Study of GSK2586881 on Acute Hypoxia and Exercise | NCT03000686

ID	Type	Description	Link
2016-002465-55	EudraCT Number

Label	Type	Description	Intervention Names
Treatment sequence AB	Experimental	Subjects will receive GSK2586881 in period 1 and saline placebo in period 2. There will be a washout period of 3-14 days between two treatments	Biological: GSK2586881 Other: Placebo
Treatment sequence BA	Experimental	Subjects will receive saline placebo in period 1 and GSK2586881 in period 2. There will be a washout period of 3-14 days between two treatments	Biological: GSK2586881 Other: Placebo

Name	Type	Description	Arm Group Labels	Other Names
GSK2586881	Biological	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.	Treatment sequence AB

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
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.	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
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.	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

Secondary Outcomes

Measure	Description	Time Frame
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.	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

Eligibility Module

Eligibility Criteria

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.

Exclusion Criteria:

ALT >1.5x Upper limit of normal (ULN).
Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
QTc > 450 millisecond (msec.)
Unable to refrain from prescription or non-prescription drugs, including agents active in the central nervous system, vitamins, herbal and dietary supplements (including St John's Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication and throughout the study, unless in the opinion of the Investigator and/or GSK Medical Monitor (if needed) the medication will not interfere with the study procedures or compromise subject safety.
History of regular alcohol consumption within 6 months of the study defined as: An average weekly intake of >21 units for males or >14 units for females. One unit is equivalent to 8 gram (g) of alcohol: a half-pint (approximately 240 milliliter [ml]) of beer, 1 glass (125 ml) of wine or 1 (25 ml) measure of spirits.
Urinary cotinine levels indicative of smoking or history or regular use of tobacco- or nicotine-containing products within 6 months prior to screening
History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or Medical Monitor, contraindicates their participation.
Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study treatment. For potent immunosuppressive agents, subjects with presence of hepatitis B core antibody (HBcAb) should also be excluded.
A positive pre-study drug/alcohol screen.
A positive test for Human Immunodeficiency Virus (HIV) antibody.
Where participation in the study would result in donation of blood or blood products in excess of 500 ml within 56 days.
The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
Exposure to more than four new chemical entities within 12 months prior to the first dosing day.

Name	Affiliation	Role
GSK Clinical Trials	GlaxoSmithKline	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
GSK Investigational Site		Hanover	Lower Saxony	30625	Germany

Arm/Group Information

ID	Title	Description
FG000	Part 1: Placebo/GSK2586881	Participants were administered a single intravenous (IV) dose of placebo in treatment period 1 followed by a washout of period of up to 14 days. In treatment period 2, participants were administered a single IV dose of 0.8 milligrams per kilogram (mg/kg) GSK2586881. During each period, approximately 30 minutes after administration of study treatment, participants entered the hypoxia chamber and were inside the chamber for approximately 80 minutes, during which they were under the full 4000 meters ± 10% hypoxic conditions. Participants then performed an exercise challenge at 70% of maximum oxygen consumption (VO2) uptake on an upright cycle ergometer within the hypoxia chamber for 10 minutes.
FG001	Part 1: GSK2586881/Placebo	Participants were administered a single IV dose of 0.8 mg/kg GSK2586881 in treatment period 1 followed by a washout of period of up to 14 days. In treatment period 2, participants were administered a single IV dose of placebo. During each period, approximately 30 minutes after administration of study treatment, participants entered the hypoxia chamber and were inside the chamber for approximately 80 minutes, during which they were under the full 4000 meters ± 10% hypoxic conditions. Participants then performed an exercise challenge at 70% of maximum VO2 uptake on an upright cycle ergometer within the hypoxia chamber for 10 minutes.
FG002	Part 2: Placebo/GSK2586881	Participants were administered a single IV dose of placebo in treatment period 1 followed by a washout of period of up to 14 days. In treatment period 2, participants were administered a single IV dose of 0.8 mg/kg GSK2586881. During each period, approximately 30 minutes after administration of study treatment, participants entered the hypoxia chamber and were inside the chamber for approximately 80 minutes, during which they were under the full 5000 meters ± 10% hypoxic conditions. Participants then performed an exercise challenge at 50% of maximum VO2 uptake on a semi-recumbent cycle ergometer within the hypoxia chamber for 10 minutes.
FG003	Part 2: GSK2586881/Placebo	Participants were administered a single IV dose of 0.8 mg/kg GSK2586881 in treatment period 1 followed by a washout of period of up to 14 days. In treatment period 2, participants were administered a single IV dose of placebo. During each period, approximately 30 minutes after administration of study treatment, participants entered the hypoxia chamber and were inside the chamber for approximately 80 minutes, during which they were under the full 5000 meters ± 10% hypoxic conditions. Participants then performed an exercise challenge at 50% of maximum VO2 uptake on a semi-recumbent cycle ergometer within the hypoxia chamber for 10 minutes.

ID	Title	Description
BG000	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.

Units	Counts
Participants	BG000

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Continuous			Mean

Outcome Measures Module

Outcome Measures

Type	Title	Description	Population Description	Reporting Status	Anticipated Posting Date	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Time Frame	Units Analyzed	Denominator Units Selected	Arm/Group Information	Denominators	Classes	Analyses
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.	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.	Posted		Median	95% Confidence Interval	Millimeters of mercury		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

Adverse Events Module

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Part 1: Placebo	Participants were administered a single IV dose of placebo in either treatment period 1 or 2 during Part 1 of the study. During each period, approximately 30 minutes after administration of study treatment, the participants entered the hypoxia chamber and were inside the chamber for approximately 80 minutes, during which they were under the full 4000 meters ± 10% hypoxic conditions. Participants then performed an exercise challenge at 70% of maximum VO2 uptake on an upright cycle ergometer within the hypoxia chamber for 10 minutes.

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Mar 6, 2018	Dec 2, 2019	Prot_000.pdf
SAP	No	Yes	No	Statistical Analysis Plan	Jun 25, 2018	Dec 2, 2019	SAP_001.pdf