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Kaplan S.A.,Cornell University | He W.,Astellas Pharma Global Development | Koltun W.D.,Medical Center for Clinical Research | Cummings J.,Astellas Pharma Global Development | And 2 more authors.
European Urology | Year: 2013

Background: Alpha blockers are prescribed to manage lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). Antimuscarinics are prescribed to treat overactive bladder (OAB). Objective: To investigate the safety of a combination of solifenacin (SOLI) and tamsulosin oral controlled absorption system (TOCAS) in men with LUTS and bladder outlet obstruction (BOO). Design, setting, and participants: Randomized, double-blind, parallel-group, placebo-controlled study in men aged >45 yr with LUTS and BOO for ≥3 mo, total International Prostate Symptom Score (IPSS) ≥8, BOO index ≥20, maximum urinary flow rate (Qmax) ≤12 ml/s, and voided volume ≥120 ml. Interventions: Once-daily coadministration of TOCAS 0.4 mg plus SOLI 6 mg, TOCAS 0.4 mg plus SOLI 9 mg, or placebo for 12 wk. Outcome measurements and statistical analysis: Primary (safety) measurements: Qmax and detrusor pressure at Qmax (PdetQ max). Other safety assessments included postvoid residual (PVR) volume. Secondary end points included bladder contractile index (BCI) score and percent bladder voiding efficiency (BVE). An analysis of covariance model compared each TOCAS plus SOLI combination with placebo. Results and limitations: Both active treatment groups were noninferior to placebo at end of treatment (EOT) for PdetQmax and Qmax. Mean change from baseline PVR was significantly higher at all time points for TOCAS 0.4 mg plus SOLI 6 mg, and at weeks 2, 12, and EOT for TOCAS 0.4 mg plus SOLI 9 mg versus placebo. Both treatment groups were similar to placebo for BCI and BVE. Urinary retention was seen in only one patient receiving TOCAS 0.4 mg plus SOLI 6 mg. Limitations of the study were that prostate size and prostate-specific antigen level were not measured. Conclusions: TOCAS 0.4 mg plus SOLI 6 mg or 9 mg was noninferior to placebo at EOT for PdetQmax and Q max in men with LUTS and BOO, and there was no clinical or statistical evidence of increased risk of urinary retention. © 2012 European Association of Urology.

Chapple C.R.,Royal Hallamshire Hospital | Kaplan S.A.,Cornell University | Mitcheson D.,St Elizabeths Medical Center | Klecka J.,University Hospital Plzen | And 4 more authors.
European Urology | Year: 2013

Background: Despite several antimuscarinic treatment options for overactive bladder (OAB), there is still a need for distinct treatment approaches to manage this condition. Mirabegron, a β3-adrenoceptor agonist, has demonstrated efficacy and tolerability for up to 12 wk in phase 3 trials. Objective: To assess the 12-mo safety and efficacy of mirabegron. Design, setting, and participants: Patients ≥18 yr of age with OAB symptoms for ≥3 mo. Interventions: After a 2-wk single-blind placebo run-in, patients with eight or more micturitions per 24 h and three or more urgency episodes in a 3-d micturition diary were randomized 1:1:1 to once-daily mirabegron 50 mg, mirabegron 100 mg, or tolterodine extended release (ER) 4 mg for 12 mo. Outcome measurements and statistical analysis: Primary variable: incidence and severity of treatment-emergent AEs (TEAEs). Secondary variables: change from baseline at months 1, 3, 6, 9, and 12 in key OAB symptoms. Results and limitations: A total of 812, 820, and 812 patients received mirabegron 50 mg, mirabegron 100 mg, and tolterodine ER 4 mg, respectively. Baseline demographic and OAB characteristics were similar across groups. TEAEs were reported in 59.7%, 61.3%, and 62.6% of patients, respectively; most were mild or moderate. Serious TEAEs were reported in 5.2%, 6.2%, and 5.4% of patients, respectively. The most common TEAEs were similar across groups. Dry mouth was reported by 2.8%, 2.3%, and 8.6% of patients, respectively. Adjusted mean changes from baseline to final visit in morning systolic blood pressure were 0.2, 0.4, and -0.5 mm Hg for mirabegron 50 mg, 100 mg, and tolterodine ER 4 mg, respectively. Mirabegron and the active control, tolterodine, improved key OAB symptoms from the first measured time point of 4 wk, and efficacy was maintained throughout the 12-mo treatment period. The study was not placebo controlled, which was a limitation. Conclusions: The safety and tolerability of mirabegron was established over 1 yr, with sustained efficacy observed over this treatment period. Trial registration: identifier: NCT00688688. © 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Drake M.J.,University of Bristol | Chapple C.,Sheffield Hallam University | Sokol R.,Private Urological Care Center | Oelke M.,Hannover Medical School | And 4 more authors.
European Urology | Year: 2015

Background Short-term trials have demonstrated the efficacy and safety of combination therapy using antimuscarinics and α-blockers in men with lower urinary tract symptoms (LUTS). The Study of Solifenacin Succinate and Tamsulosin Hydrochloride OCAS (oral controlled absorption system) in Males with Lower Urinary Tract Symptoms (NEPTUNE) II is the first long-term study using solifenacin (Soli) and the oral controlled absorption system formulation of tamsulosin (TOCAS). Objective To evaluate long-term (up to 52 wk) safety and efficacy of flexible dosing of two fixed-dose combinations (FDC) of Soli plus TOCAS in men with moderate to severe storage symptoms and voiding symptoms. Design, setting, and participants Patients with both storage and voiding LUTS, maximum urinary flow rate of 4.0-12.0 ml/s, prostate size <75 ml, and postvoid residuals ≤150 ml, who completed the 12-wk, double-blind NEPTUNE study could continue in the 40-wk, open-label NEPTUNE II study. Intervention FDC of Soli 6 mg plus TOCAS 0.4 mg, or Soli 9 mg plus TOCAS 0.4 mg; patients could switch between doses in NEPTUNE II. Outcome measurements and statistical analysis Safety and efficacy data from NEPTUNE and NEPTUNE II were combined to cover a 52-wk period. Primary efficacy end points were total International Prostate Symptom Score (IPSS) and total urgency and frequency score (TUFS); secondary end points included IPSS storage and voiding subscores, micturition diary variables, and quality of life parameters. Results In all, 1066 men completed NEPTUNE and received one dose or more of study medication in NEPTUNE II. Treatment-emergent adverse events were reported in 499 (46.8%) patients who participated in NEPTUNE II; most were mild or moderate. Urinary retention occurred in 13 of 1208 (1.1%) patients receiving one or more FDCs in NEPTUNE and/or NEPTUNE II; 8 (0.7%) required catheterisation (acute urinary retention [AUR]). Reductions in total IPSS and TUFS during NEPTUNE were maintained for up to 52 wk of FDC treatment, with mean reductions of 9.0 (standard deviation [SD]: 5.7) and 10.1 (SD: 9.2), respectively, from baseline to end of treatment. Clinically relevant improvements were also observed for secondary efficacy end points. Conclusions Long-term treatment with FDC Soli plus TOCAS was well tolerated and efficacious in men with storage and voiding LUTS, with a low incidence of AUR. Patient summary Treatment with solifenacin plus tamsulosin in a fixed-dose combination tablet was well tolerated by men with lower urinary tract symptoms. Improvements in symptoms were achieved after 4 wk of treatment, with further improvements at week 16 maintained for up to 52 wk throughout the study. © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.

News Article | December 20, 2016

INDIANAPOLIS -- Anticholinergic medications, a class of drugs very commonly used by older adults, are linked to an increased rate of emergency department and hospital utilization in the United States, according to an Indiana University Center for Aging Research, Indiana University Center for Health Innovation and Implementation Science, and Regenstrief Institute study of community-dwelling Americans age 65 and older. Drugs with anticholinergic properties are frequently prescribed or purchased over the counter for chronic conditions including depression, anxiety, pain, allergy, incontinence or sleep problems. These drugs are used by as many as half of older adults and it is not unusual for an older individual to be taking two or more anticholinergic medications regularly. The new study, published in the November 2016 issue of the peer-reviewed journal Phamacotherapy, analyzed actual prescription dispensing data from the Regenstrief Medical Record System to determine how much anticholinergic medication each person used, known as anticholinergic burden, and utilization of healthcare services such as hospital, emergency department and ambulatory visits. Prescription dispensing data are known to be more reliable than self-reported information. Fifty-eight percent of the 3344 study participants were African-American; 71 percent were female. Fewer than 10 percent were cognitively impaired. All were patients served by Eskenazi Health, an academic teaching health care system in Indianapolis. "Anticholinergics, the medications that block acetylcholine, a nervous system neurotransmitter, have previously been implicated as a potential cause of cognitive impairment, by us and by other researchers," said IU Center for Aging Research and Regenstrief Institute investigator Noll Campbell, PharmD, who led the new research. "This is the first study to calculate cumulative anticholinergic burden and determine that as burden increases, so does healthcare utilization in the U.S. -- both outpatient and inpatient." Dr. Campbell and colleagues report that taking a drug with mild anticholinergic effect daily increased the likelihood of inpatient admission by 11 percent over a year. Many drugs used to treat heart failure and hypertension fall into the mild group, such as diuretics. Taking a drug with a strong anticholinergic effect daily increased the likelihood of inpatient admission by 33 percent over a year. Sleeping pills, one of the most common medications used by elders, are in this category as are antihistamines, which are available without prescription. The IU Center for Aging Research has studied patient safety harms from anticholinergic medications in diverse populations for over a decade. In 2008, center scientists, led by the Chief Innovation and Implementation Officer of IU Center for Health Innovation and Implementation Science Malaz Boustani, MD, MPH, developed the Anti-Cholinergic Burden Scale, one of the most widely used tools to pinpoint the anticholinergic properties and anticholinergic load of specific drugs. Anticholinergic burden in this study was defined as the number of days someone was dispensed an anticholinergic medicine multiplied by the strength (mild versus strong) of the anticholinergic load. The new study was the first time that the Anti-Cholinergic Burden Scale was employed to calculate a cumulative score weighted by both number of days dispensed and strength of anticholinergic effect using prescription dispensing databases. In 2013 the IU Center for Aging Research investigators reported that continuously taking strong anticholinergics for as few as 60 days caused memory problems and other indicators of mild cognitive impairment. Taking multiple drugs with weaker anticholinergic effects, such as many common over-the-counter digestive aids, had a negative impact on cognition in only 90 days. "As baby boomers age and the number of older adults increases, it is especially important to recognize the negative impact of anticholinergic medications on the aging brain and healthcare delivery cost," said Dr. Boustani. "There is a powerful association between these harmful medications and potentially avoidable cognitive impairment and increased visits to the doctor, the ER and the hospital." "Individuals taking anticholinergics should talk with their doctors or pharmacists about possible alternatives," Dr. Campbell said. "This new study provides stronger motivation to design and conduct de-prescribing studies to determine safe ways to take individuals off anticholinergic medications in the interests of preserving brain health and decreasing healthcare utilization rates and their potential costs." Dr. Campbell is an assistant professor of pharmacy practice at Purdue University College of Pharmacy and a clinical pharmacy specialist with Eskenazi Health. In addition to Dr. Campbell and Dr. Boustani, authors of "Association of Anticholinergic Burden with Cognitive Impairment and Health Care Utilization Among a Diverse Ambulatory Older Adult Population" are Anthony J. Perkins, MS, of the IU Center for Healthcare Innovation and Implementation Science; Pamela Bradt, MD, MPH, and Daniel B. Ng, PharmD, MBA, MPH, of Astellas Pharma; and Sinem Perk, PhD and Ronald C. Wielage, MPH, of Medical Decision Modeling Inc. This work was supported by a research grant from Astellas Pharma Global Development.

Maman K.,Creativ Ceutical SARL | Aballea S.,Creativ Ceutical SARL | Nazir J.,Astellas Pharma Europe | Desroziers K.,Creativ Ceutical SARL | And 5 more authors.
European Urology | Year: 2014

Context Overactive bladder (OAB) treatment guidelines recommend antimuscarinics as first-line pharmacologic therapy. Mirabegron is a first-in-class β3-adrenoceptor agonist licensed for the treatment of OAB and has shown to be well tolerated and effective in the treatment of OAB symptoms. Objective To assess the relative efficacy and tolerability of OAB medications, specifically mirabegron 50 mg versus antimuscarinics in patients with OAB. Evidence acquisition A systematic literature search was performed on published peer-reviewed articles from 2000 to 2013. This review included randomised controlled trials (RCTs) studying changes in symptoms (micturition frequency, incontinence, and urgency urinary incontinence [UUI] episodes) and incidence of the most frequently reported adverse events (dry mouth, constipation) associated with current OAB medications. The following drugs were considered in addition to mirabegron: darifenacin, tolterodine immediate release (IR) and extended release (ER), oxybutynin IR/ER, trospium, solifenacin, and fesoterodine. Bayesian mixed treatment comparisons (MTCs) were performed for efficacy (micturition, incontinence, UUI) and tolerability (dry mouth, constipation, blurred vision). Evidence synthesis Overall, 44 RCTs involving 27 309 patients were included. The MTCs showed that mirabegron 50 mg was as efficacious as antimuscarinics in reducing the frequency of micturition incontinence and UUI episodes, with the exception of solifenacin 10 mg that was more efficacious than mirabegron 50 mg in improving micturition frequency and frequency of UUI. Mirabegron 50 mg had an incidence of dry mouth similar to placebo and significantly lower than all included antimuscarinics. Conclusions Mirabegron 50 mg had similar efficacy to most antimuscarinics and lower incidence of dry mouth, the most common adverse event reported with antimuscarinics and one of the main causes of discontinuation of treatment. Despite being a powerful tool for evidence-based health care evaluation, the Bayesian MTC method has limitations. Further head-to-head comparisons between mirabegron and antimuscarinics should be conducted to confirm our results. © 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Wagg A.,University of Alberta | Dale M.,MAC Clinical Research | Tretter R.,Astellas Pharma Global Development | Stow B.,Astellas Pharma Europe | Compion G.,Astellas Pharma Europe
European Urology | Year: 2013

Background: Compared with younger people, the elderly are more likely to suffer from overactive bladder (OAB) and to have other chronic conditions that affect physical or cognitive function. Despite this, there are few data on the cognitive safety of antimuscarinic agents in older patients and none that examine the effect of these agents on those with mild cognitive impairment (MCI). Objective: To evaluate cognitive effects during chronic stable dosing with solifenacin and oxybutynin versus placebo in older (≥75 yr) subjects with MCI. Design, setting, and participants: A randomised, double-blind, triple-crossover trial in 26 elderly volunteers with MCI. Cognitive function was assessed using Cognitive Drug Research (CDR) computerised testing. Intervention: Three treatment periods of 21 d each with solifenacin 5 mg once daily, oxybutynin 5 mg twice daily, or placebo, separated by 21-d washout periods. Outcome measurements and statistical analysis: The primary end point was change from baseline in cognitive function with solifenacin at 6 h postdose and oxybutynin at 2 h postdose (time points close to their predicted time to peak concentration). Secondary end points included change in cognitive function at additional time points, and safety and tolerability assessments. Results and limitations: Neither agent was associated with significant changes from baseline in any of the five standard, composite outcomes of cognitive function (power of attention, continuity of attention, quality of working memory, quality of episodic memory, and speed of memory). In a secondary analysis, oxybutynin was associated with significant decreases in power and continuity of attention versus placebo at 1-2 h postdose. Both agents were well tolerated, with the most frequently reported adverse event being mild or moderate dry mouth. Conclusions: Solifenacin had no detectable effect on cognition in this group of elderly people with MCI. © 2013 European Association of Urology.

News Article | December 16, 2015

Live long enough, and most men will develop prostate cancer. Globally, it is the second most common cancer in men, and in some places it takes the top spot (page S118). As the prime reproductive years fade, the gland typically begins to misbehave. The first sign that men often experience is inflammation — a condition that is sometimes, but not always, a precursor to cancer. The interplay between inflammation and cancer remains an area of intense research (page S130). Prostate-cancer screening has provoked contentious debate (page S120). Blood tests for prostate-specific antigen (PSA) have led to the discovery of cancers at earlier and more treatable stages. But they have also revealed many tumours that could safely be left untreated. Researchers are looking beyond PSA to other biomarkers that could be used to tell more reliably which cancers need treatment (page S124). Often, the best therapeutic option is just to be vigilant — 'active surveillance' is now the norm (page S126). When a trip to the operating theatre is unavoidable, robotics is making prostate surgery less likely to cause adverse effects (page S132). Hopes for a vaccine have dimmed (page S134). The only approved immunotherapy for prostate cancer — sipuleucel-T — adds mere months to survival time and is expensive. Researchers are focusing on combinations of therapies, such as a checkpoint therapy administered together with a drug that targets tumour hypoxia. Because prostate tumours are most dangerous once they escape the gland itself, intense efforts are targeting metastatic cancers that have become resistant to standard treatments (page S128). We are pleased to acknowledge support from Ferring Pharmaceuticals and a grant from Astellas Pharma Global Development, Inc. and Medivation, Inc. in producing this Outlook. As always, Nature retains sole responsibility for all editorial content.

Ball G.,Astellas Pharma Global Development
Contemporary Clinical Trials | Year: 2011

Standard methods for testing safety data are needed to ensure the safe conduct of clinical trials. In particular, objective rules for reliably identifying unsafe treatments need to be put into place to help protect patients from unnecessary harm. DMCs are uniquely qualified to evaluate accumulating unblinded data and make recommendations about the continuing safe conduct of a trial. However, it is the trial leadership who must make the tough ethical decision about stopping a trial, and they could benefit from objective statistical rules that help them judge the strength of evidence contained in the blinded data. We design objective early stopping rules for harm that act as continuous safety screens for randomized controlled clinical trials using the accumulating data with blinded treatment information, which could be used by anyone, including trial investigators and trial leadership. A Bayesian framework, with emphasis on the likelihood function, is used to allow for continuous monitoring without adjusting for multiple comparisons. Close collaboration between the statistician and the clinical investigators will be needed in order to design safety screens with good operating characteristics. Though the math underlying this procedure may be computationally intensive, implementation of the statistical rules will be easy and the continuous screening provided will give suitabley early warning when real problems were to emerge. Trial investigators and trial leadership need these safety screens to help them to effectively monitor the ongoing safe conduct of clinical trials with blinded data. © 2011 Elsevier Inc.

Kurosaki E.,Astellas Pharma Inc. | Ogasawara H.,Astellas Pharma Global Development
Pharmacology and Therapeutics | Year: 2013

Sodium-glucose cotransporter-2 (SGLT2) is expressed in the proximal tubules of the kidneys and plays a key role in renal glucose reabsorption. A novel class of antidiabetic medications, SGLT2-selective inhibitors attempt to improve glycemic control in diabetics by preventing glucose from being reabsorbed through SGLT2 and re-entering circulation. Ipragliflozin is an SGLT2 inhibitor in Phase 3 clinical development for the treatment of type 2 diabetes mellitus (T2DM). In this review, we summarize recent animal and human studies on ipragliflozin and other SGLT2 inhibitors including dapagliflozin, canagliflozin, empagliflozin, tofogliflozin, and luseogliflozin. These agents all show potent and selective SGLT2 inhibition in vitro and reduce blood glucose levels and HbA1c in both diabetic animal models and patients with T2DM. SGLT2 inhibitors offer several advantages over other classes of hypoglycemic agents. Due to their insulin-independent mode of action, SGLT2 inhibitors provide steady glucose control without major risk for hypoglycemia and may also reverse β-cell dysfunction and insulin resistance. Other favorable effects of SGLT2 inhibitors include a reduction in both body weight and blood pressure. SGLT2 inhibitors are safe and well tolerated and can easily be combined with other classes of antidiabetic medications to achieve tighter glycemic control. The long-term safety and efficacy of these agents are under evaluation. © 2013 Elsevier Inc. All rights reserved.

Marek G.J.,Astellas Pharma Global Development
Current Pharmaceutical Design | Year: 2015

Pomaglumetad methionil (LY2140023) is a mGlu2/3 receptor agonist prodrug reported in 2007 to possess antipsychotic efficacy based on results of a phase 2 trial conducted entirely in Russia using in-patients with schizophrenia. Since that time, pomaglumetad methionil failed to demonstrate antipsychotic efficacy compared to placebo in three phase 2 or phase 3 trials, despite risperidone separating from placebo in one phase 3 trial. While there was some evidence of an antipsychotic effect in these studies on an a priori specified genetically-defined subpopulation based on single nucleotide polymorphisms of the 5-hydroxytryptamine2A receptor gene (HTR2A) , these effects were modest when compared to very limited effects in the overall population of schizophrenic patients responding to SOC second generation antipsychotic drugs. Post-hoc analyses also suggested antipsychotic efficacy for pomaglumetad methionil in subjects with a disease duration equal/less than 3 years or subjects previously treated with antipsychotic drugs predominantly acting at dopamine D2 receptors compared to 5-HT2A receptors. Orthogonal to these results with the mGlu2/3 receptor agonist prodrug, a 5-HT2A receptor inverse agonist pimavanserin demonstrated antipsychotic efficacy in subjects with Parkinson’s disease (PD) psychosis despite limited and at best modest evidence of antipsychotic efficacy for a number of selective 5-HT2A receptor antagonists in subjects with schizophrenia. Based on the precedent for pimavanserin in PD psychosis, the known overlapping preclinical profile of mGlu2/3 receptor agonists and 5-HT2A receptor antagonists/inverse agonists and the neurobiology of other psychosis associated with neurodegenerative illness, there remains open a hypothesis that mGlu2/3 receptor agonists may exert clinically significant antipsychotic effects in PD psychosis, dementia with Lewy Bodies, and Alzheimer’s disease psychosis. © 2015, Bentham Science Publishers.

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