Condition category
Infections and Infestations
Date applied
21/05/2020
Date assigned
26/05/2020
Last edited
11/06/2020
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Plain English Summary

Background and study aims
COVID-19 is a condition caused by the coronavirus (called SARS-CoV-2) that was first identified in late 2019. This virus can infect the respiratory (breathing) system. Some people do not have symptoms but can carry the virus and pass it on to others. People who have developed the condition may develop a fever and/or a continuous cough among other symptoms. This can develop into pneumonia. Pneumonia is a chest infection where the small air pockets of the lungs, called alveoli, fill with liquid and make it more difficult to breathe.

In 2020, the virus has spread to many countries around the world and neither a vaccine against the virus or specific treatment for COVID-19 has yet been developed. As of March 2020, it is advised that people minimize travel and social contact, and regularly wash their hands to reduce the spread of the virus.

Groups who are at a higher risk from infection with the virus, and therefore of developing COVID-19, include people aged over 70 years, people who have long-term health conditions (such as asthma or diabetes), people who have a weakened immune system and people who are pregnant. People in these groups, and people who might come into contact with them, can reduce this risk by following the up-to-date advice to reduce the spread of the virus.

Front line medical staff are at risk of contracting this potentially deadly disease. Thus an effective pre-emptive intervention needs to be developed to decrease the occurrence of symptomatic COVID-19, and to mitigate its severity in front line medical staff, while a vaccine is developed.

There is growing evidence suggesting that Chloroquine, an anti-malarial drug that has been in common use for the last 70 years, that is a broad-spectrum anti-viral medication which, through its mode of action could potentially prevent the development of severe COVID-19 symptoms.

However, despite the potential benefit, due to immunosuppressant proprieties of chloroquine, there is the risk that this medication may increase the risk of COVID-19 and other infections, so widespread adoption should be approached with caution. There are no randomised trial or real-world data on whether or not chloroquine is effective at preventing or mitigating COVID-19 in humans thus the need for the study.

CROWN CORONATION is an international trial in healthcare workers at risk of contracting COVID-19, investigating the use of chloroquine to prevent the development of symptomatic COVID-19, reduce the severity of symptoms and to find the minimum effective dosing schedule of chloroquine to prevent symptomatic COVID-19 in at risk healthcare workers.

Who can participate?
Healthcare workers without clinical evidence of COVID-19 infection aged 18 years and older

What does the study involve?
Participants will be randomly allocated to receive one of three different doses of chloroquine, or placebo for a maximum of three months. Participants and researchers will not know which group they are in.

What are the possible benefits and risks of participating?
A benefit from this study is that the information we receive will help is improve treatment for future healthcare workers to prevent them from getting COVID-19. In addition if participants develop COVID-19 they can be provided with information about ongoing COVID-19 treatment studies.
The most important risk of taking part is that the participants may develop a side effect from taking the medication.

Where is the study run from?
Comprehensive Clinical Trial Unit at University College London

When is the study starting and how long is it expected to run for?
March 2020 to May 2021

Who is funding the study?
Bill and Melinda Gates Foundation (USA)

Who is the main contact?
Unfortunately, this study is not recruiting public volunteers at this time. This is because the research isn’t ready for volunteers yet or the researchers are directly identifying volunteers in certain areas or hospitals. Please do not contact the research team as they will not be able to respond. For more information about COVID-19 research, visit the Be Part of Research homepage.

Trial website

https://www.crowncoronation.com/

Contact information

Type

Public

Primary contact

Mrs Gemma Jones

ORCID ID

http://orcid.org/0000-0002-2235-274X

Contact details

Comprehensive Clinical Trial Unit at UCL
90 High Holborn
London
WC1V 6LJ
United Kingdom
+ 44 (0)20 3108 6833
cctu.ccoronation@ucl.ac.uk

Type

Scientific

Additional contact

Prof Laurence Lovat

ORCID ID

http://orcid.org/0000-0003-4542-3915

Contact details

University College London
Wellcome EPSRC Centre for Interventional & Surgical Sciences (WEISS)
Charles Bell House
43-45 Foley Street
London
W1W 7TY
United Kingdom
-
cctu.ccoronation@ucl.ac.uk

Additional identifiers

EudraCT number

2020-001402-38

ClinicalTrials.gov number

NCT04333732

Protocol/serial number

CTU/2020/352, CPMS 45647, IRAS 282280

Study information

Scientific title

An international, multi-site, Bayesian platform adaptive, randomised, placebo-controlled trial assessing the effectiveness of varied doses of oral Chloroquine in preventing or reducing the severity of COVID-19 disease in healthcare workers

Acronym

CROWN CORONATION

Study hypothesis

To determine the effectiveness of chloroquine prophylaxis 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), laboratory test-confirmed COVID-19 in healthcare workers with repeated exposures to SARS-CoV-2.

