Fecal Microbiota Transplantation for the Treatment of Primary Sclerosing Cholangitis.
Primary Purpose
Sclerosing Cholangitis
Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Fecal Microbiota Transplantation
Sponsored by
About this trial
This is an interventional treatment trial for Sclerosing Cholangitis focused on measuring Fecal Transplant, Primary Sclerosing Cholangitis, Fecal Microbiota Transplantation
Eligibility Criteria
Inclusion Criteria:
- Age 18 or older
- Confirmed diagnosis of PSC (with a concurrent diagnosis of inflammatory bowel disease) characterized by a cholestatic liver condition of greater than 6 months duration with confirmatory cholangiographic findings, as well as an elevation of the serum alkaline phosphatase of greater than 1.5 times the upper limit of normal.
Exclusion Criteria:
- Decompensated liver disease
- Patients who were pregnant or breastfeeding
- Use of concomitant immune modulators including methotrexate, mycophenolate mofetil, tacrolimus, cyclosporine, thalidomide, Interleukin-10, or Interleukin-11 within 4 weeks prior to receiving the FMT
- Patients who are unable to give informed consent
- Patients who are unable or unwilling to undergo colonoscopy with moderate sedation (>ASA class II)
- Patients who have previously undergone FMT Patients who have a confirmed malignancy or cancer
- Patients who are immunocompromised
- Treatment within last 8 weeks with infliximab, adalimumab, certolizumab, natalizumab, vedolizumab or thalidomide
- Antibiotic use within 2-months of start date
- Participation in a clinical trial in the preceding 30 days or simultaneously during this trial
- Probiotic use within 30 days of start date
- Congenital or acquired immunodeficiencies
- Other comorbidities including:Diabetes mellitus, cancer, systemic lupus, must be able to tolerate conscious sedation with colonoscopy
- Chronic kidney disease as defined by a GFR <60mL/min/1.73m2 44
- History of rheumatic heart disease, endocarditis, or valvular disease due to risk of bacteremia from colonoscopy
- Steroid dose >20mg/day
Sites / Locations
- Brigham and Women's Hospital
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Patients with PSC
Arm Description
This is an open label study. All patients enrolled will receive a fecal microbiota transplantation.
Outcomes
Primary Outcome Measures
Adverse Event Frequency
Number of patients with reporting adverse events irregardless of severity
Comparison of Alkaline Phosphatase Pre and Post Transplant
The primary clinical study end point is the number of patients that achieve a 50% or more decrease serum alkaline phosphatase
Secondary Outcome Measures
Microbiome
Number of patients that experienced changes in the microbiome post FMT. Measured as similarity to the donor microbiome post FMT compared to their baseline sample
Full Information
NCT ID
NCT02424175
First Posted
April 18, 2015
Last Updated
August 26, 2019
Sponsor
Brigham and Women's Hospital
1. Study Identification
Unique Protocol Identification Number
NCT02424175
Brief Title
Fecal Microbiota Transplantation for the Treatment of Primary Sclerosing Cholangitis.
Official Title
Fecal Microbiota Transplantation for the Treatment of Primary Sclerosing Cholangitis.
Study Type
Interventional
2. Study Status
Record Verification Date
August 2018
Overall Recruitment Status
Completed
Study Start Date
February 1, 2016 (Actual)
Primary Completion Date
August 30, 2017 (Actual)
Study Completion Date
May 8, 2018 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Brigham and Women's Hospital
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
This is an open-label single-arm pilot study to measure the safety, microbiological and clinical impacts of Fecal Microbiota Transplantation (FMT) in patients with Primary Sclerosing Cholangitis (PSC). The investigators will prospectively enroll 10 PSC patients Stage 1 and 2 who also have concurrent inflammatory bowel disease Donor Stool from one healthy donor will be obtained from OpenBiome. OpenBiome is a nonprofit 501(c)(3) organization that provides hospitals with screened, filtered, and frozen material ready for clinical use
Detailed Description
Background and Significance:
Primary sclerosing cholangitis (PSC) is a progressive, chronic cholestatic liver disease characterized by inflammatory and fibrotic destruction of the intrahepatic and/or extrahepatic bile ducts. PSC will progress to biliary cirrhosis, portal hypertension and liver failure (1) . It is a common indication for liver transplantation. In up to 90% of patients, ulcerative colitis or Crohn's disease will also be present (2) . Medications used for the treatment of ulcerative colitis such as sulfasalazine, corticosteroids and azathioprine or 6-mercaptopurine have not been effective in reducing inflammation or bringing about remission in PSC (3) . A number of studies of other anti-inflammatory agents have failed to demonstrate any benefit. In standard dosing, ursodeoxycholic acid (UDCA) may be of benefit in delaying the progression of disease, although a recent study showed that high dose UDCA was not only ineffective, it may also be harmful (4) . Currently there is no medical therapy that has been shown to be effective in PSC and no therapy has won FDA approval for this indication.
