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Trial registered on ANZCTR


Registration number
ACTRN12618001020279p
Ethics application status
Submitted, not yet approved
Date submitted
6/06/2018
Date registered
18/06/2018
Date last updated
11/06/2019
Date data sharing statement initially provided
11/06/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Does metronidazole improve symptoms of irritable bowel syndrome in cases of colonic spirochaetosis?
Scientific title
The effect of colonic spirochaetosis eradication on the symptoms of irritable bowel syndrome: a randomised control trial
Secondary ID [1] 295120 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Colonic spirochaetosis 308209 0
Irritable bowel syndrome 308210 0
Condition category
Condition code
Oral and Gastrointestinal 307240 307240 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon
Infection 307241 307241 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Metronidazole 400mg orally three times daily for ten days.

Adherence will be monitored through tablet return and count at the scheduled end of treatment review.
Intervention code [1] 301453 0
Treatment: Drugs
Comparator / control treatment
Identical placebo tablet (cornstarch) taken three times daily for ten days
Control group
Placebo

Outcomes
Primary outcome [1] 306189 0
Mean reduction in irritable bowel syndrome symptoms measured with the irritable bowel syndrome symptom severity score (IBS-SSS) at 3 and 12 weeks after treatment in patients with colonic spirochaetosis compared with placebo.
Timepoint [1] 306189 0
3 and 12 [primary timepoint] weeks after completion of treatment
Secondary outcome [1] 347802 0
Proportion of colonic spirochaetosis positive participants achieving a 50 point reduction in the IBS-SSS
Timepoint [1] 347802 0
3 and 12 weeks after treatment compared with placebo.
Secondary outcome [2] 347803 0
Mean reduction in irritable bowel syndrome symptoms measured with the IBS-SSS at 3 and 12 weeks after treatment in patients without colonic spirochaetosis compared with placebo.
Timepoint [2] 347803 0
3 and 12 weeks after treatment
Secondary outcome [3] 347804 0
Proportion of colonic spirochaetosis negative participants achieving a 50 point reduction in the IBS-SSS at 3 and 12 weeks after treatment compared with placebo.
Timepoint [3] 347804 0
3 and 12 weeks after treatment
Secondary outcome [4] 347805 0
Difference in mean reduction in IBS-SSS between metronidazole treatment and placebo in participants infected with colonic spirochaetosis compared with participants without colonic spirochaetosis receiving the same interventions.
Timepoint [4] 347805 0
3 and 12 weeks after treatment
Secondary outcome [5] 347806 0
Rates of colonic spirochaetosis eradication on metronidazole compared with placebo.
This will be measured with the gold standard of sigmoid biopsy and histologic analysis with warthog starry stain.
Timepoint [5] 347806 0
12 weeks after treatment

Eligibility
Key inclusion criteria
• Age > 18 years
• Able to consent
• Clear diagnosis of IBD-d in the medical record with adequate exclusion of other causes. This includes duration of symptoms for more than 3 months, stool culture for exclusion of common causes of chronic diarrhoea including parasitic infection with stool microbiology, malabsorption based on clinical impression with appropriate investigations or bile acid diarrhoea.
• Willingness to submit stool samples and take metronidazole.
• No metronidazole taken in the last 6 months.
• Not have an alcohol dependence disorder due to risk of disulfram like reaction with metronidazole.
• No other long term antibiotic use.
• No immunodeficiency (HIV, Long term steroid use, use of immunosuppressive agents)
• Not be pregnant or have a chance of falling pregnant whilst taking treatment
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Unable to consent
Immunodeficiency
Pregnancy
Inflammatory bowel disease
Antibiotic use in last 6 months

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)
Centralised random allocation in permuted blocks of four provided through our teaching hospital pharmacy.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Permuted blocks of four using randomisation software
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
Interventional randomised double blind trial with parallel double armed groups based on presence of absence of colonic spirochaetosis.
Because of the diversity of the microbiome, non-selective effect of metronidazole, and the difficulty in demonstrating that eradication of CS is causally linked with resolution of symptoms the design will have four arms: Patients with IBS-d and Brachyspira biopsy positive randomised to metronidazole or placebo and patients with IBS-d and Brachyspira biopsy negative randomised to metronidazole or placebo.
Phase
Phase 3
Type of endpoint/s
Efficacy
Statistical methods / analysis
Analysis (Performed using Stata v14, Statacorp, USA)

All analysis will use a two tailed alpha cut-off value of 0.05 as significant.

