Study of SB681323 and Prednisolone on Biomarkers in COPD (Chronic Obstructive Pulmonary Disease) Patients

Study Overview
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Brief Summary
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This study will assess the effects of single oral doses of SB681323 and prednisolone on biomarkers in induced sputum and blood COPD patients

Official Title
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A Randomised, Double-blind, Double-dummy, Placebo-controlled, Five-way Crossover Study to Assess the Effects of Single Oral Doses of SB-681323 (7.5 mg and 25 mg) and Prednisolone (10 mg and 30 mg) on Biomarkers in Induced Sputum and Blood in COPD Patients.

Conditions
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Pulmonary Disease, Chronic Obstructive

Intervention / Treatment
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* Drug: SB681323
* Drug: Prednisolone
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Subject is current smoker or ex-smoker with a smoking history of at least 10 pack years (number of pack years = [number of cigarettes per day/20] x number of years smoked). The patient has serum CRP ≥ 3 mg/L at screening Subjects able to understand and comply with protocol requirements, instructions and protocol-stated restrictions. Exclusion criteria: Any clinically relevant abnormality identified on medical assessment, laboratory examination, or 12-lead ECG which in the opinion of the investigator, will lead to an unacceptable increase in the risk of study participation or will call into question the validity of the outcome measures. Subjects who are obese, defined as having a BMI > 40 Subject has a diagnosis of asthma that is confirmed by the investigator. Subject has poorly controlled COPD, defined as the occurrence of any of the following in the 2 weeks prior to visit 1: acute worsening of COPD that is managed by the subject at home by self-treatment with corticosteroids or antibiotics, or that requires treatment by a physician. Subject has active tuberculosis, lung cancer or clinically overt bronchiectasis. Symptoms of cold or flu or any respiratory infection/symptoms at the start of the study Subject has cardiac, gastrointestinal, neurological, renal, endocrine or psychiatric disease that is uncontrolled on permitted medication Subject has history of allergic rhinitis. Subjects with a history of any type of malignancy with the exception of successfully treated basal cell cancer of the skin. Subjects with rheumatoid arthritis, connective tissue disorders and other conditions known to be associated with chronic inflammation (e.g. Inflammatory Bowel Disease). Subjects with chronic infections such as gingivitis, periodontitis, prostatitis, gastritis, and urinary tract infections. Subjects with history of hepatic disease. History of increased liver function tests (ALT, AST) above upper limit of normal in the past 6 months and/or liver function tests (bilirubin, ALT, AST) above upper limit of normal at screening. History of positive HIV, Hepatitis B /C antibody test result, a positive Hep B/C result at screen or a risk factor for these diseases. History of drug or other allergy, which, in the opinion of the Investigator precludes participation in the study.

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 75 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: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Randomised, double-blind, five-way crossover<br>A randomised, double-blind, double-dummy, placebo-controlled, five-way crossover study to assess the effects of single oral doses of SB-681323 (7.5 mg and 25 mg) and prednisolone (10 mg and 30 mg) on biomarkers in induced sputum and blood in COPD patients. | Drug: SB681323<br>* 5 mg and 2.5 mg tablets - The tablets will be round (9.0 mm in diameter) and white and provided in labelled bottles<br>Drug: Prednisolone<br>* 5 mg size DB AA capsule shell (Swedish orange) with a powder backfill (lactose Anhydrous)<br>Drug: Placebo<br>* Tablets matched to SB681323 or prednisolone<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacodynamic effect of single, oral doses of SB-681323 and prednisolone | Levels of ex-vivo LPS induced TNFα in whole blood at 1, 2, 6 and 24 hrs post-dose | 20 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Level of pHSP27 and mRNAs encoding inflammatory markers | Levels obtained in sputum and whole blood samples | 20 weeks | 
| CD11b and CD62L surface expression on neutrophils | Levels obtained in whole blood samples | 20 weeks | 
| Blood concentration of inflammatory markers | GSK's COPD multiplex biomarker assay | 20 weeks | 
| CRP levels | Levels obtained in COPD patient sera | 20 weeks | 
| Safety and tolerability of dinsgle doses of SB681323 and prednisolone | Vitals, AEs, ECGs, safety laboratory, pulmonary function FEV1 and FVC | 20 weeks | 
| Exploratory objective #1 | Transcriptomic profiles of induced sputum cells and whole blood Exploratory micro-array analysis of mRNA biomarkers in induced sputum samples at 2 hrs post-dose and whole blood samples at baseline (pre-dose), and 6 hrs post-dose (earlier post-dose blood samples (1 and 2 hrs ) may also be examined) | 20 weeks | 
| Exploratory objective #2 | Exploratory analysis of inflammatory biomarker concentrations in induced sputum supernatants (e.g. myeloperoxidase, IL-6, TNF-α, total protein) at 2 hours post-dose | 20 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COPD SB-681323 prednisolone biomarkers