- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03420482
Fecal Microbiota Transplant as Treatment of Hepatic Encephalopathy
March 13, 2023 updated by: Raymond Chung, Massachusetts General Hospital
A common complication of advanced liver disease is a condition called hepatic encephalopathy, which leads to confusion.
The current treatment options cause side effects, are costly, and do not always work.
An abnormal population of bacteria in the intestines may be causing this condition, and transplanting bacteria from the colon of a healthy person may treat it.
In this research study, the investigators will first find two healthy stool donors whose stool donation improves the gut bacteria of patients with advanced liver disease and helps them think more clearly.
Then, in a randomized controlled trial, the investigators will compare the ability of stool donation from these two best donors versus a placebo to improve the neurological function of patients with advanced liver disease.
If the investigators find the expected results, there will be a new effective therapy for patients with advanced liver disease and the very troublesome complication of hepatic encephalopathy.
Study Overview
Status
Active, not recruiting
Conditions
Intervention / Treatment
Detailed Description
Decades of investigation demonstrate that hepatic encephalopathy (HE), a common complication of cirrhosis characterized by impaired cognition, develops as a consequence of intestinal microbial products reaching the brain.
Recent investigation has found that cirrhotic patients, especially those who have developed HE, have intestinal dysbiosis compared to normal controls.
Several plausible mechanisms explain how intestinal dysbiosis could lead to HE.
There is limited prior literature on the efficacy of FMT in cirrhosis.
The largest documented study of 10 cirrhotic patients receiving a single FMT enema found no significant change in microbiome diversity as assessed by 16S rRNA sequencing.
The investigators hypothesize that aggressive manipulation of the microbial composition with fecal microbiota transplant (FMT) will improve neurological function in patients with a history of cirrhosis and HE.
The investigators additionally hypothesize that five oral FMT capsule administrations from a previously efficacious stool donor will significantly change the intestinal microbiome composition of a cirrhotic patient.
The study will consist of a 10-patient open-label pilot study to identify efficacious stool donors, defined as donors who precipitate the largest improvement in recipient neurological function and microbiome composition.
The two most efficacious pilot study stool donors will be selected to donate stool for the randomized controlled trial (RCT).
The 20-patient RCT will investigate the effect of FMT on neurological outcomes in patients with cirrhosis and a history of HE.
Subjects will be randomized to receive 5 doses of oral FMT capsules or placebo capsules over 21 days.
Cognitive testing and stool collections will occur at 4 time points, to assess for changes in neurological function and microbiome composition.
The primary outcome is change in neurological function after FMT.
The main secondary outcome is change in microbiome composition after FMT.
This study could provide valuable information about the ability of FMT to improve intestinal dysbiosis in cirrhosis and treat HE.
Study Type
Interventional
Enrollment (Anticipated)
30
Phase
- Phase 2
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Locations
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Massachusetts
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Boston, Massachusetts, United States, 02114
- Massachusetts General Hospital
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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
Ages Eligible for Study
18 years to 75 years (Adult, Older Adult)
Accepts Healthy Volunteers
No
Genders Eligible for Study
All
Description
Inclusion Criteria:
- Diagnosis of cirrhosis: Based on liver biopsy or clinical assessment of a hepatologist based on history, exam, laboratory and radiographic evidence
- History of at least one episode of overt HE, defined by West Haven Criteria Grades II to IV; episodes of HE that were precipitated by gastrointestinal hemorrhage requiring transfusion of at least 2 units of blood, by medication use, by renal failure requiring dialysis, or by injury to the central nervous system will not be counted as previous HE episodes
- Compliant with lactulose and rifaximin treatment (lactulose: at least one dose at least 5 days per week; rifaximin: at least one dose at least 5 days per week)
Exclusion Criteria:
- Current episode of overt HE as defined by West Haven Criteria Grades II to IV
- Expectation of liver transplantation within two months of the screening visit
- Current infection
- Variceal bleeding in the last 4 weeks
- Gut-absorbable or intravenous antibiotic therapy (including ciprofloxacin for SBP prophylaxis) in the last 3 months
- Alcohol or illicit drug intake within 3 months, by history and available serum testing; alcohol use will be characterized as >1 alcoholic drink / month
- PSC as etiology of liver disease, as prior literature has suggested these individuals have a unique microbiome
- History of Roux-en-Y Gastric bypass
- On immunosuppressive medications
- Positive C. difficile test
- Scoring above a threshold cut-off on the Psychometric Hepatic Encephalopathy Score (PHES)
- MELD > 17
- History of spontaneous bacterial peritonitis
- History of low ascites protein ( ≤ 1g/dL) in the last year
- Hemodialysis in the last 30 days
- Other significant laboratory abnormalities: serum creatinine > 2.0 mg/dL, hemoglobin < 8 g/dL, serum sodium < 125 mmol/L, serum calcium > 11.0 mg/dL, serum potassium < 2.5 mmol/L
- Placement of a portosystemic shunt or transjugular intrahepatic portosystemic shunt
- Unstable doses of opiates, benzodiazepines or other sedating medication
- Unable to provide consent; a. If MMSE is < 18 or the patient is deemed to not have capacity by an investigator, a legally authorized representative (surrogate) will be allowed to provide consent
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 Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Fecal Microbiota Transplant (FMT) oral capsules
Subjects will receive 15 oral capsules of FMT on days 1, 2, 7, 14, and 21.
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Donors will be healthy individuals, selected through a previously published, rigorous screening process.
Elizabeth Hohmann M.D. of MGH has demonstrated the safety and therapeutic efficacy of oral frozen FMT capsules in Clostridium difficile infection, and her lab will produce the capsules for this study.
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Placebo Comparator: Placebo capsules
Subjects will receive placebo capsules on the same schedule as the experimental arm (days 1, 2, 7, 14, and 21).
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Oral placebo capsules filled with glycerol and cocoa powder.
These capsules are identical in appearance to FMT capsules.
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Psychometric Hepatic Encephalopathy Score (PHES)
Time Frame: Before the first administration of FMT (day 0) and one week after the last administration of FMT (day 28)
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The PHES is a validated assessment tool specifically designed for HE trials to test cognitive and psychomotor processing speed and visuomotor coordination.
The PHES is a battery of 5 pencil-paper tests, completed in 15-20 minutes.
The primary outcome is the change in PHES score from immediately before FMT to 1 week after the last dose of FMT.
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Before the first administration of FMT (day 0) and one week after the last administration of FMT (day 28)
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Adverse events
Time Frame: Adverse event reporting will take place on day 2, 4, 7, 14, 21, then 1, 4 weeks after the last FMT administration.
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Adverse events will be graded based on CTCAE V.4.03.
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Adverse event reporting will take place on day 2, 4, 7, 14, 21, then 1, 4 weeks after the last FMT administration.
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Stroop Test
Time Frame: Before the first administration of FMT (day 0) and one week after the last administration of FMT (day 28)
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The Stroop Test evaluates psychomotor speed and cognitive flexibility by the interference between recognition reaction time to a colored field and a written color name.
A smartphone application software called "EncephalApp Stroop Test" will be used, validated to identify cognitive dysfunction in cirrhosis and screen for covert hepatic encephalopathy.
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Before the first administration of FMT (day 0) and one week after the last administration of FMT (day 28)
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36-Item Short Form Health Survey (SF-36)
Time Frame: Before the first administration of FMT (day 0) and one week after the last administration of FMT (day 28)
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The SF-36 is a highly utilized quality of life questionnaire.
There are 8 health concepts assessed by the survey, which includes physical functioning, bodily pain, role limitations due to physical health problems, role limitations due to personal or emotional problems, emotional well-being, social functioning, energy/fatigue, and general health perceptions.
Each of these health concepts is scored on a scale from 0 to 100.
0 is considered the worst outcome and 100 is considered the most favorable health state on each subscale.
There will be no total or summed score.
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Before the first administration of FMT (day 0) and one week after the last administration of FMT (day 28)
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Ammonia level
Time Frame: Before the first administration of FMT (day 0) and one week after the last administration of FMT (day 28)
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Ammonia is a serology with a known association with hepatic encephalopathy.
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Before the first administration of FMT (day 0) and one week after the last administration of FMT (day 28)
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Microbiome engraftment
Time Frame: Before the first administration of FMT (day 0), after 3 FMT administrations (day 14), one week after the last administration of FMT (day 28) and 4 weeks after the last administration of FMT.
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Sequence-based microbiome surveys will be carried out using metagenomic sequencing.
Computational analyses will investigate donor microbiota colonization by comparing single-nucleotide variants in strain level data between the donor and recipient.
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Before the first administration of FMT (day 0), after 3 FMT administrations (day 14), one week after the last administration of FMT (day 28) and 4 weeks after the last administration of FMT.
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Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Sponsor
Collaborators
Publications and helpful links
The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.
General Publications
- Bajaj JS, Kassam Z, Fagan A, Gavis EA, Liu E, Cox IJ, Kheradman R, Heuman D, Wang J, Gurry T, Williams R, Sikaroodi M, Fuchs M, Alm E, John B, Thacker LR, Riva A, Smith M, Taylor-Robinson SD, Gillevet PM. Fecal microbiota transplant from a rational stool donor improves hepatic encephalopathy: A randomized clinical trial. Hepatology. 2017 Dec;66(6):1727-1738. doi: 10.1002/hep.29306. Epub 2017 Oct 30.
- Youngster I, Mahabamunuge J, Systrom HK, Sauk J, Khalili H, Levin J, Kaplan JL, Hohmann EL. Oral, frozen fecal microbiota transplant (FMT) capsules for recurrent Clostridium difficile infection. BMC Med. 2016 Sep 9;14(1):134. doi: 10.1186/s12916-016-0680-9.
- Kao D, Roach B, Silva M, Beck P, Rioux K, Kaplan GG, Chang HJ, Coward S, Goodman KJ, Xu H, Madsen K, Mason A, Wong GK, Jovel J, Patterson J, Louie T. Effect of Oral Capsule- vs Colonoscopy-Delivered Fecal Microbiota Transplantation on Recurrent Clostridium difficile Infection: A Randomized Clinical Trial. JAMA. 2017 Nov 28;318(20):1985-1993. doi: 10.1001/jama.2017.17077.
- Bloom PP, Donlan J, Torres Soto M, Daidone M, Hohmann E, Chung RT. Fecal microbiota transplant improves cognition in hepatic encephalopathy and its effect varies by donor and recipient. Hepatol Commun. 2022 Aug;6(8):2079-2089. doi: 10.1002/hep4.1950. Epub 2022 Apr 5.
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 (Actual)
April 1, 2018
Primary Completion (Anticipated)
December 31, 2023
Study Completion (Anticipated)
January 31, 2024
Study Registration Dates
First Submitted
January 29, 2018
First Submitted That Met QC Criteria
January 29, 2018
First Posted (Actual)
February 5, 2018
Study Record Updates
Last Update Posted (Actual)
March 14, 2023
Last Update Submitted That Met QC Criteria
March 13, 2023
Last Verified
March 1, 2023
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- 2017P002296
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Yes
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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