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

• Register: EUCTR
• Last refreshed on: 14 March 2022
• Main ID: EUCTR2018-002448-10-PT
• Date of registration: 04/09/2018
• Prospective Registration: Yes
• Primary sponsor: Bial - Portela & Ca, S.A.
• Public title: Study to find the most promising therapeutic dosage of zamicastat for the treatment of PAH disease.
• Scientific title: An open-label, multicentre study to evaluate pharmacokinetics, safety and efficacy of zamicastat as adjunctive therapy in pulmonary arterial hypertension (PAH) - Pharmacokinetics, safety and efficacy of BIA 5-1058 in PAH
• Date of first enrolment: 26/11/2018
• Target sample size: 40
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2018-002448-10
• 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
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Austria, Belgium, France, Germany, Italy, Netherlands, Portugal, Spain, Ukraine, United Kingdom

Contacts

• Name: Development Department
• Affiliation: Bial - Portela & Ca, S.A.

• Name: Development Department
• Affiliation: Bial - Portela & Ca, S.A.

Key inclusion & exclusion criteria

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.



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

Health Condition(s) or Problem(s) studied

Pulmonary arterial hypertension
MedDRA version: 21.1 Level: PT Classification code 10064911 Term: Pulmonary arterial hypertension System Organ Class: 10038738 - Respiratory, thoracic and mediastinal disorders

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

Intervention(s)

Product Name: Zamicastat
Product Code: BIA 5-1058
Pharmaceutical Form: Tablet
INN or Proposed INN: ZAMICASTAT
CAS Number: 1080028-80-3
Current Sponsor code: BIA 5-1058
Other descriptive name: BIA 5-1058
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-

Primary Outcome(s)

Secondary Objective: 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 sample of the last patient has been analysed.

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

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 Outcome(s)

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.

Secondary ID(s)

2018-002448-10-AT

BIA-51058-201

Source(s) of Monetary Support

Bial - Portela & Ca, S.A.

Ethics review

Status: Approved
Approval date: 19/11/2018
Contact: