Condition category
Infections and Infestations
Date applied
20/07/2020
Date assigned
21/07/2020
Last edited
21/07/2020
Prospective/Retrospective
Retrospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Plain English Summary

Background and study aims
COVID-19 is a condition caused by the novel 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.

As of writing, SARS-CoV-2 has infected more than 7,000,000 individuals, killed more than 400,000 people and has spread to more than 200 countries and territories.

The study team are working to find effective treatments and preventive measures as the pandemic grows. The risks to the healthcare system, as seen with SARS-CoV (SARS) previously, and then in Wuhan with COVID-19, could be a major threat to healthcare operations overall.

Chloroquine has significant antiviral activity against SARS-CoV-2 in laboratory cell culture, as it does for the related SARS-CoV. Several other laboratory studies confirm antiviral activities for chloroquine and hydroxychloroquine. This effect occurred when the drug was given either before or after the virus was added to the cells. This occurs at relatively high concentrations of these drugs when compared to the concentrations needed in the treatment of malaria. However, this concentration of the drugs needed for this effect could be achieved in humans with daily oral (via the mouth) treatment.

Chloroquine has complex properties, and so it is not known what amount of the drug would pass from the bloodstream to the lungs in order to have the necessary concentration to have the intended effect on the virus, although estimates can be made from studies in rats.

Hydroxychloroquine was synthesised first in 1946 and has largely replaced chloroquine for the management of autoimmune diseases as it has slightly reduced adverse effects (as toxicity and damage to the retina of the eyes only occurs at a higher concentration of the drug, and less abdominal discomfort is associated with the drug). It also has approximately twice the activity of chloroquine against the SARS-CoV-2 virus when inside the human body. Hydroxychloroquine may also cause less itching than chloroquine in dark-skinned patients.

The study team think that chloroquine and hydroxychloroquine might both slow viral replication in SARS-CoV-2 exposed participants, therefore reducing or preventing the infection in these patients. even if they are shown not to work in treatment or in post-exposure prophylaxis or in treatment. It is a basic principle of infectious diseases that preventing an infection developing requires lower doses or a less active drug than treatment.

In COVID-19 illness the total amount of the virus in the body is far greater than at the time of initial infection. Therefore the window of opportunity for antiviral medicines is at the earliest stages of infection. In addition laboratory studies show that this is when chloroquine and hydroxychloroquine have the greatest anti-viral activity in cells.

The study team believe these drugs may have the greatest use in preventing COVID-19 when given before infection as a preventative measure. These drugs are already in use in the prevention of other diseases, they are low-cost, and have been seen to be safe and well-tolerated. If proven to be effective for this purpose, then it would be a readily deployable and affordable preventive measure for healthcare workers.

This study aims to determine if chloroquine or hydroxychloroquine given prior to infection can prevent symptomatic COVID-19 illness. The study will also investigate
if there is an effect on the severity of COVID-19 infections, the prevention of asymptomatic COVID-19, and the prevention of acute respiratory infections (ARI) of all causes.

Who can participate?
Healthcare workers and other staff working in a facility where there are cases of either proven or suspected COVID-19 can participate into the study. Adults from both genders aged less than 65 years will be enrolled in the study. Pregnant women and children are excluded from the study. The study is planning to recruit globally including many countries in UK, Europe, Asia and Africa.

What does the study involve?
The participant will be randomised to receive either a dummy pill or treatment with chloroquine or hydroxychloroquine (the active drug used will vary by study site). Participants will receive a slightly larger amount of the study medication for the first dose and then will take a set amount of either the drug or the dummy pill for 3 months. Participants are followed up for a maximum for 5 months.

What are the possible benefits and risk of participating?
Risks related to chloroquine phosphate/ sulphate/ hydrochloride and hydroxychloroquine sulphate are very low, unless the drug is taken in overdose. These are very safe and generally well-tolerated medications but adverse reactions relating to the cardiovascular system, the central nervous system, the skin, the gastrointestinal (digestive) system, and low blood sugar, hypersensitivity, and retinal (part of the eye) toxicity have all been described. THese adverse reactions usually occur after high doses or long-term exposures. The main adverse effect is itching, in particular with chloroquine, in dark-skinned individuals; Africans are much more commonly affected compared to Asians.
These risks will be reduced by excluding participation if people have had a previous serious adverse reaction to chloroquine, or hydroxychloroquine, 4-aminoquinoline compounds, any components of the tablet or retinal or visual field changes of any kind.

