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Trial registered on ANZCTR


Registration number
ACTRN12621000822886
Ethics application status
Approved
Date submitted
16/04/2021
Date registered
28/06/2021
Date last updated
17/09/2023
Date data sharing statement initially provided
28/06/2021
Date results information initially provided
17/09/2023
Type of registration
Retrospectively registered

Titles & IDs
Public title
PLUSS (Preventing Chronic Lung Disease in Extremely Preterm Infants Using Surfactant + Steroid)-HEARTS (Haemodynamic Echocardiogram Assessment after Receiving Therapy with Steroids) in extremely preterm infants
Scientific title
The Ductus Arteriosus and haemodynamics following intra-tracheal Budesonide and surfactant in extremely preterm infants- PLUSS HEARTS Sub study
Secondary ID [1] 303945 0
Nil known
Universal Trial Number (UTN)
Trial acronym
PLUSS-HEARTS
Linked study record
This is a linked sub-study to Australian New Zealand Clinical Trials Registry; ACTRN12617000322336

Health condition
Health condition(s) or problem(s) studied:
Extremely preterm birth 321539 0
Patent Ductus Arterious 322318 0
Condition category
Condition code
Reproductive Health and Childbirth 319288 319288 0 0
Complications of newborn
Cardiovascular 319664 319664 0 0
Other cardiovascular diseases
Respiratory 319665 319665 0 0
Other respiratory disorders / diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Infants enrolled in this sub-study will receive interventions as described in the parent study PLUSS trial (ACTRN12617000322336).
Infants enrolled in PLUSS- HEARTs will undergo a rapid cardiac ultrasound at 48-72 hours after birth. This examination is anticipated to take approximately 5 minutes. At day 6-7 of life infants will undergo a focussed cardiac ultrasound with measures of cardiac function, pulmonary circulation and measures of systemic circulation. This second longer examination is expected to take approximately 10-15 minutes .
Intervention code [1] 320253 0
Treatment: Devices
Comparator / control treatment
This sub study (PLUSS trial (ACTRN12617000322336) requires measurement of cardiac function by cardiac ultrasound at prespecified timepoints .
Infants enrolled in this sub-study and randomised to the control group will receive the control treatment (surfactant) as described in the parent study PLUSS trial (ACTRN12617000322336).
Infants enrolled in PLUSS- HEARTs will undergo a rapid cardiac ultrasound at 48-72 hours after birth, this is anticipated to take 5 minutes. At day 6-7 of life infants will undergo a focussed cardiac ultrasound with measures of cardiac function, pulmonary circulation and measures of systemic circulation, this is anticipated to take 10-15 minutes.
Control group
Active

Outcomes
Primary outcome [1] 327169 0
Ductus arteriosus closure (Closed/Patent)
Ductus arteriosus closure defined as a ductus arteriosus that is not detectable in the standard ductal view OR has no detectible flow across in colour Doppler flow mapping.

Where a PDA is present on ductal view (Rapid scan) these additional measurements will be obtained
2. Ductus arteriosus diameter (mm)
3. Ductus arteriosus flow direction and pattern

Timepoint [1] 327169 0
48 -72 hours after birth
Secondary outcome [1] 394044 0
Ductal diameter at narrowest point assessed using colour doppler
Timepoint [1] 394044 0
48 -72 hours after birth
Secondary outcome [2] 394046 0
ductal Doppler flow pattern
Timepoint [2] 394046 0
48-72 hours after birth
Secondary outcome [3] 395584 0
Left atrial to aortic root ratio (LA:Ao) assessed using 2D Doppler
Timepoint [3] 395584 0
144- 192 hours after birth (Day 6-7) and 36 weeks post menstrual age
Secondary outcome [4] 395585 0
Left ventricular output (LVO – millilitres/kilogram/minute) assessed using 2D doppler
Timepoint [4] 395585 0
144- 192 hours after birth (Day 6-7) and 36 weeks post menstrual age
Secondary outcome [5] 395586 0
Left ventricular output to right ventricular output ratio (LVO/RVO) assessed using 2D doppler
Timepoint [5] 395586 0
144hr - 192 hours after birth (Day 6-Day 7) and 36 weeks post menstrual age
Secondary outcome [6] 395588 0
Left ventricular internal diameter (LVID – millimetres) assessed using 2D doppler
Timepoint [6] 395588 0
144hr - 192 hours after birth (Day 6-Day 7) and 36 weeks post menstrual age
Secondary outcome [7] 395590 0
Fractional shortening (FS - %): assessed when using 2 D doppler
Timepoint [7] 395590 0
144hr - 192 hours after birth (Day 6-Day 7) and 36 weeks post menstrual age
Secondary outcome [8] 395591 0
Left pulmonary artery peak diastolic flow velocity (LPA – metres/second) assessed using 2D doppler
Timepoint [8] 395591 0
144hr - 192 hours after birth (Day 6-Day 7) and 36 weeks post menstrual age
Secondary outcome [9] 395593 0
Left atrial volume (LAV – mL) assessed using 2D doppler
Timepoint [9] 395593 0
144hr - 192 hours after birth (Day 6-Day 7) and 36 weeks post menstrual age
Secondary outcome [10] 395594 0
End systolic volume (ESV – mL) assessed using 2D doppler
Timepoint [10] 395594 0
144hr - 192 hours after birth (Day 6-Day 7) and 36 weeks post menstrual age
Secondary outcome [11] 395597 0
End diastolic volume (EDV – mL) assessed using 2D doppler
Timepoint [11] 395597 0
144hr - 192 hours after birth (Day 6-Day 7) and 36 weeks post menstrual age
Secondary outcome [12] 395598 0
Tissue doppler imaging: e’ assessed using 2D doppler
Timepoint [12] 395598 0
144hr - 192 hours after birth (Day 6-Day 7) and 36 weeks post menstrual age
Secondary outcome [13] 395599 0
Tissue doppler imaging: Ee’ ratio
Timepoint [13] 395599 0
144hr - 192 hours after birth (Day 6-Day 7) and 36 weeks post menstrual age
Secondary outcome [14] 395600 0
Tissue doppler imaging: EA ratio
Timepoint [14] 395600 0
144hr - 192 hours after birth (Day 6-Day 7) and 36 weeks post menstrual age
Secondary outcome [15] 395602 0
Descending aorta Doppler flow
Timepoint [15] 395602 0
144hr - 192 hours after birth (Day 6-Day 7) and 36 weeks post menstrual age
Secondary outcome [16] 395603 0
Superior mesenteric Doppler flow
Timepoint [16] 395603 0
144hr - 192 hours after birth (Day 6-Day 7) and 36 weeks post menstrual age

Eligibility
Key inclusion criteria
To be eligible for PLUSS-HEARTS, infants must be enrolled in the PLUSS trial (ACTRN12617000322336) and meet all inclusion and no exclusion criteria.

Additional inclusion criteria for the PLUSS-HEARTS trial include:

1. Infant less than 48 hours of age
2. Infants receiving mechanical ventilation via an endotracheal tube or non-invasive respiratory support including CPAP, NIPPV or nasal high flow, and a clinical decision to treat the infant with exogenous surfactant (first or subsequent dose)
Minimum age
0 Days
Maximum age
48 Hours
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Criteria for exclusion from the PLUSS Trial (ACTRN12617000322336):includes (any of the following):

1. Prior treatment with corticosteroids for the prevention of lung disease (inhaled, nebulised, intra-tracheal, or systemic)
2. Infant is considered non-viable or is not going to be admitted to intensive care
3. Known or suspected major congenital anomaly that is likely to affect respiratory status (e.g. upper airway obstruction, congenital lung malformation, major congenital heart disease); or severe pulmonary hypoplasia following premature prolonged rupture of fetal membranes with resultant severe oligo/anhydramnios, where the clinician, based on clinical assessment on the first postnatal day, feels survival is unlikely
4. Infant likely to be transferred to another non-participating NICU within 24 hours of birth

Additional exclusion criteria for PLUSS-HEARTS include (any of the following):
1. Treatment with prophylactic indomethacin (with the objective of reducing the risk of intraventricular haemorrhage)
2. Major congenital heart disease detected on cardiac ultrasound
3. Unable to perform study cardiac ultrasound due to clinical instability or redirection of care towards comfort measures.

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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
14/04/2021
Date of last participant enrolment
Anticipated
1/06/2023
Actual
27/03/2023
Date of last data collection
Anticipated
1/08/2023
Actual
27/06/2023
Sample size
Target
158
Accrual to date
Final
158
Recruitment in Australia
Recruitment state(s)
NSW,VIC
Recruitment hospital [1] 19093 0
The Royal Women's Hospital - Parkville
Recruitment hospital [2] 19094 0
Monash Children’s Hospital - Clayton
Recruitment hospital [3] 19127 0
John Hunter Children's Hospital - New Lambton
Recruitment postcode(s) [1] 33686 0
2305 - New Lambton
Recruitment postcode(s) [2] 33651 0
3052 - Parkville
Recruitment postcode(s) [3] 33652 0
3168 - Clayton
Recruitment outside Australia
Country [1] 23595 0
Canada
State/province [1] 23595 0
Alberta
Country [2] 23600 0
New Zealand
State/province [2] 23600 0
Auckland

Funding & Sponsors
Funding source category [1] 308329 0
Government body
Name [1] 308329 0
National Health and Medical Research Council
Country [1] 308329 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Melbourne Children's Trials Centre
Address
Flemington Road
Parkville, Vic 3052
Country
Australia
Secondary sponsor category [1] 309141 0
None
Name [1] 309141 0
Address [1] 309141 0
Country [1] 309141 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 308305 0
Royal Children's Hospital
Ethics committee address [1] 308305 0
Flemington Road
Parkville, Victoria 3052
Ethics committee country [1] 308305 0
Australia
Date submitted for ethics approval [1] 308305 0
14/01/2021
Approval date [1] 308305 0
22/01/2021
Ethics approval number [1] 308305 0
36383

Summary
Brief summary
Patency of the ductus arteriosus in preterm infants is dictated primarily by Prostaglandin E2 (PGE2) and the non-steroidal anti-inflammatory medications that have long been used to promote ductal closure act by reducing prostaglandin production through cyclooxygenase enzyme inhibition. There is evidence that corticosteroids may also promote ductal closure through at least two mechanisms that impact PGE2 levels. This includes increasing phospholipase A2 inhibitor production with resultant decreased PGE2 synthesis and inhibition of 15-PGHD with resultant increased PGE2 break-down. More importantly, the vast majority of randomised controlled trials evaluating administration of early systemic, inhaled, or intra-tracheal corticosteroids to very preterm infants have found decreased rates of patent ductus arteriosus (PDA) diagnosis, medical treatment of PDA and/or surgical ductal ligation in exposed infants, suggesting a possible effect on early ductus arteriosus closure. What remains unclear is whether the mechanism behind decreased rates of PDA diagnosis and treatment is a direct effect due to corticosteroids promoting early ductus arteriosus closure, or an indirect effect of corticosteroids providing a respiratory benefit that results in clinicians being less inclined to pursue or treat a PDA.

The PLUSS Trial is a multicentre, two-arm, parallel, double-blind randomised clinical trial designed to evaluate the effect of early intra-tracheal budesonide (a corticosteroid) mixed with surfactant on survival without BPD in extremely preterm infants born <28 weeks’ gestation (n = 1060). The PLUSS-HEARTS sub-study will utilise the double-blind randomised methodology of PLUSS in select participating sites to measure rates of early ductus arteriosus closure following exposure to intra-tracheal corticosteroids, compared with no exposure. This will hopefully shed light on the true effect of intratracheal corticosteroids on PDA diagnosis or treatment in this high-risk patient population.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 110238 0
A/Prof Brett Manley
Address 110238 0
The Royal Women's Hospital
Cnr Flemington Road and Grattan Street
Parkville, Vic, 3052
Country 110238 0
Australia
Phone 110238 0
+61 3 83453766
Fax 110238 0
Email 110238 0
brett.manley@thewomens.org.au
Contact person for public queries
Name 110239 0
Dr Jennifer Dawson
Address 110239 0
The Royal Women's Hospital
Cnr Flemington Road and Grattan Street
Parkville, Vic, 3052
Country 110239 0
Australia
Phone 110239 0
+61 3 8345 3791
Fax 110239 0
Email 110239 0
jennifer.dawson@thewomens.org.au
Contact person for scientific queries
Name 110240 0
Dr Sam Axford
Address 110240 0
The Royal Women's Hospital
Cnr Flemington Road and Grattan Street
Parkville, Vic, 3052
Country 110240 0
Australia
Phone 110240 0
+61 3 83453763
Fax 110240 0
Email 110240 0
Samuel.Axford@thewomens.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Only de-identified patient data described previously will be available after publication.
Individual participant data of published results from primary and secondary outcome data will be released by the Principal Investigator if the request meets criteria for IP analysis or meta analysis.
When will data be available (start and end dates)?
Following publication no end date specified
Available to whom?
Case-by-case basis at the discretion of Primary Sponsor
Available for what types of analyses?
Only to achieve the aims in an approved proposal for IPD or meta-analyses
How or where can data be obtained?
Access will be subject to approvals by Principal Investigator contacted at brett.manley@thewomens.org.au


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
11367Study protocol  brett.manley@thewomens.org.au



Results publications and other study-related documents

Documents added manually
TypeIs Peer Reviewed?DOICitations or Other DetailsAttachment
Plain language summaryNo no summary available yet

Documents added automatically
No additional documents have been identified.