Clinical trial NCT04333732
Conditions: COVID 19
Keywords: COVID 19 Health care workers M-M-R II ®
Sponsor: Washington University School of Medicine
Start date: 2020-09-04; Completion date: 2021-12-03
Enrollment: 3411 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objective of CROWN CORONATION is the prevention of symptomatic COVID-19 by using combinations of approved and safe repurposed interventions, with complementary mechanisms of action.

Detailed description:
CROWN CORONATION is an international, Bayesian platform adaptive, randomized, placebo-controlled trial assessing the effectiveness of candidate interventions in preventing COVID-19 disease in adults.

Randomization will be stratified by age (\<50 and ≥50) and site. Participants will be healthcare workers at risk of contracting SARS-CoV-2. Participants will be randomized into one of two arms:

* Education and surveillance plus MR or MMR vaccine
* Education and surveillance plus Placebo

While the initial intervention to be tested on the platform will be the MR or MMR vaccine, other interventions might be added or removed over the course of the trial. The trial will evaluate which of the intervention arms is most effective at decreasing the incidence of symptomatic COVID-19 disease, without unacceptable side effects or safety events.

All participants will require be required to have a mobile phone to participate. This is standard in all the countries in this study. Most, but not all, will also have a smartphone. Participants will complete weekly data logs via SMS texting. Follow-up information will be collected until approximately 5 months after the end of treatment or death. Participants who develop symptomatic COVID-19 during the last month of observation will at a minimum be followed-up until symptom resolution and at a maximum until 6 months after randomization (whichever comes first). Telemedicine approaches to collecting information on participants will be used where possible. The trial will provide adherence support interventions that have been shown in randomized controlled trials to improve adherence to Human Immunodeficiency Virus treatment and adapted for HIV Pre-Exposure Prophylaxis (HIV PrEP) (e.g. two-way SMS with check in for those that report symptoms or adverse events). The database will be hosted on UK-based servers which are expected to be managed by Sealed Envelope Ltd. Local investigators will have access to the part of the CRF to enable recording of outcome data and/or severity of COVID-19 symptoms. Participants will be given a secure login to enable them to complete an initial participant health questionnaire and the regular data logs. It is envisaged that these will be completed at least weekly.

Arms: arm 1: Education and surveillance plus M-M-R II ® Single dose, 0.5 mL subcutaneous injection of M-M-R II ® arm 2: Education and surveillance plus placebo Single dose, 0.5 mL subcutaneous injection of 0.9% saline
Interventions: intervention 1: MR or M-M-R II ® vaccine intervention 2: Placebo
Intervention descriptions: intervention 1: Education and surveillance plus MR or M-M-R II ® vaccine intervention 2: Placebo injection

Protocol documents:
Prot_SAP_000.pdf: 
An international, Bayesian platform adaptive, randomized, placebo-
controlled trial assessing the effectiveness of candidate 
interventions in preventing COVID-19 disease in adults 
CROWN CORONATION: COVID-19 Research Outcomes Worldwide 
Network for CORONAvirus prevenTION 
CORE PROTOCOL 
Version 8.0 dated 12 October 2021 


Core-CROWN CORONATION Protocol V8.0, dated 12 Oct 2021 
   Page 2 of 46 
Clinical Trial of Investigational Medicinal Product 
Full title of trial 
An 
international, 
Bayesian 
platform 
adaptive, 
randomized, placebo-controlled trial assessing the 
effectiveness of candidate interventions in preventing 
COVID-19 disease in adults 
Short title 
CROWN CORONATION: COVID-19 Research Outcomes 
Worldwide Network for CORONAvirus prevenTION 
Version and date of protocol 
Version 8.0 dated 12 Oct 2021 
ISRCTN / Clinicaltrials.gov no: 
NCT04333732 
ACTIVE IMP(s): 
Will vary according to study arms (see appendices) 
PLACEBO IMP(s): 
Placebo dependent on study arm (see appendices) 
Phase of trial 
Phase 3 
Sites(s) 
Multi-site, Parallel protocol 
Protocol Version History 
Version 
Number 
Date 
Protocol Update 
Finalized By (insert 
name of person):  
Reasons for Update 
1.0 
01 April 2020 
Avidan 
Initial Protocol 
2.0 
10 April 2020 
Lovat 
Peer Review and country-specific addenda 
3.0 
21 April 2020 
Avidan 
Addressing concerns of FDA, IRB/IECs and 
funders 
4.0 
12 May 2020 
du Toit, Bekker, 
Biccard, Delany-
Moretlwe, Avidan, 
Dehbi, Jones, 
Hague, Caverly, 
Araeipour, 
Demarest, 
McKinnon, 
Mbacham 
Removed Hydroxychloroquine from protocol, 
addressed inconsistencies highlighted by SA 
regulatory authorities, combines all updates to 
protocol, create SA addendum, includes 
statistical updates, updating references and 
safety issues, tightening language and 
clarifying the outcomes, SPIRIT checklist 
compliant 
5.0 
09 June 2020 
Members of 
CROWN 
COLLABORATIVE 
Separation of Core Protocol from 
Supplementary Appendices into 
complementary documents 


Core-CROWN CORONATION Protocol V8.0, dated 12 Oct 2021 
   Page 3 of 46 
6.0 
30 July 2020 
Avidan, Dehbi, 
Sikazwe, Politi, 
Biccard, Lovat, 
Delany-Moretlwe, 
du Toit, Caverly, Nel 
Updating with new interventions, factorial 
designs, and statistical plan 
7.0 
01 December 2020 
Lovat, Caverly 
Delany-Moretlwe, 
Nel, Biccard, Avidan 
Extending to include other key workers; 
additional administrative changes 
8.0 
12 October 2021 
Avidan, Dehbi 
Updating the outcomes to include the 
following secondary outcome: symptomatic 
laboratory test-confirmed COVID-19 by day 
150  
This study has been funded by a grant from the COVID-19 Therapeutics Accelerator. 


Core-CROWN CORONATION Protocol V8.0, dated 12 Oct 2021 
   Page 4 of 46 
AN INTERNATIONAL, BAYESIAN PLATFORM ADAPTIVE, RANDOMIZED, PLACEBO-CONTROLLED 
TRIAL ASSESSING THE EFFECTIVENESS OF CANDIDATE INTERVENTIONS IN PREVENTING COVID-19 
DISEASE IN ADULTS 
CROWN CORONATION: COVID-19 Research Outcomes Worldwide Network for CORONAvirus 
prevenTION 
INVESTIGATOR’S AGREEMENT 
I, _______________________, the investigator, have read this protocol and appendices and 
had the opportunity to discuss the objectives of this trial and the content of this protocol 
and appendices with the CROWN CORONATION Coordinating Center representative(s) from 
Washington University School of Medicine and/or the In-Country Sponsor.  
I agree to conduct the trial according to this protocol and appendices and to comply with its 
requirements, subject to ethical and safety considerations. 
I agree to comply with the International Council for Harmonization of Technical 
Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) 
guidelines and all applicable regulations and guidelines. 
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of the sponsor. 
__________________________________ 
__________________________ 
Investigator Signature 
Date 
__________________________________ 
___________________________ 
Principal Investigator Name 
Site Name, Country 
Micheal Avidan
Michael Avidan, MBBcH, FCA SA
Washington University In St. Louis, USA
11/04/2021


Core-CROWN CORONATION Protocol V8.0, dated 12 Oct 2021 
   Page 5 of 46 
Abstract 
The coronavirus disease 2019 (COVID-19) pandemic is a major public health crisis. As a bridge to 
specific vaccine development and rollout, we urgently need to deploy practical, affordable and 
effective interventions that prevent infection and / or mitigate the severity of COVID-19. The CROWN 
(COVID-19 Research Outcomes Worldwide Network) COLLABORATIVE is an international, 
transdisciplinary, research network, established to assess rigorously and efficiently promising 
interventions for COVID-19. CROWN CORONATION (COVID-19 Research Outcomes Worldwide 
Network for CORONAvirus prevenTION) is a Bayesian, pragmatic, participant-level randomized, multi-
center, and international placebo-controlled platform trial, assessing candidate interventions that 
either modify the host immune response or target the virus implicated in COVID-19 - severe acute 
respiratory syndrome coronavirus-2 (SARS-CoV-2). The objective of CROWN CORONATION is the 
prevention of symptomatic COVID-19 by using combinations of approved and safe agents, with 
complementary mechanisms of action. The primary outcome of CROWN CORONATION is symptomatic 
COVID-19 by day 60 after commencement of study intervention (i.e. any of the following: cough, 
shortness of breath or difficulty breathing, fever, chills, muscle pain, sore throat, new loss of taste or 
smell, nausea, vomiting, or diarrhea) with laboratory confirmation (i.e. based on viral polymerase chain 
reaction). The study design is scientifically compelling and ethically robust. Study arms that are ‘under-
performing’ may be discontinued, and additional prophylactic arms may be added. This efficient 
approach can limit participant allocation to futile or even harmful study arms. The CROWN 
COLLABORATIVE has partners across the translational continuum, spanning foundational basic science 
discovery, proof-of-principle human research, pragmatic effectiveness trials, and public health focused 
implementation science.  


Core-CROWN CORONATION Protocol V8.0, dated 12 Oct 2021 
   Page 6 of 46 
Contents 
Abstract .................................................................................................................................... 5 
Contents .................................................................................................................................... 6 
List of abbreviations ............................................................................................................... 8 
1 
Trial personnel .......................................................................................................... 10 
2 
Summary ................................................................................................................... 13 
3 
Background and Rationale ....................................................................................... 15 
3.1 
Assessment and management of risk ...................................................................... 19 
4 
Objectives .................................................................................................................. 20 
5 
Trial design ................................................................................................................ 20 
5.1 
Overall design............................................................................................................ 20 
6 
Investigational Medicinal Products (IMPs) and Non-Investigational Medicinal 
Products ..................................................................................................................... 24 
6.1 
Name and description of IMP(s) .............................................................................. 24 
6.2 
Source of IMP(s), Manufacture, Distribution and Storage .................................... 25 
6.3 
Storage and handling of IMP(s) at site .................................................................... 25 
6.4 
Accountability of IMP(s)........................................................................................... 25 
7 
Selection of Participants ........................................................................................... 26 
7.1 
Eligibility of trial participants .................................................................................. 26 
7.2 
Recruitment ............................................................................................................... 26 
7.3 
Informed consent procedure ................................................................................... 27 
8 
Trial procedures ....................................................................................................... 27 
8.1 
Screening / Pre-Enrolment Assessments ............................................................... 27 
8.2 
Enrolment / Randomization Procedures ................................................................ 28 
8.3 
Procedure for Allocating Intervention/s ................................................................ 28 
8.4 
Dose Modifications ................................................................................................... 29 
8.5 
Subsequent Assessments and Procedures ............................................................. 29 
8.6 
Laboratory Assessments and Procedures .............................................................. 30 
8.7 
Clinical Procedures and Data Collection ................................................................. 30 
8.8 
Assessment of IMP compliance ............................................................................... 30 
8.9 
Discontinuation / withdrawal of participants ....................................................... 30 
8.10 Replacements ............................................................................................................ 31 
8.11 Stopping Rules .......................................................................................................... 31 
8.12 Definition of End of Trial .......................................................................................... 31 
9 
Recording and reporting of adverse events and reactions ................................... 32 
9.1 
Definitions ................................................................................................................. 32 
9.2 
Procedures for recording and reporting of adverse events (AEs) and serious 
adverse events (SAEs) .............................................................................................. 33 
9.3 
Assessments of Adverse Events............................................................................... 33 


Core-CROWN CORONATION Protocol V8.0, dated 12 Oct 2021 
   Page 7 of 46 
9.3.1 Seriousness assessment ........................................................................................... 33 
9.3.2 Severity assessment ................................................................................................. 33 
9.3.3 Causality assessment ................................................................................................ 34 
9.3.4 Expectedness assessment ........................................................................................ 34 
9.4 
Notifications .............................................................................................................. 35 
9.4.1 Emergency Unblinding ............................................................................................. 35 
9.4.2 Unblinding for the submission of SUSAR reports .................................................. 35 
9.5 
Development Safety Update Reports ...................................................................... 36 
9.6 
Overdose .................................................................................................................... 36 
9.7 
Reporting Urgent Safety Measures and other safety events ................................. 36 
9.8 
Notification of Serious Breaches to GCP and/or the protocol .............................. 36 
10 
Data management and quality assurance ............................................................... 36 
10.1 Confidentiality ........................................................................................................... 36 
10.2 Data collection tools and source document identification .................................... 37 
10.3 Data handling and analysis ...................................................................................... 37 
11 
Statistical Considerations ......................................................................................... 37 
11.1 Outcomes ................................................................................................................... 37 
11.1.1 
Primary outcome .............................................................................................. 37 
11.1.2 
Secondary outcomes ......................................................................................... 38 
11.2 Sample size and recruitment ................................................................................... 39 
11.2.1 
Sample size calculation ..................................................................................... 39 
11.2.2 
Planned recruitment rate ................................................................................. 40 
11.3 Randomization methods .......................................................................................... 40 
11.4 Statistical analysis plan ............................................................................................ 41 
11.4.1 
Summary of baseline data and flow of participants ....................................... 41 
11.4.2 
Primary outcome analysis ................................................................................ 41 
11.4.3 
Sensitivity and other planned analyses .......................................................... 42 
11.5 Interim analyses........................................................................................................ 42 
11.6 Other statistical considerations ............................................................................... 42 
12 
Record keeping and archiving ................................................................................. 43 
13 
Oversight Committees .............................................................................................. 43 
13.1 Trial Management Group (TMG) ............................................................................. 43 
13.2 Data Monitoring Committee (DMC) ........................................................................ 43 
14 
Direct Access to Source Data/Documents .............................................................. 43 
15 
Ethics and regulatory requirements ....................................................................... 43 
16 
Monitoring requirement for the trial ...................................................................... 44 
17 
Finance ....................................................................................................................... 45 
18 
Publication policy ..................................................................................................... 45 
19 References ........................................................................................................................ 46 


Core-CROWN CORONATION Protocol V8.0, dated 12 Oct 2021 
   Page 8 of 46 
List of abbreviations 
AE 
Adverse Event 
AR 
Adverse Reaction 
ARDS 
Acute Respiratory Distress Syndrome 
ARI 
Acute Respiratory Infection 
AUC 
Area under the (receiver operator) curve  
BMGF 
Bill & Melinda Gates Foundation 
CA 
Competent Authority 
CI 
Chief Investigator 
COVID-19 
Coronavirus Disease 2019 
CRF 
Case Report Form 
CRO 
Contract Research Organisation 
CTA 
Clinical Trial Authorisation 
CTIMP 
Clinical Trial of Investigational Medicinal Product 
DI 
Designated Individual 
DMC 
Data Monitoring Committee 
DSUR 
Development Safety Update Report 
e-CRF
electronic case record form 
EC
European Commission 
EMEA
European Medicines Agency 
EU
European Union 
EUCTD
European Clinical Trials Directive 
EudraCT
European Clinical Trials Database 
EudraVigilance
European database for Pharmacovigilance 
GCP
Good Clinical Practice 
GFATM
Global Fund for AIDS, TB and Malaria 
GMP
Good Manufacturing Practice  
G6PD
Glucose-6-Phosphate Deficiency 
HTA
Human Tissue Authority 
IB
Investigator Brochure 
ICF
Informed Consent Form 
IDMC
Independent Data Monitoring Committee 
IEC
Independent Ethics Committee 
IMP
Investigational Medicinal Product 
IMPD
Investigational Medicinal Product Dossier 
IRB
Institutional Review Board 
ISF
Investigator Site File 
ISRCTN
International Standard Randomised Controlled Trial Number 
ITT
Intention-To-Treat 
LTFU
Loss to Follow-Up 
MA
Marketing Authorisation 
MERS-CoV
Middle East Respiratory Syndrome Coronavirus 
MHRA
Medicines and Healthcare products Regulatory Agency 
MIA
Manufacturer/Importer Authorisation 
MS
Member State 
NHS
National Health Service 
NHS R&D
National Health Service Research & Development   
NIMP
Non-Investigational Medicinal Product 
PI
Principal Investigator 
PIS
Participant Information Sheet 
PL
Product License 
PP
Per Protocol 


Core-CROWN CORONATION Protocol V8.0, dated 12 Oct 2021 
   Page 9 of 46 
QA 
Quality Assurance 
QC 
Quality Control 
QP 
Qualified Person (for release of trial drug) 
QTc 
Corrected QT interval 
RCT 
Randomised Controlled Trial 
REC 
Research Ethics Committee 
RSV 
Respiratory Syncytial Virus 
RT-PCR 
Reverse Transcriptase Polymerase Chain Reaction 
SAR 
Serious Adverse Reaction 
SARS-CoV 
Severe Acute Respiratory Syndrome Coronavirus 
SARS-CoV-2 
Severe Acute Respiratory Syndrome Coronavirus-2 
SAE 
Serious Adverse Event 
SDV 
Source Document Verification 
SLE 
Systemic Lupus Erythematosus 
SOP 
Standard Operating Procedure  
SPC 
Summary of Product Characteristics  
SSA 
Site Specific Assessment 
SUSAR 
Suspected Unexpected Serious Adverse Reaction  
TMG 
Trial Management Group 


Core-CROWN CORONATION Protocol V8.0, dated 12 Oct 2021 
   Page 10 of 46 
1 
Trial personnel 
Clinical Coordinating Centre 
Professor Michael Avidan 
Principal Investigator (PI) 
Dr. Seymour and Rose T. Brown  
Professor of Anesthesiology, Professor of Surgery, 
Psychiatry and Anesthesiology Washington University 
School of Medicine in St Louis, USA 
email:  avidanm@wustl.edu 
Data Coordinating 
Professor Ramani Moonesinghe 
Centre PI  
Professor of Perioperative Medicine, UCL, UK 
email: ramani.moonesinghe@ucl.ac.uk 
Data Coordinating Centre 
Professor Nick Freemantle 
Director, Comprehensive Clinical Trials Unit, UCL, UK 
email: nicholas.freemantle@ucl.ac.uk 
Gemma Jones 
Head of Clinical Trial Operations, CCTU, UCL, UK 
email: gemma.jones@ucl.ac.uk  
Emilia Caverly 
Clinical Project Manager, CCTU, UCL, UK 
email: emilia.caverly@ucl.ac.uk 
Dominic Hague 
Clinical Project Manager for Data Science, CCTU, UCL, UK 
email: d.hague@ucl.ac.uk  
Dr Dermot McGuckin 
Clinical Research Fellow, UCL, UK 
email: d.mcguckin@ucl.ac.uk   
Trial Statistician 
Hakim-Moulay Dehbi, PhD  
Comprehensive Clinical Trials Unit at UCL, London, UK 
email:  h.dehbi@ucl.ac.uk 
International Governance & 
Professor Helen Rees 
Coordination PI 
Wits Reproductive Health and HIV Institute (Wits RHI), 
University of the Witwatersrand, Johannesburg, SA 
Country teams: 
Cameroon 
Professor Wilfred Mbacham, Lab Head, & Country PI 
Professor Jean Claude Mbanya, Director, BTC-UY1  
 Professor Eugene Sobngwi. Med. Adviser, Central Hosp, 
Y’de  
The Biotechnology Centre, University of Yaounde 1 
Prof Henry Luma, Director General Hospital, Douala  
Prof Anastase Dzudie, Cardiologist General Hospital, Douala 
Canada 
Professor David Mazer, St. Michael’s Hospital, University of 
Toronto 
Dr. Jessica Spence, Population Health Research Institute, 
Hamilton, Ontario 
Professor Eric Jacobsohn, University of Manitoba 
Ghana 
Professor George Kyei 


Core-CROWN CORONATION Protocol V8.0, dated 12 Oct 2021  
 
 
 
   Page 11 of 46 
 
 
 
Professor Kwadwo Koram, University of Ghana 
 
India 
 
 
 
 
(Indian team to provide details)  
 
Netherlands 
 
 
 
Prof. Dr. Mihai G. Netea 
Department of Internal Medicine  
Radboud University Medical Center 
 
Republic of Ireland  
Professor Ellen O'Sullivan, St James's hospital, Trinity 
College Dublin 
 
Professor Colm Bergin, St James 's Hospital, Trinity College 
Dublin 
 
Dr. Eoin Kelleher, Research Fellow 
 
South Africa 
Professor Sinead Delany-Moretlwe, Wits RHI, University of 
the Witwatersrand, Johannesburg 
Professor Bruce Biccard, Professor and Second Chair, 
Groote Schuur Hospital, University of Cape Town  
 
 
Dr. Leon Du Toit, University of Cape Town and Washington 
University in St. Louis 
 
Professor Linda-Gail Bekker, The Desmond Tutu Health 
Centre, University of Cape Town 
 
Dr Annalene Nel, Wits RHI, University of the Witwatersrand, 
Johannesburg  
 
United Kingdom 
Professor Laurence Lovat, University College London 
 
 
Professor. Joseph Standing, University College London 
 
 
Dr. Andrew Hill, Liverpool University 
 
 
Dr Clare Stephens, North Central London Clinical 
Commissioning Group 
 
United States 
Professor Mary Politi, Washington University School of 
Medicine in St Louis 
Professor Erik Dubberke, Washington University School of 
Medicine in St Louis 
 
 
Professor Graham Colditz, Washington University School of 
Medicine in St Louis 
 
 
Professor Eric Lenze 
 
 
Dr. Christian Guay 
 
 
Ms. Anne DeSchryver 
 
 
Ms. Linda Yun 
 
 
Mr. Ben Swan 
 
 
Ms. Sherry McKinnon 
 
Zambia  
Dr. Izukanji Sikazwe, Chief Executive Officer and Director 
 
Dr. Roma Chilengi, Chief Scientific Officer 
 
Center for Infectious Disease Research in Zambia  
 
 
Zimbabwe 
Dr. Nyaradzo Mgodi, University of Zimbabwe College of 
Health Sciences, Clinical Trials Research Centre, Harare 
 
Dr. Teacler Nematadzira, University of Zimbabwe College of 
Health Sciences, Clinical Trials Research Centre, Harare 


Core-CROWN CORONATION Protocol V8.0, dated 12 Oct 2021  
 
 
 
   Page 12 of 46 
 
 
 
Other Partner Organizations: 
Medicines for Malaria Venture 
Helen Demarest, Director Clinical Operations 
 
 
Tim Wells, Chief Scientific Officer 
 
 
Stephan Duparc, Chief Medical Officer 
 
 
Andre Marie Tchouatieu, Director Access and Product         
Management  
 
 
Nada Araeipour, Director Business Development 
 
University of Michigan 
Dr. Jonathan Sexton, PhD, Faculty Director 
Center for Drug Repurposing 
Kevin Weatherwax, Managing Director 
 
Professor George Mashour, MD, PhD, Executive Sponsor 
 
 
 


Core-CROWN CORONATION Protocol V8.0, dated 12 Oct 2021  
 
 
 
   Page 13 of 46 
 
2 
Summary 
 
Objectives: 
Primary Objective: 
To determine the effectiveness of the trial intervention(s) in 
preventing symptomatic (i.e. any of the following: cough, 
shortness of breath or difficulty breathing, fever, chills, muscle 
pain, sore throat, new loss of taste or smell, nausea, vomiting, or 
diarrhea), laboratory test-confirmed COVID-19 in adults with 
repeated exposures to SARS-CoV-2 by day 60 after receiving trial 
interventions. 
Secondary objectives:  
1. To determine the effectiveness of the trial interventions(s) in 
preventing symptomatic (i.e. any of the following: cough, 
shortness of breath or difficulty breathing, fever, chills, muscle 
pain, sore throat, new loss of taste or smell, nausea, vomiting, 
or diarrhea), laboratory test-confirmed COVID-19 in adults 
with repeated exposures to SARS-CoV-2 by day 150 after 
receiving trial interventions.  
2. To determine the effectiveness of the trial interventions in 
mitigating the severity of COVID-19 in adults who become 
infected with SARS-CoV-2 by day 60 after receiving trial 
intervention. Severity will be graded on a simplified version of 
the ordinal WHO COVID-19 severity scale. 
3. To determine the effectiveness of the trial interventions in 
mitigating the severity of COVID-19 in adults who become 
infected with SARS-CoV-2 by day 150 after receiving trial 
interventions. Severity will be graded on a simplified version of 
the ordinal WHO COVID-19 severity scale. 
 
4. To determine the effectiveness of the trial interventions in 
preventing/reducing the incidence of SARS-CoV-2 infection (by 
serology) over up to 150 days (5 months) of follow-up (see trial 
duration per participant below).  
Type of trial: 
An international, randomized, placebo-controlled, Bayesian 
platform clinical trial. Frequent interim analyses will be performed 
in a Bayesian manner to modify the trial early for overwhelming 
evidence of efficacy, futility or harm, using pre-specified 
thresholds.  
Trial design and methods: Participants will be randomized to receive trial interventions. 
Trial duration per 
participant: 
Participants will be followed up for 150 days from randomization. 
Participants who complete 60 days of follow up (primary outcome 
ascertainment) will be followed up for a further 3 months (i.e. a 
total of 150 days (5 months) of participant follow-up). 
Estimated total trial 
duration: 
1 year 


Core-CROWN CORONATION Protocol V8.0, dated 12 Oct 2021  
 
 
 
   Page 14 of 46 
 
Planned trial sites: 
Participants will be recruited from sites in Canada, Ghana, India, 
Ireland, South Africa, UK, USA, Zambia, and Zimbabwe, as well as 
other possible countries  
Total number of 
participants planned: 
There is no fixed pre-specified target for enrolment.  
The Bayesian design includes frequent interim analyses; stopping 
rules for efficacy, harm or futility are specified. It is likely that no 
more than 30,000 participants will be included overall.  
Main inclusion/exclusion 
criteria: 
Inclusion criteria 
1. Volunteers without clinical evidence of COVID-19 infection 
aged 18 years and older. 
2. Participants who are at high risk of SARS-CoV-2 infection, 
defined as adults whose locations or circumstances put 
them at appreciable risk of exposure to SARS-CoV-2 and 
COVID-19. (see country specific addendum if needed to define 
further) 
3. Must have a mobile phone and access to the Internet for data 
collection purposes. 
4. Participants who are willing and able to provide informed 
consent via an electronic consent process. 
Exclusion criteria 
5. Weight outside range 50 kg – 120 kg (110 lbs – 265 lbs). 
6. Self-reported or laboratory confirmed previous or current 
diagnosis of SARS-CoV-2. 
7. Self-reported current acute respiratory infection.  
8. Concurrent and/or recent use of the investigational product, a 
product considered to be equivalent to the investigational 
product, or any other product that is likely to interfere with the 
investigational products in this trial or the interpretation of trial 
data .  
9. Self-reported known allergies to any of the IMPs and excipients 
of the IMPs and placebo. 
10. Self-reported presence or history of the conditions listed in the 
appendices. 
11. Self-reported current use of medication with known to interact 
with any of the medications listed in the appendices. 
12. Inability or unwillingness to be followed up for the trial period. 
Statistical methods and 
analysis: 
The analysis of the primary endpoint will be by Bayesian logistic 
regression, adjusting for age as fixed effect, and sites as random 
effects. The secondary severity endpoint will be analyzed by 
Bayesian proportional odds model, with the same adjustment 
strategy. Interim analyses will be performed regularly for efficacy, 
futility and harm.     
 
 
 


Core-CROWN CORONATION Protocol V8.0, dated 12 Oct 2021  
 
 
 
   Page 15 of 46 
 
3 
Background and Rationale 
 
BACKGROUND 
A. The Crisis of COVID-19 
Over the past few months, a health crisis wrought by the novel severe acute respiratory syndrome 
coronavirus-2 (SARS-CoV-2) has swept the world, taking a massive toll on people and nations; it has 
inflicted substantial societal and economic devastation, and threatens to overwhelm healthcare 
systems. This new deadly contagion has an estimated overall infection fatality rate of up to 2%.1 It is a 
zoonotic infection that crossed to humans in late 2019, it rapidly causes mild to severe respiratory 
symptoms, and it is readily transmitted from human to human by droplet spread (R0 = 2.5, compared 
to the 2009 H1N1 influenza pandemic that had an R0 of 1.5; the R0 of seasonal influenza is even lower). 
The resulting infectious disease has been termed COVID-19. Most infections are mild and similar in 
severity to the common cold. However, about 20-25% of those with documented infection have more 
severe symptoms, and approximately 5% of those infected have life-threatening complications (Figure 
1),2 including a severe acute respiratory syndrome, pneumonia, respiratory failure, sepsis, delirium, 
cardiogenic shock, acute kidney injury, liver injury, and multi-organ failure. SARS-CoV-2 belongs to the 
Beta-coronavirus family, which also includes severe acute respiratory syndrome coronavirus (SARS-
CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV).3 Some epidemiologists estimate 
that between 30% and 70% of the world’s adult population could contract SARS-CoV-2 over the coming 
year, although this might be modifiable with appropriate behavioral modification and other 
measures.4 There is thus an urgent need to develop and deploy multiple behavioral and pharmacologic 
interventions in order to mitigate the harm of the current SARS-CoV-2 pandemic, as well as to inform 
management of future pandemics. In addition, the disease is likely to spread more easily between 
individuals living in vulnerable areas with condensed living conditions, including many low and middle-
income countries, where large proportions of the population living together in close quarters. The 
extent of physical distancing that has proved effective in certain countries will not easily be 
implementable in many lower and middle-income countries, where living conditions are often 
informal, extremely dense and crowded. Furthermore, while suppression of the epidemic curve by 
physical distancing is known to be effective, it requires a high level of compliance that is unlikely to be 
maintainable for an extended duration even in economically advantaged countries, and it is 
economically and socially ruinous. Hence there is urgency to identify effective prophylactic, mitigation, 
and therapeutic options, as a bridge to the development of an effective vaccine. In response to this 
need, the COVID-19 Therapeutics Accelerator has been created as a collaborative initiative with 
contributions from an array of public and philanthropic donors, intended to support research and 
development in order to make effective COVID-19 treatments accessible to the world as quickly and 
as widely as possible. The COVID-19 Research Outcomes Worldwide Network (CROWN) Collaborative 
is a research platform, established with the intention of being one of the organizations to realize the 
vision of the COVID-19 Therapeutics Accelerator. 
 
 


Core-CROWN CORONATION Protocol V8.0, dated 12 Oct 2021  
 
 
 
   Page 16 of 46 
 
 
Figure 1: The incidence of mild, severe and extremely severe COVID-19. From Guan et al (2020).2 
B. The Extent of the Danger 
SARS-coronavirus-2 is extremely dangerous for several specific reasons,5 including:  
(i) 
with no prior exposure, people have no immunity and are exquisitely susceptible to 
infection;  
(ii) 
the virus is easily contracted by inhalation of viruses expelled into the air from coughs 
and sneezes (large and small droplets), and by touching infected people or 
contaminated surfaces (fomites), and then putting a hand to one’s mouth, nose, or 
eyes;  
(iii) 
infection spreads at an exponential rate through non-immune communities (R0 = 2.5);  
(iv) 
the virus can be spread from people who are asymptomatic or who are in the 
prodromal phase of illness;  
(v) 
infection is associated with a risk of pneumonia, acute respiratory failure, and death 
in a percentage of people, particularly older adults and those with comorbidities.  
 
C. Susceptible Populations 
Some groups within society are especially vulnerable to severe manifestations of COVID-19. 
Interestingly, unlike some other viral infectious diseases such as measles and influenza, this infection 
has largely spared children, or if they are becoming infected, symptoms are typically mild. On the other 
hand, morbidity and mortality are high in certain demographics, including older men, obese adults, 
those with immunosuppression, and those with various co-morbidities including cardiorespiratory 
diseases and diabetes. In these high-risk groups, mortality from COVID-19 infection is likely to be 
between 10% and 20%, with even higher rates of serious complications. As of 15 November 2020, the 
World Health Organisation (WHO) reports 53.7 million confirmed cases of COVID-19 associated with 
1.3 million deaths.6 The rate of new cases and deaths continues to increase and community 
transmission is entrenched in many countries.7  
 
D.  No Proven Prevention, Mitigation, or Treatment  
Worldwide, non-pharmacological interventions like stay-at-home regulations, travel bans, and 
universal masking policies are used to reduce the reproductive number (R0), but such measures relying 
on socials distancing are not applicable to healthcare workers who have to be in close contact with 
people as part of their job.  Whilst barrier interventions, namely personal protective equipment such 
as respirators, face protection, gowns and gloves are indicated as the minimum standard of prevention 
for healthcare workers who come into contact with SARS-CoV-2,8,9 these equipment measures are not 


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infallible and not always available. For other populations, barrier interventions such as face masks and 
personal screens are even less available. No pharmacological therapy been proven as effective for 
prevention or mitigation although remdesivir has been shown in some studies to reduce duration of 
ventilation and dexamethasone reduces mortality in severely ill patients. An ounce of mitigation is 
worth a pound of cure; this is especially true for highly virulent, pathogenic, and prevalent infectious 
diseases like SARS-CoV-2. Several specific vaccines for the SARS-CoV-2 have shown significant 
protective benefit, however several relevant caveats remain including:  
(i) 
it will take time to roll out a COVID-specific vaccine with an established safety profile 
to all at-risk populations;  
(ii) 
new strains of the virus might emerge for which the vaccine will not work.  
(iii) 
the vaccine might confer only brief immunity, since antibodies to SARS-CoV-2 often 
wane over a period of a few months.  
 
