An Exploratory Haemodynamic Study in Patients With Compensated Cirrhosis and Portal Hypertension

An Exploratory Study to Investigate the Haemodynamic Effects of Serelaxin (RLX030) in Patients With Compensated Cirrhosis and Portal Hypertension

The main purpose of this exploratory study was to investigate the effect of serelaxin (RLX030) infusion on the hepatic and renal circulation in patients with compensated cirrhosis and portal hypertension. Measurements were acquired non-invasively using magnetic resonance angiography (MRA) (study part A) and more directly via cannulation of the hepatic portal vein during a routine transjugular intrahepatic portosystemic shunt (TIPSS) check procedure (study part B), to determine the acute haemodynamic response to serelaxin (RLX030).

Study Overview

• Status: Completed
• Conditions: Compensated Cirrhosis and Portal Hypertension
• Intervention / Treatment: Drug: Terlipressin acetate; Drug: Serelaxin (RLX030)

• Study Type: Interventional
• Enrollment (Actual): 47
• Phase: Phase 2

Contacts and Locations

Study Locations

• United Kingdom
  • Edinburgh, United Kingdom, EH16 4TJ
    • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Study Parts A and B:

-Cirrhosis of alcohol aetiology according to physician's assessment prior to screening.

Part A:

-Cirrhosis with clinical and/or endoscopic evidence of portal hypertension (e.g. oesophageal varices).

Part B:

• Cirrhosis with TIPSS in situ and PPG>5mmHg.
• Fully functioning TIPSS without variceal filling as confirmed by portography.

Exclusion Criteria:

Study Parts A and B:

• Use of any drug to treat portal hypertension (e.g. vasodilators such as non-selective beta blockers or nitrates) within 1 month prior to screening.
• Decompensated cirrhosis (Child-Pugh score >9 points, and/or ascites requiring diuretics, and/or hepatic encephalopathy) at 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.

Part A:

• BMI (weight[kg] / height[m^2]) > 40 kg/m^2.
• Any contraindication to having an MRI scan

Part B:

-Contraindication to catheterization

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part A: Terlipressin acetate; Patients received terlipressin acetate 2 mg intravenous (IV) bolus injection.	Drug: Terlipressin acetate; IV bolus injection
Experimental: Part A: Serelaxin (RLX030); Randomized patients received an intravenous serelaxin infusion at two different infusion rates: 80 μg/kg/day for 60 min followed by 30 μg/kg/day for at least 60 min.; duration of infusion depends on time required for completion of magnetic resonance angiography (MRA) data acquisition	Drug: Serelaxin (RLX030); Part A2: IV infusion for 2-3 hours; duration of infusion depends on time required for completion of MRA data acquisition; Part B: IV infusion for approximately 2 hours
Experimental: Part B Serelaxin (RLX030); The patients enrolled in this part of the study received an intravenous (iv) serelaxin infusion at two different infusion rates: 80 μg/kg/day for 60 min followed by 30 μg/kg/day for at least 60 min; duration of infusion depends on time required for completion of Portal pressure gradient (PPG) data acquisition.	Drug: Serelaxin (RLX030); Part A2: IV infusion for 2-3 hours; duration of infusion depends on time required for completion of MRA data acquisition; Part B: IV infusion for approximately 2 hours

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline of the Blood Flow for the Total Renal Arteries (Study Part A (Serelaxin Treatment Group Only))	The flow is the average flow over the cardiac cycle. Total renal artery flow = left renal artery flow + right renal artery flow. These measurements were collected through magnetic resonance angiography (MRA) scans. Baseline blood flow for total renal artery is measured at pre-dose (Day 1, 0 min post-treatment)	Baseline, 120 min post serelaxin infusion
Change From Baseline of the Portal Pressure Gradient (PPG) (Study Part B)	Direct venous pressure was measured by portal pressure gradient (PPG). PPG = portal vein pressure (PVP) - inferior vena cava pressure (IVCP). Baseline blood flow for PPG was measured at pre-dose (Day 1, 0 min post-treatment). PVP was measured at 15 min intervals (i.e. prior to and at 15, 30, 45, 60, 75, 90, 105, and 120 min of serelaxin infusion).	Baseline, 120 min post-infusion start

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline of the Blood Flow for the Total Renal Arteries (Study Part A (Terlipressin Acetate Group Only))	The flow is the average flow over the cardiac cycle. Total renal artery flow = left renal artery flow + right renal artery flow. These measurements were collected through magnetic resonance angiography (MRA) scans. Baseline blood flow for total renal artery is measured at pre-dose (Day 1, 0 min post-treatment)	Baseline, 120 min post infusion
Change From Baseline of the Blood Flow for the Hepatic Artery (Study Part A (Serelaxin Treatment Group Only))	A non-contrast magnetic resonance angiography (MRA) sequence was performed to acquire phase contrast blood flow measurements from vessels of interest such as hepatic artery. The flow is the average flow over the cardiac cycle. Baseline blood flow measurements are measured at pre-dose (Day 1, 0 min post-treatment).	Baseline, 120 min post-infusion
Change From Baseline of the Blood Flow for the Superior Mesenteric Artery (Study Part A (Serelaxin Treatment Group Only))	A non-contrast magnetic resonance angiography (MRA) sequence was performed to acquire phase contrast blood flow measurements from vessels of interest such as superior mesenteric artery. The flow is the average flow over the cardiac cycle. Baseline blood flow measurements are measured at pre-dose (Day 1, 0 min post-treatment).	Baseline, 120 min post-infusion
Change From Baseline of the Blood Flow for the Descending Thoracic Aorta (Study Part A (Serelaxin Treatment Group Only))	A non-contrast magnetic resonance angiography (MRA) sequence was performed to acquire phase contrast blood flow measurements from vessels of interest such as descending thoracic aorta. The flow is the average flow over the cardiac cycle. Baseline blood flow measurements are measured at pre-dose (Day 1, 0 min post-treatment).	Baseline, 120 min post-infusion
Change From Baseline of the Blood Flow for the Portal Vein (Study Part A (Serelaxin Treatment Group Only))	A non-contrast magnetic resonance angiography (MRA) sequence was performed to acquire phase contrast blood flow measurements from vessels of interest such as the portal vein. The flow is the average flow over the cardiac cycle. Baseline blood flow measurements are measured at pre-dose (Day 1, 0 min post-treatment).	Baseline, 120 min post-infusion
Change From Baseline of the Portal Vein Pressure (PVP) (Study Part B)	Portal vein pressure was measured at 15 min intervals (i.e. prior to and at 15, 30, 45, 60, 75, 90, 105, and 120 min of serelaxin infusion).	Baseline, 120 min post infusion
Number of Patients With Total Adverse Events, Serious Adverse and Death as Assessment of Safety and Tolerability of Serelaxin	This endpoint reports patients with any adverse event, serious adverse event and death for the serelaxin group of Part A and Part B of the study.	4 weeks

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Snowdon VK, Lachlan NJ, Hoy AM, Hadoke PW, Semple SI, Patel D, Mungall W, Kendall TJ, Thomson A, Lennen RJ, Jansen MA, Moran CM, Pellicoro A, Ramachandran P, Shaw I, Aucott RL, Severin T, Saini R, Pak J, Yates D, Dongre N, Duffield JS, Webb DJ, Iredale JP, Hayes PC, Fallowfield JA. Serelaxin as a potential treatment for renal dysfunction in cirrhosis: Preclinical evaluation and results of a randomized phase 2 trial. PLoS Med. 2017 Feb 28;14(2):e1002248. doi: 10.1371/journal.pmed.1002248. eCollection 2017 Feb.

Study record dates

Study Major Dates

• Study Start: April 1, 2013
• Primary Completion (Actual): December 1, 2014
• Study Completion (Actual): December 1, 2014

Study Registration Dates

• First Submitted: June 21, 2012
• First Submitted That Met QC Criteria: July 13, 2012
• First Posted (Estimate): July 16, 2012

Study Record Updates

• Last Update Posted (Estimate): March 15, 2016
• Last Update Submitted That Met QC Criteria: March 11, 2016
• Last Verified: March 1, 2016

More Information

Terms related to this study

• Keywords: Portal hypertension, cirrhosis, TIPSS, MRI, MRA, portal pressure, portal pressure gradient
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Liver Diseases; Fibrosis; Hypertension; Liver Cirrhosis; Hypertension, Portal; Antihypertensive Agents; Vasoconstrictor Agents; Terlipressin
• Other Study ID Numbers: CRLX030X2201; 2012-000236-26 (EudraCT Number)