Efficacy and safety of ligelizumab in adults and adolescents with chronic spontaneous urticaria: results of two phase 3 randomised controlled trials.

BACKGROUND: Many patients with chronic spontaneous urticaria (CSU) do not achieve complete control of their symptoms with current available treatments. In a dose-finding phase 2b study, ligelizumab improved urticaria symptoms in patients with H1-antihistamine (H1-AH) refractory CSU. Here, we report the efficacy and safety outcomes from two ligelizumab phase 3 studies. METHODS: PEARL-1 and PEARL-2 were identically designed randomised, double-blind, active-controlled and placebo-controlled parallel-group studies. Patients aged 12 years or older with moderate-to-severe H1-AH refractory CSU were recruited from 347 sites in 46 countries and randomly allocated in a 3:3:3:1 ratio via Interactive Response Technology to 72 mg ligelizumab, 120 mg ligelizumab, 300 mg omalizumab, or placebo, dosed every 4 weeks, for 52 weeks. Patients allocated to placebo received 120 mg ligelizumab from week 24. The primary endpoint was change-from-baseline (CFB) in weekly Urticaria Activity Score (UAS7) at week 12, and was analysed in all eligible adult patients according to the treatment assigned at random allocation. Safety was assessed throughout the study in all patients who received at least one dose of the study drug. The studies were registered with ClinicalTrials.gov, NCT03580369 (PEARL-1) and NCT03580356 (PEARL-2). Both trials are now complete. FINDINGS: Between Oct 17, 2018, and Oct 26, 2021, 2057 adult patients were randomly allocated across both studies (72 mg ligelizumab n=614; 120 mg ligelizumab n=616; 300 mg omalizumab n=618, and placebo n=209). A total of 1480 (72%) of 2057 were female, and 577 (28%) of 2057 were male. Mean UAS7 at baseline across study groups ranged from 29·37 to 31·10. At week 12, estimated treatment differences in mean CFB-UAS7 were as follows: for 72 mg ligelizumab versus placebo, -8·0 (95% CI -10·6 to -5·4; PEARL-1), -10·0 (-12·6 to -7·4; PEARL-2); 72 mg ligelizumab versus omalizumab 0·7 (-1·2 to 2·5; PEARL-1), 0·4 (-1·4 to 2·2; PEARL-2); 120 mg ligelizumab versus placebo -8·0 (-10·5 to -5·4; PEARL-1), -11·1 (-13·7 to -8·5; PEARL-2); 120 mg ligelizumab versus omalizumab 0·7 (-1·1 to 2·5; PEARL-1), -0·7 (-2·5 to 1·1; PEARL-2). Both doses of ligelizumab were superior to placebo (p<0·0001), but not to omalizumab, in both studies. No new safety signals were identified for ligelizumab or omalizumab. INTERPRETATION: In the phase 3 PEARL studies, ligelizumab demonstrated superior efficacy versus placebo but not versus omalizumab. The safety profile of ligelizumab was consistent with previous studies. FUNDING: Novartis Pharma.

Confidence intervals for exposure-adjusted rate differences in randomized trials.

Exposure-adjusted event rate is a quantity often used in clinical trials to describe average event count per unit of person-time. The event count may represent the number of patients experiencing first (incident) event episode, or the total number of event episodes, including recurring events. For inference about difference in the exposure-adjusted rates between interventions, many methods of interval estimation rely on the assumption of Poisson distribution for the event counts. These intervals may suffer from substantial undercoverage both, asymptotically due to extra-Poisson variation, and in the settings with rare events even when the Poisson assumption is satisfied. We review asymptotically robust methods of interval estimation for the rate difference that do not depend on distributional assumptions for the event counts, and propose a modification of one of these methods. The new interval estimator has asymptotically nominal coverage for the rate difference with an arbitrary distribution of event counts, and good finite sample properties, avoiding substantial undercoverage with small samples, rare events, or over-dispersed data. The proposed method can handle covariate adjustment and can be implemented with commonly available software. The method is illustrated using real data on adverse events in a clinical trial.

Improved confidence intervals for a difference of two cause-specific cumulative incidence functions estimated in the presence of competing risks and random censoring.

A cause-specific cumulative incidence function (CIF) is the probability of failure from a specific cause as a function of time. In randomized trials, a difference of cause-specific CIFs (treatment minus control) represents a treatment effect. Cause-specific CIF in each intervention arm can be estimated based on the usual non-parametric Aalen-Johansen estimator which generalizes the Kaplan-Meier estimator of CIF in the presence of competing risks. Under random censoring, asymptotically valid Wald-type confidence intervals (CIs) for a difference of cause-specific CIFs at a specific time point can be constructed using one of the published variance estimators. Unfortunately, these intervals can suffer from substantial under-coverage when the outcome of interest is a rare event, as may be the case for example in the analysis of uncommon adverse events. We propose two new approximate interval estimators for a difference of cause-specific CIFs estimated in the presence of competing risks and random censoring. Theoretical analysis and simulations indicate that the new interval estimators are superior to the Wald CIs in the sense of avoiding substantial under-coverage with rare events, while being equivalent to the Wald CIs asymptotically. In the absence of censoring, one of the two proposed interval estimators reduces to the well-known Agresti-Caffo CI for a difference of two binomial parameters. The new methods can be easily implemented with any software package producing point and variance estimates for the Aalen-Johansen estimator, as illustrated in a real data example.

Power analysis for multivariable Cox regression models.

In power analysis for multivariable Cox regression models, variance of the estimated log-hazard ratio for the treatment effect is usually approximated by inverting the expected null information matrix. Because, in many typical power analysis settings, assumed true values of the hazard ratios are not necessarily close to unity, the accuracy of this approximation is not theoretically guaranteed. To address this problem, the null variance expression in power calculations can be replaced with one of the alternative expressions derived under the assumed true value of the hazard ratio for the treatment effect. This approach is explored analytically and by simulations in the present paper. We consider several alternative variance expressions and compare their performance to that of the traditional null variance expression. Theoretical analysis and simulations demonstrate that, whereas the null variance expression performs well in many nonnull settings, it can also be very inaccurate, substantially underestimating, or overestimating the true variance in a wide range of realistic scenarios, particularly those where the numbers of treated and control subjects are very different and the true hazard ratio is not close to one. The alternative variance expressions have much better theoretical properties, confirmed in simulations. The most accurate of these expressions has a relatively simple form. It is the sum of inverse expected event counts under treatment and under control scaled up by a variance inflation factor.

Asymptotically robust variance estimation for person-time incidence rates.

Person-time incidence rates are frequently used in medical research. However, standard estimation theory for this measure of event occurrence is based on the assumption of independent and identically distributed (iid) exponential event times, which implies that the hazard function remains constant over time. Under this assumption and assuming independent censoring, observed person-time incidence rate is the maximum-likelihood estimator of the constant hazard, and asymptotic variance of the log rate can be estimated consistently by the inverse of the number of events. However, in many practical applications, the assumption of constant hazard is not very plausible. In the present paper, an average rate parameter is defined as the ratio of expected event count to the expected total time at risk. This rate parameter is equal to the hazard function under constant hazard. For inference about the average rate parameter, an asymptotically robust variance estimator of the log rate is proposed. Given some very general conditions, the robust variance estimator is consistent under arbitrary iid event times, and is also consistent or asymptotically conservative when event times are independent but nonidentically distributed. In contrast, the standard maximum-likelihood estimator may become anticonservative under nonconstant hazard, producing confidence intervals with less-than-nominal asymptotic coverage. These results are derived analytically and illustrated with simulations. The two estimators are also compared in five datasets from oncology studies.

Bladder cancer incidence and mortality in patients treated with radiation for uterine cancer.

OBJECTIVE: To estimate the effect of radiation therapy (RT) administered for uterine cancer (UtC) on bladder cancer (BC) incidence, tumour characteristics at presentation, and mortality. PATIENTS AND METHODS: In this retrospective cohort study, records of 56 681 patients diagnosed with UtC as their first primary malignancy during 1980-2005 were obtained from the Surveillance, Epidemiology and End-Results (SEER) database. Follow-up for incident BC ended on 31 December 2008. Occurrences of BC diagnoses and BC deaths in patients with UtC managed with or without RT were summarised with counts and person-time incidence rates (counts divided by person-years of observation). Age adjustment of rates was performed by direct standardisation. Incident BC cases were described in terms of histological types, grades and stages. RESULTS: With a mean follow-up of 15 years, BC was diagnosed in 146 (0.93%) of 15 726 patients with UtC managed with RT, and in 197 (0.48%) of 40 955 patients with UtC managed without RT, with an age-adjusted rate ratio of 2.0 (95% confidence interval [CI] 1.6-2.5). Fatal BC occurred in 39 (0.25%) and 36 (0.09%) of patients with UtC managed with vs without RT, respectively, with an age-adjusted rate ratio of 2.9 (95% CI 1.8-4.6). Incident BC cases diagnosed in patients with UtC managed with vs without RT had similar distributions of histological types, grades, and stages. CONCLUSIONS: Use of RT for UtC is associated with increased BC incidence and mortality later in life. Heightened awareness should help identify women with new voiding symptoms or haematuria, all of which should be fully evaluated.

Bioequivalence Between a New Omalizumab Prefilled Syringe With an Autoinjector or with a Needle Safety Device Compared with the Current Prefilled Syringe: A Randomized Controlled Trial in Healthy Volunteers.

Omalizumab is an anti-IgE monoclonal antibody currently approved for the treatment of asthma, nasal polyps/chronic rhinosinusitis with nasal polyps, and chronic spontaneous urticaria. Omalizumab is available as an injection in a prefilled syringe (PFS) with a needle safety device (NSD). New product configurations were developed to reduce the number of injections per dose administration, improve patient convenience and treatment compliance. The objective of this randomized open-label 12-week study was to demonstrate pharmacokinetic bioequivalence between (1) new PFS with autoinjector (PFS-AI), (2) new PFS-NSD configuration, and (3) current PFS-NSD configuration. Each new configuration was considered bioequivalent to the current configuration if the confidence intervals (CIs) for the geometric mean ratios (GMR) were contained in the 0.80-1.25 range for maximum concentration (Cmax), area under the concentration-time curve until the last quantifiable measurement (AUClast), and AUC extrapolated to infinity (AUCinf). Safety was assessed throughout the study. In total, 193 healthy volunteers were randomized at 1:1:1 ratio to omalizumab 1×300 mg/2 mL via new PFS-AI (n = 66), omalizumab 1×300 mg/2 mL via new PFS-NSD (n = 64), or omalizumab 2×150 mg/1 mL via current PFS-NSD (n = 63). Comparing new PFS-AI versus current PFS-NSD, the GMRs were: Cmax, 1.085; AUClast, 1.093; AUCinf, 1.100. Comparing new PFS-NSD versus current PFS-NSD, the GMRs were: Cmax, 1.006; AUClast, 1.016; AUCinf, 1.027. The 95% CIs for all GMR parameters were contained within the 0.80-1.25 range. Safety findings were consistent with the known safety profile of omalizumab. Single-dose omalizumab administered as the new PFS-AI or new PFS-NSD was bioequivalent to the current PFS-NSD.

Statin use and the risk of biochemical recurrence of prostate cancer after definitive local therapy: a meta-analysis of eight cohort studies.

