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

NCT03177603 | Completed Phase 2 Results FDA Drug

• 2 other identifiers: 2062462017-000212-41
• Study Type: interventional
• Target: 23
• Locations: 3 countries
• Sites: 8

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.

Conditions

Hypertension, Pulmonary

Keywords

Pulmonary Arterial Hypertension; Dose-escalation; Safety; Tolerability; GSK2586881

Outcome Measures

Primary Outcomes (3)

• Change From Baseline in Pulmonary Vascular Resistance (PVR)

  PVR is the resistance generated by pulmonary circulation. Pulmonary arterial catheters were placed in participants and PVR values were recorded from the right heart catheterization. Baseline was defined as the latest pre-dose assessment (Day 1) with a non-missing value, including those from unscheduled visits. Change from Baseline was measured as ratio of post-dose visit value to Baseline value.

  Baseline (Day 1, Pre-dose); 1 hour, 2 hours and 4 hours post-dose (Day 1)

• Change From Baseline in Cardiac Output (CO)

  CO is the amount of blood pumped by the heart per minute. Pulmonary arterial catheters were placed in participants and CO values were recorded from the right heart catheterization. Baseline was defined as the latest pre-dose assessment (Day 1) with a non-missing value, including those from unscheduled visits. Change from Baseline was measured as ratio of post-dose visit value to Baseline value.

  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)

  The pulmonary artery pressure is a measure of the blood pressure found in the main pulmonary artery. Pulmonary arterial catheters were placed in participants and mPAP values were recorded from the right heart catheterization. Baseline was defined as the latest pre-dose assessment (Day 1) with a non-missing value, including those from unscheduled visits. Change from Baseline was measured as ratio of post-dose visit value to Baseline value.

  Baseline (Day 1, Pre-dose); 1 hour, 2 hours and 4 hours post-dose (Day 1)

Secondary Outcomes (36)

• Number of Participants With Non-serious Adverse Events (AEs)

  Up to Day 28

• Number of Participants With Serious Adverse Events (SAEs)

  Up to Day 28

• Change From Baseline in Clinical Chemistry Parameters: Alkaline Phosphatase, Alanine Amino Transferase and Aspartate Amino Transferase

  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

  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: Calcium, Glucose, Potassium, Sodium and Blood Urea Nitrogen (BUN)

  Baseline (Day 1, Pre-dose), 24 hours post-dose (Day 1) and one sample between Day 7 to Day 14 (follow up visit)

Other Outcomes (1)

• Change From Baseline in Cardiac Index (CI)

  Baseline (Day 1, Pre-dose); 1 hour, 2 hours and 4 hours post-dose (Day 1)

Study Arms (4)

GSK2586881 - 0.1 mg/kg

EXPERIMENTAL

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 - 0.2 mg/kg

EXPERIMENTAL

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 - 0.4 mg/kg

EXPERIMENTAL

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 - 0.8 mg/kg

EXPERIMENTAL

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

Interventions

GSK2586881 DRUG

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.

GSK2586881 - 0.1 mg/kg; GSK2586881 - 0.2 mg/kg; GSK2586881 - 0.4 mg/kg; GSK2586881 - 0.8 mg/kg

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (8)

GSK Investigational Site

Pittsburgh, Pennsylvania, 15213, United States

Location

GSK Investigational Site

Dallas, Texas, 75390-8550, United States

Location

GSK Investigational Site

Heidelberg, Baden-Wurttemberg, 69126, Germany

Location

GSK Investigational Site

Cologne, North Rhine-Westphalia, 50937, Germany

Location

GSK Investigational Site

Dresden, Saxony, 01307, Germany

Location

GSK Investigational Site

Berlin, 14050, Germany

Location

GSK Investigational Site

Barcelona, 08035, Spain

Location

GSK Investigational Site

Madrid, 28041, Spain

Location

MeSH Terms

Conditions

Hypertension, Pulmonary; Pulmonary Arterial Hypertension

Interventions

alunacedase alfa

Condition Hierarchy (Ancestors)

Lung Diseases; Respiratory Tract Diseases; Hypertension; Vascular Diseases; Cardiovascular Diseases

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 23, 2017
• First Posted: June 6, 2017
• Study Start: February 21, 2018
• Primary Completion: May 7, 2019
• Study Completion: May 7, 2019
• Last Updated: April 21, 2020
• Results First Posted: April 21, 2020

Record last verified: 2020-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, 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.

Locations

US (2); DE (4); ES (2)