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* Study protocol: azithromycin therapy for chronic lung disease of prematurity
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prevention of chronic lung disease of prematurity in preterm infants
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Respiratory medicine
Protocol
Study protocol: azithromycin therapy for chronic lung disease of prematurity
(AZTEC) - a randomised, placebo-controlled trial of azithromycin for the
prevention of chronic lung disease of prematurity in preterm infants
1. John Lowe1,
2. David Gillespie1,
3. Marie Hubbard2,
4. Lei Zhang3,
5. Nigel Kirby1,
6. Timothy Pickles1,
7. Emma Thomas-Jones1,
8. Mark A Turner4,
9. Nigel Klein5,
10. Julian R Marchesi6,
11. Kerenza Hood1,
12. Janet Berrington7,
13. http://orcid.org/0000-0003-3535-7627Sailesh Kotecha3
1. 1Centre for Trials Research, College of Biomedical and Life Sciences,
Cardiff University, Cardiff, UK
2. 2Neonatal Intensive Care Unit, University Hospitals of Leicester NHS Trust,
Leicester, Leicester, UK
3. 3Department of Child Health, School of Medicine, Cardiff University,
Cardiff, United Kingdom
4. 4Institute of Translational Medicine, University of Liverpool, Liverpool,
United Kingdom
5. 5GOS Institute of Child Health, University College London, London, London,
UK
6. 6School of Biosciences, Cardiff University, Cardiff, UK
7. 7Neonatal Intensive Care Unit, Newcastle Upon Tyne Hospitals NHS Foundation
Trust, Newcastle Upon Tyne, UK
1. Correspondence to Professor Sailesh Kotecha; KotechaS@cardiff.ac.uk
ABSTRACT
Introduction Chronic lung disease of prematurity (CLD), also known as
bronchopulmonary dysplasia (BPD), is a cause of significant respiratory
morbidity in childhood and beyond. Coupled with lung immaturity, infections
(especially by Ureaplasma spp) are implicated in the pathogenesis of CLD through
promotion of pulmonary inflammation. Azithromycin, which is a highly effective
against Ureaplasma spp also has potent anti-inflammatory properties. Thus,
azithromycin therapy may improve respiratory outcomes by targeting infective and
inflammatory pathways. Previous trials using macrolides have not been
sufficiently powered to definitively assess CLD rates. To address this, the
azithromycin therapy for chronic lung disease of prematurity (AZTEC) trial aims
to determine if a 10-day early course of intravenous azithromycin improves rates
of survival without CLD when compared with placebo with an appropriately powered
study.
Methods and analysis 796 infants born at less than 30 weeks’ gestational age who
require at least 2 hours of continuous respiratory support within the first 72
hours following birth are being enrolled by neonatal units in the UK. They are
being randomised to receive a double-blind, once daily dose of intravenous
azithromycin (20 mg/kg for 3 days, followed by 10 mg/kg for a further 7 days),
or placebo. CLD is being assessed at 36 weeks’ PMA. Whether colonisation with
Ureaplasma spp prior to randomisation modifies the treatment effect of
azithromycin compared with placebo will also be investigated. Secondary outcomes
include necrotising enterocolitis, intraventricular/cerebral haemorrhage,
retinopathy of prematurity and nosocomial infections, development of antibiotic
resistance and adverse reactions will be monitored.
Ethics and dissemination Ethics permission has been granted by Wales Research
Ethics Committee 2 (Ref 18/WA/0199), and regulatory permission by the Medicines
and Healthcare Products Regulatory Agency (Clinical Trials Authorisation
reference 21323/0050/001–0001). The study is registered on ISRCTN
(ISRCTN11650227). The study is overseen by an independent Data Monitoring
Committee and an independent Trial Steering Committee. We shall disseminate our
findings via national and international peer-reviewed journals, and conferences.
A summary of the findings will also be posted on the trial website.
* neonatology
* paediatric thoracic medicine
* chronic airways disease
https://creativecommons.org/licenses/by/4.0/
This is an open access article distributed in accordance with the Creative
Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to
copy, redistribute, remix, transform and build upon this work for any purpose,
provided the original work is properly cited, a link to the licence is given,
and indication of whether changes were made.
See: https://creativecommons.org/licenses/by/4.0/.
https://doi.org/10.1136/bmjopen-2020-041528
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* neonatology
* paediatric thoracic medicine
* chronic airways disease
STRENGTHS AND LIMITATIONS OF THIS STUDY
* This is a randomised, double-blind, placebo-controlled trial assessing an
important outcome, and using an intervention which could be readily
implemented in clinical practice.
* If the assumptions underlying the sample size calculation are valid, this
study will be appropriately powered for the primary outcome.
* The study will also help address the role of pulmonary Ureaplasma spp
colonisation in the development of chronic lung disease of prematurity.
* Universal administration of azithromycin may alter antibiotic resistance
patterns, which are also being investigated in this study.
* Further work will be required to investigate the mechanistic action of
azithromycin, including on the lung and gut microbiota.
INTRODUCTION
Chronic lung disease of prematurity (CLD), also known as bronchopulmonary
dysplasia (BPD), is a major cause of neonatal death in infants born prematurely.
It is clear that survivors of CLD have adverse respiratory outcomes in childhood
and beyond.1–3
Despite the advances in neonatal care, rates of CLD have not markedly changed.
