ANZCTR - Registration

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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

27/10/2023

Date data sharing statement initially provided

26/07/2019

Date results information initially provided

3/04/2023

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]

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

Extremely preterm birth

Respiratory distress syndrome

Condition category

Condition code

Reproductive Health and Childbirth

Complications of newborn

Respiratory

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]

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]

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]

36 weeks' PMA

Secondary outcome [1]

Incidence of death before 36 weeks' PMA

Timepoint [1]

36 weeks' PMA

Secondary outcome [2]

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]

36 weeks' PMA

Secondary outcome [3]

Severe brain injury on cranial ultrasound: severe (grade III or IV) intraventricular hemorrhage, and/or cystic periventricular leukomalacia

Timepoint [3]

Death or hospital discharge

Secondary outcome [4]

Incidence of retinopathy of prematurity (ROP), stage 2 or above and/or treated with laser or intraocular therapy

Timepoint [4]

Death or hospital discharge

Secondary outcome [5]

Incidence of necrotising enterocolitis (NEC), modified Bell’s criteria stage 2 or greater

Timepoint [5]

Death or hospital discharge

Secondary outcome [6]

Spontaneous intestinal perforation (perforation not associated with necrotizing enterocolitis or other known pathology)

Timepoint [6]

Death or hospital discharge

Secondary outcome [7]

Total duration of mechanical ventilation via an endotracheal tube (days)

Timepoint [7]

Death or hospital discharge

Secondary outcome [8]

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]

Death or hospital discharge

Secondary outcome [9]

Duration of supplemental oxygen therapy (days)

Assessed from medical records

Timepoint [9]

Death or hospital discharge

Secondary outcome [10]

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]

Death or hospital discharge

Secondary outcome [11]

Total length of stay in any hospital (days)

Timepoint [11]

Death or hospital discharge

Secondary outcome [12]

Pneumothorax requiring drainage (needle thoracocentesis or intercostal catheter insertion)

Assessed from medical records,

Timepoint [12]

Death or hospital discharge

Secondary outcome [13]

Incidence of patent ductus arterious (PDA) diagnosed on echocardiogram that requires medical treatment and or surgical ligation

Timepoint [13]

Death or hospital discharge

Secondary outcome [14]

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]

Death or hospital discharge

Secondary outcome [15]

Death in hospital after 36 weeks PMA

Timepoint [15]

Death or hospital discharge

Secondary outcome [16]

Respiratory status at 40 weeks' PMA, including the need for supplemental oxygen therapy or any form of respiratory support

Timepoint [16]

40 weeks' PMA

Secondary outcome [17]

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]

Death or hospital discharge

Secondary outcome [18]

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]

Up to 14 days after the initial intervention.

Secondary outcome [19]

Hypertension requiring anti-hypertensive treatment

Timepoint [19]

Up to 14 days after intervention

Secondary outcome [20]

Incidence of gastrointestinal haemorrhage (any fresh blood aspirated from indwelling gastric tube)

Timepoint [20]

Up to 14 days after intervention

Secondary outcome [21]

Z-score for weight at 36 weeks’ PMA

Assessed from medical records

Timepoint [21]

36 weeks' post menstrual age

Secondary outcome [22]

Oral candidiasis during the first 14 days after the first intervention

Timepoint [22]

death or discharge from hospital

Secondary outcome [23]

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]

2 years corrected for prematurity

Secondary outcome [24]

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]

36 weeks' post-menstrual age

Secondary outcome [25]

Z-score for length at 36 weeks’ PMA

Assessed from medical records

Timepoint [25]

36 weeks' PMA

Secondary outcome [26]

Z-score for head circumference at 36 weeks’ PMA

Assessed from medical records

Timepoint [26]

36 weeks' PMA

Secondary outcome [27]

Z-score for body mass index at 36 weeks’ PMA

Assessed from medical records

Timepoint [27]

36 weeks' PMA

Secondary outcome [28]

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]

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?

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]

The Royal Women's Hospital - Parkville

Recruitment hospital [2]

Royal Hobart Hospital - Hobart

Recruitment hospital [3]

Monash Medical Centre - Clayton campus - Clayton

Recruitment hospital [4]

John Hunter Children's Hospital - New Lambton

Recruitment hospital [5]

The Canberra Hospital - Garran

Recruitment hospital [6]

Flinders Medical Centre - Bedford Park

Recruitment hospital [7]

Royal Brisbane & Womens Hospital - Herston

Recruitment hospital [8]

King Edward Memorial Hospital - Subiaco

Recruitment hospital [9]

Mercy Hospital for Women - Heidelberg

Recruitment hospital [10]

Mater Mother's Hospital - South Brisbane

Recruitment hospital [11]

Womens and Childrens Hospital - North Adelaide

Recruitment hospital [12]

Royal North Shore Hospital - St Leonards

Recruitment hospital [13]

Royal Hospital for Women - Randwick

Recruitment hospital [14]

Wellington Health Service - Wellington

Recruitment hospital [15]

Royal Prince Alfred Hospital - Camperdown

Recruitment postcode(s) [1]

3052 - Parkville

Recruitment postcode(s) [2]

7000 - Hobart

Recruitment postcode(s) [3]

3168 - Clayton

Recruitment postcode(s) [4]

2305 - New Lambton

Recruitment postcode(s) [5]

2605 - Garran

Recruitment postcode(s) [6]

5042 - Bedford Park

Recruitment postcode(s) [7]

4029 - Herston

Recruitment postcode(s) [8]

6008 - Subiaco

Recruitment postcode(s) [9]

3084 - Heidelberg

Recruitment postcode(s) [10]

4101 - South Brisbane

Recruitment postcode(s) [11]

5006 - North Adelaide

Recruitment postcode(s) [12]

2065 - St Leonards

Recruitment postcode(s) [13]

2031 - Randwick

Recruitment postcode(s) [14]

2820 - Wellington

Recruitment postcode(s) [15]

2050 - Camperdown

Recruitment outside Australia

Country [1]

New Zealand

State/province [1]

Counties Manukau, Auckland; Auckland; Christchurch; Wellington; Waikato

Country [2]

Canada

State/province [2]

Alberta

Country [3]

Singapore

State/province [3]

Singapore

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

NHMRC Project Grant

Address [1]

GHD Building Level 1,
16 Marcus Clarke St,
Canberra ACT 2601

Country [1]

Australia

Funding source category [2]

Charities/Societies/Foundations

Name [2]

Thrasher Research Foundation

Address [2]

Thrasher Research Fund
68 S. Main Street, Suite 400
Salt Lake City, UT 84101
USA

Country [2]

United States of America

Funding source category [3]

Commercial sector/Industry

Name [3]

Chiesi Farmaceutici

Address [3]

26/A, Via Palermo 43122 Parma – Italy

Country [3]

Italy

Funding source category [4]

Commercial sector/Industry

Name [4]

Chiesi Farmaceutici

Address [4]

26/A, Via Palermo 43122 Parma – Italy

Country [4]

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]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

The Royal Childrens Hospital

Ethics committee address [1]

Flemington Road
Parkville, Vic 3052

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

08/03/2017

Approval date [1]

15/06/2017

Ethics approval number [1]

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

none

Public notes

Contacts

Principal investigator

Name

A/Prof Brett Manley

Address

Newborn Research Centre
The Royal Women's Hospital
20 Flemington Road
Parkville, Victoria 3052

Country

Australia

Phone

+61 3 8345 3763

Fax

+61 3 8345 3789

[email protected]

Contact person for public queries

Name

A/Prof Brett Manley

Address

Newborn Research Centre
The Royal Women's Hospital
20 Flemington Road
Parkville, Victoria, 3052

Country

Australia

Phone

+61 3 8345 3763

Fax

+61 3 8345 3789

[email protected]

Contact person for scientific queries

Name

A/Prof Brett Manley

Address

Newborn Research Centre
The Royal Women's Hospital
20 Flemington Road
Parkville, Victoria, 3052

Country

Australia

Phone

+61 3 8345 3763

Fax

+ 61 3 8345 3766

[email protected]

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

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.	Type	Citation	Link	Email	Other Details	Attachment
3468	Study protocol		https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-023-07257-5
18053	Statistical analysis plan				SAP will be published

Results publications and other study-related documents

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

Source	Title	Year of Publication	DOI
Embase	Surfactant as a drug carrier.	2023	https://dx.doi.org/10.1016/j.siny.2023.101499
Embase	Complex roles of TGF-b signaling pathways in lung development and bronchopulmonary dysplasia.	2023	https://dx.doi.org/10.1152/ajplung.00106.2021
Embase	Long-term effects of postnatal corticosteroids to prevent or treat bronchopulmonary dysplasia: Balancing the risks and benefits.	2019	https://dx.doi.org/10.1016/j.siny.2019.03.002
Embase	The intertemporal role of respiratory support in improving neonatal outcomes: A narrative review.	2021	https://dx.doi.org/10.3390/children8100883
Embase	Postnatal Corticosteroids to Prevent or Treat Bronchopulmonary Dysplasia.	2021	https://dx.doi.org/10.1159/000515950

N.B. These documents automatically identified may not have been verified by the study sponsor.

Trial Review

Documents added manually

Documents added automatically