A Randomised, Single Blinded Study Investigating the Role of ' Black Elderberry (Sambucus Nigra) (Sambucol®) in the Treatment, Progression and Reduction of Symptoms in Participants With Coronavirus 19
Phase: NA
Conditions: COVID-19
Sponsor: East Kent Hospitals University NHS Foundation Trust

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TRIAL TITLE 
   
A randomised, single blinded study investigating the role of 
‘Sambucol® Black Elderberry (Sambucus nigra) in the treatment, 
progression and reduction of symptoms in participants with 
Coronavirus 19  
 
 
SHORT TRIAL TITLE  
 
BERRY 
 
This protocol has regard for the HRA guidance and order of content 
 
IRAS Number: 282732        NCT:05489770 
 
SPONSORS Number: 2020/COVID19/11 
 
Funders Number: N/A 
 
PROTOCOL VERSION NUMBER AND DATE 
V6.2 22.07.2021 
 
DOCUMENT CONTROL 
V1.0 24.09.2020  
 
New Document 
V2.0 10.11.2020 
Amendments to text following REC Review 
Page 12. Section 3.1 - correction of typo 
Page 13. Section 6.1 -inclusion criterion changed to ‘capacity to provide written or electronic consent.  
Page 14. Section 7 -Trial procedures Summary Table – minor amendments to ‘Information about the 
trial’, ‘At swabbing station’ and Randomisation and collection of trial treatment’. Follow up telephone 
call now within 24 hours. Reference to written consent added to follow up visits. Note ‘c’ removed as 
no longer relevant. 
Page 15. Sections 7.1 and 7.1.1. now include references to verbal, written and electronic consent. 
Page 15. Section 7.2 paragraph added for electronic consent and verbal consent. 
Page 18. Section 7.7. Electronic consent and written consent added to table. 
Page 20. Section 8.1 - details of manufacturer removed as deemed commercially sensitive. 
Page 26. Section 9.6 – changed to ‘Participants will be asked to report any pregnancy occurring 
within 28 days of trial treatment’ 
V3.0  21.01.2021 
Changes to The trial Flow Chart, Section 7 trial Procedures and section 7.1.1 Participant ID in include 
giving out the Participant Information Sheet at the swabbing Station 
V4.0 25.01.2021 
Changes to Section 7 Trial Procedures and Section 7.6 Baseline data to add the question, Have you 
been vaccinated against COVID-19 and if so , when? 
V5.0 27.01.2021 
Changes to sections Trial summary, Trial Setting, Trial procedure, Recruitment and Participant 
identification to allow recruitment of participants from DoH swabbing sites and patients who have hear 
about the trial from external sources and who contact the Research Team directly.  
Change to the exclusion criteria to exclude anyone already taking Sambucol or any other elderberry 
supplement. 
Removal of the phrase from section 7.3.1 No out of hours randomization will occur.  

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V6.0 26.02.2021 
Addition of a key Protocol contributor. 
Clarification of time after a positive swab that a participant is eligible sections 6.1, 7, 7.11 and 7.12.  
Reminder to participants to stop taking study liquid- section 7 
Addition of extra operational definitions for (S)AEs section 9.2 
V6.1 21.07.2021 
Addition of the option of delivering the liquid to participants by courier 
V6.2 22.07.2021 
Addition of the questions about vaccination 
 
SPONSOR  
East Kent Hospitals University NHS Foundation Trust (EKHUFT) 
Site address:  Trust Head Quarters 
Kent and Canterbury Hospital 
Ethelbert Road 
Canterbury 
CT1 3NG 
 
SIGNATURE PAGE 
 
The undersigned confirm that the following protocol has been agreed and accepted and that the Chief 
Investigator agrees to conduct the trial in compliance with the approved protocol and will adhere to the 
principles outlined in the Medicines for Human Use (Clinical Trials) Regulations 2004 (SI 2004/1031), 
amended regulations (SI 2006/1928) and any subsequent amendments of the clinical trial regulations, 
GCP guidelines, the Sponsor’s (and any other relevant) SOPs, and other regulatory requirements as 
amended. 
I agree to ensure that the confidential information contained in this document will not be used for any 
other purpose other than the evaluation or conduct of the clinical investigation without the prior written 
consent of the Sponsor 
I also confirm that I will make the findings of the trial publicly available through publication or other 
dissemination tools without any unnecessary delay and that an honest accurate and transparent 
account of the trial will be given; and that any discrepancies and serious breaches of GCP from the 
trial as planned in this protocol will be explained. 
 
For and on behalf of the Trial Sponsor: 
 
Signature:  
...................................................................................................... 
 
Date: 
....../....../...... 
Name (please print): 
...................................................................................................... 
 
 
Position: 
...................................................................................................... 
 
 
 
 
 
Chief Investigator: 
 
Signature: 
...................................................................................................... 
 
Date: 
....../....../...... 
Name: (please print): 
......................................................................................................
 
 
 
 
 
 
Statistician: 
 
Signature: ...................................................................................................... 
 
 
Name: (please print): 
...................................................................................................... 
 
 

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Position: ...................................................................................................... 
 
 
 
 
KEY TRIAL CONTACTS  
 
Chief Investigator 
Ms. Jessica Evans, R&I Director/ Colorectal Consultant, 
Queen Elizabeth the Queen Mother Hospital, St Peters 
Road, Margate Kent CT4 9AN. 
 
Trial Coordinator 
Ms. Joanne Deery, Research Nurse, Queen Elizabeth the 
Queen Mother Hospital, St Peters Road, Margate Kent CT4 
9AN                                        
Sponsor 
East Kent Hospitals University NHS Foundation Trust, Trust 
Head Quarters, Kent and Canterbury Hospital, Ethelbert 
Road, Canterbury, Kent, CT1 3NG Tel: 01227 766877 
 
Joint-sponsor(s)/co-sponsor(s)  
N/A 
Funder(s) 
N/A 
Clinical Trials Unit 
N/A 
Key Protocol Contributors 
Dr Ana Alegria, Consultant Anaesthetist & Intensive Care, 
Co-Investigator, Queen Elizabeth the Queen Mother 
Hospital, St Peters Road, Margate Kent CT4 9AN 
Joanne Deery, Co-Investigator, Queen Elizabeth the Queen 
Mother Hospital, St Peters Road, Margate Kent CT4 9AN  
Andrew Gillian - Lead Clinical Trials Pharmacist, East Kent 
Hospitals University NHS Foundation Trust. 
  
Statistician 
Paul Bassett - Independent Clinical Trials Statistician  
Email: paul@statsconsultancy.co.uk  Tel: 07905530446  
 
Trials Pharmacist 
Andrew Gillian - Lead Clinical Trials Pharmacist, East Kent 
Hospitals University NHS Foundation Trust.  
Email: andrewgillian@nhs.net Tel: 07970102446  
 
Committees 
Trial Steering Committee  
 
Dr Timothy Doulton – Renal Consultant. East Kent Hospitals 
University Foundation Trust. Email: tdoulton@nhs.net  
Phone: 01227 864229 
Mr. Nigel Simpson - Senior Lecturer and Honorary 
Consultant in Obstetrics & Gynaecology. The University of 
Leeds. Email: n.a.b.simpson@leeds.ac.uk  
Phone: 07572832297 
Paul Bassett – Independent Clinical Trials Statistician 
Emails: paul@statsconsultancy.co.uk Phone: 07905530446  
 
 
 
 
 
 

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i. 
LIST of CONTENTS 
 
 
Page No. 
TITLE PAGE  
1 
RESEARCH REFERENCE NUMBERS 
 
1 
SIGNATURE PAGE 
2 
KEY TRIAL CONTACTS 
 
3 
i. LIST of CONTENTS 
4 
ii. LIST OF ABBREVIATIONS 
5 
iii. TRIAL SUMMARY  
6 
iv. FUNDING  
7 
v. ROLE OF SPONSOR AND FUNDER 
7 
vi. ROLES & RESPONSIBILITIES OF TRIAL MANAGEMENT COMMITTEES 
 
7 
vii, PROTOCOL CONTRIBUTORS 
7 
viii. KEYWORDS 
7 
ix. TRIAL FLOW CHART 
 
8 
SECTION 
1. BACKGROUND 
 
9 
2. RATIONALE 
 
10 
3. OBJECTIVES AND OUTCOME MEASURES  
11 
4. TRIAL DESIGN 
12 
5. TRIAL SETTING 
12 
6. PARTICIPANT ELIGIBILITY CRITERIA 
12 
7. TRIAL PROCEDURES 
13 
8. TRIAL TREATMENTS 
19 
9. PHARMACOVIGILANCE 
22 
10. STATISTICS AND DATA ANALYSIS 
26 
11. DATA MANAGEMENT  
28 
12. MONITORING, AUDIT & INSPECTION 
29 
13. ETHICAL AND REGULATORY CONSIDERATIONS 
29 
14. DISSEMINATION POLICY 
31 
15. REFERENCES 
32 
16. APPENDIX 1 – Manufacturers‘ Labels 
33 
17. APPENDIX 2 - Classification of COVID 19 Severity 
34 
 

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ii. 
LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
AR 
Adverse Reaction 
CI 
Chief Investigator 
CRF 
Case Report Form 
CTA 
Clinical Trial Authorisation 
DSUR 
Development Safety Update Report 
EKHUFT 
East Kent Hospitals University NHS Foundation Trust  
GCP 
Good Clinical Practice 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation of technical requirements for 
registration of pharmaceuticals for human use. 
ISF 
Investigator Site File 
ISRCTN 
International Standard Randomised Controlled Trials Number 
MHRA 
Medicines and Healthcare Products Regulatory Agency 
PI 
Principal Investigator 
PIS 
Participant Information Sheet 
RCT 
Randomised Control Trial 
REC 
Research Ethics Committee 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SOP 
Standard Operating Procedure 
SmPC 
Summary of Product Characteristics 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TMG 
Trial Management Group 
TSC 
Trial Steering Committee  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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iii. TRIAL SUMMARY 
 
Trial Title 
A randomised, single blinded study investigating the role of 
‘Sambucol® Black Elderberry (Sambucus nigra) in the 
treatment, progression and reduction of symptoms in 
participants with Coronavirus 19 
Internal ref. no. (or short title) 
BERRY 
Trial type  
Food supplement trial 
Trial Design 
Single Centre, placebo controlled, single blinded, two arm, 
randomised controlled trial.  
Trial Participants 
Outpatients over the age of 18 with a positive COVID-19 
swab result, after attending an East Kent Hospitals University 
NHS Foundation Trust site for swabbing, or a swabbing 
station booked through gov.uk website, or who contact the 
research team after seeing the approved posters or hearing 
about the trial through other external sources eg the media. 
And who have evidence of a positive test for COVID-19 within 
the last 5 days. 
Planned Sample Size 
204  
Treatment duration 
14 days 
Follow up duration 
28 days 
Planned Trial Period 
24 Months  
 
Objectives 
Outcome Measures 
Primary Objective 
 
Reduction in the severity of 
symptoms by 30% at day 10 
in people who are 
symptomatic with the SARS-
CoV-2 (COVID-19) virus 
treated with Sambucol vs. 
Placebo 
Wellness VAS score 
Secondary Objective 
 
Reduction in admission to 
hospital by day 28.  
 
Reduction the severity of 
symptoms at day 3, 7, 14 and 
28 days 
 
Admissions to hospital 
 
 
Wellness VAS score 
Treatments  
Sambucol® Black Elderberry Original (Sambucus nigra) 
Liquid 
Placebo for Sambucol® Black Elderberry Original (Sambucus 
nigra) Liquid 
Formulation, Dose, Route of 
Administration 
Liquid dose of 15ml orally, 4 times a day = Total 60ml per day 
 
 
 
 
 
 
 
 
 

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iv. 
FUNDING AND SUPPORT IN KIND 
 
FUNDER(S) 
 
FINANCIAL AND NON FINANCIALSUPPORT 
GIVEN 
Pharmacare Europe Ltd.  
Unit 3 Dialog, Fleming Way, Crawley, West 
Sussex, RH10 9NQ. 
Non-Financial – free of charge supply of 
Sambucol and placebo 
East Kent Hospitals University NHS Foundation 
Trust (EKHUFT) 
Research support staff to carry out trial as non-
funded.  
 
 
v. 
ROLE OF TRIAL SPONSOR AND FUNDER 
 
The sponsor is East Kent Hospitals University NHS Foundation Trust and will hold overall 
responsibility for the initiation and management of the trial. 
The required product and placebo will be provided by Pharmacare Europe Ltd. 
The sponsor is responsible for trial design, conduct, data analysis and interpretation, manuscript 
writing, and dissemination of results. The obligation in terms of the final decision regarding any of 
these aspects of the trial therefore lie with the sponsor.  
 
vi. ROLES AND RESPONSIBILITIES OF TRIAL MANAGEMENT COMMITEES 
 
Trial Steering Committee (TSC)  
 
The Trial Steering committee is a multidisciplinary group consisting of a group of members who jointly 
have responsibility for the design, conduct and evaluation of the clinical research project who will meet 
every 4 months and report to the sponsor. 
The role of the TSC is to provide overall supervision for a trial on behalf of the Trial Sponsor and to 
ensure that the trial is conducted to the rigorous standards set out in the Department of Health’s 
Research Governance Framework for Health and Social Care and the Guidelines for Good Clinical 
Practice.  
 
Trial Management Group 
 
The Trial Management Group will meet on a weekly basis due to the rapidly evolving nature of the 
COVID pandemic to ensure all practical details of the trial are progressing well and working well and 
everyone within the trial understands them. 
The trial will be conducted in compliance with the protocol, standard operating procedures, policies, 
local R&D management guidance, Good Clinical Practice including the Research Governance 
Framework.  
 
vii. PROTOCOL CONTRIBUTORS 
 
The protocol has been compiled with the input of clinicians, a pharmacist and an independent 
statistician who are experienced in NHS clinical trials. Overviewed by research delivery teams to 
ensure practical implementation of the protocol, and reviewed by the research and innovation 
department to ensure compliance as sponsor. Due to COVID-19 restrictions we have been unable to 
involve service users in the development of this protocol. However, results will be shared amongst the 
patient group. 
 
 
viii. KEY WORDS:  
 
Coronavirus symptoms, COVID-19, Sambucol®, Sambucus nigra, Elderberry, SARS-CoV-2 

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ix. TRIAL FLOW CHART  
 
 
 
Patient Information sheet given by 
research team and consent for 
contact gained along with contact 
details to contact the patient on a 
positive test result. 
Study poster picked up or seen in A&E, a 
swabbing station or a public place  with 
details on how to contact research team if in 
receipt of a positive test results and wish to 
participate. Or information about the trial 
obtained from other external sources eg the 
media 
Randomised liquid 
collected by a family 
member/friend, dropped 
by research team or 
delivered by a courier 

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1 BACKGROUND 
  
The outbreak of the new coronavirus SARS-CoV-2 (COVID-19) in China has rapidly progressed to 
pandemic status of global importance. The current lack of a proven anti-viral that is effective has meant 
the current management of severe respiratory coronaviruses remains supportive. The success achieved 
in treating bacterial infections is not paralleled in antivirals. The relative paucity lies in a lack of drugs 
that stop replication within a living cell, and that the peak rate of growth may occur prior to symptoms. 
 
A randomised controlled trial of lopinavir/ritonavir (an antiviral treatment commonly used to treat HIV) 
compared to standard of care in patients with severe COVID-19 demonstrated no clinical benefit and in 
13.8% treatment had to be stopped early due to adverse events (1). Prophylactic use of 
hydroxychloroquine continues worldwide both within and outside of clinical trials but concern remains 
with prescribing an unproven drug with well-known adverse neurological and cardiac effects (2).  
 
‘RECOVERY’ is a large UK randomised controlled trial established to test a range of potential treatments 
for COVID-19 in hospitalised patients, including lopinavir/ritonavir and hydroxychloroquine. Over 12,000 
patients have been enrolled from 176 NHS hospitals. It showed no benefit of hydroxychloroquine nor 
lopinavir/ritonavir in this population, and by contrast, that low-dose dexamethasone reduces the risk of 
death by about one-third among patients receiving ventilation and by one-fifth in those requiring oxygen 
alone. However, no benefit was demonstrated amongst those not requiring respiratory support. (3) 
 
Pharmacognosy is the study of medicines derived from natural sources. Plant extracts have been widely 
used to treat a number of medical conditions, with some of the best-known examples including, quinine 
isolated from Cinchona pubescens (cinchona tree) used to treat malaria, Papaver somniferum to make 
morphine and Digitalis purpurea for treating atrial fibrillation. A number of plant constituents have 
demonstrated anti-viral activity. Hippocrates, ‘Father of Medicine’ referred to Elderberry as ‘natures 
medicine chest’. 
In vitro Sambucus FormosanaNakai extract showed potent antiviral activity against human coronavirus 
NL63 in terms of decreased cytopathic effect and sub-G1 arrest in coronavirus infected cells. It produces 
a significant reduction in viral yield, plaque formation and virus attachment. The authors conclude that 
like Sambucus nigra L., Sambucus FormosanaNakai might possess  antiviral features against the broad 
spectrum of human respiratory coronaviruses (4). 
This supports the previously published data of Sambucus spp., and Sambucus nigra L. providing the 
antiviral properties against influenza A and B viruses and herpes simplex type 1 (5,6). Zakay-Rones et 
al 1995 demonstrated a significant improvement in symptoms in 93.3% of patients treated with 
standardised elderberry extract within 2 days compared to within 6 days in the control arm (p<0.001). 
Complete cure occurred in 90% of those receiving the extract in 2 to 3 days (7). In subsequent 
randomised double -blind studies Zakay-Rones et al demonstrated no adverse events and significant 
improvement in clinical symptoms and higher antibody titres in those receiving Sambuci fructus (8). 
Chen at al 2014 demonstrated with in vitro testing of coronavirus Infectious Bronchitis Virus (IBV) with 
Sambucus.nigra a reduction in virus titres by four orders of magnitude, compromised envelopes 
and  membrane vesicles. This virion disruption likely renders it non-infectious (9). Of further interest was 
that complete inhibition occurred when pre-treatment of virus in combination with post- infection 
treatment. 
 
SARS-CoV-2 (COVID-19) is a readily transmissible virus that has a wide-ranging incubation period of 
2-14 days (US Centers for Disease Control and Prevention). The symptoms are often non-specific and 
include fever, cough, fatigue, diarrhoea and loss of sense of taste and smell. Clinical features range 
from mild to severe. Varying transmission patterns and mild symptoms are of concern as they facilitate 
rapid spread. Pre-existing potential drug therapies are under investigation, and only started once the 
patient has symptoms, but do have well established side effect profiles. Prophylaxis and prevention are 
currently dependent on social distancing and isolating with vaccines remaining in development, 
potentially not for mass use in the near future. 
 
 

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Sambucus extract has well documented anti-viral properties and no known drug interactions were 
identified in the literature. Hence, Sambucus maybe well suited for limited prophylaxis or treatment of 
mild/ moderate COVID-19. There is clear in Vitro evidence of activity against coronavirus and in human 
trials of influenza. The aim of this study is to see if Sambucol® Black Elderberry Original Liquid 
(Sambucus nigra) at a dose of 15ml, 4 times a day, reduces the duration or severity of symptoms of 
COVID-19. Symptomatic patients presenting to drive through testing (i.e. non-hospitalised) who test 
positive and who consent will be randomised to placebo or Sambucol® and blinded to treatment 
allocation. Study staff/investigators responsible for assessing outcomes and data analysis will also be 
blinded to treatment allocation. Data will be collected to determine resolution of symptoms and the two 
groups compared. 
 
 
2 RATIONALE  
 
There is a paucity of other pre-existing drug treatments changing the outcomes/symptoms in non-
hospitalised patients with COVID-19. Evidence shows that Sambucus.Nigra has antiviral action 
against coronavirus in vitro and has been successful in treating influenza viruses in vivo. It is therefore 
likely that Sambucus.nigra may be effective in the treatment of COVID-19 in terms of reducing 
duration of symptoms and potentially progression to more severe disease.  
Sambucol® Black Elderberry Original Liquid (Sambucus nigra) does not require a prescription and has 
no known side effects, meaning it would be a well-tolerated treatment in early disease in comparison 
with other postulated medications. The dose and route of administration for the trial is standard. A 
placebo arm will be used to ensure any reported affect is due to the Sambucol® only. 
Currently there is no research looking into symptoms reduction on the wider outpatient community. 
This trial has the potential to target the disease progression in this outpatient population and thus 
reduce hospitalisation of COVID-19 patients. This will also have an impact on wider health economics 
enabling people to return to work sooner.  
 
 
Aim: To determine whether ‘Sambucol® Black Elderberry Original Liquid (Sambucus nigra) is effective 
in reducing the severity of symptoms of COVID-19. 
 
 
2.1 
Assessment and management of risk 
 
We anticipate this to be low risk trial given that Sambucol® Black Elderberry Original Liquid 
(Sambucus nigra) has never had reported adverse events/effects since commencing manufacture in 
1991.  
A thorough literature review has demonstrated there are no recorded side effects or drug interactions. 
Due to this it is classified as a food supplement and can be purchased freely without consultation or 
prescription, in food health shops and supermarkets, without limitation. 
Vomiting and diarrhoea has been reported with the consumption of large volumes of raw and unripe 
fruit. 
As with any product there is a potential allergy to the ingredients, hence those with known allergy will 
be excluded. As with all medicines, patients will be advised to seek urgent medical help if there are 
any signs of a severe allergy (i.e. difficulty breathing, swelling face/lips/ tongue). 
With limited data on the effect in pregnancy and breast feeding this patient group has been excluded. 
Poorly controlled diabetics will be excluded due to the high sugar content. 
The dose used is constant with no increments. 
 
 
 
 
 
 

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3 
OBJECTIVES AND OUTCOME MEASURES/ENDPOINTS 
  
3.1 
Primary objective 
  
Hypothesis - Sambucol reduces the severity of symptoms by at least 30% by day 10 in people who 
are symptomatic with the SARS-CoV-2 (COVID-19) virus, compared to placebo. 
 
To determine whether Sambucol reduces the severity of symptoms by 30% by day 10 in people who 
are symptomatic with the SARS-CoV-2 (COVID-19) virus, as determined by VAS score. 
 
 
3.2 
Secondary objectives 
To determine whether Sambucol reduces hospital admissions by day 28. 
To determine if Sambucol reduces the severity of symptoms at day 3, 7, 14 and 28 days 
 
 
3.3 
Outcome measures 
Reduction on symptom severity as per Wellness VAS Score 
Reduction in hospital admission as per participant hospital admission rates 
 
3.4 
Primary endpoint 
Primary endpoint will be the difference in number of patients by day 10 who have an improvement in 
reported SARS-CoV-2 (COVID-19) symptoms as per wellness VAS scale. 
 
3.5 
Secondary endpoints 
Reduction in hospital admissions by day 28 as measured by rates of hospital admission 
Reduction in the severity of symptoms at day 3, 7, 14 and 28 days as measured by wellness VAS 
Scale. 
Reduction in the number of patients with mild/moderate disease progressing to severe disease (ITU 
/HDU admission) 
 
3.6 
Exploratory endpoints - N/A 
 
3.7  
Table of objectives and outcome measures  
Objectives 
Outcome Measures  
Timepoint(s) of evaluation of 
this outcome measure (if 
applicable) 
Primary Objective 
Does Sambucol reduce the 
severity of symptoms by 30% at 
day 10 in people who are 
symptomatic with the SARS-
CoV-2 (COVID-19) virus?  
Patient Wellness VAS score  
 
Day 10 score 
Secondary Objectives 
Reduction in admission to 
hospital by day 28.  
Reduction in the severity of 
symptoms at day 3, 7, 14 and 
28 days 
To determine of those admitted 
to hospital the number of 
patients with mild/moderate 
disease progressing to severe 
disease (ITU /HDU admission) 
Admissions to hospital 
 
 
Wellness VAS score 
 
 
 
Number admitted to HDU/ITU 
 
 
 
Within 28 days of enrolment 
 
 
Day 3,7, 14 and 28  
 
 
 
Day 28 data 
 
 

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4 
TRIAL DESIGN 
This study is a superiority test of Sambucol to placebo in the treatment of COVID 19 positive patients, 
with a parallel design.  
Single Centre, placebo controlled, single blinded, two arm, randomised controlled trial.  
 
5 
TRIAL SETTING 
 
This trial will run as a single centre trial at East Kent Hospitals University Foundation Trust. Secondary 
care patients will be highlighted from the positive COVID 19 swab lists. These lists include all patients 
attending swabbing centres or accident and emergency departments in the trust, but who are not 
admitted. Eligibility, consent and randomisation will be completed by GCP trained research nurses and 
doctors 
: Participants will also be identified at local swabbing sites. Members of the Research Team will be 
there to approach and discuss the trial with people attending for swabbing. 
Participants may also contact the research team after seeing the approved posters or hearing about 
the trial through other external sources eg the media. 
. 
 
 
6 
PARTICIPANT ELIGIBILITY CRITERIA 
 
6.1 
Inclusion criteria 
• 
Aged over 18 years 
•    Symptomatic SARS-CoV2 infection 
• 
Positive SARS-CoV2 swab test result within the last 5 days 
• 
Capacity to provide written or electronic informed consent  
• 
Able to complete follow up visits required via phone/email 
• 
Able to provide a positive swab result 
 
6.2 
Exclusion criteria 
• Known allergy to Sambucus fructi (Elderberries) or food colourants  
• Pregnant or breast feeding  
• Poorly controlled diabetes 
• Treatment with any immunosuppressive medicines including Prednisolone 10mg daily or 
equivalent. Oral anti-inflammatory medicines such as Ibuprofen are allowed. 
• Participation in any COVID 19 research study involving prophylactic or therapeutic IMPs in the 
last 30 days. 
• Previous participation in this trial.  
• Already taking Sambucol or any form of elderberry supplement 
 
 
 
 

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7 
TRIAL PROCEDURES  
 
Research team activities 
Information about 
the trial 
The approved study posters will be available in A&E and at 
swabbing stations, to inform patients about the availability of the 
trial for those who test positive. Participant can express interest in 
participating when swabbed and details for contact can be taken 
by the research team, or patients can email the research team 
later to express interest. Participants may hear about the trial 
through other external sources eg the approved posters or the 
media and may contact the research team. 
At swabbing station 
Patients will be approached by a member of the research team at 
the swabbing station and asked if they have symptoms. If they do, 
they will be asked if they have time to talk and the research team 
member will explain about the study and ask if the patient is 
interested in taking away any further information about the study. If 
they say yes, they will be given the Patient Information Sheet. The 
research team member will ask if they are happy to provide their 
contact details so that they can be contacted after they receive 
their test result.   
Patients contacting 
the Research Team 
Directly 
Patients who have heard about the trial through the media or by 
seeing one of the approved posters may contact the Research 
Team directly. If they are able to show the positive swab test result 
that they have had a within the last 5 days, the research team will 
email them the Patient Information Sheet.  The research team will 
then contact them as below  
Telephone Contact 
Patients who have given their contact details at a swabbing station 
or A&E will be telephoned after 24hours to see if they have  tested 
positive for COVID-19, and if they have they are asked if they are 
interested in taking part in the study. The member of the research 
team will then check whether they have read the Patient 
Information Sheet and answer any questions.  
Patient Information 
Sheet (PIS) 
PIS will be emailed to patients who test positive and express 
interest in the study, for them to read and consider taking part. 
Follow up telephone 
call within 5 days of 
a positive swab; 
Verbal Consent and 
Baseline data 
collection 
Opportunity to raise and discuss any questions about the trial or 
PIS(a). Eligibility criteria will be checked and electronic or verbal 
consent will be received. An eligible patient can decline to 
participate without having to give any reason. 
After consent, the research team will collect baseline 
demographics, VAS score, patient symptoms. (a) 
Ineligible patients 
If anyone does not meet the eligibility criteria the research team 
will explain why and ensure that they have time to ask any 
questions. 
Randomisation and 
collection of trial 
treatment 
Patients will be randomised to active or placebo liquid and a 14 
day supply of study liquid dispensed to take home and start 
straight away. This can either be collected by a family member or 
friend and dropped to the patient’s doorstep – or the research team 
will drop to the doorstep so that everyone has a chance to take 
part. If a participant lives further away the liquid will be delivered to 
their home address by courier. 
Follow Up visits on 
day 3, 7, 10, 14 and 
28 
All follow up visits will occur either by phone, text or email 
depending on participant preference at day to collect the following 
data: 
• 
Current symptoms   

