 
The SG016 hospital pilot study was completed in May 2020. During this pilot study, 
101 hospitalised adults, ≥18 years of age, with confirmed or suspected SARS-CoV-2 infection 
were randomised to receive SNG001 or placebo. Results of the pilot study showed that the 
risks of developing severe COVID-19 (the disease caused by SARS-CoV-2) were markedly 
reduced in patients receiving SNG001 compared to placebo and additionally that patients who 
received SNG001 were more than twice as likely to recover from COVID-19 as those on 
placebo. In addition, there was a significant reduction in breathlessness in patients receiving 
SNG001, compared to placebo (6).  
SNG001 has been well tolerated in all clinical studies to date. Around 401 patients have been 
treated with SNG001. Of the 401 patients, approximately 67 patients had chronic obstructive 
pulmonary disease (COPD), 166 patients had confirmed COVID-19 with varying underlying 
diseases i.e. heart disease, lung disease, diabetes etc and the remaining 168 patients had 
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asthma. The majority of the 401 patients had or were suspected to have an active respiratory 
viral infection (rhinovirus, influenza, coronavirus, SARS-CoV-2, etc) at the time of 
randomisation.  
SNG001 is pH neutral, rather than acidic and does not contain excipients such as mannitol, 
human serum albumin (HSA) and arginine, which are present in the injectable IFN-β 
formulations and which may have their own unwanted effects if delivered to the lungs.  
SNG001 has historically been delivered using the 
, a mesh nebuliser made by 
 
. The 
 h
 has been tested to ensure the drug retains its activity after 
aerosolisation. A dose escalating trial established a target lung dose which induced an antiviral 
response in the lungs that was present 24 hours after dose administration.  
In this trial the 
 
 device will be used. The 
 is mesh nebuliser that is widely 
available and is better suited to single patient usage in the hospital setting. Laboratory 
assessments found that both the 
 and the 
 ha
 had similar levels of protein content in 
and similar IFN-β activity post nebulisation. 
The primary endpoints are to evaluate time to hospital discharge and time to recovery in 
patients with confirmed SARS-CoV-2 infection who are hospitalised due to moderate 
COVID-19, after administration of SNG001 compared to placebo, where moderate COVID-
19 is defined as presence of clinical signs and symptoms necessitating administration of 
oxygen therapy by mask or nasal prongs and recovery is defined as no limitation of activities 
according to the World Health Organization (WHO) Ordinal Scale of Clinical Improvement 
(OSCI), with no rebound at subsequent assessments. The WHO OSCI to be used in this trial 
is the 18 February 2020 version as recommended by the WHO (7).  
Purpose of the study: The purpose of this Phase III study is to confirm that SNG001 can 
accelerate the recovery of hospitalised patients receiving oxygen with confirmed 
SARS-CoV-2. Safety and other efficacy endpoints will also be assessed. 
Study Population:  
Adults, ≥18 years of age with SARS-CoV-2 infection confirmed by a positive virus test using 
a validated molecular assay e.g. Reverse Transcription Polymerase Chain Reaction (RT-PCR) 
or validated antigen assay e.g. Sofia 2 SARS Antigen FIA, who are hospitalised due to COVID-
19 and require oxygen therapy, either via nasal prongs or a mask, but do not require high-flow 
nasal oxygen therapy, non-invasive ventilation (continuous positive airway pressure [CPAP] 
or bilevel positive airway pressure [BiPAP]) or endotracheal intubation and invasive 
mechanical ventilation. 
Study Design:  
Eligible patients will be randomised in a 1:1 ratio to receive SNG001 two syringes or placebo 
two syringes.  
Patients who have a positive virus test for SARS-CoV-2 prior to hospitalisation will be 
randomised no later than 48 hours after hospital admission. If the virus test is performed more 
than 96 hours prior to hospitalisation, the test will have to be repeated in the hospital prior to 
randomisation. Only patients whose repeated virus test is positive will be randomised, no later 
than 48 hours after confirmation of SARS-CoV-2 infection. 
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Patients who have their first positive virus test for SARS-CoV-2 after hospitalisation will be 
randomised no later than 48 hours after confirmation of SARS-CoV-2 infection. SNG001 or 
placebo will be administered via the 
 nebuliser. Patients will receive a dose of SNG001 
or placebo once a day for 14 days and will be followed up for up to 90 days after the first dose 
of study medication (or randomisation date if the patient is not dosed). Study data will be 
collected from patients daily, as per the study schedule. Efficacy will be determined though 
differences between the groups in the WHO OSCI scores, and the secondary endpoints. 
Adverse events (AEs) and concomitant medications will be monitored throughout the study 
period.  
A Data Safety Monitoring Committee (DSMC) will perform a review of the safety data before 
100 patients complete study treatment, to ensure the safety of study patients. The DSMC will 
also meet as and when necessary, i.e. if a safety issue arises or when the DSMC requests a 
further meeting.  
Study Objectives 
Primary Objective:  
To evaluate recovery in patients with moderate COVID-19 after administration of SNG001 
compared to placebo.  
Secondary Objectives: 
a. To evaluate the efficacy of SNG001 compared to placebo in patients with moderate 
COVID-19, using a range of endpoints. 
b. To assess the general safety and tolerability of SNG001 compared to placebo when 
administered to patients with moderate COVID-19. 
Exploratory objective: 
 
Study Endpoints 
Primary Endpoints: 
a. Time to hospital discharge, defined by the WHO OSCI score of 2 or below, with no 
rebound at subsequent assessments.  
b. Time to recovery, where recovery is defined as the WHO OSCI score of 1 or below, 
with no rebound at subsequent assessments.  
Key Secondary Endpoints: 
a. Progression to severe disease or death, defined by the WHO OSCI score of 5 or above 
within 35 days of first dose (or randomisation date if the patient is not dosed). 
b. Progression to intubation or death, defined by the WHO OSCI score of 6 or above 
within 35 days of first dose (or randomisation date if the patient is not dosed). 
c. Death within 35 days of first dose (or randomisation date if the patient is not dosed).  
Secondary Endpoints: 
a. Recovery, where recovery is defined as the WHO OSCI score of 1 or below, with no 
rebound at subsequent assessments, at Days 7, 14, 21 and 28. 
b. Hospital discharge by Days 7, 14, 21 and 28. 
c. Improvement across the entire WHO OSCI by Days 7, 14, 21 and 28. 
d. Changes in breathlessness, cough and sputum scale (BCSS) score during the study 
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• 
intravaginal device (e.g., ethinylestradiol and etonogestrel), desogestrel (e.g., 
Cerazette™)  
• 
total sexual abstinence (defined as refraining from heterosexual intercourse) 
• 
vasectomised sexual partner.  
Women of childbearing potential should have been stable on their chosen method of 
birth control for a minimum of 3 months before entering the trial and should continue 
with birth control for 1 month after the last dose of inhaled IFN-β1a/matching placebo. 
In addition to the highly effective method of contraception (except for the practice of 
total sexual abstinence), a condom (in UK with spermicides) should be used by the 
male partner for sexual intercourse from randomisation (Visit 2) and for 1 month after 
the last dose of inhaled IFN-β1a/matching placebo to prevent pregnancy. 
7. Women not of childbearing potential are defined as women who are either 
permanently sterilised (hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy), or who are postmenopausal. Women will be considered post-
menopausal if they have been amenorrhoeic for 12 months prior to the planned date 
of randomisation without an alternative medical cause. The following age specific 
requirements apply:  
• Women <50 years old would be considered post-menopausal if they have been 
amenorrhoeic for 12 months or more following cessation of exogenous 
hormonal treatment and if follicle stimulating hormone (FSH) levels are in the 
postmenopausal range. 
• Women ≥50 years old would be considered post-menopausal if they have been 
amenorrhoeic for 12 months or more following cessation of all exogenous 
hormonal treatment. 
If, in the setting of the pandemic, the use of an acceptable birth control method is not 
possible, the decision to enrol a woman of childbearing potential should be based on 
the benefit-risk for the patient, which should be discussed with the patient at the time 
of the informed consent. 
Exclusion Criteria: 
A patient must not be randomised into the study if they meet any of the following criteria: 
1. Evidence of ongoing SARS-CoV-2 infection for more than 3 weeks, confirmed by a 
validated molecular assay or validated antigen assay. 
2. Non-invasive ventilation (CPAP/BiPAP) or high-flow nasal oxygen therapy (WHO 
OSCI score of 5). 
3.  Endotracheal intubation and invasive mechanical ventilation (WHO OSCI score of 
≥6) or admission to intensive care.  
4. Previous SARS-CoV-2 infection confirmed by a validated molecular assay or 
validated antigen assay. 
5. Any condition, including findings in the patients’ medical history or in the pre-
randomisation study assessments that in the opinion of the Investigator, constitute a 
risk or a contraindication for the participation of the patient into the study or that could 
interfere with the study objectives, conduct or evaluation. 
6. Participation in previous clinical trials of SNG001. 
7. Current or previous participation in another clinical trial where the patient has received 
a dose of an Investigational Medicinal Product (IMP) containing small molecules 

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within 30 days or 5 half-lives (whichever is longer) prior to entry into this study or 
containing biologicals within 3 months prior to entry into this study. 
8. Inability to use a nebuliser with a mouthpiece. 
9. Inability to comply with the requirements for storage conditions of study medication 
in the home setting. 
10. History of hypersensitivity to natural or recombinant IFN-β or to any of the excipients 
in the drug preparation. 
11. Females who are breast-feeding, lactating, pregnant or intending to become pregnant. 
Test product, dose, and mode of administration: SNG001 nebuliser solution is presented in 
glass syringes containing 
 mL of drug product solution at a concentration of 
 MIU/ml.  
The 
 d
 device will be filled with the contents of two syringes (if randomised to Arm 1). 
Patients will inhale study medication once a day.  
During administration of SNG001, study sites should ensure they adhere to any local 
requirements and guidelines for performing inhalation in patients with COVID-19. 
Reference product, dose and mode of administration: The placebo will be the same 
formulation as the study medication but without IFN-β1a (i.e. only the excipients of the 
SNG001 solution).  
The 
 device will be filled with the contents of two syringes (if randomised to Arm 2). 
Patients will inhale study medication (placebo) once a day. 
During administration of placebo, study sites should ensure they adhere to any local 
requirements and guidelines for performing inhalation in patients with COVID-19. 
Duration of Treatment: Patients will receive study medication for 14 days.  
Sample Size: Success will be determined if at least one of the primary endpoints is declared 
statistically significant by the primary analysis. A sample size of 610 patients in total using a 
1:1 randomisation ratio (305 patients per treatment arm) has been chosen to provide at least 
90% power to detect a hazard ratio of 1.45 in time to hospital discharge and a hazard ratio of 
1.7 in time to recovery and at least 95% power to declare statistical significance on at least one 
of the primary endpoints. This sample size has been calculated using a global 2-sided alpha 
level of 0.05 and allows for an interim analysis to assess futility.  
Statistical Methods 
Analysis populations 
The intention-to-treat (ITT) population is defined as all randomised patients.  
The safety population will include all randomised patients who receive at least one dose of 
study drug.  
The per protocol population will include all patients in the ITT population who do not have any 
protocol deviations with an impact on efficacy on or prior to Day 35. 
The PK population will include all patients in the safety population who have at least one valid 
PK concentration measurement available. 
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Statistical analysis methodology 
The same method of analysis will be used for both primary endpoints. The primary analysis 
will use a Cox proportional hazards model. Patients who die will be administratively censored 
at Day 28, i.e. time to hospital discharge and time to recovery for these patients will be fixed 
at 28 days. Patients who neither recover nor die will be censored at the date of their last WHO 
OSCI assessment. 
For the key secondary endpoint (progression to severe disease or death) a logistic regression 
model will be used to estimate the difference in probabilities between the treatment groups.  
Safety analyses will be based primarily on AE information which will be summarised 
descriptively, including summary of treatment-emergent AEs.  
 
 
 
 
 
 
Estimands 
Primary Estimand 
The first primary estimand will be the hazard ratio of SNG001 versus placebo for the time to 
hospital discharge of patients in the ITT population. Intercurrent events will be handled as per 
the table below. 
Intercurrent event 
Policy 
Death 
Composite variable: Patients who die on or prior to day 28 
will have time to hospital discharge right censored at 28 
days (the maximum time to discharge).   
Premature treatment 
discontinuation and missed 
doses 
Treatment policy: The time to hospital discharge will be 
used regardless of treatment discontinuation and the 
number of missed doses.  
Withdrawal from study 
following hospital discharge 
Treatment policy: The time to hospital discharge will be 
used regardless of study withdrawal and regardless of the 
duration of follow-up following hospital discharge. This 
assumes relapse is independent to the treatment effect.  
Withdrawal from study prior 
to hospital discharge 
While-on-study: Time to hospital discharge will be right 
censored at the time of withdrawal from the study or at 28 
days, whichever occurs first. The evaluation period for this 
endpoint is 28 days, therefore estimating the time to 
hospital discharge after Day 28 would not be appropriate. 
Premature study withdrawal is expected to be independent 
to the treatment effect, therefore a censoring approach in 
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this scenario is considered appropriate. However, this 
assumption will be tested by appropriate sensitivity 
analyses.    
Other protocol deviations 
and concomitant 
medications affecting 
efficacy 
Treatment policy: Time to hospital discharge will be used 
regardless of any concomitant medication use or protocol 
deviations.  
 
The second primary estimand will be the hazard ratio of SNG001 versus placebo for the time 
to recovery of patients in the ITT population. Intercurrent events will be handled as per the 
table below.  
 
Intercurrent event 
Policy 
Death 
Composite variable: Patients who die during the study 
period will have time to recovery right censored at 28 days 
(the maximum possible time to recovery). 
Premature treatment 
discontinuation and missed 
doses 
Treatment policy: The time to recovery will be used 
regardless of treatment discontinuation and the number of 
missed doses.  
Withdrawal from study 
following recovery 
Treatment policy: The time to recovery will be used 
regardless of study withdrawal and regardless of the 
duration of follow-up following recovery. This assumes 
relapse is independent to the treatment effect.  
Withdrawal from study prior 
to recovery 
While-on-study: Time to recovery will be right censored at 
the time of withdrawal from the study or at 28 days, 
whichever occurs first. The evaluation period for this 
endpoint is 28 days, therefore estimating the time to 
recovery after Day 28 would not be appropriate. Premature 
study withdrawal is expected to be independent to the 
treatment effect, therefore a censoring approach in this 
scenario is considered appropriate. However, this 
assumption will be tested by appropriate sensitivity 
analyses. 
Other protocol deviations 
and concomitant 
medications affecting 
efficacy 
Treatment policy: Time to recovery will be used regardless 
of any concomitant medication use or protocol deviations.  
 

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Key Secondary Estimands 
The first key secondary estimand will be the difference in probabilities for SNG001 versus 
placebo for progression to severe disease or death within 35 days of first dose (or 
randomisation date if the patient is not dosed) of patients in the ITT population. Intercurrent 
events will be handled as follows: 
Intercurrent event 
Policy 
Death 
Composite variable: The definition of severe disease 
includes patients who die within 35 days of first dose (or 
randomisation date if the patient is not dosed), regardless 
of their WHO OSCI assessments.  
Premature treatment 
discontinuation and missed 
doses 
Treatment policy: Severe disease will be determined 
regardless of treatment discontinuation and the number of 
missed doses.  
Withdrawal from study 
While-on-study: Patients will only be considered having 
severe disease if observed and recorded whilst 
participating in the study. This assumes the treatment 
effect is independent to reason for study withdrawal.  
Other protocol deviations 
and concomitant 
medications affecting 
efficacy 
Treatment policy: Severe disease will be determined 
regardless of any concomitant medication use or protocol 
deviations. 
The second key secondary estimand will be the difference in probabilities for SNG001 versus 
placebo for progression to intubation or death within 35 days of first dose (or randomisation 
date if the patient is not dosed) of patients in the ITT population.  
The third key secondary estimand will be the difference in probabilities for SNG001 versus 
placebo for death within 35 days of first dose (or randomisation date if the patient is not dosed) 
of patients in the ITT population. For both the second and third key secondary endpoints the 
same policies will be used for handling intercurrent events as progression to severe disease or 
death.   
Interim Analyses  
An unblinded interim analysis will be conducted by an independent team if it is feasible for the 
interim data to be analysed and interpreted within a timeframe which is ethical and of scientific 
value to the study. If feasible, it is planned to assess futility on the first 300 randomised patients 
once all of these patients have completed the Day 35 visit or have withdrawn from the study. 
The primary analyses for the two primary endpoints will be conducted for the interim analysis 
and provided to an Independent Data Monitoring Committee (IDMC). 
 
 
 

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11. The highest NEWS2 score for each calendar day should be collected. This will be assessed in hospital only during 
treatment and follow-up. 
12. Complete EQ-5D-5L questionnaire. 
13. If the EQ-5D-5L assessment is missed on Day 15, it may be completed on Day 16. 
14. Complete EQ-5D-5L questionnaire on Day 7 and Day 28 only. The mobility, self-care and usual activities dimensions 
of the questionnaire will be assessed daily from Day 1 to Day 35. 
15. Day 28 only. 
16. All sites/patients, where collection is feasible. 
17. Day 44 (+/-5 days) only 
18. During administration of study drug, study sites should ensure they adhere to any local requirements and guidelines for 
performing inhalation in patients with COVID-19. 
19. See Sections 7.7.1 and 7.8 for AE and SAE reporting requirements. 
20. For details regarding AE and SAE collection during Days 36 to 90, please see Section 5.3.4. 
21. 
 
22. 
 
 
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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ..........................................................................................................7 
TABLE OF CONTENTS .........................................................................................................18 
ABBREVIATIONS AND DEFINITIONS ..............................................................................22 
1 
INTRODUCTION ...................................................................................................24 
2 
STUDY OBJECTIVES AND ENDPOINTS ..........................................................25 
2.1 
Objectives ................................................................................................................25 
2.2 
Primary Endpoints: ..................................................................................................26 
2.3 
Key Secondary Endpoint: ........................................................................................26 
2.4 
Secondary Endpoints: ..............................................................................................26 
2.5 
Exploratory Endpoint: .............................................................................................26 
3 
STUDY DESIGN ....................................................................................................26 
3.1 
Criteria for Inclusion and Exclusion .......................................................................27 
3.1.1 
Inclusion Criteria .....................................................................................................27 
3.1.2 
Exclusion Criteria ....................................................................................................28 
4 
STUDY MEDICATION .........................................................................................29 
4.1 
Allocation to Study Medication ..............................................................................29 
4.2 
Breaking the Blind...................................................................................................29 
4.3 
Stopping Rules ........................................................................................................30 
4.3.1 
Individual Patient Stopping Rules ...........................................................................30 
4.3.2 
Trial Stopping Rule .................................................................................................30 
4.4 
Description of Investigational Medicinal Product and Device ...............................31 
4.4.1 
SNG001 ...................................................................................................................31 
4.4.2 
Placebo ....................................................................................................................31 
4.4.3 
Inhalation Device ....................................................................................................31 
4.5 
Dosage and Administration .....................................................................................31 
4.5.1 
Dose Delivery Times ...............................................................................................32 
4.5.2 
Packaging and Labelling .........................................................................................32 
4.6 
Preparation, Handling and Dispensing ....................................................................32 
4.6.1 
Preparation Time .....................................................................................................32 
4.6.2 
Timing of Doses ......................................................................................................33 
4.6.3 
Missed or Incomplete Doses ...................................................................................33 
4.7 
Storage of Study Medication ...................................................................................33 
4.8 
Drug Accountability ................................................................................................33 
4.9 
Treatment of Overdose ............................................................................................34 
5 
STUDY PROCEDURES .........................................................................................34 
5.1 
Patient Numbering ...................................................................................................34 
5.2 
Screening Failures ...................................................................................................35 

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5.3 
Study Visits .............................................................................................................35 
5.3.1 
Pre-Treatment ..........................................................................................................35 
5.3.2 
Days 1 to 14 .............................................................................................................36 
5.3.3 
End of Treatment .....................................................................................................37 
5.3.4 
Follow-up ................................................................................................................38 
5.4 
Unscheduled Visits ..................................................................................................39 
5.5 
Patient Withdrawal ..................................................................................................39 
6 
STUDY ASSESSMENTS .......................................................................................40 
6.1 
Informed Consent ....................................................................................................40 
6.2 
Medical History .......................................................................................................40 
6.3 
COVID-19 Infection History...................................................................................41 
6.4 
Patient Demography ................................................................................................41 
6.5 
Physical Examination ..............................................................................................41 
6.6 
Ordinal Scale for Clinical Improvement .................................................................41 
6.7 
BCSS .......................................................................................................................43 
6.8 
Vital Signs ...............................................................................................................43 
6.9 
NEWS2 ....................................................................................................................43 
6.10 
Quality of Life Measured Using EQ-5D-5L ...........................................................44 
6.11 
COVID-19 symptom assessment ............................................................................44 
6.12 
Assessment of Long-COVID-19 symptoms............................................................45 
6.13 
Samples for Laboratory Assessment .......................................................................45 
6.13.1 
Urine Pregnancy Test ..............................................................................................45 
6.13.2 
Blood Sample for Immunogenicity Testing ............................................................46 
6.13.3 
Blood Sample for PK Testing .................................................................................46 
6.14 
Concomitant Medications........................................................................................46 
6.15 
Prohibited Medications............................................................................................46 
6.16 
Co-Enrolment into Additional Interventional Studies.............................................47 
7 
ADVERSE EVENT REPORTING .........................................................................47 
7.1 
Adverse Events ........................................................................................................47 
7.2 
Treatment-Emergent Adverse Events .....................................................................48 
7.3 
Serious Adverse Event ............................................................................................48 
7.4 
Assessment of Adverse Event .................................................................................48 
7.4.1 
Relationship to Study Medication ...........................................................................48 
7.5 
Discontinuation of Study Medication Due to an AE ...............................................50 
7.6 
Pregnancy ................................................................................................................50 
7.7 
Adverse Events Recording and Reporting ..............................................................51 
7.7.1 
Reporting of Adverse Events ..................................................................................51 
7.7.2 
Recording of Adverse Events ..................................................................................51 
7.8 
Reporting of Serious Adverse Events .....................................................................51 

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8 
DATA ANALYSIS/STATISTICAL METHODS ..................................................53 
8.1 
Sample Size Determination .....................................................................................53 
8.2 
Randomisation .........................................................................................................53 
8.3 
Analysis Populations ...............................................................................................54 
8.4 
Estimands and Intercurrent Events ..........................................................................54 
8.4.1 
Primary Efficacy Estimands ....................................................................................54 
8.4.2 
Key Secondary Efficacy Estimands ........................................................................57 
8.5 
Statistical Analysis Methodology for Efficacy Endpoints ......................................59 
8.5.1 
Analysis of the Primary Efficacy Endpoint .............................................................59 
8.5.2 
Analysis of the Key Secondary Efficacy Endpoints ...............................................60 
8.5.3 
Analysis of Secondary Efficacy Endpoints .............................................................60 
8.5.4 
Multiple Testing Strategy ........................................................................................60 
8.5.5 
Handling of Missing Data .......................................................................................61 
8.6 
Safety Analysis ........................................................................................................61 
8.7 
...........................................................................................................61 
8.8 
Other Analyses ........................................................................................................62 
8.9 
Subgroup Analyses ..................................................................................................62 
8.10 
Interim Analyses......................................................................................................62 
8.11 
Primary Analysis .....................................................................................................63 
8.12 
Independent Data Monitoring Committee/Data Safety Monitoring Committee .....63 
9 
QUALITY CONTROL AND QUALITY ASSURANCE ......................................64 
9.1 
Quality Control (Monitoring) ..................................................................................64 
9.2 
Quality Assurance ...................................................................................................64 
10 
DATA HANDLING AND RECORD KEEPING ...................................................64 
10.1 
Source Documents and Electronic Case Report Form ............................................64 
10.2 
Record Retention .....................................................................................................65 
11 
REGULATORY AND ETHICS .............................................................................65 
11.1 
Regulatory and Ethics Considerations ....................................................................65 
11.2 
Competent Authority Approval ...............................................................................65 
11.3 
Institutional Review Board/Independent Ethics Committee and Hospital Board 
Requirements ...........................................................................................................66 
11.4 
Informed Consent and Screening Data ....................................................................66 
11.5 
Patient Confidentiality .............................................................................................66 
11.6 
Investigator Compliance..........................................................................................66 
11.7 
Progress Reports and Safety Reports ......................................................................67 
12 
DEFINITION OF END OF TRIAL ........................................................................67 
13 
SPONSOR DISCONTINUATION CRITERIA ......................................................67 
13.1 
Study Sites ...............................................................................................................67 
13.2 
Entire Study .............................................................................................................67 
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14 
PUBLICATION OF STUDY RESULTS................................................................68 
15 
APPENDICES .........................................................................................................69 
APPENDIX A: 
 
 DEVICE .......................................................................69 
APPENDIX B: WITHDRAWAL FLOW CHART .................................................................73 
APPENDIX C: BCSS QUESTIONNAIRE .............................................................................74 
APPENDIX D: EQ-5D-5L ......................................................................................................75 
APPENDIX E: LONG-COVID-19 PATIENT REPORTED OUTCOME MEASURES .......77 
APPENDIX F: COVID-19 SYMPTOM ASSESSMENT .......................................................83 
16 
REFERENCES ........................................................................................................84 
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ABBREVIATIONS AND DEFINITIONS 
Abbreviation/Terms Definition  
ADA 
Anti-drug antibody 
AE 
Adverse Event 
 
  
BCS
BCSS 
Breathlhlessne
ness, C
, Cough a
ough and S
nd Sput
putum
um S
 Scale 
BiPAP 
Bilevel Positive Airway Pressure 
BMI 
Body Mass Index 
CI 
Confidence Interval 
 
 
COP
OPD 
Chronic Obstructive Pulmonary Disease 
COVID-19 
Disease caused by SARS-CoV-2 
CPAP 
Continuous Positive Airway Pressure 
CRA 
Clinical Research Associate 
CRO 
Clinical Research Organisation 
Delegate 
A qualified member of the study team delegated to perform a task 
by the investigator 
DSMC 
Data Safety Monitoring Committee 
eCRF 
Electronic Case Report Form 
EQ-5D-5L 
EuroQuol 5-dimension 5-level (quality of life questionnaire) 
FACIT 
Functional Assessment of Chronic Illness Therapy  
FDA 
U.S. Food and Drug Administration 
FEV1 
Forced Expiratory Volume in 1 second 
FSH 
Follicle Stimulating Hormone 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
HSA 
Human Serum Albumin 
IB 
Investigator’s Brochure 
ICH  
International Council for Harmonisation 
IDMC 
Independent Data Monitoring Committee  
IEC 
Independent Ethics Committee 
IFN-β 
Interferon-beta 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
ITT 
Intention-to-treat 
LRT 
Lower Respiratory Tract 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHRA 
Medicines and Healthcare products Regulatory Agency 
MIU 
Million International Units 
MMRM 
Mixed Models with Repeated Measures 
NEWS2  
National Early Warning Score 2 
NOAEL 
No-observed-adverse-effect-level 
Placebo 
Comparator Medication Without the Active Ingredient 
R&D 
Research and Development 
Randomisation 
Random Allocation to Treatment Group 
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REC 
Research Ethics Committee 
RTI 
Respiratory Tract Infection 
RT-PCR 
Reverse Transcription Polymerase Chain Reaction 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
Severe Acute Respiratory Syndrome-Coronavirus 2 
SOC 
Standard of Care 
Source data 
Original documents, data and record (including but not limited to: 
hospital records, source documents, lab reports) 
Sponsor 
Company that takes responsibility for the initiation, management 
and financing of the trial: Synairgen Research Limited 
TEAE 
Treatment-Emergent Adverse Event 
 
 
VAS
VAS 
Visual Analogue Scale 
WHO 
World Health Organization 
 
 
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which corresponds to o 
 µg/kg/day lung deposited dose, assuming a lung deposition fraction 
of 25%. The maximum dose that will be administered to patients in this study from the two 
syringes of SNG001 will be 
 µg (
 MIU) per day. The dose of 
 µg (
 MIU) 
represents the emitted dose from the 
 nebulizer and therefore, the proportion of drug 
delivered to the lung will be lower. The estimated administered lung dose with the 
 
nebulizer will be 34.9% of the emitted dose of 
 µg (
g (
 MIU) and this equates to a lung 
dose of 
 µg (  MIU) (9). Safety margins of at least 4.2-fold between the NOAEL in the 
GLP toxicity study in monkeys and the dose of 
 μg/day (
 MIU) administered in this 
study have been calculated, based on comparative lung exposure (mg/g lung) and using the 
U.S. Food and Drug Administration (FDA)-accepted method by Tepper et al. (10).  
Safety of SNG001 has been investigated in 5 clinical studies, across a variety of patient 
populations including patients with asthma, patients with COPD and patients hospitalised due 
to severity of COVID-19. Treatment has been well tolerated, and no specific safety signals 
were observed, whether related to local tolerance or systemic effects. Based on the extensive 
experience from parenteral IFN-β1a administration, and negligible systemic exposure after 
administration of SNG001, clinically significant systemic events are not anticipated. The data 
from pre-clinical studies and the previous clinical trials with SNG001 do not indicate risk for 
local adverse effects in the lungs at the proposed doses.  
The primary endpoints of this study are to evaluate time to hospital discharge and time to 
recovery in hospitalised patients receiving oxygen with confirmed SARS-CoV-2 infection 
after administration of SNG001 compared to placebo, where recovery is defined as the World 
Health Organization (WHO) Ordinal Scale of Clinical Improvement (OSCI) score of 1 or 
below, with no rebound at subsequent assessments. The OSCI to be used in this trial is the 
18 February 2020 version as recommended by the WHO (7).  
Complete information on SNG001 is available in the Investigator’s Brochure (IB).  
2 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Objectives 
Primary objective: 
To evaluate recovery in patients with moderate COVID-19 after administration of SNG001 
compared to placebo. 
Secondary objectives: 
a. To evaluate the efficacy of SNG001 compared to placebo in patients with moderate 
COVID-19, using a range of endpoints. 
b. To assess the general safety and tolerability of SNG001 compared to placebo when 
administered to patients with moderate COVID-19. 
Exploratory objective: 
 
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receive SNG001 two syringes (approximately 305 patients) or placebo two syringes 
(approximately 305 patients). 
Patients who have positive virus test for SARS-CoV-2 prior to hospitalisation will be 
randomised no later than 48 hours after hospital admission. If the virus test is performed more 
than 96 hours prior to hospitalisation, the test will have to be repeated in the hospital prior to 
randomisation. Only patients whose repeated virus test is positive will be randomised, no later 
than 48 hours after confirmation of SARS-CoV-2 infection. 
Patients who have their first positive virus test for SARS-CoV-2 after hospitalisation will be 
randomised, no later than 48 hours after confirmation of SARS-CoV-2 infection. 
SNG001 or placebo will be administered via the 
 nebuliser. Patients will receive a dose 
of SNG001 (two syringes) or placebo (two syringes) once a day for 14 days and will be 
followed for up to 90 days after the first dose of study medication (or randomisation date if the 
patient is not dosed). Study data will be collected from patients as per the study schedule. 
Efficacy will be determined though differences between the groups in the time to recovery and 
time to hospital discharge (primary endpoints), progression to severe disease or death, 
progression to intubation or death, and death within 35 days of the first dose (or randomisation 
date if the patient is not dosed; key secondary endpoints), as well as the secondary endpoints. 
AEs and concomitant medications will be monitored throughout the study period.  
To ensure patient safety, a Data Safety Monitoring Committee (DSMC) will perform a review 
of the safety data before 100 patients complete study treatment, to ensure safety of study 
patients. The DSMC will also meet as and when necessary i.e. if a safety issue arises or when 
the DSMC requests a further meeting.  
3.1 
Criteria for Inclusion and Exclusion 
3.1.1 Inclusion Criteria 
To be eligible for randomisation into this study, each patient must fulfil the following criteria: 
1. Male or female, ≥18 years of age at the time of consent.  
2. Admitted to hospital due to the severity of their COVID-191.  
3. Positive virus test for SARS-CoV-2 using a validated molecular assay or validated 
antigen assay. 
Patients who have a positive virus test for SARS-CoV-2 prior to hospitalisation will be 
randomised no later than 48 hours after hospital admission. If the virus test is performed 
more than 96 hours prior to hospitalisation, the test will have to be repeated in the 
hospital prior to randomisation. Only patients whose repeated virus test is positive will 
be randomised, no later than 48 hours after confirmation of SARS-CoV-2 infection. 
 
1 Patients admitted to the hospital for reasons that are non-COVID-19 related, who subsequently develop 
clinical symptoms of COVID-19, test positive for SARS-CoV-2, and require prolongation of their hospital 
admission, as a consequence of COVID-19, and require treatment with supplemental oxygen (via nasal prongs 
or mask), must be discussed with the Sponsor’s medical monitor prior to randomisation, to assess suitability for 
the trial. 
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Patients who have their first positive virus test for SARS-CoV-2 after hospitalisation 
will be randomised, no later than 48 hours after confirmation of SARS-CoV-2 
infection. 
4. Require oxygen therapy via nasal prongs or mask (WHO OSCI score of 4). 
5. Provided informed consent. 
6. Female patients must be ≥1 year post-menopausal, surgically sterile, or using a highly 
effective method of contraception. Acceptable highly effective methods of 
contraception include; 
• 
bilateral tubal occlusion  
• 
intrauterine device (provided coils are copper-banded)  
• 
levonorgestrel intrauterine system (e.g., 
)  
• 
medroxyprogesterone injections (e.g., 
) )  
• 
etonogestrel implants (e.g., 
, 
)  
• 
normal and low dose combined oral pills 
• 
norelgestromin/ ethinylestradiol transdermal system  
• 
intravaginal device (e.g., ethinylestradiol and etonogestrel), desogestrel (e.g., 
)  
• 
total sexual abstinence (defined as refraining from heterosexual intercourse) 
• 
vasectomised sexual partner.  
Women of childbearing potential should have been stable on their chosen method of 
birth control for a minimum of 3 months before entering the trial and should continue 
with birth control for 1 month after the last dose of inhaled IFN-β1a/matching placebo. 
In addition to the highly effective method of contraception (except for the practice of 
total sexual abstinence), a condom (in UK with spermicides) should be used by the 
male partner for sexual intercourse from randomisation (Visit 2) and for 1 month after 
the last dose of inhaled IFN-β1a/matching placebo to prevent pregnancy. 
7. Women not of childbearing potential are defined as women who are either permanently 
sterilised (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy), or who 
are postmenopausal. Women will be considered post-menopausal if they have been 
amenorrhoeic for 12 months prior to the planned date of randomisation without an 
alternative medical cause. The following age specific requirements apply:  
• 
Women <50 years old will be considered post-menopausal if they have been 
amenorrhoeic for 12 months or more following cessation of exogenous 
hormonal treatment and if follicle stimulating hormone (FSH) levels are in 
the postmenopausal range. 
• 
Women ≥50 years old will be considered post-menopausal if they have been 
amenorrhoeic for 12 months or more following cessation of all exogenous 
hormonal treatment. 
If, in the setting of the pandemic, the use of an acceptable birth control method is not 
possible, the decision to enrol a woman of childbearing potential should be based on 
the benefit-risk for the patient, which should be discussed with the patient at the time 
of the informed consent. 
3.1.2 Exclusion Criteria  
A patient must not be randomised into the study if they meet any of the following criteria: 
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1. Evidence of ongoing SARS-CoV-2 infection for more than 3 weeks, confirmed by a 
validated molecular assay or validated antigen assay. 
2. Non-invasive ventilation (CPAP/BiPAP) or high-flow nasal oxygen therapy (WHO 
OSCI score of 5). 
3. Endotracheal intubation and invasive mechanical ventilation (WHO OSCI score of ≥6) 
or admission to intensive care. 
4. Previous SARS-CoV-2 infection confirmed by a validated molecular assay or validated 
antigen assay. 
5. Any condition, including findings in the patient’s medical history or in the pre-
randomisation study assessments that in the opinion of the Investigator, constitute a 
risk or a contraindication for the participation of the patient into the study or that could 
interfere with the study objectives, conduct or evaluation.  
6. Participation in previous clinical trials of SNG001. 
7. Current or previous participation in another clinical trial where the patient has received 
a dose of an Investigational Medicinal Product (IMP) containing small molecules 
within 30 days or 5 half-lives (whichever is longer) prior to entry into this study or 
containing biologicals within 3 months prior to entry into this study. 
8. Inability to use a nebuliser with a mouthpiece. 
9. Inability to comply with the requirements for storage conditions of study medication in 
the home setting. 
10. History of hypersensitivity to natural or recombinant IFN-β or to any of the excipients 
in the drug preparation. 
11. Females who are breast-feeding, lactating, pregnant or intending to become pregnant. 
4 
STUDY MEDICATION 
4.1 
Allocation to Study Medication 
Patients will be randomised to one of two groups (SNG001 or placebo) in a 1:1 ratio to receive 
SNG001 (two syringes [Arm 1]), or placebo (two syringes [Arm 2]), according to a pre-
specified randomisation schedule in addition to Standard of Care (SOC).  
Should a patient withdraw after randomisation, either prior to or after receiving any study 
medication, the randomisation number will not be re-assigned and the patient will not be 
replaced.  
4.2 
Breaking the Blind 
The study will be patient- and investigator-blinded with regard to SNG001 or placebo but not 
the dose. Blinding codes should only be broken in emergency situations for reasons of patient 
safety. In the event of a need to unblind the patient the investigator (or delegate) will be able 
to access the patient randomisation list 24 hours a day.  
A patient’s assignment should only be unblinded in the case of an emergency where the 
knowledge of the study medication may influence further care of the patient. If a treatment 
code is unblinded for any reason, the Investigator will notify the Sponsor and a record will be 
kept of who unblinded the code, the reason for doing so, and the date and time the unblinding 
occurred. Every attempt will be made to minimise the number of people unblinded. Specific 
unblinding procedures and instructions can found in the Investigator Site File.  

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4.3 
Stopping Rules 
4.3.1 Individual Patient Stopping Rules 
An individual patient will be discontinued permanently from the study medication for any one 
of the following reasons:  
• The patient withdraws consent for study medication only. 
• The patient is experiencing intolerable AEs. 
• A protocol deviation has occurred that is deemed by the Investigator to put the patient 
at increased risk. 
• The patient is not capable of taking the study medication. 
• The Investigator/Sponsor feels that it is in the patient’s best interest to be withdrawn 
from the study medication. 
• Pregnancy.  
• Other AEs reflecting a safety concern.  
• The patient misses more than 4 consecutive doses (i.e. 5th dose missed). 
• Other (reason to be specified by the Investigator in the electronic case report form 
[eCRF]). 
An individual patient will be discontinued permanently from the study i.e. from study treatment 
and data collection, for any one of the following reasons:  
• The patient withdraws consent for taking part in the study. 
• The patient is lost to follow-up. 
 
4.3.2 Trial Stopping Rule 
The trial will be terminated prematurely for any of the following reasons: 
• In the opinion of the Sponsor or DSMC/Independent Data Monitoring Committee 
(IDMC), an unacceptable risk to the safety and welfare of patients is posed by the 
continuation of the study in light of review of the safety data. 
• If clinically significant safety concerns arise within this trial or in any other trial with 
SNG001 which may impact on the wellbeing of patients in this trial. 
• At individual sites, if the study procedures are not being performed according to Good 
Clinical Practice (GCP) and cannot be remedied or this is a serious breach.  
• If recruitment is slow, at the Sponsor’s discretion. 
• Other (reason to be specified by the Sponsor). 
 
If the trial is terminated prematurely, the Sponsor will ensure that adequate consideration is 
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Administration of study medication to patients receiving high-flow nasal oxygen therapy is not 
permitted as it is likely to result in suboptimal doses being delivered. However, patients 
receiving high-flow nasal oxygen therapy may, during administration of study medication, 
receive oxygen via a low-flow nasal cannula or 
 
 chamber, as described above, if 
clinically tolerated.  
Patients will inhale study medication once a day for 14 days. Administration of study 
medication should be carried out in compliance with any applicable local regulations for 
inhalation in COVID-19 patients. 
The study medication should be removed from the fridge for a minimum of 15 minutes prior 
to taking the dose and for no longer than two hours.  
Once patients have been randomised, resupply of study treatment can occur if the initial supply 
of study medication is damaged or unusable. Resupply should be attempted for patients who 
are between Day 1 and Day 12 and when the patient has not taken their Day 12 dose. If the 
patient has taken their Day 12 dose, they will not be resupplied for Days 13 and 14. 
For patients who have been discharged from hospital during the 14-day treatment phase: 
Patients will have been trained before discharge from hospital to fill the device with IMP and 
use it. Study staff will call (via telephone or video call) discharged patients on a daily basis 
and will be able to address any problems and answer any questions patients have about using 
the device.  
If, after multiple training attempts, patients are not capable of taking the study medication at 
home, even with the support of study staff via phone or video link, they should be withdrawn 
from the study medication only. Study data should continue to be collected as per the study 
schedule.  
4.5.1 Dose Delivery Times 
It is anticipated that a dose of study medication will take 2 to 6 minutes to be delivered, 
depending on the patient’s inhalation/exhalation breathing pattern.  
4.5.2 Packaging and Labelling 
 
 
  
4.6 
Preparation, Handling and Dispensing  
4.6.1 Preparation Time 
The study medication will not require reconstitution and will be supplied in pre-labelled 
syringes. Study medication will be put into the 
 n nebuliser immediately prior to dosing.  
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4.6.2 Timing of Doses 
The study medication should be taken once daily at approximately the same time of day. There 
must be a gap of at least 8 hours between doses (see Section 4.9 for the treatment of overdose). 
4.6.3 Missed or Incomplete Doses 
If a dose is missed or the complete dose is not taken, the following procedure must be followed: 
1. Record in the source document and the eCRF that the dose has been missed/not 
completed with the reason why. 
2. Continue with any remaining doses as normal (see Section 5.5 for patient withdrawal 
criteria).  
4.7 
Storage of Study Medication 
Prior to dispensing, the study medication should be stored in a locked and temperature-
controlled environment. The study medication should be stored between +2°C and +8°C. A 
daily temperature log must be kept to ensure that the study medication storage temperature is 
recorded. Any deviations from the storage conditions should be reported immediately to the 
Sponsor/Clinical Research Associate (CRA), and the study medication should be placed in 
quarantine and not used until authorisation has been given by the Sponsor to do so. 
Patients who are discharged from hospital during the 14-day treatment phase should be 
instructed to keep the study medication in a refrigerator. Due to the stability data for the IMP, 
it is not necessary to keep a record of the fridge storage temperature at the patient’s home. 
Training will be given to the patients by study staff regarding storage of study medication, 
disposal of the syringes after they have been used to fill the device, what to do once they have 
completed all doses and any drug accountability that needs to be completed by the patient.  
The study medication can be transported to the patient’s home without the need for 
refrigeration. On arrival at the patient’s home, the study medication should be placed in the 
refrigerator as soon as possible. 
4.8 
Drug Accountability 
The Sponsor will provide the required documentation for study medication accountability, 
including reconciliation of drugs and maintenance of drug records.  
The Investigator must maintain study medication accountability throughout the course of the 
study in accordance with regulatory requirements.  
All patients who take the study medication whilst at home will either be asked to complete a 
drug accountability form after each dose of study medication or will be asked questions 
regarding it by study staff during their daily contact.  

