Does selective early treatment of patent ductus arteriosus in extreme preterm infants reduce the complications and improve their long-term outcome?
| ISRCTN | ISRCTN84264977 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN84264977 |
| EudraCT/CTIS number | 2013-005336-23 |
- Submission date
- 13/08/2010
- Registration date
- 15/09/2010
- Last edited
- 15/07/2024
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Neonatal Diseases
Prospectively registered
Protocol
Statistical analysis plan
Results
Individual participant data
Plain English Summary
Contact information
Prof Samir Gupta
Scientific
Scientific
Durham University
University Hospital of North Tees
Hardwick Road
Stockton-on-Tees
TS19 8PE
United Kingdom
| Phone | +974 (0)31000586; +44 (0)7584905920 |
|---|---|
| samir.gupta@durham.ac.uk |
Study information
| Study design | Multicentre randomized placebo-controlled trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | ISRCTN84264977_PIS_v7.0_10Jul2018.pdf |
| Scientific title | Outcome after Selective early Closure of patent ductus ARteriosus (PDA) in extreme preterm infants: a randomised controlled trial |
| Study acronym | Baby-OSCAR |
| Study hypothesis | Current hypothesis as of 03/08/2023: To determine if the selective treatment of echocardiographically confirmed large PDAs in extremely preterm babies with ibuprofen within 72 hours of birth reduces the incidence of death or bronchopulmonary dysplasia (BPD) at 36 weeks postmenstrual age. _____ Previous hypothesis as of 10/04/2014: To determine if the selective treatment of confirmed large PDAs in extremely preterm babies with ibuprofen within 72 hours of birth reduces the incidence of death or bronchopulmonary dysplasia (BPD) at 36 weeks postmenstrual age. _____ Previous hypothesis: Early echocardiographic screening and targeted treatment of a PDA that fails to constrict spontaneously (LARGE PDA) will result in reduced incidence of death/chronic lung disease at 36 weeks and eventually less death/neurodevelopmental disability at 2 years corrected age. - |
| Ethics approval(s) | Approved 23/05/2014, Health Research Authority NRES Committee East Midlands - Nottingham 2 (Royal Standard Place Nottingham NG1 6FS, Nottingham, NG1 6FS, United Kingdom; +44 (0)115 8839425; NRESCommittee.EastMidlands-Nottingham2@nhs.net), ref: 14/EM/0172 |
| Condition | Patent Ductus Arteriosus (PDA) |
| Intervention | Current interventions as of 10/04/2014: This trial is intending to treat infants in the same window as the prophylaxis trials using ibuprofen with recommended doses as per study protocol. Patients will be randomised (1:1 ratio) to receive study medications or placebo, intravenously. Study medication will be provided as a clear sterile preservative-free solution for intravenous injection. An initial dose of 10 mg/kg will be followed by two doses of 5 mg/kg at 24 and 48 hours apart. The solution of ibuprofen is provided at a concentration of 10 mg/ml in a 5 ml single-use vial, thus 1 ml/kg, followed by two administrations of 0.5 ml/kg, will be required. Previous interventions: This trial is intending to treat infants in the same window as the prophylaxis trials using ibuprofen with recommended doses as per study protocol. Patients will be randomised (1:1 ratio) to receive study medications or placebo, intravenously. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | Not Applicable |
| Phase | Not Applicable |
| Drug / device / biological / vaccine name(s) | Ibuprofen |
| Primary outcome measure | Current primary outcome measures as of 03/08/2023: The primary outcome is defined as a composite outcome of death by 36 weeks postmenstrual age or moderate or severe BPD at 36 weeks post-menstrual age. Severity-Based Diagnostic Criteria for BPD is defined as: Therapy with oxygen >21% and/or respiratory support for ≥28 days and the following: Mild BPD: Baby is breathing room air Moderate BPD: Baby is in 22–29% oxygen, or 0.01–1.0 L/min Severe BPD: FiO2 ≥0.3, or low flow oxygen ≥1.1 L/min, or the baby is receiving any respiratory support (ventilation, CPAP, or high flow oxygen therapy) to achieve saturations of ≥ 91% The need for oxygen is subjective and hence oxygen dependency is confirmed using an ‘oxygen reduction test’. This is based on the threshold at which the baby is able to maintain oxygen saturations ≥91% whilst breathing in air or at a given minimum FiO2. Babies unable to achieve this are considered to be oxygen-dependent. This test only applies to those babies whose oxygen requirements are <0.3, or low flow oxygen <1.1L/min, and who have not received any additional respiratory support in the previous 24h. Babies