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‘Death threats were flying around after we stopped hydroxychloroquine trials’

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Eleanor Philpotts talks to Professor Chris Butler, GP and lead of the PRINCIPLE trial researching Covid treatments in primary care

The PRINCIPLE trial is primary care-based research on the effect of different treatments for Covid, led by the University of Oxford. It is different to many other trials in that it is consistently evolving the treatment it is trialling – famously, it was evaluating hydroxychloroquine until the World Health Organization put a halt to all studies of the drug. Now, it is looking into the effect of azithromycin and doxycycline.

It also differs from other trials in that it is completely open to any patient who fits the criteria – they don’t need to be attached to a GP practice or hospital involved in the trial.

Professor Chris Butler is leading the research, and following the 1,000th patient registering for the trial, he spoke to Pulse about the importance of primary care input in finding treatments for Covid.  

Pulse: The trial’s been going on since June, so what do you hope the treatments you’re trialling will specifically achieve?

Chris Butler: We’re trying to find treatments that are safe and suitable for use in the community, that help people recover quicker, prevent the need for hospitalisation, and could be scaled-up quickly so that large numbers of people could get them.

Do you feel there should be more emphasis on different forms of therapies, as well as a vaccine?

There are two points on this. The first is that, along with everyone else on the planet, I’m hoping that we make a vaccine that works perfectly very soon. But let’s face facts, that’s unlikely.

If we do get a vaccine that’s effective, it’s unlikely to be completely effective. It’s a very cunning virus. People have been trying to make a coronavirus vaccine for decades and we haven’t succeeded yet. And even with flu, although we immunise people every year, the average effect of that is only 50%.

So, vaccine trials are critical, but so are therapeutic or treatment trials of acute illness. To get on top of this, we’ve got to help people by identifying treatments that get them better quicker, because if they recover quicker, they’re going to spread the virus around less and stay out of hospital.

The second point is that huge amounts of money and effort have gone into research in hospitals when people are already quite sick, and they’re amazing trials. But almost no research been done in the community. That is partly why this PRINCIPLE trial is so important – because it gives everybody in the UK, regardless of where they are or which practice they’re registered at, the chance to participate in the research.

Do you think you would expand the criteria to take part?

Obviously we don’t want to be giving people medication – the powerful medicine that does potentially have side effects – if they are very low risk and going to get better whatever we do. So we have suggested this trial on the higher risk population.

But even once we’ve beaten Covid, there are still other respiratory viruses out there that we will need to research and find better treatments for. We’re hoping to build on the innovation and investment in the PRINCIPLE trial, to establish a standing infrastructure platform research trial for primary care for the UK beyond Covid.

Is it fair to say you’re sort of seeing how things go in terms of getting new participants?

Yes, it’s a very flexible and innovative trial design, a ‘platform trial’. Traditionally, you would have one drug in one trial, and you would randomise people to either get the drug or not, and when you reached your sample size, you would do your analysis. This trial design allows you to analyse the trial as you go along, so that when there’s evidence either for effectiveness or for futility of the particular treatment, you could put that as the standard of care within the trial and compare the new things to it or just replace it if it is ineffective.

So, for example, hydroxychloroquine was our first drug that we had in the trial, but that arm got suspended and we replaced that with, azithromycin. And now we have doxycycline and we’re hoping to add in new drugs  as well as we go along. When you add in new drugs, you need more patients.

We started out focusing on existing, well-tried and tested drugs that could be repurposed for the purpose of Covid. Hydroxychloroquine was one but so was steroids, and the RECOVERY trial showed that for those who are very sick, steroids will save lives. But I think all of the trials now are moving on to complete the evaluations of existing licensed drugs.

They are bringing in now new, more innovative drugs, that might be more specific to Covid, and we are intending to do that soon. So hopefully it won’t be long before the PRINCIPLE trial has more interventions in it, some of which are a bit more upstream and might be more specific to the infection. We’re hoping to do that within the next couple of weeks. We have to finalise certain things before we can announce that, but the plan is certainly to introduce new treatments as we go along and we’re hoping that will happen quite soon.

What would you say has been the biggest lesson you’ve learned from the PRINCIPLE trial so far?

The most important thing so far has been on learning research methods that are fit for purpose in the world we find ourselves. We started to do the trial in the way we’d always done trials, but patients weren’t present. So we had to adapt by doing this trial almost online, where we take consent online, we follow patients, either by telephone or an online diary, or we courier medication to the patients wherever they are.

Then there is recruiting – taking research to where the patients are, for example incorporating NHS 111 in the recruitment process, with call handlers signposting potentially eligible patients to the trial. That way, people are given the opportunity to contribute to this research wherever they are.

This is the first truly national democratic trial for acute infection of Covid in the UK, if not the world.

And I say the second thing is the way we’ve designed the trial from a methodological statistical point of view – replacing drugs throughout the trial.

