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

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.

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

Study Overview

• Status: Completed
• Conditions: Pulmonary Disease, Chronic Obstructive
• Intervention / Treatment: Drug: SB681323; Drug: Prednisolone; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Lancashire
    • Manchester, Lancashire, United Kingdom, M23 9LT
      • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: DOUBLE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Randomised, double-blind, five-way crossover; 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; 5 mg and 2.5 mg tablets - The tablets will be round (9.0 mm in diameter) and white and provided in labelled bottles; Drug: Prednisolone; 5 mg size DB AA capsule shell (Swedish orange) with a powder backfill (lactose Anhydrous); Drug: Placebo; Tablets matched to SB681323 or prednisolone

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: GlaxoSmithKline

Publications and helpful links

General Publications

• Singh D, Smyth L, Borrill Z, Sweeney L, Tal-Singer R. A randomized, placebo-controlled study of the effects of the p38 MAPK inhibitor SB-681323 on blood biomarkers of inflammation in COPD patients. J Clin Pharmacol. 2010 Jan;50(1):94-100. doi: 10.1177/0091270009347873. Epub 2009 Oct 30.

Study record dates

Study Major Dates

• Study Start: June 1, 2005
• Primary Completion (ACTUAL): April 1, 2006
• Study Completion (ACTUAL): April 1, 2006

Study Registration Dates

• First Submitted: September 21, 2006
• First Submitted That Met QC Criteria: September 21, 2006
• First Posted (ESTIMATE): September 25, 2006

Study Record Updates

• Last Update Posted (ESTIMATE): June 4, 2012
• Last Update Submitted That Met QC Criteria: May 31, 2012
• Last Verified: March 1, 2012

More Information

Terms related to this study

• Keywords: COPD SB-681323 prednisolone biomarkers
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Pulmonary Disease, Chronic Obstructive; Physiological Effects of Drugs; Anti-Inflammatory Agents; Antineoplastic Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Prednisolone
• Other Study ID Numbers: IPI100477