Follow up study of infants recruited to the randomised, placebo-controlled trial of azithromycin for the prevention of chronic lung disease of prematurity in preterm infants – Study protocol for the AZTEC-FU Study

doi:10.21203/rs.3.rs-1593914/v1

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Follow up study of infants recruited to the randomised, placebo-controlled trial of azithromycin for the prevention of chronic lung disease of prematurity in preterm infants – Study protocol for the AZTEC-FU Study

https://doi.org/10.21203/rs.3.rs-1593914/v1

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Background: Preterm birth, especially at less than 30 weeks’ gestation, is significantly associated with respiratory, neurodevelopmental and growth abnormalities. The AZTEC study has recruited 799 infants born at <30 weeks’ gestation to determine if a ten-day intravenous treatment with azithromycin improves survival without development of chronic lung disease of prematurity (CLD) at 36 weeks’ post menstrual age (PMA) when compared to placebo. The follow up studies will compare respiratory, neurodevelopmental and growth outcomes up to 2 years of corrected age between infants who received azithromycin and those who received placebo in the early neonatal period.

Methods: Survivors at 36 weeks’ PMA from the main AZTEC study with parental consent will continue to be followed up to discharge from the neonatal unit and to two years of corrected age. Length of stay, rates of home oxygen, length of supplemental oxygen requirement, hospital admissions, drug usage, respiratory illness, neurodevelopmental disability and death rates will be reported. Data is being collected via parentally completed respiratory and neurodevelopmental questionnaires at one and two years of corrected age respectively and additional information is being obtained from various sources including hospital discharge and clinical letters from general practitioners and hospitals as well as from national databases including the National Database Analyses Unit and NHS Digital.

Discussion: The AZTEC-FU will assess mortality and important neonatal morbidities including respiratory, neurodevelopmental and growth outcomes. Important safety data will also be collected, including the incidence of potential consequences of early macrolide use, primarily pyloric stenosis. This study may have implications on future neonatal care.

Trial registration: The study was retrospectively registered on ISRCTN (ISRCTN47442783).

Neonates

preterm

azithromycin

neurodevelopment

chronic lung disease

bronchopulmonary dysplasia

respiratory

Survival from preterm birth, especially at extremes of gestation, has improved significantly over the last twenty years(1). However, survivors of preterm birth remain at risk of significant longer-term morbidity including for neurodevelopmental, respiratory and growth outcomes. Chronic lung disease of prematurity (CLD), also known as bronchopulmonary dysplasia, results from multiple exposures resulting in pulmonary inflammatory injury to the structurally immature lungs with subsequent altered lung growth which can adversely affect longer term lung function(2). Despite advances in neonatal intensive care, CLD remains a significant medical concern, and rates have not improved significantly, possibly due to improved survival of more extremely immature infants (<26 weeks’ gestation)(3). Despite CLD being a diagnosis of the neonatal period, it is associated with longer term morbidity including increased hospitalisation in infancy(4, 5), increased wheezing and other respiratory symptoms(6) and decreased lung function(6-9). The reduction in lung function is increasingly thought to have significant health implications for the individual’s lifespan, with premature development of chronic obstructive pulmonary disease (COPD) now considered a potential outcome of developing CLD in infancy(10).

Neurodevelopmental delay is another significant adverse outcome in survivors of preterm birth, with increased rates of cerebral palsy and moderate to severe developmental delay frequently noted at two-years corrected gestational age(11, 12). Risk factors for the development of CLD, such as low gestation, prolonged duration of respiratory support following birth, are also associated with poorer neurodevelopmental outcomes(13), and there is a strong association between CLD and longer-term adverse motor and cognitive function(14) and reduced IQ(15).

An additional adverse outcome after preterm birth is poor growth. Postnatal growth is often compromised for preterm born infants, due to an immature gastrointestinal system, prolonged periods of parenteral nutrition, increased energy requirements especially during periods of illness, periods of fluid restriction and feed intolerance or due to gastrointestinal disorders such as necrotising enterocolitis. Preterm-born infants often continue to have reduced growth velocities leading up to discharge. Following discharge, infants, especially those who had CLD, are at high risk of poorer growth attainment(16). Reduced head growth has been shown to have a link with later neurodevelopmental conditions such as cerebral palsy(17).