We’ve reached 1,000 people randomised and now we will be in the position of doing what we call ‘interim analyses’. Soon, the Data Monitoring and Safety Committee will be looking at the data and deciding what information can be released so we look forward to getting findings from the trial so could start improving care.

Are participants always contacted by their own GP or 111, or can they express interest of their own accord?

We know that it’s critical for a clinician – a trusted clinician – to tell people about the trial while they’re sick with Covid, or they’ve had a positive test.

But the patients themselves – or their family, or anybody in the country – can click onto our website and they will go through a brief streaming questionnaire. If they meet the eligibility criteria there we can take consent, randomise them, get information from their GP just to confirm that they are eligible and get them the study drugs without them having to fill out a single piece of paper and without anybody else being involved.

But we really do see this as the flagship primary care trial. It’s the nurses, doctors, receptionists, practice staff, that know about a patient who’s 50 and over with comorbidities, who has got Covid, saying: ‘Look, you could be in the trial, here’s the link, here’s the telephone number’. That would make all the difference. So general practice has got an incredible role to play in this trial.

What would be your key message to GP practices who might be keen to get involved in the trial, or who might be more generally keen to get involved in the cause, especially if they’ve never participated in clinical research before?

Our top recruiting areas are in areas where Covid is most prevalent, for example, the North, North West. In some places, I would say, research culture isn’t quite as embedded as it could be. And I think many of the doctors and practices are so busy now, they’ve got their backs to the walls, you know, trying to deliver care in the difficult circumstances.

I think some GPs are thinking: ‘Oh research, you know, I’ve done that before, and I’ve pulled out an hour long CRA case report form and it took me forever’. But we’ve got to be contributing to our discipline, generating the evidence to support care the our community, because we can’t be relying on hand-me-down evidence from hospitals.

That important finding about the steroids from the RECOVERY trial showed that, yes, steroids do great for people who are really sick on a ventilator, and actually for the less sick, they could be doing harm. And so we have to do the research in the patients that we’re going to be treating, otherwise we’ll never know.

Antibiotics are being prescribed quite a lot in GP for this illness, and it’s much better to prescribe to the patient in a trial than just giving to them without a trial, because if you don’t do it within a trial, you’ll never know if you’re doing the right thing.

Remembering the swine flu pandemic, we gave Tamiflu out by the bucketload and we didn’t randomise a single patient. So we don’t know if we did the right thing or not. And by just giving people Tamiflu without seeing them, we know we did serious harm, because we missed serious cases of pneumonia and stuff like that.

And we might have killed a few people too, but because we didn’t randomise – it’s a national disgrace that we didn’t randomise anybody in the trial. It would be a tragedy if we gave our treatments without putting anybody into the trials first, because that way we’ll never know if we did more harm than good. History is littered with examples whereby we give drugs out and we think we’re helping people, but when we do the trials we find out that maybe we were actually causing more harm.

Among participating GP practices, all of those involved seem like they’re very much on board with it – is that something you’ve found throughout the course of the trial?

Absolutely, and the GPs are astounded about how easy it is to contribute and just delighted by the support they’ve had by the study team.

Where we randomise the patient and GPs help us check the eligibility, just give us some information about the patient, then they get £50 as well, so there is a little bit of renumeration in recognition of their contribution. But the main thing GPs are telling us is they’re just so grateful to be able to be contributing to research during such an important time for our discipline to be working out better evidence to support care.

What are the main things GPs taking part should know?

It’s their trial to answer questions that face them every day, and it’s really easy to contribute.

RECOVERY is a hospital-based trial that has recruited 14,000 people and that’s amazing. And the way they’ve done that is that every doctor in the hospital dealing with acute illness knows about the trial and sees it as a matter of pride for their hospital and their discipline to contribute and get that patient into the trial – and it’s easy for them to do so.

We need to embed that consciousness on a wider scale within primary care. This is the flagship trial for general practice, and it’s answering the critical questions for our discipline, it’s easy to get people into it, and GPs have a lot of pride in delivering quality care – contributing to this trial will be a hallmark, a badge, of quality of care, for general practice.

And as I say, we just need to embed that consciousness, and the PRINCIPLE trial becomes an automatic thing for practices around the country.

Did you feel that the time after MHRA halted recruitment to the hydroxychloroquine arm dampened participants’ sense of trust, or had you always been expecting something like that to happen?

As soon as we had the instruction to suspend the hydroxychloroquine trial, we did it then and there, and no further people were given hydroxychloroquine. We immediately told the patients who were taking about it.

So we did everything by the book, and perhaps even more so than other trials, we were checking the safety very carefully so that we put nobody on hydroxychloroquine where there was a contrary indication, and we were very thorough about that. I think that generated confidence amongst GPs – we did exactly what we had to do according to the regulator.

I was very surprised at that decision by the MHRA. The decision to suspend that arm of the trial was based on research in hospitalised patients, some of which was highly questionable, and in any case, may not have been that relevant to low-dose, short-duration use in patients with less severe Covid infection managed in the community.

