Reducing Acute Severe Respiratory Events in Health Care Workers During the Covid-19 Pandemic With OM85
Phase: PHASE3
Conditions: Respiratory Viral Infection, Covid19
Sponsor: The University of Queensland

 
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Covid-19 OM85 HCW                                                                                                                           Page 1 of 
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Reducing acute severe respiratory events in health care workers during the Covid-19 
pandemic with OM85 
 
 
Clinical Study Protocol 
 
 
 
A phase 3, multi-centre study testing the reduction of acute severe respiratory events in 
health care workers during the Covid-19 pandemic with OM85 
 
 
 
 
 
 
 
 
Study Number: BV-2020/19 
 
Australia and New Zealand Clinical Trials Registry Number: ACTRN12620000473965p 
NIH Clinical Trials Registry Number:  
UTN: U1111-1250-2920 
 
Date and Version of Protocol: 2.1 23 July 2020 
 
 
 
 
 
Confidentiality Statement 
 
This document is confidential and is to be distributed for review only to site investigators, 
potential site investigators, study staff and applicable Ethics Committees. It is understood that 
this information will not be disclosed to others without written authorization from the sponsor 
except to the extent necessary to obtain informed consent from those persons to whom the 
investigational product may be administered 
 
 

 
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Covid-19 OM85 HCW                                                                                                                           Page 2 of 
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1. 
Contact Information 
Sponsor 
The University of Queensland 
 
62 Graham Street  
 
South Brisbane, QLD  4101 
 
Principal Investigators 
Professor Peter Sly, MBBS, MD, DSc, FRACP 
 
Centre for Child Health Research 
 
University of Queensland 
 
62 Graham Street  
 
South Brisbane, QLD  4101 
 
Phone: +61 7 3069 7383 
 
Email: p.sly@uq.edu.au 
 
Professor Pat Holt, PhD, DSc, FRCPI, FAA 
 
Telethon Kids Institute 
 
Perth Children’s Hospital 
 
15 Hospital Avenue 
 
Nedlands, WA 6009 
 
Phone: +61 8 6319 1000 
 
Email: Patrick.holt@telethonkids.org.au 
 
Professor Adnan Custovic, DM, MD, PhD, FRCP 
 
Imperial College London 
 
St Mary’s Campus Medical School 
 
Norfolk Place 
 
London W2 1PG 
 
Phone: +44 020 7594 3274 
 
Email: a.custovic@imperial.ac.uk 
 
Associate Professor Deborah Strickland, PhD 
 
Telethon Kids Institute  
 
15 Hospital Avenue 
 
Nedlands, WA 6009 
 
Phone: +61 8 6319 1000 
 
Email: deb.strickland@telethonkids.org.au 
 
Dr Anthony Bosco, PhD 
 
Telethon Kids Institute 
 
15 Hospital Avenue 
 
Nedlands, WA 6009 
 
Phone: +61 8 6319 1000 
 
Email: anthony.bosco@telethonkids.org.au 
 
Professor John Upham, MBBS, PhD, FRACP 
 
University of Queensland  
 
Level 7, Translational Research Institute,  
 
37 Kent Street, Woolloongabba QLD 4102  
 
Phone: +61 7 3443 8065  
 
Email: john.upham@uq.edu.au 

 
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Covid-19 OM85 HCW                                                                                                                           Page 3 of 
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Dr Emmanuelle Fantino, PhD 
 
Centre for Child Health Research 
 
University of Queensland 
 
62 Graham Street  
 
South Brisbane, QLD  4101 
 
Phone: +61 7 3069 7302 
 
Email: e.fantino@uq.edu.au 
                                                       
Associate Professor David Reid, MB, MD, FRACP 
 
The Prince Charles Hospital  
 
627 Rode Rd, 
 
Chermside Qld 4032 
 
Phone: +61 7 3139 4000  
 
Email: david.reid@health.qld.gov.au 
                                                       
Professor Robert Ware, BSc, PhD                 
 
Menzies Health Institute Queensland 
 
Griffith University  
 
170 Kessels Rd 
 
Nathan, QLD  4111 
 
Phone: +61 7 3735 7111 
 
Email: r.ware@griffith.edu.au 
                                                       
Dr Adam Irwin, MBBS, PhD 
 
Queensland Children’s Hospital 
 
501 Stanley St 
 
South Brisbane QLD  4101 
 
Phone: +61 7 3068 1111  
 
Email: a.irwin@uq.edu.au 
 
                                                  
Statistical Consultant 
Professor Robert Ware, BSc, PhD 
 
Menzies Health Institute Queensland 
                                                       
Griffith University  
 
Serious Adverse Event Reporting Children’s Health and Environment Program, (CHEP) 
Child Health Research Centre  
 
Fax: +61 7 3069 7159 
 

 
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Covid-19 OM85 HCW                                                                                                                           Page 4 of 
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2. 
Investigator Signature Page 
 
 
Reducing acute severe respiratory events in health care workers during the 
 Covid-19 pandemic with OM85 
 
 
I confirm that I have read Protocol Version 2.0 dated 12th June 2020. As the site 
investigator, I understand it, and I agree to adhere to the study conduct requirements and 
agree to conduct this protocol in accordance with International Conference on Harmonization 
Good Clinical Practice E6 (ICH-GCP), the Declaration of Helsinki, the United States (US) 
Food and Drug Administration (FDA), and local regulations and guidelines. I agree to report 
all information or data in accordance with the protocol and in particular I agree to report any 
serious adverse events. I will accept the monitors, auditors and regulatory inspector’s 
oversight of the study. I will promptly submit the protocol to the applicable ethical review 
board. 
 
 
 
Chief investigator signature 
 
 
Professor Peter D Sly 
Chief investigator printed name 
 
 
 
Date 
 
 

 
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Covid-19 OM85 HCW                                                                                                                           Page 5 of 
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Covid-19 OM85 HCW                                                                                                                           Page 6 of 
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3. 
Synopsis of Protocol 
 
 
Title 
A phase 3, multi-centre study testing the reduction of acute 
severe respiratory events in health care workers during the 
Covid-19 pandemic with OM85  
 
Clinical phase 
Phase Three 
 
Protocol number 
BV-2020/19 
 
Principal Investigators 
Prof Peter Sly 
 
Prof Patrick Holt 
 
Prof Adnan Custovic 
 
Assoc Prof Deborah Strickland  
 
Dr Anthony Bosco 
 
Prof John Upman 
  
 
Dr Emmanuelle Fantino 
 
Assoc Prof David Reid    
 
Prof Robert Ware  
                                            
Dr Adam Irwin  
 
 
Statistical consultant 
Prof Robert Ware 
 
Study design 
Parallel group, Wait-list design, with treatment delayed for 3 
months  
 
Participants will be randomized on a 1:1 ratio with 500 
participants per group in Australia and 500 per group in the UK. 
 
 
Group 1:  Wait-list control. One capsule OM85 (7.0 mg) will 
be given daily for 3 months, commencing in Month 3, with 3 
months follow-up off treatment. 
 
 
Group 2:  Initial treatment. One capsule OM85 (7.0 mg) will be 
given daily for 3 months, commencing on day 0, with 3 months 
follow-up off treatment. 
 
Accrual objective 
2000 Health Care Workers (HCW):- 
 
 
1000 from Brisbane Hospitals  
 
1000 from UK Hospitals  
 
 
 
 

 
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Covid-19 OM85 HCW                                                                                                                           Page 7 of 
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Accrual period 
4 weeks 
 
Study duration 
12 months 
 
Countries 
Australia, United Kingdom 
 
Sites 
Queensland Children’s Hospital, Brisbane (Site Investigator: 
Dr Adam Irwin) 
 
Imperial College Hospital, London (Site Investigator: Prof 
Adnan Custovic) 
 
Prince Alexandra Hospital, Brisbane (Site Investigator: Prof 
John Upham) 
 
Princess Charles Hospital, Brisbane (Site Investigator: Assoc 
Prof David Reid) 
 
Primary endpoint 
The proportion of HCW contracting an ARI necessitating 
workforce removal. 
 
Secondary endpoints 
Secondary endpoints include: 
 The time to ARI necessitating workforce removal 
 The proportion of HCW contracting an ARI necessitating 
workforce removal at end of treatment and at the end of the 
follow-up period, overall and by department 
 The total number of days with respiratory symptoms (upper 
or lower) 
 The proportion of HCW with COV infection documented 
by PCR, seroconversion and/or COV ARI necessitating 
workforce removal.  
 The time to LRI necessitating workforce removal 
 The proportion of HCW contracting an LRI necessitating 
workforce removal at end of treatment and at the end of the 
follow-up period, overall and by department 
 The proportion of HCW with COV infection documented 
by PCR, seroconversion and/or COV LRI necessitating 
workforce removal. 
 
