A phase 2 randomised controlled trial of serelaxin to lower portal pressure in cirrhosis (STOPP).

ABSTRACT

BACKGROUND: In preclinical models, recombinant human relaxin-2 (serelaxin) had anti-fibrotic effects and ameliorated portal hypertension (PH). A small exploratory study in patients with cirrhosis also suggested that serelaxin could reduce portal pressure. METHODS: In a phase 2, double-blind, randomised controlled study conducted in a single centre (Royal Infirmary of Edinburgh, UK), male and female adult participants with cirrhosis and clinically significant PH (CSPH; hepatic venous pressure gradient (HVPG) > 10 mmHg) were enrolled. Participants were allocated to serelaxin or placebo in a 31 ratio. The placebo was matched to serelaxin on appearance and administration protocol to create and maintain blinding. The primary endpoint was the change from baseline in fasting HVPG after 2 h of peripheral i.v. serelaxin infusion (80 µg/kg/day for 60 min followed by 30 µg/kg/day for at least 60 min). Secondary endpoints included the change from baseline in hepatic blood flow and systemic haemodynamics (cardiac index, systemic vascular resistance index and aortic pulse wave velocity). Short-term safety and tolerability of serelaxin were assessed. RESULTS: A total of 17 participants were screened, 15 were randomised and 11 completed the study (n = 9 serelaxin, n = 2 placebo). Reasons for withdrawal were baseline HVPG < 10 mmHg (n = 2) and technical failure (n = 2). The trial ended early due to manufacturer discontinuation of the study drug. The median age was 56 (range 43-69) years and 73% of participants were male. Alcohol was the commonest cirrhosis aetiology (n = 10). Participants had a median Model for End-Stage Liver Disease score of 10 (range 6-14). The mean baseline HVPG was 16.3 (range 10.3-21.7) mmHg. Individual responses were variable, but overall there was no statistically significant change in HVPG after 2 h of i.v. serelaxin (arithmetic mean of difference ± SD was 0.4 ± 3.5 mmHg (95% CI -2.3, 3.1; p = 0.76)). There were also no substantial changes from baseline in hepatic or systemic haemodynamics. We recorded 12 adverse events in 7 participants treated with serelaxin; none were significant, and most were unrelated to the investigational medicinal product. There were no serious adverse events. CONCLUSION: In a small randomised, phase 2, proof-of-concept study in patients with cirrhosis and CSPH, serelaxin infusion was safe and well-tolerated but had a neutral effect on HVPG. TRIAL REGISTRATION ClinicalTrials.gov, NCT02669875. Registered on 1 February 2016.