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FMT in Cirrhosis and Hepatic Encephalopathy

Primary Purpose

Cirrhosis, Hepatic Encephalopathy

Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Fecal Microbial transplant Capsules
Fecal Microbial Transplant Enema
Placebo
Sponsored by
VA Office of Research and Development
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional other trial for Cirrhosis focused on measuring fecal microbial transplant, cirrhosis, hepatic encephalopathy

Eligibility Criteria

21 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Cirrhosis diagnosed by either of the following in a patient with chronic liver disease

    • Liver Biopsy
    • Radiologic evidence of varices, cirrhosis or portal hypertension
    • Laboratory evidence of platelet count <100,000 or AST/ALT ratio>1
    • Endoscopic evidence of varices or portal gastropathy
    • Fibroscan values suggestive of cirrhosis
  • On treatment for hepatic encephalopathy (patient can be on lactulose and rifaximin)
  • Able to give written, informed consent (demonstrated by mini-mental status exam>25 at the time of consenting)
  • Women of child bearing potential must agree to use effective contraception for the duration of the study and for 10 days prior and 30 days after the study
  • Negative pregnancy test in women of childbearing age

Exclusion Criteria:

  • MELD score >22
  • WBC count <1000 cells/mm3
  • Platelet count<25,000/mm3
  • TIPS in place for less than a month
  • Currently on antibiotics apart from rifaximin
  • Infection at the time of the FMT (diagnosed by blood culture positivity, urinalysis, paracentesis as needed)
  • Hospitalization for any non-elective cause within the last 1 month
  • Patients who are aged >75 years
  • Patients who are pregnant or nursing (will be checked using a urine pregnancy test)
  • Patients who are incarcerated
  • Patients who are incapable of giving their own informed consent
  • Patients who are immuno-compromised due to the following reasons:

    • HIV infection (any CD4 count)
    • Inherited/primary immune disorders
    • Current or recent (<3 mos) treatment with anti-neoplastic agent
    • Current or recent (<3 mos) treatment with any immunosuppressant medications [including but not limited to monoclonal antibodies to B and T cells, anti-TNF agents, glucocorticoids, antimetabolites (azathioprine, 6-mercaptopurine), calcineurin inhibitors (tacrolimus, cyclosporine), mycophenolate mofetil].

      • Subjects who are otherwise immunocompetent and have discontinued any immunosuppressant medications 3 or more months prior to enrollment may be eligible to enroll
  • Patients on renal replacement therapy
  • Patients with untreated, in-situ colorectal cancer
  • Patients with a history of chronic intrinsic GI diseases such as inflammatory bowel disease

    • ulcerative colitis, Crohn's disease or microscopic colitis

      • eosinophilic gastroenteritis or celiac disease
  • Major gastro-intestinal or intra-abdominal surgery in the last three months

Other Exclusion Criteria:

  • Enema-related

    • Platelet count<25,000
    • Grade IV hemorrhoids
  • Safety-related:

    • Dysphagia
    • History of aspiration, gastroparesis, intestinal obstruction
    • Ongoing antibiotic use (except for Rifaximin)
    • Severe anaphylactic food allergy
    • Allergy to ingredients Generally Recognized As Safe in the FMT capsules (glycerol, sodium chloride, hypromellose, gellan gum, titanium dioxide, theobroma oil)
    • Adverse event attributable to prior FMT
    • ASA Class IV or V
    • Pregnant or nursing patients
    • Acute illness or fever within 48 hours of the day of planned FMT
    • Immunocompromised due to medical conditions
    • Probiotics use within the last 48 hours of the day of planned FMT
    • Any condition that the physician investigators deem unsafe, including other conditions or medications that the investigator determines puts the participant at greater risk from FMT

Sites / Locations

  • Hunter Holmes McGuire VA Medical Center, Richmond, VARecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Placebo Comparator

Active Comparator

Active Comparator

Experimental

Arm Label

Placebo

Group 3: Oral placebo and rectal FMT

Group 2: Oral FMT and rectal placebo

Group 1: Dual Oral and rectal FMT

Arm Description

Oral and rectal placebo at visit 2 Oral placebo at day 30

Oral placebo and rectal FMT at visit 2 Oral placebo at day 30

Oral FMT and rectal placebo at visit 2 Oral FMT at day 30

Dual Oral and rectal FMT at visit 2 Oral FMT at day 30

Outcomes

Primary Outcome Measures

Serious adverse events related to FMT
Number of serious adverse events between groups related to FMT

Secondary Outcome Measures

Adverse events related to FMT
Number of adverse events that do not fit the criteria of serious adverse events between groups related to FMT
Change in microbial diversity in stool
Shannon diversity index compared to baseline and engraftment related to the donor at baseline, within 30 days and then monthly till 6 months. Ranges usually from 0-10
Sickness Impact Profile change
Quality of life assessment change defined by Sickness Impact Profile total score at 30 days and 6 months between groups. This is a percentage result ranges usually from 0-100
EncephalApp performance change
Cognitive assessment change using the OffTime+OnTime in seconds between groups at 30 days, 60 days and 6 months
Psychometric hepatic encephalopathy score (PHES) change
Cognitive assessment change using the total PHES score between groups at 30 days, 60 days and 6 months. This ranges from -15 to +5
Change in microbial diversity in saliva
Shannon diversity index compared to baseline at 30 days and then monthly till 6 months. Ranges usually from 0-10

Full Information

First Posted
January 3, 2019
Last Updated
February 23, 2023
Sponsor
VA Office of Research and Development
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1. Study Identification

Unique Protocol Identification Number
NCT03796598
Brief Title
FMT in Cirrhosis and Hepatic Encephalopathy
Official Title
Fecal Microbiota Transplant in Veterans With Cirrhosis
Study Type
Interventional

2. Study Status

Record Verification Date
February 2023
Overall Recruitment Status
Recruiting
Study Start Date
July 29, 2019 (Actual)
Primary Completion Date
June 24, 2024 (Anticipated)
Study Completion Date
December 31, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
VA Office of Research and Development

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Patients with end stage of liver disease or cirrhosis can develop confusion due to high ammonia and inflammation. This confusion is brought upon by changes in the bacteria in the bowels and may not respond to current standard of care treatments. Repeated episodes of confusion can make it difficult for patients to function and may result in multiple admissions to the hospital and burden on the family. The investigators have studied using a healthy person's stool to replace the bowel bacteria, called fecal microbial transplant, in small studies with good results. In this trial the investigators propose to perform these procedures using an upper and lower route in Veterans who suffer from this condition and follow them for safety and hospitalizations over 6 months. The investigators will compare this to placebo treatments and hope that this intervention can improve the health and daily functioning of affected patients.
Detailed Description
Indication: Cirrhosis and hepatic encephalopathy Study Objectives: To evaluate the safety and tolerability of fecal transplant in patients with cirrhosis and hepatic encephalopathy Rationale and Supporting Evidence: Hepatic encephalopathy affects 30-45% of patients with cirrhosis and adversely affects survival in these patients. The mainstay of treatment for hepatic encephalopathy (HE) has long been the manipulation of the gut flora through antibiotics, prebiotics or probiotics. The current first and second line therapies for HE in the US are lactulose and rifaximin respectively that uniquely act within the confines of the gut lumen with encouraging clinical results. However, there is a subset of patients with HE that continues to recur despite being on both treatments. This patient group is at a higher risk of poor outcomes because HE has now been removed from liver transplant priority and multiple episodes of HE can result in cumulative brain injury which may be irreversible. Therefore, the prevention of recurrent HE is an important therapeutic goal. The investigators' group and other reports have shown that patients with HE and cirrhosis are more likely to have overgrowth of potentially pathogenic bacterial taxa such as Enterobacteriaceae and reduction of autochthonous species such as Lachnospiraceae and Ruminococcaceae in the stool and the colonic mucosa. This has been linked to poor performance on cognitive tests that are a hallmark of HE and with increased systemic inflammation in these patients. Therefore, a gut-based therapeutic option that can potentially improve the recurrence rate and the overall prognosis is needed. Fecal transplant has been shown to be effective in conditions with predominant gut-bacterial overgrowth or alteration such as recurrent Clostridium difficile and inflammatory bowel disease. Safe protocols have been developed across the world and studies are being performed in the US under FDA-monitored INDs. Limitations to performing fecal transplant include identifying and screening appropriate donors, which is time consuming and costly, with the cost typically falling to the patient or donor as the required screening is generally not covered by insurance. The investigators' preliminary data suggest that a one-time administration of an FMT-enema using a rationally-selected donor is safe in patients with cirrhosis and recurrent HE. However, given the small bowel overgrowth and the predominantly small bowel location for bacterial translocation in cirrhosis, which is out of the reach of an enema, an upper GI route for FMT needs to be explored. In the investigators' published experience, a single enema from a rationally-derived donor was associated with significantly lower total and HE-related hospitalizations compared to patients who were randomized to standard of care, with a stable long-term course over >1 year. The investigators' data show that FMT was associated with favorable changes in fecal bile acid (BA) profile with a decrease in proportions of fecal secondary BAs, conjugated BAs and increase in sulfated BAs, indicating a healthier milieu. The investigators also have preliminary data defining the safety of oral FMT capsules in patients with cirrhosis and HE in a current trial led by us. The use of combined oral and rectal routes of FMT, which can potentially alleviate both small bowel and colonic translocation are likely to be better than either alone. Overall aim: To determine the effect of dual oral and rectal administration of FMT from a rational donor on clinical outcomes (hospitalizations, brain function, quality of life) and host-microbiota interactions (microbial composition and bile acid composition with systemic and intestinal inflammation), compared to single route of administration and placebo, along with a second oral capsular FMT vs placebo administration in cirrhotic patients with HE using a randomized, phase II clinical trial. Design overview: Four groups of outpatients with cirrhosis will be randomized using random sequence generator into placebo and FMT groups and followed for 6 months under an FDA IND double-blind clinical trial.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cirrhosis, Hepatic Encephalopathy
Keywords
fecal microbial transplant, cirrhosis, hepatic encephalopathy

