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

• Register: ClinicalTrials.gov
• Last refreshed on: 12 December 2020
• Main ID: NCT03177603
• Date of registration: 23/05/2017
• Prospective Registration: Yes
• Primary sponsor: GlaxoSmithKline
• Public title: A Dose-escalation Study in Subjects With Pulmonary Arterial Hypertension (PAH)
• Scientific 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
• Date of first enrolment: February 21, 2018
• Target sample size: 23
• Recruitment status: Completed
• URL: https://clinicaltrials.gov/show/NCT03177603
• Study type: Interventional
• Study design: Allocation: Non-Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: None (Open Label).
• Phase: Phase 2

Countries of recruitment

Germany, Spain, United States

Contacts

• Name: GSK Clinical Trials
• Affiliation: GlaxoSmithKline

Key inclusion & exclusion 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.



Age minimum: 18 Years
Age maximum: 75 Years
Gender: All

Health Condition(s) or Problem(s) studied

Hypertension, Pulmonary

Intervention(s)

Drug: GSK2586881

Primary Outcome(s)

Change From Baseline in Pulmonary Vascular Resistance (PVR) [Time Frame: Baseline (Day 1, Pre-dose); 1 hour, 2 hours and 4 hours post-dose (Day 1)]

Change From Baseline in Mean Pulmonary Artery Pressure (mPAP) [Time Frame: Baseline (Day 1, Pre-dose); 1 hour, 2 hours and 4 hours post-dose (Day 1)]

Change From Baseline in Cardiac Output (CO) [Time Frame: Baseline (Day 1, Pre-dose); 1 hour, 2 hours and 4 hours post-dose (Day 1)]

Secondary Outcome(s)

Change From Baseline in Clinical Chemistry Parameters: Alkaline Phosphatase, Alanine Amino Transferase and Aspartate Amino Transferase [Time Frame: Baseline (Day 1, Pre-dose), 24 hours post-dose (Day 1) and one sample between Day 7 to Day 14 (follow up visit)]

Change From Baseline in Disease Biomarkers: N-terminal Pro B-type Natriuretic Peptide (NT Pro-BNP) [Time Frame: Baseline (Day 1, Pre-dose); 2 hours, 4 hours and 24 hours post-dose (Day 1)]

Maximum Observed Plasma Concentration (Cmax) of GSK2586881 [Time Frame: Pre-dose (Day 1) and 0.08, 0.5, 1, 2, 4, 8 and 24 hours post-dose (Day 1)]

Number of Participants With Positive Immunogenicity Results [Time Frame: Up to Day 28]

Number of Participants With Serious Adverse Events (SAEs) [Time Frame: Up to Day 28]

Change From Baseline in Clinical Chemistry Parameter: Total Protein [Time Frame: Baseline (Day 1, Pre-dose), 24 hours post-dose (Day 1) and one sample between Day 7 to Day 14 (follow up visit)]

Change From Baseline in Clinical Chemistry Parameters: Direct Bilirubin, Total Bilirubin and Creatinine [Time Frame: Baseline (Day 1, Pre-dose), 24 hours post-dose (Day 1) and one sample between Day 7 to Day 14 (follow up visit)]

Last Observed Quantifiable Concentration (Ct) of GSK2586881 [Time Frame: Pre-dose (Day 1) and 0.08, 0.5, 1, 2, 4, 8 and 24 hours post-dose (Day 1)]

Change From Baseline in Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP) [Time Frame: Baseline (Day 1, Pre-dose); 0.5 hour, 1 hour, 2 hours, 4 hours, 8 hours and 24 hours post-dose (Day 1); and one sample between Day 7 to Day 14 (follow up visit)]

Number of Participants With Abnormal Electrocardiogram (ECG) Findings [Time Frame: 4 hours and 24 hours post-dose (Day 1) and one sample between Day 7 to Day 14 (follow up visit)]

Change From Baseline in Disease Biomarker: Cardiac Troponin-I [Time Frame: Baseline (Day 1, Pre-dose); 2 hours, 4 hours and 24 hours post-dose (Day 1)]

Number of Participants With Urinalysis Results by Dipstick Method [Time Frame: 24 hours post-dose (Day 1)]

Apparent Terminal Phase Half-life (t1/2) of GSK2586881 [Time Frame: Pre-dose (Day 1) and 0.08, 0.5, 1, 2, 4, 8 and 24 hours post-dose (Day 1)]

Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet Count and White Blood Cell (WBC) Count [Time Frame: Baseline (Day 1, Pre-dose), 24 hours post-dose (Day 1) and one sample between Day 7 to Day 14 (follow up visit)]

Change From Baseline in Pulmonary Wedge RAS Peptides: Angiotensin II, Angiotensin (1-5) and Angiotensin (1-7) [Time Frame: Baseline (Day 1, Pre-dose); 1 hour, 2 hours and 4 hours post-dose (Day 1)]

Apparent Volume of Distribution of GSK2586881 [Time Frame: Pre-dose (Day 1) and 0.08, 0.5, 1, 2, 4, 8 and 24 hours post-dose (Day 1)]

