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Fecal Microbiota Transplant as Treatment of Hepatic Encephalopathy

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ClinicalTrials.gov Identifier: NCT03420482
Recruitment Status : Recruiting
First Posted : February 2, 2018
Last Update Posted : September 9, 2019
Sponsor:
Collaborator:
Center for Microbiome Informatics and Therapeutics
Information provided by (Responsible Party):
Raymond Chung, Massachusetts General Hospital

Tracking Information
First Submitted Date  ICMJE January 29, 2018
First Posted Date  ICMJE February 2, 2018
Last Update Posted Date September 9, 2019
Actual Study Start Date  ICMJE April 1, 2018
Estimated Primary Completion Date December 31, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 29, 2018)
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) ]
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03420482 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: February 12, 2018)
  • 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. ]
    Adverse events will be graded based on CTCAE V.4.03.
  • Stroop Test [ Time Frame: Before the first administration of FMT (day 0) and one week after the last administration of FMT (day 28) ]
    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.
  • 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) ]
    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.
  • Ammonia level [ Time Frame: Before the first administration of FMT (day 0) and one week after the last administration of FMT (day 28) ]
    Ammonia is a serology with a known association with hepatic encephalopathy.
  • 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. ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: January 29, 2018)
  • 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. ]
    Adverse events will be graded based on CTCAE V.4.03.
  • Stroop Test [ Time Frame: Before the first administration of FMT (day 0) and one week after the last administration of FMT (day 28) ]
    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.
  • SF-36 [ Time Frame: Before the first administration of FMT (day 0) and one week after the last administration of FMT (day 28) ]
    The SF-36 is a highly utilized quality of life questionnaire.
  • Ammonia level [ Time Frame: Before the first administration of FMT (day 0) and one week after the last administration of FMT (day 28) ]
    Ammonia is a serology with a known association with hepatic encephalopathy.
  • 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. ]
    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.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Fecal Microbiota Transplant as Treatment of Hepatic Encephalopathy
Official Title  ICMJE Fecal Microbiota Transplant as Treatment of Hepatic Encephalopathy
Brief Summary 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.
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  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
This is a two part study. The first part is a 10-patient pilot study, used to find 2 stool donors who precipitate the largest improvement in recipient neurological function and microbiome composition. The second part is a 20-patient RCT, where patients will be randomized to FMT or placebo.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:
Randomization will be performed by the lab producing the FMT and placebo capsules. Participants, providers, investigators and research assistants will be blinded.
Primary Purpose: Treatment
Condition  ICMJE Hepatic Encephalopathy
Intervention  ICMJE
  • Drug: Fecal Microbiota Transplant (FMT) oral capsules
    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.
  • Drug: Placebo oral capsule
    Oral placebo capsules filled with glycerol and cocoa powder. These capsules are identical in appearance to FMT capsules.
Study Arms  ICMJE
  • Experimental: Fecal Microbiota Transplant (FMT) oral capsules
    Subjects will receive 15 oral capsules of FMT on days 1, 2, 7, 14, and 21.
    Intervention: Drug: Fecal Microbiota Transplant (FMT) oral capsules
  • Placebo Comparator: Placebo capsules
    Subjects will receive placebo capsules on the same schedule as the experimental arm (days 1, 2, 7, 14, and 21).
    Intervention: Drug: Placebo oral capsule
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: January 29, 2018)
30
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 31, 2022
Estimated Primary Completion Date December 31, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Patricia P Bloom, MD 978-460-0538 PPBloom@partners.org
Contact: Jenna Gustafson 617-724-6832 jlgustafson@mgh.harvard.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03420482
Other Study ID Numbers  ICMJE 2017P002296
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Raymond Chung, Massachusetts General Hospital
Study Sponsor  ICMJE Massachusetts General Hospital
Collaborators  ICMJE Center for Microbiome Informatics and Therapeutics
Investigators  ICMJE
Principal Investigator: Raymond T Chung, MD Massachusetts General Hospital
PRS Account Massachusetts General Hospital
Verification Date September 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP