Current Treatment of Overactive Bladder in Patients with Diabetes and Obesity
A review and assessment of five current research studies for the efficacy in managing overactive bladder syndrome, particularly in patients with metabolic disease.
October 2019
Volume 1, Issue 8

Drug Preferences for Treatment of Overactive Bladder—PREFER Trial

A four way, cross-over phase 4 study was conducted to compare tolerability of tolterodine ER to mirabegron in patients with at least moderate overactive bladder syndrome.

Int Urogynecol J. 2018;29:273-283.

Evaluating Tolerability of Drug Therapies for OAB

This phase 4, prospective, double-blind, active-controlled study—the PREFER Trial—compared the tolerability of mirabegron to extended-release tolterodine (tolterodine-ER) among treatment-naïve individuals with overactive bladder syndrome (OAB).1

The study was conducted at 28 sites across the United States and eight sites in Canada. To participate in the PREFER Trial,  individuals must have experienced OAB for at least three months, faced three or more urgency episodes over three consecutive days, and had an average of eight or more micturitions over 24 hours at baseline.

The study was a two-period crossover design, which allowed the participants to serve as their own matched controls. These individuals were randomized to one of four treatment sequences in a 5:5:1:1 ratio:

  • mirabegron/tolterodine-ER
  • tolterodine-ER/mirabegron
  • mirabegron/mirabegron
  • tolterodine-ER/tolterodine-ER.

The sequences in which participants received the same drug twice allowed for the estimation of treatment effects regardless of carry-over effects.

Overall, participants were diagnosed with moderate to severe overactive bladder symptoms at baseline. After a baseline visit, participants received the first treatment in the sequence for eight weeks, then entered a two-week washout period. After the washout period, they had a second baseline visit at Week 10, then received the second treatment for 8 weeks.

Study participants were required to complete a three-day bladder diary before both baseline visits (at week 0 and  week 10) and again before office visits at weeks 4 ,8, 14, and 18. In addition, they were required to completed  Medication Tolerability scale as part the OAB Treatment Satisfaction (OAB-S) questionnaire, The questionnaire was administered at each follow-up visit during the treatment periods to assess drug toleratiblity. The responses were used to assess the level of discomfort associated with side effects such as constipation, dry mouth, drowsiness, headache, nausea, and blurred vision. These adverse effects were assessed on a scale of 1 (“bothered a lot”) to 6 (“did not have side effect”). A total score for the OAB-S Medication Tolerability scale was calculated in a range from 0 to 100. 

At the end of the second treatment period, participants used a five-point Likert scale to rate their preferences for treatment period. Participants who discontinued treatment completed a 3-day bladder diary and questionnaires for that period. The total study duration of 22 weeks included a follow-up phone call 2 weeks after the end of treatment.

Data Demonstrates Medication Preference in Overactive Bladder Therapy
Mean OAB-S Medication Tolerability scores were higher in period 2 for all treatment sequences, and they were higher for mirabegron than for tolterodine-ER in both periods (85.48 vs 82.46 in period 1, 87.10 vs 84.33 in period 2). Overall, the mean score was significantly higher among patients receiving mirabegron than among those receiving tolterodine-ER (86.29 vs 83.40, P = 0.004).

THE OAB-S Medication Tolerability Scores were higher for mirabegron than for tolterodine-ER in both men and women, but the estimated improvement in mean score was greater for women. Improved scores were also more apparent and improvements were higher for mirabegron, in participants aged 65 years or older and in those without baseline incontinence. There was no statistically significant period-by-treatment interaction, indicating that treatment sequence did not affect mean OAB-S Medication Tolerability scores.

The higher tolerability for mirabegron was not associated with a medication preference. Among patients receiving the mirabegron/tolterodine-ER or tolterodine-ER/mirabegron sequence, 69.8% expressed a preference for either treatment period, compared with 72.5% of patients receiving the same drug for both treatment periods. A higher percentage of patients reported a strong preference for mirabegron than for tolterodine (70.6% vs 63.7%), but this comparison was not tested for significance.

More participants selected “better treatment” than “tolerated better” as the reason for their preference (83.5% vs 24.7% for mirabegron, 89.0% vs 18.7% for tolterodine-ER, comparisons not tested for significance). In a post-hoc analysis, men and patients aged 65 years and older were more likely to prefer mirabegron, and women and younger patients were more likely to prefer tolterodine-ER.

There were no differences between treatments with respect bladder diary variables, daily incontinence episodes, micturition frequency, percentage of incontinent participants achieving zero incontinence episodes, or percentage of incontinent participants reducing the number of incontinence episodes by more than half.

As for adverse effects, more participants reported dry mouth on tolterodine-ER than on mirabegron (56.5% vs 44.5%), and more than half of the participants experiencing dry mouth on tolterodine-ER reported it as bothersome. Aside from that difference, most patients did not experience the adverse effects measured by the OAB-S Medication Tolerability scale.

With respect to treatment-emergent adverse effects, more participants experienced anticholinergic and gastrointestinal disorders on tolterodine-ER than on mirabegron (27.4% vs 20.4%, P = 0.042 for anticholinergic effects; 22.5% vs 14.7%, P = 0.015 for gastrointestinal disorders). These differences, which were driven by variations in the frequency of dry mouth, were consistent with the higher tolerability observed with mirabegron, according to the investigators.

Expert Commentary on Drug Treatment Tolerability from the PREFER Trial

Tolterodine-ER and mirabegron demonstrated similar improvements in objective, bladder-diary variables. Even as both medicines were well tolerated by participants, the researchers found  statistically significant higher medication tolerability scores for mirabegron over tolterodine ER. 

Not surprisingly, these findings were driven by a lower incidence of common anticholinergic treatment emergent adverse events, such as dry mouth and other gastrointestinal symptoms, among patients rating tolerability while taking mirabegron. 

Patient preference and improvements in overactive bladder symptoms were comparable between treatment groups. However, there is no clear explanation for the lack of evident differences in treatment tolerability having no influence on drug preference. The selection of a crossover design is consider to be a strength of this study, as it may allow for a more adept process for determining patient differences in both drug and symptom comparisons since patients served as their own matched controls. 

Commentary

Next Article:
Efficacy and Safety of Combination Pharmacotherapy for Overactive Bladder
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