 
Mechanistic endpoints 
Mechanistic endpoints (Brisbane only) include: 
 Seroconversion to COV 
 Host immune cell profile grouped who test respectively 
positive or negative to COV during a ARI and stratified by 
treatment (COV+/OM+, COV+/OM-, COV-/OM+, COV-
/OM-). 

 
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Covid-19 OM85 HCW                                                                                                                           Page 8 of 
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 White blood cell transcriptomic profile by group 
(COV+/OM+, COV+/OM-, COV-/OM+, COV-/OM-). 
 White blood cell cytokine production profile by group 
(COV+/OM+, COV+/OM-, COV-/OM+, COV-/OM-). 
 
 
Safety endpoints 
Safety endpoints include: 
 Treatment-related adverse events 
 Routine haematology and clinical chemistry 
 
 
Inclusion criteria 
Participants who meet all of the following criteria are eligible 
for enrolment:  
1. HCW “front line” clinical departments assessing or caring 
for patients with suspected or proven COV infection at one 
of the recruiting hospitals in Brisbane or London  
2. Participants who, in the opinion of the investigator, are able 
to comply with the protocol for its duration 
3. Written informed consent signed and dated by participant 
according to local regulations 
 
Exclusion criteria 
Participants who meet any of these criteria are not eligible for 
enrolment: 
1. Staff with prior COV infection necessitating workforce 
removal. 
 
Treatment description 
Broncho-Vaxom adult capsules® (OM85) 
 
Replacement of Participants 
Participants who withdraw consent or who are prematurely 
terminated from the study for any other reason will not be 
replaced  
 
Study procedures 
Participants will be randomized to either Group 1 (waitlist 
control, delayed treatment group) or Group 2 (initial treatment) 
for treatment for a period of 3 months with 3 months follow-up 
off treatment 
 
Statistical considerations 
Participants will be randomised in blocks Group 1 (waitlist 
control, delayed treatment group) or Group 2 (initial treatment) 
using a one-to-one ratio 
 
Stopping rules 
Study enrolment may be stopped if any of the following occur: 
 
Death of a participant that is related to study treatment 
 
The study sponsor decides to terminate the study 
 
 
 

 
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Covid-19 OM85 HCW                                                                                                                           Page 9 of 
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Covid-19 OM85 HCW                                                                                                                           Page 10 of 
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4. 
Table of contents 
 
1. 
Contact Information ........................................................................................................ 2 
2. 
Investigator Signature Page ............................................................................................ 4 
3. 
Synopsis of Protocol ......................................................................................................... 6 
4. 
Table of contents ............................................................................................................ 10 
5. 
Glossary of abbreviations .............................................................................................. 13 
6. 
Introduction .................................................................................................................... 15 
6.1 
Background ............................................................................................................... 15 
6.1.1 
Covid-19 ............................................................................................................ 15 
6.1.2 
Health Care Workers.......................................................................................... 15 
6.1.3 
Personal Protective Equipment .......................................................................... 15 
6.1.4 
Therapeutic options ............................................................................................ 16 
6.2 
Investigational product .............................................................................................. 16 
6.3 
Known and potential risks ......................................................................................... 16 
6.4 
Study population ....................................................................................................... 17 
7. 
Study objectives and purpose ....................................................................................... 18 
7.1 
Primary objective ...................................................................................................... 18 
7.2 
Secondary objectives ................................................................................................. 18 
7.3 
Mechanistic objectives .............................................................................................. 18 
7.4 
Safety objectives ....................................................................................................... 18 
8. 
Study Design ................................................................................................................... 19 
8.1 
Description ................................................................................................................ 19 
8.2 
Efficacy Endpoints .................................................................................................... 19 
8.2.1 
Primary efficacy endpoint .................................................................................. 19 
8.2.2 
Secondary efficacy endpoints ............................................................................ 19 
8.2.3 
Mechanistic endpoints ....................................................................................... 19 
8.2.4 
Safety endpoints ................................................................................................. 19 
8.3 
Stopping Rules .......................................................................................................... 20 
9. 
Selection and withdrawal of participants .................................................................... 21 
9.1 
Inclusion criteria ........................................................................................................ 21 
9.2 
Exclusion criteria....................................................................................................... 21 
9.3 
Criteria and procedures for participant withdrawal................................................... 21 

 
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Covid-19 OM85 HCW                                                                                                                           Page 11 of 
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9.3.1 
Withdrawal of participants from study .............................................................. 21 
9.3.2 
Premature termination of study/closure of centre .............................................. 22 
9.4 
Replacement of participants ...................................................................................... 22 
10. 
Study procedures ........................................................................................................ 23 
10.1 
Description of assessments and procedures........................................................... 23 
10.1.1 Informed consent ............................................................................................... 23 
10.1.2 Eligibility criteria ............................................................................................... 23 
10.1.3 Medical/ work history ........................................................................................ 23 
10.1.4 Demographic history .......................................................................................... 23 
10.1.5 Nasal swab ......................................................................................................... 23 
10.1.6 Blood tests .......................................................................................................... 23 
10.1.7 Patient daily symptom data ................................................................................ 23 
10.1.8 Telephone calls .................................................................................................. 24 
10.1.9 Adverse events ................................................................................................... 24 
10.2 
Scheduled visits ..................................................................................................... 24 
10.3 
Early withdrawal visit ............................................................................................ 26 
11. 
Study treatment ........................................................................................................... 27 
11.1 
Enrolment and randomisation ................................................................................ 27 
11.2 
Dosing, formulation and storage ........................................................................... 27 
11.3 
Accountability for investigational product ............................................................ 27 
11.4 
Treatment adherence .............................................................................................. 28 
11.5 
Prohibited medications during study ..................................................................... 28 
11.6 
Permitted medications during study ...................................................................... 28 
12. 
Assessment of safety .................................................................................................... 29 
12.1 
Adverse events ....................................................................................................... 29 
12.1.1 Grading of adverse events .................................................................................. 29 
12.1.2 Attribution of adverse events ............................................................................. 29 
12.2 
Serious adverse events ........................................................................................... 30 
12.2.1 Definition of serious adverse events .................................................................. 30 
12.2.2 Clarification of serious adverse events .............................................................. 30 
12.3 
Investigator’s responsibility for reporting serious adverse events ........................ 31 
12.4 
Reporting to regulatory authorities ........................................................................ 32 
13. 
Statistical considerations ............................................................................................ 33 
13.1 
Randomisation, stratification and blinding ............................................................ 33 

 
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Covid-19 OM85 HCW                                                                                                                           Page 12 of 
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13.2 
Sample size calculations ........................................................................................ 33 
13.2.1 Analysis sample ................................................................................................. 33 
13.2.2 Statistical analyses ............................................................................................. 33 
13.3 
Study endpoint assessments................................................................................... 33 
13.3.1 Primary efficacy endpoint .................................................................................. 33 
13.3.2 Secondary efficacy endpoints and mechanistic endpoints ................................. 34 
13.3.3 Safety endpoints ................................................................................................. 34 
13.4 
Reporting deviations from the original statistical plan .......................................... 34 
14. 
Direct access to source data/documents .................................................................... 35 
14.1 
Identification of source data .................................................................................. 35 
14.2 
Direct access to source data ................................................................................... 35 
14.3 
Case report forms................................................................................................... 35 
15. 
Quality control and quality assurance ...................................................................... 36 
15.1 
Study monitoring ................................................................................................... 36 
15.2 
Information to study personnel .............................................................................. 36 
15.3 
Termination of study ............................................................................................. 36 
15.4 
Protocol amendments, violations and deviations .................................................. 36 
15.5 
Data safety monitoring board ................................................................................ 37 
15.6 
Audits and inspections ........................................................................................... 37 
16. 
Ethics ............................................................................................................................ 38 
16.1 
Statement of compliance ....................................................................................... 38 
16.2 
Informed consent form .......................................................................................... 38 
16.3 
Ethics committee ................................................................................................... 38 
16.4 
Participant confidentiality ...................................................................................... 39 
17. 
Administrative procedures ......................................................................................... 40 
17.1 
Curriculum vitae .................................................................................................... 40 
17.2 
Participant reimbursement ..................................................................................... 40 
17.3 
Archiving ............................................................................................................... 40 
18. 
Finance and insurance ................................................................................................ 41 
19. 
Publication policy ........................................................................................................ 42 
20. 
References .................................................................................................................... 43 
Appendix 1:  Schedule of Assessments and Procedures ..................................................... 44 
 
 

 
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Covid-19 OM85 HCW                                                                                                                           Page 13 of 
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5. 
Glossary of abbreviations 
 
