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Trial registered on ANZCTR


Registration number
ACTRN12623001315606
Ethics application status
Approved
Date submitted
20/11/2023
Date registered
15/12/2023
Date last updated
29/07/2024
Date data sharing statement initially provided
15/12/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Do synbiotics reduce infections after bowel surgery?
Scientific title
Do perioperative synbiotics reduce postoperative infectious complications in patients undergoing elective colorectal resection?
Secondary ID [1] 310959 0
None
Universal Trial Number (UTN)
U1111-1300-3532
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Colorectal disease 332040 0
Postoperative infection 332042 0
Colorectal cancer 332043 0
Inflammatory bowel disease 334596 0
Condition category
Condition code
Surgery 328766 328766 0 0
Other surgery
Infection 328767 328767 0 0
Studies of infection and infectious agents
Oral and Gastrointestinal 328768 328768 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon
Oral and Gastrointestinal 328769 328769 0 0
Inflammatory bowel disease
Cancer 328943 328943 0 0
Bowel - Back passage (rectum) or large bowel (colon)

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The intervention is a synbiotic powder manufactured by the Sydney based company ProGood. Synbiotics are a combination of probiotics and prebiotics. Probiotics and synbiotics are classified as food supplements, not medicines.

The selected synbiotic product is called 'ProGood Original' and it contains the following probiotics and prebiotics:
- 15 billion Lactobacillus acidophilus
- 15 billion Bifidobacterium lactis
- Arabinoglobulin
- Inulin

This synbiotic product was selected because of the presence of two commonly used probiotic species (Lactobacillus acidophilus and Bifidobacterium lactis) that appeared to be less prevalent as sources of bacteraemia in case reports, as opposed to other probiotic species. Of note, probiotic-induced bacteraemia is a rare outcome with documentation in isolated case reports and often in patients with severe immunosuppression. Nonetheless, we wanted to focus on selecting a synbiotic product that was as safe as possible for our randomised controlled trial.

Participants randomised to the intervention group will be given a plain container containing 105g of synbiotic powder, and a scoop. They will be asked to take orally 5 grams (approximately 1 heaped teaspoon) synbiotic powder mixed in with a glass of water once daily for 1 week before surgery, in their own home. They will not take the synbiotic powder on the day of surgery, but they will bring the container to hospital for storage. They will take the synbiotic powder for two weeks after surgery. If they are nil by mouth after surgery due to a complication such as an ileus, they will not be required to take the powder on the days that they are nil by mouth. Instead, they will return to taking it when they are able to tolerate oral medications. Nursing staff will assist with administration of the synbiotic powder in hospital. The container will be required to be stored in a refrigerator to ensure that the synbiotic powder is stored at a temperature under 8 degrees. If the participant is discharged before two weeks after surgery, they will be given their synbiotic container to complete the two week course at home.

Participants will be provided with a chart to document days of successfully taking the synbiotic powder. The synbiotic container will be collected by the researcher at the end of the participant's three week course, to assess adherence.
Intervention code [1] 327391 0
Prevention
Comparator / control treatment
Participants randomised to the control group will be given a plain container containing 105g of maltodextrin powder as placebo. They will be asked to take orally 5 grams (approximately 1 teaspoon) maltodextrin powder mixed in with a glass of water once daily for 1 week before surgery. They will not take the maltodextrin powder on the day of surgery. They will take the maltodextrin powder for two weeks after surgery. If they are nil by mouth after surgery due to a complication such as an ileus, they will not be required to take the powder on the days that they are nil by mouth. Instead, they will return to taking it when they are able to tolerate oral medications. Nursing staff will assist with administration of the placebo powder in hospital. The container also be stored in a refrigerator at a temperature under 8 degrees. If the participant is discharged before two weeks after surgery, they will be given their placebo container to complete the two week course at home.

Participants will be provided with a chart to document days of successfully taking the placebo powder. The placebo container will be collected by the researcher at the end of the participant's three week course, to assess adherence.
Control group
Placebo

Outcomes
Primary outcome [1] 336575 0
Total postoperative infections within 30 days of surgery, calculated by the summation of the following infections and assessed as a composite outcome:
- Superficial incisional surgical site infection
- Deep incisional surgical site infection
- Organ/space surgical site infection (inclusive of intra-abdominal abscess and anastomotic leak)
- Pneumonia
- Urinary tract infection
- Peripheral line infection
- Central line infection
- Clostridium difficile colitis
- Sepsis of unclear cause
Timepoint [1] 336575 0
Prospectively daily reviews of clinical notes while participants are inpatients following surgery, and at 30 days following surgery, the clinical notes will be comprehensively reviewed to ensure all postoperative infection data has been collected.
Secondary outcome [1] 428856 0
Prolonged postoperative Ileus
Timepoint [1] 428856 0
Prospective daily reviews of clinical notes while participants are inpatients following surgery, and assessment of clinical notes at 30 days of surgery to assess for evidence of prolonged postoperative ileus.
Secondary outcome [2] 429034 0
Time to first bowel motion
Timepoint [2] 429034 0
Prospective daily reviews of clinical notes while participants are inpatients following surgery, and analysis of clinical notes at 30 days following surgery to assess for documentation of time to first bowel motion.
Secondary outcome [3] 429035 0
Hospital length of stay (days)
Timepoint [3] 429035 0
Prospective daily analysis of clinical notes and a dedicated analysis of clinical notes at 30 days following surgery to determine hospital length of stay in days.
Secondary outcome [4] 429036 0
Duration of postoperative antibiotics (days)
Timepoint [4] 429036 0
Prospective daily analysis of clinical notes and a dedicated analysis of clinical notes at 30 days following surgery to determine duration of postoperative antibiotics in days.
Secondary outcome [5] 429039 0
Return to theatre within 30 days of surgery
Timepoint [5] 429039 0
Prospective daily analysis of clinical notes and a dedicated analysis of clinical notes at 30 days following surgery to assess for return to theatre within 30 days of surgery.
Secondary outcome [6] 429047 0
Readmission within 30 days of surgery
Timepoint [6] 429047 0
Dedicated analysis of clinical notes at 30 days following surgery to assess for readmission over this period.
Secondary outcome [7] 429048 0
Comprehensive Complication Index (CCI)
Timepoint [7] 429048 0
Data will be collected prospectively on daily reviews of clinical notes, and a dedicated analysis will be performed at 30 days following surgery - at which time, the CCI will be calculated.
Secondary outcome [8] 429049 0
Mortality within 30 days of surgery
Timepoint [8] 429049 0
Dedicated analysis of clinical notes at 30 days following surgery to assess for mortality within this period.
Secondary outcome [9] 429050 0
Change in gut microbiome on metagenomic analysis of stool specimens
Timepoint [9] 429050 0
Stool specimens will be collected from a subset of participants within our Middlemore cohort that are able to provide samples at three time periods: 1) prior to commencing the powder, 2) prior to bowel preparation and surgery (approximately preoperative day 1), 3) after surgery (approximately postoperative day 5).
Secondary outcome [10] 438002 0
Prevalence of bacteria present in positive culture samples within 30 days (from cultures sent to the laboratory e.g. wound swabs, blood cultures).
Timepoint [10] 438002 0
Secondary outcome [11] 438003 0
Prevalence of bacteria present in positive culture samples within 30 days (from cultures sent to the laboratory e.g. wound swabs, blood cultures).
Timepoint [11] 438003 0
Within 30 days of surgery.
Secondary outcome [12] 438004 0
Absolute values and trends in white cell count following surgery.
Timepoint [12] 438004 0
Within 30 days of surgery.
Secondary outcome [13] 438005 0
Absolute values and trends in white cell count following surgery.
Timepoint [13] 438005 0
From postoperative day 1 to postoperative day 5.
Secondary outcome [14] 438006 0
Absolute values and trends in neutrophil count following surgery.
Timepoint [14] 438006 0
From postoperative day 1 to postoperative day 5.
Secondary outcome [15] 438007 0
Absolute values and trends in neutrophil count following surgery.
Timepoint [15] 438007 0
From postoperative day 1 to postoperative day 5.
Secondary outcome [16] 438008 0
Absolute values and trends in C-reactive protein (CRP) following surgery.
Timepoint [16] 438008 0
From postoperative day 1 to postoperative day 5.
Secondary outcome [17] 438009 0
Absolute values and trends in C-reactive protein (CRP) following surgery.
Timepoint [17] 438009 0
From postoperative day 1 to postoperative day 5.
Secondary outcome [18] 438010 0
Absolute values and trends in procalcitonin levels following surgery (only within the Middlemore Hospital cohort).
Timepoint [18] 438010 0
From postoperative day 1 to postoperative day 5.
Secondary outcome [19] 438011 0
Absolute values and trends in procalcitonin levels following surgery (only within the Middlemore Hospital cohort).
Timepoint [19] 438011 0
From postoperative day 1 to postoperative day 5.
Secondary outcome [20] 438012 0
Probiotic-induced bacteraemia within 30 days of surgery
Timepoint [20] 438012 0
From postoperative day 1 to postoperative day 5.
Secondary outcome [21] 438013 0
Probiotic-induced bacteraemia within 30 days of surgery
Timepoint [21] 438013 0
From date of surgery to 30 days following surgery.
Secondary outcome [22] 438014 0
Withdrawal from study
Timepoint [22] 438014 0
From date of surgery to 30 days following surgery.
Secondary outcome [23] 438015 0
Withdrawal from study
Timepoint [23] 438015 0
From date of surgery to 30 days after surgery
Secondary outcome [24] 438016 0
Compliance to powder.
Timepoint [24] 438016 0
From date of surgery to 30 days after surgery
Secondary outcome [25] 438017 0
Compliance to powder.
Timepoint [25] 438017 0
Preoperative days 7 to 1, postoperative days 1 to 14.
Secondary outcome [26] 438018 0
Participant reported outcomes - tolerance and experience of side effects will be assessed together as a composite secondary outcome.
Timepoint [26] 438018 0
Preoperative days 7 to 1, postoperative days 1 to 14.
Secondary outcome [27] 438019 0
Participant reported outcomes - tolerance and experience of side effects will be assessed together as a composite secondary outcome.
Timepoint [27] 438019 0
At 30 days following surgery.

Eligibility
Key inclusion criteria
- Adult patients undergoing elective colorectal resection for malignant or benign conditions at selected trial sites in New Zealand.
- Elective colorectal resection includes surgical planning for anastomosis +/- stoma formation.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Patients undergoing acute or emergency operation
- Patients not receiving an anastomosis
- Patients undergoing surgical planning to remove all of their colon
- Not enough time for patient to have 3 days or more preoperative powder (due to short time-frames between clinic and date of surgery)
- Intolerance to probiotics or synbiotics
- Unwilling to provide informed consent after discussions held in the participant's preferred language
- Development of acute pancreatitis during the clinical trial
- Severe immunosuppression with neutrophils less than 1 prior to enrollment in the clinical trial

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
An independent unblinded research assistant will be responsible for allocation concealment, and will inform the probiotic company which container to label as A or B. The rest of the research team will be blinded to this decision. The containers will look indistinguishable from each other and will be labelled as A or B. The participants, investigators and healthcare professionals will not be able to establish which group an individual has been allocated to. The appropriate container will be provided to the participant following randomization.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Permuted block randomisation with variable block sizes between 4 to 6, stratified by hospital site, will be computer generated and uploaded to REDCap by the research team's biostatistician.
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
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
The coordinating investigator will perform the statistical analysis for comparing the intervention and control group for all primary and secondary outcomes while blinded. A biostatistician from The University of Auckland will provide advisory support. R will be used as the statistical analysis software.

Statistical significant will be set at the 5% threshold and all tests will be two-sided. An intention-to-treat analysis will be performed as the default. Summary statistics will be presented as either proportions, mean (standard deviation) or median (interquartile range), as appropriate.

Baseline characteristics will be performed comparing the intervention and control groups to ensure that randomisation has resulted in the two groups are sufficiently comparable.

Categorical outcome data comparing intervention and control groups will be analysed using Fisher's exact test.

