AZTEC Completes Recruitment29 June 2022
We were delighted to complete recruitment to the AZTEC trial during March 2022.
I have personally been working on the study since moving to Cardiff to undertake my PhD in 2011- that’s over 10 years!
AZTEC (Azithromycin Therapy for Chronic Lung Disease) is looking at whether azithromycin given soon after the birth of a premature baby (<30 weeks of gestation in the case of the trial) can improve respiratory outcomes by the time they are preparing to go home at around 36 weeks equivalent of gestation. For the tiniest of babies, that can be a hospital stay of 10 weeks or more. Sadly, a proportion of babies will not get home and I always give this a special thought when hearing this news. I have been a parent of a very poorly baby on the neonatal unit and I understand the shock, despair, and potentially life-changing impact this can have on a family.
Obviously, this is an emotive topic, and in many ways we are fortunate that neonatal care has improved markedly over the past 30 years such that the majority of babies do survive and ultimately thrive. However, what remains a fundamental is that approximately 67% of the drugs given to children in hospital are not licenced for use or prescribed off-label (licenced for use, but not in children or for the condition being treated)1. In neonatal intensive care, this rises to 90% of drugs2. Therefore, the evidence base is poor leading to large variations in practice between hospitals.
The respiratory system is the last of the organ systems to reach maturity, not being fully prepared for the “outside” world until late in term. In the case of premature babies, the air sacs (alveoli) are poorly developed, and lack surfactant- the substance that helps oxygen dissolve and transfer to the blood vessels efficiently. This causes the airways to collapse, which requires a breathing machine to give support (ventilation), and an increased amount of oxygen is also given to ensure the baby gets enough into their bloodstream. Both ventilation and oxygen (even ambient “room air” oxygen at 21% is toxic to very premature babies) cause inflammation of the lung tissue and eventual damage. Infections, which are unfortunately common, can make thing worse still.
Our research in Cardiff, led by Professor Kotecha, has shown that prematurity is a risk factor for poor respiratory health in childhood with lower lung function, increases in wheezy episodes, airway infections and hospital admissions. Moreover, there is clear evidence that premature birth in general contributes to early development of respiratory symptoms and disease.
Peak lung function is reached in early adulthood. In the graph below, this is represented by “Forced expiratory volume in one second” or “FEV1”- the amount of air which can be forcibly exhaled in a single effort. The blue line represents healthy individuals. The red line represents individuals with a history of premature birth, who do not achieve peak lung function, and therefore may encounter earlier onset of symptoms of chronic obstructive lung disease. The dotted lines represent exposure to factors promoting lung injury, for example tobacco smoke and air pollution3.
When a baby is still requiring help with their breathing as they approach what would have been their 36 week of gestation (term being around 40 weeks), they are often given a diagnosis of Chronic Lung Disease of Prematurity (CLD). CLD is our main outcome of interest in the AZTEC trial and we propose that giving azithromycin may help reduce the burden CLD places on babies, families and the hospitals caring for them. Evidence suggests that CLD (or bronchopulmonary dysplasia, BPD, as in the graph below) reduces lung function, and that the deficit does not improve over time when compared to children who were born at term (represented by the “0” line of FEV1), or children born prematurely without CLD4.
Azithromycin is a “macrolide” antibiotic, and can treat both inflammation and infection. For the AZTEC trial, it is given intravenously for 10 days to half of the babies who entered the study. The other half will have received a placebo (dummy) version of the drug. The intervention must begin within 72 hours of the baby’s birth, since there is strong evidence that starting treatment early can eliminate a bug (called Ureaplasma) that makes lung inflammation worse. You can imagine that deciding to consent to the trial whilst undergoing such a trauma must be very difficult for parents. Notwithstanding, well over 50% of parents approached for AZTEC agreed to participate; I just find that remarkable and is in no small part down to the communication skills of the teams working at the hospitals involved. Moreover, it confirms the adage “it’s OK to ask” about research even in the most difficult circumstances.
It has been a continuing pleasure to work with the 28 neonatal units across the UK- as for north as Dundee, and as far south (west) as Plymouth, who have contributed to enrolling a staggering 799 babies over a period of 36 months. I visited the majority at least once, if not twice, and always received a warm welcome and a brisk discussion about the study. It was a shame that COVID-19 arrived in spring 2020 and everything understandably moved to remote working, and indeed a pause in recruitment for 3 months. Despite the challenges of COVID, everyone was keen to recommence as soon as possible and we experienced only a short delay in comparison to many other studies- further testament to the engagement and commitment of the hospitals involved (see www.aztec-trial.uk/index.php/recruitment/ for a full list).
Queen Alexandra Hospital, Portsmouth, took the plaudits as the highest recruiter to the study with 117 babies. An incredible achievement. It’s worth contextualising that further… that’s up to 1170 doses of the study drug prepared by a nurse looking after the baby at that particular time it was needed to be given. When you scale that up to every baby and every centre (up to 8000!), and consider that each nurse needs to be appropriately trained, it gives you an idea of what has been taken on by the local study teams. Incredible! We need to mention also that many other hospitals have helped look after AZTEC babies and continued to collect data when they have moved to be closer to home, or for further specialist care. This is not a glamourous role, but a crucial one to ensure we know the study outcomes for each and every baby. Their support it much appreciated.
Now the trial has completed enrolment, we are busy working to collect the remainder of the study data before we work on preparing the final dataset ready for analysis. We’re of course excited to know the results, which regardless of the outcome will be impactful on how treatment for babies at risk of developing CLD is managed. Moreover, we’re hopeful that with the established network of Investigators throughout the UK, we can continue to work together on other possible studies aimed at improving the respiratory health of this particularly vulnerable group of patients.
The Centre for Trials Research is a UKCRC-registered clinical trials unit. It is publicly-funded to enable applied research that informs policy in health and social care in Wales and the UK, and is currently running studies across Wales, the UK and internationally. The Centre is funded through Welsh government by Health and Care Research Wales, and Cancer Research UK.