Pulmonary Disease, Chronic Obstructive
Conditions
Brief summary
The main objective of the current trial is to investigate safety, tolerability and pharmacokinetics of BI 113608 in COPD patients with symptoms of chronic bronchitis.
Interventions
DRUGPlacebo to BI 113608 high dose b.i.d.
Film-coated tablet
DRUGPlacebo to BI 113608 low dose b.i.d.
Film-coated tablet
DRUGBI 113608 high dose b.i.d.
Film-coated tablet
DRUGPlacebo to BI 113608 medium dose b.i.d.
Film-coated tablet
DRUGBI 113608 low dose b.i.d.
Film-coated tablet
DRUGBI 113608 medium dose b.i.d.
Film-coated tablet
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
ALL
Age
40 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. All patients must sign an informed consent consistent with ICH-GCP guidelines and local legislations prior to any study-related procedures, which includes medication washout and restrictions. 2. All patients must have a documented diagnosis of COPD according to GOLD 2013. 3. Post-bronchodilator 50% = FEV1 \< 80% of predicted at screening visit. 4. Post-bronchodilator FEV1/FVC \<70% at screening visit. 5. Patients must have a history of chronic bronchitis as defined by symptoms of cough and sputum production on most days during at least three months for the past two consecutive years. 6. CAT Questionnaire at screening: a score of at least one for both cough (1st question) and sputum (2nd question). 7. Males and females between 40 and 80 years (inclusive) of age, on the day of patient´s signature of informed consent. 8. Patients must be current or ex-smokers with a smoking history of more than 10 pack years. Patients who have never smoked cigarettes must be excluded. 9. Patients must be able to perform technically acceptable pulmonary function tests (body plethysmography, forced spirometry and DLCO measurement). 10. Females must be of non-childbearing potential. Women of non-childbearing potential are defined as those who have undergone bilateral ovariectomy, bilateral salpingectomy or hysterectomy. If so, documentation confirming the surgical procedure must be available on the patient's source documents. A woman is also presumed to be infertile due to natural causes if she has been amenorrheic for more than 24 months. In questionable cases, a blood analysis of FSH and estradiol, which indicates the postmenopausal status according to the central laboratory ranges for postmenopausal females, is considered confirmatory.
Exclusion criteria
1. Significant pulmonary disease other than COPD or other medical conditions\* (as determined by medical history, examination, and clinical investigations at screening) that may, in the opinion of the investigator, result in the any of the following: 1. Put the patient at risk because of participation in the study, 2. Influence the results of the study, 3. Cause concern regarding the patient's ability to participate in the study. (\*e.g. cardiac, gastro-intestinal, hepatic, renal, metabolic, dermatologic, neurological, haematological, oncological and psychiatric; history of relevant orthostatic hypotension, fainting spells or blackouts; current chronic or relevant acute infections.) 2. Patients with any lung disease other than COPD (e.g. asthma, interstitial lung disease (ILD), cystic fibrosis, active tuberculosis, post-TB syndrome, clinically evident bronchiectasis, with a history of thoracotomy with pulmonary resection). 3. Patients with clinically relevant abnormal haematology, blood chemistry, or urinalysis at screening visit (Visit 1), if the abnormality defines a relevant disease as defined in exclusion criterion number 1. 4. All patients with a serum glutamate oxaloacetate transferase (SGOT) or serum glutamic pyruvic transaminase (SGPT) or total bilirubin higher than 1.5-fold ULN or serum creatinine higher than normal at Visit 1 (and at all repeated tests, if applicable) will be excluded regardless of the clinical condition. Laboratory evaluation can be repeated maximum two times. 5. A malignancy for which the patient has undergone resection, radiation therapy or chemotherapy within the last five years (patients with treated basal cell carcinoma are allowed). 6. Patients with current relevant psychiatric disorders based on the investigator´s judgement. 7. Patients with any respiratory infection (e.g. common cold, sinusitis, etc.) or COPD exacerbation within the six weeks prior to the screening visit (Visit 1) or between screening visit and randomization. 8. Patients with a history of two or more moderate or severe COPD exacerbations per year within the last two years. 9. Patients with a history of and/or active significant alcohol or drug abuse. See exclusion criterion number 1. 10. Patients who are being treated with non-permitted concomitant medication. 11. Patients with a recent history (i.e. three years or less) of heart failure or patients with any cardiac arrhythmia requiring drug therapy. 12. Patients who have previously been randomised in this trial. 13. Current participation in another clinical trial (as defined in the ICH Harmonised Tripartite Guideline for Good Clinical Practice (GCP)). 14. Donation of more than 100 mL of blood within the past four weeks prior to screening. 15. A history of additional risk factors for torsade-de-pointes (e.g., heart failure, relevant hypokalemia, family history of Long QT Syndrome). 16. Pregnant or nursing women. 17. Gastrointestinal tract surgery that might affect absorption and elimination of drugs. 18. Patients with known hypersensitivity / allergy to the investigational medicinal product (IMP) or its excipients. 19. Male Patients who do not agree to minimize the risk of female partners becoming pregnant from the first dosing day until two months after study completion.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number (%) of Patients With Drug-related Adverse Events (AEs) | AE's occuring upto end of treatment + 3 days follow up (Up to 31 days) | Number (%) of patients with drug-related adverse events (AEs) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| AUC Tau,ss | Pre-dose and 0:15(hours:min),0:30,0:45,1:00,1:30,2:00,3:00,4:00,6:00,9:00,11:45,71:45,167:45,611:45,623:45,635:45,647:45,648:15,648:30,648:45,649:00,649:30,650:00,651:00,652:00,654:00,657:00,660:00,672:00,696:00,720:00 hours after drug administration | AUC tau,ss (area under the concentration-time curve of the BI 113608 in plasma at steady state over a uniform dosing interval tau) |
| Tmax,ss | Pre-dose and 0:15(hours:min),0:30,0:45,1:00,1:30,2:00,3:00,4:00,6:00,9:00,11:45,71:45,167:45,611:45,623:45,635:45,647:45,648:15,648:30,648:45,649:00,649:30,650:00,651:00,652:00,654:00,657:00,660:00,672:00,696:00,720:00 hours after drug administration | Tmax,ss (time from last dosing to maximum concentration of the BI 113608 in plasma at steady state) |
| Cmax,ss | Pre-dose and 0:15(hours:min),0:30,0:45,1:00,1:30,2:00,3:00,4:00,6:00,9:00,11:45,71:45,167:45,611:45,623:45,635:45,647:45,648:15,648:30,648:45,649:00,649:30,650:00,651:00,652:00,654:00,657:00,660:00,672:00,696:00,720:00 hours after drug administration | Cmax,ss (maximum measured concentration of BI 113608 in plasma at steady state over a uniform dosing interval tau) |
| R(A,Cmax) | Pre-dose and 0:15(hours:min),0:30,0:45,1:00,1:30,2:00,3:00,4:00,6:00,9:00,11:45,71:45,167:45,611:45,623:45,635:45,647:45,648:15,648:30,648:45,649:00,649:30,650:00,651:00,652:00,654:00,657:00,660:00,672:00,696:00,720:00 hours after drug administration | R(A,Cmax) (accumulation ratio of the BI 113608 in plasma at steady state after multiple oral administration over a uniform dosing interval tau, expressed as ratio of Cmax at steady state and after first dose) |
