Clinical Trial: Study of GSK2586881 on Acute Hypoxia and Exercise

Study Status: Not yet recruiting
Recruit Status: Not yet recruiting
Study Type: Interventional

Official Title: The Effects of GSK2586881 on the Responses to Acute Hypoxia and 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.

Detailed Summary:
Sponsor: GlaxoSmithKline

Current Primary Outcome: 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.


Original Primary Outcome: 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 Ecocardiography at Baseline, predose, and post dose at 15 min, 60 min, immediately after exercise and after 30 min rest during both the treatment periods.


Current Secondary Outcome:

  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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-

    Original Secondary Outcome:

    • 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.
    • 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.
    • 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.
    • 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.
    • 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.
    • 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.
    • 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.
    • 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, Eosinoplils, Basophils.
    • 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.
    • 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).
    • 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.
    • 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.
    • 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-

      Information By: GlaxoSmithKline

      Dates:
      Date Received: December 19, 2016
      Date Started: May 4, 2017
      Date Completion: December 18, 2017
      Last Updated: April 27, 2017
      Last Verified: April 2017