UNLABELLED: What's known on the subject? and What does the study add? Over the last few years, several observational studies examined the association of statin use with the risk of biochemical recurrence of prostate cancer after definitive local therapy. The objective of our present study was to summarise available evidence on this subject using the method of meta-analysis. Combined evidence from eight cohort studies did not definitively support the hypothesis that statins influence the risk of biochemical recurrence. However, there was considerable disagreement between individual studies in reported findings and conclusions. OBJECTIVE: To perform a systematic review and meta-analysis of clinical studies with statin use as the exposure variable and biochemical recurrence after definitive local therapy for prostate cancer as the outcome. METHODS: Relevant publications were identified through PubMed/Medline/Embase databases. Pooled estimates of the hazard ratios (HRs) were computed using the inverse-variance weighting approach. Heterogeneity was assessed using the Cochran's Q test. RESULTS: We identified a total of eight eligible studies, all based on the retrospective cohort design. Five of these were based on radical prostatectomy (RP) series and three on radiotherapy (RT) series. There was evidence of heterogeneity in the entire set of eight studies (P = 0.002) as well as in the RP series (P = 0.05) and in the RT series (P = 0.01), when these were considered separately. Based on the random effects inverse-variance weighting approach, pooled estimates of the HRs for the risk of biochemical recurrence in statin users v non-users were 0.91 (95% confidence interval [CI] 0.72-1.13) for the entire set of eight studies, 1.02 (95% CI 0.80-1.29) for the RP series and 0.71 (95% CI 0.44-1.16) for the RT series. CONCLUSION: The pooled estimates of the HRs were not significantly different from the null value in this meta-analysis; however, evidence of heterogeneity between the studies was present.

Identification of causal effects using instrumental variables in randomized trials with stochastic compliance.

In randomized trials with imperfect compliance, it is sometimes recommended to supplement the intention-to-treat estimate with an instrumental variable (IV) estimate, which is consistent for the effect of treatment administration in those subjects who would get treated if randomized to treatment and would not get treated if randomized to control. The IV estimation however has been criticized for its reliance on simultaneous existence of complementary "fatalistic" compliance states. The objective of the present paper is to identify some sufficient conditions for consistent estimation of treatment effects in randomized trials with stochastic compliance. It is shown that in the stochastic framework, the classical IV estimator is generally inconsistent for the population-averaged treatment effect. However, even under stochastic compliance, with certain common experimental designs the IV estimator and a simple alternative estimator can be used for consistent estimation of the effect of treatment administration in well-defined and identifiable subsets of the study population.

A randomized trial of 2% lidocaine gel versus plain lubricating gel for minimizing pain in men undergoing flexible cystoscopy.

This article presents findings from a randomized trial of intra-urethral lidocaine versus a plain lubricating gel for pain reduction in men undergoing flexible cystoscopy. Compared with the plain gel, use of lidocaine resulted in significantly less pain during the procedure.

Global prevalence of Rett syndrome: systematic review and meta-analysis.

BACKGROUND: Rett syndrome is a rare, severe neurodevelopmental disorder. Almost all cases occur in girls, in association with spontaneous (non-inherited) mutations involving the methyl-CpG-binding protein 2 gene located on the X chromosome. Diagnostic criteria for typical Rett syndrome require a period of regression, followed by recovery or stabilization, and fulfillment of all four main criteria (loss of purposeful hand skills, loss of spoken language, gait abnormalities, and stereotypic hand movements). Our objective was to estimate the prevalence of Rett syndrome in the general population, stratified by sex. METHODS: We conducted a search of PubMed, Embase, Web of Science, Cochrane Library, LILACS, and LIVIVO to retrieve studies published in English between Jan. 1, 2000, and June 30, 2021. Pooled prevalence with a 95% confidence interval (CI) was estimated using a random-effects meta-analysis based on a generalized linear mixed model with a logit link. RESULTS: Ten eligible studies were identified (all in females), with a combined sample size of 9.57 million women and 673 Rett syndrome cases. The pooled prevalence estimate (random effects) was 7.1 per 100,000 females (95% CI: 4.8, 10.5, heterogeneity p < 0.001). Despite greatly variable precision of estimation, all estimates were compatible with a prevalence range of approximately 5 to 10 cases per 100,000 females based on their respective 95% CIs. CONCLUSION: These findings may facilitate planning of therapeutic trials in this indication in terms of target sample size and accrual times.

Prostate-specific antigen screening for prostate cancer and the risk of overt metastatic disease at presentation: analysis of trends over time.

BACKGROUND: The objective of this study was to estimate the total number of patients who would be expected to present with metastatic (M1) prostate cancer (PC) in the modern US population in a given year if the age-specific and race-specific annual incidence rates of M1 PC were the same as the rates in the era before prostate-specific antigen (PSA) testing. METHODS: The authors computed the total number of men who presented with M1 PC in the Surveillance, Epidemiology, and End Results (SEER) 9 registries area in the year 2008 (the most recent SEER year) and estimated the number of cases that would be expected to occur in this area in the year 2008 in the absence of PSA testing. The expected number was computed by multiplying each age-race-specific average annual incidence rate from the pre-PSA era (1983-1985) by the number of men in the corresponding age-race category in the year 2008 and adding the products. RESULTS: In the year 2008, the observed and expected numbers of men presenting with M1 PC in the SEER 9 registries area were 739 and 2277, respectively, with an expected-to-observed ratio of 3.1 (95% confidence interval, 3.0-3.2). If this ratio was applied to the total US population in the year 2008, then the total number of men presenting with M1 PC in that year would be equal to approximately 25,000 instead of the approximately 8000 actually observed. CONCLUSIONS: If the pre-PSA era rates were present in the modern US population, then the total number of men presenting with M1 PC would be approximately 3 times greater than the number actually observed.

Prostate cancer in the elderly: frequency of advanced disease at presentation and disease-specific mortality.

BACKGROUND: The objectives of this study were to determine the frequency of metastatic (M1) prostate cancer (PC) at presentation in different age groups, to examine the association of age with PC-specific mortality, and to calculate the relative contribution of different age groups to the pool of M1 cases and PC deaths. METHODS: Records from 464,918 patients who were diagnosed with PC from 1998 to 2007 were obtained from the Surveillance, Epidemiology, and End Results (SEER) database. The patients were categorized according to age into groups ages <50 years, 50 to 54 years, 55 to 59 years, 60 to 64 years, 65 to 69 years, 70 to 74 years, 75 to 79 years, 80 to 84 years, 85 to 89 years, and ≥ 90 years. The cumulative incidence of death from PC was computed using the Gray method. RESULTS: The frequency of M1 PC at presentation was 3% for the group aged <75 years, 5% for the group ages 75 to 79 years, 8% for the group ages 80 to 84 years, 13% for the group ages 85 to 89 years, and 17% for the group aged ≥ 90 years. The 5-year cumulative incidence of death from PC was 3% to 4% for all patients with PC in any category aged <75 years, 7% for patients ages 75 to 79 years, 13% for patients ages 80 to 84 years, 20% for patients ages 85 to 89 years, and 30% for patients aged ≥ 90 years. Although patients aged ≥ 75 years at PC diagnosis represented just over a quarter (26%) of all PC cases, they contributed almost half (48%) of all M1 cases and more than half (53%) of all PC deaths. CONCLUSIONS: Compared with younger patients (aged <75 years), older patients were more likely to present with very advanced disease, had a greater risk of death from PC despite higher death rates from competing causes, and contributed more than half of all PC deaths. Awareness of this issue may improve future outcomes for elderly patients with PC.

Neoadjuvant gemcitabine and cisplatin chemotherapy for locally advanced urothelial cancer of the bladder.

BACKGROUND: The purpose of this study was to investigate the effect of neoadjuvant chemotherapy with gemcitabine and cisplatin (GC) on pathologic down-staging of patients with locally advanced urothelial cancer (UC) of the bladder. METHODS: This was a retrospective cohort study of patients treated with radical cystectomy (RC) for clinical stage cT2-T4, N any, M0 bladder UC at Strong Memorial Hospital from 1999 to 2009. The primary exposure variable was use of neoadjuvant chemotherapy (GC vs none). The primary outcome was stage pT0 at RC. Secondary outcomes included other down-staging end points in the bladder (

Prostate-specific antigen testing in older men in the USA: data from the behavioral risk factor surveillance system.

OBJECTIVE: To examine the frequency of PSA testing in men aged ≥75 years before and after the 2008 US Preventive Services Task Force (USPSTF) recommendation to stop prostate-specific antigen (PSA) screening at age 75. MATERIALS AND METHODS: Data were obtained from the Behavioral Risk Factor Surveillance System (BRFSS) surveys completed in 2006, 2008 and 2010. Men aged ≥ 76 years at the time of survey and without a prostate cancer diagnosis were included in the study. The percentage of men who had a PSA test in the year before the survey was computed separately for survey years 2006, 2008 and 2010. RESULTS: The estimated percentages of men with a PSA test in the year before the survey were 60% (95% CI: 58-62%), based on 9033 respondents interviewed in 2006, 63% (95% CI: 62-65%), based on 12,063 respondents interviewed in 2008, and 60% (95% CI: 59-61%), based on 14,782 respondents interviewed in 2010. CONCLUSION: No substantial reduction in the frequency of PSA testing was observed in the BRFSS 2010 survey data compared with the earlier years, suggesting that the USPSTF 2008 recommendation had no major impact on the frequency of PSA testing in older men in the USA.

The burden of bladder cancer in men and women: analysis of the years of life lost.

OBJECTIVE: To estimate the average loss in life expectancy (LE) due to bladder cancer (BC) in men and women in the USA. PATIENTS AND METHODS: Cancer records for 51,528 patients diagnosed with BC during 1988-1997 were obtained from the Surveillance, Epidemiology, and End Results database. Potential follow-up ranged from 10 to 20 years (median 14 years). Loss in median LE at BC diagnosis was computed as the difference between expected median survival and observed median survival. Expected survival was calculated using two methods: method 1 used age, sex, and race-specific LE in the general population, method 2 used the hazard of death from non-BC causes in patients with BC (to account for past exposures and treatment-related toxicities not present in the general population). RESULTS: During the study period, BC death occurred in 17% of men and 23% of women and non-BC death occurred in 53% of men and 47% of women. Using LE in the general population as the reference (method 1), loss in median LE at BC diagnosis was 3.9 years for men (33% of their potential remaining years of life) and 6.5 years for women (47% of their potential remaining years of life). Using non-BC-specific hazard as the reference (method 2), loss in median LE was 2.7 years for men (26% of their potential remaining years of life) and 4.1 years for women (36% of their potential remaining years of life). CONCLUSION: Compared with men, women loose more years of life and a greater fraction of their life expectancy to BC.

A Review of the Unique Drug Development Strategy of Indacaterol Acetate/Glycopyrronium Bromide/Mometasone Furoate: A First-in-Class, Once-Daily, Single-Inhaler, Fixed-Dose Combination Treatment for Asthma.