This is largely because of the survival of the most immature infants born at the
limits viability (22 to 23 weeks’ gestation), which means that the proportion of
preterm infants born at 28 weeks or less of gestation has increased over the
last 30 years.4 Consequently, the etiological definition of CLD was modified to
represent the structural immaturity of the lungs which are in the
canalicular/saccular stages of development.5 6 The pathophysiology is complex
and results from continual lung injury caused by inflammatory processes coupled
with repair/remodelling and resultant fibrosis.7 In contrast, the historical
picture of CLD was largely characterised by parenchymal tissue damage caused by
volutrauma, barotrauma and by high levels of oxygen required to sustain life.8
Infections, both antenatal (eg, chorioamnionitis) and nosocomial, contribute to
a cytokine-mediated inflammatory cascade which peaks between 7 to 10 days of
life.9 10 Ureaplasma spp (class Mollicutes) are the smallest free living
organisms and have long been implicated in the pathogenesis of CLD.11 These
commensal bacteria form part of the normal vaginal bacteria microbiota, and thus
are readily transmitted to the uterus via the cervix or acquired during vaginal
delivery. Lacking a cell wall, they are readily transferred to the lung where
they colonise the respiratory mucosa and directly or, in conjunction with
aforementioned iatrogenic factors, indirectly promote inflammation largely
through recruitment of neutrophils to the lung. Our recent systematic review and
meta-analysis reported that Ureaplasma spp colonisation was strongly associated
with diagnosis of CLD at 36 weeks’ post-menstrual age (PMA; OR 2.22; 95% CI 1.42
to 3.47) which was largely independent of gestational age when investigated with
meta-regression.12
Current treatments for the prevention of CLD are largely supportive and include
optimising use of early non-invasive respiratory support and preventing
infections. Use of systemic corticosteroids is considered in cases where the
infant is unable to be weaned from invasive ventilation. However, although early
low-dose regimens may be beneficial in a high-risk subpopulation, it is
well-established that higher doses of corticosteroids are associated with
adverse neurodevelopmental outcomes, including cerebral palsy.13
Due to the potential risks associated with use of corticosteroids, other
treatments, or ideally preventive strategies, with improved safety profiles are
urgently required for CLD. An interest in macrolide antibiotics, and the
potential for improving lung outcomes via eradication of Ureaplasma, was
established in the 1990s. However, early trials of erythromycin were
underpowered and did not reduce the incidence or severity of CLD.14 A study
trialling clarithromycin treatment for 10 days reported a reduction in CLD (2.9%
vs 36%) when compared with placebo but importantly only initiated delayed
randomised therapy if the infant was culture-positive for Ureaplasma.15 More
contemporary data exists with azithromycin, which is an important adjunct
therapy for numerous respiratory conditions, including cystic fibrosis and
chronic obstructive pulmonary disease (COPD). Consistent with other macrolides,
azithromycin inhibits bacterial protein synthesis through blinding to the 50S
bacterial ribosomal subunit.16 Moreover, azithromycin is attractive as it also
uniquely exhibits well-characterised immunomodulatory effects through
suppression of nuclear factor-kappaB, decreasing neutrophilic pulmonary
inflammation by limiting the production of pro-inflammatory cytokines such as
interleukin (IL)-6 and IL-8.17 Furthermore, since azithromycin is concentrated
in leukocytes, it may be actively transported and released at the site of
infection.18
Several proof of concept and dose-finding studies have already been completed.
The meta-analysis by Nair and colleagues showed that azithromycin treatment is
associated with a 14% reduction in the combined outcome of CLD/death when
compared with placebo.19 Dose-finding work in respect of Ureaplasma spp
eradication has been undertaken in a series of studies by Viscardi and
colleagues.20–22 Importantly, all previous studies did not note any serious
adverse reactions to azithromycin and add to the existing safety information.23
Antimicrobial resistance among Ureaplasma remains low.24
Given the Nair meta-analyses and lack of adequately powered studies, and given
the reported association of presence of pulmonary inflammation and Ureaplasma
with development of CLD, there is a compelling case for a definitive, adequately
powered study to investigate the effectiveness of azithromycin on reducing rates
of CLD in preterm infants. The azithromycin therapy for chronic lung disease of
prematurity (AZTEC) trial is determining if a 10-day course of intravenous
azithromycin improves rates of survival without CLD at 36 weeks’ PMA when
compared with placebo.
METHODS AND ANALYSIS
PRIMARY OBJECTIVE
The primary objective of the AZTEC trial is to assess the effectiveness of a
10-day course of azithromycin on improving survival without
physiologically-defined CLD in infants born at <30 weeks’ gestational age.
DESIGN
AZTEC is a double-blind, randomised, placebo-controlled trial. The total samples
size is 796 preterm-born infants; each are randomised individually (including
infants from a multiple birth). Follow-up is undertaken at 36 weeks’ PMA to
assess CLD status at 36 weeks’ PMA, with final follow-up a discharge from
hospital.
SETTING
Infants are being enrolled from UK tertiary neonatal units, which are designated
Level III (regional neonatal intensive care units), and followed up at their
local hospital if transferred. Infants are identified by the study team on
admission and screened against the inclusion/exclusion criteria.
INCLUSION CRITERIA
1. Gestational age ≤29 weeks+6 days (including infants born as one of a
multiple birth)
2. Infants who receive respiratory support for at least 2 continuous hours’
duration during the first 72 hours of life (intubated, or by non-invasive
mechanical ventilation, including continuous positive airway pressure and
high-flow nasal cannula, or a combination thereof).
3. Presence of an indwelling intravenous line for drug administration.
4. Written informed parental/guardian consent within 72 hours of birth.
5. Anticipating administration of first dose within 72 hours of birth at the
latest (optimally targeting within 24 hours after birth for inborn and 48
hours for outborn infants).
6. Reasonable expectancy to complete 10 days of trial treatment while resident
at the recruiting site.
7. Inborn, or born at site within the recruiting site’s neonatal network where
follow-up will be possible.
8. In the opinion of the local principal investigator (PI), reasonable prospect
of survival past the first 72 hours of life.
EXCLUSION CRITERIA
1. Exposure to another systemic macrolide antibiotic (not maternal)
2. Presence of major surgical or congenital abnormalities (not including patent
ductus arteriosus or patent foramen ovale)
3. Contraindication of azithromycin as specified in the summary of product
characteristics (SPC)
4. Participation in other interventional trial that precludes participation in
AZTEC
TRIAL INTERVENTION
The investigational medicinal product (IMP) is manufactured and QP released by
Saint Mary’s Pharmaceutical Unit (SMPU), Cardiff, UK (MIA(IMP)35929).
The dosing schedule is 20 mg/kg (10 mL/kg) azithromycin for 3 days, followed by
10 mg/kg (5 mL/kg) for 7 days or placebo (10 days total). All doses are given
via intravenous infusion (central or peripheral line) over a period of at least
1 hour. Azithromycin is most likely to have an effect when administered early to
establish a sufficient concentration to eliminate Ureaplasma; a 20 mg/kg dose
for 3 days has recently been shown to be highly effective.22 Treatment for a
further 7 days is justified to treat the rise in pulmonary inflammation which
peaks between 7 and 10 days after birth.9 25 Sites have therefore been asked to
target initiation of trial treatment at the earliest opportunity (and within 72
hours after birth at the latest).
BLINDING
IMP is supplied as a patient pack of 12 blinded vials. The vial blinding method
uses a custom cardboard carton sourced by SMPU, as used previously in a similar
trial design.26 Labelling was performed by SMPU as per a randomisation list
provided by the Centre for Trials Research (CTR), Cardiff University.
ACTIVE ARM
The active arm comprises of commercially-available 500 mg vials of azithromycin
powder for solution for infusion (Aspire Pharma Ltd). As per the summary of
product characteristics (https://www.medicines.org.uk/emc/product/1276/smpc),
4.8 mL sterile water is used to reconstitute the powder to obtain a clear,
colourless solution of 100 mg/mL. The administration concentration of 2 mg/mL is
obtained by withdrawing 1 mL of solution from the vial and adding to 50 mL of an
acceptable diluent.
CONTROL ARM
The placebo arm initially comprised of an empty, sterile vial manufactured to
the same specification as the active product (released under GMP standards) and
provided to SMPU by Aspire Pharma Ltd for blinding and packaging. The same
preparation steps are followed as per the active arm to produce a solution
matching in appearance to the active arm.
OUTCOMES
PRIMARY OUTCOME
The primary outcome is a combined outcome of CLD (moderate-severe) and mortality
at 36 weeks’ PMA (or discharge, if sooner). The definition of CLD severity is
based on consensus criteria,27 table 1.
View this table:
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Table 1
Severity-based criteria for diagnosis of CLD at 36 weeks post-menstrual age
Infants meeting the initial diagnosis of moderate CLD will undergo a
physiological test to confirm their oxygen requirement (figure 1). This
physiological definition, initially developed by Quine and colleagues,28 has
been widely used in clinical trials of neonatal lung disease.29
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Figure 1
Flow diagram for assessment of CLD severity in the AZTEC trial. Modified from
the original
https://www.npeu.ox.ac.uk/downloads/files/baby-oscar/protocol/Baby-OSCAR_Protocol_v6_171116.pdf.
AZTEC, azithromycin therapy for chronic lung disease of prematurity; CLD,
chronic lung disease of prematurity; FIO2, fraction of inspired oxygen.
Secondary outcomes will include
1. Mortality rate by 36 weeks PMA.
2. CLD severity by 36 weeks of age or discharge.
3. Number of days of respiratory support/oxygen dependency.
4. Development of complications of prematurity.
1. Nosocomial infection.
2. Severe intraventricular haemorrhage (grade III/IV).
3. Necrotising enterocolitis (Bell stage II and above).
4. Treatment for retinopathy of prematurity.
5. Treatment for patent ductus arteriosus.
6. Liver and renal function.
5. Serious adverse events/reactions.
6. Resistance to macrolides among microbes isolated from stool samples.
TRIAL PROCEDURES
SITE SELECTION AND TRAINING
Site selection is based on receipt of an expression of interest via the National
Institute for Health Research (NIHR) networks and personal contact directly with
UK Level III neonatal units. A registration questionnaire captures key
information about the site, trial team and any concerns around delivery of the
protocol in the context of routine practice. Where feasible, a preliminary visit
is made by the Trial Manager to present the study background and protocol. The
Trial Management Group approved the centres selected to participate.
Formal initiation visits are held at each site to train the local trial team in
trial-specific procedures. This is supplemented with comprehensive guidance
documents for discrete elements of the study. Specific training in preparation
and administration of the IMP is cascaded down by delegated members of the local
study team to cot-side nurses; this includes a video produced by JL with support
from neonatal nurses and the medical illustration department at Cardiff and Vale
University Health Board (https://youtu.be/Xto6n5qFuYQ). The local clinical
trials pharmacy team are also provided with trial-specific training in IMP
storage, accountability and reconciliation procedures during the initiation
process. All local study teams have undertaken Good Clinical Practice training
commensurate with their roles and responsibilities.
PARTICIPANT RECRUITMENT
The trial design is summarised in figure 2. Recruitment is anticipated to take
30 months, with 25 sites participating (an average of 1.5 infants per site, per
month over the course of recruitment). Progress of the trial can be followed at
www.aztec-trial.uk
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Figure 2
Flow diagram for AZTEC study procedures and follow-up. AZTEC, azithromycin
therapy for chronic lung disease of prematurity; ETA, endotracheal aspirates;
NPA, nasopharyngeal aspirates.
SCREENING AND CONSENT
It is anticipated that all infants who meet the gestational age criteria for the
trial (ie, born <30 weeks’ gestational age) are registered on the anonymised
screening log. Reasons for exclusion, and reasons for not randomising otherwise
eligible infants (eg, declined consent) are being recorded.
A member of the local site team identifies potential eligible preterm babies
antenatally with mothers with threatened preterm labour or babies admitted to
the neonatal unit and the parent(s) receive a verbal description of the trial.
Should the parent(s) express an interest, the ethically-approved information
sheet and consent form are provided (online supplemental file). Eligibility is
confirmed by a medically qualified member of the trial team. Parents are given
sufficient time to read the information and to ask questions during a further
consultation with the study team. If the parents are willing to participate,
they are asked to sign the consent form which is countersigned by the PI or a
delegated member of the study team who engaged the parents in the informed
consent discussion. Consent for use of samples in ancillary studies, and for
future follow-up contact are optional. The right to withdraw from the study at
any time without any affecting their baby’s clinical care will be clearly
communicated.
SUPPLEMENTAL MATERIAL
[bmjopen-2020-041528supp001.pdf]
RANDOMISATION
Randomisation to the intervention is performed following confirmation of
eligibility and completion of the informed consent process. The randomisation
list prepared by an independent CTR statistician uses a 1:1 allocation ratio
with fixed block length. Allocation to azithromycin or placebo is blinded such
that the allocation will not be known to clinicians, the baby’s family or the
trial outcome assessors. The list is uploaded to a validated, user-tested,
web-based system (Sortition, Oxford University Innovation Ltd). Randomisation is
performed by a member of the local study team using a unique username and
password. The system performs treatment allocation by issuing a random
four-digit IMP pack ID (matching the IMP supplied to each site), and also a
participant ID in a standardised format. A member of the site study team
retrieves the appropriate pack of IMP from the storage location and ensures this
is appropriately prescribed on the infant’s prescription chart. Unblinding, if
required, may also be performed by the site PI (or designee) using the web-based
system.
DATA COLLECTION AND SAMPLING
CLINICAL ASSESSMENTS
Following documentation of eligibility, the focus of the baseline data
collection is on maternal history and antenatal information, and details around
the infant’s birth.
IMP administration, sample collection, use of intravenous antibiotics and
details of any positive blood/cerebrospinal fluid cultures are recorded on a
daily basis until the infant is 21 days post randomisation. Liver and kidney
function will be monitored through collection of standard laboratory values.
Should the infant be transferred from the AZTEC recruiting site to another
hospital for continuation of care, the receiving centre continues with follow-up
assessments to support collection of primary and secondary outcomes.
Infants remain in follow-up for safety and outcome purposes until 36 weeks’ PMA,
or are discharged home sooner (the last time point for recording new adverse
reactions).
DATA COLLECTION
All data are recorded on the trial electronic Case Report Form. Accumulating
data are regularly monitored and queries raised with sites should values be
missing or otherwise erroneous (eg, validation against pre-specified ranges for
laboratory values).
SAMPLING
Sites are collecting serial respiratory secretions and stool samples in a
pragmatic, opportunistic manner around nominal time points of baseline, day 5,
day 10 and days 14 to 21 post-randomisation. These procedures are timed to
mirror standard care to minimise disturbing trial infants, where possible.
Endotracheal aspirates are obtained if the infant is intubated, and
nasopharyngeal aspirates are collected if they are not. Stool samples are
collected opportunistically whenever the infants open their bowels. All samples
are refrigerated until shipment at the earliest opportunity overnight to the
central laboratory where they are processed according to a standardised
procedure and stored at −80°C pending analysis. A schematic of the sampling plan
is show in figure 3.
* Download figure
* Open in new tab
* Download powerpoint
Figure 3
AZTEC biological sampling plan* day 4 to 6 is acceptable for the day 5 samples.
Day 8 to 12 is acceptable for the day 10 samples. Day 14 to 21—one sample of
each type during this period. AZTEC, azithromycin therapy for chronic lung
disease of prematurity; CLD, chronic lung disease of prematurity; ETA,
endotracheal aspirates; NPA, nasopharyngeal aspirates.
ANALYSIS
SAMPLE SIZE
Relevant interventional studies to prevent development of CLD as an outcome
(including studies using macrolides) in preterm infants were reviewed. In
general, national and international studies consistently show rates of survival
without CLD of 50% to 60% (those with lower rates are due to highly selected
groups of sicker participants) for studies with similar inclusion criteria to
AZTEC. Thus, adopting a conservative approach using 50% survival without
developing CLD is reasonable. Similarly, the absolute differences in effect size
ranges from 10% to 20% in most studies. The study is powered to an improvement
of 12% (50% to 62%) in survival without CLD with a power of 0.90 and
significance level of 5% requiring recruitment of 796 subjects which is highly
feasible as shown by several similar UK studies in this population. Since the
primary outcome will involve formal assessment with an oxygen challenge test in
both tertiary units and in step-down units, a dropout rate of 10% has been
estimated.
STATISTICAL ANALYSIS
We are conducting an internal pilot involving the first five sites to be
activated, and for a period of 12 months (9 months of recruitment and 3 months
of follow-up). A pilot report will be produced detailing information on
recruitment rate, consent rates, treatment compliance and primary outcome
completeness. The report will be presented to the funder and the AZTEC
independent committees to help inform any adaptations necessary to facilitate
moving forward with the main trial. No formal interim analysis is planned.
The trial will be analysed and reported using the ‘Consolidated Standards of
Reporting Trials’ (CONSORT)30 and the International Conference on Harmonization
(ICH) E9 guidelines.31 A separate and full statistical analysis plan has been
developed prior to database lock. The analysis plan will be reviewed by the
AZTEC independent committees.
The principle of intention-to-treat will be applied as far as practically
possible, including all participants in the primary analysis in the group to
which they were randomly allocated. All analyses will use a 5% level of
statistical significance and 95% CI will be presented throughout. The primary
outcome will be analysed using multilevel logistic regression, within a multiple
imputation framework. The analysis will adjust for covariates balanced at
randomisation and account for clustering of both multiple births and
participants within centres. The imputation model will use the treatment arm and
gestational age variables, as well as whether or not the participant was
transferred from their recruiting site prior to the primary outcome assessment.
Furthermore, a series of sensitivity analyses, within the multiple imputation
framework, will be used to assess the robustness of conclusions.
The presence of multiple births within the same pregnancy will be explored by
including this as an additional level in the model, and this will be used as the
primary analytical approach should the model converge. Dichotomous secondary
outcomes will be analysed using the same approach. Number of days of respiratory
support will be analysed as a time to event outcome allowing for competing risk
of death. These models will also attempt to account for any clustering effects
of multiple births within the same mother. Statistical tests will not be used on
safety and tolerability outcomes. These outcomes will use descriptive statistics
only.
To explore the extent to which there may be a differential treatment effect by
presence of Ureaplasma spp, the model fitted for the primary analysis will be
extended by including a main and treatment group interaction term for Ureaplasma
spp colonisation at baseline. Since patterns of Ureaplasma colonisation may
vary,22 32 the approach to this analysis may be modified in respect of emerging
trends identified the placebo group samples. The final analytical approach will
be agreed prior to database lock. Estimates from the statistical models (main
effects and interaction terms) will be presented alongside 95% CI and p values.
