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Trial registered on ANZCTR


Registration number
ACTRN12617000322336
Ethics application status
Approved
Date submitted
10/02/2017
Date registered
28/02/2017
Date last updated
5/10/2024
Date data sharing statement initially provided
26/07/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Preventing Lung Disease Using Surfactant + Steroid (The PLUSS Trial)
Scientific title
Multicentre Randomised Controlled Trial of Surfactant Plus Budesonide to Improve Survival Free of Bronchopulmonary Dysplasia in Extremely Preterm Infants
Secondary ID [1] 291179 0
none
Universal Trial Number (UTN)
U1111-1192-6449
Trial acronym
The PLUSS Trial
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Bronchopulmonary dysplasia 301538 0
Extremely preterm birth 302053 0
Respiratory distress syndrome 302095 0
Condition category
Condition code
Reproductive Health and Childbirth 301257 301257 0 0
Complications of newborn
Respiratory 301685 301685 0 0
Other respiratory disorders / diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Infants randomised to the intervention will receive budesonide 0.25 mg/kg (0.5 mL/kg). Exogenous surfactant (Curosurf [trademark], Chiesi Farmaceutici, Parma, Italy) will be used as a carrying vehicle for the budesonide. The dose of surfactant will be 200 mg/kg for the initial dose, and 100 mg/kg for subsequent doses (if required). Each enrolled infant will receive at least one, and no more than two, interventions. The intervention will be administered intra-tracheally via an endotracheal tube or catheter, by a medical officer or appropriately credentialed neonatal nurse.
Intervention code [1] 296796 0
Treatment: Drugs
Comparator / control treatment
Infants randomised to the control group will only receive exogenous surfactant (Curosurf [trademark], Chiesi Farmaceutici, Parma, Italy).. The dose of surfactant will be 200 mg/kg for the initial dose, and 100 mg/kg for subsequent doses (if required). Each enrolled infant will receive at least one, and no more than two, control interventions. The control intervention will be administered intra-tracheally via an endotracheal tube or catheter, by a medical officer or appropriately credentialed neonatal nurse.
Control group
Active

Outcomes
Primary outcome [1] 300666 0
Rate of survival, free of physiological BPD at 36 weeks’ PMA. Physiological BPD will be assessed between 36+0 and 36+6 weeks’ PMA. Infants will be defined as having physiological BPD if any of the following criteria are met: 1. Receiving mechanical ventilation via an endotracheal tube, CPAP, NIPPV OR receiving HF greater or equal to 2L/min 2. An effective FiO2 >=0.30 if receiving supplemental oxygen or nasal prongs less than 2L/min to maintain target oxygen saturations 3. An effective FiO2 <0.30 if receiving supplemental oxygen or nasal prongs less than 2L/min to maintain target oxygen saturations AND an unsuccessful air reduction trial.

Infants discharged home prior to 36+0 weeks' gestation without any respiratory support or supplemental oxygen will be classified as not having BPD.

*Effective FiO2 will be determined using an online calculator: https://urresearch.rochester.edu/fileDownloadForInstitutionalItem.action;jsessionid=C0030541446256DA6DFC72B2E104F9EC?itemId=2913&itemFileId=4079
Timepoint [1] 300666 0
36 weeks' PMA
Secondary outcome [1] 330543 0
Incidence of death before 36 weeks' PMA
Timepoint [1] 330543 0
36 weeks' PMA
Secondary outcome [2] 330544 0
Incidence of physiological BPD at 36 weeks' PMA. The presence and/or degree of BPD will be measured using a modified Walsh test. In addition the Shift test will be applied.
Timepoint [2] 330544 0
36 weeks' PMA
Secondary outcome [3] 330545 0
Severe brain injury on cranial ultrasound: severe (grade III or IV) intraventricular hemorrhage, and/or cystic periventricular leukomalacia
Timepoint [3] 330545 0
Death or hospital discharge
Secondary outcome [4] 330547 0
Incidence of retinopathy of prematurity (ROP), stage 2 or above and/or treated with laser or intraocular therapy
Timepoint [4] 330547 0
Death or hospital discharge
Secondary outcome [5] 330548 0
Incidence of necrotising enterocolitis (NEC), modified Bell’s criteria stage 2 or greater
Timepoint [5] 330548 0
Death or hospital discharge
Secondary outcome [6] 330549 0
Spontaneous intestinal perforation (perforation not associated with necrotizing enterocolitis or other known pathology)
Timepoint [6] 330549 0
Death or hospital discharge
Secondary outcome [7] 330551 0
Total duration of mechanical ventilation via an endotracheal tube (days)
Timepoint [7] 330551 0
Death or hospital discharge
Secondary outcome [8] 330552 0
Duration of positive pressure respiratory support (mechanical ventilation via an ETT, CPAP, NIPPV, nasal high-flow, or other positive pressure respiratory support) in days

Assessed from medical records
Timepoint [8] 330552 0
Death or hospital discharge
Secondary outcome [9] 330554 0
Duration of supplemental oxygen therapy (days)

Assessed from medical records
Timepoint [9] 330554 0
Death or hospital discharge
Secondary outcome [10] 330555 0
Discharge home on oxygen, or receiving any supplemental oxygen in hospital beyond 52 weeks’ PMA (whichever comes first), assessed from medical records.

