Administrative information
Title {1} | 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 |
Trial registration {2} | Australian New Zealand Clinical Trials Registry; ACTRN12617000322336. Prospectively registered on 28th February 2017 |
Protocol version {3} | Version 8: 14th July 2020 (or any subsequent amended protocols) |
Funding {4} | 1. National Health and Medical Research Council (NHMRC), Australia (Grant No. 1158555) 2. Investigator-initiated grant from Chiesi Farmaceutici, Parma, Italy, to reimburse centers for the cost of poractant alfa used in the trial 3. Thrasher Research Fund, USA: “E.W. Thrasher Award” to fund longer-term outcome assessments at 2 years 4. Cure Kids New Zealand (Grant No. 3614) to help fund longer-term outcome assessments at 2 years in New Zealand |
Author details {5a} | BJM, COFK, PGD, JLYC, LWD, JAD, SEJ: The Royal Women’s Hospital, Melbourne, Australia; Department of Obstetrics and Gynaecology, The University of Melbourne, Melbourne, Australia; Murdoch Children’s Research Institute, Melbourne, Australia CJDM: Department of Paediatrics: Child and Youth Health, the University of Auckland, Auckland, New Zealand; Kidz First Neonatal Care, Te Whatu Ora Counties Manukau, New Zealand PAD: Royal Hobart Hospital, Hobart, Australia; Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia PB: Department of Neonatology, Mater Mother’s Hospitals South Brisbane, Brisbane, Australia SD: Murdoch Children’s Research Institute, Melbourne, Australia; Department of Paediatrics, the University of Melbourne, Melbourne, Australia LH: The University of Melbourne, Melbourne, Australia |
Name and contact information for the trial sponsor {5b} | Melbourne Children’s Trials Centre, Murdoch Children’s Research Institute (MCRI), Melbourne, Australia (mctc@mcri.edu.au) |
Role of sponsor {5c} | The trial Sponsor is responsible for the initiation, management and financing (or arranging the financing) of the trial and carries the medicolegal responsibility associated with its conduct The Sponsor is also responsible for ensuring that appropriate approvals are obtained prior to the commencement of the clinical trial, that conditions of any approvals are adhered to during the course of the clinical trial and ensuring that the ethics principles of research merit and integrity, justice, beneficence and respect are applied to the conduct of clinical trials. The Sponsor also ensures that the trial is appropriately monitored for compliance with the protocol The Trial Steering Committee, chaired by BJM, is responsible for the study design, management and analysis of data, and decision to publish the results |
Introduction
Background and rationale {6a}
Burden of Illness
Systemic corticosteroids effectively treat BPD but are associated with harm
Inhaled corticosteroids are not the solution
Intratracheal budesonide mixed with surfactant is a highly promising therapy
The PLUSS trial of intratracheal budesonide will address the critical gaps in evidence
Significance
Objectives {7}
Aim
Hypotheses
Trial design {8}
Methods: participants, interventions, and outcomes
Study setting {9}
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Australia:
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o Victoria: The Royal Women’s Hospital, Monash Children’s Hospital, Mercy Hospital for Women
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o New South Wales: Royal Hospital for Women, Royal North Shore Hospital, John Hunter Hospital, Royal Prince Alfred Hospital
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o Queensland: Royal Brisbane and Women’s Hospital, Mater Mothers’ Hospital
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o South Australia: Flinders Medical Centre, Women’s and Children’s Hospital
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o Western Australia: King Edward Memorial Hospital
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o Australian Capital Territory: Canberra Hospital
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o Tasmania: Royal Hobart Hospital
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New Zealand:
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o Kidz First Hospital (Counties Manukau, Auckland)
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o National Women’s Health (Auckland)
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o Wellington Regional Hospital
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o Christchurch Hospital
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o Waikato Hospital
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Canada:
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o Royal Alexandra Hospital, Edmonton
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Singapore:
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o KK Women’s and Children’s Hospital
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Eligibility criteria {10}
Who will take informed consent? {26a}
Additional consent provisions for collection and use of participant data and biological specimens {26b}
Interventions
Explanation for the choice of comparators {6b}
Intervention description {11a}
Setting
Preparation of the study intervention
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Poractant alfa dose (both arms): 200 mg/kg initial dose; subsequent dose 100 mg/kg (if applicable)
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Budesonide dose (intervention arm): 0.25 mg/kg (0.5 mL/kg of 1 mg in 2 mL solution) added to each dose of poractant alfa.
Criteria for discontinuing or modifying allocated interventions {11b}
Strategies to improve adherence to interventions {11c}
Relevant concomitant care permitted or prohibited during the trial {11d}
Provisions for post-trial care {30}
Outcomes {12}
Primary outcome
In-hospital secondary outcomes (to be presented with the main trial results)
Adverse events (assessed from randomization until death, primary hospital discharge, or 52 week’s PMA, whichever occurs sooner, unless otherwise specified)
Longer-term outcomes at 2 years and beyond (to be published separately to the main trial results)
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Death (from time of randomization)
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Age-standardized developmental scores for cognition, language, and motor function
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Developmental delay, defined as an age-standardized developmental score more than 1 standard deviation below the normative mean for cognition, language, or motor function
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Moderate or severe developmental delay, defined as an age-standardized developmental score more than 2 standard deviations below the normative mean for cognition, language, or motor function
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Cerebral palsy and severity (mild, moderate, severe, according to the Gross Motor Function Classification System)
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Moderate or severe neurosensory disabilities (moderate or severe cerebral palsy, blindness, and deafness)
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Sex- and age-standardized emotional-behavioral scores and proportion with emotional-behavioral difficulties
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Body size (sex- and corrected age-standardized scores for height, weight, head circumference, and body mass index)
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Incidence and severity of wheezing in the preceding 12 months
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Asthma risk score and proportion of children at high risk for school-age asthma
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Parent-reported child quality of life
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A cost-effectiveness analysis
Cost-effectiveness analysis (to be published separately to the main trial results)
Participant timeline {13}
Enrolment
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Allocation
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Post-allocation
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Post-discharge
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Timepoint
| Antenatal or postnatal (< 48 h of age) |
Within eligibility window
(< 48 h of age) | < 48 h of age |
6–59 h of age
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28 days of age
| 36 + 0–36 + 6 weeks’ PMA (primary endpoint) |
40 weeks’ PMA
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Hospital discharge*
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24–30 months’ (corrected for prematurity)
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Enrolment
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Eligibility screen | X | ||||||||
Informed consent | X | ||||||||
Maternal demographic and pregnancy data | X | ||||||||
Randomization data | X | ||||||||
Baseline infant data | X | ||||||||
Interventions
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1st intervention | X | ||||||||
2nd intervention (if applicable) | X | ||||||||
Outcome assessments
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Immediate safety of intervention | Within 14 days after randomization | ||||||||
Other in-hospital safety data | X | X | X | X | X | X | |||
Respiratory assessment day 28 | X | ||||||||
Primary outcome: BPD assessment at 36 weeks’ PMA
| X | ||||||||
“Clinical BPD” assessment at 40 weeks’ PMA | X | ||||||||
Completion of admission data | X | ||||||||
Longer-term outcome assessment | X |
Sample size {14}
Recruitment {15}
Assignment of interventions: allocation
Sequence generation {16a}
Concealment mechanism {16b}
Implementation {16c}
Assignment of interventions: blinding
Who will be blinded {17a}
Procedure for unblinding if needed {17b}
Data collection and management
Plans for assessment and collection of outcomes {18a}
Plans to promote participant retention and complete follow-up {18b}
Data management {19}
Confidentiality {27}
Plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}
Statistical methods
Statistical methods for primary and secondary outcomes {20a}
Interim analyses {21b}
Methods for additional analyses (e.g., subgroup analyses) {20b}
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}
Plans to give access to the full protocol, participant level-data and statistical code {31c}
Oversight and monitoring
Composition of the coordinating center and trial steering committee {5d}
A/Prof Brett Manley (Co-Principal Investigator) | The Royal Women’s Hospital, Melbourne, Australia The University of Melbourne, Melbourne, Australia Murdoch Children’s Research Institute, Melbourne, Australia |
Dr Omar Kamlin (Co-Principal Investigator) | The Royal Women’s Hospital, Melbourne, Australia The University of Melbourne, Melbourne, Australia Murdoch Children’s Research Institute, Melbourne, Australia |
A/Prof Chris McKinlay | Department of Paediatrics: Child and Youth Health, The University of Auckland, Auckland, New Zealand |
A/Prof Susan Jacobs | The Royal Women’s Hospital, Melbourne, Australia Murdoch Children’s Research Institute, Melbourne, Australia The University of Melbourne, Melbourne, Australia |
Prof Lex Doyle | The Royal Women’s Hospital, Melbourne, Australia The University of Melbourne, Melbourne, Australia Murdoch Children’s Research Institute, Melbourne, Australia |
Prof Peter Davis | The University of Melbourne, Melbourne, Australia Murdoch Children’s Research Institute, Melbourne, Australia |
Prof Peter Dargaville | Royal Hobart Hospital, Hobart, Australia Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia |
Prof Jeanie Cheong | The Royal Women’s Hospital, Melbourne, Australia Murdoch Children’s Research Institute, Melbourne, Australia |
A/Prof Susan Donath (Trial statistician) | Murdoch Children’s Research Institute, Melbourne, Australia |
Dr Jennifer Dawson (Trial coordinator) | The Royal Women’s Hospital, Melbourne, Australia Murdoch Children’s Research Institute, Melbourne, Australia The University of Melbourne, Melbourne, Australia |
A/Prof David Cartwright | Chair | Brisbane, Australia |
Prof Ian Marschner | Independent Statistician | Sydney, Australia |
Prof Haresh Kirpalani | Independent Expert | Hamilton, Canada |
Prof Brian Darlow | Independent Expert | Christchurch, New Zealand |
Prof Rod Hunt | Independent Expert | Melbourne, Australia |
Composition of the Data Monitoring Safety Board (DSMB), its role and reporting structure {21a}
Adverse event reporting and harms {22}
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Death (also a component of the primary outcome)
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Spontaneous intestinal perforation
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The need for cardiopulmonary resuscitation (chest compressions) and/or administration of adrenaline/epinephrine (for resuscitation) within 24 h of the intervention
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Any clinical deterioration of an infant requiring escalation of treatment that the treating clinician considers is secondary to the study intervention.