It has been postulated that bacterial components may stimulate an aberrant immune response resulting in the perpetuation of the biliary inflammation seen in PSC. Bacteria gain access to the liver and biliary tree through translocation across an abnormal and inflamed intestinal mucosa into the portal venous system (5) . Studies have shown an increased risk of portal venous bacteremia in patients with PSC. Animal models have demonstrated that enteric dysbiosis can lead to hepatobiliary inflammation with various features of PSC (6) . The pathways through which bacteria might then induce the pathology characteristic of PSC are speculative.
Bacteria might cause direct injury through colonization, though studies have not identified any particular pathogen or a consistent set of bacteria. Another potential pathway may be that a certain set of bacteria generate secondary bile acids, such as deoxycholic acid and lithocholic acid, which are injurious to the biliary system (7) . We recently found an altered serum bile acid composition in patients with PSC compared to non-cholestatic controls. Treatment with UDCA in PSC patients decreases the concentration of the toxic primary bile acid chenodeoxycholic acid but also increased the toxic secondary bile acid lithocholic acid (Abstract DDW 2014). Alteration of the gut microbiota may minimize or eliminate this injury.
There is limited experience in the use of antibiotics in treating PSC. Metronidazole has been shown to result in improvement in liver function tests (8) . Oral vancomycin has also been advanced as a potentially promising therapy (9) . An initial report of three pediatric patients and a subsequent small, uncontrolled series of oral vancomycin in 14 children showed improvement in liver tests and symptoms (10, 11) . We recently completed a study of oral vancomycin was given to 10 adults with PSC found mild improvement in serum alkaline phosphatase levels (Abstract DDW 2011).
Fecal Biotherapy (FBT) also known as fecal transplantation or fecal microbiota transplant-involves the transfer of a donor's fecal flora (bacteria) to a recipient's colon. It has become widely accepted as the standard of care for recurrent Clostridium difficile 3 infection, with a cumulative cure rate of >90% and minimal adverse events (12) . In C. diff infection, prior exposure to antibiotics diminishes the normal colonic flora, allowing C. diff organism to proliferate and release toxin (13) . This bacterial environment is similar to the major shifts in microbial diversity seen in patients with IBD. Interestingly, when patients with IBD receive FBT for C. diff. infections, their outcomes are excellent, reinforcing the notion that the enteric flora have a strong influence in the enteric immune system (14) . We currently have a robust FMT clinical program for recurrent and refractory c.difficle infections with a cure rate > 90%. We have also recently participated in an open label clinical trial for the use of FMT in crohn's disease.
We hypothesize that for patients with PSC, fecal microbiota transplantation will correct a dysbiosis that has led to hepatobiliary inflammation leading to improvement in LFTs and slow progression to cirrhosis.
Specific Aims:
Specific Aim 1: Determine the impact of fecal microbiota transplantation on the intestinal microbiome of patients with primary sclerosis cholangitis with and without inflammatory bowel disease via 16s ribosomal RNA sequencing comparing delivery modalities (colonoscopy and capsules).
Hypothesis: Fecal microbiota transplantation will result in a sustained repopulation of the patient's microbiome that corresponds to the bacteria from the donor stool.
Specific Aim 2: Assess for clinical response in patients with PSC receiving FMT comparing delivery modalities (colonoscopy and capsules).
Hypothesis: Fecal microbiota transplantation will lead to a 50% reduction in liver biochemistries in patients with PSC.
Specific Aim 3: Assess bile salt metabolomics as a therapeutic biomarker for clinical response to fecal microbiota transplantation.
Hypothesis: A decrease in the production of toxic secondary bile acids (lithocholic and deoxycholic acid) will correlate with clinical response to fecal microbiota therapy
Primary Physiological Endpoint:
12
1. Recipient's fecal microbial diversity at 12 weeks after FMT, when compared to baseline using 16s ribosomal RNA.
Primary Clinical Endpoint
1. The primary study end point is them mean change serum liver biochemistries after 3 months of treatment as compared with baseline. Treatment success was defined as an improvement in serum alkaline phosphatase, total bilirubin, alanine aminotransferase (ALT), or aspartate aminotransferase (AST) by 50 % or greater.
Secondary Endpoints Metabolomics: Bile salt profiles of the samples and associated community structure of the fecal microbiome will be assessed as a measure of the interplay between host and gut microbiota. Stool and Serum will be analyzed using the metabolomics platform at the Broad Institute, targeting bile acids. Samples will be sent to the Broad Institute where we will use liquid chromatography tandem mass spectrometry (LC-MS) to measure endogenous bile salts and their metabolite levels in fecal supernatant. Water soluble metabolites will be extracted from feces as described by Saric et al while lipids will be extracted from lypophilized samples using isopropanol. Water soluble metabolites will be measured using ion pairing chromatography and hydrophilic interaction chromatography methods, and lipids and bile acids will be measured using C4 and C18 reversed phase chromatography methods. MultiQuant software (AB SCIEX) will be used for automated peak integration and manual review of peak quality prior to statistical analyses. The GenePattern (Broad Institute) and IPA (Ingenuity Systems) software will be used to analyze and visualize results.
Clinical Endpoints:
Mean change in Harvey Bradshaw Index (HBI) and PBC 40 score between week 0 and week 1, 4, 8, and 12. Percentage of patients in clinical remission (those with an HBI score at week 12 <5)
Mean change in Mayo Risk Score at week 12 compared to baseline. The Mayo Risk Score (MRS) for PSC is calculated based using the following formula: risk = (0.0295 * (age in years)) + (0.5373 * LN(total bilirubin in mg/dL)) - (0.8389 * (serum albumin in g/dL)) + (0.5380 * LN(AST in IU/L) + (1.2426 * (points for variceal bleeding)) If your Mayo Risk Score is less than or equal to 0 then you are in the "low" risk group. If your Mayo Risk Score is greater than 0 but less than 2 then you are in the "intermediate" risk group. If your Mayo Risk Score is greater than 2 then you are in the "high" risk group.
Safety Endpoints: Number and nature of adverse events at week 1, 4, 8, 12 and 24
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Sclerosing Cholangitis
Keywords
Fecal Transplant, Primary Sclerosing Cholangitis, Fecal Microbiota Transplantation
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
10 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Patients with PSC
Arm Type
Experimental
Arm Description
This is an open label study. All patients enrolled will receive a fecal microbiota transplantation.
Intervention Type
Biological
Intervention Name(s)
Fecal Microbiota Transplantation
Primary Outcome Measure Information:
Title
Adverse Event Frequency
Description
Number of patients with reporting adverse events irregardless of severity
Time Frame
6 months
Title
Comparison of Alkaline Phosphatase Pre and Post Transplant
Description
The primary clinical study end point is the number of patients that achieve a 50% or more decrease serum alkaline phosphatase
Time Frame
Baseline and 6 months
Secondary Outcome Measure Information:
Title
Microbiome
Description
Number of patients that experienced changes in the microbiome post FMT. Measured as similarity to the donor microbiome post FMT compared to their baseline sample
Time Frame
6 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Age 18 or older
Confirmed diagnosis of PSC (with a concurrent diagnosis of inflammatory bowel disease) characterized by a cholestatic liver condition of greater than 6 months duration with confirmatory cholangiographic findings, as well as an elevation of the serum alkaline phosphatase of greater than 1.5 times the upper limit of normal.
Exclusion Criteria:
Decompensated liver disease
Patients who were pregnant or breastfeeding
Use of concomitant immune modulators including methotrexate, mycophenolate mofetil, tacrolimus, cyclosporine, thalidomide, Interleukin-10, or Interleukin-11 within 4 weeks prior to receiving the FMT
Patients who are unable to give informed consent
Patients who are unable or unwilling to undergo colonoscopy with moderate sedation (>ASA class II)
Patients who have previously undergone FMT Patients who have a confirmed malignancy or cancer
Patients who are immunocompromised
Treatment within last 8 weeks with infliximab, adalimumab, certolizumab, natalizumab, vedolizumab or thalidomide
Antibiotic use within 2-months of start date
Participation in a clinical trial in the preceding 30 days or simultaneously during this trial
Probiotic use within 30 days of start date
Congenital or acquired immunodeficiencies
Other comorbidities including:Diabetes mellitus, cancer, systemic lupus, must be able to tolerate conscious sedation with colonoscopy
Chronic kidney disease as defined by a GFR <60mL/min/1.73m2 44
History of rheumatic heart disease, endocarditis, or valvular disease due to risk of bacteremia from colonoscopy
Steroid dose >20mg/day
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Joshua Korzenik, MD
Organizational Affiliation
Brigham and Women's Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Brigham and Women's Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
12. IPD Sharing Statement
Learn more about this trial
Fecal Microbiota Transplantation for the Treatment of Primary Sclerosing Cholangitis.
We'll reach out to this number within 24 hrs