Pharmacokinetics and Safety of BI 1744 CL Plus Tiotropium Bromide in Chronic Obstructive Pulmonary Disease (COPD)
Primary Purpose
Pulmonary Disease, Chronic Obstructive
Status
Completed
Phase
Phase 1
Locations
Study Type
Interventional
Intervention
BI 1744 CL
BI 1744 CL/Tiotropium FDC
Tiotropium
Sponsored by
About this trial
This is an interventional treatment trial for Pulmonary Disease, Chronic Obstructive
Eligibility Criteria
Inclusion Criteria:
- All patients must sign an informed consent consistent with International Conference on Harmonisation (ICH) - Good Clinical Practice (GCP) guidelines and local legislations prior to any study-related procedures, which includes medication washout and restrictions
- All patients must have a diagnosis of COPD and must meet the following spirometric criteria: Patients must have relatively stable airway obstruction with a post-bronchodilator forced expiratory volume in one second (FEV1) ≥ 30 % of predicted normal and < 80% of predicted normal and a post-bronchodilator FEV1 / forced vital capacity (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 during the study period as required in the protocol
- Patients must be able to inhale medication in a competent manner from the Respimat® inhaler and from a metered dose inhalator (MDI)
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 patient's ability to participate in the study
- Patients with clinically relevant abnormal baseline haematology, blood chemistry or urinalysis; all patients with a serum glutamic oxaloacetic transaminase (SGOT) > 2.5 x ULN, serum glutamic pyruvic transaminase (SGPT) > 2.5 x ULN, bilirubin >2x upper limit of normal (ULN), creatinine >2 x ULN or creatinine clearance < 50 mL/min (Estimation of Glomerular Filtration Rate (GFR) by using the Cockcroft-Gault Formula) will be excluded regardless of clinical condition (a repeat laboratory evaluation will not be conducted in these patients)
- Patients with a history of asthma or a total blood eosinophil count ≥600/mm3
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
- a history of additional risk factors for Torsade de Pointes (TdP) (e.g. heart failure, hypokalaemia, family history of Long QT Syndrome)
Patients with any of the following conditions:
- a history of myocardial infarction within 1 year of screening visit (Visit 1)
- a diagnosis of cardiac arrhythmia, arterial hypertension or coronary heart disease
- 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 being treated with any of the following concomitant medications:
- medications that prolong the QT/QTc interval since the effects of BI 1744 CL on QT/QTc interval have yet to be fully characterized
- oral β-adrenergics
- β-blockers (topical β -blockers for ocular conditions are allowed)
- 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 investigator's 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 β-adrenergics and/or anticholinergic drugs, benzalkonium chloride, ethylenediaminetetraacetic acid or any other component of the Respimat® inhalation solution delivery system
- Pregnant or nursing women
- Women of childbearing potential not using two highly effective methods of birth control (one barrier and one non-barrier). Highly effective methods of birth control are defined as those which result in a low failure rate (i.e. less than 1% per year) when used consistently and correctly such as implants, injectables, combined oral contraceptives, some intrauterine devices (IUDs), sexual abstinence or vasectomised partner. 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
- 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 prior to randomization
- According to Inclusion Criterion No. 2, patients with a post-bronchodilator FEV1 of < 30% of predicted normal will always be excluded. Patients with a post-bronchodilator FEV1 between 30 and 50% of predicted normal will be excluded from the study, if they display additional symptoms of chronic respiratory insufficiency or right ventricular insufficiency
- Patients with narrow angle glaucoma, prostate hyperplasia, or bladder neck obstruction
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm Type
Experimental
Active Comparator
Active Comparator
Arm Label
BI 1744 CL/Tiotropium FDC
BI 1744 CL
Tiotropium
Arm Description
Outcomes
Primary Outcome Measures
AUC(0-1h,ss) of Olodaterol
Area under the concentration time curve of Olodaterol in plasma over the time interval t1=0 to t2=1 hour at steady state (AUC(0-1h,ss)).
