Hypertonic Saline Nasal Irrigation and Gargling for Suspected or Confirmed COVID-19: Pragmatic Web-based Bayesian Adaptive Randomised Controlled Trial (ELVIS COVID-19)
Phase: NA
Conditions: Upper Respiratory Tract Infections, Virus, COVID, Virus Shedding, Virus Diseases
Sponsor: University of Edinburgh

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Non-CTIMP Study Protocol 
Hypertonic saline nasal irrigation and gargling for suspected or 
confirmed COVID-19: pragmatic web-based Bayesian adaptive 
randomised controlled trial (ELVIS COVID-19) 
 
The University of Edinburgh and Lothian Health Board 
ACCORD 
The Queen’s Medical Research Institute 
47 Little France Crescent 
Edinburgh 
EH16 4TJ 
Protocol authors 
Professor Aziz Sheikh, Dr Sandeep Ramalingam 
Funder 
BREATHE Health Data Research Hub 
Funding Reference Number 
MC_PC_19004 
Chief Investigator 
Professor Aziz Sheikh 
Sponsor number 
AC20042 
REC Number 
20/ES/0056 
Project registration 
Clinicaltrials.gov: NCT04382131 
Version Number and Date 
Version 5.0 19 June 2020 
 
 
 
 
 
 
 
 
 
 
 
 

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Amendment classification and number:  
Response to REC 
Summary of change(s) 
Minor change to study title 
Clarification surrounding diary completion and reminders and 
process for missing data 
Clarification of process for contacting the study team 
Update to eligibility criteria following government isolation 
guidelines for COVID-19 
Response to REC 
 
Addition of “People ≤17 years” to exclusion criteria 
Amendment 1 
 
Addition of plan to actively monitor participants condition and 
symptoms during their participation in the study 
Addition of section 5.3 to clarify randomisation procedure 
Amendment 2 
Adapting documents to be UK wide appropriate  
Update to section recruitment strategies 

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KEY TRIAL CONTACTS 
 
Chief Investigator 
Prof. Aziz Sheikh 
Professor of Primary Care R&D, 
Director of the Usher Institute, 
Usher Institute  
University of Edinburgh  
Nine Edinburgh BioQuarter  
9 Little France Road 
Edinburgh, EH16 4UX 
 
Tel: 0131 650 8102 
Email: Aziz.Sheikh@ed.ac.uk 
 
Lead Co-sponsor Representative 
Dr Fiach O’Mahony 
Clinical Research Facilitator 
ACCORD 
The Queen’s Medical Research Institute 
47 Little France Crescent 
Edinburgh,  
EH16 4TJ 
 
 
Email: resgov@accord.scot  
Co-Investigator 
Prof. John Norrie 
Chair of Medical Statistics & Trial Methodology 
Director, ECTU 
Usher Institute 
University of Edinburgh 
Nine Edinburgh BioQuarter  
9 Little France Road 
Edinburgh, EH16 4UX 
 
Tel: 0131 651 7895 
Email: j.norrie@ed.ac.uk 
 
Co-Investigator 
Dr Sandeep Ramalingam 
Consultant Virologist 
Department of Laboratory Medicine 
Royal Infirmary of Edinburgh 
51 Little France Crescent 
Edinburgh,  
EH16 4SA 
 
 
Tel: 0131 242 6014 
Email: Sandeep.ramalingam@nhslothian.scot.nhs.uk 
Trial Manager 
Emma Ward 
ECTU, Usher Institute  
University of Edinburgh  
Level 2, Nine Edinburgh BioQuarter  
9 Little France Road 
Edinburgh, EH16 4UX 
Tel: 0131 651 9910 
Email: ELVIS-COVID19@ed.ac.uk 
 
Trial Statistician 
Cat Graham 
Lead Statistician 
Edinburgh Clinical Research Facility, 
University of Edinburgh 
Western General Hospital 
Crewe Road South 
Edinburgh, EH4 2XU 
Tel: 0131 537 3350 
Email: C.Graham@ed.ac.uk 

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CONTENTS 
1 
INTRODUCTION ........................................................................................ 7 
1.1 
BACKGROUND ................................................................................. 7 
1.2 
RATIONALE FOR STUDY ................................................................. 8 
1.2.1 
Hypotheses ..................................................................................... 9 
1.2.2 
Intervention ..................................................................................... 9 
1.2.3 
Control .......................................................................................... 10 
2 
STUDY OBJECTIVES .............................................................................. 10 
2.1 
OBJECTIVES .................................................................................. 10 
2.1.1 
Primary Objective .......................................................................... 10 
2.1.2 
Secondary Objectives ................................................................... 10 
2.2 
ENDPOINTS .................................................................................... 10 
2.2.1 
Primary Endpoint .......................................................................... 10 
2.2.2 
Secondary Endpoints .................................................................... 10 
3 
STUDY DESIGN ....................................................................................... 11 
3.1 
ELVIS COVID-19 Study Patient Pathway ......................................... 12 
4 
STUDY POPULATION ............................................................................. 13 
4.1 
NUMBER OF PARTICIPANTS ......................................................... 13 
4.2 
INCLUSION CRITERIA .................................................................... 13 
4.3 
EXCLUSION CRITERIA ................................................................... 13 
4.4 
CO-ENROLMENT ............................................................................ 14 
5 
PARTICIPANT SELECTION AND ENROLMENT .................................... 14 
5.1 
IDENTIFYING PARTICIPANTS ....................................................... 14 
5.2 
CONSENTING PARTICIPANTS ...................................................... 14 
5.2.1 
Withdrawal of Study Participants ................................................... 15 
5.3 
RANDOMISATION ........................................................................... 15 
5.3.1 
Randomisation Procedures ........................................................... 15 
6 
STUDY ASSESSMENTS ......................................................................... 15 
6.1 
STUDY ASSESSMENTS ................................................................. 15 
6.2 
LONG TERM FOLLOW UP ASSESSMENTS .................................. 16 
7 
DATA COLLECTION ............................................................................... 17 
8 
DATA MANAGEMENT ............................................................................. 17 
8.1 
PERSONAL DATA ........................................................................... 17 
8.2 
TRANSFER OF DATA ..................................................................... 17 
8.3 
DATA CONTROLLER ...................................................................... 18 
8.4 
DATA BREACHES ........................................................................... 18 
9 
STATISTICS AND DATA ANALYSIS ...................................................... 18 
9.1 
SAMPLE SIZE CALCULATION ........................................................ 18 
9.2 
PROPOSED ANALYSES ................................................................. 19 
10 
ADVERSE EVENTS ................................................................................. 19 
11 
OVERSIGHT ARRANGEMENTS ............................................................. 20 
11.1 
INSPECTION OF RECORDS .......................................................... 20 