There have been many attempts to improve these outcomes. Azithromycin is a commonly prescribed antibiotic in the paediatric and adult populations for respiratory conditions associated with infection and inflammation such as cystic fibrosis(18) and COPD(19) and has been shown to improve the long-term outcome for these patients. In the paediatric population, use of macrolides such as erythromycin and azithromycin, may be associated with a small risk of complications such as cardiac rhythm abnormalities and pyloric stenosis(20), but it is unclear if these risks extend to the preterm neonatal population, although a recent systematic review did not find any such evidence(21). The main AZTEC trial has monitored these potential complications.

Azithromycin is attractive as it is active against Ureaplasma spp which has been implicated in the development of CLD(22) and has potent anti-inflammatory effects which may target the pulmonary inflammation that is often observed at 7-10 days of age in preterm-born infants who develop CLD(23, 24). Interestingly, azithromycin has also shown improved neurodevelopmental outcomes in animal models of neuro-injury. In one study, a 30 mg/kg azithromycin administered to neonatal rat model with right carotid ligation and 8% oxygen hypoxic exposure resulted in less functional defects, less weakness in left paw grip, and less right hemisphere damage, in the treated group when compared to the placebo group(25). In another study, azithromycin (20 mg/ml for 2 days) resulted in physiological (decreased paresis and co-ordination deficits) and histological (decreased ventriculomegaly and neuronal necrosis/apoptosis) improvements in a neonatal mouse model of periventricular leukomalacia(26).

The azithromycin therapy for chronic lung disease of prematurity (AZTEC) study is an adequately powered phase III randomised, placebo-controlled trial examining whether a 10-day course of early azithromycin improves rates of survival without CLD in infants born at <30 weeks’ gestation(27). The primary outcome is survival without development of CLD when the active and placebo arms are compared. Secondary outcomes include rates of CLD and severity at 36 weeks’ PMA, mortality by 36 weeks’ PMA, number of days of respiratory support/oxygen-dependency, development of complications of prematurity, serious adverse events/reactions, and resistance to macrolides in lung and stool samples(27). It will also investigate the extent to which the outcomes differ dependent on whether participants’ lungs were colonised with effects of baseline Ureaplasma spp colonisation on the overall analyses.

It will be important to follow these infants beyond 36 weeks’ PMA to monitor any longer-term effects from the early use of azithromycin and ensure longer term safety. The AZTEC follow-up studies (AZTEC-FU) are assessing death rates, respiratory, neurodevelopmental and growth outcomes for AZTEC study participants from 36 weeks PMA up to two years of corrected age; they will also document any differences in neurodevelopmental outcomes between the two trial arms. Additional mechanistic elements are investigating underlying mechanisms of azithromycin action by studying the effects of azithromycin on the lung and stool microbiome; tracheal aspirate cytokines and proteome; and on antibiotic resistance against azithromycin in lung and stool samples obtained in the first three weeks of life.

Main Objectives

The main objectives of the AZTEC-FU are to compare respiratory, neurodevelopmental, growth and mortality outcomes at one and two years of corrected age in infants who received azithromycin or placebo in the early neonatal period.

The specific aims are to compare between the treated and placebo groups (Figure2):

Mortality:

Total number of deaths occurring from birth to one- and two-year corrected age will be reported as will those occurring (a) from birth to 36 weeks’ PMA (which will have been reported in the AZTEC trial), (b) 36 weeks to never discharged, and (c) after discharge.

