Spontaneous breathing trials (SBTs) are used to determine extubation readiness in extremely preterm neonates (gestational age ≤28 weeks), but these trials rely on empirical combinations of clinical events during endotracheal continuous positive airway pressure (ET-CPAP). To describe clinical events during ET-CPAP and to assess accuracy of comprehensive clinical event combinations in predicting successful extubation compared with clinical judgment alone. This multicenter diagnostic study used data from 259 neonates seen at 5 neonatal intensive care units from the prospective Automated Prediction of Extubation Readiness (APEX) study from September 1, 2013, through August 31, 2018. Neonates with birth weight less than 1250 g who required mechanical ventilation were eligible. Neonates deemed to be ready for extubation and who underwent ET-CPAP before extubation were included. In the APEX study, cardiorespiratory signals were recorded during 5-minute ET-CPAP, and signs of clinical instability were monitored. Four clinical events were documented during ET-CPAP: apnea requiring stimulation, presence and cumulative durations of bradycardia and desaturation, and increased supplemental oxygen. Clinical event occurrence was assessed and compared between extubation pass and fail (defined as reintubation within 7 days). An automated algorithm was developed to generate SBT definitions using all clinical event combinations and to compute diagnostic accuracies of an SBT in predicting extubation success. Of 259 neonates (139 [54%] male) with a median gestational age of 26.1 weeks (interquartile range [IQR], 24.9-27.4 weeks) and median birth weight of 830 g (IQR, 690-1019 g), 147 (57%) had at least 1 clinical event during ET-CPAP. Apneas occurred in 10% (26 of 259) of neonates, bradycardias in 19% (48), desaturations in 53% (138), and increased oxygen needs in 41% (107). Neonates with successful extubation (71% [184 of 259]) had significantly fewer clinical events (51% [93 of 184] vs 72% [54 of 75], P = .002), shorter cumulative bradycardia duration (median, 0 seconds [IQR, 0 seconds] vs 0 seconds [IQR, 0-9 seconds], P < .001), shorter cumulative desaturation duration (median, 0 seconds [IQR, 0-59 seconds] vs 25 seconds [IQR, 0-90 seconds], P = .003), and less increase in oxygen (median, 0% [IQR, 0%-6%] vs 5% [0%-18%], P < .001) compared with neonates with failed extubation. In total, 41 602 SBT definitions were generated, demonstrating sensitivities of 51% to 100% (median, 96%) and specificities of 0% to 72% (median, 22%). Youden indices for all SBTs ranged from 0 to 0.32 (median, 0.17), suggesting low accuracy. The SBT with highest Youden index defined SBT pass as having no apnea (with desaturation requiring stimulation) or increase in oxygen requirements by 15% from baseline and predicted extubation success with a sensitivity of 93% and a specificity of 39%. The findings suggest that extremely preterm neonates commonly show signs of clinical instability during ET-CPAP and that the accuracy of multiple clinical event combinations to define SBTs is low. Thus, SBTs may provide little added value in the assessment of extubation readiness.