Trial Outcomes & Findings for GSK2339345 Hypertussive Challenge Study (NCT NCT01899768)

NCT ID: NCT01899768

Last Updated: 2017-04-05

Results Overview

Total cough count (8 hours \[hr\] of recording) was conducted at Visits 1, 2 and 3. Coughs were counted by a cough monitor fitted to the participants for 8 hr post Dose 1. The cough count was calculated as the sum of two four hour cough count totals, with the first four hours starting from the time of the first dose and the second four hours starting at the time of the second dose. The cough counts were sum-up by the treatments received by the participants. Number of coughs in 8 hr period was loge transformed and used for the analysis. Values were imputed pro-rata if 8 hr epoch was less than 8 hr. Mean of the total cough counts recorded post dose of every treatment i.e. placebo or GSK2339345 1000mcg was reported.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 16 participants
• Primary outcome timeframe: Up to 8 hours post-dose at Visits 1, 2 and 3 (Part A)
• Results posted on: 2017-04-05

Participant Flow

All eligible participants (par.) received treatment of either GSK2339345 or placebo at each visit in Parts A (Visits 1-3), B (Visits 4 and 5) and Part C (Visits 6 and 7).

Participant milestones

Measure	GSK2339345 1000 µg Participants received two doses of either GSK2339345 1000 µg or matching placebo as a solution administered via an ADI with a four hour dosing interval at 3 visits (one treatment per visit) in Part A and a single dose at 2 visits (one treatment per visit) in Part B and C. Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo or GSK2339345 at each visit period in Part B and C, participants received an oral inhalation of 10 microliter (µL) of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit of Part C. The strength of capsaicin solution ranged from 0.49 to 1000 micromolar (µM) and the citric acid solution strength ranged from 0.03 to 4.0 molar.
Part A STARTED	16
Part A COMPLETED	13
Part A NOT COMPLETED	3
Part B STARTED	13
Part B COMPLETED	11
Part B NOT COMPLETED	2
Part C STARTED	11
Part C COMPLETED	11
Part C NOT COMPLETED	0

Reasons for withdrawal

Measure	GSK2339345 1000 µg Participants received two doses of either GSK2339345 1000 µg or matching placebo as a solution administered via an ADI with a four hour dosing interval at 3 visits (one treatment per visit) in Part A and a single dose at 2 visits (one treatment per visit) in Part B and C. Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo or GSK2339345 at each visit period in Part B and C, participants received an oral inhalation of 10 microliter (µL) of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit of Part C. The strength of capsaicin solution ranged from 0.49 to 1000 micromolar (µM) and the citric acid solution strength ranged from 0.03 to 4.0 molar.
Part A Adverse Event	2
Part A Withdrawal by Subject	1
Part B Adverse Event	1
Part B Withdrawal by Subject	1

Baseline Characteristics

GSK2339345 Hypertussive Challenge Study

Baseline characteristics by cohort

Measure	GSK2339345 1000 µg/Placebo n=16 Participants Participants received two doses of either GSK2339345 1000 µg or matching placebo as a solution administered via an ADI with a four hour dosing interval at 3 visits (one treatment per visit) in Part A and a single dose at 2 visits (one treatment per visit) in Part B and C. Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo or GSK2339345 at each visit period in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit of Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.
Age, Continuous	56.7 Years STANDARD_DEVIATION 9.58 • n=5 Participants
Sex: Female, Male Female	13 Participants n=5 Participants
Sex: Female, Male Male	3 Participants n=5 Participants
Race/Ethnicity, Customized White - White/Caucasian/European Heritage	16 participants n=5 Participants

PRIMARY outcome

Timeframe: Up to 8 hours post-dose at Visits 1, 2 and 3 (Part A)

Population: All Subjects Population comprised of all participants who receive at least one dose of study medication. Only participants with at least one 8 hr cough count were analyzed.

Total cough count (8 hours [hr] of recording) was conducted at Visits 1, 2 and 3. Coughs were counted by a cough monitor fitted to the participants for 8 hr post Dose 1. The cough count was calculated as the sum of two four hour cough count totals, with the first four hours starting from the time of the first dose and the second four hours starting at the time of the second dose. The cough counts were sum-up by the treatments received by the participants. Number of coughs in 8 hr period was loge transformed and used for the analysis. Values were imputed pro-rata if 8 hr epoch was less than 8 hr. Mean of the total cough counts recorded post dose of every treatment i.e. placebo or GSK2339345 1000mcg was reported.

Outcome measures

Measure	Placebo n=14 Participants Participants received two doses of placebo as a solution administered via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.	GSK2339345 1000 Microgram (mcg) n=14 Participants Participants received two doses of GSK2339345 1000 mcg via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.
Total Cough Count Over 8 Hours at Visits 1, 2 and 3 (Part A)	152.7 cough count Standard Error 0.226	192.5 cough count Standard Error 0.226

PRIMARY outcome

Timeframe: Up to 8 hours post-dose at Visits 1, 2 and 3 (Part A)

Population: All Subjects Population. Only participants with at least one 8 hr cough count were analyzed.

Total cough count (8 hr of recording) was conducted at Visits 1, 2 and 3. Coughs were counted by a cough monitor fitted to the participants for 8 hr post Dose 1. The cough count was calculated as the sum of two four hour cough count totals, with the first 4-hrs starting from the time of the first dose and the second four hours starting at the time of the second dose. The cough counts were sum-up by the treatments received by the participants. Transient cough was the total number of coughs experienced in the two mins from the start of the first inhalation of a dose. Number of coughs excluding transient cough in 8 hr period was loge transformed and used for the analysis. Values were imputed pro-rata if 8 hr epoch was less than 8 hr. Mean of the total cough counts excluding transient cough recorded post dose of every treatment i.e. placebo or GSK2339345 1000 mcg was reported.

Outcome measures

Measure	Placebo n=14 Participants Participants received two doses of placebo as a solution administered via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.	GSK2339345 1000 Microgram (mcg) n=14 Participants Participants received two doses of GSK2339345 1000 mcg via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.
Total Cough Count Excluding Transient Coughs Over 8 Hours at Visits 1, 2 and 3 (Part A)	151.5 Cough count Standard Error 0.237	153.9 Cough count Standard Error 0.237

SECONDARY outcome

Timeframe: From the start of study treatment and until the follow-up contact (up to 8 Weeks)

Population: All Subjects Population

An AE is defined as any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a 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, or is an important medical events that jeopardize the participants or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition, or a drug-induced liver injury.

Outcome measures

Measure	Placebo n=16 Participants Participants received two doses of placebo as a solution administered via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.	GSK2339345 1000 Microgram (mcg) n=14 Participants Participants received two doses of GSK2339345 1000 mcg via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.
Number of Participants With Any Adverse Events (AEs) and Any Serious Adverse Events (SAEs) Any AE	10 participants	5 participants
Number of Participants With Any Adverse Events (AEs) and Any Serious Adverse Events (SAEs) Any SAE	0 participants	0 participants

SECONDARY outcome

Timeframe: Pre-dose, 5 min, 15 min (only in Part A), 30 min, and 1 hr post each dose administered in Parts A, B and C (up to 8 weeks)

Population: All Subjects Population. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). Different participants may have been analyzed for different parameters, so the overall number of participants analyzed reflects everyone in the All Subjects Population.

Systolic blood pressure (SBP) and diastolic blood pressure (DBP) measurements were obtained at following time points: pre-dose, 5 minutes (min), 15 min (only in Part A), 30 min, and 1 hr after first administration (FA) and second administration (SA) in Part A and each dose administration of Parts B and C. FA is the first of the two doses of GSK2339345 or placebo administered at any of the three visits in Part A. SA is the second of the two doses of GSK2339345 or placebo administered at any of the three visits in Part A. Pre-Dose is the average (avg) of the triplicate readings taken at the pre-dose assessment.

Outcome measures

Measure	Placebo n=16 Participants Participants received two doses of placebo as a solution administered via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.	GSK2339345 1000 Microgram (mcg) n=14 Participants Participants received two doses of GSK2339345 1000 mcg via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.
Mean Systolic Blood Pressure and Diastolic Blood Pressure at the Indicated Time Points in Parts A, B and C SBP, Part A, SA, Dose 2 avg Pre-dose, n=7, 7	125.0 Millimeter of mercury (mmHg) Standard Deviation 11.95	112.4 Millimeter of mercury (mmHg) Standard Deviation 8.54
Mean Systolic Blood Pressure and Diastolic Blood Pressure at the Indicated Time Points in Parts A, B and C SBP, Part A, FA, Dose 2, 15 min, n=15, 14	120.7 Millimeter of mercury (mmHg) Standard Deviation 12.96	123.0 Millimeter of mercury (mmHg) Standard Deviation 16.15
Mean Systolic Blood Pressure and Diastolic Blood Pressure at the Indicated Time Points in Parts A, B and C SBP, Part A, FA, Dose 2, 30 min, n=15, 14	120.8 Millimeter of mercury (mmHg) Standard Deviation 11.97	118.2 Millimeter of mercury (mmHg) Standard Deviation 12.91
Mean Systolic Blood Pressure and Diastolic Blood Pressure at the Indicated Time Points in Parts A, B and C SBP, Part A, FA, Dose 2, 1hr, n=15, 14	124.5 Millimeter of mercury (mmHg) Standard Deviation 13.68	121.5 Millimeter of mercury (mmHg) Standard Deviation 11.31
Mean Systolic Blood Pressure and Diastolic Blood Pressure at the Indicated Time Points in Parts A, B and C SBP, Part A, SA, Dose 1, 15 min, n=7, 7	125.1 Millimeter of mercury (mmHg) Standard Deviation 22.35	117.9 Millimeter of mercury (mmHg) Standard Deviation 9.74
Mean Systolic Blood Pressure and Diastolic Blood Pressure at the Indicated Time Points in Parts A, B and C SBP, Part A, SA, Dose 1, 30 min, n=7, 7	128.0 Millimeter of mercury (mmHg) Standard Deviation 18.83	119.3 Millimeter of mercury (mmHg) Standard Deviation 10.21
Mean Systolic Blood Pressure and Diastolic Blood Pressure at the Indicated Time Points in Parts A, B and C SBP, Part A, SA, Dose 1, 1 hr, n=7, 7	134.4 Millimeter of mercury (mmHg) Standard Deviation 17.82	122.4 Millimeter of mercury (mmHg) Standard Deviation 13.13
Mean Systolic Blood Pressure and Diastolic Blood Pressure at the Indicated Time Points in Parts A, B and C SBP, Part A, SA, Dose 2, 5 min, n=7, 7	125.4 Millimeter of mercury (mmHg) Standard Deviation 16.29	118.1 Millimeter of mercury (mmHg) Standard Deviation 9.32
Mean Systolic Blood Pressure and Diastolic Blood Pressure at the Indicated Time Points in Parts A, B and C SBP, Part A, SA, Dose 2, 1hr, n=7, 7	129.9 Millimeter of mercury (mmHg) Standard Deviation 19.27	121.4 Millimeter of mercury (mmHg) Standard Deviation 15.09
Mean Systolic Blood Pressure and Diastolic Blood Pressure at the Indicated Time Points in Parts A, B and C SBP, Part B, avg Pre-dose, n=10, 11	119.2 Millimeter of mercury (mmHg) Standard Deviation 11.69	124.0 Millimeter of mercury (mmHg) Standard Deviation 10.42
Mean Systolic Blood Pressure and Diastolic Blood Pressure at the Indicated Time Points in Parts A, B and C SBP, Part B, 5 min, n=10, 11	119.6 Millimeter of mercury (mmHg) Standard Deviation 11.24	123.9 Millimeter of mercury (mmHg) Standard Deviation 13.88
Mean Systolic Blood Pressure and Diastolic Blood Pressure at the Indicated Time Points in Parts A, B and C SBP, Part B, 15 min, n=10, 11	121.5 Millimeter of mercury (mmHg) Standard Deviation 15.23	118.7 Millimeter of mercury (mmHg) Standard Deviation 10.86
Mean Systolic Blood Pressure and Diastolic Blood Pressure at the Indicated Time Points in Parts A, B and C SBP, Part B, 1 hr, n=10, 11	124.2 Millimeter of mercury (mmHg) Standard Deviation 17.00	125.5 Millimeter of mercury (mmHg) Standard Deviation 12.89
Mean Systolic Blood Pressure and Diastolic Blood Pressure at the Indicated Time Points in Parts A, B and C SBP, Part C, avg Pre-dose, n=9, 9	125.2 Millimeter of mercury (mmHg) Standard Deviation 11.37	123.0 Millimeter of mercury (mmHg) Standard Deviation 12.28
Mean Systolic Blood Pressure and Diastolic Blood Pressure at the Indicated Time Points in Parts A, B and C SBP, Part C, 5 min, n=9, 9	125.6 Millimeter of mercury (mmHg) Standard Deviation 14.75	129.3 Millimeter of mercury (mmHg) Standard Deviation 12.70
Mean Systolic Blood Pressure and Diastolic Blood Pressure at the Indicated Time Points in Parts A, B and C DBP, Part A, FA, Dose 2, 5 min, n=15, 14	66.3 Millimeter of mercury (mmHg) Standard Deviation 7.69	66.4 Millimeter of mercury (mmHg) Standard Deviation 7.69
Mean Systolic Blood Pressure and Diastolic Blood Pressure at the Indicated Time Points in Parts A, B and C DBP, Part A, FA, Dose 2, 30 min, n=15, 14	66.7 Millimeter of mercury (mmHg) Standard Deviation 7.21	67.1 Millimeter of mercury (mmHg) Standard Deviation 6.95
Mean Systolic Blood Pressure and Diastolic Blood Pressure at the Indicated Time Points in Parts A, B and C DBP, Part C, 1hr, n=9, 9	65.4 Millimeter of mercury (mmHg) Standard Deviation 6.31	67.7 Millimeter of mercury (mmHg) Standard Deviation 6.71
Mean Systolic Blood Pressure and Diastolic Blood Pressure at the Indicated Time Points in Parts A, B and C SBP, Part A, FA, Dose 1, avg Pre-dose, n=16, 14	126.1 Millimeter of mercury (mmHg) Standard Deviation 14.09	123.3 Millimeter of mercury (mmHg) Standard Deviation 15.02
Mean Systolic Blood Pressure and Diastolic Blood Pressure at the Indicated Time Points in Parts A, B and C DBP, Part B, avg Pre-dose, n=10, 11	63.9 Millimeter of mercury (mmHg) Standard Deviation 4.74	67.3 Millimeter of mercury (mmHg) Standard Deviation 4.29
Mean Systolic Blood Pressure and Diastolic Blood Pressure at the Indicated Time Points in Parts A, B and C SBP, Part A, FA, Dose 1, 5 min, n=16, 14	125.5 Millimeter of mercury (mmHg) Standard Deviation 14.37	130.2 Millimeter of mercury (mmHg) Standard Deviation 17.16
Mean Systolic Blood Pressure and Diastolic Blood Pressure at the Indicated Time Points in Parts A, B and C SBP, Part A, FA, Dose 1, 15 min, n=16, 14	125.3 Millimeter of mercury (mmHg) Standard Deviation 14.06	124.1 Millimeter of mercury (mmHg) Standard Deviation 14.44
Mean Systolic Blood Pressure and Diastolic Blood Pressure at the Indicated Time Points in Parts A, B and C DBP, Part B, 5 min, n=10, 11	63.9 Millimeter of mercury (mmHg) Standard Deviation 3.31	66.5 Millimeter of mercury (mmHg) Standard Deviation 3.67
Mean Systolic Blood Pressure and Diastolic Blood Pressure at the Indicated Time Points in Parts A, B and C SBP, Part A, FA, Dose 1, 30 min, n=16, 14	125.6 Millimeter of mercury (mmHg) Standard Deviation 14.12	124.1 Millimeter of mercury (mmHg) Standard Deviation 17.67
Mean Systolic Blood Pressure and Diastolic Blood Pressure at the Indicated Time Points in Parts A, B and C SBP, Part A, FA, Dose 1, 1 hr, n=16, 14	126.1 Millimeter of mercury (mmHg) Standard Deviation 15.66	123.6 Millimeter of mercury (mmHg) Standard Deviation 13.74
Mean Systolic Blood Pressure and Diastolic Blood Pressure at the Indicated Time Points in Parts A, B and C SBP, Part A, FA, Dose 2 avg Pre-dose, n=16, 14	117.8 Millimeter of mercury (mmHg) Standard Deviation 10.95	119.5 Millimeter of mercury (mmHg) Standard Deviation 11.42
Mean Systolic Blood Pressure and Diastolic Blood Pressure at the Indicated Time Points in Parts A, B and C SBP, Part A, FA, Dose 2, 5 min, n=15, 14	120.6 Millimeter of mercury (mmHg) Standard Deviation 13.21	128.1 Millimeter of mercury (mmHg) Standard Deviation 18.58
Mean Systolic Blood Pressure and Diastolic Blood Pressure at the Indicated Time Points in Parts A, B and C SBP, Part A, SA, Dose 1, avg Pre-dose, n=7, 7	130.8 Millimeter of mercury (mmHg) Standard Deviation 15.43	121.2 Millimeter of mercury (mmHg) Standard Deviation 8.25
Mean Systolic Blood Pressure and Diastolic Blood Pressure at the Indicated Time Points in Parts A, B and C SBP, Part A, SA, Dose 1, 5 min, n=7, 7	127.7 Millimeter of mercury (mmHg) Standard Deviation 16.23	124.1 Millimeter of mercury (mmHg) Standard Deviation 11.17
Mean Systolic Blood Pressure and Diastolic Blood Pressure at the Indicated Time Points in Parts A, B and C SBP, Part A, SA, Dose 2, 15 min, n=7, 7	118.9 Millimeter of mercury (mmHg) Standard Deviation 12.40	112.4 Millimeter of mercury (mmHg) Standard Deviation 9.71
Mean Systolic Blood Pressure and Diastolic Blood Pressure at the Indicated Time Points in Parts A, B and C SBP, Part A, SA, Dose 2, 30 min, n=7, 7	119.0 Millimeter of mercury (mmHg) Standard Deviation 11.72	116.3 Millimeter of mercury (mmHg) Standard Deviation 10.37
Mean Systolic Blood Pressure and Diastolic Blood Pressure at the Indicated Time Points in Parts A, B and C SBP, Part C, 15 min, n=9, 9	121.6 Millimeter of mercury (mmHg) Standard Deviation 12.24	124.1 Millimeter of mercury (mmHg) Standard Deviation 13.18
Mean Systolic Blood Pressure and Diastolic Blood Pressure at the Indicated Time Points in Parts A, B and C SBP, Part C, 1hr, n=9, 9	127.1 Millimeter of mercury (mmHg) Standard Deviation 15.34	135.9 Millimeter of mercury (mmHg) Standard Deviation 21.77
Mean Systolic Blood Pressure and Diastolic Blood Pressure at the Indicated Time Points in Parts A, B and C DBP, Part A, FA, Dose 1, avg Pre-dose, n=16, 14	68.8 Millimeter of mercury (mmHg) Standard Deviation 7.23	69.1 Millimeter of mercury (mmHg) Standard Deviation 4.61
Mean Systolic Blood Pressure and Diastolic Blood Pressure at the Indicated Time Points in Parts A, B and C DBP, Part A, FA, Dose 1, 5 min, n=16, 14	72.3 Millimeter of mercury (mmHg) Standard Deviation 6.88	71.6 Millimeter of mercury (mmHg) Standard Deviation 5.33
Mean Systolic Blood Pressure and Diastolic Blood Pressure at the Indicated Time Points in Parts A, B and C DBP, Part A, FA, Dose 1, 15 min, n=16, 14	69.6 Millimeter of mercury (mmHg) Standard Deviation 7.80	70.6 Millimeter of mercury (mmHg) Standard Deviation 6.20
Mean Systolic Blood Pressure and Diastolic Blood Pressure at the Indicated Time Points in Parts A, B and C DBP, Part A, FA, Dose 1, 30 min, n=16, 14	71.6 Millimeter of mercury (mmHg) Standard Deviation 10.03	69.5 Millimeter of mercury (mmHg) Standard Deviation 7.34
Mean Systolic Blood Pressure and Diastolic Blood Pressure at the Indicated Time Points in Parts A, B and C DBP, Part A, FA, Dose 1, 1 hr, n=16, 14	70.9 Millimeter of mercury (mmHg) Standard Deviation 7.53	69.9 Millimeter of mercury (mmHg) Standard Deviation 5.14
Mean Systolic Blood Pressure and Diastolic Blood Pressure at the Indicated Time Points in Parts A, B and C DBP, Part A, FA, Dose 2 avg Pre-dose, n=16, 14	64.6 Millimeter of mercury (mmHg) Standard Deviation 5.70	65.2 Millimeter of mercury (mmHg) Standard Deviation 6.55
Mean Systolic Blood Pressure and Diastolic Blood Pressure at the Indicated Time Points in Parts A, B and C DBP, Part A, FA, Dose 2, 15 min, n=15, 14	65.5 Millimeter of mercury (mmHg) Standard Deviation 7.90	66.1 Millimeter of mercury (mmHg) Standard Deviation 8.02
Mean Systolic Blood Pressure and Diastolic Blood Pressure at the Indicated Time Points in Parts A, B and C DBP, Part A, FA, Dose 2, 1hr, n=15, 14	68.4 Millimeter of mercury (mmHg) Standard Deviation 6.46	69.6 Millimeter of mercury (mmHg) Standard Deviation 8.78
Mean Systolic Blood Pressure and Diastolic Blood Pressure at the Indicated Time Points in Parts A, B and C DBP, Part A, SA, Dose 1, avg Pre-dose, n=7, 7	70.2 Millimeter of mercury (mmHg) Standard Deviation 5.74	70.6 Millimeter of mercury (mmHg) Standard Deviation 7.93
Mean Systolic Blood Pressure and Diastolic Blood Pressure at the Indicated Time Points in Parts A, B and C DBP, Part A, SA, Dose 1, 5 min, n=7, 7	68.9 Millimeter of mercury (mmHg) Standard Deviation 6.20	67.9 Millimeter of mercury (mmHg) Standard Deviation 4.45
Mean Systolic Blood Pressure and Diastolic Blood Pressure at the Indicated Time Points in Parts A, B and C DBP, Part A, SA, Dose 1, 15 min, n=7, 7	68.6 Millimeter of mercury (mmHg) Standard Deviation 4.54	67.3 Millimeter of mercury (mmHg) Standard Deviation 6.37
Mean Systolic Blood Pressure and Diastolic Blood Pressure at the Indicated Time Points in Parts A, B and C DBP, Part A, SA, Dose 1, 30 min, n=7, 7	67.0 Millimeter of mercury (mmHg) Standard Deviation 5.72	68.7 Millimeter of mercury (mmHg) Standard Deviation 3.30
Mean Systolic Blood Pressure and Diastolic Blood Pressure at the Indicated Time Points in Parts A, B and C DBP, Part A, SA, Dose 1, 1 hr, n=7, 7	72.4 Millimeter of mercury (mmHg) Standard Deviation 7.00	69.1 Millimeter of mercury (mmHg) Standard Deviation 6.49
Mean Systolic Blood Pressure and Diastolic Blood Pressure at the Indicated Time Points in Parts A, B and C DBP, Part A, SA, Dose 2 avg Pre-dose, n=7, 7	67.3 Millimeter of mercury (mmHg) Standard Deviation 5.95	63.3 Millimeter of mercury (mmHg) Standard Deviation 2.89
Mean Systolic Blood Pressure and Diastolic Blood Pressure at the Indicated Time Points in Parts A, B and C DBP, Part A, SA, Dose 2, 5 min, n=7, 7	65.1 Millimeter of mercury (mmHg) Standard Deviation 5.98	67.0 Millimeter of mercury (mmHg) Standard Deviation 4.97
Mean Systolic Blood Pressure and Diastolic Blood Pressure at the Indicated Time Points in Parts A, B and C DBP, Part A, SA, Dose 2, 15 min, n=7, 7	64.4 Millimeter of mercury (mmHg) Standard Deviation 5.91	64.0 Millimeter of mercury (mmHg) Standard Deviation 4.97
Mean Systolic Blood Pressure and Diastolic Blood Pressure at the Indicated Time Points in Parts A, B and C DBP, Part A, SA, Dose 2, 30 min, n=7, 7	63.4 Millimeter of mercury (mmHg) Standard Deviation 6.73	66.3 Millimeter of mercury (mmHg) Standard Deviation 5.25
Mean Systolic Blood Pressure and Diastolic Blood Pressure at the Indicated Time Points in Parts A, B and C DBP, Part A, SA, Dose 2, 1hr, n=7, 7	69.1 Millimeter of mercury (mmHg) Standard Deviation 7.90	71.3 Millimeter of mercury (mmHg) Standard Deviation 5.82
Mean Systolic Blood Pressure and Diastolic Blood Pressure at the Indicated Time Points in Parts A, B and C DBP, Part B, 15 min, n=10, 11	64.9 Millimeter of mercury (mmHg) Standard Deviation 6.51	66.2 Millimeter of mercury (mmHg) Standard Deviation 6.00
Mean Systolic Blood Pressure and Diastolic Blood Pressure at the Indicated Time Points in Parts A, B and C DBP, Part B, 1 hr, n=10, 11	64.3 Millimeter of mercury (mmHg) Standard Deviation 6.99	66.2 Millimeter of mercury (mmHg) Standard Deviation 2.82
Mean Systolic Blood Pressure and Diastolic Blood Pressure at the Indicated Time Points in Parts A, B and C DBP, Part C, avg Pre-dose, n=9, 9	64.9 Millimeter of mercury (mmHg) Standard Deviation 5.50	68.0 Millimeter of mercury (mmHg) Standard Deviation 8.68
Mean Systolic Blood Pressure and Diastolic Blood Pressure at the Indicated Time Points in Parts A, B and C DBP, Part C, 5 min, n=9, 9	68.0 Millimeter of mercury (mmHg) Standard Deviation 7.37	65.6 Millimeter of mercury (mmHg) Standard Deviation 5.98
Mean Systolic Blood Pressure and Diastolic Blood Pressure at the Indicated Time Points in Parts A, B and C DBP, Part C, 15 min, n=9, 9	65.7 Millimeter of mercury (mmHg) Standard Deviation 4.03	65.7 Millimeter of mercury (mmHg) Standard Deviation 7.09

SECONDARY outcome

Timeframe: Pre-dose, 5 min, 15 min (only in Part A), 30 min, and 1 hr after each dose administered in Parts A, B and C (up to 8 weeks)

Population: All Subjects Population. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). Different participants may have been analyzed for different parameters, so the overall number of participants analyzed reflects everyone in the All Subjects Population.

Heart rate measurements were obtained at following time points: pre-dose, 5 min, 15 min (only in Part A), 30 min, and 1 hr after FA and SA in Part A and each dose administration in Parts B and C. FA is the first of the two doses of GSK2339345 or placebo administered at any of the three visits in Part A. SA is the second of the two doses of GSK2339345 or placebo administered at any of the three visits in Part A. Pre-Dose is the average of the triplicate readings taken at the pre-dose assessment.

Outcome measures

Measure	Placebo n=16 Participants Participants received two doses of placebo as a solution administered via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.	GSK2339345 1000 Microgram (mcg) n=14 Participants Participants received two doses of GSK2339345 1000 mcg via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.
Mean Heart Rate at the Indicated Time Points in Parts A, B and C Part A, FA, Dose 1, avg Pre-dose, n=16, 14	68.6 Beats per minute Standard Deviation 7.44	66.3 Beats per minute Standard Deviation 9.90
Mean Heart Rate at the Indicated Time Points in Parts A, B and C Part A, FA, Dose 1, 5 min, n=16, 14	64.1 Beats per minute Standard Deviation 7.50	66.5 Beats per minute Standard Deviation 10.06
Mean Heart Rate at the Indicated Time Points in Parts A, B and C Part A, FA, Dose 1, 15 min, n=16, 14	64.0 Beats per minute Standard Deviation 6.41	64.9 Beats per minute Standard Deviation 9.57
Mean Heart Rate at the Indicated Time Points in Parts A, B and C Part A, FA, Dose 1, 30 min, n=16, 14	64.1 Beats per minute Standard Deviation 10.60	61.8 Beats per minute Standard Deviation 8.75
Mean Heart Rate at the Indicated Time Points in Parts A, B and C Part A, FA, Dose 1, 1 hr, n=16, 14	62.6 Beats per minute Standard Deviation 7.70	61.6 Beats per minute Standard Deviation 7.88
Mean Heart Rate at the Indicated Time Points in Parts A, B and C Part A, SA, Dose 1, 30 min, n=7, 7	59.1 Beats per minute Standard Deviation 8.45	62.4 Beats per minute Standard Deviation 7.16
Mean Heart Rate at the Indicated Time Points in Parts A, B and C Part A, SA, Dose 2, 1hr, n=7, 7	65.7 Beats per minute Standard Deviation 7.06	68.6 Beats per minute Standard Deviation 8.30
Mean Heart Rate at the Indicated Time Points in Parts A, B and C Part A, FA, Dose 2 avg Pre-dose, n=16, 14	72.6 Beats per minute Standard Deviation 9.27	69.4 Beats per minute Standard Deviation 11.82
Mean Heart Rate at the Indicated Time Points in Parts A, B and C Part A, FA, Dose 2, 5 min, n=16, 14	69.9 Beats per minute Standard Deviation 7.29	69.7 Beats per minute Standard Deviation 12.02
Mean Heart Rate at the Indicated Time Points in Parts A, B and C Part A, FA, Dose 2, 15 min, n=16, 14	69.0 Beats per minute Standard Deviation 7.80	68.3 Beats per minute Standard Deviation 9.52
Mean Heart Rate at the Indicated Time Points in Parts A, B and C Part A, FA, Dose 2, 30 min, n=16, 14	68.6 Beats per minute Standard Deviation 9.25	68.5 Beats per minute Standard Deviation 13.39
Mean Heart Rate at the Indicated Time Points in Parts A, B and C Part A, FA, Dose 2, 1hr, n=16, 14	68.5 Beats per minute Standard Deviation 8.30	67.6 Beats per minute Standard Deviation 11.57
Mean Heart Rate at the Indicated Time Points in Parts A, B and C Part A, SA, Dose 1, avg Pre-dose, n=7, 7	66.8 Beats per minute Standard Deviation 12.80	69.6 Beats per minute Standard Deviation 8.33
Mean Heart Rate at the Indicated Time Points in Parts A, B and C Part A, SA, Dose 1, 5 min, n=7, 7	61.3 Beats per minute Standard Deviation 8.90	65.4 Beats per minute Standard Deviation 8.08
Mean Heart Rate at the Indicated Time Points in Parts A, B and C Part A, SA, Dose 1, 15 min, n=7, 7	60.3 Beats per minute Standard Deviation 9.01	62.9 Beats per minute Standard Deviation 6.82
Mean Heart Rate at the Indicated Time Points in Parts A, B and C Part A, SA, Dose 1, 1 hr, n=7, 7	62.6 Beats per minute Standard Deviation 8.81	62.4 Beats per minute Standard Deviation 6.35
Mean Heart Rate at the Indicated Time Points in Parts A, B and C Part A, SA, Dose 2 avg Pre-dose, n=7, 7	69.0 Beats per minute Standard Deviation 7.84	70.6 Beats per minute Standard Deviation 6.20
Mean Heart Rate at the Indicated Time Points in Parts A, B and C Part A, SA, Dose 2, 5 min, n=7, 7	66.7 Beats per minute Standard Deviation 9.16	71.1 Beats per minute Standard Deviation 8.19
Mean Heart Rate at the Indicated Time Points in Parts A, B and C Part A, SA, Dose 2, 15 min, n=7, 7	66.0 Beats per minute Standard Deviation 7.37	69.6 Beats per minute Standard Deviation 10.05
Mean Heart Rate at the Indicated Time Points in Parts A, B and C Part A, SA, Dose 2, 30 min, n=7, 7	65.1 Beats per minute Standard Deviation 7.78	65.7 Beats per minute Standard Deviation 6.99
Mean Heart Rate at the Indicated Time Points in Parts A, B and C Part B, avg Pre-dose, n=10, 11	64.5 Beats per minute Standard Deviation 6.21	68.4 Beats per minute Standard Deviation 8.85
Mean Heart Rate at the Indicated Time Points in Parts A, B and C Part B, 5 min, n=10, 11	60.0 Beats per minute Standard Deviation 6.18	65.9 Beats per minute Standard Deviation 8.87
Mean Heart Rate at the Indicated Time Points in Parts A, B and C Part B, 15 min, n=10, 11	59.4 Beats per minute Standard Deviation 4.99	63.5 Beats per minute Standard Deviation 6.52
Mean Heart Rate at the Indicated Time Points in Parts A, B and C Part B, 1 hr, n=10, 11	58.6 Beats per minute Standard Deviation 6.20	61.0 Beats per minute Standard Deviation 6.07
Mean Heart Rate at the Indicated Time Points in Parts A, B and C Part C, avg Pre-dose, n=9, 9	62.4 Beats per minute Standard Deviation 4.27	66.3 Beats per minute Standard Deviation 7.07
Mean Heart Rate at the Indicated Time Points in Parts A, B and C Part C, 5 min, n=9, 9	60.3 Beats per minute Standard Deviation 9.31	65.0 Beats per minute Standard Deviation 9.15
Mean Heart Rate at the Indicated Time Points in Parts A, B and C Part C, 15 min, n=9, 9	60.8 Beats per minute Standard Deviation 6.51	60.7 Beats per minute Standard Deviation 5.50
Mean Heart Rate at the Indicated Time Points in Parts A, B and C Part C, 1hr, n=9, 9	59.2 Beats per minute Standard Deviation 6.50	61.1 Beats per minute Standard Deviation 6.47

SECONDARY outcome

Timeframe: 1 hr post the second dose administered in Part A and 1 hr post each dose administered in Parts B and C (up to 8 Weeks)

Population: All Subjects Population. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). Different participants may have been analyzed for different parameters, so the overall number of participants analyzed reflects everyone in the All Subjects Population.

Body temperature measurements were obtained at1 hr post-dose 2 FA and SA in Part A and each administration in Parts B, and C. FA is the first of the two doses of GSK2339345 or placebo administered at any of the three visits in Part A. SA is the second of the two doses of GSK2339345 or placebo administered at any of the three visits in Part A.

Outcome measures

Measure	Placebo n=16 Participants Participants received two doses of placebo as a solution administered via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.	GSK2339345 1000 Microgram (mcg) n=14 Participants Participants received two doses of GSK2339345 1000 mcg via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.
Mean Body Temperature at the Indicated Time Points in Parts A, B and C Part C, 1 hr, n=9, 9	36.54 Degree Celsius Standard Deviation 0.391	36.69 Degree Celsius Standard Deviation 0.473
Mean Body Temperature at the Indicated Time Points in Parts A, B and C Part A, FA, Dose 2, 1 hr, n=15, 12	36.84 Degree Celsius Standard Deviation 0.470	36.70 Degree Celsius Standard Deviation 0.484
Mean Body Temperature at the Indicated Time Points in Parts A, B and C Part A, SA, Dose 2, 1 hr, n=7, 7	36.56 Degree Celsius Standard Deviation 0.541	36.80 Degree Celsius Standard Deviation 0.520
Mean Body Temperature at the Indicated Time Points in Parts A, B and C Part B, 1 hr, n=10, 10	36.55 Degree Celsius Standard Deviation 0.536	36.76 Degree Celsius Standard Deviation 0.414

SECONDARY outcome

Timeframe: Pre-dose and 5min to 1 hr after each dose administered in Parts A, B and C (up to 8 Weeks)

Population: All subject population. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). Different participants may have been analyzed for different parameters, so the overall number of participants analyzed reflects everyone in the All Subjects Population.

A 12-lead ECG was recorded in a seated position after the participant was kept at rest in this position for at least 10 minutes. ECGs were obtained at pre-dose and 5 min, 15 min (only in Part A) 30 min, and 1 hr after FA and SA in Part A and each administration in Parts B, and C. FA is the first of the two doses of GSK2339345 or placebo administered at any of the three visits in Part A. SA is the second of the two doses of GSK2339345 or placebo administered at any of the three visits in Part A. Data are presented as clinically significant (CS) or not clinically significant (NCS) abnormal findings any time during study. The study investigator determined if the abnormal ECG finding was CS or NCS.

Outcome measures

Measure	Placebo n=16 Participants Participants received two doses of placebo as a solution administered via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.	GSK2339345 1000 Microgram (mcg) n=14 Participants Participants received two doses of GSK2339345 1000 mcg via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.
Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Findings in Parts A, B and C Part A, FA, Normal, n=16, 14	13 Participants	12 Participants
Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Findings in Parts A, B and C Part A, FA, Abnormal NCS, n=16, 14	2 Participants	2 Participants
Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Findings in Parts A, B and C Part A, FA Abnormal CS, n=16, 14	1 Participants	0 Participants
Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Findings in Parts A, B and C Part A, SA, Normal, n=7, 7	4 Participants	7 Participants
Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Findings in Parts A, B and C Part A, SA, Abnormal NCS, n=7, 7	2 Participants	0 Participants
Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Findings in Parts A, B and C Part A, SA, Abnormal CS, n=7, 7	1 Participants	0 Participants
Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Findings in Parts A, B and C Part B, Normal, n=10, 11	9 Participants	10 Participants
Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Findings in Parts A, B and C Part B, Abnormal NCS, n=10, 11	1 Participants	1 Participants
Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Findings in Parts A, B and C Part B, Abnormal CS, n=10, 11	0 Participants	0 Participants
Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Findings in Parts A, B and C Part C, Normal, n=9, 9	9 Participants	8 Participants
Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Findings in Parts A, B and C Part C, Abnormal NCS, n=9, 9	0 Participants	1 Participants
Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Findings in Parts A, B and C Part C, Abnormal CS, n=9, 9	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Pre-dose and 1 hr post each dose administered in Part A (up to 3 Weeks)

Population: All subject population. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). Different participants may have been analyzed for different parameters, so the overall number of participants analyzed reflects everyone in the All Subjects Population.

Blood samples were collected for the measurement of basophils, eosinophils, lymphocytes, monocytes, total neutrophils (ANC - absolute neutrophil count), platelet count, and white blood cells count at pre-dose and 1 hr after each dose of FA and SA in Part A. FA is the first of the two doses of GSK2339345 or placebo administered at any of the three visits in Part A. SA is the second of the two doses of GSK2339345 or placebo administered at any of the three visits in Part A.

