Clinical Trial to Assess Pharmacodynamic Effects on Segmental Endotoxin Induced Inflammatory Response of BI 1026706 Versus Placebo

Study Overview
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Brief Summary
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The primary and secondary objectives of the current study are the assessments of anti-inflammatory pharmacodynamic effects on segmental endotoxin induced inflammatory response after 4 weeks treatment with BI 1026706.

Official Title
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A Randomized, Double-blind, Placebo-controlled, Parallel Group, Phase I Trial in Healthy Male Current Smoker Subjects to Assess Pharmacodynamic Effects on Segmental Endotoxin Induced Inflammatory Response and Safety of 4 Weeks Oral Administration of BI 1026706

Conditions
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Healthy

Intervention / Treatment
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* Drug: BI 1026706
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Signed informed consent consistent with ICH-Good Clinical Practice (GCP) guidelines and local legislation prior to participation in the trial. Healthy volunteers of both sex between 18 and 65 years (inclusive) of age, on the day of subject's signature of informed consent. Healthy subjects as assessed by the investigator, based on a screening examination including medical history, physical examination, vital signs (blood pressure, pulse rate, body temperature), 12-lead ECG, lung function and clinical laboratory results. Forced expiratory volume (FEV1) of >80% and FEV1/Forced vital capacity(fFVC) of >70% of the predicted normal value at screening Current smokers with a smoking history of at least 1 pack year and with at least 1 cigarette per day in the previous year BMI (Body mass index) range: >18.5 and < 29.9kg/m2. Negative urine drug screening. Negative breath alcohol test. Negative skin prick test (performed within the 12 months prior to study start or at study start) Females NOT of childbearing potential are defined as: Women who are postmenopausal (12 months with no menses without an alternative medical cause; in questionable cases a blood sample with simultaneous levels of FSH above 40 U/L and estradiol below 30 ng/L is confirmatory) or who are permanently sterilized (defined as hysterectomy, bilateral oophorectomy or bilateral salpingectomy). Further inclusion criteria apply Exclusion criteria: History of any relevant lung disease (i.e. Chronic Obstructive Pulmonary Disease (COPD), asthma, chronic bronchitis, pulmonary fibrosis, pulmonary alveolar proteinosis (PAP), pneumocystis infection, active tuberculosis, silicosis or any other lung surfactant overproduction syndromes). Subjects with clinically relevant abnormal hematology, blood chemistry, or urinalysis at the screening visit Any finding of the medical examination (including blood pressure, pulse rate, body temperature and ECG) deviating from normal and of clinical relevance. Subjects with a history of any clinically significant cardiovascular, metabolic, renal (including renal stones), hepatic, gastrointestinal, hematological, dermatological, venereal, neurological, psychiatric or other major disorders. Subjects with a malignancy for which the subject has undergone resection, radiation therapy or chemotherapy within the last five years. Subjects with treated basal cell carcinoma or fully cured squamous cell carcinoma are allowed to participate. Subjects with previous surgery of the gastro-intestinal tract likely to affect drug absorption. History of relevant orthostatic hypotension, fainting spells or blackouts. Subjects with clinically relevant infection or known ongoing clinically relevant inflammatory process. History of relevant allergy/hypersensitivity including allergy to drug or its excipients or medications in line with bronchoscopy (bronchodilators, sedatives and local anesthetics). Subjects with a marked baseline prolongation of QT/QTcB interval (such as repeated demonstration of a QTcB interval >450 ms), or any other relevant ECG finding at screening visit (Visit 1) according to the investigator. Neutrophil blood count indicative of immunosuppression according to the investigator at screening visit (Visit 1). Subjects with previous surgeries that may have left ferromagnetic material in the body, ferromagnetic implants or pacemakers. Participation in another study with any investigational product within 2 months prior to screening or if screening occurs within 6 half-lives of intake of another investigational drug (whichever is greater). Male subjects who do not agree to minimize the risk of female partners becoming pregnant from the first dosing day until 3 months after the trial medication treatment has finished. Subjects who are committed to an institution by way of official or juridical order will not be enrolled in the trial. Receipt of live (attenuated) vaccine within the 4 weeks prior to screening or during the trial. Subject is assessed as unsuitable for inclusion by the investigator; for instance, because he is not considered able to understand and comply with study requirements or has a condition that would not allow safe participation in the study. For female subjects: Positive pregnancy test at screening Visit 1, pregnancy or plans to become pregnant within 30 days after study completion Lactation Further exclusion criteria apply
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BI 1026706<br> | Drug: BI 1026706<br> <br> |
| Experimental: Placebo<br> | Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Cell Count of Neutrophils in Bronchoalveolar Lavage (BAL) Fluid After 24 Hours of the Segmental Lipopolysaccharide (LPS) Challenge | Total cell count of neutrophils in Bronchoalveolar Lavage (BAL) fluid after 24 hours of the segmental Lipopolysaccharide (LPS) challenge. The adjusted geometric means (gMeans) are obtained by exponentiating the Least Square (LS) means obtained by fitting an Analysis of variance (ANOVA) model on the natural log transformed endpoint values, adjusted for treatment effect. Standard errors are derived using the delta method. | Day 29 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Differential Cell Count of Neutrophils in BAL Fluid 24 h After Segmental LPS Challenge. | Differential cell count of neutrophils in BAL fluid 24 h after segmental LPS challenge. The adjusted geometric means (gMeans) are obtained by exponentiating the LS means obtained by fitting an ANOVA model on the natural log transformed endpoint values, adjusted for treatment effect. Standard errors are derived using the delta method. | Day 29 | 
| Total Cell Count of Eosinophil in BAL Fluid After 24 Hours of the Segmental LPS Challenge | Total cell count of eosinophil in BAL fluid after 24 hours of the segmental LPS challenge. The adjusted geometric means (gMeans) are obtained by exponentiating the LS means obtained by fitting an ANOVA model on the natural log transformed endpoint values, adjusted for treatment effect. Standard errors are derived using the delta method. | Day 29 | 
| Differential Cell Count of Eosinophil in BAL Fluid 24 h After Segmental LPS Challenge. | Differential cell count of eosinophil in BAL fluid 24 h after segmental LPS challenge. The adjusted geometric means (gMeans) are obtained by exponentiating the LS means obtained by fitting an ANOVA model on the natural log transformed endpoint values, adjusted for treatment effect. Standard errors are derived using the delta method. | Day 29 | 
| Total Cell Count of Monocyte in BAL Fluid After 24 Hours of the Segmental LPS Challenge | Total cell count of monocyte in BAL fluid after 24 hours of the segmental LPS challenge. The adjusted geometric means (gMeans) are obtained by exponentiating the LS means obtained by fitting an ANOVA model on the natural log transformed endpoint values, adjusted for treatment effect. Standard errors are derived using the delta method. Monocyte cell count is the only cell count which was assessed by means of flow cytometry. | Day 29 | 
| Differential Cell Count of Monocyte in BAL Fluid 24 h After Segmental LPS Challenge. | Differential cell count of monocyte (determined by flow cytometry) in BAL fluid 24 h after segmental LPS challenge. The adjusted geometric means (gMeans) are obtained by exponentiating the LS means obtained by fitting an ANOVA model on the natural log transformed endpoint values, adjusted for treatment effect. Standard errors are derived using the delta method. Monocyte cell count is the only cell count which was assessed by means of flow cytometry. | Day 29 | 
| Total Cell Count of Macrophage+Monocyte in BAL Fluid After 24 Hours of the Segmental LPS Challenge | Total cell count of macrophage+monocyte BAL fluid after 24 hours of the segmental LPS challenge. The adjusted geometric means (gMeans) are obtained by exponentiating the LS means obtained by fitting an ANOVA model on the natural log transformed endpoint values, adjusted for treatment effect. Standard errors are derived using the delta method. Cytospin microscopy method cannot clearly differentiate between macrophages and monocytes, the total and differential cell count of macrophages and monocytes are presented together. | Day 29 | 
| Differential Cell Count of Macrophage+Monocyte in BAL Fluid 24 h After Segmental LPS Challenge. | Differential cell count of macrophage+monocyte in BAL fluid 24 h after segmental LPS challenge. The adjusted geometric means (gMeans) are obtained by exponentiating the LS means obtained by fitting an ANOVA model on the natural log transformed endpoint values, adjusted for treatment effect. Standard errors are derived using the delta method. Cytospin microscopy method cannot clearly differentiate between macrophages and monocytes, the total and differential cell count of macrophages and monocytes are presented together. | Day 29 | 
| Total Cell Count of Lymphocyte in BAL After 24 Hours of the Segmental LPS Challenge | Total cell count of lymphocyte after 24 hours of the segmental LPS challenge. The adjusted geometric means (gMeans) are obtained by exponentiating the LS means obtained by fitting an ANOVA model on the natural log transformed endpoint values, adjusted for treatment effect. Standard errors are derived using the delta method. | Day 29 | 
| Differential Cell Count of Lymphocyte in BAL Fluid 24 h After Segmental LPS Challenge. | Differential cell count of lymphocyte in BAL fluid 24 h after segmental LPS challenge. The adjusted geometric means (gMeans) are obtained by exponentiating the LS means obtained by fitting an ANOVA model on the natural log transformed endpoint values, adjusted for treatment effect. Standard errors are derived using the delta method. | Day 29 |