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The Trial Talk Podcast explores how our work at the MRC Clinical Trials Unit at UCL is improving health in the UK and worldwide. In this new series, we will hear from world-leading experts about the studies we carry out. We will get inside trials on cancer, infections, and neurodegenerative diseases, explore how public and patient involvement is shaping our studies, and discover new ways to run smarter studies.
00:00:10:20 - 00:00:37:09
Speaker 1 - Charlotte Hartley
Hello and welcome to the Trial Talk podcast. I'm your host, Charlotte Hartley, and I'm a science communication officer at the MRC Clinical Trials Unit at UCL. In this show, we explore the clinical trial landscape by talking to the clinicians and researchers behind the work we do. If you're interested in learning how our research can help improve healthcare in the UK and around the world, this is the podcast for you.
00:00:37:11 - 00:01:04:14
Speaker 1 - Charlotte Hartley
This episode is all about the PediCAP clinical trial, which tested a new treatment strategy for children in Africa who are hospitalized with severe community acquired pneumonia, aiming to bring them home from hospital sooner. We'll talk about why this trial is needed, its use at the innovative ROCI design developed by the MRC CTU at UCL, and then we'll get into the trial results and what they mean for patients and clinicians.
00:01:04:16 - 00:01:20:17
Speaker 1 - Charlotte Hartley
I'm speaking to three members of the PediCAP team. Hilda Mujuru, Julia Bielicki and Michelle Clements.
00:01:20:19 - 00:01:40:06
Speaker 2 - Hilda Mujuru
Thank you. Hi. I'm Hilda Mujuru. I'm a pediatrician at the University of Zimbabwe, Department of Paediatrics. I'm doing research mostly on children with HIV and TB and pneumonia.
00:01:40:08 - 00:01:57:00
Speaker 3 – Julia Bielicki
Hi. I'm Julia Bielick. I'm a pediatrician by training. I'm also a researcher at the Center for Neonatal and Pediatric Infections at St George's. And, I do most of my research around antibiotic trials.
00:01:57:02 –00:02:10:06
Speaker 4 - Michele Clements
Hi, I'm Michele Clements. I am a senior statistician at the MRC Clinical Trials Unit at UCL, and I work on antibiotic trials in newborn babies and children.
00:02:10:08 - 00:02:27:17
Speaker 1 - Charlotte Hartley
Okay, firstly, let's find out a bit more about community acquired pneumonia. So, Hilda, what are the main symptoms of pneumonia? And when you seeing patients in the clinic, how do you know when to categorise it as severe?
00:02:27:19 - 00:02:59:09
Speaker 2 - Hilda Mujuru
So, children with community acquired pneumonia usually present with a cough. And sometimes they've got difficulty breathing, which mum might express is a shortness of breath. And depending on the organism, they might have a hot body. Depending on the age of the child, sometimes they're not feeding well, and sometimes plus or minus vomiting when they cough a lot they can form it, but typically it's a cough.
00:02:59:09 - 00:03:33:15
Speaker 2 - Hilda Mujuru
And difficulty breathing. When they present like that for you to now identify severe pneumonia. These are now children that have not only a cough, but they're also having difficulty breathing. They can have fast breathing with severe, chest in drawing or recessions. They might also have, sinuses, which is like a greyish discoloration of their lips or their hands.
00:03:33:21 - 00:03:38:04
Speaker 2 - Hilda Mujuru
And you identify those as having severe pneumonia.
00:03:38:07 - 00:03:45:20
Speaker 1 - Charlotte Hartley
And when we're thinking about bacterial pneumonia, and what are some of the common types of bacteria that tend to cause it?
00:03:45:23 - 00:04:22:12
Speaker 2 - Hilda Mujuru
I think in our environments, the commonest organism that gives us pneumonia is Streptococcus pneumoniae. That's the one that we see in most of our children. We do get in some children, Staphylococcus aureus. It's also an organism that we see in some of our children, particularly, those who are, immunocompromised. And the commonest cause in our people of being immunocompromised it’s actually malnutrition in terms of pneumonia, though we do have HIV as well. So those would be the common, I think bacterial organisms that we see.
00:04:22:14 - 00:04:32:02
Speaker 1 - Charlotte Hartley
And in sub-Saharan African countries where the PediCAP trial took place, how big of a problem is community acquired pneumonia?
