Microbiome/Peptidome-based Model for Non-invasive Detection of High-risk Gastroesophageal Varices in Compensated Cirrhosis (CHESS1901/APPHA1901)

Microbiome/Peptidome-based Model for Non-invasive Detection of High-risk Gastroesophageal Varices in Compensated Cirrhosis (CHESS1901/APPHA1901): A Prospective Multicenter Study

Variceal hemorrhage is a lethal complication in patients with cirrhosis and portal hypertension. Identification of varices needing treatment in compensated cirrhosis is, therefore, of great therapeutic and prognostic importance. The gold standard for diagnosing gastroesophageal varices and evaluating the risk of variceal hemorrhage is esophagogastroduodenoscopy. According to the Baveno VI consensus, for those with high-risk varices (HRV), either non-selective beta blockers or endoscopic band ligation is recommended for the prevention of the first variceal bleeding. However, the invasiveness and uncomfortableness during the esophagogastroduodenoscopy procedure has hindered its use in clinical practice, especially in patients with compensated cirrhosis. Sufficient accurate non-invasive tools for detection of HRV are warranted to safely avoid the use of esophagogastroduodenoscopy.

Advanced technologies including next-generation sequencing and MALDI-TOF mass spectrometry have the potential to be applied in this field. The latter is a widespread adopted tool in clinical microbiology for rapid, accurate and cost-effective identification of cultured bacteria and fungi. Recently, microbiome and peptidome have been proved their roles in the end-stage liver disease (e.g. cirrhosis, hepatocellular carcinoma), which may exhibit predictive capacity of HRV. In the present study, the investigators aim to conduct a prospective, multicenter diagnostic trial in 12 sites in China, 1 site in Turkey and 1 site in Thailand to evaluate the diagnostic performance of the microbiome/peptidome-based model for HRV detection in compensated cirrhosis.

Study Overview

• Status: Recruiting
• Conditions: Compensated Cirrhosis
• Intervention / Treatment: Diagnostic test: esophagogastroduodenoscopy

Detailed Description

Variceal hemorrhage is a lethal complication in patients with cirrhosis and portal hypertension. Identification of varices needing treatment in compensated cirrhosis is, therefore, of great therapeutic and prognostic importance. The gold standard for diagnosing gastroesophageal varices and evaluating the risk of variceal hemorrhage is esophagogastroduodenoscopy. According to the Baveno VI consensus, for those with high-risk varices (HRV), either non-selective beta blockers or endoscopic band ligation is recommended for the prevention of the first variceal bleeding. However, the invasiveness and uncomfortableness during the esophagogastroduodenoscopy procedure has hindered its use in clinical practice, especially in patients with compensated cirrhosis. Sufficient accurate non-invasive tools for detection of HRV are warranted to safely avoid the use of esophagogastroduodenoscopy.

Advanced technologies including next-generation sequencing and MALDI-TOF mass spectrometry have the potential to be applied in this field. The latter is a widespread adopted tool in clinical microbiology for rapid, accurate and cost-effective identification of cultured bacteria and fungi. Recently, microbiome and peptidome have been proved their roles in the end-stage liver disease (e.g. cirrhosis, hepatocellular carcinoma), which may exhibit predictive capacity of HRV. In the present study, the investigators aim to conduct a prospective, multicenter diagnostic trial in 12 sites (The First Hospital of Lanzhou University; Zhujiang Hospital of Southern Medical University; Nanfang Hospital of Southern Medical University; Xingtai People's Hospital; Zhongda Hospital, Medical School, Southeast University; The Third People's Hospital affiliated to Jiangsu University; Guangdong Second Provincial General Hospital; Tianjin Infectious Disease Hospital; Lishui Municipal Central Hospital; The Second Hospital of Anhui Medical University; Xi'an Gaoxin Hospital; The Sixth People's Hospital of Shenyang) in China, 1 site (Ankara University School of Medicine) in Turkey and 1 site (King Chulalongkorn Memorial Hospital affiliated to Chulalongkorn University) in Thailand to evaluate the diagnostic performance of the microbiome/peptidome-based model for HRV detection in compensated cirrhosis.