As plasma concentrations were not expected to be quantifiable over the complete dosing interval in all patients, t2 was defined as the time-point where at least 2/3 of the patients reveal quantifiable plasma concentrations of Olodaterol. Based on the given definition AUC(0-1h,ss) was selected as primary endpoint.
The displayed values show adjusted gMeans and intra-subject variabilities calculated from the statistical model (ANOVA).
Cmax,ss of Olodaterol
Maximum measured concentration of Olodaterol in plasma at steady state (Cmax,ss).
The displayed values show adjusted gMeans and intra-subject variabilities calculated from the statistical model (ANOVA).
Ae(0-24h,ss) of Tiotropium
Amount of Tiotropium that was eliminated in urine at steady state from time point 0 to 24 h post-inhalation (Ae(0-24h,ss)).
The displayed values show adjusted gMeans and intra-subject variabilities calculated from the statistical model (ANOVA).
Secondary Outcome Measures
Ae(0-24h,ss) of Olodaterol
Amount of Olodaterol that was eliminated in urine at steady state from time point 0 to 24 h post-inhalation (Ae(0-24h,ss)).
The displayed values show adjusted gMeans and intra-subject variabilities calculated from the statistical model (ANOVA).
AUC(0-6h,ss) of Tiotropium
Area under the concentration time curve of Tiotropium in plasma over the time interval t1=0 to t2=6 h at steady state (AUC(0-6h,ss)).
As plasma concentrations were not expected to be quantifiable over the complete dosing interval in all patients, t2 was defined as the time-point where at least 2/3 of the patients reveal quantifiable plasma concentrations of Tiotropium. Based on the given definition AUC(0-6h,ss) was selected as secondary endpoint.
The displayed values show adjusted gMeans and intra-subject variabilities calculated from the statistical model (ANOVA).
Cmax,ss of Tiotropium
Maximum measured concentration of Tiotropium in plasma at steady state (Cmax,ss).
The displayed values show adjusted gMeans and intra-subject variabilities calculated from the statistical model (ANOVA).
AUC(0-2h,ss) of Olodaterol
Area under the concentration time curve of Olodaterol in plasma over the time interval 0 to 2 hours at steady state (AUC(0-2h,ss)).
The displayed values show adjusted gMeans and intra-subject variabilities calculated from the statistical model (ANOVA).
AUC(0-4h,ss) of Tiotropium
Area under the concentration time curve of Tiotropium in plasma over the time interval t1=0 to t2=4 h at steady state (AUC(0-4h,ss)).
The displayed values show adjusted gMeans and intra-subject variabilities calculated from the statistical model (ANOVA).
AUC(0-tz,ss) of Olodaterol
Area under the plasma concentration-time curve at steady state over the time interval from 0 to the time of the last quantifiable data point (AUC(0-tz)) for Olodaterol.
The displayed values show adjusted gMeans and intra-subject variabilities calculated from the statistical model (ANOVA).
AUC(0-tz,ss) of Tiotropium
Area under the plasma concentration-time curve at steady state over the time interval from 0 to the time of the last quantifiable data point (AUC(0-tz)) for Tiotropium.
The displayed values show adjusted gMeans and intra-subject variabilities calculated from the statistical model (ANOVA).
Tmax,ss of Olodaterol
Time from dosing to the maximum concentration of Olodaterol in plasma at steady state (tmax,ss).
Tmax,ss of Tiotropium
Time from dosing to the maximum concentration of Tiotropium in plasma at steady state (tmax,ss).
fe(0-24,ss) of Olodaterol
Fraction of Olodaterol eliminated in urine from 0 to 24 hours at steady state (fe(0-24,ss)).
The displayed values show gMeans and inter-subject variabilities calculated from descriptive statistics.
fe(0-24,ss) of Tiotropium
Fraction of Tiotropium eliminated in urine from 0 to 24 hours at steady state (fe(0-24,ss)).
The displayed values show gMeans and inter-subject variabilities calculated from descriptive statistics.
Cmin,ss of Olodaterol
Minimum concentration of the analyte in plasma at steady state over a uniform dosing interval (Cmin,ss).
The displayed values show gMeans and inter-subject variabilities calculated from descriptive statistics.
Cmin,ss of Tiotropium
Minimum concentration of the analyte in plasma at steady state over a uniform dosing interval (Cmin,ss).
The displayed values show gMeans and inter-subject variabilities calculated from descriptive statistics.
Tmin,ss of Olodaterol
Time from last dosing to the minimum concentration of the analyte in plasma at steady state over a uniform dosing interval (tmin,ss)
Tmin,ss of Tiotropium
Time from last dosing to the minimum concentration of the analyte in plasma at steady state over a uniform dosing interval (tmin,ss)
Concentration of Olodaterol in Plasma
Concentration of the analyte in plasma at 0.333 hours (20 minutes) after the 8th, 14th and 21st dose, C(0.333_8), C(0.333_14,ss) and C(0.333_21,ss) respectively. As steady state was anticipated to be reached by day 14 at the latest, the index 'ss' was used for days 14 and 21.
The displayed values show gMeans and inter-subject variabilities calculated from descriptive statistics.
Concentration of Tiotropium in Plasma
Concentration of the analyte in plasma at 0.333 hours (20 minutes) after the 8th, 14th and 21st dose, C(0.333_8), C(0.333_14,ss) and C(0.333_21,ss) respectively. As steady state was anticipated to be reached by day 14 at the latest, the index 'ss' was used for days 14 and 21.
The displayed values show gMeans and inter-subject variabilities calculated from descriptive statistics.
FVC Change From Baseline
Mean change from baseline in forced vital capacity (FVC). Pulmonary function test.
The baseline value was measured pre-dose on day 1 of the first treatment period.
FEV1 Change From Baseline
Mean change from baseline in forced expiratory volume in one second (FEV1). Pulmonary function test.
The baseline value was measured pre-dose on day 1 of the first treatment period.
Clinical Relevant Abnormalities in Vital Signs, Physical Examination, Blood Chemistry, Haematology, Urinanalysis and ECG
Clinically relevant abnormalities in vital signs (blood pressure and pulse rate), physical examination, blood chemistry, haematology, urinanalysis and ECG. New abnormal findings or worsening of baseline conditions were reported as Adverse Events. Any adverse events which occurred within 14 days following the last drug administration were assigned to the last study treatment administered.
Full Information
NCT ID
NCT02231177
First Posted
September 2, 2014
Last Updated
December 2, 2015
Sponsor
Boehringer Ingelheim
1. Study Identification
Unique Protocol Identification Number
NCT02231177
Brief Title
Pharmacokinetics and Safety of BI 1744 CL Plus Tiotropium Bromide in Chronic Obstructive Pulmonary Disease (COPD)
Official Title
A Randomised, Double-blind, 3-way Crossover Study to Compare Pharmacokinetics and Safety of 10 μg BI 1744 CL Plus 5 μg Tiotropium Bromide Given as Fixed Dose Combination Via the Respimat® Inhaler With the Pharmacokinetics and the Safety of the Single Agents, i.e. 10 μg BI 1744 CL and 5 μg Tiotropium Bromide, Delivered Via the Respimat® Inhaler Following 21 Day-treatment Periods in Patients With Chronic Obstructive Pulmonary Disease (COPD)
Study Type
Interventional
2. Study Status
Record Verification Date
December 2015
Overall Recruitment Status
Completed
Study Start Date
June 2008 (undefined)
Primary Completion Date
November 2008 (Actual)
Study Completion Date
undefined (undefined)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Boehringer Ingelheim
4. Oversight
5. Study Description
Brief Summary
The purpose of this study is to compare the systemic exposure to BI 1744 BS and tiotropium at steady state following inhalation of the fixed dose combination (FDC) of 10 μg BI 1744 CL plus 5 μg tiotropium bromide with the systemic exposure to BI 1744 BS and tiotropium at steady state following inhalation of the single agents, i.e., 10 μg BI 1744 CL and 5 μg tiotropium bromide, when administered once-daily via the Respimat® Inhaler for 21 days.
The secondary objectives were to compare the safety and tolerability (adverse events, 12-lead electrocardiogram recordings, pulmonary function testing) of BI 1744 CL and tiotropium bromide when administered as fixed dose combination or as single-agent therapy.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pulmonary Disease, Chronic Obstructive
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Crossover Assignment
Masking
Double
Allocation
Randomized
Enrollment
47 (Actual)
8. Arms, Groups, and Interventions
Arm Title
BI 1744 CL/Tiotropium FDC
Arm Type
Experimental
Arm Title
BI 1744 CL
Arm Type
Active Comparator
Arm Title
Tiotropium
Arm Type
Active Comparator
Intervention Type
Drug
Intervention Name(s)
BI 1744 CL
Intervention Type
Drug
Intervention Name(s)
BI 1744 CL/Tiotropium FDC
Intervention Type
Drug
Intervention Name(s)
Tiotropium
Primary Outcome Measure Information:
Title
AUC(0-1h,ss) of Olodaterol
Description
Area under the concentration time curve of Olodaterol in plasma over the time interval t1=0 to t2=1 hour at steady state (AUC(0-1h,ss)).
As plasma concentrations were not expected to be quantifiable over the complete dosing interval in all patients, t2 was defined as the time-point where at least 2/3 of the patients reveal quantifiable plasma concentrations of Olodaterol. Based on the given definition AUC(0-1h,ss) was selected as primary endpoint.
The displayed values show adjusted gMeans and intra-subject variabilities calculated from the statistical model (ANOVA).
Time Frame
Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period.
Title
Cmax,ss of Olodaterol
Description
Maximum measured concentration of Olodaterol in plasma at steady state (Cmax,ss).
The displayed values show adjusted gMeans and intra-subject variabilities calculated from the statistical model (ANOVA).
Time Frame
Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period.
Title
Ae(0-24h,ss) of Tiotropium
Description
Amount of Tiotropium that was eliminated in urine at steady state from time point 0 to 24 h post-inhalation (Ae(0-24h,ss)).
The displayed values show adjusted gMeans and intra-subject variabilities calculated from the statistical model (ANOVA).
Time Frame
Intervals 0-4, 4-8, 8-12 and 12-24 hours on Day 21 of the actual treatment period.
Secondary Outcome Measure Information:
Title
Ae(0-24h,ss) of Olodaterol
Description
Amount of Olodaterol that was eliminated in urine at steady state from time point 0 to 24 h post-inhalation (Ae(0-24h,ss)).
The displayed values show adjusted gMeans and intra-subject variabilities calculated from the statistical model (ANOVA).
Time Frame
Intervals 0-4, 4-8, 8-12 and 12-24 hours on Day 21 of the actual treatment period.
Title
AUC(0-6h,ss) of Tiotropium
Description
Area under the concentration time curve of Tiotropium in plasma over the time interval t1=0 to t2=6 h at steady state (AUC(0-6h,ss)).
As plasma concentrations were not expected to be quantifiable over the complete dosing interval in all patients, t2 was defined as the time-point where at least 2/3 of the patients reveal quantifiable plasma concentrations of Tiotropium. Based on the given definition AUC(0-6h,ss) was selected as secondary endpoint.
The displayed values show adjusted gMeans and intra-subject variabilities calculated from the statistical model (ANOVA).
Time Frame
Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period.
Title
Cmax,ss of Tiotropium
Description
Maximum measured concentration of Tiotropium in plasma at steady state (Cmax,ss).
The displayed values show adjusted gMeans and intra-subject variabilities calculated from the statistical model (ANOVA).
Time Frame
Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period.
Title
AUC(0-2h,ss) of Olodaterol
Description
Area under the concentration time curve of Olodaterol in plasma over the time interval 0 to 2 hours at steady state (AUC(0-2h,ss)).
The displayed values show adjusted gMeans and intra-subject variabilities calculated from the statistical model (ANOVA).
Time Frame
Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period.
Title
AUC(0-4h,ss) of Tiotropium
Description
Area under the concentration time curve of Tiotropium in plasma over the time interval t1=0 to t2=4 h at steady state (AUC(0-4h,ss)).
The displayed values show adjusted gMeans and intra-subject variabilities calculated from the statistical model (ANOVA).
Time Frame
Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period.
Title
AUC(0-tz,ss) of Olodaterol
Description
Area under the plasma concentration-time curve at steady state over the time interval from 0 to the time of the last quantifiable data point (AUC(0-tz)) for Olodaterol.
The displayed values show adjusted gMeans and intra-subject variabilities calculated from the statistical model (ANOVA).
Time Frame
Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period.
Title
AUC(0-tz,ss) of Tiotropium
Description
Area under the plasma concentration-time curve at steady state over the time interval from 0 to the time of the last quantifiable data point (AUC(0-tz)) for Tiotropium.
The displayed values show adjusted gMeans and intra-subject variabilities calculated from the statistical model (ANOVA).
Time Frame
Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period.
Title
Tmax,ss of Olodaterol
Description
Time from dosing to the maximum concentration of Olodaterol in plasma at steady state (tmax,ss).
Time Frame
Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period.
Title
Tmax,ss of Tiotropium
Description
Time from dosing to the maximum concentration of Tiotropium in plasma at steady state (tmax,ss).
Time Frame
Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period.
Title
fe(0-24,ss) of Olodaterol
Description
Fraction of Olodaterol eliminated in urine from 0 to 24 hours at steady state (fe(0-24,ss)).
The displayed values show gMeans and inter-subject variabilities calculated from descriptive statistics.
Time Frame
Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period.
Title
fe(0-24,ss) of Tiotropium
Description
Fraction of Tiotropium eliminated in urine from 0 to 24 hours at steady state (fe(0-24,ss)).
The displayed values show gMeans and inter-subject variabilities calculated from descriptive statistics.
Time Frame
Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period.
Title
Cmin,ss of Olodaterol
Description
Minimum concentration of the analyte in plasma at steady state over a uniform dosing interval (Cmin,ss).
The displayed values show gMeans and inter-subject variabilities calculated from descriptive statistics.
Time Frame
Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period.
Title
Cmin,ss of Tiotropium
Description
Minimum concentration of the analyte in plasma at steady state over a uniform dosing interval (Cmin,ss).
The displayed values show gMeans and inter-subject variabilities calculated from descriptive statistics.
Time Frame
Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period.
Title
Tmin,ss of Olodaterol
Description
Time from last dosing to the minimum concentration of the analyte in plasma at steady state over a uniform dosing interval (tmin,ss)
Time Frame
Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period.
Title
Tmin,ss of Tiotropium
Description
Time from last dosing to the minimum concentration of the analyte in plasma at steady state over a uniform dosing interval (tmin,ss)
Time Frame
Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period.
Title
Concentration of Olodaterol in Plasma
Description
Concentration of the analyte in plasma at 0.333 hours (20 minutes) after the 8th, 14th and 21st dose, C(0.333_8), C(0.333_14,ss) and C(0.333_21,ss) respectively. As steady state was anticipated to be reached by day 14 at the latest, the index 'ss' was used for days 14 and 21.
The displayed values show gMeans and inter-subject variabilities calculated from descriptive statistics.
Time Frame
Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period.
Title
Concentration of Tiotropium in Plasma
Description
Concentration of the analyte in plasma at 0.333 hours (20 minutes) after the 8th, 14th and 21st dose, C(0.333_8), C(0.333_14,ss) and C(0.333_21,ss) respectively. As steady state was anticipated to be reached by day 14 at the latest, the index 'ss' was used for days 14 and 21.
The displayed values show gMeans and inter-subject variabilities calculated from descriptive statistics.
Time Frame
Within 30 min before drug administration and 0:02, 0:05, 0:10, 0:15, 0:20, 0:40, 1:00, 2:00, 4:00, 6:00, 8:00, 12:00, 24:00 hours after drug administration on Day 21 of the actual treatment period.
Title
FVC Change From Baseline
Description
Mean change from baseline in forced vital capacity (FVC). Pulmonary function test.
The baseline value was measured pre-dose on day 1 of the first treatment period.
