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Trial registered on ANZCTR


Registration number
ACTRN12621000792820
Ethics application status
Approved
Date submitted
10/05/2021
Date registered
23/06/2021
Date last updated
23/06/2021
Date data sharing statement initially provided
23/06/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Targeting the gut microbiome as a treatment for Primary Sclerosing Cholangitis: The Queensland Clinical Network Study
Scientific title
The impact of targeting the gut microbiome on improvement in liver function in individuals with Primary Sclerosing Cholangitis: The Queensland Clinical Network Study.
Secondary ID [1] 304127 0
Nil Known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Primary Sclerosing Cholangitis 321815 0
Condition category
Condition code
Oral and Gastrointestinal 319545 319545 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
This is a 52 week, multi-center, randomised placebo-controlled trial (RCT) with a cross over design where 34 patients with PSC, with and without an associated IBD will be randomized to either oral vancomycin or placebo treatment, in a 1:1 ratio.
Patients will receive 250 mg vancomycin capsules orally or ONE placebo capsule twice daily for 12 weeks.
Adherance to intervention will not be monitored in this study.
There is no washout period between the arms.
Intervention code [1] 320461 0
Treatment: Drugs
Comparator / control treatment
Patients will receive the placebo for 12 weeks
Type: Gelatin Capsules
Contents: Microcrystalline Cellulose
One placebo capsule twice daily.
Control group
Placebo

Outcomes
Primary outcome [1] 327402 0
Improvement of ALP as assessed with blood test.
Timepoint [1] 327402 0
At baseline and after 12 weeks of treatment.
Secondary outcome [1] 394972 0
Clinical outcomes related to Primary Sclerosing Cholangitis activity - Liver function tests, renal profile, full blood count.
This is a composite secondary outcome.
Timepoint [1] 394972 0
After 12 weeks of treatment
Secondary outcome [2] 394973 0
FibroScan® is a non-invasive device that assesses the 'hardness' (or stiffness) of the liver via the technique of transient elastography.
Timepoint [2] 394973 0
Baseline and at the end of treatment, (week 52).
Secondary outcome [3] 394974 0
Medical Outcomes Study Questionnaire - Short Form 36 Health Survey (SF-36),
Timepoint [3] 394974 0
Baseline and during the follow-up visits weeks 12,24,36,52.
Secondary outcome [4] 394975 0
Structured Assessment of Gastrointestinal Symptoms (SAGIS) score
Timepoint [4] 394975 0
Baseline and during the follow-up visits weeks 12,24,36,52.
Secondary outcome [5] 394976 0
Hospital Anxiety and Depression Scale (HADS).
Timepoint [5] 394976 0
Baseline and during the follow-up visits weeks 12,24,36,52.
Secondary outcome [6] 394977 0
Non-invasive markers for assessment of disease activity- UC partial MAYO Score or CDAI for IBD patients.
Timepoint [6] 394977 0
Baseline and at the end of treatment, (week 52).
Secondary outcome [7] 394978 0
Glucose breath Test
Timepoint [7] 394978 0
Baseline and at end of treatment, (week 52).
Secondary outcome [8] 394979 0
Isolation of PBMCs and cell culture (to assess immune markers in PSC). The immune markers that will be assessed include Th1 (TNF-a, type 1 interferons, IL-2, IL-12,), Th17/22 (IL-17A, IL-17F, IL-22) and IL-10 and TGF cytokines will be quantified in cell culture supernatant by ELISA and intracellularly by flow cytometry.
Timepoint [8] 394979 0
Baseline and during the follow-up weeks 12,24,36,52.
Secondary outcome [9] 394980 0
Endoscopic assessment of disease severity in patients with IBD
Timepoint [9] 394980 0
Baseline and end of treatment, (week 52).

Eligibility
Key inclusion criteria
• Male and females (females of childbearing age must have negative pregnancy test within 48 hours of participation and agreement to practice contraception for the duration of the study), age =>14 years old and <75 years,
0 Established clinical diagnosis of PSC (confirmed by a hepatologist) with or without an associated IBD
o History of chronic cholestatic disease of at least 6 months duration,
o Serum alkaline phosphatase level at least 1.5 times the upper limit of normal.
o Cholangiography or MRCP demonstrating intrahepatic and/or extrahepatic biliary obstruction, beading, or narrowing consistent with PSC (without evidence for other causes of the biliary abnormalities).
0 Patients have given informed consent for study participation.
0 All other treatments for PSC and IBD need to be stable for the last 4 weeks prior to inclusion.
Minimum age
14 Years
Maximum age
74 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Findings highly suggestive of hepatobiliary disease of other aetiology complicating PSC,
• Anticipated need for liver transplantation in one year (e.g. determined by Mayo model with an estimate of <75% one year survival without transplantation),
• Recurrent variceal bleeding, presence of ascites, or encephalopathy,
• Active drug or alcohol use, pregnancy, breast feeding,
• Serum creatinine over 1.5 fold of the norm,
• Prior history of allergic reactions to antibiotics belonging to the family to be used,
• Any condition that, in the opinion of the investigator, would interfere with the patient's ability to complete the study safely or successfully.
• Evidence of active malignancy.

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 envelopes
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
computerised sequence generation
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
Crossover
Other design features
Phase
Phase 3
Type of endpoint(s)
Efficacy
Statistical methods / analysis
It is well established that in PSC patients’ spontaneous fluctuations of the primary outcome parameter ALP of ± 10% of baseline occur51. To be categorized as responder a reduction in ALP levels > 40% is a strict approach and aligned with results of previous studies52, and associated with improved survival53.
Aim 1: A sample of 34 PSC patients will provide statistical power 0.8 at the 0.05 (two-tailed) level of statistical significance (?) assuming a placebo response rate of 20% and 70% response to antibiotic therapy. The analysis will be based on a random effects logistic regression estimated via Maximum Likelihood due to multiple observations on placebo non-responders. To meet the required sample size, dropouts will be replaced by additional patients.

Aim 2: Assuming that overall 50% of patients respond to the antibiotic therapy, a sample of 34 individuals with PSC will provide statistical power 0.8 at the 0.05 (two-tailed) level of statistical significance (?) for an effect size contrasting MAM between responders and non-responders corresponding to a Cohen’s d of 1.0. Analysis will involve unpaired t-tests unless the assumption of normality is violated then the Mann-Whitney test will be employed.
Aim 3: Microbial community abundance associated with patient progression of disease will be based on logistic regression. Sample size needs for this analysis is identical to that for aim 1. Due to resource constraints, statistical significance will not be adjusted for multiple inference. However, this is quite consistent with a proof-of-concept/pilot study.
Data of participant who discontinued/deemed ineligible before completion of their study, can be included in the analysis if deemed appropriate by the investigator.

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 in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 19280 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [2] 19281 0
Sunshine Coast University Hospital - Birtinya
Recruitment hospital [3] 19282 0
Gold Coast University Hospital - Southport
Recruitment hospital [4] 19283 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [5] 19284 0
Queensland Children's Hospital - South Brisbane
Recruitment hospital [6] 19285 0
The Townsville Hospital - Douglas
Recruitment hospital [7] 19286 0
Cairns Base Hospital - Cairns
Recruitment postcode(s) [1] 33861 0
4102 - Woolloongabba
Recruitment postcode(s) [2] 33862 0
4575 - Birtinya
Recruitment postcode(s) [3] 33863 0
4215 - Southport
Recruitment postcode(s) [4] 33864 0
4029 - Herston
Recruitment postcode(s) [5] 33865 0
4101 - South Brisbane
Recruitment postcode(s) [6] 33866 0
4814 - Douglas

Funding & Sponsors
Funding source category [1] 308507 0
Government body
Name [1] 308507 0
NHMRC MRFF
Address [1] 308507 0
Administerd via
Office of Sponsored Research
Level 1, Cumbrae Stewart Building
The University of Queensland
Brisbane Qld 4072 Australia
Country [1] 308507 0
Australia
Primary sponsor type
Hospital
Name
Princess Alexandra Hospital
Address
199 Ipswich Rd
Woolloongabba
QLD 4102
Country
Australia
Secondary sponsor category [1] 309892 0
None
Name [1] 309892 0
Address [1] 309892 0
Country [1] 309892 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 308466 0
Metro South Human Research Ethics Committee
Ethics committee address [1] 308466 0
Translational Resaerch Institute
387 Kent Street
Woolloongabba QLD 4102
Ethics committee country [1] 308466 0
Australia
Date submitted for ethics approval [1] 308466 0
13/08/2020
Approval date [1] 308466 0
28/01/2021
Ethics approval number [1] 308466 0
HREC/2020/QMS/67725

Summary
Brief summary
Primary sclerosing cholangitis (PSC) is a progressive, chronic liver disease leading to
end stage liver-failure with limited treatment options. Case series and a recent systematic review and meta-analysis found that antibiotic therapy and in particular treatment with the non-absorbable antibiotic vancomycin was associated with substantial clinical improvement or even remission of PSC and the concomitant inflammation of the bowel. Against this background we aim in a placebo-controlled trial in PSC patients with and without  concomitant IBD to define the effects of antibiotic therapy on disease activity. It is hypothesised that targeted modulation of the microbiota with vancomycin will improve clinical outcomes for these patients.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 110786 0
Prof Gerald Holtmann
Address 110786 0
Princess Alexandra Hospital
199 Ipswich Rd
Woolloongabba QLD 4102
Country 110786 0
Australia
Phone 110786 0
+61 7 3176 7792
Fax 110786 0
+61 7 3176 5111
Email 110786 0
g.holtmann@uq.edu.au
Contact person for public queries
Name 110787 0
Prof Gerald Holtmann
Address 110787 0
Princess Alexandra Hospital
199 Ipswich Rd
Woolloongabba QLD 4102
Country 110787 0
Australia
Phone 110787 0
+61 7 3176 7792
Fax 110787 0
+61 7 3176 5111
Email 110787 0
g.holtmann@uq.edu.au
Contact person for scientific queries
Name 110788 0
Prof Gerald Holtmann
Address 110788 0
Princess Alexandra Hospital
199 Ipswich Rd
Woolloongabba QLD 4102
Country 110788 0
Australia
Phone 110788 0
+61 7 3176 7792
Fax 110788 0
+61 7 3176 5111
Email 110788 0
g.holtmann@uq.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
De-identified individual participant data will not be available for this study
What supporting documents are/will be available?
No other documents available
Summary results
No Results