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Trial registered on ANZCTR


Registration number
ACTRN12616001224415
Ethics application status
Approved
Date submitted
24/05/2016
Date registered
5/09/2016
Date last updated
25/09/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Evaluation of the effect of aspirin and a probiotic on functional dyspepsia
Scientific title
A randomised, double-blind placebo controlled clinical trial, will be carried out to evaluate the effect of aspirin and a probiotic on the immune system, upper gut function and gastrointestinal symptoms in controls without functional dyspepsia and patients with functional dyspepsia whether treatment improves FD symptoms.
Secondary ID [1] 288386 0
Nil
Universal Trial Number (UTN)
Nil
Trial acronym
Nil
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Functional Dyspepsia 297391 0
Condition category
Condition code
Oral and Gastrointestinal 297581 297581 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
Patients were randomly assigned to a 10-day course of one of the following treatment:

Group A, placebo - one capsule two times a day.
Group B, Aspirin 500 mg dissolved in 100 ml water and has to be taken three times a day.
Group C, Probiotic ( vivomixx ) - Sprinkle the content of sachet on Apple puree and patients have to eat whole apple puree with vivomixx over it immediately. Patients have to take one sachet at a time and it has to be taken two times a day.

Vivomixx is a food supplement containing a combination of 8 different strains of live lactic acid bacteria and bifid bacteria. Vivomixx has 450 billion freeze-dried lactic acid bacteria and bifidobacteria, maltose, anti-caking agent: silicon dioxide. matlose, anti-caking agent: silicon dioxide (nano) (Streptococcus thermophilus, Bifidobacteries (B. breve, B. longum, B. infantis), Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus paracasei, Lactobacillus delbrueckii subsp. Bulgaricus). Without gluten, lactose and soy

Vivomixx is a new highly concentrated probiotic food supplement that contains 450 billion live lyophilized bacteria with 8 carefully selected strains.

Recommended dose for vivomixx is 1-2 sachets per day. (Dissolve the content of one sachet in water, yogurt, apple juice or other cold carbonated free drinks and drink immediately.)

Aspirin - Aspirin tablet 500 mg dissolved in 100 ml water and patients have to take three times a day

Placebo - Its a capsule which has to take two times a day by patients..

All patients have been informed to keep all empty sachets and empty envelopes of IP and return it back to study site on follow up visit..

Don't require weight based dose as recommended dose for Vivomixx is 1-2 sachets per day and in this study patients also have to take one sachet at a time with apple puree two times a day.

.
Intervention code [1] 293691 0
Treatment: Drugs
Intervention code [2] 295398 0
Treatment: Other
Comparator / control treatment
Randomised, double-blind placebo controlled of 1.5 g of aspirin, Vivomixx ( 450 billion bacteria/day) or placebo.

A placebo is an inert substance, typically either a tablet or a capsule which does not contain an active drug ingredient.

Placebo is a (microcellulose) capsule and patinets will receive two placebo in a day and they act as healthy controlled group for this study.

Patients

Placebo which will be in form of (microcellulose) capsule and will have to take by patients two times a day.

Controlled patients are Iron deficiency patients and they are healthy patients which act as control for this study.
Control group
Placebo

Outcomes
Primary outcome [1] 298411 0
Activation of the immune function : Percentage of CD3+/CD4+/-CD8-/+ T cells from biopsy samples and percentage of memory/ gut homing T lymphocytes among CD4+ T cells in controls and patients with FD and assessment of the gastric and duodenal mucosa.

In Percentage of CD3+/CD4+/-CD8-/+ T cells and percentage of memory/ gut homing T lymphocytes among CD4+ T cells in controls and patients with FD.
Timepoint [1] 298411 0
Tissue samples during endoscopic procedure and blood samples collected on 6th days post commencement of treatment.
Primary outcome [2] 298412 0
Upper GI function via Gastric emptying test- the termination half life will be used as outcome measure.
Timepoint [2] 298412 0
Day 09 post commencement of treatment drug,
Primary outcome [3] 298413 0
Upper GI function-The peak and cumulative symptom responses will be determined and the cumulative scores for each symptom individually and for all symptoms combined will be used as the primary outcome variables - Gastric Emptying Test
Timepoint [3] 298413 0
Day 09 post commencement of treatment drug.
Secondary outcome [1] 324062 0
Psychological symptoms via the Hospital Anxiety and Depression Scale
Timepoint [1] 324062 0
Day 09 post commencement of treatment drug
Secondary outcome [2] 324063 0
Secondary Outcome : The number of eosinophils per mm2 will be used as the outcome measure.

