Fecal Microbiome Transplantation in Cirrhosis: Trial in Patients With Decompensated Cirrhosis (LiverGut)

Fecal Microbiome Transplantation in Cirrhosis: Randomized, Double-blinded, Placebo-Controlled Trial in Patients With Decompensated Cirrhosis

This is a phase III, multicenter, double-blind, placebo-controlled, randomized clinical trial to evaluate the safety and efficacy of Fecal Microbiota Transplantation (FMT) from healthy subjects to patients with decompensated cirrhosis.

Study Overview

• Status: Not yet recruiting
• Conditions: Decompensated Cirrhosis
• Intervention / Treatment: Drug: Fecal Microbiome Transplantation (FMT); Other: FMT Placebo

• Study Type: Interventional
• Enrollment (Estimated): 190
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Eva Bonfill; Phone Number: 4198 +34932275400; Email: BONFILL@recerca.clinic.cat

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age ≥ 18 years old.
2. Cirrhosis defined by standard clinical criteria, ultrasonographic findings and/or histology. Cirrhosis of any etiology may be included except from patients with cirrhosis due to autoimmune hepatitis, and patients with cirrhosis due to cholestatic liver disease can only be included in the study if they present clinical decompensation of cirrhosis (i.e. ascites).
3. Child-Pugh B or C patients (7- up to 12 points).
4. Women of child-bearing potential* must have a negative pregnancy test in serum before the inclusion in the study and agree to use highly effective contraceptive methods during the study. Highly effective contraceptive methods will include: intrauterine device, bilateral tubal occlusion, vasectomized partner and sexual abstinence** (only if refraining from heterosexual intercourse during the period of twelve months). Hormonal contraceptive methods will be avoided due to the risk of adverse events and impairment of liver function.

Exclusion Criteria:

1. Previous history of gastrointestinal surgery or colorectal cancer.
2. Patients with previous history of intestinal obstruction or those who are at increased risk of this complication.
3. Active Clostridium Difficile infection.
4. Patients on treatment with non-selective beta-blockers for <3 month or without stable doses.
5. Patients on treatment with any immunosuppressive drugs.
6. Patients on antiviral therapy for HCV or those who have received it within the last 12 months.
7. Patients on antiviral therapy for HBV therapy for < 12 months.
8. Patients with hepatocellular carcinoma, except for patients with early HCC (BCLC-0 or BCLC-A) or patients with previous history of HCC and absence of recurrence 2 years after treatment.

9. Patients admitted to the hospital for acute decompensation of the disease. These patients could be included after discharged as long as they do not present any of the following events:

