Serelaxin To Lower Portal Pressure (STOPP)

Serelaxin To Lower Portal Pressure in Patients With Cirrhosis and Portal Hypertension

Portal hypertension (an increase in blood pressure in the portal vein that carries the blood from the intestine and spleen to the liver) underlies most of the serious complications of liver cirrhosis. This randomised placebo controlled study in people with liver cirrhosis evaluates the acute effects serelaxin (RLX030) infusion on portal hypertension and liver blood flow.

Study Overview

• Status: Completed
• Conditions: Liver Cirrhosis; Hypertension, Portal
• Intervention / Treatment: Drug: Serelaxin; Drug: Placebo

Detailed Description

This study will investigate the effects of the investigational drug serelaxin (a recombinant form of the peptide human relaxin-2) on portal hypertension in patients with liver cirrhosis. The investigators will measure portal pressure by hepatic venous pressure gradient (HVPG) and hepatic blood flow by indocyanine green (ICG) clearance to evaluate the potential benefits of the drug. In a recently completed small exploratory open-label phase 2 study (EudraCT no. 201200023626, NCT01640964), Part B demonstrated that serelaxin can lower portal pressure.

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 2

Contacts and Locations

Study Locations

• United Kingdom
  • Edinburgh, United Kingdom, EH164TJ
    • Liver Unit, Royal Infirmary of Edinburgh

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Male or female adult subjects over 18 years of age
2. Able to provide written informed consent and able to understand and willing to comply with the requirements of the study
3. Clinical imaging-diagnosed or biopsy-proven liver cirrhosis of any aetiology
4. Evidence of portal hypertension either on imaging or previous endoscopy
5. Patients with large/grade 3 varices as identified by endoscopy within 6 months of screening must be in an endoscopic band ligation programme at the time of study entry
6. Suspected hepatic venous pressure gradient (HVPG) ≥10 mmHg at baseline

Exclusion Criteria:

1. Pregnancy or breast feeding
2. Women of child-bearing potential not using highly effective methods of contraception
3. Severe liver failure defined by one of the following: Prothrombin activity <40%, Bilirubin >5 mg/dL (85umol/L), hepatic encephalopathy > grade I
4. A history of variceal bleed within 1 month prior to visit 1
5. Presence of any non-controlled and clinically significant disease that could affect the study outcome or that would place the patient at undue risk
6. Hepatocellular carcinoma or history of malignancy of any organ system (other than localized basal cell carcinoma of the skin) treated or untreated
7. Portal vein thrombosis
8. Previous surgical shunt or TIPSS
9. Current use of beta-blockers or nitrates, any other drug therapy known to have an influence on portal pressure (diuretics permitted provided patients have been on a stable dose for at least 30 days)
10. History of drug or alcohol abuse within 1 month of enrolment
11. Sitting Systolic Blood Pressure <110 mmHg at screening visit or within 10 minutes prior to starting study drug infusion
12. Use of other investigational drugs within 5 half-lives of enrolment, or within 30 days/until the expected pharmacodynamic effect has returned to baseline, whichever is longer
13. Significant arrhythmias, which include any of the following: sustained ventricular tachycardia, bradycardia with sustained ventricular rate < 45 beats per minute or atrial fibrillation/flutter with sustained ventricular response of > 90 beats per minute at rest, or Long QT syndrome or corrected QT interval (QTc) > 450 msec (QT correction will be performed using the Fridericia correction method: QTcF = QT/RR0.33) for males and > 460 msec for females at screening visit
14. Documented hypersensitivity to intravenous contrast agents and/or iodine
15. Severe renal impairment (eGFR<30mL/min /1.73m2)
16. Significant left ventricular outflow tract obstructions (e.g., severe valvular aortic stenosis, obstructive cardiomyopathy), severe mitral stenosis, restrictive amyloid myocardiopathy, acute myocarditis
17. Severe aortic insufficiency or severe mitral regurgitation for which surgical or percutaneous intervention is indicated
18. Major neurologic event including cerebrovascular events, within 30 days prior to screening
19. Clinical evidence of acute coronary syndrome currently or within 30 days prior to enrolment
20. History of hypersensitivity to study drug serelaxin or study drug ingredients
21. Inability to follow instructions or comply with follow-up procedures.
22. Permanent pacemaker, cardiac resynchronisation device or implantable cardioverter-defibrillator in situ

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Serelaxin; IV infusion of serelaxin (RLX030) for 2 hours	Drug: Serelaxin; Serelaxin solution diluted in 5% glucose volume/volume (v/v) solution; Other Names: RLX030; Recombinant human relaxin-2
Placebo Comparator: Placebo; IV infusion of placebo (20mM sodium acetate pH5) matched to serelaxin for 2 hours	Drug: Placebo; Placebo solution (20mM sodium acetate pH5) diluted in 5% v/v glucose solution

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Change from baseline in fasting hepatic venous pressure gradient (HVPG)	Baseline, after 2 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline in fasting hepatic venous pressure gradient (HVPG)		Baseline, after 1 hour
Change from baseline in fasting hepatic blood flow	Measured from the concentration of indocyanine green (ICG) in the hepatic venous blood vs peripheral venous blood using the Fick Principle	Baseline, after 2 hours
Change from baseline in inferior vena cava pressure		Baseline, after 2 hours
Change from baseline in cardiac index		Baseline, after 2 hours
Change from baseline in systemic vascular resistance index		Baseline, after 2 hours
Number of participants with adverse events	Adverse events (AE) reporting will be summarized based on number of patients reported with abnormal laboratory values, clinically significant AE, serious adverse events or death	4 weeks
Change from baseline in blood biomarker measurements		Baseline, after 2 hours
Change from baseline in aortic pulse wave velocity		Baseline, after 2 hours

Collaborators and Investigators

• Sponsor: University of Edinburgh
• Collaborators: Novartis Pharmaceuticals; NHS Lothian

Publications and helpful links

General Publications

• Fallowfield JA, Hayden AL, Snowdon VK, Aucott RL, Stutchfield BM, Mole DJ, Pellicoro A, Gordon-Walker TT, Henke A, Schrader J, Trivedi PJ, Princivalle M, Forbes SJ, Collins JE, Iredale JP. Relaxin modulates human and rat hepatic myofibroblast function and ameliorates portal hypertension in vivo. Hepatology. 2014 Apr;59(4):1492-504. doi: 10.1002/hep.26627. Epub 2014 Mar 3.
• Kobalava Z, Villevalde S, Kotovskaya Y, Hinrichsen H, Petersen-Sylla M, Zaehringer A, Pang Y, Rajman I, Canadi J, Dahlke M, Lloyd P, Halabi A. Pharmacokinetics of serelaxin in patients with hepatic impairment: a single-dose, open-label, parallel group study. Br J Clin Pharmacol. 2015 Jun;79(6):937-45. doi: 10.1111/bcp.12572.
• Gifford FJ, Dunne PDJ, Weir G, Ireland H, Graham C, Tuck S, Hayes PC, Fallowfield JA. A phase 2 randomised controlled trial of serelaxin to lower portal pressure in cirrhosis (STOPP). Trials. 2020 Mar 12;21(1):260. doi: 10.1186/s13063-020-4203-9.

Study record dates

Study Major Dates

• Study Start (Actual): October 18, 2017
• Primary Completion (Actual): August 31, 2018
• Study Completion (Actual): August 31, 2018

Study Registration Dates

• First Submitted: January 28, 2016
• First Submitted That Met QC Criteria: January 28, 2016
• First Posted (Estimate): February 1, 2016

Study Record Updates

• Last Update Posted (Actual): October 11, 2018
• Last Update Submitted That Met QC Criteria: October 10, 2018
• Last Verified: October 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Liver Diseases; Fibrosis; Hypertension; Liver Cirrhosis; Hypertension, Portal
• Other Study ID Numbers: STOPP

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No