The project will test a drug that could raise oxygen levels in the blood in COVID-19 patients in order to improve their chances of recovery. Raising oxygen levels is important in COVID-19, because many patients with the disease die when oxygen levels in their arterial blood fall to levels that are too low to support life.
Currently, supportive therapy for COVID-19 in hospitals aims to keep oxygen levels sufficiently high with treatments such as supplementary oxygen or by using ventilators to artificially support the body’s breathing process. In normal circumstances, if the oxygen becomes too low in a part of the lung, the blood vessels in that part constrict to redirect the blood flow to other regions of the lung where the oxygen is higher. In COVID-19 patients, however, the Oxford University researchers hypothesise that this mechanism is not working properly. Consequently, the blood flow is going to the most diseased and non-functioning parts of the lung where the oxygen is low, and is not getting diverted to the healthier parts of the lung where the oxygen is higher. This means that too much blood flows through the lungs without picking up oxygen.
The research team aims to address this problem by preferentially constricting the blood vessels going through the diseased parts of the lung, thereby redirecting the blood towards the healthy parts where it can pick up oxygen. To do this, they will use an old drug first developed in France called almitrine bismesylate, which is known in the scientific community to have this effect when treating acute respiratory distress syndrome (ARDS). The drug acts to increase the sensitivity of the acute oxygen sensing mechanisms of the body. According to Lead Researcher Professor Peter Robbins: “We know that almitrine can increase oxygen levels in patients with acute respiratory distress syndrome by constricting the blood vessels in regions of the lung where the oxygen is low. We want to see if almitrine will also have this effect in COVID-19 patients.”
The team will work with the UK pharmaceutical industry to produce almitrine for clinical use and will run a trial of the drug in selected UK locations. The trial will be split into two phases. Phase A is to administer one oral dose of the drug to patients needing respiratory support to ascertain whether it is successful in increasing oxygen levels in the arterial blood. Phase B aims to administer the drug to patients for a seven-day period to ascertain whether it reduces the amount of other respiratory support the patient needs. Professor Robbins said: “If almitrine can add to the overall effectiveness of respiratory support, then the hope is that clinicians will need to mechanically ventilate fewer patients, and that they will be able successfully to support more seriously ill patients throughout the course of their illness.”
“People can recover from COVID-19 in the same way that they recover from other viral illnesses. That’s by fighting off the virus with the body’s normal defence mechanisms. But if the lung becomes so damaged that blood just doesn’t pick up enough oxygen, then the body never gets the chance to finish the job and the patient dies from the low level of oxygen. So, what we are really trying to do with supportive therapy is help the patient to continue to function whilst their body fights off the infection in the normal way.”
The almitrine will take three months to manufacture. Once the almitrine becomes available, it is anticipated that phase A of the study will take one month to complete, and phase B will take four months to complete. The results should become available one month after completion of the last patient.
The trial is a close collaboration between academic staff located across different departments at Oxford University and NHS hospital consultants. The researchers include Professor Peter Robbins and Professor Keith Dorrington at the Department of Physiology, Anatomy and Genetics, Professor Najib Rahman at the Nuffield Department of Medicine, Professor Chris Schofield at the Department of Chemistry, Dr Stuart McKechnie and Dr Matthew Rowland (Kadoorie Centre for Critical Care Research, based in the Nuffield Department of Clinical Neurosciences), Dr Nayia Petousi and Dr Nick Talbot (Respiratory Medicine) at Oxford University Hospitals’ John Radcliffe Hospital, Dr Matthew Frise at the Royal Berkshire Hospital in Reading, and Dr Matthew Wise at the University Hospital of Wales in Cardiff.
This study is being supported by a grant from the medical research charity LifeArc, as part of its activities to address the need for new therapies for COVID-19. LifeArc has made £10m available to repurpose existing medicines or those in the late stage of development as this approach offers one of the fastest routes to develop new treatments that could tackle the virus and its impact.