outside of this are not tested, but data on their oxygen requirements will be collected. _____ Previous primary outcome measures as of 10/04/2014: The primary outcome is defined as a composite outcome of death or BPD at 36 weeks post-menstrual age. BPD is defined as the need for respiratory support and/or oxygen for 28 days or more and at 36 weeks post-menstrual age. The need for oxygen is subjective and hence oxygen dependency will be confirmed using an oxygen reduction test. This is based on whether the baby is able to maintain oxygen saturations over 90% for 1 hour whilst breathing air. Babies unable to achieve this will be considered to be oxygen dependant. _____ Previous primary outcome measures: Death or severe neuro-developmental disability at 2 years corrected age. The Bayley's scale of infant development III will be used to assess outcomes. |
| Secondary outcome measures | Current secondary outcome measures as of 03/08/2023: Short-term outcomes: 1. Death by 36 weeks postmenstrual age 2. Moderate or severe BPD at 36 weeks postmenstrual age 3. Severity of BPD at 36 weeks postmenstrual age 4. Incidence or duration of the following up to discharge: 4.1. Severe intraventricular haemorrhage (IVH) (grade III/IV with ventricular dilatation or intraparenchymal abnormality) 4.2. Cystic periventricular leukomalacia (PVL) 4.3. Non-cystic PVL 4.4. Hydrocephalus 4.5. Babies treated for retinopathy of prematurity (ROP) 4.6. Significant pulmonary haemorrhage (fresh blood in endotracheal tube with increase in respiratory support) 4.7. Treated for pulmonary hypertension with pulmonary vasodilator 4.8. NEC definitive and/or complicated (Bell stage II and above) confirmed by radiology and/or histopathology 4.9. NEC requiring surgery 4.10. Gastrointestinal bleeding (leading to investigation or clinical treatment) within 7 days of the first dose of trial drug administration 4.11. Spontaneous intestinal perforation 4.12. Closed or non-significant PDA (<1.5mm) at around 3 weeks of age (range of 18–24 days), confirmed by ECHO 4.13. PDA ≥1.5mm at around 3 weeks of age (range of 18–24 days) 4.14. Medical open-label treatment of a symptomatic PDA with a COX inhibitor 4.15. Open-label treatment of a symptomatic PDA by surgical treatment 4.16. Administration and duration of inotropic support 4.17. Total duration of respiratory support: 4.17.1. Invasive ventilation through an endotracheal tube 4.17.2. Non-invasive support through nasal CPAP, nasal ventilation, humidified high-flow nasal cannula therapy, or low-flow oxygen ≥1.1L/min 4.18. Discharge home on oxygen 4.19. Duration of initial hospitalisation (birth to discharge home) 4.20. Postnatal steroid use for chronic lung disease 4.21. Tolerance of ibuprofen treatment within the foreseeable SAE reporting range 4.22. Weight gain: a change in z score between birth and discharge (or death if sooner) 4.23. Head circumference: a change in head size z score between randomisation and discharge (or death if sooner) Long-term outcomes assessed at 2 years of age corrected for prematurity: 5. Survival without moderate or severe neurodevelopmental disability (main long-term outcome) 6. Survival 7. Individual components of survival without moderate or severe neurodevelopmental disability (in the four domains of motor, cognitive, hearing and visual function). Cognitive disability will be assessed by determining the standardised non-verbal cognitive subscale and language subscale scores obtained through the Parent Report of Cognitive Abilities–Revised (PARCA-R) assessment. The PARCA-R assessment will be adapted to include questions to assess gross motor, hearing and visual function. 8. Survival without respiratory morbidity. Respiratory morbidity will be assessed by the need for oxygen or respiratory support; presence of persistent cough and/or wheeze; need for regular treatment for respiratory illness; unscheduled attendances at hospital/GP; readmission to hospital for respiratory problems 9. Duration of oxygen supplementation from randomisation 10. A cost-effectiveness analysis will be conducted of deaths and BPD events avoided and national health services used up to 2 years of age corrected for prematurity Process outcomes: 11. Number of doses of trial medication received 12. Adherence to protocol (e.g. protocol violations, incidence of non-symptomatic open-label treatment etc) 13. Study withdrawals _____ Previous secondary outcome measures as of 10/04/2014: Secondary outcomes are divided into short- and long-term outcomes: 1. Short-term outcomes: 1.1. Death before discharge 2. Incidence or duration of the following up to time of neonatal unit