Study to test a new drug to treat patients with Pulmonary Arterial Hypertension (PAH)

• Register: EUCTR
• Last refreshed on: 26 March 2024
• Main ID: EUCTR2017-000212-41-DE
• Date of registration: 27/06/2017
• Prospective Registration: Yes
• Primary sponsor: GlaxoSmithKline Research & Development Ltd
• Public title: Study to test a new drug to treat patients 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 - PH 2a, SD, DE, safety, PK/PD study of GSK2586881 in Pulmonary Arterial Hypertension pts
• Date of first enrolment: 01/09/2017
• Target sample size: 24
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2017-000212-41
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no Randomised: no Open: yes Single blind: no Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: no Number of treatment arms in the trial: 1
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Germany, Spain, United States

Contacts

• Name: GSK Clinical Support Help Desk
• Affiliation: GlaxoSmithKline Research and Development Ltd

• Name: GSK Clinical Support Help Desk
• Affiliation: GlaxoSmithKline Research and Development Ltd

Key inclusion & exclusion criteria

Inclusion criteria:
Participants are eligible to be included in the study only if all of the following criteria apply:
Age
1. Participant must be between 18-75 years of age (inclusive), at the time of signing the informed consent
Type of Participant and Disease Characteristics
2. Documented diagnosis of PAH, defined as mPAP > 25 mmHg and PWP = 15 mmHg.
3. IPAH, HPAH, or PAH associated with collagen vascular disease or appetite suppressant use.
- Note: Those with portopulmonary hypertension or PVOD are not eligible for the study
4. World Health Organization (WHO) functional class I, II, or III, stable for at least 8 weeks prior to enrollment.
5. Hemodynamically stable on background therapy with no evidence of uncontrolled right heart failure (historic data), as determined by the investigator.
6. Six minute walk (6MW) distance, as performed at screening or within 6 months prior to screening, of = 100 meters and = 500 meters.
7. Mean BP of >60 mmHg
8. 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.
NOTE: Anticoagulant therapy can be adjusted according to target INR
9. Diuretic dose stable for 8 weeks.
Weight
10. Body weight = 100 kg and body mass index (BMI) within the range 18-35 kg/m2 (inclusive).
Sex
11. Male and/or female (following confirmation of negative pregnancy test for WOCBP). Women who are pregnant or breastfeeding are excluded.
Informed Consent
12. Capable of giving signed informed consent as described in Appendix 3 (within the protocol) which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 23
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 4

Exclusion criteria:
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. History of systemic hypotension, defined as systolic BP <90 mmHg and/or diastolic BP <50 mmHg.
2. Hospitalization for PAH associated deterioration in the previous 6 months.
3. 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.
4. Complex repaired and unrepaired congenital heart disease.
5. Subjects with Eisenmenger physiology.
6. Alanine transferase (ALT) >2x upper limit of normal (ULN).
7. Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
8. Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
9. Estimated glomerular-filtration-rate (eGFR) <45mL/min/1.73m2.
10. QTc >480 msec or QTc > 500 msec in participants with bundle branch block.
NOTES:
-The QTc is the QT interval corrected for heart rate according to Bazett’s formula (QTcB), Fridericia’s formula (QTcF), and/or another method. It is either machineread or manually over-read.
-The specific formula used to determine eligibility and discontinuation for an individual participant should be determined prior to initiation of the study. In other words, several different formulas cannot be used to calculate the QTc for an individual participant and then the lowest QTc value used to include or discontinue the participant from the trial.
11. Any bleeding concerns as evidenced by INR >1.5 (in participants not receiving anticoagulation therapy) or platelet count <80,000.
12. Hb <10 g/dL
Prior/Concomitant Therapy
13. 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.
14. Any use of an 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 participant’s treating physician.
Prior/Concurrent Clinical Study Experience
15. 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.
Diagnostic assessments
16. Positive HIV antibody test.
17. Presence of Hepatitis B surface antigen (HBsAg) at screening.
18. Positive Hepatitis C antibody test result at screening or within 3 months prior to starting study treatment.
-NOTE: Participants with positive Hepatitis C antibody due to prior resolved disease can be enrolled, only if a confirmatory negative Hepatitis C ribonucleic acid (RNA) test is obtained.
19. Positive Hepatitis C RNA test result at screening or within 3 months prior to first dose of study treatment.
-NOTE: Test is optional and participants with negative Hepatitis C antibody test are not required to also undergo Hepatitis C RNA testing.
Other Exclusions
20. Participation i

