Clinical trial NCT02282176: TINN2: Treat Infection in NeoNates 2
Official title: A Randomised, Placebo Controlled Trial of Azithromycin for the Prevention of Chronic Lung Disease of Prematurity in Preterm Infants
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE3
Conditions: Bronchopulmonary Dysplasia
Keywords: Neonates
Preterm
Azithromycin
Ureaplasma
Chronic Lung disease
Bronchopulmonary dysplasia
Lead sponsor: Institut National de la Santé Et de la Recherche Médicale, France
Sponsor class: OTHER_GOV
Collaborators: name: University of Liverpool
name: Cardiff University
name: University of Nottingham
name: Erasmus Medical Center
name: Heinrich-Heine-Universität Düsseldorf (UDUS)
name: Assistance Publique - Hôpitaux de Paris
name: Mario Negri Institute (IRFMN)
name: Advanced Biological Laboratories ABL (ABL SA)
name: Simcyp Limited (SimCyp)
name: Only For Children Pharmaceuticals
name: University of Ulm
name: Karolinska Institutet
name: Centre Hospitalier Chrétien (CHC)
name: Semmelweis University
First posted: 2014-11-04
Enrollment: 0
Sex: ALL
Minimum age (years): 23
Maximum age (years): 28
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: The aim of the TINN2 study is to evaluate the efficacy of azithromycin in prevention of bronchopulmonary dysplasia in preterm neonates.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

1. Pre-term, 28w + 6d gestational age (i.e. 28 weeks and 6 days, including infants born as one of a multiple birth)
2. Requirement for respiratory support within 12hrs of birth (intubated, or by noninvasive mechanical ventilation including continuous positive airway pressure)
3. Presence of an indwelling intravenous line for drug administration
4. Inborn, or born at site within the recruiting centre's neonatal network where follow up will be possible

Exclusion Criteria:

1. In the opinion of the PI, babies unlikely to survive until 48 hours after birth
2. Exposure to another macrolide antibiotic
3. Presence of major surgical or congenital abnormalities (not including patent ductus arteriosus or patent foramen ovale)
4. Infants born as part of a multiple pregnancy of three or more (i.e. triplets or more)
5. Contraindication of azithromycin as specified in the summary of characteristics of the product.
6. Participation in other clinical trials involving Investigational Medicinal Products (IMPs)

Primary outcomes:
measure: 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.
timeFrame: 36 weeks post-menstrual age
Secondary outcomes:
measure: Mortality rate (at 28 days, 36 weeks PMA, 2 years)
timeFrame: 28 days, 36 weeks PMA, 2 years
measure: Severity of CLD (Chronic Lung Disease) according to NIH definition
timeFrame: 36 weeks PMA
measure: Microbiology assessment
timeFrame: Baseline and days 5, 10, 21
measure: Inflammation Markers
timeFrame: Baseline and days 5, 10, 21
measure: Duration of positive pressure respiratory support (i.e. conventional mechanical ventilation, nasal ventilation, continuous positive airway pressure, CPAP) and supplemental oxygen
timeFrame: up to 36 weeks PMA
measure: Emergence of resistance to azithromycin in Ureaplasma spp. isolated from endotracheal or nasopharyngeal samples at baseline, days 5, 10 and 21
timeFrame: Baseline, days 5, 10 and 21
measure: Resistance to azithromycin among microbes isolated from stool or rectal swab obtained at baseline and day 21
timeFrame: Baseline and day 21
measure: Plasma concentrations
timeFrame: days 1, 3, 6 as required
measure: Exposure to antibiotics other than azithromycin during the hospital stay
timeFrame: up to 36weeks PMA
measure: Development of complications of prematurity
timeFrame: 24 months
measure: Number of Adverse Events
timeFrame: 24 months
measure: Number of participants with dysrhythmic episodes and QTc interval
timeFrame: 24 months
measure: C-Reactive Protein
timeFrame: 24 months
measure: Neurodevelopmental assessment: Assessment of neurodevelopment using the 3rd edition of the Bayley Scales of Infant Development at the corrected age of 24 months
timeFrame: 24 months
measure: Respiratory function assessment: Assessment of respiratory symptoms using a validated International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire
timeFrame: 24 months
Other outcomes:
Locations:
city: Liège
country: Belgium
facility: Centre Hospitalier Chrétien (CHC)
city: Paris
country: France
facility: Assistance Publique Hôpitaux de Paris (APHP)
city: Paris
country: France
facility: Inserm-Transfert (IT)
city: Paris
country: France
facility: Institut National de la Santé et de la Recherche Médicale (INSERM)
city: Paris
country: France
facility: Only for children pharmaceuticals (04CP)
city: Dusseldorf
country: Germany
facility: Heinrich-Heine-Universität Düsseldorf (UDUS)
city: Ulm
country: Germany
facility: University of Ulm (UUlm)
city: Budapest
country: Hungary
facility: Semmelweis University Budapest, Faculty of Medicine (SOTE)
city: Gyula
country: Hungary
facility: Pandy Kalman County Hospital
city: Milan
country: Italy
facility: Mario Negri Institute (IRFMN)
city: Luxembourg
country: Luxembourg
facility: Advanced Biological Laboratories ABL (ABL SA)
city: Rotterdam
country: Netherlands
facility: Erasmus-University Medical Center (ERAMUS)
city: Stockholm
country: Sweden
facility: Karolinska Institutet (KI)
city: Cardiff
country: United Kingdom
facility: Cardiff University (CU)
city: Liverpool
country: United Kingdom
facility: University of Liverpool (UOL)
city: Sheffield
country: United Kingdom
facility: Simcyp Limited (SimCyp)
Study officials:
affiliation: Cardiff University
name: Sailesh Kotecha
role: PRINCIPAL_INVESTIGATOR
References:
citation: Turner MA, Jacqz-Aigrain E, Kotecha S. Azithromycin, Ureaplasma and chronic lung disease of prematurity: a case study for neonatal drug development. Arch Dis Child. 2012 Jun;97(6):573-7. doi: 10.1136/adc.2010.195180. Epub 2011 Jun 22.
citation: Pansieri C, Pandolfini C, Elie V, Turner MA, Kotecha S, Jacqz-Aigrain E, Bonati M. Ureaplasma, bronchopulmonary dysplasia, and azithromycin in European neonatal intensive care units: a survey. Sci Rep. 2014 Feb 12;4:4076. doi: 10.1038/srep04076.
citation: Lowe J, Watkins WJ, Edwards MO, Spiller OB, Jacqz-Aigrain E, Kotecha SJ, Kotecha S. Association between pulmonary ureaplasma colonization and bronchopulmonary dysplasia in preterm infants: updated systematic review and meta-analysis. Pediatr Infect Dis J. 2014 Jul;33(7):697-702. doi: 10.1097/INF.0000000000000239.