Trial Outcomes & Findings for Study of GSK2586881 on Acute Hypoxia and Exercise (NCT NCT03000686)

Results Overview

Echocardiograms (Echo) were obtained at indicated time points with the participant resting supine or lying on their left side. PASP was determined by measuring maximal tricuspid regurgitation velocity and applying the modified Bernoulli equation to convert this value into pressure values. Change from Baseline is calculated as the post-dose visit value minus the Baseline value. Analysis was performed using a Bayesian repeated measures model adjusting for: participant-level and period-adjusted Baselines, treatment, time and period. Time by treatment and time by period-adjusted Baseline interactions were included. Participant-level Baseline is the mean of two period-specific Baselines. Period-adjusted Baseline is the difference between the period-specific Baseline and participant-level Baseline for each period. No transformation has been applied to the data. Posterior median and 95% credible interval is presented.

Recruitment status

TERMINATED

Study phase

PHASE1

Target enrollment

17 participants

Primary outcome timeframe

Baseline (Day1, predose) and 15 minutes post-infusion, 60 minutes post-chamber entry, immediately post-exercise and 30 minutes post-chamber exit in each treatment period

Results posted on

2019-12-23

Participant Flow

Healthy participants who met the eligibility criteria entered a 2-period crossover study. Participants were randomized to either placebo or GSK2586881 in each Treatment Period. Total duration of participation was 8 weeks. Study was terminated for technical feasibility, operational considerations and futility in line with pre-specified criteria.

A total of 48 participants were screened, of which 31 failed screening and 17 (11 participants in Part 1 and 6 in Part 2) were enrolled in the study. The study was conducted at a single center in Germany.

Participant milestones

Participant milestones
Measure	Part 1: Placebo/GSK2586881 Participants were administered a single intravenous (IV) dose of placebo in treatment period 1 followed by a washout of period of up to 14 days. In treatment period 2, participants were administered a single IV dose of 0.8 milligrams per kilogram (mg/kg) GSK2586881. During each period, approximately 30 minutes after administration of study treatment, participants entered the hypoxia chamber and were inside the chamber for approximately 80 minutes, during which they were under the full 4000 meters ± 10% hypoxic conditions. Participants then performed an exercise challenge at 70% of maximum oxygen consumption (VO2) uptake on an upright cycle ergometer within the hypoxia chamber for 10 minutes.	Part 1: GSK2586881/Placebo Participants were administered a single IV dose of 0.8 mg/kg GSK2586881 in treatment period 1 followed by a washout of period of up to 14 days. In treatment period 2, participants were administered a single IV dose of placebo. During each period, approximately 30 minutes after administration of study treatment, participants entered the hypoxia chamber and were inside the chamber for approximately 80 minutes, during which they were under the full 4000 meters ± 10% hypoxic conditions. Participants then performed an exercise challenge at 70% of maximum VO2 uptake on an upright cycle ergometer within the hypoxia chamber for 10 minutes.	Part 2: Placebo/GSK2586881 Participants were administered a single IV dose of placebo in treatment period 1 followed by a washout of period of up to 14 days. In treatment period 2, participants were administered a single IV dose of 0.8 mg/kg GSK2586881. During each period, approximately 30 minutes after administration of study treatment, participants entered the hypoxia chamber and were inside the chamber for approximately 80 minutes, during which they were under the full 5000 meters ± 10% hypoxic conditions. Participants then performed an exercise challenge at 50% of maximum VO2 uptake on a semi-recumbent cycle ergometer within the hypoxia chamber for 10 minutes.	Part 2: GSK2586881/Placebo Participants were administered a single IV dose of 0.8 mg/kg GSK2586881 in treatment period 1 followed by a washout of period of up to 14 days. In treatment period 2, participants were administered a single IV dose of placebo. During each period, approximately 30 minutes after administration of study treatment, participants entered the hypoxia chamber and were inside the chamber for approximately 80 minutes, during which they were under the full 5000 meters ± 10% hypoxic conditions. Participants then performed an exercise challenge at 50% of maximum VO2 uptake on a semi-recumbent cycle ergometer within the hypoxia chamber for 10 minutes.
Part 1, Period 1 (1 Day) STARTED	5	6	0	0
Part 1, Period 1 (1 Day) COMPLETED	5	5	0	0
Part 1, Period 1 (1 Day) NOT COMPLETED	0	1	0	0
Part 1, Wash-out (Up to 14 Days) STARTED	5	5	0	0
Part 1, Wash-out (Up to 14 Days) COMPLETED	5	5	0	0
Part 1, Wash-out (Up to 14 Days) NOT COMPLETED	0	0	0	0
Part 1, Period 2 (1 Day) STARTED	5	5	0	0
Part 1, Period 2 (1 Day) COMPLETED	5	5	0	0
Part 1, Period 2 (1 Day) NOT COMPLETED	0	0	0	0
Part 2, Period 1 (1 Day) STARTED	0	0	3	3
Part 2, Period 1 (1 Day) COMPLETED	0	0	3	3
Part 2, Period 1 (1 Day) NOT COMPLETED	0	0	0	0
Part 2, Wash-out (Up to 14 Days) STARTED	0	0	3	3
Part 2, Wash-out (Up to 14 Days) COMPLETED	0	0	3	3
Part 2, Wash-out (Up to 14 Days) NOT COMPLETED	0	0	0	0
Part 2, Period 2 (1 Day) STARTED	0	0	3	3
Part 2, Period 2 (1 Day) COMPLETED	0	0	3	3
Part 2, Period 2 (1 Day) NOT COMPLETED	0	0	0	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Part 1: Placebo/GSK2586881 Participants were administered a single intravenous (IV) dose of placebo in treatment period 1 followed by a washout of period of up to 14 days. In treatment period 2, participants were administered a single IV dose of 0.8 milligrams per kilogram (mg/kg) GSK2586881. During each period, approximately 30 minutes after administration of study treatment, participants entered the hypoxia chamber and were inside the chamber for approximately 80 minutes, during which they were under the full 4000 meters ± 10% hypoxic conditions. Participants then performed an exercise challenge at 70% of maximum oxygen consumption (VO2) uptake on an upright cycle ergometer within the hypoxia chamber for 10 minutes.	Part 1: GSK2586881/Placebo Participants were administered a single IV dose of 0.8 mg/kg GSK2586881 in treatment period 1 followed by a washout of period of up to 14 days. In treatment period 2, participants were administered a single IV dose of placebo. During each period, approximately 30 minutes after administration of study treatment, participants entered the hypoxia chamber and were inside the chamber for approximately 80 minutes, during which they were under the full 4000 meters ± 10% hypoxic conditions. Participants then performed an exercise challenge at 70% of maximum VO2 uptake on an upright cycle ergometer within the hypoxia chamber for 10 minutes.	Part 2: Placebo/GSK2586881 Participants were administered a single IV dose of placebo in treatment period 1 followed by a washout of period of up to 14 days. In treatment period 2, participants were administered a single IV dose of 0.8 mg/kg GSK2586881. During each period, approximately 30 minutes after administration of study treatment, participants entered the hypoxia chamber and were inside the chamber for approximately 80 minutes, during which they were under the full 5000 meters ± 10% hypoxic conditions. Participants then performed an exercise challenge at 50% of maximum VO2 uptake on a semi-recumbent cycle ergometer within the hypoxia chamber for 10 minutes.	Part 2: GSK2586881/Placebo Participants were administered a single IV dose of 0.8 mg/kg GSK2586881 in treatment period 1 followed by a washout of period of up to 14 days. In treatment period 2, participants were administered a single IV dose of placebo. During each period, approximately 30 minutes after administration of study treatment, participants entered the hypoxia chamber and were inside the chamber for approximately 80 minutes, during which they were under the full 5000 meters ± 10% hypoxic conditions. Participants then performed an exercise challenge at 50% of maximum VO2 uptake on a semi-recumbent cycle ergometer within the hypoxia chamber for 10 minutes.
Part 1, Period 1 (1 Day) Adverse Event	0	1	0	0

Baseline Characteristics

Study of GSK2586881 on Acute Hypoxia and Exercise

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	All Participants-Part 1 n=11 Participants All participants who were randomized to either of the two treatment sequences Placebo/GSK2586881 or GSK2586881/Placebo and received a single IV dose of GSK2586881 and placebo in either Treatment period 1 or 2 during Part 1 of the study were included. The treatment periods were separated by a wash-out period of 3 to 14 days.	All Participants-Part 2 n=6 Participants All participants who were randomized to either of the two treatment sequences Placebo/GSK2586881 or GSK2586881/Placebo and received a single IV dose of GSK2586881 and placebo in either Treatment period 1 or 2 during Part 2 of the study were included. The treatment periods were separated by a wash-out period of 3 to 14 days.	Total n=17 Participants Total of all reporting groups
Age, Continuous	26.2 Years STANDARD_DEVIATION 4.24 • n=5 Participants	29.2 Years STANDARD_DEVIATION 6.21 • n=7 Participants	27.2 Years STANDARD_DEVIATION 5.04 • n=5 Participants
Sex: Female, Male Female	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Sex: Female, Male Male	11 Participants n=5 Participants	6 Participants n=7 Participants	17 Participants n=5 Participants
Race/Ethnicity, Customized White - White/Caucasian/European Heritage	11 Participants n=5 Participants	6 Participants n=7 Participants	17 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline (Day1, predose) and 15 minutes post-infusion, 60 minutes post-chamber entry, immediately post-exercise and 30 minutes post-chamber exit in each treatment period

Population: Modified Intent-To-Treat Part 1 (mITT1) Population comprised of all participants randomized to Part 1 of the study (planned 4000 meter altitude), excluding those randomized in error. Only those participants with data available at the specified time points were analyzed.

