Azithromycin therapy for chronic lung disease of prematurity
| ISRCTN | ISRCTN11650227 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN11650227 |
| EudraCT/CTIS number | 2018-001109-99 |
| Secondary identifying numbers | 39385; 16/111/106 |
- Submission date
- 23/07/2018
- Registration date
- 31/07/2018
- Last edited
- 22/05/2024
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Respiratory
Plain English Summary
Background and study aims
Premature births account for a tenth of all worldwide births. Babies who survive are at risk of developing Chronic Lung Disease of Prematurity (CLD) as they have underdeveloped lungs, and also because the necessary treatment (breathing machines and oxygen therapy) in itself causes harm. CLD is defined as needing oxygen at 36 weeks “corrected” gestation. Most babies will come off their oxygen therapy by the end of their hospital stay, but some babies go home on oxygen placing an enormous burden on families. CLD babies also have a higher risk of childhood breathing problems. Inflammation (like redness or soreness) of the lungs is often seen in CLD babies, and a germ called Ureaplasma is often present. Some doctors think that Ureaplasma is a simple 'bystander', but others believe that it is actively causing harm. It has been shown that babies who have Ureaplasma have much greater chances of developing CLD than those who do not. Researchers have previously used antibiotics such as azithromycin to treat the Ureaplasma. Azithromycin decreases lung inflammation and is an effective antibiotic against Ureaplasma. A recent report noted that rates of CLD may improve with azithromycin therapy but the total number of babies included was small. A large study is needed to see if azithromycin therapy can indeed improve CLD rate. The aim of this study is to find out whether ten days of azithromycin improves survival without CLD in premature babies.
Who can participate?
Premature babies receiving respiratory support (breathing tube) and an intravenous line for drug administration
What does the study involve?
Babies are randomly allocated to be treated with either azithromycin or placebo (dummy drug) intravenously (into a vein). Lung fluid samples are collected via their breathing tube or from their nose/back of the mouth, and nappy stool samples are taken. These are used to see if lung Ureaplasma is successfully treated by azithromycin, and if common germs found in the gut and lungs develop antibiotic resistance. Studying resistance is important as azithromycin will be widely used if it is found to improve rates of CLD.
What are the possible benefits and risks of participating?
There are no certain benefits of taking part although it is hoped that the results might improve the treatment of other babies in the future. Azithromycin has been used for a long time in children and has been used in other studies in premature babies, but like all medicines, antibiotics can cause side effects in some people. These are uncommon, but some babies may develop some soreness of the tummy or slightly looser stools. In older patients, azithromycin may affect the rhythm of the heart. There is no evidence that this happens in babies, but it is something that will be monitored closely.
Where is the study run from?
Cardiff University (UK)
When is the study starting and how long is it expected to run for?
January 2018 to December 2023
Who is funding the study?
National Institute for Health Research (NIHR) (UK)
Who is the main contact?
Dr John Lowe
aztec@cardiff.ac.uk
Contact information
Scientific
Centre for Trials Research
College of Biomedical & Life Sciences
Cardiff University
7th Floor, Neuadd Meirionnydd
Heath Park
Cardiff
CF14 4YS
United Kingdom
| Phone | +44 (0)29 2068 7990 |
|---|---|
| Aztec@Cardiff.ac.uk |
Study information
| Study design | Randomized; Interventional; Design type: Treatment, Drug |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | ISRCTN11650227_PIS_v3_25Jun2018.pdf |
| Scientific title | A randomised, placebo controlled trial of azithromycin for the prevention of chronic lung disease of prematurity in preterm infants |
| Study acronym | AZTEC |