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The amount of study medication received and dispensed to patients should be documented.  
Study medication dispensed to a patient should not be returned if unused. Patients will be given 
instructions for its disposal.    
Drug accountability records will include: 
• Confirmation and inventory of study medication delivery to the study site. 
• An inventory of the study medication that has been provided to each patient. 
• The serial number from the controller component of the 
 ne
 nebuliser device. 
• Confirmation of administration of each dose of study medication.  
• The return to the Sponsor or alternative disposition of unused products. 
Dates of use, expiry dates, quantities, batch numbers, and the patient’s randomisation and 
unique patient identification number should also be included on the accountability form.  
Unused study medication must not be discarded without authority from the Sponsor or used 
for any purpose other than the present study. 
During the study, where possible due to the nature of the study, the Sponsor (or delegate) will 
periodically review the drug accountability forms and check these against the actual study 
medication. Once the study has finished and the drug accountability forms have had a final 
check, the Sponsor (or delegate) will make arrangements for the return of the study medication 
or will authorise their destruction by the study site. 
4.9 
Treatment of Overdose 
An overdose is defined as any dose greater than the once-a-day dose that is being used in this 
study i.e. two doses taken less than 8 hours apart. Any overdose must be recorded as a protocol 
deviation in the source documents.  
In the event of overdose, if the patient is not in hospital, hospitalisation should be considered 
(if applicable) for observation and appropriate supportive treatment should be given. If the 
patient is in hospital, they should be observed and appropriate supportive treatment should be 
given. The Sponsor (or delegate) should be contacted in an expedient manner, whether 
associated with an AE (serious or non-serious) or not, to decide if the patient should continue 
in the study.  
If the patient is experiencing AEs that may relate to an overdose of study medication, the IB 
should be consulted for details of any specific actions to be taken. 
5 
 STUDY PROCEDURES  
5.1 
Patient Numbering 
Every patient that gives informed consent will be logged and allocated a unique patient 
identification number. The unique patient identification number will consist of 9 digits (2 for 
the study number, 2 for the country, 2 for the site number and 3 for patient number), will be 
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assigned sequentially to each patient within each site and will identify the patient throughout 
the study.  
5.2 
Screening Failures 
Screening failures are defined as patients who have given informed consent for the study, but 
who have not met the study Inclusion and/or the Exclusion Criteria. Re-screening of patients 
will be at the discretion of the Medical Monitor. If a patient is re-screened, they will be given 
a new patient identification number and must give informed consent again.  
5.3 
Study Visits  
5.3.1 Pre-Treatment 
The following assessments should be performed on Day 0 prior to the first dose preferably in 
the following order: 
• Informed consent  
• Inclusion/exclusion criteria 
• Medical history 
• COVID-19 infection history (SARS-CoV-2 variant information to also be collected if 
available) 
• Patient demographics  
• Physical examination (chest examination only unless a physical examination is deemed 
necessary by the Investigator)* 
• WHO OSCI* 
• Height and weight 
• Vital signs (to include temperature, respiratory rate, heart rate and blood pressure)* 
• BCSS 
• NEWS2 (the highest NEWS2 score for each calendar day should be collected) 
• EQ-5D-5L (complete questionnaire) 
• Height and weight 
• Urine pregnancy test, if applicable 
• Check the patient will be able to use the nebuliser 
• Randomisation 
• Blood sample for immunogenicity test (all sites/patients, where collection is feasible)  
• Recording of AEs, SAEs and concomitant medications 
*Physical examination, WHO OSCI, and vital signs assessments should be conducted together 
at approximately the same time each day. 

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Eligibility to enter the study may be aided with data captured from SOC procedures and tests 
performed as part of the admission process.  
Patients may take the first dose of study medication either on the same day as the pre-treatment 
assessments or the next day depending on timings. Day 1 is the day the first dose of study 
medication is taken. If Day 1 is the same as the day the pre-treatment assessments are 
performed then the Day 1 assessments do not need to be repeated.  
5.3.2 Days 1 to 14 
The following assessments should be performed daily from Day 1 to 14.  
For patients that remain in hospital the following assessments should be performed preferably 
in the following order: 
• WHO OSCI* 
• Physical examination (chest examination only unless a physical examination is deemed 
necessary by the Investigator)* 
• Vital signs (to include daily temperature, respiratory rate, heart rate and blood pressure)* 
• BCSS 
• EQ-5D-5L (complete questionnaire on Day 7 only. Mobility, self-care and usual activities 
dimensions from Day 1 to Day 14) 
• COVID-19 symptom assessment 
• NEWS2 (the highest NEWS2 score for each calendar day should be collected) 
• Device training (if required) 
• Administration of study medication 
• Recording of AEs, SAEs and concomitant medications. 
*Physical examination, WHO OSCI, and vital signs assessments should be conducted together 
at approximately the same time each day. 
 
 
 
• 
 
• 
 
• 
 
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For patients who have been discharged from hospital the following should be conducted over 
telephone/video call preferably in the following order: 
• WHO OSCI 
• BCSS 
• EQ-5D-5L (complete questionnaire on Day 7 only. Mobility, self-care and usual activities 
dimensions from Day 1 to Day 14) 
• COVID-19 symptom assessment 
• Device training (if required) 
• Administration of study medication 
• Recording of AEs, SAEs and concomitant medications 
 
If the patient has discontinued dosing and consents to data collection, attempts should be 
made to collect the following key data: 
• WHO OSCI 
• BCSS 
• EQ-5D-5L (complete questionnaire on Day 7 only. Mobility, self-care and usual activities 
dimensions from Day 1 to Day 14) 
• COVID-19 symptom assessment 
• Recording of AEs, SAEs and concomitant medications 
 
5.3.3 End of Treatment 
These assessments should be performed on Day 15 (see Sections 4.3.1 and 5.5). 
For patients that remain in hospital the following assessments should be performed, preferably 
in the following order: 
• WHO OSCI* 
• Physical examination (chest examination only unless a physical examination is deemed 
necessary by the Investigator)* 
• Vital signs* 
• BCSS 
• EQ-5D-5L (complete questionnaire) 
• COVID-19 symptom assessment 
• Long-COVID-19 assessment 
• NEWS2 (the highest NEWS2 score for each calendar day should be collected) 

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• Recording of AEs, SAEs and concomitant medications. 
*Physical examination, WHO OSCI, and vital signs assessments should be conducted together 
at approximately the same time each day. 
For patients who have been discharged from hospital the following should be conducted over 
telephone/video call preferably in the following order: 
• WHO OSCI 
• BCSS 
• EQ-5D-5L (complete questionnaire) 
• COVID-19 symptom assessment 
• Long-COVID-19 assessment 
• Recording of AEs, SAEs and concomitant medications. 
5.3.4 Follow-up 
All follow-up assessments can be either done face-to-face if the patient remains in hospital or 
via telephone/video call if the patient has been discharged from hospital as per the study 
schedule. 
Days 16 to 28 
WHO OSCI, BCSS, the mobility, self-care and usual activities dimensions of EQ-5D-5L, 
NEWS2, COVID-19 symptoms, AEs, SAEs, and concomitant medications should continue to 
be collected on a daily basis from the patient. In addition, the EQ-5D-5L (complete 
questionnaire) should be completed and long- COVID-19 assessment should be performed on 
Day 28. For patients who have been discharged, assessments should be performed via 
telephone/video link, if possible. 
NEWS2 will only be assessed if the patient remains in hospital. If the patient has been 
discharged from hospital NEWS2 will not be assessed. For hospitalised patients, if the 
components of NEWS2 have already been assessed on the day of the visit, this data can be 
used on the study to avoid the same procedures being conducted twice. The highest NEWS2 
score for each calendar day should be collected. 

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Days 29 to 35  
WHO OSCI, COVID-19 symptoms, the mobility, self-care and usual activities dimensions of 
EQ-5D-5L, AEs, SAEs, and concomitant medications should continue to be collected (as per 
Sections 7.7.1 and 7.7.2) on a daily basis until (and including) Day 35.  
Days 36 to 90 
Blood sample for immunogenicity testing should be obtained from the patient (all 
sites/patients, where collection is feasible) on Day 44 (+/- 5 days).  
Updates to ongoing AEs and SAEs will be collected at Days 44, 60, and 90, and at any 
unscheduled study visits during this period as per Section 7.7.1 and 7.7.2.  
New AEs and SAEs will be collected up to 28 days after the last dose of study medication and 
documented at the next scheduled or unscheduled study visits as per Section 7.7.1 and 7.7.2. 
All concomitant medications will continue to be recorded until study completion. 
In addition, BCSS, EQ-5D-5L (complete questionnaire), COVID-19 symptoms and long-
COVID-19 assessments should be performed on Day 60 (-2 to +5 days) and Day 90 (-2 to 
+5 days).  
5.4 
Unscheduled Visits 
The Investigator can request any of the study procedures described in the study schedule to be 
repeated as extra follow-up visits or to be added to a study visit where necessary. Unscheduled 
visits may be necessary if the patient is experiencing prolonged symptoms which the 
Investigator feels could be related to their study medication or if the Investigator is concerned 
about the patient’s health. Unscheduled visits/study procedures should be captured in the 
source documents.  
5.5 
Patient Withdrawal 
Patients may withdraw from the study at any time at their own request. If a patient does not 
return for a scheduled visit, every effort should be made to contact the patient. In any 
circumstance, every effort should be made to document patient outcome, if possible. The 
Investigator should enquire about the reason for withdrawal, request that the patient disposes 
of all unused study medication (as instructed) and request the patient undergoes a final visit, if 
applicable, and follow-up with the patient regarding any unresolved AEs. 
Please refer to Section 4.3.1 for individual patient stopping rules. 
If patient is withdrawn from the study or from the study medication, the reason for withdrawal 
will be documented in the source documents. If the patient is withdrawn from taking the study 
medication only but continues to give consent for data to be collected, the study schedule 
should be followed until Day 90.  

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Lost to follow-up: 
Patients will be considered as lost to follow-up if no contact is made with the patient for at 
least 5 consecutive visits up to and including the Day 35 visit. A patient would also be 
considered lost to follow-up if no contact is made with the patient after the Day 35 visit and 
contact cannot be re-established up to and including the Day 90 visit. However, since 
maximum data collection for all patients is important to support the analyses of study 
endpoints, continued attempts to contact patients lost to follow-up should be made to allow 
completion of the follow-up assessments, wherever possible, up to the scheduled Day 90 visit. 
The status of ‘lost to follow-up' should be amended in the CRF if patient contact is re-
established and additional study follow-up data can be obtained. 
For further guidance, see Appendix B. 
6 
STUDY ASSESSMENTS 
6.1 
Informed Consent 
Informed consent will be obtained from the patient after the study has been fully explained and 
the patient has been given ample time to consider the study and discuss it in detail. The method 
of obtaining consent may vary due to the nature of this study. The method of obtaining and 
documenting the informed consent and the contents of the consent will comply with 
International Conference on Harmonisation Guideline for Good Clinical Practice (ICH GCP), 
and all applicable laws and regulations. Different methods, including written, verbal or 
electronic consent may be used. Each method will be discussed and approved by the Sponsor 
(or delegate) before the site takes the first consent. Whichever method is used informed consent 
will always be obtained from the patient prior to any study related procedures being performed. 
Informed consent must be obtained by a qualified medical doctor or nurse who have received 
study training.  
If there is a new version of the patient information sheet and informed consent form, patients 
will be reconsented at their next study visit or, if they were already discharged from the 
hospital, they may be reconsented verbally over the phone/video link, or electronically. 
Patients will be informed as soon as possible of the changes and the Sponsor will determine 
whether the patients need to visit the site prior to their next study visit. 
6.2 
Medical History 
The patient’s medical history will be recorded in the source documents by the Investigator or 
their delegate to ensure the patient’s eligibility.  
The medical history should include, but is not limited to; 
• Significant current and past medical history in the last 5 years, including 
hospitalisations, operations and medical history that affects inclusion and exclusion 
criteria (including sterilisation and contraception).  
• Social history regarding smoking habits, alcohol consumption, drug allergies and 
medication use. 
• For women, a menstrual history and history of contraception (if applicable). 
• Vaccinations within 6 months prior to randomisation. 

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6.3 
COVID-19 Infection History 
The patient’s COVID-19 infection history will be recorded in the source documents by a 
medical doctor or qualified nurse from the study team. Information regarding symptoms in the 
preceding 24 hours will be recorded. 
A checklist/worksheet will be provided to study site staff to outline and help document the 
minimum symptoms to be assessed.  
In addition, SARS-CoV-2 variant information will be collected (if available). 
6.4 
Patient Demography 
Patient demographics will be recorded in the source documents. These will include age, sex, 
race/ethnicity and residence in care home, unless local laws or regulations do not permit this. 
6.5 
Physical Examination 
A physical examination will be performed by a medical doctor on Day 0 or Day 1 prior to the 
first dose as per the study schedule.  
Physical examinations may be repeated at various time points throughout the study, as 
clinically indicated. 
If sites have difficulty in completing the chest examination due to risk of contamination/local 
policies, this will not be considered a protocol deviation, but will need to be explained in a file 
note. Height and weight will be recorded pre-treatment. 
A checklist/worksheet will be available to study site staff to provide guidance on the physical 
examination. Results of the examinations will be recorded in the source documents. 
6.6 
Ordinal Scale for Clinical Improvement  
The OSCI to be used in this trial is the 18 February 2020 version as recommended by the WHO 
(7). 
Ordinal Scale for Clinical Improvement 
Patient State 
Descriptor 
Score 
Uninfected 
No clinical or virological evidence of infection 
0 
Ambulatory 
No limitation of activities 
1 
Limitation of activities 
2 
Hospitalised 
Hospitalised, no oxygen therapy 
3 
Oxygen by mask or nasal prongs 
4 
Hospitalised 
Non-invasive ventilation or high-flow oxygen 
5 
Intubation and mechanical ventilation 
6 
Ventilation + additional organ support – pressors, RRT, ECMO 
7 
Dead 
Death 
8 

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RRT – renal replacement therapy; ECMO - extracorporeal membrane oxygenation 
 
The assessment should be carried out once a day at approximately the same time each day from 
Pre-treatment until Day 35. It is recommended that this assessment should be carried out by a 
clinically qualified member of the study team, i.e. a medical doctor or a qualified nurse. The 
assessment may be carried out face to face (before discharge) or over the phone/video link 
(post-discharge).  
Patients’ status on the day of hospital discharge should be assessed as ambulatory/uninfected 
(WHO OSCI score of 0, 1 or 2). 
On the day of hospital discharge and on the days following hospital discharge, patients 
should be asked the following questions about their clinical status and return to the pre-
COVID-19 level of activity:  
 
• “In the past 24 hours, did you experience any signs or symptoms of your coronavirus 
infection?” “Yes” or “No” answer will be required. 
 
• “In the past 24 hours, did you feel that your usual activities (e.g. work, study, housework, 
family or leisure activities) have returned to the level from before your coronavirus 
infection and did not require additional assistance/support*?” “Yes” or “No” answer will 
be required. 
 
* assistance/support is defined as additional help of other people and/or requirement for 
supplemental oxygen (or a higher level of supplemental oxygen), compared to the pre-
COVID-19 state. 
In order to minimise any potential influence on the patients, the interviewers will be required 
to read the questions to patients verbatim and not to change or interpret them in any way.   
The following scoring algorithm will be applied: 
 
Presence of signs/symptoms of 
coronavirus infection (or 
virological evidence of infection)? 
Usual activities returned to 
baseline level? 
WHO OSCI 
score 
No 
Yes 
0 
Yes 
Yes 
1 
No 
No 
2 
Yes 
No 
2 
 
The result of the OSCI assessment, from the day of hospital discharge, must be based upon 
the patient’s responses to the 2 questions specified above and must not be adjusted based on 
the results from other outcome assessments (e.g. BCSS, brief pain inventory, long 
COVID-19 symptom assessment, and EQ-5D-5L), even if these data provide conflicting 
clinical information. 

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Repeated assessments of virological clearance in patients discharged from the hospital are not 
feasible within the study. Patients discharged from the hospital will be considered to have no 
virological evidence of infection unless a positive test is obtained. 
The applicable WHO OSCI score and the date of assessment should be recorded in the 
source documents. 
6.7 
BCSS 
The BCSS is a daily patient-reported outcome measure that was designed as a daily diary in 
which patients are asked to report the severity of three symptoms: breathlessness, cough and 
sputum (11).  
Each symptom is represented by a single item which is evaluated on a 5-point scale ranging 
from 0-4, with higher scores indicating more severe symptoms. A mean decline of 1 point on 
the BCSS total scale signifies a substantial reduction in symptom severity. This questionnaire 
should only be completed if an approved translation in the language required by the patient is 
available. If an approved translation is not available, this assessment will not be conducted and 
will not be recorded as a protocol deviation. 
This assessment should be carried once a day from Day 1 until Day 28 and then on Day 60 and 
Day 90 (see Appendix C).   
• This assessment should be carried out at approximately the same time each day. 
• This assessment should be completed via patient interview. Trained staff should read each 
question verbatim and ask the patient to answer using the words and the number (e.g. “none 
– unaware of coughing” and “0”).  
• For patients discharged home during treatment, the site/study staff will ask the patient the 
questions by telephone/video link and the patient should have a copy of the BCSS 
questionnaire for reference whether they are hospitalised or discharged.  
• This is a patient reported outcome, so for patients that are unable to complete the BCSS 
due to their medical condition i.e. if they are receiving ventilation, the reason for non-
completion should be recorded in the source documents.  
• The applicable score (number) for each question should be recorded in the source 
documents as well as the date, time and method of assessment.  
6.8 
Vital Signs  
Vital signs include temperature, respiratory rate, heart rate and blood pressure should be 
recorded daily whilst the patient is hospitalised. Vital signs should be assessed at the same time 
as the daily physical examination. When the patient is discharged home vital sign assessments 
will not be recorded.  
Blood pressure and pulse should be measured in the supine position and it is recommended 
that the patient should have rested quietly for at least 3 minutes prior to the measurement.  
6.9 
NEWS2 
The data required for NEWS2 will be collected by the site staff and NEWS2 will be calculated 
by the Sponsor.  

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NEWS2 is a tool developed by the Royal College of Physicians, which improves the detection 
and response to clinical deterioration in adult patients and is a key element of patient safety 
and improving patient outcomes (12). 
NEWS2 is based on a simple aggregate scoring system in which a score is allocated to 
physiological measurements, already recorded in routine practice, when patients present to, or 
are being monitored in hospital.  
Six simple physiological parameters form the basis of the scoring system:  
1. Respiration rate  
2. Oxygen saturation  
3. Any supplementary oxygen 
4. Temperature 
5. Systolic blood pressure  
6. Heart rate 
7. Alert, Voice, Pain, Unresponsive. 
The highest NEWS2 score for each calendar day should be collected. The highest NEWS2 
score will be recorded daily, for each calendar day, whilst the patient is hospitalised. When the 
patient is discharged home, NEWS2 will not be recorded.  
6.10 Quality of Life Measured Using EQ-5D-5L 
The EQ-5D-5L health-related quality of life questionnaire will be completed on Day 0, Day 7, 
Day 15, Day 28, Day 60 and Day 90 for all patients (see Appendix D). 
In addition, the mobility, self-care and usual activities dimensions of the questionnaire will be 
assessed daily from Day 1 to Day 35. 
The EQ-5D-5L provides a simple descriptive profile and a single index value for health status. 
The EQ-5D-5L self-rated questionnaire includes a visual analogue scale (VAS), which records 
the respondent's self-rated health status on a graduated (0–100) scale, with higher scores for 
higher health-related quality of life. It also includes the EQ-5D-5L descriptive system, which 
comprises 5 dimensions of health: mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression. The responses record five levels of severity (no problems/slight 
problems/moderate problems/severe problems/extreme problems) within a particular EQ-5D 
dimension. This questionnaire should only be completed if an approved translation in the 
language required by the patient is available. If an approved translation is not available, this 
assessment will not be conducted and will not be recorded as a protocol deviation. 
6.11 COVID-19 symptom assessment 
The presence of COVID-19 symptoms will be assessed as per the study schedule.   

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A checklist/worksheet will be provided to study site staff to document the COVID-19 
symptoms. The questionnaire is provided in Appendix F.  
6.12 Assessment of Long-COVID-19 symptoms 
Assessment of long-COVID-19 symptoms will be performed on Day 15, Day 28, Day 60 and 
Day 90. The following patient reported outcome measures will be used: 
• General Anxiety Disorder 7 Questionnaire (GAD-7) 
• Patient Health Questionnaire-9 (PHQ-9) 
• Functional Assessment of Chronic Illness Therapy (FACIT) - Fatigue Scale 
(Version 4) 
• Brief Pain Inventory (Short Form) 
The questionnaires are included in Appendix E and should only be completed if approved 
translations in the language(s) required by the patient(s) are available. If approved 
translations are not available, these assessments will not be conducted and will not be 
recorded as protocol deviations. 
6.13 Samples for Laboratory Assessment  
6.13.1 Urine Pregnancy Test 
Early detection pregnancy strips (minimum detection 10 MIU human chorionic 
gonadotrophin) will be used on Day 0.  
Urine pregnancy testing is not required for women who are not of child-bearing potential. 
Women not of childbearing potential are defined as women who are either permanently 
sterilised (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy), or who are 
postmenopausal. 
Women will be considered postmenopausal if they have been amenorrhoeic for 12 months 
prior to the planned date of randomisation without an alternative medical cause. The following 
age specific requirements apply: 
• Women <50 years old would be considered postmenopausal if they have been 
amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatment 
and if FSH levels are in the postmenopausal range. If the FSH result is not available at the 
time of randomisation, the patient must have a negative pregnancy test and agree to use 
approved contraceptive method. The patient must have been using this contraceptive 
method for a period of 3 month prior to randomisation.  
• Women ≥50 years old would be considered postmenopausal if they have been 
amenorrhoeic for 12 months or more following cessation of all exogenous hormonal 
treatment. 

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6.13.2 Blood Sample for Immunogenicity Testing 
A blood sample will be taken as per the study schedule for immunogenicity testing. This will 
be completed in all sites and for all patients, where collection of samples is feasible. If a site 
is not able to participate in immunogenicity sample collection, this will not preclude them 
from participation in the study. The sample will require processing to obtain serum which is 
required for the analysis and analysis testing will be completed using validated methods. A 
laboratory manual describing the requirements for the blood sample and the processing of the 
sample will be provided separately by the Sponsor (or delegate). 
Immunogenicity will be determined by the presence of anti-drug antibodies (ADAs). A tiered 
analysis approach will be followed, whereby samples positive at the screening step will be 
confirmed for ADA presence. The confirmed positive samples will then be assessed for ADA 
titre and the presence of neutralising antibodies. 
6.13.3 
 
 
 
 
 
6.14 Concomitant Medications 
Medications taken by the patient at the time of informed consent should be recorded in the 
source data. After this, patients will be asked at each visit if they have taken any new 
concomitant medications or changed any current medications. Alternatively, information can 
be obtained from the patient's hospital prescription record. The dosage information, dates of 
administration and reasons for use will be recorded.  
Any other medications which are considered necessary for the patient's welfare should be given 
at the discretion of the Investigator. 
Special care will be taken in questioning the patients on any possible self-medication. 
SOC medications for the treatment of COVID-19 (e.g. remdesivir or dexamethasone) can be 
administered, as required. SOC should be recorded as concomitant medications. 
Oxygen therapy will be recorded as concomitant medication. 
6.15 Prohibited Medications 
Interferons have been reported to reduce the activity of hepatic cytochrome P450 dependent 
enzymes in humans and animals. Caution should be exercised with patients who are taking 
medicinal products that have a narrow therapeutic index and are largely dependent on the 
hepatic cytochrome P450 system for clearance (e.g. some classes of antidepressants). 
Investigators are able to enrol these patients to the study but should be aware of the possible 
contraindication.  
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Patients who have received a prior SARS-CoV-2 vaccination may be enrolled into the study. 
However, patients enrolled into the study should be advised to refrain from receiving 
vaccinations, including SARS-CoV-2 vaccinations, during the treatment and follow-up phase 
up to Day 35, as these could interfere with study assessments.  
6.16 Co-Enrolment into Additional Interventional Studies 
Co-enrolment into other interventional studies during the treatment and follow-up phases up 
to Day 35 should be avoided, as it could interfere with study assessments. Co-enrolment into 
any study must be discussed with the Medical Monitor to clarify whether co-enrolment is 
permitted. 
7 
ADVERSE EVENT REPORTING 
7.1 
Adverse Events  
An AE is defined as any untoward medical occurrence in a clinical trial patient during the 
study; the event does not necessarily have a causal relationship with that treatment. An AE can 
therefore be any unfavourable and unintended sign (including any clinically significant 
abnormal laboratory finding), symptom or disease, temporally associated with the use of a 
medicinal product. 
AEs may include the following: 
• Apparently unrelated illnesses, including the worsening of a pre-existing illness. 
• Injury or accidents. 
Patients will be asked about AEs at every study visit. General, non-directed questioning will be 
used to elicit reports of AEs. If a patient is seen by a physician not involved with the study in 
relation to an AE, the Investigator should make every effort to contact the treating physician 
in a timely manner in order to obtain all information necessary to facilitate appropriate 
reporting of the event. 
• The terms ‘COVID-19’or ‘SARS-CoV-2’ should not be recorded as an AE.  
• Individual symptoms related to COVID-19/SARS-CoV-2 infection (e.g. fever, 
breathlessness, fatigue) present at study entry should not be reported as AEs.  
• Worsening of symptoms related to COVID-19/SARS-CoV-2 infection should be 
reported as AEs if, in the investigators’ opinion, the symptoms are clinically significant 
or lead to treatment.  
• New symptoms related to COVID-19/SARS-CoV-2 infection that start after the 
initiation of study treatment should be reported as AEs. 

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7.2 
Treatment-Emergent Adverse Events 
A treatment-emergent adverse event (TEAE) is an AE that is new in onset, or is a pre-existing 
condition that is aggravated in severity or frequency, and occurs after the administration of the 
first dose of study medication. TEAEs include any clinically significant change from baseline 
readings in any of the study assessments.  
Any abnormal result from study assessments will be recorded as an AE, if they result in study 
withdrawal, are associated with accompanying symptoms, lead to treatment, lead to further 
diagnostic tests, or is considered by the Investigator to be of clinical significance. These should 
be recorded in the source documents.  
7.3 
Serious Adverse Event 
An SAE, according to ICH GCP, is any AE that meets any of the following outcomes:  
• Results in death. 
• Is life-threatening (i.e. at immediate risk of death). 
• Requires in-patient hospitalisation or prolongation of existing hospitalisation. 
• Results in persistent or significant disability or incapacity.  
• Consists of a congenital anomaly or birth defect. 
AEs that may not result in death, may not be life-threatening, or do not require hospitalisation 
may be considered SAEs when, based upon appropriate medical judgment, they may 
jeopardise the patient or may require medical or surgical intervention to prevent one of the 
outcomes listed above. These events must be reported in the same manner as SAEs. 
Deterioration of a patient’s condition requiring admission to the intensive care unit or invasive 
mechanical ventilation, (whichever happens first) must be reported as an SAE. 
Elective and pre-planned surgeries will not be reported as SAEs. Such procedures should be 
recorded as part of the medical history.  
7.4 
Assessment of Adverse Event  
The Investigator will assess every AE to determine if it is serious or not (see Section 7.3 for 
definition criteria). This assessment will determine the reporting procedures to be followed. 
7.4.1 Relationship to Study Medication 
Investigators (or delegates) need to assess the causality and severity (intensity) between the 
study medication and/or concomitant medication and the AE; this information will be recorded 
in the source documents.  

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7.4.1.1 Causality 
Causality is the relationship between the study medication and the occurrence of the AE. 
Determination of causality is based on the Investigator’s clinical judgment regarding the 
likelihood that the study medication caused the AE and may include consideration of some or 
all of the following factors:  
• Alternative possible causes of the AE, including the patient’s underlying disease or co-morbid 
conditions, other drugs, other host and environmental factors.  
• The temporal sequence between the study medication exposure and the AE.  
• Whether the clinical or laboratory manifestations of the AE are consistent with known actions 
or toxicity of the study medication.  
 
Investigators need to assess the relationship of AEs to the study medication by consulting the 
IB and using the following definitions:  
 
Definitely related: 
A causal relationship of the onset of the event relative to 
administration of the study medication and there is no other cause 
to explain the event. 
Probably related: 
A causal relationship is clinically/biologically reasonable relative 
to the administration of the study medication and the event is more 
likely explained by exposure to the study medication than by other 
factors or causes. 
Possibly related:  
A causal relationship is clinically/biologically reasonable relative 
to the administration of the study medication, but the event could 
have been due to another equally likely cause. 
Unlikely to be 
related: 
A causal relationship is considered unlikely to be related to use of 
the study medication if there are factors (evidence) explaining the 
occurrence of the event (e.g., progression of the underlying disease, 
concomitant medication more likely associated with the event) or a 
convincing alternative explanation for the event. 
Unrelated: 
A causal relationship is not reasonably related in time to the 
administration of the study medication, or exposure to the study 
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7.4.1.2 Severity 
Severity (intensity) should be assessed according to the following definitions: 
Mild: 
The patient is aware of the event or symptom, but the event or 
symptom is easily tolerated, causing minimal discomfort to the 
patient. The event or symptom should not interfere with everyday 
activities. 
Moderate: 
The patient experiences sufficient discomfort to interfere with or 
reduce normal everyday activities, but responds to symptomatic 
therapy or rest.  
Severe: 
Significant impairment of functioning: the patient is unable to carry 
out normal everyday activities despite symptomatic therapy and/or 
the patient’s life is at risk from the AE. 
 
Note the distinction between the gravity and the severity (intensity) of an AE. Severe is a 
measure of intensity: thus, a severe reaction is not necessarily a serious reaction. For example, 
a headache may be severe in intensity, but would not be classified as serious unless it met one 
of the criteria for SAEs listed above.  
7.5 
Discontinuation of Study Medication Due to an AE 
Study medication may be discontinued (temporarily or permanently) in response to an AE at 
any time at the discretion of the patient and/or the Investigator. This will be reported on the 
AE page in the eCRF.  
The Sponsor (or delegate) will be informed as soon as possible of any patient for whom 
permanent discontinuation of study medication occurs.  
7.6 
Pregnancy 
Pregnancy itself is not an AE unless there is a suspicion that the study medication may have 
interfered with the effectiveness of a contraceptive medication. However, if a female patient 
becomes pregnant during the conduct of the study, study medication will be discontinued 
immediately, and the Sponsor (or delegate) should be notified within 24 hours using the 
Pregnancy Report Form. Follow-up information regarding the outcome of the pregnancy and 
any foetal or neonatal sequelae should be obtained and documented. For all pregnant patients, 
on behalf of the Sponsor, study staff will discuss referral for specialist counselling on the 
possible risks to the unborn baby, and arrangements will be offered to monitor the health of 
both the patient and the unborn baby. 

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7.7 
Adverse Events Recording and Reporting 
7.7.1 Reporting of Adverse Events 
All AEs and TEAEs will be reported from the day informed consent is obtained until 28 days 
after the last administration of the study medication. This includes AEs reported as a result of 
study procedures.  
All AEs and TEAEs occurring during the study assessed by the Investigator (or delegate) as 
definitely, probably or possibly related to the study medication are to be followed up until 
resolved or judged to be no longer clinically significant, or until they become chronic or stable 
to the extent that they can be fully characterised (all follow-up results are to be reported to the 
sponsor or delegated Clinical Research Organisation [CRO] if requested). 
7.7.2 Recording of Adverse Events 
Timely, accurate, and complete reporting and analysis of safety information from clinical trials 
is crucial for the protection of patients, Investigators, and the Sponsor, and is mandated by 
regulatory agencies. The Sponsor (and delegated CRO) has established standard operating 
procedures (SOPs) in conformity with regulatory requirements to ensure appropriate reporting 
of safety information. The process for reporting AEs and SAEs at each site will be assessed by 
the Sponsor to ensure full compliance with the regulatory requirements.  
The Investigator is to report all directly observed AEs and all AEs spontaneously reported by 
the trial patient using concise medical terminology.  
All AEs and TEAEs, regardless of seriousness, severity, or causal relationship to study 
medication will be recorded in the source documents. The following items are to be included:  
Description of event: whenever possible, signs and symptoms due to a common aetiology will be 
reported as an integrated diagnosis: e.g. cough, runny nose, sneezing, sore throat, and head 
congestion would be reported as “upper respiratory infection”. The diagnosis or description 
will be as specific and complete as possible (i.e. “lower extremity oedema”, rather than just 
“oedema”).  
If a medical condition is known to have caused the injury or accident (e.g. a fall secondary to 
dizziness), the medical condition (dizziness) and the accident (fall) should be reported as two 
separate AEs.  
In cases of surgical or diagnostic procedures, the condition/illness leading to the procedure is 
considered as the AE rather than the procedure itself. 
In case of a fatality, the cause of death is considered as the SAE, and death is considered as its 
outcome. 
7.8 
Reporting of Serious Adverse Events 
All AEs assessed as serious by the Investigator (or delegate) according to the criteria specified 
should be reported and recorded on a SAE form.  

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SAEs should be reported by the Investigator (or delegated person) to the Sponsor (or delegate), 
using the SAE report form provided, immediately (and not later than 24 hours) of a member 
of the site staff becoming aware of the event, whether or not the event is considered to be 
related to study medication. This initial report can be made by telephone or in writing. If the 
initial SAE report is made by telephone, a written report signed by the Investigator (or delegate) 
must be submitted immediately (and not later than 24 hours from the start of the event).   
All SAEs will be reported from the day informed consent is obtained until 28 days after the 
last administration of the study medication. SAEs are to be followed until resolution regardless 
of whether the patient is still participating in the study.  
Resolution means:  
• The patient has returned to their baseline condition or the Investigator does not expect any 
further improvement or worsening of the event, or  
• The SAE is deemed medically insignificant by the Investigator, or  
• The SAE is resolved with residual effects.  
Details of the contact numbers for SAE reporting can be found in the Investigator’s Site 
File. 
In addition to informing the Sponsor, the Investigator at the study site should notify the host 
organisation (e.g. Research and Development [R&D]) or any other department as required by 
local regulations if applicable.  
The Sponsor will be responsible for informing the following within the stipulated reporting 
timelines: 
• The Chief Investigator and site investigators 
• Institutional Review Board/Independent Ethics Committee (IRB/IEC), and 
• The appropriate local regulatory authority  
The sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRB/IEC, and investigators. 
Copies of all correspondence relating to the reporting of SAEs should be maintained in the 
Investigator Site File and provided to the Sponsor (or delegate). The Investigator will be 
informed by the Sponsor (or delegate) of any SAEs from other Investigators or clinical studies 
which have safety implications. 

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8 
DATA ANALYSIS/STATISTICAL METHODS 
Data will be entered into a database. The Sponsor (or delegate) will be responsible for data 
processing and analysis, in accordance with the appropriate data management and analysis 
procedures.  
Analysis methods for key endpoints are described below. Further details on all analyses will 
be described in the Statistical Analysis Plan (SAP). 
8.1 
Sample Size Determination 
Success will be determined if at least one of the primary endpoints is declared statistically 
significant by the primary analysis. A sample size of 610 patients in total using a 1:1 
randomisation ratio (305 patients per treatment arm) has been chosen to provide at least 90% 
power to detect a hazard ratio of 1.45 in time to hospital discharge and a hazard ratio of 1.7 in 
time to recovery and at least 95% power to declare statistical significance on at least one of the 
primary endpoints. This sample size has been calculated using a global 2-sided alpha level of 
0.05 and adjusting for the Hochberg procedure to allow for multiple comparisons. This also 
allows for an interim analysis to assess futility after the first 300 randomised patients have 
completed the Day 35 visit or have withdrawn from the study.  
The sample size calculation assumes a hospital discharge rate in the placebo treatment arm of 
70% at Day 28, a recovery rate in the placebo treatment arm of 30% at Day 28 and a dropout 
rate of 25% over the 28-day evaluation period with time to dropout exponentially distributed.  
By their definition the two primary endpoints are naturally correlated. This correlation has 
been estimated from prior study data and has also been considered in the sample size 
calculation.  
More details regarding the sample size calculation used for the study will be provided in the 
SAP.  
The key secondary endpoint of progression to severe disease or death within the 35-day study 
period will be formally tested, provided statistical significance is declared in both of the 
primary endpoints.  
8.2 
Randomisation  
This is a double-blind study. Patients will be randomised to one of two treatment groups 
(SNG001 or placebo). The randomisation will be stratified by site. A pre-specified 
randomisation schedule will be generated using a 1:1 randomisation ratio.  
Arm 1: Approximately 305 patients - SNG001 - contents of 2 syringe* per dose  
Arm 2: Approximately 305 patients - Placebo - contents of 2 syringes+ per dose 
 
*Each syringe contains 
 mL of SNG001 nebuliser solution containing 
 MIU/mL 
interferon-β1a 
+Each syringe contains 
 mL of formulation buffer 
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8.3 
Analysis Populations  
The intention-to-treat (ITT) population is defined as all randomised patients.  
The safety population will include all randomised patients who receive at least one dose of 
study drug. Patients will be analysed as treated and not per randomised treatment.  
The per protocol population will include all patients in the ITT population who do not have 
any protocol deviations with an impact on efficacy on or prior to Day 35.  
 
 
8.4 
Estimands and Intercurrent Events 
8.4.1 Primary Efficacy Estimands 
The first primary estimand will be the hazard ratio of SNG001 versus placebo for the time to 
hospital discharge of patients in the ITT population. Intercurrent events will be handled as 
follows:  
Intercurrent event 
Policy 
Death 
Composite variable: Patients who die on or prior to Day 28 
will have time to hospital discharge right censored at 28 
days (the maximum time to discharge).   
Premature treatment 
discontinuation and missed 
doses 
Treatment policy: The time to hospital discharge will be 
used regardless of treatment discontinuation and the 
number of missed doses.  
Withdrawal from study 
following hospital discharge 
Treatment policy: The time to hospital discharge will be 
used regardless of study withdrawal and regardless of the 
duration of follow-up following hospital discharge. This 
assumes relapse is independent to the treatment effect. 
Withdrawal from study prior 
to hospital discharge 
While-on-study: Time to hospital discharge will be right 
censored at the time of withdrawal from the study or at 28 
days, whichever occurs first. The evaluation period for this 
endpoint is 28 days, therefore estimating the time to 
hospital discharge after Day 28 would not be appropriate. 
Premature study withdrawal is expected to be independent 
to the treatment effect, therefore a censoring approach in 
this scenario is considered appropriate. However, this 
assumption will be tested by appropriate sensitivity 
analyses.    
Other protocol deviations 
and concomitant 
medications affecting 
efficacy 
Treatment policy: Time to hospital discharge will be used 
regardless of any concomitant medication use or protocol 
deviations.  
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A tipping point analysis will be performed to implement a treatment policy strategy for 
patients who withdraw from the study prior to hospital discharge and prior to Day 28 by 
imputing missing discharge times. The imputation will be repeated by adjusting the 
likelihood of hospital discharge in each treatment arm independently, to varying degrees. The 
first primary analysis will be performed on each of the imputed datasets to test the sensitivity 
to missing data.  
A further sensitivity analysis of the first primary estimand will test the missing at random 
assumption by imputing missing data after study withdrawal through a missing not at random 
approach.  
A supportive analysis will estimate the hazard ratio of SNG001 versus placebo for the time to 
hospital discharge of patients in the per protocol population. Intercurrent events will be 
handled as follows:  
Intercurrent event 
Policy 
Death 
Composite variable: Patients who die during the study 
period will have time to hospital discharge right censored 
at 28 days (the maximum time to discharge).   
Missed 2 of the first 3 
scheduled doses 
Hypothetical (estimand for a situation with treatment 
compliance): The time to hospital discharge will be 
considered missing if two or more doses of the randomised 
treatment were missed within the first three days of 
therapy. A single dose within the first three scheduled 
dosing days is not expected to be sufficient for the study 
drug to be effective, therefore this approach will help 
establish the true treatment effect.     
Other premature treatment 
discontinuation 
Treatment policy: The time to hospital discharge will be 
used regardless of treatment discontinuation.  
Withdrawal from study 
following hospital discharge 
Treatment policy: The time to hospital discharge will be 
used regardless of study withdrawal and regardless of the 
duration of follow-up following hospital discharge. This 
assumes relapse is independent to the treatment effect.  
Withdrawal from study prior 
to hospital discharge 
While-on-study: Time to hospital discharge will be right 
censored at the time of withdrawal from the study or at 28 
days, whichever occurs first. The evaluation period for this 
endpoint is 28 days, therefore estimating the time to 
hospital discharge after Day 28 would not be appropriate. 
Premature study withdrawal is expected to be independent 
to the treatment effect, therefore a censoring approach in 
this scenario is considered appropriate. 
Other protocol deviations 
and concomitant 
Hypothetical (estimand for a situation with no protocol 
deviations or concomitant medications affecting efficacy): 
To establish the true treatment effect the time to hospital 
discharge will be considered missing if protocol deviations 

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Intercurrent event 
Policy 
medications affecting 
efficacy 
or medications affecting efficacy are recorded on or prior 
to Day 35. 
 
The second primary estimand will be the hazard ratio of SNG001 versus placebo for the time 
to recovery of patients in the ITT population. Intercurrent events will be handled as follows:  
Intercurrent event 
Policy 
Death 
Composite variable: Patients who die during the study 
period will have time to recovery right censored at 28 days 
(the maximum possible time to recovery).  
Premature treatment 
discontinuation and missed 
doses 
Treatment policy: The time to recovery will be used 
regardless of treatment discontinuation and the number of 
missed doses.  
Withdrawal from study 
following recovery 
Treatment policy: The time to recovery will be used 
regardless of study withdrawal and regardless of the 
duration of follow-up following recovery. This assumes 
relapse is independent to the treatment effect. 
Withdrawal from study prior 
to recovery 
While-on-study: Time to recovery will be right censored at 
the time of withdrawal from the study or at 28 days, 
whichever occurs first. The evaluation period for this 
endpoint is 28 days, therefore estimating the time to 
recovery after Day 28 would not be appropriate. Premature 
study withdrawal is expected to be independent to the 
treatment effect, therefore a censoring approach in this 
scenario is considered appropriate. However, this 
assumption will be tested by appropriate sensitivity 
analyses. 
Other protocol deviations 
and concomitant 
medications affecting 
efficacy 
Treatment policy: Time to recovery will be used regardless 
of any concomitant medication use or protocol deviations.  
 
A tipping point analysis will be performed to implement a treatment policy strategy for 
patients who withdraw from the study prior to recovery and prior to Day 28 by imputing 
missing recovery times. The imputation will be repeated by adjusting the likelihood of 
recovery in each treatment arm independently, to varying degrees. The second primary 
analysis will be performed on each of the imputed datasets to test the sensitivity to missing 
data.  
A further sensitivity analysis of the second primary estimand will test the missing at random 
assumption by imputing missing data after study withdrawal through a missing not at random 
approach.  

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A supportive analysis will estimate the hazard ratio of SNG001 versus placebo for the time to 
recovery of patients in the per protocol population. Intercurrent events will be handled as 
follows:  
Intercurrent event 
Policy 
Death 
Treatment policy: Patients who die during the study period 
will have time to recovery right censored at 28 days (the 
maximum possible time to recovery). 
Missed 2 of the first 3 
scheduled doses 
Hypothetical (estimand for a situation with treatment 
compliance): The time to recovery will be considered 
missing if two or more doses of the randomised treatment 
were missed within the first three days of therapy. A single 
dose within the first three scheduled dosing days is not 
expected to be sufficient for the study drug to be effective, 
therefore this approach will help establish the true 
treatment effect.     
Other premature treatment 
discontinuation 
Treatment policy: The time to recovery will be used 
regardless of treatment discontinuation.  
Withdrawal from study 
following recovery 
Treatment policy: The time to recovery will be used 
regardless of study withdrawal and regardless of the 
duration of follow-up following recovery. This assumes 
relapse is independent to the treatment effect.  
Withdrawal from study prior 
to recovery 
While-on-study: Time to recovery will be right censored at 
the time of withdrawal from the study or at 28 days, 
whichever occurs first. The evaluation period for this 
endpoint is 28 days, therefore estimating the time to 
recovery after Day 28 would not be appropriate. Premature 
study withdrawal is expected to be independent to the 
treatment effect, therefore a censoring approach in this 
scenario is considered appropriate. 
Other protocol deviations 
and concomitant 
medications affecting 
efficacy 
Hypothetical (estimand for a situation with no deviations 
or concomitant medication affecting efficacy): To establish 
the true treatment effect the time to recovery will be 
considered missing if protocol deviations or medications 
affecting efficacy are recorded on or prior to Day 35. 
 
8.4.2 Key Secondary Efficacy Estimands 
The first key secondary estimand will be the difference in probabilities for SNG001 versus 
placebo for progression to severe disease or death within 35 days of first dose (or 
randomisation date if the patient is not dosed) of patients in the ITT population. Intercurrent 
events will be handled as follows: 

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Intercurrent event 
Policy 
Death 
Composite variable: The definition of severe disease 
includes patients who die within 35 days of first dose (or 
randomisation date if the patient is not dosed), regardless 
of their WHO OSCI assessments.  
Premature treatment 
discontinuation and missed 
doses 
Treatment policy: Severe disease will be determined 
regardless of treatment discontinuation and the number of 
missed doses.  
Withdrawal from study 
While-on-study: Patients will only be considered having 
severe disease if observed and recorded whilst 
participating in the study. This assumes the treatment 
effect is independent to reason for study withdrawal.  
Other protocol deviations 
and concomitant 
medications affecting 
efficacy 
Treatment policy: Severe disease will be determined 
regardless of any concomitant medication use or protocol 
deviations. 
 
A tipping point analysis will be performed to implement a treatment policy strategy for 
patients who withdraw from the study prior to progressing to severe disease and prior to Day 
35 by imputing severe disease for patients with missing data. The imputation will be repeated 
by adjusting the probability of severe disease in each treatment arm independently and 
recalculating the differences in proportions for each imputed dataset.  
A further sensitivity analysis will test the missing at random assumption by imputing severe 
disease for patients with missing data through a missing not at random approach. Sensitivity 
analyses will also be conducted only including patients who completed Day 28 and only 
including patients who withdrew from the study prior to Day 35. 
A supportive estimand for the key secondary endpoint will be defined as follows. The 
difference in probabilities for SNG001 versus placebo for progression to severe disease or 
death within 35 days of first dose (or randomisation date if the patient is not dosed) will be 
estimated for the per protocol population. Intercurrent events will be handled as follows: 
Intercurrent event 
Policy 
Death 
Composite variable: The definition of severe disease 
includes patients who die within 35 days of first dose (or 
randomisation date if the patient is not dosed), regardless 
of their WHO OSCI assessments.  
Missed 2 of the first 3 
scheduled doses 
Hypothetical (estimand for a situation with treatment 
compliance): WHO OSCI assessments will be considered 
missing if two or more doses of the randomised treatment 
were missed within the first three days of therapy. A single 
dose within the first three scheduled dosing days is not 
expected to be sufficient for the study drug to be effective, 

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Intercurrent event 
Policy 
therefore this approach will help establish the true 
treatment effect. 
Other premature treatment 
discontinuation 
Treatment policy: Severe disease will be determined 
regardless of treatment discontinuation.  
Withdrawal from study 
While-on-study: Patients will only be considered having 
severe disease if observed and recorded whilst 
participating in the study. This assumes the treatment 
effect is independent to reason for study withdrawal.  
Other protocol deviations 
and concomitant 
medications affecting 
efficacy 
Hypothetical (estimand for a situation with no protocol 
deviations or concomitant medications affecting efficacy): 
To establish the true treatment effect all WHO OSCI 
assessments will be considered missing if protocol 
deviations or medications affecting efficacy are recorded 
on or prior to Day 35. 
The second key secondary estimand will be the difference in probabilities for SNG001 versus 
placebo for progression to intubation or death within 35 days of first dose (or randomisation 
date if the patient is not dosed) of patients in the ITT population. The third key secondary 
estimand will be the difference in probabilities for SNG001 versus placebo for death within 35 
days of first dose (or randomisation date if the patient is not dosed) of patients in the ITT 
population. For both the second and third key secondary endpoints the same policies will be 
used for handling intercurrent events as progression to severe disease or death.   
8.5 
Statistical Analysis Methodology for Efficacy Endpoints 
A SAP will be completed prior to study unblinding and database lock.  
All collected data will be summarized using descriptive statistics. Summary statistics will 
consist of the number of observations, mean, standard deviation, minimum, median, and 
maximum for continuous parameters, and number and percent of subjects for categorical 
parameters. Changes respective to Baseline will also be evaluated where applicable. Baseline 
is defined as the last assessment prior to first dose.  
8.5.1 Analysis of the Primary Efficacy Endpoint 
The same method of analysis will be used for both primary endpoints. The primary analysis 
will use a Cox proportional hazards model. Time to hospital discharge and time to recovery 
will be determined using data collected up to Day 28 only. WHO OSCI data collected after 
Day 28 will only be used to assess relapse for patients who were discharged or recovered prior 
to Day 28. Relapse will be defined as a WHO OSCI score of >2 for hospital discharge and a 
WHO OSCI score of >1 for recovery. Patients who die will be administratively censored at 
Day 28, i.e. time to hospital discharge and time to recovery will be fixed at 28 days for these 
patients. Patients who neither recover nor die will be censored at the date of their last WHO 
OSCI assessment where discharge/recovery was not possible. Covariates will be included for 
treatment arm, age (as a continuous variable), sex, and Country/Region. Further covariates 

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may be defined in the SAP. The hazard ratio for recovery of SNG001 versus placebo, 95% 
confidence intervals (CI) and p-value will be presented.  
Ties in event times will be handled using the exact method, or the Efron approximation if 
computational difficulties arise. 
In addition, Kaplan-Meier estimates of time to hospital discharge and time to recovery for 25%, 
50% (median time) and 75% of patients will be presented.  
8.5.2 Analysis of the Key Secondary Efficacy Endpoints  
For the first key secondary endpoint of progression to severe disease or death, a logistic 
regression model will be applied. The difference in the probability of severe disease 
progression between SNG001 and placebo will be presented alongside the 95% CIs and p-
values. The covariates used for the primary analysis will also be used for the key secondary 
analysis.  
Progression to intubation or death and death will be analysed using the same methods described 
for the first key secondary endpoint, provided enough events are observed to make the analysis 
possible.  
8.5.3 Analysis of Secondary Efficacy Endpoints 
All analyses of secondary endpoints described below will include the covariates used for the 
primary analysis, unless stated otherwise. 
Recovery and hospital discharge will be analysed at Days 7, 14, 21 and 28 using a logistic 
regression model to determine the difference in proportions for SNG001 versus placebo.  
Improvement on the WHO OSCI scale will be analysed at Days 7, 14, 21 and 28 assessed using 
an ordered logistic regression model assuming proportional odds to estimate the odds ratios 
for SNG001 versus placebo. Adjacent WHO OSCI categories may be merged for some or all 
visits if the outcome frequency for some WHO OSCI levels is low for any treatment arm.  
Observed WHO OSCI scores will also be summarised descriptively.  
Change from baseline in breathlessness and cough scores according to the BCSS and total 
BCSS score will be assessed using a mixed model for repeated measures. The difference 
between SNG001 and Placebo across the treatment period (up to Day 14) will be estimated 
alongside the 95% CIs and p-values. The covariates used for the primary analysis will be used 
with an additional covariate for baseline score. 
8.5.4 Multiple Testing Strategy  
A Hochberg procedure will be used to test the primary endpoints. Therefore, if the two-sided 
p-value for the estimate of time to hospital discharge is below 0.05 and the two-sided p-value 
for the estimate of time to recovery is below 0.05 the null hypotheses for both endpoints will 
be rejected. Otherwise, if the smallest of the two-sided p-values is below 0.025 only the null 
hypothesis associated with the smallest p-value will be rejected. In any other circumstance 
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The first key secondary endpoint will be formally tested using a two-sided alpha of 0.05 only 
if both primary endpoints are statistically significant. The second and third key secondary 
endpoints will be formally tested, in sequence, using a two-sided alpha of 0.05 only if all prior 
hypothesis tests are statistically significant.   
8.5.5 Handling of Missing Data 
For analyses using the WHO OSCI, including the primary and key secondary endpoints, 
patients with a WHO OSCI score of 8, indicating death, will have any subsequent missing 
WHO OSCI assessments imputed as 8. In addition, if other data sources such as AEs indicate 
a patient has died all missing WHO OSCI scores on and after the date of death will be imputed 
as 8.  
For relevant analyses, missing WHO OSCI assessments for patients who withdraw from the 
study alive will be imputed using multiple imputation under a missing at random assumption. 
Selected analyses will be repeated using a missing not at random approach through an 
imputation model estimated from patients in the placebo group. 
For the mixed models with repeated measures (MMRM) of breathlessness, missing 
breathlessness scores will be imputed as 4 if the WHO OSCI score at the corresponding visit 
is ≥5. Cough and sputum scores at corresponding visits will be considered missing at random 
and total BCSS scores will be calculated by summing the imputed symptom scores, where 
possible. Missing breathlessness, cough and sputum scores at all other visits will be considered 
missing at random and will not explicitly be imputed but will be accounted for by the MMRM 
analysis. Missing not at random approaches may also be considered for sensitivity analyses.  
Further details regarding missing data approaches will be given in the SAP.  
8.6 
Safety Analysis  
Safety analyses will be based primarily on AE/SAE information which will be summarised 
descriptively, including a summary of treatment-emergent AEs/SAEs. AEs/SAEs will be 
summarised by Medical Dictionary for Regulatory Activities (MedDRA) preferred term and 
system organ class. Summaries by severity and drug-relatedness will also be presented. All 
SAEs and SUSARs will be summarised according to seriousness categorisation, number, event 
preferred term, duration of treatment prior to event, rechallenge information and outcomes. 
Vital signs will be summarised by time point for each treatment group and overall.  
Immunogenicity will be summarised by presentation of the number and percentage of patients 
with ADAs at each timepoint and overall. Descriptive statistics of ADA titres may be 
summarised if sufficient data are available.  
8.7 
 
 
 
 
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8.8 
Other Analyses 
Tabulations will be provided for completion/withdrawal status, protocol deviations, study 
populations, demographic and other baseline characteristics, use of concomitant medications, 
and exposure of and compliance with study drug. 
8.9 
Subgroup Analyses 
The following subgroups will be considered for analysis, other subgroups may be defined in 
the SAP: 
• Age category 
• Presence of comorbidities 
• Current smoking status 
• Sex 
• Race 
• Prior duration of symptoms 
• BMI 
The details of analyses to be performed for the subgroups will be defined in the SAP. 
8.10 Interim Analyses 
An unblinded interim analysis will be conducted by an independent team if it is feasible for 
the interim data to be analysed and interpreted within a timeframe which is ethical and of 
scientific value to the study. If feasible, it is planned to assess futility on the first 300 
randomised patients once all of these patients have completed the Day 35 visit or have 
withdrawn from the study. The primary analyses for the two primary endpoints will be 
conducted for the interim analysis and provided to an IDMC which may include some or all 
members of the DSMC. The go/no go recommendation made by an IDMC will be based on a 
non-binding criterion described in the table below.   
Criterion 
Recommendation 
1. the Z statistic from the estimate of 
treatment effect from the analysis 
for time to discharge is less than 1.4 
and  
Stop the study for futility 
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2. the Z statistic from the estimate of 
treatment effect from the analysis 
for time to recovery is less than 1.4 
Otherwise 
Continue the study so that at least 610 
patients in total are randomised. 
 
