Healthy Volunteers
Conditions
Keywords
GSK2586881, Acute hypoxia, Exercise
Brief summary
This study is conducted to examine how GSK2586881, a recombinant human ACE2 peptide, modulates the acute hypoxic pulmonary vasoconstriction (HPV) response in healthy volunteers. The study will be single-center, randomized, placebo-controlled and double blind (sponsor open). Subjects will be randomized to receive a single intravenous (IV) dose of GSK2586881 or placebo (saline) in a crossover design. The primary objective of the study is to evaluate the effect of a single IV dose of GSK2586881 on the HPV response in healthy volunteers during exercise under hypoxic conditions. Approximately 35 subjects will be enrolled for a maximum of 56 days.
Interventions
BIOLOGICALGSK2586881
GSK2586881 will be a clear colorless liquid for IV infusion over 3- 5 mins and will be administered as unit dose 0.8 mg/kg.
OTHERPlacebo
Normal saline (0.9%) will be administered as a single IV dose infusion over 3 to 5 min.
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 40 Years
Healthy volunteers
Yes
Inclusion criteria
* Between 18 and 40 years of age inclusive, at the time of signing the informed consent. * Healthy as determined by the investigator or medically qualified designee based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring. A subject with a clinical abnormality or laboratory parameter(s) which is/are not specifically listed in the inclusion or
Exclusion criteria
, outside the reference range for the population being studied may be included only if the investigator \[in consultation with the Medical Monitor if required\] agree and document that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures. Note: Screened subjects with laboratory values outside of the normal range may be repeated once for inclusion into the study at the discretion of the Investigator. * Screening echocardiogram of good quality, without clinically significant abnormalities, and with mild-moderate tricuspid regurgitation sufficient for the reliable estimation of PASP, as determined by the echocardiography core laboratory or responsible cardiologist. Screening PASP within the normal range according to site standards. * Subjects have not resided at an altitude \>1500 meter (m) for more than 7 days in the last 4 month * Able to complete all study procedures. * Any contraindication (orthopedic, cardiac etc.) to perform exercise on a bicycle ergometer. * Body weight 50 to 100 kilogram (kg) (inclusive). * Male or female (non Child Bearing Potential): Male subjects with female partners of child bearing potential must comply with the following contraception requirements from the time of first dose of study medication until at least five half-lives of study medication OR for a cycle of spermatogenesis following five terminal half-lives after the last dose of study medication. a. Vasectomy with documentation of azoospermia. b. Male condom plus partner use of one of the contraceptive options (Contraceptive subdermal implant, Intrauterine device or intrauterine system, Oral Contraceptive- either combined or progestogen alone, Injectable progestogen, Contraceptive vaginal ring, Percutaneous contraceptive patches). This is an all-inclusive list of those methods that meet the following GSK definition of highly effective: having a failure rate of less than 1% per year when used consistently and correctly and, when applicable, in accordance with the product label. For non-product methods (e.g., male sterility), the investigator determines what is consistent and correct use. The GSK definition is based on the definition provided by the International Conference on Harmonization (ICH).The investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception. A female subject is eligible to participate if she is not pregnant (as confirmed by a negative urine human chorionic gonadotrophin \[hCG\] test), not lactating, and the following condition applies: Non-reproductive potential defined as, 1. Pre-menopausal females with one of the following (Documented tubal ligation, Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion, Hysterectomy, Documented Bilateral Oophorectomy). 2. Postmenopausal defined as 12 months of spontaneous amenorrhea \[in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) and estradiol levels consistent with menopause (refer to laboratory reference ranges for confirmatory levels)\]. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the highly effective contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrolment. The investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception. * Capable of giving signed informed consent as described in study protocol which includes compliance with the requirements and restrictions listed in the consent form and in the study protocol.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline of Pulmonary Artery Systolic Pressure (PASP) Measured Via Echocardiography-Part 1 | 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 | 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. |
| Change From Baseline of PASP Measured Via Echocardiography-Part 2 | 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 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)-Part 1 | Baseline (Day 1, pre-dose), 15 to 45 minutes post-infusion, immediately post-exercise and 60 minutes post-chamber exit in each treatment period | 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. |
| Change From Baseline in SBP and DBP-Part 2 | Baseline (Day 1, pre-dose), 15 to 45 minutes post-infusion, immediately post-exercise and 60 minutes post-chamber exit in each treatment period | 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. |
| Change From Baseline in Heart Rate-Part 1 | Baseline (Day 1, pre-dose), 15 to 45 minutes post-infusion, immediately post-exercise and 60 minutes post-chamber exit in each treatment period | 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. |
| Change From Baseline in Heart Rate-Part 2 | Baseline (Day 1, pre-dose), 15 to 45 minutes post-infusion, immediately post-exercise and 60 minutes post-chamber exit in each treatment period | 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. |
| Change From Baseline in Oxygen Saturation-Part 1 | 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 | 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. |
| Change From Baseline in Oxygen Saturation-Part 2 | 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 | 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. |
| Number of Participants With Abnormal Electrocardiogram (ECG) Findings-Part 1 | pre-dose, 15 to 45 minutes post-infusion, 60 minutes post-chamber exit in each treatment period | 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. |
| Number of Participants With Abnormal ECG Findings-Part 2 | pre-dose, 15 to 45 minutes post-infusion, 60 minutes post-chamber exit in each treatment period | 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. |
| Number of Participants With Positive Immunogenicity Results-Part 2 | Up to 26 days | 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. |
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)-Part 1 | Up to 26 days | 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. |
| Number of Participants With AEs and SAEs-Part 2 | Up to 26 days | 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. |
| Number of Participants With Positive Immunogenicity Results-Part 1 | Up to 26 days | 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. |
| Number of Participants With Abnormal Hematology Parameters-Part 1 | Up to 26 days | 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. |
| Number of Participants With Abnormal Hematology Parameters-Part 2 | Up to 26 days | 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. |
| Number of Participants With Abnormal Clinical Chemistry Parameters-Part 1 | Up to 26 days | 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. |
| Number of Participants With Abnormal Clinical Chemistry Parameters-Part 2 | Up to 26 days | 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. |
| Number of Participants With Abnormal Urine Parameters-Part 1 | Up to 26 days | 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. |
| Change From Baseline in Renin-angiotensin System (RAS) Peptides-Part 1 | 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 | 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. |
| Plasma Concentrations of GSK2586881-Part 1 | 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 | 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. |
| Plasma Concentrations of GSK2586881-Part 2 | 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 | 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. |
| Area Under the Concentration-time Curve Over the Study Period (Pre-dose to 30 Minutes Rest Post Chamber Exit) (AUC[0-2.5 Hours])-Part 1 | 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 | Blood samples were collected at indicated time points for PK analysis of GSK2586881. The pharmacokinetic parameters were calculated by standard non-compartmental analysis. |
| Area Under the Concentration-time Curve Over the Study Period (Pre-dose to 30 Minutes Rest Post Chamber Exit) (AUC[0-2.5 Hours])-Part 2 | 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 | Blood samples were collected at indicated time points for PK analysis of GSK2586881. The pharmacokinetic parameters were calculated by standard non-compartmental analysis. |
| Area Under the Concentration-time Curve Over the Time Period for the Hypoxia Challenge (Immediately Prior to Chamber Entry to Chamber Exit) (AUC [0.5-2 Hours])-Part 1 | immediately prior to chamber entry, 60 minutes post-chamber entry, immediately post-exercise and immediately post-chamber exit in each treatment period | Blood samples were collected at indicated time points for PK analysis of GSK2586881. The pharmacokinetic parameters were calculated by standard non-compartmental analysis. |
| Area Under the Concentration-time Curve Over the Time Period for the Hypoxia Challenge (Immediately Prior to Chamber Entry to Chamber Exit) (AUC [0.5-2 Hours])-Part 2 | immediately prior to chamber entry, 60 minutes post-chamber entry, immediately post-exercise and immediately post-chamber exit in each treatment period | Blood samples were collected at indicated time points for PK analysis of GSK2586881. The pharmacokinetic parameters were calculated by standard non-compartmental analysis. |
| Tmax of GSK2586881-Part 2 | 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 | Blood samples were collected at indicated time points for PK analysis of GSK2586881. The pharmacokinetic parameters were calculated by standard non-compartmental analysis. |
| Maximum Observed Concentration (Cmax) of GSK2586881-Part 1 | 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 | Blood samples were collected at indicated time points for PK analysis of GSK2586881. The pharmacokinetic parameters were calculated by standard non-compartmental analysis. |
| Cmax of GSK2586881-Part 2 | 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 | Blood samples were collected at indicated time points for PK analysis of GSK2586881. The pharmacokinetic parameters were calculated by standard non-compartmental analysis. |
| Time to Reach Cmax (Tmax) of GSK2586881-Part 1 | 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 | Blood samples were collected at indicated time points for PK analysis of GSK2586881. The pharmacokinetic parameters were calculated by standard non-compartmental analysis. |
| Apparent Terminal Half-life (T1/2) of GSK2586881-Part 1 | 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 | Blood samples were collected at indicated time points for PK analysis of GSK2586881. The pharmacokinetic parameters were calculated by standard non-compartmental analysis. |
| T1/2 of GSK2586881-Part 2 | 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 | Blood samples were collected at indicated time points for PK analysis of GSK2586881. The pharmacokinetic parameters were calculated by standard non-compartmental analysis. |
| Clearance for GSK2586881-Part 1 | 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 | Blood samples were collected at indicated time points for PK analysis of GSK2586881. The pharmacokinetic parameters were calculated by standard non-compartmental analysis. |
| Clearance for GSK2586881-Part 2 | 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 | Blood samples were collected at indicated time points for PK analysis of GSK2586881. The pharmacokinetic parameters were calculated by standard non-compartmental analysis. |
| Volume of Distribution for GSK2586881-Part 1 | 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 | Blood samples were collected at indicated time points for PK analysis of GSK2586881. The pharmacokinetic parameters were calculated by standard non-compartmental analysis. |
| Volume of Distribution for GSK2586881-Part 2 | 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 | Blood samples were collected at indicated time points for PK analysis of GSK2586881. The pharmacokinetic parameters were calculated by standard non-compartmental analysis. |
| Number of Participants With Abnormal Urine Parameters-Part 2 | Up to 26 days | 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. |
| Change From Baseline in RAS Peptides-Part 2 | 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 | 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. |
Countries
Germany
Participant flow
Recruitment details
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.
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| All Participants-Part 1 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. | 11 |
| All Participants-Part 2 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. | 6 |
| Total | 17 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Part 1, Period 1 (1 Day) | Adverse Event | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | All Participants-Part 1 | All Participants-Part 2 | Total |
|---|---|---|---|
| Age, Continuous | 26.2 Years STANDARD_DEVIATION 4.24 | 29.2 Years STANDARD_DEVIATION 6.21 | 27.2 Years STANDARD_DEVIATION 5.04 |
| Race/Ethnicity, Customized White - White/Caucasian/European Heritage | 11 Participants | 6 Participants | 17 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 11 Participants | 6 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 11 | 0 / 6 | 0 / 6 |
| other Total, other adverse events | 3 / 10 | 2 / 11 | 1 / 6 | 0 / 6 |
| serious Total, serious adverse events | 0 / 10 | 0 / 11 | 0 / 6 | 0 / 6 |
Outcome results
Primary
Change From Baseline of PASP Measured Via Echocardiography-Part 2
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.
Time frame: 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).
