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Trial registered on ANZCTR


Registration number
ACTRN12618001943235p
Ethics application status
Not yet submitted
Date submitted
8/11/2018
Date registered
30/11/2018
Date last updated
30/11/2018
Date data sharing statement initially provided
30/11/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Synbiotics for reducing infections after liver transplantation - a randomised trial
Scientific title
Effect of synbiotics on bacterial infection rates after liver transplantation: a double-blind, randomised, controlled trial
Secondary ID [1] 296546 0
Nil known
Universal Trial Number (UTN)
U1111-1223-5939
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
End-stage liver disease 310328 0
Condition category
Condition code
Oral and Gastrointestinal 309060 309060 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
One dose of Synbiotic 2000 Forte (Synbiotics AB, Sweden) or placebo taken before surgery, upon notification that a donor liver is available, and then a daily beginning as soon as possible after surgery and continuing for 14 days. Each dose (powder-containing sachet) of Synbiotic 2000 Forte contains 100 billion of each of Pediococcus pentosaceus 5-33:3, Leuconostoc mesenteroides 77:1, Lactobacillus paracasei ssp. Paracasei F19 and Lactobacillus plantarum 2362 plus four bioactive fibres (2.5 g each of beta-glucan, inulin, pectin and resistant starch). Compliance with treatment will be assessed for in-hospital patients by way of daily monitoring and after discharge using returned packaging.
Intervention code [1] 312856 0
Treatment: Other
Comparator / control treatment
Placebo (wheat-based non-fermentable fibre) will be provided in powder form in identical-appearing sachets to the synbiotics.
Control group
Placebo

Outcomes
Primary outcome [1] 308030 0
Bacterial infection rate over the first 30 postoperative days will be assessed according to the Centers for Disease Control (CDC) criteria and both culture positive and negative results will be documented..
Timepoint [1] 308030 0
Bacterial infections will be assessed daily for 30 days post-operatively..
Secondary outcome [1] 353736 0
Hospital length of stay as determined form discharge date in medical records..
Timepoint [1] 353736 0
Hospital discharge day.
Secondary outcome [2] 353737 0
Duration of antibiotic use will be determined by counting the number of days on which the patients received antibiotic therapy as detailed in their medical records.
Timepoint [2] 353737 0
Start date and end date over which antibiotic therapy was provided will be used to determine duration of antibiotic therapy.
Secondary outcome [3] 353738 0
C-reactive protein and pro- and anti-inflammatory cytokines (TNF-alpha, IL-6, IL-4, IL-10, IFN-gamma) will be assayed in plasma as a composite measure of inflammatory status..
Timepoint [3] 353738 0
Immediately prior to surgery and on postoperative days 2, 4, 7 and 14
Secondary outcome [4] 353739 0
Gut barrier function will assessed using an assay for secretory IgA .in stool samples.
Timepoint [4] 353739 0
Prior to surgery and on postoperative days 7 and 14.
Secondary outcome [5] 353740 0
Lipopolysaccharide-binding protein (LBP) and anti-endotoxin core antibodies (EndoCAb®) will be assayed in plasma as markers of gut bacterial translocation.
Timepoint [5] 353740 0
Immediately prior to surgery and on postoperative days 2, 4, 7 and 14.
Secondary outcome [6] 353741 0
After DNA extraction, 16S rRNA sequencing will be performed on stool samples to determine bacterial phylogeny and taxonomy.
Timepoint [6] 353741 0
Recruitment and postoperative day 14.
Secondary outcome [7] 353742 0
Death within the first 90 postoperative days, as determined from medical records, will be recorded to provide patient survival data..
Timepoint [7] 353742 0
Postoperative day 90.
Secondary outcome [8] 354321 0
Requirement for re-transplantation due to graft failure, as determined from medical records, will be recorded within the first 90 postoperative days to provide graft survival data.
Timepoint [8] 354321 0
Postoperative day 90.

Eligibility
Key inclusion criteria
Listed for elective liver transplantation by the NZ Liver Transplant Unit (NZLTU); written informed consent.
Minimum age
16 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Acute liver failure.

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)
Sealed opaque envelope.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Permuted block randomisation, stratified by whether re-transplant or not and whether patient is well-compensated or decompensated.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Efficacy
Statistical methods / analysis
Sample size calculation based on a reduction in bacterial infection rate from 58% (local data) to 25% with synbiotic treatment. No dropouts are expected.
The primary analysis will be carried out on an intent-to-treat basis and will employ logistic regression to compare bacterial infectious complication rates between the groups with adjustment for the stratification variables and baseline imbalance in potential confounders (eg., disease aetiology and disease severity).

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment outside Australia
Country [1] 21007 0
New Zealand
State/province [1] 21007 0
Auckland

Funding & Sponsors
Funding source category [1] 301126 0
University
Name [1] 301126 0
University of Auckland
Address [1] 301126 0
University of Auckland
Private Bag 92019
Auckland 1142
Country [1] 301126 0
New Zealand
Primary sponsor type
Individual
Name
Dr Lindsay Plank
Address
Department of Surgery
University of Auckland
Private Bag 92019
Auckland 1142
Country
New Zealand
Secondary sponsor category [1] 300747 0
None
Name [1] 300747 0
Nil
Address [1] 300747 0
Nil
Country [1] 300747 0

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 301878 0
Health and Disability Ethics Committees
Ethics committee address [1] 301878 0
Ministry of Health
133 Molesworth Street
PO Box 5013
Wellington 6011
Ethics committee country [1] 301878 0
New Zealand
Date submitted for ethics approval [1] 301878 0
30/01/2019
Approval date [1] 301878 0
Ethics approval number [1] 301878 0

Summary
Brief summary
Liver transplantation is the only effective treatment for patients with advanced liver disease. This is a major operation which is associated with a high rate of complications over the early postoperative period which prolongs stay in hospital and is a major cause of early death. These complications are predominantly bacterial infections. A combination of prebiotics and probiotics (synbiotics) provided for one day before and 14 days after transplant has been shown to almost eliminate bacterial infections. This remarkable result requires confirmation for this treatment to be accepted into routine clinical practice. We propose to conduct a similar study using the same synbiotic. If this simple and inexpensive treatment reduces infections after transplant we expect it to lead to routine use in our liver transplant unit and adoption by other centres worldwide. This result and the associated reductions in antibiotic use and length of hospital stay are significant both for patients undergoing this life-saving procedure and for the hospital, given the consequential cost savings. We will also examine potential mechanisms that might explain the purported benefits of this treatment.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 88410 0
A/Prof Lindsay Plank
Address 88410 0
Department of Surgery
University of Auckland
Private Bag 92019
Auckland 1142
Country 88410 0
New Zealand
Phone 88410 0
+6499236949
Fax 88410 0
Email 88410 0
l.plank@auckland.ac.nz
Contact person for public queries
Name 88411 0
A/Prof Lindsay Plank
Address 88411 0
Department of Surgery
University of Auckland
Private Bag 92019
Auckland 1142
Country 88411 0
New Zealand
Phone 88411 0
+6499236949
Fax 88411 0
Email 88411 0
l.plank@auckland.ac.nz
Contact person for scientific queries
Name 88412 0
A/Prof Lindsay Plank
Address 88412 0
Department of Surgery
University of Auckland
Private Bag 92019
Auckland 1142
Country 88412 0
New Zealand
Phone 88412 0
+6499236949
Fax 88412 0
Email 88412 0
l.plank@auckland.ac.nz

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Individual participant data (de-identified) underlying published results.
When will data be available (start and end dates)?
Immediately following publication, no end date.
Available to whom?
Researchers who provide a methodologically sound proposal.
Available for what types of analyses?
To achieve the aims in the approved proposal.
How or where can data be obtained?
Access subject to approvals by Principal Investigator.
What supporting documents are/will be available?
No other documents available
Summary results
No Results