   1. Bacterial infection within 10 days before study inclusion.
   2. Gastrointestinal bleeding within 10 days before study inclusion.
   3. Current overt hepatic encephalopathy, defined as grade II-IV hepatic encephalopathy according to the New-Haven classification.
10. Patients with ACLF according to the criteria published by Moreau et al. (Appendix 1).
11. Severe alcoholic hepatitis requiring corticosteroid therapy (MELD > 20) in the last 6 months.
12. Patients with active alcohol consumption of more than 21 units per week.
13. HIV infection.
14. Patients with a history of significant extra hepatic disease with impaired short-term prognosis, including congestive heart failure New York Heart Association Grade III/IV, COPD GOLD >2, chronic kidney disease with serum creatinine >2mg/dL or under renal replacement therapy.
15. Patients with current extra hepatic malignancies including solid tumours and hematologic disorders.
16. Patients with previous organ transplantation.
17. Pregnancy or breastfeeding.
18. Patients included in other clinical trials in the month before inclusion.
19. Patients with mental incapacity, language barrier, bad social support or any other reason considered by the investigator precluding adequate understanding, cooperation or compliance in the study.
20. Refusal to give informed consent.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Fecal Microbiome Transplantation (FMT); A first dose of 24 capsules of FMT at baseline and a second dose of 24 capsules of FMT at 3 months. Each dose (24 capsules) contains approximately 50g of stool.	Drug: Fecal Microbiome Transplantation (FMT); Two doses: First dose: 24 capsules of FMT at baseline. Second dose: 24 capsules of FMT at 3 months.
Placebo Comparator: FMT Placebo; A first dose of 24 capsules of FMT placebo at baseline and a second dose of 24 capsules of FMT placebo at 3 months. Each dose (24 capsules) contains in total 6 g of microcrystalline cellulose or equivalent.	Other: FMT Placebo; Two doses: First dose: 24 capsules of FMT placebo at baseline. Second dose: 24 capsules of FMT placebo at 3 months.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy of treatment in halting the progression of decompensated cirrhosis.	Assessed by time to first decompensation event (acute kidney injury (AKI), ascites, bacterial infection, gastrointestinal bleeding, HE).	Screening to month 12.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to transplant-free survival	Assessed by transplant-free survival	At month 1, month 3, month 6 and month 12
Mortality rates	Assessed by mortality rates	At month 1, month 3, month 6 and month 12
Rate of patients developing/ worsening individual complications of cirrhosis.	Assessed by ascites, acute kidney injury, bacterial infections, gastrointestinal bleeding and hepatic encephalopathy.	At baseline, month 1, month 3, month 6 and month 12.
Frequency of hospital admissions due to complications of cirrhosis.	Assessed by hospital admissions due to complications of cirrhosis.	At baseline, 1 month, 3 months, 6 months and 12 months.
Development of acute-on-chronic liver failure (ACLF)	Assessed by time to first episode of ACLF	At baseline, 1 month, 3 months, 6 months and 12 months.
Development of acute-on-chronic liver failure (ACLF)	Assessed by total number of patients developing ACLF	At month 3, month 6 and month 12.
Development of acute-on-chronic liver failure (ACLF)	Assessed by severity of ACLF episodes based on ACLF grade (from grade 1 to grade 3) and CLIF-C-ACLF score	At baseline, 1 month, 3 months, 6 months and 12 months.
Development of acute-on-chronic liver failure (ACLF)	Assessed by number and type of organ failures	At baseline, 1 month, 3 months, 6 months and 12 months.
Changes from baseline in systemic inflammatory response.	Evaluated by measurement in a large array of plasma cytokine levels including, but not limited to TNFα, IL-6, IL8, IL-10, IL-1β, IFN-ɣ, G-CSF, VCAM, VEGF, as well as an oxidized form of albumin, human nonmercaptalbumin-2 (HNA2).	At baseline, 1 month, 3 months, 6 months and 12 months.
PBMCs phenotype and function.	Analysed by flow cytometry, functional analysis, and RNAseq single cell analysis.	At baseline, 1 month, 3 months, 6 months and 12 months.
Changes from baseline in different plasma and urine prognostic biomarkers.	Measurated by different plasma and urine prognostic biomarkers including, but not only, copeptin, NGAL, PD-L1, L-FABP.	At baseline, 1 month, 3 months, 6 months, and 12 months.
Changes from baseline in systemic hemodynamics and vasoactive hormones.	Measurated by systemic hemodynamics and vasoactive hormones: plasma renin concentration and plasma copeptin.	At baseline, 1 month, 3 months, 6 months and 12 months.
Changes from baseline in blood levels of bacterial DNA or bacterial products.	Measurated by blood levels of bacterial DNA or bacterial products.	At baseline, 1 month, 3 months, 6 months and 12 months.
Changes from baseline in liver function.	Evaluated by MELD (Model for End-stage Liver Disease) score.	At baseline, 1 month, 3 months, 6 months and 12 months.
Changes from baseline in liver function.	Evaluated by CLIF-AD score.	At baseline, 1 month, 3 months, 6 months and 12 months.
Changes from baseline in liver function.	Evaluated by Child Pugh Score.(from 1 point to 15 points)	At baseline, 1 month, 3 months, 6 months and 12 months.
Analyze microbiome composition from saliva and stool.	Measurated by analysis of microbial genes.	At baseline, and months 1, 3 and 6.
Changes in hepatic venous pressure gradient (HVPG) from baseline.	Measurated by the hepatic venous pressure gradient.	At baseline and month 6.
Assess Quality of life, functional assessment and in Minimal Hepatic Encephalopathy.	Evaluated with data obtained from CLDQ (Chronic Liver Disease Questionnaire) questionnaire.	At baseline, 3 months, 6 months and 12 months.
Assess Quality of life, functional assessment and in Minimal Hepatic Encephalopathy.	Evaluated with data obtained from Liver Frailty Index.	At baseline, 3 months, 6 months and 12 months.
Assess Quality of life, functional assessment and in Minimal Hepatic Encephalopathy.	Evaluated with data obtained from PHES (Psychometric Hepatic Encephalopathy Score) questionnaire.	At baseline, 3 months, 6 months and 12 months.
Changes from baseline in AUDIT test.	Evaluated from AUDIT test	AUDIT test at baseline, 3 months, 6 months and 12 months
Changes from baseline in alcohol consumption.	Evaluated from PETh measurament.	PETh measurament test at baseline, 1 month, 3 months, 6 months and 12 months.
Assess the effect of FMT in ECG (Electrocardiogram).	Evaluated by changes in ACE score.	At screening, baseline and months 3,6 and 12.
Proportion of patients with treatment-related adverse events.	Evaluated by treatment-related adverse events.	Screening to month 12.
Proportion of patients with severe treatment-related adverse events.	Evaluated by treatment-related adverse events.	Screening to month 12.

Collaborators and Investigators

• Sponsor: Consorcio Centro de Investigación Biomédica en Red (CIBER)

Study record dates

Study Major Dates

• Study Start (Estimated): December 1, 2024
• Primary Completion (Estimated): May 1, 2028
• Study Completion (Estimated): May 1, 2028

Study Registration Dates

• First Submitted: July 15, 2024
• First Submitted That Met QC Criteria: July 30, 2024
• First Posted (Actual): August 1, 2024

Study Record Updates

• Last Update Posted (Actual): August 1, 2024
• Last Update Submitted That Met QC Criteria: July 30, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Liver Diseases; Fibrosis; Liver Cirrhosis
• Other Study ID Numbers: 2023-509151-13-00

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No