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Trial registered on ANZCTR


Registration number
ACTRN12618001039279p
Ethics application status
Not yet submitted
Date submitted
13/06/2018
Date registered
21/06/2018
Date last updated
21/06/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Dual sugar blood testing to identify liver cirrhosis patients with leaky bowel wall and antibiotic use to prevent fatal intra-abdominal bacterial infections.
Scientific title
Dual sugar testing for increased gut permeability to predict and prevent spontaneous bacterial peritonitis in patients with liver cirrhosis
Secondary ID [1] 295026 0
None
Universal Trial Number (UTN)
U1111-1214-7761
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Spontaneous bacterial peritonitis 308042 0
Liver cirrhosis 308043 0
Condition category
Condition code
Oral and Gastrointestinal 307094 307094 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon
Infection 307396 307396 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
All participants will undergo dual sugar solution (rhamnose/lactulose + mannitol) ingestion. The solution contains 7.5 mL of lactulose (Duphalac®; Solvay Pharmaceuticals, Pymble, New South Wales, Australia), 1g L-rhamnose monohydrate (minimum 99%, diluted in 2 mL water; Sigma) and 1g of mannitol. This is followed by a blood test 4 hours after which is then taken to the laboratory for analysis. The plasma concentrations of lactulose, rhamnose and mannitol is determined using High Performance Liquid Chromatography (Centre for Paediatric and Adolescent Gastroenterology, Children, Youth and Women’s Health Service) and the result expressed as dual sugar ratios (lactulose/rhamnose; lactulose/mannitol). This will determine the gut permeability. Participants determined as having increased permeability will undergo concealed randomisation to either intervention or no intervention.

Intervention arm will received oral administration of Trimethoprim/Sulfamethoxazole 160mg/800mg tablet daily or oral administration of Ciprofloxacin 500mg tablet daily (if allergic to trimethoprim/sulfamethoxazole) for 6 months with standard care. Adherence to the medications will be reviewed by monthly contact with the participant either by phone call or face to face consultation.


Non-intervention arm will received standard care only. The standard care is defined as usual practice in optimising lifestyle in patients with liver cirrhosis such as absolute alcohol abstinence, high protein and no added salt diet and regular exercise. There is concurrent medical treatment with diuretics to reduce ascites and regular blood test monitoring for electrolyte derangement and renal function. Patients with refractory or diuretic intolerant ascites will receive regular ascitic drain to control their symptoms at set intervals. Patient who develop complications such as gastrointestinal bleed (variceal bleed) or infection will received prompt care with hospital protocol care for gastrointestinal bleed and appropriate targeted antibiotics as required.
Intervention code [1] 301354 0
Diagnosis / Prognosis
Intervention code [2] 301356 0
Prevention
Comparator / control treatment
.The control arm patients will received standard care for liver cirrhosis.
Control group
Active

Outcomes
Primary outcome [1] 306169 0
The primary outcome of measure is the occurrence of spontaneous bacterial peritonitis. Spontaneous bacterial peritonitis is a clinical suspicion on patients with sepsis leading to hospitalisation and treatment in hopsital with intravenous antibiotics and albumin infusion. The objective occurrence of spontaneous bacterial peritonitis will be assessed based on documented laboratory measures of ascitic fluid assessment. Diagnosis is based on either growth of typical bacterial organism from the ascitic fluid or more than 250 neutrophil count per microlitre of ascitic fluid.
Timepoint [1] 306169 0
The primary outcome will be assessed 1 monthly by either face to face consultation or phone contact until 6 months post-enrolment.
Secondary outcome [1] 347761 0
Liver cirrhosis related mortality (death secondary to complications from liver cirrhosis) will be assessed as secondary outcome.
Timepoint [1] 347761 0
The secondary outcome will be assessed 1 monthly by either face to face consultation or phone contact until 6 months post-enrolment.
Secondary outcome [2] 348273 0
Complications of liver cirrhosis defined as hepatic encephalopathy, hepatorenal syndrome or variceal bleed. These will be assessed based on clinical assessment of the treating hepatologist, blood test results, crossectional imaging and endoscopic results
Timepoint [2] 348273 0
The secondary outcome will be assessed 1 monthly by either face to face consultation or phone contact until 6 months post-enrolment.
Secondary outcome [3] 348274 0
Progression of liver disease defined by Model for end stage liver disease (MELD) score and Child-Pugh score. These will be assessed by serial documentation of blood results including sodium, creatinine, bilirubin, albumin, international normalised ratio and clinical findings of ascites and encephalopathy
Timepoint [3] 348274 0
The secondary outcome will be assessed 1 monthly by either face to face consultation or phone contact until 6 months post-enrolment.
Secondary outcome [4] 348275 0
Serious infection requiring hospitalisation. This will be assessed by examining hospitalisation records with documentation of clinical assessment, microscopic, culture, cross-sectional imaging and blood test results.
Timepoint [4] 348275 0
The secondary outcome will be assessed 1 monthly by either face to face consultation or phone contact until 6 months post-enrolment.
Secondary outcome [5] 348314 0
All cause mortality will be measured as secondary outcome
Timepoint [5] 348314 0
The secondary outcome will be assessed 1 monthly by either face to face consultation or phone contact until 6 months post-enrolment.

Eligibility
Key inclusion criteria
- Patients with established diagnosis of liver cirrhosis of any aetiology
- Clinically detectable large volume ascites
- Child-Pugh score of B or C liver cirrhosis
- Increased gut permeability

Participants subsequently found to have normal gut permeability will not be randomised but will be followed from enrolment for 6 months for both primary and secondary outcomes.
Minimum age
18 Years
Maximum age
75 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Previous history or current history of bacterial peritonitis
- Current use of antibiotics
- Non-steroidal anti-inflammatory drug (NSAIDs) use which is known to increase intestinal permeability
- Gastrointestinal disease that affects permeability including inflammatory bowel disease, coeliac disease, irritable bowel syndrome, gastrointestinal bleeding or acute gut inflammation
- Active alcohol abuse of more than 40g/day for male and 20g/day for female
- Lack of capacity to consent for the study

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)
Allocation performed by offsite personal by remote contact either by email or phone.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Sequence will be generated by using random selection of permuted block of four, concealed to the investigator.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint/s
Efficacy
Statistical methods / analysis
Both primary and secondary outcomes will be analysed by using survival analysis or chi square test using either hazard ratio or relative risk respectively with confidence intervals. Co-variate factors will be assessed for association with both primary or secondary outcomes using cox regression or multiple regression model.

Extra information on gut permeability data measurement on patients will be assessed for associated co-variate factors using both univariate and multivariate regression models.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
3/09/2018
Actual
Date of last participant enrolment
Anticipated
1/02/2019
Actual
Date of last data collection
Anticipated
1/08/2019
Actual
Sample size
Target
20
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 11079 0
The Queen Elizabeth Hospital - Woodville
Recruitment hospital [2] 11080 0
The Royal Adelaide Hospital - Adelaide
Recruitment postcode(s) [1] 22891 0
5000 - Adelaide
Recruitment postcode(s) [2] 22890 0
5011 - Woodville

Funding & Sponsors
Funding source category [1] 299606 0
Hospital
Name [1] 299606 0
Gastroenterology Department, The Queen Elizabeth hospital
Country [1] 299606 0
Australia
Primary sponsor type
Hospital
Name
Gastroenterology Department, The Queen Elizabeth hospital
Address
The Queen Elizabeth hospital
28 Woodville road
Woodville South 5011
South Australia
Country
Australia
Secondary sponsor category [1] 298927 0
Hospital
Name [1] 298927 0
Gastroenterology Department, The Queen Elizabeth hospital
Address [1] 298927 0
The Queen Elizabeth hospital
28 Woodville road
Woodville South 5011
South Australia
Country [1] 298927 0
Australia

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 300509 0
Central Adelaide Local health Network (CALHN) Human Research Ethics Committee [EC00192]
Ethics committee address [1] 300509 0
Central Adelaide Local health Network Human Research Ethics Committee.
CALHN HREC
RAH Clinical Trial Centre
3D460.02 Level 3, Royal Adelaide Hospital
Port Road
Adelaide, South Australia 5000
Ethics committee country [1] 300509 0
Australia
Date submitted for ethics approval [1] 300509 0
25/06/2018
Approval date [1] 300509 0
Ethics approval number [1] 300509 0

Summary
Brief summary
Spontaneous bacterial peritonitis or in short ‘SBP’ is a life threatening bacterial infection within the excessive abdominal fluid that accumulates in patients with advanced liver cirrhosis. SBP if discovered or treated late can cause prolonged hospitalisation and even death. The key to treatment of SBP is early detection or prophylactic antibiotic use to prevent its occurrence.
It is well known that prophylactic antibiotic use can prevent SBP occurrence but can be associated with side effects of the antibiotics and development of multi-resistant bacteria. Current research to date has limited information on which patients may best benefit from prophylactic antibiotics and there is lack of consensus between experts in this field.
The theory behind development of SBP is through the concept called bacterial translocation. The passage of pathogenic bacteria from the inside of the gut through the bowel wall barrier into the gut tissue leads to eventual infective process. One of the key changes that contribute to development of SBP in context of advanced liver cirrhosis is the change that occurs in the gut barrier. Patients with liver cirrhosis have increased permeability or ‘leakiness’ of the gut barrier, thereby allowing pathogenic bacteria to leak across the barrier into the tissue space. This is often compounded by the abnormal overgrowth of pathogenic gut flora in patients with liver cirrhosis.
We propose that by determining which patients with liver cirrhosis have highly abnormal gut permeability will allow us to predict who will best benefit from prophylactic antibiotics. We hypothesize that individuals with high gut permeability are most at risk of SBP and would have the most benefit of prophylactic antibiotic use.
There has been long standing safe method of measuring gut permeability in children with many different gut disorders since 1980 by measuring two different types of ingested sugars, namely rhmanose and lactulose on a blood or urine test. The test allows measurement of the ingested sugars which crosses the gut barrier into the blood or urine at a set time to determine the functionality of the barrier. The study aims to recruit patients with advanced liver cirrhosis and examine their gut permeability by using this dual sugar test. Subsequently patients with abnormal permeability will be randomised to antibiotics or no antibiotic prophylaxis in a controlled trial to observe its benefit.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 83886 0
Dr Seon Ho Shin
Address 83886 0
4B Endoscopy
The Queen Elizabeth hospital
28 Woodville Road
Woodville South
South Australia
5011
Country 83886 0
Australia
Phone 83886 0
+61 420 820 283
Fax 83886 0
+61 8 8222 6047
Email 83886 0
seonho.shin@sa.gov.au
Contact person for public queries
Name 83887 0
Dr Seon Ho Shin
Address 83887 0
4B Endoscopy
The Queen Elizabeth hospital
28 Woodville Road
Woodville South
South Australia
5011
Country 83887 0
Australia
Phone 83887 0
+61 420 820 283
Fax 83887 0
+61 8 8222 6047
Email 83887 0
seonho.shin@sa.gov.au
Contact person for scientific queries
Name 83888 0
Dr Seon Ho Shin
Address 83888 0
4B Endoscopy
The Queen Elizabeth hospital
28 Woodville Road
Woodville South
South Australia
5011
Country 83888 0
Australia
Phone 83888 0
+61 420 820 283
Fax 83888 0
+61 8 8222 6047
Email 83888 0
seonho.shin@sa.gov.au

No information has been provided regarding IPD availability


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No Supporting Document Provided



Results publications and other study-related documents

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