Fezolinetant impact on health-related quality of life for vasomotor symptoms due to the menopause: Pooled data from SKYLIGHT 1 and SKYLIGHT 2 randomised controlled trials.

OBJECTIVE: To assess the effect of fezolinetant treatment on health-related quality of life using pooled data from SKYLIGHT 1 and 2 studies. DESIGN: Prespecified pooled analysis. SETTING: USA, Canada, Europe; 2019-2021. POPULATION: 1022 women aged ≥40 to ≤65 years with moderate-to-severe vasomotor symptoms (VMS; minimum average seven hot flushes/day), seeking treatment for VMS. METHODS: Women were randomised to 12-week double-blind treatment with once-daily placebo or fezolinetant 30 or 45 mg. Completers entered a 40-week, active extension (those receiving fezolinetant continued that dose; those receiving placebo re-randomised to fezolinetant received 30 or 45 mg). MAIN OUTCOME MEASURES: Mean changes from baseline to weeks 4 and 12 on Menopause-Specific Quality of Life (MENQoL) total and domain scores, Work Productivity and Activity Impairment questionnaire specific to VMS (WPAI-VMS) domain scores, Patient Global Impression of Change in VMS (PGI-C VMS); percentages achieving PGI-C VMS of 'much better' (PGI-C VMS responders). Mean reduction was estimated using mixed model repeated measures analysis of covariance. RESULTS: Fezolinetant 45 mg mean reduction over placebo in MENQoL total score was -0.57 (95% confidence interval [CI] -0.75 to -0.39) at week 4 and -0.47 (95% CI -0.66 to -0.28) at week 12. Reductions were similar for 30 mg. MENQoL domain scores were also reduced and WPAI-VMS scores improved. Twice as many women receiving fezolinetant reported VMS were 'much better' than placebo based on PGI-C VMS assessment. CONCLUSIONS: Fezolinetant treatment was associated with improvement in overall QoL, measured by MENQoL, and work productivity, measured by WPAI-VMS. A high proportion receiving fezolinetant felt VMS were 'much better' based on PGI-C VMS responder analysis.

Psychometric evaluation of the PROMIS SD-SF-8b instrument in individuals experiencing vasomotor symptoms due to menopause.

BACKGROUND: Women with vasomotor symptoms (VMS) due to menopause frequently experience poor sleep quality. The Patient-Reported Outcomes Measurement Information System Sleep Disturbance - Short Form 8b (PROMIS SD-SF-8b) has been developed to assess sleep disturbance. The study objective was to use data from the fezolinetant SKYLIGHT 1 and 2 studies in individuals with VMS to assess the psychometric properties of the PROMIS SD-SF-8b. METHODS: Individuals (aged ≥ 40-≤65 years) with moderate-to-severe VMS (≥ 7 hot flashes/day) were enrolled. Besides PROMIS SD-SF-8b, eight other patient-reported outcome (PRO) measures were used for the psychometric evaluation. All the PRO assessments were completed at weeks 4 and 12 during the treatment period and most were completed at baseline. Psychometric analyses included factor analysis and reliability, construct validity, and sensitivity to change assessments. The within-patient threshold for a clinically meaningful change in sleep disturbance was derived. RESULTS: Overall, 1022 individuals were included from the SKYLIGHT 1 and 2 studies. Mean PROMIS SD-SF-8b total score at baseline was 26.80, which decreased to 22.68 at week 12, reflecting improved sleep disturbance. The confirmatory factor analysis supported the proposed PROMIS SD-SF-8b domain structure. Internal consistency was excellent, with Cronbach's alpha values of 0.915 and 0.935 and a McDonald's omega of 0.917. Item-to-item and item-total correlations were sufficient and moderate test-retest reliability was noted. The construct validity assessments showed that moderate Spearman rank correlations (r: 0.608 to 0.651) were observed between PROMIS SD-SF-8b total scores and measures of sleep disturbance and sleep-related impairment, and that significant differences were noted in the total scores across PRO categories. The responsiveness of PROMIS SD-SF-8b total scores was supported by the results from the correlations in change scores and comparisons of mean change scores by PRO categories. Statistically significant differences in mean scores were observed between responder and non-responder PRO groups. A PROMIS SD-SF-8b total score of 8 points was identified as the within-patient threshold to use to confirm a meaningful change in sleep disturbance. CONCLUSIONS: The psychometric properties of the PROMIS SD-SF-8b support its use to measure sleep disturbance in women with VMS due to menopause. TRIAL REGISTRATION: ClinicalTrials.gov numbers: NCT04003155 and NCT04003142.

Drug utilization patterns and healthcare resource use and costs in patients with neurogenic bladder in the United Kingdom: A retrospective primary care database study.

AIM: To characterize patients with neurogenic bladder (NGB), their treatment patterns, healthcare resource utilization, and associated costs based on records from a primary care database in the United Kingdom. METHODS: This was a retrospective, descriptive, observational study of anonymized data from the Clinical Practice Research Datalink and Hospital Episode Statistics databases (selection period, 1 January 2004 to 31 December 2016). Adults with a definitive or probable diagnosis of NGB and ≥1 referral to a urologist were included. RESULTS: The study cohort included 3913 patients with definitive (n = 363) or probable (n = 3550) NGB. Patients had a mean of 8.6 (standard deviation [SD], 7.6) comorbidities, and mean Anticholinergic Cognitive Burden Scale score of 6.6 (SD, 5.9). During 12 months' follow-up, urinary tract infection (UTI) and urinary incontinence were the most common complications. Most patients (92.2%) received ≥1 prescription for an antimuscarinic agent or mirabegron, and 53.9% of patients received prescriptions for UTI-specific antibiotics. The mean number of visits to a general practitioner for any cause was 67.7 (SD, 42.6) per individual. Almost half (46.7%) of the study cohort visited a specialist during the 12-month follow-up period, and 11.0% had ≥1 hospital admission. Total mean per patient costs for healthcare resource utilization was £2395. CONCLUSIONS: The burden of illness, healthcare resource needs, and associated costs among patients with NGB are considerable. Drug prescribing patterns are consistent with the symptoms and complications of NGB, although increased awareness of drugs with anticholinergic activity among prescribers may help to reduce the cumulative anticholinergic burden in this vulnerable population.

Clinical outcome of paediatric patients with traumatic brain injury (TBI) receiving 3% hypertonic saline (HTS) in the emergency room of a tertiary care hospital.

OBJECTIVE: To determine the clinical outcome and mean length of hospital stay of paediatric patients with severe blunt traumatic head injury (THI) receiving 3% hypertonic saline (HTS) in the Emergency Department (ED). METHODOLOGY: This case series study was conducted at the Department of Emergency Medicine, Aga Khan University Hospital, Karachi, from 2014 to 2015 via chart review of 105 patients. Detailed history and clinical examination of all paediatric patients aged 2-16 years was recorded which included moderate to severe head injury as classified by the Glasgow Coma Scale (GCS) by the Brain Trauma Foundation. As per routine care after admission of such a patient, for resuscitation 3% HTS was administered. GCS was recorded at 6 hours and at the time of discharge. RESULTS: Of the 105 patients, 76 (72.4%) were male and 29 (27.6%) were female, and the mean age was 61.6+45.9 months. Traumatic brain injury (TBI) was found moderate in 60 (57.1%) cases and severe in 45 (42.9%) of our patients as per the GCS. Six hours after resuscitation with 3% hypertonic saline, 45 (43%) patients normalised as per GCS, 39 (37%) patients had moderate TBI and 21 (20%) had severe TBI. Forty five patients had a hospital stay of 2-3 days. The GCS improved after resuscitation with 3% hypertonic saline in emergency department, with a mean length of stay of 4.6+3.9 and 12.6+10.7 days in moderate and severe head injury respectively with a P value of <0.001, and was normal in 94 (89.5%) patients at the time of discharge. CONCLUSIONS: Paediatric patients with TBI receiving 3% hypertonic saline results in improved GCS and a decrease in the length of hospital stay.

A comparison of the treatment recommendations for neurogenic lower urinary tract dysfunction in the national institute for health and care excellence, European Association of Urology and international consultations on incontinence guidelines.

AIMS: Healthcare guidelines are an important vehicle in establishing up-to-date evidence based medicine (EBM) in clinical practice. Due to varying development processes, clinical guidelines created by different institutions can often contain contrasting recommendations. This can have implications for optimal and standardized patient care across management settings. METHODS: The similarities and differences of treatment recommendations made in the National Institute for Health and Care Excellence (NICE), The European Association of Urology (EAU), and the International Consultation on Continence (ICI) guidelines for neurogenic lower urinary tract dysfunction (NLUTD) were assessed. RESULTS: The guidelines generally agree on their approach to conservative management, including behavioral therapies, and catheterization techniques. There was discrepancy on the benefit of using an alpha blocker in NLUTD and bladder outlet obstruction (BOO) and administering Botulinum toxin A (Onabotulinum-A) in NLUTD. The highest degree of divergence was seen in recommendations for surgical treatments, where the EAU made gender-specific recommendations, and gave continent urinary diversion higher preference than given in the NICE and ICI guidelines. CONCLUSIONS: In the absence of high-quality clinical evidence, many of the recommendations made across all three guidelines are based on expert opinion. NICE, the EAU and ICI have similarities but they place differing emphasis on costs and expert opinion, which translated in notably different recommendations. It is evident that increased research efforts, possibly in the form of prospective registries, pragmatic trials, and resource utilization studies are necessary to improve the underlying evidence base for NLUTD, and subsequently the strength and concordance of recommendations across guidelines.