Respiratory

The main outcome will be parent reported wheezing at one year of corrected age. The following outcomes will also be reported:

Length of the initial neonatal stay in hospital
Number of children discharged home on domiciliary ambulatory oxygen
Length of oxygen supplementation (including at home)

Parent reported wheeze from discharge to two years of corrected age

Number of respiratory hospital admissions up to one year and two years of corrected age
Number of prescribed respiratory drugs.
Survival (from birth) without parent reported wheeze at one year of and two years of corrected age

Neurodevelopmental

The main outcome will be survival (from birth) without combined moderate/severe neurodevelopmental disability at two years of corrected age. The following outcomes will also be reported at two years of corrected age:

Moderate/severe neurodevelopmental disability
The proportion of infants who develop moderate-severe neurodevelopmental impairment, defined as Parent Report of Children’s Abilities–Revised (PARCA-R) questionnaire score of <44
Overall motor skills as well as fine and gross motors scores
Overall language scores as well as expressive and receptive language scores
Overall cognition score

Combined moderate/severe neurodevelopmental will be defined, as previously(28, 29) as any of the following:

moderate or severe visual impairment (reduced vision uncorrected with aids, blindness in one eye with good vision in the contralateral eye, or blindness or light perception only)
moderate or severe hearing impairment (hearing loss corrected with aids, some hearing loss uncorrected by aids, or deafness)
moderate or severe gross motor impairment (inability to walk or sit independently)
moderate or severe cognitive impairment will be defined using PARCA-R or by using clinical data if PARCA-R scores are missing. Total PARCA-R scores of less than 44 (range, 0 to 158, with lower scores indicating greater impairment) will be used to identify children with moderate or severe developmental impairment

Growth

Weight, height and head circumference will be reported at one and two years of corrected age after adjusting for sex and gestation.

Adverse Events

We shall also report the rates of reported pyloric stenosis in the active treatment and placebo groups at one year of corrected age.

Biological Sample Analysis

The respiratory and stool samples collected during the AZTEC trial(27) will additionally be analysed to investigate whether, when compared to the placebo group, azithromycin alters the cytokine, proteomic and microbiome profiles in lung or stool samples as well as any modification that occurs in those colonised by Ureaplasma spp.

Design

AZTEC is a double-blind, randomised, placebo-controlled trial using azithromycin or placebo as previously described(27). The AZTEC-FU will continue to follow up the infants recruited to AZTEC up to two years of corrected age. The participants and researchers will continue to remain blinded for the AZTEC-FU.

Data between 36 weeks’ PMA and discharge from the neonatal unit are collected from a dedicated discharge clinical record form (CRF); neonatal discharge summaries and clinic letters; NDAU data; and from the parents. When the infants enrolled in the AZTEC trial reach one-year and two years of corrected age, we are contacting the parents/guardians by mailing them a validated (a) respiratory and (b) neurodevelopmental questionnaire. In addition, we are asking the parents/guardians for (c) information on any hospital admissions; and (d) growth data of their babies from the Red Book system in the UK which records growth data by Health Visitors and at local hospital follow up clinics. An option is available to complete the questionnaire on a secure online site. In parallel, we are contacting local hospitals for clinic letters from which relevant data are extracted: including a) respiratory symptoms, b) developmental progress, c) growth, d) hospital admissions, and e) any medication especially respiratory and antibiotic usage. In addition, we are also contacting the General Practitioners for clinic letters, discharge summaries and a copy of the GP record for the children to provide an additional route to collect the above information. Data will also be obtained from NHS Digital for information on hospital admissions and outpatients’ attendances and from the National Database Analyses Unit (NDAU) at Imperial College, a central repository where most of the UK neonatal units send their clinical data(30)(Figure 1).

Patient and Public Involvement

Input from parents of preterm-born children was given during the grant application on the design and conduct of the study and parents were part of the Trials Management Group and Trials Steering Committee. Parents with previous preterm-born children as well as senior neonatal nurses and doctors also reviewed the information sheets and questionnaires. Amendments were made after their input.

Setting

Infants have been enrolled on the AZTEC trial from 28 tertiary neonatal units and approximately 77 step-down units in the United Kingdom. Where parental consent permits, they are being followed up at one and two years of corrected age.

Inclusion Criteria

Participation in the AZTEC trial.
Survival at 36 weeks’ PMA
Consent provided by the parents/guardians to be contacted for follow up at one and two years of corrected age.