In addition, summaries and appropriate analyses of death, intubation or death and severe 
disease or death will be supplied to the IDMC and should be considered in their 
recommendation. Full details will be provided in an IDMC charter.   
8.11 Primary Analysis 
A primary analysis will take place once all randomised patients have completed their Day 35 
visit or have withdrawn from the study. The primary analysis will be used to assess the study 
data against the study objectives. All data summaries documented in the SAP will be produced 
for the primary analysis and will be reported in a CSR, with the exception of any Day 90 
summaries. The study will be fully unblinded at an aggregate level. Specific team members 
will be unblinded at an individual level, as required for decision making. Full details will be 
provided in the study unblinding plan. A follow-up analysis will be conducted once all patients 
have completed the Day 90 visit or have withdrawn from the study. 
8.12 Independent Data Monitoring Committee/Data Safety Monitoring Committee  
The IDMC/DSMC is an independent multidisciplinary group consisting of suitably qualified 
individuals who, collectively, have experience in the management of patients with infectious 
disease (e.g. respiratory viral infections), clinical pharmacology, and/or pharmacovigilance, 
and in the conduct and oversight of randomised clinical trials.  
The DSMC will be responsible for safeguarding the interests of trial patients, assessing the 
safety of the interventions during the study and for making recommendations about the 
progress of the study. This will include providing recommendations about necessary changes 
to the study protocol and/or whether to stop or continue the study. 
The DSMC will be advisory to the Chief Investigator, the study team and any other Sponsor 
representative. The Chief Investigator and Sponsor will be responsible for promptly reviewing 
the DSMC recommendations, to decide whether to continue, extend or terminate the trial. In 
addition, the DSMC will advise the Chief Investigator and the Sponsor whether measurements 
are to be repeated by patients, amendments to the protocol are to be made, or changes in study 
conduct are required.  
The DSMC will also (acting as the IDMC) assess the need for and feasibility of an unblinded 
interim analysis as described in Section 8.10. The IDMC/DSMC will be guided by the 
IDMC/DSMC Charter. The Charter will define the primary responsibilities of the 
IDMC/DSMC, its membership and the purpose and timing of its meetings. The Charter will 
also provide the procedures for ensuring confidentiality and proper communication and outline 
the contents of the reports that will be provided to the IDMC/DSMC.  

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9 
QUALITY CONTROL AND QUALITY ASSURANCE 
9.1 
Quality Control (Monitoring) 
In order to verify that the study is conducted in accordance with the study protocol, ICH GCP, 
local regulatory requirements and other applicable guidelines, data will be monitored at regular 
intervals. This will allow the sponsor to ensure that the data is authentic, accurate and complete. 
Source data will be verified either on site or remotely. If remote source data verification is 
required, due to its limitations, critical data such as primary efficacy data and important safety 
data will be its focus and will comply with local and national regulations. The study Monitoring 
Plan provides further details on specific monitoring activities.  
9.2 
Quality Assurance 
The Sponsor or its designated representative will assess each study site to verify the 
qualifications of each Investigator and the site staff and to ensure that the site has all of the 
required equipment. An Investigators Meeting and/or Site Initiation Meeting will occur where 
among other things the Investigator will be informed of their responsibilities and procedures 
for ensuring adequate and correct study documentation. 
The Investigator is required to complete the source documents designed to record all 
observations and other data pertinent to the study for each patient. Study data for each patient 
that gives informed consent for the study will be entered into the source documents by study 
site personnel. 
Instances of missing, discrepant, or uninterpretable data will be queried with the Investigator 
for resolution. Any changes to study data will be made to the source documents and 
documented in an audit trail, which will be maintained within the clinical database. 
In compliance with ICH GCP and regulatory requirements, the Sponsor, a third party on behalf 
of the Sponsor, regulatory agencies, IRBs or IECs may conduct quality assurance audits at any 
time during or following a study. The Investigator must agree to allow regular monitoring of 
the study according to ICH GCP requirements and other guidelines and local regulations. The 
Investigator should also agree to allow auditors direct access to all study-related documents 
including source documents. They must also agree to allocate their time and the time of their 
study staff to the auditors in order to discuss findings and issues. 
10 DATA HANDLING AND RECORD KEEPING 
10.1 Source Documents and Electronic Case Report Form 
The Investigator and their study team will be responsible for entering data into the source 
documents. The Principal Investigator is responsible for ensuring the accuracy of the data 
entered. The source documents should be completed during the study visit and once completed, 
site staff should enter the data into the eCRF.  
It is possible that source data may be captured in different locations, for example, patient 
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If permitted by local regulations, study worksheets can be provided as a tool for sites to ensure 
complete collection of source data and to support the sites in correct collection of COVID-19 
key symptoms, COVID-19 history data, physical examination and PK time point information. 
If used, the worksheets will comply with any local regulations, ICH GCP principles and will 
follow ALCOA standards to achieve data quality. The process for recording source data will 
be documented at site level and more general information included in the monitoring plan. 
For screen failures, source documents will not be monitored. The patient’s unique 
identification number, date of screening, date of informed consent and reason for screen failure 
should be entered into the eCRF. Please note, no other data need be entered into the eCRF for 
screen failures.  
10.2 Record Retention 
Essential documents as defined by ICH GCP are not limited to, but include, all signed protocols 
and any amendment(s), copies of the completed source documents, signed informed consent 
forms/other records of informed consent from all patients who consented, hospital records, 
diary cards and other source documents, R&D and IEC approvals, copies of previous versions 
of all study documentation and all related correspondence including approved documents, drug 
accountability records, study correspondence and a list of the patients’ names and addresses.  
The Investigator and/or Sponsor must retain copies of the essential documents for a minimum 
of 25 years following the end of the study.  
The Investigator will inform the Sponsor of the storage location of the essential documents and 
of any changes in the storage location should they occur. The Investigator must contact the 
Sponsor for approval before disposing of any documentation. The Investigator should take 
measures to prevent accidental or premature destruction of these documents. 
11 REGULATORY AND ETHICS 
11.1 Regulatory and Ethics Considerations 
The study will be conducted in accordance with the current ICH GCP Guidelines, which are 
consistent with the ethical principles founded in the Declaration of Helsinki, and in accordance 
with local applicable laws and regulations. 
Procedures to be followed will be those documented in the protocol, study site or Sponsor (or 
delegate’s) SOPs, manuals and guidelines. 
11.2 Competent Authority Approval 
Before the study is initiated at a site, the Sponsor will obtain approval to conduct the study 
from the Competent Authority in each of the countries in which this study will be performed 
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11.3 Institutional Review Board/Independent Ethics Committee and Hospital Board 
Requirements 
The Sponsor is responsible for ensuring IRB/IEC approval of the study. Approval of the 
protocol, informed consent form, advertising and any other information presented to, or seen 
by, potential patients must be obtained from the appropriate IRB/IEC before the study starts. 
If a substantial amendment is required during the study, IRB/IEC approval must be obtained 
prior to their implementation. The Principal Investigators are responsible for ensuring that 
these actions occur.  
If appropriate, as well as approval by the IRB/IEC, prior to starting, the study should obtain 
approval from the site Hospital Board or other relevant body (e.g. R&D department). Once 
written approval has been obtained from the country’s competent authority (e.g. MHRA), the 
IRB/IEC, and the site’s relevant hospital body, and all other necessary documentation has been 
received, the Sponsor (or delegate) will release the study drug and patient recruitment can 
commence.  
Similarly, the Investigator/Chief Investigator must inform the relevant hospital body of all 
substantial amendments and forward to them evidence of IRB/IEC and competent authority (if 
appropriate) approval. Amendment approval should be received from the relevant hospital 
body prior to implementation at site.  
11.4 Informed Consent and Screening Data 
Patient informed consent forms will be provided by the Sponsor and will be approved by the 
IRB/REC. Any changes requested by the IRB/IEC must be approved by the Sponsor (or 
delegate) prior to the documents being used. 
Informed consent will be obtained from each patient prior to any study procedures being 
performed and data reported. 
11.5 Patient Confidentiality 
The Investigator must ensure that the patients' anonymity is maintained. On the source 
documents and any other documents submitted to the Sponsor, patients should NOT be 
identified by their names, but by the assigned unique patient identification number only. 
The Investigator (or delegate) should keep a confidential log of the names of all patients and 
the patient numbers that they have been allocated in order to be able to reveal the identity of 
the patient should this be required for safety purposes. Documents not for submission to the 
Sponsor (e.g. signed informed consent forms) should be maintained by the Investigator in strict 
confidence. 
11.6 Investigator Compliance 
The Investigator must be familiar with the study protocol, the IB, the conduct of the study and 
also their responsibilities as an Investigator according to the ICH GCP guidelines. 

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No modifications to the protocol will be made without the approval of both the Chief 
Investigator and the Sponsor. Changes that significantly affect the safety of the patients, the 
scope of the investigation, or the scientific quality of the study (i.e. efficacy assessments) will 
require IRB/IEC and regulatory authority (where required) notification before implementation, 
except where the modification is necessary to eliminate an apparent immediate hazard to 
human patients.  
When circumstances require an immediate departure from procedures set forth in the protocol, 
the Investigator will contact the Sponsor to discuss the planned course of action. If possible, 
contact will be made before the implementation of any changes. Any departures from protocol 
will be fully documented in the source documentation and in the eCRF and/or a protocol 
deviation log.  
11.7 Progress Reports and Safety Reports 
Progress and Safety reports should be submitted to the IRB/IEC, competent authority and any 
necessary local site department as per the country specific requirements. It is the Sponsors 
responsibility to ensure this happens.  
12 DEFINITION OF END OF TRIAL 
End of Trial is defined as: Last Patient, Last Visit.  
13 SPONSOR DISCONTINUATION CRITERIA 
13.1 Study Sites 
The Sponsor has the authority to stop activity at any individual site at any time during the 
study. 
13.2 Entire Study 
The study will be terminated early if, in the opinion of the Sponsor or Chief Investigator, an 
unacceptable risk to the safety and welfare of patients is posed by the continuation of the study 
in light of the data generated. Premature termination of this study may also occur because of a 
regulatory authority decision, or a change in opinion of the IRB/IEC, or on the advice of the 
DSMC.  
If suspension or termination of the study is necessary, the Sponsor will endeavour to provide 
advance notification to the sites. The Sponsor should promptly inform each Investigator of its 
decision and then the Investigator (or delegate) should promptly inform the institution (where 
applicable) and also the IRB/IEC and any necessary local site department, providing them with 
a detailed written explanation of the termination or suspension. The Investigator (or delegate) 
should also promptly inform the trial patients and should assure appropriate therapy and follow 
up for the patients. In such cases, all study data and unused study medication must be returned 
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14 PUBLICATION OF STUDY RESULTS 
The Sponsor commits to publish the results of this study in a peer-reviewed journal of its 
choice. The results may also be published in a poster or oral presentation at one or more 
scientific meetings, conferences or symposia. 
A clinical study report, written in accordance with the ICH E3 Guideline, will be submitted in 
accordance with local regulations. 
Any and all scientific, commercial, and technical information disclosed by the Sponsor in this 
protocol, or elsewhere, will be considered the confidential and proprietary property of the 
Sponsor.  
The Investigator shall hold such information in confidence and shall not disclose the 
information to any third party except to the Investigator's employees and staff who have been 
made aware that the information is confidential and who are bound to treat it as such and to 
whom disclosure is necessary to evaluate that information. The Investigator shall not use such 
information for any purpose other than determining mutual interest in performing the study 
and, if the parties decide to proceed with the study, for the purpose of conducting the study. 
The Investigator understands that the information developed from this clinical study will be 
used by the Sponsor in connection with the development of SNG001 and other drugs and 
diagnostics, and, therefore, may be disclosed as required to other Clinical Investigators, 
business partners and associates and government agencies. The Investigator also understands 
that, to allow for the use of the information derived from the clinical study, the Investigator 
has the obligation to provide the Sponsor with complete test results and all data developed in 
the study. 
No publication or disclosure of study results will be permitted except under the terms and 
conditions of a separate written agreement between the Sponsor and the Investigator and/or the 
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