Outcome measures

Measure	Placebo n=16 Participants Participants received two doses of placebo as a solution administered via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.	GSK2339345 1000 Microgram (mcg) n=14 Participants Participants received two doses of GSK2339345 1000 mcg via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.
Mean Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet Count, and White Blood Cells (WBC) Count Values at the Indicated Time Points in Part A Basophils, FA, Pre-dose, n=16, 14	0.026 10^9 cells/Liter (GI/L) Standard Deviation 0.0126	0.023 10^9 cells/Liter (GI/L) Standard Deviation 0.0159
Mean Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet Count, and White Blood Cells (WBC) Count Values at the Indicated Time Points in Part A Basophils, FA, 1 hr Post-dose, n=14, 13	0.031 10^9 cells/Liter (GI/L) Standard Deviation 0.0192	0.032 10^9 cells/Liter (GI/L) Standard Deviation 0.0242
Mean Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet Count, and White Blood Cells (WBC) Count Values at the Indicated Time Points in Part A Basophils, SA, Pre-dose, n=6, 7	0.040 10^9 cells/Liter (GI/L) Standard Deviation 0.0329	0.026 10^9 cells/Liter (GI/L) Standard Deviation 0.0162
Mean Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet Count, and White Blood Cells (WBC) Count Values at the Indicated Time Points in Part A Basophils, SA, 1 hr Post-dose, n=7, 7	0.019 10^9 cells/Liter (GI/L) Standard Deviation 0.0107	0.036 10^9 cells/Liter (GI/L) Standard Deviation 0.0299
Mean Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet Count, and White Blood Cells (WBC) Count Values at the Indicated Time Points in Part A Eosinophils, FA, Pre-dose, n=16, 14	0.091 10^9 cells/Liter (GI/L) Standard Deviation 0.0604	0.063 10^9 cells/Liter (GI/L) Standard Deviation 0.0365
Mean Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet Count, and White Blood Cells (WBC) Count Values at the Indicated Time Points in Part A Eosinophils, FA, 1 hr Post-dose, n=14, 13	0.106 10^9 cells/Liter (GI/L) Standard Deviation 0.0776	0.093 10^9 cells/Liter (GI/L) Standard Deviation 0.0471
Mean Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet Count, and White Blood Cells (WBC) Count Values at the Indicated Time Points in Part A Eosinophils, SA, Pre-dose, n=6, 7	0.080 10^9 cells/Liter (GI/L) Standard Deviation 0.0510	0.064 10^9 cells/Liter (GI/L) Standard Deviation 0.0299
Mean Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet Count, and White Blood Cells (WBC) Count Values at the Indicated Time Points in Part A Eosinophils, SA, 1 hr Post-dose, n=7, 7	0.113 10^9 cells/Liter (GI/L) Standard Deviation 0.0502	0.080 10^9 cells/Liter (GI/L) Standard Deviation 0.0191
Mean Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet Count, and White Blood Cells (WBC) Count Values at the Indicated Time Points in Part A Lymphocytes, FA, Pre-dose, n=16, 14	1.801 10^9 cells/Liter (GI/L) Standard Deviation 0.4214	1.673 10^9 cells/Liter (GI/L) Standard Deviation 0.3348
Mean Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet Count, and White Blood Cells (WBC) Count Values at the Indicated Time Points in Part A Lymphocytes, FA, 1 hr Post-dose, n=14, 13	2.095 10^9 cells/Liter (GI/L) Standard Deviation 0.4572	1.977 10^9 cells/Liter (GI/L) Standard Deviation 0.5392
Mean Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet Count, and White Blood Cells (WBC) Count Values at the Indicated Time Points in Part A Lymphocytes, SA, Pre-dose, n=6, 7	1.922 10^9 cells/Liter (GI/L) Standard Deviation 0.4492	1.536 10^9 cells/Liter (GI/L) Standard Deviation 0.3406
Mean Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet Count, and White Blood Cells (WBC) Count Values at the Indicated Time Points in Part A Lymphocytes, SA, 1 hr Post-dose, n=7, 7	2.200 10^9 cells/Liter (GI/L) Standard Deviation 0.6387	1.926 10^9 cells/Liter (GI/L) Standard Deviation 0.2486
Mean Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet Count, and White Blood Cells (WBC) Count Values at the Indicated Time Points in Part A Monocytes, FA, Pre-dose, n=16, 14	0.363 10^9 cells/Liter (GI/L) Standard Deviation 0.1373	0.369 10^9 cells/Liter (GI/L) Standard Deviation 0.1957
Mean Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet Count, and White Blood Cells (WBC) Count Values at the Indicated Time Points in Part A Monocytes, FA, 1 hr Post-dose, n=14, 13	0.414 10^9 cells/Liter (GI/L) Standard Deviation 0.1249	0.434 10^9 cells/Liter (GI/L) Standard Deviation 0.1601
Mean Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet Count, and White Blood Cells (WBC) Count Values at the Indicated Time Points in Part A Monocytes, SA, Pre-dose, n=6, 7	0.390 10^9 cells/Liter (GI/L) Standard Deviation 0.1517	0.297 10^9 cells/Liter (GI/L) Standard Deviation 0.0525
Mean Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet Count, and White Blood Cells (WBC) Count Values at the Indicated Time Points in Part A Total Neutrophils, SA, Pre-dose, n=6, 7	4.238 10^9 cells/Liter (GI/L) Standard Deviation 1.4993	3.993 10^9 cells/Liter (GI/L) Standard Deviation 0.9757
Mean Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet Count, and White Blood Cells (WBC) Count Values at the Indicated Time Points in Part A Total Neutrophils, SA, 1 hr Post-dose, n=7, 7	4.847 10^9 cells/Liter (GI/L) Standard Deviation 1.4473	4.250 10^9 cells/Liter (GI/L) Standard Deviation 0.6064
Mean Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet Count, and White Blood Cells (WBC) Count Values at the Indicated Time Points in Part A Platelet count, FA, Pre-dose, n=16, 13	225.8 10^9 cells/Liter (GI/L) Standard Deviation 51.14	233.4 10^9 cells/Liter (GI/L) Standard Deviation 56.53
Mean Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet Count, and White Blood Cells (WBC) Count Values at the Indicated Time Points in Part A Platelet count, FA, 1 hr Post-dose, n=14, 13	209.1 10^9 cells/Liter (GI/L) Standard Deviation 49.01	215.7 10^9 cells/Liter (GI/L) Standard Deviation 30.69
Mean Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet Count, and White Blood Cells (WBC) Count Values at the Indicated Time Points in Part A Platelet count, SA, Pre-dose, n=6, 7	259.8 10^9 cells/Liter (GI/L) Standard Deviation 36.98	238.6 10^9 cells/Liter (GI/L) Standard Deviation 47.90
Mean Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet Count, and White Blood Cells (WBC) Count Values at the Indicated Time Points in Part A Platelet count, SA, 1 hr Post-dose, n=7, 7	238.4 10^9 cells/Liter (GI/L) Standard Deviation 53.37	232.3 10^9 cells/Liter (GI/L) Standard Deviation 49.45
Mean Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet Count, and White Blood Cells (WBC) Count Values at the Indicated Time Points in Part A WBC count, FA, Pre-dose, n=16, 14	6.54 10^9 cells/Liter (GI/L) Standard Deviation 1.565	6.33 10^9 cells/Liter (GI/L) Standard Deviation 1.315
Mean Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet Count, and White Blood Cells (WBC) Count Values at the Indicated Time Points in Part A WBC count, FA, 1 hr Post-dose, n=14, 13	7.36 10^9 cells/Liter (GI/L) Standard Deviation 1.663	7.33 10^9 cells/Liter (GI/L) Standard Deviation 1.596
Mean Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet Count, and White Blood Cells (WBC) Count Values at the Indicated Time Points in Part A WBC count, SA, Pre-dose, n=6, 7	6.67 10^9 cells/Liter (GI/L) Standard Deviation 1.560	5.91 10^9 cells/Liter (GI/L) Standard Deviation 1.263
Mean Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet Count, and White Blood Cells (WBC) Count Values at the Indicated Time Points in Part A WBC count, SA, 1 hr Post-dose, n=7, 7	7.53 10^9 cells/Liter (GI/L) Standard Deviation 1.798	6.66 10^9 cells/Liter (GI/L) Standard Deviation 0.810
Mean Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet Count, and White Blood Cells (WBC) Count Values at the Indicated Time Points in Part A Monocytes, SA, 1 hr Post-dose, n=7, 7	0.380 10^9 cells/Liter (GI/L) Standard Deviation 0.1319	0.364 10^9 cells/Liter (GI/L) Standard Deviation 0.0479
Mean Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet Count, and White Blood Cells (WBC) Count Values at the Indicated Time Points in Part A Total Neutrophils, FA, Pre-dose, n=16, 14	4.256 10^9 cells/Liter (GI/L) Standard Deviation 1.3244	4.206 10^9 cells/Liter (GI/L) Standard Deviation 1.1230
Mean Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet Count, and White Blood Cells (WBC) Count Values at the Indicated Time Points in Part A Total Neutrophils, FA, 1 hr Post-dose, n=14, 13	4.730 10^9 cells/Liter (GI/L) Standard Deviation 1.3512	4.800 10^9 cells/Liter (GI/L) Standard Deviation 1.1399

SECONDARY outcome

Timeframe: Pre-dose and 1 hr post each dose administered in Part A (up to 3 Weeks)

Population: All subject population. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). Different participants may have been analyzed for different parameters, so the overall number of participants analyzed reflects everyone in the All Subjects Population.

Blood samples were collected for the measurement of hemoglobin, MCHC, albumin and total protein at pre-dose and 1 hr after each dose of FA and SA in Part A. FA is the first of the two doses of GSK2339345 or placebo administered at any of the three visits in Part A. SA is the second of the two doses of GSK2339345 or placebo administered at any of the three visits in Part A.

Outcome measures

Measure	Placebo n=16 Participants Participants received two doses of placebo as a solution administered via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.	GSK2339345 1000 Microgram (mcg) n=14 Participants Participants received two doses of GSK2339345 1000 mcg via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.
Mean Hemoglobin, Mean Corpuscle Hemoglobin Concentration (MCHC), Albumin and Total Protein Values at the Indicated Time Points in Part A Hemoglobin, FA, Pre-dose, n=16, 14	134.1 Grams per liter (G/L) Standard Deviation 11.16	134.2 Grams per liter (G/L) Standard Deviation 11.82
Mean Hemoglobin, Mean Corpuscle Hemoglobin Concentration (MCHC), Albumin and Total Protein Values at the Indicated Time Points in Part A Hemoglobin, SA, 1 hr Post-dose, n=7, 7	125.4 Grams per liter (G/L) Standard Deviation 9.64	129.6 Grams per liter (G/L) Standard Deviation 9.78
Mean Hemoglobin, Mean Corpuscle Hemoglobin Concentration (MCHC), Albumin and Total Protein Values at the Indicated Time Points in Part A MCHC, FA, Pre-dose, n=16, 14	325.6 Grams per liter (G/L) Standard Deviation 5.76	326.3 Grams per liter (G/L) Standard Deviation 6.14
Mean Hemoglobin, Mean Corpuscle Hemoglobin Concentration (MCHC), Albumin and Total Protein Values at the Indicated Time Points in Part A MCHC, FA, 1 hr Post-dose, n=14, 13	327.0 Grams per liter (G/L) Standard Deviation 4.91	329.2 Grams per liter (G/L) Standard Deviation 5.36
Mean Hemoglobin, Mean Corpuscle Hemoglobin Concentration (MCHC), Albumin and Total Protein Values at the Indicated Time Points in Part A MCHC, SA, Pre-dose, n=6, 7	327.5 Grams per liter (G/L) Standard Deviation 7.20	324.0 Grams per liter (G/L) Standard Deviation 6.51
Mean Hemoglobin, Mean Corpuscle Hemoglobin Concentration (MCHC), Albumin and Total Protein Values at the Indicated Time Points in Part A MCHC, SA, 1 hr Post-dose, n=7, 7	327.7 Grams per liter (G/L) Standard Deviation 5.09	323.3 Grams per liter (G/L) Standard Deviation 10.24
Mean Hemoglobin, Mean Corpuscle Hemoglobin Concentration (MCHC), Albumin and Total Protein Values at the Indicated Time Points in Part A Albumin, FA, Pre-dose, n=16, 14	43.4 Grams per liter (G/L) Standard Deviation 3.10	43.1 Grams per liter (G/L) Standard Deviation 2.11
Mean Hemoglobin, Mean Corpuscle Hemoglobin Concentration (MCHC), Albumin and Total Protein Values at the Indicated Time Points in Part A Albumin, FA, 1 hr Post-dose, n=14, 14	41.7 Grams per liter (G/L) Standard Deviation 2.23	41.6 Grams per liter (G/L) Standard Deviation 1.82
Mean Hemoglobin, Mean Corpuscle Hemoglobin Concentration (MCHC), Albumin and Total Protein Values at the Indicated Time Points in Part A Albumin, SA, Pre-dose, n=6, 7	43.3 Grams per liter (G/L) Standard Deviation 3.27	43.6 Grams per liter (G/L) Standard Deviation 2.15
Mean Hemoglobin, Mean Corpuscle Hemoglobin Concentration (MCHC), Albumin and Total Protein Values at the Indicated Time Points in Part A Albumin, SA, 1 hr Post-dose, n=7, 7	41.4 Grams per liter (G/L) Standard Deviation 2.30	41.6 Grams per liter (G/L) Standard Deviation 1.99
Mean Hemoglobin, Mean Corpuscle Hemoglobin Concentration (MCHC), Albumin and Total Protein Values at the Indicated Time Points in Part A Total protein, FA, Pre-dose, n=16, 14	69.3 Grams per liter (G/L) Standard Deviation 4.32	68.5 Grams per liter (G/L) Standard Deviation 2.41
Mean Hemoglobin, Mean Corpuscle Hemoglobin Concentration (MCHC), Albumin and Total Protein Values at the Indicated Time Points in Part A Total protein, FA, 1 hr Post-dose, n=14, 14	66.1 Grams per liter (G/L) Standard Deviation 3.35	66.6 Grams per liter (G/L) Standard Deviation 2.41
Mean Hemoglobin, Mean Corpuscle Hemoglobin Concentration (MCHC), Albumin and Total Protein Values at the Indicated Time Points in Part A Total protein, SA, Pre-dose, n=6, 7	69.0 Grams per liter (G/L) Standard Deviation 4.69	69.1 Grams per liter (G/L) Standard Deviation 3.34
Mean Hemoglobin, Mean Corpuscle Hemoglobin Concentration (MCHC), Albumin and Total Protein Values at the Indicated Time Points in Part A Total protein, SA, 1 hr Post-dose, n=7, 7	65.4 Grams per liter (G/L) Standard Deviation 4.16	66.0 Grams per liter (G/L) Standard Deviation 3.61
Mean Hemoglobin, Mean Corpuscle Hemoglobin Concentration (MCHC), Albumin and Total Protein Values at the Indicated Time Points in Part A Hemoglobin, FA, 1 hr Post-dose, n=14, 13	130.1 Grams per liter (G/L) Standard Deviation 11.35	130.5 Grams per liter (G/L) Standard Deviation 11.17
Mean Hemoglobin, Mean Corpuscle Hemoglobin Concentration (MCHC), Albumin and Total Protein Values at the Indicated Time Points in Part A Hemoglobin, SA, Pre-dose, n=6, 7	127.5 Grams per liter (G/L) Standard Deviation 8.69	133.4 Grams per liter (G/L) Standard Deviation 10.34

SECONDARY outcome

Timeframe: Pre-dose and 1 hr post each dose administered in Part A (up to 3 Weeks)

Population: All subject population. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). Different participants may have been analyzed for different parameters, so the overall number of participants analyzed reflects everyone in the All Subjects Population.

Blood samples were collected for the measurement of hematocrit at pre-dose and 1 hr after each dose of FA and SA in Part A. FA is the first of the two doses of GSK2339345 or placebo administered at any of the three visits in Part A. SA is the second of the two doses of GSK2339345 or placebo administered at any of the three visits in Part A.

Outcome measures

Measure	Placebo n=16 Participants Participants received two doses of placebo as a solution administered via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.	GSK2339345 1000 Microgram (mcg) n=14 Participants Participants received two doses of GSK2339345 1000 mcg via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.
Mean Hematocrit Values at the Indicated Time Points in Part A FA, Pre-dose, n=16, 14	0.4126 Proportion of one Standard Deviation 0.03824	0.4119 Proportion of one Standard Deviation 0.04143
Mean Hematocrit Values at the Indicated Time Points in Part A FA, 1 hr Post-dose, n=14, 13	0.3979 Proportion of one Standard Deviation 0.03595	0.3973 Proportion of one Standard Deviation 0.03701
Mean Hematocrit Values at the Indicated Time Points in Part A SA, Pre-dose, n=6, 7	0.3895 Proportion of one Standard Deviation 0.02894	0.4120 Proportion of one Standard Deviation 0.03950
Mean Hematocrit Values at the Indicated Time Points in Part A SA, 1 hr Post-dose, n=7, 7	0.3826 Proportion of one Standard Deviation 0.03321	0.4010 Proportion of one Standard Deviation 0.03316

SECONDARY outcome

Timeframe: Pre-dose and 1 hr post each dose administered in Part A (up to 3 Weeks)

Population: All subject population. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). Different participants may have been analyzed for different parameters, so the overall number of participants analyzed reflects everyone in the All Subjects Population.

Blood samples were collected for the measurement of mean corpuscle hemoglobin at pre-dose and 1 hr after each dose of FA and SA in Part A. FA is the first of the two doses of GSK2339345 or placebo administered at any of the three visits in Part A. SA is the second of the two doses of GSK2339345 or placebo administered at any of the three visits in Part A.

Outcome measures

Measure	Placebo n=16 Participants Participants received two doses of placebo as a solution administered via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.	GSK2339345 1000 Microgram (mcg) n=14 Participants Participants received two doses of GSK2339345 1000 mcg via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.
Mean Corpuscle Hemoglobin Values at the Indicated Time Points in Part A FA, Pre-dose, n=16, 14	29.87 picograms per cell (pg) Standard Deviation 1.709	29.75 picograms per cell (pg) Standard Deviation 1.787
Mean Corpuscle Hemoglobin Values at the Indicated Time Points in Part A FA, 1 hr Post-dose, n=14, 13	29.75 picograms per cell (pg) Standard Deviation 1.874	29.85 picograms per cell (pg) Standard Deviation 1.859
Mean Corpuscle Hemoglobin Values at the Indicated Time Points in Part A SA, Pre-dose, n=6, 7	29.48 picograms per cell (pg) Standard Deviation 1.958	29.67 picograms per cell (pg) Standard Deviation 1.627
Mean Corpuscle Hemoglobin Values at the Indicated Time Points in Part A SA, 1 hr Post-dose, n=7, 7	29.67 picograms per cell (pg) Standard Deviation 1.864	29.40 picograms per cell (pg) Standard Deviation 1.672

SECONDARY outcome

Timeframe: Pre-dose and 1 hr post each dose administered in Part A (up to 3 Weeks)

Population: All Subjects Population. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). Different participants may have been analyzed for different parameters, so the overall number of participants analyzed reflects everyone in the All Subjects Population.

Blood samples were collected for the measurement of mean corpuscle volume at pre-dose and 1 hr after each dose of FA and SA in Part A. FA is the first of the two doses of GSK2339345 or placebo administered at any of the three visits in Part A. SA is the second of the two doses of GSK2339345 or placebo administered at any of the three visits in Part A

Outcome measures

Measure	Placebo n=16 Participants Participants received two doses of placebo as a solution administered via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.	GSK2339345 1000 Microgram (mcg) n=14 Participants Participants received two doses of GSK2339345 1000 mcg via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.
Mean Corpuscle Volume Values at the Indicated Time Points in Part A FA, Pre-dose, n=16, 14	91.8 femtoliters per cell (fL) Standard Deviation 5.03	91.3 femtoliters per cell (fL) Standard Deviation 5.21
Mean Corpuscle Volume Values at the Indicated Time Points in Part A FA, 1 hr Post-dose, n=14, 13	91.0 femtoliters per cell (fL) Standard Deviation 5.04	90.8 femtoliters per cell (fL) Standard Deviation 5.63
Mean Corpuscle Volume Values at the Indicated Time Points in Part A SA, Pre-dose, n=6, 7	90.0 femtoliters per cell (fL) Standard Deviation 6.19	91.6 femtoliters per cell (fL) Standard Deviation 5.49
Mean Corpuscle Volume Values at the Indicated Time Points in Part A SA, 1 hr Post-dose, n=7, 7	90.4 femtoliters per cell (fL) Standard Deviation 5.72	91.2 femtoliters per cell (fL) Standard Deviation 5.66

SECONDARY outcome

Timeframe: Pre-dose and 1 hr post each dose administered in Part A (up to 3 Weeks)

Population: All subject population. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). Different participants may have been analyzed for different parameters, so the overall number of participants analyzed reflects everyone in the All Subjects Population.

Blood samples were collected for the measurement of red blood cell count at pre-dose and 1 hr after each dose of FA and SA in Part A. FA is the first of the two doses of GSK2339345 or placebo administered at any of the three visits in Part A. SA is the second of the two doses of GSK2339345 or placebo administered at any of the three visits in Part A.

Outcome measures

Measure	Placebo n=16 Participants Participants received two doses of placebo as a solution administered via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.	GSK2339345 1000 Microgram (mcg) n=14 Participants Participants received two doses of GSK2339345 1000 mcg via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.
Mean Red Blood Cell Count Values at the Indicated Time Points in Part A FA, Pre-dose, n=16, 14	4.52 10^12 cells per liter (TI/L) Standard Deviation 0.452	4.54 10^12 cells per liter (TI/L) Standard Deviation 0.553
Mean Red Blood Cell Count Values at the Indicated Time Points in Part A FA, 1 hr Post-dose, n=14, 13	4.40 10^12 cells per liter (TI/L) Standard Deviation 0.470	4.39 10^12 cells per liter (TI/L) Standard Deviation 0.460
Mean Red Blood Cell Count Values at the Indicated Time Points in Part A SA, Pre-dose, n=6, 7	4.34 10^12 cells per liter (TI/L) Standard Deviation 0.296	4.51 10^12 cells per liter (TI/L) Standard Deviation 0.522
Mean Red Blood Cell Count Values at the Indicated Time Points in Part A SA, 1 hr Post-dose, n=7, 7	4.24 10^12 cells per liter (TI/L) Standard Deviation 0.436	4.42 10^12 cells per liter (TI/L) Standard Deviation 0.406

SECONDARY outcome

Timeframe: Pre-dose and 1 hr post each dose administered in Part A (up to 3 Weeks)

Population: All Subjects Population. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). Different participants may have been analyzed for different parameters, so the overall number of participants analyzed reflects everyone in the All Subjects Population.

Blood samples were collected for the measurement of ALP, ALT, AST and GGT at pre-dose and 1 hr after each dose of FA and SA in Part A. FA is the first of the two doses of GSK2339345 or placebo administered at any of the three visits in Part A. SA is the second of the two doses of GSK2339345 or placebo administered at any of the three visits in Part A.

