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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
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Scientific title
GENESIS: Qualitative gut microbiome assessment and the role of faecal microbiota transplantation (FMT) on mortality in patients with severe alcoholic hepatitis
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Secondary ID [1]
312697
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None
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Universal Trial Number (UTN)
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Trial acronym
GENESIS
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Severe alcoholic hepatitis
334719
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Condition category
Condition code
Oral and Gastrointestinal
331279
331279
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0
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Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon
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Intervention/exposure
Study type
Interventional
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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.
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Intervention code [1]
329226
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Treatment: Drugs
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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.
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Control group
Active
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Outcomes
Primary outcome [1]
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Mortality
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Assessment method [1]
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This will be reported using Kaplan-Meier survival curve
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Timepoint [1]
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28-day mortality post randomization
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Secondary outcome [1]
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Mortality
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Assessment method [1]
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This will be reported using Kaplan-Meier survival curve
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Timepoint [1]
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90-day mortality post randomization
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Secondary outcome [2]
438327
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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.
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Assessment method [2]
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Peripheral blood sample collection to measure bilirubin, albumin, INR, creatinine, and calculation of MELD score based on the above values
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Timepoint [2]
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Baseline as well as days 28 and 90 post randomization
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Secondary outcome [3]
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Gut microbial changes will be reported as a composite end point combining the relative abundance analysis as well as functional profiling.
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Assessment method [3]
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Diversity analysis, taxonomic profiling, abundance analysis and functional profiling will be performed using both 'shotgun' metagenomic sequencing and 16S RNA profiling.
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Timepoint [3]
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Baseline as well as days 28 and 90 post randomization
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Secondary outcome [4]
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Adverse events
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Assessment method [4]
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Patients self reported adverse events such as abdominal bloating and diarrhoea will be captured using a 3-point scale (mild. moderate, severe) and recorded using the REDCAP tool
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Timepoint [4]
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Days 28 and 90 post randomization
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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.
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Minimum age
18
Years
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Maximum age
70
Years
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Sex
Both males and females
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Can healthy volunteers participate?
No
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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
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Randomised controlled trial
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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)
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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).
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
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Other design features
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Phase
Phase 1
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Type of endpoint/s
Safety/efficacy
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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.
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Recruitment
Recruitment status
Not yet recruiting
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Date of first participant enrolment
Anticipated
2/09/2024
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Actual
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Date of last participant enrolment
Anticipated
29/08/2025
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Actual
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Date of last data collection
Anticipated
29/11/2025
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Actual
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Sample size
Target
40
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Accrual to date
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Final
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Recruitment in Australia
Recruitment state(s)
SA
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Recruitment hospital [1]
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Lyell McEwin Hospital - Elizabeth Vale
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Recruitment hospital [2]
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The Royal Adelaide Hospital - Adelaide
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Recruitment hospital [3]
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The Queen Elizabeth Hospital - Woodville
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Recruitment hospital [4]
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Flinders Medical Centre - Bedford Park
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Recruitment postcode(s) [1]
42984
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5112 - Elizabeth Vale
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Recruitment postcode(s) [2]
42985
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5000 - Adelaide
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Recruitment postcode(s) [3]
42986
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5011 - Woodville
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Recruitment postcode(s) [4]
42987
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5042 - Bedford Park
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Funding & Sponsors
Funding source category [1]
317129
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Charities/Societies/Foundations
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Name [1]
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Royal Australasian College of Physician (RACP) research establishment fellowship grant
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Address [1]
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Country [1]
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Australia
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Primary sponsor type
Government body
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Name
Northern Adelaide Local Health Network (NALHN)
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Address
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Country
Australia
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Secondary sponsor category [1]
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None
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Name [1]
319393
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Address [1]
319393
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Country [1]
319393
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Ethics approval
Ethics application status
Approved
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Ethics committee name [1]
315881
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Central Adelaide Local Health Network HREC
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Ethics committee address [1]
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https://www.rah.sa.gov.au/research/for-researchers/central-adelaide-local-health-network-human-research-ethics-committee
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Ethics committee country [1]
315881
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Australia
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Date submitted for ethics approval [1]
315881
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01/07/2023
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Approval date [1]
315881
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26/09/2023
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Ethics approval number [1]
315881
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2021/HRE00215
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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.
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Trial website
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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Dr Mohamed Asif Chinnaratha
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Address
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Department of Gastroenterology, Lyell McEwin Hospital, Haydown road, Elizabeth Vale. SA 5112
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Country
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Australia
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Phone
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+61 403524471
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Fax
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Email
136082
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[email protected]
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Contact person for public queries
Name
136083
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Ms Evance Pakuwal
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Address
136083
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School of health and medical sciences, The University of Adelaide, SA 5005
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Country
136083
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Australia
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Phone
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+61 449992262
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Fax
136083
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Email
136083
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[email protected]
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Contact person for scientific queries
Name
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Ms Evance Pakuwal
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Address
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School of health and medical sciences, The University of Adelaide, SA 5005
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Country
136084
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Australia
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Phone
136084
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+61 449992262
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Fax
136084
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Email
136084
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[email protected]
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Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
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What data in particular will be shared?
De-identified clinical, biochemical and microbial data will be available
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When will data be available (start and end dates)?
From Dec 2025 for a period of 5 years
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Available to whom?
Reviewers, if required for cross-checking
Researchers for similar studies in future
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Available for what types of analyses?
Systematic reviews and Meta-analysis
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How or where can data be obtained?
Contacting Principal Investigator using the email:
[email protected]
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What supporting documents are/will be available?
No Supporting Document Provided
Results publications and other study-related documents
Documents added manually
No documents have been uploaded by study researchers.
Documents added automatically
No additional documents have been identified.
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