A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome

摘要: Renin-angiotensin system (RAS) signaling and angiotensin-converting enzyme 2 (ACE2) have been implicated in the pathogenesis of acute respiratory distress syndrome (ARDS). We postulated that repleting ACE2 using GSK2586881, a recombinant form human (rhACE2), could attenuate lung injury. conducted two-part phase II trial comprising an open-label intrapatient dose escalation randomized, double-blind, placebo-controlled ten intensive care units North America. Patients were between ages 18 80 years, had American-European Consensus Criteria consensus diagnosis ARDS, mechanically ventilated for less than 72 h. In part A, GSK2586881 was administered at doses from 0.1 mg/kg to 0.8 mg/kg assess safety, pharmacokinetics, pharmacodynamics. Following review data investigation twice-daily (0.4 mg/kg) 3 days (part B). Biomarkers, physiological assessments, clinical endpoints collected over dosing period during follow-up. Dose A well-tolerated without clinically significant hemodynamic changes. Part B terminated after 39 planned 60 patients following futility analysis. Angiotensin levels decreased rapidly infusion whereas angiotensin-(1–7) angiotensin-(1–5) increased remained elevated 48 h. Surfactant protein D concentrations increased, there trend decrease interleukin-6 rhACE2-treated subjects compared with placebo. No differences noted ratio partial pressure arterial oxygen fraction inspired oxygen, oxygenation index, or Sequential Organ Failure Assessment score. rapid modulation RAS peptides suggests target engagement, although study not powered detect changes physiology outcomes. ClinicalTrials.gov, NCT01597635 . Registered on 26 January 2012.