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• 
How well are you feeling VAS score 0 -100 (0 will be recorded 
in the case of death) 
• 
What are your current symptoms?  
• 
Have you started any new medications? 
• 
Have you missed any doses of your study liquid?  
• 
Experienced any adverse events? 
• 
At day 14 – if a participant verbally consented initially, they will 
be asked to sign a paper consent form which was sent out with 
their trial liquid and return it in the research team for filing. At day 
14 they will also be reminded that they need to stop taking their 
study liquid. 
Notes 
(a) This limits the exposure of the research team to the virus during later collection of 
written consent 

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7.1 Recruitment 
Once patients notify the research team that they are happy to be contacted after a positive swab,  the 
research team will then call the patients at home to see if they are still interested in taking part and 
send out the information sheet via email if they did not receive it at the swabbing station. If the patient 
does not have an email address they can arrange collection of the information sheet from site or it can 
be read out over the phone to them. Once they have had time to consider all the information and wish 
to take part, the research team will check all inclusion / exclusion criteria and eligibility. If they are not 
eligible the research team will explain why and ensure they have time to ask any relevant question 
they may have. If patients are eligible but decline they can do so without any reason. 
 
For eligible patients wishing to take part, a link for an electronic consent form will be sent via email for 
e-signing. If this is not possible for any reason, then verbal  consent will be taken over the telephone 
with the patients and two members of the research team. This will be recorded on a telephone consent 
form which will be read fully by the research team to the patients before consent is received. A copy of 
the telephone consent form will be sent to the patient’s home with their randomised trial liquid. 
Enclosed will also be a blank copy of the full written consent form to send back via free post envelope 
supplied.  
 
After consent research team will collect basic demographics, baseline VAS scores and check the 
patient’s symptoms.  
 
Eligible patients will be randomised 1:1, with no stratification, to either active treatment or placebo 
using REDCap software and be provided with the relevant bottles at full dosage, for 14 days. 
Dosage instructions will be provided on the labelling and will be discussed by the research team over 
the telephone prior to randomisation. Participants will have a contact number to contact the research 
team if they need to ask questions at any time.  
 
7.1.1   Participant identification 
Study posters will be left in A&E telling patients how they can take part if they receive a positive swab 
result. Patients will also be approached at the hospital swabbing tent if symptomatic on presentation 
for swabbing. Outpatient nurses carrying out the swabbing clinics will notify the research team of the 
time slots of any patient who might be eligible from their daily lists. No further details will be passed to 
researchers other than this. 
A member of the research team will explain the study and ask if they would be happy to be contacted 
in the event that their swab comes back positive. If so, they will give the patient the Patient Information 
Sheet and will ask for their details to contact them after the swab result is returned. 
Alternatively, patients can contact the research team later using the details on the poster, available at 
the swabbing station, in the event of a positive swab within the last 5 days.  
At a non-EKHUFT swabbing site, patients will be approached by a member of the research team who 
will explain the study and ask if they would be happy to be contacted in the event that their swab 
comes back positive. If so, they will also give the patient the Patient Information sheet and ask for their 
details to contact them after the swab result is returned. 
Alternatively, in the event of a positive swab, patients can contact the research team using the details 
on the poster displayed at the swabbing station. 
Patients who have heard about the trial through the media or by seeing one of the approved posters 
may contact the Research Team directly. If they are able to show the positive swab test result that 
they have had a within the last 5 days, the research team will email them the Patient Information 
Sheet.   
 
7.1.2 Screening 
The only diagnostic test required will be the positive COVID result, which has already been taken. Proof 
of positive swab result will be requested at eligibility check. No other screening tests required.  

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7.1.3  Payment  
There will be no payment for taking part in this trial. 
 
7.2   Consent  
For eligible patients wishing to take part, a link for an electronic consent form will be sent via email for e-
signing. If this is not possible for any reason, then verbal consent will be taken over the telephone with the 
patients and two members of the research team. This will be recorded on a telephone consent form which  
will be read fully by the research team to the patients before consent is received. A copy of the telephone 
consent form will be sent to the patient’s home with their randomised trial liquid.  
Consent will be obtained by GCP trained research team members delegated the task by the PI. No trial 
procedures will occur before consent.  
The Chief Investigator (CI) retains overall responsibility for the conduct of research at the site. 
The taking of consent will be delegated to research staff and doctors who have been duly authorised, 
trained and competent to participate according to the ethically approved protocol, principles of Good 
Clinical Practice (GCP) and Declaration of Helsinki. A delegation log will be completed, checked and 
signed by the CI. 
Only participants over the age of 18 years and capable of informed consent will be recruited. 
Informed consent will be obtained prior to the participant being randomised and receiving Sambucol or 
placebo.  
The right of a participant to refuse participation without giving reasons will be respected.   
 
The participant will remain free to withdraw at any time from the trial without giving reasons and 
without prejudicing any further treatment and must be provided with a contact point where they may 
obtain further information about the trial. Data collected up to the point of withdrawal will only be used 
after withdrawal if the participant has consented for this on withdrawal. If a participant is required to re-
consent or new information is required to be provided to a participant it is the responsibility of the PI to 
ensure this is done in a timely manner.  
The CI takes responsibility for ensuring that all vulnerable participants are protected and participate 
voluntarily in an environment free from coercion or undue influence 
 
7.2.1 Additional consent provisions for collection and use of participant data and biological 
specimens in ancillary studies, if applicable 
No ancillary studies, no biological specimens collected. 
 
7.3 
The randomisation scheme 
The method of randomisation  
• Simple randomisation with a 1:1 allocation ratio with no stratification. 
• Using  REDCap software https://www.project-redcap.org/ 
 
7.3.1 Method of implementing the randomisation/allocation sequence 
• 
Following consent, randomisation will be via REDCap using a randomisation list generated by the 
study statistician and uploaded onto REDCap. 
• 
Team members are provided with login details and randomise patients by simply completing an 
on-screen form with patient details, inclusion and exclusion criteria. Treatment allocation is 
immediately available. 
Investigators can view the details of patients they have previously randomised. 
  
 

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7.4 
Blinding 
 
The placebo has comparable appearance and taste to Sambucol® Black Elderberry Original Liquid. 
Trial participants, trial statistician and outcome assessors will be blinded to which arm the participant has 
been randomised. Investigators, the research delivery team, clinical trial pharmacist and study staff not 
involved in assessing outcomes will not be blinded. All research delivery team members will be aware 
that they are not to divulge the randomised arm to participants at any time point.  
Participants will remain blind to their allocated trial arm for the duration of the trial.  
 
 
 
7.5 
Emergency Unblinding 
In case of serious adverse event, when deemed necessary by the investigator or treating health care 
professional, unblinding may be requested. A designated number will be provided on hospital systems 
and to patients in case unblinding needs to be performed by the research team. The CI will be 
contactable by the research team if necessary. It is thought unlikely unblinding will need to occur unless a 
new allergic reaction occurs to the food colouring in the liquid. 
Documentation of the unblinding process including the reason and person who performed the unblinding, 
will be recorded in the site file. Thereby retaining the blinding of the outcome assessors. 
An alert will be placed on the patient administration system (PAS) for the trust to advise clinicians that the 
participant is on the BERRY trial including contact details of who to contact for unblinding in an 
emergency. An assessment to unblind should be made in consultation with the clinical and research 
teams. If the decision is made to unblind the participants randomisation to the health professional, it will 
be expressed that the participant should not be given this information and that it should be shared only on 
a need to know basis. The medical team will be advised to document the act of unblinding in the patient 
notes, but not the randomised arm unless this is deemed essential for the participants ongoing care. This 
will maintain overall blinding in the trial. The treating health care professional will continue to deal with the 
participant’s medical emergency as appropriate. 
In all cases the Investigator will evaluate the causality and expectedness of SAEs as though the 
participant was receiving the active medication. 
Unblinding and the reasons for doing so will be recorded on the CRF/data collection tool, in the site file 
and medical notes. It will also be documented at the end of the trial in any final trial report and/or 
statistical report 
The CI/Investigating team will notify the Sponsor in writing as soon as possible following the unblinding 
and CI/PI will also notify the relevant authorities.  
SUSARs are required to be reported unblinded. 
 
7.6 
Baseline data 
• 
Patient details (e.g. name, NHS number, date of birth, sex) 
• 
COVID-19 symptom onset date 
• 
COVID-19 severity (appendix 2) 
• 
Date positive SARs-CoV2 test 
• 
Major comorbidity/ Medical History (e.g. heart disease, diabetes, chronic lung disease) 
• 
Regular medications 
• 
Duration symptoms and type of symptoms  
• 
Wellbeing VAS Score 
• 
Demographics 
• 
Smoking Status 
• 
Vaccinated against COVID-19? Dates? And which vaccine? 
 