AE 
Adverse event 

 
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Covid-19 OM85 HCW                                                                                                                           Page 14 of 
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AGRF 
Australian Genome Research Facility 
AID 
Australian Infectious Diseases Research 
ARDS 
Acute respiratory distress syndrome 
ARI 
Acute respiratory infection 
CBC 
Clinical blood count 
COV 
SARS-Cov-2 
CHEP 
Children’s Health and Environment Program 
CHQ 
Children’s Health Queensland 
CRF 
Case report form 
DC 
Dendritic cell  
DSMB 
Data safety monitoring board 
EC 
Ethics committee 
ED 
Emergency Department  
GCP 
Good clinical practice 
HCW 
Health Care Worker  
ICH 
International conference on harmonization 
ICU 
Intensive Care Unit 
ITT 
Intention to treat 
LRI 
Lower respiratory infection 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
mg 
milligrams 
MPV 
Mean platelet volume 
PA 
Princess Alexandra Hospital, Brisbane 
PPE 
Personal protective equipment 
QCH 
Queensland Children’s Hospital, Brisbane  
QH 
Queensland Health  
SAE 
Serious adverse events 
SAP 
Statistical analysis plan 
sLRI 
Severe lower respiratory infection 
SPT 
Skin prick test 
TGA 
Therapeutic Goods Administration 
TKI 
Telethon Kids Institute  
TPCH 
The Prince Charles Hospital, Brisbane  
UQ 
University of Queensland 
UV 
Unscheduled visit 
WLC 
Wait List Control 
 
 
 
 
 
 

 
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Covid-19 OM85 HCW                                                                                                                           Page 15 of 
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6. 
Introduction 
6.1 
Background 
6.1.1 
Covid-19 
The Covid-19 pandemic has been characterised by acute respiratory distress syndrome (ARDS) 
accompanied by a systemic cytokine-storm resulting in severe illness, respiratory failure and 
death in some. SARS-Cov-2 (COV) infection per se is not the only underlying issue here, as it 
is becoming evident that ARDS is relatively rare amongst infected subjects, and appears to be 
associated with gross dysregulation of ensuing host-anti-viral responses resulting in collateral 
immune-inflammatory-mediated damage to host tissues. Rather than waiting for susceptible 
subjects to present with COV-associated ARDS, we propose treatment of healthy health care 
workers (HCW) with a therapeutic agent which simultaneously targets front-line innate anti-
viral immune defences, together with the core mechanism that controls immune response 
intensity in the airways. This research addresses the hypothesis that resistance to development 
of severe COV-associated respiratory disease in front-line health workers, even in those who 
develop a primary infection, can be boosted via a regimen of daily dosing with the bacterial-
derived immunomodulatory agent OM85. 
6.1.2 
Health Care Workers 
HCW are at the forefront of the Covid pandemic. Figures from China show around 3300 HCW 
were infected, as were 20% of Italy’s HCW1. Infected HCW who develop lower respiratory 
illnesses (LRI) are removed from frontline services putting additional pressure on system 
ability to provide patient care. Respiratory viruses, including COV, are initially encountered 
by the nasal epithelium where infection is initiated. An adequate anti-viral response can contain 
the virus in the upper airway, with cold-like symptoms. An inadequate response can see the 
infection spreading to the lower respiratory tract and induce a severe lower respiratory illness 
(sLRI). HCW in front line clinical departments, such as emergency departments, intensive care 
units, COV isolation wards and radiology departments, are at increased risk of COV infection. 
 
6.1.3 
Personal Protective Equipment  
In theory, personal protective equipment (PPE) can protect HCW from infection. However, 
adequate PPE is in short supply and commonly used surgical masks are unlikely to protect 
HCW from virus-containing aerosols generated by infectious patients. Facemasks, originally 
introduced to protect patients from respiratory emissions from surgeons, can protect the wearer 
from inhaling particulate matter2. However, even the most efficient mask is unlikely to give 
adequate protection if not worn correctly, or if the mask does not fit3. Winter et al.3 tested the 
fit of three versions of the high-efficiency N95 respirator (commonly known as P2 in Australia) 
to 50 health care workers. They found that only 18% of health care workers achieved an 
adequate fit without training, 40% achieved an adequate fit after training, and adequate mask 
fit was not possible in 28% of subjects. These data show that assuming that a mask will provide 
protection is likely to be false in many circumstances, especially in the absence of adequate 
training. N95 respirators are certified against national standards (USA), providing at least 95% 
protection against particles in the sub-micron (0.1 to 0.3μm) range4.  N99 masks, that filter 
99% of sub-micron particles, odours and gaseous pollutants, and >99% of bacteria and viruses 
are likely to be required to adequately protect HCW from COV-infected patients. 
Most HCW rely on surgical masks that usually have a layer of 3-ply melt-blown material 
between layers of non-woven fabric. The melt-blown material acts as the filter that stops 

 
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Covid-19 OM85 HCW                                                                                                                           Page 16 of 
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microbes from entering or exiting the mask. Most surgical masks feature pleats or folds 
allowing the user to expand the mask to cover the area from the nose to the chin. The mask 
may have a metal strip the user moulds across the bridge of the nose to improve the fit, and is 
fixed to the face by elastic ear loops or ties secured behind the head. These masks are not 
designed to form a seal around the nose and mouth nor to protect the wearer from submicronic 
particulate matter5, including viruses such as COV.  
 
6.1.4 
Therapeutic options 
As the PPE available to HCW is unlikely to prevent COV infection, an alternative approach is 
required. OM85, variably known as Bronch-Vaxom, Broncho-Munal, Ommunal, 
Paxoral, or Vaxoral, has been in widespread clinical use throughout Europe and South 
America since the early 1980s for protection of infants, children and adults from the 
inflammatory sequelae of lower respiratory diseases, in clinical settings ranging from infection-
associated wheeze in infants and school children6,7 to severe winter exacerbations occasioning 
hospitalization in adult COPD patients8,9.  While its mechanism-of-action is not fully 
understood, the accumulating body of clinical and experimental/mechanistic data has been 
sufficient to attract major support from regulators and funding agencies, exemplified by the US 
NIH-funded ORBEX RCT (NCT02148796) and NHMRC-funded OMPAC RCT 
(ACTRN12612000518864)7 which both target ARIs in children. 
Evidence from numerous trials has demonstrated that OM85 treatment during periods of high 
infection risk can reduce the frequency of symptomatic ARI10,11. The mechanism-of-action 
appears to involve reduction in susceptibility to upper respiratory infection and attenuation of 
the intensity of inflammation-associated symptoms that accompany infection spread to the 
lower airways. Clinical experience with OM85 indicates it is active against a wide spectrum of 
microbial pathogens. As such, it is likely to target immunoregulatory pathways that are 
fundamental to anti-microbial immunity10, particularly those which control the intensity of host 
defence-associated inflammatory responses. Accumulating evidence relating to COV 
pathogenesis suggests that primary infection followed by successful clearance represents the 
norm, with relatively rare severe infection-triggered events being associated with 
uncontrolled/excessive local and systemic inflammatory responses. Based on its performance 
in other infection-related settings6,10, we hypothesize that OM85 pre-treatment has the capacity 
to enhance resistance to primary infection with COV, but more importantly to stabilize 
immunoregulatory mechanisms that maintain immune homeostasis during COV infection and 
lessen risk for progression to severe life-threatening symptoms. 
 
6.2 
Investigational product 
OM85 (commercial name Broncho-Vaxom adult capsule) consists of a capsule containing 
7.0mg of active bacterial soluble fractions in one dose. Investigational product is to be taken 
orally daily for 3 months  
 
6.3 
Known and potential risks 
Published clinical trials have reported OM85 to be well tolerated in children and adults. Reports 
of discontinuation of drug with an adverse event have been reported in three studies; two 
children from two separate studies discontinued drug due to rash or diarrhoea, and a study in 
adults with chronic obstructive pulmonary disease or chronic bronchitis reported 5 participants 

 
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Covid-19 OM85 HCW                                                                                                                           Page 17 of 
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in the active group (n=142) and 9 participants in the placebo group (n=131) discontinuing 
investigational product. In most clinical trials the number of participants experiencing adverse 
events were no different between the active (OM85) and placebo groups12. In adults, the most 
common reported adverse events were gastrointestinal, including nausea and diarrhoea. Six 
studies reported no adverse events. In elderly patients (>65 years), the most common adverse 
events were disease of the genitourinary (19/147, 13%), “symptoms, signs and ill-defined 
conditions” (11/147, 7%) and disease of the circulatory system (7/147, 5%). 
 