• Study Type: Observational
• Enrollment (Anticipated): 1000

Contacts and Locations

Study Locations

• China
  • Anhui
    • Hefei, Anhui, China
      • Not yet recruiting
      • The Second Affiliated Hospital of Anhui Medical University
      • Principal Investigator: Jun Ye, MD
  • 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: Jinlin Hou, MD
      • Principal Investigator: Jinlin Hou, MD
    • Guangzhou, Guangdong, China
      • Not yet recruiting
      • Zhujiang hospital of southern medical university
      • Contact: Hua Mao, MD
      • Principal Investigator: Hua Mao, MD
    • Guangzhou, Guangdong, China
      • Not yet recruiting
      • Guangdong Second Provincial General Hospital
      • Sub-Investigator: Xiaofeng Li, MD
  • Hebei
    • Xingtai, Hebei, China
      • Not yet recruiting
      • Xingtai People's Hospital
      • Sub-Investigator: Jitao Wang, MD
      • Contact: Qingge Zhang, MD
      • Principal Investigator: Qingge Zhang, 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
      • Contact: Youwen Tan, MD
      • Principal Investigator: Youwen Tan, MD
  • Liaoning
    • Shenyang, Liaoning, China
      • Not yet recruiting
      • The Sixth People's Hospital of Shenyang
      • Contact: Yiying Song, MD
      • Principal Investigator: Yiying Song, MD
  • Shanxi
    • Xi'an, Shanxi, China
      • Not yet recruiting
      • Xi'an Gaoxin Hospital
      • Contact: Ying Song, MD
      • Principal Investigator: Ying Song, MD
      • Sub-Investigator: Bojiang Zhang, MD
  • Tianjin
    • Tianjin, Tianjin, China
      • Not yet recruiting
      • Tianjin Second People's Hospital
  • Zhejiang
    • Lishui, Zhejiang, China
      • Not yet recruiting
      • Zhejiang University Lishui Hospital
      • Contact: JianSong Ji, MD
      • Principal Investigator: Jiansong Ji, MD
      • Sub-Investigator: Zhongwei Zhao, MD
• Thailand
  • Bangkok, Thailand
    • Not yet recruiting
    • King Chulalongkorn Memorial Hospital affiliated to Chulalongkorn University
    • Contact: Sombat Treeprasertsuk, MD
    • Principal Investigator: Sombat Treeprasertsuk, MD
• Turkey
  • Ankara, Turkey
    • Not yet recruiting
    • Ankara University School of Medicine
    • Contact: Necati Örmeci, MD
    • Principal Investigator: Necati Örmeci, MD

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

• Sampling Method: Non-Probability Sample

Study Population

Participants with compensated cirrhosis

Description

Inclusion Criteria:

• age 18-75 years;
• confirmed compensated cirrhosis based on liver biopsy or clinical findings;
• without decompensated events (e.g. ascites, bleeding, or overt encephalopathy);
• scheduled to undergo esophagogastroduodenoscopy;
• estimated survival time> 24 months, and model for end-stage liver disease (MELD) score< 19, and without liver transplant;
• with written informed consent.

Exclusion Criteria:

• contradictions for esophagogastroduodenoscopy;
• use of antibiotics, prebiotics, probiotics and proton pump inhibitors within 3 months upon recruitment.
• pregnancy or unknown pregnancy status.

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Overall eligible participants; Eligible participants will receive standard esophagogastroduodenoscopy and microbiome/peptidome examination.	Diagnostic test: esophagogastroduodenoscopy; standard esophagogastroduodenoscopy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Diagnostic performance of microbiome/peptidome-based model for high-risk varices	Diagnostic performance of microbiome/peptidome-based model to determine the presence or absence of high-risk varices when compared with esophagogastroduodenoscopy as the reference standard	1 day

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Diagnostic performance of microbiome/peptidome-based model for decompensation or death	Diagnostic performance of microbiome/peptidome-based model to determine the presence or absence of decompensation (defined as development of ascites, bleeding, or overt encephalopathy) or death within 3-year follow-up	3 years
Diagnostic performance of microbiome/peptidome-based model for hepatic venous pressure gradient	Diagnostic performance of microbiome/peptidome-based model to determine the level of hepatic venous pressure gradient	1 day

Collaborators and Investigators

• Sponsor: Nanfang Hospital of Southern Medical University
• Collaborators: LanZhou University; Zhongda Hospital; Ankara University; Xingtai People's Hospital; Southern Medical University, China; The Second Hospital of Anhui Medical University; Guangdong Second Provincial General Hospital; Xi'an Gaoxin Hospital; Tianjin Second People's Hospital; The Sixth People's Hospital of Shenyang; The Third Hospital of Zhenjiang Affiliated Jiangsu University; Zhejiang University Lishui Hospital; King Chulalongkorn Memorial Hospital affiliated to Chulalongkorn University
• Investigators: Principal Investigator: Hongwei Zhou, PhD, Southern Medical University, China

Publications and helpful links

General Publications

• Qi X, Berzigotti A, Cardenas A, Sarin SK. Emerging non-invasive approaches for diagnosis and monitoring of portal hypertension. Lancet Gastroenterol Hepatol. 2018 Oct;3(10):708-719. doi: 10.1016/S2468-1253(18)30232-2.
• Wang FS, Fan JG, Zhang Z, Gao B, Wang HY. The global burden of liver disease: the major impact of China. Hepatology. 2014 Dec;60(6):2099-108. doi: 10.1002/hep.27406. Epub 2014 Oct 29.
• de Franchis R; Baveno VI Faculty. Expanding consensus in portal hypertension: Report of the Baveno VI Consensus Workshop: Stratifying risk and individualizing care for portal hypertension. J Hepatol. 2015 Sep;63(3):743-52. doi: 10.1016/j.jhep.2015.05.022. Epub 2015 Jun 3. No abstract available.
• Garcia-Tsao G, Abraldes JG, Berzigotti A, Bosch J. Portal hypertensive bleeding in cirrhosis: Risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the study of liver diseases. Hepatology. 2017 Jan;65(1):310-335. doi: 10.1002/hep.28906. Epub 2016 Dec 1. No abstract available. Erratum In: Hepatology. 2017 Jul;66(1):304.
• Qi X, Li Z, Huang J, Zhu Y, Liu H, Zhou F, Liu C, Xiao C, Dong J, Zhao Y, Xu M, Xing S, Xu W, Yang C. Virtual portal pressure gradient from anatomic CT angiography. Gut. 2015 Jun;64(6):1004-5. doi: 10.1136/gutjnl-2014-308543. Epub 2014 Nov 14. No abstract available.
• Liu F, Ning Z, Liu Y, Liu D, Tian J, Luo H, An W, Huang Y, Zou J, Liu C, Liu C, Wang L, Liu Z, Qi R, Zuo C, Zhang Q, Wang J, Zhao D, Duan Y, Peng B, Qi X, Zhang Y, Yang Y, Hou J, Dong J, Li Z, Ding H, Zhang Y, Qi X. Development and validation of a radiomics signature for clinically significant portal hypertension in cirrhosis (CHESS1701): a prospective multicenter study. EBioMedicine. 2018 Oct;36:151-158. doi: 10.1016/j.ebiom.2018.09.023. Epub 2018 Sep 27.
• Qi X, An W, Liu F, Qi R, Wang L, Liu Y, Liu C, Xiang Y, Hui J, Liu Z, Qi X, Liu C, Peng B, Ding H, Yang Y, He X, Hou J, Tian J, Li Z. Virtual Hepatic Venous Pressure Gradient with CT Angiography (CHESS 1601): A Prospective Multicenter Study for the Noninvasive Diagnosis of Portal Hypertension. Radiology. 2019 Feb;290(2):370-377. doi: 10.1148/radiol.2018180425. Epub 2018 Nov 20.
• He Y, Wu W, Zheng HM, Li P, McDonald D, Sheng HF, Chen MX, Chen ZH, Ji GY, Zheng ZD, Mujagond P, Chen XJ, Rong ZH, Chen P, Lyu LY, Wang X, Wu CB, Yu N, Xu YJ, Yin J, Raes J, Knight R, Ma WJ, Zhou HW. Regional variation limits applications of healthy gut microbiome reference ranges and disease models. Nat Med. 2018 Oct;24(10):1532-1535. doi: 10.1038/s41591-018-0164-x. Epub 2018 Aug 27. Erratum In: Nat Med. 2018 Sep 24;:
• Garcia-Lezana T, Raurell I, Bravo M, Torres-Arauz M, Salcedo MT, Santiago A, Schoenenberger A, Manichanh C, Genesca J, Martell M, Augustin S. Restoration of a healthy intestinal microbiota normalizes portal hypertension in a rat model of nonalcoholic steatohepatitis. Hepatology. 2018 Apr;67(4):1485-1498. doi: 10.1002/hep.29646. Epub 2018 Feb 19.
• Hoyles L, Fernandez-Real JM, Federici M, Serino M, Abbott J, Charpentier J, Heymes C, Luque JL, Anthony E, Barton RH, Chilloux J, Myridakis A, Martinez-Gili L, Moreno-Navarrete JM, Benhamed F, Azalbert V, Blasco-Baque V, Puig J, Xifra G, Ricart W, Tomlinson C, Woodbridge M, Cardellini M, Davato F, Cardolini I, Porzio O, Gentileschi P, Lopez F, Foufelle F, Butcher SA, Holmes E, Nicholson JK, Postic C, Burcelin R, Dumas ME. Molecular phenomics and metagenomics of hepatic steatosis in non-diabetic obese women. Nat Med. 2018 Jul;24(7):1070-1080. doi: 10.1038/s41591-018-0061-3. Epub 2018 Jun 25. Erratum In: Nat Med. 2018 Aug 9;:

Study record dates

Study Major Dates

• Study Start (ACTUAL): June 13, 2019
• Primary Completion (ACTUAL): June 12, 2021
• Study Completion (ANTICIPATED): June 12, 2022

Study Registration Dates

• First Submitted: June 16, 2019
• First Submitted That Met QC Criteria: June 16, 2019
• First Posted (ACTUAL): June 19, 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: Compensated Cirrhosis; Microbiome/Peptidome; High-risk Gastroesophageal Varices
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Liver Diseases; Fibrosis; Liver Cirrhosis
• Other Study ID Numbers: CHESS1901

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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