Ethics approval

Approved 30/04/2020, East Midlands-Nottingham 2 Research Ethics Committee (The Old Chapel, Royal Standard Place, Nottingham, NG1 6FS, UK; +44 (0)0207 104 8103; nottingham2.rec@hra.nhs.uk), ref: 20/EM/0116

Study design

International multi-centre randomized placebo-controlled trial

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Prevention

Patient information sheet

Access to the participant information sheet is available through the trial website or by contacting the trial UK sponsor.

Condition

COVID-19 (SARS-CoV-2 infection)

Intervention

The CROWN CORONATION trial is an international multi-centre randomised, placebo-controlled trial.

Participants will be front line healthcare workers at risk of contracting COVID-19 (SARS-CoV-2), randomised to one of 4 groups stratified by trial site and participant age (under 50 & over 50). The four groups will be:
1. 500mg chloroquine phosphate weekly
2. 500mg chloroquine phosphate twice weekly
3. 250mg chloroquine phosphate daily
4. Placebo

All participants in the active treatment arms will receive an induction dose of 2000mg chloroquine phosphate taken divided between 4 daily doses before starting the weekly, twice weekly or daily dose regimen. Those in the placebo group will be asked to take the equivalent number of placebo tablets.

The trial will evaluate which, of the above intervention arms is the most effective at decreasing the incidence of symptomatic COVID-19 disease, without unacceptable side effects or safety events.

All participants will be asked to complete twice weekly logs via SMS message. Therefore, all participants will need to have access to a mobile phone in order to do this. In addition, participants will be asked to log into an online self-report form once a month to provide more detailed information on their health and medication adherence. Self-reported information will be collected up until 2 months after the end of treatment or death. Participants will be provided with a secure log-in to enable them to complete trial questionnaires and daily data logs.
To help participants to adhere to the treatment regime they are randomised to a support system using two way SMS messages that has been used in other research (HIV PrEP). As well as completing the daily and monthly logs, participants will be sent reminders of when to collect more medication by SMS.

At the time of randomisation, participants will be given 72 hours to collect their trial medication or placebo. They will be asked to take a form of identification to a dispensing station, where a pharmacist will dispense trial medication/placebo. Only one dispensing event will take place per participant. At the end of their time in the trial, participants will be asked to drop off any unused trial medication or placebo to the collection point. Participants will be asked to take the trial medication for a maximum of 3 months if they do not experience any trial events: the participant is diagnosed with COVID-19 and decides to join a different treatment intervention trial or are prescribed chloroquine by their treating physician; the participant reports a complication, safety concern or side effect necessitating stopping taking the trial medication or placebo; or the participant is no longer at risk from contact with SARS-CoV-2 infected patients.

All participants will have a blood test on entry and exit of the study. They will also take a self-administered nose swab if they have symptoms and think they may have contracted COVID-19.

Intervention type

Drug

Phase

Phase III

Drug names

Chloroquine phosphate

Primary outcome measure

Clinical diagnosis of COVID-19 with laboratory confirmation (i.e. based on viral PCR or serology), with limitation of activities (WHO Severity Scale 2-8) or symptoms of COVID-19 (cough, shortness of breath or difficulty breathing, fever, chills, muscle pain, sore throat, new loss of taste or smell) over the treatment period of 90 days

Secondary outcome measures

1. The severity of COVID-19 over the study period of 150 days
1.1. Uninfected – no clinical or virologic evidence of infection (Score = 0)
1.2. Ambulatory – no limitation of activities (score=1) or with limitation (Score=2)
1.3. Hospitalized – mild no oxygen (Score=3) or with oxygen (Score=4), hospitalized severe – Score=5-7*, dead (Score=8)
2. Primary endpoint, but instead of the 90-day time-window, over the course of the 1st 30 days of treatment
3. Primary endpoint, but instead of the 90-day time-window, over the course of the first 60 days of treatment
4. The incidence of: pneumonia; respiratory failure requiring intubation; acute respiratory distress syndrome; delirium; shock requiring vasopressor medications; sepsis; acute kidney injury; acute liver injury; death. Case definitions will be decided a priori
5. Duration of intensive care unit stay
6. Duration of hospital day
7. Symptomatic COVID-19 (with subsequent virological confirmation) during the 5-month study period
8. Incident COVID-19 during the 5-month study period, which includes asymptomatic infections identified by serology samples taken at the time-point of study exit
9. Safety Outcomes: Determined according to the CTCAE for grading severity of adult adverse events, with specific focus on the events of retinopathy (visual impairment), cardiomyopathy, arrhythmias, myopathies, hypoglycaemia and death, over the 150 days

Overall trial start date

20/03/2020

Overall trial end date

31/05/2021

Reason abandoned (if study stopped)

Eligibility

Participant inclusion criteria

1. Volunteers without clinical evidence of COVID-19 infection aged 18 years and older
2. Healthcare workers based in a primary, secondary or tertiary healthcare setting with a high risk of developing COVID-19 due to their potential exposure to patients with SARS-CoV-2 infection
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

Participant type

Health professional

Age group

Adult

Gender

Both

Target number of participants

30,000 (6,000 in the UK)

Participant exclusion criteria

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 diagnosed current infection with SARS-CoV-2 or previous COVID-19 diagnosis
4. Self-reported current acute respiratory infection
5. Concurrent and/or recent involvement in other research or use of chloroquine/hydroxychloroqine or any other 4-aminoquinolone or another experimental investigational medicinal product that is likely to interfere with the study medication within three months of study enrolment
6. Current use of antimalarial agents (lumefantrine, mefloquine, pyronaridine or amodiaquine), or any other drugs that may cause a dangerous drug interaction
7. Self-reported known allergies to the IMP and excipients of IMP and placebo
8. Self-reported presence or history of the following conditions: Retinopathy or retinal disease; Cardiomyopathy (structural or ischemic heart disease); Cardiac arrhythmia; known personal or family history of prolonged QTc; Psoriasis; Porphyria cutanea tarda; Epilepsy; Myasthenia gravis; Myopathy of any cause; Serious hepatic or renal disease; Electrolyte abnormalities; self reported severe depression or suicidality; currently undergoing treatment for tuberculosis
9. Self-reported current use of medication with known serious hepatotoxic effects or known interaction with chloroquine, including anti-TB treatment
10. Self-reported use of medications which prolong the QTc interval
11. Inability or unwillingness to be followed up for the trial period
12: Women who verbally state they are pregnant or breastfeeding or who intend to get pregnant within the next 3 months. (UK and IRE)

Recruitment start date

01/06/2020

Recruitment end date

31/01/2021

Locations

Countries of recruitment

Cameroon, Canada, Ghana, Ireland, Peru, South Africa, Uganda, United Kingdom, United States of America, Zambia, Zimbabwe

Trial participating centre

University College London Hospital
London
NW1 2BU
United Kingdom

Trial participating centre

The Royal Marsden Hospital
London
SW3 6JJ
United Kingdom

Trial participating centre

The Christie NHS Foundation Trust
Withington
M20 4BX
United Kingdom

Trial participating centre

Bolton NHS Foundation Trust
Bolton
BL4 0JR
United Kingdom

Trial participating centre

Harrogate and District NHS Foundation Trust
Harrogate
HG2 7SX
United Kingdom

Trial participating centre

The Rotherham NHS Foundation Trust
Rotherham
S60 2UD
United Kingdom

Trial participating centre

Norfolk and Norwich University Hospitals NHS Foundation Trust
Colney
NR4 7UY
United Kingdom

Trial participating centre

Croydon Health Services NHS Trust
London
CR7 7YE
United Kingdom

Trial participating centre

NHS Lothian
Edinburgh
EH1 3EG
United Kingdom

Trial participating centre

East Suffolk and North Essex NHS Foundation Trust
CO4 5JL
United Kingdom

Trial participating centre

Cwm Taf Morgannwg University Local Health Board
Pontypridd
CF37 1LB
United Kingdom

Trial participating centre

The Vale Hospital
Pontyclum
CF72 8JX
United Kingdom

Trial participating centre

Homerton University Hospital NHS Foundation Trust
London
E9 6SR
United Kingdom

Trial participating centre

Basildon and Thurrock University Hospitals NHS Foundation Trust
Basildon
SS16 5NL
United Kingdom

Trial participating centre

Wye Valley NHS Trust
Hereford
HR1 2ER
United Kingdom

Trial participating centre

The Walton Centre NHS Foundation Trust
Liverpool
L9 7LJ
United Kingdom

Trial participating centre

Gateshead Health NHS Foundation Trust
Gateshead
NE9 6SX
United Kingdom

Trial participating centre

University Hospitals Plymouth NHS Trust
Plymouth
PL6 8DH
United Kingdom

Trial participating centre

St George's University Hospitals NHS Foundation Trust
London
SW17 0QT
United Kingdom