It was a setback for our trial. Because people thought, mistakenly, our trial was about one drug. But it wasn’t, as we’ve already discussed. It’s a perpetual platform trial and many drugs will come and go in this trial.

We got that awareness out there that there were other interventions, that the hydroxychloroquine wasn’t the beginning and end of the story, that we had been very thorough and careful.

We’ve got a lot of experience in the PRINCIPLE trial now about early treatment of hydroxychloroquine. Yes we will be underpowered, but we will be able to contribute to meta analyses about that, and we’re already working, for example, with the Bill and Melinda Gates Foundation, who are bringing together data from trials that were stopped early around the world.

Ours wasn’t the only trial that was stopped early, and many in the US and Germany were stopped too. And we’re going to use all that data – hopefully pool it – and then share that data. So just to reassure your readers that that information is not lost, it will be useful, that evidence will be brought to bear on treatment of Covid-19, so it’s not wasted – that evidence won’t just sit on the hard drive, it’s going to be out there informing care, one way or the other.

I don’t know what the answer will be of that meta-analysis, but if it proves that hydroxychloroquine is not the right treatment, proving the negative is very important. And just because the hospital studies have proven that hydroxychloroquine is not beneficial, it’s a different question that we had in primary care. Because ours was about early treatment in the community, and yes, it’s a bit of a heavy lift for a drug like hydroxychloroquine to start saving lives when people are on death’s door. So it’s not lost, it’s not wasted.

The UK and the pharmaceutical companies have been absolutely brilliant. In the same way the UK Government and the chief medical officers and Department of Health and Social Care said: ‘Do not prescribe hydroxychloroquine or another drug’ for Covid outside of the clinical trial, and that was exactly the right call.

I mean, people were yelling that we were killing people, and death threats were flying around but that was exactly the right call. And in the same spirit, the vaccine manufacturers and trialists and Government have been saying: ‘We will not roll out this stuff until we have shown that it works and doesn’t harm people.’ That’s exactly the way clinical science should be operating. We will get vigorous answers around vaccines coming up quite soon.

Might Long Covid be something you’d look into doing a trial in in the future, or is it an area you’ve been considering much at this stage?

This is hugely important for general practice because it’s in primary care where this Long Covid is going to be managed. Our trial is very closely linked to the RCGP’s Research Surveillance Centre, and we are using that huge resource where about 1,500 practices are contributing the data to describe the issue better.

This virus is eight months old as far as we are concerned, and we don’t understand Long Covid well enough. But we are starting research and once we understand it better, we can be working out interventions that can be beneficial. Then using what we’ve learnt from the PRINCIPLE trial of acute treatment into evaluations of treatment for Long Covid is exactly the kind of research that I’d like to be doing.

I started writing the protocol for the trial in mid March. I think we recruited our first patient into the trial on 2 April, which was an amazing achievement really. I was sick with Covid during that process. I’ve recovered completely, but as it turns out, people in my family are still getting over it and are still getting recurrence of symptoms and poleaxed for a couple of days. This problem of Long Covid is very close to my family. I think we’re just beginning to understand how big a problem it is and it’s going to be, and it’s not going to go away.

People need to recognise that it’s in primary care where the research is really needing to be prioritised, because more people are getting Covid but fewer people are being admitted to hospital – it’s in primary care  where Long Covid is going to be. And we need much more research and proper investment.

I’m sorry to say that we haven’t received the urgent priority that we should – that I’d hope for. That said, the MHRA has been amazing.

Does Covid change the immune system long-term, or is it just post-viral fatigue?

This is something that’s so poorly understood, we’re only just really beginning to describe the thing, let alone understand the immunology of it, what the risk factors, what we can do about it, it’s a mystery.

While on the one hand, this is one of the simplest viruses ever, it is clearly one of the most complex and mysterious. And what it does to us – I think it’s going to be like some of these infections that affect very single organ.

When I was at medical school, if ever something was weird and wonderful, and you couldn’t put your finger on it, we were trained to think ‘syphilis and TB’. Syphilis and TB can affect every bit of your body in a strange and unpredictable way. Now, I think that Covid is going to be like this, where we’re going to find it affecting in weird and wonderful ways many different organ systems, and the future will tell us about that through careful observation and research that has to be predominantly primary care based.



Please note, only GPs are permitted to add comments to articles

John Glasspool 12 November, 2020 6:56 pm

A lot of this is music to my ears. Really early on there was a very small Chinese trial that seemed to show a halving of the time of viral shedding for patients on HCQ. It’s another example of “Hospital clever people are cleverer than GPs”, so the drug gets dumped.
Well, as to death threats: what if it can be shown that EARLY intervention with HCQ is associated with better outcomes? How many thousands of people may have died for the lack of a few pence worth of HCQ? I’d take it if I had Sx and a positive test. (And yes, I bought some in March.)

Purely anecdotally, I have a relative in HK, who says people there were talking about a mystery illness in Wuhan in JULY 2019.