Study to find the most promising therapeutic dosage of zamicastat for the treatment of PAH disease.

Phase 1

Conditions: Pulmonary arterial hypertension
MedDRA version: 21.1Level: PTClassification code 10064911Term: Pulmonary arterial hypertensionSystem Organ Class: 10038738 - Respiratory, thoracic and mediastinal disorders
Therapeutic area: Diseases [C] - Cardiovascular Diseases [C14]

Registration Number: EUCTR2018-002448-10-PT

Lead Sponsor: Bial - Portela & Ca, S.A.

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 40

Inclusion Criteria

1. Male or female patients aged 18 to 65 years.
2. Able to comprehend and willing to sign an informed consent form.
3. Diagnosis of PAH (pulmonary arterial hypertension WHO Group 1), documented by right heart catheterisation with a mean pulmonary artery pressure (mPAP) = 25 mmHg, a pulmonary artery wedge pressure (PAWP) = 15 mmHg and a pulmonary vascular resistance (PVR) > 3 WU [Galie N, et. al 2015; Lau EMT, et. al. 2017]:
a) Idiopathic, in non-vasoreactive patients
b) Heritable: Bone morphogenetic protein receptor type II (BMPR2) mutation and other mutations, in non-vasoreactive patients
c) Drugs and toxin induced, in non-vasoreactive patients
d) Associated with connective tissue disease or with simple congenital defects (atrial septal defect and/or ventricular septal defect) if closed > 12 months before inclusion.
4. WHO functional class II or III as judged by the investigator.
5. Stable treatment with at least one of the following approved PAH therapies for at least
90 days prior to V1: Ambrisentan, Bosentan, Macitentan, Riociguat, Selexipag,
Sildenafil, Tadalafil, Epoprostenol intravenous, Iloprost inhaled or Treprostinil
intravenous or subcutaneous.

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 35
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 5

Exclusion Criteria

1. Contraindication to zamicastat, i.e. known hypersensitivity to ingredients of zamicastat formulation.
2. Two or more consecutive measurements of SBP < 95 mmHg or DBP < 50 mmHg.
3. Uncontrolled diabetes mellitus with HbA1c = 8.5% within the last three months or at
screening.
4. PAH WHO Group 1 due to portal hypertension, human immunodeficiency virus (HIV) infection and schistosomiasis.
5. Any disease known to cause pulmonary hypertension other than PAH WHO Group 1.
6. Obstructive lung disease: Forced Expiratory Volume in 1 second/Forced Vital Capacity
(FEV1/FVC) < 60% and FEV1 < 60% of predicted value after bronchodilator
administration.
7. Restrictive lung disease: Total Lung Capacity (TLC) < 70% of predicted value.
8. History of moderate to severe hepatic impairment (Child-Pugh B and C).
9. Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 (measured at V1).
10. Use of the following prohibited medication or treatments during study participation: calcium channel blockers (CCBs) if used for the treatment of PAH in vasoreactive patients; drugs containing a catechol group that is metabolised by DßH e.g. rimiterole, isoprenaline, dopamine, dopexamine or dobutamide) or a- and/or ß-blockers.
11. Current or previous (within the past year) alcohol or substance abuse excluding caffeine or nicotine.
12. Presence of any other significant or progressive/unstable medical condition that, in the opinion of the investigator, would compromise evaluation of the study treatment or may jeopardise the patient’s safety, compliance or adherence to protocol requirements.
13. For women: Pregnancy or breast-feeding. Women of childbearing potential unable or
unwilling to undergo pregnancy tests and practice acceptable contraceptive measures
from the time of informed consent until 30 days after last IMP intake. Acceptable
methods for women are surgical intervention (e.g. bilateral tubal occlusion), nonhormonal
implantable intrauterine device, double-barrier methods, true sexual abstinence
(i.e. when this is in line with the preferred and usual lifestyle of the patient) and
vasectomised partner (provided that the partner is the sole sexual partner of the patient
and the partner has received medical assessment of the surgical success). Periodic
abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), hormonal
contraceptives and withdrawal are not acceptable methods of contraception.
For men: Male patients who are sexually active with a partner of childbearing potential
must use, with their partner, a condom plus an approved acceptable contraceptive measure
from the time of informed consent until 90 days after the last IMP intake. The following
methods are acceptable methods of contraception: partner’s use of combined (oestrogen
and progestogen-containing) hormonal contraception associated with inhibition of
ovulation (oral, intravaginal, transdermal); partner’s use of progestogen-only hormonal
contraception (oral, injectable/implantable, intrauterine hormone-releasing system);
partner’s use of implantable intrauterine device; surgical sterilisation (for example,
vasectomy or bilateral tubal occlusion).
14. Previous participation in any other drug investigational study within the past 30 days (or five half-lives of investigational medicinal product [IMP] whichever is longer) prior to V1.
15. Vulnerable patients according to Section 1.61 of the ICH guideline for Good Clinical
Practice E6.

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: The primary objective of this study is to evaluate the PK profile of different zamicastat doses in PAH patients to find the most promising therapeutic dosage range for the treatment of PAH disease;Secondary Objective: To assess further PK parameters, efficacy, safety and tolerability of different zamicastat doses ;Primary end point(s): To evaluate pharmacokinetic (PK) profile of different zamicastat doses in PAH patients to find the most promising therapeutic dosage range for the treatment of PAH disease;Timepoint(s) of evaluation of this end point: Once the last PK sample of the last patient has been analysed.

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): To assess further PK parameters, efficacy, safety and tolerability of different zamicastat doses;Timepoint(s) of evaluation of this end point: Once the last PK, efficacy, safety and tolerability parameters of the last patient has been analysed.

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