Safety and efficacy of continuous infusion terlipressin (BIV201): A phase 2 trial in patients with decompensated cirrhosis and refractory ascites

Abstract

Refractory ascites often requires therapeutic paracentesis, which is associated with potential risks and diminished quality of life. Terlipressin is a vasopressin analog that is indicated for i.v. bolus injection for hepatorenal syndrome, with the potential to reduce large-volume ascites and its complications. Continuous infusion of terlipressin is associated with fewer adverse effects than bolus dosing. The efficacy and safety of continuous infusion of a novel liquid formulation of terlipressin acetate (BIV201) were evaluated in this open-label phase 2 study. Patients with cirrhosis and refractory ascites were randomly assigned (2:1) to receive two 28-day cycles of continuous infusion BIV201 plus standard of care (SOC) separated by a ≤56-day washout (n=10), or SOC alone (n=5). Data analysis was limited by the small sample size and confounded by a potential interaction with gabapentinoids in the BIV201+SOC group. Nonetheless, there were differences in favor of BIV201+SOC versus SOC in the coprimary efficacy endpoints and several quality of life assessments. The beneficial effects of BIV201 on liver complications (mean: 90% CI; BIV201-completers=2.87: 1.51; 5.46 vs. SOC=2.38: 1.20; 4.73) and the change in cumulative ascites (mean: 90% CI; BIV201-completers=-10.76: -26.51; 5.00 vs. SOC=-4.99: -21.95; 11.97) were more pronounced versus SOC in the 5 BIV201+SOC patients who completed both treatment cycles. There were also greater improvements in exploratory quality of life assessments and the percent change in therapeutic paracenteses with BIV201+SOC (-27.94±41.80) versus SOC (-16.67±45.64). Despite the high rate of hyponatremia in the BIV201+SOC group (4/10 patients), the safety profile suggested that continuous BIV201 infusion was well tolerated. These findings support further development of BIV201 in confirmatory trials.

Keywords: ascites; decompensated cirrhosis; hyponatremia; outpatient; phase 2 clinical trial; terlipressin.

Graphical abstract

FIGURE 1

Study design. The study was planned to be 1 year but was terminated after the 180-day follow-up. Abbreviations: PD, pharmacodynamic; PICC, peripherally inserted central catheter; SOC, standard of care; TP, therapeutic paracentesis.

FIGURE 2

Primary efficacy endpoints. (A) Model-based rate of liver complications per patient per year, and (B) mean absolute change in cumulative ascites from the 12 weeks before to the 12 weeks after randomization. ^aData were derived from the planned ANCOVA on the full analysis set. ^bData were derived from separate ad hoc ANCOVAs comparing completers and non-completers against the SOC group. Abbreviation: SOC, standard of care.

FIGURE 3

BIV201+SOC prolonged the time to first TP relative to SOC alone. Descriptive analysis of time to first TP up to day 112 was performed using the Kaplan–Meier method stratified by treatment group for the FAS (p=0.13). Abbreviations: FAS, full analysis set; SOC, standard of care; TP, therapeutic paracentesis.

FIGURE 4

BIV201+SOC was associated with improvements in health status. Absolute change from baseline in (A) total CLDQ scores and (B) abdominal domain subscores of the CLDQ. These data represent model-based means derived from ANCOVA analyses. ^aThe CLDQ is scored on a 7-point scale ranging from 1 (all of the time) to 7 (none of the time). A positive change from baseline represents a decrease in symptoms. Abbreviations: CLDQ, chronic liver disease questionnaire; SOC, standard of care.