Outcome assessed by Biopsy samples.
Timepoint [2] 324063 0
Day 06 post commencement of treatment drug.
Secondary outcome [3] 324064 0
To investigate the microbiome through bacterial culture. These bacterial isolates will be subject to identification (utilising sequencing methods as per microbiome assessment above), and further characterisation e.g. nutrient utilisation, pro-inflammatory properties, ability to stimulate cytokine production from patient peripheral blood immune cells.
This will allow confirmation of the presence of live bacteria in the biopsy samples.

In addition, it will allow us to assess bacterial load/overgrowth in the duodenum and this can be correlated to both symptoms, immune and permeability assessments.

Therefore we can assess the contribution of particular bacteria to the pathophysiology of FD.
Timepoint [3] 324064 0
Day 06 post commencement of treatment drug.
Secondary outcome [4] 327138 0
GI Symptoms through both Gastrointestinal Symptom (GIS) score The GIS assesses the intensity of gastrointestinal symptoms in patients with FD, and addresses patient’s gastrointestinal symptoms in the past week, Each symptom is scored using a 5 point Likert scale (no problem (0) - very severe problem (4))

Outcome measures: the GIS score will be used as outcome measure for dyspeptic symptoms.
Timepoint [4] 327138 0
Day 09 post commencement of treatment drug - intestinal permeability test (Intestinal permeability- the ratio of lactulose: rhamnose will be used as intestinal permeability marker at baseline and on treatment)
Secondary outcome [5] 327139 0
The Nepean Dyspepsia Index is a reliable and valid measure of quality of life in functional dyspepsia, but responsiveness has been little studied. The Nepean Dyspepsia Index originally contained 42 items designed to measure impairment of a subject's ability to engage in relevant aspects of their life because of dyspepsia, and their enjoyment of these aspects; in addition, the individual importance of areas was assessed. It was subsequently shortened to 26 items.

Nepean Dyspepsia Index used to check the quality of life for the dyspepsia patients.
Timepoint [5] 327139 0
Day 09 post commencement of treatment drug.

Eligibility
Key inclusion criteria
Dyspepsia patients: We will study 90 consecutive patients with the diagnosis of FD according to Rome III criteria after a comprehensive negative diagnostic work-up.In order to avoid variability due to the menstrual cycle, all pre-menopausal females will be tested in the first phase of the menstrual cycle. All subjects will be H. pylori negative.
b) Controls: we will recruit 90 age and gender matched controls without GI symptoms undergoing endoscopy for assessment of iron deficiency with a normal upper endoscopy.
In order to avoid variability due to the menstrual cycle, all pre-menopausal females will be tested in the first phase of the menstrual cycle. All subjects will be H. pylori negative.
Minimum age
18 Years
Maximum age
90 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
H. pylori positive

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)
Patients will be randomised consecutively

Allocation of study treatment will be done in sealed envelopes with using blank stickers on the treatment and only mentioned about dose -1 , dose -2 and dose 3.

Same will followed for the probiotics and placebo as well.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
This will be done by the statistician using the program R
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
Randomised, double-blind placebo controlled intervention
Phase
Phase 4
Type of endpoint/s
Efficacy
Statistical methods / analysis
To assess the modification of the effect of aspirin and probiotic treatment vs placebo on a number of physiologic parameters in FD compared with normal subjects. The analysis of this 2x3 Parallel design will employ parallel analysis of variance in which the interaction between treatment and FD status will be the only hypothesis test of interest. If statistically significance (p<0.01) is achieved planned comparisons will be conducted via interaction contrasts.

We will also assess two effect modifications, one in which microbiome diversity status modifies response to aspirin and the second in which microbiome status modifies the response to probiotic, both are regardless of FD status. ;

Sample size / statistical power A sample of n=30 subjects randomized to each treatment with FD and controls will provide statistical power 0.9 at the 0.01 level of statistical significance (two-tailed) if the effect size for aspirin is 1SD larger in FD than normals but the effect size for probiotic is 1SD smaller in FD than normal. The same sample size applies to hypothesis two assuming the ratio of normal to reduced microbiome diversity is approximately 1:1. The sample recruited for hypothesis 1 will provide statistical power close 0.9 at the 0.01 level of statistical significance (two-tailed) for Cohen d effect size of 0.75

