Overactive Bladder Syndrome Clinical Trial
Official title:
Therapeutic Efficacy and Safety of Mirabegron , a β3-Adrenoceptor Agonist, Treatment on Patients With Overactive Bladder Syndrome in Taiwan - Comparison of Therapeutic Efficacy and Safety Between 25mg and 50mg
Recent phase III trials have confirmed the efficacy and safety of mirabegron in the treatment of overactive bladder (OAB) in Europeans, Australians, North Americans, Japanese and Asians. Whether mirabegron 25mg or 50mg should be used as the first line treatment for OAB has not been determined yet. The dose effectiveness relationship between 25mg and 50mg mirabegron has also not been investigated yet. Hence, investigators have conducted this post marketing study in order to evaluate the efficacy and safety between mirabegron 25mg and 50mg in Taiwanese people with symptoms of OAB.
Overactive bladder syndrome (OAB) is defined as the symptom syndrome with frequency, and
urgency with or without urgency incontinence. OAB affects more than 400 million people
worldwide and has been estimated to affect around 16% of the adult population across Europe
and the USA. In Asian countries, the prevalence of OAB has been reported to be 6% of men and
women aged ≥18 years in China; 12.2% of men and women in Korea;12.4% of men and women aged
≥40 years in Japan; and 21 to 25% of women and 16.9% of community dwelling adults in Taiwan.
Another study reported that the prevalence of OAB among adult men across 11 Asian countries
(India, Indonesia, Malaysia, Pakistan, Philippines, Singapore, South Korea, Taiwan, China,
Hong Kong and Thailand) was 29.9%.
Antimuscarinics are first line pharmacotherapy for OAB. However, some patients have a
suboptimal response to antimuscarinics and some may experience adverse effects, such as dry
mouth or constipation. Therefore, a high proportion of patients discontinue antimuscarinic
therapy, with fewer than 25% remaining on treatment at 1 year. There is an unmet need to
develop new drugs for OAB without the bothersome adverse effects of antimuscarinic agents.
β3-adrenergic receptors are known to promote urine storage in the bladder by inducing
detrusor relaxation in animal and human bladders. In humans, the β3-adrenoceptor is the
predominant β-receptor subtype in the urinary bladder. β3-adrenoceptor agonists relax the
detrusor smooth muscle during the bladder storage phase and increase bladder capacity
without accompanying changes in micturition pressure, residual volume or voiding
contraction.
Mirabegron is the first β3-adrenoceptor agonist to have been approved for the treatment of
OAB. Pooled safety data indicates that dry mouth, the chief cause of treatment
discontinuation with antimuscarinic agents, occurs with low incidence with mirabegronc.
Hence, mirabegron may be a valuable treatment option for patients with OAB.
Recent phase III trials have confirmed the efficacy and safety of mirabegron in the
treatment of OAB in Europeans, Australians, North Americans, Japanese and Asians. Whether
mirabegron 25mg or 50mg should be used as the first line treatment for OAB has not been
determined yet. The dose effectiveness relationship between 25mg and 50mg mirabegron has
also not been investigated yet. Hence, investigators have conducted this post-marketing
study in order to evaluate the efficacy and safety between mirabegron 25mg and 50mg in
Taiwanese people with symptoms of OAB.
Materials and Methods
Study Title: Therapeutic Efficacy and Safety of Mirabegron , a β3-Adrenoceptor Agonist, for
Patients with Overactive Bladder Syndrome in Taiwan
Primary objective: to evaluate the efficacy of Mirabegron 50 mg vs 25 mg in Taiwanese
patients
Secondary objective: to assess safety and tolerability of Mirabegron 50 mg vs 25 mg in
Taiwanese patients
Other objective: to investigate potential predictive factors of treatment outcome using
baseline demographic (ex. Comorbidity, age, etc.) and urodynamic study findings.
Randomization will be accomplished using a computer-generated randomization scheme (Cenduit
GmbH, Allshwil, Switzerland) with stratification by site; allocation to treatment groups at
each site was accomplished via an interactive response system with a study coordinator.
