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    Summary
    EudraCT Number:2020-002788-80
    Sponsor's Protocol Code Number:Uni-Koeln-4243
    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:2020-06-08
    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 number2020-002788-80
    A.3Full title of the trial
    An explorative study to assess the safety, tolerability, and efficacy of AZD4831 in the treatment of pulmonary arterial hypertension (PAH)
    (MPO-PAH)
    Explorative Studie zur Bewertung der Sicherheit, Verträglichkeit und Wirksamkeit von AZD4831 bei der Behandlung von Patienten mit pulmonaler arterieller Hypertonie (PAH)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study to evaluate the safety, tolerability and efficacy of AZD4831 in the
    treatment of patients with pulmonary hypertension
    Studie zur Bewertung der Sicherheit, Verträglichkeit und Wirksamkeit von
    AZD4831 bei der Behandlung von Patienten mit Lungenhochdruck
    A.4.1Sponsor's protocol code numberUni-Koeln-4243
    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 SponsorUniversity of Cologne
    B.1.3.4CountryGermany
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportAstraZeneca
    B.4.2CountrySweden
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPhilipps University Marburg, Coordinating Center for Clinical trials
    B.5.2Functional name of contact pointKKS
    B.5.3 Address:
    B.5.3.1Street AddressKarl-von-Frisch-Str. 4
    B.5.3.2Town/ cityMarburg
    B.5.3.3Post code35043
    B.5.3.4CountryGermany
    B.5.4Telephone number+4964212826598
    B.5.5Fax number+4964212866517
    B.5.6E-mailnelli.ens@kks.uni-marburg.de
    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 nameAZD4831
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    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 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
    Group 1: Pulmonary arterial hypertension (PAH)
    Group 2: Postcapillary pulmonary hypertension
    Pulmonal-arterielle Hypertonie
    E.1.1.1Medical condition in easily understood language
    Progressive disorder characterized by high blood pressure in the arteries of the lungs for no apparent reason
    Progressive Störung, die durch hohen Blutdruck in den Arterien der Lunge ohne ersichtlichen Grund gekennzeichnet ist
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    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 21.1
    E.1.2Level PT
    E.1.2Classification code 10037400
    E.1.2Term Pulmonary hypertension
    E.1.2System Organ Class 10038738 - Respiratory, thoracic and mediastinal disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess the efficacy of 12 weeks of AZD4831 in patients of two groups:
    1) Patients with PAH (pre-capillary PH) who are on established therapy (at least 1 targeted PAH drug:
    ERA, PDE5i/sGC-S, PCA/PRA), and
    2) Patients with post-capillary PH
    by measuring the change from baseline in pulmonary vascular resistance (PVR).
    E.2.2Secondary objectives of the trial
    To evaluate the preliminary efficacy of 12 weeks of AZD4831 administration in patients with pre- and post-capillary PH by measuring changes from baseline in:
    – Hemodynamic parameters other than PVR (including systolic, diastolic and mean pulmonary artery pressure, cardiac output, cardiac index, transpulmonary pressure gradient, diastolic pressure gradient, pulse pressure, pulmonary artery compliance)
    – Six minute walk distance (6MWD)
    – NTproBNP plasma levels
    – WHO functional class (WHO-FC)
    – ESC/ERS risk assessment
    – Right heart dimensions, right ventricular function and pulmonary flow as assessed by cardiac magnetic resonance imaging (cMRI)
    – Right heart dimensions and right ventricular function as assessed by echocardiography
    – Cardiopulmonary exercise capacity as assessed by cardiopulmonary exercise testing (CPET)
    – Endothelial function as measured by by flow mediated dilation (FMD) (patients of Group 2 only)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Signed written informed consent form
    2. Capability and willingness to comply with study procedures
    3. Adult patients age 18–85 years (male and female)
    4. Females must have a negative pregnancy test at the Screening Visit and on admission to the Clinical Unit, must not be lactating and must be of non-child-bearing potential, confirmed at the Screening Visit by fulfilling one of the following criteria:
    a) Postmenopausal defined as amenorrhea for at least 12 months or more following cessation of all exogenous hormonal treatments and FSH levels in the postmenopausal range.
    b) Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation.
    5. Male patients must be surgically sterile or using an acceptable method of contraception (defined as barrier methods in conjunction with spermicides) for the duration of the study (from the time they sign consent) and for 3 months after the last dose of AZD4831/matching placebo to prevent pregnancy in a partner. Male patients must not donate or bank sperm during this same time
    6. WHO Group 1 diagnosis of IPAH; HPAH; or PAH associated with connective tissue disease (CTD), drugs/toxins, HIV, repaired congenital heart defect (CHD) OR WHO group 2 diagnosis of postcapillary PH
    7. On stable therapy (≥1 approved drug) before inclusion (signed ICF) for ≥12 weeks, ≥8 weeks at same dose
    8. Symptomatic despite therapy (WHO functional class II or III)
    9. 6MWD ≥100 m at screening
    10. Hemodynamic criteria:
    Group 1:
    • mPAP ≥25 mmHg
    • PAWP or LVEDP ≤ 15 mmHg
    • PVR > 3 Wood units
    Group 2:
    • mPAP ≥25 mmHg
    • PAWP or LVEDP > 15 mmHg
    • Irrespective of PVR
    11. No chronic thromboembolic pulmonary hypertension (CTEPH) as
    documented by a negative or low probability lung ventilation/perfusion scan or negative pulmonary arteriogram
    E.4Principal exclusion criteria
    1. Only for the group 1) : PAH associated with significant venous or capillary involvement (PCWP >15 mmHg), pulmonary capillary hemangiomatosis, portal hypertension or unrepaired CHD
    2. Pulmonary hypertension belonging to WHO Groups 3–5
    3. Uncontrolled hypertension (≥160/100 mmHg), at least one value is increased
    4. Moderate stage renal disease for patients treated with AZD4831 (eGFR <30ml/min)
    5. Severe liver disease (Child-Pugh class C, with or without cirrhosis); elevation of liver enzymes (AST/ALT) to > 3x ULN
    6. Hypersensitivity to the active substance or one of the ingredients (see current IB)
    7. Participation in another interventional clinical study within 30 days before baseline
    8. Any clinically significant disease or disorder (e.g. cardiovascular, gastrointestinal, liver, renal, neurological, musculoskeletal, endocrine, metabolic, psychiatric, infectious disease or major physical impairment) which, as judged by the Investigator, might put the patient at risk because of participation in the study, or probable alternative primary reason for patient's symptoms in judgment of Investigator.
    9. Current or previous (within past 12 months) systemic fungal infection, prior screening
    10. Patients with uncontrolled or clinically significant thyroid disease as judged by the investigator
    11. Any ongoing skin disorder, history of or ongoing clinically significant allergy/hypersensitivity
    12. Drug or alcohol abuse, either current or within previous 12 months
    13. Judgement by the Investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements
    14. Intake of strong inhibitors of CYP3A4 (i.e. itraconazole and clarithromycin) or inducers of CYP3A4 (phenytoin and rifampicin)
    E.5 End points
    E.5.1Primary end point(s)
    Change from baseline to 12 weeks of treatment in pulmonary vascular resistance (PVR) as assessed by right heart catheterization
    E.5.1.1Timepoint(s) of evaluation of this end point
    week 12 or in case of premature end of treatment at the day -/+3 of the last medication intake
    Woche 12 oder bei vorzeitigem Behandlungsende am Tag (+/-3) der letzten Medikamenteneinnahme
    E.5.2Secondary end point(s)
    • Change from baseline to 12 weeks of treatment in other hemodynamic variables (PAPs, PAPd, PAPm, PAWP, CO, CI, TPG, DPG, PP, PA compliance, SVI, SvO2)
    • Change from baseline to 4 and 12 weeks of treatment in clinical variables, including 6MWD, WHO-FC, NTproBNP plasma levels
    • Change from baseline to 12 weeks of treatment in echocardiographic variables (RA area, RA volume, RVEDD, TAPSE, RV-FAC, LV-EI, TRV, PASP)
    • Change from baseline to 12 weeks of treatment in cMRI variables (RVEDV, RVESV, RV-EF, pulmonary flow)
    • Change from baseline to 12 weeks of treatment in CPET variables (peakVO2, AT, VE/VCO2)
    • Change from baseline to 12 weeks of treatment in RV contractile reserve (stress echocardiography)
    • Overall risk category (low, intermediate, high) according to the ESC/ERS guidelines risk assessment strategy at BL and at end of treatment)
    • Number of low risk criteria according to the ESC/ERS guidelines risk assessment strategy at BL and at end of treatment
    • Only for the Group 2: Change from baseline to 12 weeks of treatment in endothelial function as assessed by FMD (flow mediated dilation)
    E.5.2.1Timepoint(s) of evaluation of this end point
    week 4 and week 12
    Woche 4 und 12
    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 Yes
    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 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.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States No
    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
    The study ends with last visit of the last patient
    Das Studienende ist definiert als letzter Patient letzte Visite
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months17
    E.8.9.1In the Member State concerned days
    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: 15
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 8
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state15
    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)
    Further treatment after the EoS will be decided individually between the investigators and the patient and will take place with the active substances approved for the PAH indication, endothelin receptor antagonists (ambrisentan, bosentan, mactentan), PDE5 inhibitors (sildenafil, tadalafik) or sGC stimulators ( Riociguat) and/or prostacyclin analogues (epoprostenol, treprostinil) or prostacyclin receptor agonists (Selexipag), depending on the patient's condition and medical requirements.
    Die weitere Behandlung nach Studienende wird individuell zwischen den Prüfärzten und dem Patienten entschieden, mit den für die PAH Indikation zugelassenen Wirkstoffen Endothelinrezeptorantagonisten (Ambrisentan, Bosentan, Mactentan), PDE5-Inhibitoren (Sildenafil, Tadalafik) oder sGC-Stimulatoren (Riociguat) und / oder Prostacyclinanaloga (Epoprostenol, Treprostinil) oder Prostacyclinrezeptoragonisten (Selexipag), je nach Zustand und medizinischen Anforderungen des Patienten durchgeführt.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2020-09-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-07-07
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2021-12-21
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