Serelaxin To Lower Portal Pressure

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Liver Cirrhosis, Hypertension, Portal

Intervention / Treatment
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* Drug: Serelaxin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female adult subjects over 18 years of age Able to provide written informed consent and able to understand and willing to comply with the requirements of the study Clinical imaging-diagnosed or biopsy-proven liver cirrhosis of any aetiology Evidence of portal hypertension either on imaging or previous endoscopy 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 Suspected hepatic venous pressure gradient (HVPG) ≥10 mmHg at baseline Exclusion Criteria: Pregnancy or breast feeding Women of child-bearing potential not using highly effective methods of contraception Severe liver failure defined by one of the following: Prothrombin activity <40%, Bilirubin >5 mg/dL (85umol/L), hepatic encephalopathy > grade I A history of variceal bleed within 1 month prior to visit 1 Presence of any non-controlled and clinically significant disease that could affect the study outcome or that would place the patient at undue risk Hepatocellular carcinoma or history of malignancy of any organ system (other than localized basal cell carcinoma of the skin) treated or untreated Portal vein thrombosis Previous surgical shunt or TIPSS 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) History of drug or alcohol abuse within 1 month of enrolment Sitting Systolic Blood Pressure <110 mmHg at screening visit or within 10 minutes prior to starting study drug infusion 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 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 Documented hypersensitivity to intravenous contrast agents and/or iodine Severe renal impairment (eGFR<30mL/min /1.73m2) Significant left ventricular outflow tract obstructions (e.g., severe valvular aortic stenosis, obstructive cardiomyopathy), severe mitral stenosis, restrictive amyloid myocardiopathy, acute myocarditis Severe aortic insufficiency or severe mitral regurgitation for which surgical or percutaneous intervention is indicated Major neurologic event including cerebrovascular events, within 30 days prior to screening Clinical evidence of acute coronary syndrome currently or within 30 days prior to enrolment History of hypersensitivity to study drug serelaxin or study drug ingredients Inability to follow instructions or comply with follow-up procedures. Permanent pacemaker, cardiac resynchronisation device or implantable cardioverter-defibrillator in situ

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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 |