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    Summary
    EudraCT Number:2017-000212-41
    Sponsor's Protocol Code Number:206246
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2017-06-27
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedGermany - BfArM
    A.2EudraCT number2017-000212-41
    A.3Full title of the trial
    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
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study to test a new drug to treat patients with Pulmonary Arterial Hypertension (PAH)
    A.3.2Name or abbreviated title of the trial where available
    PH 2a, SD, DE, safety, PK/PD study of GSK2586881 in Pulmonary Arterial Hypertension pts
    A.4.1Sponsor's protocol code number206246
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorGlaxoSmithKline Research & Development Ltd
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportGlaxoSmithKline R&D
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGlaxoSmithKline Research and Development Ltd
    B.5.2Functional name of contact pointGSK Clinical Support Help Desk
    B.5.3 Address:
    B.5.3.1Street AddressIron Bridge Road
    B.5.3.2Town/ cityUxbridge
    B.5.3.3Post codeUB11 1BU
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+44 800 7839733
    B.5.6E-mailGSKClinicalSupportHD@gsk.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameGSK2586881
    D.3.2Product code GSK2586881
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNGSK2586881
    D.3.9.2Current sponsor codeGSK2586881
    D.3.9.3Other descriptive nameRecombinant Human Angiotensin-converting enzyme 2 (ACE2), APN01
    D.3.9.4EV Substance CodeSUB83581
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Pulmonary arterial hypertension
    E.1.1.1Medical condition in easily understood language
    Pulmonary arterial hypertension
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10064911
    E.1.2Term Pulmonary arterial hypertension
    E.1.2System Organ Class 10038738 - Respiratory, thoracic and mediastinal disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10077739
    E.1.2Term Pulmonary arterial hypertension WHO functional class I
    E.1.2System Organ Class 10038738 - Respiratory, thoracic and mediastinal disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10077729
    E.1.2Term Pulmonary arterial hypertension WHO functional class III
    E.1.2System Organ Class 10038738 - Respiratory, thoracic and mediastinal disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10077740
    E.1.2Term Pulmonary arterial hypertension WHO functional class II
    E.1.2System Organ Class 10038738 - Respiratory, thoracic and mediastinal disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate changes in the pulmonary hemodynamics after single IV doses of GSK2586881 administered to participants with PAH receiving background PAH therapy.
    E.2.2Secondary objectives of the trial
    -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.
    E.2.3Trial contains a sub-study No
    E.3Principal 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.
    E.4Principal 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 in the study would result in loss of blood or blood products in excess of 300mL within 65 days.
    21. Exposure to more than 4 new chemical entities within 12 months prior to the first dosing day.
    22. A known or suspected history of alcohol or drug abuse within the 2 years prior to screening
    23. Unable to refrain from smoking during the in-house treatment period.
    E.5 End points
    E.5.1Primary end point(s)
    - Change from baseline in pulmonary vascular resistance (PVR), cardiac output (CO) and mean pulmonary artery pressure (mPAP), as data permit
    E.5.1.1Timepoint(s) of evaluation of this end point
    0, 1h, 2h, 4h
    E.5.2Secondary 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.
    E.5.2.1Timepoint(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
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy No
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Tolerability
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned7
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA7
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    United States
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 23
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 4
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 16
    F.4.2.2In the whole clinical trial 24
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Participants will not receive any additional treatment from GSK after completion of the study because other treatment options are available.
    The investigator is responsible for ensuring that consideration has been given to the poststudy care of the participants medical condition, whether or not GSK is providing specific post-study treatment
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2017-08-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-09-01
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-05-07
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