| R(A,AUC) | Pre-dose and 0:15(hours:min),0:30,0:45,1:00,1:30,2:00,3:00,4:00,6:00,9:00,11:45,71:45,167:45,611:45,623:45,635:45,647:45,648:15,648:30,648:45,649:00,649:30,650:00,651:00,652:00,654:00,657:00,660:00,672:00,696:00,720:00 hours after drug administration | R(A,AUC) (accumulation ratio of the BI 113608 in plasma at steady state after multiple oral administration over a uniform dosing interval tau, expressed as ratio of AUC at steady state and after first dose) |
| T1/2,ss | Pre-dose and 0:15(hours:min),0:30,0:45,1:00,1:30,2:00,3:00,4:00,6:00,9:00,11:45,71:45,167:45,611:45,623:45,635:45,647:45,648:15,648:30,648:45,649:00,649:30,650:00,651:00,652:00,654:00,657:00,660:00,672:00,696:00,720:00 hours after drug administration | T1/2,ss (terminal half life of the BI 113608 in plasma at steady state) |
Countries
Germany
Participant flow
Recruitment details
The trial consisted of 3 sequential dose groups of 28 patients each. Within each dose group, 21 patients received BI 113608 and 7 received placebo
Participants by arm
| Arm | Count |
|---|---|
| Placebo Oral administration of Placebo matching BI 113608 | 21 |
| BI 113608 10 mg Oral administration of BI 113608 10 mg film coated tablets twice daily | 21 |
| BI 113608 25 mg Oral administration of BI 113608 25 mg film coated tablets twice daily | 21 |
| BI 113608 50 mg Oral administration of BI 113608 50 mg film coated tablets twice daily | 21 |
| Total | 84 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Other adverse event | 1 | 0 | 0 | 0 |
| Overall Study | Worsening of disease under study | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Placebo | BI 113608 10 mg | BI 113608 25 mg | BI 113608 50 mg | Total |
|---|---|---|---|---|---|
| Age, Continuous | 60.67 years STANDARD_DEVIATION 6.64 | 58.90 years STANDARD_DEVIATION 6.17 | 62.43 years STANDARD_DEVIATION 7.21 | 60.38 years STANDARD_DEVIATION 6.81 | 60.60 years STANDARD_DEVIATION 6.71 |
| Gender Female | 8 Participants | 9 Participants | 9 Participants | 8 Participants | 34 Participants |
| Gender Male | 13 Participants | 12 Participants | 12 Participants | 13 Participants | 50 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 11 / 21 | 10 / 21 | 13 / 21 | 16 / 21 |
| serious Total, serious adverse events | 1 / 21 | 0 / 21 | 0 / 21 | 1 / 21 |
Outcome results
Primary
Number (%) of Patients With Drug-related Adverse Events (AEs)
Number (%) of patients with drug-related adverse events (AEs)
Time frame: AE's occuring upto end of treatment + 3 days follow up (Up to 31 days)
Population: Treated set (TS)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number (%) of Patients With Drug-related Adverse Events (AEs) | 7 percentage of participants |
| BI 113608 10 mg | Number (%) of Patients With Drug-related Adverse Events (AEs) | 7 percentage of participants |
| BI 113608 25 mg | Number (%) of Patients With Drug-related Adverse Events (AEs) | 10 percentage of participants |
| BI 113608 50 mg | Number (%) of Patients With Drug-related Adverse Events (AEs) | 14 percentage of participants |
Secondary
AUC Tau,ss
AUC tau,ss (area under the concentration-time curve of the BI 113608 in plasma at steady state over a uniform dosing interval tau)
Time frame: Pre-dose and 0:15(hours:min),0:30,0:45,1:00,1:30,2:00,3:00,4:00,6:00,9:00,11:45,71:45,167:45,611:45,623:45,635:45,647:45,648:15,648:30,648:45,649:00,649:30,650:00,651:00,652:00,654:00,657:00,660:00,672:00,696:00,720:00 hours after drug administration
Population: PKS
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | AUC Tau,ss | 166 nmol*h/L | Geometric Coefficient of Variation 46.4 |
| BI 113608 10 mg | AUC Tau,ss | 539 nmol*h/L | Geometric Coefficient of Variation 43.3 |
| BI 113608 25 mg | AUC Tau,ss | 1160 nmol*h/L | Geometric Coefficient of Variation 42.3 |
Comparison: Dose proportionality was analysed over the dose range 10 to 50 mg for plasma PK parameters based on a power model95% CI: [1.0519, 1.3759]Regression, Linear
Secondary
Cmax,ss
Cmax,ss (maximum measured concentration of BI 113608 in plasma at steady state over a uniform dosing interval tau)
Time frame: Pre-dose and 0:15(hours:min),0:30,0:45,1:00,1:30,2:00,3:00,4:00,6:00,9:00,11:45,71:45,167:45,611:45,623:45,635:45,647:45,648:15,648:30,648:45,649:00,649:30,650:00,651:00,652:00,654:00,657:00,660:00,672:00,696:00,720:00 hours after drug administration
Population: Pharmacokinetic set (PKS): The patient set for the evaluation of PK endpoints included all evaluable patients in the treated set which provided at least 1 observation for at least 1 PK endpoint without important protocol violations relevant to the evaluation of PK.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Cmax,ss | 44.1 nmol/L | Geometric Coefficient of Variation 66.6 |
| BI 113608 10 mg | Cmax,ss | 190 nmol/L | Geometric Coefficient of Variation 45.1 |
| BI 113608 25 mg | Cmax,ss | 328 nmol/L | Geometric Coefficient of Variation 49.5 |
Comparison: Dose proportionality was analysed over the dose range 10 to 50 mg for plasma PK parameters based on a power model95% CI: [1.0636, 1.4713]Regression, Linear
Secondary
R(A,AUC)
R(A,AUC) (accumulation ratio of the BI 113608 in plasma at steady state after multiple oral administration over a uniform dosing interval tau, expressed as ratio of AUC at steady state and after first dose)
Time frame: Pre-dose and 0:15(hours:min),0:30,0:45,1:00,1:30,2:00,3:00,4:00,6:00,9:00,11:45,71:45,167:45,611:45,623:45,635:45,647:45,648:15,648:30,648:45,649:00,649:30,650:00,651:00,652:00,654:00,657:00,660:00,672:00,696:00,720:00 hours after drug administration
Population: PKS
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | R(A,AUC) | 1.40 ratio | Geometric Coefficient of Variation 35.8 |
| BI 113608 10 mg | R(A,AUC) | 1.20 ratio | Geometric Coefficient of Variation 31.4 |
| BI 113608 25 mg | R(A,AUC) | 1.37 ratio | Geometric Coefficient of Variation 27 |
Secondary
R(A,Cmax)
R(A,Cmax) (accumulation ratio of the BI 113608 in plasma at steady state after multiple oral administration over a uniform dosing interval tau, expressed as ratio of Cmax at steady state and after first dose)
Time frame: Pre-dose and 0:15(hours:min),0:30,0:45,1:00,1:30,2:00,3:00,4:00,6:00,9:00,11:45,71:45,167:45,611:45,623:45,635:45,647:45,648:15,648:30,648:45,649:00,649:30,650:00,651:00,652:00,654:00,657:00,660:00,672:00,696:00,720:00 hours after drug administration
Population: PKS
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | R(A,Cmax) | 1.36 ratio | Geometric Coefficient of Variation 56.6 |
| BI 113608 10 mg | R(A,Cmax) | 0.98 ratio | Geometric Coefficient of Variation 42.2 |
| BI 113608 25 mg | R(A,Cmax) | 1.13 ratio | Geometric Coefficient of Variation 42.2 |
Secondary
T1/2,ss
T1/2,ss (terminal half life of the BI 113608 in plasma at steady state)
Time frame: Pre-dose and 0:15(hours:min),0:30,0:45,1:00,1:30,2:00,3:00,4:00,6:00,9:00,11:45,71:45,167:45,611:45,623:45,635:45,647:45,648:15,648:30,648:45,649:00,649:30,650:00,651:00,652:00,654:00,657:00,660:00,672:00,696:00,720:00 hours after drug administration
Population: PKS
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | T1/2,ss | 17.4 hours | Geometric Coefficient of Variation 32.2 |
| BI 113608 10 mg | T1/2,ss | 15.2 hours | Geometric Coefficient of Variation 14.9 |
| BI 113608 25 mg | T1/2,ss | 16.2 hours | Geometric Coefficient of Variation 31.5 |
Secondary
Tmax,ss
Tmax,ss (time from last dosing to maximum concentration of the BI 113608 in plasma at steady state)
Time frame: Pre-dose and 0:15(hours:min),0:30,0:45,1:00,1:30,2:00,3:00,4:00,6:00,9:00,11:45,71:45,167:45,611:45,623:45,635:45,647:45,648:15,648:30,648:45,649:00,649:30,650:00,651:00,652:00,654:00,657:00,660:00,672:00,696:00,720:00 hours after drug administration
Population: PKS
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Tmax,ss | 1.00 hours |
| BI 113608 10 mg | Tmax,ss | 0.750 hours |
| BI 113608 25 mg | Tmax,ss | 1.00 hours |