Almitrine bismesylate, a drug first developed in France, has been used in treating acute respiratory distress syndrome to constrict the blood vessels in regions of the lung where the oxygen is low. University of Oxford researchers, including DPAG’s Professor Peter Robbins, Associate Professor Keith Dorrington and Dr Nick Talbot, believe that almitrine could have the same effect in patients suffering from COVID-19 pneumonia, thus raising oxygen levels in the blood. The trial team hopes that administering this drug to COVID-19 patients will consequently reduce the amount of other respiratory support that the patient needs.
The clinical trial commenced this week at the Royal Berkshire NHS Foundation Trust in Reading. Almitrine will be administered orally over a seven-day period to determine whether it is effective in reducing the need for other forms of ventilatory support.
Clinicians aim to recruit in the region of 116 patients in total across three centres. The second and third centres will be the Oxford University Hospitals’ John Radcliffe Hospital and University Hospital of Wales, Cardiff. The trial is expected to run for approximately 4 months.
The story has been released on the University of Oxford website.
DPAG’s Professor Robbins has given a special departmental Q&A to give a closer insight into the trial and how it got off the ground.
What was the idea behind the trial?
People make their own recovery from COVID-19. The primary idea behind medical treatment is that it is supportive – its aim is to keep people alive while they make their recovery from the disease. In a way, you can view the potential support from almitrine as extending people’s individual runway to make a recovery from the disease. Ultimately, the idea behind our trial is to enhance the supportive treatment – extend people’s runway for recovery if you like.
How do you expect almitrine to work?
The most striking feature of Covid-19 pneumonia is the very low level of oxygen, the profound hypoxia, that develops in the arterial blood supplying the body. People die from this hypoxia. We consider that this may happen because the underlying problem is that the virus breaks a normal process called hypoxic pulmonary vasoconstriction in the lung. This process diverts blood away from the diseased, non-functional parts of the lung, and towards the parts of the lung that are still working properly. Almitrine has the potential to help to restore this natural protective process in the lung.
Where did the idea to use almitrine come from?
The idea came from one of the many discussions over coffee that Associate Professor Keith Dorrington and I have had over the years. We have worked closely together since Keith first joined the department in 1989 on a variety of topics including the effects of different therapeutic and anaesthetic agents on the regulation of breathing and on the responses of the blood vessels in the lungs to hypoxia. These sorts of discussion are so important in academia.
What have you had to do to get the trial started?
Well, the first job was to put together a proposal with an approximate trial design to get funding. Professor Naj Rahman from the Nuffield Department of Medicine came on board to offer his expertise in trial design and brought with him the Oxford Respiratory Trials Unit that he oversees.
Professor Chris Schofield from the Department of Chemistry is part of the team because almitrine was not licensed in the UK and was unavailable as a drug elsewhere. Its original manufacturer, Servier, didn’t have any stock of active pharmaceutical ingredient (API) and had no plans to make any more, but they were supportive and provided us with all their manufacturing files. Everything was shut down back in the spring, and our biggest problem in writing the application was to provide a credible explanation of how we could obtain almitrine as a drug, or investigational medicinal product (IMP), that could be given to patients. Indeed, it was a suggestion of a neighbour of mine that eventually led us to a company that was willing to formulate the API into capsules.
The funding body, LifeArc, had rapidly put together a call for proposals like ours. As I recall, we had to have the application submitted early in April and LifeArc made a decision to fund towards the end of that month. It was then that all the hard work really started.
Were there any particular problems that you faced?
I think one of the real challenges has been the extremely tight regulatory framework around giving any trial medication to patients where there is no existing product license for its use in the UK.
I think a second real problem, somewhat perversely, has been the enormous strength of Oxford’s medical research base generating so many different projects directed towards the pandemic. For a study like ours, the University has to take a legal responsibility to act as Sponsor which is a very serious undertaking. Of course, given the regulatory environment, it is an enormous challenge for the team responsible for this – the Clinical Trials Research Governance (CTRG) group – to check everything with so much going on around it. Similar sorts of pressures have been put on the University’s contract staff, and I really do take my hat off to all of them for the way that they have responded.
How did you overcome these challenges?
There were two broad issues we had to address. The first was getting the drug. Chris Schofield had already both bought almitrine as a chemical and synthesised it in the lab. It is a simple synthesis, and costs around £1000 per kilo to buy. He analysed the samples very rigorously, and they were pure. However, to get to the position where we had around 200 grams in capsules that we were allowed to give to patients took around nine months of methods development, involved five different companies with the relevant licences, a number of regulatory applications and other matters. In all, it cost over £250,000.
The second issue was developing the trial protocol and steering that, first through CTRG, and then through the national regulatory body, the MHRA, and through the Ethics Committee – in our case, one in Liverpool. We needed someone else on the team, with experience of conducting clinical trials, who was willing to step forward, do a lot of the heavy lifting, and also accept the legal role of being the Chief Investigator for the trial. We are extremely fortunate that Dr Nick Talbot from Respiratory Medicine at Oxford University Hospitals’ John Radcliffe Hospital and who is also a Departmental Lecturer at DPAG was willing to do this, and we would never have got through to having the ‘green lights’ necessary to start the trial without all his hard work.
Finally, I should pay particular tribute to the staff at the MHRA. We are not ‘big-pharma’. There are many things we did not know. The MHRA didn’t simply fulfil their role as regulators, but went out of their way to coach us and to provide advice as to how we could most efficiently meet their regulatory requirements. I thought they were superb.
How did you find the proposed trial sites?
The Oxford University Hospitals Foundation Trust is our home ground, and the major problem here is the enormous pressure on clinical research resources because of all the other COVID-related research activity underway. The Royal Berkshire Hospital in Reading came on board because of Dr Matthew Frise, who was a graduate student with me in DPAG, and is now one of their consultants in intensive care medicine. He was particularly taken with the potential therapeutic gains from this trial and is the local Principal Investigator in Reading for the trial. University Hospital of Wales in Cardiff came on board through a contact of Dr Frise – Dr Matthew Wise – who was similarly interested. That gives us three sites. We are starting with Reading first and hope to bring the others on-stream soon afterwards.
Looking back on getting this trial started, are there things you think you have learnt?
One thing I have thought a lot more about is the nature of regulation. It really is a two-edged sword. On the one hand, everyone wants good, strong regulation. When we take medicines, we want to know that they are safe. When we step on aeroplanes, we want to know that they are safe. However, during the pandemic, the burden of regulation has also been apparent. Delays caused by regulation, or things never done because of regulation, cost lives as well as save lives. How can we have strong regulation that is focussed, not off-target, efficient, and effective without detracting too much from achieving the overall objectives? It is an area that really does need far more study – and the wisdom of Solomon.
Finally, one thing I am really pleased about was our decision to use oral, rather than intravenous, almitrine for the trial. This lower tech approach could be used in low- and middle-income countries which maybe have no, or insufficient, infrastructure to provide oxygen. It really does have the potential to extend the runway to recovery for many people.
Read more about the project on the LifeArc website - "Clinical trials testing almitrine in COVID-19 patients at three UK hospitals."