discharge: 2.1. Severity of BPD at 36 weeks postmenstrual age 2.2. Severe IVH (grade 3/4 with ventricular dilation or intraparenchymal bleeding) 2.3. Cystic periventricular leukomalacia (PVL) 2.4. Retinopathy of prematurity (ROP) requiring treatment 2.5. Pulmonary haemorrhage 2.6. Pulmonary hypertension 2.7. NEC definitive and/or complicated (Bell stage II and above) confirmed by radiology or histopathology 2.8. NEC requiring surgery 2.9. Gastrointestinal bleeding within 7 days of the first dose of study drug administration 2.10. Spontaneous intestinal perforation 2.11. PDA closure at 3 weeks of age (or hospital discharge, if discharged before this age) 2.12. Medical rescue treatment with a COX inhibitor of a symptomatic PDA 2.13. Administration and duration of inotropic support 2.14. Duration of mechanical ventilation 2.15. Total duration of respiratory support (ventilation + nCPAP/high flow oxygen therapy) 2.16. Discharge home on oxygen 2.17. Duration of initial hospitalisation (birth to neonatal unit discharge home) 2.18. Postnatal steroid use 2.19. Safety and tolerability of ibuprofen treatment 2.20. Number of doses of trial medication received during intervention period 3. Secondary long-term clinical outcomes assessed at 2 years of age corrected for prematurity 3.1. Survival without moderate or severe neurodevelopmental disability 3.2. Individual components of survival without moderate or severe neurodevelopmental disability (in the four domains of motor, cognitive, hearing and visual function) 3.3. Survival without respiratory morbidity 3.4. A cost-effectiveness analysis will be conducted of deaths and BPD events avoided and national health services used up to 2 years of age corrected for prematurity Previous secondary outcome measures: 1. Mortality 2. Complications of prematurity 3. Cardiovascular effects 4. Respiratory outcomes 5. Acute abdominal problems 6. Side effects of medicine 7. Length of hospital stay 8. Developmental outcome at 2 years |
| Overall study start date | 01/07/2014 |
| Overall study end date | 31/08/2023 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Neonate |
| Upper age limit | 3 Days |
| Sex | Both |
| Target number of participants | 730 infants |
| Total final enrolment | 653 |
| Participant inclusion criteria | Current inclusion criteria as of 03/08/2023: 1. Born at 23+0 to 28+6 weeks of gestation 2. Less than 72 hours old 3. Confirmed by echocardiography to have a large PDA which is at least 1.5 mm in diameter (determined by gain optimised colour Doppler) AND has unrestrictive pulsatile (left to right) flow (ratio of flow velocity in PDA Maximum (Vmax) to Minimum (Vmin) > 2:1)) or, growing flow pattern (< 30% right to left), and no clinical concerns of pulmonary hypertension 4. The responsible clinician is uncertain about whether this baby might benefit from treatment to close the PDA 5. Written informed consent has been obtained from the parent(s) _____ Previous inclusion criteria as of 10/04/2014: 1. Born at 23+0 to 28+6 weeks of gestation 2. Less than 72 hours old 3. Confirmed by echocardiography to have a large PDA which is at least 1.5 mm in diameter (determined by gain optimised colour Doppler) AND has unrestrictive pulsatile left to right flow 4. The responsible clinician is uncertain about whether this baby might benefit from treatment to close the PDA 5. Written informed consent has been obtained from the parent(s) _____ Previous inclusion criteria: 1. Preterm infants born between 23+0 and 28+6 weeks gestation 2. Echocardiographic assessment within 24 hours of birth meeting the enrolment criteria 3. Signed parental consent |
| Participant exclusion criteria | Current exclusion criteria as of 03/08/2023: 1. No realistic prospect of survival 2. Severe congenital anomaly 3. Clinical or echocardiography suspicion of congenital structural heart disease that contraindicates treatment with ibuprofen 4. Other conditions that would contraindicate the use of ibuprofen (active bleeding especially intracranial or gastrointestinal bleeding, coagulopathy, thrombocytopenia (platelet count <50,000), renal failure, life threatening infection, pulmonary hypertension, known or suspected necrotising enterocolitis (NEC)) 5. Indomethacin, ibuprofen, or paracetamol administration after birth _____ Previous exclusion criteria as of 10/04/2014: 1. No realistic prospect of survival 2. Severe congenital anomaly 3. Structural heart disease requiring treatment 4. Other conditions that would contraindicate the use of ibuprofen (clinically significant intracranial or gastrointestinal haemorrhage, coagulopathy, thrombocytopenia [platelet count <50,000], renal failure, pulmonary hypertension, known or suspected necrotising enterocolitis [NEC]) 5. Antenatal exposure to cyclo-oxygenase (COX) inhibitors 6. Received indomethacin, ibuprofen or paracetamol administration after birth _____ Previous exclusion criteria: 1. Baby clinically unstable and not expected to survive 2. Congenital anomalies predicted to influence neurodevelopmental outcome 3. Structural heart disease 4. Contraindication to use of ibuprofen (platelet count <50,000) 5. Unlikely to commence first dose of treatment by 24 hours of age |
