Functional MRI-based Assessment of Terlipressin vs. Octreotide on Renal Function in Cirrhotic Patients With Acute Variceal Bleeding (CHESS1903)

Sponsor

Nanfang Hospital of Southern Medical University (Other)

Overall Status

Recruiting

CT.gov ID

NCT04028323

Collaborator

LanZhou University (Other), Zhongda Hospital, Medical School, Southeast University (Other), Guangdong Second Provincial General Hospital (Other), Xingtai People's Hospital (Other), The Third Hospital of Zhenjiang Affiliated Jiangsu University (Other), Tianjin Second People's Hospital (Other), The Second Hospital of Anhui Medical University (Other), The Sixth People's Hospital of Shenyang (Other), The Second Affiliated Hospital of Baotou Medical College (Other)

Enrollment

Locations

Arms

Anticipated Duration (Months)

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Acute variceal bleeding is one of the critical complications in patients with cirrhosis. Due to remarkable improvements in diagnostic and therapeutic modalities such as vasoactive agents, endoscopic therapy and antibiotics, the overall prognosis has been improved during the past several decades. However, it is still associated with increased mortality that is still around 20% at 6 weeks.

Patients with advanced cirrhosis have an intense overactivity of the endogenous vasoactive systems characterized by arterial hypotension and low peripheral vascular resistance. Severe renal vasoconstriction in consequence of marked arterial vasodilatation in splanchnic circulation triggers the reduction of glomerular filtration rate, and thus induces acute kidney injury (AKI)/hepatorenal syndrome (HRS), which have been further implicated in the increasing mortality in patients with cirrhosis.

Renal functional magnetic resonance imaging (fMRI), a technique considered superior to the most common method used to estimate the glomerular filtration rate, allows for non-invasive, accurate measurements of renal structures and functions in both animals and humans. It has become increasingly prevalent in research and clinical applications. In recent years, renal fMRI has developed rapidly with progress in MRI hardware and emerging post-processing algorithms. Function related imaging markers could be acquired via renal fMRI, encompassing water molecular diffusion, perfusion, and oxygenation. The study will use phase contrast - MR angiography, intravoxel incoherent motion - diffusion weighted imaging (IVIM-DWI) and blood-oxgen-level-dependent (BOLD)-MRI to evaluate renal functional changes after using vasoactive medications in patients with cirrhosis.

The rationale for the use of vasoactive medications, including terlipressin and octreotide, is to produce splanchnic vasoconstriction and reduce portal blood flow and portal pressure, thereby underpinning the application of these vasoactive drugs in the management of cirrhotic patients with acute variceal bleeding. Meanwhile, terlipressin has been recommended as the international first-line pharmacological therapy for the treatment of HRS because terlipressin may improve renal hemodynamics, improve renal function and potentially enable HRS a reversible condition without the need of liver transplantation. However, the renal protection effect of terlipressin vs. octreotide remains unknown. In this study, the investigators aim to conduct a multicenter, single-blind randomized controlled trial to compare the renal protection effect of terlipressin vs. octreotide assessed by fMRI in the management of cirrhotic patients with acute variceal bleeding.

Condition or Disease	Intervention/Treatment	Phase
Renal Function Disorder Acute Variceal Bleeding	Drug: Terlipressin Drug: Octreotide	Phase 4

Detailed Description

Gastroesophageal varices, the most relevant portal-system collaterals, and acute variceal bleeding are critical complications that result directly from portal hypertension in patients with cirrhosis. Gastroesophageal varices are present approximately in 50% of patients with cirrhosis. Their presence correlates with the severity of liver disease. Only 40% of Child-Pugh A patients have varices whilst 85% of the occurrence rate in Child-Pugh C patients. Due to remarkable improvements in diagnostic and therapeutic modalities such as vasoactive agents, endoscopic therapy and antibiotics, the overall prognosis has been improved during the past several decades. However, it is still associated with increased mortality, which is still around 20% at 6 weeks. Acute variceal bleeding is also responsible for a variety of other complications in patients with cirrhosis including acute on chronic liver failure, hepatorenal syndrome, ascites liquid infection and hepatic encephalopathy. Therefore, timely and effective control of acute variceal bleeding is of crucial importance for the prognosis in patients with cirrhosis.

In the early stages of cirrhosis, when portal hypertension is moderate, increased cardiac output compensated for a modest reduction in the systemic vascular resistance, ensuring the arterial pressure and effective arterial blood volume to maintain within the normal limits. Patients with advanced cirrhosis have an intense overactivity of the endogenous vasoactive systems characterized by arterial hypotension and low peripheral vascular resistance. This cascade of events sets the stage for further renal vasoconstriction and renal sodium retention as the splanchnic and systemic vasodilatation worsens with the progression of cirrhosis. Severe renal vasoconstriction in consequence of marked arterial vasodilatation in splanchnic circulation triggers the reduction of glomerular filtration rate, and thus induces acute kidney injury (AKI)/ hepato-renal syndrome (HRS) which may implicate in the increasing mortality in patients with cirrhosis.

The rationale for the use of vasoactive medications, including terlipressin and octreotide, is to produce splanchnic vasoconstriction and reduce portal blood flow and portal pressure, thereby underpinning the application of these vasoactive drugs in the management of cirrhotic patients with acute variceal bleeding. Meanwhile, terlipressin has been recommended as the international first-line pharmacological therapy for the treatment of HRS because terlipressin may improve renal hemodynamics, improve renal function in patients and potentially enable HRS a reversible condition without the need of liver transplantation. However, the renal protection effect of terlipressin vs. octreotide remains unknown. In this study, the investigators aim to conduct a multicenter, single-blind randomized controlled trial to compare the renal protection effect of terlipressin vs. octreotide assessed by fMRI in the management of cirrhotic patients with acute variceal bleeding.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

60 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Single (Participant)

Primary Purpose:

Prevention

Official Title:

Functional MRI-based Assessment of Terlipressin vs. Octreotide on Renal Function in Cirrhotic Patients With Acute Variceal Bleeding (CHESS1903): A Multicenter, Single-blind, Randomised Controlled Trial

Actual Study Start Date :

Jul 16, 2019

Actual Primary Completion Date :

Jul 15, 2020

Anticipated Study Completion Date :

Oct 15, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Experimental group Drug: Terlipressin. Terlipressin should be administrated with an initial dose of 1-2 mg intravenously and slowly injected (over 1 minute) while monitoring the heart rate and blood pressure. The maintenance dose should be administrated every 4-6 hours. Each dose of terlipressin is 1mg. The usual duration of therapy is 3-5 days.	Drug: Terlipressin Terlipressin should be administrated intravenously while monitoring heart rate and blood pressure daily.
Active Comparator: Control group Drug: Octreotide. Octreotide should be continuously and intravenously dripped at the speed of 0.025-0.05 mg/h and could be diluted with saline with the maximum duration of 5 days. The usual duration of therapy is 3-5 days.	Drug: Octreotide Octreotide should be continuously intravenously administrated while monitoring heart rate and blood pressure daily.

Arm

Intervention/Treatment

Experimental: Experimental group

Drug: Terlipressin. Terlipressin should be administrated with an initial dose of 1-2 mg intravenously and slowly injected (over 1 minute) while monitoring the heart rate and blood pressure. The maintenance dose should be administrated every 4-6 hours. Each dose of terlipressin is 1mg. The usual duration of therapy is 3-5 days.

Drug: Terlipressin

Terlipressin should be administrated intravenously while monitoring heart rate and blood pressure daily.

Active Comparator: Control group

Drug: Octreotide. Octreotide should be continuously and intravenously dripped at the speed of 0.025-0.05 mg/h and could be diluted with saline with the maximum duration of 5 days. The usual duration of therapy is 3-5 days.

Drug: Octreotide

Octreotide should be continuously intravenously administrated while monitoring heart rate and blood pressure daily.

Outcome Measures

Primary Outcome Measures

Renal function [6 days]
Number of participants with the improvement of renal function assessed by serum creatinine

Secondary Outcome Measures

Renal perfusion [6 days]
Number of participants with the improvement of renal perfusion assessed by functional MRI measurement (intravoxel incoherent motion)
Renal blood oxygenation [6 days]
Number of participants with the improvement of renal blood oxygenation assessed by functional MRI measurement (blood oxygen level dependent)
Failure to control bleeding [6 days]
The occurrence rate of failure to control bleeding
Intra-hospital rebleeding [6 days]
The occurrence rate of intra-hospital rebleeding
Intra-hospital mortality [6 days]
The occurrence rate of intra-hospital mortality
Adverse events [6 days]
The occurrence rate of adverse events
Overall survival [90 days]
The number of participants still alive with the 90 days follow-up

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

clinically and/or pathologically diagnosed cirrhosis
with a clinical history of acute variceal bleeding (melena, hematemesis etc.) assessed as Child-Pugh class B or C
voluntarily participated in the study and able to provide written informed consent and able to understand and willing to comply with the requirements of the study

Exclusion Criteria:

pregnant or lactating woman
diagnosed or suspected malignancy (hepatocellular carcinoma, cholangiocarcinoma etc.)
with mental disease and unable to comply with MRI examination
with contraindications of terlipressin and octreotide
with other conditions judged inadequate for participation by the investigators.

Contacts and Locations

Locations

	Site	City	State	Country
1	The Second Affiliated Hospital of Anhui Medical University	Hefei	Anhui	China
2	The First Hospital of Lanzhou University	Lanzhou	Gansu	China
3	Guangdong Second Provincial General Hospital	Guangzhou	Guangdong	China
4	Nanfang Hospital of Southern Medical University	Guangzhou	Guangdong	China
5	Xingtai People's Hospital	Xingtai	Hebei	China
6	Zhongda Hospital, Medical School, Southeast University	Nanjing	Jiangsu	China
7	The Third Hospital of Zhenjiang Affiliated Jiangsu University	Zhenjiang	Jiangsu	China
8	The Sixth People's Hospital of Shenyang	Shenyang	Liaoning	China
9	The Second Affiliated Hospital of Baotou Medical University	Baotou	Neimenggu	China
10	Tianjin Second People's Hospital	Tianjin	Tianjin	China

Sponsors and Collaborators

Nanfang Hospital of Southern Medical University
LanZhou University
Zhongda Hospital, Medical School, Southeast University
Guangdong Second Provincial General Hospital
Xingtai People's Hospital
The Third Hospital of Zhenjiang Affiliated Jiangsu University
Tianjin Second People's Hospital
The Second Hospital of Anhui Medical University
The Sixth People's Hospital of Shenyang
The Second Affiliated Hospital of Baotou Medical College

Investigators

Principal Investigator: Shenghong Ju, MD, Zhongda Hospital, Medical School, Southeast University
Principal Investigator: Xingshun Qi, MD, General Hospital of Shenyang Military Area
Principal Investigator: Xiaolong Qi, MD, LanZhou University