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Trial registered on ANZCTR


Registration number
ACTRN12624000133538
Ethics application status
Approved
Date submitted
28/11/2023
Date registered
14/02/2024
Date last updated
20/06/2024
Date data sharing statement initially provided
14/02/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
Gut Bugs for C. Difficile Infection
Scientific title
Encapsulated faecal microbiome transfer versus oral vancomycin treatment for sustained cure of recurrent or refractory Clostridioides difficile infection
Secondary ID [1] 311014 0
None
Universal Trial Number (UTN)
U1111-1299-5067
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Recurrent Clostridioides difficile infection 332127 0
Refractory Clostridioides difficile infection 332311 0
Condition category
Condition code
Infection 328853 328853 0 0
Studies of infection and infectious agents
Oral and Gastrointestinal 329025 329025 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
Arm 1: FMT alone
Participants in this group will be randomly assigned to receive 20 FMT capsules over two consecutive days (days 1-2) in the morning. In addition, they will take one placebo-vancomycin capsule containing 125 mg of maltodextrin four times per day for 10 consecutive days (days 1-10). This group will remain blinded to the treatment allocation.

The FMT capsules contain concentrated gut microbiota provided by carefully screened healthy donors. The microbiota is suspended in a cryoprotective solution consisting of 15% glycerol and 0.9% saline at a concentration of 0.5 g per milliliter. The suspension is then double-encapsulated in sizes 0 and 0 delayed-release capsules (DRcapsTM, Capsugel, Australia) in 0.5 ml aliquots. The placebo-vancomycin capsules contain 125 mg of maltodextrin.

To ensure that participants adhere to the treatment and to monitor their safety, a registered nurse will supervise the administration of FMT capsules and observe for any side effects. Adherence to the FMT-placebo treatment will be monitored through text messages and phone calls. All relevant data will be recorded using the RedCap system.
Intervention code [1] 327453 0
Treatment: Other
Comparator / control treatment
Arm 2: Vancomycin alone
Participants in this group will be randomly assigned to receive 125 mg of oral vancomycin hydrochloride four times per day for 10 consecutive days (treatment days 1-10). In addition, they will swallow 20 FMT-placebo capsules containing a mixture of saline and cocoa over two consecutive days (treatment days 1 and 2). This group will remain blinded to the treatment allocation.

Arm 3: Vancomycin-FMT
Participants in this group will be randomly assigned to receive 125 mg of oral vancomycin hydrochloride four times per day for 10 consecutive days (treatment days 1-10). After completing the vancomycin treatment, they will receive 20 FMT capsules (concentration of 0.5 g/ml microbiota) over two consecutive days (treatment days 11-12). This group will not be blinded.
Control group
Active

Outcomes
Primary outcome [1] 336675 0
Rate of sustained Clostridioides difficile infection cure 12 weeks after treatment commencement with FMT alone compared to vancomycin hydrochloride alone
Timepoint [1] 336675 0
Baseline, 2, 4 and 5 days and 1, 4, and 12 weeks after treatment initiation (primary timepoint).
Secondary outcome [1] 429291 0
Clostridioides difficile infection sustained cure rate at 12 weeks after treatment initiation.
Timepoint [1] 429291 0
Baseline, 2, 4 and 5 days and 1, 4, and 12 weeks after treatment initiation (primary timepoint).
Secondary outcome [2] 431220 0
Initial treatment response at 5 days after treatment initiation.

Timepoint [2] 431220 0
At 2, 4, and 5 days (primary timepoint) and 1 week after treatment initiation.
Secondary outcome [3] 431221 0
Health-related quality of life at 12 weeks after treatment initiation.
Timepoint [3] 431221 0
Baseline and 12 weeks (primary timepoint) after treatment initiation.
Secondary outcome [4] 431222 0
Gut health at 12 weeks after treatment initiation.
Timepoint [4] 431222 0
Baseline, 2 and 4 days and 1, 4 and 12 weeks after treatment initiation.
Secondary outcome [5] 431223 0
Stool form at 12 weeks after treatment initiation.
Timepoint [5] 431223 0
At 2 and 4 days, and 1, 4 and 12 weeks after treatment initiation. Baseline measurements are not taken due to the expected presence of loose stools in participants, consistent with the trial's inclusion criteria of diagnosing first recurrent or refractory Clostridioides difficile infection.
Secondary outcome [6] 431224 0
Features of donor and recipient gut microbiome and bacteriophage populations that characterise treatment responders and non-responders in the FMT group.
Timepoint [6] 431224 0
Baseline and 12 weeks after treatment initiation.
Secondary outcome [7] 431225 0
Microbiome and/or bacteriophage population changes in relation to sustained Clostridioides difficile infection cure at 12 weeks after treatment.
Timepoint [7] 431225 0
Baseline and 12 weeks after treatment initiation.

