Reynaldo Martina

Combination Treatment with Mirabegron and Solifenacin in Patients with Overactive Bladder: Efficacy and Safety Results from a Randomised, Double-blind, Dose-ranging, Phase 2 Study (Symphony)

BACKGROUNDnCombining the β3-adrenoceptor agonist mirabegron and the antimuscarinic (AM) agent solifenacin may improve efficacy in the treatment of overactive bladder (OAB) while reducing the AM side effects.nnnOBJECTIVEnThe primary objective was to evaluate the efficacy of combinations of solifenacin/mirabegron compared with solifenacin 5mg monotherapy. The secondary objective was to explore the dose-response relationship and the safety/tolerability compared with placebo and monotherapy.nnnDESIGN, SETTING, AND PARTICIPANTSnA phase 2, factorial design, randomised, double-blind, parallel-group, placebo- and monotherapy-controlled trial, conducted at 141 sites in 20 European countries. Male and female patients were aged ≥18 yr with symptoms of OAB for ≥3 mo.nnnINTERVENTIONnA total of 1306 patients (66.4% female) were randomised to 12 wk of treatment in 1 of 12 groups: 6 combination groups (solifenacin 2.5, 5, or 10 mg plus mirabegron 25 or 50 mg), 5 monotherapy groups (solifenacin 2.5, 5, or 10 mg, or mirabegron 25 or 50 mg), or placebo.nnnOUTCOME MEASUREMENTS AND STATISTICAL ANALYSISnChange from baseline to end of treatment in mean volume voided per micturition (MVV) (primary end point) and mean numbers of micturitions per 24 h, incontinence episodes per 24 h, and urgency episodes per 24 h were analysed using an analysis of covariance model. Safety assessments included treatment-emergent adverse events (TEAEs), blood pressure, pulse rate, postvoid residual (PVR) volume, and laboratory and electrocardiography (ECG) parameters.nnnRESULTS AND LIMITATIONSnCompared with solifenacin 5 mg monotherapy, all combinations with solifenacin 5 or 10 mg significantly improved MVV, with adjusted differences ranging from 18.0 ml (95% confidence interval [CI], 5.4-30.0) to 26.3 ml (95% CI, 12.0-41.0). Three combination groups significantly reduced micturition frequency compared with solifenacin 5 mg, ranging from -0.80 (95% CI, -1.39 to -0.22) to -0.98 (95% CI, -1.68 to -0.27). Five of six combinations significantly reduced urgency episodes compared with solifenacin 5 mg, ranging from -0.98 (95% CI, -1.78, to -0.18) to -1.37 (95% CI, -2.03 to -0.70). No dose-related trends in TEAEs, blood pressure, pulse rate, PVR volume, or laboratory or ECG parameters were observed between combination and monotherapy groups, although the incidence of constipation was slightly increased with combination therapy.nnnCONCLUSIONSnCombination therapy with solifenacin/mirabegron significantly improved MVV, micturition frequency, and urgency compared with solifenacin 5 mg monotherapy. All combinations were well tolerated, with no important additional safety findings compared with monotherapy or placebo.nnnPATIENT SUMMARYnTo improve treatment of overactive bladder (OAB), mirabegron/solifenacin in combination was compared with each drug alone and placebo. Combination therapy improved OAB symptoms and had similar safety and acceptability.nnnTRIAL REGISTRATIONnClinical trials.gov: NCT01340027.

The analysis of incontinence episodes and other count data in patients with overactive bladder by Poisson and negative binomial regression

Clinical studies in overactive bladder have traditionally used analysis of covariance or nonparametric methods to analyse the number of incontinence episodes and other count data. It is known that if the underlying distributional assumptions of a particular parametric method do not hold, an alternative parametric method may be more efficient than a nonparametric one, which makes no assumptions regarding the underlying distribution of the data. Therefore, there are advantages in using methods based on the Poisson distribution or extensions of that method, which incorporate specific features that provide a modelling framework for count data. One challenge with count data is overdispersion, but methods are available that can account for this through the introduction of random effect terms in the modelling, and it is this modelling framework that leads to the negative binomial distribution. These models can also provide clinicians with a clearer and more appropriate interpretation of treatment effects in terms of rate ratios. In this paper, the previously used parametric and non-parametric approaches are contrasted with those based on Poisson regression and various extensions in trials evaluating solifenacin and mirabegron in patients with overactive bladder. In these applications, negative binomial models are seen to fit the data well.

Electronic bladder diaries of differing duration versus a paper diary for data collection in overactive bladder.

This observational study compared data values, reliability, consistency and compliance collected by electronic and paper diaries of differing durations.

qSOFA, SIRS and NEWS for predicting inhospital mortality and ICU admission in emergency admissions treated as sepsis

Background The third international consensus definition for sepsis recommended use of a new prognostic tool, the quick Sequential Organ Failure Assessment (qSOFA), based on its ability to predict inhospital mortality and prolonged intensive care unit (ICU) stay in patients with suspected infection. While several studies have compared the prognostic accuracy of qSOFA to the Systemic Inflammatory Response Syndrome (SIRS) criteria in suspected sepsis, few have compared qSOFA and SIRS to the widely used National Early Warning Score (NEWS). Methods This was a retrospective cohort study carried out in a UK tertiary centre. The study population comprised emergency admissions in whom sepsis was suspected and treated. The accuracy for predicting inhospital mortality and ICU admission was calculated and compared for qSOFA, SIRS and NEWS. Results Among 1818 patients, 53 were admitted to ICU (3%) and 265 died in hospital (15%). For predicting inhospital mortality, the area under the receiver operating characteristics curve for NEWS (0.65, 95%u2009CI 0.61 to 0.68) was similar to qSOFA (0.62, 95%u2009CI 0.59 to 0.66) (test for difference, P=0.18) and superior to SIRS (P<0.001), which was not predictive. The sensitivity of NEWS≥5 (74%, 95%u2009CI 68% to 79%) was similar to SIRS≥2 (80%, 95%u2009CI 74% to 84%) and higher than qSOFA≥2 (37%, 95%u2009CI 31% to 43%). The specificity of NEWS≥5 (43%, 95%u2009CI 41% to 46%) was higher than SIRS≥2 (21%, 95%u2009CI 19% to 23%) and lower than qSOFA≥2 (79%, 95%u2009CI 77% to 81%). The negative predictive value was 88% (86%–90%) for qSOFA, 86% (82%–89%) for SIRS and 91% (88%–93%) for NEWS. Results were similar for the secondary outcome of ICU admission. Conclusion NEWS has equivalent or superior value for most test characteristics relative to SIRS and qSOFA, calling into question the rationale of adopting qSOFA in institutions where NEWS is already in use.

A quantitative benefit–risk assessment approach to improve decision making in drug development: Application of a multicriteria decision analysis model in the development of combination therapy for overactive bladder

A multicriteria decision analysis (MCDA) approach was developed and used to estimate the benefit–risk of solifenacin and mirabegron and their combination in the treatment of overactive bladder (OAB). The objectives were 1) to develop an MCDA tool to compare drug effects in OAB quantitatively, 2) to establish transparency in the evaluation of the benefit–risk profile of various dose combinations, and 3) to quantify the added value of combination use compared to monotherapies. The MCDA model was developed using efficacy, safety, and tolerability attributes and the results of a phase II factorial design combination study were evaluated. Combinations of solifenacin 5 mg and mirabegron 25 mg and mirabegron 50 (5+25 and 5+50) scored the highest clinical utility and supported combination therapy development of solifenacin and mirabegron for phase III clinical development at these dose regimens. This case study underlines the benefit of using a quantitative approach in clinical drug development programs.

The analysis of incontinence episodes and other count data in patients with overactive bladder by Poisson and negative binomial regression: The analysis of incontinence episodes and other count data in patients with overactive bladder by Poisson and negative binomial regression

On page 153, Section 3.2, the third sentence should read: The change from baseline to end of treatment in the number of incontinence episodes per 24 h was analysed in the subpopulation of the Full Analysis Set (FAS) patients who reported 1 incontinence episode in the baseline diary (FAS-I) using a model which included treatment, sex, age group and geographic region as fixed factors and the patient’s mean number of incontinence episodes per 24 h at baseline as a covariate. On pages 154 (Table I), 155 (Table II) and 158 (Tables III and IV), ‘fatty acid synthase’ should be ‘full analysis set’.

Network Meta-Analysis of Biological Response Modifiers in Rheumatoid arthritis Including real World Evidence at Multiple time Points

free survival (PFS) and/or overall survival (OS) as reported outcomes and to create a RCT network accordingly. Fixed and random effects FP models of first/second order were applied on these data and tested for goodness of fit using deviance information criteria. Finally, the best fitting model was used to estimate the hazard function, median PFS, median OS and uncertainty of treatment effect. Results: Literature review found 8 RCTs and 5 RCTs which reported PFS and OS respectively, for 7 different mRCC treatments (interferon-alfa (IFN), bevacizumab+IFN, temisrolimus+bevacizumab, sunitinib, pazopanib, cediranib, placebo). The best fitting FP model was second order random effect model for both, PFS and OS NMA. Hazard functions varied significantly. Estimated median PFS was the longest with sunitinib (10.8 months; 95% credible interval (CI): 9.5-11.8), followed by pazopanib and temsirolimus+bevacizumab. Similarly, sunitinib was estimated with the longest median OS (28.8 months; 95% CI: 25.7-31.0) followed by pazopanib and bevacizumab+IFN. ConClusions: Synthesis of NMA evidence for 1LmRCC treatments identified sunitinib to be the treatment with favourable PFS and OS. When dealing with multiple sources, hazards proportionality assumption is violated, and proposed method should be the method of choice.

The inclusion of real world evidence in clinical development planning

BackgroundWhen designing studies it is common to search the literature to investigate variability estimates to use in sample size calculations. Proprietary data of previously designed trials in a particular indication are also used to obtain estimates of variability. Estimates of treatment effects are typically obtained from randomised controlled clinical trials (RCTs). Based on the observed estimates of treatment effect, variability and the minimum clinical relevant difference to detect, the sample size for a subsequent trial is estimated. However, data from real world evidence (RWE) studies, such as observational studies and other interventional studies in patients in routine clinical practice, are not widely used in a systematic manner when designing studies. In this paper, we propose a framework for inclusion of RWE in planning of a clinical development programme.MethodsIn our proposed approach, all evidence, from both RCTs and RWE (i.e. from studies in routine clinical practice), available at the time of designing of a new clinical trial is combined in a Bayesian network meta-analysis (NMA). The results can be used to inform the design of the next clinical trial in the programme. The NMA was performed at key milestones, such as at the end of the phase II trial and prior to the design of key phase III studies. To illustrate the methods, we designed an alternative clinical development programme in multiple sclerosis using RWE through clinical trial simulations.ResultsInclusion of RWE in the NMA and the resulting trial simulations demonstrated that 284 patients per arm were needed to achieve 90% power to detect effects of predetermined size in the TRANSFORMS study. For the FREEDOMS and FREEDOMS II clinical trials, 189 patients per arm were required. Overall there was a reduction in sample size of at least 40% across the three phase III studies, which translated to a time savings of at least 6xa0months for the undertaking of the fingolimod phase III programme.ConclusionThe use of RWE resulted in a reduced sample size of the pivotal phase III studies, which led to substantial time savings compared to the approach of sample size calculations without RWE.

Comparative effectiveness from a single-arm trial and real-world data: alectinib versus ceritinib

AIMnTo compare the overall survival of anaplastic lymphoma kinase-positive non-small-cell lung cancer patients who received alectinib with those who received ceritinib.nnnMATERIALS & METHODSnTwo treatment arms (alectinib [nxa0=xa0183] and ceritinib [nxa0=xa067]) were extracted from clinical trials and an electronic health record database, respectively. Propensity scores were applied to balance baseline characteristics. Kaplan-Meier and multivariate Cox regression were conducted.nnnRESULTSnAfter propensity score adjustment, baseline characteristics were balanced. Alectinib had a prolonged median overall survival (alectinibxa0=xa024.3 months and ceritinibxa0=xa015.6 months) and lower risk of death (hazard ratio: 0.65; 95% CI: 0.48-0.88).nnnCONCLUSIONnAlectinib was associated with prolonged overall survival versus ceritinib, which is consistent with efficacy evidence from clinical trials.

A combined proof of concept and dose finding study with multiple endpoints: A Bayesian adaptive design in chronic prostatitis/chronic pelvic pain syndrome

There is a need for identifying effective drugs or terminating ineffective drugs as early as possible to optimize efficient and cost effective drug development. The aim of the proposed trial was to simultaneously establish Proof of Concept (PoC) and dose finding (DF) for a new drug with a novel mode of action in a new indication. We simulated and executed an adaptive allocation design to investigate the effects of a drug on male patients suffering from chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). This manuscript describes the clinical trial simulations and primary analysis results. A Bayesian adaptive allocation procedure was employed to allocate patients to treatment using a normal dynamic linear model. The study was to stop early for efficacy if the probability of a clinically significant difference between an experimental arm and placebo was at least 90%. The study was to stop for futility if the probability that the maximum effective dose was better than placebo by at least the futility difference was less than 20%. During the execution phase the study was stopped early, that is 32% less than planned maximum sample size, due to futility. The final results confirmed that the predefined stopping rules were met. In conclusion, the simulations showed that, if the drug was effective, this adaptive design could accomplish both the goals of PoC and DF. However, the study stopped early for futility in line with the simulation predictions for stopping. This resulted in the early stopping of a trial recruiting patients on ineffective treatment.