A Safety Monitoring Framework for Critical Care Trials of Agents with Potential to Lower Blood Pressure

ABSTRACT

RATIONALE Based on encouraging preliminary data, we undertook a randomized, placebo-controlled trial of synthetic vasoactive intestinal peptide (aviptadil) for treatment of COVID-19 acute respiratory distress syndrome (ARDS). Aviptadil may cause vasodilation and resultant hypotension. Given the high background incidence of hypotension from many causes (e.g., sedatives, sepsis, positive pressure ventilation) in critically ill patients, an ascertainment and grading strategy for postrandomization hypotension capable of distinguishing “signal” from “noise” is essential to the trial's conduct and interpretation. METHODS: We evaluated whether existing adverse event (AE) severity frameworks were adequate to characterize hypotension occurring in critically ill patients. Based on these findings, we developed and implemented a customized framework for hypotension-related safety monitoring and outcome collection during the Therapeutics for Severely Ill Inpatients with COVID-19 (TESICO) trial of aviptadil for COVID-19 ARDS (NCT04843761). RESULTS: Hypotension severity assigned to COVID-19 ARDS patients by existing AE frameworks - largely developed for outpatients - appeared misaligned with the frameworks' own generic/conceptual severity criteria. Existing frameworks' hypotension-specific AE grading tables lacked necessary detail and reporting guidance, over-graded mild hypotension, and missed safety signals suggested by increasing vasopressor requirements. We therefore developed a novel hypotension AE grading table aligned with conceptual AE severity criteria for critically ill patients (Figure). In addition to general severity criteria, the table adds criteria specific to the investigational agent's peri-infusion period and provides guidance for evaluating the “seriousness” of a hypotensive event in the context of subjects' preexisting critical illness. In combination with detailed reporting on the components of AE events, the study's protocol committee, sponsor, and data safety monitoring board approved the customized table for use in outcome measurement as well as real-time safety monitoring and AE reporting. We implemented a strategy to efficiently collect the hypotension-related data required for safety monitoring and allow automated hypotension AE grading according to both the adopted schema and existing AE frameworks. CONCLUSIONS: We developed a framework acceptable to diverse stakeholders for hypotension safety monitoring in COVID-19 ARDS patients receiving aviptadil or placebo. The monitoring framework will be validated in the ongoing TESICO trial and could be adapted for other trials of vasoactive investigational agents targeting critically ill patients. Comprehensive AE grading criteria designed specifically for critically ill patients could improve trials' ability to meaningfully monitor and report safety outcomes in this population.