Efficacy and Safety of Xanomeline-Trospium Chloride in Schizophrenia: A Randomized Clinical Trial.

Importance: A significant need exists for new antipsychotic medications with different mechanisms of action, greater efficacy, and better tolerability than existing agents. Xanomeline is a dual M1/M4 preferring muscarinic receptor agonist with no direct D2 dopamine receptor blocking activity. KarXT combines xanomeline with the peripheral muscarinic receptor antagonist trospium chloride with the goal of reducing adverse events due to xanomeline-related peripheral muscarinic receptor activation. In prior trials, xanomeline-trospium chloride was effective in reducing symptoms of psychosis and generally well tolerated in people with schizophrenia. Objective: To evaluate the efficacy and safety of xanomeline-trospium vs placebo in adults with schizophrenia. Design, Setting, and Participants: EMERGENT-3 (NCT04738123) was a phase 3, multicenter, randomized, double-blind, placebo-controlled, 5-week trial of xanomeline-trospium in people with schizophrenia experiencing acute psychosis, conducted between April 1, 2021, and December 7, 2022, at 30 inpatient sites in the US and Ukraine. Data were analyzed from February to June 2023. Interventions: Participants were randomized 1:1 to receive xanomeline-trospium chloride (maximum dose xanomeline 125 mg/trospium 30 mg) or placebo for 5 weeks. Main Outcomes and Measures: The prespecified primary end point was change from baseline to week 5 in Positive and Negative Syndrome Scale (PANSS) total score. Secondary outcome measures were change from baseline to week 5 in PANSS positive subscale score, PANSS negative subscale score, PANSS Marder negative factor score, Clinical Global Impression-Severity score, and proportion of participants with at least a 30% reduction in PANSS total score. Safety and tolerability were also evaluated. Results: A total of 256 participants (mean [SD] age, 43.1 [11.8] years; 191 men [74.6%]; 156 of 256 participants [60.9%] were Black or African American, 98 [38.3%] were White, and 1 [0.4%] was Asian) were randomized (125 in xanomeline-trospium group and 131 in placebo group). At week 5, xanomeline-trospium significantly reduced PANSS total score compared with placebo (xanomeline-trospium , -20.6; placebo, -12.2; least squares mean difference, -8.4; 95% CI, -12.4 to -4.3; P < .001; Cohen d effect size, 0.60). Discontinuation rates due to treatment-emergent adverse events (TEAEs) were similar between the xanomeline-trospium (8 participants [6.4%]) and placebo (7 participants [5.5%]) groups. The most common TEAEs in the xanomeline-trospium vs placebo group were nausea (24 participants [19.2%] vs 2 participants [1.6%]), dyspepsia (20 participants [16.0%] vs 2 participants [1.6%]), vomiting (20 participants [16.0%] vs 1 participant [0.8%]), and constipation (16 participants [12.8%] vs 5 participants [3.9%]). Measures of extrapyramidal symptoms, weight gain, and somnolence were similar between treatment groups. Conclusions and Relevance: Xanomeline-trospium was efficacious and well tolerated in people with schizophrenia experiencing acute psychosis. These findings, together with the previously reported and consistent results from the EMERGENT-1 and EMERGENT-2 trials, support the potential of xanomeline-trospium to be the first in a putative new class of antipsychotic medications without D2 dopamine receptor blocking activity. Trial Registration: ClinicalTrials.gov Identifier: NCT04738123.

[Long-term safety and efficacy of trospium chloride for the treatment of neurogenic overactive bladder due to Parkinson's disease is there an effect on cognitive status?]

AIM: To evaluate the efficiency of long-term use of trospium chloride (Spazmex) for the treatment of patients with neurogenic overactive bladder due to Parkinson's disease (PD) and to determine the influence of therapy on the cognitive status of patients. MATERIALS AND METHODS: 60 patients with PD and neurogenic overactive bladder with stages 2.5, 3 and 4 according to Hoehn-Yahr scale were included in the main group. The mean age was 58.2+/-5.7 years. All patients were prescribed trospium chloride at entry into the study, with doses titrated gradually according to clinical efficacy (30 to 90 mg). The comparison group included 15 patients with PD and neurogenic overactive bladder at stages 2,5 and 3, who received tibial neuromodulation according to the standard technique with skin electrodes. The mean age of patients was 56.4+/-4.6 years. At baseline, both groups were comparable in terms of gender, age and cognitive status (p=0.801). All patients received treatment for 52 weeks. The efficiency of therapy was assessed according to bladder diaries, while safety outcomes included postvoid residual, side effects, cognitive status according to the MoCA scale and quality of life according to the SF-Qualiveen questionnaire. RESULTS: clinical efficacy and satisfaction were achieved in all patients who completed the study (47 patients in the main group and 15 patients in the comparison group). Good clinical efficacy was demonstrated in both groups, since there was a decrease in the number of urinations, episodes of urgency and urinary incontinence. In addition, there was an improvement in the quality of life according to the SF-Qualiveen scale. The cognitive status during the entire follow-up period remained without significant changes in both groups. CONCLUSION: Trospium chloride is an effective drug in patients with PD. It does not affect cognitive functions during long-term use. Trospium chloride should be considered as first-line drug in those with urologic manifestations of PD.