Echocardiograms (Echo) were obtained at indicated time points with the participant resting supine or lying on their left side. PASP was determined by measuring maximal tricuspid regurgitation velocity and applying the modified Bernoulli equation to convert this value into pressure values. Change from Baseline is calculated as the post-dose visit value minus the Baseline value. Analysis was performed using a Bayesian repeated measures model adjusting for: participant-level and period-adjusted Baselines, treatment, time and period. Time by treatment and time by period-adjusted Baseline interactions were included. Participant-level Baseline is the mean of two period-specific Baselines. Period-adjusted Baseline is the difference between the period-specific Baseline and participant-level Baseline for each period. No transformation has been applied to the data. Posterior median and 95% credible interval is presented.

Outcome measures

Outcome measures
Measure	Part 1: Placebo n=10 Participants Participants were administered a single IV dose of placebo in either treatment period 1 or 2 during Part 1 of the study. During each period, approximately 30 minutes after administration of study treatment, the participants entered the hypoxia chamber and were inside the chamber for approximately 80 minutes, during which they were under the full 4000 meters ± 10% hypoxic conditions. Participants then performed an exercise challenge at 70% of maximum VO2 uptake on an upright cycle ergometer within the hypoxia chamber for 10 minutes.	Part 1: GSK2586881 0.8 mg/kg n=10 Participants Participants were administered a single IV dose of 0.8 mg/kg GSK2586881 in either treatment period 1 or 2 during Part 1 of the study. During each period, approximately 30 minutes after administration of study treatment, the participants entered the hypoxia chamber and were inside the chamber for approximately 80 minutes, during which they were under the full 4000 meters ± 10% hypoxic conditions. Participants then performed an exercise challenge at 70% of maximum VO2 uptake on an upright cycle ergometer within the hypoxia chamber for 10 minutes.
Change From Baseline of Pulmonary Artery Systolic Pressure (PASP) Measured Via Echocardiography-Part 1 immediately post-exercise	1.619 Millimeters of mercury Interval -5.122 to 8.349	-0.046 Millimeters of mercury Interval -6.752 to 6.635
Change From Baseline of Pulmonary Artery Systolic Pressure (PASP) Measured Via Echocardiography-Part 1 30 minutes post-chamber exit	-0.189 Millimeters of mercury Interval -3.59 to 3.097	-1.026 Millimeters of mercury Interval -4.393 to 2.284
Change From Baseline of Pulmonary Artery Systolic Pressure (PASP) Measured Via Echocardiography-Part 1 15 minutes post-infusion	-0.715 Millimeters of mercury Interval -3.626 to 2.122	-0.695 Millimeters of mercury Interval -3.61 to 2.153
Change From Baseline of Pulmonary Artery Systolic Pressure (PASP) Measured Via Echocardiography-Part 1 60 minutes post-chamber entry	4.299 Millimeters of mercury Interval -0.052 to 8.633	0.275 Millimeters of mercury Interval -4.044 to 4.577

PRIMARY outcome

Timeframe: Baseline (Day1, predose) and 15 minutes post-infusion, 60 minutes post-chamber entry, 2 minutes post-exercise start and 30 minutes post-chamber exit in each treatment period

Population: mITT Part 2 (mITT2) Population comprised of all participants randomized to Part 2 of the study (planned 5000 meter altitude), excluding those randomized in error. Only those participants with data available at the specified time point were analyzed (represented by n=X, X in category titles).

Echocardiograms were obtained with participant resting supine or lying on their left side. Echo during exercise challenge was conducted with participant on a semi-recumbent cycle ergometer tilted by 30 to 40 degrees. PASP was determined by measuring maximal tricuspid regurgitation velocity and applying modified Bernoulli equation to convert this value into pressure values. Change from Baseline is the post-dose visit value minus Baseline value. Analysis was performed using a Bayesian repeated measures model adjusting for: participant-level and period-adjusted Baselines, treatment, time and period. Time by treatment and time by period-adjusted Baseline interactions were included. Participant-level Baseline is the mean of the two period-specific Baselines. Period-adjusted Baseline is the difference between the period-specific Baseline and participant-level Baseline for each period. No transformation has been applied to the data. Posterior median and 95% credible interval is presented.

Outcome measures

Outcome measures
Measure	Part 1: Placebo n=6 Participants Participants were administered a single IV dose of placebo in either treatment period 1 or 2 during Part 1 of the study. During each period, approximately 30 minutes after administration of study treatment, the participants entered the hypoxia chamber and were inside the chamber for approximately 80 minutes, during which they were under the full 4000 meters ± 10% hypoxic conditions. Participants then performed an exercise challenge at 70% of maximum VO2 uptake on an upright cycle ergometer within the hypoxia chamber for 10 minutes.	Part 1: GSK2586881 0.8 mg/kg n=6 Participants Participants were administered a single IV dose of 0.8 mg/kg GSK2586881 in either treatment period 1 or 2 during Part 1 of the study. During each period, approximately 30 minutes after administration of study treatment, the participants entered the hypoxia chamber and were inside the chamber for approximately 80 minutes, during which they were under the full 4000 meters ± 10% hypoxic conditions. Participants then performed an exercise challenge at 70% of maximum VO2 uptake on an upright cycle ergometer within the hypoxia chamber for 10 minutes.
Change From Baseline of PASP Measured Via Echocardiography-Part 2 15 minutes post-infusion; n=6, 6	2.756 Millimeters of mercury Interval -0.393 to 5.847	2.093 Millimeters of mercury Interval -1.009 to 5.246
Change From Baseline of PASP Measured Via Echocardiography-Part 2 60 minutes post-chamber entry; n=6, 6	9.399 Millimeters of mercury Interval 4.572 to 14.234	6.599 Millimeters of mercury Interval 1.697 to 11.439
Change From Baseline of PASP Measured Via Echocardiography-Part 2 2 minutes post-exercise start; n=6, 5	14.665 Millimeters of mercury Interval 8.972 to 20.406	14.646 Millimeters of mercury Interval 8.517 to 20.455
Change From Baseline of PASP Measured Via Echocardiography-Part 2 30 minutes post-chamber exit; n=6, 6	4.156 Millimeters of mercury Interval 0.904 to 7.468	3.867 Millimeters of mercury Interval 0.592 to 7.174

SECONDARY outcome

Timeframe: Baseline (Day1, predose) and end of infusion, 15 minutes post-infusion, 15 to 45 minutes post-infusion, 60 minutes post-chamber entry, immediately post-exercise, immediately post-chamber exit and 30 minutes post-chamber exit in each treatment period

Population: mITT1 Population. Only those participants with data available at the specified time points were analyzed (represented by n=X, X in category titles).

Blood samples were collected to analyze RAS peptide biomarkers such as angiotensin II (Ang II), Ang 1-7 and Ang 1-5. Baseline is defined as the measurement taken pre-dose during each treatment period (Day1, pre-dose). Change from Baseline is calculated as post-dose visit value minus Baseline value.

Outcome measures

Outcome measures
Measure	Part 1: Placebo n=10 Participants Participants were administered a single IV dose of placebo in either treatment period 1 or 2 during Part 1 of the study. During each period, approximately 30 minutes after administration of study treatment, the participants entered the hypoxia chamber and were inside the chamber for approximately 80 minutes, during which they were under the full 4000 meters ± 10% hypoxic conditions. Participants then performed an exercise challenge at 70% of maximum VO2 uptake on an upright cycle ergometer within the hypoxia chamber for 10 minutes.	Part 1: GSK2586881 0.8 mg/kg n=11 Participants Participants were administered a single IV dose of 0.8 mg/kg GSK2586881 in either treatment period 1 or 2 during Part 1 of the study. During each period, approximately 30 minutes after administration of study treatment, the participants entered the hypoxia chamber and were inside the chamber for approximately 80 minutes, during which they were under the full 4000 meters ± 10% hypoxic conditions. Participants then performed an exercise challenge at 70% of maximum VO2 uptake on an upright cycle ergometer within the hypoxia chamber for 10 minutes.
Change From Baseline in Renin-angiotensin System (RAS) Peptides-Part 1 Ang 1-7, 15 to 45 minutes post-infusion; n=10, 11	1.000 Picograms per milliliter Confidence interval could not be estimated as more than 75% of the values were below lower limit of quantification	1.686 Picograms per milliliter Interval 1.032 to 2.755
Change From Baseline in Renin-angiotensin System (RAS) Peptides-Part 1 Ang II, End of infusion; n=10, 11	0.551 Picograms per milliliter Interval 0.289 to 1.051	0.278 Picograms per milliliter Interval 0.149 to 0.522
Change From Baseline in Renin-angiotensin System (RAS) Peptides-Part 1 Ang II, 15 minutes post-infusion; n=10, 11	0.649 Picograms per milliliter Interval 0.392 to 1.073	0.305 Picograms per milliliter Interval 0.155 to 0.602
Change From Baseline in Renin-angiotensin System (RAS) Peptides-Part 1 Ang II, 15 to 45 minutes post-infusion; n=10, 11	0.661 Picograms per milliliter Interval 0.399 to 1.095	0.313 Picograms per milliliter Interval 0.176 to 0.556
Change From Baseline in Renin-angiotensin System (RAS) Peptides-Part 1 Ang II, 60 minutes post-chamber entry; n=10, 10	0.588 Picograms per milliliter Interval 0.288 to 1.203	0.270 Picograms per milliliter Interval 0.14 to 0.521
Change From Baseline in Renin-angiotensin System (RAS) Peptides-Part 1 Ang II, immediately post-exercise; n=10, 10	1.379 Picograms per milliliter Interval 0.675 to 2.817	0.337 Picograms per milliliter Interval 0.193 to 0.587
Change From Baseline in Renin-angiotensin System (RAS) Peptides-Part 1 Ang II, immediately post-chamber exit; n=10,10	1.001 Picograms per milliliter Interval 0.449 to 2.232	0.310 Picograms per milliliter Interval 0.17 to 0.566
Change From Baseline in Renin-angiotensin System (RAS) Peptides-Part 1 Ang II, 30 minutes post-chamber exit; n=10, 10	0.754 Picograms per milliliter Interval 0.366 to 1.553	0.263 Picograms per milliliter Interval 0.147 to 0.471
Change From Baseline in Renin-angiotensin System (RAS) Peptides-Part 1 Ang 1-7, End of infusion; n=10, 11	1.000 Picograms per milliliter Confidence interval could not be estimated as more than 75% of the values were below lower limit of quantification	1.346 Picograms per milliliter Interval 0.95 to 1.908
Change From Baseline in Renin-angiotensin System (RAS) Peptides-Part 1 Ang 1-7, 15 minutes post-infusion; n=10, 11	1.000 Picograms per milliliter Confidence interval could not be estimated as more than 75% of the values were below lower limit of quantification	1.658 Picograms per milliliter Interval 1.179 to 2.331
Change From Baseline in Renin-angiotensin System (RAS) Peptides-Part 1 Ang 1-7, 60 minutes post-chamber entry; n=10, 10	1.072 Picograms per milliliter Interval 0.916 to 1.254	2.615 Picograms per milliliter Interval 1.407 to 4.861
Change From Baseline in Renin-angiotensin System (RAS) Peptides-Part 1 Ang 1-7, immediately post-exercise; n=10, 10	1.000 Picograms per milliliter Confidence interval could not be estimated as more than 75% of the values were below lower limit of quantification	3.622 Picograms per milliliter Interval 1.612 to 8.141
Change From Baseline in Renin-angiotensin System (RAS) Peptides-Part 1 Ang 1-7, immediately post-chamber exit; n=10, 10	1.000 Picograms per milliliter Confidence interval could not be estimated as more than 75% of the values were below lower limit of quantification	4.584 Picograms per milliliter Interval 2.015 to 10.431
Change From Baseline in Renin-angiotensin System (RAS) Peptides-Part 1 Ang 1-7, 30 minutes post-chamber exit; n=10, 10	1.000 Picograms per milliliter Confidence interval could not be estimated as more than 75% of the values were below lower limit of quantification	2.179 Picograms per milliliter Interval 1.285 to 3.695
Change From Baseline in Renin-angiotensin System (RAS) Peptides-Part 1 Ang 1-5, End of infusion; n=10, 11	1.000 Picograms per milliliter Confidence interval could not be estimated as more than 75% of the values were below lower limit of quantification	1.489 Picograms per milliliter Interval 0.976 to 2.273
Change From Baseline in Renin-angiotensin System (RAS) Peptides-Part 1 Ang 1-5, 15 minutes post-infusion; n=10, 11	1.000 Picograms per milliliter Confidence interval could not be estimated as more than 75% of the values were below lower limit of quantification	2.402 Picograms per milliliter Interval 1.481 to 3.895
Change From Baseline in Renin-angiotensin System (RAS) Peptides-Part 1 Ang 1-5, 15 to 45 minutes post-infusion; n=10, 11	1.000 Picograms per milliliter Confidence interval could not be estimated as more than 75% of the values were below lower limit of quantification	2.321 Picograms per milliliter Interval 1.368 to 3.935
Change From Baseline in Renin-angiotensin System (RAS) Peptides-Part 1 Ang 1-5, 60 minutes post-chamber entry; n=10, 10	1.072 Picograms per milliliter Interval 0.916 to 1.254	3.007 Picograms per milliliter Interval 1.269 to 7.123
Change From Baseline in Renin-angiotensin System (RAS) Peptides-Part 1 Ang 1-5, immediately post-exercise; n=10, 10	1.094 Picograms per milliliter Interval 0.893 to 1.34	5.149 Picograms per milliliter Interval 2.299 to 11.532
Change From Baseline in Renin-angiotensin System (RAS) Peptides-Part 1 Ang 1-5, immediately post-chamber exit; n=10, 10	1.108 Picograms per milliliter Interval 0.879 to 1.396	5.991 Picograms per milliliter Interval 2.505 to 14.327
Change From Baseline in Renin-angiotensin System (RAS) Peptides-Part 1 Ang 1-5, 30 minutes post-chamber exit; n=10, 10	1.000 Picograms per milliliter Confidence interval could not be estimated as more than 75% of the values were below lower limit of quantification	3.020 Picograms per milliliter Interval 1.542 to 5.915

SECONDARY outcome

Timeframe: Baseline (Day1, predose) and end of infusion, 15 minutes post-infusion, 15 to 45 minutes post-infusion, 60 minutes post-chamber entry, immediately post-exercise, immediately post-chamber exit and 30 minutes post-chamber exit in each treatment period

Population: mITT2 Population. Only those participants with data available at the specified time points were analyzed (represented by n=X, X in category titles).

Blood samples were collected to analyze RAS peptides such as Ang II, Ang 1-7 and Ang 1-5. Baseline is defined as the measurement taken pre-dose during each treatment period (Day1, pre-dose). Change from Baseline is calculated as post-dose visit value minus Baseline value.

