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A Dose-escalation Study in Subjects With Pulmonary Arterial Hypertension (PAH)

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ClinicalTrials.gov Identifier: NCT03177603
Recruitment Status : Completed
First Posted : June 6, 2017
Last Update Posted : June 18, 2019
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

Brief Summary:
GSK2586881, a purified intravenous (IV) formulation of soluble recombinant human Angiotensin Converting Enzyme (rhACE2) is being investigated as a treatment for PAH. This GlaxoSmithKline (GSK) study will evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of GSK2586881 in subjects with PAH. This open-label, dose-escalation study will comprise of 4 separate groups based on the planned dose range, and subjects in each group will be administered a single dose of GSK2586881 ranging between 0.1, 0.2, 0.4 and 0.8 milligram per kilogram (mg/kg) via IV route. Dose escalation will occur after 4 subjects have been dosed per cohort and review of safety, tolerability, PK and hemodynamic data up to 24 hours post dose has taken place. A maximum of 27 subjects will be included in the study and the total duration of the study will be up to a maximum of 59 days.

Condition or disease Intervention/treatment Phase
Hypertension, Pulmonary Drug: GSK2586881 Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 23 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open-label, Dose-escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single Doses of GSK2586881 in Participants With Pulmonary Arterial Hypertension
Actual Study Start Date : February 21, 2018
Actual Primary Completion Date : May 7, 2019
Actual Study Completion Date : May 7, 2019


Arm Intervention/treatment
Experimental: GSK2586881 - 0.1 mg/kg
Eligible subjects will receive a single dose of 0.1 mg/kg GSK2586881. Dose escalation up to maximum dose of 0.8 mg/kg will occur after 4 subjects have been dosed per cohort and review of safety, tolerability, PK and hemodynamic data up to 24 hours post dose has taken place.
Drug: GSK2586881
GSK2586881 is a clear colorless liquid for IV infusion over 3- 5 minutes and will be administered a maximum dose of 0.8 mg/kg.

Experimental: GSK2586881 - 0.2 mg/kg
Eligible subjects will receive a single dose 0.2 mg/kg of GSK2586881 IV infusion. Dose escalation up to maximum dose of 0.8 mg/kg will occur after 4 subjects have been dosed per cohort and review of safety, tolerability, PK and hemodynamic data up to 24 hours post dose has taken place.
Drug: GSK2586881
GSK2586881 is a clear colorless liquid for IV infusion over 3- 5 minutes and will be administered a maximum dose of 0.8 mg/kg.

Experimental: GSK2586881 - 0.4 mg/kg
Eligible subjects will receive a single dose of 0.4 mg/kg of GSK2586881 IV infusion. Dose escalation up to maximum dose of 0.8 mg/kg will occur after 4 subjects have been dosed per cohort and review of safety, tolerability, PK and hemodynamic data up to 24 hours post dose has taken place.
Drug: GSK2586881
GSK2586881 is a clear colorless liquid for IV infusion over 3- 5 minutes and will be administered a maximum dose of 0.8 mg/kg.

Experimental: GSK2586881 - 0.8 mg/kg
Eligible subjects will receive single dose of 0.8 mg/kg of GSK2586881 IV infusion. Dose escalation will occur after 4 subjects have been dosed per cohort and review of safety, tolerability, PK and hemodynamic data up to 24 hours post dose has taken place.
Drug: GSK2586881
GSK2586881 is a clear colorless liquid for IV infusion over 3- 5 minutes and will be administered a maximum dose of 0.8 mg/kg.




Primary Outcome Measures :
  1. Change from Baseline in pulmonary vascular resistance (PVR) [ Time Frame: Baseline and up to 4 hours ]
    PVR is the resistance generated by pulmonary circulation. Pulmonary arterial catheters will be placed in subjects and PVR values will be recorded from the right heart catheterization. The catheter will be removed 4 hours post-dose.

  2. Change from Baseline in cardiac output (CO) [ Time Frame: Baseline and up to 4 hours ]
    CO is the amount of blood pumped by the heart per minute. Pulmonary arterial catheters will be placed in subjects and CO values will be recorded from the right heart catheterization. The catheter will be removed 4 hours post-dose.

  3. Change from Baseline in mean pulmonary artery pressure (mPAP) [ Time Frame: Baseline and up to 4 hours ]
    Pulmonary arterial catheters will be placed in subjects and mPAP values will be recorded from the right heart catheterization. The catheter will be removed 4 hours post-dose.


Secondary Outcome Measures :
  1. Number of subjects with adverse events (AEs) [ Time Frame: Up to 14 days post dose ]
    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 study treatment.

  2. Number of subjects with serious adverse events (SAE) [ Time Frame: Screening and up to 14 days post dose ]
    Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect, any other situation according to medical or scientific judgment that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the subject or may require medical or surgical intervention were categorized as SAE.

  3. Number of subjects with abnormal clinical laboratory parameters [ Time Frame: Screening and up to 14 days post dose ]
    Serum chemistry, hematological and urine analysis parameters will be evaluated.

  4. Assessment of pulse rate as a safety measure [ Time Frame: Screening and up to 14 days post dose ]
    Pulse rate will be measured in a supine position after at least a 5-minute rest.

  5. Assessment of respiratory rate as a safety measure [ Time Frame: Screening and up to 14 days post dose ]
    Respiratory rate will be measured in a supine position after at least a 5-minute rest.

  6. Assessment of blood pressure (BP) as a safety measure [ Time Frame: Screening and up to 14 days post dose ]
    BP will be measured in a supine position after at least a 5-minute rest.

  7. Number of subjects with abnormal electrocardiogram (ECG) findings [ Time Frame: Screening and up to 14 days post dose ]
    12-lead ECGs will be obtained at each time point using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and Corrected QT (QTc) intervals.

  8. Number of subjects with abnormal pulse oximetry findings [ Time Frame: Screening and up to 14 days post dose ]
    Oxygen saturation will be measured by pulse oximetry with each blood pressure assessment after at least a 5-minute rest.

  9. Immunogenicity as a measure of safety assessment [ Time Frame: Screening and up to 31 days post dose ]
    Blood samples will be collected at given time points for immunogenicity assessment.

  10. Change from Baseline in RAS (Renin-Angiotensin System) peptides [ Time Frame: Baseline and up to 14 days post dose ]
    Blood samples will be collected to evaluate change from Baseline in pulmonary wedge RAS peptides including Angiotensin (Ang) II, Ang (1-7), Ang (1-5), and AngII/Ang (1-7) ratio.

  11. Change from Baseline in N-terminal pro B-type natriuretic peptide (NT pro-BNP) [ Time Frame: Baseline and up to 24 hours ]
    Blood samples will be collected at specific time points to evaluate change from Baseline in NT pro-BNP, a biomarker of disease activity.

  12. Change from Baseline in nitric oxide (NO) [ Time Frame: Baseline and up to 24 hours ]
    Blood samples will be collected at specific time points to evaluate change from Baseline in NO levels.

  13. Change from Baseline in cardiac troponin-I [ Time Frame: Baseline and up to 24 hours ]
    Blood samples will be collected at specific time points to evaluate change from Baseline in cardiac troponin-I, a biomarker of disease activity.

  14. Maximum observed plasma concentration (Cmax) of GSK2586881 [ Time Frame: Pre-dose, 0.08, 0.5, 1, 2, 4, 8 and 24 hours post-dose ]
    Blood samples will be collected at indicated time points and concentrations of GSK2586881 will be determined

  15. Time to Cmax (tmax) of GSK2586881 [ Time Frame: Pre-dose, 0.08, 0.5, 1, 2, 4, 8 and 24 hours post-dose ]
    Blood samples will be collected at indicated time points and concentrations of GSK2586881 will be determined

  16. Area under the plasma concentration-time curve [AUC(0-t)] of GSK2586881 [ Time Frame: Pre-dose, 0.08, 0.5, 1, 2, 4, 8 and 24 hours post-dose ]
    Blood samples will be collected at indicated time points and concentrations of GSK2586881 will be determined

  17. Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time[AUC(0-inf)] of GSK2586881 [ Time Frame: Pre-dose, 0.08, 0.5, 1, 2, 4, 8 and 24 hours post-dose ]
    Blood samples will be collected at indicated time points and concentrations of GSK2586881 will be determined

  18. The last observed quantifiable concentration (Clast) of GSK2586881 [ Time Frame: Pre-dose, 0.08, 0.5, 1, 2, 4, 8 and 24 hours post-dose ]
    Blood samples will be collected at indicated time points and concentrations of GSK2586881 will be determined

  19. Time of the last quantifiable concentration (tlast) of GSK2586881 [ Time Frame: Pre-dose, 0.08, 0.5, 1, 2, 4, 8 and 24 hours post-dose ]
    Blood samples will be collected at indicated time points and concentrations of GSK2586881 will be determined

  20. Plasma clearance (CL) of GSK2586881 [ Time Frame: Pre-dose, 0.08, 0.5, 1, 2, 4, 8 and 24 hours post-dose ]
    Blood samples will be collected at indicated time points and concentrations of GSK2586881 will be determined

  21. Volume of distribution (V) of GSK2586881 [ Time Frame: Pre-dose, 0.08, 0.5, 1, 2, 4, 8 and 24 hours post-dose ]
    Blood samples will be collected at indicated time points and concentrations of GSK2586881 will be determined

  22. Apparent terminal phase half-life (t1/2) of GSK2586881 [ Time Frame: Pre-dose, 0.08, 0.5, 1, 2, 4, 8 and 24 hours post-dose ]
    Blood samples will be collected at indicated time points and concentrations of GSK2586881 will be determined