A critical appraisal of the principal guidelines for neurogenic lower urinary tract dysfunction using the AGREE II instrument.

AIMS: The process of identifying research questions, synthesizing and interpreting evidence, and weight given to health economics differs between the clinical guidelines (CGs) for neurogenic lower urinary tract dysfunction (NLUTD). Consequently, the quality also varies which can have implications for clinical practice. METHODS: We used the Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument to assess the quality of the National Institute for Health and Care Excellent (NICE), European Association of Urology (EAU), and the International Consultations on Incontinence (ICI) CGs on neurogenic bladder. RESULTS: The NICE CGs were deemed to be of the highest quality (overall score of 92%). NICE were the only guidelines to systematically incorporate cost-effectiveness research into their recommendations. The EAU CGs received an overall score of 83% and the ICI CGs achieved the lowest overall score (75%). The highest scoring domain among all the CGs was scope purpose (86%) and the lowest scoring domain was applicability (69%). All guidelines were recommended for use (mostly with some modifications). CONCLUSIONS: All CGs had their inherent advantages and disadvantages, though all were still deemed to be of high quality. Incorporating cost-effectiveness research would be near impossible for guidelines with a broad-country remit. Incorporating the AGREE II instrument in the development of CGs and better collaboration between the ICI, NICE, and EAU could improve the quality, and consistency between NLUTD CGs and ultimately improve health outcomes for this important patient group.

Development of an overactive bladder assessment tool (BAT): A potential improvement to the standard bladder diary.

AIMS: To develop a comprehensive patient-reported bladder assessment tool (BAT) for assessing overactive bladder (OAB) symptoms, bother, impacts, and satisfaction with treatment. METHODS: Subjects were consented and eligibility was confirmed by a recruiting physician; subjects were then scheduled for in-person interviews. For concept elicitation and cognitive interviews, 30 and 20 subjects, respectively, were targeted for recruitment from US sites. All interviews were conducted face-to-face, audio-recorded, transcribed verbatim, anonymized, and analyzed using a qualitative data analysis software program. A draft BAT was created based on the results of the concept elicitation interviews and further revised based on cognitive interviews as well as feedback from an advisory board of clinical and patient-reported outcome (PRO) experts. RESULTS: Nocturia, daytime frequency, and urgency were reported by all subjects (n = 30, 100.0%), and incontinence was reported by most subjects (n = 25, 83.3%). The most frequently reported impacts were waking up to urinate (n = 30, 100.0%), embarrassment/shame (n = 24, 80.0%), stress/anxiety (n = 23, 76.7%), and lack of control (n = 23, 76.7%). Following analysis, item generation, cognitive interviews, and advisory board feedback, the resulting BAT contains four hypothesized domains (symptom frequency, symptom bother, impacts, and satisfaction with treatment) and 17 items with a 7-day recall period. CONCLUSIONS: The BAT has been developed in multiple stages with input from both OAB patients and clinical experts following the recommended processes included in the FDA PRO Guidance for Industry. Once fully validated, we believe it will offer a superior alternative to use of the bladder diary and other PROs for monitoring OAB patients in clinical trials and clinical practice.

Does BMI, gender or age affect efficacy/tolerability of solifenacin in the management of overactive bladder?

INTRODUCTION AND HYPOTHESIS: Pooled data from seven randomized placebo-controlled trials were analysed to evaluate relationships between baseline body mass index (BMI), gender or age and the efficacy/tolerability of solifenacin (5 - 10 mg daily) in patients with overactive bladder (OAB). METHODS: Changes in efficacy variables from baseline to 12 weeks were compared in patients with symptoms at baseline between solifenacin-treated and placebo-treated groups. Normalization rates were calculated (no more than eight micturitions in 24 h, no more than one episode of nocturia per night, zero values for other variables over 24 h). Treatment-emergent adverse events (TEAEs) were recorded. RESULTS: The baseline incidence of incontinence and urgency incontinence increased with increasing BMI and age; relatively more women than men were incontinent. The baseline incidence of urgency was similar between genders and among age groups, but tended to increase with increasing BMI. The baseline frequencies of micturition and nocturia were similar in all BMI categories, between genders and in all age groups. The results from this meta-analysis of an integrated database of data from trials investigating solifenacin showed that solifenacin was more efficacious than placebo for all OAB symptoms across all BMI and age categories, and between genders. Normalization rates for micturition frequency, incontinence and urgency were greater in patients receiving solifenacin than in those receiving placebo across all categories. The overall incidence of TEAEs was higher in patients receiving solifenacin than in those receiving placebo; solifenacin was generally well tolerated in both groups. The overall frequency of TEAEs for solifenacin and placebo was slightly higher in women than in men and in older than in younger patients. The most commonly reported TEAEs were dry mouth and constipation. CONCLUSIONS: Regardless of BMI, gender or age, all patients with OAB can be considered candidates for solifenacin treatment.

Cardiovascular safety in refractory incontinent patients with overactive bladder receiving add-on mirabegron therapy to solifenacin (BESIDE).

AIMS/OBJECTIVES: In the BESIDE study, combination therapy (antimuscarinic [solifenacin] and ß3 -adrenoceptor agonist [mirabegron]) improved efficacy over solifenacin monotherapy without exacerbating anticholinergic side effects in overactive bladder (OAB) patients; however, a potential synergistic effect on the cardiovascular (CV) system requires investigation. METHODS: OAB patients remaining incontinent despite daily solifenacin 5 mg during 4-week single-blind run-in, were randomised 1:1:1 to double-blind daily combination (solifenacin 5 mg/mirabegron 25 mg, increasing to 50 mg after week 4), solifenacin 5 or 10 mg for 12 weeks. CV safety assessments included frequency of CV-related treatment-emergent adverse events (TEAEs), change from baseline in vital signs (systolic blood pressure [SBP], diastolic blood pressure [DBP], pulse rate) and electrocardiogram (ECG) parameters. RESULTS: The frequency of hypertension, tachycardia and ECG QT prolongation, respectively, was low and comparable across combination (1.1%, 0.3%, 0.1%), solifenacin 5 mg (0.7%, 0.1%, 0.1%), and solifenacin 10 mg groups (0.8%, 0%, 0.1%). Adjusted mean (SE) change from baseline to end of treatment (EoT) in SBP, DBP, and pulse rate with combination (0.07 mm Hg [0.38], -0.35 mm Hg [0.26], 0.47 bpm [0.28]), solifenacin 5 mg (-0.93 mm Hg [0.38], -0.45 mm Hg [0.26], 0.43 bpm [0.28]) and solifenacin 10 mg (-1.28 mm Hg [0.38], -0.48 mm Hg [0.26], 0.27 bpm [0.28]) was generally comparable, with the exception of a mean treatment difference of ~1 mm Hg in SBP between combination and solifenacin monotherapy; SBP was unchanged with combination and decreased with solifenacin monotherapy. Mean changes from baseline to EoT in ECG parameters were generally similar across treatment groups, except for QT interval corrected using Fridericia's formula, which was higher with solifenacin 10 mg (3.30 mseconds) vs. combination (0.49 mseconds) and solifenacin 5 mg (0.77 mseconds). CONCLUSION: The comparable frequency of CV-related TEAEs, changes in vital signs and ECG parameters indicates no synergistic effect on CV safety outcomes when mirabegron and solifenacin are combined.

Mirabegron as Add-On Treatment to Solifenacin in Patients with Incontinent Overactive Bladder and an Inadequate Response to Solifenacin Monotherapy: Responder Analyses and Patient-Reported Outcomes from the BESIDE Study [corrected].

PURPOSE: We investigated improvements in overactive bladder and patient reported outcomes in patients with overactive bladder and refractory incontinence treated with mirabegron 50 mg plus solifenacin 5 mg vs solifenacin 5 or 10 mg. MATERIALS AND METHODS: Patients with overactive bladder who were incontinent despite 4 weeks of single-blind daily solifenacin 5 mg were randomized 1:1:1 to a double-blind daily combination of mirabegron 50 mg/solifenacin 5 mg, or solifenacin 5 or 10 mg for 12 weeks. The mirabegron dose was increased from 25 to 50 mg after week 4. Symptom bother, health related quality of life and patient perception of bladder condition were assessed by OAB-q (Overactive Bladder Questionnaire) and the PPBC (Patient Perception of Bladder Condition) questionnaire, respectively. Responder rates were based on a 50% reduction in daily incontinence, zero incontinence episodes and fewer than 8 micturitions per 24 hours with minimal important differences in OAB-q and PPBC. RESULTS: Overall 2,174 patients with a median age of 59 years were randomized, including 727 to the combination, 728 to solifenacin 5 mg and 719 to solifenacin 10 mg. Symptom bother, total health related quality of life and its subscales (coping, concern and social), and PPBC were significantly improved with combination vs solifenacin monotherapy (p <0.05). The odds of achieving clinically meaningful improvements in incontinence, micturition frequency, symptom bother, health related quality of life and PPBC were significantly higher for combination than solifenacin monotherapy. The odds of becoming continent was 47% and 28% higher for combination vs solifenacin 5 and 10 mg (OR 1.47, 95% CI 1.17-1.84, p = 0.001 and OR 1.28; 95% CI 1.02-1.61, p = 0.033, respectively). CONCLUSIONS: Significantly more patients on the combination achieved clinically meaningful improvements in incontinence and micturition frequency. Improvements were accompanied by similar improvements in PPBC, symptom bother and health related quality of life.