Hypothesis 1A (Primary)
Eradication of colonic spirochaetosis with metronidazole 400mg TDS will lead to a greater mean reduction in irritable bowel syndrome symptoms severity score (IBS-SSS) when compared to placebo at 3 and 12 weeks.
Hypothesis 1B
Eradication of colonic spirochaetosis with metronidazole 400mg TDS will lead to a greater proportion of participants with a 50 point reduction in the IBS-SSS when compared to placebo at 3 and 12 weeks.
Hypothesis 2A
Treatment of colonic spirochaetosis negative patients with metronidazole 400mg TDS will lead to a greater mean reduction IBS-SSS when compared to placebo at 3 and 12 weeks.
Hypothesis 2B
Treatment of colonic spirochaetosis negative patients with metronidazole 400mg TDS will lead to a greater proportion of participants with a 50 point or greater reduction in the IBS-SSS when compared to placebo at 3 and 12 weeks.

The reduction in scores at 3 weeks and 3 months from baseline will be calculated for individuals in the intervention and placebo groups. The distribution will be tested for normality. If normal, then an independent T-test will be used to compare the means for a significant difference otherwise a Wilcoxon Rank Sum test will be used. Using a definition of clinical improvement as 50 points decrease in IBS-SSS score, a chi2 test (or Fishers exact if any group <5) will be used to test for significant difference in improvement rates between groups.

Hypothesis 3
The difference in mean reduction in IBS-SSS at 3 and 12 weeks between metronidazole and placebo will be greater in patients infected with colonic spirochaetosis than in patients without colonic spirochaetosis receiving the same interventions.
The reduction in scores at 3 weeks and 3 months from baseline will be calculated for all individuals. The mean change will then be calculated for each arm. Tests of normality will be performed. The mean difference between intervention and placebo will then be calculated for the CS positive arms and the same mean difference calculated for the CS negative arms. These two mean differences will be compared using an independent t-test.

Hypothesis 4
Metronidazole at a dose of 400mg TDS for 10 days will lead to a greater rate of eradication of CS at 3 week colonic biopsy compared to the placebo group.
This is an important requirement in the attempt to prove causality because if this outcome is not met then the other outcomes are not biologically plausible by the Bradford-Hill criteria. This can be tested using a Chi2 test comparing independent proportions.

Sample size estimation
All sample size calculations use an alpha value of 5% and a beta value of 20% (Power of 80%). Calculations made using Stata v14 (Statacorp, USA).

For hypothesis 1 and 2 the clinically significant decrease in the IBS-SSS score is 50 out of a possible 500. The validation study found a mean score of 243 for cases with moderate IBS with a standard deviation of 42. A clinically significant change is considered 50. To compare the mean change in score between arms using a t-test of independent means the sample size for each arm is calculated at 13 which would equate to a total study size of 52 patients in an equally distributed four arm group.
To compare the proportion of patients achieving clinically significant response defined as an IBS-SSS score decrease of >=50 points, a calculation was made for a chi2 test comparing independent proportions. An assumption was made that the placebo group are likely to have a 20% response rate while a response rate of 70% in the treatment group would be clinically significant. The sample size per group was calculated at 15 which equates to a total number of 60 participants.

Hypothesis 3 compares two differences in mean score change. There was inadequate literature to make sufficiently accurate estimates about the likely change and standard deviation to allow an accurate power calculation. A moderate treatment effect size was estimated in the CS positive arms of a difference of 40 points in the mean IBS-SSS score change while a more minor effect size was estimated in the CS negative arms of 10 points. Assuming a standard deviation of 10 the power calculation for a t-test of independent means was 4 individuals per group.

