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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Renal Function Disorder; Acute Variceal Bleeding
• Intervention / Treatment: Drug: Terlipressin; Drug: Octreotide

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.

• Study Type: Interventional
• Enrollment (Anticipated): 60
• Phase: Phase 4

Contacts and Locations

Study Locations

• China
  • Anhui
    • Hefei, Anhui, China
      • Not yet recruiting
      • The Second Affiliated Hospital of Anhui Medical University
  • Gansu
    • Lanzhou, Gansu, China
      • Recruiting
      • The First Hospital of Lanzhou University
  • Guangdong
    • Guangzhou, Guangdong, China
      • Not yet recruiting
      • Nanfang Hospital of Southern Medical University
      • Contact: Jinjun Chen, MD
      • Principal Investigator: Jinjun Chen, MD
    • Guangzhou, Guangdong, China
      • Not yet recruiting
      • Guangdong Second Provincial General Hospital
  • Hebei
    • Xingtai, Hebei, China
      • Not yet recruiting
      • Xingtai People's Hospital
      • Principal Investigator: Dengxiang Liu, MD
  • Jiangsu
    • Nanjing, Jiangsu, China
      • Not yet recruiting
      • Zhongda Hospital, Medical School, Southeast University
    • Zhenjiang, Jiangsu, China
      • Not yet recruiting
      • The Third Hospital of Zhenjiang Affiliated Jiangsu University
      • Principal Investigator: Shengqiang Zou, MD
  • Liaoning
    • Shenyang, Liaoning, China
      • Not yet recruiting
      • The Sixth People's Hospital of Shenyang
      • Contact: Yi Ma, MD
      • Principal Investigator: Yi Ma, MD
  • Neimenggu
    • Baotou, Neimenggu, China
      • Not yet recruiting
      • The Second Affiliated Hospital of Baotou Medical University
      • Contact: Limei Ren, MD
      • Principal Investigator: Limei Ren, MD
  • Tianjin
    • Tianjin, Tianjin, China
      • Not yet recruiting
      • Tianjin Second People's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Renal function	Number of participants with the improvement of renal function assessed by serum creatinine	6 days

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Nanfang Hospital of Southern Medical University
• Collaborators: LanZhou University; Zhongda Hospital; Xingtai People's Hospital; The Second Hospital of Anhui Medical University; Guangdong Second Provincial General Hospital; The Second Affiliated Hospital of Baotou Medical College; Tianjin Second People's Hospital; The Sixth People's Hospital of Shenyang; The Third Hospital of Zhenjiang Affiliated Jiangsu University
• Investigators: Principal Investigator: Shenghong Ju, MD, Zhongda Hospital; Principal Investigator: Xingshun Qi, MD, General Hospital of Shenyang Military Area

