Cirrhosis of the liver MedDRA version: 20.0 Level: LLT Classification code 10024667 Term: Liver cirrhosis System Organ Class: 100000004871
Conditions
Interventions
Product Name: Faecal Microbiota for Transplantation
Pharmaceutical Form: Gastroenteral liquid
Pharmaceutical form of the placebo: Gastroenteral liquid
Route of administration of the placebo: Intraduod
Sponsors
King's College London
King's College Hospital NHS Fundation Trust
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: • 18–75 years • Confirmed advanced cirrhosis of any aetiology with a MELD score between 10 and 16. The diagnosis of liver cirrhosis will be based on clinical, radiological, or histological criteria. • Patients with alcohol-related liver disease must have been abstinent from alcohol for a minimum of 6 weeks. • Patients must be deemed to have capacity to consent to study Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 32 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 32
Exclusion criteria
Exclusion criteria: • Severe or life-threatening food allergy • Pregnancy or breastfeeding • Patients treated for active variceal bleeding, infection, bacterial peritonitis, overt hepatic encephalopathy or acute-on-chronic liver failure within the past 14 days. • Patients who have received antibiotics in the past 14 days. • Active alcohol consumption of >20 grams/day. • Has had a previous liver transplant • Hepatocellular carcinoma outside of the Milan Criteria (2) • A history of prior gastrointestinal resection such as gastric bypass • Patient is not expected to survive the duration of the study (90 days). • Severe renal impairment (creatinine >150 µmol/L) • Inflammatory bowel disease (IBD) • Coeliac disease • HIV positive • Immunosuppression e.g. more than two weeks treatment with corticosteroids within 8 weeks of intervention, active treatment with tacrolimus, mycophenylate, azathioprine
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To assess whether stabilising gut dysbiosis with FMT in patients with advanced cirrhosis is both feasible and safe;Secondary Objective: The secondary objectives of the study are to provide preliminary evidence of efficacy for a larger randomised trial, with the purpose of: (i) Choosing the optimal primary outcome, and (ii)Estimating the parameters for sample size calculation. (a) As measured by an improvement in liver function tests at 90 days. (b) The development of complications of cirrhosis such as infection or bleeding. (c) The development of any infection during the 90-day follow up including chest, urine, stool, ascites (fluid accumulating in the abdominal cavity)and blood infection. (d) Stability of the transplant by comparing the composition of the patient's stool on day 7, 30 and day 90 with the donor stool. (e) Comparison of the bacterial composition of saliva with the stool at baseline, day 7, 30 and day 90 .;Primary end point(s): The primary endpoints of the study will be twofold: (i) Assessment of the feasibility of FMT c. Assess recruitment rates (including palatability of the intervention) d. Assess tolerability of FMT e.g reflux rates (ii) Assessment of the safety of FMT Success Criteria of Primary Endpoints: (i) Assessment of the feasibility and tolerability of FMT: • >25% consent rate (of all patients screened ~250) • >50% fulfil inclusion/exclusion criteria (of all patients consented ~64) • >80% randomised patients treated successfully and completing study up to day 90 (out of those randomised ~22) • Availability of obtaining sufficient stool donor samples for the study • Reflux rates of transplanted material <20% (e.g. foul taste, smell, nausea and vomiting, indigestion) • Significant gastrointestinal side effects (including diarrhoea, constipation, abdominal pain, flatulence and bloating) of <20% (ii) Assessment of the safety of FMT: •Incidence of any transmissable bacterial or viral infection that is deemed to have been acqui | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): The secondary objectives of the study are to provide preliminary evidence of efficacy for a larger randomised trial, with the purpose of: (i) Choosing the optimal primary outcome, and (ii) Estimating the parameters for sample size calculation. (a) As measured by an improvement in global liver synthetic function as assessed by the MELD score [a composite score of serum bilirubin, creatinine and INR] at 90 days. (b) Development of overt hepatic encephalopathy (grade 1 or more as measured by the Westhaven Criteria). (c) The development of organ failure (hypotension requiring inotropic support, respiratory failure requiring ventilator support or the development of acute kidney injury requiring renal replacement therapy) and infection (d) The development of any infection during the 90 day follow up including chest, urinary, stool, ascites and blood infection. (e) Stability of the transplanted gut microbiome by comparing the % composition of the stool microbiota on day 7, 30 and 90 with the donor microbiome. (f) Comparison of the composition of the salivary microbiome with the stool microbiome as a surrogate marker of gut dysbiosis at baseline, day 7, day 30 and day 90 . Mechanistic Outcome(s): (i) Plasma endotoxin and bacterial DNA quantification at 7, 30 and 90 days. (ii) Changes in faecal biomarkers (calprotectin, lactoferrin and M2-Pyruvate Kinase) at 7, 30 and 90 days. (iii) Changes in leucocyte function including measurement by lipopolysaccharide-induced macrophage tumour necrosis alpha production and immunological markers using flow cytometry (HLA-DR and TLR-4 expression) at 7, 30 and 90 days. ;Timepoint(s) of evaluation of this end point: Day 7, 30 and 90 post FMT/placebo administration | — |
Countries
United Kingdom
Contacts
Public ContactDr Charlotte Woodhouse
King's College London
Outcome results
None listed