00:04:32:04 - 00:05:04:14
Speaker 2 - Hilda Mujuru
The mortality is, remaining quite high. And, in South Africa, we're talking about like 70,000 live births in Uganda, 8,600 in Zambia, 9,800, Zimbabwe 10,200. So these are very high figures. And I think when you look at, the percentage we know that about, looking at mortality, 18% of deaths in under-fives is due to pneumonia.
00:05:04:16 - 00:05:19:16
Speaker 2 - Hilda Mujuru
And across sub-Saharan Africa or African countries, the range is around from 14 to 18%, of mortality being due to, pneumonia in under-fives.
00:05:19:18 - 00:05:26:16
Speaker 1 - Charlotte Hartley
So, Julia, how is this trend changing and things improving? Are they getting worse? What’s happening?
00:05:26:18 - 00:05:55:12
Speaker 3 – Julia Bielicki
In general, the mortality is from pneumonia is coming down, at least for children. But what we're seeing is that there's, more children accessing hospital. And what this has been interpreted as is that actually probably more of those children who have severe pneumonia are actually managing to reach a healthcare facility and, and be treated there.
00:05:55:12 - 00:06:22:02
Speaker 3 – Julia Bielicki
So this is part of the reason why, despite mortality coming down, because children no longer remain in the community and then are at risk of, of dying because then they're not receiving any treatment or any treatment enough to help them. You know, we are seeing, a trend of increasing admissions from pneumonia.
00:06:22:02 - 00:06:28:09
Speaker 3 – Julia Bielicki
And so this makes the question that PediCAP set out to answer, quite important.
00:06:28:11 - 00:06:47:05
Speaker 1 - Charlotte Hartley
So PediCAP set out to answer whether a new treatment strategy for children with severe community acquired pneumonia is as effective as the current treatment strategy that is recommended by the World Health Organization. So could we talk a bit about the current recommendations first?
00:06:47:07 - 00:07:22:11
Speaker 2 - Hilda Mujuru
I can start off you can add Julia. We know that WHO. at the moment, the recommendation is for intravenous antibiotics for five days. And we usually use, ampicillin and gentamicin or Crispin and gentamicin and those are given, in hospital for five days. And that's the current, recommendation. And that's what I think for most of our countries, we have been using following WHO guidelines.
00:07:22:13 - 00:08:02:21
Speaker 3 – Julia Bielicki
The problem is that actually there's no data to justify that approach, I think. And more recently, WHO. has been reviewing all of the trial evidence that exists in this space. For example, also in the run up to the, to, to the aware Antibiotic Handbook, and you can just see that we don't actually know for sure that, treating children with severe pneumonia for five days in hospital with something that we give intravenously is the best way of treating them.
00:08:02:23 - 00:08:28:15
Speaker 3 – Julia Bielicki
And I think the problem comes when perhaps it isn't, which we suspected from data that is available from high income, settings. It's quite limited, but there was actually some suggestion that you could treat children for a shorter period of time. You could treat adults for a shorter period of time. You could actually treat them by switching them to oral medication.
00:08:28:17 - 00:09:03:21
Speaker 3 – Julia Bielicki
So, if any of these two strategies would be found to be effective also for children with severe pneumonia in Africa, then it would be a big relief, to patients, their families and the entire health care system because having to basically commit to a hospital stay of five days brings lots of problems. So, it costs a lot of money, it costs a lot of money indirectly also to families, even if the health care costs themselves are covered because they have losses in earnings.
00:09:03:23 - 00:09:26:21
Speaker 3 – Julia Bielicki
For the caregiver who is staying with the child in the hospital, it's expensive to the health care system. It can be very inequitable. So, it can affect those, families who are most disadvantaged in the worst way. And then also, you know, hospitals are places that you want to be in when you need to be there.
00:09:26:23 - 00:09:51:03
Speaker 3 – Julia Bielicki
But there are also places where there's lots of other sick people. And so that, often, a place where you could pick up another infection or you could actually, end up carrying a germ that is more typical of the hospital environment and have more difficult to treat infections in the future. So, when you don't need to be in hospital, you definitely want to be able to go home as soon as possible.
00:09:51:03 - 00:10:05:01
Speaker 3 – Julia Bielicki
And so that is why a very fixed recommendation that isn’t strongly grounded in evidence to support it for a fixed hospital-based treatment course is not ideal.
00:10:05:03 - 00:10:18:10
Speaker 1 - Charlotte Hartley
So, what about the new treatment strategy that you tested in PediCAP? Michelle, you worked on the design of the PediCAP trials. So can you explain a bit more about what the trial was aiming to do?
00:10:18:12 - 00:10:51:22
Speaker 4 – Michelle Clements
Yes. PediCAP was an open label parallel group factorial randomised trial, and it recruited children hospitalized with severe community acquired pneumonia in 13 different African district and tertiary hospitals. And this was in Uganda, Zambia, Zimbabwe, Mozambique and South Africa. So, in PediCAP, we were wanting to look at three different questions. We were first wanting to ask whether so-called step down from IV to oral antibiotics, when the child is well enough.
00:10:51:22 - 00:11:10:16
Speaker 4 – Michelle Clements
So that means the child stops the IV antibiotics and moves on to oral antibiotics, whether that is safe compared to the World Health Organization, who recommended five days of intravenous antibiotics. And by safe in technical terms, we mean non-inferiority.
00:11:10:18 - 00:11:22:09
Speaker 1 - Charlotte Hartley
So, non-inferiority essentially means as good as or not worse than by a given pre-specified amount.
00:11:22:11 - 00:11:49:24
Speaker 4 – Michelle Clementa
Yes. So, what it means is it's, very unlikely that having the IV antibiotics and then having the oral antibiotics is going to be better than just staying on IV antibiotics. But we could think that they could be comparable. And it's very difficult in statistical terms to show that two things are very exactly, exactly the same. But what we can show instead is that we're very confident that it's unlikely to be appreciably worse.
00:11:50:01 - 00:12:14:09
Speaker 4 – Michelle Clements
And the appreciably worse is something that you have to decide before, and the amount that you say appreciably worse is called the non-inferiority margin. And you're running a non-inferiority trial in this instance. So secondly, we were comparing two different oral stepdown drugs. There was amoxicillin and then there was also amoxicillin/clavulanate sometimes known as co-amoxiclav.
00:12:14:11 - 00:12:45:24
Speaker 4 – Michelle Clements
And we were wanting to see if the rate of cure was better with amoxicillin/clavulanate. So, superior in technical terms. And then the third objective was to ask if the optimal total antibiotic treatment duration, so that's the amount of antibiotic treatment they have, including the initial IV and then the oral stepdown. What's the optimal duration that gives us good rates of clinical cure, while minimizing length of hospital stay?
00:12:46:01 - 00:12:54:04
Speaker 1 - Charlotte Hartley
Could you tell me a bit more about the characteristics of the children who were included in the trial?
00:12:54:06 - 00:13:32:23
Speaker 4 – Michelle Clements
Children were between two months and six years. And they were had to be admitted to hospital. So, it's quite a sick population with severe pneumonia. And, they had to be treated with the WHO recommended injectable regimen. And as part of the trial, we stipulated that they had to have received less than 24 hours of antibiotics. So, it's not feasible to bring children in and then not treat them while we try and randomised to them to the trial. So, they're allowed to be treated, before the randomised to the trial, but they're only for a maximum of 24 hours.
00:13:33:00 - 00:13:56:14
Speaker 4 – Michelle Clements
And we also stipulated, we used CRP test. So that's C-reactive protein. And that's indicative of a bacterial infection. And we use CRP tests in order to remove some of those children that are most likely to have the viral infection, so they wouldn't benefit from antibiotics.
00:13:56:16 - 00:14:31:17
Speaker 1 - Charlotte Hartley
And so picking up, one of those questions you mentioned before, the what is the optimal duration of total antibiotic treatment? That's quite an important point because duration is continuous. And obviously you can't test every single possible option. So, it can be tricky to know which durations to choose to test within the trial. So, in PediCAP, you used a new clinical trial design called ROCI, which stands for Response Over Continuous Intervention.
00:14:31:19 - 00:14:36:18
Speaker 1 - Charlotte Hartley
How does the ROCI design work to overcome this problem?
00:14:36:20 - 00:15:12:04
Speaker 4 – Michelle Clements
So, Response Over Continuous Intervention is a new design that has been developed in the MRC CTU, led by Matteo Quartagno. And what this differs from traditional design. So in traditional designs, if you're wanting to reduce the duration of antibiotic therapy so that the child is just getting the minimum they need to make themselves better, you could pick your normal antibiotic duration and then you pick another shorter duration, and then you have a look to see whether the shorter duration is noninferior.
00:15:12:06 - 00:15:52:24
Speaker 4 – Michelle Clements
And this picking of another duration is a kind of cross your fingers and hope that you've found something that is truly noninferior. But an alternative approach, which is what we've done is to measure different durations. And so, we had eight, seven, six, five, and four days of total antibiotics. And then instead of just comparing two durations, maybe the eight and the four, then what you can do is fit a line between all of these different durations. So, that in technical terms, that's a continuous response because we've got the whole range of the numbers.
00:15:53:01 - 00:16:09:13
Speaker 4 – Michelle Clements
And then so then you're not putting all of your eggs into one basket, as it were, of picking the duration that you hope. If seven turns out to be the minimum that children need, then we will use that. But it four turns out to be the minimum, then we would recommend that as all.
00:16:09:15 - 00:16:19:21
Speaker 1 - Charlotte Hartley
And PediCAP was actually the first clinical trial to use the ROCI design. So did this come with any additional challenges?
00:16:19:23 - 00:16:49:22
Speaker 3 – Julia Bielicki
Of course, you know, doing something for the first time is also a risk because you are not sure that everyone will understand how to implement this kind of trial. And this is a really big shout out to our sites, who all were quite convinced that this was the right design to address the question that we were trying to answer, and really and endorsed that and went with it.
00:16:49:22 - 00:17:14:02
Speaker 3 – Julia Bielicki
And we could we could actually see and this is, you know, all thanks to Michelle and the CTU team, that they also really did stick very well to that design. So, it is not just that it looked beautiful in theory, but it also worked very well as a design to address that kind of question in practice.
00:17:14:04 - 00:17:35:20
Speaker 1 - Charlotte Hartley
As well as the different durations of treatments. The trial also compared two different oral stepdown antibiotics co-amoxiclav and amoxicillin. But why did you choose these two antibiotics? And why did you think that co-amoxiclav might be the more effective option?
00:17:35:22 - 00:18:07:11
Speaker 3 – Julia Bielicki
So we picked those two antibiotics. Because amoxicillin is what is currently recommended for oral treatment of non-severe pneumonia in the community. And we know that that is an antibiotic that works very well for Pneumococcus also in places where Pneumococcus maybe has some resistance to penicillins, of which amoxicillin is one because you can give amoxicillin in quite a high dose, and it's very well tolerated, and then it can overcome that resistance.
00:18:07:11 - 00:18:44:13
Speaker 3 – Julia Bielicki
So it's, it's it's an antibiotic we know very well. And it's been used very successfully for treatment of, respiratory tract infections, including pneumonia in the past. And the reason we wanted to compare it to co-amoxiclav. And we thought that maybe co-amoxiclav might be better is because when we were preparing PediCAP, we actually did so in, a time when we could see that increasingly children in in Africa and also in most other regions of the world were being vaccinated against pneumococcus.
00:18:44:13 - 00:19:14:23
Speaker 3 – Julia Bielicki
So this Streptococcus pneumoniae and there were lots of voices who were saying, well, actually, going forward, we believe that other bacteria will become more important. And that has implications for how you treat these children, right? And amoxicillin isn't quite as good at treating a lot of a lot of, Staphylococcus aureus isolates that are circulating in the community as co-amoxiclav is.
00:19:15:00 - 00:19:25:03
Speaker 3 – Julia Bielicki
So this is where you would potentially expect if that was actually something that was true for co-amoxiclav to work better.
00:19:25:05 - 00:19:44:20
Speaker 1 - Charlotte Hartley
And one important element of the oral stepdown strategy was that children weren't stepped down until a healthcare professional had confirmed that their condition was improving. So as a pediatrician, who works in these settings, Hilda, can you explain why this was important?
00:19:44:22 - 00:20:11:24
Speaker 2 - Hilda Mujuru
Yeah, thank you very much for that important question. These are very sick children, and it was very important to make sure that they are well enough to take oral antibiotics. And this is mostly to minimise the risk to the children, risk of death, and also to be very sure that we also, make sure the children are safe.