Exclusion Criteria

Withdrawal from AZTEC
Parents/Guardians did not provide consent to follow up at one and two years corrected age
Death prior to 36 weeks’ PMA
Post-discharge Survival not confirmed

Trial Intervention

As previously described(27), infants born at <30 weeks’ gestation, within 72 hours of birth, were treated intravenously for ten days with 20 mg/kg azithromycin for 3 days, followed by a further 7 days of 10 mg/kg or with similarly constituted and administered placebo.

Trial Procedures

Site selection and training

Tertiary and step-down units who were involved in AZTEC have been invited to participate. Sites only need to provide copies of clinic letters and discharge summaries thus no formal training is required.

Participant Recruitment

During the AZTEC trial, the AZTEC-FU is also discussed, and consent obtained from the parents/guardians for follow up to two years of corrected age.

Screening and Consent

Eligible infants are being screened postnatally against the inclusion and exclusion criteria as previously described(27). At the initial consent procedure for inclusion in the AZTEC study, the parents/guardians optionally consent to follow up at one and two years of corrected age with an additional option to contact the infant’s general practitioner (GP). In addition, the parents/guardians can optionally consent for their babies’ data to be reviewed on relevant databases such as NHS Digital and NDAU. Any participant withdrawals or deaths during the initial neonatal unit stay are communicated by the AZTEC team to the AZTEC-FU team. Continued consent is also presumed if the parents/guardians complete and return the completed questionnaire at one and two years of corrected age. The parents/guardians right to withdraw from the study at any time without affecting their infant’s clinical care is clearly communicated.

Randomisation

The recruited infants were randomized to either active treatment or placebo as previously described(27). Double blinding is being maintained for the AZTEC-FU.

Data Collection

All collected data are securely and confidentially stored with restricted access on Cardiff University servers according to the University’s security policy.

Questionnaires at One- and Two-Year’s Corrected Age

For those who consented to follow up, a questionnaire including a covering letter explaining the study, an information sheet explaining the questionnaire, a stamped questionnaire return envelope and a

voucher to thank the parents for their baby’s participation in the study are mailed. The letter also contains a personalized Quick Response (QR) code and website URL link which they can use if they wish to complete the questionnaire via a secure online website(Online Surveys, Jisc, Bristol, UK).

The questionnaire at one-year corrected age captures respiratory symptoms, the infant’s and family history of atopy, number of course of antibiotics, number of hospital admissions, maternal smoking during pregnancy and current smoking in the family who share the house with the infant, information on siblings, as well as general developmental questions and entries for the infant’s weight, length/height and head circumference. The questionnaire also specifically asks if the infant has had pyloric stenosis(21).

At two years of corrected age, the questionnaire captures the same information as year one, but with greater detailed neurodevelopment data captured via using the PARCA-R questionnaire which has been validated against Bayley’s Scales of Infant Development Version III assessments(31).

Data from General Practitioners

At one and two years of corrected age for the infants whose parents/guardians have consented to the AZTEC-FU, the GPs are contacted for copies of the infant’s notes including medical or surgical consultations, hospital discharge summaries and outpatient clinic or in-patient letters. Data is being extracted from these records by the AZTEC-FU team including information on number of hospital admissions, diagnoses, duration of home oxygen therapy (if applicable) and drug history.

National Database Analyses Unit (NDAU)

NDAU collates neonatal data provided for each neonatal admission by almost units in the United Kingdom. Data collected includes information on initial neonatal admission as well as neurodevelopmental data at two years of corrected age, most commonly assessed by using Bayley’s Scales of Infant Development Version III, but during the COVID pandemic many units are increasingly using PARCA-R as a screening tool. Data are being provided annually by NDAU for each infant recruited to the AZTEC trial for infant’s whose parents/guardians have provided appropriate consent.

NHS Digital

It is anticipated that data for infants recruited to the AZTEC trial can be obtained from NHS Digital, once the relevant permissions have been obtained for infants whose parents/guardians have provided appropriate consent for access to the infant’s data from relevant databases. NHS Digital Data should provide additional and confirmatory data obtained from the various sources outlined above including hospital and general practitioner records.

