Phase 2
Completed N=4
A Dose-escalation Study in Subjects With Pulmonary Arterial Hypertension (PAH)
Hypertension, Pulmonary
Source: ClinicalTrials.gov NCT03177603 ↗
Enrolled (actual)
4
Serious AEs
0.0%
Results posted
Apr 2020
Primary outcomePrimary: Change From Baseline in Pulmonary Vascular Resistance (PVR) — 0.936; 0.885; 0.813; 1.017 Ratio
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.
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Change From Baseline in Pulmonary Vascular Resistance (PVR) |
0.936; 0.885; 0.813; 1.017; 0.926; 1.043 | — |
| PRIMARY Change From Baseline in Cardiac Output (CO) |
1.046; 1.079; 1.076; 0.990; 1.025; 1.029 | — |
| PRIMARY Change From Baseline in Mean Pulmonary Artery Pressure (mPAP) |
0.950; 0.995; 0.939; 0.989; 0.937; 0.994 | — |
| SECONDARY Number of Participants With Non-serious Adverse Events (AEs) |
1; 3; 5; 2 | — |
| SECONDARY Number of Participants With Serious Adverse Events (SAEs) |
0; 0; 0; 0 | — |
| SECONDARY Change From Baseline in Clinical Chemistry Parameters: Alkaline Phosphatase, Alanine Amino Transferase and Aspartate Amino Transferase |
4.8; -1.4; 5.3; 3.1; 6.5; 3.2 | — |
| SECONDARY Change From Baseline in Clinical Chemistry Parameters: Direct Bilirubin, Total Bilirubin and Creatinine |
2.0; 0.4; 0.3; 1.0; 1.0; 0.0 | — |
| SECONDARY Change From Baseline in Clinical Chemistry Parameters: Calcium, Glucose, Potassium, Sodium and Blood Urea Nitrogen (BUN) |
0.035; 0.012; 0.047; 0.060; 0.025; 0.064 | — |
| SECONDARY Change From Baseline in Clinical Chemistry Parameter: Total Protein |
1.3; 0.6; 1.8; 2.6; 1.5; 6.2 | — |
| SECONDARY Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet Count and White Blood Cell (WBC) Count |
-0.008; 0.013; -0.005; 0.003; 0.000; 0.002 | — |
| SECONDARY Change From Baseline in Hematology Parameter: Hemoglobin |
1.8; 2.0; 5.0; 3.0; -4.3; 3.4 | — |
| SECONDARY Change From Baseline in Hematology Parameter: Hematocrit |
0.0030; 0.0053; 0.0098; 0.0140; -0.0225; 0.0104 | — |
| SECONDARY Change From Baseline in Hematology Parameter: Mean Corpuscle Hemoglobin |
-0.08; 0.05; 0.25; -0.10; 0.10; 0.04 | — |
| SECONDARY Change From Baseline in Hematology Parameter: Mean Corpuscle Volume |
-0.5; 0.0; -0.5; 0.6; -1.5; -0.2 | — |
| SECONDARY Change From Baseline in Hematology Parameter: Red Blood Cell (RBC) Count |
0.03; 0.03; 0.13; 0.12; -0.20; 0.14 | — |
| SECONDARY Change From Baseline in Hematology Parameter: Reticulocytes |
0.0012; 0.0017; 0.0017; 0.0000; 0.0058; 0.0014 | — |
| SECONDARY Number of Participants With Urinalysis Results by Dipstick Method |
4; 5; 6; 8; 0; 0 | — |
| SECONDARY Change From Baseline in Pulse Rate |
-1.3; -0.8; 3.5; 3.6; -3.0; 0.8 | — |
| SECONDARY Change From Baseline in Respiratory Rate |
-2.5; -3.4; -2.2; 0.1; -2.8; -3.2 | — |
| SECONDARY Change From Baseline in Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP) |
-3.5; -1.0; -5.0; -3.3; -2.0; 0.6 | — |
| SECONDARY Number of Participants With Abnormal Electrocardiogram (ECG) Findings |
1; 3; 3; 7; 0; 0 | — |
| SECONDARY Change From Baseline in Pulse Oximetry Parameter: Percent Oxygen in Blood |
-1.0; -1.7; 0.8; -0.5; -0.7; -2.1 | — |
| SECONDARY Number of Participants With Positive Immunogenicity Results |
0; 0; 0; 0 | — |
| SECONDARY Change From Baseline in Systemic Renin-Angiotensin System (RAS) Peptides: Angiotensin II, Angiotensin (1-5) and Angiotensin (1-7) |
0.143; 0.185; 1.020; 0.254; 0.179; 0.210 | — |
| SECONDARY Change From Baseline in Pulmonary Wedge RAS Peptides: Angiotensin II, Angiotensin (1-5) and Angiotensin (1-7) |
0.270; 0.190; 0.394; 0.369; 0.310; 0.193 | — |
| SECONDARY Systemic RAS Peptide: Angiotensin II/Angiotensin (1-7) Ratio at Indicated Time Points |
0.752; 0.463; 1.450; 0.843; 0.718; 0.468 | — |
| SECONDARY Pulmonary Wedge RAS Peptide: Angiotensin II/Angiotensin (1-7) Ratio at Indicated Time Points |
0.888; 0.443; 0.620; 0.789; 0.858; 0.493 | — |
| SECONDARY Change From Baseline in Disease Biomarkers: N-terminal Pro B-type Natriuretic Peptide (NT Pro-BNP) |
1.034; 1.005; 0.923; 1.015; 1.025; 1.042 | — |
| SECONDARY Change From Baseline in Nitrite, Nitrate and Endogenous Nitrite (Biomarkers of Nitric Oxide [NO]) |
1.246; 1.029; 0.530; 0.858; 0.760; 0.992 | — |
| SECONDARY Change From Baseline in Disease Biomarker: Cardiac Troponin-I |
1.565; 1.320; 1.585; 1.414; 1.968; 1.149 | — |
| SECONDARY Maximum Observed Plasma Concentration (Cmax) of GSK2586881 |
1.5159; 4.0229; 8.9701; 14.8042 | — |
| SECONDARY Time to Cmax (Tmax) of GSK2586881 |
0.08333; 0.16667; 0.10000; 0.13333 | — |
| SECONDARY Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC[0-t]) of GSK2586881 |
3.941; 17.874; 46.789; 68.042 | — |
| SECONDARY Area Under the Concentration-time Curve From Time Zero (Pre-dose) Extrapolated to Infinite Time (AUC[0-inf]) of GSK2586881 |
NA; 25.26; 52.46; 76.87 | — |
| SECONDARY Last Observed Quantifiable Concentration (Ct) of GSK2586881 |
0.2563; 0.3327; 0.4800; 0.6380 | — |
| SECONDARY Time of the Last Quantifiable Concentration (Tlast) of GSK2586881 |
8.000; 24.000; 24.017; 24.117 | — |
| SECONDARY Plasma Clearance (CL) of GSK2586881 |
NA; 0.5838; 0.6207; 0.8170 | — |
| SECONDARY Apparent Volume of Distribution of GSK2586881 |
NA; 6.443; 6.593; 8.084 | — |
| SECONDARY Apparent Terminal Phase Half-life (t1/2) of GSK2586881 |
NA; 7.651; 7.362; 6.858 | — |
Eligibility 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) = 100 meters (m) and 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 2x upper limit of normal (ULN).
- Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin 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.
Data sourced from ClinicalTrials.gov (NCT03177603). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication. Informational only — not medical advice.