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7.7 
Trial assessments 
 
Trial Visit Schedule 
 
 
 
Screening 
 
Day 1 
Day 3 (+/-1) 
Day 7 (+/-1) 
Day 10 (+/-1) 
Day 14 (+/-1) 
Day 28 (+/-1) 
Early Exit 
Verbal Consent  
 
X 
 
 
 
 
 
 
 
Eligibility 
 
X 
 
 
 
 
 
 
 
Inclusion/Exclusion 
 
X 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
Medical History 
 
X 
 
 
 
 
 
 
 
Duration of Symptoms 
 
X 
 
 
 
 
 
 
 
Symptom Check 
 
X 
X 
X 
X 
X 
X 
X 
X 
Comorbidities 
 
X 
 
 
 
 
 
 
 
Concomitant Medications 
   
X 
X 
X 
X 
X 
X 
X 
X 
Smoking Status 
 
X 
 
 
 
 
 
 
 
Electronic Consent 
(telephone consent if electronic not 
possible)  
 
X 
 
 
 
 
 
 
Written Consent  
(if electronic consent not possible)  
 
 
 
 
 
X 
 
 
Randomisation 
 
 
X 
 
 
 
 
 
 
Dispense Trial Liquid  
 
 
X 
 
 
 
 
 
 
Adverse Events 
 
 
 
X 
X 
X 
X 
X 
X 
Telephone/Emails Visit  
 
 
 
X 
X 
X 
X 
X 
X 
Trial Liquid Compliance 
 
 
 
X 
X 
X 
X 
X 
X 
Wellbeing VAS Score 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 

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7.8 
Long term follow-up assessments 
With the exception of any pregnancy outcomes, Data collection will end at day 28 following 
randomisation. Research team will follow up the outcomes of any notified pregnancies. 
This will be to check to see if patients have been admitted to hospital in the 28 days following a positive 
SARS-CoV2 test. 
If admitted:  
• 
Date of hospitalisation 
Admission hospital and location (i.e. HDU/ITU) – reason and outcome.     Date discharge / death 
 
7.9 
Qualitative assessments  
N/A 
 
7.10 
Withdrawal criteria  
Subject withdrawal criteria 
• 
Patient choice (no justification required) 
• 
Responsible physician choice - medical reasons (i.e. individual adverse events or new 
information gained about a treatment).   
Patients may withdraw their consent to participate in the trial at any time without reason. No further 
trial procedures will be undertaken and no data or samples will be collected from the time of 
withdrawal.  
However, data collected up to the time of consent withdrawal will be included in the data reported for 
the trial. The Investigator should inform the coordination team as soon as possible and complete the 
consent withdrawal Case Report Form (CRF). 
  
Circumstances where the trial may be prematurely stopped include:  
 
• 
Failure to recruit participants at the required rate to meet target. 
• 
Publication of trial results for an alternative to Sambucol which shows dramatic improvement in 
symptoms when given pre-admission.  
• 
Identification of a serious safety issue 
• 
Sponsors request 
 
7.11 
Storage and analysis of clinical samples  
Not applicable – No clinical or biological samples. 
 
7.12 
End of trial 
The trial end date - 01/11/2022 
Last patient last visit date – 01/10/2022 
 
 
 
 
 
8 
TRIAL TREATMENTS 
 
8.1 
Name and description of treatments  
Sambucol® Black Elderberry Original (Sambucus nigra) Liquid  
Constituents: 29.4 % (w/w) Black Elderberry (Sambucus nigra) fruit juice, 70% (w/w) of glucose syrup.  
The main ingredient is black elderberry juice and it meets the requirements of the Directive  

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2012/12/EU relating to fruit juices. The product also contains two food additives: citric acid (E330) as 
acidity regulator and potassium sorbate (E202) as preservative. 
Primary packaging:  Plastic PET amber bottles 120ml. Caps are PP28 white tamper-proof caps with 
security seal. 
Secondary Packaging:  None. Outer Carton: Cardboard 376mm x 191mm x 116mm. 32 bottles per 
case. 
 
Placebo for Sambucol® Black Elderberry Original (Sambucus nigra)120ml 
Constituents:  70% (w/w) of glucose syrup, Flavouring agent: Elderberry Blossom. Colourants:  
Eurocert Carmoisine (311804) (E-122) and Eurocert Brilliant Black PN (419358) E-151. The product 
also contains two food additives: citric acid (E330) as acidity regulator and potassium sorbate (E202) 
as preservative. 
Primary packaging: Plastic PET amber bottles 120ml. Caps are PP28 white tamper-proof caps with 
security seal. 
Secondary Packaging:  None. Outer Carton: Cardboard 376mm x 191mm x 116mm. 32 bottles per 
case. 
 
 8.2 
Regulatory status of the treatment   
Sambucol Liquid is marketed within the EU and other countries as a food supplement. 
 
8.3 
Product Characteristics  
Sambucol® Black Elderberry Original (Sambucus nigra) Liquid has been used as a supplement since 
1991 with no reports of adverse effects received by the Manufacturer. 
 
8.4 
Treatment storage and supply  
 
8.4.1 Storage: Sambucol/placebo will be stored at ambient temperature, below 25oC there are no 
temperature monitoring requirements needed. 
 
8.4.2 Shipment:  Treatments will be supplied Free of Charge by Pharmacare (Europe) Limited. 
 
8.4.3 Ordering and Re-Ordering: Initial shipment will be shipped to site following site activation. 
Further supplies – logistics as agreed between site and Pharmacare. 
 
8.4.4 Receipt: Shipments will be received by Pharmacy Clinical Trial Staff and inspected for any 
damage or defects. In the event of product defect or damage contact 
Technical@pharmacareeurope.com and cc. Noelia.rodrigo@pharmacareurope.com 
 
8.4.5 Accountability:  Pharmacy will keep an inventory log for stock received. The Batch number will 
be recorded in the CRF of product issued to each participant. No other accountability records will be 
kept. 
 
8.4.6 Dispensing: On confirmation of eligibility, e consent and randomisation will occur. Patients will 
be randomised to active or placebo liquid and a 14 day supply of study liquid dispensed The Research 
Nurse will write the Patient’s Trial ID No. on the label and record the Batch number in the patient’s 
record The liquid can either be collected by a family member or friend and dropped to the patient’s 
doorstep – or the research team will drop to the doorstep so that everyone has a chance to take part. 
If a participant lives further away the liquid will be delivered to their home address by courier 
 
8.4.7 Recall Procedure: In the event of a product defect participants will be telephoned and asked to 
stop taking the product and either to destroy as for household waste or to return any unused product  
 
 
to site according to the seriousness of the defect. Further investigation will be by Pharmacare’s Recall 
Procedure, as appropriate. 
 

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8.4.8 Post-trial access to Sambucol Liquid: Various Sambucol® products are readily available to 
purchase from Health Food stores, Pharmacies and various on-line retailers. Sambucol will not be 
supplied to participants after the end of the trial. 
 
Blinding: Active Sambucol and Placebo will be packaged and labelled as THE BERRY TRIAL 
LIQUID. The active and placebo packs will be differentiated by – Q and Z respectively appended to 
the Batch Number. Packs will be received and stored by unblinded Pharmacy Staff and personnel 
distributing treatments to participants will also be unblinded. 
 
8.5  
Preparation and labelling of Treatments  
Active Sambucol and placebo will be packaged and labelled as ‘THE BERRY TRIAL LIQUID’ and 
supplied by the Manufacturer details of dosage and storage conditions, Batch Number and expiry 
date; PI Name; Trial name; space for Pt Trial ID no and ‘For Clinical trial Use only’ as shown in 
Appendix 1.  
Sponsor Name, address and contact telephone number will be provided on the Patient Information 
Leaflet.  
8.6 
Dosage schedules 
All participants will take a fixed dosage of 15ml orally four times a day. Total daily dose 60ml. Missed 
doses can be taken at any time. If the patient vomits shortly after taking a dose they can repeat the 
dose.  
 
8.7 
Dosage modifications  
There are no dose modifications.  If a participant feels unwell after taking a dose they should contact 
the Research Nurse to discuss whether they should continue or stop treatment and withdraw from the 
trial. Research Nurse will seek advice from the Chief Investigator. 
 
8.8 
Known drug reactions and interaction with other therapies 
There are no known drug interactions or adverse effects of Sambucol Original Liquid®. Due to the 
high sugar content of the liquid participants with unstable diabetes are excluded from the trial. 
  
8.9 
Concomitant medication 
 A record of all concomitant medication will be recorded in the CRF by the Research Nurse during the 
consent process. If the participant is admitted to Hospital they will be instructed to continue trial 
treatment to complete the 14 day course. 
 
8.10 
Trial restrictions  
• 
No contraindications whilst on the active phase of the trial including dietary 
requirements/restrictions 
• 
Due to lack of clinical data available on the use of Sambucol during pregnancy, contraception 
needs to be used for the 14 days duration for use and for 7 days after completion. This 
includes: 
o Intrauterine Device (IUD) 
• 
Hormonal based contraception (pill, contraceptive injection etc.) 
o 
Double Barrier contraception (condom and occlusive cap e.g. diaphragm or cervical 
cap with spermicide) 
o 
True abstinence 
 
8.11 
Assessment of compliance with treatment  
Participants will be asked to confirm their compliance during planned telephone interviews with 
research staff on days 3,7,10 and 14. 

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9 
PHARMACOVIGILANCE 
9.1 
Definitions 
Term 
Definition 
Adverse Event (AE) 
Any untoward medical occurrence in a participant to whom a 
medicinal product has been administered, including occurrences 
which are not necessarily caused by or related to that product. 
Adverse Reaction 
(AR) 
 
An untoward and unintended response in a participant to an 
investigational medicinal product which is related to any dose 
administered to that participant. 
The phrase "response to an investigational medicinal product" means 
that a causal relationship between a trial medication and an AE is at 
least a reasonable possibility, i.e. the relationship cannot be ruled out. 
All cases judged by either the reporting medically qualified 
professional or the Sponsor as having a reasonable suspected causal 
relationship to the trial medication qualify as adverse reactions. It is 
specifically a temporal relationship between taking the drug, the half-
life, and the time of the event or any valid alternative etiology that 
would explain the event. 
Serious Adverse 
Event (SAE) 
A serious adverse event is any untoward medical occurrence that: 
• results in death 
• is life-threatening 
• requires inpatient hospitalisation or prolongation of existing 
hospitalisation 
• results in persistent or significant disability/incapacity 
• consists of a congenital anomaly or birth defect 
Other ‘important medical events’ may also be considered serious if 
they jeopardise the participant or require an intervention to prevent 
one of the above consequences. 
NOTE: The term "life-threatening" in the definition of "serious" refers 
to an event in which the participant was at risk of death at the time of 
the event; it does not refer to an event which hypothetically might 
have caused death if it were more severe. 
Serious Adverse 
Reaction (SAR) 
An adverse event that is both serious and, in the opinion of the 
reporting Investigator, believed with reasonable probability to be due 
to one of the trial treatments, based on the information provided. 
Suspected 
Unexpected Serious 
Adverse Reaction 
(SUSAR) 
A serious adverse reaction, the nature and severity of which is not 
consistent with the information about the medicinal product in 
question set out in the reference safety information: 
 
NB: to avoid confusion or misunderstanding of the difference between the terms “serious” and 
“severe”, the following note of clarification is provided: “Severe” is often used to describe intensity of a 
specific event, which may be of relatively minor medical significance. “Seriousness” is the regulatory 
definition supplied above. 
 
 
 
9.2 
Operational definitions for (S)AEs 
 

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The following adverse events are known manifestations of COVID-19 related disease. They will not be 
recorded in the medical notes as (S)AEs as part of this COVID-19 intervention trial. 
 
 
• 
Chills  
• 
Loss of taste and/or smell 
• 
Cough  
• 
Bloody sputum  
• 
Sore throat  
• 
Nasal symptoms: blocked or runny nose  
• 
Ear pain  
• 
Wheezing  
• 
Chest tightness  
• 
Shortness of breath  
• 
Muscle aches  
• 
Joint pain /heaviness 
• 
Fatigue  
• 
Headache  
• 
Confusion  
• 
Loss of appetite  
• 
Abdominal pain  
• 
Nausea/vomiting  
• 
Diarrhoea  
• 
Sore, red, gritty eyes  
• 
Skin rash / irritation 
• 
Dry/Sore lips 
• 
Mouth Ulcers  
• 
High Temperature  
 
 
 
 
Evaluation of adverse events  
The Sponsor expects that adverse events (apart from expected AEs) are recorded in the medical 
notes from the point of Informed Consent regardless of whether a participant has yet received a 
medicinal product. Individual adverse events should be evaluated by the investigator. This includes 
the evaluation of its seriousness, and any relationship between the investigational medicinal 
product(s) and/or concomitant therapy and the adverse event (causality).  
 
Assessment of seriousness  
Seriousness is assessed against the criteria in section 9.1. This defines whether the event is an 
adverse event, serious adverse event or a serious adverse reaction  
 
Assessment of causality  
Definitely: A causal relationship is clinically/biologically certain. This is therefore an Adverse 
Reaction  
Probable: A causal relationship is clinically / biologically highly plausible and there is a plausible 
time sequence between onset of the AE and administration of the investigational medicinal 
product and there is a reasonable response on withdrawal. This is therefore an Adverse 
Reaction.  
Possible: A causal relationship is clinically / biologically plausible and there is a plausible time 
sequence between onset of the AE and administration of the investigational medicinal product. 
This is therefore an Adverse Reaction.  

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Unlikely: A causal relation is improbable and another documented cause of the AE is most 
plausible. This is therefore an Adverse Event.  
Unrelated: A causal relationship can be definitely excluded and another documented cause of the 
AE is most plausible. This is therefore an Adverse Event.  
Unlikely and Unrelated causalities are considered NOT to be trial drug related  
Definitely, Probable and Possible causalities are considered to be trial drug related  
 
 
A pre-existing condition must not be recorded as an AE or reported as an SAE unless the condition 
worsens during the trial and meets the criteria for reporting or recording in the appropriate section of 
the CRF as specified in section 9.1 and 9.2  
 
 
 
Clinical assessment of severity  
Mild: The participant is aware of the event or symptom, but the event or symptom is easily tolerated  
Moderate: The participant experiences sufficient discomfort to interfere with or reduce his or her usual 
level of activity  
Severe: Significant impairment of functioning; the subject is unable to carry out usual activities and / 
or the participant’s life is at risk from the event.  
Admissions to hospital for COVID-19 disease progression will not be reported as an SAE for the 
purpose of this trial as this is listed as a trial endpoint. 
 
There are no reported risks of taking Sambucol® Original Liquid. Any adverse reaction or adverse 
event reported during the trial will be assessed for causality by the Investigator and appropriate 
reporting undertaken where necessary. 
 
 
9.3 
Recording and reporting of SAEs, SARs AND SUSARs  
All SAEs occurring from the time of start of trial treatment until 14 days post cessation of trial 
treatment must be recorded on the Trial data collection form and scanned and emailed to the 
Sponsor within 24 hours of the research staff becoming aware of the event. The original form 
will be copied and held by the Sponsor. 
The Chief Investigator is responsible for ensuring that the assessment of all SAEs for 
relatedness and expectedness is completed and the onward notification of all SARs to the 
Sponsor immediately or not more than 24 hours of first notification. The sponsor has to keep 
detailed records of all SARs reported to them by the trial team.  
All SAEs/SARs may be reported by the trial team to Pharmacare UK. 
Adverse Reactions will be reported to the REC if they could:  
• adversely affect the health of participants  
• impact on the conduct of the trial   
• alter the risk to benefit ratio of the trial  
• alter the competent authority’s authorisation to continue the trial in accordance with Directive 
2001/20/EC  
For each SAEs the following information will be collected: 
• 
full details in medical terms and case description 
• 
event duration (start and end dates, if applicable) 
• 
action taken 
• 
outcome 
• 
seriousness criteria 
• 
causality (i.e. relatedness to trial drug / investigation), in the opinion of the investigator 
• 
whether the event would be considered anticipated. 
Events will be followed up until the event has resolved or a final outcome has been reached.”   
 

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All SAEs assigned by the PI or delegate (or following central review) as both suspected to be 
related to treatment and unexpected will be classified as SUSARs and will be subject to 
expedited reporting to the REC. The sponsor will inform the REC and Manufacturer of SUSARs 
within the required expedited reporting timescales.” 
 
 
 
9.4 
Responsibilities 
 
Principal Investigator (PI ):  
Checking for AEs and ARs when participants attend for treatment / follow-up. 
1. Using medical judgement in assigning seriousness, causality and whether the 
event/reaction was anticipated using the Reference Safety Information approved for the 
trial. 
2. Using medical judgement in assigning seriousness and causality and providing an 
opinion on whether the event/reaction was anticipated using the Reference Safety 
Information approved for the trial.  
3. Ensuring that all SAEs are recorded and reported to the sponsor within 24 hours of 
becoming aware of the event and provide further follow-up information as soon as 
available. Ensuring that SAEs are chased with Sponsor if a record of receipt is not 
received within 2 working days of initial reporting.  
4. Ensuring that AEs and ARs are recorded and reported to the sponsor in line with the 
requirements of the protocol.  
 
Chief Investigator (CI) / delegate or independent clinical reviewer: 
1. Clinical oversight of the safety of patients participating in the trial, including an ongoing 
review of the risk / benefit. 
2. Using medical judgement in assigning the SAEs seriousness, causality and whether the 
event was anticipated (in line with the Reference Safety Information) where it has not 
been possible to obtain local medical assessment. 
3. Using medical judgement in assigning whether and event/reaction was anticipated or 
expectedness in line with the Reference Safety Information [in Phase I and early Phase 
II CTIMPs]. 
4. Immediate review of all SUSARs.  
5. Review of specific SAEs and SARs in accordance with the trial risk assessment and 
protocol as detailed in the Trial Monitoring Plan. 
6. Assigning Medical Dictionary for Regulatory Activities (MedDRA) or Body System coding 
to all SAEs and SARs. 
7. Preparing the clinical sections and final sign off of the Development Safety Update 
Report (DSUR). 
Sponsor: (NB where relevant these can be delegated to CI) 
1. Central data collection and verification of AEs, ARs, SAEs, SARs and SUSARs 
according to the trial protocol onto a database.  
2. Reporting safety information to the CI, delegate or independent clinical reviewer for the 
ongoing assessment of the risk / benefit according to the Trial Monitoring Plan. 
3. Reporting safety information to the independent oversight committee identified for the 
trial Steering Committee (TSC)) according to the Trial Monitoring Plan. 
4. Expedited reporting of SUSARs to the REC within required timelines. 
5. Notifying Investigators of SUSARs that occur within the trial. 
6. The unblinding of a participant for the purpose of expedited SUSAR reporting [For 
double blind trials only]. 
7. Checking for (annually) and notifying PIs of updates to the Reference Safety Information 
for the trial. 
8. Preparing standard tables and other relevant information for the DSUR in collaboration 
with the CI and ensuring timely submission to the REC. 

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Trial Steering Committee (TSC):  
In accordance with the Trial Terms of Reference for the TSC, periodically reviewing safety data.  
 
