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In February 2013, Glaxosmithkline (GSK) Announced a Commitment To In February 2013, GlaxoSmithKline (GSK) announced a commitment to further clinical transparency through the public disclosure of GSK Clinical Study Reports (CSRs) on the GSK Clinical Study Register. The following guiding principles have been applied to the disclosure: Information will be excluded in order to protect the privacy of patients and all named persons associated with the study Patient data listings will be completely removed* to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the GSK Clinical Study Register. Aggregate data will be included; with any direct reference to individual patients excluded *Complete removal of patient data listings may mean that page numbers are no longer consecutively numbered This study includes documents that were originally reported in a language other than English. All documents that are available in English have been made available via the GSK Clinical Study Register. Any additional documents that have not been translated to English may be made available, redacted in the original language, subject to an approved research proposal. For further information please see the Patient Level Data section of the GSK Clinical Study Register. CONFIDENTIAL GM2008/00234/00GM2008/00234/00 GlaxoSmithKlineThe GlaxoSmithKline group of companiesgroup of companies IPC103711IPC103711 Division: World Wide Development Retention Category: GRS019 Information Type: Condensed Clinical Study Report A double blind, placebo controlled, repeat dose study to Title: compare the effectiveness of two doses of GSK256066 with placebo in reducing lung inflammation following segmental LPS challenge in healthy volunteers Phase: I Compound Number: GSK256066 Effective Date: 30-OCT-2008 Description: This was a single centre, randomised, double-blind, parallel-group, 7 day repeat dose study in 37 healthy volunteers. Subjects were randomised (1:1:1) to receive either placebo (N = 12), GSK256066 25 µg (N = 13) or GSK256066 87.5 µg (N = 12) as a single, once-daily inhaled dose for 7 days (via an ACCUHALER™ device). Overall, there was an observed elevation in cell counts when comparing the 2 h post-dose and the 26 h post-dose saline compartments with the 26 h post-dose lipopolysaccharide (LPS) compartment confirming sensitivity to LPS challenge. This was not formally analysed. Due to the large variability across all treatment groups, there was no statistical evidence of a treatment effect for any endpoint that was formally analysed: total neutrophils, total and differential counts in bronchoalveolar lavage (BAL) 24 h post-LPS exposure, BAL concentrations of protein inflammatory biomarkers and serum concentrations of protein inflammatory biomarkers. Urea-corrected GSK256066 concentrations were at least an order of magnitude greater and declined more slowly over time in the pellet than in the supernatant. The metabolite GSK614917 was not quantifiable in any sample from subjects providing sufficient sample for analysis. Due to sparse pharmacokinetic data, no conclusions could be drawn between the pharmacokinetic and pharmacodynamic parameters. GSK256066 25 µg and 87.5 µg QD were generally well-tolerated by healthy subjects. All adverse events were judged to be mild or moderate in intensity and no serious adverse events were reported in the study. Subject: GSK256066, cellobiose octaacetate (COA), lipopolysaccharide (LPS), healthy volunteers Authors: Initiation Date: 2 October 2007 Completion Date: 16 April 2008 Date of Report: October 2008 1 1 CONFIDENTIAL GM2008/00234/00GM2008/00234/00 GlaxoSmithKlineThe GlaxoSmithKline group of companiesgroup of companies IPC103711IPC103711 Sponsor Signatory: PhD (and Medical Officer) Director, Discovery Medicine, Respiratory CEDD This study was performed in compliance with Good Clinical Practices including the archiving of essential documents. Copyright 2008 the GlaxoSmithKline group of companies. All rights reserved. Unauthorised copying or use of this information is prohibited. 2 2 CONFIDENTIAL GM2008/00234/00GM2008/00234/00 IPC103711IPC103711 Abbreviations AE Adverse event BAL Bronchoalveolar lavage CC-16 Clara cell protein 16 CVb Between-subject coefficients of variation FVC Forced vital capacity FEV1 Forced expiratory volume in 1 second IL Interleukin LPS Lipopolysaccharide LS Least squares MPO Myeloperoxidase MSE Mean square error QD Once daily RAP Reporting and analysis plan SP-D Surfactant-associated protein D SAE Serious adverse event SAS Statistical Analysis Software TNFα Tumour necrosis factor α Trademark Information Trademarks of the GlaxoSmithKline Trademarks not owned by the group of companies GlaxoSmithKline group of companies ACCUHALER SAS 1 3 CONFIDENTIAL GM2008/00234/00GM2008/00234/00 IPC103711IPC103711 TITLE A double blind, placebo controlled, repeat dose study to compare the effectiveness of two doses of GSK256066 with placebo in reducing lung inflammation following segmental LPS challenge in healthy volunteers. INVESTIGATOR Dr. STUDY CENTRE Germany. PUBLICATIONS None at the time of this report. STUDY PERIOD Initiation Date: 2 October 2007 Completion Date: 16 April 2008 PHASE OF DEVELOPMENT I. OBJECTIVES Primary • To investigate the effects of 7 days repeat dosing with inhaled GSK256066 (25 µg and 87.5 µg) once daily (QD) on lung inflammation following segmental lipopolysaccharide (LPS) challenge in healthy volunteers. Secondary • To investigate the safety and tolerability of 7 days repeat dosing of inhaled GSK256066 (25 µg and 87.5 µg) QD in healthy volunteers. 2 4 CONFIDENTIAL GM2008/00234/00GM2008/00234/00 IPC103711IPC103711 • To investigate the response of systemic markers of inflammation following 7 days repeat dosing of inhaled GSK256066 (25 µg and 87.5 µg) QD in healthy volunteers. METHODOLOGY This was a single centre, randomised, double-blind, parallel-group, 7-day repeat dose study in healthy volunteers. All subjects attended the unit for screening within 28 days of their first dosing occasion. Subjects were randomised (1:1:1) to receive one of the following treatments, as a single, inhaled dose QD for 7 days (via an ACCUHALER™ device): • GSK256066 25 µg. • GSK256066 87.5 µg. • Placebo. Following dosing on Day 7, subjects underwent bronchoscopy, bronchoalveolar lavage (BAL) and segmental LPS challenge. Bronchoscopy and BAL were repeated after 24 h. Subjects attended the unit for a follow-up visit within 7–10 days following their final dose. The overall study duration (screening to follow-up) did not exceed 45 days. Subjects had to follow protocol-specified guidance on consumption of alcohol and contraception (female subjects). Subjects were required to fast from midnight before Day 7 and Day 8 prior to bronchoscopy. A time and events table is presented in Attachment 1. 3 5 CONFIDENTIAL GM2008/00234/00GM2008/00234/00 IPC103711IPC103711 NUMBER OF SUBJECTS Placebo GSK256066 Dose QD 25 µg 87.5 µg Number of Subjects Number of subjects planned, N: 14 14 14 Number of subjects randomised, N: 12 13 12 Number of subjects included in all subjects 12 (100) 13 (100) 12 (100) population, n (%): Number of subjects included in pharmacokinetic 0 13 (100) 12 (100) population, n (%): Number of subjects included in per-protocol 12 (100) 12 (92) 12 (100) population, n (%): Number of subjects completed as 12 (100) 13 (100) 12 (100) planned, n (%): Number of subjects withdrawn 0 0 0 (any reason), n (%): Demographics Age in Years, Mean (Range) 34.0 (21–50) 29 (19–41) 29.2 (20–47) Sex, n (%) Female: 4 (33%) 6 (46%) 5 (42%) Male: 8 (67%) 7 (54%) 7 (58%) Body Mass Index (kg/m2), Mean (Range) 24.51 23.30 23.35 (20.42–27.47) (19.92–29.26) (20.20–25.54) Height (cm), Mean (Range) 176.3 176.7 176.9 (162–191) (166–188) (164–192) Weight (kg), Mean (Range) 76.6 (59–98) 72.9 (60–98) 73.3 (57–88) Ethnicity, n (%) Hispanic or Latino: 1 (8%) 0 0 Not Hispanic or Latino: 11 (92%) 13 (100%) 12 (100%) Race, n (%) White – White/Caucasian/European Heritage 12 (100%) 12 (92%) 12 (100%) White – Arabic/North African Heritage 0 1 (8%) 0 Source Data: Table 9.1, Table 9.2 and Table 9.3 AE = adverse event, SAE = serious adverse event DIAGNOSIS AND MAIN CRITERIA FOR INCLUSION Healthy male and female volunteers aged 18 to 50 years, with a body weight ≥50 kg and body mass index within the range of 19 to 31 kg/m2 inclusive were eligible for the study. Female subjects were either of non-childbearing potential or had a negative pregnancy test at screening and agreed to use one of the acceptable protocol-specified contraceptive methods. Subjects were eligible with a screening pre-bronchodilator forced expiratory volume in one second (FEV1) ≥80% predicted and FEV1/forced vital capacity (FVC) ratio >0.7. 4 6 CONFIDENTIAL GM2008/00234/00GM2008/00234/00 IPC103711IPC103711 Predicted values were based on the European Community for Coal and Steel (1993) normal ranges. TREATMENT ADMINISTRATION Subjects were dosed in the clinical study unit on the mornings of Day 1 and Day 7. On Day 2 to Day 6, subjects self-administrated medication at home. Two ACCUHALERs were provided per subject. Each subject took one inhalation from each inhaler each morning. A summary of treatment administration is presented in Table 1. Table 1 Summary of treatment administration Description Batch Details Use by date GSK256066 12.5 µg Batch/Lot number: 071131084 30th June 2008 GSK256066 37.5 µg Batch/Lot number: 071131086 30th June 2008 GSK256066 50 µg Batch/Lot number: 071131108 30th June 2008 Placebo Batch: R230656; Lot Number: 061120114 30th June 2008 CRITERIA FOR EVALUATION The primary endpoints for this study were: • Absolute BAL neutrophils at 24 h post-LPS exposure. • The total and differential cell count in BAL (absolute and percentage cell counts) at 24 h post-LPS exposure. The secondary endpoints for this study were: • Safety and tolerability: • Vital signs: systolic and diastolic blood pressure and heart rate. • Holter monitoring. • Twelve-lead electrocardiograph (ECG) including QTc(B), QT, QRS, PR and ventricular rate. • Lung function (FEV1 and FVC). • Laboratory safety tests (haematology, clinical chemistry, urinalysis). • Adverse events.
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