7. Study Design

Primary Purpose
Other
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Model Description
Subjects will be divided into 4 groups via randomization Group 1: Dual oral and rectal FMT, Group 2: Oral FMT and rectal placebo, Group 3: Oral placebo and rectal FMT and Group 4: Oral and rectal placebo
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
60 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Oral and rectal placebo at visit 2 Oral placebo at day 30
Arm Title
Group 3: Oral placebo and rectal FMT
Arm Type
Active Comparator
Arm Description
Oral placebo and rectal FMT at visit 2 Oral placebo at day 30
Arm Title
Group 2: Oral FMT and rectal placebo
Arm Type
Active Comparator
Arm Description
Oral FMT and rectal placebo at visit 2 Oral FMT at day 30
Arm Title
Group 1: Dual Oral and rectal FMT
Arm Type
Experimental
Arm Description
Dual Oral and rectal FMT at visit 2 Oral FMT at day 30
Intervention Type
Drug
Intervention Name(s)
Fecal Microbial transplant Capsules
Intervention Description
Oral capsules of FMT
Intervention Type
Drug
Intervention Name(s)
Fecal Microbial Transplant Enema
Intervention Description
FMT enema
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
Placebo
Primary Outcome Measure Information:
Title
Serious adverse events related to FMT
Description
Number of serious adverse events between groups related to FMT
Time Frame
6 months
Secondary Outcome Measure Information:
Title
Adverse events related to FMT
Description
Number of adverse events that do not fit the criteria of serious adverse events between groups related to FMT
Time Frame
6 months
Title
Change in microbial diversity in stool
Description
Shannon diversity index compared to baseline and engraftment related to the donor at baseline, within 30 days and then monthly till 6 months. Ranges usually from 0-10
Time Frame
6 months
Title
Sickness Impact Profile change
Description
Quality of life assessment change defined by Sickness Impact Profile total score at 30 days and 6 months between groups. This is a percentage result ranges usually from 0-100
Time Frame
30 days and 6 months
Title
EncephalApp performance change
Description
Cognitive assessment change using the OffTime+OnTime in seconds between groups at 30 days, 60 days and 6 months
Time Frame
30 days, 60 days and 6 months
Title
Psychometric hepatic encephalopathy score (PHES) change
Description
Cognitive assessment change using the total PHES score between groups at 30 days, 60 days and 6 months. This ranges from -15 to +5
Time Frame
30 days, 60 days and 6 months
Title
Change in microbial diversity in saliva
Description
Shannon diversity index compared to baseline at 30 days and then monthly till 6 months. Ranges usually from 0-10
Time Frame
6 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
21 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Cirrhosis diagnosed by either of the following in a patient with chronic liver disease Liver Biopsy Radiologic evidence of varices, cirrhosis or portal hypertension Laboratory evidence of platelet count <100,000 or AST/ALT ratio>1 Endoscopic evidence of varices or portal gastropathy Fibroscan values suggestive of cirrhosis On treatment for hepatic encephalopathy (patient can be on lactulose and rifaximin) Able to give written, informed consent (demonstrated by mini-mental status exam>25 at the time of consenting) Women of child bearing potential must agree to use effective contraception for the duration of the study and for 10 days prior and 30 days after the study Negative pregnancy test in women of childbearing age Exclusion Criteria: MELD score >22 WBC count <1000 cells/mm3 Platelet count<25,000/mm3 TIPS in place for less than a month Currently on antibiotics apart from rifaximin Infection at the time of the FMT (diagnosed by blood culture positivity, urinalysis, paracentesis as needed) Hospitalization for any non-elective cause within the last 1 month Patients who are pregnant or nursing (will be checked using a urine pregnancy test) Patients who are incarcerated Patients who are incapable of giving their own informed consent Patients who are immuno-compromised due to the following reasons: HIV infection (any CD4 count) Inherited/primary immune disorders Current or recent (<3 mos) treatment with anti-neoplastic agent Current or recent (<3 mos) treatment with any immunosuppressant medications [including but not limited to monoclonal antibodies to B and T cells, anti-TNF agents, glucocorticoids, antimetabolites (azathioprine, 6-mercaptopurine), calcineurin inhibitors (tacrolimus, cyclosporine), mycophenolate mofetil]. Subjects who are otherwise immunocompetent and have discontinued any immunosuppressant medications 3 or more months prior to enrollment may be eligible to enroll Patients on renal replacement therapy Patients with untreated, in-situ colorectal cancer Patients with a history of chronic intrinsic GI diseases such as inflammatory bowel disease ulcerative colitis, Crohn's disease or microscopic colitis eosinophilic gastroenteritis or celiac disease Major gastro-intestinal or intra-abdominal surgery in the last three months Other Exclusion Criteria: Enema-related Platelet count<25,000 Grade IV hemorrhoids Safety-related: Dysphagia History of aspiration, gastroparesis, intestinal obstruction Ongoing antibiotic use (except for Rifaximin) Severe anaphylactic food allergy Allergy to ingredients Generally Recognized As Safe in the FMT capsules (glycerol, sodium chloride, hypromellose, gellan gum, titanium dioxide, theobroma oil) Adverse event attributable to prior FMT ASA Class IV or V Pregnant or nursing patients Acute illness or fever within 48 hours of the day of planned FMT Immunocompromised due to medical conditions Probiotics use within the last 48 hours of the day of planned FMT Any condition that the physician investigators deem unsafe, including other conditions or medications that the investigator determines puts the participant at greater risk from FMT
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Jasmohan S Bajaj, MD MS
Phone
(804) 675-5802
Email
Jasmohan.Bajaj@va.gov
First Name & Middle Initial & Last Name or Official Title & Degree
Edith A Gavis, RN
Phone
(804) 675-5584
Email
edith.gavis@va.gov
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jasmohan S. Bajaj, MD MS
Organizational Affiliation
Hunter Holmes McGuire VA Medical Center, Richmond, VA
Official's Role
Principal Investigator
Facility Information:
Facility Name
Hunter Holmes McGuire VA Medical Center, Richmond, VA
City
Richmond
State/Province
Virginia
ZIP/Postal Code
23249
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Edith A Gavis, RN
Phone
804-675-5584
Email
edith.gavis@va.gov
First Name & Middle Initial & Last Name & Degree
Jasmohan S Bajaj, MD MS
Phone
(804) 675-5802
Email
Jasmohan.Bajaj@va.gov
First Name & Middle Initial & Last Name & Degree
Jasmohan S. Bajaj, MD MS

12. IPD Sharing Statement

Plan to Share IPD
No

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FMT in Cirrhosis and Hepatic Encephalopathy

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