Muscarinic Cholinergic Receptor Agonist and Peripheral Antagonist for Schizophrenia.

BACKGROUND: The muscarinic receptor agonist xanomeline has antipsychotic properties and is devoid of dopamine receptor-blocking activity but causes cholinergic adverse events. Trospium is a peripherally restricted muscarinic receptor antagonist that reduces peripheral cholinergic effects of xanomeline. The efficacy and safety of combined xanomeline and trospium in patients with schizophrenia are unknown. METHODS: In this double-blind, phase 2 trial, we randomly assigned patients with schizophrenia in a 1:1 ratio to receive twice-daily xanomeline-trospium (increased to a maximum of 125 mg of xanomeline and 30 mg of trospium per dose) or placebo for 5 weeks. The primary end point was the change from baseline to week 5 in the total score on the Positive and Negative Syndrome Scale (PANSS; range, 30 to 210, with higher scores indicating more severe symptoms of schizophrenia). Secondary end points were the change in the PANSS positive symptom subscore, the score on the Clinical Global Impression-Severity (CGI-S) scale (range, 1 to 7, with higher scores indicating greater severity of illness), the change in the PANSS negative symptom subscore, the change in the PANSS Marder negative symptom subscore, and the percentage of patients with a response according to a CGI-S score of 1 or 2. RESULTS: A total of 182 patients were enrolled, with 90 assigned to receive xanomeline-trospium and 92 to receive placebo. The PANSS total score at baseline was 97.7 in the xanomeline-trospium group and 96.6 in the placebo group. The change from baseline to week 5 was -17.4 points with xanomeline-trospium and -5.9 points with placebo (least-squares mean difference, -11.6 points; 95% confidence interval, -16.1 to -7.1; P<0.001). The results for the secondary end points were significantly better in the xanomeline-trospium group than in the placebo group, with the exception of the percentage of patients with a CGI-S response. The most common adverse events in the xanomeline-trospium group were constipation, nausea, dry mouth, dyspepsia, and vomiting. The incidences of somnolence, weight gain, restlessness, and extrapyramidal symptoms were similar in the two groups. CONCLUSIONS: In a 5-week trial, xanomeline-trospium resulted in a greater decrease in the PANSS total score than placebo but was associated with cholinergic and anticholinergic adverse events. Larger and longer trials are required to determine the efficacy and safety of xanomeline-trospium in patients with schizophrenia. (Funded by Karuna Therapeutics and the Wellcome Trust; ClinicalTrials.gov number, NCT03697252.).

Cognitive Effects of Anticholinergic Load in Women with Overactive Bladder.

Overactive bladder syndrome (OAB) is defined as urinary urgency, usually accompanied by frequency and nocturia, with or without urgency incontinence, in the absence of urinary tract infection or other obvious pathology. The mainstay of treatment of OAB is anticholinergic/antimuscarinic medication. These drugs block muscarinic receptors throughout the body, not only the bladder, including in the brain, which may lead to cognitive side effects. Anticholinergic load or burden is the cumulative effect of taking drugs that are capable of producing anticholinergic adverse effects. The elderly are more susceptible to these effects, especially as there is increased permeability of the blood brain barrier. The anticholinergic drugs for OAB are able to enter the central nervous system and lead to central side effects. There is increasing evidence that a high anticholinergic load is linked to the development of cognitive impairment and even dementia. Some studies have found an increased risk of mortality. In view of this, care is needed when treating OAB in the elderly. Trospium chloride is a quaternary amine anticholinergic, which has a molecular structure, which theoretically means it is less likely to cross the blood brain barrier and exert central side effects. Alternatively, mirabegron can be used, which is a beta-3 adrenoceptor agonist, which does not add to the anticholinergic load or exert central nervous system side effects. Conservative therapy can be used as an alternative to pharmacological treatment in the form of behavioral modification, fluid management and bladder retraining. Neuromodulation or the use of botox can also be alternatives, but success may be less in the older adult and will require increased hospital attendances.

Pharmacokinetic Drug-Drug Interactions Between Trospium Chloride and Ranitidine Substrates of Organic Cation Transporters in Healthy Human Subjects.

Trospium chloride, a muscarinic receptor blocker, is poorly absorbed with different rates from areas in the jejunum and the cecum/ascending colon. To evaluate whether organic cation transporter (OCT) 1, OCT2 and multidrug and toxin extrusion (MATE) 1 and MATE2-K are involved in pharmacokinetics, competitions with ranitidine, a probe inhibitor of the cation transporters, were evaluated in transfected HEK293 cells. Furthermore, a drug interaction study with trospium chloride after intravenous (2 mg) and oral dosing (30 mg) plus ranitidine (300 mg) was performed in 12 healthy subjects and evaluated by noncompartmental analysis and population pharmacokinetic modeling. Ranitidine inhibited OCT1, OCT2, MATE1, and MATE2-K with half maximal inhibitory concentration values of 186 ± 25 µM, 482 ± 105 µM, 134 ± 37 µM, and 35 ± 11 µM, respectively. In contrast to our hypothesis, coadministration of ranitidine did not significantly decrease oral absorption of trospium. Instead, renal clearance was lowered by ∼15% (530 ± 99 vs 460 ± 120 mL/min; P < .05). It is possible that ranitidine was not available in competitive concentrations at the major colonic absorption site, as the inhibitor is absorbed in the small intestine and undergoes degradation by microbiota. The renal effects apparently result from inhibition of MATE1 and/or MATE2-K by ranitidine as predicted by in vitro to in vivo extrapolation. However, all pharmacokinetic changes were not of clinical relevance for the drug with highly variable pharmacokinetics. Intravenous trospium significantly lowered mean absorption time and relative bioavailability of ranitidine, which was most likely caused by muscarinic receptor blocking effects on intestinal motility and water turnover.

Effect of trospium chloride therapy on intraocular pressure and tear secretion in overactive bladder patients.

PURPOSE: To investigate the effect of trospium chloride, which has an anticholinergic effect, used in overactive bladder (OAB) treatment on the intraocular pressure (IOP) and tear secretion after 12 weeks of treatment. MATERIALS AND METHODS: This prospective study was performed at a single center between October 2014 and January 2016. A detailed history was obtained from the female OAB patients at the eye outpatient department. After checking the exclusion criteria, oral trospium chloride 30 mg bd was started. The patients were followed-up in terms of drug effectiveness and ophthalmic and other side effects at the 4th and 12th weeks. All procedures were repeated at both of these time-points. RESULTS: The mean age of the patients was 48.98 ± 11.98 years (range 19-75). The data of 80 OAB patients were evaluated in the study. Trospium chloride did not cause any significant change in the OAB patients regarding their 4th week and 12th week IOP measurements (p = 0.251, p = 0.340, respectively). It was found to decrease tear secretion significantly at both time-points (p = 0.020, p = 0.001, respectively). Trospium chloride treatment of one patient (1.25%) was discontinued due to dry eye. CONCLUSIONS: Trospium chloride decreases the symptoms in female OAB patients. Trospium chloride can be safely used in female OAB patients with normal IOP and no comorbidity as regards IOP changes as it did not cause a significant change in IOP in these patients. Pre-treatment and post-treatment dry eye symptoms of OAB patients about to start using trospium chloride should be queried beforehand as it can cause a statistically significant decrease in tear secretion. We concluded that it would be appropriate to refer the patients to an ophthalmologist before starting the drug if relevant symptoms are present.

[High doses of trospium chloride in patients with idiopathic overactive bladder. Data of large-scale, multicenter observational program Resource].

PURPOSE: Evaluation of the efficacy and safety of different doses of trospium chloride in patients with idiopathic overactive bladder. MATERIALS AND METHODS: Large-scale observational program "Resource" included 669 patients with idiopathic OAB - 359 women and 310 men. At the first visit, all patients were assigned to use of trospium chloride at a standard dose of 45 mg per day. The results of treatment were evaluated during follow-up visits at 3, 6, 9 and 12 weeks. Depending on the results of examination, the dose was reduced in the presence of adverse events and increased in case of insufficient treatment effects. RESULTS: After 12 weeks, 102 patients have been receiving the drug at a dose of 30 mg/day, 241 - at a dose of 45 mg/day, 257 - at a dose of 60 mg/day, and 22 - at a dose of 75 mg/day. CONCLUSIONS: Individual approach to the selection of doses of trospium chloride in patients with idiopathic OAB can be quite effective and safe measure to achieve optimal clinical outcome with a good safety profile.

Influence of antimuscarinic therapy on cognitive functions and quality of life in geriatric patients treated for overactive bladder.

OBJECTIVES: Incidences of overactive bladder (OAB) and cognitive dysfunction increase with aging. Treatment of OAB with antimuscarinic agents may result in cognitive decline, especially in patients with Alzheimer's disease (AD). The aim of this study is to evaluate the effect of antimuscarinic treatment on cognitive functions, depression, and quality of life (QOL) of patients with OAB. METHODS: This non-interventional prospective observational study was conducted in a geriatric medicine outpatient clinic. Overall, 168 OAB patients were enrolled. Patients were followed up in five groups: oxybutynin, darifenacin, tolterodine, trospium, and control groups. Follow-up visits were done at second, third, and sixth months. Comprehensive geriatric assessment, cognitive and mood assessment, QOL scales (IIQ-7, UDI-6) were performed. RESULTS: Mean age of the patients was 73.5 ± 6.1. Of the 168 patients, 92.3% were female, 83.3% benefited from the treatment, and 37.1% discontinued the medication. Discontinuation rate and frequency of side effects were more frequent in the oxybutynin group. Mini Mental State Examination scores did not decline after treatment, even in AD patients. Geriatric Depression Scale scores, Activities of Daily Living scores, and QOL scores significantly improved after treatment. CONCLUSION: Antimuscarinic agents are effective in OAB treatment. They have a positive impact on daily life activities, depression, and QOL indices. Furthermore, they do not have a negative effect on cognitive function in older adults with or without AD.

Comparative effectiveness of combined low- and standard-dose trospium and solifenacin for moderate overactive bladder symptoms in elderly men and women.

OBJECTIVE: To increase the safety and effectiveness of treatments for overactive bladder (OAB) with moderate symptoms in elderly patients. PATIENTS AND METHODS: Patients were examined at the Urodynamic Department of the Regional Diagnostic Center (Vladivostok, Russian Federation) from September 1, 2012 to December 31, 2012. The assignment of patients [n = 177, average age 69. 4 years, 98 women (55.4%) and 79 men (44.6%)] was random and blind in this placebo-controlled study. Patients were distributed into subgroups according to the method of treatment as follows: group А1: n = 57, trospium 30 mg/day + solifenacin 10 mg/day; group А2: n = 61, trospium 15 mg/day + solifenacin 5 mg/day; group А3: n = 59, placebo. All patients underwent a urodynamic examination in accordance with international standards before and 2 months after treatment. ICIQ-SF questionnaires recommended by the International Continence Society (ICS) and bladder diaries were used to evaluate the clinical results. The clinical severity of the OAB symptoms and the effectiveness of the treatment were evaluated based on the frequency of episodes of incontinence (EI) per day. Three or fewer EI per day were considered moderate dysfunction of the lower urinary tract. RESULTS: Groups of elderly patients with moderate symptoms of OAB who were treated with standard- and low-dose trospium and solifenacin demonstrated a significant increase in the median values of reflex volume, bladder capacity, and detrusor compliance and a decrease in the frequency of urination and urinary urgencies. The frequency of EI in both of the main groups decreased by almost 2-fold in comparison to the initial data and reached the following values: group А1: 1.27 (-1.08), p ≤ 0.05; group A2: 1.49 (-1.18), p ≤ 0.05. The correlation with the decrease in the frequency of EI in these groups was r = 0.85 (p ≤ 0.01). The percentage of patients with a significant decrease (EI ≥1.0) among those treated with standard- and low-dose trospium and solifenacin increased synchronously, prompting us to suppose the absence of a direct correlation between medicine dose and therapeutic effect for moderate OAB symptoms. CONCLUSION: The combination of low-dose trospium and solifenacin provides good clinical and urodynamic effects in elderly patients with moderate symptoms of OAB. Combination of these drugs in standard doses for such patients is excessive.

[Treatment of overactive bladder in older women increased doses of antimuscarinic drugs safe and effective alternative to existing methods].

The study included 95 female patients of 65 to 74 years (average age 67,1 years), who previously (more than 6 months before this study) took a course of monotherapy with hydrochloride trospium in higher dosages with unstable or weak effect. In this study, all patients were divided into three groups and were treated with two antimuscarinic drugs. The majority of older women suffering from OAB and treatment-resistant taking one antimuscarinic drug in high doses showed a significant positive progress in a state by adding a second antimuscarinic agent. The received side effects do not exceed thereof in comparison with treatment with a single drug.

Safety analysis of 10 clinical trials and for 13 years after first approval of ioflupane 123I injection (DaTscan).

Ioflupane is an analog of cocaine that binds reversibly with high affinity to the dopamine transporter (DaT) protein, a marker for presynaptic terminals in dopaminergic nigrostriatal neurons. Ioflupane (123)I Injection is also known as DaTscan or DaTSCAN ((123)I-ioflupane is also called (123)I-2-ß-carbomethoxy-3ß-(4-iodophenyl)-N-(3-fluoropropyl)nortropane or (123)I-FP-CIT). The diagnostic efficacy of DaTscan has been described elsewhere. Here, we present a comprehensive analysis of the safety of DaTscan starting from initiation of clinical development through 13 y after the date of first market approval. Safety data in the sponsor's clinical development safety database from 10 completed DaTscan clinical trials were pooled, and postapproval experience was summarized from standardized aggregate safety reports submitted to regulatory agencies. A total of 1,180 clinical trial subjects (92% of 1,284 subjects planned to receive DaTscan in the clinical trials) received DaTscan. Percentages of subjects with adverse events by category were as follows: all (22%), considered at least possibly related to DaTscan by the investigator (4%), any severe (3%), headache (4%), nausea (2%), dizziness (2%), nasopharyngitis (1%), and injection site hematoma (1%). Four percent of subjects had at least 1 serious adverse event; 5 subjects (<1%) had serious adverse events that led to death. All serious adverse events, including those that led to death, were deemed by an expert clinician to be unrelated to DaTscan. An estimated half a million market doses of DaTscan (for single use) were administered from July 2000 through the July 2013 reporting period. In postapproval safety assessment, 1 death was reported 20 d after (and unrelated to) DaTscan administration. Two spontaneously reported serious adverse drug reactions (ADRs) and 32 spontaneously reported nonserious ADRs were submitted, approximately half of which are identified in labeling. Headache (in clinical trials) and injection site pain (postapproval) were the most commonly reported events or reactions. Although adverse events were reported for 1 in 5 clinical trial subjects, most were mild and considered unrelated to DaTscan administration. Severe events were uncommon, and no serious adverse event occurring in more than 1 subject was deemed related to DaTscan administration. In postapproval experience, the frequency of ADRs spontaneously reported was less than 1 per 10,000 doses administered. Comprehensive safety data show that DaTscan was well tolerated.

Anticholinergic therapy vs. onabotulinumtoxina for urgency urinary incontinence.

BACKGROUND: Anticholinergic medications and onabotulinumtoxinA are used to treat urgency urinary incontinence, but data directly comparing the two types of therapy are needed. METHODS: We performed a double-blind, double-placebo-controlled, randomized trial involving women with idiopathic urgency urinary incontinence who had five or more episodes of urgency urinary incontinence per 3-day period, as recorded in a diary. For a 6-month period, participants were randomly assigned to daily oral anticholinergic medication (solifenacin, 5 mg initially, with possible escalation to 10 mg and, if necessary, subsequent switch to trospium XR, 60 mg) plus one intradetrusor injection of saline or one intradetrusor injection of 100 U of onabotulinumtoxinA plus daily oral placebo. The primary outcome was the reduction from baseline in mean episodes of urgency urinary incontinence per day over the 6-month period, as recorded in 3-day diaries submitted monthly. Secondary outcomes included complete resolution of urgency urinary incontinence, quality of life, use of catheters, and adverse events. RESULTS: Of 249 women who underwent randomization, 247 were treated, and 241 had data available for the primary outcome analyses. The mean reduction in episodes of urgency urinary incontinence per day over the course of 6 months, from a baseline average of 5.0 per day, was 3.4 in the anticholinergic group and 3.3 in the onabotulinumtoxinA group (P=0.81). Complete resolution of urgency urinary incontinence was reported by 13% and 27% of the women, respectively (P=0.003). Quality of life improved in both groups, without significant between-group differences. The anticholinergic group had a higher rate of dry mouth (46% vs. 31%, P=0.02) but lower rates of catheter use at 2 months (0% vs. 5%, P=0.01) and urinary tract infections (13% vs. 33%, P<0.001). CONCLUSIONS: Oral anticholinergic therapy and onabotulinumtoxinA by injection were associated with similar reductions in the frequency of daily episodes of urgency urinary incontinence. The group receiving onabotulinumtoxinA was less likely to have dry mouth and more likely to have complete resolution of urgency urinary incontinence but had higher rates of transient urinary retention and urinary tract infections. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institutes of Health Office of Research on Women's Health; ClinicalTrials.gov number, NCT01166438.).