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11.2 
PROJECT MANAGEMENT GROUP ................................................ 20 
11.3 
TRIAL STEERING COMMITTEE ..................................................... 20 
11.4 
DATA MONITORING COMMITTEE ................................................. 20 
11.5 
STUDY MONITORING AND AUDIT ................................................. 20 
12 
GOOD CLINICAL PRACTICE .................................................................. 21 
12.1 
ETHICAL CONDUCT ....................................................................... 21 
12.2 
INVESTIGATOR RESPONSIBILITIES ............................................. 21 
12.2.1 Informed Consent ......................................................................... 21 
12.2.2 Confidentiality ............................................................................... 22 
12.2.3 Data Protection ............................................................................. 22 
STUDY CONDUCT RESPONSIBILITIES ......................................................... 22 
12.3 
PROTOCOL AMENDMENTS ........................................................... 22 
12.4 
MANAGEMENT OF PROTOCOL NON COMPLIANCE ................... 22 
12.5 
SERIOUS BREACH REQUIREMENTS ........................................... 23 
12.6 
STUDY RECORD RETENTION ....................................................... 23 
12.7 
END OF STUDY .............................................................................. 23 
12.8 
INSURANCE AND INDEMNITY ....................................................... 23 
13 
REPORTING, PUBLICATIONS AND NOTIFICATION OF RESULTS ...... 24 
13.1 
AUTHORSHIP POLICY ................................................................... 24 
13.2 
PUBLICATION ................................................................................. 24 
14 
REFERENCES ......................................................................................... 24 
 

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LIST OF ABBREVIATIONS 
  
 
ACCORD 
Academic and Clinical Central Office for Research & Development - 
Joint office for The University of Edinburgh and Lothian Health Board 
BREATHE 
Health Data Research Hub for Respiratory Health 
CI 
Chief Investigator 
CRF 
Case Report Form 
COVID-19 
Coronavirus Disease-19 
DMC 
Data Monitoring Committee 
DNA 
Deoxyribonucleic acid 
ELVIS 
Edinburgh and Lothians’ Viral Intervention Study 
GCP 
Good Clinical Practice 
GP 
General Practitioner 
HOCl 
Hypochlorous acid  
HSNIG 
Hypertonic Saline Nasal Irrigation and Gargling 
ICH 
International Conference on Harmonisation 
NaCl 
Sodium Chloride 
OOH 
Out-of-hours 
PI 
Principal Investigator 
QA 
Quality Assurance 
RCT 
Randomised Controlled Trial 
REC 
Research Ethics Committee 
RNA 
Ribonucleic Acid 
SARS-CoV-2 
Severe Acute Respiratory Syndrome Coronavirus 2 
SOP 
Standard Operating Procedure 
TSC 
Trial Steering Committee 
URTI 
Upper Respiratory Tract Infection 
WURSS-24 
Wisconsin Upper Respiratory Symptom Survey-24 questionnaire 

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INTRODUCTION 
1.1 
BACKGROUND 
 
Post-hoc secondary analysis of data from our recent Edinburgh and Lothians Viral Intervention 
Study (ELVIS) pilot randomised controlled trial (RCT) indicates that hypertonic saline nasal 
irrigation and gargling (HSNIG) reduced the duration of coronavirus upper respiratory tract 
infection (URTI) by an average of two-and-a-half days.1 As such, it may offer a potentially safe, 
effective and scalable intervention in those with Coronavirus Disease-19 (COVID-19) following 
infection with the betacoronavirus Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-
CoV-2).2  
ELVIS was undertaken in 66 adults with an URTI. Results have been reported in detail 
elsewhere.3 Briefly, volunteers with URTI were, within 48 hours of symptom onset, randomised 
to intervention (n=32) or control (n=34) groups. The intervention group made hypertonic saline 
at home and performed HSNIG as many times as needed (maximum of 12 times/day). Control 
group participants dealt with their URTI as they normally did. Nose swabs collected at 
recruitment and first thing in the morning on four consecutive days were sent to the laboratory 
for testing. Both groups kept a diary (which included the Wisconsin Upper Respiratory Symptom 
Survey-21 questionnaire) for a maximum of 14 days or until they were well for two consecutive 
days. Follow-up data were available for 92% of individuals (intervention group: n=30; control 
group: n=31). HSNIG reduced the duration of URTI by 1.9 days (95% CI = 0.4 to 3.3) (p=0.01), 
over-the-counter medication use by 36% (p=0.004), transmission within household contacts by 
35% (p=0.006) and viral shedding by ≥0.5 log10/day (p=0.04) in the intervention group when 
compared to controls.3 
We also recently reported that epithelial cells mount an antiviral effect by producing 
hypochlorous acid (HOCl) from chloride ions.4 HOCl is the active ingredient in bleach. Epithelial 
cells have this innate antiviral immune mechanism to clear viral infections. Since bleach is 
effective against all virus types,5 we tested to see if a range of DNA, RNA, enveloped and non-
enveloped viruses were inhibited in the presence of chloride ions supplied via salt (NaCl). All 
the viruses we tested were inhibited in the presence of NaCl. The human viruses we tested 
were: DNA/enveloped: herpes simplex virus; RNA/enveloped: human coronavirus 229E 
(HCoV-229E), respiratory syncytial virus, influenza A virus; and RNA/non-enveloped: 
coxsackievirus B3.4 
In COVID-19, high titres of SARS-CoV-2 are detectable in the upper respiratory tract of 
asymptomatic and symptomatic individuals.6 The titres are higher in the nose than the throat 
suggesting measures that control the infection and viral shedding will help reduce 
transmission.6 In the context of the COVID-19 pandemic, we have undertaken a post-hoc re-
analysis of the ELVIS data with a focus on those infected with coronaviruses. Coronaviruses 
were the second most common cause of URTI (after rhinoviruses). Fifteen individuals were 
infected by a coronavirus (intervention group (n=7), control group (n=8)). In the intervention 

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group, four participants were infected by an alphacoronavirus (HCoV 229E=3, HCoV NL63=1) 
and three by a betacoronavirus (HCoV HKU1=3). In the control group, two were infected by an 
alphacoronavirus (HCoV NL63=2) and six by a betacoronavirus (HCoV OC43=1, HCoV 
HKU1=5). An individual in the control group with HCoV HKU1 had dual infection with rhinovirus. 
The duration of illness was lower in the intervention group compared to the control group in the 
subset of patients infected with coronavirus (mean days (SD): 5.6 (1.4) vs 8.1 (2.9)). Using a 
two-sample t-test, this was difference of -2.6 days (95%CI -5.2, 0.05; p=0.054). The difference 
in the duration of blocked nose was -3.1 days (95%CI -6.0, -0.2; p=0.04), cough -3.3 days 
(95%CI -5.9, -0.7; p=0.02) and hoarseness of voice -2.9 days (95%CI -5.6, -0.3; p=0.03) in 
favour of HSNIG.   
In the absence of a suitable antiviral agent or a vaccine, we need a safe and effective 
intervention that can be globally implemented. Our in-vitro data gives the evidence that NaCl 
has an antiviral effect that works across viral types. The findings from this post-hoc analysis of 
ELVIS need to be interpreted with caution. These data do however suggest that HSNIG may 
have a role to play in reducing symptoms and duration of illness in COVID-19. 
 
1.2 
RATIONALE FOR STUDY 
 
The mucolytic effect of NaCl is the current accepted rationale for saline irrigation in URTI. 
However, we recently reported that human epithelial (cervical-HeLa, respiratory-A549) cells 
utilise NaCl to mount a broad spectrum antiviral effect against both DNA and RNA viruses 
enveloped and non-enveloped viruses (enveloped DNA viruses: herpes simplex virus, varicella 
zoster virus; enveloped RNA viruses: respiratory syncytial virus and influenza A virus; non 
enveloped RNA virus: Coxsackievirus B3).4 The antiviral effect is dependent on the entry of 
chloride (not sodium) ions into the cell and the production of intracellular hypochlorous acid 
(HOCl). The antiviral effect was reversed when chloride (not sodium) channels were blocked. 
HOCl is the active ingredient of bleach, a broad spectrum anti-infective agent which can 
inactivate most viruses.7-10 A polymorphism causing reduction in HOCl production has been 
reported in individuals with cervical cancer.11 Since cervical cancer follows infection with high-
risk types of human papilloma viruses, it suggests a key role for local antiviral mechanisms. 
HOCl production is an important anti-bacterial mechanism in human neutrophils12. Increased 
HOCl production is reported within gut epithelial cell of fruit flies after bacterial lysate ingestion13. 
These data suggest an anti-infective role of HOCl and its precursor NaCl in epithelial cells. 
 
Recently, it has been shown that accumulation of Na+ ions in human skin helps fight 
bacterial/parasitic infections.14,15 A high salt diet increased Na+ in skin leading to a hypertonic 
environment, increased Nitric Oxide (NO) production in macrophages and thereby pathogen 
removal.14,15 Whilst our laboratory data points to the importance of Cl- in combating viral 
infections, Jantsch et al have shown the importance of Na+ in fighting bacterial infections. Taken 

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together, it suggests that innate immunity may be dependent on NaCl in epithelial cells helping 
to clear bacterial and viral infection.  
 
Given the laboratory evidence supported by our demonstration of clinical benefits in adults (i.e. 
duration of symptoms, over the counter medication, viral shedding and transmission within 
households in Edinburgh and Lothians’ Viral Intervention Study (ELVIS)), we believe a RCT in 
adults with COVID-19 symptoms to study the effects of HS on duration of illness and viral 
shedding is now needed.  
 
We have recently completed ELVIS, an open label pilot RCT of hypertonic saline nasal irrigation 
and gargling (HSNIG) in 66 adults with an URTI (www.elvisstudy.com). Most participants were 
infected with rhinovirus/coronavirus. The intervention arm had a 22% reduction in duration of 
illness (mean (SD) of intervention arm: 6.8 days (2.2) and control arm 8.7 days (3.3), difference 
of 1.9 days; p=0.01). 93% believed HSNIG helped improve symptoms of the cold. There was 
36% reduction in over-the-counter medication use (p=0.003), transmission within household 
was reduced by 35% (p=0.006), and viral shedding by ≥0.5 log10/day (p=0.04).3 The reduction 
in viral shedding and transmission within household are both in keeping with our laboratory 
results suggesting that NaCl induces an antiviral response within the cell. Since HSNIG reduced 
duration of illness, viral shedding, over the counter medication use and transmission within 
households in adults, we propose a RCT of HSNIG in adults with suspected or confirmed 
COVID-19. Since normal saline (a commonly used, safe, placebo) has NaCl in it, and sodium 
bicarbonate can be uncomfortable (PI’s personal experience) and plain water is hypotonic and 
hence painful, the study will not be placebo controlled. 
1.2.1 Hypotheses 
Primary: HSNIG is effective in reducing the duration of illness in those with clinically suspected 
or confirmed COVID-19 being managed at home. 
Secondary: HSNIG is effective in reducing complications of COVID-19 and onward household 
transmission. 
1.2.2 Intervention 
Self-isolated participant with suspected or confirmed COVID-19: HSNIG made at home 
(instructions and study videos are available to be viewed by the intervention group in the study 
website) and used as required to a maximum of 12 times/day for a maximum of 14 days. 
Participants are informed that symptoms might reduce after HSNIG, but the symptoms may 
return after a while. Symptoms could hence return as early as 30 minutes to many hours later 
after HSNIG. Participants are requested to perform HSNIG as soon as symptoms return. 
Participants are expected to perform HSNIG as many times as needed (but not more than 12 
times/day) until well or until the end of their study participation (either on day 14 or on admission 
to hospital or on withdrawal from the study) and follow standard advice from NHS on personal 

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and household hygiene and social distancing: https://www.nhs.uk/conditions/coronavirus-
covid-19/self-isolation-advice/    
1.2.3 Control 
Those randomised to the control arm will be asked to follow the guidance on personal and 
household 
hygiene 
and 
social 
distancing 
as 
advised 
by 
the 
NHS:  
https://www.nhs.uk/conditions/coronavirus-covid-19/self-isolation-advice/  
 
2 
STUDY OBJECTIVES 
2.1 
OBJECTIVES 
2.1.1 Primary Objective 
To investigate whether the use of HSNIG performed by adults with symptoms consistent with 
COVID-19 reduces the duration of symptoms when compared to participants managed using 
standard care. 
2.1.2 Secondary Objectives 
To determine the effect of HSNIG on: 
1. Severity of all symptoms 
2. Duration and severity of individual symptoms 
3. Over-the-counter medication use  
4. Contact with primary care, NHS 24/111 and out-of-hours (OOH) primary care, COVID-19 
hubs   
5. Hospital attendance (i.e. A&E attendance and/or hospital admission) and diagnosis 
6. Number of household contacts infected 
7. Side-effect of HSNIG. 
2.2 
ENDPOINTS 
2.2.1 Primary Endpoint 
Self-reported time to resolution as assessed by completion of the validated self-reported UK-
adapted short form of the Wisconsin Upper Respiratory Symptom Survey (WURSS-24), which 
will be used to collect daily symptom data16,17. 
2.2.2 Secondary Endpoints 
1. Severity of all symptoms 

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2. The length of time for individual symptoms to resolve 
3. Severity of individual symptoms 
4. Contacting healthcare (NHS 24, OOH, GP) (Number of participants and frequency of 
contacts) 
5. Participants needing GP appointments (Number of participants and frequency of contacts) 
6. Participants attending hospital (Number of participants) 
7. Length of stay in hospital if admitted 
8. Number of participants reporting over the counter medication use 
9. Reduction in transmission to household contacts 
10. Number of participants reporting side effects of nasal irrigation 
11. Types and severity of side effects reported 
12. Cost of over the counter medication used 
3 
STUDY DESIGN 
 
ELVIS COVID-19 is a pragmatic, non-CTIMP, web-based, Bayesian adaptive randomised 
controlled trial (RCT) of HSNIG vs. standard care in adults >18 years of age with suspected or 
confirmed COVID-19. The study will run throughout the course of the COVID-19 pandemic until 
numbers have been recruited for sufficient analysis. Participants are recruited within 48 hours 
of developing COVID-19 symptoms by use of study advertising through traditional media such 
as radio and internet advertisements, as well as social media. For the purposes of this study, 
symptoms or diagnosis of COVID-19 are defined as at least one of the following symptoms: 
recent onset of (i) new continuous cough and/or (ii) high temperature) and/or (iii) loss of, or 
change in, sense of smell or taste (anosmia) or those with virologically confirmed SARS-CoV-
2 infection and clinical symptoms indicative of  COVID-19. 
Willing participants will be directed by the study advertising to access a study specific webpage 
where they will be able to access further study information and documents. The affected 
individual (one per household at any one time) will be centrally randomised through an easy to 
access web-based randomisation schedule hosted at the study data centre (the Edinburgh 
Clinical Trials Unit, University of Edinburgh). All pre- and post-randomisation data will be 
collected through mobile phone/web-based questionnaires (see daily diary, end of illness 
questionnaire and day 14 questionnaire). Participants will be randomised to either a Control 
arm of standard symptomatic care, or an Intervention arm of HSNIG up to 12 times per day for 
a maximum of 14 days or until asymptomatic, alongside standard symptomatic care. All 
participants will be required to complete a daily symptom diary (WURSS-24 questionnaire) until 
asymptomatic or Day 14 and all participants will be asked to complete the Day 14 questionnaire, 
which will establish if other members of the participant’s household have developed symptoms 
of COVID-19. If a participant’s symptoms clear before Day 14, they will be invited to complete 

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the End of Illness questionnaire (healthcare use, adverse events, acceptability, infection in 
household contacts) on the day that these symptoms resolve. 
Participants who have been randomised to the Intervention arm, will be allowed access to a 
webpage featuring videos and instructions on how to prepare the hypotonic saline solution and 
how to perform HSNIG.  
At consent, participants will be given the option to consent to the future collection of samples 
for COVID-19 serological analysis. 
 
3.1 
ELVIS COVID-19 Study Patient Pathway 
Adults who are self-isolating contact the study team 
Case definition:  
Adult patients (≥18 years) who are self-isolating at home within 2 days of the start of the illness with: 
(a) clinical symptoms suggestive of COVID-19 (i.e. those who have at least one of the following symptoms: 
recent onset of (i) new continuous cough and/or (ii) high temperature) and/or (iii) loss of, or change in, 
sense of smell or taste (anosmia) or  
(b) those with virologically confirmed SARS-CoV-2 infection and clinical symptoms indicative of  COVID-19 
(as detailed in (a) above). 
 
Eligibility confirmed, Details on individual and family contacts collected and consent taken (Online) 
 
Randomisation (Online) 
Intervention groups taught how to prepare hypertonic saline (HS) and perform hypertonic saline nasal 
irrigation and gargling (HSNIG). Both groups taught to fill an online daily diary using a web link sent directly 
to their email address. 
 
 
Control Group 
Standard personal, household hygiene and 
social distancing advice: 
https://www.nhs.uk/conditions/coronavirus-
covid-19/self-isolation-advice/  
 
Intervention Group  
HSNIG started within 48 hours of symptom onset 
Number of times HSNIG should be done: As many times as 
needed (but not more than 12 times/day)  
PLUS  
Standard personal, household hygiene and social 
distancing advice:  
https://www.nhs.uk/conditions/coronavirus-covid-19/self-
isolation-advice/  
 
 
Information to be collected during study period (14 days) 
Daily diary – to be completed daily 
End of illness diary – To be completed the day participant reports feeling well or Day 14 
Day 14 questionnaire – To be completed by those whose symptoms resolved before Day 14 
 
 
Post-trial: Data to be linked to NHS records to enable assessment of virological/serological status 
 

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4 
STUDY POPULATION 
4.1 
NUMBER OF PARTICIPANTS 
We aim to recruit a total of 405 participants from within the UK. 50% of these patients 
will be randomised to the study intervention and 50% will be randomised to standard 
care. 
This sample size will be re-estimated from blinded internal data (via the independent 
Data Monitoring Committee) when the first n=100 have completed the study, and also 
from any updated relevant external data on the pathway for recovery in COVID-19.   
4.2 
INCLUSION CRITERIA 
• 
Adults (≥18 years)  
• 
Those living within the UK 
• 
Those self-isolating at home within 48 hours of the start of the illness with: 
(a) 
Clinical symptoms suggestive of COVID-19 (i.e. those who have at least one 
of the following symptoms: recent onset of (i) new continuous cough and/or 
(ii) high temperature) and/or (iii) loss of, or change in, sense of smell or taste 
(anosmia) OR 
(b) 
Those with virologically confirmed SARS-CoV-2 infection and clinical 
symptoms indicative of COVID-19 (as detailed in (a) above). 
• 
Provision of informed consent 
4.3 
EXCLUSION CRITERIA 
• 
Onset of illness >48 hours 
• 
People ≤17 years 
• 
Inability to consent 
• 
Pregnancy 
• 
Immunosuppression 
• 
Inability to perform HSNIG 
• 
Those taking part in another interventional medical trial 
• 
Those without access to a supply of salt 
• 
Those who have had a negative COVID-19 swab result for the present symptoms  
• 
Those with suspected/confirmed COVID-19 in whom hospital admission is 
recommended  
• 
Those who do not have access to email/internet 
• 
Those living in a household with another person currently participating in this study 

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4.4 
CO-ENROLMENT 
 
Co-enrolment is permitted for non-interventional trials that involve data collection only. Co-
enrolment should only be considered if it is not expected to put an unnecessary burden on the 
participant and their family and does not compromise the end point of either trial. Any co-
enrolment will follow the Sponsor Guidelines GL001. Enrolment in another interventional trial is 
not permitted and is an exclusion criterion. 
5 
PARTICIPANT SELECTION AND ENROLMENT 
5.1 
IDENTIFYING PARTICIPANTS 
 
We propose to advertise the study via traditional and social media, using videos, 
advertisements and posters. We will also promote the study via NHS Lothian and University 
of Edinburgh email lists and through collaboration with other COVID-19 studies on their 
websites and apps, with agreement from their Chief Investigators. Potential participants will 
be approached via health research registers and SHARE (within Scotland).GP networks and 
care homes may also be utilised to promote the study. Promotional material will be utilised in 
COVID-19 testing centres, GP practices and on their websites, where possible, to raise 
awareness of the study. Workplace email lists will also be used to distribute information about 
the study, with agreement from the relevant management staff. We will contact volunteer 
groups (e.g. https://covidmutualaid.org/) both for help in promoting the study and for local help 
to participants (e.g. top-up supply of salt, if needed). 
Participants will identify themselves and access the study specific website for more information 
and to view the Participant Information Sheet. If they consider themselves to be suitable and 
willing to participate in the study, they will be able to click through to the public facing pages of 
the REDCap database where they will confirm that they are eligible before consent. 
Contact information for the study team will be made available to participants in the PIS and the 
study website. This information will include the study team email address for general queries 
and this will be monitored Monday-Friday during normal working hours. If a participant has an 
urgent query regarding their participation in the study, they will be advised to contact the study 
doctor using the contact details stated on the website and PIS. 
5.2 
CONSENTING PARTICIPANTS 
 
Participants will complete an online eligibility baseline check before being directed to an online 
consent. Participants will consent themselves after having time to read the patient information 
sheet and any study information on the study website. There is no set time given to the 
participant to consider the information however at consent they must still be <48 hours of start 
of illness.  

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5.2.1 Withdrawal of Study Participants 
Participants are free to withdraw from the study at any point, without giving a reason. If the 
participant chooses to withdraw they can document this by selecting this option on the daily 
questionnaires. This will trigger the End of Illness form and we ask participants to complete this 
however, this is optional. Participants will also be asked if they are happy for the study team to 
use data collected before the time of withdrawal.  
5.3 RANDOMISATION 
5.3.1 Randomisation Procedures 
Participants will be allocated in 1:1 ratio to either HSNIG or standard care.  The randomisation 
will be performed using a web-based system utilising a block randomisation with varying block 
sizes and will be stratified on the variables: age (<50, 50-<70, ≥70) and gender (male, female).   
6 
STUDY ASSESSMENTS 
6.1 
STUDY ASSESSMENTS 
 
All participants 
Online Daily Diary: Participants in both intervention arm and control arm will complete an 
online daily diary which will be emailed directly to them first thing in the morning. The diaries 
will be maintained until the participant reports that they are well or a maximum of 14 days or if 
they withdraw or are hospitalised. If participants have not completed their online daily diary by 
approximately 11am, a reminder will automatically be generated by the REDCap database and 
sent to the participant’s email address. Reminders will subsequently be sent approx. every 5 
hours until the diary is completed. If the diary is not completed by the participant by the end of 
Study timepoints 
Screening 
Baseline 
Days 1-13 
Day 14 
Self-screening 
X 
 
 
 
