Pre-hospitAl Randomised triAl of MEDICation route in out-of-hospital cardiac arrest (PARAMEDIC3)

RESEARCH QUESTION: Population: Adults with out-of-hospital cardiac arrest Intervention: Intraosseous (IO) first strategy Comparator: Current NHS treatment (2 attempts at IV access before attempting IO access) Outcomes: Survival, favourable neurological outcome, health-related quality of life and cost effectiveness

Study design: Multi-centre, pragmatic, individually randomised, parallel group, trial and economic evaluation Timeline: 48 months.

BACKGROUND: 30,000 people sustain an out-of-hospital cardiac arrest each year. Parenteral drugs are an effective treatment and the earlier drugs are given the greater their impact. The best route for administering drugs is currently unknown, resulting in variation in practice and uncertainty about the optimal approach.

AIM: To conduct a multi-centre, pragmatic, individually randomised, parallel group, superiority trial and economic evaluation to determine the clinical and cost effectiveness of an intraosseous access first strategy, versus current NHS treatment. The trial will include an internal pilot to confirm feasibility.

OBJECTIVES: (1) Conduct an internal pilot study to confirm the feasibility of the large-scale multicentre trial

(2) Determine the clinical effectiveness of an IO first strategy for adults with out-of-hospital cardiac arrest upon survival, favourable neurological outcomes and health-related quality of life. (3) Estimate, in an integrated economic evaluation, the cost-effectiveness of an IO first strategy. METHODS:

Setting: NHS Ambulance Services across England and Wales. Randomisation: Allocation concealed, randomisation (1:1), stratified by ambulance service. Inclusion criteria: • Adult (age >18) • Out-of-hospital cardiac arrest • Requirement for vascular access to administer cardiac arrest drugs Exclusion criteria:

• Known or suspected pregnancy • Already have vascular access

Health technologies being assessed: Intraosseous first strategy compared with current NHS treatment (2 attempts at IV access before IO access) Primary outcome: • Survival to 30 days Secondary outcomes: • Any return of spontaneous circulation (ROSC) • Time to ROSC • Survived event (sustained ROSC at hospital handover)

• Survival to hospital discharge, 3 and 6 months • Neurological outcome (modified Rankin Scale) at discharge, 3, and 6 months • Health related quality of life (EQ-5D-5L) at 3 and 6 months • Hospital and intensive care length of stay Economic outcomes:

• Incremental cost per quality-adjusted life year gained from the perspective of the NHS and personal social services. • Within-trial and life-time model estimates will be generated. Sample size: 15,000 participants (90% power, 5% significance, to detect 1% absolute difference in survival). ANTICIPATED IMPACT AND DISSEMINATION:

The study will provide definitive evidence for the most effective vascular access strategy during out-of-hospital cardiac arrest. The findings will define future NHS and international practice. A 1% absolute difference in survival will translate to an additional 150 lives saved each year in the NHS.

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