We should therefore not simply rely on the development of a new vaccine and must also explore other 
pre-emptive and mitigation options. In order to have substantial positive impact, a pre-emptive 
therapy would have to either decrease the incidence of symptomatic COVID-19 or mitigate its average 
severity (duration of illness and complication rates).    
 
 
 
 
Figure 2: Sites of action of candidate therapeutic agents for preventing and treating COVID-19. COVID-19, coronavirus 
disease 2019; CQ, chloroquine; ER, endoplasmic reticulum; gRNA, genomic RNA; HCQ, hydroxychloroquine; PDTC, 
ammonium pyrrolidinedithiocarbamate, RdRp, RNA- dependent RNA polymerase; rhACE2, recombinant human 
angiotensin-converting enzyme 2; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; sgRNA, subgenomic 
RNA; TMPRSS2, transmembrane protease serine 2. Modified from Guy RK et al. Science 22 May 202010  
 
Information on the agents that will be used initially in the CROWN CORONATION trial is provided in 
the supplementary appendices. As this is a platform trial, it is important to emphasize that therapeutic 
arms might be discontinued based on external evidence (from other studies) and internal evidence 
(generated from this trial). Additional candidate therapies might be added based on emerging 
evidence. Decisions to include candidate interventions in the platform trial will be made on the basis 
of a combination of evidence for anti-SARS CoV-2 activity, safety and tolerability profile, mode of 


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delivery and adherence considerations, cost, access and potential to scale up delivery if demonstrated 
to be effective. 
 
The intention is to begin the trial with a 2-arm parallel design, in which participants will be randomized 
to receive the MR or the MMR vaccine (depending on in-country availability), or a placebo injection. 
Subsequent to an initial period of enrolment (estimated at 5,000 participants), a second agent (Drug 
A) will be added, and the trial will follow a 4-arm 2-by-2 factorial design: 
Arm 1: Education and surveillance plus placebo 
Arm 2: Education and surveillance plus MR (or MMR) vaccine 
Arm 3: Education and surveillance plus Drug A  
Arm 4: Education and surveillance plus Drug A + MR (or M/MR) vaccine 
 
After another period of enrolment (estimated at 10,000 further participants), a third agent (Drug B) 
will be added, and the trial will follow an 8-arm 2-by-2-by-2 factorial design:  
Arm 1: Education and surveillance plus placebo 
Arm 2: Education and surveillance plus MR (or MMR) vaccine 
Arm 3: Education and surveillance plus Drug A  
Arm 4: Education and surveillance plus Drug A + MR (or MMR) vaccine 
Arm 5: Education and surveillance plus Drug B  
Arm 6: Education and surveillance plus Drug B + MR (or MMR) vaccine 
Arm 7: Education and surveillance plus Drug A + Drug B 
Arm 8: Education and surveillance plus Drug A + Drug B + MR (or MMR) vaccine 
 
E. Protection 
All those who participate in the trial will benefit not only from possible effective prophylaxis and 
mitigation, but also from heightened awareness, education, and screening. If interventions used in 
this trial are effective at preventing or mitigating the severity of COVID-19, participants might be less 
likely to contract SARS-CoV-2 infection, and if they do become infected, they might have a less severe 
form of COVID-19. With the adaptive approach, the education and surveillance plus placebo arm might 
be dropped early if there is a strong signal suggesting benefit attributable to interventions, without 
safety concerns. If participants do develop symptomatic COVID-19, they could be given information 
about treatment studies with the option to participate, if available and if they are eligible. 
 
F. Strong International Representation 
This trial is being conducted by a strong trans-disciplinary group of experienced investigators around 
the world. Importantly, this will allow us to enrol participants in diverse settings. Taken together, we 
believe that implementing this trial in a number of geographic regions will provide rich information for 
the generalizability of the intervention, the current pandemic and also for future pandemics. 
 
G. Strengths and Limitations 
This study has several important strengths. Most notably, it is designed to address a clinically highly 
relevant question with great importance to society. The question is whether interventions can be 
used preemptively to prevent the occurrence of COVID-19 or to mitigate its severity at risk 
populations. As a large, pragmatic trial, conducted across multiple continents, this trial will generate 
precise estimates and generalizable results. Importantly it might provide relevant information for 
future pandemics as well as the current coronavirus pandemic. There are also important limitations. 
Event rates (incidence of COVID-19) may vary over time and are somewhat uncertain. These might be 
higher than anticipated, which would allow the study to reach a conclusion more rapidly, or lower 
than estimated, which would make this trial too small to detect a difference attributable to the 
interventions. We plan to increase enrolment at sites where COVID-19 incidence is the highest and 
decrease enrolment at sites with low event rates. It will be difficult to maintain blinding in this trial. 
This is especially challenging with a platform design, where arms can be added or dropped. Also 


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distinct tastes, mode of administration, and side effects of certain interventions can render blinding 
difficult. The difficulty in including an education and surveillance plus placebo group presents 
scientific challenges. It is possible that many participants would wish to be assigned to active 
intervention arms and would be reluctant to take an inert placebo. We aim to address this by 
conveying to participants the real uncertainty regarding the benefit of prophylactic peri-exposure 
interventions. Indeed, there is the possibility of harm with any intervention, and a potential of side 
effects and possibly toxicity with high doses, depending on which intervention is used. We also plan 
to provide benefit to all participants in the trial through education and improved surveillance of 
symptoms.  
 
H. Future Directions 
As a bridge to vaccine development and roll-out, the COVID-19 Therapeutics Accelerator has identified 
that we urgently need to test and then deploy practical, affordable and effective prophylactic and 
therapeutic interventions, as well as those that mitigate the severity of COVID-19. In line with this 
priority, the CROWN (COVID-19 Research Outcomes Worldwide Network) COLLABORATIVE is a 
research platform, established to assess rigorously and efficiently promising interventions for COVID-
19. The CROWN CORONATION trial is designed as a platform trial, such that interventions or 
combinations of interventions can be added as an arm or arms, if recommended by the Trial 
Management Group. Interventions that will be tested in this platform trial will be selected based on 
certain criteria including affordability, safety, accessibility, and scalability, particularly within low- and 
middle-income countries (LMIC).   However, there is no guarantee that participants will be able to 
access any of the interventions tested post trial. 
 
I. Conclusions 
Over the next year, the number of people who have been infected by SARS-CoV-2 is predicted to be 
substantial, with many people experiencing severe COVID-19 disease, and millions dying. Even with 
the advent of effective vaccines for this deadly pathogen, a strategy of mitigation would be most 
beneficial particularly if access if constrained. What is urgently needed is a preemptive intervention 
that can safely be administered to in order to decrease the occurrence of symptomatic COVID-19, and 
to mitigate its severity and impact on the health system.  
3.1 
Assessment and management of risk  
The risks associated with this study do not outweigh the potential benefits. There is a rare risk of 
breach of confidentiality. There is a theoretical risk that participants will be less scrupulous with 
respect to personal protection if they believe that they are receiving an intervention, which effectively 
prevents or mitigates the severity of COVID-19. However, this is unlikely given the potential severe 
consequences of COVID-19, and the unproven value of the interventions that will be used in this 
platform trial. The risks of specific interventions are addressed in the supplementary appendix. 
Participants may feel some mild discomfort or pain associated with the self-collected nasal swabs and 
the finger prick for the dried blood spot.  Participants will not incur any study-related expenses, nor 
will they be financially compensated for their participation. 
 
The trial design and procedures aim to mitigate risk to investigators. The trial has a light-touch design 
that not only reduces the burden on the participant by removing the need for follow-up visits but also 
this remote design also reduces potential exposure to investigators. At the points where investigators 
are in contact with participants (e.g. the point of dispensing Investigational Medicinal Product (IMP) 
or placebo, or at any point where investigators are required to take part in samples collection, 
appropriate PPE will be used by the investigators).  
 


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4 
Objectives 
 
Primary objective: 
To determine the effectiveness of the active arm(s) in preventing symptomatic (i.e. any of the 
following: cough, shortness of breath or difficulty breathing, fever, chills, muscle pain, sore throat, new 
loss of taste or smell, nausea, vomiting, or diarrhea), laboratory test-confirmed COVID-19 in 
participants with repeated exposures to SARS-CoV-2 by day 60 after receiving trial interventions. 
 
Secondary objectives:  
1. To determine the effectiveness of the trial interventions(s) in preventing symptomatic 
(i.e. any of the following: cough, shortness of breath or difficulty breathing, fever, chills, 
muscle pain, sore throat, new loss of taste or smell, nausea, vomiting, or diarrhea), 
laboratory test-confirmed COVID-19 in adults with repeated exposures to SARS-CoV-2 by 
day 150 after receiving trial interventions.  
 
2. To determine the effectiveness of the treatment arm(s) in mitigating the severity of 
COVID-19 in participants who become infected with SARS-CoV-2 by day 60 after 
commencement of trial intervention. Severity will be graded on a simplified Ordinal WHO 
COVID-19 severity scale. 
 
3. To determine the effectiveness of the trial interventions in mitigating the severity of 
COVID-19 in adults who become infected with SARS-CoV-2 by day 150 after receiving 
trial interventions. Severity will be graded on a simplified version of the ordinal WHO 
COVID-19 severity scale. 
4.  
5. To determine the effectiveness of the trial interventions in preventing/reducing the 
incidence of SARS-CoV-2 infection (by serology) over up to 150 days (5 months) of follow-
up (see trial duration per participant below).  
5 
Trial design 
5.1 
Overall design 
 
Study Design 
CROWN CORONATION is a large, Bayesian adaptive, pragmatic, participant-level randomized, multi-
site, international placebo-controlled trial. Randomization will be stratified by age (<50 and ≥50),site 
and previous vaccination with a SARS-C0V-2 specific vaccine. Participants will be individuals at risk of 
contracting SARS-CoV-2. Participants will be randomized to education and surveillance plus Placebo or 
to a study arm with active interventions for a period of up to 60 days. The details can be found in the 
relevant appendices.  
 
All participants will require a mobile phone to participate. This is standard in all the countries in this 
study. The participant, with help from the local trial team if required, will enrol online using the web-
based eCRF system and record basic demographic and eligibility information.   
The database will be hosted on UK-based servers which are expected to be managed by Sealed 
Envelope Ltd. Local investigators will have access to the part of the CRF to enable recording of adverse 
events, outcome data and/or severity of COVID-19 symptoms. Participants will be sent emails with a 
link to complete an initial participant health questionnaire and the regular data logs. 


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Participants will complete weekly SMS surveys. Participants who develop symptomatic COVID-19 
during the last month of observation will at a minimum be followed-up until symptom resolution and 
at a maximum until 150 days (5 months) after randomization (whichever comes first). 
 
The study flow overview is outlined in Figure 3.  In the case of oral medications, the trial will provide 
adherence support interventions that have been shown in randomized controlled trials to improve 
adherence to Human Immunodeficiency Virus (HIV) treatment and adapted for HIV Pre-Exposure 
Prophylaxis (HIV PrEP) (e.g. two-way SMS with check in for those that report symptoms or adverse 
events).  
 
 
 
 
 
 
 


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Figure 3a: Detailed chart outlining the likely flow for each participant in the trial. This may be modified by individual centers. 
 
 


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Figure 3b: Flow Diagram showing mixed use of internet and tele-messaging through the course of the trial. 
 
Sites 
CROWN CORONATION is an international, multi-site trial with sites in Canada, Ghana, India, Ireland, 
South Africa, UK, USA, Zambia and Zimbabwe. Sites will be selected in settings such as community-
based clinics, general practice facilities and hospitals where IRB/REC approval is in place that the study 
can be conducted there. Access to laboratory testing and a research pharmacy are required. The 
research site will be associated with a healthcare facility or organization whose staff are considered to 
be at high risk of contracting COVID-19 and where there are personnel who have received adequate 
GCP and protocol training and are able to conduct the study procedures. Preferably, each site should 
be able to recruit at least 20 participants during the trial period although in rural locations, this number 
may be smaller. Consideration will also be given to whether there has been a report of COVID-19 
outbreak in the local area, as this will increase the risk of individuals contracting the disease.  
 
 


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Participants 
Participants will include adults (18 years or older) who are at risk for contracting SARS-CoV-2 based on 
their work in hospitals or in the community. See the country-specific addenda for country-specific 
definitions of individuals at risk for SARS CoV-2 exposure.   
 
The reason that participants are at risk will be recorded in the CRF. Participants will be enrolled in low, 
middle, and high-income countries, including, Canada, Ghana, India, Ireland, South Africa, UK, USA, 
Zambia and Zimbabwe. Other countries may be added with time. All participants will be fully informed 
about the trial and will provide informed consent (electronically).   
 
Baseline Data 
At the time of enrolment, demographic information will be collected from participants, and relevant 
data on their medical histories, comorbidities, concurrent medication, and risk factors for severe 
COVID-19 will be documented.  They will also provide information on the nature of their work and the 
contexts in which they are likely to encounter people infected with SARS-CoV-2. They will also provide 
information on their access to and use of personal protective equipment during high-risk encounters. 
In addition, they will be asked to nominate at least one other person to contact in case they become 
unwell so that we can establish what happened to them. This will all be done in line with local data 
protection legislation. 
 
Interventions 
As this is a pragmatic trial, other than administration of the intervention, all decisions regarding other 
measures taken to prevent SARS-CoV-2 infection or to mitigate its severity (e.g. use of personal 
protective equipment, limiting high risk exposures) will be at the discretion of the participant. 
Educational material regarding both social and clinical practice that could prevent or delay infection 
will be provided alongside trial information. The trial will track participants at a minimum of weekly 
for symptoms of infection and compliance with drug self-administration, and should participants 
contract SARS-CoV-2, we would offer them the option of participating in a treatment trial if it is 
available.   
6 
Investigational Medicinal Products (IMPs) and Non-Investigational 
Medicinal Products 
6.1 
     Name and description of IMP(s) 
 
Specific details regarding the IMP(s) used in each country is elaborated in the appendices. New dosage-
based arm(s) or drugs might be added or removed following review and approval by relevant 
regulatory authorities. Each label for an IMP (active drug or placebo) will include the description of the 
study product and the information of the source (manufacturer/supplier, batch/lot number and expiry 
or best use by date). 
 
Placebo will be aligned to the active IMP in terms of dosing schedule. The interventions will be 
continued for (up to) 60 days from enrolment; or until the participant is diagnosed with COVID-19; or 
development of a complication or safety concern or side effect necessitating stopping the intervention; 
or the intervention arm is stopped; or participants are no longer at risk of contact with SARS-CoV-2 
infected patients (e.g. no longer new COVID-19 cases at the participating site). Treatment groups may 
be discontinued at interim analyses, and new treatment groups might be initiated. If a treatment group 
is discontinued due to perceived harm, participants in that group will be informed as soon as possible 
to stop taking the IMP.  


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6.2 
Source of IMP(s), Manufacture, Distribution and Storage 
The IMPs (see appendices) will be manufactured and QP released for use in the study by the holder of 
an MIA (IMP) license (or international equivalent). Sourcing of the IMP(s) is also discussed in the 
relevant site-specific IMP management plans. 
6.3 
Storage and handling of IMP(s) at site 
 
All IMP aspects of the trial at participating sites are the responsibility of the site PI, who may delegate 
this duty to the local pharmacist or other appropriately trained personnel.  The delegation of duties 
must be recorded on the Staff Signature and Delegation of Tasks log. Storage and handling (e.g., 
reconstitution, labeling) of the IMP will be completed in accordance with the relevant summary of 
product characteristics (SPC) and local IMP management plan. Treatment allocation will be sent to the 
pharmacist preparing the intervention at the point of randomization. The site pharmacist(s) will be 
unblinded to the treatment arm, they will dispense IMP(s) or placebo(s) in accordance with the 
treatment allocation and dosing regimen. Final presentation of the IMP or placebo will ensure 
participants are not aware of the treatment allocation. Detailed instructions are contained in the local 
IMP management plan.  
6.4 
Accountability of IMP(s) 
 
IMP shipping arrangement instructions for sites will be described in each local IMP management plan. 
In each country, standardized procedures for monitoring of temperature and transport conditions of 
the IMP will apply and will be documented on the IMP shipping form in accordance with local 
requirements.  
 
