NCT03000686终止1 期
The Effects of GSK2586881 on the Responses to Acute Hypoxia and Exercise
适应症
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 17
- 试验地点
- 2
- 主要终点
- Change From Baseline of Pulmonary Artery Systolic Pressure (PASP) Measured Via Echocardiography-Part 1
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Investigator)
入排标准
- 年龄范围
- 18 Years 至 40 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •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,
- •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).
- •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.
排除标准
- •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.
结局指标
主要结局
Change From Baseline of Pulmonary Artery Systolic Pressure (PASP) Measured Via Echocardiography-Part 1
时间窗: 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
时间窗: 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.
次要结局
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- Number of Participants With Abnormal Clinical Chemistry Parameters-Part 1(Up to 26 days)
- Number of Participants With Abnormal Clinical Chemistry Parameters-Part 2(Up to 26 days)
- 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)
- 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)
- 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)
- Number of Participants With AEs and SAEs-Part 2(Up to 26 days)
- 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)
- 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)
- 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)
- Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)-Part 1(Up to 26 days)
- Number of Participants With Positive Immunogenicity Results-Part 2(Up to 26 days)
- 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)
- Number of Participants With Abnormal Hematology Parameters-Part 1(Up to 26 days)
- Number of Participants With Abnormal Urine Parameters-Part 1(Up to 26 days)
- 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)
- 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)
- 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)
- 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)
- 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)
- Number of Participants With Positive Immunogenicity Results-Part 1(Up to 26 days)
- Number of Participants With Abnormal Hematology Parameters-Part 2(Up to 26 days)
- Number of Participants With Abnormal Urine Parameters-Part 2(Up to 26 days)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
研究者
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