CompletedNCT03045887Updated Jul 24, 2019Results posted

Safety, Tolerability and Pharmacokinetics of Single and Repeat Doses of GSK2292767 in Healthy Participants Who Smoke Cigarettes

A Phase 1 interventional study of GSK2292767 50 μg and GSK2292767 500 μg in Asthma, sponsored by GlaxoSmithKline. Completed at 1 site in United Kingdom. Open to participants aged 18 Years to 50 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2019-07-24.

Sponsored by GlaxoSmithKline · Phase 1, Interventional, and Treatment

Phase: Phase 1
Study type: Interventional
Enrollment: 38
Allocation: Randomized
Ages: 18 Years to 50 Years
Sex: All

Study summary

This study is the first administration of GSK2292767 to humans. The study will evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single and repeat inhaled doses of GSK2292767 in healthy smokers. This study is intended to provide sufficient confidence in the safety of the molecule and preliminary information on target engagement to allow progression to further repeat dose and proof of mechanism studies. This is a two part, single site, randomized, double-blind (sponsor open), placebo controlled study. Part A will consist of two 3-period interlocking cohorts to evaluate the safety, tolerability and pharmacokinetics of ascending single doses of GSK2292767 administered as a dry powder inhalation. Part B is planned to follow Part A and progression will be based on an acceptable safety, tolerability and pharmacokinetic profiles. Subjects will receive repeat doses of GSK2292767 once daily for 14 days during Part B.

Conditions studied

Asthma

Browse trials for

Asthma 4,012

Keywords

repeat dose
GSK2292767
smoke
tolerability
safety
dry powder inhalation
pharmacokinetics
single dose

In context

Asthma

4,012 studies on the registry are indexed under Asthma; 514 are open to participants now.

This study's enrollment of 38 is below the median of 83 across 2,814 interventional studies indexed under Asthma.

Browse Asthma studies →

Lead sponsor

GlaxoSmithKline is the lead sponsor of 3,647 studies on the registry; 118 are open to participants now.

Of its 264 completed or terminated interventional studies of FDA-regulated products, 239 (91%) have results posted.

Browse GlaxoSmithKline studies →

Counted across the registry records on this site, refreshed daily.

Who can participate

Ages eligible: 18 Years to 50 Years
Sexes eligible: All
Accepts healthy volunteers: Yes

Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.

Inclusion criteria

Participant must be 18 to 50 years of age inclusive, at the time of signing the informed consent
Participants who are overtly healthy as determined by medical evaluation including (medical history, physical examination, laboratory tests, and cardiac monitoring). A participant with a clinical abnormality or laboratory parameters outside the reference range expected for them and the population being studied may be included only if the Investigator believes that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures or outcomes
Participants who are current daily cigarette smokers (manufactured and self-rolled). Must have smoked regularly in the 12-month period preceding the screening visit
Normal spirometry (FEV1 >=80% of predicted) at screening
Body weight >=50 kilograms (kg) and body mass index (BMI) within the range 18 to 31 kg/square meter (m\^2) (inclusive)
Male and female
- Male participants: A male participant must agree to use contraception as detailed in the protocol during the treatment period and for at least from the time of first dose of study medication until at least 55 (5x11) hours plus an additional 90 days after the last dose of study medication and refrain from donating sperm during this period. GSK2292767 has a predicted half-life of approximately 11 hours
- Female participants: A female participant is eligible to participate if she is not pregnant, not breastfeeding, and not a woman of childbearing potential (WOCBP)
Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in the protocol

Exclusion criteria

Exclusion Criteria:

History or presence of current cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, haematological, or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk when taking the study treatment; or interfering with the interpretation of data
Abnormal blood pressure as determined by the investigator
Alanine transaminase (ALT) >1.5xupper limit of normal (ULN)
Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%)
Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones)
Average corrected QT interval by Fridericia's formula (QTcF) >450 milliseconds (msec) (based on triplicate ECGs)
Participants who have asthma or a history of asthma (except in childhood and which has now remitted)
Past or intended use of over-the-counter or prescription medication including herbal medications within 14 days prior to dosing. Specific concomitant medications listed in protocol may be allowed
Live vaccine(s) within 1 month prior to screening, or plans to receive such vaccines during the study
Participation in the study would result in loss of blood or blood products in excess of 500 milliliters (mL) within 56 days
Exposure to more than 4 new chemical entities within 12 months prior to the first dosing day
Current enrolment or past participation within the last 90 days of exposure to any other clinical study involving an investigational study treatment or any other type of medical research
Presence of Hepatitis B surface antigen (HBsAg) at screening Positive Hepatitis C antibody test result at screening
Positive Hepatitis C ribonucleic acid (RNA) test result at screening or within 3 months prior to first dose of study treatment
Positive pre-study drug/alcohol screen
Positive human immunodeficiency virus (HIV) antibody test
Regular use of known drugs of abuse
Regular alcohol consumption within 3 months prior to the study defined as: An average weekly intake of >14 units for males and females. One unit is equivalent to 8 grams (g) of alcohol: a half-pint (approximately 240 mL of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits
Sensitivity to any of the study treatments, or components thereof, or drug or other allergy that, in the opinion of the investigator or medical monitor, contraindicates participation in the study
Participants who are unable to produce a total weight of at least 100 milligrams (mg) of selected sputum during sputum induction at screening
Participants whose primary consumption of tobacco is via methods other than cigarettes (manufactured or self-rolled). Primary methods of tobacco consumption that are excluded include, but are not limited to pipes and cigars

Study design

Phase: Phase 1
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover assignment
Masking: Quadruple (Participant, Care provider, Investigator, Outcomes assessor)
Enrollment: 38 participants (actual)

Study arms

Experimental
Part A Cohort 1: Placebo- GSK2292767 (GSK) 200 µg-GSK 1000 µg
Subjects will receive an inhaled single dose of placebo in Period 1, GSK2292767 200 µg in Period 2, and GSK2292767 1000 µg in Period 3. There will be a washout of approximately 4 weeks between doses.
Drug: GSK2292767 50 μg · Drug: GSK2292767 500 μg · Drug: Placebo
Experimental
Part A Cohort 1: GSK 50 µg-Placebo-GSK 1000 µg
Subjects will receive an inhaled single dose of GSK2292767 50 µg in Period 1, placebo in Period 2, and GSK2292767 1000 µg in Period 3. There will be a washout of approximately 4 weeks between doses.
Drug: GSK2292767 50 μg · Drug: GSK2292767 500 μg · Drug: Placebo
Experimental
Part A Cohort 1: GSK 50 µg- GSK 200 µg-Placebo
Subjects will receive an inhaled single dose of GSK2292767 50 µg in Period 1, GSK2292767 200 µg in Period 2, and placebo in Period 3. There will be a washout of approximately 4 weeks between doses.
Drug: GSK2292767 50 μg · Drug: Placebo
Experimental
Part A Cohort 1: GSK 50 µg-GSK 200 µg-GSK 1000 µg
Subjects will receive an inhaled single dose of GSK2292767 50 µg in Period 1, GSK2292767 200 µg in Period 2, and GSK2292767 1000 µg in Period 3. There will be a washout of approximately 4 weeks between doses.
Drug: GSK2292767 50 μg · Drug: GSK2292767 500 μg
Experimental
Part A Cohort 2: Placebo-GSK 500 µg-GSK 2000 µg
Subjects will receive an inhaled single dose of placebo in Period 1, GSK2292767 500 µg in Period 2, and GSK2292767 2000 µg in Period 3. There will be a washout of approximately 4 weeks between doses.
Drug: GSK2292767 500 μg · Drug: Placebo
Experimental
Part A Cohort 2: GSK 100 µg-Placebo- GSK 2000 µg
Subjects will receive an inhaled single dose of GSK2292767 100 µg in Period 1, placebo in Period 2, and GSK2292767 2000 µg in Period 3. There will be a washout of approximately 4 weeks between doses.
Drug: GSK2292767 50 μg · Drug: GSK2292767 500 μg · Drug: Placebo
Experimental
Part A Cohort 2: GSK 100 µg-GSK 500 µg-Placebo
Subjects will receive an inhaled single dose of GSK2292767 100 µg in Period 1, GSK2292767 500 µg in Period 2 and placebo in Period 3. There will be a washout of approximately 4 weeks between doses.
Drug: GSK2292767 50 μg · Drug: GSK2292767 500 μg · Drug: Placebo
Experimental
Part A Cohort 2: GSK 100 µg-GSK 500 µg-GSK 2000 µg
Subjects will receive an inhaled single dose of GSK2292767 100 µg in Period 1, GSK2292767 500 µg in Period 2, GSK2292767 2000 µg in Period 3. There will be a washout of approximately 4 weeks between doses.
Drug: GSK2292767 50 μg · Drug: GSK2292767 500 μg
Experimental
Part B: GSK
Subjects will receive inhaled repeat dose of GSK2292767 2000 µg once daily for 14 days.
Drug: GSK2292767 500 μg
Experimental
Part B: Placebo
Subjects will receive inhaled repeat dose of placebo once daily for 14 days.
Drug: Placebo

Interventions

DrugGSK2292767 50 μg
GSK2292767 50 μg blended with lactose and magnesium stearate per blister as powder for inhalation
DrugGSK2292767 500 μg
GSK2292767 500 μg blended with lactose and magnesium stearate per blister as powder for inhalation
DrugPlacebo
Lactose as powder for inhalation

What researchers measure

Primary outcomes

Part A: Number of Participants With Any Non-serious Adverse Event (nSAE) and Any Serious Adverse Event (SAE)
An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect, any other situation according to medical or scientific judgment or all events of possible drug-induced liver injury with hyperbilirubinemia were categorized as SAE. Participants with 5 percent nSAEs and SAEs has been reported.
Time frame: Up to 12 weeks
Part B: Number of Participants With Any AE and Any SAE
An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect, any other situation according to medical or scientific judgment or all events of possible drug-induced liver injury with hyperbilirubinemia were categorized as SAE. Participants with 5 percent nSAEs and SAEs has been reported.
Time frame: Up to 4 weeks
Part A: Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
Blood pressure in part A was assessed in a semi supine position with a completely automated device. SBP and DBP measurements were preceded by at least 5 minutes of rest for the participant in a quiet setting without distractions. Baseline was defined as the latest pre-dose assessment. Change from Baseline was defined as the value at indicated time point minus Baseline value.
Time frame: Baseline, 30 minutes, 1, 6, 12 and 24 hours post-dose in each treatment period
Part B: Change From Baseline in SBP and DBP
Blood pressure in part B were assessed in semi supine position with a completely automated device. SBP and DBP preceded by at least 5 minutes of rest for the participant in a quiet setting without distractions. Baseline was defined as measurements done on Day -1. Change from Baseline was defined as the value at indicated time point minus Baseline value.
Time frame: Baseline, Pre-dose on Days 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14, 24 hours post-dose on Day 14
Part A: Change From Baseline in Heart Rate
Heart rate in part A was assessed in a semi supine position with a completely automated device. Heart rate measurement was preceded by at least 5 minutes of rest for the participant in a quiet setting without distractions. Baseline was defined as latest pre-dose measurement. Change from Baseline was defined as the value at indicated time point minus Baseline value.
Time frame: Baseline, 30 minutes, 1, 6, 12 and 24 hours post-dose in each treatment period
Part B: Change From Baseline in Heart Rate
Heart rate in part B was assessed in a semi supine position with a completely automated device. Heart rate measurement was preceded by at least 5 minutes of rest for the participant in a quiet setting without distractions. Baseline was defined as latest pre-dose measurement. Change from Baseline was defined as the value at indicated time point minus Baseline value.
Time frame: Baseline, Pre-dose on Days 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14, 24 hours post-dose on Day 14
Part A: Change From Baseline in Respiratory Rate
Respiratory rate in part A was assessed in a semi supine position after 5 minutes of rest for the participant in a quiet setting without distractions. Baseline was defined as measurements done on Day -1. Change from Baseline was defined as the value at indicated time point minus Baseline value. Baseline was defined as latest pre-dose measurement. Change from Baseline was defined as the value at indicated time point minus Baseline value.
Time frame: Baseline, 30 minutes, 1, 6, 12 and 24 hours post-dose in each treatment period
Part B: Change From Baseline in Respiratory Rate
Respiratory rate in part B was assessed in a semi supine position after 5 minutes of rest for the participant in a quiet setting without distractions. Baseline was defined as measurements done on Day -1. Change from Baseline was defined as the value at indicated time point minus Baseline value. Baseline was defined as latest pre-dose measurement. Change from Baseline was defined as the value at indicated time point minus Baseline value.
Time frame: Baseline, Pre-dose on Days 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14, 24 hours post-dose on Day 14
Part A: Change From Baseline in Tympanic Temperature
Tympanic temperature in part A was assessed in semi supine position after 5 minutes of rest for the participant in a quiet setting without distractions. Baseline was defined as measurements done on Day -1. Change from Baseline was defined as the value at indicated time point minus Baseline value. Baseline was defined as latest pre-dose measurement. Change from Baseline was defined as the value at indicated time point minus Baseline value.
Time frame: Baseline, 30 minutes, 1, 6, 12 and 24 hours post-dose in each treatment period
Part B: Change From Baseline in Tympanic Temperature
Tympanic temperature in part B was assessed in semi supine position after 5 minutes of rest for the participant in a quiet setting without distractions. Baseline was defined as measurements done on Day -1. Change from Baseline was defined as the value at indicated time point minus Baseline value. Baseline was defined as latest pre-dose measurement. Change from Baseline was defined as the value at indicated time point minus Baseline value.
Time frame: Baseline, Pre-dose on Days 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14, 24 hours post-dose on Day 14
Part A: Maximal Amount of Air Forcefully Exhaled in 1 Second (FEV1)
FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. FEV1 was measured using spirometry at the indicated time. FEV1 measurements were repeated until three technically acceptable measurements (within 150 milliliter \[mL\] of each other) were made. Data for FEV1 for part A is presented here.
Time frame: Day 1 (pre-dose and 1 hour)
Part B: Maximal Amount of Air Forcefully Exhaled in 1 Second (FEV1)
FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. FEV1 was measured using spirometry at the indicated time. Existing spirometry equipment was used. FEV1 measurements were repeated until three technically acceptable measurements (within 150 mL of each other) were made. Data for FEV1 for part B is presented here.
Time frame: Up to Day 14
Part A: Forced Vital Capacity (FVC)
FVC is a measure of lung function and is defined as total amount of air that can be exhaled during FEV1 test. FVC was planned to measured using spirometry. The FVC need to be normal at screening and is part of the Forced Expiratory ratio (FEV1/FVC) which should lie between 0.7-0.8 to indicate no chronic obstruction or restriction. The FVC was therefore only used at screening and requires no ongoing analysis during the study. All other indications of obstruction in the study, e.g. paradoxical bronchospasm was provided by the FEV1. The FVC therefore require no analysis.
Time frame: Day 1 (pre-dose and 1 hour)
Part B: Forced Vital Capacity (FVC)
FVC is a measure of lung function and is defined as total amount of air that can be exhaled during FEV1 test. FVC was planned to measured using spirometry. The FVC need to be normal at screening and is part of the Forced Expiratory ratio (FEV1/FVC) which should lie between 0.7-0.8 to indicate no chronic obstruction or restriction. The FVC was therefore only used at screening and requires no ongoing analysis during the study. All other indications of obstruction in the study, e.g. paradoxical bronchospasm was provided by the FEV1. The FVC therefore require no analysis.
Time frame: Day 1 (pre-dose and 1 hour)
Part A: Number of Participants With Electrocardiogram (ECG) Abnormalities
Triplicate/Single 12-lead ECG was obtained using an automated ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTFc intervals. Number of participants with abnormal clinically significant and abnormal-not clinically significant values at any time post-Baseline is presented.
Time frame: Day 1 of each treatment period
Part B: Number of Participants With ECG Abnormalities
Triplicate/Single 12-lead ECG was obtained using an automated ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTFc intervals. Number of participants with abnormal clinically significant and abnormal-not clinically significant values at any time post-Baseline is presented.
Time frame: Pre-dose on Days 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14, 24 hours post-dose on Day 14
Part A: Number of Participants With Clinical Chemistry Values of Potential Clinical Importance Criteria (PCC)
Number of participants with clinical chemistry values that changed from normal to high or low in part A are presented. Chemistry parameters for which PCC values were identified were: Alkaline Phosphatase, Alanine Amino Transferase, aspartate aminotransferase, Total Bilirubin, calcium, glucose, potassium and Sodium.
Time frame: 24 hours post-dose in each treatment period.
Part B: Number of Participants With Clinical Chemistry Values of PCC
Number of participants with clinical chemistry values that changed from normal to high or low in part B are presented. Chemistry parameters for which PCC values were identified were: Alkaline Phosphatase, Alanine Amino Transferase, aspartate aminotransferase, Total Bilirubin, calcium, glucose, potassium and Sodium. Only participants with data available at specified time points were analyzed (represented by n=X in category titles)
Time frame: Pre-dose on Days 2, 4, 6, 8, 10, 12, and 14, 24 hours post-dose on Day 14
Part A: Number of Participants With Hematology Values of PCC
Number of participants with hematology parameters of PCC which shifted from normal to high in part A are presented. Hematology parameters for which PCC values were identified were: Hemoglobin, Hematocrit, Lymphocytes, Total Neutrophils, Platelet count and White Blood Cell (WBC) Count. Only those participants with data available at the specified time points were analyzed (represented by n=X in category titles)
Time frame: 24 hours post-dose in each treatment period
Part B: Number of Participants With Hematology Values of PCC
Number of participants with hematology parameters of PCC which shifted from normal to high in part B are presented. Hematology parameters for which PCC values were identified were: Hemoglobin, Hematocrit, Lymphocytes, Total Neutrophils, Platelet count and WBC count
Time frame: Pre-dose on Days 2, 4, 6, 8, 10, 12, and 14, 24 hours post-dose on Day 14

Secondary outcomes

Part A: Area Under the Plasma Drug Concentration Versus Time Curve (AUC) From Zero to Time t (AUC [0 to t]), AUC From Zero to 24 Hours (AUC [0 to 24]) and AUC From Zero to Infinity (AUC [0 to Inf]) of GSK2292767
Blood samples were collected for pharmacokinetic analysis of GSK2292767 at the specified time points. Data for AUC (0 to t), AUC (0 to 24) and AUC (0 to inf) of GSK2292767 for part A is presented. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). Pharmacokinetic population comprised of participants in the 'All participant' population for whom a pharmacokinetic sample was obtained and analyzed.
Time frame: Pre-dose (5 minutes (min), 30 min, 45 min, 1 hour (hr), 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr, and 24 hr post dose in each of the 3 treatment periods
Part B: AUC (0 to t), AUC (0 to 24) and AUC (0 to Inf) of GSK2292767
Blood samples were collected for pharmacokinetic analysis of GSK2292767 at the specified time points. Data for AUC (0 to t), AUC (0 to 24) and AUC (0 to inf) of GSK2292767 for part B is presented. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles).
Time frame: Pre-dose, 5 minutes, 30 minutes, 45 minutes, 1, 2, 3, 4, 6, 8 and 12hours post dose on Day 1; pre-dose, 5 minutes, 30 minutes, 45 minutes, 1, 2, 3, 4, 6, 8 and 12hours post dose on Day 14
Part A: Maximum Observed Plasma Drug Concentration (Cmax) of GSK2292767
Blood samples were collected for pharmacokinetic analysis of GSK2292767 at the specified time points. Five min post dose concentrations on Days 2-13 were assumed to be the Cmax values. Data for Cmax of GSK2292767 for part A is presented. Cmax is defined as maximum observed plasma concentration of GSK2292767.
Time frame: Pre-dose (5 min, 30 min, 45 min, 1 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr, and 24 hr post dose in each of the 3 treatment periods
Part B: Cmax of GSK2292767
Blood samples were collected for pharmacokinetic analysis of GSK2292767 at the specified time points. Five minute post dose concentrations on Days 2-13 were assumed to be the Cmax values. Data for Cmax of GSK2292767 for part B is presented.
Time frame: Pre-dose, 5 minutes, 30 minutes, 45 minutes, 1, 2, 3, 4, 6, 8 and 12hours post dose on Day 1; pre-dose, 5 minutes, 30 minutes, 45 minutes, 1, 2, 3, 4, 6, 8 and 12hours post dose on Day 14
Part A: Time to Maximum Observed Plasma Drug Concentration (Tmax) of GSK2292767
Blood samples were collected for pharmacokinetic analysis of GSK2292767 at the specified time points. Data for Tmax of GSK2292767 for part A is presented.
Time frame: Pre-dose (5 min, 30 min, 45 min, 1 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr, and 24 hr post dose in each of the 3 treatment periods
Part B: Tmax of GSK2292767
Blood samples were collected for pharmacokinetic analysis of GSK2292767 at the specified time points. Data for Tmax of GSK2292767 for part B is presented.
Time frame: Pre-dose, 5 minutes, 30 minutes, 45 minutes, 1, 2, 3, 4, 6, 8 and 12hours post dose on Day 1; pre-dose, 5 minutes, 30 minutes, 45 minutes, 1, 2, 3, 4, 6, 8 and 12hours post dose on Day 14
Part A: Terminal Half-life (T1/2) of GSK2292767
Blood samples were collected for pharmacokinetic analysis of GSK2292767 at the specified time points. Data for T1/2 of GSK2292767 for part A is presented. T1/2 is defined as the time required for one half of the total amount of a particular substance in a biological system to be degraded by biological processes. Only those participants with data available at the specified time points were analyzed.
Time frame: Pre-dose (5 min, 30 min, 45 min, 1 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr, and 24 hr post dose in each of the 3 treatment periods
Part B: T1/2 of GSK2292767
Blood samples were collected for pharmacokinetic analysis of GSK2292767 at the specified time points. Data for T1/2 of GSK2292767 for part B is presented. T1/2 was defined as the time required for one half of the total amount of a particular substance in a biological system to be degraded by biological processes. Only those participants with data available at the specified time points were analyzed.
Time frame: Pre-dose, 5 minutes, 30 minutes, 45 minutes, 1, 2, 3, 4, 6, 8 and 12hours post dose on Day 1; pre-dose, 5 minutes, 30 minutes, 45 minutes, 1, 2, 3, 4, 6, 8 and 12hours post dose on Day 14
Part A: Trough Concentrations (Ctau) of GSK2292767
Blood samples were collected for pharmacokinetic analysis of GSK2292767 at the specified time points. Data for Ctau of GSK2292767 for part A is presented. Ctau is defined as the lowest concentration reached by a drug before the next dose is administered.
Time frame: 24 hr post dose in each of the 3 treatment periods
Part B: Ctau of GSK2292767
Blood samples were collected for pharmacokinetic analysis of GSK2292767 at the specified time points. Data for Ctau of GSK2292767 for part B is presented. Ctau is defined as the lowest concentration reached by a drug before the next dose is administered. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles).
Time frame: Pre-dose, 5 minutes, 30 minutes, 45 minutes, 1, 2, 3, 4, 6, 8 and 12hours post dose on Day 1; pre-dose, 5 minutes, 30 minutes, 45 minutes, 1, 2, 3, 4, 6, 8 and 12hours post dose on Day 14
Part B: Concentration of GSK2292767 in Bronchoalveolar Lavage (BAL)
BAL samples were collected by bronchoscopy.
Time frame: Day 15
Part B: Concentration of GSK2292767 in Lung Epithelial Lining Fluid (ELF)
ELF from the lung was extracted from BAL samples. ELF drug concentration was calculated as BAL fluid drug concentration multiplied by dilution factor where dilution factor = Plasma urea (pre-bronchoscopy) divided by BAL urea. NA indicates data not available. Only participants with data available at specified time points were analyzed (represented by n=X in category titles).
Time frame: Day 15

Results

Posted May 28, 2019

Participant flow

This is a two part, single site, randomized, double-blind (sponsor open), placebo controlled study in healthy smokers. Study was conducted in the United Kingdom.

Part A, Period (1 Day)

Participant flow — Part A, Period (1 Day)
Milestone	Part A: Placebo/200 µg GSK2292767/1000 µg GSK2292767	Part A:50 µg GSK2292767/Placebo/1000 µg GSK2292767	Part A:50 µg GSK2292767/200 µg GSK2292767/Placebo	Part A:50 µg GSK2292767/200 µg GSK2292767/1000 µg GSK2292767	Part A:Placebo/500 µg GSK2292767/2000 µg GSK2292767	Part A:100 µg GSK2292767/Placebo/2000 µg GSK2292767	Part A:100 µg GSK2292767/500 µg GSK2292767/Placebo	Part A:100 µg GSK2292767/500 µg GSK2292767/2000 µg GSK2292767
Started	7	4	5	5	4	4	4	4
Completed	7	4	5	5	4	4	4	4
Not completed	0	0	0	0	0	0	0	0

Part A,Washout Period 1(4 Weeks)

Participant flow — Part A,Washout Period 1(4 Weeks)
Milestone	Part A: Placebo/200 µg GSK2292767/1000 µg GSK2292767	Part A:50 µg GSK2292767/Placebo/1000 µg GSK2292767	Part A:50 µg GSK2292767/200 µg GSK2292767/Placebo	Part A:50 µg GSK2292767/200 µg GSK2292767/1000 µg GSK2292767	Part A:Placebo/500 µg GSK2292767/2000 µg GSK2292767	Part A:100 µg GSK2292767/Placebo/2000 µg GSK2292767	Part A:100 µg GSK2292767/500 µg GSK2292767/Placebo	Part A:100 µg GSK2292767/500 µg GSK2292767/2000 µg GSK2292767
Started	7	4	5	5	4	4	4	4
Completed	4	4	5	4	4	4	4	4
Not completed	3	0	0	1	0	0	0	0
Withdrew: Physician decision	3	0	0	0	0	0	0	0
Withdrew: Withdrawal by subject	0	0	0	1	0	0	0	0

Part A, Period 2 (1 Day)

Participant flow — Part A, Period 2 (1 Day)
Milestone	Part A: Placebo/200 µg GSK2292767/1000 µg GSK2292767	Part A:50 µg GSK2292767/Placebo/1000 µg GSK2292767	Part A:50 µg GSK2292767/200 µg GSK2292767/Placebo	Part A:50 µg GSK2292767/200 µg GSK2292767/1000 µg GSK2292767	Part A:Placebo/500 µg GSK2292767/2000 µg GSK2292767	Part A:100 µg GSK2292767/Placebo/2000 µg GSK2292767	Part A:100 µg GSK2292767/500 µg GSK2292767/Placebo	Part A:100 µg GSK2292767/500 µg GSK2292767/2000 µg GSK2292767
Started	4	4	5	4	4	4	4	4
Completed	3	4	5	4	4	4	4	4
Not completed	1	0	0	0	0	0	0	0
Withdrew: Adverse event	1	0	0	0	0	0	0	0

Part A,Washout Period 2 (4 Weeks)

Participant flow — Part A,Washout Period 2 (4 Weeks)
Milestone	Part A: Placebo/200 µg GSK2292767/1000 µg GSK2292767	Part A:50 µg GSK2292767/Placebo/1000 µg GSK2292767	Part A:50 µg GSK2292767/200 µg GSK2292767/Placebo	Part A:50 µg GSK2292767/200 µg GSK2292767/1000 µg GSK2292767	Part A:Placebo/500 µg GSK2292767/2000 µg GSK2292767	Part A:100 µg GSK2292767/Placebo/2000 µg GSK2292767	Part A:100 µg GSK2292767/500 µg GSK2292767/Placebo	Part A:100 µg GSK2292767/500 µg GSK2292767/2000 µg GSK2292767
Started	3	4	5	4	4	4	4	4
Completed	3	4	4	2	4	4	4	4
Not completed	0	0	1	2	0	0	0	0
Withdrew: Physician decision	0	0	1	1	0	0	0	0
Withdrew: Withdrawal by subject	0	0	0	1	0	0	0	0

Part A, Period 3 (1 Day)

Participant flow — Part A, Period 3 (1 Day)
Milestone	Part A: Placebo/200 µg GSK2292767/1000 µg GSK2292767	Part A:50 µg GSK2292767/Placebo/1000 µg GSK2292767	Part A:50 µg GSK2292767/200 µg GSK2292767/Placebo	Part A:50 µg GSK2292767/200 µg GSK2292767/1000 µg GSK2292767	Part A:Placebo/500 µg GSK2292767/2000 µg GSK2292767	Part A:100 µg GSK2292767/Placebo/2000 µg GSK2292767	Part A:100 µg GSK2292767/500 µg GSK2292767/Placebo	Part A:100 µg GSK2292767/500 µg GSK2292767/2000 µg GSK2292767
Started	3	4	4	2	4	4	4	4
Completed	3	4	4	2	4	4	4	4
Not completed	0	0	0	0	0	0	0	0

Part B (14 Days)

Participant flow — Part B (14 Days)
Milestone	Part B:Placebo	Part B:GSK2292767 2000 µg OD
Started	3	9
Completed	3	9
Not completed	0	0

Outcome measures

PrimaryPart A: Number of Participants With Any Non-serious Adverse Event (nSAE) and Any Serious Adverse Event (SAE)

An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect, any other situation according to medical or scientific judgment or all events of possible drug-induced liver injury with hyperbilirubinemia were categorized as SAE. Participants with 5 percent nSAEs and SAEs has been reported.

Time frame:: Up to 12 weeks
Reported as:: Count of participants · Participants

Part A: Number of Participants With Any Non-serious Adverse Event (nSAE) and Any Serious Adverse Event (SAE)
Participants	Placebo	50 µg OD	100 µg OD	200 µg OD	500 µg OD	1000 µg OD	2000 µg OD
nSAE	6	9	6	7	6	4	5
SAE	0	0	0	0	0	0	0

PrimaryPart B: Number of Participants With Any AE and Any SAE

Time frame:: Up to 4 weeks
Reported as:: Count of participants · Participants

Part B: Number of Participants With Any AE and Any SAE
Participants	Placebo	2000 µg OD
nSAE	3	8
SAE	0	0

PrimaryPart A: Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)

Blood pressure in part A was assessed in a semi supine position with a completely automated device. SBP and DBP measurements were preceded by at least 5 minutes of rest for the participant in a quiet setting without distractions. Baseline was defined as the latest pre-dose assessment. Change from Baseline was defined as the value at indicated time point minus Baseline value.

Time frame:: Baseline, 30 minutes, 1, 6, 12 and 24 hours post-dose in each treatment period
Reported as:: Mean · Millimeters of mercury

Part A: Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
Millimeters of mercury	Placebo	50 µg OD	100 µg OD	200 µg OD	500 µg OD	1000 µg OD	2000 µg OD
DBP, 30 min	0.3 ± 6.66	2.0 ± 6.48	2.4 ± 4.91	2.0 ± 5.23	2.5 ± 6.20	-1.6 ± 5.36	1.9 ± 3.58
DBP, 1 hour	0.8 ± 7.02	3.1 ± 4.98	3.8 ± 4.65	1.2 ± 3.63	4.1 ± 4.44	-0.9 ± 7.72	0.8 ± 5.04
DBP, 6 hour	0.1 ± 5.48	0.3 ± 7.41	1.8 ± 3.84	1.9 ± 7.04	3.2 ± 6.22	-2.0 ± 2.83	3.1 ± 7.93
DBP, 12 hour	2.3 ± 6.36	3.1 ± 6.72	2.9 ± 3.45	4.0 ± 7.92	2.3 ± 6.41	0.7 ± 4.39	3.1 ± 7.76
DBP, 24 hour	-1.3 ± 6.81	0.6 ± 6.32	1.5 ± 3.90	3.6 ± 8.03	3.6 ± 4.21	-2.9 ± 5.62	-0.1 ± 5.12
SBP, 30 min	-3.2 ± 6.28	-0.2 ± 5.06	-3.9 ± 9.67	0.8 ± 5.16	-2.3 ± 6.20	-6.1 ± 4.73	-3.3 ± 5.85
SBP, 1 hour	-3.4 ± 7.72	-1.5 ± 4.74	-5.6 ± 8.07	-3.4 ± 7.01	-2.2 ± 6.53	-7.1 ± 9.06	-3.9 ± 8.38
SBP, 6 hour	1.3 ± 8.79	0.7 ± 8.23	-3.8 ± 9.03	4.5 ± 7.92	2.8 ± 6.34	-0.3 ± 7.48	-0.8 ± 5.86
SBP, 12 hour	3.9 ± 6.65	3.3 ± 6.52	-1.3 ± 8.65	3.6 ± 4.93	5.0 ± 9.53	1.6 ± 4.03	3.3 ± 7.33
SBP, 24 hour	-0.7 ± 6.19	-0.9 ± 7.54	-5.3 ± 5.26	0.0 ± 8.67	-1.5 ± 6.78	-4.3 ± 5.74	-2.8 ± 5.77

PrimaryPart B: Change From Baseline in SBP and DBP

Blood pressure in part B were assessed in semi supine position with a completely automated device. SBP and DBP preceded by at least 5 minutes of rest for the participant in a quiet setting without distractions. Baseline was defined as measurements done on Day -1. Change from Baseline was defined as the value at indicated time point minus Baseline value.