Benefits of the study include access to a drug which may potentially prevent or reduce COVID-19 infection. No other proven preventive medication or vaccine exists currently exists.

The main potential benefit is to the participant in the chloroquine or hydroxychloroquine arm (direct protection) but individuals in the placebo arm may benefit from indirect protection through the decreased ability of the infection to spread.

Participants should also be aware that their participation may lead to an intervention which may save many lives around the world or, alternatively, may show chloroquine or hydroxychloroquine prevention is ineffective so trials can move on to evaluate other possible drugs with a minimum of delay, and the use of these drugs around the world for this purpose can stop.

Where is the study run from?
Mahidol Oxford Tropical Medicine Research Unit (Thailand)

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

Who is funding the study?
Wellcome Trust (UK)

Who is the main contact?
Dr William Schilling
William@tropmedres.ac

Trial website

https://www.tropmedres.ac/covid-19/copcov

Contact information

Type

Scientific

Primary contact

Dr William Schilling

ORCID ID

https://orcid.org/0000-0002-6328-8748

Contact details

Mahidol Oxford Tropical Medicine Research Unit
Bangkok
10400
Thailand
+66 2 203-6333
William@tropmedres.ac

Additional identifiers

EudraCT number

2020-001441-39

ClinicalTrials.gov number

NCT04303507

Protocol/serial number

CPMS 45731, IRAS 282109

Study information

Scientific title

Chloroquine/ hydroxychloroquine prevention of coronavirus disease (COVID-19) in the healthcare setting; a randomised, placebo-controlled prophylaxis study

Acronym

COPCOV

Study hypothesis

We hypothesise that chloroquine and hydroxychloroquine might both slow viral replication in exposed participants, attenuating or preventing the infection even if they are shown not to work in treatment or in post-exposure prophylaxis.

Ethics approval

Approved 18/03/2020, Oxford Tropical Research Ethics Committee (OxTREC) (Research Services, University of Oxford, University Offices, Wellington Square, Oxford OX1 2JD; +44(0)1865 (2)82106; oxtrec@admin.ox.ac.uk), ref: 25-20

Study design

Multi-centre double-blind, randomized placebo-controlled trial

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Prevention

Patient information sheet

Not available in web format, please use the contact details below to request a participant information sheet

Condition

COVID-19 (SARS-CoV-2 infection)

Intervention

The study will be conducted in healthcare settings and other facilities directly involved in COVID-19 case management. We will recruit healthcare workers and other staff working in a facility where there are cases of either proven, or suspected COVID-19, who can be followed reliably for 5 months.

The participant will be randomised to receive either chloroquine or placebo (1:1 randomisation), or to hydroxychloroquine or placebo (1:1 randomisation). A loading dose of 10 mg base/kg (between three and five tablets e.g., four 155-mg tablets for a 60-kg subject), followed by 155 mg daily (250 mg chloroquine phosphate salt/200 mg hydroxychloroquine sulphate) will be taken for 3 months.

A randomisation list will be prepared by a statistician using block randomisation in a 1:1 ratio for the chloroquine/ hydroxychloroquine arm versus the placebo and stratified by site. The randomisation will be computer-generated and programmed in Stata 15.

Intervention type

Drug

Phase

Phase III

Drug names

Chloroquine and hydroxychloroquine will be in the dose of 155 mg chloroquine base (250 mg of chloroquine phosphate or 200 mg of hydroxychloroquine sulphate)
It is expected that chloroquine will be used in Asian sites and hydroxychloroquine in Europe, specific drug allocation will be determined by each participating country.
Hydroxychloroquine sulphate will be used in the UK.