Informed Consent 
 
X 
 
 
Eligibility Criteria 
 
X 
 
 
Randomisation/Treatment Allocation 
 
X 
 
 
Baseline CRF  
 
X 
 
 
Intervention arm – HSNIG up to 12 times daily 
 
 
X 
 
Daily diary 
 
 
X 
 
Adverse Events 
 
 
X 
X 
End of illness diary  
 
 
X 
X 
Day 14 Questionnaire (if symptoms resolve before Day 14) 
 
 
 
X 

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the day, their link to that daily diary will expire. Participants will continue to receive daily emails 
with diary links until they either withdraw from the study, they report they are well, or they reach 
Day 14. If the diaries are not maintained regularly, a member of the trial team may contact the 
participant to remind them to document the diary. All data points in the daily diaries and the end 
of illness questionnaires will be made mandatory on the study database where possible, limiting 
the risk of missing data. In each daily diary and in the end of illness questionnaire, participants 
will be asked if they have been tested for COVID-19 and if so, what the result of this test is. 
Therefore, data regarding COVID-19 testing can be captured if a participant is tested or the 
results are not returned until after they have consented to participate and completed the initial 
testing question. There will be a number of participants who are not tested for their illness. The 
study team have taken a pragmatic approach in addressing this and therefore participants who 
deem themselves eligible for the study can take part’ 
All participants will be advised to continue with UK Government advised personal and 
household hygiene as recommended by: 
https://www.nhs.uk/conditions/coronavirus-covid-19/self-isolation-advice/    
All participants will be asked within their daily diary if they think their condition or symptoms 
have worsened significantly. If they answer yes this will prompt an email to the study clinicians 
advising that a participant has reported a worsening of symptoms. If deemed clinically 
necessary, the study clinician will then contact the participant via email or phone to discuss 
their condition or symptoms further and advise an appropriate course of action. This might 
involve contacting their GP or other clinical care, stopping the study intervention or withdrawing 
from the study. 
Intervention (HSNIG) Group Only    
Participants will have access to an online video on how to prepare the hypertonic saline solution 
and perform nasal irrigation and gargling. Participants will be asked to make use of 
bowls/cups/containers and equipment available in their own house. They can either make the 
solution fresh every time or make it in bulk and use it for up to 24 hours. Participants will be 
asked to perform the nasal irrigation and gargling at home. The number of times the participant 
will need to perform the nasal washout and gargling will depend on the severity of their 
symptoms (maximum of 12 times/day). The participant could expect to perform the procedure 
6-12 times a day in the first few days, and thereafter 3-12 times a day until or until day 14. 
6.2 
 LONG TERM FOLLOW UP ASSESSMENTS 
There are no long term follow up assessments after day 14 of COVID-19 symptoms developing. 
If a suitable antibody test becomes available in the next 6 months, we propose to contact those 
who have consented to provide further samples as part of the study.  

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7 
DATA COLLECTION 
 
Data will be collected directly from the participant on an online REDCap database. Participants 
will complete a baseline eligibility check prior to consent. Eligible participants will then be 
randomised then complete a daily diary which includes the Wisconsin Upper Respiratory 
Symptom Survey (WURSS-24) – Daily Symptom Report to analyse length and severity of 
symptoms. Participants will be asked to complete the End of Illness diary the first day they feel 
well or on day 14. Those who complete the end of illness diary before day 14 will be asked to 
answer a few questions on day 14 (day 14 questionnaire). 
Participants will be sent a daily reminder and link to the diaries via email. If participants miss 
the completion of a daily diary, the trial team will contact them with an email reminder.  
 
8 
DATA MANAGEMENT 
8.1 
PERSONAL DATA 
The following personal data will be collected as part of the research: 
Name 
Date of Birth 
Sex 
Address  
Phone number  
Email 
GP Address 
 
Personal Data will be entered by each participant onto the REDCap database using forms that 
have been generated and accessed by individualised links sent via email to participants. 
Electronic personal data will be stored securely on the REDCap database hosted on the 
University of Edinburgh server. Only certain members of the study team, including Data 
Management and Trial Management teams, can access the study database using individual 
logins. The Statistician will be given access to personal data where necessary for analysis and 
only as and when required. 
The data will be stored in a secure server in the University of Edinburgh for at least the archiving 
period. 
 
8.2 
TRANSFER OF DATA 
Data collected or generated by the study will be transferred securely via BREATHE (Health 
Data Research Hub for Respiratory Health) to be stored as an anonymised data set in the SAIL 
(Secure Anonymised Information Linkage) databank hosted on secure servers at the University 
of Swansea. SAIL is trusted data repository for BREATHE, a collaboration led by the University 
of Edinburgh.  

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All datasets held by SAIL are accessed using a secure remote desktop, after an application to 
view the dataset has been reviewed by the SAIL Information Governance Review Panel.  
 
8.3 
DATA CONTROLLER 
The University of Edinburgh and NHS Lothian are joint data controllers along with any other 
entities involved in delivering the study that may be a data controller in accordance with 
applicable laws (e.g. the site) 
 
8.4 
DATA BREACHES 
Any data breaches will be reported to the University of Edinburgh and NHS Lothian Data 
Protection Officers who will onward report to the relevant authority according to the appropriate 
timelines if required. 
9 
STATISTICS AND DATA ANALYSIS 
9.1 
SAMPLE SIZE CALCULATION 
 
There are considerable uncertainties around the dynamics of the primary outcome (self-
reported time to resolution using WURSS-24) in the context of COVID-19. There are as yet very 
little substantive data on time to recovery (despite, as at 27th March 2020, over 132,440 people 
globally defined as recovered from COVID-19 infection). However, we intend to set out our best 
assumptions based on what we know to date, and then re-estimate the required sample size 
when we have completed data on the first n=100 participants.  
For 90% power and 5% level of significance, using a two-sided two-sample t-test, the study will 
require 170 participants in total to detect a difference in time to recovery of 2 days between 
intervention and control groups assuming a common standard deviation of 4 days. Since there 
is only 1 respondent per household (the index case) there is no adjustment for clustering 
required (i.e. ICC=0). If we assume there is 25% crossover from control to active (i.e. 1 in 4 of 
the control group work out how to use the intervention) the sample size increases to 304. We 
then allow that potentially 25% will fail to provide sufficient data for the primary outcome to be 
ascertained, leading to a final sample size (total) of 405. As indicated, this sample size will be 
re-estimated from blinded internal data (via the independent Trial Steering Committee) when 
the first n=100 have completed the study, and also from any updated relevant external data on 
the pathway for recovery in COVID-19.   
 