Trial participating centre

Southend University Hospital NHS Foundation Trust
Westcliff-on-Sea
SS0 0RY
United Kingdom

Trial participating centre

Yeovil District Hospital NHS Foundation Trust
Yeovil
BA21 4AT
United Kingdom

Trial participating centre

Wellcome EPSRC Centre for Interventional & Surgical Sciences (WEISS)
W1W 7TY
United Kingdom

Trial participating centre

Welsh Ambulance Services NHS Trust
St Asaph
LL17 0WA
United Kingdom

Trial participating centre

Moorfields Eye Hospital NHS Foundation Trust
London
EC1V 2PD
United Kingdom

Trial participating centre

Salford Royal NHS Foundation Trust
Salford
M6 8HD
United Kingdom

Trial participating centre

Leeds Teaching Hospitals NHS Trust
Leeds
LS9 7TF
United Kingdom

Trial participating centre

Pennine Acute Hospitals NHS Trust
Manchester
M8 5RB
United Kingdom

Trial participating centre

Royal Devon and Exeter NHS Foundation Trust
Exeter
EX2 5DW
United Kingdom

Trial participating centre

Northern Heath & Social Care Trust
Antrim
BT41 2RL
United Kingdom

Trial participating centre

Hywel Dda University LHB
Carmarthen
SA31 3BB
United Kingdom

Trial participating centre

South East Coast Ambulance Service NHS Foundation Trust
Lewes
BN7 2XW
United Kingdom

Trial participating centre

London Ambulance Service NHS Trust
London
NW1 0PE
United Kingdom

Trial participating centre

Central and North West London NHS Foundation Trust
London
NW1 2PL
United Kingdom

Trial participating centre

University Hospitals Birmingham NHS Foundation Trust
Birmingham
B15 2GW
United Kingdom

Trial participating centre

Royal United Hospitals Bath NHS Foundation Trust
Bath
BA1 3NG
United Kingdom

Trial participating centre

Aintree University Hospital NHS Foundation Trust
Liverpool
L9 7AL
United Kingdom

Trial participating centre

North Bristol NHS Trust
Bristol
BS10 5NB
United Kingdom

Trial participating centre

The Newcastle upon Tyne Hospitals NHS Foundation Trust
Newcastle upon Tyne
NE7 7DN
United Kingdom

Trial participating centre

Guy's and St Thomas' NHS Foundation Trust
London
SE1 7EH
United Kingdom

Trial participating centre

Milton Keynes University Hospital NHS Foundation Trust
Milton Keynes
MK6 5LD
United Kingdom

Trial participating centre

NHS Greater Glasgow and Clyde
Glasgow
G12 0XH
United Kingdom

Trial participating centre

The Royal Orthopaedic Hospital NHS Foundation Trust
Birmingham
B31 2AP
United Kingdom

Sponsor information

Organisation

University College London

Sponsor details

Comprehensive Clinical Trials at UCL
90 High Holborn
2nd floor
London
WC1V 6LJ
United Kingdom
+ 44 (0)20 3108 6833
cctu-enquiries@ucl.ac.uk

Sponsor type

University/education

Website

https://www.ucl.ac.uk/comprehensive-clinical-trials-unit/

Funders

Funder type

Charity

Funder name

Bill and Melinda Gates Foundation

Alternative name(s)

Bill & Melinda Gates Foundation, Gates Foundation, 比尔及梅琳达·盖茨基金会, बिल एंड मिलिंडा गेट्स फाउंडेशन, BMGF, B&MGF

Funding Body Type

private sector organisation

Funding Body Subtype

Trusts, charities, foundations (both publically funded and privately funded)

Location

United States of America

Results and Publications

Publication and dissemination plan

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, 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 on Sharing research data and findings relevant to the novel coronavirus (COVID-19) outbreak: https://wellcome.ac.uk/press-release/sharing-research-data-and-findingsrelevant- novel-coronavirus-covid-19-outbreak.

IPD sharing statement:
The datasets generated during and/or analysed during the current study will be stored in a publically available repository.
IPD (individual patient data) pseudo-anonymised will be shared at https://www.ucl.ac.uk/library/research-support/research-data-management/ucl-research-data-repository, in line with open access policy from the funders https://www.gatesfoundation.org/How-We-Work/General-Information/Open-Access-Policy
Sharing will start when we reach database lock at the end of trial, after the last patient finishes their follow-up and all data for all patients is included in the dataset.

Intention to publish date

31/05/2022

Participant level data

Not expected to be available

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes

11/06/2020: Contact details updated. 27/05/2020: The primary contact ORCID was added. 21/05/2020: Trial’s existence confirmed by National Institute for Health Research (NIHR).