Continuous outcome data comparing intervention and control groups will be visualised using histograms, and depending on whether the data displays a normal distribution or not, parametric (independent T-test) or non-parametric (Mann-Whitney U) tests will be utilised.

Postoperative days 1, 2, 3, 4 and 5 blood tests for white cell count, neutrophils, C-reactive protein (and procalcitonin from the Middlemore Hospital cohort) will be displayed graphically and compared as continuous variables.

Metagenomic sequencing analysis will be performed by the Liggins Institute, using their previous described statistical methods.

Multivariable logistic regression modelling, adjusting for potential major confounders, will be performed for the primary outcome measure of total postoperative infections. An estimate of effect will be provided as a relative risk.

A major confounder is the use of mechanical bowel preparation (MBP) and oral antibiotics (OABs). There are four different possible regimens:
1. NO MBP + NO OABs
2. MBP + NO OABs
3. NO MBP + OABs (note this is an unlikely clinical scenario)
4. MBP + OABs

Subgroup analyses will be performed to explore whether the estimated treatment effect of synbiotics varies significantly between the following subgroups:
- Colon versus rectal
- Cancer versus non-cancer
- Open versus laparoscopic
- No MBP + no OAB versus MBP + OAB
- MBP + no OAB versus MBP + OAB

Sensitivity analyses will be performed to adjust for baseline covariates using multivariable regression modelling, and a per-protocol analysis using Fisher’s exact or independent T-test, as appropriate.

For Comprehensive Complication Index (CCI) interpretation, a reduction in 10 points will be regarding as a minimum clinically significant difference.

Recruitment
Recruitment status
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] 25976 0
New Zealand
State/province [1] 25976 0

Funding & Sponsors
Funding source category [1] 315218 0
Government body
Name [1] 315218 0
Health Research Council of New Zealand
Country [1] 315218 0
New Zealand
Primary sponsor type
University
Name
The University of Auckland
Address
85 Park Road, Grafton, Auckland 1023
Country
New Zealand
Secondary sponsor category [1] 317289 0
None
Name [1] 317289 0
Address [1] 317289 0
Country [1] 317289 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 314142 0
Northern B Health and Disability Ethics Committee.
Ethics committee address [1] 314142 0
Ethics committee country [1] 314142 0
New Zealand
Date submitted for ethics approval [1] 314142 0
20/12/2023
Approval date [1] 314142 0
22/03/2024
Ethics approval number [1] 314142 0
2024 FULL 18418

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 130566 0
Dr Claudia Paterson
Address 130566 0
South Auckland Clinical Campus, Level 2, North Wing, Esme Green Building 30, Middlemore Hospital, 100 Hospital Road, Otahuhu, Auckland 2025
Country 130566 0
New Zealand
Phone 130566 0
+64 9 276 0044
Fax 130566 0
Email 130566 0
Contact person for public queries
Name 130567 0
Claudia Paterson
Address 130567 0
South Auckland Clinical Campus, Level 2, North Wing, Esme Green Building 30, Middlemore Hospital, 100 Hospital Road, Otahuhu, Auckland 2025
Country 130567 0
New Zealand
Phone 130567 0
+64 9 276 0044
Fax 130567 0
Email 130567 0
Contact person for scientific queries
Name 130568 0
Claudia Paterson
Address 130568 0
South Auckland Clinical Campus, Level 2, North Wing, Esme Green Building 30, Middlemore Hospital, 100 Hospital Road, Otahuhu, Auckland 2025
Country 130568 0
New Zealand
Phone 130568 0
+64 9 276 0044
Fax 130568 0
Email 130568 0

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
A de-identified dataset will be made available to researchers working in this field on request.
When will data be available (start and end dates)?
Data will be available following completion of this trial - anticipated start date: 01/03/2025. This data will be available for the next 10 years (under storage at the University of Auckland as per the current local data management policy).
Available to whom?
Researchers in this field that request and demonstrate interest in progressing this field.
Available for what types of analyses?
Researchers in this field wishing to undertake meta-analyses or similar projects.
How or where can data be obtained?
Via contacting Dr Claudia Paterson (PhD Candidate) at [email protected]


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.