For hypothesis 4, a calculation was made for a chi2 test comparing independent proportions. An assumption was made that the placebo group may have up to a 10% eradication rate while an eradication rate of at least 70% should be expected in the intervention arm. The sample size for each group was calculated at 10 which equates to a CS sample size of at least 20 participants.

The conclusion is that the study requires a sample size of 30 CS positive participants with at least equal numbers in the CS negative group (n=60) and 1:1 randomisation. As CS negative participants are more prevalent and likely to be recruited more rapidly but cannot be identified until after recruitment and rectal biopsy there may be a larger proportion of patients in the CS negative trial group. This raises an ethical issue of inflicting investigation and medical trials on participants after the sample size is met. To address this issue, after recruitment of 30 CS negative individuals, further participants found to be CS negative will be offered an opt out option.

A more conservative sample size calculation was also performed with a beta value of 10%, mean IBS-SSS score of 300 and standard deviation of 50. The required numbers for comparison of means in hypothesis 1 and 2 is 23 per group (92 total) and for comparison of proportions reaching clinically significant benefit is 19 per group (76 total). If funding and recruitment allow, an interim analysis will be performed when 30 CS patients have been recruited and if there is insufficient evidence to reject the null hypothesis then recruitment will continue to the larger sample size estimate of 23 per group.

Ref: Francis CY, Morris J, Whorwell PJ. The irritiable bowel severity scoring system: a simple method of monitoring irritable bowel syndrome and its progress. Aliment Pharmacol Ther 1997;11:395-402.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
30/08/2019
Actual
Date of last participant enrolment
Anticipated
31/12/2020
Actual
Date of last data collection
Anticipated
31/03/2021
Actual
Sample size
Target
60
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 11101 0
John Hunter Hospital - New Lambton
Recruitment postcode(s) [1] 22913 0
2305 - New Lambton

Funding & Sponsors
Funding source category [1] 299798 0
Other
Name [1] 299798 0
PRC Digestive Health and Neurogastroenterology fund through the Hunter Medical Research Institute in conjunction witht he University of Newcastle
Country [1] 299798 0
Australia
Primary sponsor type
Other
Name
PRC Digestive Health and Neurogastroenterology fund through the Hunter Medical Research Institute in conjunction witht he University of Newcaslte
Address
Level 3 East Wing, HMRI, Kookaburra Circuit, New Lambton, 2305.
NSW
Country
Australia
Secondary sponsor category [1] 299147 0
None
Name [1] 299147 0
None
Address [1] 299147 0
None
Country [1] 299147 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 300601 0
Hunter New England Human Research Ethics Committee
Ethics committee address [1] 300601 0
Ethics committee country [1] 300601 0
Australia
Date submitted for ethics approval [1] 300601 0
30/05/2019
Approval date [1] 300601 0
Ethics approval number [1] 300601 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 84178 0
Prof Nicholas Talley
Address 84178 0
Level 3 East Wing, HMRI
Kookaburra Circuit
New Lambton, 2305
NSW
Australia
Country 84178 0
Australia
Phone 84178 0
+61249215855
Fax 84178 0
Email 84178 0
nicholas.talley@newcastle.edu.au
Contact person for public queries
Name 84179 0
Nicholas Talley
Address 84179 0
Level 3 East Wing, HMRI
Kookaburra Circuit
New Lambton, 2305
NSW
Australia
Country 84179 0
Australia
Phone 84179 0
+61249215855
Fax 84179 0
Email 84179 0
nicholas.talley@newcastle.edu.au
Contact person for scientific queries
Name 84180 0
Nicholas Talley
Address 84180 0
Level 3 East Wing, HMRI
Kookaburra Circuit
New Lambton, 2305
NSW
Australia
Country 84180 0
Australia
Phone 84180 0
+61249215855
Fax 84180 0
Email 84180 0
nicholas.talley@newcastle.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Demographic
Response outcomes as outlined in protocol
When will data be available (start and end dates)?
At the completion of study (start) through to 10 years after study publication.
Available to whom?
Investigators
Journal editors and reviewers on request
Available for what types of analyses?
For the aims of the study
To assist with any meta-analysis
How or where can data be obtained?
Access subject to approval by PI and ethics committee


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.