00:20:12:01 - 00:20:47:03
Speaker 2 - Hilda Mujuru
But over and above that, it would also be important in what we found was that it really brought confidence in the parents and in the healthcare workers, because if you didn't make sure the child was safe, then they would not continue in the trial. They would withdraw, and it would have been very difficult to continue with this study. And also that would have impacted, obviously, the outcomes that we were looking at, if we were not sure that step down was correct and we stepped down, children were not ready.
00:20:47:05 - 00:21:04:22
Speaker 2 - Hilda Mujuru
It meant that it would also impact our outcomes. So, for these reasons, I think it was very important for the healthcare workers to be sure that the children were now ready and could take drugs orally, and then they would be stripped down to the oral drugs.
00:21:04:24 - 00:21:13:23
Speaker 1 - Charlotte Hartley
Great. So, we've talked a lot about the design of PediCAP. But now, Michelle, could you tell us what did the trial find?
00:21:14:00 - 00:21:55:12
Speaker 4 – Michelle Clements
So, in the three different aspects that we were looking at in PediCAP, first of all, assessing whether oral step down that was safe, we found that moving from injectable to oral antibiotic treatment, when the children are showing clinical improvement, is comparable to staying on the injectable antibiotics for the full five days, as currently recommended by WHO. And then secondly, comparing stepping down to oral amoxicillin to oral co-amoxiclav, we found no evidence whatsoever that oral co-amoxiclav was better than oral amoxicillin.
00:21:55:14 - 00:22:18:24
Speaker 4 – Michelle Clements
And then thirdly, and how long to treat children? We found that children who were moved to oral antibiotics and treated for 4 to 5 days in total did no worse than the children who were treated for up to eight days in total. So, that shorter duration was shown to be noninferior to the longer duration of antibiotics.
00:22:19:04 - 00:22:25:03
Speaker 1 - Charlotte Hartley
And as a trial team, were you expecting these results or did anything in there surprise you?
00:22:25:05 - 00:22:51:01
Speaker 2 - Hilda Mujuru
I think we were all very convinced that co-amoxiclav was going to be better than amoxicillin. And everyone was ready for it actually, and everyone was already planning on how to afford co-amoxiclav, etc. so it was a surprise to us that co-amoxiclav and amoxicillin performed equally or one was not inferior to the at the
00:22:51:03 - 00:23:09:05
Speaker 2 - Hilda Mujuru
As for the total duration, it was not too much of a big surprise because it was almost close to the duration that we already use, which is five days. So, 4 or 5 days was not a big surprise. But the drugs we're a big surprise we really thought co-amoxiclav was superior.
00:23:09:07 - 00:23:27:22
Speaker 1 - Charlotte Hartley
So PediCAP found that amoxicillin and co-amoxiclav were essentially equally effective. But when choosing an oral stepdown antibiotic, amoxicillin may actually be the better option. So, Julia, can you explain why this is so?
00:23:27:22 - 00:23:50:15
Speaker 3 – Julia Bielicki
It's not it's not medically speaking the better choice. They are just very similar. But it is the better choice I think from a policy perspective, because, amoxicillin is a is a drug that, as I said before, you know, we know very well everywhere in the world, clinicians everywhere in the world use amoxicillin to, to treat children with, with pneumonia already.
00:23:50:16 - 00:24:36:00
Speaker 3 – Julia Bielicki
So it's, widely accessible and available and it's, it's, quite affordable. That's a very key difference to co-amoxiclav, which is, generally more expensive than amoxicillin. So I think it's, it's very, positive that we see I mean, we see what we see in a trial, but it's very positive that actually we can take an antibiotic that we know very well and reassure everyone to say yes, even though these vaccination rates have changed, and maybe you are seeing more severe cases actually coming to your hospital, so you might experience some uncertainty as to how to manage them.
00:24:36:00 - 00:24:42:20
Speaker 3 – Julia Bielicki
You can still use this this antibiotic that you know very well to treat those children also.
00:24:42:22 - 00:25:04:00
Speaker 1 - Charlotte Hartley
So now, thanks to the PediCAP trial, we know that stepdown with oral amoxicillin is a safe and effective treatment strategy and that be sure to treatment durations are usually enough. So, what does this mean for clinicians in sub-Saharan Africa who are treating children with community acquired pneumonia?
