A randomized, double-blind, placebo-controlled, ascending dose trial of the pharmacokinetics and safety of intravenous infusion of recombinant human plasma gelsolin in acutely ill patients with decreased plasma gelsolin levels

Abstract

RATIONALE: Exposure of cellular actin by acute injury decreases concentrations of gelsolin (GSN), the fourth most abundant plasma protein below its normal levels of 250 ± 50 mg/L. GSN depletion below disease-specific critical levels strongly predicts adverse outcomes such as ARDS, prolonged hospitalization and death, consistent with GSN’s hypothesized physiological function to localize inflammation by binding and inactivating diverse inflammatory mediators. GSN repletion in animal models of acute injury prevents complications including death. METHODS: This is the first human study in which intravenous GSN is administered. Three cohorts of patients with early sepsis defined as a Multiple Organs System Failure (MOSF) Score of 3 or below admitted to or residing in an ICU with GSN levels below 100mg/L determined by ELISA assay were enrolled for a trial of GSN (or placebo) intravenous infusion. Cohort 1 received a 3mg/kg single dose cohort 2 a 6mg/kg single dose and cohort 3 6mg/kg daily for 3 days. A fourth cohort included patients with MOSF of 4 or above and received either placebo or the same dose as Cohort 3. Baseline demographic and clinical data and pre- and post-infusion cytokine profiles and GSN levels were measured. The primary objectives were to determine the safety and pharmacokinetics of GSN infusion in these patients. RESULTS: Twenty-one subjects, 24 male, 4 female, of mean age 70.3 years received GSN and 7 placebos. Whereas placebo had no effect, GSN infusion increased GSN levels above the critical level in all patients in cohorts 1 and 2 (Table 1) and in all but one in cohorts 3 and 4 for 4 -16 hours, depending on dose. Although not statistically significant, cytokine levels changed in a manner consistent with inflammation suppression. Although serious adverse events occurred, including 7 deaths occurring at a median of 16 days (Range 2-56 days) post infusion, the Safety Monitoring Committee determined that they were not related or unlikely to be related to GSN replacement. No subject developed antibodies against GSN measured at 1 and 3 months after infusion. CONCLUSIONS: Recombinant GSN can be safely given to patients with severe sepsis and increase levels above values associated with adverse outcomes. Further evaluation of the therapeutic effect of GSN replacement is warranted.