- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02282176
TINN2: Treat Infection in NeoNates 2 (TINN2)
A Randomised, Placebo Controlled Trial of Azithromycin for the Prevention of Chronic Lung Disease of Prematurity in Preterm Infants
Study Overview
Status
Conditions
Intervention / Treatment
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.
Study Type
Phase
- Phase 3
Contacts and Locations
Study Locations
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Liège, Belgium
- Centre Hospitalier Chrétien (CHC)
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Paris, France
- Assistance Publique Hopitaux de Paris (APHP)
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Paris, France
- Inserm-Transfert (IT)
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Paris, France
- Institut National de la santé et de la recherché Médicale (INSERM)
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Paris, France
- Only for children pharmaceuticals (04CP)
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Dusseldorf, Germany
- Heinrich-Heine-Universität Düsseldorf (UDUS)
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Ulm, Germany
- University of Ulm (UUlm)
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Budapest, Hungary
- Semmelweis University Budapest, Faculty of Medicine (SOTE)
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Gyula, Hungary
- Pándy Kálmán County Hospital
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Milan, Italy
- Mario Negri Institute (IRFMN)
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Luxembourg, Luxembourg
- Advanced Biological Laboratories ABL (ABL SA)
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Rotterdam, Netherlands
- Erasmus-University Medical Center (ERAMUS)
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Stockholm, Sweden
- Karolinska Institutet (KI)
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Cardiff, United Kingdom
- Cardiff University (CU)
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Liverpool, United Kingdom
- University of Liverpool (UOL)
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Sheffield, United Kingdom
- Simcyp Limited (SimCyp)
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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)
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Prevention
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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Experimental: Azithromycin
10mg/kg azithromycin IV daily (administered over a period of at least one 1 hour) for a period of 10 days.
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Azithromycin IV 10mg/kg daily for 10 days
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Placebo Comparator: Placebo
Placebo IV daily (administered over a period of at least one 1 hour) for a period of 10 days.
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Azithromycin placebo (5% Dextrose) daily for 10 days
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
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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.
Time Frame: 36 weeks post-menstrual age
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36 weeks post-menstrual age
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
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Mortality rate (at 28 days, 36 weeks PMA, 2 years)
Time Frame: 28 days, 36 weeks PMA, 2 years
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28 days, 36 weeks PMA, 2 years
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Severity of CLD (Chronic Lung Disease) according to NIH definition
Time Frame: 36 weeks PMA
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36 weeks PMA
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Microbiology assessment
Time Frame: Baseline and days 5, 10, 21
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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
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Inflammation Markers
Time Frame: Baseline and days 5, 10, 21
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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
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Duration of positive pressure respiratory support (i.e. conventional mechanical ventilation, nasal ventilation, continuous positive airway pressure, CPAP) and supplemental oxygen
Time Frame: up to 36 weeks PMA
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up to 36 weeks PMA
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Emergence of resistance to azithromycin in Ureaplasma spp. isolated from endotracheal or nasopharyngeal samples at baseline, days 5, 10 and 21
Time Frame: Baseline, days 5, 10 and 21
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On each positive PCR a culture will be performed.
Then, an antibiotic susceptibility testing upon positive cultures
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Baseline, days 5, 10 and 21
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Resistance to azithromycin among microbes isolated from stool or rectal swab obtained at baseline and day 21
Time Frame: Baseline and day 21
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Antibiotic susceptibility testing on any identified microbes
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Baseline and day 21
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Plasma concentrations
Time Frame: days 1, 3, 6 as required
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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
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Exposure to antibiotics other than azithromycin during the hospital stay
Time Frame: up to 36weeks PMA
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up to 36weeks PMA
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Development of complications of prematurity
Time Frame: 24 months
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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
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24 months
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Number of Adverse Events
Time Frame: 24 months
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24 months
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Number of participants with dysrhythmic episodes and QTc interval
Time Frame: 24 months
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24 months
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C-Reactive Protein
Time Frame: 24 months
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24 months
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Neurodevelopmental assessment: Assessment of neurodevelopment using the 3rd edition of the Bayley Scales of Infant Development at the corrected age of 24 months
Time Frame: 24 months
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Long-term follow up at the corrected age of 24 months
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24 months
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Respiratory function assessment: Assessment of respiratory symptoms using a validated International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire
Time Frame: 24 months
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Long-term follow up at the corrected age of 24 months
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24 months
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Collaborators and Investigators
Collaborators
Investigators
- Principal Investigator: Sailesh Kotecha, Cardiff University
Publications and helpful links
General Publications
- 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.
- 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.
- 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.
Study record dates
Study Major Dates
Study Start
Primary Completion (Anticipated)
Study Completion (Anticipated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- C12-75
- 2013-003889-14 (EudraCT Number)
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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