Upon receipt of the IMP, the site pharmacy will confirm receipt of the IMPs by emailing back the 
accompanying shipping form to the coordinating center and copies retained at the trial site’s file. In 
cases where the IMP was damaged or not stored correctly this will warrant an urgent notification to 
the supplier and a replacement will be arranged. The supplier will be responsible for dispatching 
replacement IMPs to sites.  Site pharmacy will be responsible for logging receipt of the IMPs on the 
site accountability log within the site pharmacy file. Site pharmacy will be responsible for storing the 
IMP in line with storage requirements as per the local IMP management plan. Site pharmacy will 
monitor temperature of IMP storage and report to the sponsor any temperature excursions that have 
occurred. Details of reporting temperature excursion are in the IMP management plan or country 
specific SOP for IMP Management. Full IMP accountability will be conducted during the trial. All IMP 
dispensed by pharmacy will be logged on the site accountability log within the site pharmacy file. In 
case of delay in drugs reaching the participants, it is important that the drug should have stability data 
supplied by the supplier to show that it is stable for at least 4 months and ideally longer than this. 
 
IMP administration will be specific to the intervention and is detailed in the relevant appendix. 
Additionally, where relevant, participants will be reminded to adhere during the weekly SMS 
messaging. In vaccine arms, the IMP or placebo will be administered as a single dose by study 
personnel, making proper use of PPE.  
 
All used/unused IMPs will be reconciled with site pharmacy, to be then updated in the IMP 
accountability log in the pharmacy site file. IMP destruction or disposal will be conducted, once 
authorized by the sponsor and in accordance with local practice, and this will be documented in the 
IMP destruction log in the site pharmacy file. 


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7 
Selection of Participants 
7.1 
Eligibility of trial participants 
7.1.1  Trial participant inclusion criteria 
1. Volunteers without clinical evidence of COVID-19 infection aged 18 years and older 
2. Participants who are at high risk of SARS-CoV-2 infection, defined as adults whose 
locations or circumstances put them at appreciable risk of exposure to SARS-CoV-2 
and COVID-19.  (see country specific addendum if needed to define further) 
3.     The participant must have a mobile phone and access to the Internet for data collection 
purposes. 
4. Participants who are willing and able to provide informed consent via an electronic consent 
process. 
 
7.1.2 Trial participant exclusion criteria 
Exclusion criteria (these could be modified depending on the choice of interventions in the platform 
trial)  
1. Weight outside range 50 kg – 120 kg (110 lbs – 265 lbs). 
2. Prior enrolment into this or other COVID-19 interventional prevention or treatment trials 
(observational trials not excluded). 
3. Self-reported or laboratory confirmed previous or current diagnosis of SARS-CoV-2 or COVID-
19. 
4. Self-reported current acute respiratory infection.  
5. Concurrent and/or recent use of the investigational product/s, a product considered to be 
equivalent to the investigational product/s, or any other product that is likely to interfere with 
the investigational products in this trial or the interpretation of the trial data.  
6. Self-reported known allergies to any of the IMPs and excipients of the IMPs and placebo. 
7. Self-reported presence or history of the conditions listed in the appendix relevant to that IMP 
8. Self-reported current use of medication with known to interact with any of the medications 
listed in the appendices. 
9. Inability or unwillingness to be followed up for the trial period. 
Additional to the set of exclusions in the core protocol, each arm of the trial (e.g. “MR vs Placebo” arm 
or “MMR vs Placebo” arm) will have their own set of additional exclusion criteria (refer to the 
appendix). Participants will only be randomized to those arms for which they are eligible.  
7.2 
Recruitment 
 
Each region will adopt an approach that is appropriate for enrolment according to local conditions, 
and one that is in compliance with its IRB/REC and national regulatory body guidelines. Recruitment 
may include advertisements (via posters, emails and social media messages at each site) that will alert 
relevant potential at risk participants to the study. Participants will self-identify and self-enrol by 
reading the participant information sheet (PIS) and then offering electronic informed consent through 
an online website using computer or smartphone. Participants will be asked to confirm their eligibility, 
i.e. that they meet all the inclusion criteria and that they do not meet any of the exclusion criteria. 
Formal verification based on participant responses will be needed by the site PI of the suitability of the 
proposed participant.                         
Participant recruitment at a site will only commence when the trial has:  
• 
Been initiated by the Sponsor (or the delegated representative), and  
• 
Issued with the ‘Open to Recruitment’ letter. 


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7.3 
Informed consent procedure 
Informed consent procedures will be implemented in accordance with local IRB/IEC and national 
regulatory authority requirements. The participant must sign the approved version of the informed 
consent form online before any study specific procedures are performed. See country-specific 
addenda for further details on site-specific procedures and documents.  
 
The online participant information will be presented and will detail the exact nature of the study, what 
it will involve for the participant, the implications and constraints of the protocol, the known side 
effects and risks involved in taking part. Additional consent may be sought for long-term sample 
storage in selected jurisdictions. This will be detailed in the country-specific addenda. All the site-
specific participant information sheets (PIS) describe the safety issues associated with interventions as 
described in the relevant package inserts. It will be clearly stated that the participant is free to 
withdraw from the study at any time for any reason without prejudice to future care and with no 
obligation to give the reason for withdrawal.  
 
For this trial, all consent will be obtained electronically after the participant has read the information. 
Given the urgency of the clinical question, the pressure under which staff members are working and 
the simplicity of the trial design, if a participant wishes to enrol online after reading the PIS, this will 
be permitted, unless specifically excluded in an individual country specific appendix, with the site PI 
able to remotely approve the application without physically examining the participant. The participant 
will be given as much time as wished to consider the information, and to question the PI and study 
team before they decide whether they will participate in the study. The consent process may be 
modified as required to meet local regulatory requirements. 
 
The participant will confirm they have read the PIS via the consent form. It will be clearly stated that 
participants are under no obligation to enter the trial and that they can withdraw at any time during 
the trial, without having to give a reason. They will be asked for consent to access their medical records 
for study purposes should they become ill. No clinical trial procedures will be conducted prior to the 
participant giving consent by signing the electronic consent form. Consent will not denote enrolment 
into trial. The PIS and consent form will be reviewed and updated if necessary, throughout the trial 
(e.g. where new safety information becomes available) and participants will be re-consented as 
appropriate.  
8 
Trial procedures  
 
Given the infectious nature of COVID-19, the traditional approach to trials will be adapted to data 
collection through telephone interviews or self-data collection. For this reason, we aim to ensure that 
all participant-reported data are collected through a combination of an online system and SMS 
messaging. See appendix 1 for the trial schedule of evaluations. 
8.1 
Screening / Pre-Enrolment Assessments  
 
The following pre-enrolment assessments and procedures will be performed: 
● The participant will be invited to view the trial website. 
● Potential participants will be shown the participant information online and asked to complete a 
simple e-questionnaire to ensure that they understand the nature of the trial. 
● If potential participants wish to speak to a member of the study team before giving consent, a 
mechanism will be offered for them to do so.  
● Participants will be invited to offer consent online. 


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● They will be asked screening and eligibility questions. Eligibility will be confirmed by the online 
system based on the responses given. 
● Participants will also confirm that they expect to continue to have a mobile phone and will have 
access to the Internet for the duration of the trial directly or indirectly (i.e. via local center in 
remote settings). 
● Participants will be asked for details of at least one alternative contact in case they become sick 
and are unable to respond to the study team. This will allow the study team to find out what has 
happened 
● If required by country legislation, the alternative contact person will be invited to confirm that 
they are prepared to be registered for this purpose within the trial in line with prevailing data 
security legislation. 
● Site lead will confirm that the participant meets eligibility criteria through the online platform. 
● A new case record will be created on the secure online platform. Basic demographic information 
and details of past medical history, concomitant medications, allergies, smoking, alcohol and other 
drug intake will be noted.  
● Baseline samples will be collected for batched SARS CoV2 serology testing.  
● Screening failures (i.e. participants who do not meet eligibility criteria at time of screening) will be 
allowed to be rescreened once.  
 
See country-specific addenda for details on alternate contacts. 
8.2 
Enrolment / Randomization Procedures  
Participant registration will be undertaken online using computer or smartphone.  
Following participant consent, and confirmation of eligibility (see section 8.1 for pre-treatment 
assessments) the registration and randomization procedure described below will be carried out.  
 
Coordinated on-line registration and allocation of participant trial numbers will be required to enrol 
participants. Blocked randomization list will be used to allocate study participants to one of the groups, 
stratified by age, study location. The lists will be created by the study statistician based at the UCL 
CCTU and will be implemented through the online randomization portal, supplied by Sealed Envelope 
Ltd.   
 
Participants will be assigned to treatment groups through consecutive allocation of subject numbers, 
and the use of a Trial Subject Enrolment Log which will be stored on the Sealed Envelope system. 
Participants will only be randomized to arms that they are eligible for (refer to section 7.1 and relevant 
appendix).   
 
Participants are considered to be enrolled into the trial following: consent, pre-treatment assessments 
(see section 8.1) including confirmation of eligibility, completion of the registration/randomization 
process, allocation of the participant trial number and treatment by the central coordinating 
team/remote system.  
8.3 
Procedure for Allocating Intervention/s 
 
The site PI or designee will be notified when a new participant has joined the study. The site PI will 
satisfy themselves that the participant meets the study eligibility requirements. Once e-consent and 
PI verification are complete the participant can be randomized in the system and the unblinded 
pharmacist will be sent the treatment allocation. The local IMP supplier (usually the facility’s pharmacy 
or a research pharmacy) will be alerted that a new participant has joined the study. IMP will be 
prescribed and prepared for the participant using a locally agreed standard operating procedure. Once 
the IMP is ready, it will be dispensed to the participant after verifying ID.   


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8.4 
Dose Modifications  
 
If an adverse event is recorded (see Section 9), the site PI or designee will be immediately alerted. If 
the site PI or designee deems that the adverse event is not related to the IMP and is therefore not an 
adverse reaction, and if the site PI or designee deems it safe for the participant to continue in the trial, 
the participant may continue to take the IMP, where relevant. If the site PI or designee deems it better 
for clinical reasons to stop taking the IMP, the participant should do so. No dose reductions or other 
modifications will be included in the trial.  
8.5 
Subsequent Assessments and Procedures  
 
All participants will complete online questionnaires of symptoms, general well-being (and compliance 
with drug taking where relevant) at enrolment and then at days 30 and 60 and further timepoints up 
to 150 days after enrolment to the study. The system is currently expected to be supplied by Sealed 
Envelope Ltd, a UK company that stores data in the UK. At each time point, where relevant, participants 
will also be asked to confirm their current concomitant medication use. This study is taking place in 
individuals at a time of great concern about COVID-19 so we do not expect adherence will be a major 
challenge but as this is a pragmatic trial, the outcomes are likely to reflect real world drug adherence. 
If participants are aware that they are receiving placebo, adherence might be decreased. All efforts 
will be made to conceal the treatment allocation.  
 
All participants will also receive an SMS message once a week to ask about their health. If relevant it 
will also remind them to take their study medications. The platform used is currently expected to be 
Telerivet Inc and will integrate with the Sealed Envelope system. Telerivet stores its data in EU data 
centers.  If the participant does not respond for one week, the site PI or designee will be prompted to 
contact the participant. If the participant cannot be contacted, the site PI or designee will contact the 
alternate contacts provided (see section 8.1).   
 
If a participant experiences symptoms consistent with COVID-19 they will be asked to register this on 
the online system. They will then be asked to complete an extra online questionnaire regarding 
symptoms, general well-being, and compliance with study product at the time of diagnosis. They will 
also be asked to confirm their current medication use.  They will be prompted to undergo testing for 
active infection to confirm the COVID-19 diagnosis if this has not been done as part of their routine 
clinical care.  We anticipate that the sequence of events will be that a participant experiences 
symptoms, reports those and is prompted to arrange or self-collect samples for testing for active 
infection. Those with a negative test and ongoing symptoms may need a second test. This may be 
collected from their routine health care provider. We plan to evaluate sample integrity under the 
storage/transport conditions we will be using to collect mid-nasal swab specimens or equivalent 
sample collection.13,14 Where feasible, we will attempt to quantify viral RNA in participants with SARS-
CoV-2 infection. A confirmed diagnosis would then prompt additional follow up. Participants who 
receive a confirmed diagnosis elsewhere will be asked to register this online. Similar questions about 
symptoms and study product compliance will be assessed. Where a participant may undergo testing 
for active infection outside of the trial procedures, consent will be sought at baseline to enable 
research staff to access the data. In addition, permission will be sought at baseline to access other data 
sources such as hospital records and death records. 
 
Dried blood spots will be collected from all participants to test for antibodies to SARS-CoV-2 at the 
time of entry, 60 days, and at 150 days when follow-up is completed. 
 
For any woman who is pregnant on starting the study or becomes pregnant during the 60-day study 
primary outcome period, an assessment of pregnancy outcome will be conducted at 6 weeks post-
partum. 
 


Core-CROWN CORONATION Protocol V8.0, dated 12 Oct 2021  
 
 
 
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See Appendix 1 for schedule of assessments. 
8.6 
Laboratory Assessments and Procedures  
 
The primary outcome of the trial is symptomatic (i.e. any of the following: cough, shortness of breath 
or difficulty breathing, fever, chills, muscle pain, sore throat, new loss of taste or smell, nausea, 
vomiting, or diarrhea) COVID-19 infection confirmed by a RT-PCR test. This will be assessed in 
symptomatic participants by (self-collected) mid-turbinate nasal swab or equivalent if not otherwise 
collected for local clinical purposes. These have been shown to have equivalent sensitivity to health 
care worker collected nasopharyngeal (NP) swabs but faster, better tolerated, and with less potential 
for sneezing, coughing and gagging, than an NP swab.15 Depending on local circumstances, at 
enrolment participants may be provided with a pack which includes step-by-step instructions for 
sample self-collection. A swab plus viral transport medium (or saline) will be packaged together for 
ease of use. Participants will be advised to place the swab in the transport medium and to place the 
tube in a transport bag provided. If a participant prefers not to take their own swab they can seek 
assistance with sample collection at their nearest COVID-19 testing center or to their regular 
healthcare provider. We will describe the methodology and performance characteristics of the 
quantitative RT-PCR assay(s) used in this study in a laboratory analytical manual. Where feasible, we 
will attempt to quantify viral RNA when viral shedding is assessed in the nasal swab samples collected 
from participants with SARS-CoV-2 infection. RT-PCR testing will take place in the country of 
participation.    
 
The purpose of serology is to provide additional information for secondary analyses. A sample 
collected at baseline will provide information on the proportion of participants exposed to infection 
prior to randomization. Given that optimization of serological assays is still underway, we will collect 
these samples for testing later. Details of testing will be specified in the laboratory manuals. 
Participants will be provided with the necessary equipment and instructions for obtaining dried blood 
spots (e.g. alcohol swab, lancet, filter paper). Each site will have a procedure for obtaining the dried 
blood spot specimens from participants. Sample processing and storage will be completed per site-
specific standard operating procedures. The DBS might also to conduct serology for measles and 
rubella antibody titers to evaluate against immunization history and also because there are cases of 
reported primary vaccination failure.  
 
Additional sampling and testing procedures will be detailed in country-specific addenda. 
8.7 
Clinical Procedures and Data Collection  
 
Participants will respond to weekly SMS surveys in combination with secure CRF login to a self-report 
online system, to be completed monthly, with questions around symptoms, exposure and self-
reported treatment adherence and SAEs.   
 