Time frame:: Baseline, Pre-dose on Days 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14, 24 hours post-dose on Day 14
Reported as:: Mean · Millimeters of mercury

Part B: Change From Baseline in SBP and DBP
Millimeters of mercury	Placebo	2000 µg OD
DBP, Day 2, pre-dose	-6.0 ± 10.15	-3.0 ± 4.72
DBP, Day 3, pre-dose	-8.3 ± 9.45	-1.3 ± 5.85
DBP, Day 4, pre-dose	-7.3 ± 12.10	-3.4 ± 4.90
DBP, Day 5, pre-dose	-10.7 ± 11.72	-2.2 ± 5.09
DBP, Day 6, pre-dose	-7.7 ± 10.02	-3.7 ± 4.72
DBP, Day 7, pre-dose	-8.3 ± 9.45	-2.3 ± 3.57
DBP, Day 8, pre-dose	-5.7 ± 12.42	-4.3 ± 3.91
DBP, Day 9, pre-dose	-6.3 ± 11.93	-2.8 ± 4.02
DBP, Day 10, pre-dose	-8.7 ± 11.93	-0.6 ± 6.21
DBP, Day 11, pre-dose	-9.3 ± 12.74	-2.1 ± 4.46
DBP, Day 12, pre-dose	-7.3 ± 7.51	-2.9 ± 4.23
DBP, Day 13, pre-dose	-7.0 ± 10.58	-3.0 ± 5.43
DBP, Day 14, pre-dose	-8.3 ± 10.97	-3.2 ± 3.83
DBP, Day 14, 24 hours	-1.3 ± 1.53	-1.0 ± 5.17
SBP, Day 2, pre-dose	3.3 ± 11.24	-5.4 ± 7.60
SBP, Day 3, pre-dose	-0.7 ± 9.07	-0.1 ± 8.70
SBP, Day 4, pre-dose	2.3 ± 10.50	-4.1 ± 7.75
SBP, Day 5, pre-dose	-1.0 ± 9.85	-5.1 ± 8.74
SBP, Day 6, pre-dose	-1.7 ± 8.50	-7.2 ± 7.26
SBP, Day 7, pre-dose	-4.7 ± 5.86	-5.0 ± 9.50
SBP, Day 8, pre-dose	-1.3 ± 8.08	-7.6 ± 10.01
SBP, Day 9, pre-dose	0.0 ± 3.61	-5.8 ± 4.27
SBP, Day 10, pre-dose	-4.7 ± 5.13	-5.2 ± 6.65
SBP, Day 11, pre-dose	-6.3 ± 5.51	-4.4 ± 9.06
SBP, Day 12, pre-dose	-6.3 ± 4.73	-5.4 ± 6.54
SBP, Day 13, pre-dose	2.3 ± 4.93	-4.9 ± 6.51
SBP, Day 14, pre-dose	-1.7 ± 7.57	-4.6 ± 7.33
SBP, Day 14, 24 hours	-0.7 ± 2.08	-3.7 ± 6.71

PrimaryPart A: Change From Baseline in Heart Rate

Heart rate in part A was assessed in a semi supine position with a completely automated device. Heart rate measurement was preceded by at least 5 minutes of rest for the participant in a quiet setting without distractions. Baseline was defined as latest pre-dose measurement. Change from Baseline was defined as the value at indicated time point minus Baseline value.

Time frame:: Baseline, 30 minutes, 1, 6, 12 and 24 hours post-dose in each treatment period
Reported as:: Mean · Beats per minute

Part A: Change From Baseline in Heart Rate
Beats per minute	Placebo	50 µg OD	100 µg OD	200 µg OD	500 µg OD	1000 µg OD	2000 µg OD
30 min	-5.3 ± 5.39	-5.8 ± 5.40	-8.9 ± 8.46	-6.1 ± 5.25	-6.3 ± 5.37	-12.4 ± 6.80	-6.1 ± 7.24
1 hour	-8.0 ± 5.60	-4.8 ± 3.57	-9.0 ± 8.90	-7.2 ± 5.27	-4.3 ± 7.63	-13.0 ± 7.98	-9.8 ± 7.55
6 hour	4.3 ± 9.45	4.3 ± 5.58	1.0 ± 9.55	4.9 ± 5.42	7.4 ± 6.37	-1.3 ± 7.42	2.4 ± 7.98
12 hour	4.2 ± 7.11	6.4 ± 7.80	-0.3 ± 10.17	3.7 ± 6.24	3.7 ± 5.85	-1.8 ± 8.61	5.3 ± 10.38
24 hour	-2.3 ± 6.24	-1.7 ± 6.69	-1.8 ± 8.70	-3.0 ± 7.23	-1.8 ± 8.02	-6.9 ± 5.88	-4.0 ± 8.18

PrimaryPart B: Change From Baseline in Heart Rate

Heart rate in part B was assessed in a semi supine position with a completely automated device. Heart rate measurement was preceded by at least 5 minutes of rest for the participant in a quiet setting without distractions. Baseline was defined as latest pre-dose measurement. Change from Baseline was defined as the value at indicated time point minus Baseline value.

Time frame:: Baseline, Pre-dose on Days 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14, 24 hours post-dose on Day 14
Reported as:: Mean · Beats per minute

Part B: Change From Baseline in Heart Rate
Beats per minute	Placebo	2000 µg OD
Day 2, pre-dose	-0.3 ± 6.11	-0.7 ± 7.14
Day 3, pre-dose	3.0 ± 6.56	0.0 ± 6.76
Day 4, pre-dose	6.7 ± 11.50	-2.2 ± 8.03
Day 5, pre-dose	-2.3 ± 9.45	-3.2 ± 9.26
Day 6, pre-dose	-2.7 ± 8.14	-6.4 ± 7.80
Day 7, pre-dose	3.7 ± 9.07	-0.8 ± 11.12
Day 8, pre-dose	4.7 ± 13.50	-3.2 ± 5.85
Day 9, pre-dose	1.7 ± 5.13	-3.4 ± 8.49
Day 10, pre-dose	1.0 ± 11.79	-2.7 ± 10.28
Day 11, pre-dose	-1.3 ± 14.64	-2.8 ± 11.98
Day 12, pre-dose	-5.7 ± 7.23	-4.9 ± 6.47
Day 13, pre-dose	4.0 ± 15.00	-4.4 ± 6.13
Day 14, pre-dose	6.0 ± 11.27	-5.8 ± 9.36
Day 14, 24 hours	-2.3 ± 7.57	-2.2 ± 7.56

PrimaryPart A: Change From Baseline in Respiratory Rate

Respiratory rate in part A was assessed in a semi supine position after 5 minutes of rest for the participant in a quiet setting without distractions. Baseline was defined as measurements done on Day -1. Change from Baseline was defined as the value at indicated time point minus Baseline value. Baseline was defined as latest pre-dose measurement. Change from Baseline was defined as the value at indicated time point minus Baseline value.

Time frame:: Baseline, 30 minutes, 1, 6, 12 and 24 hours post-dose in each treatment period
Reported as:: Median · Breaths per minute

Part A: Change From Baseline in Respiratory Rate
Breaths per minute	Placebo	50 µg OD	100 µg OD	200 µg OD	500 µg OD	1000 µg OD	2000 µg OD
30 min	-0.2 ± 1.78	-1.1 ± 2.81	-1.5 ± 1.98	0.8 ± 2.48	0.3 ± 2.01	0.3 ± 2.74	-0.2 ± 1.95
1 hour	-0.3 ± 2.27	-1.0 ± 2.76	-1.2 ± 2.17	0.8 ± 2.03	0.6 ± 2.23	-0.3 ± 2.35	-0.8 ± 2.41
6 hour	0.1 ± 2.18	0.0 ± 3.67	1.0 ± 1.95	1.0 ± 2.97	0.8 ± 3.33	0.6 ± 2.74	0.3 ± 2.23
12 hour	0.7 ± 2.31	0.7 ± 3.11	-0.4 ± 2.43	1.3 ± 2.14	0.6 ± 2.75	0.3 ± 2.55	-0.3 ± 1.86
24 hour	-0.6 ± 2.29	-0.9 ± 3.20	-1.0 ± 2.63	0.4 ± 2.50	-0.8 ± 2.08	-0.8 ± 3.15	-0.4 ± 1.68

PrimaryPart B: Change From Baseline in Respiratory Rate

Respiratory rate in part B was assessed in a semi supine position after 5 minutes of rest for the participant in a quiet setting without distractions. Baseline was defined as measurements done on Day -1. Change from Baseline was defined as the value at indicated time point minus Baseline value. Baseline was defined as latest pre-dose measurement. Change from Baseline was defined as the value at indicated time point minus Baseline value.

Time frame:: Baseline, Pre-dose on Days 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14, 24 hours post-dose on Day 14
Reported as:: Mean · Breaths per minute

Part B: Change From Baseline in Respiratory Rate
Breaths per minute	Placebo	2000 µg OD
Day 2, pre-dose	-2.3 ± 0.58	-0.6 ± 3.17
Day 3, pre-dose	-2.3 ± 2.31	-1.0 ± 3.20
Day 4, pre-dose	-2.3 ± 2.08	-0.3 ± 2.96
Day 5, pre-dose	-2.7 ± 2.31	-1.4 ± 2.65
Day 6, pre-dose	-2.7 ± 0.58	-1.6 ± 2.92
Day 7, pre-dose	-2.3 ± 2.31	-0.8 ± 2.59
Day 8, pre-dose	-2.7 ± 0.58	-0.7 ± 2.45
Day 9, pre-dose	-2.0 ± 2.00	0.1 ± 2.98
Day 10, pre-dose	-1.7 ± 2.31	-1.2 ± 2.54
Day 11, pre-dose	-3.3 ± 0.58	-0.9 ± 3.62
Day 12, pre-dose	-2.3 ± 1.15	-1.0 ± 2.74
Day 13, pre-dose	-1.3 ± 1.15	-0.1 ± 3.06
Day 14, pre-dose	-2.0 ± 1.73	-1.1 ± 2.89
Day 14, 24 hours	-2.3 ± 1.53	-1.1 ± 2.26

PrimaryPart A: Change From Baseline in Tympanic Temperature

Tympanic temperature in part A was assessed in semi supine position after 5 minutes of rest for the participant in a quiet setting without distractions. Baseline was defined as measurements done on Day -1. Change from Baseline was defined as the value at indicated time point minus Baseline value. Baseline was defined as latest pre-dose measurement. Change from Baseline was defined as the value at indicated time point minus Baseline value.

Time frame:: Baseline, 30 minutes, 1, 6, 12 and 24 hours post-dose in each treatment period
Reported as:: Mean · Celsius

Part A: Change From Baseline in Tympanic Temperature
Celsius	Placebo	50 µg OD	100 µg OD	200 µg OD	500 µg OD	1000 µg OD	2000 µg OD
30 min	0.03 ± 0.313	0.07 ± 0.210	0.04 ± 0.574	0.05 ± 0.395	-0.05 ± 0.366	0.03 ± 0.287	0.16 ± 0.385
1 hour	-0.10 ± 0.348	0.06 ± 0.173	0.05 ± 0.498	-0.06 ± 0.287	0.05 ± 0.478	0.12 ± 0.311	0.10 ± 0.449
6 hour	0.20 ± 0.390	0.08 ± 0.259	0.18 ± 0.566	0.07 ± 0.446	0.17 ± 0.409	0.14 ± 0.361	0.19 ± 0.493
12 hour	0.14 ± 0.478	0.31 ± 0.370	0.27 ± 0.542	0.26 ± 0.355	0.20 ± 0.591	0.46 ± 0.400	0.18 ± 0.622
24 hour	-0.06 ± 0.375	-0.02 ± 0.233	-0.02 ± 0.513	0.03 ± 0.287	0.07 ± 0.392	0.11 ± 0.326	0.02 ± 0.497

PrimaryPart B: Change From Baseline in Tympanic Temperature

Tympanic temperature in part B was assessed in semi supine position after 5 minutes of rest for the participant in a quiet setting without distractions. Baseline was defined as measurements done on Day -1. Change from Baseline was defined as the value at indicated time point minus Baseline value. Baseline was defined as latest pre-dose measurement. Change from Baseline was defined as the value at indicated time point minus Baseline value.

Time frame:: Baseline, Pre-dose on Days 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14, 24 hours post-dose on Day 14
Reported as:: Mean · Celsius

Part B: Change From Baseline in Tympanic Temperature
Celsius	Placebo	2000 µg OD
Day 2, pre-dose	0.17 ± 0.058	0.26 ± 0.477
Day 3, pre-dose	0.03 ± 0.379	0.37 ± 0.450
Day 4, pre-dose	0.13 ± 0.153	0.26 ± 0.416
Day 5, pre-dose	0.13 ± 0.404	0.34 ± 0.445
Day 6, pre-dose	0.10 ± 0.265	0.31 ± 0.322
Day 7, pre-dose	-0.10 ± 0.100	0.41 ± 0.448
Day 8, pre-dose	-0.27 ± 0.231	0.29 ± 0.462
Day 9, pre-dose	-0.03 ± 0.153	0.21 ± 0.326
Day 10, pre-dose	0.13 ± 0.451	0.31 ± 0.392
Day 11, pre-dose	0.13 ± 0.306	0.34 ± 0.343
Day 12, pre-dose	0.00 ± 0.265	0.32 ± 0.415
Day 13, pre-dose	0.07 ± 0.513	0.33 ± 0.466
Day 14, pre-dose	0.17 ± 0.115	0.32 ± 0.458
Day 14, 24 hours	0.17 ± 0.115	0.32 ± 0.502

PrimaryPart A: Maximal Amount of Air Forcefully Exhaled in 1 Second (FEV1)

FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. FEV1 was measured using spirometry at the indicated time. FEV1 measurements were repeated until three technically acceptable measurements (within 150 milliliter \[mL\] of each other) were made. Data for FEV1 for part A is presented here.

Time frame:: Day 1 (pre-dose and 1 hour)
Reported as:: Mean · Liters

Part A: Maximal Amount of Air Forcefully Exhaled in 1 Second (FEV1)
Liters	Placebo	50 µg OD	100 µg OD	200 µg OD	500 µg OD	1000 µg OD	2000 µg OD
Pre-dose	4.389 ± 0.6781	4.044 ± 0.6717	4.768 ± 0.8348	3.896 ± 0.7292	4.288 ± 0.5288	4.036 ± 0.4806	4.391 ± 0.5072
1 hour	4.347 ± 0.6781	4.028 ± 0.7177	4.461 ± 0.4693	3.811 ± 0.6757	4.223 ± 0.5153	4.024 ± 0.5971	4.435 ± 0.5851

PrimaryPart B: Maximal Amount of Air Forcefully Exhaled in 1 Second (FEV1)

FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. FEV1 was measured using spirometry at the indicated time. Existing spirometry equipment was used. FEV1 measurements were repeated until three technically acceptable measurements (within 150 mL of each other) were made. Data for FEV1 for part B is presented here.

Time frame:: Up to Day 14
Reported as:: Mean · Liters

Part B: Maximal Amount of Air Forcefully Exhaled in 1 Second (FEV1)
Liters	Placebo	2000 µg OD
Day -1	4.333 ± 0.1739	4.570 ± 0.6275
Day 1,pre-dose	4.277 ± 0.0987	4.408 ± 0.6852
Day 1,1 hour	4.323 ± 0.0981	4.413 ± 0.6931
Day 2,pre-dose	4.357 ± 0.0551	4.446 ± 0.7230
Day 2,1 hour	4.373 ± 0.0569	4.486 ± 0.6828
Day 3,pre-dose	4.407 ± 0.1504	4.474 ± 0.6999
Day 3,1 hour	4.460 ± 0.2771	4.493 ± 0.6548
Day 4,pre-dose	4.447 ± 0.1159	4.483 ± 0.7241
Day 4,1 hour	4.307 ± 0.1060	4.519 ± 0.7444
Day 5,pre-dose	4.290 ± 0.1082	4.494 ± 0.8042
Day 5,1 hour	4.480 ± 0.2600	4.486 ± 0.7647
Day 6,pre-dose	4.300 ± 0.0173	4.498 ± 0.7086
Day 6,1 hour	4.533 ± 0.3177	4.573 ± 0.7994
Day 7,pre-dose	4.467 ± 0.2386	4.503 ± 0.8559
Day 7,1 hour	4.400 ± 0.2207	4.581 ± 0.8018
Day 8,pre-dose	4.383 ± 0.0351	4.449 ± 0.7952
Day 8,1 hour	4.440 ± 0.1229	4.572 ± 0.6952
Day 9,pre-dose	4.483 ± 0.2458	4.512 ± 0.7483
Day 9,1 hour	4.470 ± 0.1179	4.627 ± 0.7737
Day 10,pre-dose	4.443 ± 0.1419	4.473 ± 0.6942
Day 10,1 hour	4.583 ± 0.1914	4.582 ± 0.7609
Day 11,pre-dose	4.423 ± 0.1422	4.570 ± 0.7944
Day 11,1 hour	4.463 ± 0.2540	4.609 ± 0.7460
Day 12,pre-dose	4.417 ± 0.1258	4.599 ± 0.7469
Day 12,1 hour	4.440 ± 0.0917	4.600 ± 0.7029
Day 13,pre-dose	4.400 ± 0.2252	4.514 ± 0.7352
Day 13,1 hour	4.653 ± 0.2146	4.768 ± 0.7609
Day 14,pre-dose	4.533 ± 0.0666	4.541 ± 0.8512
Day 14,1 hour	4.557 ± 0.1701	4.609 ± 0.8102

PrimaryPart A: Forced Vital Capacity (FVC)

FVC is a measure of lung function and is defined as total amount of air that can be exhaled during FEV1 test. FVC was planned to measured using spirometry. The FVC need to be normal at screening and is part of the Forced Expiratory ratio (FEV1/FVC) which should lie between 0.7-0.8 to indicate no chronic obstruction or restriction. The FVC was therefore only used at screening and requires no ongoing analysis during the study. All other indications of obstruction in the study, e.g. paradoxical bronchospasm was provided by the FEV1. The FVC therefore require no analysis.

Time frame:: Day 1 (pre-dose and 1 hour)

No measurements were reported for this outcome.

PrimaryPart B: Forced Vital Capacity (FVC)

Time frame:: Day 1 (pre-dose and 1 hour)

No measurements were reported for this outcome.

PrimaryPart A: Number of Participants With Electrocardiogram (ECG) Abnormalities

Triplicate/Single 12-lead ECG was obtained using an automated ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTFc intervals. Number of participants with abnormal clinically significant and abnormal-not clinically significant values at any time post-Baseline is presented.

Time frame:: Day 1 of each treatment period
Reported as:: Count of participants · Participants

Part A: Number of Participants With Electrocardiogram (ECG) Abnormalities
Participants	Placebo	50 µg OD	100 µg OD	200 µg OD	500 µg OD	1000 µg OD	2000 µg OD
Abnormal - not clinically significant	2	2	1	0	1	0	1
Abnormal - clinically significant	0	0	0	0	0	0	0

PrimaryPart B: Number of Participants With ECG Abnormalities

Time frame:: Pre-dose on Days 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14, 24 hours post-dose on Day 14
Reported as:: Count of participants · Participants

Part B: Number of Participants With ECG Abnormalities
Participants	Placebo	2000 µg OD
Abnormal - not clinically significant	1	2
Abnormal - clinically significant	0	0

PrimaryPart A: Number of Participants With Clinical Chemistry Values of Potential Clinical Importance Criteria (PCC)

Number of participants with clinical chemistry values that changed from normal to high or low in part A are presented. Chemistry parameters for which PCC values were identified were: Alkaline Phosphatase, Alanine Amino Transferase, aspartate aminotransferase, Total Bilirubin, calcium, glucose, potassium and Sodium.