Primary outcome measure

The number of symptomatic COVID-19 infections will be compared between participants randomised to chloroquine or hydroxychloroquine, and placebo groups between baseline and 90 days

Secondary outcome measures

1. The symptoms severity and duration of COVID-19 illness, in those who become infected during the study will be compared between the two groups using a respiratory severity score between baseline and 90 days
2. The number of asymptomatic cases of COVID-19 will be determined by comparing serology in all participants at time of enrolment and at the end of 5 months
3. The number and severity of symptomatic acute respiratory illnesses will be compared in participants randomised to chloroquine or hydroxychloroquine, and placebo groups between baseline and 90 days

Tertiary outcome measures
1. Genetic loci and levels of biochemical components will be correlated with occurrence of and disease severity of COVID-19 or other Acute Respiratory Infections (ARIs) between baseline and 90 days
2. The days lost to work, and the relationship between the subjective assessment of well-being and the decision to self-isolate when unwell (i.e. not go to work) will be examined in relation to the infection and treatment arm between baseline and 90 days
3. Monetary costs associated with the use of healthcare resources between baseline and 90 days
4. Health-related quality of life measured using the quality of life questionnaire (EQ-5D-3L) at baseline and 90 days

Overall trial start date

13/02/2020

Overall trial end date

30/09/2021

Reason abandoned (if study stopped)

Eligibility

Participant inclusion criteria

1. Willing and able to give informed consent for participation in the study and agrees with the study and its conduct
2. Agrees not to self-medicate with chloroquine, hydroxychloroquine or other potential antivirals
3. Adults (exact age is dependent on countries) <70 years old at the time of consent
4. Not previously diagnosed with COVID-19
5. Not currently symptomatic with an ARI
6. Working in a facility where there are cases of either proven or suspected COVID-19
7. Possesses an internet-enabled smartphone (Android or iOS)

Participant type

Healthy volunteer

Age group

Adult

Gender

Both

Target number of participants

40,000 total participants. UK sample size will be expected to be 8,000 to 10,000 participants.

Participant exclusion criteria

1. Hypersensitivity reaction to chloroquine, hydroxychloroquine or 4-aminoquinolines
2. Contraindication to taking chloroquine as prophylaxis e.g. known epileptic, known creatinine clearance <10 ml/min
3. Already taking chloroquine, hydroxychloroquine or 4-aminoquinolines
4. Taking a concomitant medication
5. Known retinal disease
6. Inability to be followed up for the trial period
7. Known prolonged QT syndrome (however ECG is not required at baseline)
8. Known pregnancy or women who are actively trying to become pregnant
9. Prior diagnosis of porphyria

Recruitment start date

29/04/2020

Recruitment end date

30/04/2021

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Brighton and Sussex University Hospitals
Brighton
BN2 5BE
United Kingdom

Trial participating centre

Oxford University Hospital
Oxford
OX3 9DU
United Kingdom

Trial participating centre

Imperial College Healthcare
London
W2 1NY
United Kingdom

Sponsor information

Organisation

University of Oxford

Sponsor details

Research Services
University of Oxford University Offices
Wellington Square
Oxford
OX1 2JD
United Kingdom
+44 (0)1865 (2)82585
research.services@admin.ox.ac.uk

Sponsor type

University/education

Website

http://www.ox.ac.uk/

Funders

Funder type

Research organisation

Funder name

Wellcome Trust

Alternative name(s)

Funding Body Type

private sector organisation

Funding Body Subtype

International organizations

Location

United Kingdom

Funder name

Bill and Melinda Gates Foundation

Alternative name(s)

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

Funding Body Type

private sector organisation

Funding Body Subtype

Trusts, charities, foundations (both public and private)

Location

United States of America

Funder name

Mastercard Foundation

Alternative name(s)

Funding Body Type

private sector organisation

Funding Body Subtype

Trusts, charities, foundations (both public and private)

Location

Canada

Results and Publications

Publication and dissemination plan

All publications will abide by the International Committee of Medical Journal Editors (ICMJE) recommendations of the role of authors and contributors.

The results of the study will be summarised in lay language, in both English and the language(s) commonly spoken at the study sites, and disseminated to key stakeholders, user communities and caretakers of study participants.

IPD sharing statement:
With the participant’s consent, clinical data and results from blood analyses stored in the database may be shared according to the terms defined in the MORU data sharing policy with other researchers to use in the future.

Data generated from this study will adhere to the 2016 Statement on data sharing in public health emergencies (https://wellcome.ac.uk/press-release/statement-data-sharing-public-health-emergencies).

Intention to publish date

31/05/2021

Participant level data

Available on request

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes

20/07/2020: Trial’s existence confirmed by the National Institute of Health Research (NIHR).