Open access article
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Source: Courtesy of Richard Hobbs
The ‘Platform Randomised Trial of Interventions Against COVID-19 in Older People’ (PRINCIPLE) study is one of several nationally prioritised COVID-19 clinical trials in the UK and is the first clinical trial of potential COVID-19 treatments to take place in GP practices.
It initially started out evaluating the anti-malarial drug, hydroxychloroquine, but has now added a second arm to investigate the antibiotic, azithromycin.
On 26 May 2020, The Pharmaceutical Journal sat down — virtually — with Richard Hobbs, the co-principal investigator on the PRINCIPLE trial, head of the Nuffield Department of Primary Care Health Sciences and national director of the National Institute for Health Research School for Primary Care Research, to discuss the trial so far.
Since this interview was conducted, the Medicines and Healthcare products Regulatory Agency (MHRA) has instructed all UK clinical trials investigating hydroxychloroquine as a treatment or prophylactic for COVID-19 to stop recruiting further participants. No new participants will be recruited to these trials until further data justifying their continuation have been provided.
What is the PRINCIPLE study and how does it differ from the other COVID-19 treatment trials?
PRINCIPLE is a platform trial, which means it’s been set up with the intention of us adding arms as the trial progresses; enabling us to test more than one intervention.
It’s also a randomised trial. Although it’s not blinded with placebo, it’s randomised against standard care — that is whatever the doctor who is seeing the patient recommends — and the endpoints are blinded to the investigators, so we collect all the endpoints without knowing which group the patient was allocated to.
It’s different from the other studies because it is looking at patients prior to admission to hospital. There are very few international trials of potential interventions against COVID-19 that are outside of hospital, and that’s an important consideration since it’s possible that by the time patients are sick enough to require admission to the hospital, they may respond less well to interventions that might work if used earlier.
How did you organise the trial so quickly?
There was an enormous effort in both writing the protocol and then putting it through all the approvals
It took a huge amount of effort. Shortly after the crisis started, we wound down most of the research in the department and probably about 150 staff have been working on COVID-19 or COVID-19-linked studies or evidence since then.
There was an enormous effort in both writing the protocol and then putting it through all the approvals. Fast-track approvals have been in place in the UK since the start of this and it’s taken a much shorter time to actually get permission to do things, but it was a monumental task.
How are participants recruited?
There are nearly 700 GP practices signed up for the trial across the UK, and they can recruit patients who contact them and have typical symptoms. Over the past month or so we’ve also gone national so patients can contact us directly too, and we then contact their practices to check eligibility and whether it’s safe for them to be included. And there’s also recruitment through NHS 111 and nursing homes as well.
How do you monitor participants throughout the trial?
They keep a diary and fill in case record forms, which are all electronic, and we’re also linking into their clinical record and are capturing endpoint success through that route.
How are the medicines being dispensed?
That’s been a complete nightmare. When we originally designed this at the beginning of March 2020, we were hoping that we would be able to issue prescriptions, as in routine practice, but all the supplies for hydroxychloroquine were elected nationally. This means we have had to arrange for central recruitment and central couriering of both swabs and drug supplies directly to patients; normally within 24, occasionally 48, hours of being randomised.
But this has added massive complexity and cost. We spent most of the time desperately trying to source swabs centrally, so that we can get a participant’s viral status, because we’re recruiting people prior to knowing whether they’ve got COVID-19 or not. We’re working on the principle that as long as 25% of patients with typical COVID-19 symptoms test positive, then the study power will be secure. But, because it’s outside of a hospital setting, it’s been difficult to source swabs, so it’s often taken quite a long time before we get the results back.
How many patients have you recruited so far?
Just under 450. We’re aiming to recruit 3,000 for each arm.
Is that going to be achievable with new cases of COVID-19 starting to reduce?
If we fail because the virus goes away then I’d be a very happy man; unfortunately, I think we will continue to accrue patients.
It probably isn’t going to be achievable in the first wave of COVID-19, although we are continuing to recruit patients. The ‘Randomised Evaluation of COVID-19 Therapy’ (RECOVERY) trial has been remarkable because they’re up to over 10,000 participants now, but in some ways they had an easier task — all trusts were mandated to support the clinical trials and they had a principal investigator at every major hospital in the UK. Theirs is the fastest-recruiting trial in history.
It has been difficult for us, but there will be a second wave as we come out of lockdown, and there will be future waves as well. Plus, we probably won’t get a vaccine anytime soon. We should recruit the numbers we need during 2020. If we fail because the virus goes away then I’d be a very happy man; unfortunately, I think we will continue to accrue patients.
How did you choose which therapies were going to be included in the trial?
Right from the start, there was quite a lot of anecdotal data about drugs that had been used experimentally, in different parts of the world, for severe acute respiratory syndrome and Middle East respiratory syndrome. There were quite a few animal studies and in vitro studies suggesting candidate agents which might be useful.
In terms of the PRINCIPLE trial, not only did there have to be some evidence that the drug might theoretically work — i.e. a potential mechanism that may result in it working — but also it had to be a drug that was on licence and had a good safety profile, because we were using it in the community.
With hydroxychloroquine there had been quite a lot of evidence suggesting it reduced viral replication and shedding, which suggested it might attenuate the degree of infectivity in the individual and the dose of virus that the person got, on the basis that the more virus you get loaded with, potentially, the more likely you are to suffer adverse outcomes.
There is a national group that assesses the interventions that we’re thinking of using, so we come up with a proposal and a scientific rationale, and send that to the national panel. If they agree, we can then get approval through the MHRA to add the arm. Thus far, it’s just been hydroxychloroquine and azithromycin.
How often are you analysing the results to decide when therapies could be dropped from the trial?
There’s a Data and Safety Monitoring Board that meets monthly and they get the data. If there was any extraordinary signal regarding either safety or efficacy, then we would be informed.
How long is it likely to be until you’re able to share some results?
Expect results probably towards the end of 2020, unless there’s a big second wave. Some of the arms for RECOVERY will probably share results in autumn as well — one of their arms is hydroxychloroquine. If they show benefit, then I think it’ll mean we can drop the hydroxychloroquine arm from PRINCIPLE because one would assume that you could start it early. If they don’t show benefit, it doesn’t undermine the use of PRINCIPLE because it may be that the drug needs to be used earlier. [Since this interview was conducted, on 5 June 2020, the RECOVERY trial has stopped enrolling patients to their hydroxychloroquine arm after preliminary results showed the drug had no beneficial effect in patients hospitalised with the virus.]
Are pharmacists involved in the setup or the running of the trial at all?
At the moment, we’ve got special dispensation temporarily from the MHRA for doctors to be doing the labelling of medicines for the trial, and this is being checked by a pharmacist.
The president of the United States has been very vocal about his thoughts on hydroxychloroquine. Are you at all concerned about the press around the drug?
I think the recent controversy may well have affected both doctors and patients in questioning whether it’s safe to use or not
We were worried that people would get hold of hydroxychloroquine, which would make it incredibly difficult to analyse these data, but that has not happened because of the centralisation of drug supply.
Having said that, I think the recent controversy may well have affected both doctors and patients in questioning whether it’s safe to use or not. But to be honest, I think if there was a safety signal, we would have heard about it by now.
What impact has the hydroxychloroquine study published in The Lancet*
had on progress of the PRINCIPLE trial?
All the clinical trials in the UK that were randomising hydroxychloroquine were paused by the MHRA.
I think that the analysis in The
Lancet was potentially quite flawed in some of the ways they analysed the data. It was a large registry study across a number of countries, but there was no analysis by country or by hospital, which is important because in lots of countries they may have only initiated treatment in patients who were more ill — in which case, there would then be an association between use and outcomes.
There was not sufficient detail in the paper to check whether they adequately adjusted for potential confounders, either — the authors themselves said you can’t really judge drug safety on the data that they were using, which you can’t. And therefore, you need randomised control trials, which is why trials like RECOVERY and PRINCIPLE exist.
There was a much better controlled trial in the New England Journal of Medicine, which was very carefully adjusted for confounders and showed no risk.
Having said that, the MHRA’s primary purposes is safety, so I can understand them being cautious.
Having said that, the MHRA’s primary purpose is safety, so I can understand them being cautious. But, what we need is more reliable evidence on these things and hydroxychloroquine is obviously used quite extensively already. It’s probably also worth noting that the dose that we’re using in PRINCIPLE is lower than the doses that were used in the hospitals in the analysis published in The Lancet.
*This study was retracted by The Lancet shortly after this interview was conducted.