Pattern of relapse in paediatric acute lymphoblastic leukaemia in a tertiary care unit.

OBJECTIVE: To determine the frequency, site and time to relapse from diagnosis, and to see the relationship of relapse with important prognostic factors. METHODS: The prospective descriptive observational study was conducted at the National Institute of Child Health, Karachi, June 2005 to May 2007, and comprised newly-diagnosed cases of acute lymphoblastic leukaemia. Bone marrow aspiration was done on reappearance of blast cells in peripheral smear and cerebrospinal fluid. Detailed report was done each time when intra-thecal chemotherapy was given or there were signs and symptoms suggestive of central nervous system relapse. SPSS 12 was used for data analysis. RESULTS: Of the 60 patients enrolled, 4(6.6%) expired and 1(1.7%) was lost to follow-up. Of the 55(91.6%) who comprised the study sample, 35(58%) were males and 25(42%) females. Mean age of relapse was 6.8±3.27 years. Mean time to relapse from diagnosis was 1.3±0.54 years; 12(20%) patients suffered relapse, and of them 5(14%) were boys. Central nervous system relapse in 8(67%) patients was the most common site, with 3(25%) bone-marrow relapses. Out of 12 patient with relapses, 9(75%) had white blood cell count less than 50,000/cm. CONCLUSIONS: Relapse in acute lymphoblastic leukaemia was common, although treatment modalities are improving day by day.

Impact of delay in admission on the outcome of critically ill patients presenting to the emergency department of a tertiary care hospital from low income country.

OBJECTIVE: To assess the impact of admission delay on the outcome of critical patients. METHODS: The retrospective chart review was done at Aga Khan University Hospital, Karachi, and comprised adult patients visiting the Emergency Department during 2010. Outcome measures assessed were total hospital length of stay, total cost of the visit and in-hospital mortality. Patients admitted within 6 hours of presentation at Emergency Department were defined as non-delayed. Data was analysed using SPSS 19. RESULTS: Of the 49,532 patients reporting at the Emergency Department during the study period, 17,968 (36.3%) were admitted. Of them 2356(13%) were admitted to special or intensive care units, 1595(67.7%) of this sub-group stayed in the Emergency Department for >6 hours before being shifted to intensive care. The study focussed on 325(0.65%) of the total patients; 164(50.5%) in the non-delayed group and 161(49.5%) in the delayed group. The admitting diagnosis of myocardial infarction (p=0.00) and acute coronary syndrome (p=0.01) was significantly more common in the non-delayed group compared to other diagnoses like cerebrovascular attacks (p=0.03) which was significantly more common in the delayed group. There was no significant difference in the hospital length of stay between the two groups (p>0.05). The Emergency Department cost was significantly increased in the delayed group (p<0.05), but there was no difference in the overall hospital cost between the groups (p>0.05). CONCLUSIONS: There was no significant difference in the delayed and non-delayed groups, but long Emergency Department stays are distressing for both physicians and patients.

Frequency of metabolic syndrome in psychiatric patients, is this the time to develop a standardized protocol to reduce the morbidity from an acute care psychiatry unit.

OBJECTIVE: To determine the frequency of Metabolic Syndrome among psychiatric patients and to look for the correlation between the two medical conditions. METHODS: The cross-sectional study was conducted from February to April 2013 at the acute care psychiatry in-patient unit at Kingston General Hospital, Ontario, Canada, and comprised adult patients of both genders diagnosed under the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. For Metabolic Syndrome, definitions outlined by the International Diabetes Federation were used. The patients were divided into two groups on the basis of presence or absence of the Syndrome and were compared for clinical and demographic characteristics. SPSS 22 was used for statistical analysis. RESULTS: Of the 50 patients in the study, 24(48%) were found to have Metabolic Syndrome. Besides, 40 (80%) patients were taking atypical antipsychotics regardless of the diagnosis; 20(83%) among those with the Syndrome, and 20(77%) among those without it. CONCLUSIONS: Patients at high risk of developing metabolic syndrome need to be identified early so that an individualised care plan can be formulated. Identifying the variables to make a management plan is vital.

Onset of action of the ß3-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 ß3-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.

Mirabegron in overactive bladder: a review of efficacy, safety, and tolerability.

AIMS: Mirabegron, the first ß3 -adrenoceptor agonist to enter clinical practice, has a different mechanism of action from antimuscarinic agents. This review presents data on the efficacy, safety, and tolerability of mirabegron in studies conducted to date. METHODS: All clinical data on mirabegron that are currently in the public domain are included, including some in-press manuscripts. RESULTS: In Phase III clinical trials in patients with overactive bladder (OAB), mirabegron at daily doses of 25, 50, and 100 mg demonstrated significant efficacy in treating the symptoms of OAB, including micturition frequency, urgency incontinence, and urgency. Significant improvements in micturition frequency, urgency incontinence, and mean volume voided/micturition were seen as early as the first assessment (week 4) for mirabegron 50 and 100 mg, and were maintained throughout treatment. Responder analyses showed a significant improvement with mirabegron 50 and 100 mg in terms of dry rates, ≥50% reduction in mean number of incontinence episodes/24 hr, and the proportion of patients with ≤8 micturitions/24 hr at final visit. The benefit of mirabegron 50 and 100 mg was also evident in patients ≥65 years of age, and in both treatment-naïve patients and those who previously discontinued antimuscarinic therapy. These data therefore demonstrate a clinically meaningful benefit with mirabegron in the objective endpoints of OAB. Assessment of measures of health-related quality of life and treatment satisfaction showed that patients perceived treatment with mirabegron as meaningful. In OAB clinical trials of up to 12 months mirabegron appeared to be well tolerated. The most common adverse events (AEs) observed with mirabegron in clinical trials of up to 12 months were hypertension, nasopharyngitis, and urinary tract infection. The incidence of dry mouth was similar to placebo, and was between three and fivefold less than for tolterodine extended release 4 mg. Since dry mouth is the most bothersome AE associated with antimuscarinic drugs and often a reason for treatment discontinuation, mirabegron may be a valuable treatment option for these patients. CONCLUSIONS: In Phase III clinical trials, mirabegron at daily doses of 25, 50, and 100 mg demonstrated significant efficacy in treating symptoms of OAB and, at doses of 50 and 100 mg, demonstrated significant improvements versus placebo on key secondary endpoints, as early as the first assessment (week 4), and these were maintained throughout treatment. In OAB clinical trials of up to 12 months, mirabegron appeared to be well tolerated.

The efficacy and tolerability of the ß3-adrenoceptor agonist mirabegron for the treatment of symptoms of overactive bladder in older patients.

INTRODUCTION: mirabegron is a ß3-adrenoceptor agonist developed for the treatment of symptoms of overactive bladder (OAB). As the prevalence of OAB increases with age, a prospective subanalysis of individual and pooled efficacy and tolerability data from three 12-week, randomised, Phase III trials, and of tolerability data from a 1-year safety trial were conducted in order to evaluate the efficacy and tolerability of mirabegron in subgroups of patients aged ≥65 and ≥75 years. METHODS: primary efficacy outcomes were change from baseline to final visit in the mean number of incontinence episodes/24 h and the mean number of micturitions/24 h. Tolerability was assessed by the incidence of treatment-emergent adverse events (TEAEs). RESULTS: over 12 weeks mirabegron 25 mg and 50 mg once-daily reduced the mean numbers of incontinence episodes and micturitions/24 h from baseline to final visit in patients aged ≥65 and ≥75 years. Mirabegron was well tolerated: in both age groups, hypertension and urinary tract infection were among the most common TEAEs over 12 weeks and 1 year. The incidence of dry mouth, a typical anticholinergic TEAE, was up to sixfold higher among the older patients randomised to tolterodine than any dose of mirabegron. CONCLUSIONS: these analyses have demonstrated the efficacy of mirabegron over 12 weeks and the tolerability of mirabegron over 12 weeks and 1 year in OAB patients aged ≥65 and ≥75 years, supporting mirabegron as a therapeutic option in older patients with OAB.

Mirabegron 50 mg once-daily for the treatment of symptoms of overactive bladder: an overview of efficacy and tolerability over 12 weeks and 1 year.

The aim of the present review article was to summarize the efficacy and tolerability for mirabegron 50 mg over 12 weeks and 1 year versus placebo (SCORPIO) or tolterodine ER 4 mg (SCORPIO and TAURUS). After a 2-week placebo run-in, adults with overactive bladder symptoms for ≥3 months were randomized if, during a 3-day micturition diary period before baseline, they had an average of ≥8 micturitions/24 h and ≥3 urgency episodes. Efficacy end-points were change from baseline to each study visit and final visit in incontinence, micturitions, volume voided/micturition, urgency incontinence, urgency (grades 3 or 4), level of urgency and nocturia. Additional secondary efficacy variables included patient-reported outcomes. Safety variables included changes in treatment-emergent adverse events and vital signs. For SCORPIO, statistically significant improvements from baseline in efficacy variables and patient-reported outcomes were seen with mirabegron versus placebo from week 4, and were maintained over time. For TAURUS, numerical improvements in efficacy were evident from month 1, and were maintained throughout 12 months. Treatment-emergent adverse events incidence was similar between groups, except for dry mouth, which was reported by fourfold (SCORPIO) and threefold (TAURUS) more patients taking tolterodine than mirabegron. Mirabegron 50 mg for 12 weeks was associated with statistically significant improvements in objective measures of efficacy and patient-reported outcomes. At final visit, improvements with mirabegron 50 mg were statistically greater versus placebo. The efficacy profile of mirabegron 50 mg appears to be maintained over 12 months.

Psychometric Evaluation of the MENQOL Instrument in Women Experiencing Vasomotor Symptoms Associated with Menopause.

INTRODUCTION: Vasomotor symptoms (VMS) associated with menopause can negatively affect health-related quality of life (HRQoL). The Menopause-Specific Quality of Life (MENQOL) questionnaire has been developed to assess QOL specific to menopause. The objective of the current study was to assess the psychometric properties, sensitivity to change, and clinically meaningful within-patient change of the MENQOL using data from the fezolinetant SKYLIGHT 1 and 2 studies in individuals with VMS. METHODS: Individuals aged ≥ 40 to ≤ 65 years with moderate-to-severe VMS (≥ seven hot flashes/day) were enrolled. In addition to MENQOL, eight patient-reported outcome (PRO) measures were used for the psychometric evaluation. All PRO assessments were completed at weeks 4 and 12 during the treatment period, and most were completed at baseline. Psychometric analyses included factor analysis and reliability, construct validity, and sensitivity to change assessments. The within-patient threshold for a clinically meaningful change in MENQOL was derived. RESULTS: In total, 1022 individuals were included from SKYLIGHT 1 and 2. Mean MENQOL total score at baseline was 4.30, improving to 3.16 at week 12. The confirmatory factor analysis supported established MENQOL domain structure, including the overall score. The internal consistency of the MENQOL overall and domain scores was supported using Cronbach's alpha and McDonald's omega, and MENQOL construct validity was supported for overall and domain scores. Item-to-item and item-total correlations were generally sufficient, and moderate test-retest reliability was noted. The scales against which construct validity and responsiveness for MENQOL domains were examined were moderately related to the MENQOL domains in general, providing additional support for acceptable measurement properties of MENQOL in this population. A reduction in MENQOL overall score of ≥ 0.9 points was identified as responding to treatment (a clinically important threshold). Thresholds of 2.0 points for the vasomotor domain and 0.9 for the psychosocial domain were estimated, in addition to distribution-based threshold estimates of 0.8 and 1.2 for the physical and sexual domains, respectively. CONCLUSIONS: The psychometric properties of the MENQOL overall and domain scores support use of this instrument to capture experiences among individuals with moderate-to-severe VMS associated with menopause and assess related endpoints in clinical trials. TRIAL REGISTRATION: ClinicalTrials.gov identifiers NCT04003155 and NCT04003142.

Systematic review and network meta-analysis comparing the efficacy of fezolinetant with hormone and nonhormone therapies for treatment of vasomotor symptoms due to menopause.