Study visits took place at Week 0 (Visit 1; confirmation of eligibility criteria); Weeks 4,
8 and 12 (Visits 2, 3 and 4).
The study will be approved by the institutional review board of each study site and
conducted in accordance with the ethical principles that have their origin in the
Declaration of Helsinki, Good Clinical Practice, International Conference on Harmonisation
guidelines, and all applicable laws and regulations.
Efficacy End-points:
Primary endpoint(s): The percentage of patients with a change from baseline to the final
visit in the urgency episodes per 24 hours by 2 or greater.
Secondary endpoint(s):
1. Secondary efficacy end-points are change from baseline to the final visit in OABSS
score, Patient Perception on Intensity of Urgency Scale (PPIUS), mean number of
frequency episodes, urinary incontinence episodes, urgency incontinence episodes and
nocturia episodes per 24 hours, and mean volume voided per micturition. Change from
baseline to each study visit in each efficacy variable will also be measured. An
additional secondary end-point is change from baseline to final visit in the Patient
Perception of the ladder Condition (PPBC) to assess patients' subjective satisfaction
of treatment drugs on bladder conditions. Paper diary will be used in this trial.
2. Adverse events (AEs) are assessed at all visits. Safety endpoints are incidence and
severity of AEs, and changes from baseline to end-of-treatment in vital signs (heart
rate, systolic and diastolic blood pressures) and laboratory tests (hematology,
biochemistry and urinalysis).
3. To determine the predictive factors of treatment outcome using baseline demographic
(ex. comorbidity, age, etc.) and urodynamic study findings.
PPIUS (Patient Perception of Intensity of Urgency Scale):
0. No urgency, I felt no need to empty my bladder, but did so for other reasons.
1. Mild urgency, I could postpone voiding as long as necessary, without fear of wetting
myself.
2. Moderate urgency, I could postpone voiding for a short while, without fear of wetting
myself.
3. Severe urgency, I could postpone voiding, but had to rush to the toilet in order not to
wet myself.
4. Urge incontinence, I leaked before reaching the toilet.
Patient Perception of the ladder Condition (PPBC):
Which of the following statements describes your bladder condition best at the moment? 0: My
bladder condition does not cause me any problems at all.
1. My bladder condition causes me some very minor problems.
2. My bladder condition causes me some minor problems.
3. My bladder condition causes me (some) moderate problems.
4. My bladder condition causes me severe problems.
5. My bladder condition causes me many severe problems.
Safety Assessment:
Safety assessments included reporting of adverse events (AEs, all unfavorable signs and
symptoms observed from the start of the run-in period until the end of the follow-up
period). Exacerbation of the symptoms of OAB was not defined as an AE in this clinical
study.
Sample size: 574 patients within two years Justification:The sample size for this study was
based on results from a 12-week Phase III study (178-CL-074). In 074 study, the responder
analysis for reduction in urgency episodes for minimum important difference of 1.54 episodes
was 47.1% in the M25 group and 57.7% in the M50 group. In this ISR, the primary efficacy
end-point is the percentage of patients with a change from baseline to the final visit in
the urgency episodes per 24 hours by 2 or greater. The responding rate is assumed as 60% in
the M50 group and 45% in the M25 group. The number of patients per group necessary to
demonstrate superiority to the first group (mirabegron 25mg for 12 weeks) would be 244 at a
two-sided significance level of 5% and power of 90%. Assuming a dropout rate of 15% during
the treatment period, 287 subjects per group are to be enrolled for randomization.
Expected Results:
The results of this study will demonstrate that:
1. Mirabegron 25mg once-daily for 12 weeks is effective and safe in treatment of patients
with OAB (group 1).
2. Mirabegron 50mg is effective in improving OAB symptoms when the therapeutic efficacy of
the dose of 25mg mirabegron for 4 weeks is suboptimal (group 2)
3. Investigators will try to search for predictive factors for responders to mirabegron
25mg alone, escalating to mirabegron 50mg, based on the baseline demographics and
urodynamic study findings,
;
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