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    Summary
    EudraCT Number:2018-003414-40
    Sponsor's Protocol Code Number:LTI-201
    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:2018-11-06
    Trial 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 number2018-003414-40
    A.3Full title of the trial
    A Two Part, Phase 2 Open-label, Multi-Centre, Dose Escalation Hemodynamic Study to Evaluate Dose-Response and Safety of Inhaled LIQ861 (Treprostinil) in Pulmonary Arterial Hypertension (WHO Group 1) Subjects
    Zweiteilige, unverblindete, multizentrische Dosiseskalationsstudie der Phase 2 zur Untersuchung der hämodynamischen Dosis-Wirkungs-Beziehung und der Sicherheit von inhalativem LIQ861 (Treprostinil) bei Patienten mit pulmonalarterieller Hypertonie (WHO-Gruppe 1)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Two Part Clinical Study to Evaluate the Effect of Different Doses and the Safety of Inhaled Treprostinil Dry Powder in Pulmonary Arterial Hypertension Patients
    Zweiteilige klinische Studie zur Untersuchung des Effektes bei verschiedenen Dosierungen und der Sicherheit von inhalativem Treprostinil-Trockenpulver bei Patienten mit pulmonalarteriellem Bluthochdruck
    A.4.1Sponsor's protocol code numberLTI-201
    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 SponsorLiquidia Technologies, Inc.
    B.1.3.4CountryUnited States
    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 supportLiquidia Technologies, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationLiquidia Technologies, Inc.
    B.5.2Functional name of contact pointLiquidia Technologies Headquarters
    B.5.3 Address:
    B.5.3.1Street Address419 Davis Dr. Suite 100
    B.5.3.2Town/ cityMorrisville
    B.5.3.3Post codeNC 27560
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1919 328-4400
    B.5.5Fax number+1919 328-4402
    B.5.6E-mailClinicalTrials@liquidia.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 nameLIQ861 26.5 μg
    D.3.4Pharmaceutical form Inhalation powder, hard capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPInhalation use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTreprostinil Sodium
    D.3.9.1CAS number 289480-64-4
    D.3.9.3Other descriptive nameTREPROSTINIL SODIUM
    D.3.9.4EV Substance CodeSUB22911
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number26.5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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 Yes
    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 No
    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.IMP: 2
    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 nameLIQ861 53 μg
    D.3.4Pharmaceutical form Inhalation powder, hard capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPInhalation use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTreprostinil Sodium
    D.3.9.1CAS number 289480-64-4
    D.3.9.3Other descriptive nameTREPROSTINIL SODIUM
    D.3.9.4EV Substance CodeSUB22911
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number53
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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 Yes
    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 No
    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.IMP: 3
    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 nameLIQ861 79.5 μg
    D.3.4Pharmaceutical form Inhalation powder, hard capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPInhalation use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTreprostinil Sodium
    D.3.9.1CAS number 289480-64-4
    D.3.9.3Other descriptive nameTREPROSTINIL SODIUM
    D.3.9.4EV Substance CodeSUB22911
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number79.5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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 Yes
    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 No
    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.IMP: 4
    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 nameLIQ861 106 μg
    D.3.4Pharmaceutical form Inhalation powder, hard capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPInhalation use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTreprostinil Sodium
    D.3.9.1CAS number 289480-64-4
    D.3.9.3Other descriptive nameTREPROSTINIL SODIUM
    D.3.9.4EV Substance CodeSUB22911
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number106
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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 Yes
    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 No
    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.IMP: 5
    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 Yes
    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 nameNitric Oxide
    D.3.4Pharmaceutical form Medicinal gas, compressed
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPEndotracheopulmonary use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNITRIC OXIDE
    D.3.9.1CAS number 10102-43-9
    D.3.9.4EV Substance CodeSUB12540MIG
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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 No
    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 Yes
    D.3.11.13.1Other medicinal product typeInhalation gas
    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 (WHO Group 1)
    Pulmonalarterielle Hypertonie (WHO-Gruppe 1)
    E.1.1.1Medical condition in easily understood language
    Increased blood pressure within the arteries of the lungs
    Bluthochdruck in den Lungenarterien
    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 LLT
    E.1.2Classification code 10077739
    E.1.2Term Pulmonary arterial hypertension WHO functional class I
    E.1.2System Organ Class 100000004855
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of this study is to characterize the hemodynamic dose-response relationships for LIQ861.
    E.2.2Secondary objectives of the trial
    The secondary objective of this study is to evaluate the acute and chronic safety and tolerability of LIQ861 in subjects with Pulmonary Arterial Hypertension.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Subjects with WHO Group 1 PAH who are
    • Taking no more than 2 approved, non-prostacyclin PAH therapies and are on stable doses of pharmacologic therapies for ≥ 3 months

    INCLUSION CRITERIA:

    A subject will be eligible for inclusion in this study only if all of the following criteria are met:

    1. An Institutional Review Board (IRB) approved informed consent is signed and dated by the subject prior to any study-related activities.

    2. The subject is 18 years of age or older.

    3. If the subject is a female of childbearing potential, then the subject has a negative pregnancy test at the Day 1 Visit (tests performed within 2 days before Day 1 are accepted) and agrees to practice a highly effective (failure rate of less than 1% per year when used consistently and correctly) method of birth control until 24 hours after completion of all study assessments defined in Appendix 1. If the subject is postmenopausal or has documented surgical sterilization, a pregnancy test and birth control is not necessary. It is the Investigator's responsibility for determining whether the subject hasadequate birth control for study participation.

    4. The subject has been diagnosed with PAH belonging to one of the following subgroups of the updated Nice Clinical Classification Group 1, which includes:
    a. Idiopathic PAH (1.1), or
    b. Heritable PAH (1.2), or
    c. Drug and toxin induced PAH (1.3), or
    d. PAH associated with connective tissue disease (1.4.1), HIV infection (1.4.2), or congenital heart disease (1.4.4) with simple
    systemic-to-pulmonary shunt at least 1 year after surgical repair

    5. The subject is NYHA Functional Class II - IV at Screening and:
    a. has not previously been treated for PAH, or
    b. has documented stable doses of no more than 2 approved nonprostacyclin PAH-disease specific therapies for at least
    3 months prior to Screening, is willing and able to add LIQ861 to their treatment regimen and is willing to hold the dosing of these therapies for at least 12 hours prior to study-mandated right heart catheterization
    procedures.

    6. The subject can complete a baseline six-minute walk distance (6MWD) ≥150 m.

    7. The subject has had evidence of Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) ≥60% of predicted values and FEV1/FVC ratio ≥60% during the 6-month period prior to consent.
    E.4Principal exclusion criteria
    EXCLUSION CRITERIA:

    A subject is not eligible for inclusion in the study if any of the following criteria apply:

    1. The subject's clinical condition is such that, in the opinion of the Investigator, they are not expected to remain clinically stable for the duration of the study.

    2. Subjects with pulmonary hypertension (PH) in the Updated Nice Classification Groups 2-5, or PAH Group 1 subgroups not covered by the inclusion criteria (e.g., associated with portal hypertension [1.4.3] or with schistosomiasis [1.4.5]).

    3. The subject is currently taking prostacyclin analogues or agonists, including treprostinil, iloprost, epoprostenol or selexipag.

    4. The subject has discontinued any medication (except for anticoagulants, but otherwise including and not limited to oxygen, a different class of vasodilator, diuretic, digoxin, and digitalis) for pulmonary hypertension within 14 days prior to Day 1.

    5. The subject has had a new type of therapy (including but not limited to oxygen, a different class of vasodilator, diuretic, digoxin, and digitalis) for pulmonary hypertension added within 30 days prior to Day 1.

    6. The subject has uncontrolled systemic hypertension as evidenced by systolic blood pressure greater than 160 mmHg or diastolic blood pressure greater than 100 mmHg at the time of screening or Day 1.

    7. The subject has a history of hemodynamically significant left-sided heart disease including, but not limited to: aortic or mitral valve disease, pericardial constriction, restrictive or congestive cardiomyopathy, or symptomatic coronary artery disease (CAD).

    8. The subject has had an atrial septostomy.

    9. The subject has a history of prolongation of QT interval on ECG as follows: Male subjects with a corrected QT interval using Fridericia’s formula (QTcF) >450 msec and female subjects with QTcF >470 msec.

    10. The subject has any serious or life-threatening disease other than conditions associated with PAH.

    11. The subject is taking any excluded medications listed in the Investigator’s Brochure, namely inhibitors and inducers of CYP2C8.

    12. The subject has a hypersensitivity or allergy to any of the ingredients of LIQ861, NO, or other clinically relevant allergies (clinical relevance per Investigator judgment).

    13. The subject has had an acute pulmonary embolus within 6 months prior to Baseline.

    14. The subject has had a stroke or transient ischemic attack within 6 months prior to Baseline.

    15. The subject has evidence of an active uncontrolled sepsis or systemic infection in the period after informed consent up to Baseline.

    16. The subject is pregnant or lactating.

    17. The subject has any musculoskeletal disease or any other disease that limits evaluation of 6MWD.

    18. The subject has participated in an investigational product or device study within the 30 days prior to Baseline.

    19. The subject has current evidence of drug abuse in the opinion of the Investigator.

    20. The subject has severe hepatic impairment as evidenced by any history of ascites AND encephalopathy.

    21. The subject has severe renal impairment (estimated glomerular filtration rate [eGFR] <35 mL/min utilizing the Modification of Diet in Renal Disease (MDRD) study equation at Screening or requires dialytic support).