IMPORTANCE: The neurokinin 3 receptor antagonist fezolinetant 45 mg/d significantly reduced frequency/severity of moderate to severe vasomotor symptoms (VMS) of menopause compared with placebo in two phase 3 randomized controlled trials. Its efficacy relative to available therapies is unknown. OBJECTIVE: We conducted a systematic review and Bayesian network meta-analysis to compare efficacy with fezolinetant 45 mg and hormone therapy (HT) and non-HT for VMS in postmenopausal women. EVIDENCE REVIEW: Using OvidSP, we systematically searched multiple databases for phase 3 or 4 randomized controlled trials in postmenopausal women with ≥7 moderate to severe VMS per day or ≥50 VMS per week published/presented in English through June 25, 2021. Mean change in frequency and severity of moderate to severe VMS from baseline to week 12 and proportion of women with ≥75% reduction in VMS frequency at week 12 were assessed using fixed-effect models. FINDINGS: The network meta-analysis included data from the pooled phase 3 fezolinetant trials plus 23 comparator publications across the outcomes analyzed (frequency, 19 [34 regimens]; severity, 6 [7 regimens]; ≥75% response, 9 [15 regimens]). Changes in VMS frequency did not differ significantly between fezolinetant 45 mg and any of the 27 HT regimens studied. Fezolinetant 45 mg reduced the frequency of moderate to severe VMS events per day significantly more than all non-HTs evaluated: paroxetine 7.5 mg (mean difference [95% credible interval {CrI}], 1.66 [0.63-2.71]), desvenlafaxine 50 to 200 mg (mean differences [95% CrI], 1.12 [0.10-2.13] to 2.16 [0.90-3.40]), and gabapentin ER 1800 mg (mean difference [95% CrI], 1.63 [0.48-2.81]), and significantly more than placebo (mean difference, 2.78 [95% CrI], 1.93-3.62]). Tibolone 2.5 mg (the only HT regimen evaluable for severity) significantly reduced VMS severity compared with fezolinetant 45 mg. Fezolinetant 45 mg significantly reduced VMS severity compared with desvenlafaxine 50 mg and placebo and did not differ significantly from higher desvenlafaxine doses or gabapentin ER 1800 mg. For ≥75% responder rates, fezolinetant 45 mg was less effective than tibolone 2.5 mg (not available in the United States) and conjugated estrogens 0.625 mg/bazedoxifene 20 mg (available only as 0.45 mg/20 mg in the United States), did not differ significantly from other non-HT regimens studied and was superior to desvenlafaxine 50 mg and placebo. CONCLUSIONS: The only HT regimens that showed significantly greater efficacy than fezolinetant 45 mg on any of the outcomes analyzed are not available in the United States. Fezolinetant 45 mg once daily was statistically significantly more effective than other non-HTs in reducing the frequency of moderate to severe VMS. RELEVANCE: These findings may inform decision making with regard to the individualized management of bothersome VMS due to menopause.

Validation and Application of Thresholds to Define Meaningful Change in Vasomotor Symptoms Frequency: Analysis of Pooled SKYLIGHT 1 and 2 Data.

INTRODUCTION: Vasomotor symptoms (VMS), the characteristic symptoms of menopausal transition, are often the primary reason women seek treatment. Current treatment options for VMS include fezolinetant, a nonhormonal, selective neurokinin 3 receptor antagonist. This study aimed to define a clinically meaningful threshold for reduction of moderate-to-severe VMS in postmenopausal women treated with fezolinetant and then apply it in a responder analysis of the pooled trial data. METHODS: This analysis pooled data from two identical phase 3, double-blind, placebo-controlled studies that randomized women with moderate-to-severe VMS to once-daily fezolinetant 30 mg, 45 mg, or placebo (SKYLIGHT 1 and 2). The frequency of VMS was collected daily using an electronic diary. Patients completed the Patient Global Impression of Change in VMS (PGI-C VMS) instrument, which assessed changes in hot flushes/night sweats at weeks 4 and 12 compared with baseline using a seven-point Likert scale. VMS frequency data were anchored to PGI-C VMS data; the anchor level for meaningful within-patient change in PGI-C VMS was "moderately better." RESULTS: In the pooled population (N = 1022), the mean (standard deviation) estimated thresholds for a meaningful within-patient change in moderate-to-severe VMS frequency were - 5.73 (3.47) at week 4 and - 6.20 (5.18) at week 12. Applying the thresholds for meaningful within-patient change to responder analyses ("missing as non-responder" imputation method) indicated a favorable clinical benefit: greater proportions of responders were observed in the fezolinetant 30-mg and 45-mg groups compared with placebo at week 4 (odds ratio range 2.48-2.91; P < 0.001) and week 12 (odds ratio range 1.908-2.68; P < 0.001). CONCLUSION: PGI-C VMS is sensitive to change and correlates with VMS frequency: a reduction of approximately six VMS episodes per day from baseline to week 12 was meaningful at the individual patient level. Fezolinetant provides a meaningful clinical benefit for women with moderate-to-severe VMS associated with menopause and represents an important nonhormonal treatment option. TRIAL REGISTRATION NUMBER: NCT04003155 and NCT04003142.