Last updated: 01/18/2022 12:40:13
A dose-escalation study in subjects with Pulmonary Arterial Hypertension (PAH)
EudraCT ID
EU CT Number
Not applicable
Trial status
Completed
Completed
Trial overview
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
Trial description: 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.
Primary purpose:
Treatment
Trial design:
Parallel Assignment
Masking:
None (Open Label)
Allocation:
Non-randomized
Primary outcomes:
Change from Baseline in pulmonary vascular resistance (PVR)
Timeframe: Baseline and up to 4 hours
Change from Baseline in cardiac output (CO)
Timeframe: Baseline and up to 4 hours
Change from Baseline in mean pulmonary artery pressure (mPAP)
Timeframe: Baseline and up to 4 hours
Secondary outcomes:
Number of subjects with adverse events (AEs)
Timeframe: Up to 14 days post dose
Number of subjects with serious adverse events (SAE)
Timeframe: Screening and up to 14 days post dose
Number of subjects with abnormal clinical laboratory parameters
Timeframe: Screening and up to 14 days post dose
Assessment of pulse rate as a safety measure
Timeframe: Screening and up to 14 days post dose
Assessment of respiratory rate as a safety measure
Timeframe: Screening and up to 14 days post dose
Assessment of blood pressure (BP) as a safety measure
Timeframe: Screening and up to 14 days post dose
Number of subjects with abnormal electrocardiogram (ECG) findings
Timeframe: Screening and up to 14 days post dose
Number of subjects with abnormal pulse oximetry findings
Timeframe: Screening and up to 14 days post dose
Immunogenicity as a measure of safety assessment
Timeframe: Screening and up to 31 days post dose
Change from Baseline in RAS (Renin-Angiotensin System) peptides
Timeframe: Baseline and up to 14 days post dose
Change from Baseline in N-terminal pro B-type natriuretic peptide (NT pro-BNP)
Timeframe: Baseline and up to 24 hours
Change from Baseline in nitric oxide (NO)
Timeframe: Baseline and up to 24 hours
Change from Baseline in cardiac troponin-I
Timeframe: Baseline and up to 24 hours
Maximum observed plasma concentration (Cmax) of GSK2586881
Timeframe: Pre-dose, 0.08, 0.5, 1, 2, 4, 8 and 24 hours post-dose
Time to Cmax (tmax) of GSK2586881
Timeframe: Pre-dose, 0.08, 0.5, 1, 2, 4, 8 and 24 hours post-dose
Area under the plasma concentration-time curve [AUC(0-t)] of GSK2586881
Timeframe: Pre-dose, 0.08, 0.5, 1, 2, 4, 8 and 24 hours post-dose
Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time[AUC(0-inf)] of GSK2586881
Timeframe: Pre-dose, 0.08, 0.5, 1, 2, 4, 8 and 24 hours post-dose
The last observed quantifiable concentration (Clast) of GSK2586881
Timeframe: Pre-dose, 0.08, 0.5, 1, 2, 4, 8 and 24 hours post-dose
Time of the last quantifiable concentration (tlast) of GSK2586881
Timeframe: Pre-dose, 0.08, 0.5, 1, 2, 4, 8 and 24 hours post-dose
Plasma clearance (CL) of GSK2586881
Timeframe: Pre-dose, 0.08, 0.5, 1, 2, 4, 8 and 24 hours post-dose
Volume of distribution (V) of GSK2586881
Timeframe: Pre-dose, 0.08, 0.5, 1, 2, 4, 8 and 24 hours post-dose
Apparent terminal phase half-life (t1/2) of GSK2586881
Timeframe: Pre-dose, 0.08, 0.5, 1, 2, 4, 8 and 24 hours post-dose
Interventions:
Drug: GSK2586881
Enrollment:
23
Observational study model:
Not applicable
Primary completion date:
2019-07-05
Time perspective:
Not applicable
Clinical publications:
Marc A. Simon, Kate Hanrott, David C. Budd, Fernando Torres, Ekkehard Grünig, Pilar Escribano-Subias, Manuel López Meseguer, Michael Halank, Christian Opitz, David A. Hall, Deborah Hewens, William M. Powley, Sarah Siederer, Andrew I. Bayliffe, Aili L. Lazaar, Anthony Cahn, Stephan Rosenkranz. 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. Pulm Circ. 2021;
DOI: 10.1002/pul2.12024
PMID: NULL
Medical condition
Hypertension, Pulmonary
Product
GSK2586881
Collaborators
Not applicable
Study date(s)
February 2018 to May 2019
Type
Interventional
Phase
2
Participation criteria
Sex
Female & Male
Age
18 - 75 years
Accepts healthy volunteers
No
- Inclusion Criteria
- Subjects must be between 18-75 years of age (inclusive), at the time of signing the informed consent.
Inclusion and exclusion criteria
Inclusion 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.
Trial location(s)
Location
GSK Investigational Site
Dallas, Texas, United States, 75390-8550
Status
Study Complete
Location
GSK Investigational Site
Heidelberg, Baden-Wuerttemberg, Germany, 69126
Status
Study Complete
Location
GSK Investigational Site
Koeln, Nordrhein-Westfalen, Germany, 50937
Status
Study Complete
Location
GSK Investigational Site
Pittsburgh, Pennsylvania, United States, 15213
Status
Study Complete
Study documents
Protocol
Available language(s): English
Statistical analysis plan
Available language(s): English
If you wish to request for full study report, please contact - [email protected]
Results overview
Results posted on ClinicalTrials.gov
Recruitment status
Completed
Actual primary completion date
2019-07-05
Actual study completion date
2019-07-05
Plain language summaries
Plain language summaries of clinical trial results for Phase 2-4 clinical trials that were initiated on or after January 2022 will be posted by GSK within one year following study completion.
Additional information about the trial
Additional information
Not applicable
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