 

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9.2 
PROPOSED ANALYSES 
 
The study will be monitored in a flexible way using a Bayesian approach. Full details of the 
Bayesian monitoring and the final analysis will be pre-specified in a comprehensive Statistical 
Analysis Plan (SAP), authored by the study statistician, Dr Cat Graham, with the assistance of 
Professor John Norrie, Chair of Medical Statistics at The University of Edinburgh.  
In summary we will perform an intention to treat analysis with a sensitivity analysis of the 
primary outcome using those considered to be compliant with the study protocol.  The primary 
outcome of ‘time to resolution of symptoms’ will be defined by the single question ‘how unwell 
do you feel today’ will be presented descriptively by treatment with a comparison made between 
intervention and control using a two-sample t-test.  The change over the study duration will also 
be presented graphically. 
Time to resolution of individual symptoms will be analysed in the same way as the primary 
outcome. 
The number of participants contacting healthcare, attending GPs, being hospitalised and using 
over the counter medications will be compared between groups using a binomial test for the 
comparison of proportions.  Where participants are admitted to hospital comparison in the 
length of hospital stay will be made between groups using a Mann-Whitney test.  Where over 
the counter medications have been used the comparison will be made between groups using 
a two-sample t-test. 
Registration and reporting 
The trial will be registered with ClinicalTrials.gov. The SAP will be published in advance of 
commencing any analysis. The trial will be reported using the CONSORT reporting guidelines 
for randomised controlled trials18 together with the COVID-19 reporting guidelines, which are 
currently in development (Sinead Langan, personal communication, 29 March 2020). Trial 
meta-data will be deposited in the HDRUK Gateway and trial data will be made available 
through the BREATHE Hub, which sits on the ISO accredited SAIL Databank UK Secure 
Research Platform (SeRP). 
10 
ADVERSE EVENTS 
 
A few individuals reported irritation of nose and throat in ELVIS study. Information on these 
adverse events will be gathered. There is a remote possibility that HSNIG could by itself 
increase transmission, which will be assessed once we have gathered data for the first 100 
participants by analysing the data for increase in illness amongst household contacts.  

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Symptoms and side effects from the Daily Diary will be recorded in the CRF but will not be 
recorded as AEs/ARs on the AE log.  Hospitalisation is a study outcome and is exempt from 
reporting to the Sponsor as an SAE.  
 
 
11 
OVERSIGHT ARRANGEMENTS 
11.1 INSPECTION OF RECORDS 
 
Investigators and institutions involved in the study will permit trial related monitoring and audits 
on behalf of the sponsor, REC review, and regulatory inspection(s).  In the event of audit or 
monitoring, the Investigator agrees to allow the representatives of the sponsor direct access to 
all study records. In the event of regulatory inspection, the Investigator agrees to allow 
inspectors direct access to all study records and documentation. 
11.2 PROJECT MANAGEMENT GROUP 
The trial will be coordinated by a Project Management Group (PMG), consisting of the Chief 
Investigator, Trial Managers, and Statistician. 
The Trial Managers will oversee the study and will be accountable to the Chief Investigator.   
The trial will be led by Professor Aziz Sheikh, an experienced clinical trialist and Director of the 
Usher Institute. Dr Sandeep Ramalingam, Consultant Virologist at the Royal Infirmary 
Edinburgh and affiliate of the Usher Institute at the University of Edinburgh will support the study 
as Co-Investigator. The trial statistician will be Dr Cat Graham, who will work under the 
oversight of Professor John Norrie, Director of the Edinburgh Clinical Trials Unit. The study will 
be supported by the Edinburgh Clinical Trials Unit (a fully registered UKCRC Clinical Trials Unit 
#15) for all its data management and web programming needs, and trial management. 
A Delegation Log will be prepared, detailing the responsibilities of each member of staff working 
on the trial.   
11.3 TRIAL STEERING COMMITTEE 
A Trial Steering Committee (TSC) will be established to oversee the conduct progress and 
safety of the trial. The terms of reference of the Trial Steering Committee, the draft template for 
reporting and the names and contact details are detailed in CR015 DMC & TSC Charters. 
11.4 DATA MONITORING COMMITTEE 
An independent Data Monitoring Committee (DMC) will be established to oversee the safety of 
participants in the trial.   
11.5 STUDY MONITORING AND AUDIT 
The ACCORD Sponsor Representative will assess the study to determine if an independent 
risk assessment is required.  If required, the independent risk assessment will be carried out by 

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the ACCORD Quality Assurance Group to determine if an audit should be performed 
before/during/after the study and, if so, at what frequency. 
Risk assessment, if required, will determine if audit by the ACCORD QA group is required. 
Should audit be required, details will be captured in an audit plan. Audit of Investigator sites, 
study management activities and study collaborative units, facilities and 3rd parties may be 
performed. 
12 
GOOD CLINICAL PRACTICE 
12.1 ETHICAL CONDUCT 
The study will be conducted in accordance with the principles of the International Conference 
on Harmonisation Tripartite Guideline for Good Clinical Practice (ICH GCP). 
Before the study can commence, all required approvals will be obtained and any conditions of 
approvals will be met. 
12.2 INVESTIGATOR RESPONSIBILITIES 
The Investigator is responsible for the overall conduct of the study at the site and compliance 
with the protocol and any protocol amendments.  In accordance with the principles of ICH GCP, 
the following areas listed in this section are also the responsibility of the Investigator.  
Responsibilities may be delegated to an appropriate member of study site staff.   
12.2.1 Informed Consent 
The Investigator is responsible for ensuring informed consent is obtained before any protocol 
specific procedures are carried out and therefore eligibility is confirmed and consent is given 
online before participants enter any personal information. The decision of a participant to 
participate in clinical research is voluntary and should be based on a clear understanding of 
what is involved. 
Participants will receive adequate written information – appropriate Participant Information and 
Informed Consent Forms will be provided.  
The participant will be given sufficient time to consider the information provided.  The participant 
may withdraw their consent to participate at any time without loss of benefits to which they 
otherwise would be entitled. 
The participant will be informed and agree to their medical records being inspected by 
regulatory authorities and representatives of the sponsor(s). 
As the consent for the study is done by the participant online, the study team will not sign the 
consent forms. Instead, PDF copies of the participants’ consent forms will be stored securely 
on the REDCap database and a PDF of the participant consent will be made available to 
download or print for their files. 

