Efficacy and safety of Vilobelimab (IFX-1), a novel monoclonal anti-C5a antibody, in patients with early severe sepsis or septic shock — a randomized, placebo-controlled, double-blind, multicenter, phase IIa Trial (SCIENS Study)

IMPORTANCE:. Anaphylatoxin C5a, a proinflammatory complement split product, plays a central role in mediating organ dysfunction. OBJECTIVES:. This phase II clinical trial was conducted to study safety, tolerability, pharmacokinetics, and pharmacodynamics of vilobelimab, a recombinant monoclonal antibody against C5a, in patients with severe sepsis or septic shock. DESIGN:. Multicenter, randomized, and placebo-controlled study. SETTING AND PARTICIPANTS:. Eleven multidisciplinary ICUs across Germany. Adult patients with severe sepsis or septic shock and with early onset of infection-associated organ dysfunction. MAIN OUTCOMES AND MEASURES:. Patients were randomly assigned in a ratio of 2:1 to three subsequent dosing cohorts for IV vilobelimab or placebo receiving either 2 × 2 mg/kg (0 and 12 hr), 2 × 4 mg/kg (0 and 24 hr), and 3 × 4 mg/kg (0, 24, and 72 hr). Co-primary endpoints were pharmacodynamics (assessed by C5a concentrations), pharmacokinetics (assessed by vilobelimab concentrations), and safety of vilobelimab. Preliminary efficacy was evaluated by secondary objectives. RESULTS:. Seventy-two patients were randomized (16 patients for each vilobelimab dosing cohort and eight patients for each placebo dosing cohort). Vilobelimab application was associated with dosing dependent decrease in C5a compared with baseline (p < 0.001). Duration of C5a decrease increased with more frequent dosing. Membrane attack complex lysis capacity measured by 50% hemolytic complement was not affected. Vilobelimab was well tolerated with similar safety findings in all dose cohorts. No vilobelimab-specific adverse events emerged. For vilobelimab-treated patients, investigators attributed less treatment-emergent adverse events as related compared with placebo. Dosing cohorts 2 and 3 had the highest ICU-free and ventilator-free days. There was no difference in mortality, vasopressor-free days, or renal replacement therapy-free days between the groups. CONCLUSIONS AND RELEVANCE:. Administration of vilobelimab in patients with severe sepsis and septic shock selectively neutralizes C5a in a dose-dependent manner without blocking formation of the membrane attack complex and without resulting in detected safety issues. The data warrant further investigation of C5a inhibition in sepsis

Grazer diversity effects in an eelgrass–epiphyte–microphytobenthos system

The dramatic loss of biodiversity and its consequences for ecosystem processes have been of considerable interest in recent ecological studies. However, the complex and interacting processes influencing diversity effects in multitrophic systems are still poorly understood. We used an experimental eelgrass system to study the effects of changing richness of three consumer species on the biomass, diversity and taxonomic composition of both epiphytic and benthic microalgal assemblages. After 1 week, consumer richness enhanced the grazing impact on epiphyte biomass relative to single consumer treatments and a positive effect of consumer richness on prey diversity was found. Moreover, strong effects of consumer species identity on taxonomic composition were found in both microalgal assemblages. However, the effects of consumer richness were not consistent over time. The consequences of high nutrient availability seemed to have masked consumer richness effects