Bronchopulmonary DysplasiaPhase 3TINN2NCT02282176
TINN2: Treat Infection in NeoNates 2
A Phase 3 study testing Azithromycin in people with Bronchopulmonary Dysplasia, run by Institut National de la Santé Et de la Recherche Médicale, France at 16 sites in 9 countries.
Trial summary
The aim of the TINN2 study is to evaluate the efficacy of azithromycin in prevention of bronchopulmonary dysplasia in preterm neonates. Read more about this study
- Who is it for?
- Ages 23 to 28 weeks
- Conditions the study is for
- Bronchopulmonary Dysplasia
- What is being tested?
- Azithromycin
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 0 participants
- Where
- 16 sitesin 9 countries
- Study dates
- Jan 2015to Jan 2018
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 23 to 28 weeks
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- 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
Who cannot join
- 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)
Trial locations and contacts
16 sites in 9 countries.
16 sites in 9 countries
France4 sites
Assistance Publique Hôpitaux de Paris (APHP)
Paris
Inserm-Transfert (IT)
Paris
Institut National de la Santé et de la Recherche Médicale (INSERM)
Paris
Only for children pharmaceuticals (04CP)
Paris
United Kingdom3 sites
Cardiff University (CU)
Cardiff
University of Liverpool (UOL)
Liverpool
Simcyp Limited (SimCyp)
Sheffield
Germany2 sites
Heinrich-Heine-Universität Düsseldorf (UDUS)
Düsseldorf
University of Ulm (UUlm)
Ulm
Hungary2 sites
Semmelweis University Budapest, Faculty of Medicine (SOTE)
Budapest
Pandy Kalman County Hospital
Gyula
About this study
Official title: A Randomised, Placebo Controlled Trial of Azithromycin for the Prevention of Chronic Lung Disease of Prematurity in Preterm Infants
The aim of the TINN2 study is to evaluate the efficacy of azithromycin in prevention of bronchopulmonary dysplasia in preterm neonates.
Read the 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.
- Conditions
- Bronchopulmonary Dysplasia
- Being tested
- Azithromycin, Placebo
- Keywords
- Neonates, Preterm, Azithromycin, Ureaplasma, Chronic Lung disease, Bronchopulmonary dysplasia
- Medical subject headings
- Bronchopulmonary Dysplasia, Premature Birth
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AzithromycinDrug
Azithromycin IV 10mg/kg daily for 10 days
PlaceboDrug
Also called 5% Dextrose
Azithromycin placebo (5% Dextrose) daily for 10 days
| Study group | Role | What they receive |
|---|---|---|
| Azithromycin | Experimental | 10mg/kg azithromycin IV daily (administered over a period of at least one 1 hour) for a period of 10 days. Receives: Drug: Azithromycin |
| Placebo | Placebo comparator | Placebo IV daily (administered over a period of at least one 1 hour) for a period of 10 days. Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 36 weeks post-menstrual age
Secondary outcomes (15)
Mortality rate (at 28 days, 36 weeks PMA, 2 years)
Measured: 28 days, 36 weeks PMA, 2 years
Severity of CLD (Chronic Lung Disease) according to NIH definition
Measured: 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)
Measured: 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.
Measured: 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
Measured: 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
Measured: 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
Measured: 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)
Measured: days 1, 3, 6 as required
Exposure to antibiotics other than azithromycin during the hospital stay
Measured: 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
Measured: 24 months
Number of Adverse Events
Measured: 24 months
Number of participants with dysrhythmic episodes and QTc interval
Measured: 24 months
C-Reactive Protein
Measured: 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
Measured: 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
Measured: 24 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted4 Nov 2014 (estimated)
- Study startJan 2015
- Primary completionJan 2017 (estimated)
- Study completionJan 2018 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Bronchopulmonary DysplasiaStudies of the same condition, open and under way.
- More trials run by Institut National de la Santé Et de la Recherche Médicale, FranceThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Sponsor type
- Other government
- Collaborators
- 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
- Responsible party
- Sponsor
- Investigators
- Sailesh Kotecha, Principal investigator, Cardiff University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02282176
- Sponsor's protocol ID
- C12-75
- Other IDs
- 2013-003889-14
- Acronym
- TINN2
- Status last verified
- Feb 2016
- First submitted
- 17 Oct 2014
- Last updated
- 25 Feb 2016
- Results posted
- No
- Data monitoring committee
- Yes
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.
PubMed 21697219Pansieri 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.
PubMed 24518104Lowe 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.
PubMed 24445836
Study at a glance
From the registry record, last updated by the sponsor on 25 Feb 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Randomised, Placebo Controlled Trial of Azithromycin for the Prevention of Chronic Lung Disease of Prematurity in Preterm Infants
- ClinicalTrials.gov ID
- NCT02282176
- Acronym / sponsor ID
- TINN2 / C12-75
- Conditions
- Bronchopulmonary Dysplasia
- Keywords
- Neonates, Preterm, Azithromycin, Ureaplasma, Chronic Lung disease, Bronchopulmonary dysplasia
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Withdrawn
- Enrolment
- 0 participants (actual)
- Lead sponsor
- Institut National de la Santé Et de la Recherche Médicale, FranceOther government
- Collaborators
- 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
- Study start
- Jan 2015
- Primary completion
- Jan 2017 (estimated)
- Study completion
- Jan 2018 (estimated)
- First posted
- 4 Nov 2014 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Azithromycin | Experimental | Drug: Azithromycin10mg/kg azithromycin IV daily (administered over a period of at least one 1 hour) for a period of 10 days. |
| Placebo | Placebo comparator | Drug: PlaceboPlacebo IV daily (administered over a period of at least one 1 hour) for a period of 10 days. |
Who may qualify
- Ages
- 23 to 28 weeks
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (4 listed)
- 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
Key exclusion criteria (6 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| AzithromycinAzithromycin IV 10mg/kg daily for 10 days | Drug | Azithromycin |
| PlaceboAlso: 5% DextroseAzithromycin placebo (5% Dextrose) daily for 10 days | Drug | Placebo |
Primary outcome
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
15 secondary outcomes
Mortality rate (at 28 days, 36 weeks PMA, 2 years)
Time frame: 28 days, 36 weeks PMA, 2 years
Severity of CLD (Chronic Lung Disease) according to NIH definition
Time frame: 36 weeks PMA
Microbiology assessment
Time frame: Baseline and days 5, 10, 21
Inflammation Markers
Time frame: 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
Time frame: 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
Time frame: Baseline, days 5, 10 and 21
Resistance to azithromycin among microbes isolated from stool or rectal swab obtained at baseline and day 21
Time frame: Baseline and day 21
Plasma concentrations
Time frame: days 1, 3, 6 as required
Exposure to antibiotics other than azithromycin during the hospital stay
Time frame: up to 36weeks PMA
Development of complications of prematurity
Time frame: 24 months
Number of Adverse Events
Time frame: 24 months
Number of participants with dysrhythmic episodes and QTc interval
Time frame: 24 months
C-Reactive Protein
Time frame: 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
Time frame: 24 months
Respiratory function assessment: Assessment of respiratory symptoms using a validated International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire
Time frame: 24 months
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 25 Feb 2016.
- Background: PubMed 21697219Turner 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.
- Background: PubMed 24518104Pansieri 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.
- Background: PubMed 24445836Lowe 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.
- TINN2 websiteLink provided by the sponsor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Sailesh Kotecha principal investigator
Cardiff University
16 sites in 9 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Azithromycin in people with Bronchopulmonary Dysplasia, run by Institut National de la Santé Et de la Recherche Médicale, France at 16 sites in 9 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: withdrawn, as of the sponsor's last update on 25 Feb 2016. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 16 sites in France, United Kingdom, Germany, Hungary, Belgium and 4 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was withdrawn before enrolling participants, so there are no results.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome 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. (time frame: 36 weeks post-menstrual age). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02282176, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 Feb 2016.