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Trial registered on ANZCTR


Registration number
ACTRN12616000410459
Ethics application status
Approved
Date submitted
15/03/2016
Date registered
30/03/2016
Date last updated
21/04/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
Can recurrent UTIs in post-menopausal women be prevented with aspirin?
Scientific title
Prevention of recurrent urinary tract infections in post-menopausal women using a non-antibacterial approach; a randomised, double-blinded, crossover, placebo-controlled trial of aspirin.
Secondary ID [1] 288770 0
Nil known
Universal Trial Number (UTN)
U1111-1180-8702
Trial acronym
DISURIA
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Recurrent Urinary Tract Infections 298032 0
Condition category
Condition code
Infection 298185 298185 0 0
Other infectious diseases
Renal and Urogenital 298186 298186 0 0
Other renal and urogenital disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Aspirin (either 100mg or 300mg) or matching placebo tablets along with one Ural sachet (4mg, containining Sodium Bicarbonate 1.76 g, Anhydrous Sodium Citrate 0.63 g,
Anhydrous Citric Acid 0.72 g, Tartaric Acid 0.89 g). The satchet contents will be dissolved in 250 ml water and taken orally. This is given .to optimize excretion of salicylic acid into alkaline urine taken at night. Participants are randomised to aspirin or placebo for 6 months, then cross-over to placebo or aspirin for another 6 months.. In this way, participants are randomised to both either 100 or 300 mg Aspirin and the order they receive aspirin and placebo.
There is 1 week wash- out period in between cross-over.
Trials medication will be provided for 2-month periods and participants will have 2-monthly clinic reviews at THHS.
A monthly, interval telephone call will be made to discuss trial medication compliance, details of recurrent UTIs and any side-effects.
Intervention code [1] 294211 0
Treatment: Drugs
Comparator / control treatment
Matching plabeco (microcellulose) tablets.
Control group
Placebo

Outcomes
Primary outcome [1] 297690 0
To assess for a difference in frequency of UTI in subjects randomized to aspirin or control.

Study participants will be provided with pre-printed pathology request forms for Mid stream urine samples which they provide for every infection episode. These forms will have Professors Eisen and Rane (co-investigator) address so that results are sent to these investigators automatically. This will enable the number of recurrent UTIs to be calculated for each participant.
Timepoint [1] 297690 0
1 year after randomisation and at every 2 monthly clinic reviews.
Primary outcome [2] 297691 0
To assess the time to first breakthrough UTI in subjects randomized to aspirin or control.
Time to first breakthrough UTI is the time taken for the first UTI recurrence to occur since starting aspirin or placebo.

This will be calculated from the pathology results automatically sent to the co-investigators, every time the participant experiences an UTI and provides a mid stream urine sample for microscopy/culture/sensitivity.
Timepoint [2] 297691 0
1 year after randomisation and will be assessed in every 2 monthly clinic review until break through infection occurs.
Secondary outcome [1] 321847 0
To assess the safety of aspirin in these subjects.

The safety parameters include:
1. Episodes of clinically idenitfied major bleeding consisting of gastrointestinal haemorrhage or intracranial haemorrhage.
2. Episodes of clinically identified and patient reported hypersensitivity to aspirin shown by new onset or worsening of asthma and nasal polyps.
These will be assessed by review of medical records and patient self-reporting in clinic reviews.
Timepoint [1] 321847 0
1 year after randomisation.

Eligibility
Key inclusion criteria
: Post-menopausal women who have a documented history of at least three UTIs per year.
Minimum age
18 Years
Maximum age
75 Years
Sex
Females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Increased bleeding risk.
2. Hypersensitivity to aspirin.
3. Requirement for surgery to correct anatomical abnormalities predisposing to UTI.
4. Dependence on intermittent self-catheterisation.
5. Medical illness requiring continued aspirin treatment.

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)
This is a double- blinded trial. Allocation to trial arm will be managed by the unblinded trials pharmacist who will open a sealed envelope to reveal the daily dose of aspirin and the sequence of aspirin and placebo.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
As the recruitment is at a single site, randomisation will be a simple process consisting of random numbers being allocated to an ordered list of aspirin dose and placebo sequence combinations. This list when then be sorted into descending numbers to determine randomisation order.
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
Safety/efficacy
Statistical methods / analysis
Differences in the frequency of UTIs in the treatment and placebo groups will be measured using comparison of means by unpaired t-test. Cox-proportional hazards survival analysis will determine the impact of aspirin on time to the first recurrence of UTI. Analyses will be by Intention To Treat.

Recent trials for recurrent UTIs intervention have shown that the rate of microbiological recurrence is 70% at one year, with a time to first recurrence of between 19 and 180 days. We have chosen a clinically relevant effect size of 30% reduction in the frequency of recurrences of UTI over one year. Using a crossover design, this allows us to have an adequately powered study with 95% two-sided significance with 33 participants in each of the two intervention arms and 65 in our control group (predicted odds ratio 0.29). With this sample size we are able to proceed to a Phase III trial. We will aim to recruit 43 participants in each of the trial arms and 86 controls to allow for 30% drop out and to increase the trial’s power to detect smaller differences in recurrence rate. The total number of participants will be 172.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/05/2017
Actual
Date of last participant enrolment
Anticipated
1/04/2018
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
172
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 5449 0
The Townsville Hospital - Douglas
Recruitment postcode(s) [1] 12934 0
4814 - Douglas

Funding & Sponsors
Funding source category [1] 293136 0
Hospital
Name [1] 293136 0
Townsville Hospital Health Service Study Education Research Trust Account grants
Country [1] 293136 0
Australia
Primary sponsor type
Individual
Name
Prof Damon Eisen
Address
JCU Clinical School
IMB 52, The Townsville Hospital
100 Angus Smith Dr, Douglas QLD 4814
Country
Australia
Secondary sponsor category [1] 291931 0
University
Name [1] 291931 0
James Cook University
Address [1] 291931 0
1 James Cook Dr, Townsville City QLD 4811
Country [1] 291931 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 294633 0
The Townsville Hospital and Health Service Human Research Ethics Committee
Ethics committee address [1] 294633 0
Research Support Unit
IMB 52, PO Box 670
Townsville QLD 4810
Ethics committee country [1] 294633 0
Australia
Date submitted for ethics approval [1] 294633 0
03/03/2016
Approval date [1] 294633 0
25/12/2016
Ethics approval number [1] 294633 0

Summary
Brief summary
UTIs are the commonest bacterial infections. They range from cystitis to life-threatening urosepsis. Recurrent UTIs are also common, particularly in women. Recurrent UTIs are debilitating, leading to high usage of medical resources including frequent prescription of antibiotics. There is an increasing frequency of antibiotic resistance among recurrent UTI causative organisms that are unresponsive not only to the routine antibiotics used for UTI, but increasingly, to more potent antibiotics reserved for severe infections. Suppressive antibiotics for recurrent UTI are not totally effective, are associated with substantial toxicity and select resistant bacteria.
The bacteria that cause UTI are predominantly gram-negative, most commonly E. coli. Uropathogenic E. coli strains produce type I fimbriae; ‘arms’ of the bacteria, that allow it to attach to the lining of the urinary tract. These and other fimbriae are also involved in biofilm formation that is required for infections of urinary catheters as well as recurrent UTI. These bacterial factors; type I fimbriae production and biofilm formation in E. coli and other uropathogens, are both reduced by salicylic acid, the biometabolite of aspirin, and this drug may be useful in prevention of recurrent UTIs.
The minimum salicylic acid concentration required for Type I fimbrial suppression is 0.1-0.5mM. This is exceeded by 300mg doses of aspirin as 30% of the total dose is excreted in alkaline urine. The safety of the 300mg dose has been precisely determined in large-scale studies. The rate of major haemorrhage (requiring transfusion or hospitalisation) in patients taking greater than 200mg aspirin/day is 2.29%. This Is significantly higher than those on doses <100mg, but even here the rate of major haemorrhage (1.56%) remains substantial. These risks must be balanced against the morbidity of recurrent UTIs and the toxicity of prophylactic antibiotics like nitrofurantoin. We will trial both doses of aspirin and hope to show that 100mg is as effective as 300mg.
This randomised controlled trial aims to examine the efficacy of Aspirin, 100 mg and 300 mg, compared with matching placebo in reducing the frequency of UTIs in post menopausal women with recurrent UTIs. The time to first breakthrough UTI will be another primary endpoint measured. The secondary endpoints will be the safety of low dose Aspirin in these subject. Another secondary microbiological end point is the effect of Aspirin on biofilm formation.
Trial website
Trial related presentations / publications
Public notes
Attachments [1] 806 806 0 0
/AnzctrAttachments/370341-Clinical trial protocol 3.0.docx

Contacts
Principal investigator
Name 64422 0
Prof Damon Eisen
Address 64422 0
JCU Clinical School, James Cook University
1st Floor
Townsville Hospital, 100 Angus Smith Drive
Douglas, QLD 4814
Country 64422 0
Australia
Phone 64422 0
+61 7 4433 1351
Fax 64422 0
Email 64422 0
[email protected]
Contact person for public queries
Name 64423 0
Prof Damon Eisen
Address 64423 0
JCU Clinical School, James Cook University
1st Floor
Townsville Hospital, 100 Angus Smith Drive
Douglas, QLD 4814
Country 64423 0
Australia
Phone 64423 0
4433 1351
Fax 64423 0
Email 64423 0
[email protected]
Contact person for scientific queries
Name 64424 0
Prof Damon Eisen
Address 64424 0
JCU Clinical School, James Cook University
1st Floor
Townsville Hospital, 100 Angus Smith Drive
Douglas, QLD 4814
Country 64424 0
Australia
Phone 64424 0
+61 7 4433 1351
Fax 64424 0
Email 64424 0
[email protected]

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Results publications and other study-related documents

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