TINN2: Treat Infection in NeoNates 2

Bronchopulmonary Dysplasia Clinical Trial

— TINN2  

Official title:

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

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT02282176
• Other study ID #: C12-75
• Secondary ID: 2013-003889-14
• Status: Withdrawn
• Phase: Phase 3
• First received: October 17, 2014
• Last updated: February 24, 2016
• Start date: January 2015
• Est. completion date: January 2018

Study information

• Verified date: February 2016
• Source: Institut National de la Santé Et de la Recherche Médicale, France
• Contact: n/a
• Is FDA regulated: No
• Health authority: France: Agence Nationale de Sécurité du Médicament et des produits de santéGermany: Federal Institute for Drugs and Medical DevicesHungary: National Institute for Quality and Organizational Development in Healthcare and MedicinesItaly: The Italian Medicines AgencyNetherlands: The Central Committee on Research Involving Human Subjects (CCMO)Sweden: Medical Products AgencyUnited Kingdom: Medicines and Healthcare Products Regulatory Agency
• Study type: Interventional

Clinical Trial Summary

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

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.

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: January 2018
• Est. primary completion date: January 2017
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 23 Weeks to 28 Weeks

Eligibility

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)

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Prevention

Related Conditions & MeSH terms

• Bronchopulmonary Dysplasia

Intervention

Drug:
• Azithromycin
Azithromycin IV 10mg/kg daily for 10 days
• Placebo
Azithromycin placebo (5% Dextrose) daily for 10 days

Locations

Country	Name	City	State
Belgium	Centre Hospitalier Chrétien (CHC)	Liège
France	Assistance Publique Hôpitaux de Paris (APHP)	Paris
France	Inserm-Transfert (IT)	Paris
France	Institut National de la Santé et de la Recherche Médicale (INSERM)	Paris
France	Only for children pharmaceuticals (04CP)	Paris
Germany	Heinrich-Heine-Universität Düsseldorf (UDUS)	Dusseldorf
Germany	University of Ulm (UUlm)	Ulm
Hungary	Semmelweis University Budapest, Faculty of Medicine (SOTE)	Budapest
Hungary	Pandy Kalman County Hospital	Gyula
Italy	Mario Negri Institute (IRFMN)	Milan
Luxembourg	Advanced Biological Laboratories ABL (ABL SA)	Luxembourg
Netherlands	Erasmus-University Medical Center (ERAMUS)	Rotterdam
Sweden	Karolinska Institutet (KI)	Stockholm
United Kingdom	Cardiff University (CU)	Cardiff
United Kingdom	University of Liverpool (UOL)	Liverpool
United Kingdom	Simcyp Limited (SimCyp)	Sheffield

Sponsors (16)

Lead Sponsor

Collaborator

Institut National de la Santé Et de la Recherche Médicale, France

Advanced Biological Laboratories ABL (ABL SA), Assistance Publique - Hôpitaux de Paris, Cardiff University, Centre Hospitalier Chrétien (CHC), Erasmus-University Medical Center (ERAMUS), Heinrich-Heine-Universität Düsseldorf (UDUS), Inserm-Transfert (IT), Karolinska Institutet (KI), Mario Negri Institute (IRFMN), Only For Children Pharmaceuticals, Semmelweis University, Simcyp Limited (SimCyp), University of Liverpool, University of Nottingham, University of Ulm

Countries where clinical trial is conducted

Belgium,  France,  Germany,  Hungary,  Italy,  Luxembourg,  Netherlands,  Sweden,  United Kingdom, 

References & Publications (3)

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. Review. — View 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. — View 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. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Yes
Secondary	Mortality rate (at 28 days, 36 weeks PMA, 2 years)		28 days, 36 weeks PMA, 2 years	Yes
Secondary	Severity of CLD (Chronic Lung Disease) according to NIH definition		36 weeks PMA	Yes
Secondary	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	Yes
Secondary	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	Yes
Secondary	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	Yes
Secondary	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	Yes
Secondary	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	Yes
Secondary	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	No
Secondary	Exposure to antibiotics other than azithromycin during the hospital stay		up to 36weeks PMA	Yes
Secondary	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	Yes
Secondary	Number of Adverse Events		24 months	Yes
Secondary	Number of participants with dysrhythmic episodes and QTc interval		24 months	Yes
Secondary	C-Reactive Protein		24 months	Yes
Secondary	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	Yes
Secondary	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	Yes

External Links

•   TINN2 website