Paediatric Intensive Care Adaptive Platform Trial (PIVOTAL)

RESEARCH QUESTION: In critically ill children [Population] is/are A) a strategy of conservative fluid management, B) alpha2-agonists as first-line agents for sedation, or C) restrictive red blood cell transfusions, [Interventions]

superior to control (usual care) [Comparators] in terms of death or days alive and free from organ support to day 30 (clinical effectiveness) and incremental net benefit at 180 days (cost effectiveness) [Outcome]?

BACKGROUND: ~20,000 critically ill children are admitted to UK PICUs annually. Of these, ~4% do not survive to discharge, and 10-15% of survivors suffer serious life-long consequences. High quality evidence to support treatment decisions is therefore vital but many basic aspects of care such as ventilation, sedation, transfusion, and fluids. A platform trial is needed to efficiently evaluate multiple interventions in view to improving care and outcomes in the shortest possible timeframe.

AIM & OBJECTIVES: to simultaneously evaluate multiple widely-used therapies to improve clinical care in the shortest possible time, initially focusing on evaluating three treatment ‘domains’: • Conservative fluid management (Domain A) • Different primary sedative agents (Domain B) • Restrictive blood transfusion thresholds (Domain C)

Additional objectives are to provide a national platform that can: • evaluate additional treatments and domains • allow new investigators to lead domains • provide junior researchers opportunities to develop their research experience • ensure that young people and parents/carers are meaningfully involved

DESIGN: Multi-centre, randomised, Bayesian adaptive platform trial with an integrated economic evaluation and internal pilot phase.

SETTING: 20 NHS PICUs participating in the PICANet national clinical audit, including underserved regions and communities. TARGET PLATFORM POPULATION: Critically ill children receiving organ support. DOMAIN A: FLUIDS INTERVENTION: Conservative fluid management, consisting of: conservative fluid administration and active fluid removal.

COMPARATOR: Usual fluid management. DOMAIN B: SEDATION INTERVENTIONS: (i) Continuous IV infusion of dexmedetomidine (ii) Continuous IV infusion of clonidine COMPARATOR: Continuous IV infusion of midazolam DOMAIN C: TRANSFUSION THRESHOLDS INTERVENTION: Restrictive transfusion strategy. COMPARATOR: Liberal transfusion strategy.

SAMPLE SIZE: Based on data obtained from PICANet, across the 20 sites, we anticipate recruiting 320 platform eligible patients per month (70% in non-cardiac and 30% in cardiac stratum).? Assuming the interventions for all domains/strata have MCID, on average we will recruit ~9500 patients with mean 1.5 randomisations per patient. These figures rise to 11,400 and 1.6 if no interventions are effective. Costs for the maximum 12,900 patients over the potential 4-year recruitment period are included.

TIMELINE FOR DELIVERY: 01/09/2024 to 30/11/2029 (63 months).

ANTICPATED IMPACT & DISSEMINATION: PIVOTAL has been designed to maximise impact and inform clinical care. The team have extensive experience of publications in high-impact journals, and as leaders in PICU, have key links to ensure rapid translation into practice. We will also use the platform to monitor the potential impact of the emerging results, helping to promote the platform as a learning health system.