This is a single dichotomous outcome: babies will either be discharged home on oxygen or be receiving oxygen beyond 52 weeks PMA, but can't be both - it is whichever comes first. It is not two separate outcomes.

Assessed from medical records.
Timepoint [10] 330555 0
Death or hospital discharge
Secondary outcome [11] 330557 0
Total length of stay in any hospital (days)
Timepoint [11] 330557 0
Death or hospital discharge
Secondary outcome [12] 330558 0
Pneumothorax requiring drainage (needle thoracocentesis or intercostal catheter insertion)

Assessed from medical records,
Timepoint [12] 330558 0
Death or hospital discharge
Secondary outcome [13] 330560 0
Incidence of patent ductus arterious (PDA) diagnosed on echocardiogram that requires medical treatment and or surgical ligation
Timepoint [13] 330560 0
Death or hospital discharge
Secondary outcome [14] 330561 0
Incidence of late onset sepsis after 48 hours of age, defined as positive bacterial or fungal culture from a normally sterile site or negative blood culture but clinical suspicion to treat with antibiotics for at least 5 days
Timepoint [14] 330561 0
Death or hospital discharge
Secondary outcome [15] 331389 0
Death in hospital after 36 weeks PMA
Timepoint [15] 331389 0
Death or hospital discharge
Secondary outcome [16] 331390 0
Respiratory status at 40 weeks' PMA, including the need for supplemental oxygen therapy or any form of respiratory support
Timepoint [16] 331390 0
40 weeks' PMA
Secondary outcome [17] 331417 0
Cost effectiveness analysis incorporating costs of the intervention and of hospital care (including complications). Cost-effectiveness will be reported as cost per life year gained and cost per infant with BPD prevented for the intervention group compared to control. The longer term costs associated with BPD will be constructed via systematic review and updated with Australian unit costs.
Timepoint [17] 331417 0
Death or hospital discharge
Secondary outcome [18] 331881 0
Hyperglycemia >=10 mmol/L and/or receiving insulin therapy during the 14 days after the first intervention, assessed from medical records and pathology results

This is a single dichotomous outcome, not 2 outcomes: babies will be classed as YES if they have either high blood sugar >=10 OR get insulin OR both.

Assessed from medical records and pathology results.
Timepoint [18] 331881 0
Up to 14 days after the initial intervention.
Secondary outcome [19] 331883 0
Hypertension requiring anti-hypertensive treatment
Timepoint [19] 331883 0
Up to 14 days after intervention
Secondary outcome [20] 331884 0
Incidence of gastrointestinal haemorrhage (any fresh blood aspirated from indwelling gastric tube)
Timepoint [20] 331884 0
Up to 14 days after intervention
Secondary outcome [21] 331885 0
Z-score for weight at 36 weeks’ PMA

Assessed from medical records
Timepoint [21] 331885 0
36 weeks' post menstrual age
Secondary outcome [22] 331902 0
Oral candidiasis during the first 14 days after the first intervention
Timepoint [22] 331902 0
death or discharge from hospital
Secondary outcome [23] 393138 0
Survival to 2 years of age (corrected for prematurity) without moderate-severe neurodevelopmental disability, defined as any one or more of: moderate or severe developmental delay, moderate or severe cerebral palsy, deafness or blindness.
Timepoint [23] 393138 0
2 years corrected for prematurity
Secondary outcome [24] 417539 0
BPD severity/grade at 36 weeks’ postmenstrual age, as defined by Jensen et al. (Jensen EA, Dysart K, Gantz MG, McDonald S, Bamat NA, Keszler M, et al. The Diagnosis of Bronchopulmonary Dysplasia in Very Preterm Infants. An Evidence-based Approach. Am J Respir Crit Care Med. 2019;200(6):751-9)
Timepoint [24] 417539 0
36 weeks' post-menstrual age
Secondary outcome [25] 428216 0
Z-score for length at 36 weeks’ PMA

Assessed from medical records
Timepoint [25] 428216 0
36 weeks' PMA
Secondary outcome [26] 428217 0
Z-score for head circumference at 36 weeks’ PMA

Assessed from medical records
Timepoint [26] 428217 0
36 weeks' PMA
Secondary outcome [27] 428218 0
Z-score for body mass index at 36 weeks’ PMA

Assessed from medical records
Timepoint [27] 428218 0
36 weeks' PMA
Secondary outcome [28] 428219 0
Mode of respiratory support received at time of BPD assessment
- Mechanical ventilation via an endotracheal tube
- CPAP or NIPPV
- Nasal high-flow >=2 L/min
- Supplemental oxygen only
- None

Assessed from medical records
Timepoint [28] 428219 0
36 weeks' PMA

Eligibility
Key inclusion criteria
1.Infants inborn or outborn (and transferred to a particpating centre) at < 28 weeks’ gestation (completed weeks) and admitted to a participating neonatal intensive care unit (NICU) for intensive care AND
2. Receiving respiratory support:defined as mechanical ventilation via an endotracheal tube, or non-invasive ventilation including continuous positive airway pressure (CPAP) , nasal intermittent positive pressure ventilation (NIPPV), or nasal high-flow therapy (nHF) AND a clinician decision to administer surfactant AND
3. Infants are < 48 hours of age
Minimum age
0 Hours
Maximum age
48 Hours
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. More than one prior surfactant dose
2. Prior treatment with postnatal corticosteroids for the prevention of lung disease (inhaled, nebulised, intratracheal, or systemic)
3. The infant is considered unlikely to survive the immediate postnatal transition and/or is not going to be admitted to the NICU
4. Known or suspected major congenital anomaly that is likely to affect respiratory status including a postnatal clinical diagnosis of severe pulmonary hypoplasia following premature prolonged rupture of fetal membranes with resultant severe oligo- or anhydramnios, where the clinician feels survival is unlikely
5. The infant is likely to be transferred to a non-participating NICU within 24 h of birth.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
When eligibility of an infant is confirmed, and prospective consent obtained, the infant will be assigned to either receive surfactant with budesonide, or surfactant alone, using a web-based randomisation system with an allocation ratio of 1:1. A sealed, opaque envelope will be identified by the unique study ID generated from the web based server.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation with balanced variable block sizes will be used, stratified by study centre, gestational age (22-25 weeks’ vs. 26-27 weeks’ completed gestation) and by prior surfactant therapy prior to enrollment and mode of respiratory support (ventilation via an endotracheal tube vs non-invasive respiratory support) .
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Statistical analysis will follow standard methods for randomised trials. The primary analysis will be by intention-to-treat. For dichotomous outcomes, including the primary outcome, the two treatment groups will be compared using relative risk with 95% CI, both overall, and within the pre-specified subgroups. The individual components of the primary outcome, death or physiological BPD at 36 weeks’ PMA, will be compared between the two treatment groups using relative risk with 95% CI, both overall, and within the pre-specified subgroups. For dichotomous secondary outcomes, analysis will be limited to the two treatment groups, using relative risk with 95% CI. For continuous outcomes, the two treatment groups will be compared using difference of means, together with 95% CI, for outcome variables which are normally distributed; for outcome variables, which are not normally distributed, the comparison will be difference of medians, with 95% CI. All comparisons (relative risk, difference of means, difference of medians) will be estimated using regression models with standard errors adjusted to take into account the clustering due to multiple births. Where there are differences in the baseline characteristics between the two treatment groups that might be associated with outcomes, an additional “adjusted” multivariable analysis will be carried out using generalized linear model methods. Reporting of findings will be done in accordance with CONSORT guidelines. Pre-specified sub-group analyses will be performed to determine if there is an interaction between treatment effect and gestational age strata or exposure to surfactant prior to randomisation.

Cost effectiveness analysis will incorporate costs of the intervention and of hospital care (including complications) for the birth admission until death or first discharge home from all health care facilities which includes the primary birth hospital and where appropriate, secondary hospital(s). A decision analysis will be constructed based on the primary outcome and associated hospital costs. Cost-effectiveness will be reported as cost per life year gained and cost per infant with BPD prevented for the intervention group compared to control. Extensive one-way and probabilistic sensitivity analyses will be conducted. The longer term costs associated with BPD will be constructed via systematic review and updated with Australian unit costs.

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
18/12/2017
Actual
4/01/2018
Date of last participant enrolment
Anticipated
24/03/2023
Actual
27/03/2023
Date of last data collection
Anticipated
30/09/2025
Actual
Sample size
Target
1060
Accrual to date
Final
1061
Recruitment in Australia
Recruitment state(s)
ACT,NSW,QLD,SA,TAS,WA,VIC
Recruitment hospital [1] 7227 0
The Royal Women's Hospital - Parkville
Recruitment hospital [2] 7228 0
Royal Hobart Hospital - Hobart
Recruitment hospital [3] 7447 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [4] 9855 0
John Hunter Children's Hospital - New Lambton
Recruitment hospital [5] 14315 0
The Canberra Hospital - Garran
Recruitment hospital [6] 15437 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [7] 15438 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [8] 15439 0
King Edward Memorial Hospital - Subiaco
Recruitment hospital [9] 15440 0
Mercy Hospital for Women - Heidelberg
Recruitment hospital [10] 15441 0
Mater Mother's Hospital - South Brisbane
Recruitment hospital [11] 15442 0
Womens and Childrens Hospital - North Adelaide
Recruitment hospital [12] 17188 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [13] 17189 0
Royal Hospital for Women - Randwick
Recruitment hospital [14] 23836 0
Wellington Health Service - Wellington
Recruitment hospital [15] 23837 0
Royal Prince Alfred Hospital - Camperdown
Recruitment postcode(s) [1] 14992 0
3052 - Parkville
Recruitment postcode(s) [2] 14993 0
7000 - Hobart
Recruitment postcode(s) [3] 15267 0
3168 - Clayton
Recruitment postcode(s) [4] 18640 0
2305 - New Lambton
Recruitment postcode(s) [5] 27315 0
2605 - Garran
Recruitment postcode(s) [6] 28764 0
5042 - Bedford Park
Recruitment postcode(s) [7] 28765 0
4029 - Herston
Recruitment postcode(s) [8] 28766 0
6008 - Subiaco
Recruitment postcode(s) [9] 28767 0
3084 - Heidelberg
Recruitment postcode(s) [10] 28768 0
4101 - South Brisbane
Recruitment postcode(s) [11] 28769 0
5006 - North Adelaide
Recruitment postcode(s) [12] 30893 0
2065 - St Leonards
Recruitment postcode(s) [13] 30894 0
2031 - Randwick
Recruitment postcode(s) [14] 39291 0
2820 - Wellington
Recruitment postcode(s) [15] 39292 0
2050 - Camperdown
Recruitment outside Australia
Country [1] 8550 0
New Zealand
State/province [1] 8550 0
Counties Manukau, Auckland; Auckland; Christchurch; Wellington; Waikato
Country [2] 8628 0
Canada
State/province [2] 8628 0
Alberta
Country [3] 22174 0
Singapore
State/province [3] 22174 0
Singapore

Funding & Sponsors
Funding source category [1] 295285 0
Government body
Name [1] 295285 0
NHMRC Project Grant
Country [1] 295285 0
Australia
Funding source category [2] 312983 0
Charities/Societies/Foundations
Name [2] 312983 0
Thrasher Research Foundation
Country [2] 312983 0
United States of America
Funding source category [3] 314954 0
Commercial sector/Industry
Name [3] 314954 0
Chiesi Farmaceutici
Country [3] 314954 0
Italy
Funding source category [4] 315102 0
Commercial sector/Industry
Name [4] 315102 0
Chiesi Farmaceutici
Country [4] 315102 0
Italy
Primary sponsor type
Other Collaborative groups
Name
The Melbourne Children's Trial Centre
Address
Flemington Road
Parkville, Victoria, 3052
Country
Australia
Secondary sponsor category [1] 294106 0
None
Name [1] 294106 0
Address [1] 294106 0
Country [1] 294106 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 296615 0
The Royal Childrens Hospital
Ethics committee address [1] 296615 0
Flemington Road
Parkville, Vic 3052
Ethics committee country [1] 296615 0
Australia
Date submitted for ethics approval [1] 296615 0
08/03/2017
Approval date [1] 296615 0
15/06/2017
Ethics approval number [1] 296615 0
HREC 36383A

Summary
Brief summary
Bronchopulmonary dysplasia (BPD) is a chronic inflammatory lung disease characterised by disordered alveolar and vascular development, most commonly affecting extremely preterm infants exposed to mechanical ventilation and oxygen therapy for respiratory distress syndrome (RDS). BPD is associated with mortality, and adverse long-term pulmonary and neurodevelopmental outcomes. Despite advances in neonatal care including antenatal corticosteroids, exogenous surfactant, and the increasing use of ‘non-invasive’ ventilation, the incidence of BPD is not decreasing. BPD remains the most important pulmonary complication in extremely preterm infants occurring in about 50% of survivors to 36 weeks post menstrual age, with no new therapies shown to prevent it.
Laboratory and clinical studies suggest a crucial role for lung inflammation (pre- and post-natal) and host immune response in the pathogenesis of BPD. A subcommittee of perinatal experts of the National Health, Lung, Blood Institute summarised the current state of knowledge regarding BPD and identified potential points in its pathogenesis susceptible to therapeutic interventions. One recommendation was to study the use of selective anti-inflammatory therapies, to attenuate the inflammatory response in the developing lung to potentially prevent BPD. As inflammation is a primary mediator of injury in the pathogenesis of BPD, anti-inflammatory agents such as postnatal corticosteroids have long been the focus of preventive interventions. Whilst systemic (intravenous or oral) corticosteroids reduce inflammation and improve respiratory function, their early use may be associated with many side effects. Given the serious adverse effects of systemic corticosteroid administration, safer alternatives are sought.Inhaled or nebulised corticosteroids are technically challenging to deliver with conflicting results from trials as the dose, optimal timing of initiating treatment and the duration are unknown. Local administration of corticosteroids to the lung via the intra-tracheal route has the potential to maximise anti-inflammatory effects on the distal airway, minimise systemic absorption and decrease the risk of adverse effects. Exogenous surfactant is a proven effective therapy for RDS in preterm infants. Combining budesonide with surfactant is a simple intervention that may prevent BPD in the high-risk population of extremely preterm infants.
The aim of the PLUSS trial is to evaluate the safety and efficacy of early intratracheal corticosteroid (budesonide) combined with exogenous surfactant as the vehicle for distribution compared with exogenous surfactant alone to increase survival without BPD at 36 weeks’ PMA in extremely preterm infants born <28 weeks’ gestation.
This is a multicentre, double-blind, two-arm, parallel 1:1 placebo-controlled randomised trial. Families, healthcare providers, outcome assessors and data analysts will be blinded to the randomisation group.
Infants enrolled in the study will be randomised to receive intratracheal surfactant and budesonide or surfactant alone.
Trial website
plusstrial.org
Trial related presentations / publications
Hot Topics in Neonatology, Washington DC, USA, December 2023
Perinatal Society of Australia and New Zealand, Christchurch, NZ, March 2024
Pediatric Academic Societies, Toronto, Canada, April 2024
Public notes

Contacts
Principal investigator
Name 71498 0
Prof Brett Manley
Address 71498 0
Newborn Research Centre
The Royal Women's Hospital
20 Flemington Road
Parkville, Victoria 3052
Country 71498 0
Australia
Phone 71498 0
+61 3 8345 3763
Fax 71498 0
+61 3 8345 3789
Email 71498 0
[email protected]
Contact person for public queries
Name 71499 0
Brett Manley
Address 71499 0
Newborn Research Centre
The Royal Women's Hospital
20 Flemington Road
Parkville, Victoria, 3052
Country 71499 0
Australia
Phone 71499 0
+61 3 8345 3763
Fax 71499 0
+61 3 8345 3789
Email 71499 0
[email protected]
Contact person for scientific queries
Name 71500 0
Brett Manley
Address 71500 0
Newborn Research Centre
The Royal Women's Hospital
20 Flemington Road
Parkville, Victoria, 3052
Country 71500 0
Australia
Phone 71500 0
+61 3 8345 3763
Fax 71500 0
+ 61 3 8345 3766
Email 71500 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Data will be made available as per a Data Sharing Plan that is being finalised and will be added here when available.


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
3468Study protocolManley BJ, Kamlin COF, Donath S, Huang L, Birch P, Cheong JLY, Dargaville PA, Dawson JA, Doyle LW, Jacobs SE, Wilson R, Davis PG, McKinlay CJD. Intratracheal budesonide mixed with surfactant to increase survival free of bronchopulmonary dysplasia in extremely preterm infants: study protocol for the international, multicenter, randomized PLUSS trial. Trials. 2023 May 9;24(1):320. doi: 10.1186/s13063-023-07257-5. PMID: 37161488; PMCID: PMC10169381.https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-023-07257-5 
18053Statistical analysis planFrancis KL, McKinlay CJD, Kamlin COF, Cheong JLY, Dargaville PA, Dawson JA, Doyle LW, Jacobs SE, Davis PG, Donath SM, Manley BJ. Intratracheal budesonide mixed with surfactant to increase survival free of bronchopulmonary dysplasia in extremely preterm infants: statistical analysis plan for the international, multicenter, randomized PLUSS trial. Trials. 2023 Nov 6;24(1):709. doi: 10.1186/s13063-023-07650-0. PMID: 37932774; PMCID: PMC10629198.https://pubmed.ncbi.nlm.nih.gov/37932774/ 



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