Outcome measures

Measure	Placebo n=16 Participants Participants received two doses of placebo as a solution administered via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.	GSK2339345 1000 Microgram (mcg) n=14 Participants Participants received two doses of GSK2339345 1000 mcg via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.
Mean Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points in Part A ALP, FA, Pre-dose, n=16, 14	67.9 International Units/Liter (IU/L) Standard Deviation 19.33	64.1 International Units/Liter (IU/L) Standard Deviation 15.01
Mean Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points in Part A ALP, FA, 1 hr Post-dose, n=14, 14	63.7 International Units/Liter (IU/L) Standard Deviation 16.70	60.6 International Units/Liter (IU/L) Standard Deviation 13.67
Mean Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points in Part A ALP, SA, Pre-dose, n=6, 7	69.7 International Units/Liter (IU/L) Standard Deviation 15.11	57.4 International Units/Liter (IU/L) Standard Deviation 13.36
Mean Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points in Part A ALP, SA, 1 hr Post-dose, n=7, 7	69.0 International Units/Liter (IU/L) Standard Deviation 17.45	55.9 International Units/Liter (IU/L) Standard Deviation 13.59
Mean Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points in Part A ALT, FA, Pre-dose, n=16, 14	15.8 International Units/Liter (IU/L) Standard Deviation 5.36	13.9 International Units/Liter (IU/L) Standard Deviation 4.62
Mean Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points in Part A ALT, FA, 1 hr Post-dose, n=14, 14	15.2 International Units/Liter (IU/L) Standard Deviation 5.83	14.1 International Units/Liter (IU/L) Standard Deviation 5.77
Mean Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points in Part A ALT, SA, Pre-dose, n=6, 7	16.5 International Units/Liter (IU/L) Standard Deviation 2.07	13.6 International Units/Liter (IU/L) Standard Deviation 5.74
Mean Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points in Part A ALT, SA, 1 hr Post-dose, n=7, 7	15.3 International Units/Liter (IU/L) Standard Deviation 2.75	12.9 International Units/Liter (IU/L) Standard Deviation 6.54
Mean Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points in Part A AST, FA, Pre-dose, n=16, 14	23.1 International Units/Liter (IU/L) Standard Deviation 10.37	19.6 International Units/Liter (IU/L) Standard Deviation 3.98
Mean Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points in Part A GGT, FA, 1 hr Post-dose, n=14, 14	24.6 International Units/Liter (IU/L) Standard Deviation 13.89	22.4 International Units/Liter (IU/L) Standard Deviation 9.85
Mean Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points in Part A GGT, SA, Pre-dose, n=6, 7	20.7 International Units/Liter (IU/L) Standard Deviation 9.18	22.9 International Units/Liter (IU/L) Standard Deviation 12.82
Mean Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points in Part A GGT, SA, 1 hr Post-dose, n=7, 7	25.0 International Units/Liter (IU/L) Standard Deviation 15.58	22.0 International Units/Liter (IU/L) Standard Deviation 13.17
Mean Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points in Part A AST, FA, 1 hr Post-dose, n=14, 13	21.4 International Units/Liter (IU/L) Standard Deviation 9.87	20.7 International Units/Liter (IU/L) Standard Deviation 7.51
Mean Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points in Part A AST, SA, Pre-dose, n=6, 7	18.5 International Units/Liter (IU/L) Standard Deviation 4.28	21.6 International Units/Liter (IU/L) Standard Deviation 6.45
Mean Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points in Part A AST, SA, 1 hr Post-dose, n=6, 7	16.5 International Units/Liter (IU/L) Standard Deviation 3.51	19.7 International Units/Liter (IU/L) Standard Deviation 7.11
Mean Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Gamma Glutamyl Transferase (GGT) Values at the Indicated Time Points in Part A GGT, FA, Pre-dose, n=16, 14	24.6 International Units/Liter (IU/L) Standard Deviation 12.93	22.8 International Units/Liter (IU/L) Standard Deviation 9.95

SECONDARY outcome

Timeframe: Pre-dose and 1 hr post each dose administered in Part A (up to 3 Weeks)

Population: All Subjects Population. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). Different participants may have been analyzed for different parameters, so the overall number of participants analyzed reflects everyone in the All Subjects Population.

Blood samples were collected for the measurement ofdirect bilirubin, total bilirubin, creatinine and uric acid at pre-dose and 1 hr after each dose of FA and SA in Part A. FA is the first of the two doses of GSK2339345 or placebo administered at any of the three visits in Part A. SA is the second of the two doses of GSK2339345 or placebo administered at any of the three visits in Part A.

Outcome measures

Measure	Placebo n=16 Participants Participants received two doses of placebo as a solution administered via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.	GSK2339345 1000 Microgram (mcg) n=14 Participants Participants received two doses of GSK2339345 1000 mcg via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.
Mean Direct Bilirubin, Total Bilirubin, Creatinine and Uric Acid Values at the Indicated Time Points in Part A Direct bilirubin, FA, Pre-dose, n=13, 11	1.77 Micromoles per liter (µmol/L) Standard Deviation 0.832	1.64 Micromoles per liter (µmol/L) Standard Deviation 0.809
Mean Direct Bilirubin, Total Bilirubin, Creatinine and Uric Acid Values at the Indicated Time Points in Part A Direct bilirubin, FA, 1 hr Post-dose, n=10, 11	1.80 Micromoles per liter (µmol/L) Standard Deviation 0.919	1.45 Micromoles per liter (µmol/L) Standard Deviation 0.522
Mean Direct Bilirubin, Total Bilirubin, Creatinine and Uric Acid Values at the Indicated Time Points in Part A Direct bilirubin, SA, Pre-dose, n=4, 6	1.75 Micromoles per liter (µmol/L) Standard Deviation 0.957	1.83 Micromoles per liter (µmol/L) Standard Deviation 0.753
Mean Direct Bilirubin, Total Bilirubin, Creatinine and Uric Acid Values at the Indicated Time Points in Part A Direct bilirubin, SA, 1 hr Post-dose, n=5, 6	1.20 Micromoles per liter (µmol/L) Standard Deviation 0.447	1.50 Micromoles per liter (µmol/L) Standard Deviation 0.548
Mean Direct Bilirubin, Total Bilirubin, Creatinine and Uric Acid Values at the Indicated Time Points in Part A Total bilirubin, FA, Pre-dose, n=16, 14	8.07 Micromoles per liter (µmol/L) Standard Deviation 3.999	8.04 Micromoles per liter (µmol/L) Standard Deviation 3.709
Mean Direct Bilirubin, Total Bilirubin, Creatinine and Uric Acid Values at the Indicated Time Points in Part A Total bilirubin, FA, 1 hr Post-dose, n=14, 14	7.04 Micromoles per liter (µmol/L) Standard Deviation 4.185	6.34 Micromoles per liter (µmol/L) Standard Deviation 2.453
Mean Direct Bilirubin, Total Bilirubin, Creatinine and Uric Acid Values at the Indicated Time Points in Part A Total bilirubin, SA, Pre-dose, n=6, 7	7.35 Micromoles per liter (µmol/L) Standard Deviation 3.075	7.71 Micromoles per liter (µmol/L) Standard Deviation 2.928
Mean Direct Bilirubin, Total Bilirubin, Creatinine and Uric Acid Values at the Indicated Time Points in Part A Total bilirubin, SA, 1 hr Post-dose, n=7, 7	6.59 Micromoles per liter (µmol/L) Standard Deviation 3.204	5.87 Micromoles per liter (µmol/L) Standard Deviation 1.928
Mean Direct Bilirubin, Total Bilirubin, Creatinine and Uric Acid Values at the Indicated Time Points in Part A Creatinine, FA, Pre-dose, n=16, 14	65.1 Micromoles per liter (µmol/L) Standard Deviation 12.99	64.0 Micromoles per liter (µmol/L) Standard Deviation 11.21
Mean Direct Bilirubin, Total Bilirubin, Creatinine and Uric Acid Values at the Indicated Time Points in Part A Creatinine, FA, 1 hr Post-dose, n=14, 14	65.0 Micromoles per liter (µmol/L) Standard Deviation 12.29	60.5 Micromoles per liter (µmol/L) Standard Deviation 8.49
Mean Direct Bilirubin, Total Bilirubin, Creatinine and Uric Acid Values at the Indicated Time Points in Part A Creatinine, SA, Pre-dose, n=6, 7	61.1 Micromoles per liter (µmol/L) Standard Deviation 11.82	66.5 Micromoles per liter (µmol/L) Standard Deviation 11.72
Mean Direct Bilirubin, Total Bilirubin, Creatinine and Uric Acid Values at the Indicated Time Points in Part A Creatinine, SA, 1 hr Post-dose, n=7, 7	63.0 Micromoles per liter (µmol/L) Standard Deviation 10.92	65.1 Micromoles per liter (µmol/L) Standard Deviation 7.83
Mean Direct Bilirubin, Total Bilirubin, Creatinine and Uric Acid Values at the Indicated Time Points in Part A Uric acid, FA, Pre-dose, n=16, 14	283.1 Micromoles per liter (µmol/L) Standard Deviation 66.30	272.8 Micromoles per liter (µmol/L) Standard Deviation 59.36
Mean Direct Bilirubin, Total Bilirubin, Creatinine and Uric Acid Values at the Indicated Time Points in Part A Uric acid, FA, 1 hr Post-dose, n=14, 14	269.3 Micromoles per liter (µmol/L) Standard Deviation 68.09	259.2 Micromoles per liter (µmol/L) Standard Deviation 57.65
Mean Direct Bilirubin, Total Bilirubin, Creatinine and Uric Acid Values at the Indicated Time Points in Part A Uric acid, SA, Pre-dose, n=6, 7	270.0 Micromoles per liter (µmol/L) Standard Deviation 30.61	273.7 Micromoles per liter (µmol/L) Standard Deviation 74.40
Mean Direct Bilirubin, Total Bilirubin, Creatinine and Uric Acid Values at the Indicated Time Points in Part A Uric acid, SA, 1 hr Post-dose, n=7, 7	275.4 Micromoles per liter (µmol/L) Standard Deviation 43.08	257.7 Micromoles per liter (µmol/L) Standard Deviation 65.80

SECONDARY outcome

Timeframe: Pre-dose and 1 hr post each dose administered in Part A (up to 3 Weeks)

Population: All Subjects Population. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). Different participants may have been analyzed for different parameters, so the overall number of participants analyzed reflects everyone in the All Subjects Population.

Blood samples were collected for the measurement of calcium, chloride, glucose, potassium, sodium, and urea/blood urea nitrogen (BUN) at pre-dose and 1 hr after each dose of FA and SA in Part A. FA is the first of the two doses of GSK2339345 or placebo administered at any of the three visits in Part A. SA is the second of the two doses of GSK2339345 or placebo administered at any of the three visits in Part A.

Outcome measures

Measure	Placebo n=16 Participants Participants received two doses of placebo as a solution administered via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.	GSK2339345 1000 Microgram (mcg) n=14 Participants Participants received two doses of GSK2339345 1000 mcg via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.
Mean Calcium, Chloride, Glucose, Potassium, Sodium, and Urea/Blood Urea Nitrogen (BUN) Values at the Indicated Time Points in Part A Calcium, FA, Pre-dose, n=16, 14	2.37 Millimoles per liter (mmol/L) Standard Deviation 0.085	2.39 Millimoles per liter (mmol/L) Standard Deviation 0.107
Mean Calcium, Chloride, Glucose, Potassium, Sodium, and Urea/Blood Urea Nitrogen (BUN) Values at the Indicated Time Points in Part A Calcium, FA, 1 hr Post-dose, n=14, 13	2.34 Millimoles per liter (mmol/L) Standard Deviation 0.099	2.34 Millimoles per liter (mmol/L) Standard Deviation 0.091
Mean Calcium, Chloride, Glucose, Potassium, Sodium, and Urea/Blood Urea Nitrogen (BUN) Values at the Indicated Time Points in Part A Chloride, SA, Pre-dose, n=6, 7	103.6 Millimoles per liter (mmol/L) Standard Deviation 3.02	103.0 Millimoles per liter (mmol/L) Standard Deviation 1.73
Mean Calcium, Chloride, Glucose, Potassium, Sodium, and Urea/Blood Urea Nitrogen (BUN) Values at the Indicated Time Points in Part A Glucose, FA, Pre-dose, n=16, 14	5.28 Millimoles per liter (mmol/L) Standard Deviation 0.884	5.19 Millimoles per liter (mmol/L) Standard Deviation 0.791
Mean Calcium, Chloride, Glucose, Potassium, Sodium, and Urea/Blood Urea Nitrogen (BUN) Values at the Indicated Time Points in Part A Glucose, FA, 1 hr Post-dose, n=14, 14	5.59 Millimoles per liter (mmol/L) Standard Deviation 1.124	5.69 Millimoles per liter (mmol/L) Standard Deviation 1.279
Mean Calcium, Chloride, Glucose, Potassium, Sodium, and Urea/Blood Urea Nitrogen (BUN) Values at the Indicated Time Points in Part A Glucose, SA, Pre-dose, n=6, 7	5.03 Millimoles per liter (mmol/L) Standard Deviation 1.108	5.06 Millimoles per liter (mmol/L) Standard Deviation 0.629
Mean Calcium, Chloride, Glucose, Potassium, Sodium, and Urea/Blood Urea Nitrogen (BUN) Values at the Indicated Time Points in Part A Glucose, SA, 1 hr Post-dose, n=7, 7	5.46 Millimoles per liter (mmol/L) Standard Deviation 1.165	5.24 Millimoles per liter (mmol/L) Standard Deviation 0.873
Mean Calcium, Chloride, Glucose, Potassium, Sodium, and Urea/Blood Urea Nitrogen (BUN) Values at the Indicated Time Points in Part A Potassium, SA, Pre-dose, n=6, 7	4.22 Millimoles per liter (mmol/L) Standard Deviation 0.240	4.11 Millimoles per liter (mmol/L) Standard Deviation 0.241
Mean Calcium, Chloride, Glucose, Potassium, Sodium, and Urea/Blood Urea Nitrogen (BUN) Values at the Indicated Time Points in Part A Potassium, SA, 1 hr Post-dose, n=6, 7	4.12 Millimoles per liter (mmol/L) Standard Deviation 0.736	3.93 Millimoles per liter (mmol/L) Standard Deviation 0.206
Mean Calcium, Chloride, Glucose, Potassium, Sodium, and Urea/Blood Urea Nitrogen (BUN) Values at the Indicated Time Points in Part A Sodium, FA, Pre-dose, n=16, 14	138.6 Millimoles per liter (mmol/L) Standard Deviation 1.59	138.9 Millimoles per liter (mmol/L) Standard Deviation 1.51
Mean Calcium, Chloride, Glucose, Potassium, Sodium, and Urea/Blood Urea Nitrogen (BUN) Values at the Indicated Time Points in Part A Urea/BUN, FA, Pre-dose, n=16, 14	4.91 Millimoles per liter (mmol/L) Standard Deviation 1.909	4.86 Millimoles per liter (mmol/L) Standard Deviation 1.934
Mean Calcium, Chloride, Glucose, Potassium, Sodium, and Urea/Blood Urea Nitrogen (BUN) Values at the Indicated Time Points in Part A Urea/BUN, FA, 1 hr Post-dose, n=14, 14	5.04 Millimoles per liter (mmol/L) Standard Deviation 2.008	5.21 Millimoles per liter (mmol/L) Standard Deviation 2.104
Mean Calcium, Chloride, Glucose, Potassium, Sodium, and Urea/Blood Urea Nitrogen (BUN) Values at the Indicated Time Points in Part A Calcium, SA, Pre-dose, n=6, 7	2.41 Millimoles per liter (mmol/L) Standard Deviation 0.102	2.37 Millimoles per liter (mmol/L) Standard Deviation 0.095
Mean Calcium, Chloride, Glucose, Potassium, Sodium, and Urea/Blood Urea Nitrogen (BUN) Values at the Indicated Time Points in Part A Calcium, SA, 1 hr Post-dose, n=6, 7	2.34 Millimoles per liter (mmol/L) Standard Deviation 0.061	2.32 Millimoles per liter (mmol/L) Standard Deviation 0.110
Mean Calcium, Chloride, Glucose, Potassium, Sodium, and Urea/Blood Urea Nitrogen (BUN) Values at the Indicated Time Points in Part A Chloride, FA, Pre-dose, n=16, 14	103.6 Millimoles per liter (mmol/L) Standard Deviation 2.31	103.4 Millimoles per liter (mmol/L) Standard Deviation 2.13
Mean Calcium, Chloride, Glucose, Potassium, Sodium, and Urea/Blood Urea Nitrogen (BUN) Values at the Indicated Time Points in Part A Chloride, FA, 1 hr Post-dose, n=14, 14	103.6 Millimoles per liter (mmol/L) Standard Deviation 2.06	104.3 Millimoles per liter (mmol/L) Standard Deviation 2.20
Mean Calcium, Chloride, Glucose, Potassium, Sodium, and Urea/Blood Urea Nitrogen (BUN) Values at the Indicated Time Points in Part A Chloride, SA, 1 hr Post-dose, n=7, 7	104.9 Millimoles per liter (mmol/L) Standard Deviation 4.26	103.6 Millimoles per liter (mmol/L) Standard Deviation 1.40
Mean Calcium, Chloride, Glucose, Potassium, Sodium, and Urea/Blood Urea Nitrogen (BUN) Values at the Indicated Time Points in Part A Potassium, FA, Pre-dose, n=16, 14	4.18 Millimoles per liter (mmol/L) Standard Deviation 0.246	4.18 Millimoles per liter (mmol/L) Standard Deviation 0.229
Mean Calcium, Chloride, Glucose, Potassium, Sodium, and Urea/Blood Urea Nitrogen (BUN) Values at the Indicated Time Points in Part A Potassium, FA, 1 hr Post-dose, n=14, 13	3.94 Millimoles per liter (mmol/L) Standard Deviation 0.318	4.55 Millimoles per liter (mmol/L) Standard Deviation 1.028
Mean Calcium, Chloride, Glucose, Potassium, Sodium, and Urea/Blood Urea Nitrogen (BUN) Values at the Indicated Time Points in Part A Sodium, FA, 1 hr Post-dose, n=14, 14	138.8 Millimoles per liter (mmol/L) Standard Deviation 1.93	138.1 Millimoles per liter (mmol/L) Standard Deviation 1.99
Mean Calcium, Chloride, Glucose, Potassium, Sodium, and Urea/Blood Urea Nitrogen (BUN) Values at the Indicated Time Points in Part A Sodium, SA, Pre-dose, n=6, 7	139.0 Millimoles per liter (mmol/L) Standard Deviation 1.26	138.4 Millimoles per liter (mmol/L) Standard Deviation 0.98
Mean Calcium, Chloride, Glucose, Potassium, Sodium, and Urea/Blood Urea Nitrogen (BUN) Values at the Indicated Time Points in Part A Sodium, SA, 1 hr Post-dose, n=7, 7	140.0 Millimoles per liter (mmol/L) Standard Deviation 4.58	138.7 Millimoles per liter (mmol/L) Standard Deviation 1.60
Mean Calcium, Chloride, Glucose, Potassium, Sodium, and Urea/Blood Urea Nitrogen (BUN) Values at the Indicated Time Points in Part A Urea/BUN, SA, Pre-dose, n=6, 7	4.03 Millimoles per liter (mmol/L) Standard Deviation 1.791	4.81 Millimoles per liter (mmol/L) Standard Deviation 1.732
Mean Calcium, Chloride, Glucose, Potassium, Sodium, and Urea/Blood Urea Nitrogen (BUN) Values at the Indicated Time Points in Part A Urea/BUN, SA, 1 hr Post-dose, n=7, 7	5.00 Millimoles per liter (mmol/L) Standard Deviation 2.309	5.24 Millimoles per liter (mmol/L) Standard Deviation 1.706

SECONDARY outcome

Timeframe: Pre-dose and 1 hr post each dose administered in Part A (up to 3 Weeks)

Population: All Subjects Population. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). Different participants may have been analyzed for different parameters, so the overall number of participants analyzed reflects everyone in the All Subjects Population.

Blood samples were collected for the measurement of troponin I at pre-dose and 1 hr after each dose of FA and SA in Part A. FA is the first of the two doses of GSK2339345 or placebo administered at any of the three visits in Part A. SA is the second of the two doses of GSK2339345 or placebo administered at any of the three visits in Part A. Cardiac troponin values that were below the quantification limit [0.02 or 0.04 microgram (mcg/L)] were imputed as 0.01 (mcg/L).

Outcome measures

Measure	Placebo n=16 Participants Participants received two doses of placebo as a solution administered via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.	GSK2339345 1000 Microgram (mcg) n=14 Participants Participants received two doses of GSK2339345 1000 mcg via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.
Mean Troponin I Values at the Indicated Time Points in Part A FA, 1 hr Post-dose, n=15, 13	0.010 mcg/L Standard Deviation 0.0000	0.010 mcg/L Standard Deviation 0.0000
Mean Troponin I Values at the Indicated Time Points in Part A SA, Pre-dose, n=7, 7	0.010 mcg/L Standard Deviation 0.0000	0.010 mcg/L Standard Deviation 0.0000
Mean Troponin I Values at the Indicated Time Points in Part A FA, Pre-dose, n=16, 14	0.011 mcg/L Standard Deviation 0.0034	0.010 mcg/L Standard Deviation 0.0000
Mean Troponin I Values at the Indicated Time Points in Part A SA, 1 hr Post-dose, n=7, 7	0.010 mcg/L Standard Deviation 0.0000	0.010 mcg/L Standard Deviation 0.0000

SECONDARY outcome

Timeframe: Pre-dose and 30 min post each dose administered in Parts A, B and C (up to 8 Weeks)

Population: All Subjects Population. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). Different participants may have been analyzed for different parameters, so the overall number of participants analyzed reflects everyone in the All Subjects Population.

