Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT02424175 |
| Other study ID # |
2014P002475 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 1/Phase 2
|
| First received |
|
| Last updated |
|
| Start date |
February 1, 2016 |
| Est. completion date |
May 8, 2018 |
Study information
| Verified date |
August 2018 |
| Source |
Brigham and Women's Hospital |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial 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
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:
1. 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)
2. 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