Time Frame
0:30 and 1:00 h after drug administration on the first day of each treatment period
Title
FEV1 Change From Baseline
Description
Mean change from baseline in forced expiratory volume in one second (FEV1). Pulmonary function test.
The baseline value was measured pre-dose on day 1 of the first treatment period.
Time Frame
0:30 and 1:00 h after drug administration on the first day of each treatment period
Title
Clinical Relevant Abnormalities in Vital Signs, Physical Examination, Blood Chemistry, Haematology, Urinanalysis and ECG
Description
Clinically relevant abnormalities in vital signs (blood pressure and pulse rate), physical examination, blood chemistry, haematology, urinanalysis and ECG. New abnormal findings or worsening of baseline conditions were reported as Adverse Events. Any adverse events which occurred within 14 days following the last drug administration were assigned to the last study treatment administered.
Time Frame
From drug administration until 14 days following the last drug administration
10. Eligibility
Sex
All
Minimum Age & Unit of Time
40 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
All patients must sign an informed consent consistent with International Conference on Harmonisation (ICH) - Good Clinical Practice (GCP) guidelines and local legislations prior to any study-related procedures, which includes medication washout and restrictions
All patients must have a diagnosis of COPD and must meet the following spirometric criteria: Patients must have relatively stable airway obstruction with a post-bronchodilator forced expiratory volume in one second (FEV1) ≥ 30 % of predicted normal and < 80% of predicted normal and a post-bronchodilator FEV1 / forced vital capacity (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 during the study period as required in the protocol
Patients must be able to inhale medication in a competent manner from the Respimat® inhaler and from a metered dose inhalator (MDI)
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 patient's ability to participate in the study
Patients with clinically relevant abnormal baseline haematology, blood chemistry or urinalysis; all patients with a serum glutamic oxaloacetic transaminase (SGOT) > 2.5 x ULN, serum glutamic pyruvic transaminase (SGPT) > 2.5 x ULN, bilirubin >2x upper limit of normal (ULN), creatinine >2 x ULN or creatinine clearance < 50 mL/min (Estimation of Glomerular Filtration Rate (GFR) by using the Cockcroft-Gault Formula) will be excluded regardless of clinical condition (a repeat laboratory evaluation will not be conducted in these patients)
Patients with a history of asthma or a total blood eosinophil count ≥600/mm3
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
a history of additional risk factors for Torsade de Pointes (TdP) (e.g. heart failure, hypokalaemia, family history of Long QT Syndrome)
Patients with any of the following conditions:
a history of myocardial infarction within 1 year of screening visit (Visit 1)
a diagnosis of cardiac arrhythmia, arterial hypertension or coronary heart disease
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 being treated with any of the following concomitant medications:
medications that prolong the QT/QTc interval since the effects of BI 1744 CL on QT/QTc interval have yet to be fully characterized
oral β-adrenergics
β-blockers (topical β -blockers for ocular conditions are allowed)
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 investigator's 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 β-adrenergics and/or anticholinergic drugs, benzalkonium chloride, ethylenediaminetetraacetic acid or any other component of the Respimat® inhalation solution delivery system
Pregnant or nursing women
Women of childbearing potential not using two highly effective methods of birth control (one barrier and one non-barrier). Highly effective methods of birth control are defined as those which result in a low failure rate (i.e. less than 1% per year) when used consistently and correctly such as implants, injectables, combined oral contraceptives, some intrauterine devices (IUDs), sexual abstinence or vasectomised partner. 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
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 prior to randomization
According to Inclusion Criterion No. 2, patients with a post-bronchodilator FEV1 of < 30% of predicted normal will always be excluded. Patients with a post-bronchodilator FEV1 between 30 and 50% of predicted normal will be excluded from the study, if they display additional symptoms of chronic respiratory insufficiency or right ventricular insufficiency
Patients with narrow angle glaucoma, prostate hyperplasia, or bladder neck obstruction
12. IPD Sharing Statement
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Pharmacokinetics and Safety of BI 1744 CL Plus Tiotropium Bromide in Chronic Obstructive Pulmonary Disease (COPD)
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