00:25:04:02 - 00:25:28:03
Speaker 2 - Hilda Mujuru
This was really good news for us I must say, because, firstly, we know that, we now have evidence that what we were doing is not far from what is correct because we used to discharge them earlier than the five days and use amoxicillin with no evidence. Now the evidence is there. So I think that was a very good thing.
00:25:28:05 - 00:25:50:19
Speaker 2 - Hilda Mujuru
And the second good thing is that amoxicillin, like what Julia says, is affordable, relatively affordable, and it's already there in most of our health care centers. So, people are happy that we are not going to start moving from what we know to a new drug. We are also happy that it's affordable. It's something that falls within what we can afford.
00:25:50:19 - 00:26:13:20
Speaker 2 - Hilda Mujuru
But what is also nice is that now it's confirmed that early discharge is relatively safe. If the step down was properly, and then after assessing that the child is, well, you step down, people can go home early and mothers can continue with their life while the child is at home. So, it's also a decongest the hospitals. Our hospitals are relatively busy.
00:26:13:20 - 00:26:25:12
Speaker 2 - Hilda Mujuru
So if we can send children home early, we know that it's safe and it works, then it is good for us. So it is good positives for both the health systems and the parents.
00:26:25:14 - 00:26:34:21
Speaker 1 - Charlotte Hartley
And can you apply these results universally? Or were there any groups that weren't included in the trial. and so maybe were a bit less sure?
00:26:34:23 - 00:27:02:11
Speaker 2 - Hilda Mujuru
In this study we know that we were excluding children who had been on antibiotics before. And most of our HIV infected children are on co-trimoxazoles or prophylaxis. So just by being on co-trimoxazoles they were mostly excluded, except for the very few with new diagnosis. So, we know that HIV infected children were not well represented.
00:27:02:13 - 00:27:24:16
Speaker 2 - Hilda Mujuru
And then our, malnourished children, which is another very important group. It's children who came in with severe pneumonia. We're not well represented as well in this cohort. So, we know that for, the rest of the children, these results apply, but we can't generalise them to those populations.
00:27:24:18 - 00:27:29:11
Speaker 1 - Charlotte Hartley
Great. And finally, what are the next steps for this research?
00:27:29:13 - 00:28:03:11
Speaker 3 – Julia Bielicki
So there's a few, ongoing, data collection activities within PediCAP, which is actually a larger project than just, this particular trial. So we're also looking at some pharmacokinetic questions. We are looking at this question of do children actually acquire carriage of, of difficult to treat bacteria. So not making them sick, but while they're in hospital and they're exposed to the environment, do they do they acquire these bacteria.
00:28:03:11 - 00:28:26:04
Speaker 3 – Julia Bielicki
And is that related to how long they stay in hospital for? So, there's still a few bits to tie up. From, from that, I say this a bit glibly, but that's a lot of work still to be done. Then I think we are, considering how best to communicate the results of the actual trial to relevant stakeholders.
00:28:26:04 - 00:28:52:08
Speaker 3 – Julia Bielicki
And that's a very wide group. In fact, we're very pleased that, we have very engaged local investigators who are all already championing some of the findings locally in the countries that were represented within the trial. So that's, I think, often a very good way to disseminate, research findings, because that's almost like a grassroots movement.
00:28:52:08 - 00:29:23:16
Speaker 3 – Julia Bielicki
If you so want to put it. But we are also thinking about how to share this information with, global policy setting bodies like the World Health Organization. And then inevitably, from every trial, they there come new questions for the next trial. So maybe some of the investigators and the partners, that worked on this particular trial will have an appetite for tackling those in the future.
00:29:23:18 - 00:29:51:03
Speaker 1 - Charlotte Hartley
And that is the end of this episode of Trial Talk. Thank you for listening. We've shared some resources for more information about the PediCAP trial in the podcast description, so please check them out if you want to find out more. And don't forget to follow us on our social media for all the latest updates. We're now on BlueSky at the ACTU, Dot blue Sky Dot social, and we're still on LinkedIn at MRC Clinical Trials Unit at UCL.
00:29:51:05 - 00:29:53:07
Speaker 1 - Charlotte Hartley
Thank you for listening and we'll see you next time.