Mirabegron (1) – Betmiga®

• Clinical trials
  • To demonstrate additional benefit, the pharmaceutical manufacturer has submitted five comparative randomised controlled trials: trial 178-CL-049 (TAURUS) with a study duration of 52 weeks, as well as four studies, each lasting 12 weeks: 178-CL-044 (DRAGON), 178-CL-046 (SCORPIO), 178-CL-048 and 178-CL-090.
  • Study 049 was a blinded, randomised, actively controlled Phase III trial.

a) symptomatic treatment of urgent urinary urgency, increased urinary frequency and/or urge incontinence, which may occur in adults with overactive bladder (OAB)

• For the symptomatic treatment with mirabegron of patients with an urgent urge to urinate, increased urinary frequency and/or urge incontinence, which may occur in adults with overactive bladder (OAB, ‘overactive bladder’), additional benefit is not proven compared with the appropriate comparator therapy.
• mortality
  • For the endpoint of all-cause mortality, the differences in outcomes were not statistically significant given the minor event rate at the 52-week evaluation point.
  • No additional benefit or greater harm from mirabegron compared with the appropriate comparator therapy is not proven for this endpoint.
• morbidity
  • The burden on patients caused by symptoms of overactive bladder was assessed using the Perception of Bladder Condition (PPBC) and Overactive Bladder Questionnaire (OABq) questionnaires.
  • Neither of these instruments revealed any statistically significant differences between the treatment groups.
  • Nor were there any statistically significant differences in the frequency of micturition, urgent urge to urinate and nocturnal micturition.
  • Regarding the endpoints of the frequency of incontinence and urge incontinence episodes, the dossier submitted by pU contained data only for the sub-population of patients who were already suffering from incontinence at the start of the study.
  • As it is possible that symptoms of incontinence or urge incontinence may also develop during the course of the study in patients who did not exhibit such symptoms at the start of the study, data from the overall population are required for an assessment.
  • As these are missing, the results for the patient population cannot be used to demonstrate additional benefit.
  • During the commenting procedure, the pharmaceutical manufacturer submitted analyses based on the study’s overall population.
  • The subsequently submitted analyses lack a descriptive presentation of the data that would allow an assessment of the underlying distribution, as well as a precise description of the statistical methods used and the underlying assumptions.
  • Furthermore, information on the proportion of missing values in the analysis is missing, as is a discussion of the imputation method used for missing values.
  • Due to the missing information, the analyses submitted by the pharmaceutical company with its response regarding the endpoints of incontinence and urge incontinence cannot be meaningfully interpreted on the basis of the available information.
  • With regard to these endpoints, the equivalent efficacy of mirabegron has not been proven with sufficient certainty.
  • In summary, no valid conclusions regarding the additional benefit of mirabegron compared with the appropriate comparator therapy can be drawn from the morbidity data.
• quality of life
  • Quality of life was assessed in Study 049 using the Overactive Bladder Questionnaire (OABq).
  • Over the course of the study, no statistically significant differences were observed between the treatment groups, either in the overall OABq score or in the individual domains.
  • In summary, the additional benefit or greater harm from mirabegron compared with the appropriate comparator therapy is not proven in terms of quality of life.
• Side effects
  • No statistically significant differences were found between the treatment groups for the endpoints of adverse events (AE), serious adverse events (SAE) and study withdrawal due to AE.
  • The AE ‘dry mouth’ was statistically significantly more common in the group treated with the appropriate comparator therapy, tolterodine.
  • The incidence of study withdrawal due to dry mouth did not differ between the treatment groups and affected only a small proportion of patients (0.4% and 0.5%, respectively).
  • No statistically significant difference was observed between the treatment groups for other anticholinergic side effects.
  • Furthermore, there are no subgroup analyses for specific patient groups, in particular for patients with neurological conditions, such as Parkinson’s disease or multiple sclerosis, and for those on polypharmacy.
• Overall assessment
  • On balance, it is not possible to weigh up the additional benefit against the harm.
  • Consequently, the additional benefit of mirabegron compared with the appropriate comparator therapy is not proven.

Courtesy translation only, please refer to the German original.