Pulmonary function was measured by FEV1, defined as the maximal amount of air that can be forcefully exhaled in one second. FEV1 was measured by spirometry at pre-dose and 30 min after FA and SA in Part A and each administration in Parts B, and C. FA is the first of the two doses of GSK2339345 or placebo administered at any of the three visits in Part A. SA is the second of the two doses of GSK2339345 or placebo administered at any of the three visits in Part A.

Outcome measures

Measure	Placebo n=16 Participants Participants received two doses of placebo as a solution administered via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.	GSK2339345 1000 Microgram (mcg) n=14 Participants Participants received two doses of GSK2339345 1000 mcg via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.
Mean Forced Expiratory Volume in One Second (FEV1) Values at the Indicated Time Points in Parts A, B and C Part A, FA, Dose 2, Pre-dose, n=16, 14	2.55 Liters Standard Deviation 2.22	2.37 Liters Standard Deviation 2.10
Mean Forced Expiratory Volume in One Second (FEV1) Values at the Indicated Time Points in Parts A, B and C Part A, SA, Dose 2, Pre-dose, n=7, 7	2.41 Liters Standard Deviation 1.99	2.36 Liters Standard Deviation 1.83
Mean Forced Expiratory Volume in One Second (FEV1) Values at the Indicated Time Points in Parts A, B and C Part A, SA, Dose 2, 30 min Post-dose, n=7, 7	2.42 Liters Standard Deviation 1.97	2.32 Liters Standard Deviation 1.80
Mean Forced Expiratory Volume in One Second (FEV1) Values at the Indicated Time Points in Parts A, B and C Part B, Pre-dose, n=10, 11	2.26 Liters Standard Deviation 2.07	2.31 Liters Standard Deviation 2.05
Mean Forced Expiratory Volume in One Second (FEV1) Values at the Indicated Time Points in Parts A, B and C Part B, 30 min Post-dose, n=10, 11	2.17 Liters Standard Deviation 2.01	2.30 Liters Standard Deviation 2.05
Mean Forced Expiratory Volume in One Second (FEV1) Values at the Indicated Time Points in Parts A, B and C Part A, FA, Dose 2, 30 min Post-dose, n=15, 13	2.44 Liters Standard Deviation 2.06	2.29 Liters Standard Deviation 2.02
Mean Forced Expiratory Volume in One Second (FEV1) Values at the Indicated Time Points in Parts A, B and C Part A, SA, Dose 1, Pre-dose, n=7, 7	2.54 Liters Standard Deviation 2.16	2.44 Liters Standard Deviation 1.97
Mean Forced Expiratory Volume in One Second (FEV1) Values at the Indicated Time Points in Parts A, B and C Part A, SA, Dose 1, 30 min Post-dose, n=7, 7	2.42 Liters Standard Deviation 2.00	2.31 Liters Standard Deviation 1.76
Mean Forced Expiratory Volume in One Second (FEV1) Values at the Indicated Time Points in Parts A, B and C Part C, Pre-dose, n=9, 9	2.23 Liters Standard Deviation 2.08	2.24 Liters Standard Deviation 1.98
Mean Forced Expiratory Volume in One Second (FEV1) Values at the Indicated Time Points in Parts A, B and C Part C, 30 min Post-dose, n=9, 9	2.13 Liters Standard Deviation 1.96	2.22 Liters Standard Deviation 1.98
Mean Forced Expiratory Volume in One Second (FEV1) Values at the Indicated Time Points in Parts A, B and C Part A, FA, Dose 1, Pre-dose, n=16, 14	2.55 Liters Standard Deviation 2.18	2.43 Liters Standard Deviation 2.17
Mean Forced Expiratory Volume in One Second (FEV1) Values at the Indicated Time Points in Parts A, B and C Part A, FA, Dose 1, 30 min Post-dose, n=16, 14	2.49 Liters Standard Deviation 2.12	2.39 Liters Standard Deviation 2.10

SECONDARY outcome

Timeframe: From 2 min -2 hr post each dose administered at Visits 1, 2 and 3 in Part A (up to 8 weeks)

Population: All Subjects Population. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). Different participants may have been analyzed for different parameters, so the overall number of participants analyzed reflects everyone in the All Subjects Population.

The perception of change in oropharyngeal sensation was assessed by a 4 point scale where participants were asked to describe sensitivity and perception of numbness and the responses were recorded. The following information was collected: 0 = no anaesthesia (A), 1 = mild anaesthesia, 2 = moderate anaesthesia and 3 = severe anaesthesia. Oropharyngeal examination was performed at 2 min, 5 min, 15 min, 30 min, 1 hr and 2 hr after FA and SA in Part A. FA is the first of the two doses of GSK2339345 or placebo administered at any of the three visits in Part A. SA is the second of the two doses of GSK2339345 or placebo administered at any of the three visits in Part A

Outcome measures

Measure	Placebo n=16 Participants Participants received two doses of placebo as a solution administered via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.	GSK2339345 1000 Microgram (mcg) n=14 Participants Participants received two doses of GSK2339345 1000 mcg via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A No A, FA, Dose 2, 2 min Post-dose, n=15, 14	15 Participants	14 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A Moderate A, FA, Dose 1, 15 min Post-dose, n=16, 14	0 Participants	0 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A Moderate A, FA, Dose 2, 1 hr Post-dose, n=15, 14	0 Participants	0 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A Severe A, FA, Dose 1, 2 min Post-dose, n=16, 14	0 Participants	0 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A Severe A, FA, Dose 1, 5 min Post-dose, n=16, 14	0 Participants	0 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A Severe A, FA, Dose 2, 5 min Post-dose, n=15, 14	0 Participants	0 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A Severe A, FA, Dose 2, 15 min Post-dose, n=15, 14	0 Participants	0 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A Severe A, SA, Dose 2, 1 hr Post-dose, n=7, 7	0 Participants	0 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A No A, FA, Dose 1, 2 min Post-dose, n=16, 14	16 Participants	14 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A No A, FA, Dose 1, 5 min Post-dose, n=16, 14	16 Participants	14 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A No A, FA, Dose 1, 15 min Post-dose, n=16, 14	16 Participants	14 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A No A, FA, Dose 1, 30 min Post-dose, n=16, 14	16 Participants	14 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A No A, FA, Dose 1, 1 hr Post-dose, n=16, 14	16 Participants	14 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A No A, FA, Dose 2, 5 min Post-dose, n=15, 14	15 Participants	14 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A No A, FA, Dose 2, 15 min Post-dose, n=15, 14	15 Participants	14 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A No A, FA, Dose 2, 30 min Post-dose, n=15, 14	15 Participants	14 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A No A, FA, Dose 2, 1 hr Post-dose, n=15, 14	15 Participants	14 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A No A, SA, Dose 1, 2 min Post-dose, n=7, 7	7 Participants	7 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A No A, SA, Dose 1, 5 min Post-dose, n=7, 7	7 Participants	7 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A No A, SA, Dose 1, 15 min Post-dose, n=7, 7	7 Participants	7 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A No A, SA, Dose 1, 30 min Post-dose, n=7, 7	7 Participants	7 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A No A, SA, Dose 1, 1 hr Post-dose, n=7,7	7 Participants	7 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A Severe A, SA, Dose 1, 5 min Post-dose, n=7, 7	0 Participants	0 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A No A, SA, Dose 2, 2 min Post-dose, n=7, 7	7 Participants	7 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A No A, SA, Dose 2, 5 min Post-dose, n=7, 7	7 Participants	7 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A No A, SA, Dose 2, 15 min Post-dose, n=7, 7	7 Participants	7 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A No A, SA, Dose 2, 30 min Post-dose, n=7, 7	7 Participants	7 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A No A, SA, Dose 2, 1 hr Post-dose, n=7, 7	7 Participants	7 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A Mild A, FA, Dose 1, 2 min Post-dose, n=16, 14	0 Participants	0 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A Mild A, FA, Dose 1, 5 min Post-dose, n=16, 14	0 Participants	0 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A Mild A, FA, Dose 1, 15 min Post-dose, n=16, 14	0 Participants	0 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A Mild A, FA, Dose 1, 30 min Post-dose, n=16, 14	0 Participants	0 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A Mild A, FA, Dose 1, 1 hr Post-dose, n=16, 14	0 Participants	0 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A Mild A, FA, Dose 2, 2 min Post-dose, n=15, 14	0 Participants	0 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A Mild A, FA, Dose 2, 5 min Post-dose, n=15, 14	0 Participants	0 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A Mild A, FA, Dose 2, 15 min Post-dose, n=15, 14	0 Participants	0 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A Mild A, FA, Dose 2, 30 min Post-dose, n=15, 14	0 Participants	0 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A Mild A, FA, Dose 2, 1 hr Post-dose, n=15, 14	0 Participants	0 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A Mild A, SA, Dose 1, 2 min Post-dose, n=7, 7	0 Participants	0 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A Mild A, SA, Dose 1, 5 min Post-dose, n=7, 7	0 Participants	0 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A Mild A, SA, Dose 1, 15 min Post-dose, n=7, 7	0 Participants	0 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A Mild A, SA, Dose 1, 30 min Post-dose, n=7, 7	0 Participants	0 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A Mild A, SA, Dose 1, 1 hr Post-dose, n=7,7	0 Participants	0 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A Mild A, SA, Dose 2, 2 min Post-dose, n=7, 7	0 Participants	0 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A Mild A, SA, Dose 2, 5 min Post-dose, n=7, 7	0 Participants	0 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A Mild A, SA, Dose 2, 15 min Post-dose, n=7, 7	0 Participants	0 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A Mild A, SA, Dose 2, 30 min Post-dose, n=7, 7	0 Participants	0 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A Mild A, SA, Dose 2, 1 hr Post-dose, n=7, 7	0 Participants	0 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A Moderate A, FA, Dose 1, 2 min Post-dose, n=16, 14	0 Participants	0 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A Moderate A, FA, Dose 1, 5 min Post-dose, n=16, 14	0 Participants	0 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A Moderate A, FA, Dose 1, 30 min Post-dose, n=16, 14	0 Participants	0 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A Moderate A, FA, Dose 1, 1 hr Post-dose, n=16, 14	0 Participants	0 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A Moderate A, FA, Dose 2, 2 min Post-dose, n=15, 14	0 Participants	0 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A Moderate A, FA, Dose 2, 5 min Post-dose, n=15, 14	0 Participants	0 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A Moderate A, FA, Dose 2, 15 min Post-dose, n=15, 14	0 Participants	0 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A Moderate A, FA, Dose 2, 30 min Post-dose, n=15, 14	0 Participants	0 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A Moderate A, SA, Dose 1, 2 min Post-dose, n=7, 7	0 Participants	0 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A Moderate A, SA, Dose 1, 5 min Post-dose, n=7, 7	0 Participants	0 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A Moderate A, SA, Dose 1, 15 min Post-dose, n=7, 7	0 Participants	0 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A Moderate A, SA, Dose 1, 30 min Post-dose, n=7, 7	0 Participants	0 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A Moderate A, SA, Dose 1, 1 hr Post-dose, n=7,7	0 Participants	0 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A Moderate A, SA, Dose 2, 2 min Post-dose, n=7, 7	0 Participants	0 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A Moderate A, SA, Dose 2, 5 min Post-dose, n=7, 7	0 Participants	0 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A Moderate A, SA, Dose 2, 15 min Post-dose, n=7, 7	0 Participants	0 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A Moderate A, SA, Dose 2, 30 min Post-dose, n=7, 7	0 Participants	0 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A Moderate A, SA, Dose 2, 1 hr Post-dose, n=7, 7	0 Participants	0 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A Severe A, FA, Dose 1, 15 min Post-dose, n=16, 14	0 Participants	0 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A Severe A, FA, Dose 1, 30 min Post-dose, n=16, 14	0 Participants	0 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A Severe A, FA, Dose 1, 1 hr Post-dose, n=16, 14	0 Participants	0 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A Severe A, FA, Dose 2, 2 min Post-dose, n=15, 14	0 Participants	0 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A Severe A, FA, Dose 2, 30 min Post-dose, n=15, 14	0 Participants	0 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A Severe A, FA, Dose 2, 1 hr Post-dose, n=15, 14	0 Participants	0 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A Severe A, SA, Dose 1, 2 min Post-dose, n=7, 7	0 Participants	0 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A Severe A, SA, Dose 1, 15 min Post-dose, n=7, 7	0 Participants	0 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A Severe A, SA, Dose 1, 30 min Post-dose, n=7, 7	0 Participants	0 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A Severe A, SA, Dose 1, 1 hr Post-dose, n=7, 7	0 Participants	0 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A Severe A, SA, Dose 2, 2 min Post-dose, n=7, 7	0 Participants	0 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A Severe A, SA, Dose 2, 5 min Post-dose, n=7, 7	0 Participants	0 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A Severe A, SA, Dose 2, 15 min Post-dose, n=7, 7	0 Participants	0 Participants
Number of Participants With Perception of Change in Oropharyngeal Sensation at the Indicated Time Points in Part A Severe A, SA, Dose 2, 30 min Post-dose, n=7, 7	0 Participants	0 Participants

SECONDARY outcome

Timeframe: 0-4 hr, 4-8 hr, 0-8 hr post each dose at Visits 1, 2 and 3 in Part A (up to 8 weeks)

Population: All Subjects Population.Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). Different participants may have been analyzed for different time points, so the overall number of participants analyzed reflects everyone in the All Subjects Population.

Cough counts (8 hours of recording) was conducted at Visits 1, 2 and 3 (4 hours of post-dose recording for each of the two doses administered). Coughs was counted by a cough monitor fitted to the participants for 8 hours post Dose 1. Transient coughing was calculated as the total number of coughs experienced in the two minutes from the start of the first inhalation of a dose. FA is the first of the two doses of GSK2339345 or placebo administered at any of the three visits in Part A. SA is the second of the two doses of GSK2339345 or placebo administered at any of the three visits in Part A

Outcome measures

Measure	Placebo n=14 Participants Participants received two doses of placebo as a solution administered via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.	GSK2339345 1000 Microgram (mcg) n=14 Participants Participants received two doses of GSK2339345 1000 mcg via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.
Mean Transient Cough Counts at the Indicated Time Points in Part A FA, 0-4 hr, n=14, 14	1.7 Cough count Standard Deviation 3.41	17.8 Cough count Standard Deviation 16.27
Mean Transient Cough Counts at the Indicated Time Points in Part A FA, 4-8 hr, n=14, 14	0.9 Cough count Standard Deviation 1.88	19.0 Cough count Standard Deviation 10.91
Mean Transient Cough Counts at the Indicated Time Points in Part A FA, 0-8 hr, n=14, 14	2.6 Cough count Standard Deviation 4.11	36.8 Cough count Standard Deviation 25.41
Mean Transient Cough Counts at the Indicated Time Points in Part A SA, 0-4 hr, n=7, 7	0.0 Cough count Standard Deviation 0.0	18.3 Cough count Standard Deviation 13.51
Mean Transient Cough Counts at the Indicated Time Points in Part A SA, 4-8 hr, n=7, 7	2.0 Cough count Standard Deviation 3.42	15.9 Cough count Standard Deviation 12.02
Mean Transient Cough Counts at the Indicated Time Points in Part A SA, 0-8 hr, n=7, 7	2.0 Cough count Standard Deviation 3.42	34.1 Cough count Standard Deviation 24.83

SECONDARY outcome

Timeframe: From 0-4 hr post each dose administered at Visits 1, 2 and 3 in Part A (up to 3 weeks)

Population: The Pharmacokinetic (PK) Population comprised of participants in the All Subjects Population for whom a pharmacokinetic sample was obtained and analysed. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles).

Plasma concentrations of GSK2339345 following the first dose and second dose at each visit in Part A was measured. Samples were collected at the following time points: pre-dose, 2 min, 5 min, 10 min, 30 min, 1 hr and 2 hr (only after Dose 1) after each dose administration at Visits 1, 2 and 3. All non-quantifiable (NQ) values after the pre-first dose value imputed to half lower limit of quantification (LLQ) (LLQ=0.2 nanogram per milliliter [ng/mL]). Different participants may have been analyzed for different parameters, so the overall number of par. analyzed reflects everyone in the pharmacokinetic population.

Outcome measures

Measure	Placebo n=14 Participants Participants received two doses of placebo as a solution administered via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.	GSK2339345 1000 Microgram (mcg) Participants received two doses of GSK2339345 1000 mcg via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.
Plasma Concentrations of GSK2339345 at the Indicated Time Points at Visits 1, 2 and 3 (Part A) FA, Dose 1, Pre-dose, n=14	0.000 nanogram per milliliter (ng/mL) Interval 0.0 to 0.0	—
Plasma Concentrations of GSK2339345 at the Indicated Time Points at Visits 1, 2 and 3 (Part A) FA, Dose 1, 2 min Post-dose, n=14	1.3985 nanogram per milliliter (ng/mL) Full Range 1.4881 • Interval 0.1 to 5.54	—
Plasma Concentrations of GSK2339345 at the Indicated Time Points at Visits 1, 2 and 3 (Part A) FA, Dose 1, 5 min Post-dose, n=14	0.9565 nanogram per milliliter (ng/mL) Full Range 0.9955 • Interval 0.1 to 2.886	—
Plasma Concentrations of GSK2339345 at the Indicated Time Points at Visits 1, 2 and 3 (Part A) FA, Dose 1, 10 min Post-dose, n=14	0.6925 nanogram per milliliter (ng/mL) Full Range 0.5075 • Interval 0.1 to 1.522	—
Plasma Concentrations of GSK2339345 at the Indicated Time Points at Visits 1, 2 and 3 (Part A) FA, Dose 1, 1 hr Post-dose, n=13	0.2950 nanogram per milliliter (ng/mL) Full Range NA • Interval 0.1 to 0.559	—
Plasma Concentrations of GSK2339345 at the Indicated Time Points at Visits 1, 2 and 3 (Part A) FA, Dose 2, 5 min Post-dose, n=14	1.4315 nanogram per milliliter (ng/mL) Full Range 2.3894 • Interval 0.1 to 9.686	—
Plasma Concentrations of GSK2339345 at the Indicated Time Points at Visits 1, 2 and 3 (Part A) FA, Dose 1, 30 min Post-dose, n=14	0.2820 nanogram per milliliter (ng/mL) Full Range NA • Interval 0.1 to 0.628	—
Plasma Concentrations of GSK2339345 at the Indicated Time Points at Visits 1, 2 and 3 (Part A) FA, Dose 2, 10 min Post-dose, n=14	1.0740 nanogram per milliliter (ng/mL) Full Range 0.9082 • Interval 0.1 to 3.119	—
Plasma Concentrations of GSK2339345 at the Indicated Time Points at Visits 1, 2 and 3 (Part A) FA, Dose 2, 30 min Post-dose, n=13	0.5230 nanogram per milliliter (ng/mL) Full Range 0.4645 • Interval 0.1 to 1.745	—
Plasma Concentrations of GSK2339345 at the Indicated Time Points at Visits 1, 2 and 3 (Part A) FA, Dose 2, Pre-dose, n=14	0.1000 nanogram per milliliter (ng/mL) Interval 0.1 to 0.705	—
Plasma Concentrations of GSK2339345 at the Indicated Time Points at Visits 1, 2 and 3 (Part A) FA, Dose 2, 1 hr Post-dose, n=14	0.5475 nanogram per milliliter (ng/mL) Full Range 0.2788 • Interval 0.1 to 0.989	—
Plasma Concentrations of GSK2339345 at the Indicated Time Points at Visits 1, 2 and 3 (Part A) FA, Dose 1, 2 hr Post-dose, n=13	0.2010 nanogram per milliliter (ng/mL) Full Range NA • Interval 0.1 to 0.421	—
Plasma Concentrations of GSK2339345 at the Indicated Time Points at Visits 1, 2 and 3 (Part A) FA, Dose 2, 2 min Post-dose, n=14	1.8735 nanogram per milliliter (ng/mL) Full Range 3.4305 • Interval 0.1 to 13.483	—
Plasma Concentrations of GSK2339345 at the Indicated Time Points at Visits 1, 2 and 3 (Part A) SA, Dose 1, 5 min Post-dose, n=7	1.5680 nanogram per milliliter (ng/mL) Full Range 1.0466 • Interval 0.1 to 2.642	—
Plasma Concentrations of GSK2339345 at the Indicated Time Points at Visits 1, 2 and 3 (Part A) SA, Dose 1, 10 min Post-dose, n=7	0.7790 nanogram per milliliter (ng/mL) Full Range 0.5366 • Interval 0.1 to 1.351	—
Plasma Concentrations of GSK2339345 at the Indicated Time Points at Visits 1, 2 and 3 (Part A) SA, Dose 1, 30 min Post-dose, n=7	0.2470 nanogram per milliliter (ng/mL) Full Range 3.1688 • Interval 0.1 to 8.619	—
Plasma Concentrations of GSK2339345 at the Indicated Time Points at Visits 1, 2 and 3 (Part A) SA, Dose 1, 1 hr Post-dose, n=7	0.2900 nanogram per milliliter (ng/mL) Full Range 0.1135 • Interval 0.1 to 0.38	—
Plasma Concentrations of GSK2339345 at the Indicated Time Points at Visits 1, 2 and 3 (Part A) SA, Dose 1, 2 hr Post-dose, n=7	0.1000 nanogram per milliliter (ng/mL) Full Range NA • Interval 0.1 to 0.826	—
Plasma Concentrations of GSK2339345 at the Indicated Time Points at Visits 1, 2 and 3 (Part A) SA, Dose 2, Pre-dose, n=7	0.1000 nanogram per milliliter (ng/mL) Full Range NA • Interval 0.1 to 0.541	—
Plasma Concentrations of GSK2339345 at the Indicated Time Points at Visits 1, 2 and 3 (Part A) SA, Dose 2, 2 min Post-dose, n=7	1.8280 nanogram per milliliter (ng/mL) Full Range 3.0811 • Interval 0.1 to 9.026	—
Plasma Concentrations of GSK2339345 at the Indicated Time Points at Visits 1, 2 and 3 (Part A) SA, Dose 2, 5 min Post-dose, n=7	1.4750 nanogram per milliliter (ng/mL) Full Range 1.7052 • Interval 0.1 to 5.13	—
Plasma Concentrations of GSK2339345 at the Indicated Time Points at Visits 1, 2 and 3 (Part A) SA, Dose 2, 10 min Post-dose, n=7	0.9030 nanogram per milliliter (ng/mL) Full Range 0.8469 • Interval 0.1 to 2.603	—
Plasma Concentrations of GSK2339345 at the Indicated Time Points at Visits 1, 2 and 3 (Part A) SA, Dose 2, 30 min Post-dose, n=7	0.4260 nanogram per milliliter (ng/mL) Full Range NA • Interval 0.1 to 0.737	—
Plasma Concentrations of GSK2339345 at the Indicated Time Points at Visits 1, 2 and 3 (Part A) SA, Dose 2, 1 hr Post-dose, n=7	0.4290 nanogram per milliliter (ng/mL) Full Range 0.4640 • Interval 0.1 to 1.456	—
Plasma Concentrations of GSK2339345 at the Indicated Time Points at Visits 1, 2 and 3 (Part A) SA, Dose 1, Pre-dose, n=7	0.0000 nanogram per milliliter (ng/mL) Full Range NA • Interval 0.0 to 0.441	—
Plasma Concentrations of GSK2339345 at the Indicated Time Points at Visits 1, 2 and 3 (Part A) SA, Dose 1, 2 min Post-dose, n=7	1.5010 nanogram per milliliter (ng/mL) Full Range 1.6036 • Interval 0.1 to 3.877	—

SECONDARY outcome

Timeframe: From 0-4 hr post each dose administered at Visits 1, 2 and 3 in Part A (up to 3 weeks)

Population: PK Population. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). Different participants may have been analyzed for different parameters, so the overall number of participants analyzed reflects everyone in the PK Population.

