E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Bronchopulmonary Dysplasia |
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E.1.1.1 | Medical condition in easily understood language |
Chronic Lung Disease of Prematurity |
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E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10006475 |
E.1.2 | Term | Bronchopulmonary dysplasia |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10066204 |
E.1.2 | Term | Chronic lung disease of prematurity |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To assess the efficacy azithromycin on the rate of survival without CLD in preterm infants of ≤28 weeks (28+6) gestation |
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E.2.2 | Secondary objectives of the trial |
Mortality rate at 28 days of life, 36 weeks PMA, 2 years of life ; Severity of CLD according to NIH definition; Pulmonary colonisation by Ureaplasma spp.; Duration of positive pressure respiratory support; Inflammatory markers in bronchoalveolar lavage; Microbiological markers including Ureaplasma spp, Mycoplasma spp; Resistance to azithromycin in Ureaplasma; Resistance to azithromycin among microbes isolated from stool or rectal swab; Exposure to supplemental antibiotics; Development of complications of prematurity; Safety and tolerability assessment; Pharmacokinetics; Respiratory, neurological and cognitive development the corrected age of 24 months |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
PK study as included in the main trial protocol: This sub-study will be conducted in selected centres only to include 100 infants.
The objective of the PK study is to validate the simulation used to identify the appropriate dose of azithromycin to eradicate Ureaplasma.
Inflammatory markers study as included in the main protocol: This sub-study will This sub-study will be conducted in selected centres only to include 200 infants.
The objective it so assess the difference in levels of cytokines in lung fluid between the azithromycin and placebo. Cytokines (such as IL6 and IL8) are 'biomarkers' of inflammation and a reduction of these in the treatment group will point towards the efficacy of azithromycin as an anti-inflammatory.
Pharmacogenetic sub-study as included in the main protocol: The objective of the genetic sub-study are 1) to assess the impact of genetic factors on the distribution of azithromycin inside white blood cells important for instigating an immune response (macrophages); 2) to explore the genetic influence on predisposition to infections |
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E.3 | Principal inclusion criteria |
a) Pre-term, ≤28 weeks gestational age (i.e. 28 weeks and 6 days, including infants born as one of a multiple birth)
b) Requirement for respiratory support within 12hrs of birth (intubated, or by non-invasive mechanical ventilation inc. continuous positive airway pressure)
c) Presence of an indwelling intravenous line for drug administration
d) Inborn, or born at site within the recruiting centre’s neonatal network where follow up will be possible
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E.4 | Principal exclusion criteria |
a) In the opinion of the PI, babies unlikely to survive until 48 hours after birth
b) Exposure to another macrolide antibiotic
c) Presence of major surgical or congenital abnormalities (not including patent ductus arteriosus or patent foramen ovale)
d) Infants born as part of a multiple pregnancy of three or more (i.e. triplets or more)
e) Participation in other clinical trials involving IMPs
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E.5 End points |
E.5.1 | Primary end point(s) |
Chronic Lung disease or Death |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
36 weeks postmenstrual age |
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E.5.2 | Secondary end point(s) |
1. Mortality
2. Severity of CLD according to NIH definition
3. Pulmonary colonisation by Ureaplasma spp.
4. Duration of positive pressure respiratory support
5. Inflammatory markers in bronchoalveolar lavage
6. Resistance to azithromycin in Ureaplasma
7. Resistance to azithromycin among microbes isolated from stool or rectal swab
7. Exposure to supplementary antibiotics
8. Development of complications of prematurity
9. Safety and tolerability
10. Pharmacokinetics
11. Respiratory, neurological and cognitive measurements
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. 28 days of life; 36 weeks postmenstrual age; 2 years of life
2. 36 weeks postmenstrual age
3. Baseline, days 5/10/21 following first dose
4. Discharge from hospital
5. Baseline, days 5/10/21 following first dose
6. Baseline, day 21 following first dose
7. Until discharge from hospital
8. Until discharge from hospital
9. Until discharge from hospital
10. Days 1, 3 and 5 following first dose
11. 24 months corrected age |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | Yes |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 30 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |