PLatform for Adaptive Trials In Perinatal UnitS - [Core Protocol]

PLATIPUS is a multi-domain, multi-centre international adaptive platform trial and innovative approach to perinatal research.

Preterm birth (birth before 37 weeks' gestation) is a global issue. More than 15 million babies (1 in 10) are born preterm each year. Complications of preterm birth are the leading cause of death and disability among children under five years of age. These contribute to increased risk of all-cause mortality and early death from cardiovascular disease, diabetes and chronic lung disease in later life. There is no single cause of, or pathway to, preterm birth. Treatments during pregnancy aim to prevent or treat complications that can lead to preterm birth in pregnant women and people or reduce the impact of prematurity on neonatal outcomes. Treatments in the neonatal period (period shortly after birth) aim to improve survival and reduce potential morbidities in the preterm infant.

PLATIPUS will initially assess interventions given to pregnant women and people during pregnancy (Participant Group 1) and to preterm infants (Participant Group 2) in the first few days of life. Participants will be randomly allocated to all relevant domains for which they are eligible and provide consent. Using a trial-developed Ordinal Outcome Scale, the effect of pregnancy and/or neonatal interventions on neonatal outcome will be assessed at 42 weeks' post-menstrual age OR at primary hospital discharge, whichever occurs earliest. Secondary outcomes will examine the effect of interventions on individual pregnancy and/or neonatal endpoints, and may be domain-specific. All pregnancy domains will include a 'Maternal Outcome Set' to assess maternal health and intervention safety.

In contrast to conventional clinical trials, PLATIPUS has been designed to examine multiple different treatment options at once within the same platform. Both pregnant and neonatal participants will be randomly assigned to different concurrent treatment options, with an initial focus on treatments already considered as part of clinical care. As the trial advances, novel interventions may also be included. Interventions will be evaluated within domains. A domain is defined as a set of interventions that are intended for a specific health problem or specific therapeutic option.

Bayesian adaptive statistical modelling will be used to evaluate treatment efficacy at regular interim adaptive analyses of the pre-specified outcomes for each intervention in each domain. This will allow determination of the effectiveness of interventions once sufficient data has been accrued, rather than when a pre-specified sample size is reached. Adaptive analyses will compute the posterior probabilities of superiority, futility, inferiority, or equivalence for pre-specified comparisons within domains. Each of these potential conclusions will be pre-defined prior to commencing the intervention domain. Decisions about trial results (e.g., concluding superiority or equivalence) will be based on pre-specified threshold values for posterior probability.

All trial procedures are outlined in the "core" protocol described in this registration. Separate domain protocols with information specific to each intervention included in PLATIPUS will be linked to this registration at separate clinicaltrials.gov records:

• Number of well liveborn infants [Time frame: At any time prior to 42 weeks' postmenstrual age or first discharge home from hospital (whichever is earlier).]
• Number of infants admitted to the neonatal unit during primary hospital admission for 48 hours or more. [Time frame: At any time prior to 42 weeks' postmenstrual age or first discharge home from hospital (whichever is earlier).]
• Number of infants admitted to neonatal unit during primary hospital admission for <48 hours. [Time frame: At any time prior to 42 weeks' postmenstrual age or first discharge home from hospital (whichever is earlier).]
• Number of infants who received non-invasive positive pressure respiratory support for ≥ 4 hours (excluding delivery room) and less than 5 days. [Time frame: At any time prior to 42 weeks' postmenstrual age or first discharge home from hospital (whichever is earlier).]
• Number of infants who received non-invasive positive pressure respiratory support for 5 days or more. [Time frame: At any time prior to 42 weeks' postmenstrual age or first discharge home from hospital (whichever is earlier).]
• Number of infants who received mechanical ventilation via endotracheal tube for ≥ 4 hours (excluding delivery room) and <7 days. [Time frame: At any time prior to 42 weeks' postmenstrual age or first discharge home from hospital (whichever is earlier).]
• Number of infants who received mechanical ventilation via endotracheal tube for 7 days or more. [Time frame: At any time prior to 42 weeks' postmenstrual age or first discharge home from hospital (whichever is earlier).]
• Number of infants with moderate respiratory morbidity. [Time frame: At any time prior to 42 weeks' postmenstrual age or first discharge home from hospital (whichever is earlier).]
• Number of infants with necrotising enterocolitis OR sepsis. [Time frame: At any time prior to 42 weeks' postmenstrual age or first discharge home from hospital (whichever is earlier).]
• Number of infants with severe respiratory morbidity. [Time frame: At any time prior to 42 weeks' postmenstrual age or first discharge home from hospital (whichever is earlier).]
• Number of participants who underwent major surgery. [Time frame: At any time prior to 42 weeks' postmenstrual age or first discharge home from hospital (whichever is earlier).]
• Number of infants with brain injury. [Time frame: At any time prior to 42 weeks' postmenstrual age or first discharge home from hospital (whichever is earlier).]