Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12623001273673
Ethics application status
Approved
Date submitted
16/10/2023
Date registered
7/12/2023
Date last updated
7/12/2023
Date data sharing statement initially provided
7/12/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Effect of 8-week prebiotic supplementation on gut health in Prosthetic Joint Infection patients
Scientific title
An 8-week randomised double blind placebo-controlled trial assessing the effect of a prebiotic fiber versus corn starch on gut microbiome and surgical outcomes of patients with prosthetic joint infection
Secondary ID [1] 310055 0
None
Universal Trial Number (UTN)
Trial acronym
PENGUIN Study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Prosthetic Joint Infection 330593 0
Gut Dysbiosis 330594 0
Condition category
Condition code
Infection 327427 327427 0 0
Studies of infection and infectious agents
Diet and Nutrition 328636 328636 0 0
Other diet and nutrition disorders
Musculoskeletal 328637 328637 0 0
Other muscular and skeletal disorders
Surgery 328638 328638 0 0
Other surgery
Inflammatory and Immune System 328702 328702 0 0
Other inflammatory or immune system disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a randomized double blind placebo controlled study.
The participants will be recruited when they present to the Department of Orthopaedics for the treatment of Prosthetic Joint Infection (PJI). Patients who are planned to undergo two stage revision for the treatment of PJI will be approached face to face to discuss participation in the study by the treating surgeons. Potential participants may have family members or others present to discuss the process. The consent process will primarily be done by the registrar on-call when patients are seen and admitted to the hospital or when patients are seen in the outpatient clinic by the Orthopaedic doctors. Each enrolled participant will be assigned a code and randomised to the placebo group or the control group using a computer-generated block randomisation plan by one of the study investigator. Treating surgeon will be blinded to the randomization plan.
Once enrolled, all patients will undergo standard-of-care treatment for their PJI which includes optimization by a multidisciplinary team comprising of anaesthetist, infectious diseases consultant, orthopaedic doctors and joint replacement nurses as required. All patients will be given the required antibiotic therapy. This is independent of participant consent.
After the first stage of revision surgery, the recruited patients are randomized to intervention group that will be adminstered one sachet of a prebiotic fiber supplement (64g) either mixed with milk or juice or food of their choice before or with the meals once a day for 8-weeks.
All in-patients will be given the product with breakfast, supervised by the study dietician.

On discharge, the patients will be given the clinical supplies to complete the supplementation period of daily for 8 weeks with a copy of printed instructions. All patients will be asked to bring the empty sachets to their follow-up appointments to record compliance. One of the investigators will ensure compliance through regular phone calls.
Supplementation will start soon after the first stage revision when the patient is well enough to take oral foods. Some patients are sick and need longer ICU stay, hence the start of supplementation will vary from case to case.

The supplementation phase will be for 8-weeks. The first stage revision surgery comprises of inserting a temporary antibiotic coated spacer for treatment of local infection. After the first stage revision, patients will be monitored for infection resolution through physical and blood examinations. Once the blood tests confirm infection resolution, which may vary from 12-24 weeks postop, patients will undergo second stage revision surgery which is the definitive replacement surgery and involves inserting a permanent prosthesis.
Intervention code [1] 326464 0
Treatment: Other
Comparator / control treatment
The placebo will be corn based custard powder in equivalent sachets
Control group
Placebo

Outcomes
Primary outcome [1] 335290 0
Stool Analysis
pH and short-chain fatty acids will be measured using published protocols. Stool DNA will be extracted following publsihed protocols. The abundance of known enteric pathogens will be assessed by real-time polymerase chain reaction. Deep sequencing of the DNA will be done to assess the nature of the microbiota. Specifically, laboratory assessments will focus on the abundance of the following bacteria in the stool samples: Prevotella, Ruminococcus, Lactobacillus, and Bifidobacterium and aggressive bacteria. Fecal biomarkers including fecal calprotectin will be measured with ELISA.

This is a composite primary outcome which includes all the above stated outcomes.
Timepoint [1] 335290 0
A single stool specimen will be collected on four separate occasions:
1. After the first stage revision before the start of supplementation (baseline),
2. At four weeks post-supplementation.
3. At eight weeks post-supplementation.
4. At the time of second surgery, The nursing staff will collect an additional stool specimen from the participants.

Primary endpoint is 8 weeks

Note: Please note that the time of second surgery is not fixed, it will vary from patient to patient and ranges anywhere between 12 weeks- 24 weeks after first stage surgery. The time is dependent on absence of infection confirmed using blood tests and/or joint aspirate and will vary form patient to patient.
Primary outcome [2] 335291 0
Change in Interleukin-6 (IL-6) will be assessed by Enzyme-Linked Immunosorbent Assay (ELISA)
Timepoint [2] 335291 0
1. After the first stage revision before the start of supplementation (baseline),
2. At four weeks post-supplementation
3. At eight weeks post-supplementation.
4. At the time of second surgery

Primary endpoint is 8 weeks


Note: Please note that the time of second surgery is not fixed, it will vary from patient to patient and ranges anywhere between 12 weeks- 24 weeks after first stage surgery. The time is dependent on absence of infection confirmed using blood tests and/or joint aspirate and will vary form patient to patient.
Primary outcome [3] 335292 0
Change in serum CD4/CD8 count will be measured using flow cytometry
Timepoint [3] 335292 0
1. After the first stage revision before the start of supplementation (baseline),
2. At four weeks post-supplementation
3. At eight weeks post-supplementation.
4. At the time of second surgery

Primary endpoint is 8 weeks


Note: Please note that the time of second surgery is not fixed, it will vary from patient to patient and ranges anywhere between 12 weeks- 24 weeks after first stage surgery. The time is dependent on absence of infection confirmed using blood tests and/or joint aspirate and will vary form patient to patient.
Secondary outcome [1] 423786 0
Change in serum Tumor-necrosis factor (TNF-alpha) will be measured by Enzyme-Linked Immunosorbent Assay (ELISA) assay.
Timepoint [1] 423786 0
1. After the first stage revision before the start of supplementation (baseline),
2. At four weeks post-supplementation
3. At eight weeks post-supplementation.
4. At the time of second surgery

Primary endpoint for this secondary outcome is 8 weeks post-supplementation.

Note: Please note that the time of second surgery is not fixed, it will vary from patient to patient and ranges anywhere between 12 weeks- 24 weeks after first stage surgery. The time is dependent on absence of infection confirmed using blood tests and/or joint aspirate and will vary form patient to patient.
Secondary outcome [2] 423787 0
Change in serum C-reactive protein by particle-enhanced immunoturbidimetry assay on the automated Roche platform
Timepoint [2] 423787 0
1. After the first stage revision before the start of supplementation (baseline),
2. At four weeks post-supplementation
3. At eight weeks post-supplementation.
4. At the time of second surgery

Primary endpoint for this secondary outcome is 8 weeks post-supplementation

Note: Please note that the time of second surgery is not fixed, it will vary from patient to patient and ranges anywhere between 12 weeks- 24 weeks after first stage surgery. The time is dependent on absence of infection confirmed using blood tests and/or joint aspirate and will vary form patient to patient.
Secondary outcome [3] 427851 0
Changes in Patient reported outcome measure: Knee injury and Osteoarthritis Outcome Score (KOOS) for knee PJI patients and Hip disability and Osteoarthritis Outcome Score (HOOS) for hip PJI patients
Timepoint [3] 427851 0
1. After the first stage revision before the start of supplementation (baseline),
2. Six months after second stage revision
Note: Please note that the time of second surgery is not fixed, it will vary from patient to patient and ranges anywhere between 12 weeks- 24 weeks after first stage surgery. The time is dependent on absence of infection confirmed using blood tests and/or joint aspirate and will vary form patient to patient.
Secondary outcome [4] 428572 0
Change in Plasma Zonulin levels using valiadted Elisa Kit, Cusabio
Timepoint [4] 428572 0
1. After the first stage revision before the start of supplementation (baseline),
2. At four weeks post-supplementation
3. At eight weeks post-supplementation
4. At the time of second surgery

Primary endpoint for this secondary outcome is 8 weeks post-supplementation
Please note that the time of second surgery is not fixed, it will vary from patient to patient and ranges anywhere between 12 weeks- 24 weeks after first stage surgery. The time is dependent on absence of infection confirmed using blood tests and/or joint aspirate and will vary form patient to patient.

Eligibility
Key inclusion criteria
•Adult patients with a first-time diagnosis of PJI as per Musculoskeletal Infection Society (MSIS) criterion and scheduled to undergo two-stage revision at the Royal Adelaide Hospital
· Under the care of orthopaedic surgeons at the RAH
•Willing to participate in the study.
•Well enough to undergo two-stage revision surgery.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Patients with chronic PJI
• Patients who do not consent to the study.
• Pregnant and Breast-feeding women
• Patients who cannot tolerate prebiotic fibres
• Patients who are immunosuppressed and on dietary restrictions

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)
The supplementation and the placebo product will be repacked in unlabeled sachets in an accredited food packing facility.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Block randomisation (blocks of 5) using a randomization table created using a computer software
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving 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
Efficacy
Statistical methods / analysis
a) Descriptive analysis: The baseline descriptive data of the placebo and supplemented group participants will be presented as mean, standard deviation (SD) or median and interquartile range (IQR).

b) Changes in gut and blood microbiome profile before and after supplementation:
Within-group differences in alpha-diversity, SCFA, specific taxa, genes and metabolites before and after supplementation will be tested using paired t-test or Wilcoxon test.
Between-group differences, post-supplementation will be assessed using an independent t-test or Mann-Whitney test. Group differences in microbiota beta diversity at various time points between and within the group will be assessed using repeated measures of ANOVA.

c) KOOS and Hip scores will be compared between and within the groups using independent t-test and paired t test, respectively. If the data is not normally distribited, then the correponding non-parametric test will be used.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
11/12/2023
Actual
Date of last participant enrolment
Anticipated
20/12/2024
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
50
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 25733 0
The Royal Adelaide Hospital - Adelaide
Recruitment postcode(s) [1] 41556 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 314222 0
University
Name [1] 314222 0
The University of Adelaide
Country [1] 314222 0
Australia
Primary sponsor type
Hospital
Name
Royal Adelaide Hospital
Address
Port Road, Adelaide, SA 5000
Country
Australia
Secondary sponsor category [1] 316155 0
University
Name [1] 316155 0
THE UNIVERSITY OF ADELAIDE
Address [1] 316155 0
Adelaide Health and Medical Science Building, Adelaide Medical School, The University of Adelaide, 4 North Terrace, Adelaide SA 5000
Country [1] 316155 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 313345 0
Central Adelaide Local Health Network Human Research Ethics Committee
Ethics committee address [1] 313345 0
Ethics committee country [1] 313345 0
Australia
Date submitted for ethics approval [1] 313345 0
01/08/2023
Approval date [1] 313345 0
18/09/2023
Ethics approval number [1] 313345 0
2023HRE00206

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

Contacts
Principal investigator
Name 127818 0
A/Prof Boopalan Ramasamy
Address 127818 0
5G 581, Department of Orthopaedics and Trauma, Royal Adelaide Hospital, 1 Port Road, Adelaide SA 5000
Country 127818 0
Australia
Phone 127818 0
+61 8 7074 1991
Fax 127818 0
Email 127818 0
[email protected]
Contact person for public queries
Name 127819 0
Boopalan Ramasamy
Address 127819 0
5G 581, Department of Orthopaedics and Trauma, Royal Adelaide Hospital, 1 Port Road, Adelaide SA 5000
Country 127819 0
Australia
Phone 127819 0
+61 8 7074 1991
Fax 127819 0
Email 127819 0
[email protected]
Contact person for scientific queries
Name 127820 0
Deepti Sharma
Address 127820 0
5E 330, Desk 52, Department of Orthopaedics and Trauma, Royal Adelaide Hospital, 1 Port Road, Adelaide SA 5000
Country 127820 0
Australia
Phone 127820 0
+61 8 7074 2126
Fax 127820 0
Email 127820 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
19658Ethical approval    386190-(Uploaded-13-10-2023-15-26-43)-Study-related document.pdf



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.