There are no formal stopping rules but the safety data will be regularly
reviewed by the Trial Management Group, and at least annually by the independent
Data Monitoring Committee.
MICROBIOLOGY
Respiratory samples are being processed via centrifugation to separate the
supernatant and obtain a cell pellet from which DNA will be extracted.
Identification of Ureaplasma urealyticum, Ureaplasma parvum and Mycoplasma
hominis is being performed using multiplex quantitative PCR (qPCR) assay as
previously described.33 34 All DNA extractions and qPCR assays are being
performed in collaboration with Central Biotechnology Services (Cardiff
University, UK) according to standard operating procedures and GCP to minimise
contamination.
Stool samples are being cultured aerobically and non-aerobically, and in the
presence and absence of azithromycin to assess baseline and new development of
azithromycin-resistant organisms.
DISCUSSION
As the survival of preterm infants increases, decreasing morbidity associated
with prematurity, including CLD, is becoming increasingly important. AZTEC is an
example of evaluating drug development35 in infants as a large, pragmatic and
adequately powered trial of a macrolide antibiotic to prevent development of CLD
with widespread support by the neonatal community.36 37 The importance of
improving outcomes for preterm infants at risk of developing CLD is highlighted
by the potential impacts on later pulmonary function, especially the prospect of
early decline in lung function and early-onset COPD.38 Moreover, the evidence
base to treat graduates of the neonatal unit when they present with symptoms in
childhood is poor,39 largely because the mechanisms of prematurity-associated
respiratory morbidity remain poorly understood.40
Whether modification of pulmonary inflammation and treatment of Ureaplasma
infection would reduce rates of CLD has been debated for three decades. Use of
postnatal corticosteroids is associated with long-term adverse effects; however,
the safety profile of azithromycin is superior and is unlikely to affect
neurological outcomes. Plans to follow-up neurodevelopment and respiratory
outcomes at 1 and 2 years of age are in place. This study includes ascertainment
of whether each infant is colonised with Ureaplasma spp and randomisation of
treatment to azithromycin or placebo. Given the time lag between randomisation
and the results of tests for Ureaplasma spp, the randomisation will not be
balanced for Ureaplasma status. Nevertheless, this study design will allow an
assessment of the causative role of Ureaplasma in the development of CLD.
If effectiveness of azithromycin therapy is demonstrated, integration into
standard care would be relatively straightforward since the majority of
candidates for treatment would have intravenous access for 7 to 10 days.
Establishing whether azithromycin alters antibiotic resistance patterns will
provide important information to the clinician who may have concerns around
adding an adjunct treatment to a wide array of antimicrobials already given to
this vulnerable group of patients. Although AZTEC will not specifically address
mechanistic actions of azithromycin, including its effect on the lung and gut
microbiota, samples will be banked to permit such work in the near future using
established25 and novel methodologies such as metagenomics.41
In summary, the AZTEC trial is addressing an important therapeutic need in an
area where treatment based on high-quality evidence is severely lacking. Should
antimicrobial resistance not be affected, azithromycin therapy should be
appealing to clinicians due to the anti-inflammatory properties and proven
ability to eradicate Ureaplasma. Treatment may yield fewer intensive care days
and fewer discharges on home oxygen, resulting in considerable reduction in
costs to the National Health Service (NHS), as well as decreasing the
significant burden on parents. On the other hand, should the treatment not be
clinically effective, the neonatal research community can turn their attention
to alternative options for combating CLD. Identification of an effective
treatment to prevent CLD would be of exceptional value to the NHS, infants and
their families.
ETHICS AND DISSEMINATION
The current version of the AZTEC protocol is 3.0, dated 20 June 2020. Ethics
permission has been granted by the Wales Research Ethics Committee 2 (Ref
18/WA/0199), and regulatory permission by the Medicines and Healthcare Products
Regulatory Agency (CTA reference 21323/0050/001–0001). NHS permission has been
granted by the Health Research Authority (HRA) and capacity and capability
confirmed by each individual NHS organisation. The study is registered on
EudraCT (2018-001109-99), ISRCTN (ISRCTN11650227) and on the NIHR portfolio
(CPMS 39385). Cardiff University is the Sponsor (resgov@cardiff.ac.uk), and were
not involved in the preparation of this manuscript or the decision to submit.
Personal data is held with the explicit consent of participants, independently
of study data. The CTR has policies and procedures relating to data requests:
https://www.cardiff.ac.uk/centre-for-trials-research/about-us/data-requests. We
shall disseminate our findings via national and international peer-reviewed
journals, and conferences. A summary of the findings will also be posted on the
trial website.
Oversight of the study is being performed by an independent Data Monitoring
Committee (comprising two expert neonatologists, and an expert statistician) and
an independent Trial Steering Committee (comprising two expert neonatologists,
an expert statistician and a lay representative). Appointments to these
committees were made with approval of the NIHR HRA and meeting a being held at
least annually.
PATIENT AND PUBLIC INVOLVEMENT
Parental input was obtained during the grant application on the design and
conduct of the study. Parent representatives also reviewed public-facing
information (eg, information sheets and consent form) and are members of the
Trial Management Group. An independent parent representative is a member of the
Trial Steering Committee.
ACKNOWLEDGMENTS
We are very grateful for the support provided from both the independent Data
Monitoring Committee and Trial Steering Committee. The Centre for Trials
Research receives core funding from the Welsh Government via Health & Care
Research Wales and Cancer Research UK. We would like to acknowledge and thank
the expert help we received from many parents and nursing staff to develop the
initial application and protocol. In particular, we would like to thank the
babies and their parents who have started to be enrolled to AZTEC.
