Serelaxin To Lower Portal Pressure

NCT ID: NCT02669875

Last Updated: 2018-10-11

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 15 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-10-18
• Study Completion Date: 2018-08-31

Brief 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.

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.

Conditions

Liver Cirrhosis; Hypertension, Portal

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Serelaxin

IV infusion of serelaxin (RLX030) for 2 hours

Group Type: ACTIVE_COMPARATOR

Serelaxin

Intervention Type: DRUG

Serelaxin solution diluted in 5% glucose volume/volume (v/v) solution

Placebo

IV infusion of placebo (20mM sodium acetate pH5) matched to serelaxin for 2 hours

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Placebo solution (20mM sodium acetate pH5) diluted in 5% v/v glucose solution

Interventions

Serelaxin

Serelaxin solution diluted in 5% glucose volume/volume (v/v) solution

Intervention Type: DRUG

Placebo

Placebo solution (20mM sodium acetate pH5) diluted in 5% v/v glucose solution

Intervention Type: DRUG

Other Intervention Names

RLX030; Recombinant human relaxin-2

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Novartis Pharmaceuticals

INDUSTRY

Sponsor Role: collaborator

NHS Lothian

OTHER_GOV

Sponsor Role: collaborator

University of Edinburgh

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Liver Unit, Royal Infirmary of Edinburgh

Edinburgh, , United Kingdom

Countries

United Kingdom

References

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.

Reference Type: BACKGROUND

PMID: 23873655 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 25511105 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 32164767 (View on PubMed)

Other Identifiers

STOPP

Identifier Type: -

Identifier Source: org_study_id