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

• Register: EUCTR
• Last refreshed on: 8 November 2021
• Main ID: EUCTR2018-002448-10-AT
• Date of registration: 08/08/2018
• 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: 31/10/2018
• 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, Germany, Italy, 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 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 or 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 or 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. 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 measured at V1.
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, 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. 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 highly effective contraceptive measures in combination with a barrier method e.g. condom (without spermicidal foam/gel/film/cream/suppository or fat- or oil-containing lubricants), occlusive cap (diaphragm or cervical/vault caps) 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 (e.g. bilateral tubal occlusion), 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,

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

Health Condition(s) or Problem(s) studied

Pulmonary arterial hypertension

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)

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

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

Secondary Outcome(s)

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 end point(s): To assess further PK parameters, efficacy, safety and tolerability of different zamicastat doses

Secondary ID(s)

BIA-51058-201

Source(s) of Monetary Support

Bial - Portela & Ca, S.A.

Ethics review

Status: Approved
Approval date: 31/10/2018
Contact: