Project Summary Although pediatric acute respiratory distress syndrome (PARDS) is a life-threatening and frequent problem experienced by thousands of children each year, little evidence supports best ventilation practices. For 25 years, pediatric critical care clinicians have debated the risk-benefit ratio of supine versus prone positioning and conventional mechanical ventilation (CMV) versus high-frequency oscillatory ventilation (HFOV). The purpose of the proposed clinical trial PROSpect (PRone and OScillation PEdiatric Clinical Trial) is to provide evidence to support best ventilation practices in critically ill children with severe PARDS. The proposed study is a two-by-two factorial, response-adaptive, randomized controlled clinical trial of supine/prone positioning and CMV/HFOV in 45 pediatric intensive care units (PICUs; 30 U.S., 15 international) with at least 5 years of experience with these interventions. Up to 1000 patients with severe PARDS will be randomized to one of four groups (supine/CMV; prone/CMV; supine/HFOV; prone/HFOV), stratified by age group (<1; 1-7; 8- 17 years) and direct/indirect lung injury. Response adaptive randomization will begin after 400 patients provide complete data on the primary outcome, ventilator-free days. Any group demonstrating inferiority at pre-planned randomization update analyses will be eliminated to increase allocation to the remaining groups. PROSpect will close enrollment when any one group demonstrates superiority or for futility in answering the research question. Data will be analyzed per intention-to-treat for the primary analyses and per-protocol received. In conjunction with the Clinical Coordinating Center, the PROSpect Data Coordinating Center (DCC) will achieve the launch, execution and completion of the proposed trial by accomplishing these specific aims (SA): SA1: To provide state-of-the-art data management and data monitoring processes for U.S. and international enrollment for PROSpect, for post-discharge follow-up and for eventual data archiving. SA2: To monitor study enrollment and progress, site performance, protocol adherence and patient safety in support of study coordination and Data and Safety Monitoring Board (DSMB) needs. SA3: To perform randomization update analyses to aid in decision-making regarding response adaptive randomization as well as interim analyses for review of outcomes and safety data for DSMB reports. SA4: To provide high-quality statistical analyses for primary and secondary study papers using modern statistical methodology and graphical procedures and to assist with the rapid dissemination of findings. This clinical trial will provide the definitive evidence necessary for the field to consider a major change in clinical practice in the care of critically ill children with severe PARDS.