Change From Baseline in Pulse Oximetry Parameter: Percent Oxygen in Blood [Time Frame: Baseline (Day 1, Pre-dose); 0.5 hour, 1 hour, 2 hours, 4 hours, 8 hours and 24 hours post-dose (Day 1); and one sample between Day 7 to Day 14 (follow up visit)]

Area Under the Concentration-time Curve From Time Zero (Pre-dose) Extrapolated to Infinite Time (AUC[0-inf]) of GSK2586881 [Time Frame: Pre-dose (Day 1) and 0.08, 0.5, 1, 2, 4, 8 and 24 hours post-dose (Day 1)]

Change From Baseline in Nitrite, Nitrate and Endogenous Nitrite (Biomarkers of Nitric Oxide [NO]) [Time Frame: Baseline (Day 1, Pre-dose); 2 hours, 4 hours and 24 hours post-dose (Day 1)]

Change From Baseline in Clinical Chemistry Parameters: Calcium, Glucose, Potassium, Sodium and Blood Urea Nitrogen (BUN) [Time Frame: Baseline (Day 1, Pre-dose), 24 hours post-dose (Day 1) and one sample between Day 7 to Day 14 (follow up visit)]

Change From Baseline in Pulse Rate [Time Frame: Baseline (Day 1, Pre-dose); 0.5 hour, 1 hour, 2 hours, 4 hours, 8 hours, 24 hours post-dose (Day 1); and one sample between Day 7 to Day 14 (follow up visit)]

Change From Baseline in Hematology Parameter: Reticulocytes [Time Frame: Baseline (Day 1, Pre-dose), 24 hours post-dose (Day 1) and one sample between Day 7 to Day 14 (follow up visit)]

Time to Cmax (Tmax) of GSK2586881 [Time Frame: Pre-dose (Day 1) and 0.08, 0.5, 1, 2, 4, 8 and 24 hours post-dose (Day 1)]

Change From Baseline in Respiratory Rate [Time Frame: Baseline (Day 1, Pre-dose); 0.5 hour, 1 hour, 2 hours, 4 hours, 8 hours and 24 hours post-dose (Day 1); and one sample between Day 7 to Day 14 (follow up visit)]

Time of the Last Quantifiable Concentration (Tlast) of GSK2586881 [Time Frame: Pre-dose (Day 1) and 0.08, 0.5, 1, 2, 4, 8 and 24 hours post-dose (Day 1)]

Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC[0-t]) of GSK2586881 [Time Frame: Pre-dose (Day 1) and 0.08, 0.5, 1, 2, 4, 8 and 24 hours post-dose (Day 1)]

Pulmonary Wedge RAS Peptide: Angiotensin II/Angiotensin (1-7) Ratio at Indicated Time Points [Time Frame: 1 hour, 2 hours and 4 hours post-dose (Day 1)]

Change From Baseline in Hematology Parameter: Hematocrit [Time Frame: Baseline (Day 1, Pre-dose), 24 hours post-dose (Day 1) and one sample between Day 7 to Day 14 (follow up visit)]

Change From Baseline in Hematology Parameter: Hemoglobin [Time Frame: Baseline (Day 1, Pre-dose), 24 hours post-dose (Day 1) and one sample between Day 7 to Day 14 (follow up visit)]

Change From Baseline in Hematology Parameter: Mean Corpuscle Volume [Time Frame: Baseline (Day 1, Pre-dose), 24 hours post-dose (Day 1) and one sample between Day 7 to Day 14 (follow up visit)]

Change From Baseline in Hematology Parameter: Mean Corpuscle Hemoglobin [Time Frame: Baseline (Day 1, Pre-dose), 24 hours post-dose (Day 1) and one sample between Day 7 to Day 14 (follow up visit)]

Change From Baseline in Hematology Parameter: Red Blood Cell (RBC) Count [Time Frame: Baseline (Day 1, Pre-dose), 24 hours post-dose (Day 1) and one sample between Day 7 to Day 14 (follow up visit)]

Change From Baseline in Systemic Renin-Angiotensin System (RAS) Peptides: Angiotensin II, Angiotensin (1-5) and Angiotensin (1-7) [Time Frame: Baseline (Day 1, Pre-dose); 0.08 hour, 0.5 hour, 1 hour, 2 hours, 4 hours, 8 hours and 24 hours post-dose (Day 1); and one sample between Day 7 to Day 14 (follow up visit)]

Number of Participants With Non-serious Adverse Events (AEs) [Time Frame: Up to Day 28]

Plasma Clearance (CL) of GSK2586881 [Time Frame: Pre-dose (Day 1) and 0.08, 0.5, 1, 2, 4, 8 and 24 hours post-dose (Day 1)]

Systemic RAS Peptide: Angiotensin II/Angiotensin (1-7) Ratio at Indicated Time Points [Time Frame: 0.08 hour, 0.5 hour, 1 hour, 2 hours, 4 hours, 8 hours and 24 hours post-dose (Day 1) and one sample between Day 7 to Day 14 (follow up visit)]

Secondary ID(s)

206246

2017-000212-41

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Results

• Results available: Yes
• Date Posted: 21/04/2020
• URL: https://clinicaltrials.gov/ct2/show/results/NCT03177603