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

Renal Function Disorder Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04028323
• Other study ID #: CHESS1903
• Status: Recruiting
• Phase: Phase 4
• Start date: July 16, 2019
• Est. completion date: October 15, 2022

Study information

• Verified date: August 2021
• Source: Nanfang Hospital of Southern Medical University
• Contact: Xiaolong Qi, MD
• Phone: 86-18588602600
• Email: qixiaolong[@]vip.163.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 60
• Est. completion date: October 15, 2022
• Est. primary completion date: July 15, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

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.

Related Conditions & MeSH terms

• Acute Variceal Bleeding
• Hemorrhage
• Renal Function Disorder

Intervention

Drug:
• Terlipressin
Terlipressin should be administrated intravenously while monitoring heart rate and blood pressure daily.
• Octreotide
Octreotide should be continuously intravenously administrated while monitoring heart rate and blood pressure daily.

Locations

Country	Name	City	State
China	The Second Affiliated Hospital of Baotou Medical University	Baotou	Neimenggu
China	Guangdong Second Provincial General Hospital	Guangzhou	Guangdong
China	Nanfang Hospital of Southern Medical University	Guangzhou	Guangdong
China	The Second Affiliated Hospital of Anhui Medical University	Hefei	Anhui
China	The First Hospital of Lanzhou University	Lanzhou	Gansu
China	Zhongda Hospital, Medical School, Southeast University	Nanjing	Jiangsu
China	The Sixth People's Hospital of Shenyang	Shenyang	Liaoning
China	Tianjin Second People's Hospital	Tianjin	Tianjin
China	Xingtai People's Hospital	Xingtai	Hebei
China	The Third Hospital of Zhenjiang Affiliated Jiangsu University	Zhenjiang	Jiangsu

Sponsors (10)

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

Country where clinical trial is conducted

China, 

References & Publications (10)

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. — View Citation

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. — View Citation

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. — View Citation

Ginès P, Schrier RW. Renal failure in cirrhosis. N Engl J Med. 2009 Sep 24;361(13):1279-90. doi: 10.1056/NEJMra0809139. Review. Erratum in: N Engl J Med. 2011 Jan 27;364(4):389. — View Citation

Ibrahim M, Mostafa I, Devière 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. Review. — View Citation

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. — View Citation

Martín-Llahí M, Pépin MN, Guevara M, Díaz F, Torre A, Monescillo A, Soriano G, Terra C, Fábrega E, Arroyo V, Rodés J, Ginès 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. — View Citation

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. — View Citation

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. — View Citation

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. Review. — View Citation

Outcome

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