Serelaxin To Lower Portal Pressure

Liver Cirrhosis Clinical Trial

— STOPP  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02669875
• Other study ID #: STOPP
• Status: Completed
• Phase: Phase 2
• Start date: October 18, 2017
• Est. completion date: August 31, 2018

Study information

• Verified date: October 2018
• Source: University of Edinburgh
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 15
• Est. completion date: August 31, 2018
• Est. primary completion date: August 31, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Fibrosis
• Hypertension
• Hypertension, Portal
• Liver Cirrhosis

Intervention

Drug:
• Serelaxin
Serelaxin solution diluted in 5% glucose volume/volume (v/v) solution
• Placebo
Placebo solution (20mM sodium acetate pH5) diluted in 5% v/v glucose solution

Locations

Country	Name	City	State
United Kingdom	Liver Unit, Royal Infirmary of Edinburgh	Edinburgh

Sponsors (3)

Lead Sponsor	Collaborator
University of Edinburgh	NHS Lothian, Novartis Pharmaceuticals

Country where clinical trial is conducted

United Kingdom, 

References & Publications (2)

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change from baseline in fasting hepatic venous pressure gradient (HVPG)		Baseline, after 2 hours
Secondary	Change from baseline in fasting hepatic venous pressure gradient (HVPG)		Baseline, after 1 hour
Secondary	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
Secondary	Change from baseline in inferior vena cava pressure		Baseline, after 2 hours
Secondary	Change from baseline in cardiac index		Baseline, after 2 hours
Secondary	Change from baseline in systemic vascular resistance index		Baseline, after 2 hours
Secondary	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
Secondary	Change from baseline in blood biomarker measurements		Baseline, after 2 hours
Secondary	Change from baseline in aortic pulse wave velocity		Baseline, after 2 hours