A Study to Characterize Pharmacokinetics of Tiotropium + Olodaterol Fixed-dose Combination in Japanese Patients With COPD.

Study Overview
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Brief Summary
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The primary objective of this study is to assess pharmacokinetics of tiotropium + olodaterol fixed-dose combination (2.5 µg/ 5 µg, 5 µg/ 5 µg) delivered by the RESPIMAT inhaler after 3 weeks once daily treatment in Japanese patients with COPD.

Official Title
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A Randomised, Open-label, Parallel-group Trial to Assess Pharmacokinetics and Safety of Tiotropium + Olodaterol Fixed-dose Combination (2.5 µg/ 5 µg, 5 µg/ 5 µg) Delivered by the RESPIMAT Inhaler After 3 Weeks Once Daily Treatment in Japanese Patients With Chronic Obstructive Pulmonary Disease (COPD)

Conditions
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Pulmonary Disease, Chronic Obstructive

Intervention / Treatment
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* Drug: Tiotropium (high dose) + Olodaterol
* Drug: Tiotropium (low dose) + Olodaterol


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Diagnosis of chronic obstructive pulmonary disease Relatively stable airway obstruction with post FEV1=<30% of predicted normal and< 80% predicted normal and post FEV1/FVC <70% Male or female Japanese patients, 40 years of age or older Smoking history of more than 10 pack years Exclusion criteria: Significant disease other than COPD Clinically relevant abnormal lab values History of asthma Diagnosis of thyrotoxicosis Diagnosis of paroxysmal tachycardia A marked baseline prolongation of QT/QTc interval A history of additional risk factors for Torsade de Pointes (TdP) History of myocardial infarction within 1 year of screening visit Unstable or life-threatening cardiac arrhythmia Hospitalization for heart failure within the past year Known active tuberculosis Malignancy for which patient has undergone resection, radiation therapy or chemotherapy within last five years History of life-threatening pulmonary obstruction History of cystic fibrosis Clinically evident bronchiectasis History of significant alcohol or drug abuse Thoracotomy with pulmonary resection Oral ß-adrenergics Oral corticosteroid medication at unstable doses Regular use of daytime oxygen therapy for more than one hour per day Pulmonary rehabilitation program in the six weeks prior to the screening visit Investigational drug within one month or six half lives (whichever is greater) prior to screening visit Known hypersensitivity to ß-adrenergic drugs, anticholinergics, BAC, EDTA Pregnant or nursing women Women of childbearing potential not using a highly effective method of birth control Patients who have previously been randomized in this study or are currently participating in another study Patients who are unable to comply with pulmonary medication restrictions Patients with narrow-angle glaucoma or micturition disorder due to prostatic hyperplasia etc Patients being treated with medications that prolong the QT/QTc interval

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tiotropium + Olodaterol (high dose)<br>Tiotropium and Olodaterol fixed dose combination (FDC) solution for inhalation - RESPIMAT | Drug: Tiotropium (high dose) + Olodaterol<br>* Tiotropium + Olodaterol solution for inhalation<br>|
| Experimental: Tiotropium + Olodaterol (low dose)<br>Tiotropium and Olodaterol fixed dose combination (FDC) solution for inhalation - RESPIMAT | Drug: Tiotropium (low dose) + Olodaterol<br>* Tiotropium + Olodaterol solution for inhalation<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax,ss (Olodaterol) | Maximum measured concentration of olodaterol after multiple inhaled administration of tiotropium+olodaterol in plasma at steady state (Cmax,ss). Per Protocol there are no primary endpoints defined. Therefore this pharmacokinetic endpoint was selected for primary outcome measure type. | 15 minutes (min) pre-dose and 5, 10, 20, 40 min, 1, 2, 3, and 4 hours (h) following drug administration on day 21 | 
| AUCt1-t2,ss (Olodaterol) | Area under the concentration-time curve of olodaterol in plasma after multiple inhaled administration of tiotropium+olodaterol over the time interval 0 to 4 hours at steady state (AUCt1-t2,ss). Per Protocol there are no primary endpoints defined. Therefore this pharmacokinetic endpoint was selected for primary outcome measure type. | 15 min pre-dose and 5, 10, 20, 40 min, 1, 2, 3, and 4 h following drug administration on day 21 | 
| AUC0-tz,ss (Olodaterol) | Area under the concentration-time curve of olodaterol after multiple inhaled administration of tiotropium+olodaterol in plasma over the time interval from 0 to the time of the last quantifiable data point at steady state (AUC0-tz,ss). Per Protocol there are no primary endpoints defined. Therefore this pharmacokinetic endpoint was selected for primary outcome measure type. | 15 min pre-dose and 5, 10, 20, 40 min, 1, 2, 3, and 4 h following drug administration on day 21 | 
| Tmax,ss (Olodaterol) | Time from dosing to the maximum concentration of Olodaterol after multiple inhaled administration of tiotropium+olodaterol in plasma at steady state (tmax,ss). Per Protocol there are no primary endpoints defined. Therefore this pharmacokinetic endpoint was selected for primary outcome measure type. | 15 min pre-dose and 5, 10, 20, 40 min, 1, 2, 3 and 4 hours (h) following drug administration on day 21 | 
| Aet1-t2,ss (Olodaterol) | Amount of olodaterol that is eliminated in urine after multiple inhaled administration of tiotropium+olodaterol over the time interval 0 to 4 hours at steady state (Aet1-t2,ss). Per Protocol there are no primary endpoints defined. Therefore this pharmacokinetic endpoint was selected for primary outcome measure type. | from 0 to 4 hours following drug administration on day 21 | 
| fe t1-t2,ss (Olodaterol) | Fraction eliminated in urine from the time point t1 (0 h) to time point t2 (4 h) at steady state (fet1-t2,ss). Per Protocol there are no primary endpoints defined. Therefore this pharmacokinetic endpoint was selected for primary outcome measure type. | from 0 to 4 hours following drug administration on day 21 | 
| CLR,t1-t2,ss (Olodaterol) | Renal clearance from the time point t1 (0 h) until the time point t2 (4 h) at steady state (CLR,t1-t2,ss). Per Protocol there are no primary endpoints defined. Therefore this pharmacokinetic endpoint was selected for primary outcome measure type. | from 0 to 4 hours following drug administration on day 21 | 
| Cmax,ss (Tiotropium) | Maximum measured concentration of tiotropium after multiple inhaled administration of tiotropium+olodaterol in plasma at steady state (Cmax,ss). Per Protocol there are no primary endpoints defined. Therefore this pharmacokinetic endpoint was selected for primary outcome measure type. | 15 minutes (min) pre-dose and 5, 10, 20, 40 min, 1, 2, 3, and 4 hours (h) following drug administration on day 21 | 
| AUCt1-t2,ss (Tiotropium) | Area under the concentration-time curve of tiotropium in plasma after multiple inhaled administration of tiotropium+olodaterol over the time interval 0 to 2 hours at steady state (AUCt1-t2,ss). Per Protocol there are no primary endpoints defined. Therefore this pharmacokinetic endpoint was selected for primary outcome measure type. | 15 min pre-dose and 5, 10, 20, 40 min, 1 and 2 h following drug administration on day 21 | 
| AUC0-tz,ss (Tiotropium) | Area under the concentration-time curve of tiotropium after multiple inhaled administration of tiotropium+olodaterol in plasma over the time interval from 0 to the time of the last quantifiable data point at steady state (AUC0-tz,ss). Per Protocol there are no primary endpoints defined. Therefore this pharmacokinetic endpoint was selected for primary outcome measure type. | 15 min pre-dose and 5, 10, 20, 40 min, 1, 2, 3, and 4 h following drug administration on day 21 | 
| Tmax,ss (Tiotropium) | Time from dosing to the maximum concentration of tiotropium after multiple inhaled administration of tiotropium+olodaterol in plasma at steady state (tmax,ss). Per Protocol there are no primary endpoints defined. Therefore this pharmacokinetic endpoint was selected for primary outcome measure type. | 15 min pre-dose and 5, 10, 20, 40 min, 1, 2, 3, 4 hours following drug administration on day 21 | 
| Aet1-t2,ss (Tiotropium) | Amount of tiotropium that is eliminated in urine after multiple inhaled administration of tiotropium+olodaterol over the time interval 0 to 4 hours at steady state (Aet1-t2,ss). Per Protocol there are no primary endpoints defined. Therefore this pharmacokinetic endpoint was selected for primary outcome measure type. | from 0 to 4 hours following drug administration on day 21 | 
| fe t1-t2,ss (Tiotropium) | Fraction eliminated in urine from the time point t1 (0 h) to time point t2 (4 h) at steady state (fet1-t2,ss). Per Protocol there are no primary endpoints defined. Therefore this pharmacokinetic endpoint was selected for primary outcome measure type. | from 0 to 4 hours following drug administration on day 21 | 
| CLR,t1-t2,ss (Tiotropium) | Renal clearance from the time point t1 (0 h) until the time point t2 (4 h) at steady state (CLR,t1-t2,ss). Per Protocol there are no primary endpoints defined. Therefore this pharmacokinetic endpoint was selected for primary outcome measure type. Plasma concentration of tiotropium could not be quantified up to 4 hours for Tiotropium + Olodaterol (2.5μg/5μg). | from 0 to 4 hours following drug administration on day 21 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events (Including Assessment Based on Physical Examination) | Outcome data show are the number of patients with an adverse event including the assessment based on physical examination. | up to 6 weeks (3 weeks treatment and 3 weeks follow-up) post dose | 
| Number of Participants With Clinically Relevant Abnormalities in Vital Signs, Clinical Laboratory Tests and ECG | Outcome data show are the number of participants with clinically relevant abnormalities reported as an adverse event (AE) related to the vital signs (pulse rate and blood pressure in supine position), clinical laboratory (routine blood chemistry, haematology, and urinalysis) tests and ECG (12-lead holter monitoring Electrocardiography). Relevant findings or worsening of baseline conditions were reported as adverse events. There were no clinically relevant abnormalities reported as an AE related to the vital signs and ECG. | up to 6 weeks (3 weeks treatment and 3 weeks follow-up) post dose |