If the participant becomes ill and is admitted to hospital, the study team may review the hospital 
records in line with hospital policies, and if the participant has consented to medical record access.  
8.8 
Assessment of IMP compliance  
 
Adherence (where applicable) will be assessed at each monthly questionnaire along with weekly SMS 
prompts.  
8.9 
Discontinuation / withdrawal of participants  
 
In consenting to participate in the trial, participants are consenting to trial treatment, assessments, 
follow-up and data collection. The importance of safety follow-up will be emphasized to the participant 
in the PIS. Each participant has the right to withdraw from the study at any time. If a participant 


Core-CROWN CORONATION Protocol V8.0, dated 12 Oct 2021  
 
 
 
   Page 31 of 46 
 
expresses their wish to withdraw from trial treatment, sites will seek permission to allow use of routine 
follow-up data from routine health records to be used for trial purposes. The participant may choose 
to decline this request.  
 
The decision of the participant to withdraw from treatment will be recorded in the CRF/online 
database. The participant may withhold their reason for withdrawal however, if the participant gives 
a reason for their withdrawal, this will be recorded in the CRF/online database. If a participant explicitly 
states they do not wish to contribute further data to the trial their decision will be respected and 
recorded in the CRF/online database. Trial data already collected will not be deleted.  
 
Additionally, a participant may be withdrawn from trial treatment whenever the site lead investigator 
considers it necessary. Reasons for discontinuing IMP may include: 
● 
if the safety risk in an arm warrants discontinuation of all participants in that arm in the 
opinion of the Data Monitoring Committee (DMC); 
● 
if the participant develops confirmed symptomatic COVID-19 they will stop the trial 
intervention where applicable; 
● 
unacceptable toxicity; either self-reported on based on assessment by the site PI using 
grading tables; 
● 
intercurrent illness which prevents further IMP administration; 
● 
participants withdrawing consent to further trial treatment; 
● 
any alterations in the participant’s condition which justifies the discontinuation of IMP in 
the site investigator’s opinion; 
● 
persistent non-compliance to protocol requirements. 
 
The decision to discontinue IMP, where applicable, must be recorded in the electronic CRF. For 
participants who remain in the trial for the purposes of follow-up for safety and / or data analysis, they 
will be managed according to the treatment arms to which they have been originally randomised. 
Loss to follow-up 
If a participant moves from the area where they started the study, every effort will be made for the 
participant to be followed up at another participating trial site and for this new site to take over the 
responsibility for the participant. If a participant is lost to follow-up at a site, efforts will be made to 
contact the participant’s alternate contact or relevant laboratory, healthcare or hospital network (if 
the participant has given consent), to obtain information on the participant’s status. 
8.10 Replacements  
 
Withdrawn participants will not be replaced. 
8.11 Stopping Rules  
 
The trial may be stopped before completion for the following reasons: 
● 
On the recommendation of the DMC (see section 13). 
● 
On the recommendation of the sponsors and CI.  
 
If a safety trigger is reached safety data will be reviewed and a decision on continuation will be made 
by the DMC with input from the sponsor.  
8.12 Definition of End of Trial 
 
The expected duration of the trial is one year from recruitment of the first participant. The end of trial 
is five months after the last participant is enrolled when the database is locked, and all queries are 


Core-CROWN CORONATION Protocol V8.0, dated 12 Oct 2021  
 
 
 
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resolved. If further resources become available and the Trial Management Group (TMG) recommends 
continuation, the trial may be extended for up to two years from enrolment of the last participant.   
9 
Recording and reporting of adverse events and reactions 
9.1 
Definitions 
Definitions of harm of the EU Directive 2001/20/EC Article 2 based on the principles of ICH GCP apply 
to this trial in all sites. 
 
Table 1: Safety Event Definitions 
 
Term 
Definition 
Adverse Event (AE) 
Any untoward medical occurrence in a patient or clinical trial 
participant administered a medicinal product and which does not 
necessarily have a causal relationship with this treatment.  
Adverse Reaction (AR) 
Any untoward and unintended response in a participant to an 
investigational medicinal product which is related to any dose 
administered to that participant.  
This includes medication errors, uses outside of protocol (including 
misuse and abuse of product). 
Serious Adverse Event 
(SAE), Serious Adverse 
Reaction (SAR) or 
Unexpected Serious 
Adverse Reaction  
Any adverse event, adverse reaction or unexpected adverse reaction, 
respectively, that: 
● results in death, 
● is life-threatening*, 
● requires hospitalization or prolongation of existing 
hospitalization**, 
● results in persistent or significant disability or incapacity, or 
● consists of a congenital anomaly or birth defect 
* A life- threatening event, this 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. 
** Hospitalization is defined as an in-patient admission, regardless of length of stay. 
Hospitalization for pre-existing conditions, including elective procedures do not constitute an 
SAE. 
Suspected Unexpected 
Serious Adverse 
Reaction (SUSAR) 
An unexpected adverse reaction which is also categorized as serious. 
Important Medical 
Event 
These events may jeopardize the participant or may require an 
intervention to prevent one of the above 
characteristics/consequences. Such events should also be considered 
‘serious’. 
 
 
In addition to the definition above, Adverse Events (AEs) include but are not limited to the following: 


Core-CROWN CORONATION Protocol V8.0, dated 12 Oct 2021  
 
 
 
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● 
an exacerbation (i.e. increase in the frequency or intensity) of a pre-existing illness, 
episodic event or symptom (initially observed at the screening), that is detected after IMP 
administration/trial intervention 
● 
Occurrence of a new illness, episodic event or symptom, that is detected after IMP 
administration/trial intervention 
 
AEs do NOT include: 
● 
Medical or surgical procedures: the condition that leads to the procedure is the AE 
● 
Pre-existing disease or a condition present before treatment that does not worsen 
● 
Hospitalization where no untoward or unintended response has occurred e.g. elective 
cosmetic surgery 
● 
Overdose of medication without signs or symptoms 
9.2 
Procedures for recording and reporting of adverse events (AEs) and 
serious adverse events (SAEs) 
 
Non-serious AEs as well as SAEs will be self-reported by the participant via online platform or SMS 
system. Participants are requested to provide details of any symptoms they have experienced and 
details of any hospitalizations. The investigator will be notified by the online system of all events self-
reported by the participant in order to perform their assessment of the event and complete the 
‘Investigator Adverse Event Report. If the participant becomes very unwell, they will not be able to 
respond to the weekly SMS messages. As long as they have given consent for an alternative contact to 
be contacted (in line with local data protection requirements), the alternate contacts will be contacted. 
If the alternative contact confirms that the participant is unwell, or if they cannot be contacted, the 
site PI will be informed. The PI or delegate will investigate, assess the event and complete an AE form, 
called ‘Investigator Adverse Event Report’ on the online system, immediately and no later than within 
24 hours if the event meets SAE criteria.  
 
A notification will be also sent to the sponsor for all AEs meeting serious criteria, including those self-
reported by the participant or assessed as SAEs by the PI or delegate. Treatment should be 
discontinued in line with Section 8.5. Automated reminders will be sent to participant or investigator 
if safety event related forms are not completed in the expected timelines. 
9.3 
Assessments of Adverse Events 
Adverse events will be assessed for causality, seriousness and expectedness as described below. 
9.3.1 Seriousness assessment  
When an AE occurs, the investigator will confirm if the event is serious as per the definition given in 
section 9.1.  If the self-reported adverse event details provided by the participant are not sufficient for 
the investigator to make an assessment, they will contact the participant for further information.  If 
the event is classified as ‘serious’ then additional information may be requested to be completed by 
the participant to aid in the assessment of causality. 
9.3.2 Severity assessment 
The investigator will assess all SAEs for severity. Where possible the system used by CTCAE (Common 
Terminology Criteria for Adverse Events) v5.0 27-Nov-2017 should be used for event name and severity 
as outlined here: 
 
Table 2: Severity Grade Definitions  
 


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GRADE 1 
MILD 
GRADE 2  
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY LIFE 
THREATENING 
GRADE 5 
DEATH 
Mild; 
asymptomatic 
or mild 
symptoms; 
clinical or 
diagnostic 
observations 
only 
Moderate; minimal, 
local or 
noninvasive 
intervention 
indicated; limiting 
age appropriate 
instrumental ADL 
 Severe or 
medically 
significant but 
not immediately 
life-threatening; 
hospitalization 
or prolongation 
of 
hospitalization 
indicated; 
disabling; 
limiting self-care 
ADL 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death related to 
AE 
9.3.3 Causality assessment 
The site investigator or delegated medically trained person, will assess the causality of all adverse 
events or reactions in relation to the IMP using the definitions in the table 3 below. 
 
Once an AE is self-reported by a participant a notification will be sent to the site investigator or a 
delegated medically trained person. The causality assessment will be based on the information 
provided by the participant when the AE is reported. If this information is not sufficient to assess 
causality the assessor will contact the participant for further details to complete the process.  If the 
assessor gets further relevant AE information from the participant that has not been added on the self-
reported form, the assessor will provide new details on the online ‘Investigator Adverse Event Report’.  
 
Table 3: Causality Definitions 
 
Category 
Definition 
Related 
A causal relationship between an IMP/investigational treatment and an adverse event is at 
least a reasonable possibility, i.e., the relationship cannot be ruled out. 
Not related 
There is no reasonable possibility of a causal relationship between an IMP/investigational 
treatment and an adverse event. 
9.3.4 Expectedness assessment 
If there is at least a possible involvement of the trial interventions, the medically qualified staff 
delegated by sponsor must assess the expectedness of the event. An unexpected adverse reaction is 
one that is not reported in the current and approved version of the SPCs, or one that is more frequently 
reported or more severe than previously reported. See section 4.8 of the current and approved SPCs 
for a list of expected toxicities associated with IMPs used in this trial. If a SAR is assessed as being 
unexpected it becomes a SUSAR (suspected, unexpected, serious adverse reaction) and relevant 
Regulatory Authorities and Ethics Committees reporting guidelines apply.  


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9.4 
Notifications 
The site Investigator or designee will receive an automated notification of the AE when it is initially 
self-reported by the participant. The investigator (or delegated medically trained person) must 
complete the causality and seriousness assessment. CCTU will receive notifications of all SAEs.  
Automated reminders will be sent to participant or investigator if safety event forms are not 
completed in the expected timelines.  The site investigator will be notified of AEs via the electronic 
system, occurring from the time of randomization until 150 days after randomization. The Clinical 
Reviewer (medically qualified staff delegated by sponsor) will review all SAE reports received. In the 
event of disagreement between the causality assessment given by the investigator (or delegated 
medically trained person) and the Clinical Reviewer, both opinions and any justifications will be 
provided in subsequent reports. The Clinical Reviewer will review the assessment of expectedness 
based on possible wider knowledge of the reference material for the treatment. Country leads are 
responsible for the reporting of SUSARs to principal investigators and for ensuring reporting to relevant 
IRB/REC and national regulatory authorities as appropriate. Fatal and life threatening SUSARs must be 
reported to the regulatory authorities within 7 days of becoming aware of the event; other SUSARs 
must be reported within 15 days. Sponsor will keep country leads informed of any safety issues that 
arise during the course of the trial. 
9.4.1 Emergency Unblinding  
Every effort will be made to conceal the treatment allocation from participants and the trial teams. 
The trial code should only be broken for valid medical or safety reasons e.g. in the case of a severe 
adverse event where it is necessary for the investigator or treating health care professional to know 
which treatment the participant is receiving before the participant can be treated. Subject always to 
clinical need, where possible, members of the research team should remain blinded.  
 
If the person requiring the unblinded information is not the coordinating PI or national PI then that 
healthcare professional will contact the Investigating team to request the code break. Unblinding will 
take place if in the opinion of a treating physician a participant’s health is compromised.  The 
authorized individual will break the code and immediately inform the treating healthcare professional 
of the participant’s treatment allocation. The treating physician has the ultimate decision and right to 
unblind the participant.  
 
The code breaks for the trial are held on the online system and are the responsibility of the local site 
PI. The local site PI who will be authorized and delegated to perform code break by the national PI. If 
the person requiring the unblinded information is a member of the Investigating team then a request 
to the authorized individual to unblind will be made and the treatment allocation information 
obtained. 
 
On receipt of the treatment allocation details the site PI or treating health care professional will treat 
the participant’s medical emergency as appropriate. The site PI will document the breaking of the code 
and the reasons for doing so on the CRF and unblinding log and will file this in the site file. It will also 
be documented at the end of the trial in any final trial report and/or statistical report. 
 
The Investigating team will notify the CCTU in writing as soon as possible following the code break 
detailing the necessity of the code break.  
9.4.2 Unblinding for the submission of SUSAR reports  
The following procedure will be used to unblind for the submission of a SUSAR report to the regulatory 
agencies. The Sponsor will be authorized to access the code break system for the purposes of 
unbinding for the submission of a SUSAR. On receipt of the treatment allocation, the Sponsor will 


Core-CROWN CORONATION Protocol V8.0, dated 12 Oct 2021  
 
 
 
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provide the unblinded SUSAR information to the relevant regulatory agencies. SUSAR reports will be 
disseminated to Investigators at site(s) and will remain blinded. The unblinded information will not be 
forwarded to the trial team and will be kept in a separated file with limited access. 
9.5 
Development Safety Update Reports 
 
The sponsor will provide the main IRB/REC and relevant national drug regulatory agencies with 
Development Safety Update Reports (DSUR). 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. 
 
9.6 
Overdose  
 
IMP adherence and SAEs will be self-reported. In the event of an SAE associated with an overdose, the 
site, national and coordinating PIs and sponsor will be informed. Incidents will be recorded on the 
deviation log.  
 
9.7 
Reporting Urgent Safety Measures and other safety events 
 
If any urgent protocol deviations for safety measures are taken the site PI shall immediately and in any 
event no later than 3 days from the date the measures are taken, give written notice to the national 
PI and sponsor who will inform the relevant IRB/REC and national medicines regulatory authority of 
the measures taken and the circumstances giving rise to those measures. Data Coordinating Centre 
(DCC) or global CRO (PRA) will provide a report on all SAEs for submission to all national IRB/RECs and 
relevant national drug regulatory authorities in accordance with local requirements.  
 
9.8 
Notification of Serious Breaches to GCP and/or the protocol  
 
 A “serious breach” is a breach which is likely to affect 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. 
The sponsor of a clinical trial shall notify the licensing authority in writing of any serious breach of: 
(a) the conditions and principles of GCP in connection with that trial; or (b) the protocol relating to that 
trial, as amended from time to time, within 7 days of becoming aware of that breach. 
The sponsor will be notified immediately of any case where the above definition applies during the 
trial conduct phase.  
10 
Data management and quality assurance 
10.1 
Confidentiality 
 
All data will be handled in accordance with the UK Data Protection Act 2018 and GDPR, and any 
relevant local country-specific guidance. Participants and trial investigators will record data on using 
SMS messaging and password-protected electronic CRF, both of which are hosted on a secure, access-
restricted server. Participants registering on the secure electronic CRF will be assigned a 
pseudonymized identifier, which will be used for identification within the dataset. The dataset 
accessible for analysis will not bear any personally identifiable data. The site PIs will have access to 
participants’ names and contact details to enable verification of eligibility, consent and in the event of 
an SAR or other medically important event. Participant contact details (mobile phone number) will be 
shared with the SMS service to enable data collection.  This will be clearly explained to the participant 
in the Participant Information Sheet.  Participant consent for this will be sought. 


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10.2 Data collection tools and source document identification 
 
Data will be collected using SMS messaging in combination with a trial specific electronic CRF (eCRF), 
directly entered by participants and trial investigators. Standard Operating Procedures (SOP) for 
completing the e-CRF will be implemented prior to the start of the trial. Text messages, push 
notifications and e-mail reminders will be used to maximize completeness of data. A system will be 
included to enable users to recover lost login IDs and passwords. Data will be entered into the eCRF by 
participants and trial investigators. The site investigator will be responsible for confirming the data in 
the CRF prior to data lock. Investigators may enter on behalf of the participants without internet 
access, where assistance is required or for those that become too unwell to respond. The eCRF system 
will audit when this has taken place and it should be documented by site. The delegation log will 
identify all those personnel with responsibilities for data collection and handling, including those who 
have access to the trial database. 
 
The source data will be the eCRF with the exception of when participants are hospitalized and 
information may be recorded in the medical notes. 
10.3 Data handling and analysis 
 
The data for the CROWN CORONATION trial will be owned jointly by all the participating international 
sites. The Data Coordinating Centre (DCC) will be at University College London (UCL). The DCC will take 
responsibility for governance in relation to the data. Data will be de-identified and mirrored in a data 
warehouse curated by the Gates Medical Research Institute. A global CRO (PRA) will assist with data 
chases and querying. Pseudonymised data will be provided to them by the DCC and stored in the USA. 
 
A trial specific data management SOP will be in place for the trial. This will contain details of the 
software to be used for the database, the process of database design, data entry, data quality checks, 
data queries, data security and database lock. 
 