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/10/2018
Actual
Date of last participant enrolment
Anticipated
31/12/2018
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
180
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 5840 0
Princess Alexandra Hospital - Woolloongabba
Recruitment postcode(s) [1] 13285 0
4102 - Buranda

Funding & Sponsors
Funding source category [1] 293662 0
Government body
Name [1] 293662 0
National Health & Medical Research Council grant
Country [1] 293662 0
Australia
Primary sponsor type
University
Name
University of Queensland,
Address
University of Queensland,
School of Medicine,
St Lucia Campus
St Lucia QLD- 4072
Country
Australia
Secondary sponsor category [1] 292497 0
None
Name [1] 292497 0
None
Address [1] 292497 0
None
Country [1] 292497 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295101 0
Metro South HREC
Ethics committee address [1] 295101 0
Metro South Hospital and Health Service
Level 7 Translational Research Institute,
37 Kent Street
Woolloongabba QLD 4102
Ethics committee country [1] 295101 0
Australia
Date submitted for ethics approval [1] 295101 0
20/11/2014
Approval date [1] 295101 0
21/12/2014
Ethics approval number [1] 295101 0
HREC/13/QPAH/690

Summary
Brief summary
Functional dyspepsia (FD) affects a considerable proportion of Australians and results in significant personal and economic cost. There is as yet no cure for this condition and current treatments are only satisfactory in a subset of patients. New insights into the pathophysiology of FD have found that activation of both mucosal and systemic
immune responses are important and have been shown to be linked to symptoms in patients with FD. Specifically, increased mucosal permeability has been linked with mucosal inflammation and our pilot work has shown increased mucosal permeability occurs in FD. In this study we aim to define the effects of pharmacologically
induced changes of intestinal permeability on immune activation, upper gut function (sensory & motor function) and symptoms in healthy controls and patients with FD. FD patients and controls will be randomised to receive a nonsteroidal antiinflammtory
drug (aspirin) which is known to increase FD symptoms and mucosal permeability or
a probiotic (Vivomixx), which is known to reduce the severity of dyspeptic symptoms, and intestinal permeability. In addition recent evidence suggests that that the intestinal microbiome plays a critical role in mucosal inflammation but to date this has not been properly investigated in FD. We aim to define the role of the intestinal microbiome in
response to treatment with aspirin and the probiotic Vivomixx using a novel device we have developed and patented that allows targeted aseptic biopsies to be obtained from defined areas of the gastrointestinal mucosa utilising routine endoscopic tests. We will also compare the microbiome in intestinal biopsies from patients with FD and
healthy controls to study the link between the diversity of the microbiome and mucosal inflammation. To do this study we will recruit 90 patients with functional dyspepsia and 90 age and sex matched controls without GI symptoms undergoing endoscopy for assessment of iron deficiency with a normal upper endoscopy. They will be
randomised to receive either aspirin, Vivomaxx or placebo. They will undergo pre and post treatment testing including fill in questionnaires, donate a blood sample, donate a tissue sample (at baseline only), breath test and a standard nutrient drink challenge. This study will significantly advance the pathophysiology of FD and has the potential to pave
the way for future cure of the disease.
Trial website
Nil
Trial related presentations / publications
Nil
Public notes

Contacts
Principal investigator
Name 62966 0
Prof Gerald Holtmann
Address 62966 0
Department of Gastroenterology
Princess Alexandra Hospital
199 Ipswich Rd
Woolloongabba QLD 4102
Country 62966 0
Australia
Phone 62966 0
+61 7 3176 7792
Fax 62966 0
Email 62966 0
g.holtmann@uq.edu.au
Contact person for public queries
Name 62967 0
Natasha Koloski
Address 62967 0
Department of Gastroenterology
Princess Alexandra Hospital
199 Ipswich Rd
Woolloongabba QLD 4102
Country 62967 0
Australia
Phone 62967 0
+61 407126897
Fax 62967 0
Email 62967 0
Natasha.Koloski@health.qld.gov.au
Contact person for scientific queries
Name 62968 0
Natasha Koloski
Address 62968 0
Department of Gastroenterology
Princess Alexandra Hospital
199 Ipswich Rd
Woolloongabba QLD 4102
Country 62968 0
Australia
Phone 62968 0
+61 407126897
Fax 62968 0
Email 62968 0
natasha.Koloski@health.qld.gov.au

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No Supporting Document Provided



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