Double blind, placebo-controlled trial of antibiotics in women with refractory Detrusor Overactivity: Effect on urge incontinence and quality of life.

Moore K1, Mansfield K2, Chen Z1, Allen W1, Parkin K1, Gebski V3

Research Type

Clinical

Abstract Category

Overactive Bladder

Abstract 184
Overactive Bladder
Scientific Podium Short Oral Session 8
Wednesday 4th September 2019
15:07 - 15:15
Hall K
Detrusor Overactivity Pad Test Clinical Trial Infection, Urinary Tract Urgency Urinary Incontinence
1.Department of Urogynaecology, University of New South Wales at St. George Hospital, Kogarah NSW 2217, Australia., 2.Illawara Health and Medical Research Institute, School of Medicine, University of Wollongong, Wollongong NSW 2522, Australia., 3.NHMRC Clincial Trials Centre, University of Sydney, Sydney, NSW 2522, Australia
Presenter
K

Kate H Moore

Links

Abstract

Hypothesis / aims of study
There have been two observational, non-randomised studies of antibiotic therapy in patients with OAB (Phase IIA studies), in view of the known predilection of such patients to develop UTI. For example, 147 patients with OAB and evidence of cystitis were treated in 2011 with Nitrofurantoin or Cephalexin (combined with antimuscarinic drugs + bladder training), versus 212 patients with OAB but without evidence of cystitis who received standard therapy, over 7 years. The response to treatment [on voids/ day] was significantly greater in the antibiotic group versus standard treatment group [1]. In 2013, women with refractory urge incontinence (n=39) were given a 6 week course of rotating antibiotics, yielding a significant benefit in urge incontinence, voiding frequency, urgency scores, and Quality of Life [2]. However, these studies were not RCT’s and were not placebo controlled. 

We aimed to undertake a double-blind placebo controlled RCT to examine the effect of antibiotics in addition to anticholinergics in women with refractory Detrusor Overactivity (DO). The primary outcome was 24hour pad test, secondary outcomes were Patient Perception of Intensity of Urgency Scale (PPIUS), ICIQ, leaks/day and voids/ day on frequency volume chart (FVC).
Study design, materials and methods
Women with refractory DO were recruited to a double-blind randomised placebo-controlled trial of antibiotics; a Phase II trial, registered with ACTRN12613000285752. Recruitment has been ongoing since May 2014. Inclusion criteria; women > 50 years, urodynamically proven DO refractory to treatment; [defined as persistent disabling urge incontinence (1 or more leaks/ day) with frequency and nocturia, (>9 voids/ 24h) after 12 months of bladder retraining and >2 anticholinergic drugs]. Exclusions were; unable to give informed consent, eGFR<60ml/min, previous pelvic radiotherapy, neurogenic DO or voiding dysfunction. 

After a 2.5 week washout period to stop all drugs related to refractory DO, baseline symptoms were established. Prior to randomisation, symptomatic UTI was treated, asymptomatic bacteriuria was not. Patients were then randomised into 6 week antibiotic or placebo group (2:1 ratio). Randomisation was stratified by severity of leakage on pad test, voids/ day and history of recurrent UTI. The antibiotic arm received 2 weeks each of Norfloxacin, Augmentin Duo and Nitrofurantoin.  All patients received Darifenacin 15mg daily for the 6 months of the trial. The primary outcome was 24 pad test. Secondary outcomes were PPIUS, 3 day FVC (to assess leaks/ day and voids/ day) and ICIQ. These outcomes were collected at baseline, 6 weeks treatment with antibiotics/ placebo and at 6 months.

Midstream urine (MSU) samples were collected at randomisation (0 weeks), then at weeks 2, 4, and 6 (after antibiotic/ placebo treatment).  A diagnosis of UTI was reported by the Microbiology Department as the presence of a single bacterial species (>106CFU/L). Following recruitment of 36 women (24 to the antibiotic treatment group and 12 to placebo) an interim analysis has been undertaken by the team scientists to assess futility. These data are presented as a difference from baseline and a percentage change from baseline. Analysis was by t-test.
Results
The mean age and other variables revealed adequate stratified randomisation. At randomisation, 8.33% of the antibiotic arm had proven bacterial cystitis compared to 25% in placebo group. During the 6 weeks of treatment, microbiology demonstrated that women treated with antibiotics were less likely to have a UTI (Antibiotic: 10 UTI per 96 patient episodes = 10.41% vs Placebo 14 UTI per 48 patient episodes = 29.1%, Figure 1). 

The trial outcome measures at baseline and after 6 weeks treatment are shown in Table 1 (Six month data will be analysed in future). These data are presented as a difference from baseline and a percentage change from baseline.
Interpretation of results
For all outcomes, there were no statistically significant differences between the antibiotic or placebo groups (Table 1). However a clinically relevant trend was observed, in that active treatment was associated with a greater reduction in urge leakage on pad test (Antibiotic 18.9% vs Placebo 7.5%) and urge incontinence episodes on FVC (Antibiotic 23.6% vs Placebo 0.2%). The PPIUS was very disappointing in terms of discriminating differences between groups on Urgency. Furthermore, across all outcomes measures, the degree of variability was greater than anticipated. Although randomisation was stratified for History of UTI, there was an unintended predominance of bacterial cystitis in the placebo arm at baseline.
Concluding message
To our knowledge, this is the first randomised controlled trial of rotating antibiotics versus placebo, with anticholinergics, for treatment of refractory DO.  Patient recruitment became exceedingly difficult during the second year when intravesical Botox A injections became publicly funded for refractory DO. This created an ethical dilemma amongst all recruiting clinicians/ recruitment sites.
Figure 1 Figure 1. Incidence of UTI as a % of total number of patients per trial group during the 6 weeks of antibiotic or placebo
Figure 2 Table 1. Difference from baseline in outcome measures at 6 weeks in antibiotic and placebo treated women [Mean (SD)]
References
  1. Gill K, Khasriya R, Kupelian A, Brackenridge L, Horsley H, Sathiananthamoorthy S, Malone-Lee J (2011) The antibiotic treatment of OAB cohort. Int J Urogynea 22; S192
  2. Vijaya G, Cartwright R, et al., (2013) Changes in nerve growth factor level & symptom severity following antibiotic treatment for refractory OAB. Int Urogynecol J. Feb 2
Disclosures
<span class="text-strong">Funding</span> This trial was funded by a grant from BUPA Health Foundation <span class="text-strong">Clinical Trial</span> Yes <span class="text-strong">Registration Number</span> Australia and New Zealand Clinical Trials Registry, Registration number: ACTRN12613000285752 <span class="text-strong">RCT</span> Yes <span class="text-strong">Subjects</span> Human <span class="text-strong">Ethics Committee</span> South East Sydney Area Health Service Human Research Ethics Committee <span class="text-strong">Helsinki</span> Yes <span class="text-strong">Informed Consent</span> Yes