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12.2.2 Confidentiality 
All records will be kept in a secure storage area with limited access.  Clinical information will 
not be released without the written permission of the participant.  The Investigator and study 
staff involved with this study may not disclose or use for any purpose other than performance 
of the study, any data, record, or other unpublished information, which is confidential or 
identifiable, and has been disclosed to those individuals for the purpose of the study..  Prior 
written agreement from the sponsor or its designee will be obtained for the disclosure of any 
said confidential information to other parties. 
12.2.3 Data Protection 
All Investigators and study staff involved with this study must comply with the requirements of 
GDPR with regard to the collection, storage, processing and disclosure of personal information 
and will uphold the Act’s core principles. Access to collated participant data will be restricted to 
individuals from the research team treating the participants, representatives of the sponsor(s) 
and representatives of regulatory authorities. Computers used to collate the data will have 
limited access measures via user names and passwords. Published results will not contain any 
personal data that could allow identification of individual participants. 
The website for the study will include a GDPR statement for the participant to review before 
consenting. Caldicott approval will be sought where necessary. 
STUDY CONDUCT RESPONSIBILITIES 
12.3 PROTOCOL AMENDMENTS 
Any changes in research activity, except those necessary to remove an apparent, immediate 
hazard to the participant in the case of an urgent safety measure, must be reviewed and 
approved by the Chief Investigator.   
Amendments will be submitted to a sponsor representative for review and authorisation before 
being submitted in writing to the appropriate REC, and local R&D for approval prior to 
participants being enrolled into an amended protocol. 
12.4 MANAGEMENT OF PROTOCOL NON COMPLIANCE 
Prospective protocol deviations, i.e. protocol waivers, will not be approved by the sponsors and 
therefore will not be implemented, except where necessary to eliminate an immediate hazard 
to study participants. If this necessitates a subsequent protocol amendment, this will be 
submitted to the REC, and local R&D for review and approval if appropriate. 
Protocol deviations will be recorded in a protocol deviation log and logs will be submitted to the 
sponsors every 3 months. Each protocol violation will be reported to the sponsor within 3 days 
of becoming aware of the violation.  All protocol deviation logs and violation forms should be 
emailed to QA@accord.scot 

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Deviations and violations are non-compliance events discovered after the event has occurred.  
.  An alternative frequency of deviation log submission to the sponsors may be agreed in writing 
with the sponsors. 
 
12.5 SERIOUS BREACH REQUIREMENTS 
A serious breach is a breach which is likely to effect to a significant degree: 
(a) the safety or physical or mental integrity of the participants of the trial; or 
(b) the scientific value of the trial. 
If a potential serious breach is identified by the Chief investigator, Principal Investigator or 
delegates, the co-sponsors (seriousbreach@accord.scot) must be notified within 24 hours.  It 
is the responsibility of the co-sponsors to assess the impact of the breach on the scientific value 
of the trial, to determine whether the incident constitutes a serious breach and report to research 
ethics committees as necessary.  
12.6 STUDY RECORD RETENTION 
All study documentation will be kept for a minimum of 3 years from the protocol defined end of 
study point. When the minimum retention period has elapsed, study documentation will not be 
destroyed without permission from the sponsor. 
12.7 END OF STUDY 
The Investigators or the co-sponsor(s) have the right at any time to terminate the study for 
clinical or administrative reasons.  
The end of the study will be reported to the RECand co-sponsors within 90 days, or 15 days if 
the study is terminated prematurely. The Investigators will inform participants of the premature 
study closure and ensure that the appropriate follow up is arranged for all participants involved. 
End of study notification will be reported to the co-sponsors via email to resgov@accord.scot 
A summary report of the study will be provided to the REC within 1 year of the end of the study. 
 
12.8 INSURANCE AND INDEMNITY 
The co-sponsors are responsible for ensuring proper provision has been made for insurance or 
indemnity to cover their liability and the liability of the Chief Investigator and staff. 
The following arrangements are in place to fulfil the co-sponsors' responsibilities: 
The Protocol has been designed by the Chief Investigator and researchers employed by the 
University and collaborators.  The University has insurance in place (which includes no-fault 
compensation) for negligent harm caused by poor protocol design by the Chief Investigator and 
researchers employed by the University. 

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13 
REPORTING, PUBLICATIONS AND NOTIFICATION OF 
RESULTS 
13.1 AUTHORSHIP POLICY 
 
The ECTU Publication Policy will be followed. Ownership of the data arising from this study 
resides with the study team. On completion of the study, the study data will be analysed and 
tabulated, and a clinical study report will be prepared in accordance with ICH guidelines.  
13.2 PUBLICATION 
The Clinical Study Report (CSR) will be submitted to the Sponsor and REC within 1 year of the 
end of the study. Where acceptable, a published journal article may be submitted as the CSR. 
The Chief Investigator will provide the CSR to ACCORD, for review, prior to finalization. The 
clinical study report may be used for publication and presentation at scientific meetings. 
Investigators have the right to publish orally or in writing the results of the study. The results of 
the study, together with other mandated information, will be uploaded to the European clinical 
trials database within 1 year of the end of the study. 
14 
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