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Trial registered on ANZCTR


Registration number
ACTRN12624001051538
Ethics application status
Approved
Date submitted
10/08/2024
Date registered
29/08/2024
Date last updated
29/08/2024
Date data sharing statement initially provided
29/08/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
Faecal microbiota transplantation in patients with severe alcoholic hepatitis
Scientific title
GENESIS: Qualitative gut microbiome assessment and the role of faecal microbiota transplantation (FMT) on mortality in patients with severe alcoholic hepatitis
Secondary ID [1] 312697 0
None
Universal Trial Number (UTN)
Trial acronym
GENESIS
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Severe alcoholic hepatitis 334719 0
Condition category
Condition code
Oral and Gastrointestinal 331279 331279 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Faecal microbiota transplantation (FMT) using oral FMT capsules.
Those randomised to FMT arm will have 6 capsules/day for the first 6 days (36 capsules in total) amounting to ~25g of stool in total. Most patiets will be in-patients during the treatment period and capsule swallow will be directly observed. Those patients who are discharged prior to day 6 will have a phone consultation by the study co-ordinator every morning to confirm taking the capsules till they complete the 36 capsules.
Intervention code [1] 329226 0
Treatment: Drugs
Comparator / control treatment
Those randomised to the Prednisolone group will receive Prednisolone 40mg/ day for the first 7 days following which Lille score will be calculated. If they are responders, the treatment will continue for a total duration of 4 weeks and then rapidly weaned down (25mg for 4 days followed by 12.5mg for 3 days and then ceased). For non-responders on Day 7, treatment will be stopped, they will continue to be monitored and included in the final analysis.
Control group
Active

Outcomes
Primary outcome [1] 339039 0
Mortality
Timepoint [1] 339039 0
28-day mortality post randomization
Secondary outcome [1] 438326 0
Mortality
Timepoint [1] 438326 0
90-day mortality post randomization
Secondary outcome [2] 438327 0
Liver synthetic function will be assessed using the composite Model for End-stage Liver Disease (MELD) score using the variables bilirubin, International Normalized Ration (INR) and creatinine.
Timepoint [2] 438327 0
Baseline as well as days 28 and 90 post randomization
Secondary outcome [3] 438328 0
Gut microbial changes will be reported as a composite end point combining the relative abundance analysis as well as functional profiling.
Timepoint [3] 438328 0
Baseline as well as days 28 and 90 post randomization
Secondary outcome [4] 438329 0
Adverse events
Timepoint [4] 438329 0
Days 28 and 90 post randomization

Eligibility
Key inclusion criteria
Individuals meeting the clinical and biochemical criteria for severe alcoholic hepatitis as defined by:
1) Rapid development or worsening jaundice and liver related complications
2) Serum total bilirubin > 80 mmol/L, ALT and AST levels <400 U/L, with the AST/ALT ratio >1.5
3) Documentation of persistent heavy alcohol use until 8 weeks before onset of symptoms
4) Average alcohol consumption of >80g/ day for men and >60g/day for women
5) Maddrey’s Discriminant Function (DF) score greater than or equal to 32 AND MELD score 21-30

Liver biopsy is not required to confirm the diagnosis of severe alcoholic hepatitis.
Minimum age
18 Years
Maximum age
70 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1) Cessation of alcohol consumption for >2 months prior to randomization
2) Concomitant liver disease including viral hepatitis, autoimmune hepatitis, drug induced liver injury, acute pancreatitis, HIV and active tuberculosis
3) High grade encephalopathy requiring endotracheal intubation for airway support
4) Uncontrolled upper gastrointestinal bleeding
5) Acute kidney injury (AKI) or hepato-renal syndrome (HRS) with serum creatinine >500 mmol/L or requirement for renal replacement therapy
6) Hepatic or extrahepatic malignancy
7) Pregnancy or nursing
8) Uncontrolled infections or sepsis
9) Anaphylactic food allergy
10) Prebiotic, probiotic or antibiotic use within 4 weeks of enrolment
11) Participant unable to provide informed consent

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
This is an open label, randomised controlled trial. Following informed consent, randomization (20 patients in each arm) will occur via phone call to a third party (Central randomization by phone)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
A stratified, block randomization (block size of 2) will be performed, and stratification will be based on the Maddrey’s DF (32-60 and >60).
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 1
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Analysis will be performed on an intention-to-treat basis. Survival analysis will be performed using cox regression with results presented as Kaplan Meier survival curves. Wilcoxon signed rank test will be used to calculate the changes in Maddrey DF and MELD scores from baseline to day 28 and 90.

