Efficacy and Safety of Fecal Microbiota Transplant for Secondary Prophylaxis of Hepatic Encephalopathy

Efficacy and Safety of Fecal Microbiota Transplant for Secondary Prophylaxis of Hepatic Encephalopathy: A Randomized Controlled Trial

Despite standard of care, the recurrence of hepatic encephalopathy remains the primary cause for readmissions in individuals with cirrhosis. Patients with cirrhosis have disturbed gut microbiota, which is exacerbated by repeated antibiotic usage. FMT is a promising therapy to restore a healthy microbiota. FMT causes change in composition of gut microbiota which will lead to increase in commensal bacterial diversity which will increase colonization resistance to pathogenic bacteria and thereby decrease the bacterial overgrowth. Healthy bacteria also increase the SCFA production in colon with is and nutrient for endothelial cells and thereby protect the endothelial integrity and decreases bacterial translocation and endotoxemia. Current standard of care mainly focuses on the treatment of precipitating factors of the HE. The goal of our open-label, randomised clinical trial is to evaluate the safety, efficacy of addition of FMT to SOC in preventing subsequent episodes of hepatic encephalopathy.

Study Overview

• Status: Not yet recruiting
• Conditions: Hepatic Encephalopathy
• Intervention / Treatment: Other: Standard Medical Treatment; Other: Fecal Microbiota Transplant

Detailed Description

Hypothesis Engraftment of healthy donor microbiota in cirrhotic patients with hepatic encephalopathy curtails dysbiosis which subsequently prevent further episodes of hepatic encephalopathy and thereby increasing the transplant free survival

AIM:-To study efficacy and safety of fecal microbiota transplantation in preventing recurrence of hepatic encephalopathy in patients with cirrhosis who have recovered from first episode of hepatic encephalopathy

Methodology Study population: All cirrhotic patients between 18 years to 70 years, who have recovered within 7 days from hepatic encephalopathy after hospitalization.

Study design: A Randomized Controlled Trial Study period: December 2021- December 2022 Sample size: 66 (44:22 cases in each group) Randomization: The randomization will be done in 2:1 ratio by block randomization method with block size of 6. The allocation concealment will be done by using SNOSE method.

There are no Indian studies (RCT) available for suggesting role of FMT in hepatic encephalopathy.

In the RCT by BAJAJ ET AL. HEPATOLOGY, December 2017, the incidence of HE in standard group was 60% (6/10) and 0%(0/10) in experimental group.

But this was and underpowered study and possibility of type 2 error is there. Assuming that there is 5% risk of development of HE in Experimental group (FMT with SMT) and 60% in SMT group with alpha 5%, power 90% with 2:1 allocation and considering 10% drop out rate, investigator decided to enroll 66 patients, 44 patients in experiential group and 22 patients in standard group

Intervention: This RCT will be conducted at ILBS New Delhi All cirrhotic patients between 18 years to 70 years, who have recently recovered from hepatic encephalopathy will be randomized into two groups.

Both groups will be given standard medical therapy,

Standard medical therapy (SMT):

Lactulose (Titrated to 2-3 soft bowel movements per day) Oral LOLA can be used as an alternative or additional agent to treat patients non-responsive to conventional therapy Oral BCAAs can be used as an alternative or additional agent to treat patients non-responsive to conventional therapy Diet Daily energy intakes of 35-40 kcal/kg ideal body weight Daily protein intake 1.2-1.5 g/kg/day Small meals or liquid nutritional supplements evenly distributed throughout the day Oral BCAA supplementation in patient's intolerant of dietary protein (to allow recommended nitrogen intake to be achieved and maintained) Group 1 will receive standard medical therapy only Group 2 will be given FMT along with SMT Healthy donor will be screen as per ILBS FMT proforma

Stool collection:

Donors will be supplied clean, sealable containers for collection and transport of stool. Containers will be labelled with the name, UHID and date/time of stool collection.

Collected stool will be immediately transferred to the laboratory facility for processing and used within 6 hours collection Stool sample from Healthy donor will be processed

Patient preparation:

Patients will have completed at least 3-day antibiotic course in hospital No antibiotics will be given 12 hours before administration of FMT however he will he/she will continue on SMT for HE (precipitating event, lactulose and rifaximin) No antibiotic or will be given for at least a day after instillation of FMT For administration of FMT, Endoscopy or fluoroscopy guided NJ tube will be placed Testing for Small intestinal bacterial overgrowth (SIBO) using breath test will be performed in a small set of patients (~30% of study population i.e 20 patients) Methods of FMT infusion. Three doses (30ml one dose) of FMT will be given via jejunal port of NJ/NG tube

The following data will be recorded for each patient:

Day 0: CBC, LFT, KFT, Ammonia, MELD, CTP, Sr Bile acid, Stool Microbiome and bile acid profile, IL-6 Cognitive Assessment: Overt HE - WHC, Covert HE- PHES and CFF At discharge: CBC, LFT, KFT, Ammonia, MELD, CTP, Sr Bile acid, Stool Microbiome and bile acid profile, IL-6, Cognitive Assessment: Over-WHC, Covert- PHES and CFF, Marker of neuroinflammation (IL-1β, OX-42)[Biobank], Urinary metabolomics {hippurate, formate, and reduced phenylacetylglutamine (PAG)}[Biobank] At 1 month: CBC, LFT, KFT, Ammonia, MELD, CTP, Sr Bile acid, Stool Microbiome and bile acid profile, IL-6, Cognitive Assessment: Over-WHC, Covert- PHES and CFF, Marker of neuroinflammation (IL-1β, OX-42)[Biobank], Urinary metabolomics {hippurate, formate, and reduced phenylacetylglutamine (PAG)}[Biobank] At 3 month: CBC, LFT, KFT, Ammonia, MELD, CTP, Sr Bile acid, Stool Microbiome and bile acid profile, IL-6, Cognitive Assessment: Over-WHC, Covert- PHES and CFF, Marker of neuroinflammation (IL-1β, OX-42)[Biobank], Urinary metabolomics {hippurate, formate, and reduced phenylacetylglutamine (PAG)}[Biobank] At 6 month: CBC, LFT, KFT, Ammonia, MELD, CTP, Sr Bile acid, Stool Microbiome and bile acid profile, IL-6, Cognitive Assessment: Over-WHC, Covert- PHES and CFF, Marker of neuroinflammation (IL-1β, OX-42)[Biobank], Urinary metabolomics {hippurate, formate, and reduced phenylacetylglutamine (PAG)}[Biobank] During follow up If any patient develops an episode of hepatic encephalopathy, he will be treated with standard medical therapy and after stabilization patient will be started on oral rifaximin 550 mg per day, and patient will be followed up till 6 months from day of FMT

Monitoring and assessment: All the parameters of the objective and also noted any adverse effects.

Adverse effects: Nausea, Vomiting, Fever with chills, dyspnea Stopping rule: If patient decided to withdraw from study Ethical issues in the study and plans to address these issues. None

• Study Type: Interventional
• Enrollment (Anticipated): 66
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Dr Tushar Madhav Madke, MD; Phone Number: 01146300000; Email: drtusharmadke@gmail.com

Study Locations

• India
  • Delhi
    • New Delhi, Delhi, India, 110070
      • Institute of Liver & Biliary Sciences
      • Contact: Dr Tushar Madhav Madke, MD; Phone Number: 01146300000; Email: drtusharmadke@gmail.com

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:

- All cirrhotic patients between 18 years to 70 years, who have recovered within 7 days from hepatic encephalopathy after hospitalization

Exclusion Criteria:

1. Patient having hepatic encephalopathy after obvious precipitants (eg. diuretics, dehydration)
2. Patients on immunosuppressive medications
3. Active Infection (documented blood culture positive, Imaging diagnosis or SIRS>=1)
4. AKI (Defined as per KIDGO guidelines)
5. GI Bleed (In past 14 days)
6. Hepatocellular carcinoma
7. Patient with portosystemic shunt with size >10mm
8. Patients with previous TIPS or shunt surgery
9. Patients with significant comorbid illness such as heart, respiratory, or renal failure
10. Any neurologic diseases such as Alzheimer's disease, Parkinson's disease
11. Non hepatic metabolic encephalopathies
12. Not willing for the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: FMT along with SMT; FMT + Standard medical therapy (SMT): Lactulose (Titrated to 2-3 soft bowel movements per day) Oral LOLA can be used as an alternative or additional agent to treat patients non-responsive to conventional therapy Oral BCAAs can be used as an alternative or additional agent to treat patients non-responsive to conventional therapy Diet Daily energy intakes of 35-40 kcal/kg ideal body weight Daily protein intake 1.2-1.5 g/kg/day Small meals or liquid nutritional supplements evenly distributed throughout the day Oral BCAA supplementation in patient's intolerant of dietary protein (to allow recommended nitrogen intake to be achieved and maintained)	Other: Standard Medical Treatment; Standard medical therapy (SMT): Lactulose (Titrated to 2-3 soft bowel movements per day) Oral LOLA can be used as an alternative or additional agent to treat patients non-responsive to conventional therapy Oral BCAAs can be used as an alternative or additional agent to treat patients non-responsive to conventional therapy Diet Daily energy intakes of 35-40 kcal/kg ideal body weight Daily protein intake 1.2-1.5 g/kg/day Small meals or liquid nutritional supplements evenly distributed throughout the day Oral BCAA supplementation in patient's intolerant of dietary protein (to allow recommended nitrogen intake to be achieved and maintained); Other: Fecal Microbiota Transplant; Fecal Microbiota Transplant
ACTIVE_COMPARATOR: Standard Medical Treatment; Standard medical therapy (SMT): Lactulose (Titrated to 2-3 soft bowel movements per day) Oral LOLA can be used as an alternative or additional agent to treat patients non-responsive to conventional therapy Oral BCAAs can be used as an alternative or additional agent to treat patients non-responsive to conventional therapy Diet Daily energy intakes of 35-40 kcal/kg ideal body weight Daily protein intake 1.2-1.5 g/kg/day Small meals or liquid nutritional supplements evenly distributed throughout the day Oral BCAA supplementation in patient's intolerant of dietary protein (to allow recommended nitrogen intake to be achieved and maintained)	Other: Standard Medical Treatment; Standard medical therapy (SMT): Lactulose (Titrated to 2-3 soft bowel movements per day) Oral LOLA can be used as an alternative or additional agent to treat patients non-responsive to conventional therapy Oral BCAAs can be used as an alternative or additional agent to treat patients non-responsive to conventional therapy Diet Daily energy intakes of 35-40 kcal/kg ideal body weight Daily protein intake 1.2-1.5 g/kg/day Small meals or liquid nutritional supplements evenly distributed throughout the day Oral BCAA supplementation in patient's intolerant of dietary protein (to allow recommended nitrogen intake to be achieved and maintained)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Proportion of patients developing an episode of hepatic encephalopathy within 6 months	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patients developing adverse event related to FMT within 6 months		6 months
Number of Participants with Transplant free survival at day 28		Day 28
Number of Participants with Transplant free survival at day 90		Day 90
Number of Participants with Transplant free survival at day 180		Day 180
Change in Ammonia level at day baseline, 28 days		28 days
Change in Psychometric test/CFF pre and post FMT at day baseline, 28 days		28 days
Change in Psychometric test/CFF pre and post FMT at day baseline,90 days		90 days
Change in Ammonia level pre and post FMT at day baseline,90 days		90 days
Change in Ammonia level pre and post FMT at day baseline, 180 days.		180 days
Change in Psychometric test/CFF pre and post FMT at day baseline, 180 days.		180 days
Change in inflammatory markers pre and post FMT at day baseline		0 day
Change in inflammatory markers pre and post FMT at 28 days		28 days
Change in inflammatory markers pre and post FMT at 90 days.		90 days
Change in inflammatory markers pre and post FMT at 180 days.		180 days
Change in urinary metabolomics pre and post FMT at baseline, 28 days		28 days
Change in Stool microbiome and metabolomics pre and post FMT at baseline, 28 days		28 days
Change in Stool microbiome and metabolomics pre and post FMT at baseline, 90 days		90 days
Change in urinary metabolomics pre and post FMT at baseline, 90 days		90 days
Change in urinary metabolomics pre and post FMT at baseline, 180 days		180 days
Change in Stool microbiome and metabolomics pre and post FMT at baseline, 180 days		180 days
Change in CTP score	Child-Turcotte-Pugh ranges from 5 to 15. 5 is good and 15 is worse.	28 days
Change in MELD score	Model for End Stage Liver Disease (MELD) score ranges from 6 to 40, 6 is good and 40 is worse.	28 days
Change in CTP score	Child-Turcotte-Pugh ranges from 5 to 15, 5 is good and 15 is worse	90 days
Change in MELD score	Model for End Stage Liver Disease (MELD) score ranges from 6 to 40, 6 is good and 40 is worse.	90 days
Change in CTP score	Child-Turcotte-Pugh ranges from 5 to 15, 5 is good and 15 is worse.	180 days
Change in MELD score	Model for End Stage Liver Disease (MELD) score ranges from 6 to 40, 6 is good and 40 is worse.	180 days

Collaborators and Investigators

• Sponsor: Institute of Liver and Biliary Sciences, India

Study record dates

Study Major Dates

• Study Start (ANTICIPATED): January 31, 2022
• Primary Completion (ANTICIPATED): December 31, 2022
• Study Completion (ANTICIPATED): December 31, 2022

Study Registration Dates

• First Submitted: December 24, 2021
• First Submitted That Met QC Criteria: January 27, 2022
• First Posted (ACTUAL): February 8, 2022

Study Record Updates

• Last Update Posted (ACTUAL): February 8, 2022
• Last Update Submitted That Met QC Criteria: January 27, 2022
• Last Verified: December 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Failure; Hepatic Insufficiency; Metabolic Diseases; Central Nervous System Diseases; Nervous System Diseases; Liver Diseases; Brain Diseases, Metabolic; Hepatic Encephalopathy; Brain Diseases
• Other Study ID Numbers: ILBS- Cirrhosis-40

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