REFERENCES
1. ↵
1. Simpson SJ,
2. Turkovic L,
3. Wilson AC, et al
. Lung function trajectories throughout childhood in survivors of very
preterm birth: a longitudinal cohort study. Lancet Child Adolesc Health
2018;2:350–9.doi:10.1016/S2352-4642(18)30064-6pmid:http://www.ncbi.nlm.nih.gov/pubmed/30169268
OpenUrlPubMedGoogle Scholar
2. ↵
1. Edwards MO,
2. Kotecha SJ,
3. Lowe J, et al
. Management of Prematurity-Associated wheeze and its association with
atopy. PLoS One 2016;11:e0155695.
doi:10.1371/journal.pone.0155695pmid:http://www.ncbi.nlm.nih.gov/pubmed/27203564
OpenUrlPubMedGoogle Scholar
3. ↵
1. Kotecha SJ,
2. Edwards MO,
3. Watkins WJ, et al
. Effect of preterm birth on later FEV1: a systematic review and
meta-analysis. Thorax
2013;68:760–6.doi:10.1136/thoraxjnl-2012-203079pmid:http://www.ncbi.nlm.nih.gov/pubmed/23604458
OpenUrlAbstract/FREE Full TextGoogle Scholar
4. ↵
1. Blencowe H,
2. Cousens S,
3. Oestergaard MZ, et al
. National, regional, and worldwide estimates of preterm birth rates in the
year 2010 with time trends since 1990 for selected countries: a systematic
analysis and implications. Lancet
2012;379:2162–72.doi:10.1016/S0140-6736(12)60820-4pmid:http://www.ncbi.nlm.nih.gov/pubmed/22682464
OpenUrlCrossRefPubMedWeb of ScienceGoogle Scholar
5. ↵
1. Higgins RD,
2. Jobe AH,
3. Koso-Thomas M, et al
. Bronchopulmonary dysplasia: Executive summary of a workshop. J Pediatr
2018;197:300–8.doi:10.1016/j.jpeds.2018.01.043pmid:http://www.ncbi.nlm.nih.gov/pubmed/29551318
OpenUrlCrossRefPubMedGoogle Scholar
6. ↵
1. Kotecha S
. Lung growth for beginners. Paediatr Respir Rev
2000;1:308–13.doi:10.1053/prrv.2000.0069pmid:http://www.ncbi.nlm.nih.gov/pubmed/16263457
OpenUrlCrossRefPubMedGoogle Scholar
7. ↵
1. Chakraborty M,
2. McGreal EP,
3. Kotecha S
. Acute lung injury in preterm newborn infants: mechanisms and management.
Paediatr Respir Rev 2010;11:162–70. quiz
70.doi:10.1016/j.prrv.2010.03.002pmid:http://www.ncbi.nlm.nih.gov/pubmed/20692631
OpenUrlCrossRefPubMedGoogle Scholar
8. ↵
1. Abman SH,
2. Bancalari E,
3. Jobe A
. The evolution of bronchopulmonary dysplasia after 50 years. Am J Respir
Crit Care Med
2017;195:421–4.doi:10.1164/rccm.201611-2386EDpmid:http://www.ncbi.nlm.nih.gov/pubmed/28199157
OpenUrlCrossRefPubMedGoogle Scholar
9. ↵
1. Kotecha S,
2. Chan B,
3. Azam N, et al
. Increase in interleukin-8 and soluble intercellular adhesion molecule-1
in bronchoalveolar lavage fluid from premature infants who develop chronic
lung disease. Arch Dis Child Fetal Neonatal Ed
1995;72:F90–6.doi:10.1136/fn.72.2.f90pmid:http://www.ncbi.nlm.nih.gov/pubmed/7712280
OpenUrlAbstract/FREE Full TextGoogle Scholar
10. ↵
1. Maxwell NC,
2. Davies PL,
3. Kotecha S
. Antenatal infection and inflammation: what's new? Curr Opin Infect Dis
2006;19:253–8.doi:10.1097/01.qco.0000224819.42729.2epmid:http://www.ncbi.nlm.nih.gov/pubmed/16645486
OpenUrlPubMedWeb of ScienceGoogle Scholar
11. ↵
1. Waites KB,
2. Schelonka RL,
3. Xiao L, et al
. Congenital and opportunistic infections: Ureaplasma species and
Mycoplasma hominis. Semin Fetal Neonatal Med
2009;14:190–9.doi:10.1016/j.siny.2008.11.009pmid:http://www.ncbi.nlm.nih.gov/pubmed/19109084
OpenUrlCrossRefPubMedWeb of ScienceGoogle Scholar
12. ↵
1. Lowe J,
2. Watkins WJ,
3. Edwards MO, et al
. Association between pulmonary Ureaplasma colonization and
bronchopulmonary dysplasia in preterm infants: updated systematic review
and meta-analysis. Pediatr Infect Dis J
2014;33:697–702.doi:10.1097/INF.0000000000000239pmid:http://www.ncbi.nlm.nih.gov/pubmed/24445836
OpenUrlCrossRefPubMedGoogle Scholar
13. ↵
1. Filippone M,
2. Nardo D,
3. Bonadies L, et al
. Update on postnatal corticosteroids to prevent or treat bronchopulmonary
dysplasia. Am J Perinatol
2019;36:S58–62.doi:10.1055/s-0039-1691802pmid:http://www.ncbi.nlm.nih.gov/pubmed/31238361
OpenUrlPubMedGoogle Scholar
14. ↵
1. Mabanta CG,
2. Pryhuber GS,
3. Weinberg GA, et al
. Erythromycin for the prevention of chronic lung disease in intubated
preterm infants at risk for, or colonized or infected with Ureaplasma
urealyticum. Cochrane Database Syst Rev 2003;4:CD003744.
OpenUrlPubMedGoogle Scholar
15. ↵
1. Ozdemir R,
2. Erdeve O,
3. Dizdar EA, et al
. Clarithromycin in preventing bronchopulmonary dysplasia in Ureaplasma
urealyticum-positive preterm infants. Pediatrics
2011;128:e1496–501.doi:10.1542/peds.2011-1350pmid:http://www.ncbi.nlm.nih.gov/pubmed/22123897
OpenUrlAbstract/FREE Full TextGoogle Scholar
16. ↵
1. Alvarez-Elcoro S,
2. Enzler MJ
. The macrolides: erythromycin, clarithromycin, and azithromycin. Mayo Clin
Proc
1999;74:613–34.doi:10.4065/74.6.613pmid:http://www.ncbi.nlm.nih.gov/pubmed/10377939
OpenUrlCrossRefPubMedWeb of ScienceGoogle Scholar
17. ↵
1. Aghai ZH,
2. Kode A,
3. Saslow JG, et al
. Azithromycin suppresses activation of nuclear factor-kappa B and
synthesis of pro-inflammatory cytokines in tracheal aspirate cells from
premature infants. Pediatr Res
2007;62:483–8.doi:10.1203/PDR.0b013e318142582dpmid:http://www.ncbi.nlm.nih.gov/pubmed/17667842
OpenUrlCrossRefPubMedWeb of ScienceGoogle Scholar
18. ↵
1. Legrand T,
2. Elie V,
3. Kotecha S, et al
. An optimal LC-MS/MS method for determination of azithromycin in white
blood cells: application to pediatric samples. Bioanalysis
2014;6:2317–28.doi:10.4155/bio.14.81pmid:http://www.ncbi.nlm.nih.gov/pubmed/25383741
OpenUrlCrossRefPubMedGoogle Scholar
19. ↵
1. Nair V,
2. Loganathan P,
3. Soraisham AS
. Azithromycin and other macrolides for prevention of bronchopulmonary
dysplasia: a systematic review and meta-analysis. Neonatology
2014;106:337–47.doi:10.1159/000363493pmid:http://www.ncbi.nlm.nih.gov/pubmed/25278176
OpenUrlCrossRefPubMedGoogle Scholar
20. ↵
1. Hassan HE,
2. Othman AA,
3. Eddington ND, et al
. Pharmacokinetics, safety, and biologic effects of azithromycin in
extremely preterm infants at risk for Ureaplasma colonization and
bronchopulmonary dysplasia. J Clin Pharmacol
2011;51:1264–75.doi:10.1177/0091270010382021pmid:http://www.ncbi.nlm.nih.gov/pubmed/21098694
OpenUrlCrossRefPubMedWeb of ScienceGoogle Scholar
21. ↵
1. Merchan LM,
2. Hassan HE,
3. Terrin ML, et al
. Pharmacokinetics, microbial response, and pulmonary outcomes of multidose
intravenous azithromycin in preterm infants at risk for Ureaplasma
respiratory colonization. Antimicrob Agents Chemother
2015;59:570–8.doi:10.1128/AAC.03951-14pmid:http://www.ncbi.nlm.nih.gov/pubmed/25385115
OpenUrlAbstract/FREE Full TextGoogle Scholar
22. ↵
1. Viscardi RM,
2. Terrin ML,
3. Magder LS, et al
. Randomised trial of azithromycin to in preterm infants. Archives of
Disease in Childhood - Fetal and Neonatal Edition
2020:fetalneonatal-2019-318122.
Google Scholar
23. ↵
1. Smith C,
2. Egunsola O,
3. Choonara I, et al
. Use and safety of azithromycin in neonates: a systematic review. BMJ Open
2015;5:e008194.
doi:10.1136/bmjopen-2015-008194pmid:http://www.ncbi.nlm.nih.gov/pubmed/26656010
OpenUrlAbstract/FREE Full TextGoogle Scholar
24. ↵
1. Beeton ML,
2. Chalker VJ,
3. Jones LC, et al
. Antibiotic resistance among clinical Ureaplasma isolates recovered from
neonates in England and Wales between 2007 and 2013. Antimicrob Agents
Chemother
2016;60:52–6.doi:10.1128/AAC.00889-15pmid:http://www.ncbi.nlm.nih.gov/pubmed/26459899
OpenUrlAbstract/FREE Full TextGoogle Scholar
25. ↵
1. Gallacher D,
2. Mitchell E,
3. Alber D, et al
. Dissimilarity of the gut-lung axis and dysbiosis of the lower airways in
ventilated preterm infants. Eur Respir J
2020;55:1–3.doi:10.1183/13993003.01909-2019pmid:http://www.ncbi.nlm.nih.gov/pubmed/32060060
OpenUrlPubMedGoogle Scholar
26. ↵
1. Bruynseels D,
2. Solomon C,
3. Hallam A, et al
. Commentary on reconstituting fibrinogen concentrate to maintain blinding
in a double-blind, randomized trial in an emergency setting. J Emerg Med
2016;50:104–7.doi:10.1016/j.jemermed.2015.09.017pmid:http://www.ncbi.nlm.nih.gov/pubmed/26508700
OpenUrlPubMedGoogle Scholar
27. ↵
1. Jobe AH,
2. Bancalari E
. Bronchopulmonary dysplasia. Am J Respir Crit Care Med
2001;163:1723–9.doi:10.1164/ajrccm.163.7.2011060pmid:http://www.ncbi.nlm.nih.gov/pubmed/11401896
OpenUrlCrossRefPubMedGoogle Scholar
28. ↵
1. Quine D,
2. Wong CM,
3. Boyle EM, et al
. Non-invasive measurement of reduced ventilation:perfusion ratio and shunt
in infants with bronchopulmonary dysplasia: a physiological definition of
the disease. Arch Dis Child Fetal Neonatal Ed
2006;91:F409–14.doi:10.1136/adc.2006.095406pmid:http://www.ncbi.nlm.nih.gov/pubmed/16798787
OpenUrlAbstract/FREE Full TextGoogle Scholar
29. ↵
1. BOOST-II Australia and United Kingdom Collaborative Groups,
2. Tarnow-Mordi W,
3. Stenson B, et al
. Outcomes of two trials of oxygen-saturation targets in preterm infants. N
Engl J Med
2016;374:749–60.doi:10.1056/NEJMoa1514212pmid:http://www.ncbi.nlm.nih.gov/pubmed/26863265
OpenUrlCrossRefPubMedGoogle Scholar
30. ↵
1. Moher D,
2. Schulz KF,
3. Altman D, et al
. The CONSORT statement: revised recommendations for improving the quality
of reports of parallel-group randomized trials. JAMA
2001;285:1987–91.doi:10.1001/jama.285.15.1987pmid:http://www.ncbi.nlm.nih.gov/pubmed/11308435
OpenUrlCrossRefPubMedWeb of ScienceGoogle Scholar
31. ↵
1. International Council for Harmonisation
. ICH E9: statistical principles for clinical trials, step 5 1998, 2020.