Time frame:: 24 hours post-dose in each treatment period.
Reported as:: Count of participants · Participants

Part A: Number of Participants With Clinical Chemistry Values of Potential Clinical Importance Criteria (PCC)
Participants	100 µg OD	500 µg OD
Alkaline Phosphatase; to high	0	0
Alanine Amino Transferase; to high	0	1
Aspartate Amino Transferase; to high	0	0
Total Bilirubin; to high	0	0
Calcium; to high	0	0
Calcium; to low	0	0
Glucose; to high	1	0
Glucose; to low	0	0
Potassium; to high	0	0
Potassium; to low	0	0
Sodium; to high	0	0
Sodium; to low	0	0

PrimaryPart B: Number of Participants With Clinical Chemistry Values of PCC

Number of participants with clinical chemistry values that changed from normal to high or low in part B are presented. Chemistry parameters for which PCC values were identified were: Alkaline Phosphatase, Alanine Amino Transferase, aspartate aminotransferase, Total Bilirubin, calcium, glucose, potassium and Sodium. Only participants with data available at specified time points were analyzed (represented by n=X in category titles)

Time frame:: Pre-dose on Days 2, 4, 6, 8, 10, 12, and 14, 24 hours post-dose on Day 14
Reported as:: Count of participants · Participants

Part B: Number of Participants With Clinical Chemistry Values of PCC
Participants	Placebo	2000 µg OD
Alkaline Phosphatase,Day 2;to high,n=3,9	0	0
Alkaline Phosphatase,Day 4;to high,n=3,9	0	0
Alkaline Phosphatase,Day 6;to high,n=3,9	0	0
Alkaline Phosphatase,Day 8;to high,n=3,9	0	0
Alkaline Phosphatase,Day 10;to high,n=3,9	0	0
Alkaline Phosphatase,Day 12;to high,n=3,9	0	0
Alkaline Phosphatase,Day 14,pre-dose;to high,n=3,9	0	0
Alkaline Phosphatase,Day 14,24 hour;to high,n=3,9	0	0
Alanine Amino Transferase,Day 2;to high,n=3,9	0	0
Alanine Amino Transferase,Day 4;to high,n=3,9	0	0
Alanine Amino Transferase,Day 6;to high,n=3,9	0	0
Alanine Amino Transferase,Day 8;to high,n=3,9	0	0
Alanine Amino Transferase,Day 10;to high,n=3,9	0	0
Alanine Amino Transferase,Day 12;to high,n=3,9	0	0
Alanine Amino Transferase,Day 14,pre dose;to n=3,9	0	0
Alanine Amino Transferase,Day 14,24 hour;to hn=3,9	0	0
Aspartate Amino Transferase,Day 2;to high,n=3,8	0	0
Aspartate Amino Transferase,Day 4;to high,n=3,9	0	0
Aspartate Amino Transferase,Day 6;to high,n=3,9	0	0
Aspartate Amino Transferase,Day 8;to high,n=3,9	0	0
Aspartate Amino Transferase,Day 10;to high,n=3,9	0	0
Aspartate Amino Transferase,Day 12;to high,n=3,9	0	0
Aspartate Amino Transferase,Day 14,pre dose;n=2,9	0	0
Aspartate Amino Transferase,Day 14,24 hour,n=3,8	0	0
Total Bilirubin,Day 2,;to high,n=3,9	0	0
Total Bilirubin,Day 4;to high,n=3,9	0	0
Total Bilirubin,Day 6;to high,n=3,9	0	0
Total Bilirubin,Day 8;to high,n=3,9	0	0
Total Bilirubin,Day 10;to high,n=3,9	0	0
Total Bilirubin,Day 12;to high,n=3,9	0	0
Total Bilirubin,Day 14,pre dose,n=3,9	0	0
Total Bilirubin,Day 14,24 hours,n=3,9	0	0
Calcium,Day 2;to high,n=3,9	0	0
Calcium,Day 2;to low,n=3,9	0	0
Calcium,Day 4;to high,n=3,9	0	0
Calcium,Day 4;to low,n=3,9	0	0
Calcium,Day 6;to high,n=3,9	0	0
Calcium,Day 6;to low,n=3,9	0	0
Calcium,Day 8;to high,n=3,9	0	0
Calcium,Day 8;to low,n=3,9	0	0
Calcium,Day 10;to high,n=3,9	0	0
Calcium,Day 10;to low,n=3,9	0	0
Calcium,Day 12;to high,n=3,9	0	0
Calcium,Day 12;to low,n=3,9	0	0
Calcium,Day 14,pre dose,to high,n=3,9	0	0
Calcium,Day 14,pre dose,to low,n=3,9	0	0
Calcium,Day 14,24 hour,to high,n=3,9	0	0
Calcium,Day 14,24 hour,to low,n=3,9	0	0
Glucose,Day 2;to high,n=3,9	0	0
Glucose,Day 2;to low,n=3,9	0	0
Glucose,Day 4;to high,n=3,9	0	0
Glucose,Day 4;to low,n=3,9	0	0
Glucose,Day 6;to high,n=3,9	0	0
Glucose,Day 6;to low, n=3,9	0	0
Glucose,Day 8;to high,n=3,9	0	0
Glucose,Day 8;to low,n=3,9	0	0
Glucose,Day 10;to high,n=3,9	0	0
Glucose,Day 10;to low,,n=3,9	0	0
Glucose,Day 12;to high,n=3,9	0	0
Glucose,Day 12;to low,n=3,9	0	0
Glucose,Day 14;pre dose,to high,n=3,9	0	0
Glucose,Day 14;pre dose,to low,n=3,9	0	0
Glucose,Day 14;24 hours,to high,n=3,9	0	0
Glucose,Day 14;24 hours,to low,n=3,9	0	0
Potassium,Day 2;to high,n=3,9	0	0
Potassium,Day 2;to low,n=3,9	0	0
Potassium,Day 4;to high,n=3,9	0	0
Potassium,Day 4,n=3,9	0	0
Potassium,Day 6;to high,n=3,9	0	0
Potassium,Day 6,to low,n=3,9	0	0
Potassium,Day 8;to high,n=3,9	0	0
Potassium,Day 8, to low,n=3,9	0	0
Potassium,Day 10;to high,,n=3,9	0	0
Potassium,Day 10,to low,n=3,9	0	0
Potassium,Day 12;to high,,n=3,9	0	0
Potassium,Day 12,to low,n=3,9	0	0
Potassium,Day 14,pre dose,to high,n=3,9	0	0
Potassium,Day 14,pre dose,to low,n=3,9	0	0
Potassium,Day 14,24 hour ,to low,n=3,9	0	0
Potassium,Day 14,24 hour,to low,n=3,9	0	0
Sodium,Day 2, to high,n=3,9	0	0
Sodium,Day 2, to low,n=3,9	0	0
Sodium,Day 4, to high,n=3,9	0	0
Sodium,Day 4, to low,n=3,9	0	0
Sodium,Day 6, to high,n=3,9	0	0
Sodium,Day 6, to low,n=3,9	0	0
Sodium,Day 8, to high,n=3,9	0	0
Sodium,Day 8, to low,n=3,9	0	0
Sodium,Day 10, to high,n=3,9	0	0
Sodium,Day 10, to low,n=3,9	0	0
Sodium,Day 12, to high,n=3,9	0	0
Sodium,Day 12, to low,n=3,9	0	0
Sodium,Day 14,pre dose, to high,n=3,9	0	0
Sodium,Day 14,pre dose, to low,n=3,9	0	0
Sodium,Day 14,24 hour, to high,n=3,9	0	0
Sodium,Day 14,24 hour, to low,n=3,9	0	0

PrimaryPart A: Number of Participants With Hematology Values of PCC

Number of participants with hematology parameters of PCC which shifted from normal to high in part A are presented. Hematology parameters for which PCC values were identified were: Hemoglobin, Hematocrit, Lymphocytes, Total Neutrophils, Platelet count and White Blood Cell (WBC) Count. Only those participants with data available at the specified time points were analyzed (represented by n=X in category titles)

Time frame:: 24 hours post-dose in each treatment period
Reported as:: Count of participants · Participants

Part A: Number of Participants With Hematology Values of PCC
Participants	Placebo	50 µg OD	100 µg OD	200 µg OD	500 µg OD	1000 µg OD	2000 µg OD
Hemoglobin; to high,n=23,12,12,13,12,9,12	0	0	0	0	0	0	0
Hematocrit; to high,n=23,12,12,13,12,9,12	0	0	0	0	0	0	0
Lymphocytes; to low,n=23,12,12,13,12,9,12	0	0	0	0	0	0	0
Total Neutrophils; to low,n=23,12,12,13,12,9,12	0	0	0	0	0	0	0
Platelet count;to high;n=23, 12, 11, 13, 11, 9, 11	0	0	0	0	0	0	0
Platelet count; to low;n=23, 12, 11, 13, 11, 9, 11	0	0	0	0	0	0	0
WBC count,to high,n=23, 12, 12, 13, 12, 9, 12	0	0	0	0	0	0	0
WBC count,to low,n=23, 12, 12, 13, 12, 9, 12	0	0	0	0	0	0	0

PrimaryPart B: Number of Participants With Hematology Values of PCC

Number of participants with hematology parameters of PCC which shifted from normal to high in part B are presented. Hematology parameters for which PCC values were identified were: Hemoglobin, Hematocrit, Lymphocytes, Total Neutrophils, Platelet count and WBC count

Time frame:: Pre-dose on Days 2, 4, 6, 8, 10, 12, and 14, 24 hours post-dose on Day 14
Reported as:: Count of participants · Participants

Part B: Number of Participants With Hematology Values of PCC
Participants	Placebo	2000 µg OD
Hemoglobin,Day 2	0	0
Hemoglobin,Day 4	0	0
Hemoglobin,Day 6	0	0
Hemoglobin,Day 8	0	0
Hemoglobin,Day 10	0	0
Hemoglobin,Day 12	0	0
Hemoglobin,Day 14,pre dose	0	0
Hemoglobin,Day 14,24 hour	0	0
Hematocrit,Day 2	0	0
Hematocrit,Day 4	0	0
Hematocrit,Day 6	0	0
Hematocrit,Day 8	0	0
Hematocrit,Day 10	0	0
Hematocrit,Day 12	0	0
Hematocrit,Day 14,pre dose	0	0
Hematocrit,Day 14,24 hour	0	0
Lymphocytes,Day 2	0	0
Lymphocytes,Day 4	0	0
Lymphocytes,Day 6	0	0
Lymphocytes,Day 8	0	0
Lymphocytes,Day 10	0	0
Lymphocytes,Day 12	0	0
Lymphocytes,Day 14,pre dose	0	0
Lymphocytes,Day 14,24 hour	0	0
Total Neutrophils,Day 2	0	0
Total Neutrophils,Day 4	0	0
Total Neutrophils,Day 6	0	0
Total Neutrophils,Day 8	0	0
Total Neutrophils,Day 10	0	0
Total Neutrophils,Day 12	0	0
Total Neutrophils,Day 14,pre dose	0	0
Total Neutrophils,Day 14,24 hour	0	0
Platelet count,Day 2	0	0
Platelet count,Day 4	0	0
Platelet count,Day 6	0	0
Platelet count,Day 8	0	0
Platelet count,Day 10	0	0
Platelet count,Day 12	0	0
Platelet count,Day 14,pre dose	0	0
Platelet count,Day 14,24 hour	0	0
WBC count,Day 2	0	0
WBC count,Day 4	0	0
WBC count,Day 6	0	0
WBC count,Day 8	0	0
WBC count,Day 10	0	0
WBC count,Day 12	0	0
WBC count,Day 14,pre dose	0	0
WBC count,Day 14,24 hour	0	0

SecondaryPart A: Area Under the Plasma Drug Concentration Versus Time Curve (AUC) From Zero to Time t (AUC [0 to t]), AUC From Zero to 24 Hours (AUC [0 to 24]) and AUC From Zero to Infinity (AUC [0 to Inf]) of GSK2292767

Blood samples were collected for pharmacokinetic analysis of GSK2292767 at the specified time points. Data for AUC (0 to t), AUC (0 to 24) and AUC (0 to inf) of GSK2292767 for part A is presented. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). Pharmacokinetic population comprised of participants in the 'All participant' population for whom a pharmacokinetic sample was obtained and analyzed.