6.4 
Study population  
The study population will include Health Care workers (adults) in emergency departments, 
radiology departments, isolation wards, intensive care units or other “front line” clinical 
departments of major Brisbane hospitals (CHQ, PA, TPCH) in Australia and at UK Hospitals 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Covid-19 OM85 HCW                                                                                                                           Page 18 of 
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7. 
Study objectives and purpose 
7.1 
Primary objective 
To reduce the proportion of HCW contracting an ARI necessitating workforce removal. 
 
7.2 
Secondary objectives 
The secondary objectives of this study are to assess whether treating “front line” HCW at 
high risk of ARI, including LRI, with COV infection: 
 Decreases time to ARI, including LRI, necessitating workforce removal 
 Reduces the proportion of HCW contracting an ARI, including LRI,  necessitating 
workforce removal at end of treatment and at the end of the follow-up period, overall and 
by department. 
 Reduces the total number of days with respiratory symptoms (upper or lower) 
 Reduces the proportion of HCW with COV infection documented by PCR, seroconversion 
and/or COV ARI, including LRI,  necessitating workforce removal. 
 
7.3 
Mechanistic objectives 
Mechanistic objectives of this study are to determine if OM85 modulates: 
 Seroconversion to COV 
 Host immune cell profile grouped who test respectively positive or negative to COV during 
an ARI, including LRI,  and stratified by treatment (COV+/OM+, COV+/OM-, COV-/OM+, 
COV-/OM-). 
 White blood cell transcriptomic profile by group (COV+/OM+, COV+/OM-, COV-/OM+, 
COV-/OM-). 
 White blood cell cytokine production profile by group (COV+/OM+, COV+/OM-, COV-
/OM+, COV-/OM-). 
 
7.4 
Safety objectives 
The safety objective of this study is to determine if administration of OM85 is safe when 
treating front line HCW. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Covid-19 OM85 HCW                                                                                                                           Page 19 of 
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8. 
Study Design 
8.1 
Description 
This study will be conducted as a multi-centre, parallel group, wait list design clinical trial 
testing the reduction of acute severe respiratory events requiring workforce removal in HCW 
with OM85. Health Care Workers who are eligible will receive daily OM85 for 3 months.  
Group 1 “Wait-list group” will be given daily OM85 for 3 months commencing in Month 3, 
with 3 months follow-up off treatment. Group 2 “Initial treatment group” will be given daily 
OM85 for 3 months commencing in on day 0, with 3 months follow-up off treatment 
 
8.2 
Efficacy Endpoints 
8.2.1 
Primary efficacy endpoint 
The primary endpoint is the proportion of HCW contracting an ARI necessitating workforce 
removal  
 
8.2.2 
Secondary efficacy endpoints 
Secondary endpoints include: 
 The time to ARI necessitating workforce removal 
 The proportion of HCW contracting an ARI necessitating workforce removal at end 
of treatment and at the end of the follow-up period, overall and by department 
 The total number of days with respiratory symptoms (upper or lower) 
 The proportion of HCW with COV infection documented by PCR, seroconversion 
and/or COV ARI necessitating workforce removal.  
 The time to LRI necessitating workforce removal 
 The proportion of HCW contracting an LRI necessitating workforce removal at end of 
treatment and at the end of the follow-up period, overall and by department 
 The proportion of HCW with COV infection documented by PCR, seroconversion 
and/or COV LRI necessitating workforce removal. 
 
8.2.3 
Mechanistic endpoints 
 Seroconversion to COV 
 Host immune cell profile grouped who test respectively positive or negative to COV during 
an ARI, including LRI, and stratified by treatment (COV+/OM+, COV+/OM-, COV-/OM+, 
COV-/OM-). 
 White blood cell transcriptomic profile by group (COV+/OM+, COV+/OM-, COV-/OM+, 
COV-/OM-). 
 
White blood cell cytokine production profile by group (COV+/OM+, COV+/OM-, COV-
/OM+, COV-/OM-).  
 
8.2.4 
Safety endpoints 
 
Treatment-related adverse events. 

 
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Covid-19 OM85 HCW                                                                                                                           Page 20 of 
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 
Routine haematology and clinical chemistry. 
 
8.3 
Stopping Rules 
Study enrolment may be stopped if death of a participant that is related to the study treatment 
occurs. 
 
Safety data will be presented by group in a blinded fashion to the Data Safety and Monitoring 
Board (DSMB) at scheduled DSMB meetings during the trial. The DSMB will have the 
authority to request un-blinded data if necessary. The DSMB may recommend that enrolment 
or study treatment be discontinued for the safety of participants.  
Resumption of the study will be contingent upon a favourable decision by the Sponsor, and 
the DSMB after review of the adverse event data. 
 

 
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Covid-19 OM85 HCW                                                                                                                           Page 21 of 
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9. 
Selection and withdrawal of participants 
Deviations from the eligibility criteria will not be permitted as they may potentially 
jeopardise patient safety and the scientific integrity of the study. 
 
9.1 
Inclusion criteria 
Participants who meet all of the following criteria are eligible for enrolment:  
1. HCW in front line clinical departments assessing or caring for patients with suspected or 
verified COV infection in one of the recruiting hospitals in Brisbane or the UK, 
2. Participants who, in the opinion of the investigator, are able to comply with the protocol 
for its duration, 
3. Written informed consent signed and dated according to local regulations. 
 
9.2 
Exclusion criteria 
Participants who meet any of these criteria are not eligible for enrolment: 
 Staff with prior COV infection necessitating workforce removal  
 
9.3 
Criteria and procedures for participant withdrawal 
9.3.1 
Withdrawal of participants from study 
Participants will be withdrawn from the study if any of the following conditions are met: 
 
The participant withdraws their consent 
 
The participant fails to return to the clinic (i.e., they are lost to follow-up or death) 
 
The site investigator or his/her designee believes that continuation in the study is no longer 
in the participant’s best interests (which may be as a result of the occurrence of adverse 
events (AE) or clinically relevant laboratory results)  
 
The participant is unable to comply with the protocol, including completing required study 
treatments, procedures, tests and/or examinations 
 
The Sponsor reserve the right to terminate the entire study or any participants involvement 
at any time 
 
Participants who prematurely discontinue investigational product will be encouraged to 
continue with the study visit schedule and assessments. For further information regarding 
Early Withdraw Visits refer to Section 10.4. 
 
Those participants that cease the investigational product before the end of the study, but 
continue to be assessed for all other aspects of the study, will be regarded as members of the 
intention to treat (ITT) sample. All remaining study medication (including used and unused 
medication and packaging) will be collected.  
 
In all cases, the reason and date of withdrawal from the study, or investigational product, will 
be completed in the source documentation and the CRF. If the withdrawal is due to an 
adverse event or a clinically significant laboratory result, the participant will be followed 
until the AE is resolved or is clinically stabilised. The AE or laboratory result must be 
recorded in the CRF. 
 

 
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Covid-19 OM85 HCW                                                                                                                           Page 22 of 
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If a participant tests positive to a clinical test (not part of the study) they will follow the 
hospital isolation protocol. The study Covid testing is done by measuring antibodies, which 
are not suitable for acute surveillance as it detects past infection. Results (positive or 
negative) will be returned to participant for their own information 
 
9.3.2 
Premature termination of study/closure of centre 
The Sponsor or the Therapeutic Goods Administration (TGA) may stop the study for any 
reason. They may also prematurely close any study centre following consultation with the 
parties involved. 
 
In the event that the study is terminated prematurely, written notification must be sent to the 
ethics committee (EC), according to local regulations. The site investigator must also 
promptly inform all study participants and if appropriate, should assure appropriate medical 
follow-up. All study materials, except those documents that must remain on site, should be 
returned to the sponsor. 
 
 
9.4 
Replacement of participants 
Participants who withdraw consent or who discontinue the study for any reason will not be 
replaced. 
 
 
 

 
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Covid-19 OM85 HCW                                                                                                                           Page 23 of 
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10. 
Study procedures 
The study procedures are listed in the Schedule of Assessments and Procedures in Appendix 
1. 
 
10.1 
Description of assessments and procedures 
Procedures conducted as a part of the participant’s routine clinical management and obtained 
prior to informed consent may be used for screening purposes or assessing eligibility. However, 
the procedure must meet the protocol-defined criteria and have been performed within the 
timelines permitted by the protocol. 
 
10.1.1 Informed consent 
A signed, written informed consent must be obtained from the participant and will be 
undertaken prior to any study-specific assessments or procedures. In accordance with Good 
Clinical Practice (GCP) guidelines, informed consent is an ongoing process throughout the 
study. 
 
10.1.2 Eligibility criteria 
To be eligible for enrolment into the study, participants must meet all the inclusion criteria and 
none of the exclusion criteria. 
 
10.1.3 Medical/ work history 
A comprehensive general medical history will be taken by the site investigator to determine 
significant previous and current medical conditions, diseases, procedures and surgeries that 
may increase the risk of developing a ARI necessitating workforce removal. Exposure data, 
including time on the front line, also be collected.  
 
10.1.4 Demographic history 
Participant’s date of birth, ethnicity, sex, smoking information will be collected at Visit 1. 
 
10.1.5 Nasal swab 
Nasal swab will be collected at four time points (shown in Figure 1).  
One swab will be collected from each nostril. Nasal swab will be used for viral detection and 
identification, including COV. 
 
10.1.6 Blood tests 
Venous blood samples will be collected at four time points (shown in Figure 1) for viral 
serology and immune profiling.  
 
10.1.7 Patient daily symptom data 
Following randomisation, the process will be explained to participants concerning their 
documentation of /response to daily SMS regarding any respiratory symptoms. These 
symptoms and/or condition related to the symptoms will be recorded as adverse events. 
Unclear or missing entries will be clarified with the participant and any correction annotated 
by site staff as appropriate. Annotations made by site staff will be clearly identified and 
initialled and dated. 

 
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Covid-19 OM85 HCW                                                                                                                           Page 24 of 
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10.1.8 Telephone calls 
Telephone calls may be conducted during the study to ensure patient compliance with 
investigational product and completion of daily symptom data. If required, telephone calls 
will be conducted to assess adverse event data and review of concomitant medications and 
therapies will be undertaken. These may be conducted via SMS or email if participant 
prefers. 
 
10.1.9 Adverse events 
AEs will be collected from the time the medicinal product is administered. Further 
information regarding the collection and reporting of AEs can be found in Section 12. 
 
10.2 
Scheduled visits 
This study consists of 5 visits (Group 1 - WLC) or 4 visits (Group 2 – initial treatment) over 
6 or 9 months respectively (see Figure 1) Study procedures to be performed at each visit are 
detailed in the Schedule of Assessments and Procedures in Appendix 1. 
 
Visits should be conducted within the specified visit windows where possible. 
 
Group 1 (WLC)  
 
Visit 1 – Screening and randomisation 
The following assessments and procedures will be performed and recorded at this visit: 
 Obtain written informed consent 
 Evaluate inclusion and exclusion criteria  
 Obtain demographic history 
 Obtain medical history 
 Vital signs 
 Explain daily respiratory symptom data collection and assist with collection for Day 0 
Once all screening procedures have been completed and eligibility confirmed, the participant 
will be registered with the Sponsor. Further information on the registration process is 
provided in the Study Reference Manual. 
 
Visit 2: Treatment initiation 3 months post randomisation (±5 days) 
 Update demographic & medical history 
 Vital signs 
Figure 1: Study timeline and procedures. Nasal swab collection (blue arrow), blood 
collection (red arrow). 
 

 
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Covid-19 OM85 HCW                                                                                                                           Page 25 of 
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 Nasal swab 
 Collection of blood samples 
 Dispense study medication and explain administration 
 Adverse event assessment 
 
Visit 3: Treatment cessation 6 months post randomisation (±5 days) 
 Vital signs 
 Nasal swab 
 Collection of blood samples 
 Clarify any missing data (daily respiratory symptoms) with participant, if not previously 
addressed by email/SMS 
 Adverse event assessment  
 Collect used investigational product packaging and unused investigational product  
 
Visit 4: Follow up cessation 9 months post randomisation (±5 days) 
 Vital signs 
 Nasal swab 
 Collection of blood samples 
 Clarify any missing data (daily respiratory symptoms) with participant, if not previously 
addressed by email/SMS 
 Adverse event assessment 
 
Unscheduled Visit: at time of ARI necessitating workforce removal 
 Vital signs 
 Nasal swab 
 Collection of blood samples 
 Clarify any missing data (daily respiratory symptoms) with participant, if not previously 
addressed by email/SMS 
 Adverse event assessment 
 
Group 2 (Initial Treatment) 
 
Visit 1 – Screening, randomisation, and treatment initiation 
The following assessments and procedures will be performed and recorded at this visit: 
 Obtain written informed consent 
 Evaluate inclusion and exclusion criteria  
 Obtain demographic history 
 Obtain medical history 
 Vital signs 
 Nasal swab 
 Collection of blood samples 
 Drug delivery 
 Dispense study medication and explain administration 
 Explain daily respiratory symptom data collection and assist with collection for Day 0 

 
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Covid-19 OM85 HCW                                                                                                                           Page 26 of 
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 Adverse event assessment 
 
Once all screening procedures have been completed and eligibility confirmed, the participant 
will be registered with the Sponsor. Further information on the registration process is 
provided in the Study Reference Manual. 
 
Visit 2: Treatment cessation 3 months post randomisation (±5 days) 
 Vital signs 
 Nasal swab 
 Collection of blood samples 
 Clarify any missing data (daily respiratory symptoms) with participant, if not previously 
addressed by email/SMS 
 Adverse event assessment 
 Collect used investigational product packaging and unused investigational product  
 
Visit 3: Follow up cessation 6 months post randomisation (±5 days) 
 Vital signs 
 Nasal swab 
 Collection of blood samples 
 Clarify any missing data (daily respiratory symptoms) with participant, if not previously 
addressed by email/SMS 
 Adverse event assessment 
 
Unscheduled Visit: at time of ARI necessitating workforce removal 
 Vital signs 
 Nasal swab 
 Collection of blood samples 
 Clarify any missing data (daily respiratory symptoms) with participant, if not previously 
addressed by email/SMS 
 Adverse event assessment 
 
10.3 
Early withdrawal visit 
Participants who discontinue from the study for reasons other than ARI necessitating 
workforce remove, will be asked to attend an Early Withdrawal Visit. Where practicable, the 
study procedures scheduled for the current visit should be completed, or in the case of early 
withdrawal between visits, the procedures scheduled for the next study visit should be 
completed if the participant is agreeable. 
 
For safety follow-up, participants should be encouraged to provide a blood sample. All used 
and unused study medication (including packaging) should be collected or arrangements 
made for its return to the clinic at this visit. Where possible, stop dates for ongoing AEs  
should be obtained. 
 
 
 

 
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Covid-19 OM85 HCW                                                                                                                           Page 27 of 
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11. 
Study treatment 
11.1 
Enrolment and randomisation 
Once all required screening assessments are completed and eligibility is confirmed, 
participants will be registered with the Sponsor. Upon approval of registration, participants 
will be assigned a unique participant number that will remain consistent for the duration of 
the study. 
 
Participants who sign an informed consent form, but do not fulfil the inclusion/exclusion 
criteria, will not be allocated a participant identification number. 
 
Participants will be randomised into one of the following two groups on a 1:1 ratio with 500 
participants per group: 
 Group 1 (WLC): OM85 7.0 mg will be given daily for three months from Month 3 
 
 
 Group B (Initial Treatment): OM85 7.0 mg will be given daily for three months from Day 
0 
 
Please see the Study Reference Manual for randomisation instructions. 
 
 
11.2 
Dosing, formulation and storage 
 
OM85 (as Broncho-Vaxom adult capsules) is presented in a box with blister packs, 
containing 7.0 mg (30 doses). 7.0mg of OM85 is administered orally each day for 3 months.  
 
Excipients: each capsule contains pregelatinised starch, magnesium stearate, anhydrous 
propyl gallate (E 310), monosodium glutamate, and mannitol. 
 
The investigational product used throughout the study will be stored at the site’s pharmacy in 
accordance with the instructions supplied by the Sponsor. Access to the investigational 
product will be restricted to authorised study staff only. OM85 (as Broncho-Vaxom adult 
capsules) will be kept below a temperature of 30°C. The product must not be frozen or 
refrigerated. The product should not be used for more than 3 months after opening. 
 
11.3 
Accountability for investigational product 
Under Title 21 of the Code of Federal Regulations (21CFR 312.62), the site investigator is 
required to maintain adequate records of the disposition of the investigational product, 
including the date and quantity of product received, to whom the product was dispensed 
(participant-by-participant accounting) and a detailed accounting of any investigational 
product accidentally or deliberately destroyed. 
 
All records regarding the disposition of the investigational product will be available for 
inspection by the monitor. 
 

 
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Covid-19 OM85 HCW                                                                                                                           Page 28 of 
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Participants will be requested to return all unused drug and empty blister packs & boxes at 
each visit. All efforts should be made by the site to follow up any bottles not returned. 
 
11.4 
Treatment adherence 
The site will record the number of boxes dispensed to participants. Each box will have a 
unique identifying number. To enable the site to perform accountability, the participants will 
be asked to return all used and unused investigational product at each study visit. In the case 
where a participant is withdrawn from the study or becomes non-compliant with their 
allocated treatment, all efforts should be made to collect each previously dispensed study 
medication bottles. Dispensing and treatment compliance information will be recorded in the 
CRF. 
 
11.5 
Prohibited medications during study 
There are no prohibited medications. 
 
11.6 
Permitted medications during study 
During the study, participants will be allowed to take medications routinely used in the 
management of fever, cough or wheezing attacks, including inhaled and oral steroids. All 
medications will be recorded in the source documentation and CRF. 
 
 
 
 
 

 
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Covid-19 OM85 HCW                                                                                                                           Page 29 of 
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12. 
Assessment of safety 
The site investigator is responsible for the assessment and documentation of any event that 
meets the criteria of an AE (see Section 12.1) or an SAE (see Section 12.2). 
 
AEs and SAEs will be collected from the time of first dose of investigational product until the 
participant has completed the study at their final visit, even if the participant ceases the 
investigational product prematurely. 
 
12.1 
 Adverse events 
In accordance with the TGA GCP guidelines (CPMP/ICH/135/95), an AE is any untoward 
medical occurrence in a participant administered a medicinal product and which does not 
necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of the investigational product, whether or not 
considered related to the investigational product. 
 
All AE should be well documented in the participant’s source notes and CRF. Start and stop 
dates, outcome and whether the participant required treatment will be recorded. The site 
investigator will determine the title of the AE, severity, relationship to investigational product 
and seriousness. 
  
An AE does not include: 
 
Pre-existing disease or condition that was present prior to the first administration of the 
investigational product, and that does not have a clinically significant increase in severity 
and/or frequency during the study 
 
Medical or surgical procedures. The disease or condition that led to the procedure should 
be recorded as the AE, not the procedure itself. 
 
AEs will be followed up until they have returned to baseline status or stabilised. Follow-up of 
AEs should continue until the overall clinical outcome has been ascertained or the final visit 
completed. 
 
If an AE later escalates to meet the criteria for a SAE (see Section 12.2), then it must be 
reported to the Sponsor as an SAE. See Section 12.3 for Investigator’s responsibilities for 
reporting SAEs.  
 
12.1.1 Grading of adverse events 
The severity of AEs experienced by study participants will be graded as mild, moderate, 
severe, life threatening or death by the site investigator.   
 
12.1.2 Attribution of adverse events 
The relationship, or attribution, of an AE to the investigational product will be determined by 
the site investigator. The relationship of the AE to the investigational product will be coded 
according to the following definitions: 
 

 
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Covid-19 OM85 HCW                                                                                                                           Page 30 of 
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Unrelated:  
The AE is due to an underlying or concurrent illness or effect of another drug 
and is clearly not related to the investigational product (e.g. has no temporal relationship to 
study drug or has a much more likely alternative aetiology). 
 
Unlikely:  The AE has little or no temporal relationship to the investigational product and a 
more likely aetiology exists.  
 
Possibly: The AE has a strong temporal relationship to the investigational product and an 
alternative aetiology is equally or less likely compared to the potential relationship to the 
investigational product. 
 
Probably: The AE has a strong temporal relationship to the investigational product or recurs 
on re-challenge. Another aetiology is unlikely or significantly less likely. 
 
The site investigator should attempt to provide an alternative aetiology for all AEs considered 
to be unrelated, unlikely or possibly related to the investigational product. This will be 
recorded in the source documentation. 
 
For the purposes of reporting to the relevant regulatory agencies, unrelated and unlikely AEs 
will be classified as Not Related, while possible and probably related will reported as 
Related. 
 
12.2 
Serious adverse events 
12.2.1 Definition of serious adverse events 
A SAE or reaction is any untoward medical occurrence that results in one or more of the 
following: 
 results in death  
 is life-threatening 
 requires inpatient hospitalization or results in prolongation of existing hospitalization 
 results in persistent or significant disability/incapacity 
 is a medically important event or reaction  
 
12.2.2 Clarification of serious adverse events 
Death is an outcome of an AE and not an AE in itself. 
 
A “life threatening” event is any adverse therapy experience that, in the view of the site 
investigator, places the participant at immediate risk of death from the reaction as it occurred.  
 
An “inpatient hospitalisation” occurs when a participant is formally admitted to hospital for 
any length of time. It does not refer to Emergency Department or Accident & Emergency 
visits where the patient is observed and not admitted.  
 
“Hospital in the home” or equivalent programs are not considered inpatient hospitalisations, 
and therefore do not need to be recorded as SAE’s. 
 

 
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Covid-19 OM85 HCW                                                                                                                           Page 31 of 
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Hospitalisations considered to be “routine” and therefore not SAEs will include 
hospitalisation for procedures unrelated to respiratory system or to the trial. Site staff will 
notify the Sponsor of routine hospitalisations within one week of the admission. Reporting 
instructions are provided in the Study Reference Manual. 
 
If a routine hospitalization is prolonged due to an AE or results in any of the other definitions 
in Section 12.2.1, it should be reported to the Sponsor as a SAE. 
 
Medical and scientific judgment should be exercised in deciding whether other situations than 
those listed in Section 12.2.1 should be considered serious. This may include important 
medical events that might not be immediately life-threatening or result in death or 
hospitalization but might jeopardise the participant or might require intervention to prevent 
one of the other outcomes listed in Section 12.2.1.  
 
Regardless of the relationship of the event to the investigational product, the event must be 
reported as a SAE if it meets any of the definitions listed in Section 12.2.1. 
 
12.3 
Investigator’s responsibility for reporting serious adverse events 
All SAEs will be reported within 24 hours of the site staff becoming aware of the event. The 
SAE (Initial) Form will be completed and faxed to the Sponsor on +61 7 3609 7159 using all 
information known at the time. A minimum of the SAE title, onset date and date the last 
investigational product was delivered should be provided, and if possible, the form should be 
reviewed and signed by the site investigator prior to faxing. 
 
Further guidance on SAE reporting, including instructions for completion of the SAE form 
can be found in Study Reference Manual. 
 
If site staff becomes aware of new information regarding an SAE, a SAE (Follow Up) form 
should be completed and forwarded to the Sponsor within five days. New information may 
include recurrent episodes, complications, or progression of the initial SAE, acquisition of 
relevant hospital records, reports and/or laboratory results. The follow-up information should 
describe whether the event has resolved or continues, if and how it was treated, and whether 
the patient continued or withdrew from study participation. 
 
SAEs, regardless of suspected causality, occurring after the patient had provided informed 
consent and until 30 days after the patient has stopped study participation/ withdrawn, must 
be reported. Any SAEs experienced after this 30 day period should only be reported if the 
Investigator suspects a causal relationship to the study drug. SAEs that are ongoing at the end 
of the study should be followed up until a final assessment is possible, and until all queries 
from the Sponsor have been resolved.  
 
In accordance with local requirements, the site investigator must also notify their local EC of 
any SAEs. 
 

 
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Covid-19 OM85 HCW                                                                                                                           Page 32 of 
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12.4 
Reporting to regulatory authorities 
It is important that all known information at the time of the SAE is forwarded to the Sponsor 
within the protocol required time frame, as expedited  reporting to the appropriate regulatory 
authorities may be required based on the following criteria: 
 
No Reporting 
This requirement applies if the SAE is deemed not serious by the Principal Investigators. 
 
Standard Reporting 
This requirement applies if the SAE is classified as any of the following: 
 Serious, expected, and related to the investigational product 
 Serious, expected and not related to the investigational product 
 Serious, unexpected and not related to the investigational product 
 
Expedited Reporting 
This requirement applies if the SAE is classified as serious, unexpected and related to the 
investigational product. During these circumstances, the Sponsor must notify the appropriate 
health authorities within 15 days, however fatal or life-threatening events must be reported 
within 7 days.  
 
 
 

 
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Covid-19 OM85 HCW                                                                                                                           Page 33 of 
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13. 
Statistical considerations 
13.1 
Randomisation, stratification and blinding 
Participants will be randomised to the wait list group (Group 1) or the initial intervention 
group (Group 2) using a one-to-one ratio, stratified by Country (Australia, UK), hospital 
(QCH, PA, TPCH) and department [High risk (ED, ICU, isolation wards), lower risk 
(radiology, general wards, other)].  
 
13.2 
Sample size calculations 
There are no data in the literature on use of OM85 for the primary prevention of ARI, in 
relation to COV. However, 20% of Italy’s HCW are infected with COV1 If we assume 20% 
infection in Gp 1, then with 500 HCW in each group we will be able to detect a reduction in 
ARI in Gp 2 by 32.5% (to 13.5%) with 80% power (alpha=0.05). Combined with 1000 UK-
recruited HCW, we will be able to detect a 25% reduction (80% power, alpha=0.05). 
 
13.2.1 Analysis sample 
All participants randomised who receive at least one dose of study treatment will be included 
in the “intention-to-treat” group for statistical analyses. 
Participants who complete the treatment period and take at least 80% of scheduled doses will 
be included in the “per protocol” group for statistical analyses. 
 
