Study to evaluate the safety, tolerability and efficacy of AZD4831 in the treatment of patients with pulmonary hypertension

• Register: EUCTR
• Last refreshed on: 21 March 2022
• Main ID: EUCTR2020-002788-80-DE
• Date of registration: 08/06/2020
• Prospective Registration: Yes
• Primary sponsor: University of Cologne
• Public title: Study to evaluate the safety, tolerability and efficacy of AZD4831 in the treatment of patients with pulmonary hypertension
• Scientific title: An explorative study to assess the safety, tolerability, and efficacy of AZD4831 in the treatment of pulmonary arterial hypertension (PAH) (MPO-PAH)
• Date of first enrolment: 09/09/2020
• Target sample size: 15
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2020-002788-80
• 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

Contacts

• Name: KKS
• Affiliation: Philipps University Marburg, Coordinating Center for Clinical trials

• Name: KKS
• Affiliation: Philipps University Marburg, Coordinating Center for Clinical trials

Key inclusion & exclusion criteria

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
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 15
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range 8

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)


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

Health Condition(s) or Problem(s) studied

Group 1: Pulmonary arterial hypertension (PAH) Group 2: Postcapillary pulmonary hypertension
MedDRA version: 21.1 Level: PT Classification code 10064911 Term: Pulmonary arterial hypertension System Organ Class: 10038738 - Respiratory, thoracic and mediastinal disorders
MedDRA version: 21.1 Level: PT Classification code 10037400 Term: Pulmonary hypertension System Organ Class: 10038738 - Respiratory, thoracic and mediastinal disorders

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

Intervention(s)

Product Name: AZD4831
Pharmaceutical Form: Tablet

Primary Outcome(s)

Main Objective: 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).

Secondary Objective: 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)

Timepoint(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

Primary end point(s): Change from baseline to 12 weeks of treatment in pulmonary vascular resistance (PVR) as assessed by right heart catheterization

Secondary Outcome(s)

Secondary 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)

Timepoint(s) of evaluation of this end point: week 4 and week 12

Secondary ID(s)

Uni-Koeln-4243

Source(s) of Monetary Support

AstraZeneca

Ethics review

Status: Approved
Approval date: 07/07/2020
Contact: