Conditions: Severe Acute Respiratory Syndrome Coronavirus 2 COVID-19
Keywords: Coronavirus disease-2019 (COVID-19) Interferon beta
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 623
Healthy volunteers: no

Brief summary:
The purpose of this Phase III study is to confirm that SNG001 can accelerate the recovery of hospitalised patients receiving oxygen with confirmed Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2). Safety and other efficacy endpoints will also be assessed.

Detailed description:
Eligible patients with SARS-CoV-2 infection confirmed by a positive virus test and who are hospitalised due to COVID-19 and require oxygen therapy, will be randomised in a 1:1 ratio to receive SNG001 two syringes or placebo two syringes. SNG001 or placebo will be administered via the Ultra 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. Study data will be collected from patients daily, as per the study schedule.

Arms:
arm 1: SNG001 via inhalation using Ultra device, once a day for 14 days arm 2: Placebo via inhalation using Ultra device, once a day for 14 days

Interventions: intervention 1: SNG001 intervention 2: Placebo
Intervention descriptions: intervention 1: SNG001 nebuliser solution, 2 syringes each containing 0.65 mL once a day intervention 2: Placebo nebuliser solution, 2 syringes each containing 0.65 mL solution containing excipients of the SNG001 solution

Protocol document:
Prot_000.pdf: 
Protocol: SG018 
IMP: SNG001 – IFN-β1a nebuliser solution 
Version 5, 09 September 2021 
 
Page 1 of 84 
Synairgen Research Limited 
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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. 
 
 
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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. 
 
 
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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 
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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 
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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 
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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 
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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 
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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 
medication has not occurred. 


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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 
CCI
CCI
CCI


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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.  
CCI


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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 
neither null hypothesis will be rejected.  


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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.  
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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  
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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 
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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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16 REFERENCES 
1. 
Mantlo E, Bukreyeva N, Maruyama J, Paessler S, Huang C. Antiviral activities of type 
I interferons to SARS-CoV-2 infection. Antiviral Res. 2020;179:104811. 
2. 
Agrawal A. Mechanisms and implications of age-associated impaired innate interferon 
secretion by dendritic cells: a mini-review. Gerontology. 2013;59(5):421-6. 
3. 
Singanayagam A, Loo SL, Calderazzo M, Finney LJ, Trujillo Torralbo MB, 
Bakhsoliani E, et al. Antiviral immunity is impaired in COPD patients with frequent 
exacerbations. Am J Physiol Lung Cell Mol Physiol. 2019;317(6):L893-L903. 
4. 
Wark PA, Johnston SL, Bucchieri F, Powell R, Puddicombe S, Laza-Stanca V, et al. 
Asthmatic bronchial epithelial cells have a deficient innate immune response to 
infection with rhinovirus. J Exp Med. 2005;201(6):937-47. 
5. 
Epidemiology Working Group for Ncip Epidemic Response Chinese Center for 
Disease Control Prevention. The epidemiological characteristics of an outbreak of 2019 
novel coronavirus diseases (COVID-19) in China. Zhonghua Liu Xing Bing Xue Za 
Zhi. 2020;41(2):145-51. 
6. 
Synairgen announces positive results from trial of SNG001 in hospitalised COVID-19 
patients [press release]. 20th July 2020 2020. 
7. 
World Health Organisation. WHO R&D Blueprint novel Coronavirus COVID-19 
Therapeutic Trial Synopsis. 2020. 
8. 
Dmitrienko A, Tamhane AC, Wiens BL. General multistage gatekeeping procedures. 
Biom J. 2008;50(5):667-77. 
9. 
Dugernier J, Hesse M, Vanbever R, Depoortere V, Roeseler J, Michotte JB, et al. 
SPECT-CT Comparison of Lung Deposition using a System combining a Vibrating-
mesh Nebulizer with a Valved Holding Chamber and a Conventional Jet Nebulizer: a 
Randomized Cross-over Study. Pharmaceutical research. 2017;34(2):290-300. 
10. 
Tepper JS, Kuehl PJ, Cracknell S, Nikula KJ, Pei L, Blanchard JD. Symposium 
Summary: "Breathe In, Breathe Out, Its Easy: What You Need to Know About 
Developing Inhaled Drugs". International journal of toxicology. 2016;35(4):376-92. 
11. 
Leidy NK, Rennard SI, Schmier J, Jones MK, Goldman M. The breathlessness, cough, 
and sputum scale: the development of empirically based guidelines for interpretation. 
Chest. 2003;124(6):2182-91. 
12. 
Royal College of Physicians. National Early Warning Score (NEWS) 2: Standardising 
the assessment of acute-illness severity in the NHS. Updated report of a working party. 
2017. 
 

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STATISTICAL ANALYSIS PLAN (RotW) 
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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 
SAP/Amendment Number 
Date 
Final v1.0 
08FEB2022 
 
Prepared for: 
Synairgen Research Ltd. 
 
Prepared by: 
Approved by 
Signature 
Date 
 
 
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1 
Table of Contents 
1 
Table of Contents ..................................................................................................................................................... 2 
2 
Abbreviations and Definitions .................................................................................................................................. 6 
3 
Introduction.............................................................................................................................................................. 8 
4 
Study Objectives and Endpoints ............................................................................................................................... 8 
4.1 
Study Objectives .................................................................................................................................... 8 
4.1.1 
Primary Objective .................................................................................................................................. 8 
4.1.2 
Secondary Objective .............................................................................................................................. 8 
4.1.3 
Exploratory Objective ............................................................................................................................ 8 
4.2 
Endpoints ............................................................................................................................................... 8 
4.2.1 
Primary Endpoints ................................................................................................................................. 8 
4.2.2 
Key Secondary Endpoints ...................................................................................................................... 8 
4.2.3 
Secondary Endpoints ............................................................................................................................. 9 
4.2.4 
Exploratory Endpoint ............................................................................................................................. 9 
5 
Study Methods ......................................................................................................................................................... 9 
5.1 
General Study Design and Plan.............................................................................................................. 9 
5.2 
Randomisation and Blinding .................................................................................................................. 9 
5.3 
Derived variables ................................................................................................................................. 10 
5.3.1 
Derivations from the Ordinal Scale for Clinical Improvement ............................................................. 10 
5.3.1.1 Hospital Discharge ............................................................................................................................... 10 
5.3.1.2 Recovery .............................................................................................................................................. 11 
5.3.1.3 Progression to Severe Disease or Death within 35 days of First Dose or Randomisation .................... 11 
5.3.1.4 Progression to Intubation or Death within 35 days of First Dose or Randomisation ........................... 11 
5.3.1.5 Death within 35 days of First Dose or Randomisation ......................................................................... 12 
5.3.2 
Derivation of NEWS2 Scores ................................................................................................................ 12 
5.3.3 
Derivation of Duration of Symptoms at Baseline ................................................................................ 13 
5.3.4 
Derivation of EQ-5D-5L Index Values .................................................................................................. 13 
5.3.5 
Derivation of the General Anxiety Disorder-7 Total Score .................................................................. 13 
5.3.6 
Derivation of the Patient Health Questionnaire-9 Total Score ........................................................... 14 
5.3.7 
Derivation Functional Assessment of Chronic Illness Therapy Fatigue Scale Total Score ................... 14 
5.3.8 
Derivation of the Brief Pain Inventory Composite Scores ................................................................... 15 
5.3.9 
Derivation of Oxygen Variables ........................................................................................................... 15 
6 
Sample Size ............................................................................................................................................................. 16 
7 
General Considerations .......................................................................................................................................... 18 
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7.1 
Analysis Populations ............................................................................................................................ 18 
7.1.1 
Intent-to-Treat Population .................................................................................................................... 18 
7.1.2 
Per Protocol Population ........................................................................................................................ 18 
7.1.3 
Safety Population .................................................................................................................................. 19 
7.1.4 
 ................................
........................................................................................................................................ 19 
7.1.5 
Immunogenicity Population .................................................................................................................. 19 
7.2 
Covariates and Subgroups ................................................................................................................... 19 
7.3 
Missing Data ........................................................................................................................................ 22 
7.3.1 
OSCI ....................................................................................................................................................... 22 
7.3.1.1 General Imputation Rules .................................................................................................................... 22 
7.3.1.2 Imputation Rules for Time to Event Derived Endpoints ....................................................................... 22 
7.3.1.3 Imputation Rules for Binary Endpoints ................................................................................................ 22 
7.3.2 
BCSS ...................................................................................................................................................... 22 
7.3.3 
Partial Dates .......................................................................................................................................... 22 
7.4 
Interim Analyses and Data Monitoring................................................................................................ 23 
7.4.1 
Purpose of Interim Analyses ................................................................................................................. 23 
7.4.2 
Planned Schedule of Interim Analyses .................................................................................................. 23 
7.4.3 
Scope of Adaptations ............................................................................................................................ 23 
7.4.4 
Adjustment of Confidence Intervals and p-values ................................................................................ 24 
7.4.5 
Practical Measures to Minimise Bias .................................................................................................... 24 
7.4.6 
Documentation of Interim Analyses ..................................................................................................... 24 
7.5 
Multi-centre Studies ............................................................................................................................ 24 
7.6 
Multiple Testing ................................................................................................................................... 25 
8 
Summary of Study Data .......................................................................................................................................... 25 
8.1 
Subject Disposition .............................................................................................................................. 25 
8.2 
Protocol Deviations ............................................................................................................................. 26 
8.3 
Demographic and Baseline Variables .................................................................................................. 26 
8.4 
Medical History.................................................................................................................................... 27 
8.5 
Medications ......................................................................................................................................... 27 
8.6 
Treatment Compliance ........................................................................................................................ 28 
8.7 
Treatment Exposure ............................................................................................................................ 28 
9 
Efficacy Analyses .................................................................................................................................................... 28 
9.1 
Primary Efficacy Endpoints .................................................................................................................. 29 
9.1.1 
Time to Hospital Discharge ................................................................................................................... 29 
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9.1.1.1 
Primary Estimand ............................................................................................................................. 29 
9.1.1.2 
Primary Analysis of the Primary Estimand ....................................................................................... 30 
9.1.1.3 
Sensitivity Analyses of the Primary Estimand ................................................................................... 30 
9.1.1.4 
Supportive Estimands ....................................................................................................................... 32 
9.1.1.5 
Analysis of the Supportive Estimands ............................................................................................... 34 
9.1.2 
Time to Recovery .................................................................................................................................. 34 
9.1.2.1 
Primary Estimand ............................................................................................................................. 34 
9.1.2.2 
Analysis of the Primary Estimand ..................................................................................................... 35 
9.1.2.3 
Sensitivity Analyses of the Primary Estimand ................................................................................... 35 
9.1.2.4 
Supportive Estimands ....................................................................................................................... 35 
9.1.2.5 
Analysis of the Supportive Estimands ............................................................................................... 38 
9.2 
Key Secondary Endpoints .................................................................................................................... 38 
9.2.1 
Progression to Severe Disease or Death ............................................................................................... 38 
9.2.1.1 
Key Secondary Estimand ................................................................................................................... 38 
9.2.1.2 
Analysis of the Key Secondary Estimand .......................................................................................... 38 
9.2.1.3 
Sensitivity Analyses of the Key Secondary Estimand ........................................................................ 39 
9.2.1.3.1 
Sensitivity to the Severe Disease Definition .................................................................................. 40 
9.2.1.4 
Supportive Estimands ....................................................................................................................... 40 
9.2.1.5 
Analysis of the Supportive Estimands ............................................................................................... 42 
9.2.2 
Progression to Intubation or Death ...................................................................................................... 42 
9.2.2.1 
Key Secondary Estimand ................................................................................................................... 42 
9.2.2.2 
Analysis of the Key Secondary Estimand .......................................................................................... 43 
9.2.2.3 
Sensitivity Analyses of the Key Secondary Estimand ........................................................................ 43 
9.2.2.3.1 
Sensitivity to the Severe Disease Definition .................................................................................. 43 
9.2.2.4 
Supportive Estimands ....................................................................................................................... 43 
9.2.2.5 
Analysis of the Supportive Estimands ............................................................................................... 45 
9.2.3 
Death .................................................................................................................................................... 45 
9.2.3.1 
Key Secondary Estimand ................................................................................................................... 45 
9.2.3.2 
Analysis of the Key Secondary Estimand .......................................................................................... 46 
9.2.3.3 
Sensitivity Analyses of the Key Secondary Estimand ........................................................................ 46 
9.2.3.3.1 
Sensitivity to the Severe Disease Definition .................................................................................. 46 
9.2.3.4 
Supportive Estimands ....................................................................................................................... 46 
9.2.3.5 
Analysis of the Supportive Estimands ............................................................................................... 47 
9.3 
Secondary Efficacy Endpoints .............................................................................................................. 48 
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9.3.1 
Secondary Estimands ............................................................................................................................ 48 
9.3.2 
Analysis of Secondary Estimands .......................................................................................................... 49 
9.3.2.1 
Recovery at days 7, 14, 21 and 28 .................................................................................................... 49 
9.3.2.2 
Hospital discharge at days 7, 14, 21 and 28 ..................................................................................... 49 
9.3.2.3 
Improvement across the entire OSCI scale at days 7, 14, 21 and 28 ................................................ 49 
9.3.2.4 
Change in total BCSS score ............................................................................................................... 50 
9.3.2.5 
Change in breathlessness and cough scores ..................................................................................... 51 
9.3.3 
NEWS2 Score ........................................................................................................................................ 51 
9.3.4 
Quality of Life ........................................................................................................................................ 51 
9.3.5 
General Anxiety .................................................................................................................................... 51 
9.3.6 
Depression ............................................................................................................................................ 51 
9.3.7 
Fatigue .................................................................................................................................................. 51 
9.3.8 
Pain ....................................................................................................................................................... 51 
9.3.9 
COVID-19 Symptom Assessments ......................................................................................................... 52 
10 
Safety Analyses .................................................................................................................................................. 52 
10.1 
Adverse Events .................................................................................................................................... 52 
10.2 
Vital Signs ............................................................................................................................................ 53 
10.3 
Level of Consciousness or new Confusion ........................................................................................... 53 
10.4 
Physical Examination ........................................................................................................................... 53 
11 
Immunogenicity ................................................................................................................................................. 53 
12 
.............................................................................................................................................. 54 
13 
Reporting Conventions ...................................................................................................................................... 54 
14 
Technical Details ................................................................................................................................................ 55 
15 
Summary of Changes to the Protocol ................................................................................................................ 55 
16 
References ......................................................................................................................................................... 55 
17 
Appendices ......................................................................................................................................................... 57 
17.1 
APPENDIX I – NEWS2 Scoring System .................................................................................................. 57 
17.2 
APPENDIX II – Simulation Report ......................................................................................................... 57 
17.3 
APPENDIX III – MedDRA Internationally Agreed Order for System Organ Class ................................. 58 
 
 
 
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2 
Abbreviations and Definitions 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
ATC 
Anatomical Therapeutic Chemical 
 
 
BCSS 
Breathlessness, Cough and Sputum Score 
BMI 
Body Mass Index 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
Confidence Interval  
CIF 
Cumulative Incidence Function 
 
 
COPD 
Chronic Obstructive Pulmonary Disease 
COVID-19 
Coronavirus Disease 2019 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
DSMC 
Data Safety Monitoring Committee 
ECG 
Electrocardiogram 
EQ-5D-5L 
EuroQol-5 Dimensions-5 Levels Quality of Life Questionnaire 
FACIT 
Functional Assessment of Chronic Illness Therapy 
GAD-7 
General Anxiety Disorder-7 Questionnaire  
ICH 
International Council for Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IMP 
Investigational Medical Product 
ITT 
Intent-to-Treat 
LS 
Least Square 
LSS 
Level Sum Score 
MAR 
Missing at Random 
MCMC 
Monte Carlo Markov Chain 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIU 
Million International Units 
MMRM 
Mixed Model for Repeated Measures 
NEWS2 
National Early Warning Score 2 
OSCI 
Ordinal Scale for Clinical Improvement 
PHQ-9 
Patient Health Questionnaire-9 
PP 
Per Protocol 
PT 
Preferred Term 
PK 
Pharmacokinetics 
RMST 
Restricted Mean Survival Time 
RT-PCR 
Reverse Transcription Polymerase Chain Reaction 
SAE 
Serious Adverse Events 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
Severe Acute Respiratory Syndrome Coronavirus 2 
SDTM 
Study Data Tabulation Model 
SMF 
Study Master File 
SNG001 
The investigational drug product - an inhaled IFN-β1a formulation for 
nebulisation 
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SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 
TFLs 
Tables, Figures and Listings 
 
 
TMF 
Trial Master File 
VAS 
Visual Analogue Scale  
WHODD 
World Health Organisation Drug Dictionary 
 
 
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3 
Introduction 
The purpose of this Statistical Analysis Plan (SAP) is to provide all information that is necessary to perform 
the required statistical analyses of study SG018 for submission to all regulatory authorities outside of the 
the United States of America. It also defines the summary Tables, Figures and Listings (TFLs) to be included 
in the final clinical study report according to the protocol. The SAP is based upon, and assumes familiarity, 
with the study protocol, version 5.0, dated 9th September 2021.  
If a future protocol amendment necessitates a substantial change to the statistical analysis of the study 
data, this SAP will be amended accordingly. The content of this SAP is compatible with the International 
Council of Harmonisation (ICH) E9 Guidance document. 
4 
Study Objectives and Endpoints 
4.1 
Study Objectives 
4.1.1 
Primary Objective 
To evaluate recovery in patients with moderate Coronavirus Disease 2019 (COVID-19) after administration 
of SNG001 compared to placebo. 
4.1.2 
Secondary Objective 
 
To evaluate the efficacy of SNG001 compared to placebo in patients with moderate COVID-19, using a 
range of endpoints. 
 
To assess the general safety and tolerability of SNG001 compared to placebo when administered to 
patients with moderate COVID-19. 
4.1.3 
Exploratory Objective 
 
4.2 
Endpoints 
4.2.1 
Primary Endpoints 
 
Time to hospital discharge, defined by the WHO OSCI score of 2 or below, with no rebound at 
subsequent assessments.   
 
 Time to recovery, where recovery is defined as the World Health Organisation (WHO) OSCI score of 1 
or below, with no rebound at subsequent assessments. 
 
4.2.2 
Key Secondary Endpoints 
 
Progression to severe disease or death, defined by the WHO OSCI score of 5 or above within 35 days 
of first dose. 
 
Progression to intubation or death, defined by the WHO OSCI score of 6 or above within 35 days of 
first dose. 
 
Death within 35 days of first dose.   
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Data provided for Data Safety Monitoring Committee (DSMC) meetings will be unblinded, starting from 
the second DSMC meeting as per DSMC charter version 2. An independent statistical team will be 
responsible for generating the unblinded outputs provided to the DSMC and will not be involved in any 
future decisions regarding study conduct. 
Unblinded data will also be provided for the futility analysis and will therefore be provided by an 
independent statistical team who will not be involved in any future decisions regarding study conduct. 
Futility analysis outputs will be reviewed by the DSMC acting as the Independent Data Monitoring 
Committee (IDMC), as documented in the DSMC charter.   
The main study team will remain blinded until the primary analysis, which will be conducted once all 
patients have withdrawn, or completed the day 35 assessment.  
For further information regarding study unblinding, refer to the study unblinding plan.  
5.3 
Derived variables 
Unless otherwise specified, baseline is defined as the last non-missing pre-treatment assessment prior to 
first dose. For patients who are randomised but do not receive any study treatment baseline will be 
defined as the pre-treatment assessment.  
5.3.1 
Derivations from the Ordinal Scale for Clinical Improvement 
5.3.1.1 
Hospital Discharge 
Hospital discharge will be defined as the first post baseline score of ≤2 which is sustained for a minimum 
of 7 days and up to the date of the Day 35 assessment or study withdrawal, whichever occurs first (see 
Section 15 for changes from the protocol) according to the WHO 9-point Ordinal Scale for Clinical 
Improvement (OSCI)[1]. If any OSCI assessments are missing following discharge, sustained hospital 
discharge will be confirmed by the subject’s location on the assessment day, which will be recorded in the 
CRF as “In Hospital” or “Not in Hospital” and may be entered retrospectively. If location is missing, the 
patient will be assumed to be not in hospital under the assumption that any hospitalisations prior to the 
last completed assessment will be recorded in the clinical database. This will not include assessments 
missing following study withdrawal if study withdrawal occurs within 7 days of hospital discharge. If a 
patient withdraws from the study within 7 days of hospital discharge, they will not be considered as 
discharged. Hospital discharge will be derived for all scheduled post-baseline assessments up to day 28.  
Time to hospital discharge (in days) for discharged patient will be calculated as the following: 
Date of first hospital discharge – date of randomisation + 1 
Because OSCI score is collected up to day 35, the latest possible hospital discharge date will be at the Day 
28 assessment (because it must be sustained for a minimum of 7 days). Patients who die will be 
administratively censored at the maximum time to hospital discharge. Patients who are not discharged for 
a minimum of 7 days will be considered censored at the date of their last OSCI assessment of 3 or above. 
Time to censoring will be calculated as the following: 
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Date of last OSCI assessment >2 on or before Day 28 – date of randomisation + 1. 
 
5.3.1.2 
Recovery 
Recovery will be defined as the first post baseline OSCI score of ≤1 which is sustained for 7 days (see 
Section 15 for changes from the protocol). A maximum of 3 missing OSCI assessments will be permitted 
during the rebound period, provided all observed OSCI assessments in the rebound period are 1 or below. 
If more than 3 assessments are missing the patient will not be considered as recovered at that date and 
sustained recovery will be reassessed at the subsequent OSCI assessment ≤1, if applicable, or otherwise 
censored according the rules below. This will not include assessments missing due to study withdrawal. If 
a patient withdraws from the study during the 7 day rebound period they will be considered not 
recovered. Recovery will be derived for all scheduled post-baseline assessments up to Day 28.  
Time to recovery (in days) for recovered patients will be calculated as the following: 
Date of first OSCI score of ≤1 – date of randomisation + 1. 
Because OSCI score is collected up to day 35 the latest date of recovery will be at the Day 28 assessment. 
Patients who die will be administratively censored at the maximum time to recovery. Patients who 
potentially recover, but cannot be confirmed due to missing data (i.e. after an OSCI ≤1 all observed 
assessments in the subsequent 7 days were ≤1 but more than 3 assessments were missing) will be 
censored at the assessment immediately prior to the potential date of recovery. All other patients who do 
not recover for a minimum of 7 days will be considered censored at the date of their last OSCI assessment 
of 2 or above on or before day 28. Time to censoring will be calculated as the following: 
Date of last OSCI assessment >1 on or before day 28 – date of randomisation + 1 
5.3.1.3 
Progression to Severe Disease or Death within 35 days of First Dose or Randomisation 
Severe disease is defined by the OSCI as a score between 5 and 7. Death is defined by an OSCI score of 8. 
Any patient with an OSCI score at any post baseline assessment up to and including Day 35 of 5 or more 
will be considered as progressed to severe disease or death. 
All patients should have an OSCI score of 4 at baseline, however in the event a patient is randomised with 
an OSCI score of ≥5 at baseline this patient will be excluded from all analyses of progression to severe 
disease or death.  
Day 35 will be determined by the study schedule, which may be more than 35 days after randomisation if 
randomisation occurs before Day 1. 
5.3.1.4 
Progression to Intubation or Death within 35 days of First Dose or Randomisation 
Intubation is defined by the OSCI as a score between 6 and 7. Death is defined by an OSCI score of 8. Any 
patient with an OSCI score at any post baseline assessment up to and including Day 35 of 6 or more will be 
considered as progressed to intubation or death. 
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NEWS2 score of 7 or more 
High 
If a patient meets the criteria for more than one category the worst category will be selected.  
5.3.3 
Derivation of Duration of Symptoms at Baseline 
Duration of symptoms at baseline, which will be considered for subgrouping, will be calculated as date of 
randomisation – date of initial COVID-19 symptoms + 1. 
5.3.4 
Derivation of EQ-5D-5L Index Values  
Index values will be calculated for patients in the home setting from their EQ-5D-5L profiles using the 
method proposed by van Hout B, Janssen MF et al [2], as described below.  
The EQ-5D-5L profile for an individual is found by combining the scores from each of the five dimensions 
to form a five-digit number in the following order: mobility, self-care, usual activities, pain/discomfort and 
anxiety/depression. Each dimension is graded with a score between 1 and 5 where 1 indicates no 
problems and 5 indicates unable to/extreme problems. Therefore, a patient with no problems in any of 
the five dimensions will have a profile 11111 and a patient with no problems with mobility, slight 
problems with washing or dressing, moderate problems with doing usual activities, severe pain or 
discomfort and extreme anxiety or depression will have a profile of 12345.    
Each profile score is used to calculate an index value for the country of residence. Index values can be a 
maximum of 1 and a higher index value indicates a better quality of life, e.g. someone with a profile of 
11111, indicating no problems would have an index value of 1.000.   
The crosswalk value sets found on the EuroQol website: https://euroqol.org/eq-5d-instruments/eq-5d-5l-
about/valuation-standard-value-sets/crosswalk-index-value-calculator/. 
Because this international study includes a number of countries where a crosswalk index is not available 
the UK crosswalk index will be used for all patients. To help interpret quality of life internationally the 
Level Sum Score (LSS) will also be calculated as proposed in Feng et al 2021 [10].  The LSS is calculated by 
assigning a numerical value to each response level (i.e., 1 for “no problems”, 5 for “extreme 
problems”/”unable to”) and summing these values across the five items, resulting in a score from 5 
(11111, no problems on any dimension) to 25 (55555, extreme problems on all dimensions) for the EQ-5D-
5L. 
5.3.5 
Derivation of the General Anxiety Disorder-7 Total Score 
General Anxiety Disorder-7 (GAD-7) scores seven individual item scales by assigning scores of 0, 1, 2, and 
3, to the response categories of “not at all”, “several days”, “more than half the days”, and “nearly every 
day”, respectively. The GAD-7 total score  is calculated using the method described in the instruction 
manual [3], by summing the individual item scales to give a total score between 0 and 21. If any of the 
individual item scores are missing the total score will not be calculated.  
Total aggregated score will be used to categorise severity of generalised anxiety disorder as per table 2. 
Table 2: Anxiety severity categories for GAD-7 total score 
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 
a median time to discharge (50% discharge) of approximately 16.1 days and a 70% discharge at 
exactly 28 days 
Assumed hazard ratios (SNG vs Placebo) for recovery and discharge of 1.35 and 1.7 respectively, this data 
can be simulated: 
𝐴𝑐𝑡𝑖𝑣𝑒 𝑇𝑖𝑚𝑒 𝑡𝑜 𝑆𝑢𝑠𝑡𝑎𝑖𝑛𝑒𝑑 𝑅𝑒𝑐𝑜𝑣𝑒𝑟𝑦 ~ 𝐸𝑥𝑝(
𝑙𝑜𝑔(100
70 )
28∗1.35 ) and 
𝐴𝑐𝑡𝑖𝑣𝑒 𝑇𝑖𝑚𝑒 𝑡𝑜 𝑆𝑢𝑠𝑡𝑎𝑖𝑛𝑒𝑑 𝐷𝑖𝑠𝑐ℎ𝑎𝑟𝑔𝑒 ~ 𝐸𝑥𝑝(
𝑙𝑜𝑔(100
30 )
28 ∗1.7 ) 
This gives the active arm: 
 
a median time to recovery (50% recovery) of approximately 40.3 days and a 30% recovery at 
approximately 21.5 days 
 
a median time to discharge (50% discharge) of approximately 9.5 days and a 70% discharge at 
approximately 16.5 days 
It was additionally assumed that study withdrawal followed an exponential distribution on both treatment 
arms 
𝑊𝑖𝑡ℎ𝑑𝑟𝑎𝑤𝑎𝑙 𝐹𝑟𝑜𝑚 𝑆𝑡𝑢𝑑𝑦 ~ min (𝐸𝑥𝑝(
𝑙𝑜𝑔(100
75 )
28
) , 28) 
so that in the simulations, on average 25% of patients withdraw early from the study (i.e. before Day 35), 
and the other 75% have complete follow-up. 
All patients were assumed to contribute to the primary endpoints up to their withdrawal from the study, 
thus patients who withdrew may still meet one or both primary endpoints. Patients who withdrew early 
without meeting the primary endpoint(s) were censored in the simulation analyses. All patients were 
administratively censored at the last time point (on Day 28). 
An interim analysis at which both primary endpoints were assessed was simulated using the data from the 
first 300 randomised subjects (150 on each treatment arm). The simulated study was stopped for futility if 
the Z statistic (calculated as the partial likelihood log hazard ratio for SNG vs Placebo divided by its 
standard error) for both primary analyses was less than 1.4. Otherwise the simulated study continued to 
recruit the remaining 310 subjects (155 on each treatment arm) and the pooled (pre-interim and post-
interim) simulated data was analysed at the final analysis. 
The power of the overall study to meet both primary endpoints was simulated as over 90%. The power to 
meet at least one primary endpoint was approximately 95%.  
In the case of the complete absence of efficacy in one of the primary endpoints the power to meet the 
other primary endpoint was approximately 85%. 
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Additional simulations were performed in which a statistical dependency was created between the two 
primary endpoints while maintaining the same marginal distributions. The power to show statistical 
significance in at either endpoint was maintained but the power to reach statistical significance in both 
primary endpoints was (as expected) slightly increased. 
For further information refer to the simulation report in Appendix II.  
7 
General Considerations 
7.1 
Analysis Populations 
7.1.1 
Intent-to-Treat Population 
The Intent-to-Treat (ITT) analysis population will include all randomised patients. The ITT population will 
be the primary analysis population for efficacy analyses and will summarise patients by their randomised 
treatment group. 
7.1.2 
Per Protocol Population 
The Per Protocol (PP) analysis population will include all patients within the ITT population who do not 
have any protocol deviations with an impact on efficacy on or prior to Day 35 and will be used for 
supportive analyses of efficacy endpoints, as appropriate. Relevant protocol deviations may include, but 
are not limited to the following: 
 
Patient was not admitted to hospital due to the severity of their COVID-19. 
 
Patient did not have a positive RT-PCR virus test by RT-PCR at screening. Evidence of ongoing SARS-CoV-
2 infection for more than 3 weeks, confirmed by a validated molecular assay or validated antigen assay. 
 
OSCI score at baseline was ≠ 4. 
 
Patient is receiving mechanical ventilation or is in intensive care prior to randomisation. 
 
Patient could not use a nebuliser with a mouthpiece at baseline.  
 
Patient failed to receive at least two full doses of the scheduled doses in the first 3 days after 
randomisation.  
 
No post baseline OSCI assessments were performed. 
 
Patient was not discharged from hospital for reasons other than the severity of their condition. 
Blinded protocol deviation data will be reviewed routinely in accordance with the protocol deviation plan. 
Decisions regarding the exclusion of patients from the PP population who have completed the day 35 
assessments or who have withdrawn from the study and have all data available and no outstanding data 
queries will be made during these meetings. Following completion of the study database the status of all 
patients with regards to the PP population will be reviewed and confirmed.  
Following study unblinding, the randomisation schedule will be used to confirm if the randomised drug 
was correctly administered at each assessment by comparing the syringe numbers entered into the 
database against the syringe numbers in the material lists. Patients randomised to SNG001 will be 
excluded from the PP population if SNG001 was administered on less than 2 occasions in the first 3 days of 
treatment (either missed doses or incorrectly treated with placebo). For patients randomised to Placebo, 
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assessments of OSCI, BCSS, NEWS2 and EQ-5D-5L conducted on or after the first dose of SNG001 will be 
excluded from analyses of the PP population. 
7.1.3 
Safety Population 
The Safety analysis population will include all patients in the ITT population who receive at least one dose 
of study drug. Subjects within the Safety population will be summarised under the treatment they actually 
received. The treatment received will be identified by merging the randomisation schedule with the study 
drug administration page of the Case Report Form (CRF) by the IMP box number, if available. Any patients 
who receive SNG001 at any time will be summarised under the SNG001 treatment arm. Patients who 
receive placebo for every dose will be summarised under the placebo treatment arm. The safety 
population will be used for analysis and summaries of safety endpoints.  
 
 
 
 
  
7.1.5 
Immunogenicity Population  
The Immunogenicity Population will include patients enrolled at sites where immunogenicity sample 
collection was feasible and who have at least one valid immunogenicity result. 
7.2 
Covariates and Subgroups 
The variables below have been selected because they are probable risk factors relating to severity and 
recovery from SARS-CoV-2. 
The following subgroups will be analysed: 
 
Age category: 
o < Median age 
o ≥ Median age 
o <40 
o 40 - 49 
o 50 - 65 
o 66 - 75 
o >75 
 
Co-morbid conditions at screening of  cancer, cerebrovascular disease, chronic kidney disease, chronic 
lung diseases, chronic liver disease, diabetes mellitus type 1 and type 2, heart conditions (such as 
heart failure, coronary artery disease, or cardiomyopathies), mental health disorders or tuberculosis. 
These comorbidities are listed by the Centres for Disease Control and Prevention [11] as supported by 
at least one meta-analysis or systematic review. Obesity and smoking are also listed as comorbidities, 
however these are covered by other subgroups listed below.   
o Does not have comorbidity at screening. 
o Has one comorbidity at screening 
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o Has more than one comorbidity at screening 
 
Current smoking status: 
o Current smoker 
o Current e-cig user 
o Former smoker 
o Does not smoke 
 
Sex: 
o Male 
o Female 
 
BMI category: 
o < 30 
o ≥ 30 
 
Race: 
o White 
o Non-White 
 
Prior duration of symptoms (in days): 
o < Median duration 
o ≥ Median duration 
o ≤ 7 
o > 7 
 
 
Geographic region (See Section 7.5) 
 
Breathlessness at Baseline 
o 4 
o < 4 
o ≥ 3  
o <3 
o ≥ 2 
o < 2 
 
 
COVID-19 vaccine status at randomisation: 
o No prior COVID-19 vaccination 
o Partially vaccinated 
o Fully vaccinated (two doses received for vaccines required to be double dosed, or one dose 
received for vaccines required to be a single dose [e.g. Janssen/Johnson and Johnson 
vaccine]).  
 
 
S/F Ratio at randomisation will be categorised as ‘Low’, ‘Medium’ or ‘High’. There is no agreed 
definition for these classifications, therefore the categorisation will be data driven and defined using 
percentiles: 
o Low (≤ 33rd percentile) 
o Medium (> 33rd percentile to ≤ 66th percentile) 
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o High (> 66th percentile) 
The following variables are factors of interest which have been selected so show homogeneity of the 
treatment effect: 
 
COVID-19 Related Therapy at randomisation 
o Remdesivir by any route 
o Corticosteroids by any systemic route (Dexamethasone, Methylprednisolone, Prednisolone, 
Hydrocortisone) 
o Dexamethasone by any route 
o Dexamethasone administered orally  
o Dexamethasone administered intravenously   
All cases of the above medication use will be included, regardless of whether indicated for COVID-19 
or a comorbidity.  
 
 
SNG001 Manufacturing Batch  
o SNG001 manufactured using 
 derived material  
o SNG001 manufactured using 
 derived material. 
The following covariates will be included in statistical models: 
 
Age as a continuous variable  
 
Sex: 
o Male 
o Female 
 
Prior duration of symptoms as a continuous variable 
 
Geographic region (See Section 7.5) 
 
COVID-19 vaccine status at randomisation: 
o No prior COVID-19 vaccination 
o Partially vaccinated 
o Fully vaccinated  
Patients who receive different types of COVID-19 vaccination will be pooled into a single subgroup.    
Only subgroups with at least 20 patients in total will be included in any summaries or analyses.  
For analyses of change from baseline for variables other than OSCI the baseline value will also be included 
as a covariate.  
For subgroup analyses the subgroup variable will not be included in the models. The study has not been 
powered for any of the subgroups defined above, therefore all subgroup analyses should be considered 
exploratory.   
 
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7.3 
Missing Data 
7.3.1 
OSCI 
7.3.1.1 
General Imputation Rules  
For analyses using the OSCI, including the primary and key secondary endpoints, subjects with an 
OSCI score of 8, indicating death, will have any subsequent missing OSCI assessments set as 8. In 
addition, if other data sources such as AEs indicate a patient has died all missing OSCI scores on and 
after the date of death will be set as 8. Any missing baseline OSCI scores will be imputed as 4, as per 
the study inclusion criteria.  
7.3.1.2 
Imputation Rules for Time to Event Derived Endpoints 
Primary analyses of time to hospital discharge and time to recovery will use a censoring approach for 
missing OSCI data for patients who discontinue the study prior to hospital discharge or recovery. I.e. 
patients who discontinue the study prior to hospital discharge or recovery and prior to day 28 will be 
censored at the date of their last OSCI assessment. However, this assumption of independent 
censoring will be tested in sensitivity analyses by multiple imputation of the time to hospital 
discharge and time to recovery. Further details are given in Section 9.1.1.3.  
7.3.1.3 
Imputation Rules for Binary Endpoints 
Key secondary analyses will use the available data. Therefore, for subjects who withdraw from the 
study prior to day 35 this assumes that any progression to severe disease, intubation or death can 
only occur prior to study withdrawal. This assumption will be tested by using multiple imputation 
methods to impute the missing data. Further details are given in Section 9.2.1.3. 
7.3.2 
BCSS 
Missing breathlessness scores will be imputed according to the OSCI score at the corresponding date 
of assessment. If the OSCI score ≥ 5 at the same assessment as the missing breathlessness score then 
the breathlessness score will be imputed as 4 (the maximum breathlessness). At all other 
assessments breathlessness will be assumed Missing at Random (MAR). Missing cough and sputum 
scores will be assumed MAR at all days. MAR assessments will not be explicitly imputed but will be 
assessed as such by the analysis method. For the calculation of total BCSS score at days where 
breathlessness has been imputed as 4, the cough and sputum scores from the last observed days will 
not be imputed if missing and therefore the total BCSS score will be missing at these days.  
7.3.3 
Partial Dates 
For adverse events, partial dates will only be imputed for the purposes of determining treatment 
emergence. The following rules will be applied: 
 
If only the AE start day is missing and the AE start month is on or after the month of first dose 
then the AE will be considered treatment emergent.  
 
If the AE start day and month are missing and the AE start year is on or after the year of first dose, 
then the AE will be considered treatment emergent.  
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 
If the AE start date is completely missing, then the AE will be considered treatment emergent.  
Due to the requirement that dosing is started within 24 hours of consent AE end dates will not be taken 
into consideration.  
For medications, partial end dates will be imputed only to determine medication categorisation as prior or 
concomitant. If the end date is missing the medication will be assumed concomitant. Otherwise, partial 
end dates will be imputed as the latest possible date (last day of the month if the day is missing or 31st 
December if the day and month are missing). If the imputed date is after the first dose date the 
medication will be assumed concomitant.   
7.4 
Interim Analyses and Data Monitoring 
7.4.1 
Purpose of Interim Analyses 
Two types of interim analysis will be used during the trial: 
 
DSMC meetings for the purpose of ongoing review of safety data.  
 
An interim analysis of unblinded efficacy data to allow for early stopping of the trial due to futility will 
be conducted 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.   
In addition, a primary analysis will be conducted once all patients have completed their day 35 assessment 
or have withdrawn from the study (i.e. once all data required for the evaluation of the primary and 
secondary endpoints has been entered into the clinical study database and that data has been locked). 
This analysis will be conducted by the main statistical team, who will be fully unblinded at the point of 
database lock.  
7.4.2 
Planned Schedule of Interim Analyses 
The first DSMC meeting will occur prior to the 100th patient completing study treatment. Further DSMC 
meetings will be organised as required or as requested by the DSMC. For further details refer to the DSMC 
charter.  
The interim analysis for futility will occur after the first 300 randomised patients have completed day 35 or 
have withdrawn from the study 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. 
7.4.3 
Scope of Adaptations 
As per the DSMC charter the DSMC may provide recommendations about necessary changes to the study 
protocol and also whether to stop or continue the study.  
Regarding the interim analysis for futility, non-binding futility rules will be documented in the Independent 
Data Monitoring Committee (IDMC) charter. Following the futility analysis, the IDMC will meet to review 
the unblinded data and will make a recommendation to either continue the study or to stop the study due 
to futility. The IDMC may also recommend stopping the study due to safety concerns or due to evidence of 
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a paradoxical treatment effect between recovery/discharge and disease progression or death regardless 
of success versus the futility criteria. No sample size adjustments are planned.   
7.4.4 
Adjustment of Confidence Intervals and p-values 
The interim analysis will be used to assess futility only. The trial will not be stopped due to efficacy. 
Therefore, no alpha adjustment is required for the inclusion of the interim analysis and the global alpha of 
0.05 will be preserved for the final analysis.  
7.4.5 
Practical Measures to Minimise Bias 
As per the DSMC charter version 2, unblinded outputs will be provided from the second DSMC meeting 
onwards. An independent statistical team will generate unblinded outputs and those results will be shared 
with unblinded team members only.  In addition, an independent statistician who will have no input to the 
study conduct post unblinding will attend the DSMC closed sessions. The unblinded statistical team will 
have no input to the study conduct post unblinding and will not be involved in the programming or 
generation of blinded outputs post unblinding.  
The interim analysis for futility will be produced by an independent statistical team who will have no input 
to the study conduct post unblinding and will not be involved in the programming or generation of blinded 
outputs post unblinding. Unblinded results will be shared with unblinded team members only. The 
recommendation to continue or stop the study will be guided by pre-defined criteria documented in the 
DSMC charter. 
The main statistical team will be fully unblinded at the point of the primary analysis database lock. 
However, it is expected this will occur prior to the completion of all follow-up assessments. Therefore, to 
ensure these uncompleted assessments are not biased by knowledge of the randomised treatment to 
individual subjects, unblinded outputs will be released to the unblinded team at an aggregate level only. 
Individual randomisation assignments may be released to study team members who will have no further 
input into the study conduct, where required for decision making. Any changes to the planned analysis 
following unblinding for the primary analysis will be documented as such in the Clinical Study Report 
(CSR).   
Full details will be documented in an unblinding plan.  
7.4.6 
Documentation of Interim Analyses 
A snapshot of the data, programs, Study Data Tabulation Model (SDTM) and ADaM datasets and outputs 
for DSMC and IDMC meetings and the primary analysis will be archived at the point of delivery and 
included in the blinded/unblinded study master file (SMF) and trial master file (TMF), as appropriate.  
7.5 
Multi-centre Studies 
This study will be conducted by multiple investigators at multiple centres internationally. Randomisation 
to treatment arms is stratified by centre. When specified, statistical analysis will be adjusted for 
geographic region. Geographic region will be categorised as per table 4. If not many patients are recruited 
in the sites of the Latin American region resulting in analytical issues such as non-convergence, Latin 
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 
Safety analysis population (summarised under actual treatment arm). 
 
Treatment status 
o Was not treated 
o Completed treatment  
o Discontinued treatment 
o Principal reason for premature treatment discontinuation. 
 
Study status 
o Completed study 
o Ongoing (in treatment phase, in short term follow-up [Day 15 – Day 35], In long term follow-
up [after Day 35] – all categories to be included for the purposes of DSMC meetings and the 
interim analysis, just an ‘Ongoing – after Day 35’ category will be included for the primary 
analysis and to be removed completely for the final analysis). 
o Discontinued from the study 
 
At any time 
 
Day 1 – Day 14 
 
Day 15 – Day 35 
 
Day 36 – Day 90 
 
Principal reason for premature study withdrawal. 
Study discontinuation will be plotted by treatment using mosaic plots for the patients discontinued based 
on the above defined visit periods.  
8.2 
Protocol Deviations 
Important protocol deviations will be summarised for the ITT population. The number and percentage of 
patients with at least one important protocol deviation will be presented as well as the number and 
percentage of patients with at least one protocol deviation within each protocol deviation category and 
subcategory, overall and by country and site.  
8.3 
Demographic and Baseline Variables 
The following demographic and baseline information will be summarised for the ITT population. Data 
collected at the Day 0/ Day 1 visit will be used, unless otherwise indicated below.  
 
Age 
 
Sex  
 
Race  
 
Ethnic origin  
 
Care home residence (yes, no) 
 
Height, weight and BMI at screening. 
 
Presence of selected co-morbidities (hypertension, cardiovascular disease (excluding hypertension), 
diabetes, a chronic lung condition or cancer). 
 
Number of distinct co-morbidities (0, 1, 2, 3+). 
 
Smoking status (never smoked, former smoker, current tobacco user, current e-cig user). 
 
Duration of symptoms at baseline.  
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The summary of demographic and baseline information will be repeated for each of the subgroups 
defined in Section 7.2. The number and percentage of patients within each subgroup will also be 
summarised.   
A summary of oxygen use at randomisation will also be presented. Summary statistics will be presented 
for the baseline percentage FiO2, the baseline percentage oxygen saturation and the baseline S/F ratio. 
8.4 
Medical History 
Medical history will be coded using the version 23 of the Medical Dictionary for Regulatory Activities 
(MedDRA). 
Medical history will be summarised for the ITT population by System Organ Class (SOC) and Preferred 
Term (PT). Summary tables will contain the number and percentage of patients. A patient who has 
multiple conditions in the same SOC or with the same PT will be counted only once in the patient counts. 
Medical history summaries will be sorted by the internationally agreed SOC order (Appendix III) and 
decreasing frequency of PT within SOC in the total column. 
SARS-CoV-2 infection history at screening will be summarised for the ITT population. The number and 
percentage of patients experiencing each symptom of COVID-19 on admission to hospital will be 
displayed. In addition, the number and percentage of patients with each COVID-19 variant will be 
presented, where data are available.      
The number and percentage of patients with comorbidities will be summarised by the comorbidity groups 
defined in Section 7.2 and preferred term. Preferred terms falling under each comorbidity group will be 
identified by a blinded medical review of the study data.  
8.5 
Medications 
Medications will be coded according to the 2009 version of the World Health Organisation Drug Dictionary 
(WHODD) combined with the online 2020 version.   
Medications will be defined as prior or concomitant in the hospital setting and prior, concomitant or post 
study treatment in the home setting. Prior and concomitant medications will be summarised for the ITT 
population by Anatomical Therapeutic Chemical (ATC) class level 3 and preferred drug name, where; 
 
‘Prior’ medications are medications which started and stopped prior to the first dose of study 
drug. 
 
‘Concomitant’ medications are medications which started prior to, on or after the first dose of 
study drug and up to 24 hours after the last dose of study drug and ended on or after the date of 
first dose of study drug or were ongoing at the end of the study. 
 
‘Post study treatment’ medications will be defined as medications which were started more than 
24 hours after the last dose of study treatment.  
See Section 7.3.3 for handling of partial dates for medications. In cases where it is not possible to define a 
medication as prior or concomitant the medication will be classified by the worst case; i.e. concomitant. 
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Concomitant and post study treatment medications which are used for direct treatment of COVID-19 will 
be summarised, including the number and percentage of subjects receiving such treatment, broken down 
by treatment name. Medications used for treatment of COVID-19 will be identified by a blinded medical 
review of the study data.  
COVID-19 vaccinations prior to study enrolment will be summarised, including the number and percentage 
of vaccinated subjects, the type of vaccine received, whether a single dose or double dose vaccine was 
received, whether the same vaccine was received for both doses and the time since each vaccination 
dose. Post randomisation COVID-19 vaccinations will also be summarised, including the number and 
percentage of non-vaccinated and vaccinated patients as well as the patients with the first dose pre-
randomisation and second dose in follow-up period. 
8.6 
Treatment Compliance 
Percentage treatment compliance will be summarised for the Safety population.   
Treatment compliance is calculated as total number of received doses/ total number of scheduled doses x 
100, where the total number of scheduled doses only includes doses prior to study withdrawal.  
Percentage treatment compliance will be summarised through descriptive statistics and the number and 
percentage of patients with < 80%, 80% - <100% and 100% compliance will be presented. 
Treatment compliance will also be summarised as the number and percentage of patients that missed 
dose due to: 
 
OSCI score of 5 or above 
 
Other reasons  
The number of patients who received partially administered doses will also be summarised alongside the 
reason for partial administration.    
8.7 
Treatment Exposure 
The duration of exposure and number of doses administered will be summarised for the Safety 
population. The duration of exposure is calculated as the number of days between first dose and last dose 
(inclusive), regardless of any missed doses. The number of doses administered will be summarised in the 
form of cumulative frequencies showing the number and percentage of patients receiving ≥ 1 dose, ≥ 2 
doses, ≥ 3 doses etc., up to 14 doses. The number of doses missed will also be summarised. In addition, 
the number and percentage of patients fulfilling the study drug exposure criteria for the PP population 
(i.e. patients who receive at least two doses in the first 3 days) will be summarised.  
9 
Efficacy Analyses 
All efficacy analyses and summaries described in this section will use the ITT population. Some efficacy 
analyses will be repeated for other populations and for the subgroups defined in Section 7.2 as per table 7 
below.  
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of motivation/lack of time to continue participating in the 
study rather than relapse.  
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. 
9.1.1.2 
Primary Analysis of the Primary Estimand  
The primary analysis of time to hospital discharge will be a Cox proportional hazards model with time to 
hospital discharge calculated according to Section 5.3.1.1.    
Covariates will be included in the proportional hazards model as per Section 7.2.  
The hazard ratio for hospital discharge of SNG001 versus placebo, 95% confidence intervals (CI) and p-
value will be presented. In addition, unadjusted quartile estimates will be calculated through the Kaplan-
Meier method with 95% CI calculated by the Brookmeyer-Crowley method.  
Ties in event times will be handled using the exact method, or the Efron approximation if computational 
difficulties arise. Schoenfeld residuals will be plotted to assess the proportional hazards assumption.  
The Restricted Mean Survival Time (RMST) will also be presented. 
The statistical significance of the primary analysis of time to hospital discharge will be formally assessed by 
the Hochberg procedure, as detailed in Section 7.6, and a statistically significant p-value according to the 
multiple testing strategy will be indicated in the output.  
The hazard ratios for hospital discharge and for recovery in SNG001 versus placebo and their 
corresponding 95% CI and p-values will be presented in a forest plot, in which the x-axis will represent the 
hazard ratio and the y-axis will stand for the estimates of the two co-primary endpoints. 
The proportion (%) of patients who were discharged from hospital on or before visit up to Day 28 will be 
presented in a table alongside the probability of survival calculated from a Kaplan-Meier analysis and 
Greenwood 95% confidence intervals. Plots will be produced of Kaplan-Meier estimates over time and the 
proportion (%) of patients who were discharged from hospital on or before visit up to Day 28 for SNG001 
versus placebo. 
9.1.1.3 
Sensitivity Analyses of the Primary Estimand  
The sensitivity of the primary analysis to missing data due to withdrawal from study prior to hospital 
discharge/ recovery will be assessed through a tipping point analysis, where missing data will be imputed 
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as described by Jackson et al [6]. To perform the multiple imputation M datasets will first be created 
through bootstrapping. The bootstrapping will be applied independently for each treatment group (a 
treatment stratified bootstrap). Each created dataset will therefore contain 𝑛1 Placebo patients and 𝑛2 
SNG001 patients where 𝑛1 and 𝑛2 are the number of patients randomised to Placebo and SNG001 
respectively. The primary analysis method will be used to assess each of the bootstrapped datasets to 
generate estimates of the model coefficients within each dataset. The vector of model coefficients can be 
written algebraically for the jth dataset as 𝛽𝑗
∗ and the vector of covariates values for the ith patient as 𝑍𝑖. 
Missing hospital discharge and recovery times for patients censored prior to day 28 will be estimated as 
𝑚𝑖𝑛(𝑇𝑖𝑗= 𝐶𝑖+ 𝐴𝑖𝑗, 28), where 𝑇𝑖𝑗 is the imputed time to discharge/recovery in the jth dataset for the ith 
patient, 𝐶𝑖 is the observed censored time and 𝐴𝑖𝑗 is the simulated time between censoring and the time to 
event. A maximum constraint of 28 days is applied to the imputed times because the rate and time to 
hospital discharge and recovery beyond this time cannot be assessed due to the limitations of the study 
design. 𝐴𝑖𝑗 will be estimated using the Bender et al method [7], by the following calculation: 
𝐴𝑖𝑗= 𝐻𝐴𝑖𝑗
−1[−𝑙𝑜𝑔(𝑈𝑖𝑗)𝑒𝑥𝑝(−𝛽𝑗
∗𝑍𝑖−𝛾𝑖)], 
where 𝑈𝑖𝑗 is randomly generated from a Uniform(0,1) distribution, 𝐻𝐴𝑖𝑗
−1 is the inverse cumulative baseline 
hazard function for 𝐴𝑖𝑗 and 𝛾𝑖 is a sensitivity parameter. If 𝛾𝑖 is set to 0 this will represent a Missing at 
Random (MAR) approach, if 𝛾𝑖 < 0 the time to discharge/recovery will occur earlier than  that of the MAR 
approach and if 𝛾𝑖 > 0 discharge/recovery will occur later than that of the MAR approach. Values of 𝛾 will 
be varied independently for each treatment group.   
The M imputed datasets will be analysed using the primary analysis model and the M estimates will be 
combined with Rubin’s variance formula. 
The value of M will be chosen large enough such that the choice of the seed used in sampling functions 
has a negligible impact on estimates. 
For each imputed dataset and for each value of 𝛾𝑖 the primary analysis method will be repeated. The 
estimates from the imputed datasets will be combined for each value of 𝛾𝑖 using Rubin’s rules [8]. The 
results for the different combinations of 𝛾𝑖 for Placebo and SNG001 patients will be plotted on a heat map 
to identify, if applicable, where the p-values becomes non-significant. This ‘tipping point’ will also be 
tabulated along with specific values of 𝛾𝑖 on the exponentiated scale.    
A jump to reference Missing Not at Random (MNAR) data imputation will also be performed using similar 
a method, but only assuming all patients who withdraw early follow the same pattern as patients who are 
randomised to placebo. 𝛾𝑖 will be set to 0 for this imputation. 
These sensitivity analyses will assess the robustness of the results to a departure from the censored at 
random assumption of a Cox proportional hazards model. To aid interpretation the average proportion of 
patients who were discharged from hospital will be presented alongside the average difference in the 
restricted mean survival time.    
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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.  
9.1.2.2 
Analysis of the Primary Estimand  
Time to recovery will be analysed using the same methods as time to hospital discharge, as detailed in 
Section 9.1.1.2.  
9.1.2.3 
Sensitivity Analyses of the Primary Estimand  
The sensitivity to missing data will be assessed in the same way as described for time to hospital discharge 
in Section 9.1.1.3. 
The primary estimand will be further evaluated for each of the subgroups described in Section 7.2. The 
analysis method for time to hospital discharge described in Section 9.1.1.2 will be used to evaluate each 
subgroup.  
9.1.2.4 
Supportive Estimands  
A supportive estimand of the primary endpoint will estimate the hazard ratio of SNG001 versus placebo 
for the time to recovery of patients in the per protocol population. Reasons for excluding patients from 
the PP population are described in Section 7.1.2. Of note, many of the reasons are based on assessments 
prior to randomisation and treatment and so the exclusions are independent of treatment. Intercurrent 
events will be handled as per table 12. 
Table 12: Intercurrent events and policies for the supportive estimand of time to recovery 
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The Hochberg procedure used in the primary analysis will dictate whether the statistical significance of the 
key secondary analysis of progression to severe disease or death will be formally assessed, as detailed in 
Section 7.6 and a statistically significant p-value according to the multiple testing strategy will be indicated 
in the output.  
The odds ratios for severe disease or death, intubation or death and death in SNG001 versus placebo and 
their corresponding 95% CI and p-values will be presented in a forest plot, in which the x-axis will 
represent the odds ratios and the y-axis will stand for the estimates of the three key secondary endpoints. 
9.2.1.3 
Sensitivity Analyses of the Key Secondary Estimand  
The sensitivity of the key secondary analysis to missing data due to withdrawal from study prior to 
progression to severe disease or death will be assessed firstly through a tipping point analysis for a range 
of sensitivity parameters, 𝛿𝑖, for each ith patient. 𝛿𝑖 represents the change to the odds of severe 
disease or death. If 𝛿𝑖 is set to 1 this will represent a Missing at Random (MAR) approach, if 𝛿𝑖 < 1 the 
imputed OSCI score will be lower than that of the MAR approach and progression to severe disease 
will be less common. If 𝛿𝑖 > 1 the imputed OSCI score will be higher than that of the MAR approach 
and progression to severe disease will be more common. Values of 𝛿 will be varied independently for 
each treatment group. 
Missing data will be imputed in M datasets. OSCI will be considered a categorical variable and the 
imputation algorithm will use a monotone logistic regression method to impute missing OSCI scores. 
Each of the covariates used in the primary analysis, including treatment group, will be included as 
covariates in the logistic regression. Missing data will be imputed iteratively by day, starting at day 2. 
For each subsequent day, the OSCI scores at prior days will be included as covariates, including the 
OSCI scores imputed in earlier iterations. This will not include the OSCI score at day 1 because this will 
always be 4, by design. However, because there are 34 scheduled visit days to be imputed in this way 
it is likely as the imputation progresses that the imputation model will become over-parameterised. 
To avoid this issue and to account for the fact that the most recent days are most likely to be 
predictive, only the OSCI score at the previous two days will be used as continuous covariates. Any 
imputations of 8 (death) will be “carried forward” to all future missing days after each step and not 
imputed again. 
For each imputed dataset and for each value of 𝛿𝑖 the primary analysis method will be repeated. The 
estimates from the imputed datasets will be combined for each value of 𝛿𝑖 using Rubin’s rules. The 
results for the different combinations of 𝛿𝑖 for Placebo and SNG001 patients will be plotted on a heat 
map to identify, if applicable, where the p-values becomes insignificant. This ‘tipping point’ will also 
be tabulated along with specific values of 𝛿𝑖.    
A second sensitivity of the primary analysis to missing data will follow the jump to reference MNAR 
method of imputation detailed in Section 9.1.1.3. The key secondary analysis model will be repeated for 
each imputed dataset and the combined estimates, as calculated by Rubin’s rules will be tabulated.  
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9.3.2 
Analysis of Secondary Estimands 
9.3.2.1 
Recovery at days 7, 14, 21 and 28 
Logistic regression models will be applied to OSCI recovery by days 7, 14, 21 and 28. For recovery by visit a 
patient will be considered recovered at every visit following the first confirmed recovery. E.g. a patient 
who recovers at Day 6 will be considered recovered at Days 7, 14, 21 and 28 regardless of what happens 
after the confirmed recovery.  
Covariates will be included in the logistic regression model as per Section 7.2.  
The number and percentage of patient who recovered within each treatment group will be presented with 
the difference in the proportions of patients who recovered between the treatment groups alongside the 
odds ratios, 95% CI of the odds ratios and p-value from the logistic regression.  
If quasi-complete separation of a covariate occurs at any visit the Firth logistic regression method will be 
used across all visits to avoid using maximum likelihood estimation when calculating the estimates.  
The odds ratios for recovery, hospital discharge and improvement across the entire OSCI scale by days 7, 
14, 21 and 28 in SNG001 versus placebo and their corresponding 95% CI and p-values will be presented in 
a forest plot, in which the x-axis will represent the odds ratios and the y-axis will stand for the estimates of 
the above mentioned secondary endpoints. 
The same analysis methods will be used to use to assess both of the estimands in Section 9.3.1. 
9.3.2.2 
Hospital discharge at days 7, 14, 21 and 28 
Hospital discharge by days 7, 14, 21 and 28 will be assessed using the same methods as recovery at days 7, 
14, 21 and 28, as described in Section 9.3.2.1. 
9.3.2.3 
 Improvement across the entire OSCI scale at days 7, 14, 21 and 28 
Improvement across the entire OSCI scale at days 7, 14, 21 and 28 will be analysed through an ordered 
logistic regression model, assuming proportional odds across the treatment groups. 
averaged over the whole 
study period 
Change in 
breathlessness 
score over the 
study period 
ITT  
Treatment policy: Regardless of protocol deviations, 
treatment adherence and any concomitant therapies 
received for the treatment of SARS-CoV-2.  
Difference in LS means 
between each SNG001 
arm versus placebo 
averaged over the whole 
study period  
Per Protocol 
Hypothetical: Estimand for a situation with treatment 
compliance and no protocol deviations affecting efficacy. 
Change in cough 
score over the 
study period 
ITT  
Treatment policy: Regardless of protocol deviations, 
treatment adherence and any concomitant therapies 
received for the treatment of SARS-CoV-2.  
Difference in LS means 
between each SNG001 
arm versus placebo 
averaged over the whole 
study period  
Per Protocol 
Hypothetical: Estimand for a situation with treatment 
compliance and no protocol deviations affecting efficacy. 
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Covariates will be included in the logistic regression model as per Section 7.2.  
The odds ratios will be presented for each visit alongside their 95% CIs and p-values.  
If quasi-complete separation occurs due to low incidence of some OSCI levels then neighbouring OSCI 
levels may be pooled for the purpose of the analysis to a minimum of two levels (≤3 and ≥4), in which case 
the analysis will simplify to a binary logistic regression. Also, covariates may be dropped from the analysis 
if it is clear that the cause of quasi-complete separation is a particular categorised covariate.  
The proportional odds assumption will be tested by re-running the ordered logistic regression model with 
both unequal and equal slopes for the treatment effect and equal slopes for all other covariates. 
Proportionality will be assessed by the statistical significance of the treatment effect for unequal slopes, at 
the 5% significance level.      
The same analysis methods will be used to use to assess both of the estimands in Section 9.3.1. 
A sensitivity analysis of the estimand using the ITT population will be performed where OSCI levels of 0 
and 1 will be derived based on the COVID-19 symptom assessments. An OSCI score of 0 will be assigned if 
no COVID-19 symptoms are present, regardless of the OSCI score recorded in the clinical database. An 
OSCI score of 1 will be assigned if any COVID-19 symptoms are present and an OSCI score of 0 was 
recorded in the clinical trial database. The number and percentage of patients with a rederived OSCI score 
will be presented at each time point along with the odds ratios and their 95% CIs and p-values.        
The number and percentage of patients with each OSCI score at each post baseline visit will also be 
presented.   
9.3.2.4 
Change in total BCSS score  
Change in total BCSS score over the treatment period will be assessed by an MMRM.  
Covariates will be included in the MMRM as per Section 7.2, plus covariates for baseline total BCSS score, 
scheduled visit, an interaction term for treatment by visit and an interaction term for baseline total BCSS 
score by visit.  
Also, estimates of the mean change (± 95% CI) in total BCSS score as well as the estimated mean change (± 
SE) in the individual BCSS scales over the treatment period as calculated by the MMRM analysis will be 
presented for SNG001 versus placebo in a panel plot. 
Data from the follow-up visits or early withdrawal visits after day 15 will not be included in the analysis. 
The model will be fit for absolute score and change from baseline in score: the baseline BCSS covariate 
ensures that these models have identical treatment effects. Least Squares (LS) means for absolute scores 
and change from baseline scores and the LS mean difference between treatment groups will be presented 
for each post baseline visit up to day 15 and across the entire post baseline treatment period (day 2 – 15) 
with 95% CIs and p-values.  
A covariance matrix will be used to account for the within patient correlation. If an unstructured matrix 
can be used this will be the first choice, otherwise a compound symmetry structure will be used. The 
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observed margin option will be used to ensure the model coefficients are weighted to reflect the actual 
proportions of each class level within the data. 
Missing data will be handled as per Section 7.3.2.  
Absolute values and the change from baseline in total BCSS score will also be summarised over the entire 
study period.  
9.3.2.5 
Change in breathlessness and cough scores  
Change in breathlessness and cough scores over the treatment period will be analysed using the same 
methods described for total BCSS score in Section 9.3.2.4. 
Absolute values and the change from baseline in breathlessness, cough and sputum score will be 
summarised over the entire study period. The change from baseline in each symptom score will also be 
summarised in shift tables.  
9.3.3 
NEWS2 Score  
The absolute NEWS2 scores and the change from baseline in NEWS2 score will be summarised for 
hospitalised patients at each scheduled assessment. Generally, NEWS2 score will only be calculated from 
the data recorded in the NEWS2 CRF. However, baseline NEWS2 score will be the calculated from the data 
entered in the vital signs and level of confusion CRFs for the last assessment prior to first dose. NEWS2 
scores will be calculated and summarised from data collected in the NEWS2 CRF for the Pre-dose and Day 
1 assessments, however the change from baseline will not be summarised because as per the protocol 
these assessments could be pre or post dose.  
9.3.4 
Quality of Life  
Quality of life as measured by the EQ-5D-5L will be summarised by descriptive statistics of the crosswalk 
index value, the LSS, the Visual Analogue Scale (VAS) and the usual activities dimension at each scheduled 
visit. 
9.3.5 
General Anxiety 
GAD-7 total scores will be summarised by descriptive statistics and the number and percentage of patients 
within each anxiety severity category will be displayed at each scheduled assessment. 
9.3.6 
Depression 
PHQ-9 total scores will be summarised by descriptive statistics and the number and percentage of patients 
within each depression severity category will be displayed at each scheduled assessment. 
9.3.7 
Fatigue 
FACIT-FS total scores will be summarised by descriptive statistics at each scheduled assessment. 
9.3.8 
Pain 
Descriptive statistics will be presented at each post baseline visit for each pain severity score category, the 
overall pain severity score and the pain interference score.  
 
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9.3.9 
COVID-19 Symptom Assessments 
The number and percentage of patients with any symptom, each individual symptom and any other 
symptoms associated with COVID-19 will be presented both overall and at each scheduled time point.  
10 Safety Analyses 
All outputs for safety outcomes will use the Safety analysis population.   
10.1 Adverse Events 
Adverse events will be recorded from the time informed consent is given 28 days after the last 
administration of the study medication. All AEs will be coded using the latest available version of the 
MedDRA and will be categorized by intensity (mild/moderate/severe) and relationship (unrelated/unlikely 
to be related/possibly related/probably related/definitely related).  
A treatment-emergent adverse event (TEAE) is defined as any event not present prior to the 
administration of study drug or any unresolved event already present before administration of study drug 
that worsens in intensity following exposure to the treatment. Where dates are missing or partially 
missing, AEs will be assumed to be treatment-emergent unless they clearly started prior to treatment (as 
indicated by the month/year if the day is missing etc.). 
Summary tables will contain the cumulative incidence rate and the number of events where applicable. A 
subject who has multiple events in the same SOC and PT will be counted only once in the subject counts 
but all events will be included. Adverse event summaries will be ordered by the international SOC order 
(Appendix III) and decreasing frequency of PT within SOC, in the active arm overall column. 
Summaries of TEAEs by SOC and PT will include the following: 
 
Incidence of TEAEs  
 
Incidence of serious TEAEs  
 
Incidence of serious related TEAEs 
 
Incidence of TEAEs by relationship 
 
Incidence of TEAEs by severity  
 
Incidence of TEAEs leading to discontinuation 
 
Incidence of TEAEs leading to death 
 
Incidence of related TEAEs leading to death. 
 
Incidence of TEAEs of special interest.  
 
 
An adverse event summary will summarise the number of TEAEs in each of the above categories alongside 
95% Newcombe confidence intervals for the differences in proportions between treatment arms.  
Summaries of TEAEs by PT will include the following: 
 
Incidence of TEAEs  
 
Incidence of serious TEAEs 
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 
Common TEAEs (occurring in at least 5% of the total study population).  
 
The summary of common TEAE will include 95% Newcombe confidence intervals for the differences in 
proportions between treatment arms.   
In summaries including relationship to study treatment, the following relationships will be considered 
related: ‘Definitely related’, ‘Probably Related’, ‘Possibly Related’. ‘Unlikely to be Related’ and ‘Not 
related’ will be considered unrelated.  
In summaries including intensity, the following intensity categories will be summarized: ‘Mild’, ‘Moderate’, 
‘Severe’. Subjects will be counted once under each severity category if the same event was observed at 
different severities.  
An adverse event of special interest (AESI) is an AE that meets the following criteria: 
 
Moderate or worse palpitations during the dosing period and up to 24 hours after last dose. 
 
Severe bronchospasm with 4 hours of investigational agent/placebo administration (symptoms 
causing inability to perform usual social and functional activities and deemed related to the study 
product as determined by the site investigator). 
Adverse events which are coded to more than one preferred term will be counted once under each term.  
A listing of serious AEs will also be produced.   
10.2 Vital Signs 
Systolic blood pressure, diastolic blood pressure, heart rate, body temperature, respiratory rate and 
oxygen saturation absolute and change from baseline values will be summarised by descriptive statistics 
for each study day. The number and percentage of patients receiving oxygen at each assessment will also 
be presented. Vital signs will not be collected following discharge from hospital.  
10.3 Level of Consciousness or new Confusion 
Level of consciousness or new confusion will be summarised by shift tables from baseline to each post 
baseline timepoint. Data will be collected whilst patients are hospitalised only.  
10.4 Physical Examination  
Physical examination findings will be listed only. 
11 Immunogenicity  
The number and percentage of patients with anti-drug antibodies at day 44 will be presented. In addition, 
the number and percentage of patients with anti-drug antibodies at day 44 who did not have anti-drug 
antibodies at screening will also be presented. Antibody titres will be listed, if available.  
 
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12 
 
13 Reporting Conventions 
When reporting relative frequencies or other percentage values, the following rules apply: 
 
For values where all subjects fulfil certain criteria, the percentage value will be displayed as 100. 
 
For values where the absolute frequency is 0, there will be no percentage presented at all. 
 
All other percentage displays will use 1 decimal place. 
When reporting descriptive statistics, the following rules will apply in general: 
 
n will be an integer 
 
Mean (arithmetic and geometric), and median will use 1 decimal place more than the original 
data. 
 
Coefficient of variation and geometric CV will be reported as a percentage to 1 decimal place. 
 
SD will use 2 decimal places more than the original data. 
 
Minimum and maximum will be reported using the same number of decimal places as the original 
value. 
 
If no subjects have data at a given timepoint then only n=0 will be presented. However, if n < 3, 
present the n, min and maximum only. If n = 3, n, mean, median, minimum and maximum will be 
presented only. The other descriptive statistics will be left blank. 
 
P-values ≥ 0.001 will be reported to 3 decimal places; p-values less than 0.001 will be reported as 
“<0.001”; p-values greater than 0.999 will be reported as “>0.999”. 
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 
Estimated parameters, not on the same scale as raw observations (e.g. regression coefficients) will 
be reported to 3 significant figures. 
14 Technical Details 
Statistical evaluation will be performed by 
 
 and
 and supervised by Synairgen unless otherwise 
indicated. 
The datasets will follow Clinical Data Interchange Standards Consortium (CDISC) standards.  
All analyses will be performed using 
 (
) ) or 
 
 o or higher.  
15 Summary of Changes to the Protocol 
The protocol defines hospital discharge as an OSCI  ≤ 2 without rebound and similarly recovery is defined 
as an OSCI ≤ 1 without rebound. However, the protocol does not give a time period for assessing rebound. 
If all subsequent assessments are included to assess rebound this creates a bias because earlier hospital 
discharge/recovery times require a longer period of sustainability. Also, patients who withdraw from the 
study immediately after hospital/discharge recovery cannot be assessed for rebound.  
To address this issue a fixed rebound period of 7 days has been defined for assessing hospital discharge 
and recovery, which will be applied regardless of when hospital discharge or recovery happens and 
regardless of study withdrawal.  
In addition, the protocol defines a list of covariates to be included in each analysis, however to simplify the 
planned analyses these have been reduced to a smaller set of covariates which are considered the best 
predictors for COVID-19 progression and recovery.  
In addition, the estimands based on the per protocol population have been modified with regards to 
medications affecting efficacy (approved COVID-19 therapies) because it has been recognised that use of 
such therapies is not a protocol deviation. Therefore, a second supportive estimand has been included 
which accounts for intercurrent events related to medications affecting efficacy. Although such 
medications are allowed by the protocol it is thought that initiating such therapies during the study may 
reflect a prior lack of efficacy and starting such therapies prior to the study may impact the true effect of 
the study treatment.   
16  References 
[1] World Health Organisation. WHO R&D Blueprint novel Coronavirus COVID-19 Therapeutic Trial 
Synopsis. 2020.  
[2] van Hout B, Janssen MF, et al. Interim scoring for the EQ-5D-5L: Mapping the EQ-5D-5L to EQ-5D-
3L value sets. Value in Health  2012 Jul-Aug;15(5):708-15. 
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[3] Instructions for Patient Health Questionnaire (PHQ) and GAD-7 Measures. 
[4] FACIT-Fatigue Subscale Scoring Guidelines (Version 4). 
[5] The Brief Pain Inventory User Guide, Charles S. Cleeland. 
[6] Jackson D, White IR, Seaman S, Evans H, Baisley K, Carpenter JR. Relaxing the independent 
censoring assumption in the Cox proportional hazards model using multiple imputation. Stat Med. 
2014;33:4681‐4694. 
[7] Bender R, Augustin T, Bletter M. Generating survival times to simulate Cox proportional hazards 
models. Statistics in Medicine 2005; 24:1713–1723. 
[8] Rubin, D.B.  Multiple Imputations for Nonresponse in Surveys. New York, NY: John Wiley & Sons, 
Inc. 1987. 
[9] Ge, Miaomiao, et al. "Covariate-adjusted difference in proportions from clinical trials using logistic 
regression and weighted risk differences." Drug information journal: DIJ/Drug Information Association 
45.4 (2011): 481-493. 
[10] Feng, YS., Jiang, R., Pickard, A.S. et al. Combining EQ-5D-5L items into a level summary score: 
demonstrating feasibility using non-parametric item response theory using an international dataset. 
Qual Life Res (2021). https://doi.org/10.1007/s11136-021-02922-1 
[11] https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-care/underlyingconditions.html 
[12] Richard B Wettstein et al. Delivered Oxygen Concentrations Using Low-Flow and High-Flow Nasal 
Cannulas. Respiratory care, May 2005, VOL 50 NO 5 
 
 
 
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17 Appendices 
 
 
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