 
13.2.2 Statistical analyses 
The interim analysis, undertaken at month 1 on both the “intention-to-treat” and “per protocol” 
groups, will examine the primary outcome: if the treatment difference is statistically significant 
in favour of OM85 the DSMB will consider immediately switching WLC participants to 
OM85. 
Between-group differences in the primary outcome at 3 months will be assessed using log-
binomial regression. Secondary outcomes measured to follow-up cessation will be assessed 
using mixed-effects models with group and stage (treatment/follow-up) (main effects and 
interaction) as fixed effects and HCW as random effect. Time-to-ARI analyses will use the log-
rank test. Analyses will be undertaken on both the “intention-to-treat” and “per protocol” 
groups. 
 
13.3 
Study endpoint assessments  
Study endpoint analyses will be conducted 3 months after enrolment and at completion of the 
study, with an interim analysis planned at month 1.  
 
13.3.1 Primary efficacy endpoint 
The primary endpoint, defined in Section 7.2.1, will be analysed 3 months after enrollment 
using data collected prior to the WLC group commencing treatment, by comparing between-
group differences in rates of ARI that necessitated workforce removal. The primary analysis 
will be conducted using log-binomial regression on both the “intention-to-treat” and “per 
protocol” groups. 
 
 

 
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Covid-19 OM85 HCW                                                                                                                           Page 34 of 
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13.3.2 Secondary efficacy endpoints and mechanistic endpoints 
The secondary endpoints, defined in Section 7.2.2, and mechanistic evaluations, defined in 
Section 7.2.3, will be assessed using mixed-effects models with group and stage 
(treatment/follow-up) (main effects and interaction) as fixed effects and HCW as random 
effect. Time-to-ARI, including LRI, analyses will use the log-rank test. 
These analyses will be undertaken, on both the “intention-to-treat” and “per protocol” groups, 
regardless of the outcome of the primary endpoint analysis. 
 
13.3.3 Safety endpoints 
All participants will be included in all safety analyses. All AEs reported during the study will 
be included in the analysis. The goal of the statistical evaluation of all AE data will be evaluated 
using a standardised tabulation of frequency and incidence rates of all observed AEs. The 
frequencies and incidence rates will be calculated on a per patient basis and not on an even 
basis. 
 
13.4 
Reporting deviations from the original statistical plan 
Any deviations from the statistical analysis plan will be described and a justification given in 
the final clinical study report. 
 

 
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Covid-19 OM85 HCW                                                                                                                           Page 35 of 
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14. 
Direct access to source data/documents 
It is the responsibility of the site investigator to maintain adequate and accurate source 
documentation to record all observations and other data pertinent to the study. All CRFs 
should be completed in their entirety to ensure accurate interpretation of the data. 
 
The Investigator’s Study Site File should include, but not limited to, approved Protocols and 
any subsequent Amendments, staff curricula vitae, sample Patient Information and Consent 
Forms, and other appropriate documents and correspondence used for the study. 
 
14.1 
Identification of source data 
Data entered into the CRF should be consistent with and substantiated by original source 
documentation. Source documentation should be legible, complete and attributable to an 
originator. 
 
14.2 
Direct access to source data 
The study sites will maintain the highest degree of confidentiality permitted for the clinical 
and research information obtained from the participants in this study. All medical and 
research records will be maintained in the strictest confidence. However, as a part of the 
quality assurance and legal responsibilities of any study, the sites must permit authorised 
representative of the Sponsor and health authorities to examine (and when required by 
applicable law) to copy clinical records for the purpose of quality assurance reviews, audits, 
and evaluations of the study safety and progress. 
 
14.3 
Case report forms 
Study data will be captured in a Case Report Form (CRF). Each participant will have their 
own CRF. All participant study records will be completed by site study staff in a timely 
manner. 
 
Throughout the study the site may receive queries from the monitor to clarify discrepancies 
or request further data. It is important for the data validation process of the study that all 
queries are resolved in a timely manner and completed as accurately as possible. 
 
 
 

 
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Covid-19 OM85 HCW                                                                                                                           Page 36 of 
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15. 
Quality control and quality assurance 
The site investigator must retain all study records in a secure facility for 15 years after the 
study closes. Approval to destroy a study-specific documentation should be obtained from the 
Sponsor prior to the destruction of any study records. 
 
15.1 
Study monitoring 
The Sponsor monitor (or designee) will regularly inspect the various records of the study, 
including source documents, CRFs and other pertinent documents. 
 
The monitor will confirm the completeness, consistency, and accuracy of all documented data 
and verify that all study activities are carried out by the appropriate designated staff. The 
average monitoring frequency will be determined according to the rate of participant 
recruitment. In accordance with Good Clinical Practice, the monitor will visit the study site 
frequently enough to assure that the facilities used by the site investigator continue to be 
acceptable for the purposes of the study as well as tracking that the study protocol is being 
adhered to and has been approved by the EC. 
 
15.2 
Information to study personnel 
It is the investigator’s responsibility to ensure that all study personnel who are listed on the 
Site Responsibility Log receive training on the protocol and are qualified to carry out their 
delegated study tasks. Evidence of training on the study protocol must be provided for any 
new personnel that become involved in the study after site initiation has taken place. 
 
It is the monitor’s responsibility for initiating the site, ensuring that all study procedures are 
adhered to according to the approved protocol and for closing out the site at the end of the 
study. 
 
15.3 
Termination of study 
The Sponsor reserves the right to terminate the study at any time. If the study is terminated 
for any reason, the Sponsor will promptly inform the site investigator. The site investigator 
should provide appropriate follow-up and/or therapy for their study participants. Site 
investigators should inform their local EC.  
 
15.4 
Protocol amendments, violations and deviations 
The protocol may be amended by the Sponsor if there are changes that may significantly 
affect the safety of the participants, scope of the investigation, or the scientific quality of the 
study. Any protocol amendments must be signed by the site investigator. It must also be 
submitted to the local EC, with any changes from the final approved protocol not initiated at 
the study site until appropriate written approval is received by the EC, except when necessary 
to eliminate an immediate safety risk to the participants, or when the change only involves 
logistics or administration. 
 
A protocol violation is any failure to comply with the final study protocol as approved by the 
EC. This includes but is not limited to, the final detailed protocol, patient information and 
consent form, questionnaires, and other study-related documents. Circumstances which may 
impact participant safety, affect the integrity of the study data and/or affect a participant’s 

 
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willingness to participate in the study may be deemed as protocol violations. All protocol 
violations must be immediately reported to the Sponsor as well as the local EC in accordance 
with local regulations. A protocol violation page must also be completed. 
 
A protocol deviation involves any modification or alteration to the final study protocol as 
approved by the EC, but does not fulfil the criteria above for a protocol violation. Examples 
of protocol deviations may include inappropriate documentation of the informed consent 
document, implementation of unapproved recruitment procedures, study visits outside of set 
windows and missing tests and/or laboratory values. All deviations from the protocol and the 
reason for the deviation will be documented in the source documentation. 
 
15.5 
Data safety monitoring board 
Prior to the start of the study a DSMB will be assembled consisting of appropriate clinical 
and statistical experts who are independent of the conduct of the study. The DSMB will 
provide an ongoing independent review of data from the study to address any safety 
concerns. The DSMB will review whether the study data are properly collected, analysed and 
reported. The DSMB will review blinded study results at regular intervals, but may also 
request unscheduled analysis or additional analysis during the course of the study. They will 
evaluate periodic assessments of data quality and timeliness, as well as details such as 
participant recruitment, accrual and retention. The DSMB will make recommendations 
concerning the continuation or conclusion of the study and will notify the Sponsor 
accordingly. 
 
15.6 
Audits and inspections 
All source documents for this study must be made available to staff from the Sponsor or its 
designees or to health authority inspectors after the appropriate notification. The verification 
of CRF data will be by direct inspection of source documents. 
 
 

 
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Covid-19 OM85 HCW                                                                                                                           Page 38 of 
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16. 
Ethics 
16.1 
Statement of compliance  
This study will be conducted in compliance with the criteria specified in this study protocol, 
the ethical principles stated in the current revision of the “Declaration of Helsinki”, the 
International Conference on Harmonization Good Clinical Practice E6 (ICH-GCP) or with 
the laws and regulations of the country in which the research is conducted, whichever 
represents the greater protection of the individual.  
 
16.2 
Informed consent form 
The informed consent form is a means of providing information about the study to a 
prospective participant and allows for an informed decision about participation in the study. 
In accordance with GCP, informed consent remains an ongoing process throughout the study. 
 