Effect of anticholinergic use for the treatment of overactive bladder on cognitive function in postmenopausal women.

BACKGROUND: Overactive bladder (OAB) is a common condition affecting the elderly. The mainstay of treatment for OAB is medical therapy with anticholinergics. However, adverse events have been reported with this class of drugs, including cognitive changes. OBJECTIVE: The objective of this study was to investigate the effect of an anticholinergic medication, trospium chloride, on cognitive function in postmenopausal women being treated for OAB. METHODS: This was a prospective cohort study conducted at a urogynaecology clinic at one academic medical centre from January to December 2010, with 12-week follow-up after medication initiation. Women aged 55 years or older seeking treatment for OAB and opting for anticholinergic therapy were recruited. Baseline cognitive function was assessed via the Hopkins Verbal Learning Test-Revised Form (HVLT-R) [and its five subscales], the Orientation, Memory & Concentration (OMC) short form, and the Mini-Cog evaluation. After initiation of trospium chloride extended release, cognitive function was reassessed at Day 1, Week 1, Week 4 and Week 12. Bladder function was assessed via three condition-specific quality-of-life questionnaires. Secondary outcomes included change in bladder symptoms, correlation between cognitive and bladder symptoms, and overall medication compliance. The main outcome measure was change in HVLT-R score at Week 4 after medication initiation, compared with baseline (pre-medication) score. RESULTS: Of 50 women enrolled, 35 completed the assessment. The average age was 70.4 years and 77.1% had previously taken anticholinergic medication for OAB. At enrollment 65.7% had severe overactive bladder and 71.4% had severe urge incontinence. Cognitive function showed an initial decline on Day 1 in HVLT-R total score (p = 0.037), HVLT-R Delayed Recognition subscale (p = 0.011) and HVLT-R Recognition Bias subscale (p = 0.01). At Week 1 the HVLT-R Learning subscale declined from baseline (p = 0.029). All HVLT-R scores normalized by Week 4. OMC remained stable throughout. The Mini-Cog nadired at a 90.9% pass rate at Week 4. OAB symptoms did not improve until Week 4, based on questionnaire scores (p < 0.05). CONCLUSION: Cognitive function exhibited early changes after initiation of trospium chloride but normalized within 4 weeks. Cognitive changes occurred weeks prior to OAB symptom improvement. Surveillance for cognitive changes with anticholinergic use should be part of OAB management.

Benefits and harms of pharmacologic treatment for urinary incontinence in women: a systematic review.

BACKGROUND: Urinary incontinence (UI) in women adversely affects quality of life. PURPOSE: To conduct a systematic literature review of drugs for urgency UI in women. DATA SOURCES: MEDLINE, the Cochrane Central Register of Controlled Trials, SCIRUS, and Google Scholar were searched for articles published from 1966 to November 2011. STUDY SELECTION: Randomized, controlled trials (RCTs) reported in English. DATA EXTRACTION: Rates of outcomes and risk of bias were extracted by using a standardized form to pool absolute risk differences and calculate the number of attributable events per 1000 patients treated, with 95% CIs. DATA SYNTHESIS: 94 RCTs were eligible. Pooled analyses showed that among drugs for urgency UI, per 1000 treated women, continence was restored in 130 with fesoterodine (CI, 58 to 202), 85 with tolterodine (CI, 40 to 129), 114 with oxybutynin (CI, 64 to 163), 107 with solifenacin (CI, 58 to 156), and 114 with trospium (CI, 83 to 144). Rates of treatment discontinuation due to adverse effects were 31 per 1000 treated with fesoterodine (CI, 10 to 56), 63 with oxybutynin (CI, 12 to 127), 18 with trospium (CI, 4 to 33), and 13 with solifenacin (CI, 1 to 26). The studies' inconsistent definitions of reduction in UI and quality of life hampered synthesis of evidence. LIMITATION: Evidence for quality-of-life improvements and comparative effectiveness with drugs was limited, and evidence for the effects of race, baseline severity of UI, and comorbid conditions on treatment success was insufficient. CONCLUSION: Overall, drugs for urgency UI showed similar small benefit. Therapeutic choices should consider the harms profile. Evidence for long-term adherence and safety of treatments is lacking.

Once-daily trospium chloride 60 mg extended-release provides effective, long-term relief of overactive bladder syndrome symptoms.

AIMS: Once-daily extended-release (XR) trospium chloride has been evaluated for the treatment of overactive bladder syndrome (OAB) in two 12-week randomized, double-blind, placebo-controlled studies. This pooled analysis of the 9-month open-label extensions to these studies evaluated the long-term efficacy and tolerability of trospium XR. METHODS: Following double-blind treatment, subjects with OAB could enter the open-label period, during which they received trospium 60 mg XR once daily for 36 weeks. The primary efficacy variables were changes from baseline in the number of toilet voids and urgency urinary incontinence (UUI) episodes per day at Week 48. Adverse events (AEs) were also recorded. RESULTS: Of the 1,027 subjects who completed double-blind treatment, 944 (92%) continued into the open-label period (placebo-to-trospium, N = 483; trospium-to-trospium, N = 461); 332 (68.7%) and 335 (72.7%), respectively, completed the open-label period. At Week 48, the mean change from baseline in the number of toilet voids/day was -3.21 in the placebo-to-trospium group and -3.35 in the trospium-to-trospium group, and the median change from baseline in the number of UUI episodes/day was -2.33 in both groups. Efficacy was maintained relative to Week 12 in trospium-to-trospium subjects, while improvement was seen following trospium initiation in placebo-to-trospium subjects. Improvement from baseline was also observed on secondary efficacy parameters at Week 48. Trospium was well tolerated; dry mouth and constipation were the most common class treatment-emergent AEs. Central nervous system AEs were rare and did not increase with long-term treatment. CONCLUSIONS: Long-term treatment of OAB with once-daily trospium 60 mg XR is effective and well tolerated.

Once-daily trospium chloride 60 mg extended release in subjects with overactive bladder syndrome who use multiple concomitant medications: Post hoc analysis of pooled data from two randomized, placebo-controlled trials.

BACKGROUND: Overactive bladder syndrome (OAB) is associated with various co-morbidities; treatment of these frequently results in multiple medication use (MMU) and the potential for drug-drug interactions, which may lead to adverse events and altered efficacy. With the aging population, the prevalence of MMU is likely to increase in the overall population, an increase due in part to treatment of co-morbidities that are more common in the elderly. OBJECTIVE: To assess safety and efficacy outcomes with once-daily trospium chloride 60 mg extended release (XR) in subjects with OAB who were taking multiple concomitant medications. STUDY DESIGN: Post hoc analysis of pooled data from two 12-week randomized, placebo-controlled studies. SETTING: Urology, urogynaecology, and primary care offices/clinics. PATIENTS: Subjects aged ≥18 years with OAB for ≥6 months who had baseline urinary frequency of ≥30 toilet voids/3 days; ≥1 'severe' urgency severity rating/3 days (on the Indevus Urgency Severity Scale); and pure urge urinary incontinence (UUI) or mixed incontinence with predominant UUI, with ≥3 UUI episodes/3 days. This analysis utilized data from subjects taking concomitant medications, focusing on those taking seven or more. INTERVENTION: Once-daily trospium chloride 60 mg XR or placebo. MAIN OUTCOME MEASURE: Predictors of treatment-emergent adverse events (TEAEs) identified by multivariate logistic regression analysis. RESULTS: Concomitant medications were being taken by 1135 subjects (placebo, n = 576; trospium chloride XR, n = 559); 427 were taking seven or more (placebo, n = 199; trospium XR, n = 228). Among subjects taking seven or more concomitant medications, there was no significant difference between trospium chloride XR and placebo in the proportion of subjects experiencing one or more TEAEs (64.5% vs 58.3%). Logistic regression analysis indicated that the odds of experiencing a TEAE were influenced by concomitant medication use, but not by randomization assignment to trospium chloride XR or to placebo, suggesting that concomitant drugs contribute more to TEAEs than trospium chloride XR. Compared with subjects taking one to two concomitant medications, the adjusted odds ratio (OR) for experiencing any TEAE was 3.39 (95% CI 2.39, 4.80; p < 0.0001) for subjects taking seven or more concomitant medications. The adjusted OR for experiencing any TEAE for subjects randomized to active treatment compared with placebo was 1.19 (95% CI 0.85, 1.67; p = 0.31). Efficacy in subjects taking seven or more concomitant medications was similar to that in the overall pooled study population. CONCLUSIONS: Trospium chloride XR does not increase the likelihood of a TEAE compared with placebo. The probability of experiencing a TEAE was significantly influenced by use of multiple concomitant medications. Trospium chloride XR was as effective in subjects with OAB taking seven or more concomitant medications as in the overall pooled study population. The data support the conclusion that trospium chloride XR is safe and effective in patients with OAB taking multiple concomitant medications.

Safety and efficacy of once-daily trospium chloride extended-release in male patients with overactive bladder.

OBJECTIVES: This study used pooled data from 2 large, phase III, double-blind, randomized, placebo-controlled studies for a subgroup analysis of the safety and efficacy of trospium chloride extended-release (XR) in men with overactive bladder (OAB). METHODS: A subgroup analysis was performed on data from the 176 male patients (trospium XR, 94; placebo, 82) who participated in 1 of the 2 studies. Patients received either trospium XR 60 mg or placebo once daily for 12 weeks. RESULTS: The mean age was 66.2 years for trospium XR and 63.1 years for placebo. A history of benign prostatic hyperplasia was recorded for 29 trospium XR recipients (30.9%) and 23 placebo recipients (28.0%). A total of 19 patients (20.2%) receiving trospium XR and 15 (18.3%) receiving placebo experienced ≥1 treatment-emergent adverse event considered at least possibly related to the study medication. Two trospium XR patients (2.1%) developed urinary retention; both were aged ≥75 years, and 1 had a history of prostate enlargement. Treatment with trospium XR compared with placebo resulted in significantly greater decreases from baseline in the mean number of daily toilet voids (-2.5 vs -1.5; P < .05) and urgency urinary incontinence episodes (-2.3 vs -1.4; P < .05) in men at week 12 (the coprimary efficacy variables). CONCLUSIONS: Trospium XR is safe and effective in men with OAB. The risk of urinary retention is low and may be further decreased by careful patient selection.

Comparison of different treatment protocols in the treatment of idiopathic detrusor overactivity: a randomized controlled trial.

OBJECTIVE: To investigate and compare the effectiveness of various treatment protocols for the treatment of women with idiopathic detrusor overactivity. DESIGN: Prospective, randomized controlled trial. SETTING: Departments of Physiotherapy and Rehabilitation and Obstetrics and Gynaecology, Hacettepe University. SUBJECTS: Forty-six subjects were randomized to three groups. INTERVENTIONS: The first group received only pharmacotherapy, the second group received only physiotherapy and in the third group pharmacotherapy was combined with physiotherapy (combined therapy group). MAIN MEASURES: All patients were evaluated at the beginning and at the end of treatment. Assessment parameters were maximum cystometric capacity, electromyographic activity of pelvic floor muscles, voiding diary parameters, the amount of urine leakage and the quality of life score. RESULTS: The maximum cystometric capacity and the electromyographic activity of pelvic floor muscles increased significantly and the number of voids/day and incontinence episodes/day, and the amount of urine leakage reduced significantly (P < 0.05) in both physiotherapy and combined therapy groups while there was no significant difference in the pharmacotherapy group. After treatment, the number of voids/day increased by 0.3 ± 3.4 in the pharmacotherapy group (P > 0.05) and decreased by 5.1 ± 5.5 and 4.7 ± 5.6 in the physiotherapy and combined therapy groups, respectively (P < 0.05). Statistically significant improvements were observed in all groups according to the number of voids/night and the quality of life scores at the end of the treatment. CONCLUSION: The physiotherapy protocol we introduced in the present study with or without anticholinergic therapy has a substantial positive impact on the treatment of female patients with idiopathic detrusor overactivity.

Trospium chloride once-daily extended release is efficacious and tolerated in elderly subjects (aged ≥ 75 years) with overactive bladder syndrome.

OBJECTIVE: • To evaluate the safety and efficacy of once-daily trospium chloride extended release (ER) in overactive bladder syndrome (OAB) in subjects aged ≥ 75 years. SUBJECTS AND METHODS: • The analysis included subjects ≥ 75 years of age with OAB. • A subgroup analysis of pooled data was performed for subjects aged ≥ 75 years from two randomized, double-blind, multicenter studies of subjects with OAB receiving once-daily trospium 60 mg extended release (ER) or placebo for 12 weeks, followed by 9-month open-label extension periods during which all subjects received trospium ER. A total of 143 of the 1165 subjects from two phase III registration trials who were aged ≥ 75 years (85 trospium ER, 58 placebo; mean age 79 years and ranging up to 90 years; 73% female) were evaluated. • Dual primary efficacy variables were the changes from baseline in the average number of toilet voids per day and urge urinary incontinence episodes per day. RESULTS: • At week 12 of the double-blind period, trospium ER produced greater improvements from baseline than placebo in voiding diary parameters, OAB Patient Global Assessment, and quality of life. • Efficacy and tolerability persisted among subjects receiving open-label trospium ER for up to 1 year. CONCLUSIONS: • Once-daily trospium chloride 60 mg ER demonstrated efficacy vs placebo and was tolerated in subjects aged ≥ 75 years with OAB. • For subjects who continued into the open-label treatment period, efficacy and tolerability were observed for up to 1 year.