For microbiome analysis, between-group comparison of alpha diversity metrics will be performed using Mann-Whitney test. Alterations in microbiota composition will be analysed by a permutation-based ANOVA (PERMANOVA) test, and the contribution of specific taxa to between group compositional differences will be determined using a Mann-Whitney test with false discovery rate (FDR) correction for multiple comparisons.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
2/09/2024
Actual
Date of last participant enrolment
Anticipated
29/08/2025
Actual
Date of last data collection
Anticipated
29/11/2025
Actual
Sample size
Target
40
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 26920 0
Lyell McEwin Hospital - Elizabeth Vale
Recruitment hospital [2] 26921 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [3] 26922 0
The Queen Elizabeth Hospital - Woodville
Recruitment hospital [4] 26923 0
Flinders Medical Centre - Bedford Park
Recruitment postcode(s) [1] 42984 0
5112 - Elizabeth Vale
Recruitment postcode(s) [2] 42985 0
5000 - Adelaide
Recruitment postcode(s) [3] 42986 0
5011 - Woodville
Recruitment postcode(s) [4] 42987 0
5042 - Bedford Park

Funding & Sponsors
Funding source category [1] 317129 0
Charities/Societies/Foundations
Name [1] 317129 0
Royal Australasian College of Physician (RACP) research establishment fellowship grant
Country [1] 317129 0
Australia
Primary sponsor type
Government body
Name
Northern Adelaide Local Health Network (NALHN)
Address
Country
Australia
Secondary sponsor category [1] 319393 0
None
Name [1] 319393 0
Address [1] 319393 0
Country [1] 319393 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 315881 0
Central Adelaide Local Health Network HREC
Ethics committee address [1] 315881 0
https://www.rah.sa.gov.au/research/for-researchers/central-adelaide-local-health-network-human-research-ethics-committee
Ethics committee country [1] 315881 0
Australia
Date submitted for ethics approval [1] 315881 0
01/07/2023
Approval date [1] 315881 0
26/09/2023
Ethics approval number [1] 315881 0
2021/HRE00215

Summary
Brief summary
Alcoholic hepatitis is an acute deterioration in liver function in the context of excessive alcohol consumption. Those with severe Alcoholic Hepatitis (sAH) have a high short-term mortality. Prednisolone has a modest efficacy in reducing short-term mortality in sAH, but it cannot used in many patients because of contraindications, and if used, it is associated with increased risk of infections. The gut-liver axis modulation through healthy donor faecal microbiota transplantation (FMT) has been proposed as a therapeutic alternative in managing patients with sAH. FMT has been shown to alleviate gut dysbiosis and restore gut microbial diversity. The role of orally delivered FMT capsules in sAH is yet to be explored.

We hypothesize that orally delivered FMT capsules is a safe and efficacious therapy in patients with sAH.

Aims of this study are: (i) to assess the gut microbial signatures in those with sAH, followed by (ii) A pilot randomised controlled trial to assess the safety and efficacy (primary outcome: 28- day mortality) of FMT compared to prednisolone in patients with sAH.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 136082 0
Dr Mohamed Asif Chinnaratha
Address 136082 0
Department of Gastroenterology, Lyell McEwin Hospital, Haydown road, Elizabeth Vale. SA 5112
Country 136082 0
Australia
Phone 136082 0
+61 403524471
Fax 136082 0
Email 136082 0
[email protected]
Contact person for public queries
Name 136083 0
Ms Evance Pakuwal
Address 136083 0
School of health and medical sciences, The University of Adelaide, SA 5005
Country 136083 0
Australia
Phone 136083 0
+61 449992262
Fax 136083 0
Email 136083 0
[email protected]
Contact person for scientific queries
Name 136084 0
Ms Evance Pakuwal
Address 136084 0
School of health and medical sciences, The University of Adelaide, SA 5005
Country 136084 0
Australia
Phone 136084 0
+61 449992262
Fax 136084 0
Email 136084 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
De-identified clinical, biochemical and microbial data will be available
When will data be available (start and end dates)?
From Dec 2025 for a period of 5 years
Available to whom?
Reviewers, if required for cross-checking
Researchers for similar studies in future
Available for what types of analyses?
Systematic reviews and Meta-analysis
How or where can data be obtained?
Contacting Principal Investigator using the email: [email protected]


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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