AUC curve from time zero (pre-dose) to 1 hours AUC(0-1) and from time zero to the last time AUC(0-t) of quantifiable concentration of GSK2339345 following the first dose and second dose at each visit in Part A was measured. Samples were collected at the following time points: pre-dose; 2 min, 5 min, 10 min, 30 min, 1 hr and 2hr (only after Dose 1) post every dose administration at Visits 1, 2 and 3. For , AUC(0-1) and AUC(0-t), non calculable (NC) were imputed prior to derivation of summary statistics and NCs were imputed as 0.1093 and 0.0855 respectively (=half the lowest observed value).

Outcome measures

Measure	Placebo n=14 Participants Participants received two doses of placebo as a solution administered via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.	GSK2339345 1000 Microgram (mcg) Participants received two doses of GSK2339345 1000 mcg via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.
Area Under the Concentration (AUC) Time (0-1) and AUC(0-t) of GSK2339345 Following Two Repeated Doses AUC(0-1), FA, Dose 1, n=11	0.3968 hour*nanogram per milliliter (h*ng/mL) Geometric Coefficient of Variation 109.1924	—
Area Under the Concentration (AUC) Time (0-1) and AUC(0-t) of GSK2339345 Following Two Repeated Doses AUC(0-1), FA, Dose 2, n=10	0.8168 hour*nanogram per milliliter (h*ng/mL) Geometric Coefficient of Variation 76.8324	—
Area Under the Concentration (AUC) Time (0-1) and AUC(0-t) of GSK2339345 Following Two Repeated Doses AUC(0-1), SA, Dose 1, n=7	0.4509 hour*nanogram per milliliter (h*ng/mL) Geometric Coefficient of Variation 174.9418	—
Area Under the Concentration (AUC) Time (0-1) and AUC(0-t) of GSK2339345 Following Two Repeated Doses AUC(0-1), SA, Dose 2, n=6	NA hour*nanogram per milliliter (h*ng/mL) Geometric Coefficient of Variation NA Due to insufficient data, NA was entered.	—
Area Under the Concentration (AUC) Time (0-1) and AUC(0-t) of GSK2339345 Following Two Repeated Doses AUC(0-t), FA, n=14	2.0076 hour*nanogram per milliliter (h*ng/mL) Geometric Coefficient of Variation 174.1325	—
Area Under the Concentration (AUC) Time (0-1) and AUC(0-t) of GSK2339345 Following Two Repeated Doses AUC(0-t), SA, n=7	1.2425 hour*nanogram per milliliter (h*ng/mL) Geometric Coefficient of Variation 559.1820	—

SECONDARY outcome

Timeframe: From 0-4 hr post each dose administered at Visits 1, 2 and 3 in Part A (up to 3 weeks)

Population: PK Population. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). Different participants may have been analyzed for different time points, so the overall number of participants analyzed reflects everyone in the PK Population.

Cmax is defined as the maximum observed concentration of GSK2339345 following two repeated doses at each visit in Part A. Samples were collected at the following time points: pre-dose; 2 min, 5 min, 10 min, 30 min, 1 hr and 2hr (only after Dose 1) post every dose administration at Visits 1, 2 and 3. FA is the first of the two doses of GSK2339345 or placebo administered at any of the three visits in Part A. SA is the second of the two doses of GSK2339345 or placebo administered at any of the three visits in Part A. For Cmax, NCs were imputed prior to derivation of summary statistics and NCs were imputed with 0.5*LLQ (LLQ=0.20 ng/mL).

Outcome measures

Measure	Placebo n=14 Participants Participants received two doses of placebo as a solution administered via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.	GSK2339345 1000 Microgram (mcg) Participants received two doses of GSK2339345 1000 mcg via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.
Maximum Observed Concentration (Cmax) of GSK2339345 Following Two Repeated Doses FA, Dose 1, n=14	0.9485 nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 224.0451	—
Maximum Observed Concentration (Cmax) of GSK2339345 Following Two Repeated Doses FA, Dose 2, n=14	1.9212 nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 138.2018	—
Maximum Observed Concentration (Cmax) of GSK2339345 Following Two Repeated Doses SA, Dose 1, n=7	1.0835 nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 474.4072	—
Maximum Observed Concentration (Cmax) of GSK2339345 Following Two Repeated Doses SA, Dose 2, n=7	1.0448 nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 416.3398	—

SECONDARY outcome

Timeframe: From 0-4 hr post each dose administered at Visits 1, 2 and 3 in Part A (up to 3 weeks)

Population: PK Population. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). Different participants may have been analyzed for different time points, so the overall number of participants analyzed reflects everyone in the PK Population.

Tmax is defined as the time to reach the observed maximum GSK2339345concentration following two repeated doses at each visit in Part A. Samples were collected at the following time points: pre-dose; 2 min, 5 min, 10 min, 30 min, 1 hr and 2hr (only after Dose 1) post every dose administered at Visits 1, 2 and 3. FA is the first of the two doses of GSK2339345 or placebo administered at any of the three visits in Part A. SA is the second of the two doses of GSK2339345 or placebo administered at any of the three visits in Part A.

Outcome measures

Measure	Placebo n=14 Participants Participants received two doses of placebo as a solution administered via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.	GSK2339345 1000 Microgram (mcg) Participants received two doses of GSK2339345 1000 mcg via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.
Time to Reach the Observed Maximum Concentration (Tmax) of GSK2339345 Following Two Repeated Doses FA, Dose 1, n=11	0.03333 Hours Interval 0.0167 to 0.1	—
Time to Reach the Observed Maximum Concentration (Tmax) of GSK2339345 Following Two Repeated Doses FA, Dose 2, n=14	0.03333 Hours Interval 0.0167 to 0.516	—
Time to Reach the Observed Maximum Concentration (Tmax) of GSK2339345 Following Two Repeated Doses SA, Dose 1, n=5	0.06667 Hours Interval 0.0333 to 0.416	—
Time to Reach the Observed Maximum Concentration (Tmax) of GSK2339345 Following Two Repeated Doses SA, Dose 2, n=5	0.03333 Hours Interval 0.0167 to 1.05	—

SECONDARY outcome

Timeframe: Up to 8 hours post-dose at Visits 1, 2 and 3 (Part A)

Population: All Subjects Population. Only participants with at least one 4 hr cough count were analyzed.

Total cough count (8 hr of recording) was conducted at Visits 1, 2 and 3 (4- hrs of post-dose recording for each of the two doses administered). Coughs were counted by a cough monitor fitted to the participants for 8 hr post Dose 1. The cough count over 4-hrs was done by using the sum of first 4-hrs starting from the time of first dose and the second 4-hrs starting at the time of the second dose respectively. Number of coughs in 0-4 hr and 4-8 hr period was log-e transformed and used for the analysis. Values were imputed pro-rata if 4 hr epoch was less than 4 hr. Mean of the total cough counts over 4-hrs recorded post dose of every treatment i.e. placebo or GSK2339345 1000 mcg was reported.

Outcome measures

Measure	Placebo n=14 Participants Participants received two doses of placebo as a solution administered via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.	GSK2339345 1000 Microgram (mcg) n=14 Participants Participants received two doses of GSK2339345 1000 mcg via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.
Mean Cough Count Over 4 Hours at Visits 1, 2 and 3 (Part A) 0-4 hr	70.5 Cough count Standard Error 0.257	86.7 Cough count Standard Error 0.257
Mean Cough Count Over 4 Hours at Visits 1, 2 and 3 (Part A) 4-8 hr	65.1 Cough count Standard Error 0.234	88.4 Cough count Standard Error 0.234

SECONDARY outcome

Timeframe: Up to 8 hours post-dose at Visits 1, 2 and 3 (Part A)

Population: All Subjects Population. Only participants with at least one 4 hr cough count were analyzed.

Total cough count (8 hr of recording) was conducted at Visits 1, 2 and 3 (4-hrs of post-dose recording for each of the two doses administered). Coughs were counted by a cough monitor fitted to the participants for 8 hr post Dose 1. Total count excluding transient cough over 4-hrs was done by using the sum of first 4-hrs starting from the time of first dose and the second 4-hrs starting at the time of the second dose respectively. Number of coughs excluding transient cough in 0-4 hr and 4-8 hr period was log-e transformed and used for the analysis. Values were imputed pro-rata if 4-hr epoch was less than 4-hrs. Mean of the total cough counts over 4-hrs recorded post dose of every treatment i.e. placebo or GSK2339345 1000 mcg was reported.

Outcome measures

Measure	Placebo n=14 Participants Participants received two doses of placebo as a solution administered via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.	GSK2339345 1000 Microgram (mcg) n=14 Participants Participants received two doses of GSK2339345 1000 mcg via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.
Total Cough Count Excluding Transient Coughs Over 4 Hours at Visits 1, 2 and 3 (Part A) 0-4 Hr	70.2 Cough count Standard Error 0.270	68.3 Cough count Standard Error 0.270
Total Cough Count Excluding Transient Coughs Over 4 Hours at Visits 1, 2 and 3 (Part A) 4-8 Hr	64.6 Cough count Standard Error 0.250	67.0 Cough count Standard Error 0.250

SECONDARY outcome

Timeframe: Up to 8 hours post-dose at Visits 1, 2 and 3 in Part A (up to 3 weeks)

Population: All Subjects Population. Only those participants with a 1 hr cough count value were analyzed.

Cough counts (8 hr of recording) were conducted at Visits 1, 2 and 3 (4-hr of post-dose recording for each of the two doses administered). Coughs were counted by a cough monitor fitted to the participant for 8 hr post Dose 1. The first epoch started at the time of the first dose, and the 60 min time periods continued until an epoch ended immediately before the second dose (or 4-hr after the first dose if earlier). The epochs were then re-started at the start of the second dose at 60 min intervals, finishing with an epoch which ran to 4-hrs after the start of the second dose. The cough counts were sum-up by the treatments received by the participants. Mean cough count was calculated per participant if the same treatment was taken during different periods. Values were imputed pro-rata if 1 hr epoch is less than 60 min.

Outcome measures

Measure	Placebo n=14 Participants Participants received two doses of placebo as a solution administered via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.	GSK2339345 1000 Microgram (mcg) n=14 Participants Participants received two doses of GSK2339345 1000 mcg via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.
Mean Cough Counts by 1 hr Epoch at Visits 1, 2 and 3 (Part A) 0 to 1 hr	41.5 Cough count Standard Deviation 30.25	46.8 Cough count Standard Deviation 35.58
Mean Cough Counts by 1 hr Epoch at Visits 1, 2 and 3 (Part A) 1 to 2 hr	13.9 Cough count Standard Deviation 9.86	15.7 Cough count Standard Deviation 11.20
Mean Cough Counts by 1 hr Epoch at Visits 1, 2 and 3 (Part A) 2 to 3 hr	11.0 Cough count Standard Deviation 11.68	17.0 Cough count Standard Deviation 11.75
Mean Cough Counts by 1 hr Epoch at Visits 1, 2 and 3 (Part A) 3 to 4 hr	38.4 Cough count Standard Deviation 35.63	36.6 Cough count Standard Deviation 26.40
Mean Cough Counts by 1 hr Epoch at Visits 1, 2 and 3 (Part A) 4 to 5 hr	20.4 Cough count Standard Deviation 14.78	54.7 Cough count Standard Deviation 61.49
Mean Cough Counts by 1 hr Epoch at Visits 1, 2 and 3 (Part A) 5 to 6 hr	25.3 Cough count Standard Deviation 43.09	28.9 Cough count Standard Deviation 51.83
Mean Cough Counts by 1 hr Epoch at Visits 1, 2 and 3 (Part A) 6 to 7 hr	28.7 Cough count Standard Deviation 44.03	18.7 Cough count Standard Deviation 22.79
Mean Cough Counts by 1 hr Epoch at Visits 1, 2 and 3 (Part A) 7 to 8 hr	32.5 Cough count Standard Deviation 54.26	28.2 Cough count Standard Deviation 42.78

SECONDARY outcome

Timeframe: Up to 8 hours post-dose in Visits 1, 2 and 3 in Part A (up to 3 weeks)

Population: All Subjects Population. Only those participants with a 30 min cough count value were analyzed.

Cough counts (8 hr of recording) were conducted at Visits 1, 2 and 3 (4-hr of post-dose recording for each of the two doses administered). Coughs were counted by a cough monitor fitted to the participant for 8 hr post Dose 1. The first epoch started at the time of the first dose, and the 30 min time periods continued until an epoch ended immediately before the second dose (or 4-hr after the first dose if earlier). The epochs were then re-started at the start of the second dose at 30 min intervals, finishing with an epoch which ran to 4-hr after the start of the second dose. The cough counts were sum-up by the treatments received by the participants. Mean cough count was calculated per participant if the same treatment was taken during different periods.

Outcome measures

Measure	Placebo n=14 Participants Participants received two doses of placebo as a solution administered via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.	GSK2339345 1000 Microgram (mcg) n=14 Participants Participants received two doses of GSK2339345 1000 mcg via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.
Mean Cough Counts by 30 Min Epoch at Visits 1, 2 and 3 (Part A) 0 to 0.5 hr	15.3 Cough count Standard Deviation 17.93	25.7 Cough count Standard Deviation 21.17
Mean Cough Counts by 30 Min Epoch at Visits 1, 2 and 3 (Part A) 0.5 to 1 hr	26.2 Cough count Standard Deviation 22.58	21.1 Cough count Standard Deviation 22.18
Mean Cough Counts by 30 Min Epoch at Visits 1, 2 and 3 (Part A) 1 to 1.5 hr	7.1 Cough count Standard Deviation 7.80	9.1 Cough count Standard Deviation 8.29
Mean Cough Counts by 30 Min Epoch at Visits 1, 2 and 3 (Part A) 1.5 to 2 hr	6.7 Cough count Standard Deviation 4.86	6.6 Cough count Standard Deviation 6.10
Mean Cough Counts by 30 Min Epoch at Visits 1, 2 and 3 (Part A) 2 to 2.5 hr	5.9 Cough count Standard Deviation 8.35	10.4 Cough count Standard Deviation 10.29
Mean Cough Counts by 30 Min Epoch at Visits 1, 2 and 3 (Part A) 2.5 to 3 hr	5.1 Cough count Standard Deviation 7.41	6.6 Cough count Standard Deviation 8.67
Mean Cough Counts by 30 Min Epoch at Visits 1, 2 and 3 (Part A) 3 to 3.5 hr	19.2 Cough count Standard Deviation 21.84	16.5 Cough count Standard Deviation 15.60
Mean Cough Counts by 30 Min Epoch at Visits 1, 2 and 3 (Part A) 3.5 to 4 hr	19.2 Cough count Standard Deviation 28.72	20.1 Cough count Standard Deviation 23.39
Mean Cough Counts by 30 Min Epoch at Visits 1, 2 and 3 (Part A) 4 to 4.5 hr	5.4 Cough count Standard Deviation 6.24	35.5 Cough count Standard Deviation 44.15
Mean Cough Counts by 30 Min Epoch at Visits 1, 2 and 3 (Part A) 4.5 to 5 hr	15.0 Cough count Standard Deviation 12.17	19.2 Cough count Standard Deviation 21.38
Mean Cough Counts by 30 Min Epoch at Visits 1, 2 and 3 (Part A) 5 to 5.5 hr	19.1 Cough count Standard Deviation 31.94	21.1 Cough count Standard Deviation 49.66
Mean Cough Counts by 30 Min Epoch at Visits 1, 2 and 3 (Part A) 5.5 to 6 hr	6.2 Cough count Standard Deviation 11.75	7.8 Cough count Standard Deviation 10.60
Mean Cough Counts by 30 Min Epoch at Visits 1, 2 and 3 (Part A) 6 to 6.5 hr	12.0 Cough count Standard Deviation 17.57	7.4 Cough count Standard Deviation 8.26
Mean Cough Counts by 30 Min Epoch at Visits 1, 2 and 3 (Part A) 6.5 to 7 hr	16.7 Cough count Standard Deviation 29.71	11.3 Cough count Standard Deviation 16.92
Mean Cough Counts by 30 Min Epoch at Visits 1, 2 and 3 (Part A) 7 to 7.5 hr	16.5 Cough count Standard Deviation 18.71	11.4 Cough count Standard Deviation 15.10
Mean Cough Counts by 30 Min Epoch at Visits 1, 2 and 3 (Part A) 7.5 to 8 hr	16.0 Cough count Standard Deviation 37.36	16.6 Cough count Standard Deviation 33.54

SECONDARY outcome

Timeframe: Up to 8 hours post-dose at Visits 1, 2 and 3 in Part A (up to 3 weeks)

Population: All Subjects Population. Only those participants with a 15 min cough count value were analyzed.

Cough counts (8 hr of recording) were conducted at Visits 1, 2 and 3 (4-hr of post-dose recording for each of the two doses administered). Coughs were counted by a cough monitor fitted to the participant for 8 hr post Dose 1. The first epoch started at the time of the first dose, and the 15 min time periods continued until an epoch ended immediately before the second dose (or 4h after the first dose if earlier). The epochs were then re-started at the start of the second dose at 15 min intervals, finishing with an epoch which ran to 4-hr after the start of the second dose. The cough counts were sum-up by the treatments received by the participants. Mean cough count was calculated per participant if the same treatment was taken during different periods.