Hospital Data

At one and two years corrected age the infant’s local hospital is being contacted if we have the relevant consent from the parents/guardians to supply the infant’s hospital discharge summaries and clinic letters.

Data Analysis

Sample size

The initial sample size was calculated for the main AZTEC trial: for 12% improvement of survival without CLD, with an alpha of 0.05 and power of 0.90, would require 796 including 10% drop out. The study recruitment completed in March 2022 recruiting 799 infants. For the current study, the power available will depend on returns of questionnaires and collection of data from a wide variety of sources. Mortality between 36⁺¹ weeks and one year of corrected age is estimated to be <5% (with negligible occurring in the second year) and the baseline wheezing rate at one year of corrected age for children born ≤30 weeks’ gestation is estimated at 60-65%(6) and 50-55% for moderate/severe neurodevelopmental disability (28, 29). The tables show the effect size for the parent-reported wheezing at any time during first year of life (Table 1) and for survival without developing moderate/severe neurodevelopmental at two years corrected age (Table 2) at an alpha of 0.05 and power of 0.80 and 0.90. It is reasonable to expect approximately 70-75% outcome data from the anticipated 700-725 survivors at 36 weeks’ PMA for the follow up studies, i.e. approximately 500. These should be able to detect differences of 12.7% at power of 0.80 and alpha of 0.05 for parent reported wheezing at one-year corrected age between the azithromycin and placebo groups. A similar 12.7% difference should be detectable for in survival without developing moderate/severe neurodisability at two years of corrected age between the two treatment arms.

Table 1 – Estimated effect size for respiratory outcome (wheeze at any time during first year of life) for anticipated questionnaire returns:

Power 0.8, alpha 0.05, initial incidence of wheeze 65%
Size per group	Prevalence of wheezing after treatment	Detectable effect size
350	54.3%	10.7%
300	53.5%	11.5%
250	52.3%	12.7%
200	50.7%	14.3%
Power 0.9, alpha 0.05, initial incidence of wheeze 65%
Size per group	Prevalence of wheezing after treatment	Detectable effect size
350	52.7%	12.3%
300	51.7%	13.3%
250	50.4%	14.6%
200	48.5%	16.5%

Table 2 – Estimated effect size for neurodevelopmental outcome (survival at two years without moderate/severe neurodevelopmental impairment) for anticipated questionnaire returns:

Power 0.8, alpha 0.05, initial incidence of survival without moderate/severe neurodevelopmental impairment of 50%
Size per group		Detectable effect size
350	60.7%	10.7%
300	61.6%	11.6%
250	62.7%	12.7%
200	64.4%	14.6%
Power 0.9, alpha 0.05, initial incidence of survival without moderate/severe neurodevelopmental impairment of 50%
Size per group		Detectable effect size
350	62.3%	12.3%
300	63.3%	12.3%
250	64.6%	14.6%
200	66.4%	16.4%

Statistical Analysis

A statistical analysis plan will be developed prior to the end of the study. Baseline descriptors will be given. Data analyses will be conducted to identify any differences in the respiratory, neurodevelopmental, and growth outcomes; as well as hospital admissions between the placebo and the treatment group using two-by-two tables and Chi-square testing. We shall consider p<0.05 as statistically significant and report 95% confidence intervals. We shall also model the data, as in our previous publications(6), to identify early life factors that may result in long-term respiratory/neurodevelopmental abnormalities including presence/absence of Ureaplasma spp at baseline before intervention commenced in the neonatal period; and if the treatment effect is influenced by early life factors e.g. gestation, sex, use of mechanical ventilation, etc. Initially, we shall report the univariable data with a view to including any relevant factors into a model (using linear or logistic regression as appropriate). Missing data will be included in the analysis as missing data.

Secondary Analysis

Presence of Ureaplasma spp at baseline (i.e., before randomisation) will be added as an interaction term for the main analyses of parent reported wheezing at one-year corrected age and for survival without development of moderate/severe neurodevelopmental disability at two-year of corrected age. Main effects and interactions will be reported, as well as the p-value for the interaction term. Subgroup-specific estimates (with accompanying 95% confidence intervals) for each outcome will also be derived from model estimates.

The AZTEC trial’s main outcome is to assess if 10-day treatment with azithromycin, versus placebo improves survival without development of CLD. The AZTEC-FU will follow up AZTEC trial participants up two years corrected age, assessing mortality and important neonatal morbidities including respiratory, neurodevelopmental and growth outcomes. Important safety data will also be collected, including the incidence of potential consequences of early macrolide use, primarily pyloric stenosis.

The use of azithromycin for the prevention of CLD has been examined previously in smaller populations. A meta-analysis of six studies combining data for 469 infants reported potentially reduced rates CLD following neonatal azithromycin administration (32), but highlighted the need for an adequately powered study. A phase IIb study of 121 infants born at <29 weeks’ gestation assessed Ureaplasma-free survival using an early three-day course of 20mg/kg intravenous azithromycin. Whilst this treatment course proved effective in eradicating Ureaplasma, rates of CLD were not significantly different between the groups (33). When this cohort was followed up at two years corrected age, there were no significant differences reported for respiratory or neurological outcomes between the treated and placebo groups, with comparable rates of cough, wheezing, hospitalization, respiratory medication use and Bayley-III/neurodevelopment questionnaire scores between the two groups(34). The longer, ten-day course of azithromycin being studied in AZTEC may not only provides an antimicrobial effect against Ureaplasma, but aims to provide an effective anti-inflammatory effect against the often reported early pulmonary inflammation(23, 35), that may confer additional benefit for the prevention of CLD. Not only is the AZTEC trial sufficiently powered to address this question but will also provide a larger cohort for follow-up and assessment of longer-term outcomes following early azithromycin use. Infants with CLD are known to be at increased risk of poorer respiratory health in the first two-years of life, with increased parent-reported wheeze(36), and increased hospital admissions for respiratory diseases(4, 5), with a longer-term risk of decreased lung function(8). If AZTEC proves effective at reducing rates of CLD for infants born <30 weeks gestation, it will be important to follow these infants to see if there are longer-term benefits. For the AZTEC-FU, we are aiming to recruit 500 infants which will enable detection of 12.7% improvement in parent reported wheeze and a similar difference for survival (from birth) without development of moderate/severe neurodevelopmental impairment between the azithromycin and placebo groups. Regardless of the success of the AZTEC trial, it is important to continue to follow up these infants, as previous follow up studies examining early neonatal interventions have demonstrated longer-term respiratory benefits, often without showing short-term benefits(37). For example, despite early elective high frequency oscillatory ventilation not conferring a benefit on reducing rates of death or CLD in the neonatal period, infants treated with this ventilation modality had significantly improved lung function at 11-14 years of age(38).

Neurodevelopmental outcome following preterm birth is a key metric for parents and the neonatal community(39). Preterm birth is inherently associated with increased risk of poorer neurodevelopment (11, 12), with a strong association, and shared risk factors, between CLD and functional and cognitive outcomes(15). Human studies have shown that azithromycin is widely distributed in the brain tissue(40), with animal models suggesting that azithromycin may also confer neuroprotective benefits. However, human data for the neuroprotective efficacy of azithromycin is currently lacking. Whilst we postulate improved neurodevelopmental outcomes at two-years corrected age for those infants treated with azithromycin, we shall also investigate if there are detrimental neurodevelopmental effects from the early use of early azithromycin by using two-tailed comparisons. With our anticipated 500 responses, we have estimated that we should be able to detect 12.7% differences for the main respiratory and neurodevelopmental outcomes at one and two years of corrected age respectively.

