This clinical study synopsis is provided in line with Boehringer Ingelheim s Policy on Transparency and Publication of Clinical Study Data.

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1 abcd Clinical Study Synopsis for Public Disclosure This clinical study synopsis is provided in line with s Policy on Transparency and Publication of Clinical Study Data. The synopsis which is part of the clinical study report had been prepared in accordance with best practice and applicable legal and regulatory requirements at the time of study completion. The synopsis may include approved and non approved uses, doses, formulations, treatment regimens and/or age groups; it has not necessarily been submitted to regulatory authorities. A synopsis is not intended to provide a comprehensive analysis of all data currently available regarding a particular drug. More current information regarding a drug is available in the approved labeling information which may vary from country to country.. Additional information on this study and the drug concerned may be provided upon request based on s Policy on Transparency and Publication of Clinical Study Data. The synopsis is supplied for informational purposes only in the interests of scientific disclosure. It must not be used for any commercial purposes and must not be distributed, published, modified, reused, posted in any way, or used for any other purpose without the express written permission of.

2 Page 1 of 4 Tiotropium (SPIRIVA ) RESPIMAT : Evaluation of Fatal Events Febuary 2010 SYNOPSIS 12 JULY 2010 Pooled analysis Title of trial: Tiotropium (SPIRIVA ) RESPIMAT : Evaluation of Fatal Events February 2010 Coordinating Investigator: Trial sites: Publication (reference): Clinical phase: International and multicentre from 6 COPD trials including tiotropium Respimat 5 mcg and a matching placebo as a treatment group The pooled analysis has not been published Phase III/IV Objectives: The objective of this analysis was to describe fatal events observed in tiotropium Respimat 5 mcg clinical trials in patients with COPD Methodology: Pooled analysis of tiotropium Respimat 5 mcg trials meeting the following criteria: COPD indication, randomized, double-blind, placebo controlled, parallel group, >4 weeks duration. Subgroup of pooled analysis of Respimat 5 mcg trials limited to trials in which vital status information of prematurely discontinued patients was collected. No. of patients: planned: actual: Tiotropium: 3,228 Placebo: 3,229

3 Page 2 of 4 Diagnosis and main criteria for inclusion: Test product: dose: mode of admin.: batch no.: Reference therapy: dose: mode of admin.: batch no.: Outpatients of either sex, aged 40 years with a diagnosis of COPD (prebronchodilator FEV 1 60% predicted [ECSC criteria] and FEV 1 70% of FVC), current or ex-smoker (smoking history 10 pack years). iotropium Inhalation solution 5 µg (2 puffs of 2.5 µg) oral inhalation by Respimat inhaler Placebo not applicable oral inhalation by Respimat inhaler Duration of treatment: 48 weeks in trials , , and ; 24 week in trial ; 12 weeks in trials and Criteria for evaluation: Efficacy / clinical pharmacology: Safety: Statistical methods: trough FEV 1, trough FVC, exacerbations of COPD, transition dyspnea index focal score, St. George s Respiratory Questionnaire total score For each event, an incidence rate (IR) was calculated from the number of patients with an event divided by the cumulative time at risk within a treatment group and expressed as patient-years. Incidence rate differences (tiotropium placebo) were estimated based on the method described by Greenland and Robins (R ) with trial as stratum. The 95% confidence interval was calculated for each rate difference in order to describe the precision of the effect estimate. Fatal cases based on information including vital status of prematurely discontinued patients were analyzed using incidence rate ratios (i.e. IR (tiotropium) / IR (placebo)).

4 Page 3 of 4 SUMMARY CONCLUSIONS: Efficacy / clinical pharmacology results: A total of six trials involving tiotropium Respimat 5 mcg met the same selection criteria for pooling of trials (i.e. randomized, placebo-controlled, double-blind, parallel group studies with a treatment duration of at least 4 weeks). One of these studies is a recently completed 6 month trial ( ) from a different development program which was included in the safety assessment, but not the efficacy assessment. The trials demonstrated improvements in lung function over 24 hours with once daily dosing along with improvements in dyspnea, healthrelated quality of life and a reduced risk for exacerbations of COPD. Safety results: In 4 trials ( , , , ), vital status information of prematurely discontinued patients was collected. In a pooled analysis of these three 1-year ( , , ) and one 6-month ( ) placebocontrolled trials with 5 mcg including 6,096 patients, a numerical increase in all-cause mortality was seen in patients treated with tiotropium Respimat (68; incidence rate (IR) 2.64 cases per 100 patient-years) compared with placebo (51, IR 1.98) showing a rate ratio (95% confidence interval) of 1.33 (0.93, 1.92) for the planned treatment period. Subgroup analyses including but not limited to respiratory co-medication, demographic factors and cardiac disorders at baseline describe that the imbalance in mortality was observed in patients with known cardiac rhythm disorders at randomization (rate ratio (95%CI)=3.42; 1.29, 9.07), whereas the incidence rates were similar between the tiotropium and placebo groups in the subgroups without cardiac disorders at baseline and cardiac disorders excluding rhythm disorders at baseline. However, it is recognized that these analyses are retrospective and without correction for multiple comparisons. Similar analyses performed in the tiotropium HandiHaler pooled clinical trial safety database did not indicate an increased rate. The mortality observations from the Respimat database (6,448 patients, 5,487 patientyears at risk) are inconsistent with the larger tiotropium HandiHaler database (17,014 patients, 23,934 patient years at risk). In addition, the tiotropium

5 Page 4 of 4 HandiHaler database includes a large study of 4-years duration, whereas the Respimat database is limited to studies of up to 1-year in duration. Additional analysis with both formulations did not show an increased risk for a fatal event in patients with known coronary artery disease or for those receiving cardiovascular medications at baseline. An examination of the formulation properties indicated no known scientific mechanisms that would explain a difference based on the pharmacology of the substance, the pharmacokinetics of the formulations or the excipients of each formulation. Reasons for the apparent difference in the risk of all-cause mortality between the HandiHaler and Respimat formulations are unclear, should be interpreted with caution, and may reflect trial related factors or variability of outcomes. Conclusions: Retrospective pooled analyses of long term Respimat clinical trials; including three one-year and one six-month clinical trial showed a numerically greater incidence of all-cause fatality in the tiotropium group compared with the placebo group. The increased rate for fatal events was observed in patients with known cardiac rhythm disorders. The contribution of a rhythm disorder to the fatal outcome is uncertain and a causal relationship with tiotropium Respimat has not been established. An imbalance in fatal events has not been observed in a large database with tiotropium HandiHaler.