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part 1: Placebo | Change From Baseline of PASP Measured Via Echocardiography-Part 2 | 15 minutes post-infusion; n=6, 6 | 2.756 Millimeters of mercury |
| Part 1: Placebo | Change From Baseline of PASP Measured Via Echocardiography-Part 2 | 60 minutes post-chamber entry; n=6, 6 | 9.399 Millimeters of mercury |
| Part 1: Placebo | Change From Baseline of PASP Measured Via Echocardiography-Part 2 | 2 minutes post-exercise start; n=6, 5 | 14.665 Millimeters of mercury |
| Part 1: Placebo | Change From Baseline of PASP Measured Via Echocardiography-Part 2 | 30 minutes post-chamber exit; n=6, 6 | 4.156 Millimeters of mercury |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline of PASP Measured Via Echocardiography-Part 2 | 30 minutes post-chamber exit; n=6, 6 | 3.867 Millimeters of mercury |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline of PASP Measured Via Echocardiography-Part 2 | 15 minutes post-infusion; n=6, 6 | 2.093 Millimeters of mercury |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline of PASP Measured Via Echocardiography-Part 2 | 2 minutes post-exercise start; n=6, 5 | 14.646 Millimeters of mercury |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline of PASP Measured Via Echocardiography-Part 2 | 60 minutes post-chamber entry; n=6, 6 | 6.599 Millimeters of mercury |
95% CI: [-5.037, 3.815]
95% CI: [-9.729, 4.027]
95% CI: [-8.475, 8.086]
95% CI: [-4.96, 4.386]
Primary
Change From Baseline of Pulmonary Artery Systolic Pressure (PASP) Measured Via Echocardiography-Part 1
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part 1: Placebo | Change From Baseline of Pulmonary Artery Systolic Pressure (PASP) Measured Via Echocardiography-Part 1 | 15 minutes post-infusion | -0.715 Millimeters of mercury |
| Part 1: Placebo | Change From Baseline of Pulmonary Artery Systolic Pressure (PASP) Measured Via Echocardiography-Part 1 | 60 minutes post-chamber entry | 4.299 Millimeters of mercury |
| Part 1: Placebo | Change From Baseline of Pulmonary Artery Systolic Pressure (PASP) Measured Via Echocardiography-Part 1 | immediately post-exercise | 1.619 Millimeters of mercury |
| Part 1: Placebo | Change From Baseline of Pulmonary Artery Systolic Pressure (PASP) Measured Via Echocardiography-Part 1 | 30 minutes post-chamber exit | -0.189 Millimeters of mercury |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline of Pulmonary Artery Systolic Pressure (PASP) Measured Via Echocardiography-Part 1 | 30 minutes post-chamber exit | -1.026 Millimeters of mercury |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline of Pulmonary Artery Systolic Pressure (PASP) Measured Via Echocardiography-Part 1 | 15 minutes post-infusion | -0.695 Millimeters of mercury |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline of Pulmonary Artery Systolic Pressure (PASP) Measured Via Echocardiography-Part 1 | immediately post-exercise | -0.046 Millimeters of mercury |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline of Pulmonary Artery Systolic Pressure (PASP) Measured Via Echocardiography-Part 1 | 60 minutes post-chamber entry | 0.275 Millimeters of mercury |
95% CI: [-2.249, 2.295]
95% CI: [-9.168, 1.146]
95% CI: [-10.576, 7.231]
95% CI: [-4.142, 2.506]
Secondary
Apparent Terminal Half-life (T1/2) of GSK2586881-Part 1
Blood samples were collected at indicated time points for PK analysis of GSK2586881. The pharmacokinetic parameters were calculated by standard non-compartmental analysis.
Time frame: 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
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Part 1: Placebo | Apparent Terminal Half-life (T1/2) of GSK2586881-Part 1 | NA Hours |
Secondary
Area Under the Concentration-time Curve Over the Study Period (Pre-dose to 30 Minutes Rest Post Chamber Exit) (AUC[0-2.5 Hours])-Part 1
Blood samples were collected at indicated time points for PK analysis of GSK2586881. The pharmacokinetic parameters were calculated by standard non-compartmental analysis.
Time frame: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Placebo | Area Under the Concentration-time Curve Over the Study Period (Pre-dose to 30 Minutes Rest Post Chamber Exit) (AUC[0-2.5 Hours])-Part 1 | 19.977 Hours*micrograms per milliliter | Geometric Coefficient of Variation 14.3 |
Secondary
Area Under the Concentration-time Curve Over the Study Period (Pre-dose to 30 Minutes Rest Post Chamber Exit) (AUC[0-2.5 Hours])-Part 2
Blood samples were collected at indicated time points for PK analysis of GSK2586881. The pharmacokinetic parameters were calculated by standard non-compartmental analysis.
Time frame: 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
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Placebo | Area Under the Concentration-time Curve Over the Study Period (Pre-dose to 30 Minutes Rest Post Chamber Exit) (AUC[0-2.5 Hours])-Part 2 | 32.400 Hours*micrograms per milliliter | Geometric Coefficient of Variation 9.2 |
Secondary
Area Under the Concentration-time Curve Over the Time Period for the Hypoxia Challenge (Immediately Prior to Chamber Entry to Chamber Exit) (AUC [0.5-2 Hours])-Part 1
Blood samples were collected at indicated time points for PK analysis of GSK2586881. The pharmacokinetic parameters were calculated by standard non-compartmental analysis.
Time frame: immediately prior to chamber entry, 60 minutes post-chamber entry, immediately post-exercise and immediately post-chamber exit in each treatment period
Population: PK1 Population. Only those participants with data available at the specified time points were analyzed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Placebo | Area Under the Concentration-time Curve Over the Time Period for the Hypoxia Challenge (Immediately Prior to Chamber Entry to Chamber Exit) (AUC [0.5-2 Hours])-Part 1 | 12.470 Hours*micrograms per milliliter | Geometric Coefficient of Variation 14.3 |
Secondary
Area Under the Concentration-time Curve Over the Time Period for the Hypoxia Challenge (Immediately Prior to Chamber Entry to Chamber Exit) (AUC [0.5-2 Hours])-Part 2
Blood samples were collected at indicated time points for PK analysis of GSK2586881. The pharmacokinetic parameters were calculated by standard non-compartmental analysis.
Time frame: immediately prior to chamber entry, 60 minutes post-chamber entry, immediately post-exercise and immediately post-chamber exit in each treatment period
Population: PK2 Population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Placebo | Area Under the Concentration-time Curve Over the Time Period for the Hypoxia Challenge (Immediately Prior to Chamber Entry to Chamber Exit) (AUC [0.5-2 Hours])-Part 2 | 18.838 Hours*micrograms per milliliter | Geometric Coefficient of Variation 7.8 |
Secondary
Change From Baseline in Heart Rate-Part 1
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.
Time frame: 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)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Placebo | Change From Baseline in Heart Rate-Part 1 | immediately post-exercise; n=10, 10 | 32.0 Beats per minute | Standard Deviation 7.48 |
| Part 1: Placebo | 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 |
| Part 1: Placebo | 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 |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline in Heart Rate-Part 1 | 15 to 45 minutes post infusion; n=10, 11 | 1.2 Beats per minute | Standard Deviation 5.36 |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline in Heart Rate-Part 1 | immediately post-exercise; n=10, 10 | 37.7 Beats per minute | Standard Deviation 10.92 |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline in Heart Rate-Part 1 | 60 minutes post-chamber exit; n=10, 10 | 7.7 Beats per minute | Standard Deviation 7.26 |
Secondary
Change From Baseline in Heart Rate-Part 2
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.
