BI 113608 Administered as Tablets Twice Daily Over 4 Weeks in Patients With Chronic Obstructive Pulmonary Disease Associated With Chronic Bronchitis

Study Overview
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Brief Summary
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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.

Official Title
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Randomized, Placebo-controlled, Double-blind Within Dose Groups, Multiple Rising-dose Study to Evaluate Safety, Tolerability, and PK of Oral BI 113608 Administered as Tablets Twice Daily Over 4 Weeks in Patients With COPD Associated With Chronic Bronchitis

Conditions
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Pulmonary Disease, Chronic Obstructive

Intervention / Treatment
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* Drug: Placebo to BI 113608 high dose b.i.d.
* Drug: Placebo to BI 113608 low dose b.i.d.
* Drug: BI 113608 high dose b.i.d.
* Drug: Placebo to BI 113608 medium dose b.i.d.
* Drug: BI 113608 low dose b.i.d.
* Drug: BI 113608 medium dose b.i.d.


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: 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. All patients must have a documented diagnosis of COPD according to GOLD 2013. Post-bronchodilator 50% = FEV1 < 80% of predicted at screening visit. Post-bronchodilator FEV1/FVC <70% at screening visit. 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. CAT Questionnaire at screening: a score of at least one for both cough (1st question) and sputum (2nd question). Males and females between 40 and 80 years (inclusive) of age, on the day of patient´s signature of informed consent. 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. Patients must be able to perform technically acceptable pulmonary function tests (body plethysmography, forced spirometry and DLCO measurement). 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: 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: Put the patient at risk because of participation in the study, Influence the results of the study, 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.) 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). 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. 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. 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). Patients with current relevant psychiatric disorders based on the investigator´s judgement. 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. Patients with a history of two or more moderate or severe COPD exacerbations per year within the last two years. Patients with a history of and/or active significant alcohol or drug abuse. See exclusion criterion number 1. Patients who are being treated with non-permitted concomitant medication. Patients with a recent history (i.e. three years or less) of heart failure or patients with any cardiac arrhythmia requiring drug therapy. Patients who have previously been randomised in this trial. Current participation in another clinical trial (as defined in the ICH Harmonised Tripartite Guideline for Good Clinical Practice (GCP)). Donation of more than 100 mL of blood within the past four weeks prior to screening. A history of additional risk factors for torsade-de-pointes (e.g., heart failure, relevant hypokalemia, family history of Long QT Syndrome). Pregnant or nursing women. Gastrointestinal tract surgery that might affect absorption and elimination of drugs. Patients with known hypersensitivity / allergy to the investigational medicinal product (IMP) or its excipients. 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.

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 80 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: Single Group Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BI 113608 low dose b.i.d.<br>Film-coated tablet, oral administration with 240 mL water | Drug: Placebo to BI 113608 low dose b.i.d.<br>* Film-coated tablet<br>Drug: BI 113608 low dose b.i.d.<br>* Film-coated tablet<br>|
| Experimental: BI 113608 medium dose b.i.d.<br>Film-coated tablet, oral administration with 240 mL water | Drug: Placebo to BI 113608 medium dose b.i.d.<br>* Film-coated tablet<br>Drug: BI 113608 medium dose b.i.d.<br>* Film-coated tablet<br>|
| Experimental: BI 113608 high dose b.i.d.<br>Film-coated tablet, oral administration with 240 mL water | Drug: Placebo to BI 113608 high dose b.i.d.<br>* Film-coated tablet<br>Drug: BI 113608 high dose b.i.d.<br>* Film-coated tablet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number (%) of Patients With Drug-related Adverse Events (AEs) | Number (%) of patients with drug-related adverse events (AEs) | AE's occuring upto end of treatment + 3 days follow up (Up to 31 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax,ss | Cmax,ss (maximum measured concentration of BI 113608 in plasma at steady state over a uniform dosing interval tau) | 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 | AUC tau,ss (area under the concentration-time curve of the BI 113608 in plasma at steady state over a uniform dosing interval tau) | 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 | Tmax,ss (time from last dosing to maximum concentration of the BI 113608 in plasma at steady state) | 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 | T1/2,ss (terminal half life of the BI 113608 in plasma at steady state) | 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) | 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) | 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) | 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) | 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 |