UCL will be responsible for data analysis for the whole study. Direct access will be granted to authorized 
representatives of University College London and any host institution for monitoring and/or audit of 
the study to ensure compliance with regulations. Each participating site will have the right to request 
access to its own data. Access to unblinded data (by participating sites) will not be granted until the 
trial is unblinded. The trial’s three coordinating principal investigators (Avidan, Moonesinghe and Rees) 
will arbitrate disputes regarding requests for data access.  
 
Where data are transferred electronically this will be in accordance with the UK Data Protection Act 
2018 and GDPR as well as UCL Information Security Policy and Trust Information Governance Policy, 
and relevant local, country-specific requirements.  There will be a documented record of data transfer 
and measures in place for the recovery of original information after transfer. Appropriate measures 
will be taken to ensure non-disclosure of information that is potentially harmful to participants. All 
data will be stored in the UK or the EU. Only non-identifiable data will be transferred outside the EU in 
line with GDPR regulations. 
11 
Statistical Considerations  
11.1 Outcomes 
11.1.1 Primary outcome 
Symptomatic COVID-19: Clinical diagnosis of COVID-19 with laboratory confirmation (i.e. based on viral 
PCR), and symptoms of COVID-19 (cough, shortness of breath or difficulty breathing, fever, chills, 


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muscle pain, sore throat, new loss of taste or smell, nausea, vomiting, or diarrhea) by day 60 after 
receiving trial intervention. An independent endpoint adjudication committee will be established to 
adjudicate endpoints across the trial. The terms of reference of this committee will be detailed in a 
separate document. 
11.1.2 
Secondary outcomes 
The following secondary outcome is of special interest: Severity of COVID-19 over the study period  
i)  
Uninfected – no clinical or virologic evidence of infection (Score = 0) 
ii)  Ambulatory – no limitation of activities (score=1) or with limitation (Score=2) 
iii)  Hospitalized – mild no oxygen (Score=3) or with oxygen (Score=4), hospitalized severe – 
Score=5-7*, dead (Score=8) 
*Score 5 is non-invasive ventilation or high flow oxygen; Score 6 is intubation with mechanical 
ventilation; Score 7 is intubation with additional organ support (e.g. vasopressors, renal replacement 
therapy (RRT), extra corporeal membrane oxygenation [ECMO]). 
These outcome definitions are based on WHO R&D Blueprint consensus definitions for COVID-19. The 
study period refers to the 60 days following commencement of trial intervention and an additional 3 
months of observation period of participants i.e. 150 days in total. Moreover, severity will be reported 
based on a 60-day timeframe.   
 
The secondary clinical outcomes consist of: 
● Primary endpoint, but instead of the 60-day timeframe, over the course of the first 30 days 
after receiving trial interventions; 
● Primary endpoint, but instead of the 60-day timeframe, over the course of the first 150 days 
after receiving trial interventions; 
● Symptomatic COVID-19 (with subsequent virological confirmation) during the 150-day study 
period;  
● Incident COVID-19 during the 60-day study period, which includes asymptomatic infections 
identified by serology samples taken at the time-point of study exit. 
 
Table 4: Classification of Outcomes 
Outcome  
Baseline serology 60-day serology 150-day serology 
RT PCR while 
symptomatic 
COVID-19 
symptoms 
1. Nucleic acid 
confirmed COVID-19  
+/- 
+/- 
+/- 
+ 
+ 
2.  Severe COVID-19 
+/- 
+/- 
+/- 
+ 
+ (scaled 
according to 
WHO ordinal 
severity scale) 
3. Asymptomatic COVID-
19  
- 
At least one of 
2- or 5-month 
serology must 
be + 
At least one of 
2- or 5-month 
serology must 
be + 
Not done 
- 
4. Presumed prior 
infection 
+ 
+/- 
+/- 
- / not done 
+/- 
5. Other acute 
respiratory illness 
during trial 
+/- 
+/- 
+/- 
- 
+ 


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6. Symptomatic nucleic 
acid negative COVID-
19; not primary 
outcome 
- 
At least one of 
2- or 5-month 
serology must 
be + 
At least one of 
2- or 5-month 
serology must 
be + 
- 
+ 
 
Safety Outcomes 
Safety outcomes will be determined according to the CTCAE (Common Terminology Criteria for 
Adverse Events) v5.0 27-Nov-2017 for grading severity of adult adverse events. 
 
Implementation and Process Outcomes 
In addition to monthly confirmation of treatment adherence, where appropriate, we will ask 
participants to self-report on their compliance with the assigned regimen at the time they exit the trial, 
or at the time they develop the primary outcome. At the same time point we will ask participants to 
self-report on whether they used open label treatments that are used in the active arms of the trial 
(outside of the trial protocol) during the trial.  
11.2 Sample size and recruitment 
11.2.1 
Sample size calculation 
We considered different event rates, depending on the following assumptions. Firstly, we assumed 
that 30-50% of the participants may become infected with SARS-CoV-2 over the course of the study 
period. Of these, the percentage of participants who will experience the primary endpoint or 
laboratory test-confirmed symptomatic COVID-19 (i.e. any of the following: cough, shortness of breath 
or difficulty breathing, fever, chills, muscle pain, sore throat, new loss of taste or smell, nausea, 
vomiting, or diarrhea) is uncertain. We use a range of 15-50%. The estimated event rate is therefore 
0.15 * 0.30 = 0.045 (or 4.5%, rounded to 5%) to 0.50*0.50 = 0.25.  
 
We declare the superiority of a treatment arm if the probability that the Odds Ratio (OR) of the 
treatment is less or equal to 1 is greater than 95%, i.e. P(OR < 1) > 95%. The remaining Bayesian 
statistical triggers of the adaptive trial are specified in section 11.5.   
 
A 2-arm trial was simulated to assess the required sample size for the study. The OR was assumed to 
be 0.7. Three event rates for control arm were used: 5%, 10% and 15%. We are interested in the lower 
end of the 5-25% range for the control rate since a higher sample size is required when the event rate 
in the control arm decreases for a given effect size. 
   
Figure 5 below reports the probability that the simulated trial concludes superiority of the treatment 
arm depending on the sample size per arm.  
 


Core-CROWN CORONATION Protocol V8.0, dated 12 Oct 2021  
 
 
 
   Page 40 of 46 
 
 
 
Figure 5: Sample size estimation for the first phase of the trial (2-arm) 
 
The simulations show that the probability of declaring efficacy depends on the event rate in the 
placebo arm. With 2000-2500 participants per arm, even if the event rate is 5% in the control arm, the 
study has >80% chance to declare efficacy.  
 
We propose to retain the option of reaching a maximum of 2,500 participants per arm. We will aim to 
enrol a maximum of 5,000 participants in total in the first phase of the trial to allow for possible loss-
to-follow-up (LTFU), withdrawal, protocol deviation, non-adherence and other methodological 
challenges. Further phases may be added to the trial until a maximum of 30,000 participants is 
reached.   
 
The assumptions underlying the sample size calculations will be reviewed at each interim analysis 
based on the observed data. 
11.2.2 
Planned recruitment rate 
The participants for the first phase of the study are estimated to be recruited within 12 months, 
depending on the rate of site activation.  
11.3 Randomization methods 
 
Participant-level randomization will be used in the study.  
 
The randomization sequence will be computer generated with permuted blocks. There will be initially 
equal numbers of participants (1:1) in each of the groups. Randomization will be stratified by age (<50 
and ≥50) and site.  
 
If the education and surveillance plus placebo arm is discontinued at an interim analysis, participants 
from this arm will be randomized to the remaining arms.  
Modifications to the number of active treatment arms  
Other arms can be added to CROWN CORONATION if evidence emerges that there are other suitable 
candidate prophylaxis options.  


Core-CROWN CORONATION Protocol V8.0, dated 12 Oct 2021  
 
 
 
   Page 41 of 46 
 
 
Participants will only be randomized to arms for which they are eligible. (e.g. pregnant women will 
not be randomized to the “vaccine vs placebo” arm).  
11.4 Statistical analysis plan 
 
This section provides a general overview of the statistical analysis plan (SAP). A more detailed SAP will 
be written by the trial statistician and approved by the TMG and Data Monitoring Committee (DMC) 
prior to any substantial analysis of the data.  
11.4.1 Summary of baseline data and flow of participants 
A CONSORT diagram will be produced to report of the flow of participants in the study.  
 
Summary of baseline characteristics, by study arms, will be by frequency and percentage for 
categorical variables, and for continuous variables by mean and standard deviation (or median and 
inter-quartile range for non-normally distributed data).  
11.4.2 Primary outcome analysis 
The threshold for declaring that an education and surveillance plus therapeutic agent(s) arm is superior 
to education and surveillance plus placebo will be based on the OR for the specific arm compared to 
education and surveillance plus placebo. The objective is to obtain sufficient certainty (95% at least) 
that OR < 1. In mathematical terms, this quantity is referred to as P(OR < 1) > 95%.   
 
Primary analysis models: 
The primary endpoint of incidence of symptomatic laboratory-confirmed COVID-19 infection will be 
analysed using a Bayesian logistic regression, including as covariates the treatment arm, age (<50 vs. 
≥50), and a random effect for site.  
 
The prior distribution corresponding to the education and surveillance plus placebo arm will be such 
that it is centered on 15% for the event rate, midway between the 5%-25% range that we consider. 
The prior distribution corresponding to the OR of the treatment arm will be such that the OR is 
centered on 1. Further details on the prior distributions are provided in the SAP. 
 
Additional multivariable analyses will be conducted, taking into account the following variables: sex, 
smoking, body mass index, HIV infection, pre-existing respiratory disease, diabetes (recent HbA1c), 
hypertension, and coronary artery disease.  
 
Secondary outcomes: 
 
The endpoint of severity of symptoms on the WHO scale will be analysed using a Bayesian proportional 
odds model, using the same adjustment approach as the primary endpoint.  
 
Other secondary outcomes that are binary in nature will be analysed using Bayesian logistic regression, 
using the same adjustment methods as previously described.  
 
In addition, time-to-event models will be used to assess the effect of the interventions on the time to 
incidence of symptomatic laboratory-confirmed COVID-19 infection over the 150-day period since 
receiving trial interventions. 


Core-CROWN CORONATION Protocol V8.0, dated 12 Oct 2021  
 
 
 
   Page 42 of 46 
 
11.4.3 Sensitivity and other planned analyses 
Subgroup analyses will be pre-specified and performed using an interaction term in the model 
between the treatment arm and the characteristics of interest. The factors of interest are: age, HIV 
status, geographic region, ethnicity and sex. 
 
11.5 Interim analyses 
 
This Bayesian trial will perform frequent interim analyses for efficacy, futility and harm. This means 
that the DMC will regularly consider the balance of benefit and risk. Strong evidence of benefit, futility, 
or harm will result in the advice to modify or stop the trial. 
 
The objective of interim analyses is two-fold: 1/ identify whether an active arm is futile, if the 
probability that its OR≥0.9 is high, greater than 95%, 2/ identify whether there is sufficient evidence 
that an active arm is superior to the control arm. The following table contains the statistical triggers 
for efficacy, futility and harm at interim analyses and for the final analysis.  
 
 
Probability 
Threshold at interim 
analysis 
Threshold 
at 
final 
analysis 
Evidence for: 
P0 = P (OR < 1 | data) 
99% 
95% 
Clinical benefit 
P1 = P (OR < 0.8 | 
data) 
99% 
95% 
Marked clinical benefit 
P2 = P (OR ≥ 0.9 | 
data) 
99% 
95% 
Non clinically relevant 
(i.e. futile) treatment 
(or harm when OR ≥ 1) 
 
Posterior predictive probabilities will also be calculated at each interim analysis to inform the potential 
adaptation decisions.  
Platform trial 
In the study there exists a possibility of adding treatment arm(s) at interim analysis or during the course 
of the study. If a treatment arm is added, all comparisons will be made with concurrent control 
participants.     
 
For the main effects of individual treatments (i.e. when given on their own), the thresholds for 
superiority and futility described above will apply to the same manner to the additional treatment(s).   
 
For treatments that are given in combination in the context of a potential factorial design, the quantity 
of interest will be P(interaction term < 1 | data) ≥ 0.95% (or 99% at interim analysis) to declare evidence 
of synergy. The prior distribution for the interaction term will be specified in exactly the same way as 
the prior of the OR of the individual treatments. Only its interpretation changes. 
 
The SAP contains additional details regarding the monitoring of the trial, including the cumulative 
probability of declaring efficacy depending on the underlying simulated hazard ratio. 
11.6 Other statistical considerations 
 
All randomized participant data will be included in the Intention-To-Treat (ITT) analysis according to 
the arm they were randomized to, irrespective of the actual study drug that they took. This ITT analysis 
will be the main strategy for the primary outcome and will be followed by a per protocol analysis. 


Core-CROWN CORONATION Protocol V8.0, dated 12 Oct 2021  
 
 
 
   Page 43 of 46 
 
Moreover, a modified ITT analysis will be performed at the end of the study, based on serology results. 
Participants with evidence of COVID-19 infection at the start of the study will be removed from the 
analysis set.  
12 
Record keeping and archiving 
 
At the end of the trial, all essential documentation will be archived securely by the CI and trial sites for 
a minimum of 10 years or as required by local regulation from the declaration of end of trial. Essential 
documents are those which enable both the conduct of the trial and the quality of the data produced 
to be evaluated and show whether the site complied with the principles of Good Clinical Practice and 
all applicable regulatory requirements. The sponsor will notify sites when trial documentation can be 
archived. All archived documents must continue to be available for inspection by appropriate 
authorities upon request.  
13 
Oversight Committees  
The following committees will be in place for the trial: Trial Management Group (TMG) and 
independent Data Monitoring Committee (DMC). The terms of reference for these committees will 
need to be provided in separate documents. 
13.1 Trial Management Group (TMG) 
The TMG will include the three coordinating Principal Investigators, national principal investigators 
and key trial staff.  The TMG will be responsible for overseeing the trial.  The group will meet regularly 
(monthly) and will send updates to site PIs. The TMG will review recruitment figures, SAEs and 
substantial amendments to the protocol prior to submission to the IRB/REC and/or relevant national 
drug authority.  All site PIs will be kept informed of substantial amendments through the sponsor or 
designee and/or national PIs.  
The TMG acts on behalf of the funder(s) and Sponsors.  
13.2 Data Monitoring Committee (DMC)  
The role of the DMC is to provide independent advice on data and safety aspects of the trial.  A specific 
DMC charter will be developed to outline the terms of reference, membership, and frequency of 
meetings.  The DMC is advisory to the TMG and can recommend premature closure of the trial.  
14 
Direct Access to Source Data/Documents 
The investigator(s)/ institution(s) will permit trial-related monitoring, audits, REC review, and 
regulatory inspection(s), providing direct access to source data/documents.  Trial participants are 
informed of this during the informed consent discussion.  Participants will consent to provide access 
to their medical notes. Source data for most self-reported data points will be the original entry on to 
the SMS or electronic CRF system.  
15 
Ethics and regulatory requirements 
All international participating sites will obtain approval from the relevant local IRB/REC and national 
regulatory authorities. The national Principal Investigators and sponsor will ensure that the trial 
protocol, PIS, consent form and submitted supporting documents have been approved by the 


Core-CROWN CORONATION Protocol V8.0, dated 12 Oct 2021  
 
 
 
   Page 44 of 46 
 
appropriate regulatory body and the appropriate research ethics committees responsible for the 
proposed recruitment sites. The protocol, all other supporting documents including and agreed 
amendments, will be documented, and submitted for ethical and regulatory approval as required. 
Amendments will not be implemented prior to receipt of the required approval(s), except where 
necessary to eliminate apparent immediate hazards to trial participants. The in-country sponsor is 
responsible for obtaining insurance coverage. Details on each specific country are not included in this 
core protocol.  
16 
Monitoring requirement for the trial 
The sponsor will determine the appropriate level and nature of monitoring required for the trial.  Risk 
will be assessed on an ongoing basis and adjustments made accordingly. The degree of monitoring will 
be proportionate to the objective, purpose, phase, design, size, complexity, blinding, endpoints, and 
risks associated with the trial. A trial specific oversight and monitoring plan will be established. The 
trial will be monitored in accordance with the agreed plan. The research team will monitor the study 
for adverse events. All serious adverse events will be reported to the relevant IRB/REC, according to 
the local stipulations. The monitoring plan for this study is appropriate for the planned pragmatic trial.  
 
The CROWN CORONATION trial will have an appropriate data and safety monitoring plan. There will 
be a charter to guide the functions of the DMC, and the DMC will produce reports in accordance with 
relevant guidelines. The DMC will provide independent oversight of the CROWN CORONATION trial 
and will review the general conduct of the trial as well as study data for participant safety. The DMC 
will comprise independent, multidisciplinary experts who will make recommendations regarding the 
continuation, modification, or termination of the trial. The members will have the requisite expertise 
to examine accumulating data, to protect the integrity of the clinical experiments in which the 
participants have consented to partake, and to assure the regulatory bodies and the public (and 
possibly funding agencies) that conflicts of interest do not compromise either participant safety or trial 
integrity. There will be a provision for early stoppage for safety concerns, as well as for efficacy and for 
futility.  
 
Attempts will be made to track adherence to the treatment regimens (based on daily or minimum 
twice weekly participant logs from their mobile phone). Questions will also be asked about use of other 
mitigation, including personal protective equipment. Participants will also be asked to document the 
frequency of high-risk contacts (e.g., number of patients with COVID-19 they had contact with every 
day).  
 
Local investigators at all participating sites will report serious adverse events, or unanticipated 
problems involving risks to participants or others, to their IRB/REC and to the Trial management group. 
If such problems are considered related to the trial, then they will also be reported to IRB/RECs at 
other participating sites and to the chairperson of the DMC.  
 
The members of the DMC will have no direct involvement in the conduct of the CROWN CORONATION 
trial. Neither will they have financial, proprietary, or professional conflicts of interest, which may affect 
the impartial, independent decision-making responsibilities of the DMC. Letters of invitation to 
prospective DMC members will include language similar to the following: “Acceptance of this invitation 
to serve on the DMC confirms that I do not have any financial or other interest with any of the 
collaborating or competing pharmaceutical firms or other organizations involved in the COVID-19 trials 
that constitute a potential conflict of interest.” All DMC members will sign a Conflict of Interest 
Certification to confirm that no conflict exists. The DMC will be advisory rather than executive on the 
basis that it is the sponsor and the CROWN CORONATION trial investigators who are ultimately 
responsible for the conduct of the trial. 
 


Core-CROWN CORONATION Protocol V8.0, dated 12 Oct 2021  
 
 
 
   Page 45 of 46 
 
The risks associated with this study are low. There is a rare risk of breach of confidentiality. Side effects 
of the IMPs will be listed in the IMP appendices.  
 
As part of the informed consent process for this study, participants will be informed of the risks. In the 
unlikely event that serious side effects occur, they will be documented and also reported to the 
IRB/REC in accordance with local regulatory requirements and to the study's DMC. Participants will not 
incur any study-related expenses, and nor will they be financially compensated for their participation. 
17 
Finance 
 
Funding has been secured from the COVID-19 Therapeutics Accelerator. Further funding is being 
sought from other international and national funding bodies for individual countries.  
18 
Publication policy 
The findings from the trial will be published in peer-reviewed journals. Discussions are in place to 
ensure that meta-analyses will be possible with other studies in the field. The coordinating principal 
investigators together with all the country lead investigators in participating countries will discuss, 
review and agree on publications. They will also jointly make decisions on authorship. Disputes will be 
resolved by the three principal investigators (Avidan, Moonesinghe and Rees).  
 
Data generated from this study will adhere to the 2020 statement from the Wellcome Trust: 
Coronavirus (COVID-19): sharing research data. They will also adhere to the Bill & Melinda Gates 
Foundation Open Access Policy - Bill & Melinda Gates Foundation. 
 
 


Core-CROWN CORONATION Protocol V8.0, dated 12 Oct 2021  
 
 
 
   Page 46 of 46 
 
19 References 
1. 
Velavan TP, Meyer CG. The COVID-19 epidemic. Trop Med Int Health 2020; 25(3): 278-80. 
2. 
Guan WJ, Ni ZY, Hu Y, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N 
Engl J Med 2020. 
3. 
Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the recently 
emerged novel coronavirus (2019-nCoV) in vitro. Cell Res 2020; 30(3): 269-71. 
4. 
Lewnard J, Lo N. Scientific and ethical basis for social-distancing interventions against COVID-
19. The Lancet Infectious Disease 2020. 
5. 
Wang Y, Wang Y, Chen Y, Qin Q. Unique epidemiological and clinical features of the emerging 
2019 novel coronavirus pneumonia (COVID-19) implicate special control measures. J Med 
Virol 2020. 
6. 
https://www.who.int/publications/m/item/weekly-epidemiological-update---17-
november-2020. 
7. 
DOI: 10.1056/nejmoa2021436 
DOI: 10.1001/jama.2020.17023 
DOI: 10.1056/nejmoa2007764 
8. 
WHO. Rational use of personal protective equipment for coronavirus disease 2019 (COVID-
19) Interim guidance. 27 February 2020. 2020. 
https://apps.who.int/iris/bitstream/handle/10665/331215/WHO-2019-nCov-IPCPPE_use-
2020.1-eng.pdf (accessed 27 April 2020. 
9. 
CDC. Interim Infection Prevention and Control Recommendations for Patients with Suspected 
or Confirmed Coronavirus Disease 2019 (COVID-19) in Healthcare Settings. Update April 13, 
2020. 2020. https://www.cdc.gov/coronavirus/2019-ncov/hcp/infection-control-
recommendations.html#minimize (accessed 27 April 2020. 
10. 
Guy RK, DiPaola RS, Romanelli F, Dutch RE. Rapid repurposing of drugs for COVID-19. Science 
2020; 368(6493): 829-30. 
11. 
Green A. Remembering health workers who died from Ebola in 2014. Lancet 2014; 
384(9961): 2201-6. 
12. 
Brolin Ribacke KJ, Saulnier DD, Eriksson A, von Schreeb J. Effects of the West Africa Ebola 
Virus Disease on Health-Care Utilization - A Systematic Review. Frontiers in public health 
2016; 4: 222. 
13. 
Cheng MP, Papenburg J, Desjardins M, et al. Diagnostic Testing for Severe Acute Respiratory 
Syndrome-Related Coronavirus-2: A Narrative Review. Ann Intern Med 2020. 
14. 
Udugama B, Kadhiresan P, Kozlowski HN, al. e. Diagnosing COVID-19: The Disease and Tools 
for Detection. ACS Nano 2020. 
15. 
Tu Y-P, Jennings R, Hart B, et al. Patient-collected tongue, nasal, and mid-turbinate swabs for 
SARS-CoV-2 yield equivalent sensitivity to health care worker collected nasopharyngeal 
swabs. medRxiv 2020: 2020.04.01.20050005. 
 
 

ICF_001.pdf: 
 
FOR IRB USE ONLY 
IRB ID #: 202004099 
APPROVAL DATE: 01/05/21 
RELEASED DATE: 01/05/21 
EXPIRATION DATE: 05/06/21 
 
 
INFORMED CONSENT DOCUMENT 
 
Project Title: 
An international, Bayesian platform adaptive, randomized, placebo-controlled 
trial assessing the effectiveness candidate interventions in preventing COVID-19 disease in 
healthcare workers 
 
Principal Investigator: 
Michael Avidan, MBBCh 
 
 
 
 
 
Research Team Contact: 
Linda Yun, 314-273-2240 or 636-751-1089 
 
This consent form describes the research study and helps you decide if you want to participate.  It 
provides important information about what you will be asked to do during the study, about the risks and 
benefits of the study, and about your rights and responsibilities as a research participant. By signing this 
form you are agreeing to participate in this study. 
 You should read and understand the information in this document including the procedures, 
risks and potential benefits.  
 If you have questions about anything in this form, you should ask the research team for more 
information before you agree to participate.   
 You may also wish to talk to your family or friends about your participation in this study. 
 Do not agree to participate in this study unless the research team has answered your 
questions and you decide that you want to be part of this study.  
 
WHAT IS THE PURPOSE OF THIS STUDY? 
 
This is a research study.  We invite you to participate in this research study because you are a health care 
or essential worker who is at risk of exposure to the SARS-CoV-2 virus that causes COVID-19.  
Essential workers are the personnel needed to maintain essential services. Examples of essential services 
include but are not limited to: Health Care / Public Health / Human Services; Teachers; Law 
Enforcement, Public Safety, First Responders; Food Services and Accommodations; and Transportation 
 
The purpose of this research study is to determine if the MMR vaccine reduces incidence or severity of 
COVID-19 infection in exposed health care and essential workers.  
 
The MMR vaccine is approved by the U.S. Food and Drug Administration for the prevention of measles, 
mumps, and rubella.  However, the use of the MMR vaccine is considered investigational in this study. 
In this study, the MMR vaccine will be used as a prophylaxis and will be compared to a placebo (an 
inactive substance).  
 
WHAT WILL HAPPEN DURING THIS STUDY? 
 
You will be randomly assigned to one of two (2) study groups. This means that the study group you are 
assigned to will be determined purely by chance, like flipping a coin.  You will have a 1 out of 2 chance 
of being in the study treatment group.  Neither you nor the research team will know which study group 
you are in, but we will be able to get this information quickly if we need it to ensure your safety.  


 
FOR IRB USE ONLY 
IRB ID #: 202004099 
APPROVAL DATE: 01/05/21 
RELEASED DATE: 01/05/21 
EXPIRATION DATE: 05/06/21 
 
12/16/20 
Page 2 of 12 
Study groups:  
- Education and surveillance plus placebo 
- Education and surveillance plus MMR vaccine  
The study groups above may be removed and new ones added depending on the efficacy of the 
treatment.  The study team will notify you if the study groups are changed.  
 
The study drug will be administered one time at Washington University School of Medicine within 7 
days of being randomly assigned to a study group.   You will need to come to the medical center to 
receive the study injection. You will need to bring your Healthcare worker ID to this visit.  This visit 
should last about 45 minutes. 
You will be provided educational materials about social and clinical practice that could prevent or delay 
infection.  
 
You will be asked to complete a self-finger stick approximately at 3 times points; at study entry, and 
approximately day 60 and day 150.  We will provide you with kits and shipping materials to return the 
self-collected samples.   
 
You will be asked to enter information on how you are feeling physically and emotionally through a 
secure online system or through short message service (SMS) on a mobile smart phone.  Through SMS 
you will be reminded to answer a simple question about your health daily or at minimum, once per 
week.  These questions will take about 10 seconds to answer.  You will be able to skip any questions 
you would prefer not to answer.  
 
If you are tested for COVID-19 you will be asked to enter additional information about how you are 
feeling physically and emotionally through an online system or through short message service (SMS). 
You may also be asked to self-collect a nose swab and/or a throat swab, or come to the medical center to 
be swabbed to confirm the COVID-19 diagnosis, if this has not been done as part of your care. If you 
self-collect your swab, your results will be uploaded to your medical record. If testing has been 
completed as part of your routine care or from you place of work, we will collect your test results from 
your medical record or ask for documentation of the confirmed diagnosis. We may ask you to upload the 
results to a secured folder. We will try to collect any residual specimen available that was submitted for 
COVID testing after the test is done. 
 
We will follow-up with you for approximately 150 days after you begin the study to check on your 
health status. If resources are available, the follow-up may be extended to 2 years.  We might also check 
your medical and laboratory results in your health record. 
 
We will ask you to provide the contact information of a family member or friend who we can contact if 
you become sick.  
  
If you are a woman of childbearing potential and become pregnant during the study we would like to ask 
additional questions about your pregnancy. You will be asked to sign a separate consent form so that we 
can collect this information. 
 
You may not be in any other interventional COVID-19 prevention or treatment research studies while 
you are on this study.  


 
FOR IRB USE ONLY 
IRB ID #: 202004099 
APPROVAL DATE: 01/05/21 
RELEASED DATE: 01/05/21 
EXPIRATION DATE: 05/06/21 
 
12/16/20 
Page 3 of 12 
  
Will you collect my social security number?  
You will be asked to provide your social security number on an electronic form that is used to enter you 
into the medical record system so that we can provide study drug to you.  
 
Will you save my research information and/or biospecimens to use in future research studies? 
We would like to use the data and specimens we are obtaining in this study for studies going on right 
now as well as studies that are conducted in the future.  These studies may provide additional 
information that will be helpful in understanding COVID-19, or other diseases or conditions, including 
research to develop investigational tests, treatments, drugs or devices that are not yet approved by the 
U.S. Food and Drug Administration.  It is unlikely that what we learn from these studies will have a 
direct benefit to you.  There are no plans to provide financial compensation to you should this occur.  By 
allowing us to use your data and specimens, you give up any property rights you may have in the data 
and blood. 
 
We will share your data and specimens with other researchers. They may be doing research in areas 
similar to this research or in other unrelated areas.  These researchers may be at Washington University, 
at other research centers and institutions, or industry sponsors of research.  We may also share your 
research data with large data repositories (a repository is a database of information) for broad sharing 
with the research community.  If your individual research data is placed in one of these repositories only 
qualified researchers, who have received prior approval from individuals that monitor the use of the 
data, will be able to look at your information.   
 
If you change your mind and do not want us to store and use your data and specimens for future research 
you should contact the research team member identified at the top of this document.  The data and 
specimens will no longer be used for research purposes. However, if some research with your data and 
specimens has already been completed, the information from that research may still be used. Also, if the 
data or specimens has been shared with other researchers it might not be possible to withdraw the data or 
specimens to the extent it has been shared. 
 
Please place your initials in the blank next to Yes or No for each of the questions below: 
 
My data and specimens may be stored and used for future research as described above. 
 
_____ Yes 
_____ No 
 
My data and specimens may be shared with other researchers and used by these researchers for 
the future research as described above. 
 
_____ Yes  
_____ No 
 
 
 
 
 Identifiers may be removed from your private information including data and specimens and 
used for future research or shared with others. If this occurs, we will not ask you for additional 
consent.  
 


 
FOR IRB USE ONLY 
IRB ID #: 202004099 
APPROVAL DATE: 01/05/21 
RELEASED DATE: 01/05/21 
EXPIRATION DATE: 05/06/21 
 
12/16/20 
Page 4 of 12 
 
HOW MANY PEOPLE WILL PARTICIPATE? 
 
Approximately 5,000 people will take part in this study conducted by investigators at Washington 
University.  Approximately 30,000 people will take part study wide.  
 
HOW LONG WILL I BE IN THIS STUDY? 
 
If you agree to take part in this study, your involvement will last for approximately 5 months.  Study 
participation is approximately 2 months and we will follow you for 3 additional months using surveys, 
phone calls, SMS and medical record review.   
 
WHAT ARE THE RISKS OF THIS STUDY? 
 
You could experience one or more of the risks indicated below from being in this study. In addition to 
these, there may be other unknown risks, or risks that we did not anticipate, associated with being in this 
study.  
 
Some risks described in this consent document, if severe, could cause death.  
 
MMR Vaccine 
Likely: 
 Pain at the injection site 
Less Likely: 
 Rash 
 Fever 
 Malaise (feeling of discomfort, illness, or uneasiness whose exact cause is difficult to identify) 
 Loss of appetite 
 
Rare: 
 Trouble breathing 
 
Panniculitis (painful bumps under the skin) 
 
Atypical measles (altered expression of measles, AMS begins suddenly with high fever, 
headache, cough, and abdominal pain) 
 
Syncope (fainting) 
 
Headache 
 
Dizziness 
 
Irritability 
 
Vasculitis (inflammation of blood vessels) 
 
Pancreatitis (swelling of parotid glands) 
 
Diarrhea  
 
Vomiting 
 
Parotitis (swollen parotid glands) 
 
Nausea 
 
Thrombocytopenia (low platelet count) 


 
FOR IRB USE ONLY 
IRB ID #: 202004099 
APPROVAL DATE: 01/05/21 
RELEASED DATE: 01/05/21 
EXPIRATION DATE: 05/06/21 
 
12/16/20 
Page 5 of 12 
 
Purpura (purple colored spots noticeable on the skin) 
 
Regional lymphadenopathy (lymph nodes of abnormal size or consistency) 
 
Leukocytosis (increased white blood cell count) 
 
Anaphylaxis (potentially life-threatening allergic reaction) 
 
Anaphylactoid reactions (reactions similar to anaphylaxis) 
 
Angioedema (rapid swelling beneath the skin) 
 
Bronchial spasm (muscle contractions in the airway that cause difficulty breathing in patients 
suffering from serious respiratory diseases.) 
 
Arthritis (the swelling and tenderness of one or more of your joints) 
 
Arthralgia (joint pain) 
 
Myalgia (muscle pain) 
 
Encephalitis (inflammation of the brain) 
 
Encephalopathy (any brain disease that alters brain function or structure) 
 
Measles inclusion body encephalitis (MIBE) a disease of the immunocompromised host and 
typically occurs within 1 year of acute measles infection or vaccination 
 
Subacute sclerosis pan encephalitis (SSPE) viral infection caused by defective measles virus 
 
Guillain-Barre Syndrome (GBS) is a rare neurological disorder in which the body's immune 
system mistakenly attacks part of its peripheral nervous system 
 
Acute disseminated encephalomyelitis (ADEM) 
 
Transverse myelitis (inflammation of the spinal  cord) 
 
Convulsions or seizures (a medical condition where body muscles contract and relax rapidly and 
repeatedly, resulting in uncontrolled actions of the body) 
 
Ataxia (degenerative disease of the nervous system) 
 
Polyneuritis (disorders that affects peripheral nerves) 
 
Polyneuropathy (damage to peripheral nerves) 
 
Ocular palsies (damage to ocular nerves) 
 
Pareshtesia (burning or prickling sensation) 
 
Pneumonia (infection that inflames the air sacs in one or both lungs) 
 
Pnumonitis (inflammation of lung tissue) 
 
Sore throat 
 
Cough 
 
Rhinitis (irritation or inflammation of membranes inside the nose) 
 
Stevens-Johnson syndrome a rare, serious disorder of the skin and mucous membranes. It's 
usually a reaction to medication that starts with flu-like symptoms, followed by a painful rash 
that spreads and blisters. Then the top layer of affected skin dies, sheds and begins to heal after 
several days. 
 
Henoch-Schönlein purpura a disorder that causes the small blood vessels in your skin, joints, 
intestines, and kidneys to become inflamed and bleed. 
 
Erythema multiforme (skin reaction) 
 
Urticaria (hives) 
 
Measles-like-rash 
 
Pruritis (itchy skin) 
 
Nerve deafness (a type of hearing loss from damage to the inner ear) 
 
Otitis media (inflammation of middle ear) 
 
Retinitis (inflammation of the retina of the eye) 
 
Optic neuritis (inflammation of the optic nerve) 


 
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RELEASED DATE: 01/05/21 
EXPIRATION DATE: 05/06/21 
 
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 
Papillitis (specific type of optic neuritis)  
 
Conjunctivitis (commonly known as "pink eye") 
 
Epididymitis (inflammation of the tube at the back of the testicles) 
 
Orchitis (inflammation of one or both testicles) 
You could receive a placebo (an inactive substance) during this study.  This means that you would 
receive no active study treatment while participating and your symptoms could get worse. 
 
Finger Stick 
The finger stick may cause bleeding, bruising, or pain.  Some people become dizzy or feel faint. There is 
also a rare risk of infection. 
 
Mandated Reporting of Disease Status 
If you decide to participate in this study, we may test you for COVID-19.  The results of these tests 
could indicate that you have this condition.  If that happens, we will refer you to a doctor who 
specializes in treating your condition.  We will make every effort to keep your personal information 
confidential.  However, we are required by law to report certain positive tests to the State of Missouri 
and/or local and agencies.  The test results could also be reported to the Centers for Disease Control 
(CDC).  You may be contacted by these agencies for more information.  Becoming aware of a new 
diagnosis could have serious health, personal and/or social consequences.  For more information about 
the risks of this testing, please talk to your study doctor. 
 
Breach of Confidentiality 
One risk of participating in this study is that confidential information about you may be accidentally 
disclosed.  We will use our best efforts to keep the information about you secure.  Please see the section 
in this consent form titled “How will you keep my information confidential?” for more information. 
 
WHAT ARE THE BENEFITS OF THIS STUDY? 
 
You may or may not benefit from being in this study. 
 
We hope that, in the future, other people might benefit from this study if the MMR vaccine is found to 
reduce the prevalence or severity of COVID-19. 
 
WILL IT COST ME ANYTHING TO BE IN THIS STUDY? 
 
You will not have any additional costs for being in this research study. 
You and/or your medical/hospital insurance provider will remain responsible for your regular medical 
care expenses. 
 
WILL I BE PAID FOR PARTICIPATING? 
 
You will not be paid for being in this research study.  However, the research team will provide you a 
parking voucher if you have to pay for parking at your vaccine administration visit. 
 
 
 


 
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APPROVAL DATE: 01/05/21 
RELEASED DATE: 01/05/21 
EXPIRATION DATE: 05/06/21 
 
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WHO IS FUNDING THIS STUDY? 
 
The COVID-19 Therapeutics Accelerator, and the University are funding this study.  The University and 
the research team are not receiving payment from any other agencies, organizations, or companies to 
conduct this research study.  
 
 
WHAT IF I AM INJURED AS A RESULT OF THIS STUDY? 
 
Washington University investigators and staff will try to reduce, control, and treat any complications 
from this research. If you feel you are injured because of the study, please contact the investigator Dr. 
Erik Dubberke at 314-454-8296 and/or the Human Research Protection Office at 1-(800)-438-0445.  
 
Decisions about whether payment for medical treatment for injuries relating to your participation in 
research will be made by Washington University.  If you need to seek medical care for a research-related 
injury, please notify the investigator as soon as possible.  
 
The federal government has issued a declaration under a law known as the Public Readiness and 
Emergency Preparedness (PREP) Act to address the coronavirus (COVID-19) public health emergency.  
If you are injured or harmed as a result of participating in this study, that federal government declaration 
may limit your ability to obtain damages by filing a lawsuit against the study’s researchers, health care 
providers, study site, study sponsor, and/or manufacturer or distributer of the drug.  However, if you are 
injured or harmed as a result of participating in this study, the federal government has established a 
program that may provide compensation to you or your family. To find out more about this program, 
known as the “Countermeasures Injury Compensation Program” (CICP), go to 
https://www.hrsa.gov/cicp/about/index.html or call 1-855-266-2427.  The CICP is the payer of last 
resort, meaning that the CICP would generally only reimburse or pay for items or services to the extent 
such items or services are not covered by other third-party payers, such as your health insurance or 
workers’ compensation you receive. 
 
HOW WILL YOU KEEP MY INFORMATION CONFIDENTIAL? 
 
Other people such as those indicated below may become aware of your participation in this study and 
may inspect and copy records pertaining to this research.  Some of these records could contain 
information that personally identifies you. We will keep your participation in this research study 
confidential to the extent permitted by law.   
 
 Government representatives (including the Office for Human Research Protections) to complete 
federal or state responsibilities 
 The U.S. Food and Drug Administration 
 COVID-19 Therapeutics Accelerator 
 PRA Health Sciences, the contract research organization  
 Your primary care physician if a medical condition that needs urgent attention is discovered 
 Public health agencies to complete public health reporting requirements. 
 Hospital or University representatives to complete hospital or University responsibilities 


 
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APPROVAL DATE: 01/05/21 
RELEASED DATE: 01/05/21 
EXPIRATION DATE: 05/06/21 
 
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 Off-site laboratories to analyze samples  
 Information about your participation in this study may be documented in your health care records 
and will be available to anyone with access to your health care record, including your health 
insurance company.  This information may also be released as part of a release of information 
request. 
 Mobile phone number with Telerivet.com and Messagebird.com for data collection. 
 
Sealed Envelope Ltd the online platform for data collection 
 The last four digits of your social security number may be used in hospital or University systems 
to track billing information for research procedures. 
 Washington University’s Institutional Review Board (a committee that oversees the conduct of 
research involving human participants) and the Human Research Protection Office. The 
Institutional Review Board has reviewed and approved this study.  
 Protected health information (PHI) may be shared with the data safety monitoring committee to 
make sure the study is safe and with University College London the data coordinating center 
 Any report or article that we write will not include information that can directly identify you.  
The journals that publish these reports or articles require that we share your information that was 
collected for this study with others to make sure the results of this study are correct and help 
develop new ideas for research. Your information will be shared in a way that cannot directly 
identify you. 
 
To help protect your confidentiality, we will only collect information pertinent to the research.  This 
information with be de-identified when possible. All study records will be stored and transmitted 
securely with access limited to the research team.  
 
Research monitors, auditors, the study sponsor, the Institutional Review Board, and other regulatory 
authorities will be granted directed access to your original health care record to verify the conduct of the 
clinical trial procedures and/or data. This access will be permitted to the extent permitted by the 
applicable laws and regulations without violating the confidentiality of your information. By signing this 
form you are authorizing such access. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. 
Law. This Web site will not include information that can identify you. At most, the Web site will 
include a summary of the results. You can search this Web site at any time.  
 
Are there additional protections for my health information? 
 
Protected Health Information (PHI) is health information that identifies you. PHI is protected by federal 
law under HIPAA (the Health Insurance Portability and Accountability Act). To take part in this 
research, you must give the research team permission to use and disclose (share) your PHI for the study 
as explained in this consent form.  The research team will follow state and federal laws and may share 
your health information with the agencies and people listed under the previous section titled, “How will 
you keep my information confidential?” 
 
Once your health information is shared with someone outside of the research team, it may no longer be 
protected by HIPAA.   


 
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APPROVAL DATE: 01/05/21 
RELEASED DATE: 01/05/21 
EXPIRATION DATE: 05/06/21 
 
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The research team will only use and share your information as talked about in this form or as permitted or 
required by law.  When possible, the research team will make sure information cannot be linked to you 
(de-identified).  Once information is de-identified, it may be used and shared for other purposes not 
discussed in this consent form. If you have questions or concerns about your privacy and the use of your 
PHI, please contact the University’s Privacy Officer at 866-747-4975.  
 
Although you will not be allowed to see the study information, you may be given access to your health 
care records by contacting your health care provider.  
 
If you decide not to sign this form, it will not affect 
 your treatment or the care given by your health provider. 
 your insurance payment or enrollment in any health plans.   
 any benefits to which you are entitled. 
However, it will not be possible for you to take part in the study. 
 
If you sign this form: 
 You authorize the use of your PHI for this research 
 This authorization does not expire. 
 You may later change your mind and not let the research team use or share your information 
(you may revoke your authorization).  
 To revoke your authorization, complete the withdrawal letter, found in the Participant section 
of the Human Research Protection Office website at 
https://hrpo.wustl.edu/participants/withdrawing-from-a-study/ or you may request that the 
investigator send you a copy of the letter.    
 
 
 
o If you revoke your authorization: 
 The research team may only use and share information already collected for 
the study. 
 Your information may still be used and shared as necessary to maintain the 
integrity of the research, for example, to account for a participant’s 
withdrawal from the research study or for safety reasons. 
 You will not be allowed to continue to participate in the study. 
 
Can we contact you by email? 
We need to contact you by email for the purposes listed below.  Some of these emails may contain 
health information that identifies you. 
 To collect information about how you are feeling 
 Remind you to answer electronic surveys 
 Remind you to take the drug 
 Confirm receipt of the drug 
  
Only the research team will have access to your email communications.  We will only communicate by 
email to send you the information listed above.  If you have any questions or need to contact us for an 
urgent or emergent situation, please contact the research team member identified at the top of this 
document. 


 
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APPROVAL DATE: 01/05/21 
RELEASED DATE: 01/05/21 
EXPIRATION DATE: 05/06/21 
 
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You should be aware that there are risks associated with sending your health information via email.   
There is always a risk that the message could be intercepted or sent to the wrong email address.  When 
using any computer you should be careful to protect your username and password.  Make sure you log-
out before getting up from the computer.   
 
If you share a home computer with other family members, and do not want them to know you are 
participating in this study make sure you provide an email address that only you can access.  
Your employer will have access to any email communications sent or received on any electronic devices 
used for work or through a work server. 
  
Can we contact you by short message service (SMS)? 
We will contact you by SMS for the purposes listed below.  Some of these messages may contain health 
information that identifies you. 
 To collect information about how you are feeling 
 Remind you to answer electronic surveys 
 Remind you to take the drug 
 Confirm receipt of the drug 
 
Only the research team will have access to your SMS communications.  We will only communicate by 
SMS to send you the information listed above.  If you have any questions or need to contact us for an 
urgent or emergent situation, please contact the research team member identified at the top of this 
document. 
 
You should be aware that there are risks associated with sending your health information via SMS.   
 There is always a risk that the message could be intercepted or sent to the wrong phone 
number.  To avoid sending messages to the wrong person, the first message we send you will 
be a test message to ensure we have the correct phone number. 
 When using any phone, you should be careful to protect your username and password or pin 
code.   
 Your employer will have access to any messages sent or received on any electronic devices 
used for work. 
  
IS BEING IN THIS STUDY VOLUNTARY? 
 
Taking part in this research study is completely voluntary.  You may choose not to take part at all.  If 
you decide to be in this study, you may stop participating at any time. Any data that was collected as 
part of your participation in the study will remain as part of the study records and cannot be removed.   
 
If you decide not to be in this study, or if you stop participating at any time, you won’t be penalized or 
lose any benefits for which you otherwise qualify.   
 
What if I decide to withdraw from the study? 
 
You may withdraw by telling the study team you are no longer interested in participating in the study or 


 
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APPROVAL DATE: 01/05/21 
RELEASED DATE: 01/05/21 
EXPIRATION DATE: 05/06/21 
 
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you may send in a withdrawal letter. A sample withdrawal letter can be found at 
https://hrpo.wustl.edu/participants/withdrawing-from-a-study/ under Withdrawing from a Research 
Study. 
 
 
Will I receive new information about the study while participating? 
If we obtain any new information during this study that might affect your willingness to continue 
participating in the study, we’ll promptly provide you with that information. 
 
Can someone else end my participation in this study? 
Under certain circumstances, the investigator or the study sponsor might decide to end your participation 
in this research study earlier than planned.  This might happen for no reason, because you do not 
complete study requirements, or because the investigator feels it is no longer safe for you to participate 
due to one or more of the following reasons: you develop confirmed symptomatic COVID-19 or another 
illness which prevents you from completing further study requirements, your condition worsens, or you 
choose to enroll in a treatment trial. 
 
WHAT IF I HAVE QUESTIONS? 
We encourage you to ask questions.  If you have any questions about the research study itself, please 
contact: Linda Yun, 314-273-2240 or 636-751-1089. If you experience a research-related injury, please 
contact: Dr. Erik Dubberke, 314-454-8296.  
 
If you have questions, concerns, or complaints about your rights as a research participant, please contact 
the Human Research Protection Office 1-(800)-438-0445, or email hrpo@wustl.edu.   General 
information about being a research participant can be found on the Human Research Protection Office 
web site, http://hrpo.wustl.edu.  To offer input about your experiences as a research participant or to 
speak to someone other than the research staff, call the Human Research Protection Office at the number 
above. 
 
 
 
 


 
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APPROVAL DATE: 01/05/21 
RELEASED DATE: 01/05/21 
EXPIRATION DATE: 05/06/21 
 
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This consent form is not a contract. It is a written explanation of what will happen during the study if 
you decide to participate. You are not waiving any legal rights by agreeing to participate in this study. 
As a participant you have rights and responsibilities as described in this document and including: 
 To be given enough time before signing below to weigh the risks and potential benefits and 
decide if you want to participate without any pressure from the research team or others. 
 To understand all of the information included in the document, have your questions answered, 
and receive an explanation of anything you do not understand. 
 To follow the procedures described in this document and the instructions of the research team to 
the best of your ability unless you choose to stop your participation in the research study. 
 To give the research team accurate and complete information. 
 To tell the research team promptly about any problems you have related to your participation, or 
if you are unable to continue and wish to stop participating in the research study. 
 
Your signature indicates that this research study has been explained to you, that your questions have 
been answered, and that you agree to take part in this study.  You will receive a signed and dated copy 
of this form. 
 
 
Do not sign this form if today’s date is after EXPIRATION DATE: 05/06/21. 
 
 
__________________________________________ 
_______________________________ 
(Signature of Participant) 
 
 
 
 
(Date) 
 
 
____________________________________________ 
(Participant's name – printed) 
 
 
 
Statement of Person Who Obtained Consent 
 
The information in this document has been discussed with the participant or, where appropriate, with the 
participant’s legally authorized representative.  The participant has indicated that they understand the 
risks, benefits, and procedures involved with participation in this research study. 
 
 
__________________________________________ 
_______________________________ 
(Signature of Person who Obtained Consent) 
 
(Date) 
 
 
___________________________________________ 
(Name of Person who Obtained Consent - printed)