TINN2: Treat Infection in NeoNates 2

Study Overview
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Brief Summary
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The aim of the TINN2 study is to evaluate the efficacy of azithromycin in prevention of bronchopulmonary dysplasia in preterm neonates.

Detailed Description
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In contrast to the situation in adults, most medicines used to treat the children of Europe have not been tested and are not authorised for use in children. In particular, 46% medicines prescribed to children in hospital are either unlicensed for their age group or, if licensed, are prescribed off label. Of the children who receive at least one medication in hospital, 67% receive an unlicensed or off-label drug, and in the context of intensive care, this rises to up to 90% of patients. The new Paediatric Regulation entered into force in early 2007 ensure that medicines for use in children are of high quality, ethically evaluated and authorised appropriately. The Paediatric-Use Marketing Authorisation (PUMA) is a new type of marketing authorisation for drugs not covered by a patent, already available on the market for adults. PUMA applies to medicines lacking information and/or appropriate formulation for children of all ages. Thus, the European Medicines Agency (EMA) has published a list of drugs, which azithromycin belongs, as priority medicinal products needing an evaluation in the paediatric population. Bronchopulmonary dysplasia (BPD) is a specific disease of prematurity accompanied by pulmonary inflammation. Multiple factors may contribute to the occurrence of BPD. In infants who are at risk of developing CLD, one frequent finding is colonisation of the preterm lung with the microbe Ureaplasma. Two Meta-Analyses and recent studies have suggested an association between the presence of pulmonary Ureaplasma and the development of BPD. Azithromycin is a macrolide antibiotic active against Ureaplasma spp with anti-inflammatory properties. Thus, it may be effective in reducing the severity of bronchopulmonary diseases in which both infection and inflammation play a role. TINN2 project: the aim of the TINN2 study is to evaluate the efficacy of azithromycin in prevention of bronchopulmonary dysplasia in preterm neonates. TINN2 is a consortium involving European leaders in neonatology, paediatric pharmacology, methodology and several SMEs that will establish links with ethical bodies and regulatory authorities.

Official Title
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A Randomised, Placebo Controlled Trial of Azithromycin for the Prevention of Chronic Lung Disease of Prematurity in Preterm Infants

Conditions
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Bronchopulmonary Dysplasia

Intervention / Treatment
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* Drug: Azithromycin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pre-term, 28w + 6d gestational age (i.e. 28 weeks and 6 days, including infants born as one of a multiple birth) Requirement for respiratory support within 12hrs of birth (intubated, or by noninvasive mechanical ventilation including continuous positive airway pressure) Presence of an indwelling intravenous line for drug administration Inborn, or born at site within the recruiting centre's neonatal network where follow up will be possible Exclusion Criteria: In the opinion of the PI, babies unlikely to survive until 48 hours after birth Exposure to another macrolide antibiotic Presence of major surgical or congenital abnormalities (not including patent ductus arteriosus or patent foramen ovale) Infants born as part of a multiple pregnancy of three or more (i.e. triplets or more) Contraindication of azithromycin as specified in the summary of characteristics of the product. Participation in other clinical trials involving Investigational Medicinal Products (IMPs)

Ages Eligible for Study
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Minimum Age: 23 Weeks
Maximum Age: 28 Weeks

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Azithromycin<br>10mg/kg azithromycin IV daily (administered over a period of at least one 1 hour) for a period of 10 days. | Drug: Azithromycin<br>* Azithromycin IV 10mg/kg daily for 10 days<br>|
| Placebo Comparator: Placebo<br>Placebo IV daily (administered over a period of at least one 1 hour) for a period of 10 days. | Drug: Placebo<br>* Azithromycin placebo (5% Dextrose) daily for 10 days<br>* Other names: 5% Dextrose;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The proportion of surviving infants without CLD (Chronic Lung Disease) in the azithromycin treatment group when compared to placebo at 36 weeks post-menstrual age. |  | 36 weeks post-menstrual age | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mortality rate (at 28 days, 36 weeks PMA, 2 years) |  | 28 days, 36 weeks PMA, 2 years | 
| Severity of CLD (Chronic Lung Disease) according to NIH definition |  | 36 weeks PMA | 
| Microbiology assessment | Microbiology assessment at baseline and days 5, 10, 21: Pulmonary colonisation by Ureaplasma spp. and Mycoplasma spp. (respiratory culture of endotracheal/nasopharyngeal aspirates and nasogastric aspirates (nasogastric only for Ureaplasma spp. at baseline) and species-specific quantitative PCR) | Baseline and days 5, 10, 21 | 
| Inflammation Markers | Subroup of patients: Inflammatory markers at baseline and days 5, 10, 21 in plasma and bronchoalveolar lavage Identification of the following: IL-1, IL-6, IL-8, TNF-a, MCP-1, PMN/Am/TCC, C5a. | Baseline and days 5, 10, 21 | 
| Duration of positive pressure respiratory support (i.e. conventional mechanical ventilation, nasal ventilation, continuous positive airway pressure, CPAP) and supplemental oxygen |  | up to 36 weeks PMA | 
| Emergence of resistance to azithromycin in Ureaplasma spp. isolated from endotracheal or nasopharyngeal samples at baseline, days 5, 10 and 21 | On each positive PCR a culture will be performed. Then, an antibiotic susceptibility testing upon positive cultures | Baseline, days 5, 10 and 21 | 
| Resistance to azithromycin among microbes isolated from stool or rectal swab obtained at baseline and day 21 | Antibiotic susceptibility testing on any identified microbes | Baseline and day 21 | 
| Plasma concentrations | Each patients to be allocated two sample timepoints from the following schedule: Sample1: 1 sample within 5 min after the end of dose administration (day 1) Or 1 sample at 6 hours after start of infusion (day 1) Or 1 sample at 12 hours after start of infusion (day 1) Sample 2: 1 sample at 48 hours - just prior to the third administration (day 3) Or 1 sample at 144 hours- just prior to the sixth administration (day 6) | days 1, 3, 6 as required | 
| Exposure to antibiotics other than azithromycin during the hospital stay |  | up to 36weeks PMA | 
| Development of complications of prematurity | Development of complications of prematurity: Nosocomial infection (sepsis, meningitis, pneumonia); intraventricular haemorrhage; necrotising enterocolitis; retinopathy of prematurity; patent ductus arteriosus; pulmonary hemorrhage, pneumothorax and pulmonary interstitial emphysema during hospital stay | 24 months | 
| Number of Adverse Events |  | 24 months | 
| Number of participants with dysrhythmic episodes and QTc interval |  | 24 months | 
| C-Reactive Protein |  | 24 months | 
| Neurodevelopmental assessment: Assessment of neurodevelopment using the 3rd edition of the Bayley Scales of Infant Development at the corrected age of 24 months | Long-term follow up at the corrected age of 24 months | 24 months | 
| Respiratory function assessment: Assessment of respiratory symptoms using a validated International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire | Long-term follow up at the corrected age of 24 months | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neonates, Preterm, Azithromycin, Ureaplasma, Chronic Lung disease, Bronchopulmonary dysplasia