It is the responsibility of the site investigator, or a person designated by the site investigator 
(if acceptable by local regulations), to obtain written informed consent from each participant 
after adequate explanation of the study. After ample time to have all their questions answered 
by the site investigator or designee, the participant must read, sign and date the informed 
consent form before they may enter the study, take study treatment, or undergoe any study-
specific procedures. 
 
The site investigator or designee must also explain to the prospective participant that 
enrolling in the study is entirely voluntary and that he, she or they may withdraw from the 
study at any time, for any reason. 
 
A copy of the informed consent form will be given to the prospective participant for review. 
 
The informed consent form must be revised whenever important new safety information is 
available that results in significant changes in the risk/benefit assessment or whenever any 
new information becomes available that may affect participation in the study. The 
prospective participant (including those already being treated) should be informed of the new 
information, given a copy of the updated informed consent form and give their consent to 
continue their participation in the study. 
 
16.3 
Ethics committee 
This protocol, informed consent form (including the participant information sheet and any 
other material provided to the participant) and any advertising material must be approved by 
the local EC and the appropriate written approvals made available to the Sponsor before the 
site may begin screening potential participants.  
 
Any modifications made to the protocol or informed consent form after receipt of the EC’s 
original approval must be submitted by the site investigator to the committee in accordance 
with local procedures and regulatory requirements. Approval must be awaited before any 
changes can be implemented, except for changes necessary to eliminate immediate hazards to 
study participants. 
 

 
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Covid-19 OM85 HCW                                                                                                                           Page 39 of 
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The site investigator will ensure that prior to the initiation of the study, and also whenever 
subsequent modifications to the protocol and informed consent form are made, that copies of 
all EC approvals are sent to the Sponsor. 
 
16.4 
Participant confidentiality 
The site investigator must ensure that a participant’s anonymity will be respected throughout 
the study and that their identities are protected from unauthorised parties. A participant’s 
privacy and confidentiality will be maintained by the assignment of a unique identification 
number. On participant records and other documents submitted to the Sponsor, participants 
should not be identified by their names, rather their unique identification number. These 
numbers will be used to collect, store and report participant information. The site investigator 
should keep a Subject Enrolment Log showing codes, names and date of birth of the 
participants. Confidentiality and protection of data will be maintained according to local 
regulatory requirements. 
 
All information disclosed or provided by the Sponsor, including, but not limited to, the 
protocol,  participant records, and the results obtained during the course of the study, is 
confidential, prior to the publication of the results. 
 
The site investigator and any person under his/her authority must maintain this confidentiality 
and must not disclose the information to any third party without the prior written approval of 
the Sponsor. 
 
 

 
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Covid-19 OM85 HCW                                                                                                                           Page 40 of 
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17. 
Administrative procedures 
17.1 
Curriculum vitae 
A current copy of the curriculum vitae describing the experience, qualification and training of 
each site investigator, pharmacist and study personnel listed on the Site Responsibility Log 
will be provided to the Sponsor prior to the beginning of the study. Other relevant 
documentation such as current medical or professional licenses should also be forwarded at 
the request of the Sponsor. 
 
17.2 
Participant reimbursement 
Participants will not receive payment for taking part in this study.  
 
17.3 
Archiving 
The site investigator shall retain all study related material including study site folders and 
participants’ case histories. This includes, but is not limited to, signed and dated consent 
forms, medical records and physician progress notes. These study materials must be 
maintained by the site investigator for the appropriate period of time as determined by local 
regulations and ICH-GCP. 
 
 
 

 
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Covid-19 OM85 HCW                                                                                                                           Page 41 of 
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18. 
Finance and insurance 
An application for funding for this study has been submitted to the Medical Research Future 
Fund 2020 Respiratory Medicine Clinical Trials on COVID 19 Funding commencing 2020. 
OM Pharma has agreed to supply investigational product. 
Insurance will be provided by The University of Queensland. 
All site investigators at the study site may be asked to complete a financial disclosure form at 
the discretion of the Sponsor. 
 
 
 

 
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Covid-19 OM85 HCW                                                                                                                           Page 42 of 
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19. 
Publication policy 
The results of this study will be published and/or presented at scientific meetings. The site 
investigators participating in this study will not have the right to publish or present any 
finding from this study without prior written consent from the Sponsor. 
 
 
 

 
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Covid-19 OM85 HCW                                                                                                                           Page 43 of 
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20. 
References 
 
1.    COVID-19: Protecting healthcare workers. Lancet 2020;395:922.   
2.    Checchi L, et al. Efficacy of three face masks in preventing inhalation of airborne   
       contaminants in dental practice. J Am Dental Assoc 2005;136:877-82.  
3.    Winter S, et al. Particulate face masks for protection against airborne pathogens - one  
       size does not fit all: an observational study. Crit Care Resus 2010;12:24-7.  
4.    Qian Y, et al. Performance of N95 respirators: filtration efficiency for airborne microbial   
       and inert particles. Am Industr Hygiene Assoc J 1998;59:128-32.  
5.   Respiratory protection against airborne infectious agents for health care workers. 2016.   
       www.ccohs.ca/oshanswers/prevention/respiratory_protection.html. Accessed 3/4/20. 
6.    Razi Cet al. OM85 BV prevents wheezing attacks in preschool children. JACI   
       2010;126:763-9.  
7.    Sly PD, et al. Primary prevention of severe lower respiratory illnesses in at-risk infants  
       using the immunomodulator OM85. JACI 2019;144:870-2.  
8.    Collet J, et al. Effects of an immunostimulating agent on acute exacerbations and  
       hospitalizations in patients with chronic obstructive pulmonary disease. AJRCCM   
       1997;156:1719-24.  
9.    Solèr M, et al. Double-blind study of OM85 in patients with chronic bronchitis or mild  
       chronic obstructive pulmonary disease. Respiration 2007;74:26-32.  
10.  Esposito S, et al.  Nonspecific immunomodulators for recurrent respiratory tract  
       infections, wheezing and asthma in children. Curr Opin Allergy Clin Immunol  
       2018;18:198-209.  
11.  Schaad UB. OM85 BV, an immunostimulant in pediatric recurrent respiratory tract  
       infections: a systematic review. World J Pediatr 2010;6:5-12.  
12. Jiang Z, Nagata N, Molina E, Bakaletz L, Hawkins H, Patel J. Fimbria-mediated 
enhanced attachment of nontypeable Haemophilus influenzae to respiratory syncytial 
virus-infected respiratory epithelial cells. Infect Immun. 1999;67:187-92. 
 

 
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Covid-19 OM85 HCW                                                                                                                           Page 44 of 45 
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Appendix 1:  Schedule of Assessments and Procedures 
Group =1 (Wait List Control)   
 
Recruitment and 
Randomisation  
Treatment 
initiation  
Treatment 
Cessation   
Follow-up 
Cessation 
Unscheduled visit 
 
Visit 
1 
2 
3 
4 
5 
Day 
0 
90  
180  
270 
 
Visit Window 
 
±5 days 
±5 days 
±5 days 
 
Informed consent 
x 
 
 
 
 
Eligibility criteria 
x 
 
 
 
 
Randomisation 
x 
 
 
 
 
Medical history 
x 
x 
 
 
 
Demographic history 
x 
 
 
 
 
Vital signs 
x 
x 
x 
x 
x 
Nasal swab 
 
x 
x 
x 
x 
Study bloods 
 
x 
x 
x 
x 
Drug delivery 
 
x 
 
 
 
Drug distribution 
 
x 
 
 
 
Drug collection 
 
 
x 
 
 
Daily symptom  data explained 
& first day completed  
x 
 
 
 
 
Diary Daily symptom  data 
reviewed 
 
x 
x 
x 
x 
Adverse events 
 
x 
x 
x 
x 
 
 
 

 
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Covid-19 OM85 HCW                                                                                                                           Page 45 of 45 
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Group 2 (Initial Treatment) 
 
Recruitment Randomisation 
and Treatment   
Treatment Cessation  
  
Follow-up Cessation 
Unscheduled visit 
 
Visit 
1 
2 
3 
4 
Day 
0 
90 
120 
 
Visit Window 
 
±5 days 
±5 days 
 
Informed consent 
x 
 
 
 
Eligibility criteria 
x 
 
 
 
Randomisation 
x 
 
 
 
Medical history 
x 
 
 
 
Demographic history 
x 
 
 
 
Vital signs 
x 
x 
x 
x 
Nasal swab 
x 
x 
x 
x 
Study bloods 
x 
x 
x 
x 
Drug delivery 
x 
 
 
 
Drug distribution 
x 
 
 
 
Drug collection 
 
x 
 
 
Daily symptom  data explained 
& first day completed  
x 
 
 
 
Diary Daily symptom  data 
reviewed 
 
x 
x 
x 
Adverse events 
 
x 
x 
x