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-IT

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 75 years, inclusive.
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
e) Associated with simple congenital defects (atrial septal defect and/or ventricular septal defect) if closed > 12 months before inclusion.
4. The patient’s last right heart catheterisation results, which were measured at the study site, must not be older than 90 days before V1 (will be considered as baseline value). Otherwise, a right heart catheterisation has to be performed as part of the study at visit A1.
5. WHO functional class II or III as judged by the investigator.
6. 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.
7. For women: Agree not to donate ova from the time of informed consent until 30 days after the last IMP intake. For men: Agree not to donate sperm from the time of informed consent until 90 days after the last IMP intake.
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. Two or more consecutive measurements of SBP < 95 mmHg or DBP < 50 mmHg measured at V1. 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, HIV infection and schistosomiasis.5. Any disease known to cause pulmonary hypertension other than PAH WHO Group 1. 6. Obstructive lung disease: FEV1/FVC < 60% and FEV1 < 60% of predicted value after bronchodilator administration, as demonstrated and documented by previous spirometry data which, in the opinion of the investigator, represent the clinical state of the patient at the time of the screening visit. 7. Restrictive lung disease: Total Lung Capacity (TLC) < 70% of predicted value, as demonstrated and documented by previous spirometry data which, in the opinion of the investigator, represent the clinical state of the patient at the time of the screening visit. 8. History of moderate to severe hepatic impairment (Child-Pugh B and C). 9. eGFR < 30 mL/min/1.73 m2 (at V1).
10. Use of the following prohibited medication or treatments during study participation: 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 highly effective contraceptive measures in combination with a barrier method e.g. condom, occlusive cap with spermicidal gel/film/cream/suppository from the time of informed consent until 30 days after last IMP intake. Highly effective methods for women are surgical intervention, non-hormonal implantable intrauterine device, 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 d

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method

Secondary Outcome Measures

Name	Time	Method

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