 
 
 
9.5 
Notification of deaths  
The procedure for notification of death which does not constitute a SAR or SUSAR will be notification 
to sponsor by the chief investigator of only deaths that are assessed to be caused by the treatment will 
be reported to the sponsor. This report will be immediate. 
 
9.6 Pregnancy Reporting Participants will be asked to report any pregnancy occurring within 28 days of 
trial enrolment. GPs will be asked for their assistance in relaying information regarding any pregnancies 
to the trial team. Any such pregnancies must be reported to the Chief Investigator and the Sponsor using 
the relevant Pregnancy Reporting Form. Pregnancy is not considered an AE unless a negative or 
consequential outcome is recorded for the mother or child/foetus. If the outcome meets the serious 
criteria, this would be considered an SAE. 
 
9.7 
Overdose  
Participants will be advised in the PIS to contact the research team on for advice if they believe they 
have taken too much Sambucol/Placebo or an overdose. Participants will also be asked about their 
compliance with the recommended dosage during telephone consultations with the Research Staff. 
Emergency contact for 24hr  
Overdose definition: More than 50 % excess dosage (> 90ml) in any 24 hour period. Identified during 
participant consultations. In the event of a confirmed overdose the participant will be withdrawn from 
the trial.  
Any overdose event will be recorded as a protocol deviation and reported to the Sponsor. 
 
9.8 
Reporting urgent safety measures  
If any urgent safety measures are taken the CI/Sponsor shall immediately and in any event no later 
than 3 days from the date the measures are taken, give written notice to the REC of the measures 
taken and the circumstances giving rise to those measures. 
 
9.9 
The type and duration of the follow-up of participants after adverse reactions. 
Adverse reactions are extremely unlikely, however, after clinical assessment by the Investigator follow 
up will be advised accordingly as either no follow-up required, follow-up via patient’s GP or via a 
Hospital appointment. 
Any SUSAR will be reported to the Sponsor irrespective of how long after treatment administration the 
reaction has occurred until resolved. 
 
9.10 
Development safety update reports (DSURs) 
The CI will provide (in addition to the expedited reporting above) DSURs once a year throughout the 
clinical trial, or as necessary, to the Research Ethics Committee and the sponsor.   
 
The report will be submitted within 60 days of the Developmental International Birth Date (DIBD) of the 
trial each year until the trial is declared ended. 
 
 
10 
STATISTICS AND DATA ANALYSIS 
10.1 
Sample size calculation 
The sample size was based on detecting a difference in the primary outcome, VAS symptoms score at 
10 days, between groups. The standard deviation of the outcome is estimated to be 20 units, and a 
difference between groups of 10 units is regarded as being of clinical importance. With a 5% 

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significance level and 90% power, it is calculated that 86 patients per group, 172 in total, are required. 
To allow for a 15% dropout, it is proposed that 204 patients are recruited into the study.  
 
10.2 
Planned recruitment rate 
204 participants over 24 months 
 
 
10.3 
Statistical analysis plan 
A full Statistical Analysis Plan (SAP) will be developed and agreed in advance of any data analysis. 
 
10.3.1 Summary of baseline data and flow of patients 
Summary statistics of all patient demographics and baseline data will be produced for each of the two 
study groups separately. Categorical variables will be summarised by the number and percentage of 
patients in each category. Continuous variables will be summarised by the mean and standard 
deviation if found to follow a Normal distribution, and the median and inter-quartile range otherwise.  
 
The flow of patients through the trial will be illustrated by a Consort diagram.  
 
10.3.2 Primary outcome analysis 
The primary outcome, VAS symptoms score at 10 days, will be analysed using Analysis of Covariance 
(ANCOVA). The scores at 10 days will be used as the outcome variable, with the symptom scores at 
baseline included as a covariate.  
 
The primary analysis will be performed on an Intention to Treat (ITT) basis. Participants will be 
analysed in the arm to which they were randomised, irrespective of whether they received their 
allocated treatment. 
 
If the population varies for the ITT analysis, a per protocol analysis will be performed, as a sensitivity 
analysis.  
 
10.3.3 Secondary outcome analysis 
Secondary outcomes with a baseline measurement at baseline will be analysed using equivalent 
methods to the primary outcome.  Secondary endpoints measured on a categorical scale will be 
compared between groups using the Chi-square test.  
 
10.4 Subgroup analyses 
None planned. 
 
10.5 Adjusted analysis 
No adjustments for baseline or demographic factors are planned 
 
10.6 
Interim analysis and criteria for the premature termination of the trial 
No interim analyses will be performed. See 7.10 for stopping criteria. 
 
10.7 Participant population 
The primary analyses for all analysis (primary, secondary, safety) will be done on an ITT basis, 
with patients included in the groups to which they were randomised, irrespective of whether they 
received their allocated treatment. 
 
10.8 Procedure(s) to account for missing or spurious data  
Spurious data will be identified and checked with original source documentation. If found to still be 
spurious, based on clinical values may be excluded from the analysis. Any omissions will be 
noted and justified. 
 
Patients with missing data for any given variable will be omitted from the analysis. No imputations 
of missing data will be performed.  
 

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10.9 Other statistical considerations 
None noted 
 
 
 
 
 
11 
DATA MANAGEMENT  
 
11.1 
Data collection tools and source document identification 
 
CRF  
All data will be transferred into a Case Report Form (CRF) which will be labelled using a participant’s 
unique trial ID. All trial data in the CRF must be extracted from and be consistent with, the relevant 
source documents. The CRFs must be completed, dated and signed by the investigator or designee in 
a timely manner. It remains the responsibility of the investigator for the timing, completeness, legibility 
and accuracy of the CRF pages. The CRF will be accessible to trial coordinators, data managers, the 
investigators, Clinical Trial Monitors, Auditors and Inspectors as required.  
The institution will keep records of all participating patients (sufficient information to link records e.g., 
CRFs, hospital records and samples), all original signed informed consent forms and copies of the 
CRF pages. 
 
All CRF pages must be clear, legible and completed in ink. Any errors should be crossed with a single 
stroke so that the original entry can still be seen. Corrections should be inserted and the change dated 
and initialled by the investigator or designee. If it is not clear why the change has been made, an 
explanation should be written next to the change. Typing correction fluid must not be used.  
The CRF contains the validated VAS scoring system and will be used to record patient wellness. 
 
To enable peer review, monitoring, audit and/or inspection records of all participating participants 
(sufficient information to link records e.g., CRFs, hospital records), all original signed informed consent 
forms and copies of the CRF pages.  
Source data may include but is not limited to:  
• Signed informed consent forms  
• Patient medical records (electronic or paper)  
                 • Clinical research forms/folders  
 
11.2 
Data handling and record keeping - Data Protection & Participant Confidentiality 
Paper CRFs will be kept in a securely locked room with restricted access. Data will be uploaded to the 
REDCap database for analysis. Access is password -protected. All patient data will be collected and 
stored in accordance with the Data Protection Act 1998 and the General Data Protection Regulation. 
 
 
11.3 
Access to Data 
Direct access will be granted to authorised representatives from the Sponsor, host institution and the 
regulatory authorities to permit trial-related monitoring, audits and inspections- in line with participant 
consent. 
 
11.4 
Archiving 
• 
archiving will be authorised by the Sponsor following submission of the end of trial report 
• 
if the sponsor and trial site are the same, archiving will occur as per standard procedure.  
• 
the location and duration of record retention for:  

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o essential documents 5 years 
o the trial database 10 years 
• 
destruction of essential documents will require authorisation from the Sponsor 
 
 
• 
If a study participant becomes an inpatient, their medical records are source data and must 
be retained for the same retention period as the essential documents. 
• 
If a study participant becomes an inpatient, their medical records should be clearly marked 
that the patient has taken part in a clinical trial and they should not be destroyed (this should 
apply to all volumes of patient’s medical records) 
• 
The label must clearly state the retention period 
• 
The hospital notes of patients will not be archived with the TSF, as they may still be 
important for any on-going medical care.  Only certified copies of the patient notes that are 
directly relevant to the study can be archived with the TSF, if necessary. 
 
12 
MONITORING, AUDIT & INSPECTION 
A Trial Monitoring Plan will be developed and agreed by the Trial Management Group (TMG), TSC 
and CI based on the trial risk assessment. A detailed monitoring plan will be generated detailing the 
frequency and scope of the monitoring for the trial. This will be dependent on a documented risk 
assessment of the trial. Throughout the course of the trial, the risk assessment will be reviewed and 
the monitoring frequency adjusted as necessary.  
 
The investigator will make all trial documentation and related records available should an Inspection 
occur. Should a monitoring visit or audit be requested, the investigator will make the trial 
documentation and source data available to the Sponsor’s representative. All participant data will be 
handled and treated confidentially.   
 
 
13  
ETHICAL AND REGULATORY CONSIDERATIONS 
13.1  Research Ethics Committee (REC) review& reports 
• 
Before the start of the trial, approval will be sought from a REC for the trial protocol, 
informed consent forms and other relevant documents e.g. advertisements and GP 
information letters. Substantial amendments that require review by REC will not be 
implemented until the REC grants a favourable opinion for the trial.  
• 
All correspondence with the REC will be retained in the Trial Master File/Investigator Site 
File  
• 
An annual progress report (APR) will be submitted to the REC within 30 days of the 
anniversary date on which the favourable opinion was given, and annually until the trial is 
declared ended 
 
• 
It is the Chief Investigator’s responsibility to produce the annual reports as required. 
• 
The Chief Investigator will notify the REC of the end of the trial 
• 
If the trial is ended prematurely, the Chief Investigator will notify the REC, including the 
reasons for the premature termination 
• 
Within one year after the end of the trial, the Chief Investigator will submit a final report with 
the results, including any publications/abstracts, to the REC 

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13.2  
Peer review 
No external Peer Review has been undertaken.  
 