Outcome measures

Outcome measures
Measure	Part 1: Placebo n=4 Participants Participants were administered a single IV dose of placebo in either treatment period 1 or 2 during Part 1 of the study. During each period, approximately 30 minutes after administration of study treatment, the participants entered the hypoxia chamber and were inside the chamber for approximately 80 minutes, during which they were under the full 4000 meters ± 10% hypoxic conditions. Participants then performed an exercise challenge at 70% of maximum VO2 uptake on an upright cycle ergometer within the hypoxia chamber for 10 minutes.	Part 1: GSK2586881 0.8 mg/kg n=5 Participants Participants were administered a single IV dose of 0.8 mg/kg GSK2586881 in either treatment period 1 or 2 during Part 1 of the study. During each period, approximately 30 minutes after administration of study treatment, the participants entered the hypoxia chamber and were inside the chamber for approximately 80 minutes, during which they were under the full 4000 meters ± 10% hypoxic conditions. Participants then performed an exercise challenge at 70% of maximum VO2 uptake on an upright cycle ergometer within the hypoxia chamber for 10 minutes.
Change From Baseline in RAS Peptides-Part 2 Ang II, End of infusion; n=4, 5	0.603 Picograms per milliliter Interval 0.139 to 2.621	0.500 Picograms per milliliter Interval 0.143 to 1.743
Change From Baseline in RAS Peptides-Part 2 Ang II, 15 minutes post-infusion; n=4, 5	0.564 Picograms per milliliter Interval 0.146 to 2.178	0.391 Picograms per milliliter Interval 0.122 to 1.255
Change From Baseline in RAS Peptides-Part 2 Ang II, 15 to 45 minutes post-infusion; n=4, 5	0.596 Picograms per milliliter Interval 0.14 to 2.536	0.391 Picograms per milliliter Interval 0.122 to 1.255
Change From Baseline in RAS Peptides-Part 2 Ang II, 60 minutes post-chamber entry; n=4, 5	0.532 Picograms per milliliter Interval 0.181 to 1.568	0.467 Picograms per milliliter Interval 0.142 to 1.532
Change From Baseline in RAS Peptides-Part 2 Ang II, immediately post-exercise; n=4, 5	0.447 Picograms per milliliter Interval 0.127 to 1.57	0.452 Picograms per milliliter Interval 0.14 to 1.454
Change From Baseline in RAS Peptides-Part 2 Ang II, immediately post-chamber exit; n=4, 5	0.604 Picograms per milliliter Interval 0.212 to 1.725	0.391 Picograms per milliliter Interval 0.122 to 1.255
Change From Baseline in RAS Peptides-Part 2 Ang II, 30 minutes post-chamber exit; n=4, 5	0.358 Picograms per milliliter Interval 0.06 to 2.151	0.472 Picograms per milliliter Interval 0.143 to 1.559
Change From Baseline in RAS Peptides-Part 2 Ang 1-7, End of infusion; n=4, 5	1.000 Picograms per milliliter Confidence interval could not be estimated as more than 75% of the values were below lower limit of quantification	1.285 Picograms per milliliter Interval 0.64 to 2.581
Change From Baseline in RAS Peptides-Part 2 Ang 1-7, 15 minutes post-infusion; n=4, 5	1.000 Picograms per milliliter Confidence interval could not be estimated as more than 75% of the values were below lower limit of quantification	2.123 Picograms per milliliter Interval 0.762 to 5.913
Change From Baseline in RAS Peptides-Part 2 Ang 1-7, 15 to 45 minutes post-infusion; n=4, 5	1.000 Picograms per milliliter Confidence interval could not be estimated as more than 75% of the values were below lower limit of quantification	1.782 Picograms per milliliter Interval 0.659 to 4.821
Change From Baseline in RAS Peptides-Part 2 Ang 1-7, 60 minutes post-chamber entry; n=4, 5	1.000 Picograms per milliliter Confidence interval could not be estimated as more than 75% of the values were below lower limit of quantification	2.469 Picograms per milliliter Interval 0.844 to 7.229
Change From Baseline in RAS Peptides-Part 2 Ang 1-7, immediately post-exercise; n=3, 5	1.000 Picograms per milliliter Confidence interval could not be estimated as more than 75% of the values were below lower limit of quantification	1.992 Picograms per milliliter Interval 0.833 to 4.763
Change From Baseline in RAS Peptides-Part 2 Ang 1-7, immediately post-chamber exit; n=4, 5	1.000 Picograms per milliliter Confidence interval could not be estimated as more than 75% of the values were below lower limit of quantification	1.668 Picograms per milliliter Interval 0.644 to 4.319
Change From Baseline in RAS Peptides-Part 2 Ang 1-7, 30 minutes post-chamber exit; n=4, 5	1.000 Picograms per milliliter Confidence interval could not be estimated as more than 75% of the values were below lower limit of quantification	2.105 Picograms per milliliter Interval 0.865 to 5.123
Change From Baseline in RAS Peptides-Part 2 Ang 1-5, End of infusion; n=4, 5	1.000 Picograms per milliliter Confidence interval could not be estimated as more than 75% of the values were below lower limit of quantification	1.998 Picograms per milliliter Interval 0.814 to 4.901
Change From Baseline in RAS Peptides-Part 2 Ang 1-5, 15 minutes post-infusion; n=4, 5	1.000 Picograms per milliliter Confidence interval could not be estimated as more than 75% of the values were below lower limit of quantification	2.151 Picograms per milliliter Interval 0.849 to 5.452
Change From Baseline in RAS Peptides-Part 2 Ang 1-5, 15 to 45 minutes post-infusion; n=4, 5	1.000 Picograms per milliliter Confidence interval could not be estimated as more than 75% of the values were below lower limit of quantification	2.722 Picograms per milliliter Interval 1.222 to 6.063
Change From Baseline in RAS Peptides-Part 2 Ang 1-5, 60 minutes post-chamber entry; n=4, 5	1.426 Picograms per milliliter Interval 0.461 to 4.417	3.053 Picograms per milliliter Interval 0.786 to 11.861
Change From Baseline in RAS Peptides-Part 2 Ang 1-5, immediately post-exercise; n=4, 5	1.000 Picograms per milliliter Confidence interval could not be estimated as more than 75% of the values were below lower limit of quantification	2.498 Picograms per milliliter Interval 0.814 to 7.673
Change From Baseline in RAS Peptides-Part 2 Ang 1-5, immediately post-chamber exit; n=4, 5	2.246 Picograms per milliliter Interval 0.481 to 10.493	2.417 Picograms per milliliter Interval 0.842 to 6.937
Change From Baseline in RAS Peptides-Part 2 Ang 1-5, 30 minutes post-chamber exit; n=4, 5	1.000 Picograms per milliliter Confidence interval could not be estimated as more than 75% of the values were below lower limit of quantification	2.561 Picograms per milliliter Interval 1.14 to 5.752

SECONDARY outcome

Timeframe: Baseline (Day 1, pre-dose), 15 to 45 minutes post-infusion, immediately post-exercise and 60 minutes post-chamber exit in each treatment period

Population: mITT1 Population. Only those participants with data available at the specified time points were analyzed (represented by n=X, X in category titles)

SBP and DBP were measured in a semi-supine position after 5 minutes of rest for the participant. Baseline is defined as the measurement taken pre-dose during each treatment period (Day1, pre-dose). Change from Baseline is calculated as the post-dose visit value minus the Baseline value.

Outcome measures

Outcome measures
Measure	Part 1: Placebo n=10 Participants Participants were administered a single IV dose of placebo in either treatment period 1 or 2 during Part 1 of the study. During each period, approximately 30 minutes after administration of study treatment, the participants entered the hypoxia chamber and were inside the chamber for approximately 80 minutes, during which they were under the full 4000 meters ± 10% hypoxic conditions. Participants then performed an exercise challenge at 70% of maximum VO2 uptake on an upright cycle ergometer within the hypoxia chamber for 10 minutes.	Part 1: GSK2586881 0.8 mg/kg n=11 Participants Participants were administered a single IV dose of 0.8 mg/kg GSK2586881 in either treatment period 1 or 2 during Part 1 of the study. During each period, approximately 30 minutes after administration of study treatment, the participants entered the hypoxia chamber and were inside the chamber for approximately 80 minutes, during which they were under the full 4000 meters ± 10% hypoxic conditions. Participants then performed an exercise challenge at 70% of maximum VO2 uptake on an upright cycle ergometer within the hypoxia chamber for 10 minutes.
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)-Part 1 SBP; 15 to 45 minutes post infusion; n=10, 11	-1.0 Millimeters of mercury Standard Deviation 3.30	-5.9 Millimeters of mercury Standard Deviation 6.88
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)-Part 1 SBP; immediately post-exercise; n=10, 10	5.4 Millimeters of mercury Standard Deviation 12.89	-3.0 Millimeters of mercury Standard Deviation 14.02
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)-Part 1 SBP; 60 minutes post-chamber exit; n=10, 10	-4.0 Millimeters of mercury Standard Deviation 4.14	-6.2 Millimeters of mercury Standard Deviation 7.28
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)-Part 1 DBP; 15 to 45 minutes post infusion; n=10, 11	0.3 Millimeters of mercury Standard Deviation 6.41	-1.2 Millimeters of mercury Standard Deviation 4.24
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)-Part 1 DBP; immediately post-exercise; n=10, 10	6.7 Millimeters of mercury Standard Deviation 12.40	0.3 Millimeters of mercury Standard Deviation 7.78
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)-Part 1 DBP; 60 minutes post-chamber exit; n=10, 10	0.0 Millimeters of mercury Standard Deviation 7.94	-1.4 Millimeters of mercury Standard Deviation 7.57

SECONDARY outcome

Timeframe: Baseline (Day 1, pre-dose), 15 to 45 minutes post-infusion, immediately post-exercise and 60 minutes post-chamber exit in each treatment period

Population: mITT2 Population

SBP and DBP were measured in a semi-supine position after 5 minutes of rest for the participant. Baseline is defined as the measurement taken pre-dose during each treatment period (Day1, pre-dose). Change from Baseline is calculated as the post-dose visit value minus the Baseline value.

Outcome measures

Outcome measures
Measure	Part 1: Placebo n=6 Participants Participants were administered a single IV dose of placebo in either treatment period 1 or 2 during Part 1 of the study. During each period, approximately 30 minutes after administration of study treatment, the participants entered the hypoxia chamber and were inside the chamber for approximately 80 minutes, during which they were under the full 4000 meters ± 10% hypoxic conditions. Participants then performed an exercise challenge at 70% of maximum VO2 uptake on an upright cycle ergometer within the hypoxia chamber for 10 minutes.	Part 1: GSK2586881 0.8 mg/kg n=6 Participants Participants were administered a single IV dose of 0.8 mg/kg GSK2586881 in either treatment period 1 or 2 during Part 1 of the study. During each period, approximately 30 minutes after administration of study treatment, the participants entered the hypoxia chamber and were inside the chamber for approximately 80 minutes, during which they were under the full 4000 meters ± 10% hypoxic conditions. Participants then performed an exercise challenge at 70% of maximum VO2 uptake on an upright cycle ergometer within the hypoxia chamber for 10 minutes.
Change From Baseline in SBP and DBP-Part 2 SBP; 15 to 45 minutes post infusion	-3.3 Millimeters of mercury Standard Deviation 7.00	-2.2 Millimeters of mercury Standard Deviation 7.36
Change From Baseline in SBP and DBP-Part 2 SBP; immediately post-exercise	-9.0 Millimeters of mercury Standard Deviation 14.64	-9.5 Millimeters of mercury Standard Deviation 12.85
Change From Baseline in SBP and DBP-Part 2 SBP; 60 minutes post-chamber exit	0.0 Millimeters of mercury Standard Deviation 8.94	-1.5 Millimeters of mercury Standard Deviation 4.37
Change From Baseline in SBP and DBP-Part 2 DBP; 15 to 45 minutes post infusion	-5.3 Millimeters of mercury Standard Deviation 5.39	-0.8 Millimeters of mercury Standard Deviation 8.50
Change From Baseline in SBP and DBP-Part 2 DBP; immediately post-exercise	-9.0 Millimeters of mercury Standard Deviation 10.75	-6.0 Millimeters of mercury Standard Deviation 8.10
Change From Baseline in SBP and DBP-Part 2 DBP; 60 minutes post-chamber exit	1.5 Millimeters of mercury Standard Deviation 9.77	3.3 Millimeters of mercury Standard Deviation 7.09

SECONDARY outcome

Timeframe: Baseline (Day 1, pre-dose), 15 to 45 minutes post-infusion, immediately post-exercise and 60 minutes post-chamber exit in each treatment period

Population: mITT1 Population. Only those participants with data available at the specified time points were analyzed (represented by n=X, X in category titles)

Heart rate was measured in a semi-supine position after 5 minutes of rest for the participant. Baseline is defined as the measurement taken pre-dose during each treatment period (Day1, pre-dose). Change from Baseline is calculated as the post-dose visit value minus the Baseline value.

Outcome measures

Outcome measures
Measure	Part 1: Placebo n=10 Participants Participants were administered a single IV dose of placebo in either treatment period 1 or 2 during Part 1 of the study. During each period, approximately 30 minutes after administration of study treatment, the participants entered the hypoxia chamber and were inside the chamber for approximately 80 minutes, during which they were under the full 4000 meters ± 10% hypoxic conditions. Participants then performed an exercise challenge at 70% of maximum VO2 uptake on an upright cycle ergometer within the hypoxia chamber for 10 minutes.	Part 1: GSK2586881 0.8 mg/kg n=11 Participants Participants were administered a single IV dose of 0.8 mg/kg GSK2586881 in either treatment period 1 or 2 during Part 1 of the study. During each period, approximately 30 minutes after administration of study treatment, the participants entered the hypoxia chamber and were inside the chamber for approximately 80 minutes, during which they were under the full 4000 meters ± 10% hypoxic conditions. Participants then performed an exercise challenge at 70% of maximum VO2 uptake on an upright cycle ergometer within the hypoxia chamber for 10 minutes.
Change From Baseline in Heart Rate-Part 1 15 to 45 minutes post infusion; n=10, 11	-3.6 Beats per minute Standard Deviation 4.45	1.2 Beats per minute Standard Deviation 5.36
Change From Baseline in Heart Rate-Part 1 immediately post-exercise; n=10, 10	32.0 Beats per minute Standard Deviation 7.48	37.7 Beats per minute Standard Deviation 10.92
Change From Baseline in Heart Rate-Part 1 60 minutes post-chamber exit; n=10, 10	7.4 Beats per minute Standard Deviation 6.33	7.7 Beats per minute Standard Deviation 7.26

SECONDARY outcome

Timeframe: Baseline (Day 1, pre-dose), 15 to 45 minutes post-infusion, immediately post-exercise and 60 minutes post-chamber exit in each treatment period

Population: mITT2 Population

Heart rate was measured in a semi-supine position after 5 minutes of rest for the participant. Baseline is defined as the measurement taken pre-dose during each treatment period (Day1, pre-dose). Change from Baseline is calculated as the post-dose visit value minus the Baseline value.

Outcome measures

Outcome measures
Measure	Part 1: Placebo n=6 Participants Participants were administered a single IV dose of placebo in either treatment period 1 or 2 during Part 1 of the study. During each period, approximately 30 minutes after administration of study treatment, the participants entered the hypoxia chamber and were inside the chamber for approximately 80 minutes, during which they were under the full 4000 meters ± 10% hypoxic conditions. Participants then performed an exercise challenge at 70% of maximum VO2 uptake on an upright cycle ergometer within the hypoxia chamber for 10 minutes.	Part 1: GSK2586881 0.8 mg/kg n=6 Participants Participants were administered a single IV dose of 0.8 mg/kg GSK2586881 in either treatment period 1 or 2 during Part 1 of the study. During each period, approximately 30 minutes after administration of study treatment, the participants entered the hypoxia chamber and were inside the chamber for approximately 80 minutes, during which they were under the full 4000 meters ± 10% hypoxic conditions. Participants then performed an exercise challenge at 70% of maximum VO2 uptake on an upright cycle ergometer within the hypoxia chamber for 10 minutes.
Change From Baseline in Heart Rate-Part 2 15 to 45 minutes post infusion	-3.7 Beats per minute Standard Deviation 3.44	0.0 Beats per minute Standard Deviation 3.90
Change From Baseline in Heart Rate-Part 2 immediately post-exercise	11.8 Beats per minute Standard Deviation 7.78	16.3 Beats per minute Standard Deviation 7.37
Change From Baseline in Heart Rate-Part 2 60 minutes post-chamber exit	-1.5 Beats per minute Standard Deviation 4.51	1.5 Beats per minute Standard Deviation 4.42

SECONDARY outcome

Timeframe: Baseline (Day 1, pre-dose), 15 minutes post-infusion, 60 minutes post-chamber entry, immediately post-exercise, 30 minutes post-chamber exit in each treatment period

Population: mITT1 Population. Only those participants with data available at the specified time points were analyzed.

Oxygen saturation was monitored continuously using pulse oximetry. Analysis was performed using a Bayesian repeated measures model adjusting for: participant-level and period-adjusted Baselines, treatment, time and period. Time by treatment and time by period-adjusted baseline interactions were included. Participant-level Baseline is defined as the mean of the two period-specific baselines. Period-adjusted baseline is defined as the difference between the period-specific baseline and participant-level baseline for each period. No transformation has been applied to the data. Non-informative priors used. Baseline is defined as the measurement taken pre-dose during each treatment period (Day1, pre-dose). Change from Baseline is the post-dose visit value minus Baseline value. Posterior median and 95% credible interval is presented.

Outcome measures

Outcome measures
Measure	Part 1: Placebo n=10 Participants Participants were administered a single IV dose of placebo in either treatment period 1 or 2 during Part 1 of the study. During each period, approximately 30 minutes after administration of study treatment, the participants entered the hypoxia chamber and were inside the chamber for approximately 80 minutes, during which they were under the full 4000 meters ± 10% hypoxic conditions. Participants then performed an exercise challenge at 70% of maximum VO2 uptake on an upright cycle ergometer within the hypoxia chamber for 10 minutes.	Part 1: GSK2586881 0.8 mg/kg n=10 Participants Participants were administered a single IV dose of 0.8 mg/kg GSK2586881 in either treatment period 1 or 2 during Part 1 of the study. During each period, approximately 30 minutes after administration of study treatment, the participants entered the hypoxia chamber and were inside the chamber for approximately 80 minutes, during which they were under the full 4000 meters ± 10% hypoxic conditions. Participants then performed an exercise challenge at 70% of maximum VO2 uptake on an upright cycle ergometer within the hypoxia chamber for 10 minutes.
Change From Baseline in Oxygen Saturation-Part 1 15 minutes post-infusion	1.626 Percentage of oxygen Interval 0.614 to 2.635	1.478 Percentage of oxygen Interval 0.467 to 2.493
Change From Baseline in Oxygen Saturation-Part 1 60 minutes post-chamber entry	-10.663 Percentage of oxygen Interval -13.599 to -7.733	-11.835 Percentage of oxygen Interval -14.772 to -8.897
Change From Baseline in Oxygen Saturation-Part 1 immediately post-exercise	-14.257 Percentage of oxygen Interval -17.397 to -11.109	-14.426 Percentage of oxygen Interval -17.59 to -11.279
Change From Baseline in Oxygen Saturation-Part 1 30 minutes post-chamber exit	0.235 Percentage of oxygen Interval -0.774 to 1.251	-0.132 Percentage of oxygen Interval -1.144 to 0.88

SECONDARY outcome

Timeframe: Baseline (Day 1, pre-dose), 15 minutes post-infusion, 60 minutes post-chamber entry, 2 minutes post-exercise start, 30 minutes post-chamber exit in each treatment period

Population: mITT2 Population

Oxygen saturation was monitored continuously using pulse oximetry. Analysis was performed using a Bayesian repeated measures model adjusting for: participant-level and period-adjusted Baselines, treatment, time and period. Time by treatment and time by period-adjusted baseline interactions were included. Participant-level Baseline is defined as the mean of the two period-specific baselines. Period-adjusted baseline is defined as the difference between the period-specific baseline and participant-level baseline for each period. No transformation has been applied to the data. Non-informative priors used. Baseline is defined as the measurement taken pre-dose during each treatment period (Day1, pre-dose). Change from Baseline is the post-dose visit value minus Baseline value. Posterior median and 95% credible interval is presented.

