Clinical trial NCT04028323: Functional MRI-based Assessment of Terlipressin vs. Octreotide on Renal Function in Cirrhotic Patients With Acute Variceal Bleeding (CHESS1903)
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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Renal Function Disorder
Acute Variceal Bleeding
Keywords: Functional MRI
Terlipressin
Octreotide
Renal function disorder
Acute variceal bleeding
Lead sponsor: Nanfang Hospital, Southern Medical University
Sponsor class: OTHER
Collaborators: name: LanZhou University
name: Zhongda Hospital
name: Guangdong Second Provincial General Hospital
name: Xingtai People's Hospital
name: The Third Hospital of Zhenjiang Affiliated Jiangsu University
name: Tianjin Second People's Hospital
name: The Second Hospital of Anhui Medical University
name: The Sixth People's Hospital of Shenyang
name: The Second Affiliated Hospital of Baotou Medical College
First posted: 2019-07-22
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

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.

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 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Renal function
timeFrame: 6 days
Secondary outcomes:
measure: Renal perfusion
timeFrame: 6 days
measure: Renal blood oxygenation
timeFrame: 6 days
measure: Failure to control bleeding
timeFrame: 6 days
measure: Intra-hospital rebleeding
timeFrame: 6 days
measure: Intra-hospital mortality
timeFrame: 6 days
measure: Adverse events
timeFrame: 6 days
measure: Overall survival
timeFrame: 90 days
Other outcomes:
Locations:
city: Hefei
country: China
facility: The Second Affiliated Hospital of Anhui Medical University
state: Anhui
city: Lanzhou
country: China
facility: The First Hospital of Lanzhou University
state: Gansu
city: Guangzhou
country: China
facility: Guangdong Second Provincial General Hospital
state: Guangdong
city: Guangzhou
country: China
facility: Nanfang Hospital of Southern Medical University
state: Guangdong
city: Xingtai
country: China
facility: Xingtai People's Hospital
state: Hebei
city: Nanjing
country: China
facility: Zhongda Hospital, Medical School, Southeast University
state: Jiangsu
city: Zhenjiang
country: China
facility: The Third Hospital of Zhenjiang Affiliated Jiangsu University
state: Jiangsu
city: Shenyang
country: China
facility: The Sixth People's Hospital of Shenyang
state: Liaoning
city: Baotou
country: China
facility: The Second Affiliated Hospital of Baotou Medical University
state: Neimenggu
city: Tianjin
country: China
facility: Tianjin Second People's Hospital
state: Tianjin
Study officials:
affiliation: Zhongda Hospital
name: Shenghong Ju, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: General Hospital of Shenyang Military Area
name: Xingshun Qi, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: LanZhou University
name: Xiaolong Qi, MD
role: PRINCIPAL_INVESTIGATOR
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