A Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Dose-Response Relationship of Multiple Doses of GSK2269557 Administered as a Dry Powder to Chronic Obstructive Pulmonary Disease (COPD) Patients

Sponsor

GlaxoSmithKline (Industry)

Overall Status

Completed

CT.gov ID

NCT02130635

Collaborator

(none)

Enrollment

Locations

Arms

12.6

Actual Duration (Months)

Patients Per Site

2.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a randomised, double-blind, placebo controlled, parallel group study to evaluate the safety, tolerability, pharmacokinetics and dose response of multiple doses of GSK2269557 administered as a dry powder in COPD subjects. Pharmacodynamic effects on biomarkers will also be assessed. This study will have two parts. In Part A, subjects will be randomized to active or placebo treatment in a 3:1 ratio and in Part B, to placebo or one of the six doses of active treatment in an equal ratio. A sufficient number of COPD subjects (male and female of non-child bearing potential) will be screened to ensure that approximately 30 subjects are enrolled and at least 20 evaluable subjects are obtained for Part A and approximately 35 subjects will be enrolled for Part B. In both the parts, subjects will receive study treatment once daily for 14 consecutive days. Placebo control will be included for a valid evaluation of adverse events attributable to treatment versus those independent of treatment.

Condition or Disease	Intervention/Treatment	Phase
Pulmonary Disease, Chronic Obstructive	Drug: GSK2269557 100 MCG Drug: GSK2269557 500 MCG Drug: PLACEBO	Phase 2

Study Design

Study Type:

Interventional

Actual Enrollment :

64 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double (Participant, Investigator)

Primary Purpose:

Treatment

Official Title:

A Double-Blind (Sponsor Unblind), Placebo Controlled, Randomised, Parallel Group Study to Evaluate the Safety, Tolerability and Pharmacokinetics of Multiple Doses of GSK2269557 Administered as a Dry Powder to COPD Patients and Assessment of Dose Response Using Sputum Biomarkers

Actual Study Start Date :

Jul 31, 2014

Actual Primary Completion Date :

Aug 18, 2015

Actual Study Completion Date :

Aug 18, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Part A: GSK2269557 1000 MCG Subjects will receive 2 inhalations (2 x GSK2269557 500 mcg = total dose of 1000 mcg GSK2269557) 30 seconds apart, once daily for 14 consecutive days	Drug: GSK2269557 500 MCG 500 mcg of GSK2269557 blended with lactose per blister administered using a dry powder inhaler device
Placebo Comparator: Part A: PLACEBO Subjects will receive 2 inhalations of placebo once daily for 14 consecutive days	Drug: PLACEBO Lactose administered using a matching dry powder inhaler device
Experimental: Part B: GSK2269557 100 MCG Subjects will receive 4 inhalations (1 x GSK2269557 100 mcg and 3 x Placebo = total dose of 100 mcg GSK2269557) 30 seconds apart, once daily for 14 consecutive days	Drug: GSK2269557 100 MCG 100 mcg of GSK2269557 blended with lactose per blister administered using a dry powder inhaler device Drug: PLACEBO Lactose administered using a matching dry powder inhaler device
Experimental: Part B: GSK2269557 200 MCG Subjects will receive 4 inhalations (2 x GSK2269557 100 mcg and 2 x Placebo = total dose of 200 mcg GSK2269557) 30 seconds apart, once daily for 14 consecutive days	Drug: GSK2269557 100 MCG 100 mcg of GSK2269557 blended with lactose per blister administered using a dry powder inhaler device Drug: PLACEBO Lactose administered using a matching dry powder inhaler device
Experimental: Part B: GSK2269557 500 MCG Subjects will receive 4 inhalations (1 x GSK2269557 500 mcg and 3 x Placebo = total dose of 500 mcg GSK2269557) 30 seconds apart, once daily for 14 consecutive days, once daily for 14 consecutive days	Drug: GSK2269557 500 MCG 500 mcg of GSK2269557 blended with lactose per blister administered using a dry powder inhaler device Drug: PLACEBO Lactose administered using a matching dry powder inhaler device
Experimental: Part B: GSK2269557 700 MCG Subjects will receive 4 inhalations (1 x GSK2269557 500 mcg, 2 x GSK2269557 100 mcg and 1 x Placebo = total dose of 700 mcg GSK2269557) 30 seconds apart, once daily for 14 consecutive days	Drug: GSK2269557 100 MCG 100 mcg of GSK2269557 blended with lactose per blister administered using a dry powder inhaler device Drug: GSK2269557 500 MCG 500 mcg of GSK2269557 blended with lactose per blister administered using a dry powder inhaler device Drug: PLACEBO Lactose administered using a matching dry powder inhaler device
Experimental: Part B: GSK2269557 1000 MCG Subjects will receive 4 inhalations (2 x GSK2269557 100 mcg and 2 x Placebo = total dose of 1000 mcg GSK2269557) 30 seconds apart, once daily for 14 consecutive days	Drug: GSK2269557 500 MCG 500 mcg of GSK2269557 blended with lactose per blister administered using a dry powder inhaler device Drug: PLACEBO Lactose administered using a matching dry powder inhaler device
Experimental: Part B: GSK2269557 2000 MCG Subjects will receive 4 inhalations (2 x GSK2269557 100 mcg and 2 x Placebo = total dose of 2000 mcg GSK2269557) 30 seconds apart, once daily for 14 consecutive days	Drug: GSK2269557 500 MCG 500 mcg of GSK2269557 blended with lactose per blister administered using a dry powder inhaler device
Placebo Comparator: Part B: PLACEBO Subjects will receive 4 inhalations of placebo once daily for 14 consecutive days	Drug: PLACEBO Lactose administered using a matching dry powder inhaler device

Outcome Measures

Primary Outcome Measures

Part A: Number of Participants With at Least One Non-serious Adverse Event (AE), Serious Adverse Event (SAE), or Drug-related Adverse Event [From the start of study treatment until follow-up (assessed for approximately 19 days)]
An AE is defined as any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect, may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed in this definition, associated with liver injury and impaired liver function defined as alanine aminotransferase >=3 x upper limit of normal (ULN), and total bilirubin >=2 x ULN or international normalized ratio >1.5. AEs were classified as potentially drug-related, based on the investigator's judgment. Refer to the general AE/SAE module for a list of AEs and SAEs.
Part A: Change From Baseline in Counts of White Blood Cells (WBC), Total Neutrophils (Total Absolute Neutrophil Count [ANC]), Lymphocytes, Monocytes, Eosinophils, Basophils, and Platelets at the Indicated Time Points [Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 hours [h] post-dose)]
Blood samples were collected for measurement for the indicated tests. Baseline is Day 1 pre-dose. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.
Part A: Change From Baseline in Hemoglobin and Mean Corpuscle Hemoglobin Concentration (MCHC) at the Indicated Time Points [Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 h post-dose)]
Blood samples were collected for measurement for the indicated tests. Baseline is Day 1 pre-dose. MCHC is one of the red blood cell (RBC) indices. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.
Part A: Change From Baseline in Hematocrit at the Indicated Time Points [Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 hours [h] post-dose)]
Blood samples were collected for measurement for the indicated tests. Baseline is Day 1 pre-dose. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.
Part A: Change From Baseline in Counts of RBCs and Reticulocytes at the Indicated Time Points [Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 hours [h] post-dose)]
Blood samples were collected for measurement for the indicated tests. Baseline is Day 1 pre-dose. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.
Part A: Change From Baseline in Mean Corpuscle Hemoglobin (MCH) at the Indicated Time Points [Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 hours [h] post-dose)]
Blood samples were collected for measurement for the indicated tests. Baseline is Day 1 pre-dose. MCH is one of the red blood cell indices. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.
Part A: Change From Baseline in Mean Corpuscle Volume (MCV) at the Indicated Time Points [Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 hours [h] post-dose)]
Blood samples were collected for measurement for the indicated tests. Baseline is Day 1 pre-dose. MCV is one of the RBC indices. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.
Part A: Change From Baseline in Albumin and Total Protein at the Indicated Time Points [Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 hours [h] post-dose)]
Blood samples were collected for measurement for the indicated tests. Baseline is Day 1 pre-dose. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.
Part A: Change From Baseline in Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP), Aspartate Aminotransferase (AST), and Gamma Glutamyl Transferase (GGT) at the Indicated Time Points [Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 hours [h] post-dose)]
Blood samples were collected for measurement for the indicated tests. Baseline is Day 1 pre-dose. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.
Part A: Change From Baseline in Creatinine, Bilirubin, and Total Bilirubin at the Indicated Time Points [Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 hours [h] post-dose)]
Blood samples were collected for measurement for the indicated tests. Baseline is Day 1 pre-dose. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.
Part A: Change From Baseline in Calcium, Potassium, Sodium, Glucose, and Blood Urea Nitrogen (BUN) at the Indicated Time Points [Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 hours [h] post-dose)]
Blood samples were collected for measurement for the indicated tests. Baseline is Day 1 pre-dose. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.
Part A: Number of Participants Meeting Criteria of Potential Clinical Importance for Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP), and Heart Rate (HR) at Any Visit Post-Baseline [Day 1, Day 7, and Day 14]
Baseline was the Day 1 pre-dose measurement. Vital signs (SBP, DBP, and HR) were measured at Day 1 (30 minutes [min] and 6 h post-dose), Day 7 (pre-dose), and Day 14 (24 h post-dose). Potential clinical concern range for SBP was <85 millimeters of mercury (mmHg) (low) and >160 mmHg (high), for DBP <45 mmHg (low) and >100 mmHg (high) and for HR <40 bpm and >110 bpm. All measurements were obtained in supine position, after a 5-minute rest. Day 7 assessments could be conducted on Day 7 or Day 8.
Part A: Number of Participants With Normal and Abnormal (Clinically Significant or Not Clinically Significant) Findings in 12-lead Electrocardiogram (ECG) at Any Visit Post-Baseline [Day 1, Day 7, and Day 14]
Baseline was the Day 1 (pre-dose) measurement. Single 12-lead ECGs were obtained using an ECG machine that automatically calculates the HR and measures PR, QRS, QT, and corrected QT intervals. Clinical significance was judged by the investigator. Day 7 assessments could be conducted on Day 7 or Day 8.
Part A: Change From Baseline in Forced Expiratory Volume in One Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points [Baseline (Day 1 [pre-dose]), Day 1 (1 h post-dose), Day 7 (pre-dose and 1 h post-dose), and Day 14 (24 h post-dose)]
Baseline is Day 1 pre-dose. FEV1 and FVC are measures of lung function. FEV1 is defined as the maximal amount of air that can be forcefully exhaled in one second. FVC is defined as the maximum amount of air that can be forcibly blown out after a maximum inspiration. FEV1 and FVC measurements were repeated until three technically acceptable measurements (within 150 milliliters of each other) had been made. Only the best of three measurements were recorded. Baseline was the maximum of the planned pre-dose measurements on Day 1. Change from Baseline at any post-dose time point was calculated as the post-dose value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.
Part B: Adjusted Median Response of Cytokine (Interleukin 6 [IL6], Interleukin 8 [IL8], Tumor Necrosis Factor Alpha [TNFalpha]) Concentrations in Induced Sputum, on Day 7 and Day 14 [Day 7 (pre-dose) and Day 14 (24 h post-dose)]
This outcome measure was used to estimate the inhibition levels of various doses of GSK2269557 by analyzing inflammatory cytokines IL6, IL8, and TNF alpha using Bayesian methods of statistical analysis, using non-informative prior distributions for all modeling parameters. Posterior medians (adjusted median response) and 95% credible intervals are reported here as medians and 95% confidence intervals respectively. 95% credible interval is reported as 2-sided 95% confidence in the statistical analyses. Day 7 assessments could be conducted on Day 7 or Day 8.

Secondary Outcome Measures

Part A: Day 1 Plasma Concentration of GSK2269577 up to 6 Hours Post Dose [Day 1 (Pre-dose, 5 min, 30 min, 1, 2, 4 & 6 hours post-dose)]
A 2 mL blood sample for pharmacokinetic (PK) analysis was collected at each of the indicated time point. Only those participants who were available at the indicated time points were analyzed (represented by n=X in the category titles). A value of NA indicates that the geometric mean or 95% confidence interval is not available.
Part B: Day 1 Plasma Concentration of GSK2269577 up to 6 Hours Post Dose [Pre-dose, and 5 min, 30 min, 1 h, 2 h, 4 h, and 6 h post-dose on Day 1]
A 2 mL blood sample for pharmacokinetic (PK) analysis was collected at each of the indicated time point. Concentration measurements were log-transformed. Only those participants who were available at the indicated time points were analyzed (represented by n=X,X in the category titles). A value of NA indicates that the geometric mean or 95% confidence interval is not available.
Part A: Maximum Observed Plasma Concentration (Cmax) of GSK2269577 on Day 7 [Day 7 immediately after dosing]
Blood samples were collected to determine the plasma concentrations of GSK2269577 immediately after dosing on Day 7. Day 7 sampling could be done on Day 7 or Day 8.
Part B: Maximum Observed Plasma Concentration (Cmax) of GSK2269577 on Day 7 [Day 7 immediately after dosing]
Blood samples were collected to determine the plasma concentrations of GSK2269577 immediately after dosing on Day 7. Concentration values were log-transformed. Day 7 sampling could be done on Day 7 or Day 8.
Part A: Trough Concentration (Ctau) of GSK2269577 on Day 7 and Day 15 [Day 7 and Day 15]
Blood samples were collected to determine the (trough) plasma concentration of GSK2269577 on Day 7 (pre-dose) and Day 15 (24 hours after dosing on Day 14). Day 7 assessments could be done either on Day 7 or on Day 8.
Part B: Trough Concentration (Ctau) of GSK2269577 on Day 7 and Day 15 [Day 7 and Day 15]
Blood samples were collected to determine the (trough) plasma concentration of GSK2269577 on Day 7 (pre-dose) and Day 15 (24 hours after dosing on Day 14). Day 7 assessments could be done either on Day 7 or on Day 8.
Part B: Number of Times Rescue Medication Was Used by Participants Daily, During the Treatment Period [Day 1 to Day 15]
Rescue medication was identified from concomitant medication records and the patient diaries which were provided to the participants to record data throughout the treatment period. Only participants who used rescue medication were analyzed. The value NA indicates that the standard deviation could not be calculated as only one participant was analyzed.
Part B: Number of Participants With at Least One Non-serious Adverse Event (AE), Serious Adverse Event (SAE), or Drug-related Adverse Event [From the start of study treatment until follow-up (assessed for approximately 19 days)]
An AE is defined as any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect, may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed in this definition, associated with liver injury and impaired liver function defined as alanine aminotransferase >=3 x upper limit of normal (ULN), and total bilirubin >=2 x ULN or international normalized ratio >1.5. AEs were classified as potentially drug-related, based on the investigator's judgment. Refer to the general AE/SAE module for a list of AEs and SAEs.
Part B: Change From Baseline in Counts of Basophils, Eosinophils, Lymphocytes, Monocytes, Platelets, White Blood Cells (WBC), Total Neutrophils (Total ANC) at the Indicated Time Points [Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 hours [h] post-dose)]
Blood samples were collected for measurement for the indicated tests. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.
Part B: Change From Baseline in Hemoglobin and Mean Corpuscle Hemoglobin Concentration (MCHC) at the Indicated Time Points [Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 hours [h] post-dose)]
Blood samples were collected for measurement for the indicated tests. MCHC is one of the red blood cell (RBC) indices. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.
Part B: Change From Baseline in Counts of RBCs and Reticulocytes at the Indicated Time Points [Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 hours [h] post-dose)]
Blood samples were collected for measurement for the indicated tests. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.
Part B: Change From Baseline in Hematocrit at the Indicated Time Points [Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 hours [h] post-dose)]
Blood samples were collected for measurement for the indicated tests. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.
Part B: Change From Baseline in Mean Corpuscle Hemoglobin (MCH) at the Indicated Time Points [Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 hours [h] post-dose)]
Blood samples were collected for measurement for the indicated tests. MCH is one of the red blood cell indices. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.
Part B: Change From Baseline in Mean Corpuscle Volume (MCV) at the Indicated Time Points [Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 hours [h] post-dose)]
Blood samples were collected for measurement for the indicated tests. MCV is one of the RBC indices. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.
Part B: Change From Baseline in Albumin and Total Protein at the Indicated Time Points [Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 hours [h] post-dose)]
Blood samples were collected for measurement for the indicated tests. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.
Part B: Change From Baseline in Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP), Aspartate Aminotransferase (AST), and Gamma Glutamyl Transferase (GGT) at the Indicated Time Points [Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 hours [h] post-dose)]
Blood samples were collected for measurement for the indicated tests. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.
Part B: Change From Baseline in Creatinine, Bilirubin, and Total Bilirubin at the Indicated Time Points [Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 hours [h] post-dose)]
Blood samples were collected for measurement for the indicated tests. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.
Part B: Change From Baseline in Calcium, Potassium, Sodium, Glucose, and Blood Urea Nitrogen (BUN) at the Indicated Time Points [Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 hours [h] post-dose)]
Blood samples were collected for measurement for the indicated tests. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.
Part B: Number of Participants Meeting Criteria of Potential Clinical Importance for Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP), and Heart Rate (HR) at Any Visit Post-Baseline [Day 1, Day 7, and Day 14]
Baseline was the Day 1 pre-dose measurement. Vital signs (SBP, DBP, and HR) were measured at Day 1 (30 minutes [min] and 6 h post-dose), Day 7 (pre-dose), and Day 14 (24 h post-dose). All measurements were obtained in supine position, after a 5-minute rest. Day 7 assessments could be conducted on Day 7 or Day 8.
Part B: Number of Participants With Normal and Abnormal (Clinically Significant or Not Clinically Significant) Findings in 12-lead Electrocardiogram (ECG) at Any Visit Post-Baseline [Day 1, Day 7, and Day 14]
Baseline was the Day 1 (pre-dose) measurement. Single 12-lead ECGs were obtained using an ECG machine that automatically calculates the HR and measures PR, QRS, QT, and corrected QT intervals. Day 7 assessments could be conducted on Day 7 or Day 8.
Part B: Forced Expiratory Volume in One Second (FEV1) and Forced Vital Capacity (FVC) at Screening and Follow-up [Screening (up to 30 days prior to Day 1) and Follow-up (approximately Day 19)]
FEV1 and FVC are measures of lung function. FEV1 is defined as the maximal amount of air that can be forcefully exhaled in one second. FVC is defined as the maximum amount of air that can be forcibly blown out after a maximum inspiration. FEV1 and FVC measurements were repeated until three technically acceptable measurements (within 150 milliliters of each other) had been made. Only the best of three measurements were recorded.

Eligibility Criteria

Criteria

Ages Eligible for Study:

40 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

The subject has a confirmed and established diagnosis of COPD, as defined by the Global Initiative for Chronic Obstructive lung Disease (GOLD) guidelines.
Male or female of non-child bearing potential between 40 and 75 years of age inclusive, at the time of signing the informed consent.
The subject has a post-bronchodilator [400 microgram (mcg) salbutamol] Maximal amount of air FEV1/FVC <0.7 and FEV1 >=40% to <=80% of predicted (Predictions should be according to the European Community of Coal and Steel (ECCS) equations).
Subject is a smoker or an ex-smoker with a smoking history of at least 10 pack years (pack years = (cigarettes per day smoked/20) x number of years smoked)).
The subject is able to produce >100 milligram (mg) of sputum at screening.
Body weight >=45 kilogram (kg) and body mass index (BMI) within the range 17 - 32 kg/square meter (m^2) (inclusive).
A female subject is eligible to participate if she is of: Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation, hysterectomy, salpingo-oophrectomy or oophrectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) > 40 milli-International units (MIU)/millilitre (mL) and estradiol < 40 picogram (pg)/mL (<147 picomole(pmol)/Liter [L]) is confirmatory]. [Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods, if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrolment. For most forms of HRT, at least 2-4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method.]; or has only same-sex partners, when this is her preferred and usual lifestyle.
Male subjects with female partners of child-bearing potential must agree to use one of the contraception methods. This criterion must be followed from the time of the first dose of study medication until the follow-up visit.
Based on averaged QTcF values of triplicate ECGs obtained over a brief recording period (e.g. 5 minutes): QTcF <450 millisecond (msec); or QTcF<480 msec in subjects with right bundle branch block.
Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
A subject with a clinical abnormality or laboratory parameter(s) which is/are not specifically listed in the inclusion or exclusion criteria, outside the reference range for the population being studied may be included if the investigator [in consultation with the Glaxosmithkline (GSK) medical monitor if required] documents that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.

Exclusion Criteria:

Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome, asymptomatic gallstones and cholecystectomy).
Subjects who have a past or current medical condition or diseases that are not well controlled and, which as judged by the Investigator, may affect subject safety or influence the outcome of the study. (Note: Patients with adequately treated and well controlled concurrent medical conditions (e.g. hypertension) are permitted to be entered into the study).
Subject has a diagnosis of active tuberculosis, lung cancer, clinically overt bronchiectasis, pulmonary fibrosis, asthma or any other respiratory condition that might, in the opinion of the Investigator, compromise the safety of the subject or affect the interpretation of the results.
History of regular alcohol consumption within 6 months of the study defined as an average weekly intake of >28 units for males or >21 units for females. One unit is equivalent to 8 gram of alcohol: a half-pint (approximately 240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits.
History of sensitivity to any of the study medications, or components (such as lactose) thereof or a history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation.
A positive test for Human immunodeficiency virus (HIV) antibody - tested according to local policies.
The subject has a positive pre-study drug/alcohol screen. A minimum list of drugs that will be screened for include cannabinoids, amphetamines, barbiturates, cocaine and opiates. The detection of drugs (e.g. benzodiazepines, opiates) taken for a legitimate medical purpose would not necessarily be an exclusion to study participation. The detection of alcohol would not be an exclusion at screening but would need to be negative pre-dose and during the study.
A positive pre-study Hepatitis B surface antigen (HBs-Ag) or positive total hepatitis B core antibody (anti-HBc IgM) or positive Hepatitis C antibody result within 3 months of screening.
Pregnant females as determined by positive urine human chorionic gonadotropin (hCG) test at screening or prior to dosing.
Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.
Lactating females.
The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
Exposure to more than four new chemical entities within 12 months prior to the first dosing day.
Subject has poorly controlled or unstable COPD, defined as the occurrence of any of the following: Either: acute worsening of COPD (an exacerbation) that is managed by the subject at home requiring treatment with corticosteroids and/or antibiotics in the 4 weeks prior to the screening visit; or more than two exacerbations in the previous 2 months prior to the screening visit that required a course of oral corticosteroids and/or antibiotics, or for which the subject was hospitalised.
Subject has had a respiratory tract infection treated with antibiotics in the 4 weeks prior to first dose.
Subject requires regular treatment with oral corticosteroids or has received oral or parenteral corticosteroids within 4 weeks of screening.
Vulnerable subject (e.g., person kept in detention).
The subject is not able to understand and communicate in German or native language.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	GSK Investigational Site	Grosshansdorf	Schleswig-Holstein	Germany	22927
2	GSK Investigational Site	Berlin		Germany	14050

Sponsors and Collaborators

GlaxoSmithKline

Investigators

Study Director: GSK Clinical Trials, GlaxoSmithKline

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

IPD for this study will be made available via the Clinical Study Data Request site.

Publications

None provided.

Responsible Party:

GlaxoSmithKline

ClinicalTrials.gov Identifier:

NCT02130635

Other Study ID Numbers:

115119

First Posted:

May 5, 2014

Last Update Posted:

Oct 11, 2018

Last Verified:

Sep 1, 2018

Individual Participant Data (IPD) Sharing Statement:

Yes

Plan to Share IPD:

Yes

Keywords provided by GlaxoSmithKline

Additional relevant MeSH terms:

Lung Diseases

Pulmonary Disease, Chronic Obstructive

Nemiralisib

Study Results

Participant Flow

Recruitment Details
Pre-assignment Detail	This study was comprised of two parts. In Part A, participants were randomized to active or placebo treatment in a 3:1 ratio and in Part B, to placebo or one of the six doses of active treatment in an equal ratio. Each part comprised a separate sample of participants.

Arm/Group Title	Part A: Placebo	Part A: GSK2269577 1000 µg	Part B: Placebo	Part B: GSK2269577 100 µg	Part B: GSK2269577 200 µg	Part B: GSK2269577 500 µg	Part B: GSK2269577 700 µg	Part B: GSK2269577 1000 µg	Part B: GSK2269577 2000 µg
Arm/Group Description	Participants received 2 inhalations of matching placebo once daily for 14 consecutive days.	Participants received repeat doses of GSK2269557 1000 micrograms (µg) (2 inhalations of 500 µg each from a single device) administered as a dry powder inhalation, once daily for 14 consecutive days.	Participants received four inhalations of matching placebo (from four inhalation devices) once daily for 14 consecutive days.	Participants received repeat doses of GSK2269557 100 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 100 µg or placebo.	Participants received repeat doses of GSK2269557 200 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 100 µg or placebo.	Participants received repeat doses of GSK2269557 500 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 500 µg or placebo.	Participants received repeat doses of GSK2269557 700 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing GSK2269557 100 µg, 500 µg, or placebo.	Participants received repeat doses of GSK2269557 1000 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 500 µg or placebo.	Participants received repeat doses of GSK2269557 2000 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing GSK2269557 500 µg.
Period Title: Part A-Safety and Tolerability
STARTED	7	21	0	0	0	0	0	0	0
COMPLETED	7	21	0	0	0	0	0	0	0
NOT COMPLETED	0	0	0	0	0	0	0	0	0
Period Title: Part A-Safety and Tolerability
STARTED	0	0	5	5	5	5	6	5	5
COMPLETED	0	0	5	5	5	5	6	5	5
NOT COMPLETED	0	0	0	0	0	0	0	0	0

Baseline Characteristics

Arm/Group Title	Part A: Placebo	Part A: GSK2269577 1000 µg	Part B: Placebo	Part B: GSK2269577 100 µg	Part B: GSK2269577 200 µg	Part B: GSK2269577 500 µg	Part B: GSK2269577 700 µg	Part B: GSK2269577 1000 µg	Part B: GSK2269577 2000 µg	Total
Arm/Group Description	Participants received 2 inhalations of matching placebo once daily for 14 consecutive days.	Participants received repeat doses of GSK2269557 1000 micrograms (µg) (2 inhalations of 500 µg each from a single device) administered as a dry powder inhalation, once daily for 14 consecutive days.	Participants received four inhalations of matching placebo (from four inhalation devices) once daily for 14 consecutive days.	Participants received repeat doses of GSK2269557 100 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 100 µg or placebo.	Participants received repeat doses of GSK2269557 200 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 100 µg or placebo.	Participants received repeat doses of GSK2269557 500 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 500 µg or placebo.	Participants received repeat doses of GSK2269557 700 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing GSK2269557 100 µg, 500 µg, or placebo.	Participants received repeat doses of GSK2269557 1000 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 500 µg or placebo.	Participants received repeat doses of GSK2269557 2000 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing GSK2269557 500 µg.	Total of all reporting groups
Overall Participants	7	21	5	5	5	5	6	5	5	64
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	65.1 (5.81)	60.5 (6.68)	61.7 (6.68)
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	64.4 (4.45)	61.6 (4.56)	62.2 (8.23)	65.4 (5.81)	64.7 (7.26)	62.4 (9.24)	62.4 (6.43)	63.3 (6.34)
Sex: Female, Male (Count of Participants)
Female	1 14.3%	7 33.3%	2 40%	4 80%	1 20%	0 0%	3 50%	3 60%	3 60%	24 37.5%
Male	6 85.7%	14 66.7%	3 60%	1 20%	4 80%	5 100%	3 50%	2 40%	2 40%	40 62.5%
Race/Ethnicity, Customized (Number) [Number]
White-White/Caucasian/European Heritage	7 100%	21 100%	5 100%	5 100%	5 100%	5 100%	6 100%	5 100%	5 100%	64 100%

Outcome Measures

1. Primary Outcome

Title	Part A: Number of Participants With at Least One Non-serious Adverse Event (AE), Serious Adverse Event (SAE), or Drug-related Adverse Event
Description	An AE is defined as any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect, may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed in this definition, associated with liver injury and impaired liver function defined as alanine aminotransferase >=3 x upper limit of normal (ULN), and total bilirubin >=2 x ULN or international normalized ratio >1.5. AEs were classified as potentially drug-related, based on the investigator's judgment. Refer to the general AE/SAE module for a list of AEs and SAEs.
Time Frame	From the start of study treatment until follow-up (assessed for approximately 19 days)

Outcome Measure Data

Analysis Population Description
Safety Population: all participants who received at least one dose of study treatment.

Arm/Group Title	Part A: Placebo	Part A: GSK2269577 1000 µg
Arm/Group Description	Participants received 2 inhalations of matching placebo once daily for 14 consecutive days.	Participants received repeat doses of GSK2269557 1000 micrograms (µg) (2 inhalations of 500 µg each from a single device) administered as a dry powder inhalation, once daily for 14 consecutive days.
Measure Participants	7	21
At least one AE	2 28.6%	9 42.9%
At least one SAE	0 0%	1 4.8%
At least one drug-related AE	2 28.6%	6 28.6%

2. Primary Outcome

Title	Part A: Change From Baseline in Counts of White Blood Cells (WBC), Total Neutrophils (Total Absolute Neutrophil Count [ANC]), Lymphocytes, Monocytes, Eosinophils, Basophils, and Platelets at the Indicated Time Points
Description	Blood samples were collected for measurement for the indicated tests. Baseline is Day 1 pre-dose. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.
Time Frame	Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 hours [h] post-dose)

Outcome Measure Data

Analysis Population Description
Safety Population

Arm/Group Title	Part A: Placebo	Part A: GSK2269577 1000 µg
Arm/Group Description	Participants received 2 inhalations of matching placebo once daily for 14 consecutive days.	Participants received repeat doses of GSK2269557 1000 micrograms (µg) (2 inhalations of 500 µg each from a single device) administered as a dry powder inhalation, once daily for 14 consecutive days.
Measure Participants	7	21
WBC; Day 7/Day 8, pre-dose	-0.736 (0.937)	-0.080 (1.387)
WBC; Day 14, 24 h post dose	-0.140 (1.220)	-0.510 (0.947)
Total ANC; Day 7/Day 8, pre-dose	-0.664 (0.624)	-0.363 (1.342)
Total ANC; Day 14, 24 h post dose	-0.153 (0.887)	-0.547 (0.977)
Lymphocytes; Day 7/Day 8, pre-dose	-0.033 (0.321)	0.172 (0.597)
Lymphocytes; Day 14, 24 h post dose	-0.049 (0.197)	0.030 (0.245)
Monocytes; Day 7/Day 8, pre-dose	-0.036 (0.074)	0.046 (0.149)
Monocytes; Day 14, 24 h post dose	0.039 (0.178)	-0.022 (0.116)
Eosinophils; Day 7/Day 8, pre-dose	-0.006 (0.051)	0.032 (0.074)
Eosinophils; Day 14, 24 h post dose	0.001 (0.085)	0.010 (0.075)
Basophils; Day 7/Day 8, pre-dose	-0.001 (0.006)	0.006 (0.015)
Basophils; Day 14, 24 h post dose	-0.003 (0.013)	0.002 (0.018)
Platelets; Day 7/Day 8, pre-dose	1.6 (20.58)	17.9 (36.44)
Platelets; Day 14, 24 h post dose	14.7 (21.80)	23.5 (37.43)

3. Primary Outcome

Title	Part A: Change From Baseline in Hemoglobin and Mean Corpuscle Hemoglobin Concentration (MCHC) at the Indicated Time Points
Description	Blood samples were collected for measurement for the indicated tests. Baseline is Day 1 pre-dose. MCHC is one of the red blood cell (RBC) indices. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.
Time Frame	Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 h post-dose)

Outcome Measure Data

Analysis Population Description
Safety Population

Arm/Group Title	Part A: Placebo	Part A: GSK2269577 1000 µg
Arm/Group Description	Participants received 2 inhalations of matching placebo once daily for 14 consecutive days.	Participants received repeat doses of GSK2269557 1000 micrograms (µg) (2 inhalations of 500 µg each from a single device) administered as a dry powder inhalation, once daily for 14 consecutive days.
Measure Participants	7	21
Hemoglobin; Day 7/Day 8, pre-dose	-1.3 (6.63)	1.6 (4.17)
Hemoglobin; Day 14, 24 h post dose	0.3 (6.97)	1.0 (4.12)
MCHC; Day 7/Day 8, pre-dose	-5.3 (7.32)	-2.2 (4.54)
MCHC; Day 14, 24 h post dose	-8.4 (4.39)	-2.4 (6.45)

4. Primary Outcome

Title	Part A: Change From Baseline in Hematocrit at the Indicated Time Points
Description	Blood samples were collected for measurement for the indicated tests. Baseline is Day 1 pre-dose. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.
Time Frame	Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 hours [h] post-dose)

Outcome Measure Data

Analysis Population Description
Safety Population

Arm/Group Title	Part A: Placebo	Part A: GSK2269577 1000 µg
Arm/Group Description	Participants received 2 inhalations of matching placebo once daily for 14 consecutive days.	Participants received repeat doses of GSK2269557 1000 micrograms (µg) (2 inhalations of 500 µg each from a single device) administered as a dry powder inhalation, once daily for 14 consecutive days.
Measure Participants	7	21
Hematocrit; Day 7/Day 8, pre-dose	0.003 (0.023)	0.007 (0.013)
Hematocrit; Day 14, 24 h post dose	0.011 (0.019)	0.006 (0.016)

5. Primary Outcome

Title	Part A: Change From Baseline in Counts of RBCs and Reticulocytes at the Indicated Time Points
Description	Blood samples were collected for measurement for the indicated tests. Baseline is Day 1 pre-dose. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.
Time Frame	Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 hours [h] post-dose)

Outcome Measure Data

Analysis Population Description
Safety Population

Arm/Group Title	Part A: Placebo	Part A: GSK2269577 1000 µg
Arm/Group Description	Participants received 2 inhalations of matching placebo once daily for 14 consecutive days.	Participants received repeat doses of GSK2269557 1000 micrograms (µg) (2 inhalations of 500 µg each from a single device) administered as a dry powder inhalation, once daily for 14 consecutive days.
Measure Participants	7	21
RBCs; Day 7/Day 8, pre-dose	0.023 (0.230)	0.060 (0.141)
RBCs; Day 14, 24 h post dose	0.119 (0.201)	0.063 (0.160)
Reticulocytes; Day 7/Day 8, pre-dose	0.005 (0.014)	0.003 (0.009)
Reticulocytes; Day 14, 24 h post dose	0.009 (0.014)	0.003 (0.010)

6. Primary Outcome

Title	Part A: Change From Baseline in Mean Corpuscle Hemoglobin (MCH) at the Indicated Time Points
Description	Blood samples were collected for measurement for the indicated tests. Baseline is Day 1 pre-dose. MCH is one of the red blood cell indices. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.
Time Frame	Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 hours [h] post-dose)

Outcome Measure Data

Analysis Population Description
Safety Population

Arm/Group Title	Part A: Placebo	Part A: GSK2269577 1000 µg
Arm/Group Description	Participants received 2 inhalations of matching placebo once daily for 14 consecutive days.	Participants received repeat doses of GSK2269557 1000 micrograms (µg) (2 inhalations of 500 µg each from a single device) administered as a dry powder inhalation, once daily for 14 consecutive days.
Measure Participants	7	21
MCH; Day 7/Day 8, pre-dose	-0.46 (0.602)	-0.06 (0.440)
MCH; Day 14, 24 h post dose	-0.76 (0.586)	-0.23 (0.593)

7. Primary Outcome

Title	Part A: Change From Baseline in Mean Corpuscle Volume (MCV) at the Indicated Time Points
Description	Blood samples were collected for measurement for the indicated tests. Baseline is Day 1 pre-dose. MCV is one of the RBC indices. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.
Time Frame	Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 hours [h] post-dose)

Outcome Measure Data

Analysis Population Description
Safety Population

Arm/Group Title	Part A: Placebo	Part A: GSK2269577 1000 µg
Arm/Group Description	Participants received 2 inhalations of matching placebo once daily for 14 consecutive days.	Participants received repeat doses of GSK2269557 1000 micrograms (µg) (2 inhalations of 500 µg each from a single device) administered as a dry powder inhalation, once daily for 14 consecutive days.
Measure Participants	7	21
MCV; Day 7/Day 8, pre-dose	0.11 (0.687)	0.43 (0.697)
MCV; Day 14, 24 h post dose	0.07 (0.848)	-0.03 (1.193)

8. Primary Outcome

Title	Part A: Change From Baseline in Albumin and Total Protein at the Indicated Time Points
Description	Blood samples were collected for measurement for the indicated tests. Baseline is Day 1 pre-dose. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.
Time Frame	Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 hours [h] post-dose)

Outcome Measure Data

Analysis Population Description
Safety Population

Arm/Group Title	Part A: Placebo	Part A: GSK2269577 1000 µg
Arm/Group Description	Participants received 2 inhalations of matching placebo once daily for 14 consecutive days.	Participants received repeat doses of GSK2269557 1000 micrograms (µg) (2 inhalations of 500 µg each from a single device) administered as a dry powder inhalation, once daily for 14 consecutive days.
Measure Participants	7	21
Albumin; Day 7/Day 8, pre-dose	0.56 (2.230)	0.80 (1.576)
Albumin; Day 14, 24 h post doseTotal protein; Day	0.53 (2.379)	0.52 (2.004)
Total protein; Day 7/Day 8, pre-dose	0.56 (3.619)	1.28 (2.599)
Total protein; Day 14, 24 h post dose	0.84 (3.887)	1.15 (2.606)

9. Primary Outcome

Title	Part A: Change From Baseline in Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP), Aspartate Aminotransferase (AST), and Gamma Glutamyl Transferase (GGT) at the Indicated Time Points
Description	Blood samples were collected for measurement for the indicated tests. Baseline is Day 1 pre-dose. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.
Time Frame	Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 hours [h] post-dose)

Outcome Measure Data

Analysis Population Description
Safety Population

Arm/Group Title	Part A: Placebo	Part A: GSK2269577 1000 µg
Arm/Group Description	Participants received 2 inhalations of matching placebo once daily for 14 consecutive days.	Participants received repeat doses of GSK2269557 1000 micrograms (µg) (2 inhalations of 500 µg each from a single device) administered as a dry powder inhalation, once daily for 14 consecutive days.
Measure Participants	7	21
ALT; Day 7/Day 8, pre-dose	2.46 (2.585)	-0.61 (2.208)
ALT; Day 14, 24 h post dose	1.51 (2.667)	-0.40 (4.117)
ALP; Day 7/Day 8, pre-dose	-0.64 (6.937)	1.14 (8.586)
ALP; Day 14, 24 h post dose	-2.23 (6.522)	-0.21 (9.785)
AST; Day 7/Day 8, pre-dose	3.14 (7.674)	-1.03 (3.081)
AST; Day 14, 24 h post dose	1.83 (4.750)	-0.71 (2.592)
GGT; Day 7/Day 8, pre-dose	-0.91 (2.203)	0.11 (2.550)
GGT; Day 14, 24 h post dose	-1.96 (2.873)	-0.46 (4.187)

10. Primary Outcome

Title	Part A: Change From Baseline in Creatinine, Bilirubin, and Total Bilirubin at the Indicated Time Points
Description	Blood samples were collected for measurement for the indicated tests. Baseline is Day 1 pre-dose. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.
Time Frame	Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 hours [h] post-dose)

Outcome Measure Data

Analysis Population Description
Safety Population

Arm/Group Title	Part A: Placebo	Part A: GSK2269577 1000 µg
Arm/Group Description	Participants received 2 inhalations of matching placebo once daily for 14 consecutive days.	Participants received repeat doses of GSK2269557 1000 micrograms (µg) (2 inhalations of 500 µg each from a single device) administered as a dry powder inhalation, once daily for 14 consecutive days.
Measure Participants	7	21
Creatinine; Day 7/Day 8, pre-dose	2.31 (4.385)	-0.62 (5.104)
Creatinine; Day 14, 24 h post dose	3.64 (6.035)	0.07 (3.259)
Direct bilirubin; Day 7/Day 8, pre-dose	0.33 (0.419)	0.04 (0.398)
Direct bilirubin; Day 14, 24 h post dose	0.27 (0.496)	0.10 (0.329)
Total bilirubin; Day 7/Day 8, pre-dose	1.23 (2.447)	0.02 (2.590)
Total bilirubin; Day 14, 24 h post dose	0.90 (2.805)	0.78 (1.720)

11. Primary Outcome

Title	Part A: Change From Baseline in Calcium, Potassium, Sodium, Glucose, and Blood Urea Nitrogen (BUN) at the Indicated Time Points
Description	Blood samples were collected for measurement for the indicated tests. Baseline is Day 1 pre-dose. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.
Time Frame	Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 hours [h] post-dose)

Outcome Measure Data

Analysis Population Description
Safety Population

Arm/Group Title	Part A: Placebo	Part A: GSK2269577 1000 µg
Arm/Group Description	Participants received 2 inhalations of matching placebo once daily for 14 consecutive days.	Participants received repeat doses of GSK2269557 1000 micrograms (µg) (2 inhalations of 500 µg each from a single device) administered as a dry powder inhalation, once daily for 14 consecutive days.
Measure Participants	7	21
Calcium; Day 7/Day 8, pre-dose	0.033 (0.0535)	0.033 (0.0617)
Calcium; Day 14, 24 h post dose	0.033 (0.0850)	0.029 (0.0588)
Glucose; Day 7/Day 8, pre-dose	-0.053 (0.3333)	0.012 (0.2888)
Glucose; Day 14, 24 h post dose	0.161 (0.2659)	0.024 (0.4914)
Potassium; Day 7/Day 8, pre-dose	0.103 (0.2279)	0.011 (0.3539)
Potassium; Day 14, 24 h post dose	0.161 (0.2562)	0.065 (0.3347)
Sodium; Day 7/Day 8, pre-dose	1.21 (2.800)	0.88 (1.560)
Sodium; Day 14, 24 h post dose	0.81 (1.297)	0.83 (1.390)
BUN; Day 7/Day 8, pre-dose	-0.530 (1.0830)	-0.192 (0.8124)
BUN; Day 14, 24 h post dose	-0.464 (1.1979)	0.111 (1.2147)

12. Primary Outcome

Title	Part A: Number of Participants Meeting Criteria of Potential Clinical Importance for Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP), and Heart Rate (HR) at Any Visit Post-Baseline
Description	Baseline was the Day 1 pre-dose measurement. Vital signs (SBP, DBP, and HR) were measured at Day 1 (30 minutes [min] and 6 h post-dose), Day 7 (pre-dose), and Day 14 (24 h post-dose). Potential clinical concern range for SBP was <85 millimeters of mercury (mmHg) (low) and >160 mmHg (high), for DBP <45 mmHg (low) and >100 mmHg (high) and for HR <40 bpm and >110 bpm. All measurements were obtained in supine position, after a 5-minute rest. Day 7 assessments could be conducted on Day 7 or Day 8.
Time Frame	Day 1, Day 7, and Day 14

Outcome Measure Data

Analysis Population Description
Safety Population

Arm/Group Title	Part A: Placebo	Part A: GSK2269577 1000 µg
Arm/Group Description	Participants received 2 inhalations of matching placebo once daily for 14 consecutive days.	Participants received repeat doses of GSK2269557 1000 micrograms (µg) (2 inhalations of 500 µg each from a single device) administered as a dry powder inhalation, once daily for 14 consecutive days.
Measure Participants	7	21
SBP high	1 14.3%	1 4.8%
SBP low	0 0%	0 0%
DBP high	0 0%	0 0%
DBP low	1 14.3%	0 0%
HR high	0 0%	1 4.8%
HR low	0 0%	0 0%

13. Primary Outcome

Title	Part A: Number of Participants With Normal and Abnormal (Clinically Significant or Not Clinically Significant) Findings in 12-lead Electrocardiogram (ECG) at Any Visit Post-Baseline
Description	Baseline was the Day 1 (pre-dose) measurement. Single 12-lead ECGs were obtained using an ECG machine that automatically calculates the HR and measures PR, QRS, QT, and corrected QT intervals. Clinical significance was judged by the investigator. Day 7 assessments could be conducted on Day 7 or Day 8.
Time Frame	Day 1, Day 7, and Day 14

Outcome Measure Data

Analysis Population Description
Safety Population

Arm/Group Title	Part A: Placebo	Part A: GSK2269577 1000 µg
Arm/Group Description	Participants received 2 inhalations of matching placebo once daily for 14 consecutive days.	Participants received repeat doses of GSK2269557 1000 micrograms (µg) (2 inhalations of 500 µg each from a single device) administered as a dry powder inhalation, once daily for 14 consecutive days.
Measure Participants	7	21
Normal	2 28.6%	13 61.9%
Abnormal - not clinically significant	5 71.4%	8 38.1%
Abnormal - clinically significant	0 0%	0 0%

14. Primary Outcome

Title	Part A: Change From Baseline in Forced Expiratory Volume in One Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points
Description	Baseline is Day 1 pre-dose. FEV1 and FVC are measures of lung function. FEV1 is defined as the maximal amount of air that can be forcefully exhaled in one second. FVC is defined as the maximum amount of air that can be forcibly blown out after a maximum inspiration. FEV1 and FVC measurements were repeated until three technically acceptable measurements (within 150 milliliters of each other) had been made. Only the best of three measurements were recorded. Baseline was the maximum of the planned pre-dose measurements on Day 1. Change from Baseline at any post-dose time point was calculated as the post-dose value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.
Time Frame	Baseline (Day 1 [pre-dose]), Day 1 (1 h post-dose), Day 7 (pre-dose and 1 h post-dose), and Day 14 (24 h post-dose)

Outcome Measure Data

Analysis Population Description
Safety Population

Arm/Group Title	Part A: Placebo	Part A: GSK2269577 1000 µg
Arm/Group Description	Participants received 2 inhalations of matching placebo once daily for 14 consecutive days.	Participants received repeat doses of GSK2269557 1000 micrograms (µg) (2 inhalations of 500 µg each from a single device) administered as a dry powder inhalation, once daily for 14 consecutive days.
Measure Participants	7	21
FEV1, Day 1, 1 h post dose	0.15	0.10
FEV1, Day 7/8, Pre-dose	0.03	-0.04
FEV1, Day 7/8, 1 h post dose	0.27	0.18
FEV1, Day 14, 24 h post dose	-0.01	0.01
FVC, Day 1, 1 h post dose	0.17	0.16
FVC, Day 7/8, Predose	0.02	0.00
FVC, Day 7/8, 1 h post dose	0.33	0.22
FVC, Day 14, 24 h post dose	-0.04	0.10

15. Primary Outcome

Title	Part B: Adjusted Median Response of Cytokine (Interleukin 6 [IL6], Interleukin 8 [IL8], Tumor Necrosis Factor Alpha [TNFalpha]) Concentrations in Induced Sputum, on Day 7 and Day 14
Description	This outcome measure was used to estimate the inhibition levels of various doses of GSK2269557 by analyzing inflammatory cytokines IL6, IL8, and TNF alpha using Bayesian methods of statistical analysis, using non-informative prior distributions for all modeling parameters. Posterior medians (adjusted median response) and 95% credible intervals are reported here as medians and 95% confidence intervals respectively. 95% credible interval is reported as 2-sided 95% confidence in the statistical analyses. Day 7 assessments could be conducted on Day 7 or Day 8.
Time Frame	Day 7 (pre-dose) and Day 14 (24 h post-dose)

Outcome Measure Data

Analysis Population Description
Safety Population

Arm/Group Title	Part B: Placebo	Part B: GSK2269577 100 µg	Part B: GSK2269577 200 µg	Part B: GSK2269577 500 µg	Part B: GSK2269577 700 µg	Part B: GSK2269577 1000 µg	Part B: GSK2269577 2000 µg
Arm/Group Description	Participants received four inhalations of matching placebo (from four inhalation devices) once daily for 14 consecutive days.	Participants received repeat doses of GSK2269557 100 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 100 µg or placebo.	Participants received repeat doses of GSK2269557 200 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 100 µg or placebo.	Participants received repeat doses of GSK2269557 500 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 500 µg or placebo.	Participants received repeat doses of GSK2269557 700 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing GSK2269557 100 µg, 500 µg, or placebo.	Participants received repeat doses of GSK2269557 1000 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 500 µg or placebo.	Participants received repeat doses of GSK2269557 2000 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing GSK2269557 500 µg.
Measure Participants	5	5	5	5	6	5	5
IL6, Day 7/Day 8	41.30	37.40	28.23	30.82	52.23	31.25	33.40
IL6, Day 14	35.15	37.60	28.27	22.68	35.19	42.56	41.52
IL8, Day 7/Day 8	2633.21	2118.15	1860.78	1523.63	2650.13	2636.08	2279.48
IL8, Day 14	2942.28	2664.75	1879.92	1619.12	1356.35	2394.65	2170.41
TNFalpha, Day 7/Day 8	3.35	1.55	1.16	1.54	7.32	3.68	2.62
TNFalpha, Day 14	2.91	3.02	1.25	1.26	3.99	3.00	1.53

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part A: Placebo, Part A: GSK2269577 1000 µg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.599
	Comments	Posterior Probability the True Treatment Ratio <1 for Day 7
	Method	Bayesian repeated measures
	Comments

Method of Estimation	Estimation Parameter	Adjusted Median Ratio
	Estimated Value	0.90
	Confidence Interval	(2-Sided) 95% 0.39 to 2.07
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison of IL6 concentrations at Day 7. This is the baseline corrected ratio of 100ug/placebo for day 7.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Part A: Placebo, Part A: GSK2269577 1000 µg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.442
	Comments	Posterior Probability the True Treatment Ratio <1 for Day 14
	Method	Bayesian repeated measures
	Comments

Method of Estimation	Estimation Parameter	Adjusted Median Ratio
	Estimated Value	1.07
	Confidence Interval	(2-Sided) 95% 0.43 to 2.59
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison of IL6 concentrations at Day 14. This is the baseline corrected ratio of 100ug/placebo for day 14.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Part A: Placebo, Part B: GSK2269577 200 µg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.823
	Comments	Posterior Probability the True Treatment Ratio <1 for Day 7
	Method	Bayesian repeated measures
	Comments

Method of Estimation	Estimation Parameter	Adjusted Median Ratio
	Estimated Value	0.68
	Confidence Interval	(2-Sided) 95% 0.30 to 1.57
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison of IL6 concentrations at Day 7. This is the baseline corrected ratio of 200ug/placebo for day 7.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Part A: Placebo, Part B: GSK2269577 200 µg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.690
	Comments	Posterior Probability the True Treatment Ratio <1 for Day 14
	Method	Bayesian repeated measures
	Comments

Method of Estimation	Estimation Parameter	Adjusted Median Ratio
	Estimated Value	0.81
	Confidence Interval	(2-Sided) 95% 0.33 to 1.97
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison of IL6 concentrations at Day 14. This is the baseline corrected ratio of 200ug/placebo for day 14.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Part A: Placebo, Part B: GSK2269577 500 µg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.764
	Comments	Posterior Probability the True Treatment Ratio <1 for Day 7
	Method	Bayesian repeated measures
	Comments

Method of Estimation	Estimation Parameter	Adjusted Median Ratio
	Estimated Value	0.75
	Confidence Interval	(2-Sided) 95% 0.33 to 1.71
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison of IL6 concentrations at Day 7. This is the baseline corrected ratio of 500ug/placebo for day 7.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Part A: Placebo, Part B: GSK2269577 500 µg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.841
	Comments	Posterior Probability the True Treatment Ratio <1 for Day 14
	Method	Bayesian repeated measures
	Comments

Method of Estimation	Estimation Parameter	Adjusted Median Ratio
	Estimated Value	0.64
	Confidence Interval	(2-Sided) 95% 0.27 to 1.56
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison of IL6 concentrations at Day 14. This is the baseline corrected ratio of 500ug/placebo for day 14.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Part A: Placebo, Part A: GSK2269577 1000 µg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.702
	Comments	Posterior Probability the True Treatment Ratio <1 for Day 7
	Method	Bayesian repeated measures
	Comments

Method of Estimation	Estimation Parameter	Adjusted Median Ratio
	Estimated Value	0.81
	Confidence Interval	(2-Sided) 95% 0.35 to 1.81
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison of IL8 concentrations at Day 7.This is the baseline corrected ratio of 100ug/placebo for day 7.

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Part A: Placebo, Part A: GSK2269577 1000 µg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.578
	Comments	Posterior Probability the True Treatment Ratio <1 for Day 14
	Method	Bayesian repeated measures
	Comments

Method of Estimation	Estimation Parameter	Adjusted Median Ratio
	Estimated Value	0.91
	Confidence Interval	(2-Sided) 95% 0.33 to 2.47
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison of IL8 concentrations at Day 14. This is the baseline corrected ratio of 100ug/placebo for day 14.

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Part A: Placebo, Part B: GSK2269577 200 µg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.783
	Comments	Posterior Probability the True Treatment Ratio <1 for Day 7
	Method	Bayesian repeated measures
	Comments

Method of Estimation	Estimation Parameter	Adjusted Median Ratio
	Estimated Value	0.71
	Confidence Interval	(2-Sided) 95% 0.29 to 1.70
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison of IL8 concentrations at Day 7. This is the baseline corrected ratio of 200ug/placebo for day 7.

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Part A: Placebo, Part B: GSK2269577 200 µg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.797
	Comments	Posterior Probability the True Treatment Ratio <1 for Day 14
	Method	Bayesian repeated measures
	Comments

Method of Estimation	Estimation Parameter	Adjusted Median Ratio
	Estimated Value	0.64
	Confidence Interval	(2-Sided) 95% 0.22 to 1.87
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison of IL8 concentrations at Day 14. This is the baseline corrected ratio of 200ug/placebo for day 14.

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Part A: Placebo, Part B: GSK2269577 500 µg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.919
	Comments	Posterior Probability the True Treatment Ratio <1 for Day 7
	Method	Bayesian repeated measures
	Comments

Method of Estimation	Estimation Parameter	Adjusted Median Ratio
	Estimated Value	0.58
	Confidence Interval	(2-Sided) 95% 0.27 to 1.26
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison of IL8 concentrations at Day 7. This is the baseline corrected ratio of 500ug/placebo for day 7.

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Part A: Placebo, Part B: GSK2269577 500 µg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.892
	Comments	Posterior Probability the True Treatment Ratio <1 for Day 14
	Method	Bayesian repeated measures
	Comments

Method of Estimation	Estimation Parameter	Adjusted Median Ratio
	Estimated Value	0.55
	Confidence Interval	(2-Sided) 95% 0.21 to 1.43
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison of IL8 concentrations at Day 14. This is the baseline corrected ratio of 500ug/placebo for day 14.

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Part A: Placebo, Part A: GSK2269577 1000 µg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.860
	Comments	Posterior Probability the True Treatment Ratio <1 for Day 7
	Method	Bayesian repeated measures
	Comments

Method of Estimation	Estimation Parameter	Adjusted Median Ratio
	Estimated Value	0.47
	Confidence Interval	(2-Sided) 95% 0.11 to 1.93
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison of TNFalpha concentrations at Day 7. This is the baseline corrected ratio of 100ug/placebo for day 7.

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Part A: Placebo, Part A: GSK2269577 1000 µg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.463
	Comments	Posterior Probability the True Treatment Ratio <1 for Day 14
	Method	Bayesian repeated measures
	Comments

Method of Estimation	Estimation Parameter	Adjusted Median Ratio
	Estimated Value	1.05
	Confidence Interval	(2-Sided) 95% 0.38 to 2.86
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison of TNFalpha concentrations at Day 14. This is the baseline corrected ratio of 100ug/placebo for day 14.

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Part A: Placebo, Part B: GSK2269577 200 µg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.932
	Comments	Posterior Probability the True Treatment Ratio <1 for Day 7
	Method	Bayesian repeated measures
	Comments

Method of Estimation	Estimation Parameter	Adjusted Median Ratio
	Estimated Value	0.35
	Confidence Interval	(2-Sided) 95% 0.09 to 1.42
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison of TNFalpha concentrations at Day 7. This is the baseline corrected ratio of 200ug/placebo for day 7.

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Part A: Placebo, Part B: GSK2269577 200 µg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.952
	Comments	Posterior Probability the True Treatment Ratio <1 for Day 14
	Method	Bayesian repeated measures
	Comments

Method of Estimation	Estimation Parameter	Adjusted Median Ratio
	Estimated Value	0.43
	Confidence Interval	(2-Sided) 95% 0.16 to 1.17
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison of TNFalpha concentrations at Day 14. This is the baseline corrected ratio of 200ug/placebo for day 14.

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Part A: Placebo, Part B: GSK2269577 500 µg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.873
	Comments	Posterior Probability the True Treatment Ratio <1 for Day 7
	Method	Bayesian repeated measures
	Comments

Method of Estimation	Estimation Parameter	Adjusted Median Ratio
	Estimated Value	0.46
	Confidence Interval	(2-Sided) 95% 0.12 to 1.81
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison of TNFalpha concentrations at Day 7. This is the baseline corrected ratio of 500ug/placebo for day 7.

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Part A: Placebo, Part B: GSK2269577 500 µg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.953
	Comments	Posterior Probability the True Treatment Ratio <1 for Day 14
	Method	Bayesian repeated measures
	Comments

Method of Estimation	Estimation Parameter	Adjusted Median Ratio
	Estimated Value	0.43
	Confidence Interval	(2-Sided) 95% 0.16 to 1.16
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison of TNFalpha concentrations at Day 14. This is the baseline corrected ratio of 500ug/placebo for day 14.

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	Part A: Placebo, Part B: GSK2269577 700 µg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.281
	Comments	Posterior Probability the True Treatment Ratio <1 for Day 7
	Method	Bayesian repeated measures
	Comments

Method of Estimation	Estimation Parameter	Adjusted Median Ratio9
	Estimated Value	1.26
	Confidence Interval	(2-Sided) 95% 0.56 to 2.82
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison of IL6 concentrations at Day 7. This is the baseline corrected ratio of 700ug/placebo for day 7.

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	Part A: Placebo, Part B: GSK2269577 700 µg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.500
	Comments	Posterior Probability the True Treatment Ratio <1 for Day 14
	Method	Bayesian repeated measures
	Comments

Method of Estimation	Estimation Parameter	Adjusted Median Ratio
	Estimated Value	1.00
	Confidence Interval	(2-Sided) 95% 0.42 to 2.35
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison of IL6 concentrations at Day 14. This is the baseline corrected ratio of 700ug/placebo for day 14.

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	Part A: Placebo, Part B: GSK2269577 1000 µg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.744
	Comments	Posterior Probability the True Treatment Ratio <1 for Day 7
	Method	Bayesian repeated measures
	Comments

Method of Estimation	Estimation Parameter	Adjusted Median Ratio
	Estimated Value	0.76
	Confidence Interval	(2-Sided) 95% 0.32 to 1.77
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison of IL6 concentrations at Day 7. This is the baseline corrected ratio of 1000ug/placebo for day 7.

Statistical Analysis 22

Statistical Analysis Overview	Comparison Group Selection	Part A: Placebo, Part B: GSK2269577 1000 µg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.334
	Comments	Posterior Probability the True Treatment Ratio <1 for Day 14
	Method	Bayesian repeated measures
	Comments

Method of Estimation	Estimation Parameter	Adjusted Median Ratio
	Estimated Value	1.21
	Confidence Interval	(2-Sided) 95% 0.49 to 3.04
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison of IL6 concentrations at Day 14. This is the baseline corrected ratio of 1000ug/placebo for day 14.

Statistical Analysis 23

Statistical Analysis Overview	Comparison Group Selection	Part A: Placebo, Part B: GSK2269577 2000 µg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.698
	Comments	Posterior Probability the True Treatment Ratio <1 for Day 7
	Method	Bayesian repeated measures
	Comments

Method of Estimation	Estimation Parameter	Adjusted Median Ratio
	Estimated Value	0.81
	Confidence Interval	(2-Sided) 95% 0.35 to 1.85
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison of IL6 concentrations at Day 7. This is the baseline corrected ratio of 2000ug/placebo for day 7.

Statistical Analysis 24

Statistical Analysis Overview	Comparison Group Selection	Part A: Placebo, Part B: GSK2269577 2000 µg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.353
	Comments	Posterior Probability the True Treatment Ratio <1 for Day 14
	Method	Bayesian repeated measures
	Comments

Method of Estimation	Estimation Parameter	Adjusted Median Ratio
	Estimated Value	1.18
	Confidence Interval	(2-Sided) 95% 0.48 to 2.88
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison of IL6 concentrations at Day 14. This is the baseline corrected ratio of 2000ug/placebo for day 14.

Statistical Analysis 25

Statistical Analysis Overview	Comparison Group Selection	Part A: Placebo, Part B: GSK2269577 700 µg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.489
	Comments	Posterior Probability the True Treatment Ratio <1 for Day 7
	Method	Bayesian repeated measures
	Comments

Method of Estimation	Estimation Parameter	Adjusted Median Ratio9
	Estimated Value	1.01
	Confidence Interval	(2-Sided) 95% 0.45 to 2.26
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison of IL8 concentrations at Day 7. This is the baseline corrected ratio of 700ug/placebo for day 7.

Statistical Analysis 26

Statistical Analysis Overview	Comparison Group Selection	Part A: Placebo, Part B: GSK2269577 700 µg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.940
	Comments	Posterior Probability the True Treatment Ratio <1 for Day 14
	Method	Bayesian repeated measures
	Comments

Method of Estimation	Estimation Parameter	Adjusted Median Ratio
	Estimated Value	0.46
	Confidence Interval	(2-Sided) 95% 0.17 to 1.23
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison of IL8 concentrations at Day 14. This is the baseline corrected ratio of 700ug/placebo for day 14.

Statistical Analysis 27

Statistical Analysis Overview	Comparison Group Selection	Part A: Placebo, Part B: GSK2269577 1000 µg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.495
	Comments	Posterior Probability the True Treatment Ratio <1 for Day 7
	Method	Bayesian repeated measures
	Comments

Method of Estimation	Estimation Parameter	Adjusted Median Ratio
	Estimated Value	1.01
	Confidence Interval	(2-Sided) 95% 0.42 to 2.40
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison of IL8 concentrations at Day 7. This is the baseline corrected ratio of 1000ug/placebo for day 7.

Statistical Analysis 28

Statistical Analysis Overview	Comparison Group Selection	Part A: Placebo, Part B: GSK2269577 1000 µg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.647
	Comments	Posterior Probability the True Treatment Ratio <1 for Day 14
	Method	Bayesian repeated measures
	Comments

Method of Estimation	Estimation Parameter	Adjusted Median Ratio
	Estimated Value	0.82
	Confidence Interval	(2-Sided) 95% 0.28 to 2.37
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison of IL8 concentrations at Day 14. This is the baseline corrected ratio of 1000ug/placebo for day 14.

Statistical Analysis 29

Statistical Analysis Overview	Comparison Group Selection	Part A: Placebo, Part B: GSK2269577 2000 µg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.646
	Comments	Posterior Probability the True Treatment Ratio <1 for Day 7
	Method	Bayesian repeated measures
	Comments

Method of Estimation	Estimation Parameter	Adjusted Median Ratio
	Estimated Value	0.87
	Confidence Interval	(2-Sided) 95% 0.40 to 1.86
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison of IL8 concentrations at Day 7. This is the baseline corrected ratio of 2000ug/placebo for day 7.

Statistical Analysis 30

Statistical Analysis Overview	Comparison Group Selection	Part A: Placebo, Part B: GSK2269577 2000 µg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.741
	Comments	Posterior Probability the True Treatment Ratio <1 for Day 14
	Method	Bayesian repeated measures
	Comments

Method of Estimation	Estimation Parameter	Adjusted Median Ratio
	Estimated Value	0.74
	Confidence Interval	(2-Sided) 95% 0.29 to 1.90
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison of IL8 concentrations at Day 14. This is the baseline corrected ratio of 2000ug/placebo for day 14.

Statistical Analysis 31

Statistical Analysis Overview	Comparison Group Selection	Part A: Placebo, Part B: GSK2269577 700 µg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.109
	Comments	Posterior Probability the True Treatment Ratio <1 for Day 7
	Method	Bayesian repeated measures
	Comments

Method of Estimation	Estimation Parameter	Adjusted Median Ratio9
	Estimated Value	2.18
	Confidence Interval	(2-Sided) 95% 0.62 to 7.95
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison of TNFalpha concentrations at Day 7. This is the baseline corrected ratio of 700ug/placebo for day 7.

Statistical Analysis 32

Statistical Analysis Overview	Comparison Group Selection	Part A: Placebo, Part B: GSK2269577 700 µg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.240
	Comments	Posterior Probability the True Treatment Ratio <1 for Day 14
	Method	Bayesian repeated measures
	Comments

Method of Estimation	Estimation Parameter	Adjusted Median Ratio
	Estimated Value	1.37
	Confidence Interval	(2-Sided) 95% 0.55 to 3.45
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison of TNFalpha concentrations at Day 14. This is the baseline corrected ratio of 700ug/placebo for day 14.

Statistical Analysis 33

Statistical Analysis Overview	Comparison Group Selection	Part A: Placebo, Part B: GSK2269577 1000 µg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.447
	Comments	Posterior Probability the True Treatment Ratio <1 for Day 7
	Method	Bayesian repeated measures
	Comments

Method of Estimation	Estimation Parameter	Adjusted Median Ratio
	Estimated Value	1.10
	Confidence Interval	(2-Sided) 95% 0.27 to 4.44
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison of TNFalpha concentrations at Day 7. This is the baseline corrected ratio of 1000ug/placebo for day 7.

Statistical Analysis 34

Statistical Analysis Overview	Comparison Group Selection	Part A: Placebo, Part B: GSK2269577 1000 µg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.472
	Comments	Posterior Probability the True Treatment Ratio <1 for Day 14
	Method	Bayesian repeated measures
	Comments

Method of Estimation	Estimation Parameter	Adjusted Median Ratio
	Estimated Value	1.03
	Confidence Interval	(2-Sided) 95% 0.39 to 2.74
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison of TNFalpha concentrations at Day 14. This is the baseline corrected ratio of 1000ug/placebo for day 14.

Statistical Analysis 35

Statistical Analysis Overview	Comparison Group Selection	Part A: Placebo, Part B: GSK2269577 2000 µg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.698
	Comments	Posterior Probability the True Treatment Ratio <1 for Day 7
	Method	Bayesian repeated measures
	Comments

Method of Estimation	Estimation Parameter	Adjusted Median Ratio
	Estimated Value	0.78
	Confidence Interval	(2-Sided) 95% 0.21 to 2.90
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison of TNFalpha concentrations at Day 7. This is the baseline corrected ratio of 2000ug/placebo for day 7.

Statistical Analysis 36

Statistical Analysis Overview	Comparison Group Selection	Part A: Placebo, Part B: GSK2269577 2000 µg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.911
	Comments	Posterior Probability the True Treatment Ratio <1 for Day 14
	Method	Bayesian repeated measures
	Comments

Method of Estimation	Estimation Parameter	Adjusted Median Ratio
	Estimated Value	0.53
	Confidence Interval	(2-Sided) 95% 0.21 to 1.37
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison of TNFalpha concentrations at Day 14. This is the baseline corrected ratio of 2000ug/placebo for day 14.

16. Secondary Outcome

Title	Part A: Day 1 Plasma Concentration of GSK2269577 up to 6 Hours Post Dose
Description	A 2 mL blood sample for pharmacokinetic (PK) analysis was collected at each of the indicated time point. Only those participants who were available at the indicated time points were analyzed (represented by n=X in the category titles). A value of NA indicates that the geometric mean or 95% confidence interval is not available.
Time Frame	Day 1 (Pre-dose, 5 min, 30 min, 1, 2, 4 & 6 hours post-dose)

Outcome Measure Data

Analysis Population Description
PK Population: participants in the Safety Population for whom a PK sample was obtained and analyzed.

Arm/Group Title	Part A: GSK2269577 1000 µg
Arm/Group Description	Participants received repeat doses of GSK2269557 1000 micrograms (µg) (2 inhalations of 500 µg each from a single device) administered as a dry powder inhalation, once daily for 14 consecutive days.
Measure Participants	21
Pre-dose; n=0	NA
5 min; n=21	386.2
30 min; n=21	337.2
1 h; n=21	379.1
2 h; n=21	531.1
4 h; n=21	419.5
6 h; n=21	334.4

17. Secondary Outcome

Title	Part B: Day 1 Plasma Concentration of GSK2269577 up to 6 Hours Post Dose
Description	A 2 mL blood sample for pharmacokinetic (PK) analysis was collected at each of the indicated time point. Concentration measurements were log-transformed. Only those participants who were available at the indicated time points were analyzed (represented by n=X,X in the category titles). A value of NA indicates that the geometric mean or 95% confidence interval is not available.
Time Frame	Pre-dose, and 5 min, 30 min, 1 h, 2 h, 4 h, and 6 h post-dose on Day 1

Outcome Measure Data

Analysis Population Description
PK Population

Arm/Group Title	Part B: GSK2269577 100 µg	Part B: GSK2269577 200 µg	Part B: GSK2269577 500 µg	Part B: GSK2269577 700 µg	Part B: GSK2269577 1000 µg	Part B: GSK2269577 2000 µg
Arm/Group Description	Participants received repeat doses of GSK2269557 100 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 100 µg or placebo.	Participants received repeat doses of GSK2269557 200 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 100 µg or placebo.	Participants received repeat doses of GSK2269557 500 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 500 µg or placebo.	Participants received repeat doses of GSK2269557 700 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing GSK2269557 100 µg, 500 µg, or placebo.	Participants received repeat doses of GSK2269557 1000 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 500 µg or placebo.	Participants received repeat doses of GSK2269557 2000 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing GSK2269557 500 µg.
Measure Participants	5	5	5	6	5	5
Pre-dose; n=0,0,0,0,0,0	NA	NA	NA	NA	NA	NA
5 min; n=5,5,5,6,5,5	55.3	80.4	173.1	466.6	853.4	982.9
30 min; n=5,5,5,6,5,5	51.7	73.8	203	402.3	556.9	1011.6
1 h; n=5,5,5,6,5,5	61.3	77.2	253.2	429.1	599.7	1203.3
2 h; n=5,5,5,6,5,5	60.6	88.8	300.9	556.7	672.3	1402
4 h; n=5,5,5,6,5,5	45.0	73.4	251	391.6	468.7	1098.5
6 h; n=5,5,5,6,5,5	38.3	63.8	201.5	294.6	466.5	900.8

18. Secondary Outcome

Title	Part A: Maximum Observed Plasma Concentration (Cmax) of GSK2269577 on Day 7
Description	Blood samples were collected to determine the plasma concentrations of GSK2269577 immediately after dosing on Day 7. Day 7 sampling could be done on Day 7 or Day 8.
Time Frame	Day 7 immediately after dosing

Outcome Measure Data

Analysis Population Description
PK Population

Arm/Group Title	Part A: GSK2269577 1000 µg
Arm/Group Description	Participants received repeat doses of GSK2269557 1000 micrograms (µg) (2 inhalations of 500 µg each from a single device) administered as a dry powder inhalation, once daily for 14 consecutive days.
Measure Participants	21
Geometric Mean (95% Confidence Interval) [pg/mL]	1109.1

19. Secondary Outcome

Title	Part B: Maximum Observed Plasma Concentration (Cmax) of GSK2269577 on Day 7
Description	Blood samples were collected to determine the plasma concentrations of GSK2269577 immediately after dosing on Day 7. Concentration values were log-transformed. Day 7 sampling could be done on Day 7 or Day 8.
Time Frame	Day 7 immediately after dosing

Outcome Measure Data

Analysis Population Description
PK Population

Arm/Group Title	Part B: GSK2269577 100 µg	Part B: GSK2269577 200 µg	Part B: GSK2269577 500 µg	Part B: GSK2269577 700 µg	Part B: GSK2269577 1000 µg	Part B: GSK2269577 2000 µg
Arm/Group Description	Participants received repeat doses of GSK2269557 100 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 100 µg or placebo.	Participants received repeat doses of GSK2269557 200 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 100 µg or placebo.	Participants received repeat doses of GSK2269557 500 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 500 µg or placebo.	Participants received repeat doses of GSK2269557 700 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing GSK2269557 100 µg, 500 µg, or placebo.	Participants received repeat doses of GSK2269557 1000 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 500 µg or placebo.	Participants received repeat doses of GSK2269557 2000 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing GSK2269557 500 µg.
Measure Participants	5	5	5	6	5	5
Geometric Mean (95% Confidence Interval) [pg/mL]	109.6	203.4	511.8	1022.2	1655.1	2923.4

20. Secondary Outcome

Title	Part A: Trough Concentration (Ctau) of GSK2269577 on Day 7 and Day 15
Description	Blood samples were collected to determine the (trough) plasma concentration of GSK2269577 on Day 7 (pre-dose) and Day 15 (24 hours after dosing on Day 14). Day 7 assessments could be done either on Day 7 or on Day 8.
Time Frame	Day 7 and Day 15

Outcome Measure Data

Analysis Population Description
PK Population

Arm/Group Title	Part A: GSK2269577 1000 µg
Arm/Group Description	Participants received repeat doses of GSK2269557 1000 micrograms (µg) (2 inhalations of 500 µg each from a single device) administered as a dry powder inhalation, once daily for 14 consecutive days.
Measure Participants	21
Day 7/Day 8	604.1
Day 15	711.2

21. Secondary Outcome

Title	Part B: Trough Concentration (Ctau) of GSK2269577 on Day 7 and Day 15
Description	Blood samples were collected to determine the (trough) plasma concentration of GSK2269577 on Day 7 (pre-dose) and Day 15 (24 hours after dosing on Day 14). Day 7 assessments could be done either on Day 7 or on Day 8.
Time Frame	Day 7 and Day 15

Outcome Measure Data

Analysis Population Description
PK Population

Arm/Group Title	Part B: GSK2269577 100 µg	Part B: GSK2269577 200 µg	Part B: GSK2269577 500 µg	Part B: GSK2269577 700 µg	Part B: GSK2269577 1000 µg	Part B: GSK2269577 2000 µg
Arm/Group Description	Participants received repeat doses of GSK2269557 100 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 100 µg or placebo.	Participants received repeat doses of GSK2269557 200 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 100 µg or placebo.	Participants received repeat doses of GSK2269557 500 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 500 µg or placebo.	Participants received repeat doses of GSK2269557 700 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing GSK2269557 100 µg, 500 µg, or placebo.	Participants received repeat doses of GSK2269557 1000 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 500 µg or placebo.	Participants received repeat doses of GSK2269557 2000 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing GSK2269557 500 µg.
Measure Participants	5	5	5	6	5	5
Day 7/Day 8	55.3	119.17	314.38	588.09	724.33	1468.94
Day 15	74.93	128.71	237.36	665.9	1218.5	1767.34

22. Secondary Outcome

Title	Part B: Number of Times Rescue Medication Was Used by Participants Daily, During the Treatment Period
Description	Rescue medication was identified from concomitant medication records and the patient diaries which were provided to the participants to record data throughout the treatment period. Only participants who used rescue medication were analyzed. The value NA indicates that the standard deviation could not be calculated as only one participant was analyzed.
Time Frame	Day 1 to Day 15

Outcome Measure Data

Analysis Population Description
Safety Population

Arm/Group Title	Part B: Placebo	Part B: GSK2269577 100 µg	Part B: GSK2269577 200 µg	Part B: GSK2269577 500 µg	Part B: GSK2269577 700 µg	Part B: GSK2269577 1000 µg	Part B: GSK2269577 2000 µg
Arm/Group Description	Participants received four inhalations of matching placebo (from four inhalation devices) once daily for 14 consecutive days.	Participants received repeat doses of GSK2269557 100 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 100 µg or placebo.	Participants received repeat doses of GSK2269557 200 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 100 µg or placebo.	Participants received repeat doses of GSK2269557 500 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 500 µg or placebo.	Participants received repeat doses of GSK2269557 700 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing GSK2269557 100 µg, 500 µg, or placebo.	Participants received repeat doses of GSK2269557 1000 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 500 µg or placebo.	Participants received repeat doses of GSK2269557 2000 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing GSK2269557 500 µg.
Measure Participants	3	1	1	0	1	3	1
Mean (Standard Deviation) [Number of times]	2.00 (0.00)	2.3 (NA)	2.2 (NA)	1.0 (NA)	1.4 (0.63)	1.0 (NA)

23. Secondary Outcome

Title	Part B: Number of Participants With at Least One Non-serious Adverse Event (AE), Serious Adverse Event (SAE), or Drug-related Adverse Event
Description	An AE is defined as any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect, may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed in this definition, associated with liver injury and impaired liver function defined as alanine aminotransferase >=3 x upper limit of normal (ULN), and total bilirubin >=2 x ULN or international normalized ratio >1.5. AEs were classified as potentially drug-related, based on the investigator's judgment. Refer to the general AE/SAE module for a list of AEs and SAEs.
Time Frame	From the start of study treatment until follow-up (assessed for approximately 19 days)

Outcome Measure Data

Analysis Population Description
Safety Population

Arm/Group Title	Part B: Placebo	Part B: GSK2269577 100 µg	Part B: GSK2269577 200 µg	Part B: GSK2269577 500 µg	Part B: GSK2269577 700 µg	Part B: GSK2269577 1000 µg	Part B: GSK2269577 2000 µg
Arm/Group Description	Participants received four inhalations of matching placebo (from four inhalation devices) once daily for 14 consecutive days.	Participants received repeat doses of GSK2269557 100 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 100 µg or placebo.	Participants received repeat doses of GSK2269557 200 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 100 µg or placebo.	Participants received repeat doses of GSK2269557 500 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 500 µg or placebo.	Participants received repeat doses of GSK2269557 700 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing GSK2269557 100 µg, 500 µg, or placebo.	Participants received repeat doses of GSK2269557 1000 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 500 µg or placebo.	Participants received repeat doses of GSK2269557 2000 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing GSK2269557 500 µg.
Measure Participants	5	5	5	5	6	5	5
At least one AE	3 42.9%	3 14.3%	2 40%	1 20%	3 60%	4 80%	2 33.3%
At least one SAE	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
At least one drug-related AE	0 0%	0 0%	1 20%	0 0%	3 60%	4 80%	2 33.3%

24. Secondary Outcome

Title	Part B: Change From Baseline in Counts of Basophils, Eosinophils, Lymphocytes, Monocytes, Platelets, White Blood Cells (WBC), Total Neutrophils (Total ANC) at the Indicated Time Points
Description	Blood samples were collected for measurement for the indicated tests. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.
Time Frame	Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 hours [h] post-dose)

Outcome Measure Data

Analysis Population Description
Safety Population

Arm/Group Title	Part B: Placebo	Part B: GSK2269577 100 µg	Part B: GSK2269577 200 µg	Part B: GSK2269577 500 µg	Part B: GSK2269577 700 µg	Part B: GSK2269577 1000 µg	Part B: GSK2269577 2000 µg
Arm/Group Description	Participants received four inhalations of matching placebo (from four inhalation devices) once daily for 14 consecutive days.	Participants received repeat doses of GSK2269557 100 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 100 µg or placebo.	Participants received repeat doses of GSK2269557 200 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 100 µg or placebo.	Participants received repeat doses of GSK2269557 500 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 500 µg or placebo.	Participants received repeat doses of GSK2269557 700 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing GSK2269557 100 µg, 500 µg, or placebo.	Participants received repeat doses of GSK2269557 1000 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 500 µg or placebo.	Participants received repeat doses of GSK2269557 2000 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing GSK2269557 500 µg.
Measure Participants	5	5	5	5	6	5	5
Basophils; Day 7/Day 8, pre-dose	0.014 (0.0241)	-0.002 (0.0228)	0.01 (0.0187)	0.004 (0.0182)	0.007 (0.0052)	-0.005 (0.01)	0 (0.01)
Basophils; Day 14, 24 h post dose	0.004 (0.0167)	-0.006 (0.0261)	0.01 (0.0122)	-0.002 (0.0192)	0.007 (0.0175)	-0.008 (0.0189)	0.01 (0.0122)
Eosinophils; Day 7/Day 8, pre-dose	-0.002 (0.0576)	0.01 (0.0485)	-0.034 (0.0702)	-0.026 (0.0498)	0.022 (0.1289)	-0.002 (0.0287)	0.012 (0.0438)
Eosinophils; Day 14, 24 h post dose	0.046 (0.0472)	-0.01 (0.0292)	-0.046 (0.0378)	-0.054 (0.1498)	0.025 (0.1078)	0.023 (0.0222)	0.022 (0.0396)
Lymphocytes; Day 7/Day 8, pre-dose	0.242 (0.4797)	-0.178 (0.5657)	-0.022 (0.1326)	-0.094 (0.3092)	0.093 (0.2813)	-0.118 (0.3223)	-0.218 (0.6236)
Lymphocytes; Day 14, 24 h post dose	-0.09 (0.4499)	-0.264 (0.3134)	-0.216 (0.208)	0.092 (0.9722)	0.21 (0.3855)	-0.243 (0.3054)	-0.398 (0.736)
Monocytes; Day 7/Day 8, pre-dose	-0.062 (0.0867)	0.05 (0.0941)	-0.02 (0.0806)	0.05 (0.2108)	0.018 (0.1209)	0.165 (0.5166)	-0.08 (0.1398)
Monocytes; Day 14, 24 h post dose	-0.022 (0.0676)	-0.012 (0.0926)	-0.036 (0.0829)	-0.004 (0.1313)	0.03 (0.0699)	0.108 (0.3437)	-0.11 (0.0834)
Platelets; Day 7/Day 8, pre-dose	-13.8 (14.22)	-0.8 (18.07)	10 (24.52)	15.6 (17.78)	11.7 (15.41)	26.5 (32.77)	-0.6 (14.4)
Platelets; Day 14, 24 h post dose	-3.3 (22.25)	-13 (26.52)	-7.2 (20.41)	-1.4 (44.86)	7 (19.81)	-8.3 (51.57)	-11.4 (29.39)
WBC; Day 7/Day 8, pre-dose	0.372 (1.5852)	-0.024 (1.1519)	0.102 (1.1107)	0.926 (3.1314)	0.497 (0.8673)	0.5 (2.676)	-0.802 (0.7889)
WBC; Day 14, 24 h post dose	-0.49 (0.5204)	-0.864 (1.4151)	-0.164 (0.7907)	-0.178 (2.2899)	0.648 (1.143)	0.825 (1.6016)	-1.012 (1.3388)
Total ANC; Day 7/Day 8, pre-dose	0.164 (0.9782)	0.09 (0.6553)	0.17 (1.0481)	1.018 (2.6669)	0.335 (0.5921)	0.448 (2.153)	-0.51 (0.285)
Total ANC; Day 14, 24 h post dose	-0.44 (0.4288)	-0.538 (1.1027)	0.134 (0.801)	-0.18 (1.469)	0.385 (1.2151)	0.958 (1.8925)	-0.51 (0.7931)

25. Secondary Outcome

Title	Part B: Change From Baseline in Hemoglobin and Mean Corpuscle Hemoglobin Concentration (MCHC) at the Indicated Time Points
Description	Blood samples were collected for measurement for the indicated tests. MCHC is one of the red blood cell (RBC) indices. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.
Time Frame	Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 hours [h] post-dose)

Outcome Measure Data

Analysis Population Description
Safety Population

Arm/Group Title	Part B: Placebo	Part B: GSK2269577 100 µg	Part B: GSK2269577 200 µg	Part B: GSK2269577 500 µg	Part B: GSK2269577 700 µg	Part B: GSK2269577 1000 µg	Part B: GSK2269577 2000 µg
Arm/Group Description	Participants received four inhalations of matching placebo (from four inhalation devices) once daily for 14 consecutive days.	Participants received repeat doses of GSK2269557 100 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 100 µg or placebo.	Participants received repeat doses of GSK2269557 200 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 100 µg or placebo.	Participants received repeat doses of GSK2269557 500 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 500 µg or placebo.	Participants received repeat doses of GSK2269557 700 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing GSK2269557 100 µg, 500 µg, or placebo.	Participants received repeat doses of GSK2269557 1000 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 500 µg or placebo.	Participants received repeat doses of GSK2269557 2000 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing GSK2269557 500 µg.
Measure Participants	5	5	5	5	6	5	5
Hemoglobin; Day 7/Day 8, pre-dose	3 (2.55)	0.8 (5.76)	3.8 (6.76)	1 (4.74)	0.3 (5.65)	6 (5.89)	1 (3.39)
Hemoglobin; Day 14, 24 h post dose	4.2 (6.14)	-1.2 (6.14)	-0.6 (8.02)	-2 (6.86)	-2.2 (2.14)	-0.3 (4.65)	-0.2 (4.44)
MCHC; Day 7/Day 8, pre-dose	-2.4 (2.07)	-0.6 (8.17)	-4.0 (7.31)	-4.4 (9.61)	0.5 (5.17)	3.3 (8.18)	7.8 (10.85)
MCHC; Day 14, 24 h post dose	3.8 (5.07)	-2.6 (3.51)	-4.4 (8.73)	3.0 (4.00)	2.5 (3.83)	-8.5 (7.59)	1.6 (11.76)

26. Secondary Outcome

Title	Part B: Change From Baseline in Counts of RBCs and Reticulocytes at the Indicated Time Points
Description	Blood samples were collected for measurement for the indicated tests. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.
Time Frame	Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 hours [h] post-dose)

Outcome Measure Data

Analysis Population Description
Safety Population

Arm/Group Title	Part B: Placebo	Part B: GSK2269577 100 µg	Part B: GSK2269577 200 µg	Part B: GSK2269577 500 µg	Part B: GSK2269577 700 µg	Part B: GSK2269577 1000 µg	Part B: GSK2269577 2000 µg
Arm/Group Description	Participants received four inhalations of matching placebo (from four inhalation devices) once daily for 14 consecutive days.	Participants received repeat doses of GSK2269557 100 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 100 µg or placebo.	Participants received repeat doses of GSK2269557 200 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 100 µg or placebo.	Participants received repeat doses of GSK2269557 500 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 500 µg or placebo.	Participants received repeat doses of GSK2269557 700 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing GSK2269557 100 µg, 500 µg, or placebo.	Participants received repeat doses of GSK2269557 1000 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 500 µg or placebo.	Participants received repeat doses of GSK2269557 2000 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing GSK2269557 500 µg.
Measure Participants	5	5	5	5	6	4	5
RBC; Day 7/Day 8, pre-dose	0.076 (0.1148)	0.036 (0.1549)	0.18 (0.2703)	0.058 (0.1314)	-0.023 (0.1508)	0.14 (0.0879)	-0.058 (0.1252)
RBC; Day 14, 24 h post dose	0.11 (0.1891)	-0.038 (0.1663)	0.034 (0.1785)	-0.07 (0.1815)	-0.083 (0.0958)	0.042 (0.1031)	-0.084 (0.1496)
Reticulocytes; Day 7/Day 8, pre-dose	-0.00064 (0.01328)	0.00714 (0.020838)	0.01298 (0.011129)	0.01258 (0.014565)	0.00397 (0.008856)	0.00882 (0.018576)	0.01792 (0.012824)
Reticulocytes; Day 14, 24 h post dose	0.0034 (0.014934)	0.0006 (0.010183)	0.01032 (0.015404)	0.0156 (0.013092)	-0.00172 (0.005382)	-0.01063 (0.018329)	0.00884 (0.015546)

27. Secondary Outcome

Title	Part B: Change From Baseline in Hematocrit at the Indicated Time Points
Description	Blood samples were collected for measurement for the indicated tests. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.
Time Frame	Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 hours [h] post-dose)

Outcome Measure Data

Analysis Population Description
Safety Population

Arm/Group Title	Part B: Placebo	Part B: GSK2269577 100 µg	Part B: GSK2269577 200 µg	Part B: GSK2269577 500 µg	Part B: GSK2269577 700 µg	Part B: GSK2269577 1000 µg	Part B: GSK2269577 2000 µg
Arm/Group Description	Participants received four inhalations of matching placebo (from four inhalation devices) once daily for 14 consecutive days.	Participants received repeat doses of GSK2269557 100 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 100 µg or placebo.	Participants received repeat doses of GSK2269557 200 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 100 µg or placebo.	Participants received repeat doses of GSK2269557 500 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 500 µg or placebo.	Participants received repeat doses of GSK2269557 700 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing GSK2269557 100 µg, 500 µg, or placebo.	Participants received repeat doses of GSK2269557 1000 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 500 µg or placebo.	Participants received repeat doses of GSK2269557 2000 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing GSK2269557 500 µg.
Measure Participants	5	5	5	5	6	5	5
Day 7/Day 8, pre-dose	0.012 (0.0084)	0.004 (0.0182)	0.018 (0.0259)	0.01 (0.01)	0 (0.0141)	0.015 (0.0058)	-0.010 (0.0235)
Day 14, 24 h post dose	0.008 (0.0217)	0 (0.0212)	0.006 (0.0152)	-0.012 (0.0217)	-0.01 (0.0063)	0.01 (0.0082)	-0.004 (0.0207)

28. Secondary Outcome

Title	Part B: Change From Baseline in Mean Corpuscle Hemoglobin (MCH) at the Indicated Time Points
Description	Blood samples were collected for measurement for the indicated tests. MCH is one of the red blood cell indices. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.
Time Frame	Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 hours [h] post-dose)

Outcome Measure Data

Analysis Population Description
Safety Population

Arm/Group Title	Part B: Placebo	Part B: GSK2269577 100 µg	Part B: GSK2269577 200 µg	Part B: GSK2269577 500 µg	Part B: GSK2269577 700 µg	Part B: GSK2269577 1000 µg	Part B: GSK2269577 2000 µg
Arm/Group Description	Participants received four inhalations of matching placebo (from four inhalation devices) once daily for 14 consecutive days.	Participants received repeat doses of GSK2269557 100 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 100 µg or placebo.	Participants received repeat doses of GSK2269557 200 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 100 µg or placebo.	Participants received repeat doses of GSK2269557 500 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 500 µg or placebo.	Participants received repeat doses of GSK2269557 700 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing GSK2269557 100 µg, 500 µg, or placebo.	Participants received repeat doses of GSK2269557 1000 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 500 µg or placebo.	Participants received repeat doses of GSK2269557 2000 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing GSK2269557 500 µg.
Measure Participants	5	5	5	5	6	4	5
Day 7/Day 8, pre-dose	0.18 (0.415)	-0.06 (0.397)	-0.36 (0.351)	-0.08 (0.669)	0.2 (0.529)	0.35 (0.961)	0.58 (0.46)
Day 14, 24 h post dose	0.18 (0.626)	0.02 (0.259)	-0.34 (0.74)	0.12 (0.396)	0.1 (0.363)	-0.33 (0.754)	0.52 (0.268)

29. Secondary Outcome

Title	Part B: Change From Baseline in Mean Corpuscle Volume (MCV) at the Indicated Time Points
Description	Blood samples were collected for measurement for the indicated tests. MCV is one of the RBC indices. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.
Time Frame	Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 hours [h] post-dose)

Outcome Measure Data

Analysis Population Description
Safety Population

Arm/Group Title	Part B: Placebo	Part B: GSK2269577 100 µg	Part B: GSK2269577 200 µg	Part B: GSK2269577 500 µg	Part B: GSK2269577 700 µg	Part B: GSK2269577 1000 µg	Part B: GSK2269577 2000 µg
Arm/Group Description	Participants received four inhalations of matching placebo (from four inhalation devices) once daily for 14 consecutive days.	Participants received repeat doses of GSK2269557 100 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 100 µg or placebo.	Participants received repeat doses of GSK2269557 200 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 100 µg or placebo.	Participants received repeat doses of GSK2269557 500 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 500 µg or placebo.	Participants received repeat doses of GSK2269557 700 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing GSK2269557 100 µg, 500 µg, or placebo.	Participants received repeat doses of GSK2269557 1000 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 500 µg or placebo.	Participants received repeat doses of GSK2269557 2000 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing GSK2269557 500 µg.
Measure Participants	5	5	5	5	6	4	5
MCV; Day 7/Day 8, pre-dose	1.24 (0.706)	-0.14 (1.794)	-0.12 (1.708)	0.88 (1.085)	0.42 (2.302)	0.20 (0.583)	-0.70 (2.719)
MCV; Day 14, 24 h post dose	-0.66 (1.537)	0.80 (1.257)	0.26 (1.935)	-0.62 (1.281)	-0.53 (1.601)	1.53 (0.699)	0.98 (3.155)

30. Secondary Outcome

Title	Part B: Change From Baseline in Albumin and Total Protein at the Indicated Time Points
Description	Blood samples were collected for measurement for the indicated tests. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.
Time Frame	Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 hours [h] post-dose)

Outcome Measure Data

Analysis Population Description
Safety Population

Arm/Group Title	Part B: Placebo	Part B: GSK2269577 100 µg	Part B: GSK2269577 200 µg	Part B: GSK2269577 500 µg	Part B: GSK2269577 700 µg	Part B: GSK2269577 1000 µg	Part B: GSK2269577 2000 µg
Arm/Group Description	Participants received four inhalations of matching placebo (from four inhalation devices) once daily for 14 consecutive days.	Participants received repeat doses of GSK2269557 100 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 100 µg or placebo.	Participants received repeat doses of GSK2269557 200 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 100 µg or placebo.	Participants received repeat doses of GSK2269557 500 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 500 µg or placebo.	Participants received repeat doses of GSK2269557 700 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing GSK2269557 100 µg, 500 µg, or placebo.	Participants received repeat doses of GSK2269557 1000 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 500 µg or placebo.	Participants received repeat doses of GSK2269557 2000 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing GSK2269557 500 µg.
Measure Participants	5	5	5	5	6	5	5
Albumin; Day 7/Day 8, pre-dose	0.96 (1.773)	1.22 (1.571)	0.96 (3.012)	0.88 (0.887)	-0.6 (1.814)	1.18 (1.069)	0.3 (1.49)
Albumin; Day 14, 24 h post dose	0.9 (2.965)	0.7 (2.134)	-0.12 (2.538)	-1.16 (2.157)	-1.13 (1.365)	0.44 (1.001)	0.26 (1.187)
Total protein; Day 7/Day 8, pre-dose	1.34 (2.46)	0.72 (1.203)	2.22 (4.953)	0.98 (2.039)	-1.4 (2.662)	1.78 (2.338)	1.12 (1.571)
Total protein; Day 14, 24 h post dose	0.96 (3.392)	0.96 (2.393)	-0.16 (3.737)	-1.96 (3.635)	-2.13 (2.156)	0.72 (1.154)	0.7 (2.277)

31. Secondary Outcome

Title	Part B: Change From Baseline in Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP), Aspartate Aminotransferase (AST), and Gamma Glutamyl Transferase (GGT) at the Indicated Time Points
Description	Blood samples were collected for measurement for the indicated tests. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.
Time Frame	Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 hours [h] post-dose)

Outcome Measure Data

Analysis Population Description
Safety Population

Arm/Group Title	Part B: Placebo	Part B: GSK2269577 100 µg	Part B: GSK2269577 200 µg	Part B: GSK2269577 500 µg	Part B: GSK2269577 700 µg	Part B: GSK2269577 1000 µg	Part B: GSK2269577 2000 µg
Arm/Group Description	Participants received four inhalations of matching placebo (from four inhalation devices) once daily for 14 consecutive days.	Participants received repeat doses of GSK2269557 100 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 100 µg or placebo.	Participants received repeat doses of GSK2269557 200 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 100 µg or placebo.	Participants received repeat doses of GSK2269557 500 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 500 µg or placebo.	Participants received repeat doses of GSK2269557 700 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing GSK2269557 100 µg, 500 µg, or placebo.	Participants received repeat doses of GSK2269557 1000 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 500 µg or placebo.	Participants received repeat doses of GSK2269557 2000 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing GSK2269557 500 µg.
Measure Participants	5	5	5	5	6	5	5
ALP; Day 7/Day 8, pre-dose	1.88 (5.45)	1.62 (5.756)	1.64 (7.946)	5.7 (9.986)	-0.95 (7.807)	-0.92 (22.572)	1.66 (5.465)
ALP; Day 14, 24 h post dose	1.54 (4.503)	4.78 (7.294)	-0.2 (6.109)	0.26 (9.829)	-1.1 (8.535)	-5.34 (19.016)	5.2 (4.038)
ALT; Day 7/Day 8, pre-dose	1.58 (2.24)	3.66 (6.057)	-2.44 (7.23)	2.6 (4.994)	-0.1 (2.994)	-2.4 (5.036)	1.42 (2.791)
ALT; Day 14, 24 h post dose	0.36 (2.268)	2.18 (3.17)	-2.76 (6.176)	0.84 (5.223)	-0.72 (4.63)	-2.86 (5.478)	1.58 (3.754)
AST; Day 7/Day 8, pre-dose	1.38 (2.464)	3.76 (11.142)	-0.42 (3.13)	0.26 (5.185)	-0.22 (3.672)	-2.56 (5.607)	3.04 (2.048)
AST; Day 14, 24 h post dose	0.44 (1.691)	0.16 (1.673)	-2.44 (3.443)	-1.64 (6.027)	0.02 (3.129)	-1.66 (4.536)	2.66 (1.25)
GGT; Day 7/Day 8, pre-dose	-0.6 (2.119)	-0.3 (1.856)	-0.96 (4.556)	-0.3 (4.471)	1.88 (4.747)	-3.18 (9.7)	0.74 (1.141)
GGT; Day 14, 24 h post dose	-0.64 (0.934)	0.1 (2.625)	-2.64 (6.532)	-0.72 (5.485)	1.52 (5.783)	-6.16 (17.113)	0.54 (1.923)

32. Secondary Outcome

Title	Part B: Change From Baseline in Creatinine, Bilirubin, and Total Bilirubin at the Indicated Time Points
Description	Blood samples were collected for measurement for the indicated tests. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.
Time Frame	Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 hours [h] post-dose)

Outcome Measure Data

Analysis Population Description
Safety Population

Arm/Group Title	Part B: Placebo	Part B: GSK2269577 100 µg	Part B: GSK2269577 200 µg	Part B: GSK2269577 500 µg	Part B: GSK2269577 700 µg	Part B: GSK2269577 1000 µg	Part B: GSK2269577 2000 µg
Arm/Group Description	Participants received four inhalations of matching placebo (from four inhalation devices) once daily for 14 consecutive days.	Participants received repeat doses of GSK2269557 100 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 100 µg or placebo.	Participants received repeat doses of GSK2269557 200 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 100 µg or placebo.	Participants received repeat doses of GSK2269557 500 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 500 µg or placebo.	Participants received repeat doses of GSK2269557 700 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing GSK2269557 100 µg, 500 µg, or placebo.	Participants received repeat doses of GSK2269557 1000 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 500 µg or placebo.	Participants received repeat doses of GSK2269557 2000 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing GSK2269557 500 µg.
Measure Participants	5	5	5	5	6	5	5
Direct bilirubin; Day 7/Day 8, pre-dose	-0.02 (0.327)	0.24 (0.493)	-0.28 (0.881)	0.16 (0.261)	0.23 (0.65)	-0.18 (1.36)	-0.32 (0.37)
Direct bilirubin; Day 14, 24 h post dose	-0.1 (0.453)	-0.02 (0.192)	-0.58 (0.581)	0.22 (0.409)	0.2 (0.429)	0.02 (0.554)	-0.14 (0.456)
Total bilirubin; Day 7/Day 8, pre-dose	0.28 (2.255)	0.56 (2.151)	-0.7 (4.049)	0.72 (2.196)	1.08 (2.775)	-0.86 (1.75)	-1.5 (1.739)
Total bilirubin; Day 14, 24 h post dose	-0.5 (3.389)	0.08 (0.87)	-2.08 (2.387)	0.52 (2.7)	1.22 (3.008)	0.5 (2.804)	-1.06 (1.479)
Creatinine; Day 7/Day 8, pre-dose	4.52 (4.533)	1.6 (3.77)	4.38 (2.217)	-0.3 (4.567)	0.52 (4.397)	3.48 (3.084)	0.76 (5.421)
Creatinine; Day 14, 24 h post dose	1.58 (7.276)	0.76 (3.319)	4.84 (4.636)	-0.46 (6.98)	2.05 (3.17)	1.36 (2.545)	1.42 (5.058)

33. Secondary Outcome

Title	Part B: Change From Baseline in Calcium, Potassium, Sodium, Glucose, and Blood Urea Nitrogen (BUN) at the Indicated Time Points
Description	Blood samples were collected for measurement for the indicated tests. Change from Baseline at any post-dose visit was calculated as the post-dose visit value minus the Baseline value. Day 7 assessments could be conducted on Day 7 or Day 8.
Time Frame	Baseline (Day 1 [pre-dose]), Day 7 (pre-dose), and Day 14 (24 hours [h] post-dose)

Outcome Measure Data

Analysis Population Description
Safety Population

Arm/Group Title	Part B: Placebo	Part B: GSK2269577 100 µg	Part B: GSK2269577 200 µg	Part B: GSK2269577 500 µg	Part B: GSK2269577 700 µg	Part B: GSK2269577 1000 µg	Part B: GSK2269577 2000 µg
Arm/Group Description	Participants received four inhalations of matching placebo (from four inhalation devices) once daily for 14 consecutive days.	Participants received repeat doses of GSK2269557 100 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 100 µg or placebo.	Participants received repeat doses of GSK2269557 200 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 100 µg or placebo.	Participants received repeat doses of GSK2269557 500 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 500 µg or placebo.	Participants received repeat doses of GSK2269557 700 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing GSK2269557 100 µg, 500 µg, or placebo.	Participants received repeat doses of GSK2269557 1000 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 500 µg or placebo.	Participants received repeat doses of GSK2269557 2000 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing GSK2269557 500 µg.
Measure Participants	5	5	5	5	6	5	5
Calcium; Day 7/Day 8, pre-dose	0.048 (0.0444)	0.044 (0.0397)	0.06 (0.0579)	0.01 (0.0648)	-0.008 (0.0655)	0.066 (0.0811)	0.044 (0.0365)
Calcium; Day 14, 24 h post dose	0.024 (0.0865)	-0.012 (0.0482)	0.05 (0.0696)	-0.01 (0.0758)	-0.042 (0.0422)	0.03 (0.0292)	0.036 (0.0568)
Glucose; Day 7/Day 8, pre-dose	-0.06 (0.2939)	0.054 (0.4057)	0.05 (0.1937)	-0.43 (1.4084)	-0.11 (0.5658)	0.11 (0.4369)	-0.246 (0.273)
Glucose; Day 14, 24 h post dose	-0.086 (0.3743)	-0.142 (0.3746)	0.26 (0.5456)	0.054 (0.2294)	-0.34 (0.7332)	-0.076 (0.3518)	-0.314 (0.3871)
Potassium; Day 7/Day 8, pre-dose	0.246 (0.3088)	0.09 (0.2793)	0.434 (0.5451)	-0.204 (0.2563)	0.135 (0.3172)	0.276 (0.3566)	0.192 (0.4587)
Potassium; Day 14, 24 h post dose	0.19 (0.1944)	0.12 (0.4282)	0.336 (0.5268)	-0.128 (0.3241)	0.013 (0.203)	0.14 (0.1259)	0.072 (0.5946)
Sodium; Day 7/Day 8, pre-dose	0 (1.206)	0.6 (1.626)	-0.12 (1.714)	1.18 (1.139)	-0.33 (2.072)	0.7 (1.815)	-0.84 (2.137)
Sodium; Day 14, 24 h post dose	-0.16 (1.301)	-0.04 (3.233)	0.58 (1.399)	0.46 (1.447)	-0.18 (2.515)	1.06 (1.074)	-0.4 (2.72)
Urea/BUN; Day 7/Day 8, pre-dose	0.314 (0.7077)	-0.504 (0.6955)	0.342 (0.8193)	-0.91 (1.0653)	-0.29 (0.4396)	-0.244 (1.2909)	0.162 (1.2285)
Urea/BUN; Day 14, 24 h post dose	-0.232 (0.3592)	-0.124 (0.7502)	0.142 (1.0269)	-0.906 (1.6431)	-0.335 (0.2793)	-0.364 (0.8554)	0.186 (2.0478)

34. Secondary Outcome

Title	Part B: Number of Participants Meeting Criteria of Potential Clinical Importance for Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP), and Heart Rate (HR) at Any Visit Post-Baseline
Description	Baseline was the Day 1 pre-dose measurement. Vital signs (SBP, DBP, and HR) were measured at Day 1 (30 minutes [min] and 6 h post-dose), Day 7 (pre-dose), and Day 14 (24 h post-dose). All measurements were obtained in supine position, after a 5-minute rest. Day 7 assessments could be conducted on Day 7 or Day 8.
Time Frame	Day 1, Day 7, and Day 14

Outcome Measure Data

Analysis Population Description
Safety Population

Arm/Group Title	Part B: Placebo	Part B: GSK2269577 100 µg	Part B: GSK2269577 200 µg	Part B: GSK2269577 500 µg	Part B: GSK2269577 700 µg	Part B: GSK2269577 1000 µg	Part B: GSK2269577 2000 µg
Arm/Group Description	Participants received four inhalations of matching placebo (from four inhalation devices) once daily for 14 consecutive days.	Participants received repeat doses of GSK2269557 100 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 100 µg or placebo.	Participants received repeat doses of GSK2269557 200 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 100 µg or placebo.	Participants received repeat doses of GSK2269557 500 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 500 µg or placebo.	Participants received repeat doses of GSK2269557 700 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing GSK2269557 100 µg, 500 µg, or placebo.	Participants received repeat doses of GSK2269557 1000 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 500 µg or placebo.	Participants received repeat doses of GSK2269557 2000 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing GSK2269557 500 µg.
Measure Participants	5	5	5	5	6	5	5
SBP high	0 0%	0 0%	1 20%	1 20%	1 20%	0 0%	0 0%
SBP low	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
DBP high	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
DBP low	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
HR high	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
HR low	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%

35. Secondary Outcome

Title	Part B: Number of Participants With Normal and Abnormal (Clinically Significant or Not Clinically Significant) Findings in 12-lead Electrocardiogram (ECG) at Any Visit Post-Baseline
Description	Baseline was the Day 1 (pre-dose) measurement. Single 12-lead ECGs were obtained using an ECG machine that automatically calculates the HR and measures PR, QRS, QT, and corrected QT intervals. Day 7 assessments could be conducted on Day 7 or Day 8.
Time Frame	Day 1, Day 7, and Day 14

Outcome Measure Data

Analysis Population Description
Safety Population

Arm/Group Title	Part B: Placebo	Part B: GSK2269577 100 µg	Part B: GSK2269577 200 µg	Part B: GSK2269577 500 µg	Part B: GSK2269577 700 µg	Part B: GSK2269577 1000 µg	Part B: GSK2269577 2000 µg
Arm/Group Description	Participants received four inhalations of matching placebo (from four inhalation devices) once daily for 14 consecutive days.	Participants received repeat doses of GSK2269557 100 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 100 µg or placebo.	Participants received repeat doses of GSK2269557 200 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 100 µg or placebo.	Participants received repeat doses of GSK2269557 500 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 500 µg or placebo.	Participants received repeat doses of GSK2269557 700 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing GSK2269557 100 µg, 500 µg, or placebo.	Participants received repeat doses of GSK2269557 1000 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 500 µg or placebo.	Participants received repeat doses of GSK2269557 2000 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing GSK2269557 500 µg.
Measure Participants	5	5	5	5	6	5	5
Normal	4 57.1%	5 23.8%	3 60%	2 40%	5 100%	5 100%	4 66.7%
Abnormal - not clinically significant	1 14.3%	0 0%	2 40%	3 60%	1 20%	0 0%	1 16.7%
Abnormal - clinically significant	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%

36. Secondary Outcome

Title	Part B: Forced Expiratory Volume in One Second (FEV1) and Forced Vital Capacity (FVC) at Screening and Follow-up
Description	FEV1 and FVC are measures of lung function. FEV1 is defined as the maximal amount of air that can be forcefully exhaled in one second. FVC is defined as the maximum amount of air that can be forcibly blown out after a maximum inspiration. FEV1 and FVC measurements were repeated until three technically acceptable measurements (within 150 milliliters of each other) had been made. Only the best of three measurements were recorded.
Time Frame	Screening (up to 30 days prior to Day 1) and Follow-up (approximately Day 19)

Outcome Measure Data

Analysis Population Description
Safety Population

Arm/Group Title	Part B: Placebo	Part B: GSK2269577 100 µg	Part B: GSK2269577 200 µg	Part B: GSK2269577 500 µg	Part B: GSK2269577 700 µg	Part B: GSK2269577 1000 µg	Part B: GSK2269577 2000 µg
Arm/Group Description	Participants received four inhalations of matching placebo (from four inhalation devices) once daily for 14 consecutive days.	Participants received repeat doses of GSK2269557 100 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 100 µg or placebo.	Participants received repeat doses of GSK2269557 200 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 100 µg or placebo.	Participants received repeat doses of GSK2269557 500 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 500 µg or placebo.	Participants received repeat doses of GSK2269557 700 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing GSK2269557 100 µg, 500 µg, or placebo.	Participants received repeat doses of GSK2269557 1000 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 500 µg or placebo.	Participants received repeat doses of GSK2269557 2000 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing GSK2269557 500 µg.
Measure Participants	5	5	5	5	6	5	5
FEV1, Screening	1.586	1.387	1.533	1.558	1.573	1.36	1.407
FEV1, Follow-up	1.494	1.272	1.523	1.34	1.501	1.405	1.431
FVC, Screening	3.05	3.08	3.632	4.348	3.277	2.958	3.156
FVC, Follow-up	2.96	3.042	3.764	4.192	3.137	3.03	3.192

Adverse Events

	Part A: Placebo		Part A: GSK2269577 1000 µg		Part B: Placebo		Part B: GSK2269577 100 µg		Part B: GSK2269577 200 µg		Part B: GSK2269577 500 µg		Part B: GSK2269577 700 µg		Part B: GSK2269577 1000 µg		Part B: GSK2269577 2000 µg
Time Frame	On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs), defined as those events occurring from the start of treatment until follow-up (up to approximately 19 days), are reported.
Adverse Event Reporting Description	SAEs and non-serious AEs are reported for members of the Safety Population, comprised of all participants who received at least one dose of study treatment.

Arm/Group Title	Part A: Placebo		Part A: GSK2269577 1000 µg		Part B: Placebo		Part B: GSK2269577 100 µg		Part B: GSK2269577 200 µg		Part B: GSK2269577 500 µg		Part B: GSK2269577 700 µg		Part B: GSK2269577 1000 µg		Part B: GSK2269577 2000 µg
Arm/Group Description	Participants received 2 inhalations of matching placebo once daily for 14 consecutive days.		Participants received repeat doses of GSK2269557 1000 micrograms (µg) (2 inhalations of 500 µg each from a single device) administered as a dry powder inhalation, once daily for 14 consecutive days.		Participants received four inhalations of matching placebo (from four inhalation devices) once daily for 14 consecutive days.		Participants received repeat doses of GSK2269557 100 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 100 µg or placebo.		Participants received repeat doses of GSK2269557 200 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 100 µg or placebo.		Participants received repeat doses of GSK2269557 500 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 500 µg or placebo.		Participants received repeat doses of GSK2269557 700 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing GSK2269557 100 µg, 500 µg, or placebo.		Participants received repeat doses of GSK2269557 1000 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing either GSK2269557 500 µg or placebo.		Participants received repeat doses of GSK2269557 2000 µg administered as a dry powder inhalation, once daily for 14 consecutive days. To maintain blinding, the total dose was delivered through four inhalation devices, each device containing GSK2269557 500 µg.
All Cause Mortality
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/7 (0%)		0/21 (0%)		0/5 (0%)		0/5 (0%)		0/5 (0%)		0/5 (0%)		0/6 (0%)		0/5 (0%)		0/5 (0%)
Serious Adverse Events
	Part A: Placebo		Part A: GSK2269577 1000 µg		Part B: Placebo		Part B: GSK2269577 100 µg		Part B: GSK2269577 200 µg		Part B: GSK2269577 500 µg		Part B: GSK2269577 700 µg		Part B: GSK2269577 1000 µg		Part B: GSK2269577 2000 µg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/7 (0%)		1/21 (4.8%)		0/5 (0%)		0/5 (0%)		0/5 (0%)		0/5 (0%)		0/6 (0%)		0/5 (0%)		0/5 (0%)
Cardiac disorders
Atrial fibrillation	0/7 (0%)		1/21 (4.8%)		0/5 (0%)		0/5 (0%)		0/5 (0%)		0/5 (0%)		0/6 (0%)		0/5 (0%)		0/5 (0%)
Other (Not Including Serious) Adverse Events
	Part A: Placebo		Part A: GSK2269577 1000 µg		Part B: Placebo		Part B: GSK2269577 100 µg		Part B: GSK2269577 200 µg		Part B: GSK2269577 500 µg		Part B: GSK2269577 700 µg		Part B: GSK2269577 1000 µg		Part B: GSK2269577 2000 µg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/7 (28.6%)		7/21 (33.3%)		3/5 (60%)		3/5 (60%)		2/5 (40%)		1/5 (20%)		3/6 (50%)		4/5 (80%)		2/5 (40%)
Eye disorders
Lacrimation increased	0/7 (0%)		0/21 (0%)		0/5 (0%)		0/5 (0%)		0/5 (0%)	0	0/5 (0%)	0	0/6 (0%)	0	0/5 (0%)	0	1/5 (20%)	0
Gastrointestinal disorders
Diarrhoea	1/7 (14.3%)		0/21 (0%)		0/5 (0%)		1/5 (20%)		0/5 (0%)		0/5 (0%)		0/6 (0%)		0/5 (0%)		0/5 (0%)
Dry mouth	0/7 (0%)		0/21 (0%)		0/5 (0%)		1/5 (20%)		0/5 (0%)		0/5 (0%)		0/6 (0%)		0/5 (0%)		0/5 (0%)
Toothache	0/7 (0%)		0/21 (0%)		1/5 (20%)		0/5 (0%)		0/5 (0%)		0/5 (0%)		0/6 (0%)		0/5 (0%)		0/5 (0%)
General disorders
Catheter site haematoma	0/7 (0%)		0/21 (0%)		0/5 (0%)		0/5 (0%)		0/5 (0%)		0/5 (0%)		0/6 (0%)		0/5 (0%)		1/5 (20%)
Vessel puncture site inflammation	0/7 (0%)		0/21 (0%)		0/5 (0%)		0/5 (0%)		0/5 (0%)		0/5 (0%)		0/6 (0%)		0/5 (0%)		1/5 (20%)
Infections and infestations
Gastroenteritis	1/7 (14.3%)		0/21 (0%)		0/5 (0%)		0/5 (0%)		0/5 (0%)		0/5 (0%)		0/6 (0%)		0/5 (0%)		0/5 (0%)
Nasopharyngitis	1/7 (14.3%)		1/21 (4.8%)		0/5 (0%)		0/5 (0%)		1/5 (20%)		0/5 (0%)		0/6 (0%)		0/5 (0%)		0/5 (0%)
Oral herpes	1/7 (14.3%)		0/21 (0%)		0/5 (0%)		0/5 (0%)		0/5 (0%)		0/5 (0%)		0/6 (0%)		0/5 (0%)		0/5 (0%)
Rhinitis	0/7 (0%)		0/21 (0%)		0/5 (0%)		1/5 (20%)		0/5 (0%)		0/5 (0%)		0/6 (0%)		1/5 (20%)		1/5 (20%)
Sinusitis	0/7 (0%)		0/21 (0%)		0/5 (0%)		0/5 (0%)		0/5 (0%)		0/5 (0%)		1/6 (16.7%)		0/5 (0%)		0/5 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/7 (0%)		2/21 (9.5%)		0/5 (0%)		1/5 (20%)		0/5 (0%)		0/5 (0%)		0/6 (0%)		0/5 (0%)		0/5 (0%)
Neck pain	0/7 (0%)		0/21 (0%)		1/5 (20%)		0/5 (0%)		0/5 (0%)		0/5 (0%)		0/6 (0%)		0/5 (0%)		0/5 (0%)
Pain in extremity	0/7 (0%)		0/21 (0%)		0/5 (0%)		1/5 (20%)		0/5 (0%)		0/5 (0%)		0/6 (0%)		0/5 (0%)		1/5 (20%)
Spinal pain	0/7 (0%)		0/21 (0%)		0/5 (0%)		0/5 (0%)		0/5 (0%)		0/5 (0%)		0/6 (0%)		0/5 (0%)		1/5 (20%)
Nervous system disorders
Headache	1/7 (14.3%)		3/21 (14.3%)		1/5 (20%)		1/5 (20%)		0/5 (0%)		0/5 (0%)		1/6 (16.7%)		1/5 (20%)		1/5 (20%)
Dizziness	0/7 (0%)		0/21 (0%)		0/5 (0%)		0/5 (0%)		0/5 (0%)		1/5 (20%)		0/6 (0%)		0/5 (0%)		1/5 (20%)
Psychiatric disorders
Sleep disorder	0/7 (0%)		0/21 (0%)		0/5 (0%)		1/5 (20%)		0/5 (0%)		0/5 (0%)		0/6 (0%)		0/5 (0%)		0/5 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	1/7 (14.3%)		4/21 (19%)		0/5 (0%)		0/5 (0%)		1/5 (20%)		0/5 (0%)		3/6 (50%)		4/5 (80%)		2/5 (40%)
Oropharyngeal pain	0/7 (0%)		0/21 (0%)		1/5 (20%)		0/5 (0%)		0/5 (0%)		0/5 (0%)		0/6 (0%)		0/5 (0%)		0/5 (0%)
Skin and subcutaneous tissue disorders
Eczema	0/7 (0%)		0/21 (0%)		1/5 (20%)		0/5 (0%)		0/5 (0%)		0/5 (0%)		0/6 (0%)		0/5 (0%)		0/5 (0%)
Hyperhidrosis	0/7 (0%)		0/21 (0%)		1/5 (20%)		0/5 (0%)		0/5 (0%)		0/5 (0%)		0/6 (0%)		0/5 (0%)		0/5 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.

Results Point of Contact

Name/Title	GSK Response Center
Organization	GlaxoSmithKline
Phone	866-435-7343
Email

Responsible Party:

GlaxoSmithKline

ClinicalTrials.gov Identifier:

NCT02130635

Other Study ID Numbers:

115119

First Posted:

May 5, 2014

Last Update Posted:

Oct 11, 2018

Last Verified:

Sep 1, 2018