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TINN2: Treat Infection in NeoNates 2 (TINN2)

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ClinicalTrials.gov Identifier: NCT02282176
Recruitment Status : Withdrawn
First Posted : November 4, 2014
Last Update Posted : February 25, 2016
Sponsor:
Collaborators:
Inserm-Transfert (IT)
University of Liverpool
Cardiff University
University of Nottingham
Erasmus Medical Center
Heinrich-Heine-Universität Düsseldorf (UDUS)
Assistance Publique - Hôpitaux de Paris
Mario Negri Institute (IRFMN)
Advanced Biological Laboratories ABL (ABL SA)
Simcyp Limited (SimCyp)
Only For Children Pharmaceuticals
University of Ulm
Karolinska Institutet
Centre Hospitalier Chrétien (CHC)
Semmelweis University
Information provided by (Responsible Party):
Institut National de la Santé Et de la Recherche Médicale, France

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

Condition or disease Intervention/treatment Phase
Bronchopulmonary Dysplasia Drug: Azithromycin Drug: Placebo Phase 3

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 : Interventional  (Clinical Trial)
Actual Enrollment : 0 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: A Randomised, Placebo Controlled Trial of Azithromycin for the Prevention of Chronic Lung Disease of Prematurity in Preterm Infants
Study Start Date : January 2015
Estimated Primary Completion Date : January 2017
Estimated Study Completion Date : January 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lung Diseases

Arm Intervention/treatment
Experimental: Azithromycin
10mg/kg azithromycin IV daily (administered over a period of at least one 1 hour) for a period of 10 days.
Drug: Azithromycin
Azithromycin IV 10mg/kg daily for 10 days

Placebo Comparator: Placebo
Placebo IV daily (administered over a period of at least one 1 hour) for a period of 10 days.
Drug: Placebo
Azithromycin placebo (5% Dextrose) daily for 10 days
Other Name: 5% Dextrose




Primary Outcome Measures :
  1. 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 ]

Secondary Outcome Measures :
  1. Mortality rate (at 28 days, 36 weeks PMA, 2 years) [ Time Frame: 28 days, 36 weeks PMA, 2 years ]
  2. Severity of CLD (Chronic Lung Disease) according to NIH definition [ Time Frame: 36 weeks PMA ]
  3. Microbiology assessment [ Time Frame: Baseline and days 5, 10, 21 ]

    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)


  4. Inflammation Markers [ Time Frame: Baseline and days 5, 10, 21 ]

    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.


  5. 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 ]
  6. 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 ]
    On each positive PCR a culture will be performed. Then, an antibiotic susceptibility testing upon positive cultures

  7. Resistance to azithromycin among microbes isolated from stool or rectal swab obtained at baseline and day 21 [ Time Frame: Baseline and day 21 ]
    Antibiotic susceptibility testing on any identified microbes

  8. Plasma concentrations [ Time Frame: days 1, 3, 6 as required ]

    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)


  9. Exposure to antibiotics other than azithromycin during the hospital stay [ Time Frame: up to 36weeks PMA ]
  10. Development of complications of prematurity [ Time Frame: 24 months ]
    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

  11. Number of Adverse Events [ Time Frame: 24 months ]
  12. Number of participants with dysrhythmic episodes and QTc interval [ Time Frame: 24 months ]
  13. C-Reactive Protein [ Time Frame: 24 months ]
  14. 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 ]
    Long-term follow up at the corrected age of 24 months

  15. Respiratory function assessment: Assessment of respiratory symptoms using a validated International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire [ Time Frame: 24 months ]
    Long-term follow up at the corrected age of 24 months



Information from the National Library of Medicine

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Ages Eligible for Study:   23 Weeks to 28 Weeks   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02282176


Locations
Belgium
Centre Hospitalier Chrétien (CHC)
Liège, Belgium
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, France
Germany
Heinrich-Heine-Universität Düsseldorf (UDUS)
Dusseldorf, Germany
University of Ulm (UUlm)
Ulm, Germany
Hungary
Semmelweis University Budapest, Faculty of Medicine (SOTE)
Budapest, Hungary
Pandy Kalman County Hospital
Gyula, Hungary
Italy
Mario Negri Institute (IRFMN)
Milan, Italy
Luxembourg
Advanced Biological Laboratories ABL (ABL SA)
Luxembourg, Luxembourg
Netherlands
Erasmus-University Medical Center (ERAMUS)
Rotterdam, Netherlands
Sweden
Karolinska Institutet (KI)
Stockholm, Sweden
United Kingdom
Cardiff University (CU)
Cardiff, United Kingdom
University of Liverpool (UOL)
Liverpool, United Kingdom
Simcyp Limited (SimCyp)
Sheffield, United Kingdom
Sponsors and Collaborators
Institut National de la Santé Et de la Recherche Médicale, France
Inserm-Transfert (IT)
University of Liverpool
Cardiff University
University of Nottingham
Erasmus Medical Center
Heinrich-Heine-Universität Düsseldorf (UDUS)
Assistance Publique - Hôpitaux de Paris
Mario Negri Institute (IRFMN)
Advanced Biological Laboratories ABL (ABL SA)
Simcyp Limited (SimCyp)
Only For Children Pharmaceuticals
University of Ulm
Karolinska Institutet
Centre Hospitalier Chrétien (CHC)
Semmelweis University
Investigators
Principal Investigator: Sailesh Kotecha Cardiff University

Additional Information:
Publications:
Responsible Party: Institut National de la Santé Et de la Recherche Médicale, France
ClinicalTrials.gov Identifier: NCT02282176     History of Changes
Other Study ID Numbers: C12-75
2013-003889-14 ( EudraCT Number )
First Posted: November 4, 2014    Key Record Dates
Last Update Posted: February 25, 2016
Last Verified: February 2016

Keywords provided by Institut National de la Santé Et de la Recherche Médicale, France:
Neonates
Preterm
Azithromycin
Ureaplasma
Chronic Lung disease
Bronchopulmonary dysplasia

Additional relevant MeSH terms:
Bronchopulmonary Dysplasia
Ventilator-Induced Lung Injury
Lung Injury
Lung Diseases
Respiratory Tract Diseases
Infant, Premature, Diseases
Infant, Newborn, Diseases