Publications and helpful links

General Publications

• Abid S, Jafri W, Hamid S, Salih M, Azam Z, Mumtaz K, Shah HA, Abbas Z. Terlipressin vs. octreotide in bleeding esophageal varices as an adjuvant therapy with endoscopic band ligation: a randomized double-blind placebo-controlled trial. Am J Gastroenterol. 2009 Mar;104(3):617-23. doi: 10.1038/ajg.2008.147. Epub 2009 Feb 17.
• Martin-Llahi M, Pepin MN, Guevara M, Diaz F, Torre A, Monescillo A, Soriano G, Terra C, Fabrega E, Arroyo V, Rodes J, Gines P; TAHRS Investigators. Terlipressin and albumin vs albumin in patients with cirrhosis and hepatorenal syndrome: a randomized study. Gastroenterology. 2008 May;134(5):1352-9. doi: 10.1053/j.gastro.2008.02.024. Epub 2008 Feb 14.
• Cavallin M, Kamath PS, Merli M, Fasolato S, Toniutto P, Salerno F, Bernardi M, Romanelli RG, Colletta C, Salinas F, Di Giacomo A, Ridola L, Fornasiere E, Caraceni P, Morando F, Piano S, Gatta A, Angeli P; Italian Association for the Study of the Liver Study Group on Hepatorenal Syndrome. Terlipressin plus albumin versus midodrine and octreotide plus albumin in the treatment of hepatorenal syndrome: A randomized trial. Hepatology. 2015 Aug;62(2):567-74. doi: 10.1002/hep.27709. Epub 2015 Feb 13.
• Gines P, Schrier RW. Renal failure in cirrhosis. N Engl J Med. 2009 Sep 24;361(13):1279-90. doi: 10.1056/NEJMra0809139. No abstract available. Erratum In: N Engl J Med. 2011 Jan 27;364(4):389.
• Ibrahim M, Mostafa I, Deviere J. New Developments in Managing Variceal Bleeding. Gastroenterology. 2018 May;154(7):1964-1969. doi: 10.1053/j.gastro.2018.02.023. Epub 2018 Mar 2.
• Wong F. Recent advances in our understanding of hepatorenal syndrome. Nat Rev Gastroenterol Hepatol. 2012 May 22;9(7):382-91. doi: 10.1038/nrgastro.2012.96.
• Levacher S, Letoumelin P, Pateron D, Blaise M, Lapandry C, Pourriat JL. Early administration of terlipressin plus glyceryl trinitrate to control active upper gastrointestinal bleeding in cirrhotic patients. Lancet. 1995 Sep 30;346(8979):865-8. doi: 10.1016/s0140-6736(95)92708-5.
• Seo YS, Park SY, Kim MY, Kim JH, Park JY, Yim HJ, Jang BK, Kim HS, Hahn T, Kim BI, Heo J, An H, Tak WY, Baik SK, Han KH, Hwang JS, Park SH, Cho M, Um SH. Lack of difference among terlipressin, somatostatin, and octreotide in the control of acute gastroesophageal variceal hemorrhage. Hepatology. 2014 Sep;60(3):954-63. doi: 10.1002/hep.27006. Epub 2014 Jul 25.
• Wang YC, Tang A, Chang D, Zhang SJ, Ju S. Significant perturbation in renal functional magnetic resonance imaging parameters and contrast retention for iodixanol compared with iopromide: an experimental study using blood-oxygen-level-dependent/diffusion-weighted magnetic resonance imaging and computed tomography in rats. Invest Radiol. 2014 Nov;49(11):699-706. doi: 10.1097/RLI.0000000000000073.
• Chang D, Wang YC, Xu TT, Peng XG, Cai Y, Wang L, Bai YY, Ju S. Noninvasive Identification of Renal Hypoxia in Experimental Myocardial Infarctions of Different Sizes by Using BOLD MR Imaging in a Mouse Model. Radiology. 2018 Jan;286(1):129-139. doi: 10.1148/radiol.2017161998. Epub 2017 Aug 4.
• Yan X, Shao R, Wang Y, Mao X, Lei J, Zhang L, Zheng J, Liu A, Zhao H, Gao F, Wang J, Li P, Yao S, Xu M, Xu J, Liu D, Mi Y, Gong X, Ye J, Deng M, Dang T, Ji J, Shao C, Liu C, Gu Y, Wu Y, Wang F, Teng G, Li X, Qi X, Ju S, Qi X. Functional magnetic resonance imaging-based assessment of terlipressin vs. octreotide on renal function in cirrhotic patients with acute variceal bleeding (CHESS1903): study protocol of a multicenter randomized controlled trial. Ann Transl Med. 2019 Oct;7(20):586. doi: 10.21037/atm.2019.09.141.

Study record dates

Study Major Dates

• Study Start (Actual): July 16, 2019
• Primary Completion (Actual): July 15, 2020
• Study Completion (Anticipated): October 15, 2022

Study Registration Dates

• First Submitted: July 17, 2019
• First Submitted That Met QC Criteria: July 19, 2019
• First Posted (Actual): July 22, 2019

Study Record Updates

• Last Update Posted (Actual): August 17, 2021
• Last Update Submitted That Met QC Criteria: August 16, 2021
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Keywords: Octreotide; Functional MRI; Terlipressin; Acute variceal bleeding; Renal function disorder
• Additional Relevant MeSH Terms: Pathologic Processes; Hemorrhage; Antihypertensive Agents; Antineoplastic Agents; Gastrointestinal Agents; Antineoplastic Agents, Hormonal; Vasoconstrictor Agents; Octreotide; Terlipressin
• Other Study ID Numbers: CHESS1903

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No