Outcome measures

Measure	Placebo n=14 Participants Participants received two doses of placebo as a solution administered via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.	GSK2339345 1000 Microgram (mcg) n=14 Participants Participants received two doses of GSK2339345 1000 mcg via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.
Mean Cough Counts by 15 Min Epoch in Part A 0 to 0.25 hr	4.6 Cough count Standard Deviation 7.84	21.1 Cough count Standard Deviation 18.23
Mean Cough Counts by 15 Min Epoch in Part A 0.25 to 0.5 hr	10.7 Cough count Standard Deviation 14.99	4.6 Cough count Standard Deviation 9.21
Mean Cough Counts by 15 Min Epoch in Part A 0.5 to 0.75 hr	22.5 Cough count Standard Deviation 21.10	18.7 Cough count Standard Deviation 19.54
Mean Cough Counts by 15 Min Epoch in Part A 5.25 to 5.5 hr	9.5 Cough count Standard Deviation 16.54	9.1 Cough count Standard Deviation 21.65
Mean Cough Counts by 15 Min Epoch in Part A 0.75 to 1 hr	3.7 Cough count Standard Deviation 6.11	2.4 Cough count Standard Deviation 3.91
Mean Cough Counts by 15 Min Epoch in Part A 1 to 1.25 hr	4.9 Cough count Standard Deviation 7.53	5.7 Cough count Standard Deviation 6.91
Mean Cough Counts by 15 Min Epoch in Part A 1.25 to 1.5 hr	2.3 Cough count Standard Deviation 4.13	3.5 Cough count Standard Deviation 4.19
Mean Cough Counts by 15 Min Epoch in Part A 1.5 to 1.75 hr	3.5 Cough count Standard Deviation 3.08	3.4 Cough count Standard Deviation 3.67
Mean Cough Counts by 15 Min Epoch in Part A 1.75 to 2 hr	3.3 Cough count Standard Deviation 2.96	3.1 Cough count Standard Deviation 3.61
Mean Cough Counts by 15 Min Epoch in Part A 2 to 2.25 hr	4.0 Cough count Standard Deviation 7.26	6.9 Cough count Standard Deviation 9.04
Mean Cough Counts by 15 Min Epoch in Part A 2.25 to 2.5 hr	1.9 Cough count Standard Deviation 3.04	3.5 Cough count Standard Deviation 4.77
Mean Cough Counts by 15 Min Epoch in Part A 2.5 to 2.75 hr	0.4 Cough count Standard Deviation 0.94	1.5 Cough count Standard Deviation 4.39
Mean Cough Counts by 15 Min Epoch in Part A 2.75 to 3 hr	4.6 Cough count Standard Deviation 7.26	5.1 Cough count Standard Deviation 6.34
Mean Cough Counts by 15 Min Epoch in Part A 3 to 3.25 hr	8.4 Cough count Standard Deviation 14.45	8.8 Cough count Standard Deviation 13.61
Mean Cough Counts by 15 Min Epoch in Part A 3.25 to 3.5 hr	10.9 Cough count Standard Deviation 13.44	7.7 Cough count Standard Deviation 11.34
Mean Cough Counts by 15 Min Epoch in Part A 3.5 to 3.75 hr	7.7 Cough count Standard Deviation 11.21	5.5 Cough count Standard Deviation 8.60
Mean Cough Counts by 15 Min Epoch in Part A 3.75 to 4 hr	11.5 Cough count Standard Deviation 20.13	14.6 Cough count Standard Deviation 21.35
Mean Cough Counts by 15 Min Epoch in Part A 4 to 4.25 hr	1.6 Cough count Standard Deviation 2.88	23.0 Cough count Standard Deviation 17.97
Mean Cough Counts by 15 Min Epoch in Part A 4.25 to 4.5 hr	3.8 Cough count Standard Deviation 5.97	12.5 Cough count Standard Deviation 28.66
Mean Cough Counts by 15 Min Epoch in Part A 4.5 to 4.75 hr	12.4 Cough count Standard Deviation 13.16	15.6 Cough count Standard Deviation 19.11
Mean Cough Counts by 15 Min Epoch in Part A 4.75 to 5 hr	2.6 Cough count Standard Deviation 4.79	3.5 Cough count Standard Deviation 5.51
Mean Cough Counts by 15 Min Epoch in Part A 5 to 5.25 hr	9.6 Cough count Standard Deviation 17.34	12.0 Cough count Standard Deviation 28.61
Mean Cough Counts by 15 Min Epoch in Part A 5.5 to 5.75 hr	2.1 Cough count Standard Deviation 3.35	3.9 Cough count Standard Deviation 6.34
Mean Cough Counts by 15 Min Epoch in Part A 5.75 to 6 hr	4.1 Cough count Standard Deviation 8.91	3.9 Cough count Standard Deviation 6.24
Mean Cough Counts by 15 Min Epoch in Part A 6 to 6.25 hr	6.8 Cough count Standard Deviation 13.83	3.2 Cough count Standard Deviation 4.39
Mean Cough Counts by 15 Min Epoch in Part A 6.25 to 6.5 hr	5.2 Cough count Standard Deviation 6.60	4.3 Cough count Standard Deviation 6.01
Mean Cough Counts by 15 Min Epoch in Part A 6.5 to 6.75 hr	7.2 Cough count Standard Deviation 14.53	2.8 Cough count Standard Deviation 4.67
Mean Cough Counts by 15 Min Epoch in Part A 6.75 to 7 hr	9.5 Cough count Standard Deviation 16.17	8.5 Cough count Standard Deviation 12.80
Mean Cough Counts by 15 Min Epoch in Part A 7 to 7.25 hr	6.9 Cough count Standard Deviation 7.63	7.1 Cough count Standard Deviation 11.20
Mean Cough Counts by 15 Min Epoch in Part A 7.25 to 7.5 hr	9.6 Cough count Standard Deviation 15.81	4.3 Cough count Standard Deviation 5.51
Mean Cough Counts by 15 Min Epoch in Part A 7.5 to 7.75 hr	6.9 Cough count Standard Deviation 18.06	4.9 Cough count Standard Deviation 6.24
Mean Cough Counts by 15 Min Epoch in Part A 7.75 to 8 hr	9.1 Cough count Standard Deviation 19.35	11.7 Cough count Standard Deviation 33.10

SECONDARY outcome

Timeframe: Prior to first dose and 1hr post second dose at Visits 1, 2 and 3 in Part A (up to 3 weeks)

Population: All Subjects Population. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). Different participants may have been analyzed for different parameters, so the overall number of participants analyzed reflects everyone in the All Subjects Population.

VAS for urge to cough and severity of cough were recorded prior to first dose and 1 hour following the second dose of GSK2339345 or placebo at Visits 1, 2 and 3.VAS is a 100-mm linear scales on which participants indicated the severity of their cough (0 mm represents no severity and 100 mm maximum severity ever experienced) and urge to cough (0 represents no urge to cough, 100 represents maximum urge to cough ever experienced). Mean of replicate values per participants used where the same treatment taken during different periods.

Outcome measures

Measure	Placebo n=16 Participants Participants received two doses of placebo as a solution administered via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.	GSK2339345 1000 Microgram (mcg) n=14 Participants Participants received two doses of GSK2339345 1000 mcg via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.
Mean Visual Analogue Scale (VAS) Score of Cough Severity and Urge to Cough at the Indicated Time Points at Visits 1, 2 and 3 (Part A) Cough severity, Dose 2, 1 hr Post-dose, n=15, 14	26.7 Scores on a scale Standard Deviation 15.03	39.3 Scores on a scale Standard Deviation 21.70
Mean Visual Analogue Scale (VAS) Score of Cough Severity and Urge to Cough at the Indicated Time Points at Visits 1, 2 and 3 (Part A) Urge to cough, Dose 1, Pre-dose, n=16, 14	42.9 Scores on a scale Standard Deviation 20.51	42.2 Scores on a scale Standard Deviation 25.94
Mean Visual Analogue Scale (VAS) Score of Cough Severity and Urge to Cough at the Indicated Time Points at Visits 1, 2 and 3 (Part A) Urge to cough, Dose 2, 1 hr Post-dose, n=15, 14	25.1 Scores on a scale Standard Deviation 15.40	41.5 Scores on a scale Standard Deviation 22.60
Mean Visual Analogue Scale (VAS) Score of Cough Severity and Urge to Cough at the Indicated Time Points at Visits 1, 2 and 3 (Part A) Cough severity, Dose 1, Pre-dose, n=16, 14	42.8 Scores on a scale Standard Deviation 16.71	37.3 Scores on a scale Standard Deviation 23.03

SECONDARY outcome

Timeframe: After the administration of GSK2339345 or placebo (first and second 15 seconds following each dose) at Visits 4 and 5 in Part B (up to 2 weeks)

Population: CC population. Population comprised of par. in the All Subjects Population for whom any CC data were available for one or both Part B study visits. Only those participants available at the specified time points we re analyze d (represented by n=X, X in the category titles).

Capsaicin was administered using a dosimeter through a nebulizer pot with flow-limitation. Inhalation of increased concentrations (Conc.) was continued until the maximum dose was tolerated by the par. or highest available Conc. was used. The dose-response relationship between dose of capsaicin and cough response was investigated using non-linear mixed effect modeling using Poisson and Negative Binomial distributions. When using a Poisson distribution, there was some evidence for a reduction in capsaicin Emax with GSK2339345 of 17.6%, however, this was not confirmed when using a Negative Binomial distribution. The Negative Binomial distribution described the data marginally better, but the dataset was too small to make definitive conclusions. There was no treatment difference in capsaicin ED50.

Outcome measures

Measure	Placebo n=10 Participants Participants received two doses of placebo as a solution administered via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.	GSK2339345 1000 Microgram (mcg) n=11 Participants Participants received two doses of GSK2339345 1000 mcg via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.
Mean Number of Cough Counts at Each Dose of the Challenge Agent for the Capsaicin Challenge (CC) at Visits 4 and 5 (Part B) 0 to 15 sec, CC Conc.0.49 µmol/L, n=10, 11	0.0 Cough count Standard Deviation 0.00	0.3 Cough count Standard Deviation 0.90
Mean Number of Cough Counts at Each Dose of the Challenge Agent for the Capsaicin Challenge (CC) at Visits 4 and 5 (Part B) 0 to 15 sec, CC Conc.0.97 µmol/L, n=10, 11	0.0 Cough count Standard Deviation 0.00	0.2 Cough count Standard Deviation 0.60
Mean Number of Cough Counts at Each Dose of the Challenge Agent for the Capsaicin Challenge (CC) at Visits 4 and 5 (Part B) 0 to 15 sec, CC Conc.1.95 µmol/L, n=10, 11	2.0 Cough count Standard Deviation 4.64	1.8 Cough count Standard Deviation 3.19
Mean Number of Cough Counts at Each Dose of the Challenge Agent for the Capsaicin Challenge (CC) at Visits 4 and 5 (Part B) 0 to 15 sec, CC Conc.3.9 µmol/L, n=10, 11	4.7 Cough count Standard Deviation 5.79	3.3 Cough count Standard Deviation 6.20
Mean Number of Cough Counts at Each Dose of the Challenge Agent for the Capsaicin Challenge (CC) at Visits 4 and 5 (Part B) 0 to 15 sec, CC Conc. 7.81 µmol/L, n=10, 11	5.1 Cough count Standard Deviation 6.45	5.3 Cough count Standard Deviation 6.08
Mean Number of Cough Counts at Each Dose of the Challenge Agent for the Capsaicin Challenge (CC) at Visits 4 and 5 (Part B) 0 to 15 sec, CC Conc. 15.62 µmol/L, n=10, 11	8.3 Cough count Standard Deviation 5.96	6.9 Cough count Standard Deviation 4.66
Mean Number of Cough Counts at Each Dose of the Challenge Agent for the Capsaicin Challenge (CC) at Visits 4 and 5 (Part B) 0 to 15 sec, CC Conc. 31.25 µmol/L, n=10, 11	8.7 Cough count Standard Deviation 6.63	6.0 Cough count Standard Deviation 4.36
Mean Number of Cough Counts at Each Dose of the Challenge Agent for the Capsaicin Challenge (CC) at Visits 4 and 5 (Part B) 0 to 15 sec, CC Conc. 62.5 µmol/L, n=6, 10	8.3 Cough count Standard Deviation 6.15	6.8 Cough count Standard Deviation 3.55
Mean Number of Cough Counts at Each Dose of the Challenge Agent for the Capsaicin Challenge (CC) at Visits 4 and 5 (Part B) 0 to 15 sec, CC Conc. 125 µmol/L, n=5, 9	6.0 Cough count Standard Deviation 1.22	7.1 Cough count Standard Deviation 3.02
Mean Number of Cough Counts at Each Dose of the Challenge Agent for the Capsaicin Challenge (CC) at Visits 4 and 5 (Part B) 0 to 15 sec, CC Conc. 250 µmol/L, n=3, 6	6.3 Cough count Standard Deviation 0.58	5.7 Cough count Standard Deviation 1.21
Mean Number of Cough Counts at Each Dose of the Challenge Agent for the Capsaicin Challenge (CC) at Visits 4 and 5 (Part B) 0 to 15 sec, CC Conc. 500 µmol/L, n=3, 4	7.3 Cough count Standard Deviation 2.52	7.3 Cough count Standard Deviation 2.22
Mean Number of Cough Counts at Each Dose of the Challenge Agent for the Capsaicin Challenge (CC) at Visits 4 and 5 (Part B) 0 to 15 sec, CC Conc. 1000 µmol/L, n=1, 1	6.0 Cough count Standard Deviation NA Only one of participant analyzed at this time point. Hence SD is not calculated.	7.0 Cough count Standard Deviation NA Only one of participant analyzed at this time point. Hence SD is not calculated.
Mean Number of Cough Counts at Each Dose of the Challenge Agent for the Capsaicin Challenge (CC) at Visits 4 and 5 (Part B) 0 to 30 sec, CC Conc.0.49 µmol/L, n=10, 11	0.0 Cough count Standard Deviation 0.00	0.5 Cough count Standard Deviation 1.81
Mean Number of Cough Counts at Each Dose of the Challenge Agent for the Capsaicin Challenge (CC) at Visits 4 and 5 (Part B) 0 to 30 sec, CC Conc.0.97 µmol/L, n=10, 11	0.0 Cough count Standard Deviation 0.00	0.2 Cough count Standard Deviation 0.60
Mean Number of Cough Counts at Each Dose of the Challenge Agent for the Capsaicin Challenge (CC) at Visits 4 and 5 (Part B) 0 to 30 sec, CC Conc.1.95 µmol/L, n=10, 11	2.0 Cough count Standard Deviation 4.64	1.9 Cough count Standard Deviation 3.36
Mean Number of Cough Counts at Each Dose of the Challenge Agent for the Capsaicin Challenge (CC) at Visits 4 and 5 (Part B) 0 to 30 sec, CC Conc.3.9 µmol/L, n=10, 11	5.4 Cough count Standard Deviation 6.59	4.3 Cough count Standard Deviation 6.83
Mean Number of Cough Counts at Each Dose of the Challenge Agent for the Capsaicin Challenge (CC) at Visits 4 and 5 (Part B) 0 to 30 sec, CC Conc. 7.81 µmol/L, n=10, 11	6.7 Cough count Standard Deviation 9.57	5.5 Cough count Standard Deviation 6.42
Mean Number of Cough Counts at Each Dose of the Challenge Agent for the Capsaicin Challenge (CC) at Visits 4 and 5 (Part B) 0 to 30 sec, CC Conc. 15.62 µmol/L, n=10, 11	12.2 Cough count Standard Deviation 9.47	7.5 Cough count Standard Deviation 5.47
Mean Number of Cough Counts at Each Dose of the Challenge Agent for the Capsaicin Challenge (CC) at Visits 4 and 5 (Part B) 0 to 30 sec, CC Conc. 31.25 µmol/L, n=10, 11	11.0 Cough count Standard Deviation 9.87	6.5 Cough count Standard Deviation 5.01
Mean Number of Cough Counts at Each Dose of the Challenge Agent for the Capsaicin Challenge (CC) at Visits 4 and 5 (Part B) 0 to 30 sec, CC Conc. 62.5 µmol/L, n=6, 10	9.2 Cough count Standard Deviation 7.19	7.4 Cough count Standard Deviation 4.12
Mean Number of Cough Counts at Each Dose of the Challenge Agent for the Capsaicin Challenge (CC) at Visits 4 and 5 (Part B) 0 to 30 sec, CC Conc. 125 µmol/L, n=5, 9	6.0 Cough count Standard Deviation 1.22	8.2 Cough count Standard Deviation 4.24
Mean Number of Cough Counts at Each Dose of the Challenge Agent for the Capsaicin Challenge (CC) at Visits 4 and 5 (Part B) 0 to 30 sec, CC Conc. 250 µmol/L, n=3, 6	6.3 Cough count Standard Deviation 0.58	6.7 Cough count Standard Deviation 1.37
Mean Number of Cough Counts at Each Dose of the Challenge Agent for the Capsaicin Challenge (CC) at Visits 4 and 5 (Part B) 0 to 30 sec, CC Conc. 500 µmol/L, n=3, 4	8.7 Cough count Standard Deviation 4.73	8.5 Cough count Standard Deviation 3.51
Mean Number of Cough Counts at Each Dose of the Challenge Agent for the Capsaicin Challenge (CC) at Visits 4 and 5 (Part B) 0 to 30 sec, CC Conc. 1000 µmol/L, n=1, 1	6.0 Cough count Standard Deviation NA Only one of participant analyzed at this time point. Hence SD is not calculated.	7.0 Cough count Standard Deviation NA Only one of participant analyzed at this time point. Hence SD is not calculated.

SECONDARY outcome

Timeframe: After the administration of GSK2339345 or placebo (first and second 15 seconds following each dose) at Visits 6 and 7 in Part C (up to 2 weeks)

Population: CAC Population comprised of participants in the All Subjects Population for whom any CAC data were available for one or both Part C study visits. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles).

Citric acid was administered using a dosimeter through a nebulizer pot with flow-limitation. Inhalation of increased Conc. was continued until the maximum dose was tolerated by the par. or the highest available Conc. was used. The dose-response relationship between the dose of citric acid and cough response was investigated using non-linear mixed effect modelling using Poisson and Negative Binomial distributions. When using a Poisson distribution, there was some evidence for an increase in citric acid ED50 with GSK2339345 of 41.6%, however, this was not confirmed when using a Negative Binomial distribution. The Negative Binomial distribution described the data marginally better, but the dataset was too small to make definitive conclusions. There was no treatment difference in citric acid Emax

Outcome measures

Measure	Placebo n=9 Participants Participants received two doses of placebo as a solution administered via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.	GSK2339345 1000 Microgram (mcg) n=9 Participants Participants received two doses of GSK2339345 1000 mcg via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.
Mean Number of Cough Counts at Each Dose of the Challenge Agent for the Citric Acid Challenge (CAC)at Visits 6 and 7 (Part C) 0 to 30 sec, CAC Conc. 0.03 mol/L, n=9, 9	0.2 Cough count Standard Deviation 0.44	0.2 Cough count Standard Deviation 0.67
Mean Number of Cough Counts at Each Dose of the Challenge Agent for the Citric Acid Challenge (CAC)at Visits 6 and 7 (Part C) 0 to 15 sec, CAC Conc. 0.03 mol/L, n=9, 9	0.2 Cough count Standard Deviation 0.44	0.2 Cough count Standard Deviation 0.67
Mean Number of Cough Counts at Each Dose of the Challenge Agent for the Citric Acid Challenge (CAC)at Visits 6 and 7 (Part C) 0 to 15 sec, CAC Conc. 0.06 mol/L, n=9, 9	0.2 Cough count Standard Deviation 0.67	0.6 Cough count Standard Deviation 1.33
Mean Number of Cough Counts at Each Dose of the Challenge Agent for the Citric Acid Challenge (CAC)at Visits 6 and 7 (Part C) 0 to 30 sec, CAC Conc. 0.06 mol/L, n=9, 9	0.2 Cough count Standard Deviation 0.67	0.6 Cough count Standard Deviation 1.33
Mean Number of Cough Counts at Each Dose of the Challenge Agent for the Citric Acid Challenge (CAC)at Visits 6 and 7 (Part C) 0 to 15 sec, CAC Conc. 0.125 mol/L, n=9, 9	3.0 Cough count Standard Deviation 4.66	1.8 Cough count Standard Deviation 1.92
Mean Number of Cough Counts at Each Dose of the Challenge Agent for the Citric Acid Challenge (CAC)at Visits 6 and 7 (Part C) 0 to 15 sec, CAC Conc. 0.25 mol/L, n=9, 9	3.7 Cough count Standard Deviation 4.09	2.7 Cough count Standard Deviation 3.43
Mean Number of Cough Counts at Each Dose of the Challenge Agent for the Citric Acid Challenge (CAC)at Visits 6 and 7 (Part C) 0 to 15 sec, CAC Conc. 0.5 mol/L, n=9, 9	6.1 Cough count Standard Deviation 5.13	4.3 Cough count Standard Deviation 3.43
Mean Number of Cough Counts at Each Dose of the Challenge Agent for the Citric Acid Challenge (CAC)at Visits 6 and 7 (Part C) 0 to 15 sec, CAC Conc. 1 mol/L, n=9, 9	6.0 Cough count Standard Deviation 3.50	6.6 Cough count Standard Deviation 3.40
Mean Number of Cough Counts at Each Dose of the Challenge Agent for the Citric Acid Challenge (CAC)at Visits 6 and 7 (Part C) 0 to 15 sec, CAC Conc. 2 mol/L, n=5,7	5.8 Cough count Standard Deviation 4.02	4.1 Cough count Standard Deviation 3.29
Mean Number of Cough Counts at Each Dose of the Challenge Agent for the Citric Acid Challenge (CAC)at Visits 6 and 7 (Part C) 0 to 15 sec, CAC Conc. 4 mol/L, n=5, 6	4.0 Cough count Standard Deviation 3.81	5.3 Cough count Standard Deviation 4.46
Mean Number of Cough Counts at Each Dose of the Challenge Agent for the Citric Acid Challenge (CAC)at Visits 6 and 7 (Part C) 0 to 30 sec, CAC Conc. 0.125 mol/L, n=9, 9	3.2 Cough count Standard Deviation 4.55	2.0 Cough count Standard Deviation 2.06
Mean Number of Cough Counts at Each Dose of the Challenge Agent for the Citric Acid Challenge (CAC)at Visits 6 and 7 (Part C) 0 to 30 sec, CAC Conc. 0.25 mol/L, n=9, 9	4.6 Cough count Standard Deviation 6.00	2.7 Cough count Standard Deviation 3.43
Mean Number of Cough Counts at Each Dose of the Challenge Agent for the Citric Acid Challenge (CAC)at Visits 6 and 7 (Part C) 0 to 30 sec, CAC Conc. 0.5 mol/L, n=9, 9	7.3 Cough count Standard Deviation 6.34	5.0 Cough count Standard Deviation 4.09
Mean Number of Cough Counts at Each Dose of the Challenge Agent for the Citric Acid Challenge (CAC)at Visits 6 and 7 (Part C) 0 to 30 sec, CAC Conc. 1 mol/L, n=9, 9	7.2 Cough count Standard Deviation 4.55	9.3 Cough count Standard Deviation 6.32
Mean Number of Cough Counts at Each Dose of the Challenge Agent for the Citric Acid Challenge (CAC)at Visits 6 and 7 (Part C) 0 to 30 sec, CAC Conc. 2 mol/L, n=5, 7	6.8 Cough count Standard Deviation 4.82	6.4 Cough count Standard Deviation 5.32
Mean Number of Cough Counts at Each Dose of the Challenge Agent for the Citric Acid Challenge (CAC)at Visits 6 and 7 (Part C) 0 to 30 sec, CAC Conc. 4 mol/L, n=5, 6	4.8 Cough count Standard Deviation 3.83	6.2 Cough count Standard Deviation 5.34

SECONDARY outcome

Timeframe: After the administration of GSK2339345 or placebo at Visits 4 and 5 in Part B (up to 2 weeks)

Population: CC population. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). Different participants may have been analyzed for different parameters, so the overall number of participants analyzed reflects everyone in the CC Population.

CC was performed following the administration of GSK2339345 or placebo at Visits 4 and 5. Capsaicin was administered using a dosimeter through a nebulizer. The number of coughs in the first and second 15 sec following each dose of CC agent were recorded. Inhalation of increased conc. was continued until the maximum dose was tolerated by the participant or the highest available conc. was used. CC agent dose concentration required to achieve C2 (2 coughs were first observed [FO]), C5 (5 coughs were FO) and C6 (6 coughs were FO) are presented. All instances of missing values occurred where a participant did not achieved the required number of coughs for a parameter.

Outcome measures

Measure	Placebo n=10 Participants Participants received two doses of placebo as a solution administered via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.	GSK2339345 1000 Microgram (mcg) n=11 Participants Participants received two doses of GSK2339345 1000 mcg via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.
CC Agent Dose Concentration Required to Achieve C2, C5 and C6 at Visits 4 and 5 (Part B) C2, 0-15 sec, n=10, 11	4.181 µmol/L Geometric Coefficient of Variation 88.924	5.697 µmol/L Geometric Coefficient of Variation 207.575
CC Agent Dose Concentration Required to Achieve C2, C5 and C6 at Visits 4 and 5 (Part B) C2, 0-30 sec, n=10, 11	4.181 µmol/L Geometric Coefficient of Variation 88.924	5.022 µmol/L Geometric Coefficient of Variation 194.425
CC Agent Dose Concentration Required to Achieve C2, C5 and C6 at Visits 4 and 5 (Part B) C5, 0-30 sec, n=10, 11	8.367 µmol/L Geometric Coefficient of Variation 110.360	10.050 µmol/L Geometric Coefficient of Variation 535.013
CC Agent Dose Concentration Required to Achieve C2, C5 and C6 at Visits 4 and 5 (Part B) C6, 0-15 sec, n=10, 9	11.834 µmol/L Geometric Coefficient of Variation 229.845	12.391 µmol/L Geometric Coefficient of Variation 438.063
CC Agent Dose Concentration Required to Achieve C2, C5 and C6 at Visits 4 and 5 (Part B) C6, 0-30 sec, n=10, 10	10.300 µmol/L Geometric Coefficient of Variation 229.859	14.575 µmol/L Geometric Coefficient of Variation 908.133
CC Agent Dose Concentration Required to Achieve C2, C5 and C6 at Visits 4 and 5 (Part B) C5, 0-15 sec, n=10, 11	8.967 µmol/L Geometric Coefficient of Variation 124.989	11.394 µmol/L Geometric Coefficient of Variation 378.087

SECONDARY outcome

Timeframe: After the administration of GSK2339345 or placebo at Visits 6 and 7 in Part C (up to 2 weeks)

Population: CAC population: Only those participants available at the specified time points were analyzed (represented by n=X,X in the category titles). Different participants may have been analyzed for different parameters, so the overall number of participants analyzed reflects everyone in the CAC Population.

CAC was performed following the administration of GSK2339345 or placebo at Visits 6 and 7. CA was administered using a dosimeter through a nebulizer pot with flow-limitation. Number of coughs in the first and second 15 sec following each dose of CAC agent were recorded. Inhalation of increased conc. was continued until the maximum dose was tolerated by the participants or the highest available Conc. was used. CAC agent dose concentration required to achieve C2 (2 coughs were first observed [FO]), C5 (5 coughs were FO) and C6 (6 coughs were FO) are presented. All instances of missing values occurred where a participant did not achieved the required number of coughs for a parameter.

Outcome measures

Measure	Placebo n=9 Participants Participants received two doses of placebo as a solution administered via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.	GSK2339345 1000 Microgram (mcg) n=9 Participants Participants received two doses of GSK2339345 1000 mcg via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.
CAC Agent Dose Concentration Required to Achieve C2, C5 and C6 at Visits 6 and 7 (Part C) C6, 0-30 sec, n= 7, 8	0.336 mol/L Geometric Coefficient of Variation 141.375	0.771 mol/L Geometric Coefficient of Variation 98.463
CAC Agent Dose Concentration Required to Achieve C2, C5 and C6 at Visits 6 and 7 (Part C) C2, 0-15 sec, n=8, 9	0.209 mol/L Geometric Coefficient of Variation 111.073	0.156 mol/L Geometric Coefficient of Variation 142.342
CAC Agent Dose Concentration Required to Achieve C2, C5 and C6 at Visits 6 and 7 (Part C) C2, 0-30 sec, n=8, 9	0.192 mol/L Geometric Coefficient of Variation 113.563	0.156 mol/L Geometric Coefficient of Variation 142.342
CAC Agent Dose Concentration Required to Achieve C2, C5 and C6 at Visits 6 and 7 (Part C) C5, 0-15 sec, n=7, 7	0.305 mol/L Geometric Coefficient of Variation 138.956	0.610 mol/L Geometric Coefficient of Variation 90.153
CAC Agent Dose Concentration Required to Achieve C2, C5 and C6 at Visits 6 and 7 (Part C) C5, 0-30 sec, n=7, 8	0.276 mol/L Geometric Coefficient of Variation 101.609	0.707 mol/L Geometric Coefficient of Variation 127.046
CAC Agent Dose Concentration Required to Achieve C2, C5 and C6 at Visits 6 and 7 (Part C) C6, 0-15 sec, n=7, 7	0.371 mol/L Geometric Coefficient of Variation 158.730	0.743 mol/L Geometric Coefficient of Variation 76.173

SECONDARY outcome

Timeframe: After the administration of GSK2339345 or placebo at Visits 4 and 5 in Part B (up to 2 weeks)

Population: CC Population

CC was performed following the administration of GSK2339345 or placebo at Visits 4 and 5. Capsaicin was administered using a dosimeter through a nebulizer. The number of coughs in the first and second 15 sec following each dose of CC agent were recorded. Inhalation of increased Conc. was continued until the maximum dose was tolerated by the participant or the highest available Conc. was used. CC agent imputed dose concentration required to achieve C2 (at which 2 coughs were first observed [FO]), C5 (at which 5 coughs were FO) and C6 (at which 6 coughs were FO) are presented. For participants who did not complete the challenge and not reached the endpoint, values were imputed to the next dose in the challenge sequence after stopping. For participants who completed the challenge and had not reached the endpoint, values were imputed to 2000 (=twice the highest dose of capsaicin).

Outcome measures

Measure	Placebo n=10 Participants Participants received two doses of placebo as a solution administered via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.	GSK2339345 1000 Microgram (mcg) n=11 Participants Participants received two doses of GSK2339345 1000 mcg via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.
CC Agent Imputed Dose Concentration Required to Achieve C2, C5 and C6 at Visits 4 and 5 (Part B) C2, 0-15 sec	4.181 µmol/L Geometric Coefficient of Variation 88.924	5.697 µmol/L Geometric Coefficient of Variation 207.575
CC Agent Imputed Dose Concentration Required to Achieve C2, C5 and C6 at Visits 4 and 5 (Part B) C2, 0-30 sec	4.181 µmol/L Geometric Coefficient of Variation 88.924	5.022 µmol/L Geometric Coefficient of Variation 194.425
CC Agent Imputed Dose Concentration Required to Achieve C2, C5 and C6 at Visits 4 and 5 (Part B) C5, 0-15 sec	8.967 µmol/L Geometric Coefficient of Variation 124.989	11.394 µmol/L Geometric Coefficient of Variation 378.087
CC Agent Imputed Dose Concentration Required to Achieve C2, C5 and C6 at Visits 4 and 5 (Part B) C5, 0-30 sec	8.367 µmol/L Geometric Coefficient of Variation 110.360	10.050 µmol/L Geometric Coefficient of Variation 535.013
CC Agent Imputed Dose Concentration Required to Achieve C2, C5 and C6 at Visits 4 and 5 (Part B) C6, 0-15 sec	11.834 µmol/L Geometric Coefficient of Variation 229.845	25.850 µmol/L Geometric Coefficient of Variation 1279.694
CC Agent Imputed Dose Concentration Required to Achieve C2, C5 and C6 at Visits 4 and 5 (Part B) C6, 0-30 sec	10.300 µmol/L Geometric Coefficient of Variation 229.859	20.100 µmol/L Geometric Coefficient of Variation 1288.571

SECONDARY outcome

Timeframe: After the administration of GSK2339345 or placebo at Visits 6 and 7 in Part C (up to 2 weeks)

Population: CAC Population

CAC was performed following the administration of GSK2339345 or placebo at Visits 6 and 7. CA was administered using a dosimeter through a nebulizer pot with flow-limitation. Number of coughs in the first and second 15 sec following each dose of CAC agent were recorded. Inhalation of increased Conc. was continued until the maximum dose was tolerated by the participants or the highest available Conc. was used. CAC agent imputed dose concentration required to achieve C2 (at which 2 coughs were first observed [FO]), C5 (at which 5 coughs were FO) and C6 (at which 6 coughs were FO) are presented. For participants who did not complete the challenge and not reached the endpoint, values were imputed to the next dose in the challenge sequence after stopping. For participants who completed the challenge and had not reached the endpoint, values were imputed to 2000 (=twice the highest dose of CA).

Outcome measures

Measure	Placebo n=9 Participants Participants received two doses of placebo as a solution administered via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.	GSK2339345 1000 Microgram (mcg) n=9 Participants Participants received two doses of GSK2339345 1000 mcg via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.
CAC Agent Imputed Dose Concentration Required to Achieve C2, C5 and C6 at Visits 6 and 7 (Part C) C2, 0-15 sec	0.314 mol/L Geometric Coefficient of Variation 279.912	0.156 mol/L Geometric Coefficient of Variation 142.342
CAC Agent Imputed Dose Concentration Required to Achieve C2, C5 and C6 at Visits 6 and 7 (Part C) C2, 0-30 sec	0.290 mol/L Geometric Coefficient of Variation 294.833	0.156 mol/L Geometric Coefficient of Variation 142.342
CAC Agent Imputed Dose Concentration Required to Achieve C2, C5 and C6 at Visits 6 and 7 (Part C) C5, 0-15 sec	0.630 mol/L Geometric Coefficient of Variation 410.643	1.080 mol/L Geometric Coefficient of Variation 216.073
CAC Agent Imputed Dose Concentration Required to Achieve C2, C5 and C6 at Visits 6 and 7 (Part C) C5, 0-30 sec	0.583 mol/L Geometric Coefficient of Variation 379.787	0.926 mol/L Geometric Coefficient of Variation 185.962
CAC Agent Imputed Dose Concentration Required to Achieve C2, C5 and C6 at Visits 6 and 7 (Part C) C6, 0-15 sec	0.735 mol/L Geometric Coefficient of Variation 387.993	1.260 mol/L Geometric Coefficient of Variation 179.623
CAC Agent Imputed Dose Concentration Required to Achieve C2, C5 and C6 at Visits 6 and 7 (Part C) C6, 0-30 sec	0.680 mol/L Geometric Coefficient of Variation 387.993	1.000 mol/L Geometric Coefficient of Variation 152.443

Adverse Events

Placebo

Serious events: 0 serious events

Other events: 10 other events

Deaths: 0 deaths

GSK2339345 1000 µg

Serious events: 0 serious events

Other events: 5 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	Placebo n=16 participants at risk Participants received two doses of placebo as a solution administered via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.	GSK2339345 1000 µg n=14 participants at risk Participants received two doses of GSK2339345 1000 µg via an ADI with a four hour dosing interval, either at one or two visits in Part A (Visits 1, 2 and 3) and a single dose at one of the 2 visits in Parts B (Visits 4 and 5) and Part C (Visits 6 and 7). Dose 1 was administered on each treatment day at the same time each morning throughout all of Parts A, B and C. The follow-up of each participant occurred 3-14 days after the last dose. There was a washout of 48 hours to 7 days between visits. Additionally, 5 minutes after the administration of placebo at each visit in Part B and C, participants received an oral inhalation of 10 µL of a capsaicin solution at each visit in Part B and 10 µL of a citric acid solution at each visit in Part C. The strength of capsaicin solution ranged from 0.49 to 1000 µM and the citric acid solution strength ranged from 0.03 to 4.0 molar.
Nervous system disorders Hypoaesthesia oral	6.2% 1/16 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study treatment until follow-up (up to 8 weeks). SAEs and non-serious AEs were collected in participants of the All Subjects Population, comprised of all participants who received at least one dose of study medication.	0.00% 0/14 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study treatment until follow-up (up to 8 weeks). SAEs and non-serious AEs were collected in participants of the All Subjects Population, comprised of all participants who received at least one dose of study medication.
Nervous system disorders Paraesthesia oral	6.2% 1/16 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study treatment until follow-up (up to 8 weeks). SAEs and non-serious AEs were collected in participants of the All Subjects Population, comprised of all participants who received at least one dose of study medication.	7.1% 1/14 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study treatment until follow-up (up to 8 weeks). SAEs and non-serious AEs were collected in participants of the All Subjects Population, comprised of all participants who received at least one dose of study medication.
Respiratory, thoracic and mediastinal disorders Cough	0.00% 0/16 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study treatment until follow-up (up to 8 weeks). SAEs and non-serious AEs were collected in participants of the All Subjects Population, comprised of all participants who received at least one dose of study medication.	7.1% 1/14 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study treatment until follow-up (up to 8 weeks). SAEs and non-serious AEs were collected in participants of the All Subjects Population, comprised of all participants who received at least one dose of study medication.
Respiratory, thoracic and mediastinal disorders Dyspnoea	6.2% 1/16 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study treatment until follow-up (up to 8 weeks). SAEs and non-serious AEs were collected in participants of the All Subjects Population, comprised of all participants who received at least one dose of study medication.	0.00% 0/14 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study treatment until follow-up (up to 8 weeks). SAEs and non-serious AEs were collected in participants of the All Subjects Population, comprised of all participants who received at least one dose of study medication.
Respiratory, thoracic and mediastinal disorders Rhinorrhoea	6.2% 1/16 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study treatment until follow-up (up to 8 weeks). SAEs and non-serious AEs were collected in participants of the All Subjects Population, comprised of all participants who received at least one dose of study medication.	0.00% 0/14 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study treatment until follow-up (up to 8 weeks). SAEs and non-serious AEs were collected in participants of the All Subjects Population, comprised of all participants who received at least one dose of study medication.
Respiratory, thoracic and mediastinal disorders Throat irritation	0.00% 0/16 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study treatment until follow-up (up to 8 weeks). SAEs and non-serious AEs were collected in participants of the All Subjects Population, comprised of all participants who received at least one dose of study medication.	7.1% 1/14 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study treatment until follow-up (up to 8 weeks). SAEs and non-serious AEs were collected in participants of the All Subjects Population, comprised of all participants who received at least one dose of study medication.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	6.2% 1/16 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study treatment until follow-up (up to 8 weeks). SAEs and non-serious AEs were collected in participants of the All Subjects Population, comprised of all participants who received at least one dose of study medication.	0.00% 0/14 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study treatment until follow-up (up to 8 weeks). SAEs and non-serious AEs were collected in participants of the All Subjects Population, comprised of all participants who received at least one dose of study medication.
Gastrointestinal disorders Tongue disclouration	6.2% 1/16 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study treatment until follow-up (up to 8 weeks). SAEs and non-serious AEs were collected in participants of the All Subjects Population, comprised of all participants who received at least one dose of study medication.	0.00% 0/14 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study treatment until follow-up (up to 8 weeks). SAEs and non-serious AEs were collected in participants of the All Subjects Population, comprised of all participants who received at least one dose of study medication.
Gastrointestinal disorders Vomiting	0.00% 0/16 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study treatment until follow-up (up to 8 weeks). SAEs and non-serious AEs were collected in participants of the All Subjects Population, comprised of all participants who received at least one dose of study medication.	7.1% 1/14 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study treatment until follow-up (up to 8 weeks). SAEs and non-serious AEs were collected in participants of the All Subjects Population, comprised of all participants who received at least one dose of study medication.
Investigations Electrocardiogram QT prolonged	6.2% 1/16 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study treatment until follow-up (up to 8 weeks). SAEs and non-serious AEs were collected in participants of the All Subjects Population, comprised of all participants who received at least one dose of study medication.	0.00% 0/14 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study treatment until follow-up (up to 8 weeks). SAEs and non-serious AEs were collected in participants of the All Subjects Population, comprised of all participants who received at least one dose of study medication.
Investigations QRS axis abnormal	6.2% 1/16 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study treatment until follow-up (up to 8 weeks). SAEs and non-serious AEs were collected in participants of the All Subjects Population, comprised of all participants who received at least one dose of study medication.	0.00% 0/14 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study treatment until follow-up (up to 8 weeks). SAEs and non-serious AEs were collected in participants of the All Subjects Population, comprised of all participants who received at least one dose of study medication.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	0.00% 0/16 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study treatment until follow-up (up to 8 weeks). SAEs and non-serious AEs were collected in participants of the All Subjects Population, comprised of all participants who received at least one dose of study medication.	7.1% 1/14 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study treatment until follow-up (up to 8 weeks). SAEs and non-serious AEs were collected in participants of the All Subjects Population, comprised of all participants who received at least one dose of study medication.
Nervous system disorders Dizziness	6.2% 1/16 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study treatment until follow-up (up to 8 weeks). SAEs and non-serious AEs were collected in participants of the All Subjects Population, comprised of all participants who received at least one dose of study medication.	7.1% 1/14 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study treatment until follow-up (up to 8 weeks). SAEs and non-serious AEs were collected in participants of the All Subjects Population, comprised of all participants who received at least one dose of study medication.
Nervous system disorders Dysgeusia	6.2% 1/16 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study treatment until follow-up (up to 8 weeks). SAEs and non-serious AEs were collected in participants of the All Subjects Population, comprised of all participants who received at least one dose of study medication.	7.1% 1/14 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study treatment until follow-up (up to 8 weeks). SAEs and non-serious AEs were collected in participants of the All Subjects Population, comprised of all participants who received at least one dose of study medication.
Nervous system disorders Headache	6.2% 1/16 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study treatment until follow-up (up to 8 weeks). SAEs and non-serious AEs were collected in participants of the All Subjects Population, comprised of all participants who received at least one dose of study medication.	7.1% 1/14 • Serious adverse events (SAEs) and non-serious AEs were collected from the start of study treatment until follow-up (up to 8 weeks). SAEs and non-serious AEs were collected in participants of the All Subjects Population, comprised of all participants who received at least one dose of study medication.

Additional Information

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Phone: 866-435-7343

Results disclosure agreements

• Principal investigator is a sponsor employee 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.
• Publication restrictions are in place

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