Co-administration of Olodaterol Respimat® and Tiotropium Handihaler®

Study Overview
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Brief Summary
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The overall objective of this study is to assess efficacy and safety of 12 weeks, once daily, orally inhaled co-administration of olodaterol 5 µg (delivered by the Respimat® Inhaler) and tiotropium (delivered by the Handihaler® as Spiriva Handihaler®), compared to tiotropium (Spiriva Handihaler®) monotherapy on lung function in patients with COPD.

Official Title
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A Randomised, Double Blind, Parallel Group Study to Assess the Efficacy and Safety of 12 Weeks of Once Daily, Orally Inhaled, Co-administration of Olodaterol 5µg (Delivered by the Respimat® Inhaler) and Tiotropium 18µg (Delivered by the HandiHaler®) Compared to Once Daily, Orally Inhaled, Co-administration of Placebo (Delivered by the Respimat® Inhaler) and Tiotropium 18µg (Delivered by the HandiHaler®) in Patients With Chronic Obstructive Pulmonary Disease (COPD)[ANHELTO TM 2]

Conditions
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Pulmonary Disease, Chronic Obstructive

Intervention / Treatment
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* Drug: Tiotropium
* Drug: Placebo matching Olodaterol
* Drug: Tiotropium
* Drug: Olodaterol


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: All patients must sign an informed consent consistent with International Conference on Harmonization-Good Clinical Practice (ICH-GCP) guidelines prior to participation in the trial, which includes medication washout and restrictions. All patients must have a diagnosis of chronic obstructive pulmonary disease and must meet the following spirometric criteria: Patients must have a relatively stable airway obstruction with a post-bronchodilator FEV1 ≥ 30 % and < 80% of predicted normal and a post-bronchodilator FEV1/FVC <70% at Visit 1. Male or female patients, 40 years of age or older. Patients must be current or ex-smokers with a smoking history of more than 10 pack years Patients must be able to: perform technically acceptable pulmonary function tests, and maintain records(paper diary). Patients must be able to inhale medication in a competent manner from the Respimat Inhaler as well as the Handihaler. Exclusion criteria: Patients with a significant disease other than COPD; a significant disease is defined as a disease which, in the opinion of the investigator, may (i) put the patient at risk because of participation in the study, (ii) influence the results of the study, or (iii) cause concern regarding the patients ability to participate in the study. Patients with clinically relevant abnormal baseline haematology, blood chemistry, or urinalysis; all patients with an AST >x2 ULN, ALT >x2 ULN, bilirubin >x2 ULN or creatinine >x2 ULN will be excluded regardless of clinical condition (a repeat laboratory evaluation will not be conducted in these patients). Patients with a history of asthma. For patients with allergic rhinitis or atopy, source documentation is required to verify that the patient does not have asthma. If a patient has a total blood eosinophil count ≥600/mm3, source documentation is required to verify that the increased eosinophil count is related to a non-asthmatic condition. A diagnosis of thyrotoxicosis (due to the known class side effect profile of ß2-agonists). A diagnosis of paroxysmal tachycardia (>100 beats per minute) (due to the known class side effect profile of ß2-agonists). A history of myocardial infarction within 1 year of screening visit (Visit 1). Unstable or life-threatening cardiac arrhythmia. Hospitalization for heart failure within the past year. Known active tuberculosis. A malignancy for which patient has undergone resection, radiation therapy or chemotherapy within last five years (patients with treated basal cell carcinoma are allowed). A history of life-threatening pulmonary obstruction. A history of cystic fibrosis. Clinically evident bronchiectasis. A history of significant alcohol or drug abuse. Patients who have undergone thoracotomy with pulmonary resection (patients with a history of thoracotomy for other reasons should be evaluated as per exclusion criterion No. 1). Patients being treated with oral or patch ß-adrenergics. Patients being treated with oral corticosteroid medication at unstable doses (i.e., less than six weeks on a stable dose) or at doses in excess of the equivalent of 10 mg of prednisone per day or 20 mg every other day. Patients who regularly use daytime oxygen therapy for more than one hour per day and in the investigators opinion will be unable to abstain from the use of oxygen therapy during clinic visits. Patients who have completed a pulmonary rehabilitation program in the six weeks prior to the screening visit (Visit 1) or patients who are currently in a pulmonary rehabilitation program. Patients who have taken an investigational drug within one month or six half lives (whichever is greater) prior to screening visit (Visit 1). Patients with known hypersensitivity to ß-adrenergic drugs, BAC, EDTA, or any other component of the Respimat® inhalation solution. Patients with known hypersensitivity to anticholinergic drugs, lactose, or any other components of the HandiHaler®. Pregnant or nursing women. Women of childbearing potential not using a highly effective method of birth control*. Female patients will be considered to be of childbearing potential unless surgically sterilised by hysterectomy or bilateral tubal ligation, or post-menopausal for at least two years. * as per ICH M3(R2) a highly effective method of birth control is defined as those which result in a low failure rate (i.e. less than 1% per year). Patients who have previously been randomised in this study or are currently participating in another study. Patients who are unable to comply with pulmonary medication restrictions prior to randomisation.

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Olodaterol andTiotropium<br>2 puffs Olodaterol from Respimat and one capsule Tiotropium by Handihaler once daily in am, co-administered | Drug: Tiotropium<br>* marketed product<br>Drug: Olodaterol<br>* one dose<br>|
| Other: Placebo and Tiotropium<br>2 puffs placebo inhalation solution from Respimat and one capsule Tiotropium by Handihaler once daily in am, co-administered | Drug: Tiotropium<br>* marketed product<br>Drug: Placebo matching Olodaterol<br>* one dose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| FEV1 AUC0-3h Response at 12 Weeks; Defined as Change From Baseline to Week 12 | FEV1 (Forced expiratory volume in 1 second) AUC0-3h (area under the curve) response at 12 weeks; defined as change from baseline to Week 12. AUC was standardized by dividing by time unit. | baseline and 12 weeks | 
| Trough FEV1 Response at 12 Weeks; Defined as Change From Baseline to Week 12 | Trough FEV1 (Forced expiratory volume in 1 second) response at 12 weeks; defined as change from baseline to Week 12 | baseline and 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Saint George Respiratory Questionnaire - (Total Score) Based on Combined 1222.51 and 1222.52 Data | The Saint George Respiratory Questionnaire (SGRQ) is designed to measure health impairment in patients with asthma and chronic obstructive pulmonary disease (COPD). It is divided into two parts. Part I produces the Symptoms score (several scales), and Part II the Activity and Impacts scores [dichotomous (true/false) except last question (4-point Likert scale)]. A Total score is also produced with scores ranging from 0 to 100, with higher scores indicating more limitations. Since the SGRQ analysis is based on the combined data from both this study and protocol 1222.51 (NCT01694771), only combined SGRQ results will be included in the latest clinical trial report. Hence there will only be one SGRQ analysis from both studies, which will not appear in the first clinical trial report. For this same reason, another covariate - study - will also be included in the MMRM for SGRQ analysis. The combined data for this outcome measure was pre-specified in both protocols. | 12 weeks | 
| Peak FEV1 Response at 12 Weeks - Defined as Change From Baseline | Peak FEV1 (Forced Expiratory Volume in 1 second) response at 12 Weeks - defined as change from baseline. All p-values for these measures are only descriptive. | baseline and 12 weeks | 
| FVC AUC0-3h Response at 12 Weeks; Defined as Change From Baseline | Forced Vital Capacity (FVC) AUC0-3h response at 12 weeks - defined as change from baseline. AUC was standardized by dividing by time unit. | baseline and 12 Weeks | 
| Peak FVC Response at 12 Weeks; Defined as Change From Baseline | Peak FVC response at 12 weeks - defined as change from baseline. | baseline and 12 weeks | 
| Trough FVC Response at 12 Weeks; Defined as Change From Baseline | Trough Forced Vital Capacity (FVC) response at 12 weeks- defined as change from baseline. | baseline and 12 weeks | 
| Rescue Medication Usage - Percentage of Rescue Free Days | Rescue medication usage - the percentage of rescue free days. The percentage of rescue free days is defined as: number of rescue free days divided by total exposure, multiplied by 100%. The baseline for the number of rescue-free days was defined as the number of rescue-free days observed during the last week of the baseline period (i.e., the 7 days prior to administration of the first dose of randomized treatment). Results are from non-MMRM ANCOVA models by week with LOCF up to each week. Fixed effects include treatment and baseline. Number of patients contributing to models: Tio+Placebo (559), Tio+Olo 5ug (552) | over 12 weeks | 
| Rescue Medication Usage - Mean Weekly Rescue Usage (Total Daily) | Rescue medication usage - mean weekly rescue usage (total daily). The baseline for the rescue use was the mean of the observations during the last week of the baseline period. Administration of rescue medication could occur at any point during the trial as deemed necessary by the patient or the investigator. Open label albuterol metered dose inhaler (MDI) (100 μg per puff) was provided as rescue medication . Daily, between clinic visits, patients recorded the number of puffs of albuterol in a paper diary. Results are from non-MMRM ANCOVA models by week with LOCF up to each week. Fixed effects include treatment and baseline. Number of patients contributing to models: Tio+Placebo (559), Tio+Olo 5ug (555) | over 12 weeks | 
| Rescue Medication Usage - Mean Weekly Rescue Usage (Daytime) | Rescue medication usage - Mean weekly rescue usage during daytime hours. Administration of rescue medication could occur at any point during the trial as deemed necessary by the patient or the investigator. Open label albuterol MDI (100 μg per puff) was provided as rescue medication by BI, and only the albuterol MDI provided by BI was allowed for rescue medication use. Daily, between clinic visits, patients recorded the number of puffs of albuterol in a paper diary. Results are from non-MMRM ANCOVA models by week with LOCF up to each week. Fixed effects include treatment and baseline. Number of patients contributing to models: Tio+Placebo (559), Tio+Olo 5ug (555) | over 12 weeks | 
| Rescue Medication Usage - Mean Weekly Rescue Usage (Nighttime) | Rescue medication usage - Mean weekly rescue usage during nighttime hours. Administration of rescue medication could occur at any point during the trial as deemed necessary by the patient or the investigator. Open label albuterol MDI (100 μg per puff) was provided as rescue medication by BI, and only the albuterol MDI provided by BI was allowed for rescue medication use. Daily, between clinic visits, patients recorded the number of puffs of albuterol in a paper diary. Results are from non-MMRM ANCOVA models by week with LOCF up to each week. Fixed effects include treatment and baseline. Number of patients contributing to models: Tio+Placebo (559), Tio+Olo 5ug (555) | over 12 weeks |