Source: Walter & Eliza Hall Institute of Medical Research
COVID SHIELD is a major collaborative effort led by the Walter and Eliza Hall Institute in partnership with human data science company IQVIA and healthcare providers across Australia, which began in May 2020.
The trial will assess whether the drug hydroxychloroquine is useful in preventing COVID-19 disease, caused by SARS-CoV-2 infection, in frontline and allied healthcare workers.
This group is at increased risk of infection due to repeated exposure caring for COVID-19 patients.
The trial will enrol 2250 healthcare workers through participating hospitals. Half the participants will be given hydroxychloroquine, and the other half will receive a placebo tablet. Individual participants will receive doses of hydroxychloroquine or the placebo control for a maximum of four months. Results from the trial are expected in six to eight months.
At the time of trial commencement, more than 10 per cent of COVID-19 cases in Australia had occurred in health care workers. These health care workers are often at higher risk of infection due to their contact with moderately to critically ill COVID-19 patients and may be exposed on a recurring basis. As such, it is important to find suitable approaches to protecting these at-risk people from COVID-19.
Why are you conducting a clinical trial using hydroxychloroquine?
Hydroxychloroquine has been identified as having potential antiviral activity against SARS-CoV-2 in preclinical (laboratory-based) research conducted at the Institute and substantiated by research that has been replicated by other laboratories around the world.
The COVID SHIELD trial is exclusively looking at hydroxychloroquine as a preventative therapy for COVID-19. The trial is not using the drug in people who have tested positive for COVID-19 or as a treatment for people who are sick with COVID-19.
There are several examples of drugs that are effective in preventing diseases but less effective in treating them, such as antiretroviral drugs used for pre-exposure prophylaxis (PrEP) to HIV and neuraminidase inhibitor drugs (oseltamivir (Tamiflu®) and zanamivir (Relenza®)) used for influenza.
Hydroxychloroquine has been in clinical use for decades and is currently being taken by thousands of Australians for rheumatic conditions. Like any medication, hydroxychloroquine has certain side effects, but fortunately these are well known and quite uncommon.
What is the proposed mechanism by which hydroxychloroquine may prevent SARS-CoV-2 infections?
Laboratory research has shown that hydroxychloroquine prevents a biochemical change within cells called endosome acidification. Without this change, cellular entry and replication of SARS-CoV-2 virus is thought to be blocked. Hydroxychloroquine has also been speculated to boost the entry of zinc into cells, which may also inhibit viral replication.
If the number of infections is very low, will it be futile to perform the study?
COVID-19 is a pandemic that will not disappear. We have seen second and even third waves of infections that have compromised many countries. These outbreaks occur very quickly and if we wait for them to happen, we miss the opportunity to provide pre-exposure prevention.
Because we are performing a prevention study people must be taking the drug before exposure and we cannot predict when exposure will happen. The number of infected people regularly goes up and down, and we will continue to see outbreaks, particularly as restrictions are lifted.
Even if there is only one case of COVID-19 per month in any Australian state, this one case, in seeking medical attention, has opportunity to infect five or more health care workers.
For our study to be able to establish if hydroxychloroquine can prevent infection, we need approximately 28-30 cases of COVID-19 in health care workers. Even if there are very few infections in the general community, health care workers remain at increased risk because they will be the first port of call for people with COVID-19.
Have there been other studies done on the use of hydroxychloroquine and COVID-19?
Hydroxychloroquine has not been rigorously trialled in humans as a pre-exposure preventative therapy for COVID-19 in healthy people.
There is currently no evidence from randomised, double-blinded clinical trials to suggest that hydroxychloroquine will either work or not work as a pre-exposure preventative agent in healthy people, which is why this trial is being pursued.
Several other trials are looking at hydroxychloroquine. These include trials for treating people who have severe COVID-19, examining the use of the drug in mild cases, assessing the ability of the drug to prevent disease in settings that are very different to our situation in Australia, and as a post-exposure preventative agent.
Most recently a study was published in the New England Journal of Medicine (Boulware et al.) reporting the results of a randomised trial of hydroxychloroquine as post-exposure prophylaxis (pre-emptive therapy) for COVID-19.
This trial is different to COVID SHIELD as a higher dose of hydroxychloroquine was administered to participants 3-4 days after exposure to individuals with confirmed COVID-19 infections in their home or workplace. Very few participants in the study were tested to confirm whether or not they had acquired COVID-19 from exposure to an infected person. The authors primarily relied on a description of symptoms to decide if people had COVID-19.
In response to the article, the editors of the New England Journal of Medicine have noted that “the potential prevention benefits of hydroxychloroquine remain to be determined.”
For the COVID SHIELD trial, participants will receive hydroxychloroquine prior to exposure to the virus. All participants will be carefully tested to ensure definitive scientific results.
Why is the COVID SHIELD trial continuing when the WHO has temporarily suspended some clinical trials using hydroxychloroquine?
The World Health Organization (WHO) temporarily suspended some clinical trials of hydroxychloroquine as a treatment for COVID-19 pending review of the data from a report in The Lancet (Mehra et al) that has now been retracted.
On 3 June WHO announced that it would resume its trials of hydroxychloroquine.
The COVID SHIELD clinical trial does not involve the use of hydroxychloroquine for the treatment of COVID-19. It is exclusively being trialled in healthy individuals as a preventative or prophylactic therapy. The dose of hydroxychloroquine used in COVID SHIELD for prevention is lower than the doses used in most published clinical trials for treatment.