Available:
https://www.ema.europa.eu/en/documents/scientific-guideline/ich-e-9-statistical-principles-clinical-trials-step-5_en.pdf
[Accessed 17 Apr 2020].
Google Scholar
32. ↵
1. Castro-Alcaraz S,
2. Greenberg EM,
3. Bateman DA, et al
. Patterns of colonization with Ureaplasma urealyticum during neonatal
intensive care unit hospitalizations of very low birth weight infants and
the development of chronic lung disease. Pediatrics 2002;110:e45.
doi:10.1542/peds.110.4.e45pmid:http://www.ncbi.nlm.nih.gov/pubmed/12359818
OpenUrlAbstract/FREE Full TextGoogle Scholar
33. ↵
1. Payne MS,
2. Goss KCW,
3. Connett GJ, et al
. A quantitative analysis of Ureaplasma urealyticum and Ureaplasma parvum
compared with host immune response in preterm neonates at risk of
developing bronchopulmonary dysplasia. J Clin Microbiol
2012;50:909–14.doi:10.1128/JCM.06625-11pmid:http://www.ncbi.nlm.nih.gov/pubmed/22189123
OpenUrlAbstract/FREE Full TextGoogle Scholar
34. ↵
1. Férandon C,
2. Peuchant O,
3. Janis C, et al
. Development of a real-time PCR targeting the yidC gene for the detection
of Mycoplasma hominis and comparison with quantitative culture. Clin
Microbiol Infect
2011;17:155–9.doi:10.1111/j.1469-0691.2010.03217.xpmid:http://www.ncbi.nlm.nih.gov/pubmed/20298269
OpenUrlCrossRefPubMedGoogle Scholar
35. ↵
1. Turner MA,
2. Jacqz-Aigrain E,
3. Kotecha S
. Azithromycin, Ureaplasma and chronic lung disease of prematurity: a case
study for neonatal drug development. Arch Dis Child
2012;97:573–7.doi:10.1136/adc.2010.195180pmid:http://www.ncbi.nlm.nih.gov/pubmed/21697219
OpenUrlAbstract/FREE Full TextGoogle Scholar
36. ↵
1. Maxwell NC,
2. Nuttall D,
3. Kotecha S
. Does Ureaplasma spp. cause chronic lung disease of prematurity: ask the
audience? Early Hum Dev
2009;85:291–6.doi:10.1016/j.earlhumdev.2008.12.002pmid:http://www.ncbi.nlm.nih.gov/pubmed/19144476
OpenUrlCrossRefPubMedWeb of ScienceGoogle Scholar
37. ↵
1. Pansieri C,
2. Pandolfini C,
3. Elie V, et al
. Ureaplasma, bronchopulmonary dysplasia, and azithromycin in European
neonatal intensive care units: a survey. Sci Rep 2014;4:4076.
doi:10.1038/srep04076pmid:http://www.ncbi.nlm.nih.gov/pubmed/24518104
OpenUrlPubMedGoogle Scholar
38. ↵
1. Stocks J,
2. Hislop A,
3. Sonnappa S
. Early lung development: lifelong effect on respiratory health and
disease. Lancet Respir Med
2013;1:728–42.doi:10.1016/S2213-2600(13)70118-8pmid:http://www.ncbi.nlm.nih.gov/pubmed/24429276
OpenUrlPubMedGoogle Scholar
39. ↵
1. Duijts L,
2. van Meel ER,
3. Moschino L, et al
. European respiratory Society guideline on long-term management of
children with bronchopulmonary dysplasia. Eur Respir J
2020;55:1–3.doi:10.1183/13993003.00788-2019pmid:http://www.ncbi.nlm.nih.gov/pubmed/31558663
OpenUrlPubMedGoogle Scholar
40. ↵
1. Lowe J,
2. Kotecha SJ,
3. Kotecha S
. Long Term Effects Following Extreme Prematurity: Respiratory Problems.
In: Boyle EM, Cusack J, eds. Emerging topics and controversies in
neonatology. Switzerland: Springer, 2020: 351–66.
Google Scholar
41. ↵
1. Mack I,
2. Sharland M,
3. Berkley JA, et al
. Antimicrobial resistance following azithromycin mass drug administration:
potential surveillance strategies to assess public health impact. Clin
Infect Dis
2020;70:1501–8.doi:10.1093/cid/ciz893pmid:http://www.ncbi.nlm.nih.gov/pubmed/31633161
OpenUrlPubMedGoogle Scholar
FOOTNOTES
* Contributors SK is the Chief Investigator who developed the research question
and secured funding together with JL, MT and JB, with subsequent input from
JRM, NK, KH, DG and ETJ. JL and SK wrote the protocol with input from all
authors. JL is the Trial Manager, managed by ETJ, Senior Trial Manager, and
is responsible for coordinating the operational delivery of the protocol and
recruitment. DG and TP are the Trial Statisticians and authored the
statistical analysis plan. JL and NKi led the development of the case report
forms; NKi supervises data management. LZ is the Laboratory Analyst; expert
microbiology advice is provided by NK and JRM. SK, MT, MH and JB provide
expert clinical input; MH provides nursing and clinical expertise. JL wrote
the first draft of the manuscript supervised by SK. All authors provided
critical review and final approval of the manuscript.
* Funding This work is supported by the National Institute of Health Research
Health Technology Assessment programme (Ref 16/111/106). The study duration
is 01 January 2019 to 30 September 2022.
* Competing interests None declared.
* Patient and public involvement Patients and/or the public were involved in
the design, or conduct, or reporting, or dissemination plans of this
research. Refer to the Methods section for further details.
* Patient consent for publication Not required.
* Provenance and peer review Not commissioned; externally peer-reviewed.
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