Researchers at the University of Oxford are rolling out a U.K. trial to assess whether low-risk treatment in the community can help to reduce symptoms of COVID-19 in older patients, help them to recover more quickly, and so reduce the need for hospitalization. The Platform Randomized Trial of Interventions against COVID-19 in Older People (PRINCIPLE) study will initially evaluate the malaria drug, hydroxychloroquine, in patients with COVID-19 symptoms, including those aged 50–64 years who have certain pre-existing illnesses, and any individual aged over 65 years who has had COVID-19 symptoms for less than 15 days.
The trial design will also allow other drugs to be incorporated into the study, explained Oghenekome Gbinigie, MD, a Wellcome Trust funded DPhil student at the Nuffield Department of Primary Care Health Sciences, University of Oxford. “There are other studies that have been registered with the purpose of assessing hydroxychloroquine as a treatment for COVID-19 in the community,” Gbinigie told GEN. “However, we are not aware of any other studies of COVID-19 in the community that employ the unique design of PRINCIPLE. The PRINCIPLE trial has been designed such that as new candidate treatments for COVID-19 come to our attention, they can be added part-way through the study. Furthermore, if we find that one treatment is performing better than another treatment, we can randomly assign more people in the study to the treatment that is performing best. This means that more people in the study have a chance of being assigned to the most effective study treatment.”
Co-chief investigator for the PRINCIPLE Trial is Christopher Butler, MD, professor of primary care in the Nuffield Department of Primary Care Health Sciences, professorial fellow at Trinity College, and clinical director of the University of Oxford Primary Care Clinical Trials Unit. He commented to GEN, “PRINCIPLE is a truly democratic trial and U.K.-wide trial, anyone with symptoms who is eligible can now join. This means that participation is not limited by where you live, which hospital you attend, or which health care facility you consult with.”
More than 500 general practitioner (GP) surgeries are now recruiting patients aged 50–64 years who have certain pre-existing illnesses, or those aged more than 65 years—whatever their background health status—into PRINCIPLE, which will initially evaluate hydroxychloroquine. Over-65s with COVID-19 symptoms can prescreen for the trial at home via an online questionnaire—whichever GP practice they are registered with—to see whether they may be included.
“PRINCIPLE aims to recruit over 3,000 people, Gbinigie commented. “This number will be increased if additional treatments are introduced and may also be adjusted in light of results that emerge during the course of the trial. The potential reach of this trial is considerably more than hospital-based studies that are finding treatments for very ill people—we are looking for treatments that can be used by many hundreds of thousands potentially.”
The PRINCIPLE has an intentionally adaptable design. The primary aim of the study is to see if outcomes can be improved for patients who are at higher risk of more serious disease if infected with COVID-19. “We know that older age is a risk factor for having a poorer outcome with COVID-19,” Gbinigie said. “However, we are constantly evaluating our eligibility criteria and can amend these criteria in light of emerging evidence.”
PRINCIPLE will aim to trial a number of low-risk treatments recommended by an expert panel that advises the Chief Medical Officer for England, and compare their effectiveness with that of current best available care. In this first phase, the trial is evaluating whether a seven-day course of hydroxychloroquine can reduce the severity of COVID-19 in vulnerable groups. “Azithromycin, as a monotherapy, will soon be added as a second drug,” Gbinigie noted. Participants will be closely monitored for the first 28 days of the trial, with a health record notes review taking place for up to three months to understand the longer-term effects of the illness on their health. “PRINCIPLE is a platform trial,” she continued, which means that “unlike most traditional types of clinical trials where a single treatment is evaluated, the design of PRINCIPLE allows for the evaluation of several treatments at the same time, and for more people in the trial to get the most effective trial intervention.”
Primary endpoint of the trial is an assessment of how effectively the treatment reduces hospital admissions or death, GEN was told. “We are assessing a number of secondary endpoints, including how effectively trial treatments reduce symptom severity, how quickly they speed up recovery, whether they help to reduce the number of antibiotics consumed by participants, whether they reduce the need for oxygen therapy, whether they reduce the need for mechanical ventilation, and also whether they impact on the duration of viral shedding.”
Gbinigie acknowledged that it is not possible to predict how long it will take to get either a positive or a negative signal from the trial. “This will depend on how quickly we recruit participants and on how effective the different treatments are,” she said. “As soon as we find that any one of the drugs in our trial is making a critical difference to people’s health, we want it to be part of clinical practice as soon as it can be introduced—though this is largely out of our hands.” A decision would need to be taken to determine whether a drug could then be prescribed by clinicians outside of the trial. “In the U.K., the Medicines and Healthcare products Regulatory Agency (MHRA) is responsible for ensuring that drugs that are used in clinical practice are safe and effective.”
PRINCIPLE is being carried out in parallel with the Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial in the U.K., which is claimed to represent the world’s largest randomized controlled trial of potential COVID-19 treatments. Also headed by researchers at the University of Oxford, RECOVERY is evaluating a number of drugs, including hydroxychloroquine, and also the HIV drug lopinavir/ritonavir, and the steroid dexamethasone. But while PRINCIPLE is evaluating treatments in a community setting, RECOVERY is enrolling hospitalized patients. More than 130 NHS hospitals across the U.K. are participating in RECOVERY.
There are some similarities in the design of the two trials, Gbinigie noted. “For example, RECOVERY has the ability to add and remove different trial treatments according to emerging evidence, just like PRINCIPLE. However, there are many differences, largely because the participant populations and goals of the studies are so different. PRINCIPLE is specifically for patients with COVID-19 in the community, whereas RECOVERY is taking place in patients who are in hospital with COVID-19. PRINCIPLE aims to see whether we can prevent hospital admissions, whereas RECOVERY is assessing the outcomes of patients once they have been admitted to the hospital.”
Butler is also a part-time GP for the Cwm Taf Morgannwg University Health Board. In a recent statement he commented, “With enough people recruited, this trial will give us the vital information we need to understand whether existing drugs can help people recover sooner and at home, without needing to be admitted to hospital—a significant milestone in the course of this pandemic … As soon as we find that any one of the drugs in our trial is making a critical difference to people’s health, we want it to be part of clinical practice as soon as it can be introduced.”
Co-chief investigator, Richard Hobbs, is professor of primary care and head of Oxford University’s Nuffield Department of Primary Care Health Sciences. He added, “The challenges in developing PRINCIPLE were unprecedented in terms of speed in finalizing design, seeking permissions, and then operationalizing this key platform trial. It has required months of work to be completed in just a matter of days and weeks.”
The PRINCIPLE trial platform has received £1.7 million from UK Research and Innovation (UKRI) and the Department of Health and Social Care through the National Institute for Health Research (NIHR). It is part of a wider £24.6 million rapid research response investment by the U.K. government to support looking at ways to tackle the coronavirus outbreak.
There are currently 1,358 clinical trials for COVID-19/SARS-CoV-2 listed on ClinicalTrials.Gov, including 178 for hydroxychloroquine. A retrospective study reported in the Journal of the American Medical Association (JAMA) yesterday found no benefit of hydroxychloroquine therapy on mortality in already hospitalized COVID-19 patients. Last week an observational study reported in the New England Journal of Medicine (NEJM) similarly found that hydroxychloroquine therapy had no effect on mortality among patients hospitalized with COVID-19.