Time frame:: Pre-dose (5 minutes (min), 30 min, 45 min, 1 hour (hr), 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr, and 24 hr post dose in each of the 3 treatment periods
Reported as:: Geometric mean · Hours*picograms per milliliter

Part A: Area Under the Plasma Drug Concentration Versus Time Curve (AUC) From Zero to Time t (AUC [0 to t]), AUC From Zero to 24 Hours (AUC [0 to 24]) and AUC From Zero to Infinity (AUC [0 to Inf]) of GSK2292767
Hours*picograms per milliliter	50 µg OD	100 µg OD	200 µg OD	500 µg OD	1000 µg OD	2000 µg OD
AUC (0-24);n=0,2,5,10,8,11	—	596.1161 ± 10.0	721.9301 ± 57.9	2460.3695 ± 70.3	3689.7545 ± 36.0	7781.2593 ± 52.5
AUC(0-inf);n=0,2,5,7,6,10	—	596.4042 ± 10.1	724.6058 ± 57.8	2211.9120 ± 81.5	3709.6509 ± 40.6	8383.6427 ± 57.8
AUC (0-t);n=12,12,12,12,9,12	69.5822 ± 133.1	337.0775 ± 48.3	633.3267 ± 59.6	2164.3817 ± 72.3	3440.6354 ± 37.1	7758.9831 ± 50.9

Statistical analysis

50 µg OD vs 100 µg OD · Ratio: 0.41 · 90% CI 0.27 to 0.61AUC(0-t). Standard error of mean was on logged scale
100 µg OD vs 200 µg OD · Ratio: 0.98 · 90% CI 0.65 to 1.47AUC(0-t).Standard error of mean was on logged scale
100 µg OD vs 500 µg OD · Ratio: 1.33 · 90% CI 1.01 to 1.74AUC(0-t).Standard error of mean was on logged scale
100 µg OD vs 1000 µg OD · Ratio: 1.06 · 90% CI 0.69 to 1.62AUC(0-t).Standard error of mean was on logged scale
100 µg OD vs 2000 µg OD · Ratio: 1.25 · 90% CI 0.95 to 1.64AUC(0-t).Standard error of mean was on logged scale

SecondaryPart B: AUC (0 to t), AUC (0 to 24) and AUC (0 to Inf) of GSK2292767

Blood samples were collected for pharmacokinetic analysis of GSK2292767 at the specified time points. Data for AUC (0 to t), AUC (0 to 24) and AUC (0 to inf) of GSK2292767 for part B is presented. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles).

Time frame:: Pre-dose, 5 minutes, 30 minutes, 45 minutes, 1, 2, 3, 4, 6, 8 and 12hours post dose on Day 1; pre-dose, 5 minutes, 30 minutes, 45 minutes, 1, 2, 3, 4, 6, 8 and 12hours post dose on Day 14
Reported as:: Geometric mean · Hours*picograms per milliliter

Part B: AUC (0 to t), AUC (0 to 24) and AUC (0 to Inf) of GSK2292767
Hours*picograms per milliliter	2000 µg OD
AUC (0-24); Day 1; n=8	8163.4986 ± 71.7
AUC (0-24); Day 14; n=9	9941.5681 ± 53.5
AUC(0-inf); Day 1; n=7	10162.0636 ± 66.1
AUC(0-inf);Day 14; n=7	13798.7637 ± 66.7
AUC (0-t); Day 1; n=9	7506.5587 ± 72.3
AUC (0-t); Day 14; n=9	11861.0783 ± 59.5

Statistical analysis

2000 µg OD · Ratio: 1.22 · 90% CI 1.01 to 1.47Treatment ratio of adjusted geometric mean (Day 14/Day 1) for AUC(0-24) is presented

SecondaryPart A: Maximum Observed Plasma Drug Concentration (Cmax) of GSK2292767

Blood samples were collected for pharmacokinetic analysis of GSK2292767 at the specified time points. Five min post dose concentrations on Days 2-13 were assumed to be the Cmax values. Data for Cmax of GSK2292767 for part A is presented. Cmax is defined as maximum observed plasma concentration of GSK2292767.

Time frame:: Pre-dose (5 min, 30 min, 45 min, 1 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr, and 24 hr post dose in each of the 3 treatment periods
Reported as:: Geometric mean · Picograms per milliliter

Part A: Maximum Observed Plasma Drug Concentration (Cmax) of GSK2292767
Picograms per milliliter	50 µg OD	100 µg OD	200 µg OD	500 µg OD	1000 µg OD	2000 µg OD
Part A: Maximum Observed Plasma Drug Concentration (Cmax) of GSK2292767	36.9018 ± 31.9	90.8927 ± 30.6	170.7836 ± 43.7	356.0719 ± 39.4	579.8303 ± 39.5	1325.3877 ± 44.9

Statistical analysis

50 µg OD vs 100 µg OD · Ratio: 0.78 · 90% CI 0.61 to 0.99
100 µg OD vs 200 µg OD · Ratio: 0.96 · 90% CI 0.75 to 1.22
100 µg OD vs 500 µg OD · Ratio: 0.81 · 90% CI 0.68 to 0.97
100 µg OD vs 1000 µg OD · Ratio: 0.66 · 90% CI 0.51 to 0.86
100 µg OD vs 2000 µg OD · Ratio: 0.76 · 90% CI 0.63 to 0.90

SecondaryPart B: Cmax of GSK2292767

Blood samples were collected for pharmacokinetic analysis of GSK2292767 at the specified time points. Five minute post dose concentrations on Days 2-13 were assumed to be the Cmax values. Data for Cmax of GSK2292767 for part B is presented.

Time frame:: Pre-dose, 5 minutes, 30 minutes, 45 minutes, 1, 2, 3, 4, 6, 8 and 12hours post dose on Day 1; pre-dose, 5 minutes, 30 minutes, 45 minutes, 1, 2, 3, 4, 6, 8 and 12hours post dose on Day 14
Reported as:: Geometric mean · Picograms per milliliter

Part B: Cmax of GSK2292767
Picograms per milliliter	2000 µg OD
Day 1	1145.7369 ± 45.9
Day 2	804.0363 ± 40.9
Day 3	871.6343 ± 38.0
Day 4	836.4375 ± 36.0
Day 5	764.7799 ± 35.5
Day 6	785.9632 ± 49.0
Day 7	877.1960 ± 37.7
Day 8	780.2829 ± 42.0
Day 9	745.6613 ± 35.2
Day 10	829.2395 ± 41.8
Day 11	952.5536 ± 40.1
Day 12	881.2328 ± 46.0
Day 13	888.9151 ± 42.9
Day 14	1305.8068 ± 41.9

Statistical analysis

2000 µg OD · Ratio: 1.14 · 90% CI 0.96 to 1.36Treatment ratio of adjusted geometric mean (Day 14/Day 1) for Cmax is presented

SecondaryPart A: Time to Maximum Observed Plasma Drug Concentration (Tmax) of GSK2292767

Blood samples were collected for pharmacokinetic analysis of GSK2292767 at the specified time points. Data for Tmax of GSK2292767 for part A is presented.

Time frame:: Pre-dose (5 min, 30 min, 45 min, 1 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr, and 24 hr post dose in each of the 3 treatment periods
Reported as:: Median · Hours

Part A: Time to Maximum Observed Plasma Drug Concentration (Tmax) of GSK2292767
Hours	50 µg OD	100 µg OD	200 µg OD	500 µg OD	1000 µg OD	2000 µg OD
Part A: Time to Maximum Observed Plasma Drug Concentration (Tmax) of GSK2292767	1.0046 (0.083 to 3.006)	0.7540 (0.086 to 4.002)	0.7500 (0.085 to 3.006)	0.7583 (0.085 to 4.001)	1.0264 (0.509 to 2.000)	1.0125 (0.502 to 3.010)

SecondaryPart B: Tmax of GSK2292767

Blood samples were collected for pharmacokinetic analysis of GSK2292767 at the specified time points. Data for Tmax of GSK2292767 for part B is presented.

Time frame:: Pre-dose, 5 minutes, 30 minutes, 45 minutes, 1, 2, 3, 4, 6, 8 and 12hours post dose on Day 1; pre-dose, 5 minutes, 30 minutes, 45 minutes, 1, 2, 3, 4, 6, 8 and 12hours post dose on Day 14
Reported as:: Median · Hours

Part B: Tmax of GSK2292767
Hours	2000 µg OD
Day 1	1.0056 (0.083 to 4.004)
Day 14	1.0050 (0.085 to 3.008)

SecondaryPart A: Terminal Half-life (T1/2) of GSK2292767

Blood samples were collected for pharmacokinetic analysis of GSK2292767 at the specified time points. Data for T1/2 of GSK2292767 for part A is presented. T1/2 is defined as the time required for one half of the total amount of a particular substance in a biological system to be degraded by biological processes. Only those participants with data available at the specified time points were analyzed.

Time frame:: Pre-dose (5 min, 30 min, 45 min, 1 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr, and 24 hr post dose in each of the 3 treatment periods
Reported as:: Geometric mean · Hours

Part A: Terminal Half-life (T1/2) of GSK2292767
Hours	50 µg OD	100 µg OD	200 µg OD	500 µg OD	1000 µg OD	2000 µg OD
Part A: Terminal Half-life (T1/2) of GSK2292767	—	1.6658 ± 32.1	2.3157 ± 16.9	3.9789 ± 57.6	3.1712 ± 30.2	6.3179 ± 35.8

SecondaryPart B: T1/2 of GSK2292767

Blood samples were collected for pharmacokinetic analysis of GSK2292767 at the specified time points. Data for T1/2 of GSK2292767 for part B is presented. T1/2 was defined as the time required for one half of the total amount of a particular substance in a biological system to be degraded by biological processes. Only those participants with data available at the specified time points were analyzed.

Time frame:: Pre-dose, 5 minutes, 30 minutes, 45 minutes, 1, 2, 3, 4, 6, 8 and 12hours post dose on Day 1; pre-dose, 5 minutes, 30 minutes, 45 minutes, 1, 2, 3, 4, 6, 8 and 12hours post dose on Day 14
Reported as:: Geometric mean · Hours

Part B: T1/2 of GSK2292767
Hours	2000 µg OD
Day 1	6.4625 ± 35.0
Day 14	11.7665 ± 48.6

SecondaryPart A: Trough Concentrations (Ctau) of GSK2292767

Blood samples were collected for pharmacokinetic analysis of GSK2292767 at the specified time points. Data for Ctau of GSK2292767 for part A is presented. Ctau is defined as the lowest concentration reached by a drug before the next dose is administered.

Time frame:: 24 hr post dose in each of the 3 treatment periods
Reported as:: Geometric mean · Picograms per milliliter

Part A: Trough Concentrations (Ctau) of GSK2292767
Picograms per milliliter	50 µg OD	100 µg OD	200 µg OD	500 µg OD	1000 µg OD	2000 µg OD
Part A: Trough Concentrations (Ctau) of GSK2292767	—	—	—	43.5566 ± 65.9	44.1985 ± 46.4	71.6727 ± 55.6

SecondaryPart B: Ctau of GSK2292767

Blood samples were collected for pharmacokinetic analysis of GSK2292767 at the specified time points. Data for Ctau of GSK2292767 for part B is presented. Ctau is defined as the lowest concentration reached by a drug before the next dose is administered. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles).

Time frame:: Pre-dose, 5 minutes, 30 minutes, 45 minutes, 1, 2, 3, 4, 6, 8 and 12hours post dose on Day 1; pre-dose, 5 minutes, 30 minutes, 45 minutes, 1, 2, 3, 4, 6, 8 and 12hours post dose on Day 14
Reported as:: Geometric mean · Pico grams per milliliter

Part B: Ctau of GSK2292767
Pico grams per milliliter	2000 µg OD
Day 1;n=8	78.4862 ± 91.4
Day 2;n=9	103.4247 ± 83.8
Day 3;n=9	98.3515 ± 84.1
Day 4;n=9	112.5132 ± 83.4
Day 5;n=9	98.4430 ± 87.6
Day 6;n=9	106.6896 ± 96.2
Day 7;n=9	101.1219 ± 88.3
Day 8;n=8	116.9160 ± 62.4
Day 9;n=9	105.3676 ± 81.7
Day 10;n=9	117.8348 ± 80.5
Day 11;n=9	112.3146 ± 66.4
Day 12;n=8	129.6370 ± 62.8
Day 13;n=8	154.5480 ± 52.6
Day 14;n=9	138.2161 ± 96.7

Statistical analysis

2000 µg OD · Ratio: 2.06 · 90% CI 1.67 to 2.55Treatment ratio of adjusted geometric mean (Day 14/Day 1) for Ctau is presented.

SecondaryPart B: Concentration of GSK2292767 in Bronchoalveolar Lavage (BAL)

BAL samples were collected by bronchoscopy.

Time frame:: Day 15
Reported as:: Geometric mean · Picograms per milliliter

Part B: Concentration of GSK2292767 in Bronchoalveolar Lavage (BAL)
Picograms per milliliter	2000 µg OD
Part B: Concentration of GSK2292767 in Bronchoalveolar Lavage (BAL)	8852.94 ± 236.8

SecondaryPart B: Concentration of GSK2292767 in Lung Epithelial Lining Fluid (ELF)

ELF from the lung was extracted from BAL samples. ELF drug concentration was calculated as BAL fluid drug concentration multiplied by dilution factor where dilution factor = Plasma urea (pre-bronchoscopy) divided by BAL urea. NA indicates data not available. Only participants with data available at specified time points were analyzed (represented by n=X in category titles).

Time frame:: Day 15
Reported as:: Geometric mean · Picograms per milliliters

Part B: Concentration of GSK2292767 in Lung Epithelial Lining Fluid (ELF)
Picograms per milliliters	2000 µg OD
24 Hr Wash 2,n=8	9777.25 ± 290.8
24 Hr Wash 3,n=7	11921.13 ± 251.4

Adverse events

Collected over nSAEs and SAEs were collected from start of study treatment up to 16 weeks. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
Group	Deaths	Serious	Other
Part A: Placebo	0/23 (0%)	0/23 (0%)	6/23 (26.1%)
Part A: 50 µg OD	0/12 (0%)	0/12 (0%)	9/12 (75%)
Part A: 100 µg OD	0/12 (0%)	0/12 (0%)	6/12 (50%)
Part A: 200 µg OD	0/13 (0%)	0/13 (0%)	7/13 (53.8%)
Part A: 500 µg OD	0/12 (0%)	0/12 (0%)	6/12 (50%)
Part A: 1000 µg OD	0/9 (0%)	0/9 (0%)	4/9 (44.4%)
Part A: 2000 µg OD	0/12 (0%)	0/12 (0%)	5/12 (41.7%)
Part B: Placebo	0/3 (0%)	0/3 (0%)	3/3 (100%)
Part B: 2000ug OD	0/9 (0%)	0/9 (0%)	8/9 (88.9%)

Most frequent other events

Showing 10 of 42

Most frequent other events
Event	Part A: Placebo	Part A: 50 µg OD	Part A: 100 µg OD	Part A: 200 µg OD	Part A: 500 µg OD	Part A: 1000 µg OD	Part A: 2000 µg OD	Part B: Placebo	Part B: 2000ug OD
Bronchoscopy abnormalInvestigations	0/23	0/12	0/12	0/13	0/12	0/9	0/12	3/3	2/9
Dermatitis contactSkin and subcutaneous tissue disorders	3/23	2/12	0/12	2/13	1/12	0/9	0/12	1/3	4/9
HeadacheNervous system disorders	3/23	4/12	2/12	1/13	2/12	2/9	2/12	0/3	2/9
Vessel puncture site bruiseGeneral disorders	0/23	0/12	0/12	0/13	0/12	0/9	0/12	0/3	3/9
Nasal obstructionRespiratory, thoracic and mediastinal disorders	0/23	0/12	0/12	0/13	0/12	0/9	0/12	1/3	0/9
Visual impairmentEye disorders	0/23	2/12	0/12	0/13	0/12	0/9	0/12	0/3	0/9
Viral upper respiratory tract infectionInfections and infestations	0/23	0/12	2/12	1/13	2/12	1/9	0/12	0/3	0/9
ContusionInjury, poisoning and procedural complications	0/23	0/12	0/12	0/13	2/12	0/9	1/12	0/3	0/9
Back painMusculoskeletal and connective tissue disorders	1/23	2/12	0/12	0/13	0/12	0/9	0/12	0/3	1/9
DizzinessNervous system disorders	0/23	1/12	0/12	2/13	0/12	0/9	0/12	0/3	1/9

Baseline characteristics

Data is presented for Part A and Part B. In Part B, 12 participants were included, 11 of them were taken from Part A and 1 additional participant only for Part B. Thus total number of participants included were 38 and not 49.

Age, Categorical
Age, Categorical(Participants)	Part A:Placebo/200 µg GSK2292767/1000 µg GSK2292767	Part A:50 µg GSK2292767/Placebo/1000 µg GSK2292767	Part A:50 µg GSK2292767/200 µg GSK2292767/Placebo	Part A:50 µg GSK2292767/200 µg GSK2292767/1000 µg GSK2292767	Part A:Placebo/500 µg GSK2292767/2000 µg GSK2292767	Part A:100 µg GSK2292767/Placebo/2000 µg GSK2292767	Part A:100 µg GSK2292767/500 µg GSK2292767/Placebo	Part A:100 µg GSK2292767/500 µg GSK2292767/2000 µg GSK2292767	Part B: Placebo	Part B: GSK2292767 2000 µg OD	Total
<=18 years	0	1	0	0	0	0	0	0	0	0	1
Between 18 and 65 years	7	2	5	6	4	4	4	4	3	9	48
>=65 years	0	0	0	0	0	0	0	0	0	0	0

Sex: Female, Male
Sex: Female, Male(Participants)	Part A:Placebo/200 µg GSK2292767/1000 µg GSK2292767	Part A:50 µg GSK2292767/Placebo/1000 µg GSK2292767	Part A:50 µg GSK2292767/200 µg GSK2292767/Placebo	Part A:50 µg GSK2292767/200 µg GSK2292767/1000 µg GSK2292767	Part A:Placebo/500 µg GSK2292767/2000 µg GSK2292767	Part A:100 µg GSK2292767/Placebo/2000 µg GSK2292767	Part A:100 µg GSK2292767/500 µg GSK2292767/Placebo	Part A:100 µg GSK2292767/500 µg GSK2292767/2000 µg GSK2292767	Part B: Placebo	Part B: GSK2292767 2000 µg OD	Total
Female	0	0	0	0	0	0	0	0	0	0	0
Male	7	3	5	6	4	4	4	4	3	9	49

Race/Ethnicity, Customized
Race/Ethnicity, Customized(Participants)	Part A:Placebo/200 µg GSK2292767/1000 µg GSK2292767	Part A:50 µg GSK2292767/Placebo/1000 µg GSK2292767	Part A:50 µg GSK2292767/200 µg GSK2292767/Placebo	Part A:50 µg GSK2292767/200 µg GSK2292767/1000 µg GSK2292767	Part A:Placebo/500 µg GSK2292767/2000 µg GSK2292767	Part A:100 µg GSK2292767/Placebo/2000 µg GSK2292767	Part A:100 µg GSK2292767/500 µg GSK2292767/Placebo	Part A:100 µg GSK2292767/500 µg GSK2292767/2000 µg GSK2292767	Part B: Placebo	Part B: GSK2292767 2000 µg OD	Total
African American/African Heritage	2	0	0	0	0	0	0	0	0	0	2
Asian - Central/South Asian Heritage	0	0	1	0	0	0	0	0	0	0	1
White	5	3	4	6	4	4	4	4	3	9	46

Study locations

1 site

GSK Investigational Site
Cambridge, CB2 2GG, United Kingdom

References and documents

Publications

Begg M, Edwards CD, Hamblin JN, Pefani E, Wilson R, Gilbert J, Vitulli G, Mallett D, Morrell J, Hingle MI, Uddin S, Ehtesham F, Marotti M, Harrell A, Newman CF, Fernando D, Clark J, Cahn A, Hessel EM. Translation of Inhaled Drug Optimization Strategies into Clinical Pharmacokinetics and Pharmacodynamics Using GSK2292767A, a Novel Inhaled Phosphoinositide 3-Kinase delta Inhibitor. J Pharmacol Exp Ther. 2019 Jun;369(3):443-453. doi: 10.1124/jpet.119.257311. Epub 2019 Apr 2. PubMed 30940692 ↗

Study documents

Study protocol · Jan 5, 2017
Statistical analysis plan · May 23, 2017

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: Yes — IPD for this study will be made available via the Clinical Study Data Request site.

Supporting information: Study protocol, Statistical analysis plan, Informed consent form, Clinical study report

Time frame: IPD is available via the Clinical Study Data Request site (click on the link provided below)

Access criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.

Data sharing details ↗ · www.clinicalstudydatarequest.com

Updates

Tracking since Sep 25, 2026

No changes since tracking began. The registry record was last updated on Jul 24, 2019, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗

Registry details

Key details

Study ID: NCT03045887
Lead sponsor: GlaxoSmithKline
Responsible party: Sponsor
First posted: Feb 8, 2017
Start date: Feb 6, 2017
Primary completion: Aug 11, 2017
Completion: Aug 16, 2017
Results posted: May 28, 2019
Last update: Jul 24, 2019

Study contacts

GSK Clinical Trials

study director · GlaxoSmithKline (for GlaxoSmithKline; Human Genome Sciences Inc., a GSK Company; Sirtris, a GSK Company; Stiefel, a GSK Company; ViiV Healthcare)

Oversight

Data monitoring committee: No
FDA-regulated drug: No
FDA-regulated device: No

View the source record on ClinicalTrials.gov ↗

Not currently enrolling

This study is completed, as verified in Jul 2019. You cannot join it, but the record below documents what was studied.

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Discussion

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