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Cardiovascular Diseases [C14]

Pulmonary arterial hypertension
MedDRA version: 20.0 Level: PT Classification code 10064911 Term: Pulmonary arterial hypertension System Organ Class: 10038738 - Respiratory, thoracic and mediastinal disorders
MedDRA version: 20.0 Level: LLT Classification code 10077739 Term: Pulmonary arterial hypertension WHO functional class I System Organ Class: 10038738 - Respiratory, thoracic and mediastinal disorders
MedDRA version: 20.0 Level: LLT Classification code 10077729 Term: Pulmonary arterial hypertension WHO functional class III System Organ Class: 10038738 - Respiratory, thoracic and mediastinal disorders
MedDRA version: 20.0 Level: LLT Classification code 10077740 Term: Pulmonary arterial hypertension WHO functional class II System Organ Class: 10038738 - Respiratory, thoracic and mediastinal disorders

Intervention(s)

Product Name: GSK2586881
Product Code: GSK2586881
Pharmaceutical Form: Solution for injection
INN or Proposed INN: GSK2586881
Current Sponsor code: GSK2586881
Other descriptive name: Recombinant Human Angiotensin-converting enzyme 2 (ACE2), APN01
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 5-

Primary Outcome(s)

Secondary Objective: -To evaluate the safety and tolerability of single IV doses of GSK2586881
administered to participants with PAH receiving background PAH therapy.
-To evaluate the effect of single IV doses of GSK2586881 on RAS peptide responses in participants with PAH receiving background PAH therapy.
-To evaluate the effect on biomarkers of disease activity after single IV doses of GSK2586881 administered to participants with PAH receiving background PAH therapy.
-To evaluate the pharmacokinetics of GSK2586881 after single IV doses of GSK2586881 in participants with PAH receiving background PAH therapy.

Main Objective: To evaluate changes in the pulmonary hemodynamics after single IV doses of GSK2586881 administered to participants with PAH receiving background PAH therapy.

Primary end point(s): - Change from baseline in pulmonary vascular resistance (PVR), cardiac output (CO) and mean pulmonary artery pressure (mPAP), as data permit

Timepoint(s) of evaluation of this end point: 0, 1h, 2h, 4h

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: • 0.08h
• 0.5h
• 1h
• 2h
• 4h
• 8h
• 24h
• 7-14 days after dose,
• immunogenicity also collected at 28 +/- 3 days after dose

Secondary end point(s): -Adverse events (AE), clinical laboratory values, vital signs, ECG, pulse oximetry and immunogenicity.
-Change from baseline of RAS peptides (e.g. Ang II, Ang(1-7), Ang(1-5),
transpulmonary gradient of AngII/Ang (1-7) ratio).
-Change from baseline in NT pro-BNP, NO and cardiac troponin I.
-Plasma concentrations of GSK2586881 and derived PK parameters.

Secondary ID(s)

2017-000212-41-ES

206246

Source(s) of Monetary Support

GlaxoSmithKline R&D

Ethics review

Status: Approved
Approval date: 01/09/2017
Contact:

Results

• Results available: Yes
• Date Posted: 23/04/2020
• Date Completed: 07/05/2019
• URL: https://www.clinicaltrialsregister.eu/ctr-search/trial/2017-000212-41/results