 
 
13.3  
Public and Patient Involvement 
Patients have not been involved in the formulation of the study due to constraints of time. 
Dissemination of results will be publicised for patients to review.  
 
13.4  Regulatory Compliance  
• 
The trial will not commence until Favourable REC and HRA approval is received.  
• 
For any amendment to the study, the Chief Investigator or designee, in agreement with the 
sponsor will submit information to the appropriate body in order for them to issue approval 
for the amendment. The Chief Investigator or designee will work with sites (R&D 
departments at NHS sites as well as the study delivery team) so they can put the necessary 
arrangements in place to implement the amendment to confirm their support for the study as 
amended. 
 
13.5  Protocol compliance  
Prospective, planned deviations or waivers to the protocol are not allowed under the UK regulations 
on Clinical Trials and must not be used. 
 
Protocol deviations, non-compliances, or breaches will be adequately documented on the relevant 
forms and reported to the Chief Investigator and Sponsor immediately.  
Deviations from the protocol which are found to occur repeatedly will not be accepted and will require 
immediate action and could potentially be classified as a serious breach.  
 
 
13.6  Notification of Serious Breaches to GCP and/or the protocol  
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 
(c) the conditions and principles of GCP in connection with that trial; or the protocol relating 
to that trial, as amended from time to time.  
 
The sponsor will be notified immediately of any case where the above definition applies during the trial 
conduct phase.  
The sponsor of a clinical trial will notify the competent authority in writing of any serious breach of the 
protocol within 7 days of becoming aware of that breach. 
 
13.7  Data protection and patient confidentiality  
 
All investigators and trial site staff involved in this trial must comply with the requirements of the 
General Data Protection Regulation 2018, Data Protection Act 2018 and Trust Policy with regards to  
 
the collection, storage, processing, transfer and disclosure of personal information and will uphold the 
Act’s core principles. 
There will be no transfer of data between organisations as all recruitment will be undertaken at one 
Trust. 

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Data will be stored for 5 years in a secured locked room which can only be accessed by the minimum 
number of required people, to include the Trial team and those undertaking quality control, audit and 
analysis. 
 
 
 
 
 
13.8  Financial and other competing interests for the chief investigator, PIs at each site and 
committee members for the overall trial management  
There are no ownership interests from any member of the current research team that are related to 
products, services, or interventions considered for use in the trial or that may be significantly affected 
by the trial. 
There are no commercial ties to the research team. 
There are no non-commercial potential conflicts relating to the current research team. 
When new members of the research team join they will be asked to declare if any competing 
interest/conflict of interest through the signing of such a form which will be stored in the Investigator 
Site File. 
 
13.9  Indemnity 
East Kent Hospitals University NHS Foundation Trust is an NHS body and is therefore legally liable for 
the negligent acts and omissions of their employees under the NHS Indemnity Arrangements for 
clinical negligence claims in the NHS, issued under cover of HSG 96/48.  Anyone harmed whilst taking 
part in a clinical trial as a result of negligence on the part of a member of the study team this liability 
cover would apply. 
Non-negligent harm is not covered by the NHS indemnity scheme. East Kent Hospitals University NHS 
Foundation Trust, therefore, cannot agree in advance to pay compensation in these circumstances. In 
exceptional circumstances an ex-gratia payment may be offered. 
 
13.10  Amendments  
Protocol amendments must be reviewed and agreement received from the Sponsor for all proposed 
amendments prior to submission to the HRA and REC.  
The only circumstance in which an amendment may be initiated prior to HRA and REC approval is 
where the change is necessary to eliminate apparent, immediate risks to the participants (Urgent 
Safety Measures). In this case, accrual of new participants will be halted until the HRA and REC has 
been obtained.  
 
13.11  Post trial care 
 
There will be no post trial care. However, all SAEs/AEs will be followed up until resolved or if they are 
not going to be resolved, monitoring will end at 3 months post the 28 day end of study date and 
reported accordingly. 
 
13.12  Access to the final trial dataset 
 
The final data set will be accessible to the Chief Investigator, TSC and statistician. 
 
14  
DISSEMINIATION POLICY 
14.1  
Dissemination policy 
Ownership of the data arising from this trial resides with the trial team and the sponsor. On completion 
of the trial the data will be analysed and tabulated and a Final Trial Report prepared. However, given 
the nature of this international pandemic, preliminary data may be reported prior to the completion the  
 

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study, or if interim analyses are adequate for dissemination of critical safety or efficacy data.  The 
sponsor will provide, if practicable, advanced notice of any publications to Pharmacare Europe Ltd. 
At conclusion of the study a fully anonymised dataset will be placed in the public domain. Data sharing 
within a federated consortium of UK investigators across the four nations will be adopted.  
 
 
 
 
 
14.2  Authorship eligibility guidelines and any intended use of professional writers 
Final authorship of the final trial report will be authorised by the Chief Investigator. 
Anyone listed as an author will approve the final version of the paper and accept responsibility for 
ensuring that he/ she is familiar with its contents and can identify his/her contribution to it. 
The study will be written up by the trial group, professional medical writers will not be hired. 
 
15 
REFERENCES 
 
1) A trial of Lopinavir-Ritonavir in Adults Hospitalised with severe COVID-19. Cao B, Wang Y, Wen D et 
al. N Engl J Med. 2020 Mar 18. 
2) Chloroquine and hydroxychloroquine in COVID-19.  Ferner R & Aronson J. BMJ 2020;369:m1432 
3) RECOVERY Trial news https://www.recoverytrial.net/news  accessed 21.57 on 28.07.2020. 
4) Antiviral activity of Sambucus FormosanaNakai ethanol extract and related phenolic acid constituents 
against human coronavirus NL63. Weng J, Lin C, Lai H et al Virus Res. 2019 Nov;273 197767 
5) Inhibitory activity of a standardized elderberry liquid extract against clinically-relevant human 
respiratory bacterial pathogens and influenza A and B viruses. Krawitz C, Mraheil M, Imirzalioglu C et 
al. BMC Complement Altern Med. 2011;11:16 
6) Antiviral activity of the infusion (SHS-174) from flowers of Sambucus Nigra L., aerial parts of 
Hypericum Perforatum L., and roots of Saponaria Officinalis L. Against influenza and herpes simplex 
viruses. Serkedijeva J, Manolova N, Zgorniak-Nowosielska I et al.Phytother. Res.4, 97-100. 
7) Inhibition of several strains of influenza virus in Vitro and reduction of symptoms by an Elderberry 
extract (Sambucus nigra L) during an outbreak of Influenza B Panama. Zakay-Rones Z, Varsano N, 
Zlotnik M et al. J Altern. Complement. Med. 1(4),361-369. 
8) Randomized study of the efficacy and safety of oral elderberry extract in the treatment of influenza A 
and B virus infections. Zakay-Rones Z, Thom E, Wollan T et al. J Int Med Res 2004;32:132-40 
 
9) Sambucus nigra extracts inhibit infectious bronchitis virus at an early point during replication. Chen 
C, Zuckerman D, Brantley S et al. BMC veterinary research; Jan 2014;10:24. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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16  APPENDIX 1. Manufacturer’s Labels. 
 
Sambucol (Active) BN: 104170Q 
 
 
 
 
 
 
 
 
 
 
 
Placebo BN:104170Z 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
THE BERRY TRIAL LIQUID 
Directions: 15ml (3 teaspoons) four times daily 
Store in a dry place below 25°C 
Investigator: Ms J. Evans Trial ID No: …………………… 
Batch No:104170 Q 
Best Before End: 05/2023 
BERRY TRIAL 
For Clinical Trial Use Only 
THE BERRY TRIAL LIQUID 
Directions: 15ml (3 teaspoons) four times daily 
Store in a dry place below 25°C 
Investigator: Ms J. Evans Trial ID No: …………………… 
Batch No:104170 Z 
Best Before End: 01/2023 
BERRY TRIAL 
For Clinical Trial Use Only 
 

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Appendix 2: 
 
Classification of COVID19 severity 
 
 
 
 
 
Severity 
Symptoms/ signs 
MILD 
Patients with uncomplicated upper respiratory tract viral 
infection, may have non-specific symptoms such as fever, 
fatigue, cough (with or without sputum production), 
anorexia, malaise, muscle pain, sore throat, dyspnoea, 
nasal congestion, or headache. Rarely, patients may also 
present with diarrhoea, nausea and vomiting. 
The elderly and immunosuppressed may present with 
atypical symptoms. 
 
Adult with pneumonia but no signs of severe pneumonia 
and no need for supplemental oxygen. 
 
MODERATE 
Fever or suspected respiratory infection, plus one of: 
respiratory rate > 30 breaths/min; severe respiratory 
distress; or SpO2 ≤ 93% on room air. 
Includes those managed on ward requiring oxygen 
support via nasal specs or mask 
SEVERE/ CRITICAL 
Patient requiring HDU/ITU support. 
Invasive ventilation. 
Acute Respiratory Distress Syndrome. 
Sepsis- life-threatening organ dysfunction caused by a 
dysregulated host response to suspected or proven 
infection. 
Septic shock defined as persisting hypotension despite 
volume resuscitation, requiring vasopressors to maintain 
MAP ≥ 65 mmHg and serum lactate level > 2 mmol/L