In this study we would like to investigate whether repetitive allogeneic (lean donor) fecal transplantations can reduce liversteatosis and if so which (small) intestinal bacteria cause this inflammation in the liver resulting in subsequent chronic…
ID
Source
Brief title
Condition
- Endocrine and glandular disorders NEC
- Hepatic and hepatobiliary disorders
- Arteriosclerosis, stenosis, vascular insufficiency and necrosis
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Effect op NAFLD/NASH:
- Primary outcome is reducting in hepatic steatosis without worsening of
fibrosis as determined by liverbiopsy (Bruntclassification) and liver MRI after
6 months
Secondary outcome
- Changes in bacerial composition of small intestine, large intestine and liver
- Changes in vascular function (normalized wall index en mean wall thickness as
measured with 3T MRI of the carotid artery
- Changes in inflammatory tone (plasma TMAO/betaine and TNFalfa/CD68 expression
on monocyte and in subcutanous adipose tissue)
Background summary
Non alcoholic fatty liver disease (NAFLD) is intricately related to obesity,
insulin resistentance and dyslipidemia. The worldwide prevalence of this
disease is increasing at a rapid pace. When NAFLD progresses into non alcoholic
steatohepatitis (NASH) it is strongly associated with increased cardiovascular
disease risk as well as that it can lead to livercirrhosis and subsequent
livercancer. It is expected that within 20 years this will be the number 1
reason for orthotopic livertransplantation. Despite several efforts, there is
no effective treatment option for NASH .
Recent animal and human data have implicated that the intestinal microbiota may
play an important rol in the development of NAFLD/NASHas well obesity thus
implying a potential therapeutic treatment target. Underlying mechanisms
including translocation of (small) intestinal bacterial strains that are
transported via the blood to the lever and there cause chronic inflammation
resulting in NASH. Earlier research from our group has shown that fecal
transplantation using a lean donor (allogeneic fecaltransplant cures
clostridium difficile associated diarrhea and reduces chronic inflammation and
insulin resistance in obese subjects . Using an algorithm to calculate NASH in
obese subjects treated with allogeneic fecal transplantation showed a
significant reduction in NASH upon treatment .We thus hypothesize that
repetitive fecal transplantation can normalize (small) intestinal bacterial
composition therefore reducing bacterial translocation and thus inflammation.
This could provide us with novel therapeutic targets (bacterial strains) to
treat NASH.
Study objective
In this study we would like to investigate whether repetitive allogeneic (lean
donor) fecal transplantations can reduce liversteatosis and if so which (small)
intestinal bacteria cause this inflammation in the liver resulting in
subsequent chronic inflammation and vascular dysfunction.
Study design
This is a double blind single center randomized controlled trial.
Patients will be randomized to the following 2 treatment arms:
1. three allogenic (lean donor) fecal transplantations (at baseline, 8 and 16
weeks)
2. three autologous (own) fecal transplantations (at baseline, 8 and 16 weeks)
Intervention
Patients will be treated with infusion of either allogenic or autologous
microbial transplantion by duodenal tube after bowel lavage.
Fecal transplantation therapy (week 0, 8 and 16 weeks) consists of:
1. Morning stool sample is collected by recipient & donor and handed over to
study phycisian in the AMC for processing
2. Meanwhile, gastroduodenoscopy ( 0 en 6 months including biopsies) or
Coretrack at 2 en 4 months) positioning of the duodenal tube will be performed,
including an abdominal X-ray(only at 0. and 6 months) to ensure the
intraduodenal position of the tube.
4. Thereafter, bowel lavage with 2-3 liters of Klean-prep
(macrogol/electrolytes) through the duodenal tube (according to standard
protocols) will be performed to ensure complete bowel lavage (duration 3-4
hours)
5. Finally, allogenic or autologous feces mixed in ~ 500 cc saline (filtered, <
2 hours after processing) will be infused in the duodenum through positioned
duodenal tube.
Study burden and risks
in the last 5 years we have performed over 200 fecal transplantations at the
AMC in several patientgroups without seeing any short/long term complications .
Although in theory there is always the risk of transferring (unknown)
infectious diseases (just like with bloodtransfusions), however using a
thorough donor screening protocol can minize this risk. Risk of complications
during gastroduodenoscopy and liver biopsy is low (<0.01%). There is currently
no effective treatment for NASH and this disease is strongly associated with
increased cardiovascular disease as well as cirrhosis and livercancer, Since
at the one hand animal studies have implicated translocation of intestinal
microbiota in the developement of NASH and on the other we have shown
beneficial metabolic effect of fecal transplantation in human obese subjects ,
we hypothesize that this study can provide us with pathophysiological
mechanisms leading to a potential treatment for NASH We therefore think that
the data from this study are very important to understand and treat NASH in the
future that they outweight the intermediate risk of participating in this
study
Meibergdreef 9
Amsterdam 1105 AZ
NL
Meibergdreef 9
Amsterdam 1105 AZ
NL
Listed location countries
Age
Inclusion criteria
Recipients:
- Caucasian
- Male or postmenopausal female
- Aged 21-69 years
- Scheduled for liver biopsy on clinical indication (suspicion of NASH)
- No concomitant medication;Donors
- Male / postmenopausal female
- Lean (BMI 20-25 kg/m2)
- Aged 21-69 years
- No concomittant medication
Exclusion criteria
Recipients:
- Cardiovascular disease
- Cholecystectomy
- Use of any concomittant medication including PPI , oral anticonceptivesand antibiotics in the past three months
- Plasma ALAT / ASAT > 2.5 times the upper limit of normal
- Other causes of liver disease besides NAFLD/NASH (e.g. hemachromatosis, auto-immune hepatitis, viral hepatitis, alcoholic steatohepatitis).
- History of heavy alcohol use (>12 to 15 gram / day).
- Renal disease (creatinin clearance < 60 ml/min)
- Fasting glucose > 13.3 mmol/l
- History of anaphylaxis, known allergy for gadolinium of other contrast agents, or other contra-indication for the use of gadolinium;Donors:
- Diarrhea
- Cholecystectomy
- Unsafe sex practice
- Any medication use including PPI, oral anticonceptives and antibiotics in the past three months
- Serological presence of HIV, hepatitis A, B and/or C, active cytomegalovirus (CMV), active Eppstein-Barr virus (EBV), lues, amoebiasis or strongyloides
- Presence of fecal bacterial pathogens (Salmonella, Shigella, Campylobacter, Yersinia, enteropathogenic E. coli), transmittable viruses (Rotavirus, Norovirus, enterovirus, parechovirus, sapovirus, adenovirus 40/41/52, astrovirus) or parasites
- Positive C. difficile stool test
- Individuals with an increased risk for one of the above conditions (e.g. homosexual contacts, recent blood transfusions) will be excluded.
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL45172.018.13 |