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

  • Subjects must be between 18-75 years of age (inclusive), at the time of signing the informed consent.
  • Documented diagnosis of PAH, defined as mPAP > 25 millimeter of mercury (mmHg) and pulmonary wedge pressure (PWP) <= 15.
  • Idiopathic PAH (IPAH), Hereditary PAH (HPAH), or PAH associated with collagen vascular disease, or appetite suppressant use.
  • World Health Organization (WHO) functional class I, II, or III, stable for at least 8 weeks prior to enrollment.
  • Hemodynamically stable on background therapy with no evidence of uncontrolled right heart failure (historic data), as determined by the investigator.
  • Six minute walk (6MW) distance, as performed at screening or within 6 months prior to screening, of >= 100 meters (m) and <= 500 m.
  • Mean BP of >60 mmHg.
  • Receiving stable doses of one or more medications that are approved for treatment of PAH, including endothelin receptor antagonists, phosphodiesterase 5 inhibitors, and/or prostanoids/prostacyclin receptor agonists, for a minimum of 12 consecutive weeks before enrollment.
  • Diuretic dose stable for 8 weeks.
  • Body weight <= 100 kg and body mass index (BMI) within the range 18-35 kg per m square (kg/m^2) (inclusive).
  • Male and/or female (following confirmation of negative pregnancy test for Women of Childbearing Potential [WOCBP]). Women who are pregnant or breastfeeding are excluded.
  • Capable of giving signed informed consent.

Exclusion Criteria

  • History of systemic hypotension, defined as systolic BP <90 mmHg and/or diastolic BP <50 mmHg.
  • Hospitalization for PAH associated deterioration in the previous 6 months.
  • Any additional medical condition, serious intercurrent illness, or other extenuating circumstance that, in the opinion of the Investigator, may significantly interfere with study compliance, including all prescribed evaluations and follow-up activities. Concurrent disease or condition that may interfere with study participation or safety include bleeding disorders, arrhythmia, organ transplant, organ failure, current neoplasm, poorly controlled diabetes mellitus, and serious neurological disorders.
  • Complex repaired and unrepaired congenital heart disease.
  • Subjects with Eisenmenger physiology.
  • Alanine transferase (ALT) >2x upper limit of normal (ULN).
  • Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35 percent).
  • Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
  • Estimated glomerular-filtration-rate (eGFR) <45 milliliter per minute per 1.73 meter square (mL/min/1.73m^2).
  • QTc >480 millisecond (msec) or QTc > 500 msec in subjects with bundle branch block.
  • Any bleeding concerns as evidenced by International normalized ratio (INR) >1.5 (in subjects not receiving anticoagulation therapy) or platelet count <80,000.
  • Hemoglobin (Hb) <10 gram per deciliter (g/dL).
  • Sensitivity to any of the study treatments, or components thereof, or drug or other allergy that, in the opinion of the investigator or Medical Monitor, contraindicates participation in the study.
  • Any use of an Angiotensin-converting enzyme (ACE) inhibitor or Angiotensin receptor blocker or renin inhibitors within 14 days prior to dosing. Therapy can be stopped to enable inclusion if deemed safe by the subject's treating physician.
  • Use of any investigational product (IP) or device within 30 days prior to dosing, or known requirement for any investigational agent prior to completion of all scheduled study assessments.
  • Positive human immunodeficiency virus (HIV) antibody test.
  • Presence of Hepatitis B surface antigen (HBsAg) at screening.
  • Positive Hepatitis C antibody test result at screening or within 3 months prior to starting study treatment.
  • Positive Hepatitis C ribonucleic acid (RNA) test result at screening or within 3 months prior to first dose of study treatment.
  • Participation in the study would result in loss of blood or blood products in excess of 300mL within 65 days.
  • Exposure to more than 4 new chemical entities within 12 months prior to the first dosing day.
  • A known or suspected history of alcohol or drug abuse within the 2 years prior to screening.
  • Unable to refrain from smoking during the in-house treatment period.

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): NCT03177603


Locations
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United States, Pennsylvania
GSK Investigational Site
Pittsburgh, Pennsylvania, United States, 15213
United States, Texas
GSK Investigational Site
Dallas, Texas, United States, 75390-8550
Germany
GSK Investigational Site
Heidelberg, Baden-Wuerttemberg, Germany, 69126
GSK Investigational Site
Koeln, Nordrhein-Westfalen, Germany, 50937
GSK Investigational Site
Dresden, Sachsen, Germany, 01307
GSK Investigational Site
Berlin, Germany, 14050
Spain
GSK Investigational Site
Barcelona, Spain, 08035
GSK Investigational Site
Madrid, Spain, 28041
Sponsors and Collaborators
GlaxoSmithKline
Investigators
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Study Director: GSK Clinical Trials GlaxoSmithKline

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Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT03177603     History of Changes
Other Study ID Numbers: 206246
2017-000212-41 ( EudraCT Number )
First Posted: June 6, 2017    Key Record Dates
Last Update Posted: June 18, 2019
Last Verified: June 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: IPD for this study will be made available via the Clinical Study Data Request site.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Time Frame: IPD will be made available within 6 months of publishing the results of the primary endpoints of the study.
Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.
URL: http://clinicalstudydatarequest.com

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by GlaxoSmithKline:
Pulmonary Arterial Hypertension
Dose-escalation
Safety
Tolerability
GSK2586881
Additional relevant MeSH terms:
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Hypertension, Pulmonary
Hypertension
Vascular Diseases
Cardiovascular Diseases
Lung Diseases
Respiratory Tract Diseases