| Study hypothesis | Premature births account for a tenth of all world-wide births. Babies who survive are at risk of developing Chronic Lung Disease of Prematurity (CLD) as they have underdeveloped lungs, and also because the necessary treatment (breathing machines and oxygen therapy) in itself causes harm. CLD is defined as needing oxygen at 36 weeks “corrected” gestation. Most babies will come off their oxygen therapy by the end of their hospital stay, however, some babies go home on oxygen placing enormous burden on families. CLD babies also have a higher risk of childhood breathing problems. Inflammation (like redness or soreness) of the lungs is often seen in CLD babies, and a germ called Ureaplasma is often present. Some doctors’ think that Ureaplasma is a simple 'bystander', but others believe that it is actively causing harm - it has been shown that babies who have Ureaplasma have much greater chances of developing CLD than those who do not. Researchers have previously used antibiotics, such as azithromycin, to treat the Ureaplasma. Azithromycin decreases lung inflammation and is an effective antibiotic against Ureaplasma. A recent report combining 3 studies noted that rates of CLD may improve with azithromycin therapy but the total number of babies included were small. A large study is needed to see if azithromycin therapy can indeed improve CLD rate. This study will investigate if ten days of intravenous azithromycin improves survival without CLD in premature babies. Lung fluid samples will be collected via their breathing tube or from their nose/back of the mouth, and nappy stool samples. These will be used to see if lung Ureaplasma is successfully treated by azithromycin, and if common germs found in the gut and lungs develop antibiotic resistance. Studying resistance is important as azithromycin will be widely used if it is shown that the therapy improves rates of CLD. |
| Ethics approval(s) | Approved 26/06/2018, Wales REC 2 (15-19 Cowbridge Road East, Cardiff, CF11 9AB, United Kingdom; +44 (0)29 2078 5738; Wales.REC2@wales.nhs.uk), ref: 18/WA/0199 |
| Condition | Chronic lung disease of prematurity |
| Intervention | The method of randomisation will be web-based. Azithromycin or placebo will be commenced within 72 hours (20 mg/kg once daily iv for 3 days then 10 mg/kg once daily iv for 7 days). The dosage and duration are based on achieving therapeutic levels of the drug to eradicate Ureaplasma colonisation and to utilise the drug's anti-inflammatory activities on pulmonary inflammation that is frequently observed in babies who develop CLD. Oxygen dependency at 36 weeks' postmenstrual age will be physiologically assessed to define CLD. Secondary outcomes will be based on safety parameters (survival rates, adverse reactions, complications of prematurity including NEC, ROP); rates of Ureaplasma colonisation, and on development of antibiotic resistance in commensal microbes. Routinely collected data including duration/type of ventilation, overall length of respiratory support and hospital stay will be recorded. Additional resources will be sought to obtain respiratory and neurodevelopmental data at two years of corrected age, which most units now routinely collect and feed into national databases. Given the early antibiotic exposure and potential for development of antibiotic resistance, the trialists shall also assess the carriage of resistant organisms in the gut and respiratory tract. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Not Applicable |
| Drug / device / biological / vaccine name(s) | Azithromycin |
| Primary outcome measure | Survival without physiologically defined CLD at 36 weeks postmenstrual age |
| Secondary outcome measures | 1. Death at or before 36 weeks postmenstrual age 2. Number of days of respiratory support required, assessed from birth to 36 weeks postmenstrual age or discharge or death (whichever occurs earlier): 2.1. Conventional mechanical ventilation/HFOV 2.2. Continuous positive airway pressure 2.3. High flow nasal cannula 2.4. Number of days of oxygen dependency 3. Development of complications of prematurity, assessed from birth to 36 weeks postmenstrual age or discharge or death (whichever occurs earlier): 3.1. Nosocomial infection (line- sepsis, meningitis, pneumonia); confirmed microbiologically or antibiotic treatment for 5 days or more 3.2. Severe intraventricular haemorrhage (grade III/IV) 3.3. Necrotising enterocolitis (Bell stage II and above) 3.4. Treatment for retinopathy of prematurity 3.5. Treatment for patent ductus arteriosus 3.6. Serious adverse events/reactions 4. Resistance to macrolides among microbes isolated from respiratory and stool samples at baseline and day 14-21 5. Presence of ureaplasma identified through qPCR analysis of endotracheal and nasopharyngeal aspirate samples at baseline 6. Respiratory symptoms, measured using modified Liverpool questionnaire at 2 years corrected age 7. Neurodevelopmental symptoms, measured using modified Liverpool questionnaire at 2 years corrected age 8. Neurodevelopmental score (e.g. Bayley assessment) obtained from recruiting hospital or national databases at 2 years corrected age |
| Overall study start date | 01/01/2018 |
| Overall study end date | 06/12/2023 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Neonate |
| Sex | Both |
| Target number of participants | Planned Sample Size: 796; UK Sample Size: 796 |
| Participant inclusion criteria | 1. Gestational age ≤29w+6d (including infants born as one of a multiple birth) 2. Neonates who have had 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 consent within 72 hours of birth 5. Anticipating administration of first dose within 72 hours 6. Reasonable to expect completion of 10 days of trial treatment whilst resident at the recruiting site 7. Inborn, or born at site within the recruiting site’s neonatal network where follow up will be possible |
| Participant exclusion criteria | 1. In the opinion of the Principal Investigator (PI), babies unlikely to survive until 48 hours after birth 2. Exposure to another systemic macrolide antibiotic (not maternal) 3. Presence of major surgical or congenital abnormalities (not including patent ductus arteriosus or patent foramen ovale) 4. Known contraindication of azithromycin as specified in the summary of characteristics of the product 5. Participation in other interventional trials that precludes participation in AZTEC |
| Recruitment start date | 19/09/2019 |
| Recruitment end date | 31/07/2022 |
Locations
Countries of recruitment
- England
- Scotland
- United Kingdom
- Wales
Study participating centres
Cardiff
CF14 4XW
United Kingdom
BS10 5NB
United Kingdom
PO6 3LY
United Kingdom
BD9 6RJ
United Kingdom
LE1 5WW
United Kingdom
SO16 6YD
United Kingdom
Nottingham
NG7 2UH
United Kingdom
Nottingham
NG5 1PB
United Kingdom
Hull
HU3 2JZ
United Kingdom
Newcastle upon Tyne
NE1 4LP
United Kingdom
Oldham
OL1 2JH
United Kingdom
London
SE1 7EH
United Kingdom
Brighton
BN2 5BE
United Kingdom
Glasgow
G31 2ER
United Kingdom
Preston
PR2 9HT
United Kingdom
Gillingham
ME7 5NY
United Kingdom
Sponsor information
Hospital/treatment centre
Research and Innovation Services
Cardiff
CF24 0DE
Wales
United Kingdom
| Phone | +44 (0)29 2087 9130 |
|---|---|
| resgov@cardiff.ac.uk | |
"ROR" |
https://ror.org/03kk7td41 |
Funders
Funder type
Government
No information available
Results and Publications
| Intention to publish date | 31/12/2024 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Data sharing statement to be made available at a later date |
| Publication and dissemination plan | Current publication and dissemination plan as of 22/05/2024: Main trial results published in Lancet Respiratory Medicine Previous publication and dissemination plan: Planned publication in a high-impact peer-reviewed journal. |
| IPD sharing plan | The data is currently unavailable since blinded follow-up is still active |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Participant information sheet | version v3 | 25/06/2018 | 31/07/2018 | No | Yes |
| Protocol article | 06/10/2020 | 13/08/2021 | Yes | No | |
| Statistical Analysis Plan | 23/08/2022 | 24/08/2022 | Yes | No | |
| HRA research summary | 28/06/2023 | No | No | ||
| Results article | 25/04/2024 | 22/05/2024 | Yes | No |
Additional files
- ISRCTN11650227_PIS_v3_25Jun2018.pdf
- Uploaded 31/07/2018
Editorial Notes
22/05/2024: The following changes were made to the study record:
1. Publication reference and ethics approval details added.
2. The overall study end date was changed from 30/09/2022 to 06/12/2023.
3. Publication and dissemination plan and IPD sharing plan updated.
18/09/2023: The intention to publish date was changed from 31/01/2023 to 31/12/2024.
24/08/2022: Publication reference added.
13/08/2021: Internal review.
30/06/2021: The following changes have been made:
1. The recruitment end date has been changed from 28/02/2022 to 31/07/2022.
2. Publication reference added.
3. The trial website has been added.
17/06/2020: The following changes were made to the trial record:
1. The recruitment start date was changed from 01/10/2018 to 19/09/2019.
2. The recruitment end date was changed from 31/03/2021 to 28/02/2022.
3. The following trial participating centres were added: Queens Medical Centre, City Hospital, Hull Royal Infirmary, Royal Victoria Hospital, The Royal Oldham Hospital, Evelina London Children’s Hospital, Royal Sussex and County Hospital, Princess Royal Maternity Hospital, Royal Preston Hospital, Medway Maritime Hospital.
15/05/2019: The following changes ave been made:
1. Dr John Lowe has replaced Dr Tom Kearns as the scientific contact.
2. The overall trial end date has been changed from 31/01/2022 to 30/09/2022.
3. The plain English summary has been updated to reflect these changes.
22/03/2019: The condition was updated from "Specialty: Children, Primary sub-specialty: Respiratory and Cystic Fibrosis; UKCRC code/ Disease: Respiratory/ Lung diseases due to external agents" to "Chronic lung disease of prematurity".
31/07/2018: The participant information sheet has been uploaded.
