O09 A double blind, randomised, placebo-controlled study to assess safety and tolerability of oral enterosorbent Carbalive (Yaq-001) in cirrhotic patients

Background

Yaq-001 is a non-absorbable, synthetic carbon with high adsorptive capacity for bacterial products including lipopolysaccharide (LPS) and pro-inflammatory cytokines. Studies in cirrhotic rats showed reduced endotoxemia, improvements in end-organ dysfunction and reduced sensitisation to LPS. The aims of this study were to evaluate the safety and tolerability of Yaq-001 in decompensated cirrhotic (DC) patients and characterise immunological and metabolic effects.

Methods

This EU-funded H2020 study (CARBALIVE:634579) recruited patients with diuretic-responsive cirrhotic ascites. 28-patients from 8-EU centres were randomised to receive 4 g of Yaq-001 (Y) or placebo (P) for 12-weeks. Safety assessments were performed at baseline, weeks 1, 4, 8 and 12. Endotoxin activity assay (EAA, data used for analysis: CV<20%), organ function, nutrition, markers of systemic and gut inflammation, gut permeability, urinary 1HMRS, and next generation sequencing of stool were evaluated at baseline, W4 and W12. Data were summarized by group and visit as means (SD) with select efficacy parameters modeled using MMRM.

Results

14-patients were randomised to each group (Y: Age: 57.8±7 yrs, M: 71%, MELD: 12.4±0.9; P: Age: 57.3±10, M: 75%, MELD: 13.9±1). Safety: Yaq-001 was well tolerated with no SAEs, stable MELD score, decompensation events and nutritional status. Compliance: 93%(Y) 67%(P). Endotoxemia: Trends to reduction in EAA ratio (Y:-2.4% vs P:29.6%) and constitutive whole blood ROS (Y:-37.3% vs P:+34.3%) were observed in the active group (figure 1). Systemic inflammation: Reductions in WCC, CRP, IL6 and CXCL10 in the active group were observed compared with placebo (Y(%):-8.8,-4.3,-3.6,-16.7; P(%)+0.4,+23.9,+13.8,+31.8) (figure 1). Gut inflammation/permeability: Improvements in faecal cytokines in Yaq-001 patients trended towards published values for healthy control. Reduction in plasma D-lactate was observed in Yaq-001 compared to placebo suggestive of an improvement in gut barrier integrity (figure 1). Metabolism: Yaq-001 reduced stool ammonia with a trend to increased urinary hippurate. Microbiome: No change in bacterial diversity was observed.

Conclusion

Yaq-001 was safe and well tolerated. The data suggest proof of mechanism that Yaq-001, modulates systemic endotoxemia and inflammation by impacting gut inflammation and its permeability.