Study of GSK2586881 on Acute Hypoxia and Exercise
Condition: Healthy Volunteers
MeSH terms: Hypoxia
Intervention: GSK2586881; Placebo
Intervention description: 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.; Normal saline (0.9%) will be administered as a single IV dose infusion over 3 to 5 min.
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 17.0
Sex: All
Minimum age: 18 Years
Maximum age: 40 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: GSK2586881, Acute hypoxia, Exercise

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.
    

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.