40 research outputs found
Onset of action of the beta 3-adrenoceptor agonist, mirabegron, in Phase II and III clinical trials in patients with overactive bladder
Purpose Long-term persistence with pharmacotherapy for
overactive bladder (OAB) requires a drug with an early onset
of action and good efficacy and tolerability profile. Although
antimuscarinics improve OAB symptoms within 1–2 weeks
of initiating treatment, adherence after 3 months is relatively
poor due to bothersome side effects (e.g., dry mouth and
constipation). Mirabegron, a b3-adrenoceptor agonist, has
demonstrated significant improvements in key symptoms of
OAB and good tolerability after 12 weeks in Phase III studies.
Methods This was a prespecified pooled analysis of three
randomized, double-blind, placebo-controlled, 12-week
studies, and a Phase II study, to evaluate efficacy and tolerability
of mirabegron 25 and 50 mg versus placebo. The
main efficacy endpoints were change from baseline to
week 1 (Phase II only), week 4, and final visit in mean
number of incontinence episodes/24 h, micturitions/24 h,
and mean volume voided/micturition (MVV).
Results A significant benefit for mirabegron 25 and 50 mg
versus placebo was evident at the first assessment point,
4 weeks after initiation of therapy, in Phase III studies for
incontinence, micturitions, and MVV. The earliest measured
benefit was after 1 week, in the Phase II study. Quality-of-life
parameters also significantly improved with mirabegron 25
and 50 mg as early as week 4. Significant benefits continued
throughout the studies. Mirabegron was well tolerated.
Conclusions The early onset of action and good overall
efficacy and tolerability balance that mirabegron offers
may lead to high rates of persistence with mirabegron in
the long-term treatment of OAB
A phase II dose-ranging study of mirabegron in patients with overactive bladder
Introduction and hypothesis Mirabegron is a potent and
selective β3-adrenoceptor agonist that may represent an
alternative treatment option in place of antimuscarinics for
patients with overactive bladder.
Methods Patients completed a single-blinded, 2-week placebo
run-in period followed by 12 weeks of randomized
(n=928) double-blinded treatment with mirabegron oral
controlled absorption system (OCAS) 25, 50, 100, or
200 mg once-daily (QD), placebo or tolterodine extended
release (ER) 4 mg QD. The primary endpoint was
change from baseline to end-of-treatment in mean number
of micturition episodes/24 h. Secondary endpoints
included changes in mean volume voided per micturition;
mean number of urinary incontinence, urgency urinary
incontinence, and urgency episodes/24 h; severity of urgency;
nocturia; and quality of life measures. Safety
parameters included vital signs, adverse events, laboratory
tests, electrocardiogram measurements and post-void residual
volume.
Results Mirabegron 25, 50, 100, and 200 mg resulted in dosedependent
reductions (improvements) from baseline to end-oftreatment
in micturition frequency of 1.9, 2.1, 2.1, and 2.2
micturitions/24 h respectively, versus 1.4 micturitions/24 h with
placebo (p≤0.05 for the mirabegron 50-, 100-, and 200-mg
comparisons). There was a statistically significant improvement
with mirabegron compared with placebo for most secondary
endpoints including quality of life variables. While there was a
significant (p<0.05) increase from baseline in pulse rate in the
mirabegron 100-mg and 200-mg groups, this was not associated
with an increased incidence of cardiovascular adverse events.
Conclusions The favorable efficacy and tolerability of mirabegron
in this phase II dose-finding study has led to its successful
advancement into a phase III clinical development program
Neoadjuvant chemoradiotherapy plus surgery versus active surveillance for oesophageal cancer: A stepped-wedge cluster randomised trial
Background: Neoadjuvant chemoradiotherapy (nCRT) plus surgery is a standard treatment for locally advanced oesophageal cancer. With this treatment, 29% of patients have a pathologically complete response in the resection specimen. This provides the rationale for investigating an active surveillance approach. The aim of this study is to assess the (cost-)effectiveness of active surveillance vs. standard oesophagectomy after nCRT for oesophageal cancer. Methods: This is a phase-III multi-centre, stepped-wedge cluster randomised controlled trial. A total of 300 patients with clinically complete response (cCR, i.e. no local or disseminated disease proven by histology) after nCRT will be randomised to show non-inferiority of active surveillance to standard oesophagectomy (non-inferiority margin 15%, intra-correlation coefficient 0.02, power 80%, 2-sided α 0.05, 12% drop-out). Patients will undergo a first clinical response evaluation (CRE-I) 4-6 weeks after nCRT, consisting of endoscopy with bite-on-bite biopsies of the primary tumour site and other suspected lesions. Clinically complete responders will undergo a second CRE (CRE-II), 6-8 weeks after CRE-I. CRE-II will include 18F-FDG-PET-CT, followed by endoscopy with bite-on-bite biopsies and ultra-endosonography plus fine needle aspiration of suspected lymph nodes and/or PET- positive lesions. Patients with cCR at CRE-II will be assigned to oesophagectomy (first phase) or active surveillance (second phase of the study). The duration of the first phase is determined randomly over the 12 centres, i.e., stepped-wedge cluster design. Patients in the active surveillance arm will undergo diagnostic evaluations similar to CRE-II at 6/9/12/16/20/24/30/36/48 and 60 months after nCRT. In this arm, oesophagectomy will be offered only to patients in whom locoregional regrowth is highly suspected or proven, without distant dissemination. The main study parameter is overall survival; secondary endpoints include percentage of patients who do not undergo surgery, quality of life, clinical irresectability (cT4b) rate, radical resection rate, postoperative complications, progression-free survival, distant dissemination rate, and cost-effectiveness. We hypothesise that active surveillance leads to non-inferior survival, improved quality of life and a reduction in costs, compared to standard oesophagectomy. Discussion: If active surveillance and surgery as needed after nCRT leads to non-inferior survival compared to standard oesophagectomy, this organ-sparing approach can be implemented as a standard of care