Outcome measures

Outcome measures
Measure	Part 1: Placebo n=6 Participants Participants were administered a single IV dose of placebo in either treatment period 1 or 2 during Part 1 of the study. During each period, approximately 30 minutes after administration of study treatment, the participants entered the hypoxia chamber and were inside the chamber for approximately 80 minutes, during which they were under the full 4000 meters ± 10% hypoxic conditions. Participants then performed an exercise challenge at 70% of maximum VO2 uptake on an upright cycle ergometer within the hypoxia chamber for 10 minutes.	Part 1: GSK2586881 0.8 mg/kg n=6 Participants Participants were administered a single IV dose of 0.8 mg/kg GSK2586881 in either treatment period 1 or 2 during Part 1 of the study. During each period, approximately 30 minutes after administration of study treatment, the participants entered the hypoxia chamber and were inside the chamber for approximately 80 minutes, during which they were under the full 4000 meters ± 10% hypoxic conditions. Participants then performed an exercise challenge at 70% of maximum VO2 uptake on an upright cycle ergometer within the hypoxia chamber for 10 minutes.
Change From Baseline in Oxygen Saturation-Part 2 15 minutes post-infusion	0.644 Percentage of oxygen Interval -0.602 to 1.892	0.847 Percentage of oxygen Interval -0.416 to 2.09
Change From Baseline in Oxygen Saturation-Part 2 60 minutes post-chamber entry	-23.707 Percentage of oxygen Interval -26.345 to -21.053	-19.945 Percentage of oxygen Interval -22.585 to -17.302
Change From Baseline in Oxygen Saturation-Part 2 2 minutes post-exercise start	-22.399 Percentage of oxygen Interval -26.372 to -18.415	-23.433 Percentage of oxygen Interval -27.4 to -19.484
Change From Baseline in Oxygen Saturation-Part 2 30 minutes post-chamber exit	1.691 Percentage of oxygen Interval 0.614 to 2.763	0.821 Percentage of oxygen Interval -0.246 to 1.918

SECONDARY outcome

Timeframe: pre-dose, 15 to 45 minutes post-infusion, 60 minutes post-chamber exit in each treatment period

Population: mITT1 Population. Only those participants with data available at the specified time points were analyzed (represented by n=X, X in category titles)

Twelve lead ECGs were obtained using an automated ECG machine that automatically calculated the heart rate and measured PR, QRS, QT and corrected QT (QTc) intervals. ECG was measured in a semi-supine position after 5 minutes rest. Clinically significant (CS) and not clinically significant (NCS) abnormal ECG findings have been presented. CS abnormal findings are those which are not associated with the underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition.

Outcome measures

Outcome measures
Measure	Part 1: Placebo n=10 Participants Participants were administered a single IV dose of placebo in either treatment period 1 or 2 during Part 1 of the study. During each period, approximately 30 minutes after administration of study treatment, the participants entered the hypoxia chamber and were inside the chamber for approximately 80 minutes, during which they were under the full 4000 meters ± 10% hypoxic conditions. Participants then performed an exercise challenge at 70% of maximum VO2 uptake on an upright cycle ergometer within the hypoxia chamber for 10 minutes.	Part 1: GSK2586881 0.8 mg/kg n=11 Participants Participants were administered a single IV dose of 0.8 mg/kg GSK2586881 in either treatment period 1 or 2 during Part 1 of the study. During each period, approximately 30 minutes after administration of study treatment, the participants entered the hypoxia chamber and were inside the chamber for approximately 80 minutes, during which they were under the full 4000 meters ± 10% hypoxic conditions. Participants then performed an exercise challenge at 70% of maximum VO2 uptake on an upright cycle ergometer within the hypoxia chamber for 10 minutes.
Number of Participants With Abnormal Electrocardiogram (ECG) Findings-Part 1 NCS; pre-dose; n=10, 11	8 Participants	5 Participants
Number of Participants With Abnormal Electrocardiogram (ECG) Findings-Part 1 CS; pre-dose; n=10, 11	0 Participants	0 Participants
Number of Participants With Abnormal Electrocardiogram (ECG) Findings-Part 1 NCS; 15 to 45 minutes post-infusion; n=10, 11	7 Participants	7 Participants
Number of Participants With Abnormal Electrocardiogram (ECG) Findings-Part 1 CS; 15 to 45 minutes post-infusion; n=10, 11	0 Participants	0 Participants
Number of Participants With Abnormal Electrocardiogram (ECG) Findings-Part 1 NCS: 60 minutes post-chamber exit; n=10, 10	1 Participants	3 Participants
Number of Participants With Abnormal Electrocardiogram (ECG) Findings-Part 1 CS: 60 minutes post-chamber exit; n=10, 10	0 Participants	0 Participants

SECONDARY outcome

Timeframe: pre-dose, 15 to 45 minutes post-infusion, 60 minutes post-chamber exit in each treatment period

Population: mITT2 Population

Twelve lead ECGs were obtained using an automated ECG machine that automatically calculated the heart rate and measured PR, QRS, QT and QTc intervals. ECG was measured in a semi-supine position after 5 minutes rest. Clinically significant (CS) and not clinically significant (NCS) abnormal ECG findings have been presented. CS abnormal findings are those which are not associated with the underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition.

Outcome measures

Outcome measures
Measure	Part 1: Placebo n=6 Participants Participants were administered a single IV dose of placebo in either treatment period 1 or 2 during Part 1 of the study. During each period, approximately 30 minutes after administration of study treatment, the participants entered the hypoxia chamber and were inside the chamber for approximately 80 minutes, during which they were under the full 4000 meters ± 10% hypoxic conditions. Participants then performed an exercise challenge at 70% of maximum VO2 uptake on an upright cycle ergometer within the hypoxia chamber for 10 minutes.	Part 1: GSK2586881 0.8 mg/kg n=6 Participants Participants were administered a single IV dose of 0.8 mg/kg GSK2586881 in either treatment period 1 or 2 during Part 1 of the study. During each period, approximately 30 minutes after administration of study treatment, the participants entered the hypoxia chamber and were inside the chamber for approximately 80 minutes, during which they were under the full 4000 meters ± 10% hypoxic conditions. Participants then performed an exercise challenge at 70% of maximum VO2 uptake on an upright cycle ergometer within the hypoxia chamber for 10 minutes.
Number of Participants With Abnormal ECG Findings-Part 2 CS; 15 to 45 minutes post-infusion	0 Participants	0 Participants
Number of Participants With Abnormal ECG Findings-Part 2 NCS; pre-dose	3 Participants	6 Participants
Number of Participants With Abnormal ECG Findings-Part 2 CS; pre-dose	0 Participants	0 Participants
Number of Participants With Abnormal ECG Findings-Part 2 NCS; 15 to 45 minutes post-infusion	4 Participants	5 Participants
Number of Participants With Abnormal ECG Findings-Part 2 NCS: 60 minutes post-chamber exit	3 Participants	4 Participants
Number of Participants With Abnormal ECG Findings-Part 2 CS: 60 minutes post-chamber exit	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Up to 26 days

Population: mITT1 Population

An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. 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 or incapacity; is a congenital anomaly/birth defect; other important medical events that may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed before.

Outcome measures

Outcome measures
Measure	Part 1: Placebo n=10 Participants Participants were administered a single IV dose of placebo in either treatment period 1 or 2 during Part 1 of the study. During each period, approximately 30 minutes after administration of study treatment, the participants entered the hypoxia chamber and were inside the chamber for approximately 80 minutes, during which they were under the full 4000 meters ± 10% hypoxic conditions. Participants then performed an exercise challenge at 70% of maximum VO2 uptake on an upright cycle ergometer within the hypoxia chamber for 10 minutes.	Part 1: GSK2586881 0.8 mg/kg n=11 Participants Participants were administered a single IV dose of 0.8 mg/kg GSK2586881 in either treatment period 1 or 2 during Part 1 of the study. During each period, approximately 30 minutes after administration of study treatment, the participants entered the hypoxia chamber and were inside the chamber for approximately 80 minutes, during which they were under the full 4000 meters ± 10% hypoxic conditions. Participants then performed an exercise challenge at 70% of maximum VO2 uptake on an upright cycle ergometer within the hypoxia chamber for 10 minutes.
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)-Part 1 AEs	3 Participants	2 Participants
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)-Part 1 SAEs	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Up to 26 days

Population: mITT2 Population

An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. 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 or incapacity; is a congenital anomaly/birth defect; other important medical events that may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed before.

Outcome measures

Outcome measures
Measure	Part 1: Placebo n=6 Participants Participants were administered a single IV dose of placebo in either treatment period 1 or 2 during Part 1 of the study. During each period, approximately 30 minutes after administration of study treatment, the participants entered the hypoxia chamber and were inside the chamber for approximately 80 minutes, during which they were under the full 4000 meters ± 10% hypoxic conditions. Participants then performed an exercise challenge at 70% of maximum VO2 uptake on an upright cycle ergometer within the hypoxia chamber for 10 minutes.	Part 1: GSK2586881 0.8 mg/kg n=6 Participants Participants were administered a single IV dose of 0.8 mg/kg GSK2586881 in either treatment period 1 or 2 during Part 1 of the study. During each period, approximately 30 minutes after administration of study treatment, the participants entered the hypoxia chamber and were inside the chamber for approximately 80 minutes, during which they were under the full 4000 meters ± 10% hypoxic conditions. Participants then performed an exercise challenge at 70% of maximum VO2 uptake on an upright cycle ergometer within the hypoxia chamber for 10 minutes.
Number of Participants With AEs and SAEs-Part 2 AEs	1 Participants	0 Participants
Number of Participants With AEs and SAEs-Part 2 SAEs	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Up to 26 days

Population: mITT1 Population

Blood samples were collected for immunogenicity testing. Blood samples were tested for anti-angiotensin converting enzyme 2 (ACE2) binding antibodies by screening and confirmation assay steps. The post-dose samples tested positive for anti-ACE2 binding antibodies were further characterized for anti-ACE2 neutralizing antibodies. Number of participants with positive incidences for anti-ACE2 binding and neutralizing antibodies is reported.

Outcome measures

Outcome measures
Measure	Part 1: Placebo n=10 Participants Participants were administered a single IV dose of placebo in either treatment period 1 or 2 during Part 1 of the study. During each period, approximately 30 minutes after administration of study treatment, the participants entered the hypoxia chamber and were inside the chamber for approximately 80 minutes, during which they were under the full 4000 meters ± 10% hypoxic conditions. Participants then performed an exercise challenge at 70% of maximum VO2 uptake on an upright cycle ergometer within the hypoxia chamber for 10 minutes.	Part 1: GSK2586881 0.8 mg/kg n=11 Participants Participants were administered a single IV dose of 0.8 mg/kg GSK2586881 in either treatment period 1 or 2 during Part 1 of the study. During each period, approximately 30 minutes after administration of study treatment, the participants entered the hypoxia chamber and were inside the chamber for approximately 80 minutes, during which they were under the full 4000 meters ± 10% hypoxic conditions. Participants then performed an exercise challenge at 70% of maximum VO2 uptake on an upright cycle ergometer within the hypoxia chamber for 10 minutes.
Number of Participants With Positive Immunogenicity Results-Part 1	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Up to 26 days

Population: mITT2 Population

Blood samples were collected for immunogenicity testing. Blood samples were tested for anti-ACE2 binding antibodies by screening and confirmation assay steps. The post-dose samples tested positive for anti-ACE2 binding antibodies were further characterized for anti-ACE2 neutralizing antibodies. Number of participants with positive incidences for anti-ACE2 binding and neutralizing antibodies is reported.

Outcome measures

Outcome measures
Measure	Part 1: Placebo n=6 Participants Participants were administered a single IV dose of placebo in either treatment period 1 or 2 during Part 1 of the study. During each period, approximately 30 minutes after administration of study treatment, the participants entered the hypoxia chamber and were inside the chamber for approximately 80 minutes, during which they were under the full 4000 meters ± 10% hypoxic conditions. Participants then performed an exercise challenge at 70% of maximum VO2 uptake on an upright cycle ergometer within the hypoxia chamber for 10 minutes.	Part 1: GSK2586881 0.8 mg/kg n=6 Participants Participants were administered a single IV dose of 0.8 mg/kg GSK2586881 in either treatment period 1 or 2 during Part 1 of the study. During each period, approximately 30 minutes after administration of study treatment, the participants entered the hypoxia chamber and were inside the chamber for approximately 80 minutes, during which they were under the full 4000 meters ± 10% hypoxic conditions. Participants then performed an exercise challenge at 70% of maximum VO2 uptake on an upright cycle ergometer within the hypoxia chamber for 10 minutes.
Number of Participants With Positive Immunogenicity Results-Part 2	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Up to 26 days

Population: mITT1 Population

Blood samples were collected to analyze the following hematology parameters: platelet count, red blood cell (RBC) count, hemoglobin, hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), white blood cell (WBC) count with differential: neutrophils, lymphocytes, monocytes, eosinophils and basophils. Number of participants with abnormal hematology parameters are presented.

Outcome measures

Outcome measures
Measure	Part 1: Placebo n=10 Participants Participants were administered a single IV dose of placebo in either treatment period 1 or 2 during Part 1 of the study. During each period, approximately 30 minutes after administration of study treatment, the participants entered the hypoxia chamber and were inside the chamber for approximately 80 minutes, during which they were under the full 4000 meters ± 10% hypoxic conditions. Participants then performed an exercise challenge at 70% of maximum VO2 uptake on an upright cycle ergometer within the hypoxia chamber for 10 minutes.	Part 1: GSK2586881 0.8 mg/kg n=11 Participants Participants were administered a single IV dose of 0.8 mg/kg GSK2586881 in either treatment period 1 or 2 during Part 1 of the study. During each period, approximately 30 minutes after administration of study treatment, the participants entered the hypoxia chamber and were inside the chamber for approximately 80 minutes, during which they were under the full 4000 meters ± 10% hypoxic conditions. Participants then performed an exercise challenge at 70% of maximum VO2 uptake on an upright cycle ergometer within the hypoxia chamber for 10 minutes.
Number of Participants With Abnormal Hematology Parameters-Part 1	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Up to 26 days

Population: mITT2 Population

Blood samples were collected to analyze the following hematology parameters: platelet count, RBC count, hemoglobin, hematocrit, MCV, MCH, WBC count with differential: neutrophils, lymphocytes, monocytes, eosinophils and basophils. Number of participants with abnormal hematology parameters are presented.

Outcome measures

Outcome measures
Measure	Part 1: Placebo n=6 Participants Participants were administered a single IV dose of placebo in either treatment period 1 or 2 during Part 1 of the study. During each period, approximately 30 minutes after administration of study treatment, the participants entered the hypoxia chamber and were inside the chamber for approximately 80 minutes, during which they were under the full 4000 meters ± 10% hypoxic conditions. Participants then performed an exercise challenge at 70% of maximum VO2 uptake on an upright cycle ergometer within the hypoxia chamber for 10 minutes.	Part 1: GSK2586881 0.8 mg/kg n=6 Participants Participants were administered a single IV dose of 0.8 mg/kg GSK2586881 in either treatment period 1 or 2 during Part 1 of the study. During each period, approximately 30 minutes after administration of study treatment, the participants entered the hypoxia chamber and were inside the chamber for approximately 80 minutes, during which they were under the full 4000 meters ± 10% hypoxic conditions. Participants then performed an exercise challenge at 70% of maximum VO2 uptake on an upright cycle ergometer within the hypoxia chamber for 10 minutes.
Number of Participants With Abnormal Hematology Parameters-Part 2	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Up to 26 days

Population: mITT1 Population

Blood samples were collected to analyze the following clinical chemistry parameters: blood urea nitrogen (BUN), creatinine, glucose, potassium, sodium, calcium, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, total and direct bilirubin, total protein and albumin. Number of participants with abnormal clinical chemistry parameters are presented.

Outcome measures

Outcome measures
Measure	Part 1: Placebo n=10 Participants Participants were administered a single IV dose of placebo in either treatment period 1 or 2 during Part 1 of the study. During each period, approximately 30 minutes after administration of study treatment, the participants entered the hypoxia chamber and were inside the chamber for approximately 80 minutes, during which they were under the full 4000 meters ± 10% hypoxic conditions. Participants then performed an exercise challenge at 70% of maximum VO2 uptake on an upright cycle ergometer within the hypoxia chamber for 10 minutes.	Part 1: GSK2586881 0.8 mg/kg n=11 Participants Participants were administered a single IV dose of 0.8 mg/kg GSK2586881 in either treatment period 1 or 2 during Part 1 of the study. During each period, approximately 30 minutes after administration of study treatment, the participants entered the hypoxia chamber and were inside the chamber for approximately 80 minutes, during which they were under the full 4000 meters ± 10% hypoxic conditions. Participants then performed an exercise challenge at 70% of maximum VO2 uptake on an upright cycle ergometer within the hypoxia chamber for 10 minutes.
Number of Participants With Abnormal Clinical Chemistry Parameters-Part 1	0 Participants	3 Participants

SECONDARY outcome

Timeframe: Up to 26 days

Population: mITT2 Population

Blood samples were collected to analyze the following clinical chemistry parameters: BUN, creatinine, glucose, potassium, sodium, calcium, AST, ALT, alkaline phosphatase, total and direct bilirubin, total protein and albumin. Number of participants with abnormal clinical chemistry parameters are presented.

Outcome measures

Outcome measures
Measure	Part 1: Placebo n=6 Participants Participants were administered a single IV dose of placebo in either treatment period 1 or 2 during Part 1 of the study. During each period, approximately 30 minutes after administration of study treatment, the participants entered the hypoxia chamber and were inside the chamber for approximately 80 minutes, during which they were under the full 4000 meters ± 10% hypoxic conditions. Participants then performed an exercise challenge at 70% of maximum VO2 uptake on an upright cycle ergometer within the hypoxia chamber for 10 minutes.	Part 1: GSK2586881 0.8 mg/kg n=6 Participants Participants were administered a single IV dose of 0.8 mg/kg GSK2586881 in either treatment period 1 or 2 during Part 1 of the study. During each period, approximately 30 minutes after administration of study treatment, the participants entered the hypoxia chamber and were inside the chamber for approximately 80 minutes, during which they were under the full 4000 meters ± 10% hypoxic conditions. Participants then performed an exercise challenge at 70% of maximum VO2 uptake on an upright cycle ergometer within the hypoxia chamber for 10 minutes.
Number of Participants With Abnormal Clinical Chemistry Parameters-Part 2	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Up to 26 days

Population: mITT1 Population

Urine samples were collected to analyze the following urine parameters: specific gravity, potential of hydrogen (pH), glucose, protein, blood and ketones by dipstick. Microscopic examination was performed for any abnormal dipstick results. Number of participants with abnormal urine parameters are presented.

