A British researcher hopes his proposal for a Covid-19 treatment will prove successful during trials in India and Russia – after the idea was cold-shouldered in his home country.
Prof Sir Christopher Edwards suggested that lives were being lost needlessly because of an overly bureaucratic testing system, after he was unable to find a UK-based trial able or willing to test a combination of two drugs, spironolactone and dexamethasone.
On one occasion when his idea was rejected, Sir Christopher, the former vice-chancellor of Newcastle University in the UK, was told it would have taken three months to secure ethics approval to run trials.
"There's something called a global pandemic going on," Sir Christopher, a highly regarded endocrinologist, told The National.
“If you take three months to get ethics approval, I’m afraid a lot of people are going to turn round and say ‘Why, why was this not available earlier? Why was this not trialled earlier?’
“It is highly likely that this is going to be effective. We are effectively going through a process which, certainly in the UK, is incredibly bureaucratic.”
An acronym for Randomised Evaluation of Covid-19 Therapy, Recovery began in March 2020 and is run by the University of Oxford.
The scientific case for testing spironolactone with dexamethasone was considered by an independent panel of experts and they did not consider the data sufficiently compelling to warrant evaluation within Recovery.
What is Recovery?
The world’s largest trial for Covid-19 treatments, it has enrolled more than 34,000 participants at 178 sites. It identified that dexamethasone cuts death rates in people with severe Covid-19 complications, and the drug is now used worldwide.
Recovery also showed that the antimalarial drug hydroxychloroquine – which was hailed as a potential life-saver early on – did not reduce mortality.
The UK’s Recovery trial of Covid-19 treatments was one programme that decided against testing spironolactone with dexamethasone. The latter, a low-cost steroid, is used on its own to treat severely ill coronavirus patients.
“This massive Recovery trial is good in some ways, but very, very cumbersome,” he said.
He said he did not understand why some drugs, such as aspirin, were included in trials.
When Sir Christopher’s daughter-in-law fell ill with Covid-19, she was, on his suggestion, prescribed spironolactone – which he said costs pennies – with dexamethasone. Her condition improved initially, only to deteriorate when the spironolactone ran out and improve again when further supplies were available.
Sir Christopher’s hypothesis is that, in patients where the infection has spread deep into the airways, spironolactone and dexamethasone prevent endothelial cells lining the blood vessels of the lungs from releasing what are known as Weibel-Palade bodies.
These tiny particles contain two types of molecule, von Willebrand factor and Angiopoietin-2. VWF comes out like a spider’s web from the surface of the cells and attracts cells called platelets, causing small clots. These are 10 times as common with Covid-19 as with influenza.
Angiopoietin-2 produces a dramatic increase in the leakiness of blood vessels and results in the accumulation of fluid in the lung that slowly drowns patients by making it difficult for the lungs to provide the oxygen the body needs.
The hope is that, by stopping the release of the Weibel-Palade bodies, the drugs will prevent the major complications that cause death from Covid-19.
“The mechanism I’m hoping to block is a mechanism that’s been used by all coronaviruses,” said Sir Christopher. “It’s not one altered by mutations in the virus.
“If we can stop these two molecules being pushed out of the cell, we can make a fantastic difference.”
Trials of spironolactone and dexamethasone involving hundreds of patients in total are now starting at Maulana Azad Medical College in Delhi, one of India’s top-ranked hospitals, and at Sechenov University hospital in Moscow, with initial results expected within weeks.
Sir Christopher’s proposal was presented to the Recovery trial early in the pandemic by Prof Sir John Bell, regius professor of medicine at the University of Oxford.
Sir John said there was a logic behind the idea and he would not have proposed it had he not thought it “interesting”.
While the Recovery trial had “become more bureaucratic over time”, he said, it had been managed in an “incredibly light-touch way”.
“It’s been a real tour de force for the UK,” he said. “I don’t think there’s any debate about that, and it’s all been done within the NHS [National Health Service], which is even better.”
By contrast, earlier on in the pandemic, he said there was “a lot of flailing around” with scores of trials in the US and UK that failed.
“I can understand why Chris is upset and it’s always bad when you’re outside the tent and no one is listening to you,” he said.
“But there’s a system and the system might not be great, but it’s better than not having a system.”
Combining spironolactone and dexamethasone “seems plausible”, said Prof David Taylor, professor emeritus of pharmaceutical and public health policy at University College London.
“There are many theories which are plausible which don’t turn out to be true,” he said. “We need trials to demonstrate, especially in areas like endocrinology.”
Prof Peter Horby, joint chief investigator of Recovery, said in a statement that the UK had “led the way in its efficient research response to the pandemic”. As well as enrolling patients rapidly, Recovery provided results within 100 days that had “changed global practice”.
“We can add new treatments within one or two weeks,” he said. “The scientific case for testing spironolactone with dexamethasone was considered by an independent panel of experts and they did not consider the data sufficiently compelling to warrant evaluation within Recovery.”
Although Recovery did not include spironolactone, Sir Christopher said a previous trial in Italy indicated that his approach may offer benefits. Patients in hospital in Milan with moderate to severe respiratory failure were given a drug called canrenone, which is also produced by the body when it metabolises spironolactone.
In patients given canrenone, mortality was 13 per cent, compared with 36 per cent for patients on conventional treatment. Only 20 per cent of patients on canrenone had to go on a ventilator, compared with 49 per cent undergoing conventional treatment.
