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Trial registered on ANZCTR


Registration number
ACTRN12610000630011
Ethics application status
Approved
Date submitted
25/07/2010
Date registered
2/08/2010
Date last updated
14/12/2015
Type of registration
Prospectively registered

Titles & IDs
Public title
Does Intestinal microflora play a role in the symptom scores and life quality of people with Coeliac disease?
Scientific title
Intestinal microbiota in Coeliac disease (CD) compared to non-coeliac patients using Deoxyribonucleic Acid (DNA) methods of analysis, followed by a double-blind placebo controlled study assessing the microbiological and quality of life improvements after supplementation with a specific probiotic supplement.
Secondary ID [1] 252248 0
Nil
Universal Trial Number (UTN)
U1111-116-1408
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Coeliac Disease 257766 0
Condition category
Condition code
Oral and Gastrointestinal 257941 257941 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
An online survey, designed on Survey Monkey software, has been sent via the NSW Coeliac Disease Association e-mail database to small bowel biopsy confirmed Coeliac Disease members residing in the Sydney metropolitan area. The questionnaire elicited information thought to be associated with alterations in gastrointestinal microflora, e.g. birth methods, infant feeding practice, medication use and current dietary practice, and on lifestyle. A questionnaire to assess gastrointestinal and general symptoms was also be included in the online survey. Of those who have responded to the questionnaire, 50 people will be invited to participate in a randomised controlled trial (RCT). An interview will be conducted with the trial participants where the protocol will be explained to them. The participants will be asked to have a blood test for pre trial safety monitoring, this test will include a Full Blood Count, Liver and Renal function assay. The participants will be given a collection kit and asked to provide a stool and urine sample later in the privacy of their home for DNA faecal microbial analysis by Metametrix Laboratories. This group will then be randomised by age and sex into two groups: those receiving a probiotic supplement containing 450 billion colony forming units of a composite of lactobacillus spp, bifiodbacteria spp, and streptococcus thermophilus (CDP+, n=25), and those receiving placebo (CDP-, n=25). The supplement will be once taken daily via the oral route. Supplement duration will be twelve weeks. The placebo will be a taste and visually identical powder of maltose. At the end of the trial another stool and urine sample will be collected and participants will be required to complete the questionnaire again. Post clincial trial blood saftey monitoring tests will be repeated. All participants will have their test results forwarded to their general practitioner for their records.
Stool samples, urine samples and answers to the questionnaires pre- and post-supplementation will be compared for each participant to establish links between supplementation, microflora and symptom scores. Comparisons will be made between the CDP+ and CDP- groups, and data from healthy, non-CD people (data already held by the laboratory).
Data Analysis; The pilot study has shown larger counts of gram positive bacteria in CD subjects compared to controls. Research testing the GI microflora in chronic fatigue patients has also shown an increase in gram positive bacteria compared to controls (25). The ratio of gram negative to gram positive bacteria has therefore been chosen as a suitable primary outcome measure. A 1-tailed independent group t-test on the change in the logarithms of the ratio of gram negative to gram positive organisms was deemed to be an appropriate test of the outcome.
The sample size was estimated with PASS 2008. The data used were the mean of the ln(gram negative/gram positive) from the pilot study (CD group, n=30) and the mean of the laboratory data of healthy people (control group, n=117). In the CD group ln(gram negative/gram positive) was 1.97 with a standard deviation of 3.0, whereas in the control group the ln(gram negative/gram positive) was 6.85.
It was estimated that sample sizes of 19 per group have 80% power (1-beta) to detect a difference between groups in a mean change of 2.5 with standard deviations of the changes of 3.0 in each group at alpha=0.05 (1-tailed). This would occur if there were a mean increase of 2.5 from 2.0 to 4.5 in the treatment group and no change in the placebo group. It is thought that the improvement in intestinal microflora half-way between the CD pilot group and the control group is achievable in twelve weeks of supplementation. For the trial 50 people with CD will be recruited, 25 in each arm, to allow for drop-outs in each group.
A statistician will be consulted for the data analysis.
Anticipated outcomes and significance
It is anticipated that statistically significant abnormalities in the levels of bacteria will be found in the intestines of the CD subjects. Therapeutic intervention using competitive inhibition with probiotic strains of bacteria is thought to result in improvements in both subjective symptom scores and faecal microflora. Reduction of any associated symptoms and/or co-morbidity, it is hoped, will enhance the health and quality of life in individuals affected by CD.
Intervention code [1] 256828 0
Other interventions
Intervention code [2] 256832 0
Treatment: Other
Comparator / control treatment
Existing laboratory faecal microbial analysis and urinary organic acid test results of non-coeliac indviduals will serve as the control data. The test results of the coeliac participants will be compared to this data to determine if there are differences in the gastrointestinal microflora between the two groups.
The placebo group will act as the control during the clinical trial i.e 25 of the participants will be randomly assigned to take either an active or placebo supplement. The placebo will be taken via the oral route once daily, and will be identical in taste and visual presentation containing a medically inert substance, maltose. The placebo group will still have the same laboratory tests and complete the symptom and quality of life questionairres as the participants receiving the active supplement. They will also have all their laboratory results forwarded to their Medical Practitioner (with thier permission)
Control group
Placebo