Who is funding COVID SHIELD?
Funding for the trial has come from the Australian Government through the Medical Research Future Fund (MRFF) after independent, expert peer review that was overseen by the National Health and Medical Research Council (NHMRC). The Walter and Eliza Hall Institute is providing some direct financial support to the trial, including through direct community fundraising activities. The trial is not currently funded by any other government, private or industry sources.
Who approved the COVID SHIELD trial?
COVID SHIELD is a multi-centre trial that has been reviewed and approved by an independent NHMRC Human Research Ethics Committee (HREC) accredited to perform single ethical review of multi-centre research. The Walter and Eliza Hall Institute and and each participating hospital’s HREC and or Research Governance Office have similarly reviewed the project. COVID SHIELD conforms to the NHMRC Statement on Ethical Conduct in Human Research.
COVID SHIELD has been independently peer-reviewed and endorsed by the Australasian Society of Infectious Diseases and MRFF, and further endorsed by the Melbourne Academic Centre for Health, an NHMRC-recognised Advanced Health Research and Translation Centre.
Is the trial registered?
The clinical trial is registered with Australian and New Zealand Clinical Trial Registry and the World Health Organization International Clinical Trials Registry Platform.
Is hydroxychloroquine safe?
Many thousands of patients in Australia are currently taking hydroxychloroquine as a prescribed treatment for rheumatic conditions.
More than 20 internationally recognised clinical trialists have been involved with the development and implementation of this study. Many of the clinical trialists have been using hydroxychloroquine in patients for more than 20 years and they understand the drug and its side effects.
Why not study people who are already taking hydroxychloroquine for other conditions?
COVID SHIELD is a randomised, controlled, double-blind clinical trial – the gold standard of clinical trials.
In this study participants will provide informed consent, meet stringent selection criteria (including criteria related to their health status) and follow strict protocols around dosage to obtain a definitive outcome. Neither the participants nor the trial team will know until the conclusion of the trial whether they were taking hydroxychloroquine or placebo (sugar) tablets. This ensures the trial outcomes are unbiased and provides the most scientifically meaningful results.
A definitive result cannot be obtained using historical data of patients with existing conditions who have all been taking different doses of hydroxychloroquine for different time periods and have potentially been taking other medications or supplements.
Australian Clinical Trials provides more detailed information about how clinical trials are designed.
Can I participate or contribute samples if I am already taking hydroxychloroquine for another condition?
We are not currently seeking blood samples for the COVID SHIELD trial.
Frontline and allied healthcare workers in Australia who wish to participate can visit the COVID SHIELD trial website to check details on inclusion and exclusion criteria to see if they can proceed to be screened for the study. The trial is not open to participants outside Australia.
Will this trial impact on access to hydroxychloroquine for people who need it for other conditions, such as lupus or rheumatoid arthritis?
The hydroxychloroquine to be used in the study has been supplied by the manufacturer for this specific purpose. The trial will not divert hydroxychloroquine for routine use from pharmacies, hospitals or other patient supply chains.
How will the safety of participants be ensured?
The trial has been carefully designed to mitigate risk of any harm or side effects. All participants will be closely monitored through medical screening, assessment of ECGs and reporting. Participants experiencing any unwanted reactions to the drug will be withdrawn from the trial immediately.
This rigorous process has been reviewed by the aforementioned bodies and the study protocol was endorsed. As per regulatory requirements, the study will be also be independently audited by unblinded medical monitors, with any unwanted reactions to the drug reported and all blinded data reviewed by an independent data safety monitoring board.
Do healthcare workers have to participate?
Participation in the trial is completely voluntary and participants must meet certain requirements to ensure that they can safely participate.
How do I participate in the trial?
Frontline and allied healthcare workers in Australia who wish to participate can visit the COVID SHIELD trial website to check details on inclusion and exclusion criteria to see if they can proceed to be screened for the study. The trial is not open to participants outside Australia.
Given the volume of infection in Australia is low, can you still get a valid trial result?
At the commencement of the trial more than 10 per cent of COVID-19 cases in Australia had occurred in health care workers. COVID-19 is a disease that will remain in Australia for a long time and, as restrictions are lifted, we anticipate that the number of cases is likely to increase – and some of these cases will result in exposure of healthcare workers to the virus.
Due to the rate of spread of SARS-CoV-2 virus, just a single case within a hospital has the potential to infect a large number of workers. As a result, the study can still produce valid results with very few cases in hospital. The likely infection rate used to inform the trial has been based on expert epidemiological forecasts.
Will zinc be used in the trial?
Hydroxychloroquine is not being tested with a zinc supplement in the COVID SHIELD trial.
Current advice is to incorporate zinc supplementation with hydroxychloroquine in the treatment of certain conditions on a case-by-case basis, and most commonly in people who are zinc deficient.
Pre-screening will ensure the participants in the COVID SHIELD trial meet certain health criteria which means they will be less likely to be zinc deficient.
Can I have details of the clinical trial protocols?
We are unable to share the research protocol to ensure that research integrity is maintained and to protect participants. The formal review process is designed to ensure research integrity, safety, confidentiality, equipoise, rationale and scientific merit. We have welcomed this scrutiny by highly qualified, internationally recognised experts and accredited reviewers during the trial development and approval phase.
For further information
- National Health and Medical Research Council: Research Integrity
- Australian Government Medical Research Future Fund
- The regulatory process for clinical trials in Australia (Clinical Trials Australia)
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