Faecal Microbiota Transplantation for Liver Cirrhosis

Study Overview
=================
Brief Summary
-----------------
The purpose is to investigate the effect of fecal microbiota transplantation (FMT)on complications, progression, and mortality of cirrhosis. Further, the investigators want to examine the impact of FMT on gut barrier function, systemic inflammation, and immune responses.

Detailed Description
-----------------
Patients with liver disease have a disturbed gut microbiota. This is often associated with disease progression and development of complications, so called episodes of decompensation. In this study we will change the microbiota of these patients by transferring a healthy microbiota through faeces from a healthy donor, a procedure known as a faecal microbiota transplantation (FMT). In this this study we will examine the effect of FMT on the prognosis and disease progression of the patients. Further, we will examine the mechanistic effects of FMT in these patients. We will at random divide 220 patients admitted with decompensation of liver cirrhosis evenly into two groups. One group will receive FMT and the other group will receive placebo. After the treatment, we will follow the patients for one year and examine disease progression as well as changes in their gut microbiota, gut barrier, and immune function.

Official Title
-----------------
Faecal Microbiota Transplantation to Prevent Complications, Progression and Mortality of Liver Cirrhosis

Conditions
-----------------
Liver Cirrhosis

Intervention / Treatment
-----------------
* Biological: Faecal microbiota transplantation
* Biological: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age 18-75 years Liver cirrhosis with Child-Pugh score 7-12 Hospital admission due to acute decompensation (ascites, gastrointestinal bleeding, bacterial infections, hepatic encephalopathy, alcoholic hepatitis) Maximum of 1 organ failure defined by CLIF-SOFA score Exclusion Criteria: Untreated malignancy apart from hepatocellular carcinoma within the Milan criteria or non-melanoma skin cancer Untreated viral hepatitis HIV Inflammatory bowel disease Celiac disease Pregnancy Unable to participate based on medical judgement

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Faecal microbiota transplantation<br>The patients will receive three applications of FMT consisting of 50 g cryopreserved, homogenized faeces from healthy donors. The faecal material will be dispensed into double-coated, acid-resistant enterocapsules or cryobags. Faeces will be screened according to international guidelines. | Biological: Faecal microbiota transplantation<br>* All participant will receive three applications of either FMT or placebo and afterwards followed for 1 year.<br>* Other names: FMT;|
| Placebo Comparator: Placebo<br>The placebo products is produced from a suspension of glycerol, saline and food colouring and cannot be distinguished from the active FMT products. | Biological: Placebo<br>* Placebo<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to death or re-admission due to episode of acute decompensation in FMT treated versus placebo treated patients. | Using data from the patient journals, we will be able to examine the exact time to event in each of the patients. To compare the to groups, hazard ratios will be calculated. | 1 year | 
| Frequency of patients who have died or experienced a new episode of decompensation at 3 months of follow-up in FMT treated versus placebo treated patients. | At three months follow-up of the first 40 patients, we will conduct an interim analyses. The primary outcome measure is frequency of patients, who have died or developed a new episode of decompensation. We will draw the data from electronic patient charts and from follow-up visits. The frequency will be compared using Chi2 test. | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in gut microbiota beta-diversity (Bray-Curtis index, taxonomic abundance) during one year in FMT treated versus placebo treated patients by 16S sequencing. | In stool and saliva samples collected before and at 5 time points following the intervention, we will measure the gut microbiota composition. | 1 year | 
| Change in plasma concentration of gut translocation markers; lipopolysaccharide binding protein, soluble CD14, fatty acid binding protein 1 during one year in FMT treated versus placebo treated patients by ELISA. | In blood samples collected at baseline and at follow-up visits, we will measure these plasma proteins by ELISA. | 1 year | 
| Change in plasma concentration of pro- and antiinflammatory cytokines; IL-6, IL-1beta, TNF-alpha, IL-8, IL-10 in response to the intervention by luminex. | In blood samples collected at baseline and at follow-up visits, we will measure these plasma proteins by luminex. | 1 year | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Hepatic encephalopathy, Ascites, Gastrointestinal bleeding, Spontaneous bacterial peritonitis, Hepatorenal syndrome, Alcoholic hepatitis