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      Testing Two Different Doses of Tiotropium Respimat® in Cystic Fibrosis: Phase 2 Randomized Trial Results

      research-article
      1 , 2 , 2 , 3 , 4 , 5 , 6 , * , on behalf of the Tiotropium Cystic Fibrosis Study Group
      PLoS ONE
      Public Library of Science

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          Abstract

          Background

          Tiotropium is a once-daily, long-acting anticholinergic bronchodilator with the potential to alleviate airway obstruction in cystic fibrosis. Our objective was to evaluate the efficacy and safety of 2.5 and 5 µg once-daily tiotropium delivered via the Respimat Soft Mist Inhaler vs. placebo in people with cystic fibrosis.

          Methods

          This phase 2, 12-week, randomized, double-blind, placebo-controlled parallel-group study of tiotropium Respimat as add-on to usual cystic fibrosis maintenance therapy included people with cystic fibrosis with pre-bronchodilator forced expiratory volume in 1 second (FEV 1) ≥25% predicted. Co-primary efficacy end points were change from baseline in percent-predicted FEV 1 area under the curve from 0 to 4 hours (FEV 1 AUC 0–4h), and trough FEV 1 at the end of week 12.

          Findings

          A total of 510 subjects with cystic fibrosis aged 5–69 years were randomized. Both doses of tiotropium resulted in significant improvement compared with placebo in the co-primary efficacy end points at the end of week 12 (change from baseline in percent-predicted FEV 1 AUC 0–4h: 2.5 µg: 2.94%, 95% confidence interval 1.19–4.70, p = 0.001; 5 µg: 3.39%, 95% confidence interval 1.67–5.12, p = 0.0001; in percent-predicted trough FEV 1∶2.5 µg: 2.24%, p = 0.2; 5 µg: 2.22%, p = 0.02). There was a greater benefit with tiotropium 5 vs. 2.5 µg. No treatment-related adverse events or unexpected safety findings were observed in patients taking tiotropium.

          Conclusions

          Tiotropium significantly improved lung function in people with cystic fibrosis. The improvement was greater with the higher dose than the lower dose, with no difference in adverse events.

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          Most cited references24

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          The CONSORT statement: revised recommendations for improving the quality of reports of parallel group randomized trials

          To comprehend the results of a randomized controlled trial (RCT), readers must understand its design, conduct, analysis and interpretation. That goal can only be achieved through complete transparency from authors. Despite several decades of educational efforts, the reporting of RCTs needs improvement. Investigators and editors developed the original CONSORT (Consolidated Standards of Reporting Trials) statement to help authors improve reporting by using a checklist and flow diagram. The revised CONSORT statement presented in this paper incorporates new evidence and addresses some criticisms of the original statement. The checklist items pertain to the content of the Title, Abstract, Introduction, Methods, Results and Discussion. The revised checklist includes 22-items selected because empirical evidence indicates that not reporting the information is associated with biasedestimates of treatment effect or the information is essential to judge the reliability or relevance of the findings. We intended the flow diagram to depict the passage of participants through an RCT. The revised flow diagram depicts information from four stages of a trial (enrolment, intervention allocation, follow-up, and analysis). The diagram explicitly includes the number of participants, for each intervention group, included in the primary data analysis. Inclusion of these numbers allows the reader to judge whether the authors have performed an intention-to-treat analysis. In sum, the CONSORT statement is intended to improve the reporting of an RCT, enabling readers to understand a trial's conduct and to assess the validity of its results.
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            Standardisation of spirometry

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              Exacerbations in cystic fibrosis. 1: Epidemiology and pathogenesis.

              With the improving survival of patients with cystic fibrosis (CF), the clinical spectrum of this complex multisystem disease continues to evolve. One of the most important clinical events for patients with CF in the course of this disease is an acute pulmonary exacerbation. Clinical and microbial epidemiology studies of CF pulmonary exacerbations continue to provide important insight into the course, prognosis and complications of the disease. This review provides a summary of the pathophysiology, clinical epidemiology and microbial epidemiology of a CF pulmonary exacerbation.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2014
                4 September 2014
                : 9
                : 9
                : e106195
                Affiliations
                [1 ]Institute of Nursing and Health Research, University of Ulster, Ulster, Northern Ireland
                [2 ]Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, Connecticut, United States of America
                [3 ]Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim, Germany
                [4 ]The Hospital for Sick Children, Toronto, Ontario, Canada
                [5 ]Florida State University College of Medicine, Orlando, Florida, United States of America
                [6 ]Centre for Infection and Immunity, Queen’s University Belfast, Belfast, Northern Ireland
                University of Modena and Reggio Emilia, Italy
                Author notes

                Competing Interests: The authors have read the journal’s policy, declare the following conflicts of interest, and confirm that these do not alter their adherence to PLOS ONE policies on sharing data and materials: JSE acted as a consultant for Boehringer Ingelheim and was principal investigator for this study; JMB declares no conflicts; PK, QD, and PMZ are employees of Boehringer Ingelheim; FR acts as a consultant for Boehringer Ingelheim and is the principal investigator for the phase 3 study of tiotropium in CF; DEG declares no conflicts related to bronchodilators in CF.

                Performed the experiments: JB PK QD PMZ FR DG JSE. Analyzed the data: JB PK QD PMZ FR DG JSE. Wrote the paper: JB PK QD PMZ FR DG JSE. Contributed to the planning and design of the trial: JB PK QD PMZ FR DG JSE.

                Membership of the Tiotropium Cystic Fibrosis Study Group is provided in the Acknowledgments.

                Article
                PONE-D-14-04826
                10.1371/journal.pone.0106195
                4154718
                25188297
                845dd37e-247b-4a40-820f-03bab7f18833
                Copyright @ 2014

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 6 February 2014
                : 25 July 2014
                Page count
                Pages: 9
                Funding
                This study was funded by Boehringer Ingelheim. Boehringer Ingelheim was involved in the study design, data collection and analysis, decision to publish, and preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Developmental Biology
                Fibrosis
                Cystic Fibrosis
                Genetics
                Genetic Dominance
                Autosomal Recessive Traits
                Human Genetics
                Medicine and health sciences
                Clinical medicine
                Clinical trials
                Phase II clinical investigation
                Pediatrics
                Pediatric Pulmonology
                Pulmonology
                Research and Analysis Methods
                Research Design
                Clinical Research Design

                Uncategorized
                Uncategorized

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