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

January 27, 2022 updated by: Institute of Liver and Biliary Sciences, India

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

Status

Indicates the current recruitment status or the expanded access status.
Not yet recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

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

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Anticipated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
66

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Locations

  • India
    • Delhi
      • New Delhi, Delhi, India, 110070
        • Institute of Liver & Biliary Sciences
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

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

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
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

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Time Frame
Proportion of patients developing an episode of hepatic encephalopathy within 6 months
Time Frame: 6 months
6 months

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Proportion of patients developing adverse event related to FMT within 6 months
Time Frame: 6 months
6 months
Number of Participants with Transplant free survival at day 28
Time Frame: Day 28
Day 28
Number of Participants with Transplant free survival at day 90
Time Frame: Day 90
Day 90
Number of Participants with Transplant free survival at day 180
Time Frame: Day 180
Day 180
Change in Ammonia level at day baseline, 28 days
Time Frame: 28 days
28 days
Change in Psychometric test/CFF pre and post FMT at day baseline, 28 days
Time Frame: 28 days
28 days
Change in Psychometric test/CFF pre and post FMT at day baseline,90 days
Time Frame: 90 days
90 days
Change in Ammonia level pre and post FMT at day baseline,90 days
Time Frame: 90 days
90 days
Change in Ammonia level pre and post FMT at day baseline, 180 days.
Time Frame: 180 days
180 days
Change in Psychometric test/CFF pre and post FMT at day baseline, 180 days.
Time Frame: 180 days
180 days
Change in inflammatory markers pre and post FMT at day baseline
Time Frame: 0 day
0 day
Change in inflammatory markers pre and post FMT at 28 days
Time Frame: 28 days
28 days
Change in inflammatory markers pre and post FMT at 90 days.
Time Frame: 90 days
90 days
Change in inflammatory markers pre and post FMT at 180 days.
Time Frame: 180 days
180 days
Change in urinary metabolomics pre and post FMT at baseline, 28 days
Time Frame: 28 days
28 days
Change in Stool microbiome and metabolomics pre and post FMT at baseline, 28 days
Time Frame: 28 days
28 days
Change in Stool microbiome and metabolomics pre and post FMT at baseline, 90 days
Time Frame: 90 days
90 days
Change in urinary metabolomics pre and post FMT at baseline, 90 days
Time Frame: 90 days
90 days
Change in urinary metabolomics pre and post FMT at baseline, 180 days
Time Frame: 180 days
180 days
Change in Stool microbiome and metabolomics pre and post FMT at baseline, 180 days
Time Frame: 180 days
180 days
Change in CTP score
Time Frame: 28 days
Child-Turcotte-Pugh ranges from 5 to 15. 5 is good and 15 is worse.
28 days
Change in MELD score
Time Frame: 28 days
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
Time Frame: 90 days
Child-Turcotte-Pugh ranges from 5 to 15, 5 is good and 15 is worse
90 days
Change in MELD score
Time Frame: 90 days
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
Time Frame: 180 days
Child-Turcotte-Pugh ranges from 5 to 15, 5 is good and 15 is worse.
180 days
Change in MELD score
Time Frame: 180 days
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

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Institute of Liver and Biliary Sciences, India

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ANTICIPATED)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
January 31, 2022

Primary Completion (ANTICIPATED)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
December 31, 2022

Study Completion (ANTICIPATED)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
December 31, 2022

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
December 24, 2021

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
January 27, 2022

First Posted (ACTUAL)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
February 8, 2022

Study Record Updates

Last Update Posted (ACTUAL)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
February 8, 2022

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
January 27, 2022

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
December 1, 2021

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant 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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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