Time frame: 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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Placebo | Change From Baseline in Heart Rate-Part 2 | immediately post-exercise | 11.8 Beats per minute | Standard Deviation 7.78 |
| Part 1: Placebo | Change From Baseline in Heart Rate-Part 2 | 60 minutes post-chamber exit | -1.5 Beats per minute | Standard Deviation 4.51 |
| Part 1: Placebo | Change From Baseline in Heart Rate-Part 2 | 15 to 45 minutes post infusion | -3.7 Beats per minute | Standard Deviation 3.44 |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline in Heart Rate-Part 2 | immediately post-exercise | 16.3 Beats per minute | Standard Deviation 7.37 |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline in Heart Rate-Part 2 | 15 to 45 minutes post infusion | 0.0 Beats per minute | Standard Deviation 3.9 |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline in Heart Rate-Part 2 | 60 minutes post-chamber exit | 1.5 Beats per minute | Standard Deviation 4.42 |
Secondary
Change From Baseline in Oxygen Saturation-Part 1
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part 1: Placebo | Change From Baseline in Oxygen Saturation-Part 1 | 15 minutes post-infusion | 1.626 Percentage of oxygen |
| Part 1: Placebo | Change From Baseline in Oxygen Saturation-Part 1 | immediately post-exercise | -14.257 Percentage of oxygen |
| Part 1: Placebo | Change From Baseline in Oxygen Saturation-Part 1 | 30 minutes post-chamber exit | 0.235 Percentage of oxygen |
| Part 1: Placebo | Change From Baseline in Oxygen Saturation-Part 1 | 60 minutes post-chamber entry | -10.663 Percentage of oxygen |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline in Oxygen Saturation-Part 1 | 30 minutes post-chamber exit | -0.132 Percentage of oxygen |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline in Oxygen Saturation-Part 1 | 15 minutes post-infusion | 1.478 Percentage of oxygen |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline in Oxygen Saturation-Part 1 | 60 minutes post-chamber entry | -11.835 Percentage of oxygen |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline in Oxygen Saturation-Part 1 | immediately post-exercise | -14.426 Percentage of oxygen |
95% CI: [-1.264, 0.973]
95% CI: [-5.271, 2.942]
95% CI: [-4.624, 4.258]
95% CI: [-1.498, 0.753]
Secondary
Change From Baseline in Oxygen Saturation-Part 2
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.
Time frame: 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
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part 1: Placebo | Change From Baseline in Oxygen Saturation-Part 2 | 60 minutes post-chamber entry | -23.707 Percentage of oxygen |
| Part 1: Placebo | Change From Baseline in Oxygen Saturation-Part 2 | 15 minutes post-infusion | 0.644 Percentage of oxygen |
| Part 1: Placebo | Change From Baseline in Oxygen Saturation-Part 2 | 2 minutes post-exercise start | -22.399 Percentage of oxygen |
| Part 1: Placebo | Change From Baseline in Oxygen Saturation-Part 2 | 30 minutes post-chamber exit | 1.691 Percentage of oxygen |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline in Oxygen Saturation-Part 2 | 30 minutes post-chamber exit | 0.821 Percentage of oxygen |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline in Oxygen Saturation-Part 2 | 2 minutes post-exercise start | -23.433 Percentage of oxygen |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline in Oxygen Saturation-Part 2 | 15 minutes post-infusion | 0.847 Percentage of oxygen |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline in Oxygen Saturation-Part 2 | 60 minutes post-chamber entry | -19.945 Percentage of oxygen |
95% CI: [-1.578, 1.968]
95% CI: [-0.001, 7.495]
95% CI: [-6.673, 4.578]
95% CI: [-2.38, 0.669]
Secondary
Change From Baseline in RAS Peptides-Part 2
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.
Time frame: 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).
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Part 1: Placebo | Change From Baseline in RAS Peptides-Part 2 | Ang II, 60 minutes post-chamber entry; n=4, 5 | 0.532 Picograms per milliliter |
| Part 1: Placebo | Change From Baseline in RAS Peptides-Part 2 | Ang II, End of infusion; n=4, 5 | 0.603 Picograms per milliliter |
| Part 1: Placebo | Change From Baseline in RAS Peptides-Part 2 | Ang II, 15 minutes post-infusion; n=4, 5 | 0.564 Picograms per milliliter |
| Part 1: Placebo | Change From Baseline in RAS Peptides-Part 2 | Ang II, 15 to 45 minutes post-infusion; n=4, 5 | 0.596 Picograms per milliliter |
| Part 1: Placebo | Change From Baseline in RAS Peptides-Part 2 | Ang II, immediately post-exercise; n=4, 5 | 0.447 Picograms per milliliter |
| Part 1: Placebo | Change From Baseline in RAS Peptides-Part 2 | Ang II, immediately post-chamber exit; n=4, 5 | 0.604 Picograms per milliliter |
| Part 1: Placebo | Change From Baseline in RAS Peptides-Part 2 | Ang II, 30 minutes post-chamber exit; n=4, 5 | 0.358 Picograms per milliliter |
| Part 1: Placebo | Change From Baseline in RAS Peptides-Part 2 | Ang 1-7, End of infusion; n=4, 5 | 1.000 Picograms per milliliter |
| Part 1: Placebo | Change From Baseline in RAS Peptides-Part 2 | Ang 1-7, 15 minutes post-infusion; n=4, 5 | 1.000 Picograms per milliliter |
| Part 1: Placebo | 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 |
| Part 1: Placebo | Change From Baseline in RAS Peptides-Part 2 | Ang 1-7, 60 minutes post-chamber entry; n=4, 5 | 1.000 Picograms per milliliter |
| Part 1: Placebo | Change From Baseline in RAS Peptides-Part 2 | Ang 1-7, immediately post-exercise; n=3, 5 | 1.000 Picograms per milliliter |
| Part 1: Placebo | Change From Baseline in RAS Peptides-Part 2 | Ang 1-7, immediately post-chamber exit; n=4, 5 | 1.000 Picograms per milliliter |
| Part 1: Placebo | Change From Baseline in RAS Peptides-Part 2 | Ang 1-7, 30 minutes post-chamber exit; n=4, 5 | 1.000 Picograms per milliliter |
| Part 1: Placebo | Change From Baseline in RAS Peptides-Part 2 | Ang 1-5, End of infusion; n=4, 5 | 1.000 Picograms per milliliter |
| Part 1: Placebo | Change From Baseline in RAS Peptides-Part 2 | Ang 1-5, 15 minutes post-infusion; n=4, 5 | 1.000 Picograms per milliliter |
| Part 1: Placebo | 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 |
| Part 1: Placebo | Change From Baseline in RAS Peptides-Part 2 | Ang 1-5, 60 minutes post-chamber entry; n=4, 5 | 1.426 Picograms per milliliter |
| Part 1: Placebo | Change From Baseline in RAS Peptides-Part 2 | Ang 1-5, immediately post-exercise; n=4, 5 | 1.000 Picograms per milliliter |
| Part 1: Placebo | Change From Baseline in RAS Peptides-Part 2 | Ang 1-5, immediately post-chamber exit; n=4, 5 | 2.246 Picograms per milliliter |
| Part 1: Placebo | Change From Baseline in RAS Peptides-Part 2 | Ang 1-5, 30 minutes post-chamber exit; n=4, 5 | 1.000 Picograms per milliliter |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline in RAS Peptides-Part 2 | Ang 1-5, 15 minutes post-infusion; n=4, 5 | 2.151 Picograms per milliliter |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline in RAS Peptides-Part 2 | Ang II, 60 minutes post-chamber entry; n=4, 5 | 0.467 Picograms per milliliter |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline in RAS Peptides-Part 2 | Ang 1-7, 15 minutes post-infusion; n=4, 5 | 2.123 Picograms per milliliter |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline in RAS Peptides-Part 2 | Ang 1-7, immediately post-exercise; n=3, 5 | 1.992 Picograms per milliliter |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline in RAS Peptides-Part 2 | Ang 1-7, 60 minutes post-chamber entry; n=4, 5 | 2.469 Picograms per milliliter |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline in RAS Peptides-Part 2 | Ang II, End of infusion; n=4, 5 | 0.500 Picograms per milliliter |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline in RAS Peptides-Part 2 | Ang 1-5, immediately post-exercise; n=4, 5 | 2.498 Picograms per milliliter |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline in RAS Peptides-Part 2 | Ang II, 15 minutes post-infusion; n=4, 5 | 0.391 Picograms per milliliter |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline in RAS Peptides-Part 2 | Ang 1-5, 15 to 45 minutes post-infusion; n=4, 5 | 2.722 Picograms per milliliter |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline in RAS Peptides-Part 2 | Ang II, 15 to 45 minutes post-infusion; n=4, 5 | 0.391 Picograms per milliliter |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline in RAS Peptides-Part 2 | Ang 1-7, immediately post-chamber exit; n=4, 5 | 1.668 Picograms per milliliter |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline in RAS Peptides-Part 2 | Ang II, immediately post-exercise; n=4, 5 | 0.452 Picograms per milliliter |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline in RAS Peptides-Part 2 | Ang 1-5, 30 minutes post-chamber exit; n=4, 5 | 2.561 Picograms per milliliter |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline in RAS Peptides-Part 2 | Ang II, immediately post-chamber exit; n=4, 5 | 0.391 Picograms per milliliter |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline in RAS Peptides-Part 2 | Ang 1-7, 30 minutes post-chamber exit; n=4, 5 | 2.105 Picograms per milliliter |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline in RAS Peptides-Part 2 | Ang II, 30 minutes post-chamber exit; n=4, 5 | 0.472 Picograms per milliliter |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline in RAS Peptides-Part 2 | Ang 1-5, 60 minutes post-chamber entry; n=4, 5 | 3.053 Picograms per milliliter |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline in RAS Peptides-Part 2 | Ang 1-7, End of infusion; n=4, 5 | 1.285 Picograms per milliliter |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline in RAS Peptides-Part 2 | Ang 1-5, End of infusion; n=4, 5 | 1.998 Picograms per milliliter |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline in RAS Peptides-Part 2 | Ang 1-5, immediately post-chamber exit; n=4, 5 | 2.417 Picograms per milliliter |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline in RAS Peptides-Part 2 | Ang 1-7, 15 to 45 minutes post-infusion; n=4, 5 | 1.782 Picograms per milliliter |
Secondary
Change From Baseline in Renin-angiotensin System (RAS) Peptides-Part 1
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.
Time frame: 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).
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Part 1: Placebo | 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 |
| Part 1: Placebo | 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 |
| Part 1: Placebo | 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 |
| Part 1: Placebo | 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 |
| Part 1: Placebo | 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 |
| Part 1: Placebo | 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 |
| Part 1: Placebo | 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 |
| Part 1: Placebo | 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 |
| Part 1: Placebo | 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 |
| Part 1: Placebo | 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 |
| Part 1: Placebo | 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 |
| Part 1: Placebo | 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 |
| Part 1: Placebo | 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 |
| Part 1: Placebo | 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 |
| Part 1: Placebo | 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 |
| Part 1: Placebo | Change From Baseline in Renin-angiotensin System (RAS) Peptides-Part 1 | Ang II, End of infusion; n=10, 11 | 0.551 Picograms per milliliter |
| Part 1: Placebo | 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 |
| Part 1: Placebo | Change From Baseline in Renin-angiotensin System (RAS) Peptides-Part 1 | Ang II, immediately post-exercise; n=10, 10 | 1.379 Picograms per milliliter |
| Part 1: Placebo | 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 |
| Part 1: Placebo | 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 |
| Part 1: Placebo | 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 |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline in Renin-angiotensin System (RAS) Peptides-Part 1 | Ang 1-7, immediately post-chamber exit; n=10, 10 | 4.584 Picograms per milliliter |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline in Renin-angiotensin System (RAS) Peptides-Part 1 | Ang 1-5, 15 minutes post-infusion; n=10, 11 | 2.402 Picograms per milliliter |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline in Renin-angiotensin System (RAS) Peptides-Part 1 | Ang II, 15 to 45 minutes post-infusion; n=10, 11 | 0.313 Picograms per milliliter |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline in Renin-angiotensin System (RAS) Peptides-Part 1 | Ang 1-7, 30 minutes post-chamber exit; n=10, 10 | 2.179 Picograms per milliliter |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline in Renin-angiotensin System (RAS) Peptides-Part 1 | Ang 1-5, immediately post-chamber exit; n=10, 10 | 5.991 Picograms per milliliter |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline in Renin-angiotensin System (RAS) Peptides-Part 1 | Ang II, End of infusion; n=10, 11 | 0.278 Picograms per milliliter |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline in Renin-angiotensin System (RAS) Peptides-Part 1 | Ang 1-5, 30 minutes post-chamber exit; n=10, 10 | 3.020 Picograms per milliliter |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline in Renin-angiotensin System (RAS) Peptides-Part 1 | Ang II, immediately post-chamber exit; n=10,10 | 0.310 Picograms per milliliter |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline in Renin-angiotensin System (RAS) Peptides-Part 1 | Ang 1-5, End of infusion; n=10, 11 | 1.489 Picograms per milliliter |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline in Renin-angiotensin System (RAS) Peptides-Part 1 | Ang II, 30 minutes post-chamber exit; n=10, 10 | 0.263 Picograms per milliliter |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline in Renin-angiotensin System (RAS) Peptides-Part 1 | Ang 1-5, 15 to 45 minutes post-infusion; n=10, 11 | 2.321 Picograms per milliliter |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline in Renin-angiotensin System (RAS) Peptides-Part 1 | Ang 1-7, End of infusion; n=10, 11 | 1.346 Picograms per milliliter |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline in Renin-angiotensin System (RAS) Peptides-Part 1 | Ang II, 60 minutes post-chamber entry; n=10, 10 | 0.270 Picograms per milliliter |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline in Renin-angiotensin System (RAS) Peptides-Part 1 | Ang 1-7, 15 minutes post-infusion; n=10, 11 | 1.658 Picograms per milliliter |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline in Renin-angiotensin System (RAS) Peptides-Part 1 | Ang 1-5, 60 minutes post-chamber entry; n=10, 10 | 3.007 Picograms per milliliter |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline in Renin-angiotensin System (RAS) Peptides-Part 1 | Ang 1-7, 15 to 45 minutes post-infusion; n=10, 11 | 1.686 Picograms per milliliter |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline in Renin-angiotensin System (RAS) Peptides-Part 1 | Ang II, immediately post-exercise; n=10, 10 | 0.337 Picograms per milliliter |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline in Renin-angiotensin System (RAS) Peptides-Part 1 | Ang 1-7, 60 minutes post-chamber entry; n=10, 10 | 2.615 Picograms per milliliter |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline in Renin-angiotensin System (RAS) Peptides-Part 1 | Ang 1-5, immediately post-exercise; n=10, 10 | 5.149 Picograms per milliliter |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline in Renin-angiotensin System (RAS) Peptides-Part 1 | Ang 1-7, immediately post-exercise; n=10, 10 | 3.622 Picograms per milliliter |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline in Renin-angiotensin System (RAS) Peptides-Part 1 | Ang II, 15 minutes post-infusion; n=10, 11 | 0.305 Picograms per milliliter |
Secondary
Change From Baseline in SBP and DBP-Part 2
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.
Time frame: 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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Placebo | Change From Baseline in SBP and DBP-Part 2 | SBP; 15 to 45 minutes post infusion | -3.3 Millimeters of mercury | Standard Deviation 7 |
| Part 1: Placebo | Change From Baseline in SBP and DBP-Part 2 | SBP; immediately post-exercise | -9.0 Millimeters of mercury | Standard Deviation 14.64 |
| Part 1: Placebo | Change From Baseline in SBP and DBP-Part 2 | SBP; 60 minutes post-chamber exit | 0.0 Millimeters of mercury | Standard Deviation 8.94 |
| Part 1: Placebo | 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 |
| Part 1: Placebo | Change From Baseline in SBP and DBP-Part 2 | DBP; immediately post-exercise | -9.0 Millimeters of mercury | Standard Deviation 10.75 |
| Part 1: Placebo | Change From Baseline in SBP and DBP-Part 2 | DBP; 60 minutes post-chamber exit | 1.5 Millimeters of mercury | Standard Deviation 9.77 |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline in SBP and DBP-Part 2 | DBP; immediately post-exercise | -6.0 Millimeters of mercury | Standard Deviation 8.1 |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline in SBP and DBP-Part 2 | SBP; 15 to 45 minutes post infusion | -2.2 Millimeters of mercury | Standard Deviation 7.36 |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline in SBP and DBP-Part 2 | DBP; 15 to 45 minutes post infusion | -0.8 Millimeters of mercury | Standard Deviation 8.5 |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline in SBP and DBP-Part 2 | SBP; immediately post-exercise | -9.5 Millimeters of mercury | Standard Deviation 12.85 |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline in SBP and DBP-Part 2 | DBP; 60 minutes post-chamber exit | 3.3 Millimeters of mercury | Standard Deviation 7.09 |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline in SBP and DBP-Part 2 | SBP; 60 minutes post-chamber exit | -1.5 Millimeters of mercury | Standard Deviation 4.37 |
Secondary
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)-Part 1
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.
Time frame: 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)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Placebo | 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 3.3 |
| Part 1: Placebo | 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 |
| Part 1: Placebo | 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 |
| Part 1: Placebo | 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 |
| Part 1: Placebo | 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 12.4 |
| Part 1: Placebo | 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 |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)-Part 1 | DBP; immediately post-exercise; n=10, 10 | 0.3 Millimeters of mercury | Standard Deviation 7.78 |
| Part 1: GSK2586881 0.8 mg/kg | 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 | -5.9 Millimeters of mercury | Standard Deviation 6.88 |
| Part 1: GSK2586881 0.8 mg/kg | 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 | -1.2 Millimeters of mercury | Standard Deviation 4.24 |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)-Part 1 | SBP; immediately post-exercise; n=10, 10 | -3.0 Millimeters of mercury | Standard Deviation 14.02 |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)-Part 1 | DBP; 60 minutes post-chamber exit; n=10, 10 | -1.4 Millimeters of mercury | Standard Deviation 7.57 |
| Part 1: GSK2586881 0.8 mg/kg | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)-Part 1 | SBP; 60 minutes post-chamber exit; n=10, 10 | -6.2 Millimeters of mercury | Standard Deviation 7.28 |
Secondary
Clearance for GSK2586881-Part 1
Blood samples were collected at indicated time points for PK analysis of GSK2586881. The pharmacokinetic parameters were calculated by standard non-compartmental analysis.
Time frame: 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
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Part 1: Placebo | Clearance for GSK2586881-Part 1 | NA Liters per hour per kilogram |
Secondary
Clearance for GSK2586881-Part 2
Blood samples were collected at indicated time points for PK analysis of GSK2586881. The pharmacokinetic parameters were calculated by standard non-compartmental analysis.
Time frame: 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
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Part 1: Placebo | Clearance for GSK2586881-Part 2 | NA Liters per hour per kilogram |
Secondary
Cmax of GSK2586881-Part 2
Blood samples were collected at indicated time points for PK analysis of GSK2586881. The pharmacokinetic parameters were calculated by standard non-compartmental analysis.
Time frame: 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
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Placebo | Cmax of GSK2586881-Part 2 | 20.343 Micrograms per milliliter | Geometric Coefficient of Variation 6.5 |
Secondary
Maximum Observed Concentration (Cmax) of GSK2586881-Part 1
Blood samples were collected at indicated time points for PK analysis of GSK2586881. The pharmacokinetic parameters were calculated by standard non-compartmental analysis.
Time frame: 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
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Placebo | Maximum Observed Concentration (Cmax) of GSK2586881-Part 1 | 11.296 Micrograms per milliliter | Geometric Coefficient of Variation 17.5 |
Secondary
Number of Participants With Abnormal Clinical Chemistry Parameters-Part 1
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.
Time frame: Up to 26 days
Population: mITT1 Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1: Placebo | Number of Participants With Abnormal Clinical Chemistry Parameters-Part 1 | 0 Participants |
| Part 1: GSK2586881 0.8 mg/kg | Number of Participants With Abnormal Clinical Chemistry Parameters-Part 1 | 3 Participants |
Secondary
Number of Participants With Abnormal Clinical Chemistry Parameters-Part 2
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.
Time frame: Up to 26 days
Population: mITT2 Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1: Placebo | Number of Participants With Abnormal Clinical Chemistry Parameters-Part 2 | 0 Participants |
| Part 1: GSK2586881 0.8 mg/kg | Number of Participants With Abnormal Clinical Chemistry Parameters-Part 2 | 0 Participants |
Secondary
Number of Participants With Abnormal ECG Findings-Part 2
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.
Time frame: pre-dose, 15 to 45 minutes post-infusion, 60 minutes post-chamber exit in each treatment period
Population: mITT2 Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1: Placebo | Number of Participants With Abnormal ECG Findings-Part 2 | CS; 15 to 45 minutes post-infusion | 0 Participants |
| Part 1: Placebo | Number of Participants With Abnormal ECG Findings-Part 2 | NCS; pre-dose | 3 Participants |
| Part 1: Placebo | Number of Participants With Abnormal ECG Findings-Part 2 | NCS: 60 minutes post-chamber exit | 3 Participants |
| Part 1: Placebo | Number of Participants With Abnormal ECG Findings-Part 2 | NCS; 15 to 45 minutes post-infusion | 4 Participants |
| Part 1: Placebo | Number of Participants With Abnormal ECG Findings-Part 2 | CS: 60 minutes post-chamber exit | 0 Participants |
| Part 1: Placebo | Number of Participants With Abnormal ECG Findings-Part 2 | CS; pre-dose | 0 Participants |
| Part 1: GSK2586881 0.8 mg/kg | Number of Participants With Abnormal ECG Findings-Part 2 | CS: 60 minutes post-chamber exit | 0 Participants |
| Part 1: GSK2586881 0.8 mg/kg | Number of Participants With Abnormal ECG Findings-Part 2 | CS; pre-dose | 0 Participants |
| Part 1: GSK2586881 0.8 mg/kg | Number of Participants With Abnormal ECG Findings-Part 2 | NCS; 15 to 45 minutes post-infusion | 5 Participants |
| Part 1: GSK2586881 0.8 mg/kg | Number of Participants With Abnormal ECG Findings-Part 2 | CS; 15 to 45 minutes post-infusion | 0 Participants |
| Part 1: GSK2586881 0.8 mg/kg | Number of Participants With Abnormal ECG Findings-Part 2 | NCS: 60 minutes post-chamber exit | 4 Participants |
| Part 1: GSK2586881 0.8 mg/kg | Number of Participants With Abnormal ECG Findings-Part 2 | NCS; pre-dose | 6 Participants |
Secondary
Number of Participants With Abnormal Electrocardiogram (ECG) Findings-Part 1
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.
Time frame: 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)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1: Placebo | Number of Participants With Abnormal Electrocardiogram (ECG) Findings-Part 1 | NCS; pre-dose; n=10, 11 | 8 Participants |
| Part 1: Placebo | Number of Participants With Abnormal Electrocardiogram (ECG) Findings-Part 1 | CS; pre-dose; n=10, 11 | 0 Participants |
| Part 1: Placebo | Number of Participants With Abnormal Electrocardiogram (ECG) Findings-Part 1 | NCS; 15 to 45 minutes post-infusion; n=10, 11 | 7 Participants |
| Part 1: Placebo | Number of Participants With Abnormal Electrocardiogram (ECG) Findings-Part 1 | CS; 15 to 45 minutes post-infusion; n=10, 11 | 0 Participants |
| Part 1: Placebo | Number of Participants With Abnormal Electrocardiogram (ECG) Findings-Part 1 | NCS: 60 minutes post-chamber exit; n=10, 10 | 1 Participants |
| Part 1: Placebo | Number of Participants With Abnormal Electrocardiogram (ECG) Findings-Part 1 | CS: 60 minutes post-chamber exit; n=10, 10 | 0 Participants |
| Part 1: GSK2586881 0.8 mg/kg | Number of Participants With Abnormal Electrocardiogram (ECG) Findings-Part 1 | NCS: 60 minutes post-chamber exit; n=10, 10 | 3 Participants |
| Part 1: GSK2586881 0.8 mg/kg | Number of Participants With Abnormal Electrocardiogram (ECG) Findings-Part 1 | NCS; pre-dose; n=10, 11 | 5 Participants |
| Part 1: GSK2586881 0.8 mg/kg | Number of Participants With Abnormal Electrocardiogram (ECG) Findings-Part 1 | CS; 15 to 45 minutes post-infusion; n=10, 11 | 0 Participants |
| Part 1: GSK2586881 0.8 mg/kg | Number of Participants With Abnormal Electrocardiogram (ECG) Findings-Part 1 | CS; pre-dose; n=10, 11 | 0 Participants |
| Part 1: GSK2586881 0.8 mg/kg | Number of Participants With Abnormal Electrocardiogram (ECG) Findings-Part 1 | CS: 60 minutes post-chamber exit; n=10, 10 | 0 Participants |
| Part 1: GSK2586881 0.8 mg/kg | Number of Participants With Abnormal Electrocardiogram (ECG) Findings-Part 1 | NCS; 15 to 45 minutes post-infusion; n=10, 11 | 7 Participants |
Secondary
Number of Participants With Abnormal Hematology Parameters-Part 1
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.
Time frame: Up to 26 days
Population: mITT1 Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1: Placebo | Number of Participants With Abnormal Hematology Parameters-Part 1 | 0 Participants |
| Part 1: GSK2586881 0.8 mg/kg | Number of Participants With Abnormal Hematology Parameters-Part 1 | 0 Participants |
Secondary
Number of Participants With Abnormal Hematology Parameters-Part 2
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.
Time frame: Up to 26 days
Population: mITT2 Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1: Placebo | Number of Participants With Abnormal Hematology Parameters-Part 2 | 0 Participants |
| Part 1: GSK2586881 0.8 mg/kg | Number of Participants With Abnormal Hematology Parameters-Part 2 | 0 Participants |
Secondary
Number of Participants With Abnormal Urine Parameters-Part 1
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.
Time frame: Up to 26 days
Population: mITT1 Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1: Placebo | Number of Participants With Abnormal Urine Parameters-Part 1 | 0 Participants |
| Part 1: GSK2586881 0.8 mg/kg | Number of Participants With Abnormal Urine Parameters-Part 1 | 0 Participants |
Secondary
Number of Participants With Abnormal Urine Parameters-Part 2
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.
Time frame: Up to 26 days
Population: mITT2 Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1: Placebo | Number of Participants With Abnormal Urine Parameters-Part 2 | 0 Participants |
| Part 1: GSK2586881 0.8 mg/kg | Number of Participants With Abnormal Urine Parameters-Part 2 | 0 Participants |
Secondary
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)-Part 1
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.
Time frame: Up to 26 days
Population: mITT1 Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1: Placebo | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)-Part 1 | AEs | 3 Participants |
| Part 1: Placebo | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)-Part 1 | SAEs | 0 Participants |
| Part 1: GSK2586881 0.8 mg/kg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)-Part 1 | AEs | 2 Participants |
| Part 1: GSK2586881 0.8 mg/kg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)-Part 1 | SAEs | 0 Participants |
Secondary
Number of Participants With AEs and SAEs-Part 2
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.
Time frame: Up to 26 days
Population: mITT2 Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1: Placebo | Number of Participants With AEs and SAEs-Part 2 | AEs | 1 Participants |
| Part 1: Placebo | Number of Participants With AEs and SAEs-Part 2 | SAEs | 0 Participants |
| Part 1: GSK2586881 0.8 mg/kg | Number of Participants With AEs and SAEs-Part 2 | AEs | 0 Participants |
| Part 1: GSK2586881 0.8 mg/kg | Number of Participants With AEs and SAEs-Part 2 | SAEs | 0 Participants |
Secondary
Number of Participants With Positive Immunogenicity Results-Part 1
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.
Time frame: Up to 26 days
Population: mITT1 Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1: Placebo | Number of Participants With Positive Immunogenicity Results-Part 1 | 0 Participants |
| Part 1: GSK2586881 0.8 mg/kg | Number of Participants With Positive Immunogenicity Results-Part 1 | 0 Participants |
Secondary
Number of Participants With Positive Immunogenicity Results-Part 2
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.
Time frame: Up to 26 days
Population: mITT2 Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1: Placebo | Number of Participants With Positive Immunogenicity Results-Part 2 | 0 Participants |
| Part 1: GSK2586881 0.8 mg/kg | Number of Participants With Positive Immunogenicity Results-Part 2 | 0 Participants |
Secondary
Plasma Concentrations of GSK2586881-Part 1
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.
Time frame: 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)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Placebo | Plasma Concentrations of GSK2586881-Part 1 | 30 minutes post-chamber exit; n=10 | 5209.130 Nanograms per milliliter | Standard Deviation 543.4398 |
| Part 1: Placebo | Plasma Concentrations of GSK2586881-Part 1 | pre-dose; n=11 | NA Nanograms per milliliter | — |
| Part 1: Placebo | Plasma Concentrations of GSK2586881-Part 1 | At infusion; n=11 | 10256.935 Nanograms per milliliter | Standard Deviation 2667.2276 |
| Part 1: Placebo | Plasma Concentrations of GSK2586881-Part 1 | 15 minutes post-infusion; n=11 | 10862.467 Nanograms per milliliter | Standard Deviation 1765.2731 |
| Part 1: Placebo | Plasma Concentrations of GSK2586881-Part 1 | 15 to 45 minutes post-infusion; n=11 | 9646.325 Nanograms per milliliter | Standard Deviation 1351.103 |
| Part 1: Placebo | Plasma Concentrations of GSK2586881-Part 1 | 60 minutes post-chamber entry; n=10 | 6934.842 Nanograms per milliliter | Standard Deviation 860.4466 |
| Part 1: Placebo | Plasma Concentrations of GSK2586881-Part 1 | immediately post-exercise; n=10 | 6698.518 Nanograms per milliliter | Standard Deviation 726.7099 |
| Part 1: Placebo | Plasma Concentrations of GSK2586881-Part 1 | immediately post-chamber exit; n=10 | 6304.675 Nanograms per milliliter | Standard Deviation 731.1517 |
Secondary
Plasma Concentrations of GSK2586881-Part 2
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.
Time frame: 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)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Placebo | Plasma Concentrations of GSK2586881-Part 2 | pre-dose; n=5 | NA Nanograms per milliliter | — |
| Part 1: Placebo | Plasma Concentrations of GSK2586881-Part 2 | At infusion; n=6 | 20032.735 Nanograms per milliliter | Standard Deviation 2026.2004 |
| Part 1: Placebo | Plasma Concentrations of GSK2586881-Part 2 | 15 minutes post-infusion; n=6 | 18269.882 Nanograms per milliliter | Standard Deviation 1790.1483 |
| Part 1: Placebo | Plasma Concentrations of GSK2586881-Part 2 | 15 to 45 minutes post-infusion; n=6 | 17484.102 Nanograms per milliliter | Standard Deviation 1374.5418 |
| Part 1: Placebo | Plasma Concentrations of GSK2586881-Part 2 | 60 minutes post-chamber entry; n=6 | 11617.538 Nanograms per milliliter | Standard Deviation 1572.8006 |
| Part 1: Placebo | Plasma Concentrations of GSK2586881-Part 2 | immediately post-exercise; n=6 | 11818.457 Nanograms per milliliter | Standard Deviation 1950.1873 |
| Part 1: Placebo | Plasma Concentrations of GSK2586881-Part 2 | immediately post-chamber exit; n=6 | 10956.927 Nanograms per milliliter | Standard Deviation 1319.8536 |
| Part 1: Placebo | Plasma Concentrations of GSK2586881-Part 2 | 30 minutes post-chamber exit; n=6 | 9886.477 Nanograms per milliliter | Standard Deviation 1428.663 |
Secondary
T1/2 of GSK2586881-Part 2
Blood samples were collected at indicated time points for PK analysis of GSK2586881. The pharmacokinetic parameters were calculated by standard non-compartmental analysis.
Time frame: 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
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Part 1: Placebo | T1/2 of GSK2586881-Part 2 | NA Hours |
Secondary
Time to Reach Cmax (Tmax) of GSK2586881-Part 1
Blood samples were collected at indicated time points for PK analysis of GSK2586881. The pharmacokinetic parameters were calculated by standard non-compartmental analysis.
Time frame: 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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: Placebo | Time to Reach Cmax (Tmax) of GSK2586881-Part 1 | 0.28333 Hours |
Secondary
Tmax of GSK2586881-Part 2
Blood samples were collected at indicated time points for PK analysis of GSK2586881. The pharmacokinetic parameters were calculated by standard non-compartmental analysis.
Time frame: 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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: Placebo | Tmax of GSK2586881-Part 2 | 0.08333 Hours |
Secondary
Volume of Distribution for GSK2586881-Part 1
Blood samples were collected at indicated time points for PK analysis of GSK2586881. The pharmacokinetic parameters were calculated by standard non-compartmental analysis.
Time frame: 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
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Part 1: Placebo | Volume of Distribution for GSK2586881-Part 1 | NA Liters per kilogram |
Secondary
Volume of Distribution for GSK2586881-Part 2
Blood samples were collected at indicated time points for PK analysis of GSK2586881. The pharmacokinetic parameters were calculated by standard non-compartmental analysis.
Time frame: 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
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Part 1: Placebo | Volume of Distribution for GSK2586881-Part 2 | NA Liters per kilogram |