The AZTEC-FU studies are also monitoring survival up to two years of age, separately reporting deaths at important timepoints up to two years of corrected age. Growth is another important postnatal factor, with preterm infants having poorer inpatient growth velocities(41), and those with CLD noted to have poorer growth once discharged home(16). We are collecting anthropomorphic measurements, including weight, length, and head circumference at discharge, and over the first two years of life from routine clinic appointments and health visitor assessments. If azithromycin proves effective at reducing rates of CLD, it will be important to assess whether that confers growth benefits following discharge home.

In summary, the AZTEC-FU studies are assessing the impact of a 10-day treatment course of early azithromycin in infants born <30 weeks’ gestation on their mortality, respiratory morbidity, neurodevelopmental outcome and growth during the first two years of life. If azithromycin proves beneficial in improving survival without developing CLD in the neonatal period, the AZTEC-FU should be sufficiently powered to demonstrate if improvements in respiratory symptoms, neurodevelopment outcome or growth occurs by two years of corrected age. Most importantly, the AZTEC-FU studies will ensure safety of the neonatal intervention and provide confidence in establishing azithromycin into routine care of preterm-born infants to improve survival without developing CLD.

AZTEC azithromycin therapy for chronic lung disease of prematurity

AZTEC-FU azithromycin therapy for chronic lung disease of prematurity follow up studies

CLD Chronic lung disease

PMA Post menstrual age

COPD Chronic obstructive pulmonary disease

PARCA-R Parent Report of Children’s Abilities–Revised

NDAU National Database Analyses Unit

QR Quick response

Ethics and Dissemination

The current version of the AZTEC-FU Protocol is 6.0, dated 21^st April 2021. Wales Research Ethics Committee 3 (Ref 19/WA/0267) has granted ethics permissions and approved all amendments. Health Research Authority (HRA) has granted NHS permissions. The study is registered on the NIHR portfolio. Cardiff University is the Sponsor. The Follow Up studies are an investigator-led project funded by ASPIRE Pharma Ltd. Results will be disseminated in peer-reviewed journals, and national and international conferences.

Trial status

Protocol version 6 dated 20/4/21. Recruitment began in December 2019 and should complete in October 2024.

Ethics approval and consent to participate

Wales Research Ethics Committee 3 (Ref 19/WA/0267) has granted ethics permissions and approved all amendments. At the initial consent procedure for inclusion in the AZTEC study, the parents/guardians optionally consent to follow up at one and two years of corrected age with an additional option to contact the infant’s general practitioner (GP). In addition, the parents/guardians can optionally consent for their babies’ data to be reviewed on relevant databases such as NHS Digital and NDAU. Any participant withdrawals or deaths during the initial neonatal unit stay are communicated by the AZTEC team to the AZTEC-FU team. Continued consent is also presumed if the parents/guardians complete and return the completed questionnaire at one and two years of corrected age. The parents/guardians right to withdraw from the study at any time without affecting their infant’s clinical care is clearly communicated.

Consent for publication

Not applicable

Availability of data and materials

CWC, SJK, WJW and SK will have access to the final dataset.

Competing interests

None

Funding

This work is supported by Aspire Pharma Ltd. The funder and sponsor have no role in in study design; collection, management, analysis, and interpretation of data; writing of the report; and the decision to submit the report for publication,

Contributorship Statement

SK is the Chief Investigator who developed the research question and secured funding together with SJK and WJW. SJK, WJW and SK wrote the protocol. JB provides expert clinical input. DG provides expert statistical advice. SJK and CWC wrote the first draft of the manuscript supervised by SK. All authors provided critical review and final approval of the manuscript.

Acknowledgements

We would like to thank the infants and their parents who participated in the main AZTEC trial and in the Follow Up studies. We would also like to thank all neonatal units whose staff recruited infants to the main AZTEC trial and to also thank them and the General Practitioners for their assistance in the Follow up Studies. The original AZTEC study is funded by the UK’s National Institute for Health Research’s Health Technology Assessment Programme and the Follow Up studies by Aspire Pharma.

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Follow up study of infants recruited to the randomised, placebo-controlled trial of azithromycin for the prevention of chronic lung disease of prematurity in preterm infants – Study protocol for the AZTEC-FU Study

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