The 24 hour lung function time profile of olodaterol once daily versus placebo and tiotropium in patients with moderate to very severe chronic obstructive pulmonary disease

Background: Olodaterol is a once-daily long-acting β2-agonist being investigated for the treatment of chronic obstructive pulmonary disease, with ≥ 24 hour bronchodilator activity. Methods: Two replicate, randomized, double-blind, four-way crossover (6-week treatment periods), active (tiotropium 18 μg via HandiHaler®)- and placebo-controlled trials were conducted to evaluate the 24 hour forced expiratory volume in 1 second (FEV1) profile of olodaterol (5 and 10 μg) once daily (via Respimat®). Patients continued with inhaled corticosteroids and xanthines. Spirometry was performed at baseline and over the entire 24 hour post-dose period at week 6 of each treatment phase. Co-primary end points were change from study baseline (response) in FEV1 area under the curve from 0–12 hours (AUC0–12) and FEV1 AUC from 12–24 hours (AUC12–24); key secondary end point was FEV1 AUC from 0–24 hours response. Results: In study 1222.39, there was a significant difference from placebo in FEV1 AUC0–12 and AUC12–24 responses (P<0.0001) with olodaterol 5 μg (0.185 and 0.131 L) and 10 μg (0.207 and 0.178 L) at 6 weeks; similar results were observed for tiotropium (0.173 and 0.123 L). In study 1222.40, responses were 0.197 and 0.153 L with olodaterol 5 μg, 0.221 and 0.170 L with 10 μg, and 0.221 and 0.164 L with tiotropium versus placebo (P<0.0001). Incidence of adverse events was comparable across treatments. Conclusions: These data confirm the 24 hour lung-function efficacy profile of once-daily olodaterol, with FEV1 responses comparable to tiotropium

Exacerbation Recovery Patterns in Newly Diagnosed or Maintenance Treatment-Naïve Patients with COPD: Secondary Analyses of TICARI 1 Trial Data

Background: Little is known about the recovery patterns from acute exacerbations of chronic obstructive pulmonary disease (AECOPD) in newly diagnosed or maintenance treatment-naïve patients with COPD. This study describes the course of AECOPD in these patients at the time of treatment for the symptoms of acute respiratory tract infection (RTI). Methods: This study was a secondary analysis of data from a 12-week, randomized clinical trial (TICARI 1) testing the efficacy and safety of once-daily tiotropium 18 µg maintenance therapy versus placebo in newly diagnosed or maintenance treatment-naïve COPD patients with acute RTI symptoms for ≤7 days. Patients received standard care for AECOPD and RTI. Due to under-recruitment, the trial ended early and hence was underpowered to detect treatment differences. Data were pooled and exacerbation recovery patterns examined by using the EXAcerbation of Chronic Pulmonary Disease Tool (EXACT), forced expiratory volume in 1 second, rescue medication use, COPD Assessment Test™, Functional Assessment of Chronic Illness Therapy-Short Form, and Work Productivity and Activity Impairment Questionnaire: Respiratory Symptoms. Results: Of 140 patients, 73.6% had a prior COPD diagnosis without maintenance therapy; 80.0% had moderate-to-severe airflow obstruction. In addition to study drug, 40.0% were prescribed pharmacologic therapy (corticosteroids [34.3%], antibiotics [16.4%], and short-acting β2-adrenergic agonists [5.0%]) within ±7 days of randomization. Over 12 weeks, 78.6% exhibited symptomatic recovery (EXACT score) in a median of 5.0 days. Across all patients, 49.3% recovered without relapse, 29.3% recovered and then relapsed, and 21.4% had persistent symptoms (recovery criteria unmet). Conclusion: A substantial portion of newly diagnosed or maintenance treatment-naïve patients with COPD experience relapse or persistent symptoms following a clinic visit for AECOPD with symptoms of RTI. Whether initiating maintenance therapy could improve outcomes and reduce exacerbation risk requires further study

Dose Finding In Drug Development

Dose Finding In Drug Developmen

How to implement the ‘one patient, one vote’ principle under the framework of estimand

The scientific foundation of a modern clinical trial is randomization – each patient is randomized to a treatment group, and statistical comparisons are made between treatment groups. Because the study units are individual patients, this ‘one patient, one vote’ principle needs to be followed – both in study design and in data analysis. From the physicians' point of view, each patient is equally important, and they need to be treated equally in data analysis. It is critical that statistical analysis should respect design and study design is based on randomization. Hence from both statistical and medical points of view, data analysis needs to follow this ‘one patient, one vote’ principle. Under ICH E9 (R1), five strategies are recommended to establish ‘estimand’. This paper discusses how to implement these strategies using the ‘one patient, one vote’ principle

Bayesian sample size determination for a Phase III clinical trial with diluted treatment effect

<p>When Phase III treatment effect is diluted from what was observed from Phase II results, we propose to determine the Bayesian sample size for a Phase III clinical trial based on the normal, uniform, and truncated normal prior distributions of the treatment effects on an interval, which starts from an acceptable treatment effect to the observed treatment effect from Phase II. After incorporating the prior information of the treatment effects, the Bayesian sample size is the number of patients of the Phase III trial for a given Bayesian Predictive Power (BPP) or Bayesian Historical Predictive Power (BHPP). After that, the numerical simulations are carried out to determine the Bayesian sample size for the Phase III clinical trial. In particular, there exists a hook phenomenon for the BHPP when the number of patients of the Phase II trial equals 70 assuming the normal, uniform, or truncated normal treatment effect. Moreover, we add some sensitivity analysis of the Bayesian sample size about the parameters in the simulations. Finally, we determine the Bayesian sample size (number of events or deaths) of the Phase III trial for a fixed power, Bayesian Historical Power (BHP), and BHPP in the axitinib example.</p

Design and analysis of subgroups with biopharmaceutical applications

This book provides an overview of the theories and applications on subgroups in the biopharmaceutical industry. Drawing from a range of expert perspectives in academia and industry, this collection offers an overarching dialogue about recent advances in biopharmaceutical applications, novel statistical and methodological developments, and potential future directions. The volume covers topics in subgroups in clinical trial design; subgroup identification and personalized medicine; and general issues in subgroup analyses, including regulatory ones. Included chapters present current methods, theories, and case applications in the diverse field of subgroup application and analysis. Offering timely perspectives from a range of authoritative sources, the volume is designed to have wide appeal to professionals in the pharmaceutical industry and to graduate students and researchers in academe and government

A Prospective, Randomized, Open-Label Study to Evaluate Two Management Strategies for Gastrointestinal Symptoms in Patients Newly on Treatment with Dabigatran

<p><b>Article full text</b></p> <p><br></p> <p>The full text of this article can be found here<b>. </b><a href="https://link.springer.com/article/10.1007/s40119-016-0071-5">https://link.springer.com/article/10.1007/s40119-016-0071-5</a></p><p></p> <p><br></p> <p><b>Provide enhanced content for this article</b></p> <p><br></p> <p>If you are an author of this publication and would like to provide additional enhanced content for your article then please contact <a href="http://www.medengine.com/Redeem/”mailto:[email protected]”"><b>[email protected]</b></a>.</p> <p><br></p> <p>The journal offers a range of additional features designed to increase visibility and readership. All features will be thoroughly peer reviewed to ensure the content is of the highest scientific standard and all features are marked as ‘peer reviewed’ to ensure readers are aware that the content has been reviewed to the same level as the articles they are being presented alongside. Moreover, all sponsorship and disclosure information is included to provide complete transparency and adherence to good publication practices. This ensures that however the content is reached the reader has a full understanding of its origin. No fees are charged for hosting additional open access content.</p> <p><br></p> <p>Other enhanced features include, but are not limited to:</p> <p><br></p> <p>• Slide decks</p> <p>• Videos and animations</p> <p>• Audio abstracts</p> <p>• Audio slides</p

One-sided confidence intervals on nonnegative sums of variance components

Let nqS2q/[theta]q for q = 1,...,Q represent independently distributed chi-squared random variables with nq degrees of freedom. This paper considers the construction of one-sided confidence intervals on [gamma] = [Sigma]Qqcq[theta]q where cq [greater-or-equal, slanted] 0 for all q.random model

22nd annual Applied Statistics Symposium of the International Chinese Statistical Association (ICSA), jointly with the International Society for Biopharmaceutical Statistics (ISBS)

This volume is a unique combination of papers that cover critical topics in biostatistics from academic, government, and industry perspectives. The six sections cover Bayesian methods in biomedical research; Diagnostic medicine and classification; Innovative clinical trials design; Modelling and data analysis; Personalized medicine; and Statistical genomics. The real world applications are in clinical trials, diagnostic medicine and genetics. The peer-reviewed contributions were solicited and selected from some 400 presentations at the annual meeting of the International Chinese Statistical Association (ICSA), held with the International Society for Biopharmaceutical Statistics (ISBS). The conference was held in Bethesda in June 2013, and the material has been subsequently edited and expanded to cover the most recent developments