Outcome measures

Outcome measures
Measure	Part 1: Placebo n=10 Participants Participants were administered a single IV dose of placebo in either treatment period 1 or 2 during Part 1 of the study. During each period, approximately 30 minutes after administration of study treatment, the participants entered the hypoxia chamber and were inside the chamber for approximately 80 minutes, during which they were under the full 4000 meters ± 10% hypoxic conditions. Participants then performed an exercise challenge at 70% of maximum VO2 uptake on an upright cycle ergometer within the hypoxia chamber for 10 minutes.	Part 1: GSK2586881 0.8 mg/kg n=11 Participants Participants were administered a single IV dose of 0.8 mg/kg GSK2586881 in either treatment period 1 or 2 during Part 1 of the study. During each period, approximately 30 minutes after administration of study treatment, the participants entered the hypoxia chamber and were inside the chamber for approximately 80 minutes, during which they were under the full 4000 meters ± 10% hypoxic conditions. Participants then performed an exercise challenge at 70% of maximum VO2 uptake on an upright cycle ergometer within the hypoxia chamber for 10 minutes.
Number of Participants With Abnormal Urine Parameters-Part 1	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Up to 26 days

Population: mITT2 Population

Urine samples were collected to analyze the following urine parameters: specific gravity, pH, glucose, protein, blood and ketones by dipstick. Microscopic examination was performed for any abnormal dipstick results. Number of participants with abnormal urine parameters is presented.

Outcome measures

Outcome measures
Measure	Part 1: Placebo n=6 Participants Participants were administered a single IV dose of placebo in either treatment period 1 or 2 during Part 1 of the study. During each period, approximately 30 minutes after administration of study treatment, the participants entered the hypoxia chamber and were inside the chamber for approximately 80 minutes, during which they were under the full 4000 meters ± 10% hypoxic conditions. Participants then performed an exercise challenge at 70% of maximum VO2 uptake on an upright cycle ergometer within the hypoxia chamber for 10 minutes.	Part 1: GSK2586881 0.8 mg/kg n=6 Participants Participants were administered a single IV dose of 0.8 mg/kg GSK2586881 in either treatment period 1 or 2 during Part 1 of the study. During each period, approximately 30 minutes after administration of study treatment, the participants entered the hypoxia chamber and were inside the chamber for approximately 80 minutes, during which they were under the full 4000 meters ± 10% hypoxic conditions. Participants then performed an exercise challenge at 70% of maximum VO2 uptake on an upright cycle ergometer within the hypoxia chamber for 10 minutes.
Number of Participants With Abnormal Urine Parameters-Part 2	0 Participants	0 Participants

SECONDARY outcome

Timeframe: pre-dose, at infusion, 15 minutes post-infusion, 15 to 45 minutes post-infusion, 60 minutes post-chamber entry, immediately post-exercise, immediately post-chamber exit and 30 minutes post-chamber exit in each treatment period

Population: PK1 Population. Only those participants with data available at the specified time points were analyzed (represented by n=X in category titles)

Blood samples were collected at indicated time points for pharmacokinetic (PK) analysis of GSK2586881. Pharmacokinetic Part1 (PK1) Population comprised of participants in the mITT population, randomized in Part 1 of the study, for whom a pharmacokinetic sample was obtained and analyzed and on active treatment.

Outcome measures

Outcome measures
Measure	Part 1: Placebo n=11 Participants Participants were administered a single IV dose of placebo in either treatment period 1 or 2 during Part 1 of the study. During each period, approximately 30 minutes after administration of study treatment, the participants entered the hypoxia chamber and were inside the chamber for approximately 80 minutes, during which they were under the full 4000 meters ± 10% hypoxic conditions. Participants then performed an exercise challenge at 70% of maximum VO2 uptake on an upright cycle ergometer within the hypoxia chamber for 10 minutes.	Part 1: GSK2586881 0.8 mg/kg Participants were administered a single IV dose of 0.8 mg/kg GSK2586881 in either treatment period 1 or 2 during Part 1 of the study. During each period, approximately 30 minutes after administration of study treatment, the participants entered the hypoxia chamber and were inside the chamber for approximately 80 minutes, during which they were under the full 4000 meters ± 10% hypoxic conditions. Participants then performed an exercise challenge at 70% of maximum VO2 uptake on an upright cycle ergometer within the hypoxia chamber for 10 minutes.
Plasma Concentrations of GSK2586881-Part 1 pre-dose; n=11	NA Nanograms per milliliter Standard Deviation NA No concentration values detected for pre-dose	—
Plasma Concentrations of GSK2586881-Part 1 At infusion; n=11	10256.935 Nanograms per milliliter Standard Deviation 2667.2276	—
Plasma Concentrations of GSK2586881-Part 1 15 minutes post-infusion; n=11	10862.467 Nanograms per milliliter Standard Deviation 1765.2731	—
Plasma Concentrations of GSK2586881-Part 1 15 to 45 minutes post-infusion; n=11	9646.325 Nanograms per milliliter Standard Deviation 1351.1030	—
Plasma Concentrations of GSK2586881-Part 1 60 minutes post-chamber entry; n=10	6934.842 Nanograms per milliliter Standard Deviation 860.4466	—
Plasma Concentrations of GSK2586881-Part 1 immediately post-exercise; n=10	6698.518 Nanograms per milliliter Standard Deviation 726.7099	—
Plasma Concentrations of GSK2586881-Part 1 immediately post-chamber exit; n=10	6304.675 Nanograms per milliliter Standard Deviation 731.1517	—
Plasma Concentrations of GSK2586881-Part 1 30 minutes post-chamber exit; n=10	5209.130 Nanograms per milliliter Standard Deviation 543.4398	—

SECONDARY outcome

Timeframe: pre-dose, at infusion, 15 minutes post-infusion, 15 to 45 minutes post-infusion, 60 minutes post-chamber entry, immediately post-exercise, immediately post-chamber exit and 30 minutes post-chamber exit in each treatment period

Population: PK2 Population. Only those participants with data available at the specified time points were analyzed (represented by n=X in category titles)

Blood samples were collected at indicated time points for PK analysis of GSK2586881. Pharmacokinetic Part2 (PK2) Population comprised of participants in the mITT population, randomized in Part 2 of the study, for whom a pharmacokinetic sample was obtained and analyzed and on active treatment.

Outcome measures

Outcome measures
Measure	Part 1: Placebo n=6 Participants Participants were administered a single IV dose of placebo in either treatment period 1 or 2 during Part 1 of the study. During each period, approximately 30 minutes after administration of study treatment, the participants entered the hypoxia chamber and were inside the chamber for approximately 80 minutes, during which they were under the full 4000 meters ± 10% hypoxic conditions. Participants then performed an exercise challenge at 70% of maximum VO2 uptake on an upright cycle ergometer within the hypoxia chamber for 10 minutes.	Part 1: GSK2586881 0.8 mg/kg Participants were administered a single IV dose of 0.8 mg/kg GSK2586881 in either treatment period 1 or 2 during Part 1 of the study. During each period, approximately 30 minutes after administration of study treatment, the participants entered the hypoxia chamber and were inside the chamber for approximately 80 minutes, during which they were under the full 4000 meters ± 10% hypoxic conditions. Participants then performed an exercise challenge at 70% of maximum VO2 uptake on an upright cycle ergometer within the hypoxia chamber for 10 minutes.
Plasma Concentrations of GSK2586881-Part 2 pre-dose; n=5	NA Nanograms per milliliter Standard Deviation NA No concentration values detected for pre-dose	—
Plasma Concentrations of GSK2586881-Part 2 At infusion; n=6	20032.735 Nanograms per milliliter Standard Deviation 2026.2004	—
Plasma Concentrations of GSK2586881-Part 2 15 minutes post-infusion; n=6	18269.882 Nanograms per milliliter Standard Deviation 1790.1483	—
Plasma Concentrations of GSK2586881-Part 2 15 to 45 minutes post-infusion; n=6	17484.102 Nanograms per milliliter Standard Deviation 1374.5418	—
Plasma Concentrations of GSK2586881-Part 2 60 minutes post-chamber entry; n=6	11617.538 Nanograms per milliliter Standard Deviation 1572.8006	—
Plasma Concentrations of GSK2586881-Part 2 immediately post-exercise; n=6	11818.457 Nanograms per milliliter Standard Deviation 1950.1873	—
Plasma Concentrations of GSK2586881-Part 2 immediately post-chamber exit; n=6	10956.927 Nanograms per milliliter Standard Deviation 1319.8536	—
Plasma Concentrations of GSK2586881-Part 2 30 minutes post-chamber exit; n=6	9886.477 Nanograms per milliliter Standard Deviation 1428.6630	—

SECONDARY outcome

Timeframe: pre-dose, at infusion, 15 minutes post-infusion, 15 to 45 minutes post-infusion, 60 minutes post-chamber entry, immediately post-exercise, immediately post-chamber exit and 30 minutes post-chamber exit in each treatment period

Population: PK1 Population. Only those participants with data available at the specified time points were analyzed.