Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT03796598 |
| Other study ID # |
GAST-001-18S |
| Secondary ID |
CX001076 |
| Status |
Completed |
| Phase |
Phase 1/Phase 2
|
| First received |
|
| Last updated |
|
| Start date |
July 29, 2019 |
| Est. completion date |
December 20, 2023 |
Study information
| Verified date |
December 2023 |
| Source |
VA Office of Research and Development |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial 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 HE and related 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.
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 (HE and related 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 patients with
cirrhosis and 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.