A novel, once-daily (o.d.), fixed-dose combination (FDC) of indacaterol acetate (IND), glycopyrronium bromide (GLY), and mometasone furoate (MF), delivered by the inhaler Breezhaler® device, is the first long-acting beta2-adrenergic agonist/long-acting muscarinic antagonist/inhaled corticosteroid (LABA/LAMA/ICS) therapy to be approved for maintenance treatment of asthma in adults inadequately controlled on LABA/ICS. The approval of IND/GLY/MF in the European Union (EU) also included an optional electronic sensor and smartphone (or other suitable device) application, making it the first "digital companion" that can be prescribed with an asthma medication. As a result, the European Medicines Agency included this approval as one of the "outstanding contributions to public health" (for Pneumology/Allergology) in their 2020 highlights report. Alongside IND/GLY/MF, an o.d. LABA/ICS FDC, IND/MF, was also developed and approved. This review outlines the unique strategy used in the accelerated development of IND/GLY/MF that combined various approaches: (1) selecting individual components with established efficacy/safety, (2) bridging doses to optimize efficacy/safety of IND/GLY/MF and IND/MF delivered via the Breezhaler® device, (3) developing IND/GLY/MF and IND/MF in parallel, and (4) submission for regulatory approval before formal completion of the pivotal phase III studies. IND/GLY/MF and IND/MF were combined in a single-development plan (PLATINUM program), which comprised four phase III studies: QUARTZ and PALLADIUM evaluated IND/MF while IRIDIUM and ARGON evaluated IND/GLY/MF. A unique feature was the inclusion of two LABA/ICS comparators in the pivotal IRIDIUM study-IND/MF as an internal comparator, and high-dose salmeterol xinafoate/fluticasone propionate (SAL/FLU) as a marketed comparator. In the ARGON study, IND/GLY/MF was compared against o.d. tiotropium (via Respimat®) plus twice-daily (b.i.d.) high-dose SAL/FLU (via Diskus®). As a result of this development strategy, the development and approval of IND/GLY/MF was accelerated by ca. 4 years as against what would be expected from a traditional approach, novel data were generated, and a unique optional digital companion was approved in the EU. A Video Abstract by Dr Dominic Brittain, Global Drug Development, Novartis. (MP4 228293 kb).

International Country-Level Trends, Factors, and Disparities in Compassionate Use Access to Unlicensed Products for Patients With Serious Medical Conditions.

Importance: Compassionate use (CU) is a treatment option for patients with serious or life-threatening medical conditions that provides access to locally unlicensed medications (generally free of charge) when all available treatment options have been exhausted and enrollment in a clinical trial is not possible. Objective: To examine the disparity in CU access observed across countries and explore the key driving factors. Design Settings and Participants: This study analyzed all Novartis CU requests (for individual/named patients and cohort programs) received between January 1, 2018, and December 31, 2020, and investigated selected country-specific factors for association with request activity. Data analysis was performed from February 2021 to February 2022. Main Outcomes and Measures: Country-specific request activity was quantified using request counts and rates per million population and examined in stratified and multivariable analyses (negative-binomial regression) for association with the following covariates: existence of local CU regulations and their public availability, clinical trial activity, population size, and gross domestic product. Results: During the 36-month observation period, 31 711 CU requests were received from 110 countries, 23 194 (73%) of which came from only 10 high-income countries. All high-income countries combined accounted for 27 612 (87%) of all requests, while lower-middle-income and low-income countries contributed only 1021 (3%). Of all requests, 29 870 (94%) were from countries with CU regulations made publicly available on the internet, and higher request activity was demonstrated in countries conducting more clinical trials. Presence and public availability of CU regulations, population size, gross domestic product, and clinical trial activity were independently associated with the CU request activity in multivariable analysis. Conclusions and Relevance: In this cohort study analyzing Novartis CU requests over a 3-year period, existence and public availability of CU regulations and local clinical trial activity were positively associated with higher CU request rates. The analysis also identified an association between macroeconomic factors and CU request activity, despite the generally free provision of unlicensed therapeutic products. Similar analyses of other comparable experiences are needed to supplement these initial observations. Ultimately, better understanding of factors associated with CU request activity would translate into improved early access to novel lifesaving products for patients with unmet medical needs around the world.

Do mixed histological features affect survival benefit from neoadjuvant platinum-based combination chemotherapy in patients with locally advanced bladder cancer? A secondary analysis of Southwest Oncology Group-Directed Intergroup Study (S8710).

OBJECTIVE: • To determine whether the effect of neoadjuvant chemotherapy with methotrexate, vinblastine, doxorubicin and cisplatin (MVAC) on the survival of patients with locally advanced urothelial carcinoma (UC) of the bladder treated with radical cystectomy varies with the presence of non-urothelial components in the tumour. PATIENTS AND METHODS: • This is a secondary analysis of the Southwest Oncology Group-directed intergroup randomized trial S8710 of neoadjuvant MVAC followed by cystectomy versus cystectomy alone for treatment of locally advanced UC of the bladder. • For the purpose of these analyses, tumours were classified based on the presence of non-urothelial components as either pure UC (n= 236) or mixed tumours (n= 59). Non-urothelial components included squamous and glandular differentiation. • Cox regression models were used to estimate the effect of neoadjuvant MVAC on all-cause mortality for patients with pure UC and for patients with mixed tumours, with adjustment for age and clinical stage. RESULTS: • There was evidence of a survival benefit from chemotherapy in patients with mixed tumours (hazard ratio 0.46; 95% CI 0.25-0.87; P= 0.02). Patients with pure UC had improved survival on the chemotherapy arm but the survival benefit was not statistically significant (hazard ratio 0.90; 95% CI 0.67-1.21; P= 0.48). • There was marginal evidence that the survival benefit of chemotherapy in patients with mixed tumours was greater than it was for patients with pure UC (interaction P= 0.09). CONCLUSION: • Presence of squamous or glandular differentiation in locally advanced UC of the bladder does not confer resistance to MVAC and in fact may be an indication for the use of neoadjuvant chemotherapy before radical cystectomy.

Cardiovascular safety of mometasone/indacaterol and mometasone/indacaterol/glycopyrronium once-daily fixed-dose combinations in asthma: pooled analysis of phase 3 trials.

OBJECTIVE: To evaluate cardiovascular safety of two new inhaled fixed-dose combinations for treatment of asthma: (i) the inhaled corticosteroid/long-acting beta2-agonist (ICS/LABA) mometasone furoate/indacaterol acetate (MF/IND), (ii) the ICS/LABA/long-acting muscarinic antagonist (LAMA) MF/IND/glycopyrronium bromide (GLY). METHODS: Patient-level data were pooled from four randomized trials, including 52-week studies PALLADIUM (n = 2216) and IRIDIUM (n = 3092), 24-week study ARGON (n = 1426), and 12-week study QUARTZ (n = 802). Cardio-/cerebrovascular (CCV) event frequencies were examined in the following comparisons: (1) LABA effect: pooled-dose MF/IND vs. pooled-dose MF; (2) LAMA effect: pooled-dose MF/IND/GLY vs. pooled-dose MF/IND; (3) ICS-dose effects: (a) high-dose MF/IND vs. medium-dose MF/IND, (b) high-dose MF/IND/GLY vs. medium-dose MF/IND/GLY; (4) intra-class effects: (a) high-dose MF/IND vs. Fluticasone/Salmeterol (F/S), (b) high-dose MF/IND/GLY vs. F/S + Tiotropium (TIO). Risk estimates (percentage of patients with ≥1 CCV event) and risk differences (RDs) with 95% confidence intervals (CIs) were calculated for each comparison. RESULTS: The frequency of CCV events was low, without notable differences between comparison groups. Risk estimates and corresponding RDs (95% CIs) were as follows: (1) pooled-dose MF/IND = 2.35%, pooled-dose MF = 2.18%, RD = 0.17% (-1.00%, 1.34%); (2) pooled-dose MF/IND/GLY = 3.65%, pooled-dose MF/IND = 3.77%, RD = -0.12% (-1.63%, 1.39%); (3a) high-dose MF/IND = 3.69%, medium-dose MF/IND = 3.35%, RD = 0.34% (-1.25%, 1.94%); (3b) high-dose MF/IND/GLY = 2.84%, medium-dose MF/IND/GLY = 2.02%, RD = 0.82% (-0.49%, 2.13%); (4a) high-dose MF/IND = 3.69%, F/S = 2.82%, RD = 0.87% (-0.66%, 2.40%); (4b) high-dose MF/IND/GLY = 1.26%, F/S + TIO = 1.05%, RD = 0.21% (-1.26%, 1.68%). CONCLUSIONS: There was no evidence of increased cardiovascular risk attributable to the addition of IND to MF or addition of GLY to MF/IND. Similarly, no evidence of increased cardiovascular risk was observed with an increase in the ICS-dose or relative to F/S ± TIO.