Outcomes
Primary outcome [1] 258808 0
Gastrointestinal Microbial Ecology Profiles of faecal samples will be measured by the ratio of gram negative to gram positive bacteria. A 1-tailed independent group t-test on the change in the logarithms of the ratio of gram negative to gram positive organisms will be conducted.
Timepoint [1] 258808 0
Microbial Ecology Profiles will be assessed prior to commencing the probiotic and again 12 weeks later after the probiotic or placebo supplementation have been taken.
Primary outcome [2] 258811 0
Urinary organic acid levels will be assessed for the detection of seven microbial metabolites associated with small bowel bacterial overgrowth. The presence of each of the seven microbial metabolites will be compared;
(a) between the laboratory control data of non-coeliac individuals and the coeliac participants.
(b) between the pre and post supplemented coeliac participants undertaking the clinical trial.
The exact statistical tests that will be used are yet to be decided.
Timepoint [2] 258811 0
The Urinary acid levels will be assessed in urine samples prior to the commencement of the probiotic or placebo and again 12 weeks later after the probiotic or placebo has been taken.
Secondary outcome [1] 264875 0
Improvements in life quality and symptom scores as measured by Haussers Coeliac Disease Specific Symptom and Quality of Life Questionaire (CDSQ).
Timepoint [1] 264875 0
The CDSQ will be completed prior to commencing the placebo or probiotic at the beginning of week 1 of the clincial trial and then again at weeks 4, 8 and 12 weeks. Approximately 4 weeks after completing the clinical trial the participants will be asked to complete the CDSQ one more time.

Eligibility
Key inclusion criteria
1. Participants who have had Coeliac disease confirmed by small bowel biopsy
2. Participants who have followed a gluten free diet for at least 12 months
3. At least 12 months since small bowel biopsy diagnosis
Minimum age
18 Years
Maximum age
70 Years
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Pregnant women
2. Participants under the age of 18
3. Individuals with cancer or who are HIV positive
4. Patients who have been diagnosed with Coeliac disease in the past 12 months
5. Patients who consume a gluten containing diet
6. Individuals with gastrointestinal pathology such as cancer, Crohn’s disease or ulcerative colitis
7. Individuals with short bowel syndrome
8. Individuals who have had recent oral or bowel surgery
9. Individuals currently being treated with chemotherapy or radiotherapy
10. People who are using or have used non-steroidal or steroidal anti-inflammatory drugs, antibiotics, antipyretics or the oral contraceptive pill in the four weeks prior to the start of the trial
11. Individuals with serum urea, electrolytes and creatinine greater than 2 times the upper limit of normal at baseline
12. Individuals with liver function tests greater than 3 times the upper limit of normal at baseline
13. Participants unwilling to comply with the study protocol
14. Any other condition which, in the opinion of the investigators, could compromise the study
15. Individuals with active alcohol and or illicit drug dependence.

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)
As each participant enrolls they will be allocated a computer generated sequence number, that determines whether they are in the placebo or treatment group. The protocol number allocated to participants will have been previously coded as placebo or active. Once this automated allocation has taken place the participants number will be placed in an opaque envelope in the Clinical Reference File (CRF) until the end of the study and given to the clinical trial coordinator at Southern Cross University. The study is double blinded therefore the clinical trial coordinator at Southern Cross University will also allocate the medicines in keeping with these codes. Only in the event of an adverse reaction will the code be revealed prior to the completion of the trial.
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?



Intervention assignment
Factorial
Other design features
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Completed
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)
ACT,NSW

Funding & Sponsors
Funding source category [1] 257300 0
Commercial sector/Industry
Name [1] 257300 0
Sigma Pharmaceuticals Pty Ltd (incorporating Orphan) Australia
Address [1] 257300 0
96 Merrindale Drive South Croydon Victoria 3136
Country [1] 257300 0
Australia
Funding source category [2] 257302 0
Commercial sector/Industry
Name [2] 257302 0
Metametrix Clinical Laboratory
Address [2] 257302 0
3425 Corporate Way Duluth Atlanta Georgia 30096
Country [2] 257302 0
United States of America
Funding source category [3] 257338 0
Commercial sector/Industry
Name [3] 257338 0
Diagnostic Insight
Address [3] 257338 0
The business Diagnostic Insight no longer operates or has a business address.
Country [3] 257338 0
Australia
Primary sponsor type
University
Name
Southern Cross University
Address
Rifle Range Road Lismore New South Wales 2480
Country
Australia
Secondary sponsor category [1] 256578 0
Individual
Name [1] 256578 0
Joanna Harnett
Address [1] 256578 0
The new contact address is
Dr Joanna Harnett
Faculty of Pharmacy
The University of Sydney, building A15 Camperdown
Sydney 2006
Joanna.harnett@sydney.edu.au
Country [1] 256578 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 259329 0
Southern Cross University Human Research Ethics Commitee
Ethics committee address [1] 259329 0
Division of Research
Southern Cross University
PO Box 157 LISMORE NSW 2480
Ethics committee country [1] 259329 0
Australia
Date submitted for ethics approval [1] 259329 0
Approval date [1] 259329 0
02/02/2010
Ethics approval number [1] 259329 0
ECN-12-021

Summary
Brief summary
This clinical trial is investigating the role different bacteria may play in the symptoms and quality of life of people with Coeliac disease. The study is looking to see whether there are differences in the different types of bacteria, yeasts and parasites that colonise the intestine of people with Coeliac disease compared to people without Coelaic disease. In addition this clincial trial will see if a specific blend of beneficial bacteria known as a probiotic can improve the ongoing symptoms and quality of life issues experienced by some people with Coeliac disease.
Trial website
Trial related presentations / publications
Journal publications are currently being prepared and the following peer reviewed presentations have presented the results of this research project
A. September 2013: The 15th International Coeliac Disease Symposium in Chicago, USA. Three posters arising from the PhD findings were reviewed and presented:
i. A double blind randomised controlled trial investigating the effect of probiotics on intestinal microbiota and quality of life of patients with Coeliac disease
ii. The intestinal microbiota of people with Coeliac disease reporting persistent symptoms despite adherence to a gluten-free diet compared to people without Coeliac disease
iii. Results of a survey exploring the incidence of early childhood health events on the intestinal microflora and the medical, social and dietetic management of CD in New South Wales Australia.

B. May 2013: The 3rd Science of Nutrition and Medicine in Health Care, Sydney, Australia. Plenary Session - Profiled Oral abstract presentation ‘Probiotics, Coeliac Disease and Gastrointestinal Microbiota’

C. September 2010: Northern New South Wales Department of Health and Research, Lismore Australia. “Results of a New South Wales Survey: Nutritional Environmental and Epidemiological Factors in Coeliac Disease

Public notes

Contacts
Principal investigator
Name 31407 0
Dr Dr Tini Gruner
Address 31407 0
School of Health and Human Sciences
Southern Cross University, Military Rd, Lismore NSW 2480 Australia
Country 31407 0
Australia
Phone 31407 0
+612 6620 3000
Fax 31407 0
Email 31407 0
Tini.gruner@scu.edu.au
Contact person for public queries
Name 14654 0
Dr Joanna Harnett
Address 14654 0
Dr Joana Harnett
Faculty of Pharmacy
Building A15 - Science Road
The University of Sydney
Camperdown Campus
New South Wales
Sydney 2006




Country 14654 0
Australia
Phone 14654 0
+61 2 9966 9993 or +61 429 707 740
Fax 14654 0
Email 14654 0
joanna.harnett@optusnet.com.au
Contact person for scientific queries
Name 5582 0
Dr Joanna Harnett
Address 5582 0
Dr Joanna Harnett
Faculty of Pharmacy
Building A15 - Science Road
The University of Sydney
Camperdown Campus
New South Wales, 2006
Sydney 2006As above
Country 5582 0
Australia
Phone 5582 0
+612 9351 7009
Fax 5582 0
Email 5582 0
joanna.harnett@sydney.edu.au

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary