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Study of GSK2586881 on Acute Hypoxia and Exercise

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ClinicalTrials.gov Identifier: NCT03000686
Recruitment Status : Terminated (Study terminated for technical feasibility, operational considerations and futility in line with pre-specified criteria.)
First Posted : December 22, 2016
Last Update Posted : January 28, 2019
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

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.

Condition or disease Intervention/treatment Phase
Healthy Volunteers Biological: GSK2586881 Other: Placebo Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 17 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: The Effects of GSK2586881 on the Responses to Acute Hypoxia and Exercise
Actual Study Start Date : May 17, 2017
Actual Primary Completion Date : January 4, 2019
Actual Study Completion Date : January 4, 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Treatment sequence AB
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
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.

Other: Placebo
Normal saline (0.9%) will be administered as a single IV dose infusion over 3 to 5 min.

Experimental: Treatment sequence BA
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
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.

Other: Placebo
Normal saline (0.9%) will be administered as a single IV dose infusion over 3 to 5 min.




Primary Outcome Measures :
  1. Change from baseline in Pulmonary Artery Systolic Pressure (PASP) [ Time Frame: Baseline and up to 16 days ]
    PASP will be determined by measuring maximal tricuspid regurgitation velocity and applying the modified Bernoulli equation to convert this value into pressure values. It will be measured via Echocardiography at Baseline, predose, and post dose at 15 min, 60 min, immediately after exercise and after 30 min rest during both the treatment periods.


Secondary Outcome Measures :
  1. Change from baseline in Renin-Angiotensin System (RAS) peptides in response to hypoxia and exercise [ Time Frame: Baseline and up to 16 days ]
    RAS peptides including but not limited to Angiotensin (Ang) II, Ang (1-7) and Ang (1-5) will be analyzed as data permit. Samples will be taken at on Day 1 predose, and post dose at 0 hour, 15 min 15-45 min, 60 min, immediately after exercise, after 30 min rest on exit from chamber, and after 30 min rest during both the treatment periods.

  2. Safety as assessed by Heart rate [ Time Frame: Up to 26 days ]
    Heart rate will be measured in semi-supine position after 5 min rest. Heart rate will be measured on Day 1 at predose, and post dose at 15 to 45 min, immediately after exercise and 60 min after exit from chamber during both the treatment periods.

  3. Safety as assessed by Blood pressure [ Time Frame: Up to 26 days ]
    Systolic and diastolic blood pressure will be measured in semi-supine position after 5 min rest. Blood pressure will be measured on Day 1 at predose, and post dose at 15 to 45 min, immediately after exercise and 60 min after exit from chamber during both the treatment periods.

  4. Oxygen saturation by continuous pulse oximetry [ Time Frame: Up to 16 days ]
    Oxygen saturation will be continuously monitored via pulse oximetry on Day 1 post dose from 0 hour, 60 to 70 min, and immediately after exercise, 30 min rest on extension from chamber, after 30 min rest, 60 min after exit from chamber during both the treatment periods.

  5. Electrocardiogram (ECG) assessment as a measure of safety [ Time Frame: Up to 26 days ]
    ECGs will be obtained at each time point during the study using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and corrected QT interval (QTc) intervals. ECG will be measured in a semi-supine position after 5 min rest. ECG will be obtained on Day 1 at predose, and post dose at 15 to 45 min and 60 min after exit from chamber during both the treatment periods.

  6. Number of subjects with any adverse event(s) (AE) [ Time Frame: Up to 26 days ]
    An AE is any untoward medical occurrence in a subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.

  7. Number of subjects with positive anti- Angiotensin converting enzyme type 2 (ACE2) binding and neutralizing antibodies [ Time Frame: Day 1 predose (treatment period 2) ]
    Samples will be collected on Day 1at predose during treatment period 2 only.

  8. Number of subjects with abnormal hematology laboratory parameters, as a measure of safety [ Time Frame: Up to 26 days ]
    Blood samples will be collected to analyze 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, Basophils.

  9. Number of subjects with abnormal clinical chemistry parameters, as a measure of safety [ Time Frame: Up to 26 days ]
    Blood samples will be collected to analyze Blood urea nitrogen (BUN), Creatinine, Glucose, Potassium, Sodium, Calcium, Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), Alkaline phosphatase, Total and direct bilirubin, Total Protein, Albumin.

  10. Number of subjects having abnormal urinalysis as a measure of safety [ Time Frame: Up to 26 days ]
    Urine samples will be collected to analyze Specific gravity, pH, Glucose, Protein, blood and ketones by dipstick, microscopic examination (if blood or protein is abnormal).

  11. Measurement of plasma concentrations of a single IV dose of GSK2586881 [ Time Frame: Predose and post dose at 0 hour, 15 min, 15 to 45 min, 60 min, immediately after exercise, 30 min rest on exit from chamber and after 30 min rest during both the treatment periods ]
    Blood sample will be collected to analyze maximum observed plasma concentration (Cmax) over given timeframe if data permits.

  12. Measurement of time to Cmax (tmax) of a single IV dose of GSK2586881 [ Time Frame: Predose and post dose at 0 hour, 15 min, 15 to 45 min, 60 min, immediately after exercise, 30 min rest on exit from chamber and after 30 min rest during both the treatment periods ]
    Blood sample will be collected to analyze tmax over the given timeframe if data permits.

  13. Measurement of area under the plasma concentration-time curve (AUC) (0 to 2.5 hours) post dose [ Time Frame: Predose and post dose at 0 hour, 15 min, 15 to 45 min, 60 min, immediately after exercise, 30 min rest on exit from chamber and after 30 min rest during both the treatment periods ]
    Blood sample will be collected to analyze AUC (0-2.5hours) post dose over the given timeframe if data permits.

  14. Measurement of AUC (0.5 to 2.0 hours) post dose [ Time Frame: Predose and post dose at 0 hour, 15 min, 15 to 45 min, 60 min, immediately after exercise, 30 min rest on exit from chamber and after 30 min rest during both the treatment periods ]
    Blood sample will be collected to analyze AUC over the hypoxia challenge (nominally AUC (0.5-2.0hours post-dose) over the given timeframe if data permits.

  15. Measurement of plasma clearance [ Time Frame: Predose and post dose at 0 hour, 15 min, 15 to 45 min, 60 min, immediately after exercise, 30 min rest on exit from chamber and after 30 min rest during both the treatment periods ]
    Blood sample will be collected to analyze plasma clearance over given timeframe if data permits.

  16. Measurement of volume of distribution [ Time Frame: Predose and post dose at 0 hour, 15 min, 15 to 45 min, 60 min, immediately after exercise, 30 min rest on exit from chamber and after 30 min rest during both the treatment periods ]
    Blood sample will be collected to analyze volume of distribution over given timeframe if data permits.

  17. Measurement of apparent terminal phase half-life (t1/2) [ Time Frame: Predose and post dose at 0 hour, 15 min, 15 to 45 min, 60 min, immediately after exercise, 30 min rest on exit from chamber and after 30 min rest during both the treatment periods ]
    Blood sample will be collected to analyze apparent terminal phase half-life (t1/2) over given timeframe if data permits.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 40 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03000686


Locations
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Germany
GSK Investigational Site
Hannover, Niedersachsen, Germany, 30625
Sponsors and Collaborators
GlaxoSmithKline
Investigators
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Study Director: GSK Clinical Trials GlaxoSmithKline
Study Director: GSK Clinical Trials GlaxoSmithKline (for GlaxoSmithKline; Human Genome Sciences Inc., a GSK Company; Sirtris, a GSK Company; Stiefel, a GSK Company; ViiV Healthcare)

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Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT03000686     History of Changes
Other Study ID Numbers: 204987
2016-002465-55 ( EudraCT Number )
First Posted: December 22, 2016    Key Record Dates
Last Update Posted: January 28, 2019
Last Verified: January 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by GlaxoSmithKline:
GSK2586881, Acute hypoxia, Exercise
Additional relevant MeSH terms:
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Hypoxia
Signs and Symptoms, Respiratory
Signs and Symptoms