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

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)

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.

Study Overview

• Status: Completed
• Conditions: Pulmonary Disease, Chronic Obstructive
• Intervention / Treatment: Drug: Tiotropium (high dose) + Olodaterol; Drug: Tiotropium (low dose) + Olodaterol

• Study Type: Interventional
• Enrollment (Actual): 32
• Phase: Phase 1

Contacts and Locations

Study Locations

• Japan
  • Toshima-ku, Tokyo, Japan
    • 1237.24.24001 Boehringer Ingelheim Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

1. Diagnosis of chronic obstructive pulmonary disease
2. Relatively stable airway obstruction with post FEV1=<30% of predicted normal and< 80% predicted normal and post FEV1/FVC <70%
3. Male or female Japanese patients, 40 years of age or older
4. Smoking history of more than 10 pack years

Exclusion criteria:

1. Significant disease other than COPD
2. Clinically relevant abnormal lab values
3. History of asthma
4. Diagnosis of thyrotoxicosis
5. Diagnosis of paroxysmal tachycardia
6. A marked baseline prolongation of QT/QTc interval
7. A history of additional risk factors for Torsade de Pointes (TdP)
8. History of myocardial infarction within 1 year of screening visit
9. Unstable or life-threatening cardiac arrhythmia
10. Hospitalization for heart failure within the past year
11. Known active tuberculosis
12. Malignancy for which patient has undergone resection, radiation therapy or chemotherapy within last five years
13. History of life-threatening pulmonary obstruction
14. History of cystic fibrosis
15. Clinically evident bronchiectasis
16. History of significant alcohol or drug abuse
17. Thoracotomy with pulmonary resection
18. Oral ß-adrenergics
19. Oral corticosteroid medication at unstable doses
20. Regular use of daytime oxygen therapy for more than one hour per day
21. Pulmonary rehabilitation program in the six weeks prior to the screening visit
22. Investigational drug within one month or six half lives (whichever is greater) prior to screening visit
23. Known hypersensitivity to ß-adrenergic drugs, anticholinergics, BAC, EDTA
24. Pregnant or nursing women
25. Women of childbearing potential not using a highly effective method of birth control
26. Patients who have previously been randomized in this study or are currently participating in another study
27. Patients who are unable to comply with pulmonary medication restrictions
28. Patients with narrow-angle glaucoma or micturition disorder due to prostatic hyperplasia etc
29. Patients being treated with medications that prolong the QT/QTc interval

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: October 1, 2012
• Primary Completion (Actual): March 1, 2013
• Study Completion (Actual): March 1, 2013

Study Registration Dates

• First Submitted: October 8, 2012
• First Submitted That Met QC Criteria: October 8, 2012
• First Posted (Estimate): October 11, 2012

Study Record Updates

• Last Update Posted (Estimate): July 15, 2015
• Last Update Submitted That Met QC Criteria: June 19, 2015
• Last Verified: June 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Pulmonary Disease, Chronic Obstructive; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Parasympatholytics; Autonomic Agents; Peripheral Nervous System Agents; Cholinergic Antagonists; Cholinergic Agents; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Tiotropium Bromide; Olodaterol
• Other Study ID Numbers: 1237.24