    22. The subject is an employee or an immediate family member to an employee of the Sponsor or the Investigator.

    23. The subject is not a member or beneficiary of a social security scheme.

    24. The subject lacks a legal protection measure.

    25. The subject has been deprived of their liberty by a judicial or administrative decision.

    26. The subject has a known Hepatitis B or Hepatitis C infection with active viral replication.

    27. The subject has a known HIV infection with CD4 count less than 200 and more than undetectable viral load, defined as less than 50 copies/mL.

    28. The subject required use of intravenous inotropes including, but not limited to, Levosimendan, Dopamine, Dobutamine, Dopexamine, Epinephrine, Isoprenaline (isoproterenol), Norepinephrine (noradrenaline), Milrinone, or Amrinone, within 30 days prior to Baseline.

    29. The subject has been administered intravenous diuretic within 30 days prior to Baseline.

    30. Subjects taking vitamin K antagonist therapy with a known INR ≥3.5 (assessed per local care standards) at the time of screening assessments or at Baseline.
    E.5 End points
    E.5.1Primary end point(s)
    Hemodynamic Endpoints:

    For Part A of the study, the change in Pulmonary Vascular Resistance (PVR) measured from Baseline (pre-dose) to maximal response (eMAX) at Day 1 will be considered the primary efficacy endpoint.

    For Part B of the study, the change in PVR measured from Baseline (predose) to post dose at Week 16 will be considered the primary efficacy endpoint.

    During the open-label extension period, change in PVR and other hemodynamic endpoints will not be assessed.
    -----

    Safety Endpoints:

    The primary safety endpoint in Part A, Part B and the open-label extension period will be the incidence and severity of AEs and Serious Adverse Events (SAEs) grouped by Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class, dose level, time on drug, and relationship to dose.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Throughout the whole study
    E.5.2Secondary end point(s)
    Hemodynamic Endpoints:

    For part A:
    • PVRI, Mean SBP, Mean PAP, PCWP, RAP, CO, CI, SVR, SVRI, PAO2%, SvO2, SaO2 and HR.

    For part B:
    • PVRI, Mean SBP, Mean PAP, PCWP, RAP, CO, CI, SVR, SVRI, PAO2%, SvO2, SaO2 and HR.

    During the open-label extension period, change in PVR and other hemodynamic endpoints will not be assessed.

    -----

    Secondary Acute Safety endpoints are as follows:

    • Incidence of drug-related AEs within 4 hours of dosing.

    • Change from baseline measurements to 240 minutes in vital signs.

    • Change from baseline measurements to 120 minutes in ECG/heart monitor assessments.


    Secondary Chronic Safety endpoints are as follows:

    • Incidence of drug-related AEs.

    • Changes from Day 1 (Baseline) measurements to Week 16/Early Termination/Week 126 in vital signs, clinical laboratory, and physical exam findings.

    -----

    Pharmacokinetic Endpoints:

    Individual PK parameters for treprostinil will be summarized by treatment using descriptive statistics. PK parameters such as the
    maximum observed plasma concentration (Cmax), time to Cmax (tmax), the area under the plasma concentration versus time curve from time 0 (pre-dose) to time infinity (AUCinf), AUC from time 0 to time of last measurable plasma concentration (AUClast), the percentage of AUC that is extrapolated beyond the last measurable concentration (AUCext), the terminal phase rate constant (λz), the apparent systemic clearance (CL/F), the apparent volume of distribution in the terminal phase (Vz/F), mean residence time (MRT), and the terminal phase half-life (t½) will be calculated using non-compartmental analyses.

    -----

    Exploratory Endpoints:

    For all subjects in Part B:

    • Change from Day 1 (Baseline) to Weeks 4, 8, and 16 in 6MWD.

    • Time to first significant change in 6MWD.

    • Change from Day 1 (Baseline) to Weeks 4, 8, and 16 in NYHA Functional Class status.

    • Change from Day 1 (Baseline) to Weeks 4, 8, and 16 in NT-proBNP levels.

    • Change from Day 1 (Baseline) to Week 16 in the REVEAL registry risk score version 2.0.

    • Change from Day 1 to Week 16 in the number and percentage of subjects to attain or maintain four, versus three, two, or one, low risk characteristics defined as:
    o NYHA Functional Class I or II
    o 6MWD >440 m
    o RAP <8 mmHg and CI ≥2.5 L/min/m²
    o NT-proBNP less than 300 ng/L.

    • Time to and reason for discontinuation of LIQ861.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Throughout the whole study
    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 Yes
    E.6.4Safety Yes
    E.6.5Efficacy No
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    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.8.3 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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA6
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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 years2
    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 years2
    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: 19
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 13
    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 state16
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 32
    F.4.2.2In the whole clinical trial 32
    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)
    - Following completion of Part A, subjects at participating centers in Germany may take part in part B, beginning immediately after part A.
    - Following completion of Part B, subjects will continue in the open-label extension period of the study on four times a day treatment with the IMP until Week 126.

    Part B and the following open-label extension period will not be conducted in France.
    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 Decision2018-12-27
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-01-31
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2021-05-12
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