| Recruitment start date | 01/07/2014 |
| Recruitment end date | 31/12/2020 |
Locations
Countries of recruitment
- England
- United Kingdom
Study participating centre
Professor of Neonatology
Stockton-on-Tees
TS19 8PE
United Kingdom
TS19 8PE
United Kingdom
Sponsor information
University of Oxford (UK)
University/education
University/education
Clinical Trials and Research Governance Team (CTRG)
Joint Research Office
Block 60
Churchill Hospital
Old Road
Headington
Oxford
OX3 7LE
England
United Kingdom
| Phone | N/A |
|---|---|
| ctrg@admin.ox.ac.uk | |
"ROR" |
https://ror.org/052gg0110 |
Funders
Funder type
Government
NIHR Health Technology Assessment Programme - HTA (UK)
No information available
Results and Publications
| Intention to publish date | 01/09/2023 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| Publication and dissemination plan | Not provided at time of registration |
| IPD sharing plan | The NPEU is committed to sharing data with the research community. Data will be shared in accordance with the National Perinatal Epidemiology Unit Data Sharing policy. Requests for access to the data will be considered by the National Perinatal Epidemiology Unit Data Sharing Committee. Access to anonymized data can be requested from ctu@npeu.ox.ac.uk. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Protocol article | protocol | 26/02/2021 | 01/03/2021 | Yes | No |
| Statistical Analysis Plan | statistical analysis plan | 26/05/2021 | 28/05/2021 | No | No |
| Statistical Analysis Plan | version 1.0 | 20/04/2023 | 20/06/2023 | No | No |
| Participant information sheet | version 7.0 | 10/07/2018 | 03/08/2023 | No | Yes |
| Results article | 25/01/2024 | 25/01/2024 | Yes | No | |
| Other files | 2 year form version 2.0 |
10/07/2018 | 15/07/2024 | No | No |
Additional files
Editorial Notes
15/07/2024: 2 year form uploaded.
25/01/2024: Publication reference added.
03/08/2023: The following changes have been made:
1. The study hypothesis has been changed.
2. The primary outcome measures have been changed.
3. The secondary outcome measures have been changed.
4. The participant inclusion criteria have been changed.
5. The participant exclusion criteria have been changed.
6. The participant information sheet has been linked and uploaded.
23/06/2023: IPD sharing statement added.
20/06/2023: Statistical analysis plan and ethics approval details added.
15/03/2023: The following changes were made to the trial record:
1. Contact details updated.
2. The recruitment end date was changed from 31/03/2019 to 31/12/2020.
3. The overall trial end date was changed from 31/01/2021 to 31/08/2023.
4. The intention to publish date was changed from 31/01/2022 to 01/09/2023.
5. Total final enrolment added.
28/05/2021: Publication reference added.
01/03/2021: Publication reference added.
26/03/2018: The following changes were made:
1. The overall trial end date was changed from 30/12/2020 to 31/01/2021.
2. The recruitment end date was changed from 30/12/2020 to 31/03/2019.
10/04/2014: The following changes were made to the trial record:
1. The acronym was changed from 'OSCAR' to 'Baby-OSCAR'
2. The study design was changed from 'Double-blind randomised placebo-controlled multicentre trial' to 'Multicentre randomised placebo-controlled trial'
3. The anticipated start date was changed from 10/04/2011 to 01/07/2014
4. The anticipated end date was changed from 09/04/2016 to 30/12/2020
5. The target number of participants was changed from 512 to 730
6. The public title was changed from 'Does selective early treatment of foetal shunt (patent ductus arteriosus) in extreme preterm infants reduce the complications and improve their long term outcome?' to 'Does selective early treatment of patent ductus arteriosus in extreme preterm infants reduce the complications and improve their long-term outcome?'
7. The previous sponsor for this trial (up to 10/04/2014) was:
North Tees and Hartlepool NHS Foundation Trust (UK)
University Hospital of North Tees
Hardwick
Stockton-on-Tees
TS19 8PE
United Kingdom
The current address can be found in the sponsor section.
