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 3:1 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.

Relaxin-2 plasma levels in atrial fibrillation are linked to inflammation and oxidative stress markers

“…During the last twenty years, a large number of clinical trials have been performed in order to evaluate the effect of relaxin-2 in different physiological and pathological circumstances 15 , 16 . At the same time, although numerous works have analyzed the plasma levels of relaxin-2 in patients with established cardiovascular diseases (including AF), it was not analyzed the potential relationship between relaxin-2 circulating levels and different risk and/or prognostic markers related to the metabolic state and body composition 8 , 9 , 17 , 18 .…”

Emerging Therapeutic Targets for Portal Hypertension

“…Important vasodilatory and antifibrotic properties have already been shown in pre-clinical studies [ 192 – 194 ], including a decrease in portal pressure. However, a small clinical trial with IV serelaxin, a human relaxin-2 analog, failed to show any decrease in HVPG after a 2-h infusion [ 183 ]. Innovative delivery methods may perhaps hold promise for serelaxin as a therapeutic agent [ 195 ].…”

Relaxin-2 as a Potential Biomarker in Cardiovascular Diseases

“…The availability of serelaxin has permitted the study of relaxin-2’s effects in cardiovascular, renal, hepatic, and brain tissues, as well as its evaluation in several randomized placebo-controlled clinical trials [ 13 , 14 ]. To date, the pharmacology and specific mechanisms of the systemic action of treatment with serelaxin have been studied in more than 15 human clinical trials, including in healthy subjects [ 9 , 15 , 16 ] and in pregnancy [ 17 , 18 ], preeclampsia [ 19 ] (clinicaltrials.gov identifiers NCT00333307 and NCT01566630), acute and chronic heart failure (HF) [ 20 , 21 , 22 , 23 , 24 , 25 , 26 ], systemic sclerosis [ 27 , 28 , 29 ], renal and hepatic impairment [ 30 , 31 ], and cirrhosis [ 32 ].…”