Eligibility
Key inclusion criteria
Study participants (recipients) will have to meet the following inclusion criteria:

1. Aged 16 to 90 years; AND
2. Ability to swallow all treatment capsules; AND
3. Having:
a. First recurrent Clostridioides difficile infection; OR
b. Refractory Clostridioides difficile infection.
Minimum age
16 Years
Maximum age
90 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
As a real-world trial examining FMT effectiveness, there will be minimal exclusion criteria. However, patients meeting the three below will be excluded:

1. Current systemic antibiotic treatment except if prescribed for Clostridioides difficile infection
2. Severe allergy to foods and/or common medications
3. Current hospitalisation because of severe Clostridioides difficile infection, defined as having at least one of the following that is not directly attributable to a non-clostridioides difficile infection illness (e.g., infection):
a. Fever (core body temperature of greater than 38.5°C);
b. Marked leukocytosis (leucocyte count greater than 15 x109/L);
c. Serum creatinine rise greater than 50% above baseline or if no baseline available greater than 50% above the upper limit of the age-specific reference range;

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)
Central randomization by computer software.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Computerised sequence generation in a 1:1:1 allocation ratio.
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

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/03/2024
Actual
Date of last participant enrolment
Anticipated
28/02/2026
Actual
Date of last data collection
Anticipated
31/08/2026
Actual
Sample size
Target
84
Accrual to date
0
Final
Recruitment outside Australia
Country [1] 25991 0
New Zealand
State/province [1] 25991 0

Funding & Sponsors
Funding source category [1] 315277 0
Other
Name [1] 315277 0
Rockfield Trust
Country [1] 315277 0
New Zealand
Primary sponsor type
University
Name
University of Auckland
Address
Liggins Institute University of Auckland 85 Park Road Grafton 1023 Auckland
Country
New Zealand
Secondary sponsor category [1] 317335 0
None
Name [1] 317335 0
Address [1] 317335 0
Country [1] 317335 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 314196 0
Northern B Health and Disability Ethics Committee 
Ethics committee address [1] 314196 0
https://ethics.health.govt.nz/about/northern-b-health-and-disability-ethics-committee/
Ethics committee country [1] 314196 0
New Zealand
Date submitted for ethics approval [1] 314196 0
14/09/2023
Approval date [1] 314196 0
22/11/2023
Ethics approval number [1] 314196 0
2023 FULL 18301
Ethics committee name [2] 314576 0
Standing Committee on Therapeutic Trials
Ethics committee address [2] 314576 0
https://www.hrc.govt.nz/resources/standing-committee-therapeutic-trials-scott
Ethics committee country [2] 314576 0
New Zealand
Date submitted for ethics approval [2] 314576 0
14/11/2023
Approval date [2] 314576 0
19/02/2024
Ethics approval number [2] 314576 0

Summary
Brief summary
Background: Clostridioides difficile infection is the commonest cause of drug treatment-induced infectious diarrhea, which is often recurrent with high mortality. Current treatments mainly include antibiotics, which have low sustained cure rates of 30-35%. Therefore, alternative or additive treatments are required.

Hypothesis: In the treatment of the first recurrent or refractory Clostridioides difficile infection, FMT alone leads to a greater sustained cure rate than oral vancomycin hydrochloride treatment alone but to a comparable rate to vancomycin hydrochloride plus FMT combination.

Design: Randomized controlled trial that will allocate participants in a 1:1:1 ratio to one of three groups: (1) FMT alone, (2) vancomycin alone, and (3) vancomycin followed by FMT. Groups 1 and 2 will be double-blinded because these are the primary outcome comparison groups. Group 3 will remain unblinded because the treatment days differ, and there is no justifiable reason to blind them.

Participants: Eighty-four people aged 16-90 diagnosed with recurrent or refractory Clostridioides difficile infection who can swallow capsules.

Donors: Eight healthy donors aged 16-40 years who pass a strict screening process.

Interventions: FMT capsules vs vancomycin hydrochloride capsules vs vancomycin hydrochloride capsules, followed by FMT.

Assessments: Data on treatment response, gut symptoms and composition, well-being, quality of life and safety will be collected over 12-weeks.

Assessment measures include a clinical evaluation, the Bristol Stool Chart, the Gastrointestinal Symptom Rating Scale (GSRS), the Short Warwick Edinburgh Mental Well-Being Scale (SWEMWBS) and the the EQ-5D-5L.. The stool microbiome from donors and participants (baseline and 12 weeks after treatment) will be characterized by metagenomic sequencing.
Trial website
https://www.auckland.ac.nz/en/liggins/in-the-community/clinical-studies/clinical-studies-adults/gut-bugs-for-c--difficile-infection--cdi-.html
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 130754 0
Prof Wayne Cutfield
Address 130754 0
Liggins Institute University of Auckland 85 Park Road Grafton 1023 Auckland
Country 130754 0
New Zealand
Phone 130754 0
+64021734441
Fax 130754 0
Email 130754 0
[email protected]
Contact person for public queries
Name 130755 0
Taygen Edwards
Address 130755 0
Liggins Institute University of Auckland 85 Park Road Grafton 1023 Auckland
Country 130755 0
New Zealand
Phone 130755 0
+64 0211070814
Fax 130755 0
Email 130755 0
[email protected]
Contact person for scientific queries
Name 130756 0
Wayne Cutfield
Address 130756 0
Liggins Institute University of Auckland 85 Park Road Grafton 1023 Auckland
Country 130756 0
New Zealand
Phone 130756 0
+64021734441
Fax 130756 0
Email 130756 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?
Clinical de-identified data and associated meta-data documentation and de-identified post-filtered metagenomic sequencing data.
When will data be available (start and end dates)?
Data will be available to approved applicants after the publication of the main findings within three years of the trial finishing.
Available to whom?
Clinical data will be made available to other researchers with approval from the Liggins Institute CDRH Data Access Committee and de-identified metagenomic sequencing data will be accessible to the public via NCBI's SRA.
Available for what types of analyses?
FMT and/or clostridioides difficile infection focused analysis and gut microbiome characterization studies.
How or where can data be obtained?
Clinical data access requests to be sent to the Liggins Institute's Clinical Data Research Hub Data Access Committee (email: [email protected]).

Metagenomic sequencing data will be shared on NCBI's Sequence Read Archive (SRA).


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
21043Study protocol  [email protected]
21044Informed consent form  [email protected]
21045Ethical approval  [email protected]



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