Efficacy and Safety of 4 Weeks Treatment With Inhaled BI 1744 CL in Japanese Patients With COPD

Pulmonary Disease, Chronic Obstructive Clinical Trial

Official title:

Randomised, Double-blind, Placebo-controlled, Parallel Group Study to Assess the Efficacy and Safety of 4 Weeks of Once Daily Treatment of Orally Inhaled BI 1744 CL Delivered by the Respimat Inhaler in Japanese Patients With COPD

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00824382
• Other study ID #: 1222.22
• Status: Completed
• Phase: Phase 2
• First received: January 15, 2009
• Last updated: June 17, 2014
• Start date: January 2009

Study information

• Verified date: May 2014
• Source: Boehringer Ingelheim
• Contact: n/a
• Is FDA regulated: No
• Health authority: Japan: Ministry of Health, Labor and Welfare
• Study type: Interventional

Clinical Trial Summary

The primary objective of this study is to determine the optimum dose(s) of BI 1744 CL inhalation solution delivered by the Respimat inhaler once daily for 4 weeks in Japanese patients with chronic obstructive pulmonary disease (COPD). The selection of the optimum dose(s) will be based on bronchodilator efficacy, safety evaluations and pharmacokinetic evaluations.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 328
• Est. primary completion date: March 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 40 Years and older

Eligibility

Inclusion Criteria:

1. All patients must sign an informed consent consistent with GCP guidelines prior to participation in the trial.

2. All patients must have a diagnosis of chronic obstructive pulmonary disease and must meet the following spirometric criteria: Patients must have relatively stable, moderate to severe airway obstruction with a post-bronchodilator FEV1 >=30% of predicted normal and <80% of predicted normal and a post-bronchodilator FEV1/FVC <70% at Visit 1

3. Male or female patients, 40 years of age or older

4. Patients must be current or ex-smokers with a smoking history of more than 10 pack-years. Pack-Years = [Number of cigarettes/day/20] — years of smoking Patients who have never smoked cigarettes must be excluded.

5. Patients must be able to perform technically acceptable pulmonary function tests (both supervised and unsupervised) and PEFR measurements, and must be able to record a patient diary during the study period as required in the protocol.

6. Patients must be able to inhale medication in a competent manner from the Respimat inhaler and from a MDI.

Exclusion Criteria:

1. 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 patient's ability to participate in the study

2. Patients with clinically relevant abnormal baseline haematology, blood chemistry, or urinalysis; all patients with an AST >80 IU/L, ALT >80 IU/L, bilirubin >1.5 x ULN or creatinine >1.5 x ULN will be excluded regardless of clinical condition (a repeat laboratory evaluation will not be conducted in these patients)

3. Patients with a history of asthma or a total blood eosinophil count >=600/mm3. A repeat eosinophil count will not be conducted in these patients

4. Patients with any of the following conditions:

• a diagnosis of thyrotoxicosis

• a diagnosis of paroxysmal tachycardia (>100 beats per minute)

• a marked baseline prolongation of QT/QTc interval (e.g. repeated demonstration of a QTc interval >450 ms) as recommended by ICH E14. For patients who have a QTc interval between 450 ms and 500 ms, as judged by site personnel, there will be a confirmatory reading by centralized evaluation institute. If the confirmatory reading is still greater than 450 ms, patient will be excluded. Patients with a QTc interval >=500 ms will immediately be excluded from the study.

• a history of additional risk factors for Torsade de Pointes (TdP) (e.g. heart failure, hypokalemia, family history of Long QT Syndrome) as recommended by ICH E14.

5. Patients with any of the following conditions:

• a history of myocardial infarction within 1 year

• a diagnosis of clinically relevant cardiac arrhythmia

• known active tuberculosis

• a malignancy for which patient has undergone resection, radiation therapy or chemotherapy within last 5 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

6. 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)

7. Patients being treated with any of the following concomitant medications:

• medications that prolong the QT/QTc interval

• oral beta-adrenergics and beta-adrenergics patchs

• beta-blockers (topical beta-blockers for ocular conditions are allowed)

• oral corticosteroid medication at unstable doses (i.e. less than 6 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.

8. Patients who regularly use daytime oxygen therapy for more than 1 hour per day and in the investigator's opinion will be unable to abstain from the use of oxygen therapy during clinic visits

9. Patients who have completed a pulmonary rehabilitation program in the 6 weeks prior to the screening visit (Visit 1) or patients who are currently in a pulmonary rehabilitation program

10. Patients who have taken an investigational drug within 1 month or 6 half lives (whichever is greater) prior to screening visit

11. Patients with known hypersensitivity to beta-adrenergics drugs, BAC, EDTA or any other component of the Respimat inhalation solution delivery system

12. Pregnant or suspect of pregnant or women who are willing to become pregnant during the study period or nursing women

13. Patients who have previously been participated in this study or are currently participating in another study

14. Patients who are unable to comply with pulmonary medication restrictions prior to randomisation

15. The randomization of patients with any respiratory infection or COPD exacerbation in the 6 weeks prior to the screening visit or during the screening period should be postponed. Patients may be randomised 6 weeks following recovery from the infection or exacerbation

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double-Blind, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Chronic Disease
• Pulmonary Disease, Chronic Obstructive

Intervention

Drug:
• BI 1744 CL 2 µg
2 puffs of 1 µg/actuation delivered by the Respimat® inhaler
• BI 1744 CL 5 µg
2 puffs of 2.5 µg/actuation delivered by the Respimat® inhaler
• BI 1744 CL 10 µg
2 puffs of 5 µg/actuation delivered by Respimat®
• Placebo
2 puffs delivered by the Respimat® inhaler

Locations

Country	Name	City	State
Japan	1222.22.048 Boehringer Ingelheim Investigational Site	Asahikawa, Hokkaido
Japan	1222.22.044 Boehringer Ingelheim Investigational Site	Bunkyo-ku, Tokyo
Japan	1222.22.008 Boehringer Ingelheim Investigational Site	Chiba, Chiba
Japan	1222.22.002 Boehringer Ingelheim Investigational Site	Fukuoka, Fukuoka
Japan	1222.22.041 Boehringer Ingelheim Investigational Site	Fukuoka, Fukuoka
Japan	1222.22.027 Boehringer Ingelheim Investigational Site	Himeji, Hyogo
Japan	1222.22.028 Boehringer Ingelheim Investigational Site	Himeji, Hyogo
Japan	1222.22.018 Boehringer Ingelheim Investigational Site	Hiroshima, Hiroshima
Japan	1222.22.021 Boehringer Ingelheim Investigational Site	Hitachi, Ibaraki
Japan	1222.22.010 Boehringer Ingelheim Investigational Site	Inashiki-gun, Ibaraki
Japan	1222.22.012 Boehringer Ingelheim Investigational Site	Itabashi-ku, Tokyo
Japan	1222.22.009 Boehringer Ingelheim Investigational Site	Kamogawa, Chiba
Japan	1222.22.023 Boehringer Ingelheim Investigational Site	Kawasaki, Kanagawa
Japan	1222.22.025 Boehringer Ingelheim Investigational Site	Kawasaki, Kanagawa
Japan	1222.22.017 Boehringer Ingelheim Investigational Site	Kishiwada, Osaka
Japan	1222.22.004 Boehringer Ingelheim Investigational Site	Kitakyusyu, Fukuoka
Japan	1222.22.020 Boehringer Ingelheim Investigational Site	Koga, Fukuoka
Japan	1222.22.014 Boehringer Ingelheim Investigational Site	Komaki, Aichi
Japan	1222.22.032 Boehringer Ingelheim Investigational Site	Kumamoto, Kumamoto
Japan	1222.22.005 Boehringer Ingelheim Investigational Site	Kurume, Fukuoka
Japan	1222.22.029 Boehringer Ingelheim Investigational Site	Kurume, Fukuoka
Japan	1222.22.033 Boehringer Ingelheim Investigational Site	Kyoto, Kyoto
Japan	1222.22.050 Boehringer Ingelheim Investigational Site	Kyoto, Kyoto
Japan	1222.22.022 Boehringer Ingelheim Investigational Site	Matsumoto, Nagano
Japan	1222.22.015 Boehringer Ingelheim Investigational Site	Nagoya, Aichi
Japan	1222.22.043 Boehringer Ingelheim Investigational Site	Nagoya, Aichi
Japan	1222.22.001 Boehringer Ingelheim Investigational Site	Naka-gun, Ibaraki
Japan	1222.22.007 Boehringer Ingelheim Investigational Site	Niigata, Niigata
Japan	1222.22.040 Boehringer Ingelheim Investigational Site	Obihiro, Hokkaido
Japan	1222.22.042 Boehringer Ingelheim Investigational Site	Okinawa, Okinawa
Japan	1222.22.034 Boehringer Ingelheim Investigational Site	Osaka, Osaka
Japan	1222.22.038 Boehringer Ingelheim Investigational Site	Osaka, Osaka
Japan	1222.22.049 Boehringer Ingelheim Investigational Site	Osaka, Osaka
Japan	1222.22.045 Boehringer Ingelheim Investigational Site	Osaka-sayama, Osaka
Japan	1222.22.019 Boehringer Ingelheim Investigational Site	Sakai, Oasaka
Japan	1222.22.006 Boehringer Ingelheim Investigational Site	Sapporo, Hokkaido
Japan	1222.22.051 Boehringer Ingelheim Investigational Site	Sashima-gun, Ibaraki
Japan	1222.22.031 Boehringer Ingelheim Investigational Site	Sendai, Miyagi
Japan	1222.22.013 Boehringer Ingelheim Investigational Site	Seto, Aichi
Japan	1222.22.024 Boehringer Ingelheim Investigational Site	Shibata-gun, Miyagi
Japan	1222.22.003 Boehringer Ingelheim Investigational Site	Takarazuka, Hyogo
Japan	1222.22.026 Boehringer Ingelheim Investigational Site	Tsukuba, Ibaraki
Japan	1222.22.030 Boehringer Ingelheim Investigational Site	Ube, Yamaguchi
Japan	1222.22.037 Boehringer Ingelheim Investigational Site	Uji, Kyoto
Japan	1222.22.047 Boehringer Ingelheim Investigational Site	Wakayama, Wakayama
Japan	1222.22.016 Boehringer Ingelheim Investigational Site	Yamagata, Yamagata
Japan	1222.22.036 Boehringer Ingelheim Investigational Site	Yao, Osaka
Japan	1222.22.011 Boehringer Ingelheim Investigational Site	Yokohama, Kanagawa

Sponsors (1)

Lead Sponsor	Collaborator
Boehringer Ingelheim

Country where clinical trial is conducted

Japan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Trough FEV1 Response at Week 4	The change from baseline in trough FEV1 after 4 weeks of treatment. Trough FEV1 is defined as the mean of the two FEV1 values (performed at -1 hour and -10 minutes prior to next test-drug inhalation) at the end of the dosing interval, 24 hours post-drug administration. Trough FEV1 response is defined as the change from baseline . Baseline trough FEV1 is the mean of the two pre-treatment FEV1 values measured at Visit 2 prior to administration of the first dose of study medication.	baseline and after 4 weeks treatment	No
Secondary	Trough FEV1 Response at Week 2	Trough FEV1 is defined as the mean of the two FEV1 values (performed at -1 hour and -10 minutes prior to next test-drug inhalation) at the end of the dosing interval, 24 hours post-drug administration. Trough FEV1 response is defined as the change from baseline in trough FEV1. Baseline trough FEV1 is the mean of the two pre-treatment FEV1 values measured at Visit 2 prior to administration of the first dose of study medication	baseline and after 2 weeks treatment	No
Secondary	FEV1 AUC(0-3) Response at 4 Weeks	The change from baseline in FEV1 AUC(0-3) after 4 weeks of treatment. FEV1 AUC 0-3h was calculated from 0-3 hours post-dose using the trapezoidal rule, divided by the observation time (3h) to report in liters.; Due to normalization the unit is liters.	baseline and after 4 weeks treatment	No
Secondary	FEV1 Peak(0-3) Response at 4 Weeks	The change from baseline in FEV1 peak(0-3) after 4 weeks of treatment.	baseline and after 4 weeks treatment	No
Secondary	Trough FVC Response at Week 4	The change from baseline in Trough FVC after 4 weeks of treatment	baseline and after 4 weeks treatment	No
Secondary	FVC AUC(0-3) Response	The change from baseline in FVC AUC(0-3) response after 4 weeks of treatment. FVC AUC 0-3h was calculated from 0-3 hours post-dose using the trapezoidal rule, divided by the observation time (3h) to report in liters.; Due to normalization the unit is liters.	baseline and after 4 weeks treatment	No
Secondary	FVC Peak(0-3) Response	The change from baseline in FVC peak(0-3) response after 4 weeks of treatment.	baseline and after 4 weeks treatment	No
Secondary	Forced Expiratory Volume in 1 Second (FEV1) (Unsupervised) Area Under Curve 0-6h (AUC 0-6h) Response After 4 Weeks	Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the available pre-dose FEV1 values prior to the first dose of randomized treatment. Means are adjusted using a model with treatment (trt), baseline as fixed effects and centre as random effect.; FEV1 AUC 0-6h was calculated from 0-6 hours post-dose using the trapezoidal rule, divided by the observation time (6h) to report in liters.	baseline and after 4weeks treatment	No
Secondary	Forced Expiratory Volume in 1 Second (FEV1) (Unsupervised) Area Under Curve 6-12 h (AUC 6-12h) Response After 4 Weeks	Response was defined as change from baseline. Study baseline FEV1 was defined as the mean of the available pre-dose FEV1 values prior to the first dose of randomized treatment. Means are adjusted using a model with treatment (trt), baseline as fixed effects and centre as random effect.; FEV1 AUC 6-12h was calculated from 6-12 hours post-dose using the trapezoidal rule, divided by the observation time (6h) to report in liters.	Baseline and after 4weeks treatment	No
Secondary	Weekly Mean Pre-dose Morning Peak Expiratory Flow Rate (PEFR) After 4 Weeks	PEFR measurements were recorded by means of a patient diary on a daily basis. This diary was used to record the twice daily PEFs,; Morning measurements were performed immediately upon arising before administration of trial and/or rescue medication.The highest of three readings for each measurement were recorded.	Week 4	No
Secondary	Weekly Mean Evening PEFR After 4 Weeks	PEFR measurements were recorded by means of a patient diary on a daily basis. This diary was used to record the twice daily PEFs,; Evening measurements were performed at bedtime.The highest of three readings for each measurement were recorded.	Week 4	No
Secondary	Weekly Mean Number of Occasions of Rescue Therapy After 4 Weeks	Weekly mean number of occasions of rescue therapy used per day (PRN salbutamol )	Week 4	No
Secondary	Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis, ECG and Physical Examination	Clinical relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis, ECG and Physical examination. New abnormal findings or worsenings of baseline conditions were reported as Adverse Events related to treatment (cardiac disorders and investigations).	4 weeks	No
Secondary	Difference From Baseline in Potassium	Difference from baseline in Potassium (normalized values). Normalization means that the values from different laboratories are transformed in such a way that they are directly comparable.	Baseline, Week 4	No
Secondary	Cmax (Maximum Measured Concentration of the Analyte in Plasma)	Cmax only calculated if >1/3 of the patients have available pharmacokinetic parameters,thus not applicable for the Olodaterol 2 mcg	after first inhalated administration	No
Secondary	Cmax,ss (Maximum Measured Concentration of the Analyte in Plasma at Steady State)	Cmax,ss only calculated if >1/3 of the patients have available pharmacokinetic parameters, thus not applicable for the Olodaterol 2 mcg	visit at week 4	No
Secondary	AUC0-1	Area under the concentration curve from 0 to 1 hour using trapezoid rule, only calculated if >1/3 of the patients have available pharmacokinetic parameters,thus not applicable for Olodaterol 2mcg group	after first inhalated administration	No
Secondary	AUC0-1,ss	Area under the concentration curve from 0 to 1 hour at steady state using trapezoid rule, only calculated if >1/3 of the patients have available pharmacokinetic parameters, thus not applicable for Olodaterol 2mcg group	visit at week 4	No

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