Safety and Efficacy of BIA 5-1058 in PAH

Bial - Portela C S.A.20 enrolled

Overview

This study aims to assess the safety and tolerability of the individual highest tolerated zamicastat doses, achieved in the study BIA-51058-201, during long-term treatment in Pulmonary Arterial Hypertension (PAH) disease.

This is an extension study with Pulmonary Arterial Hypertension (PAH) patients who are under treatment with zamicastat as adjunctive therapy in the study BIA-51058-201. For patients participating in this extension study, visit "Maintenance Period Visit 3" (MPV3) of the study BIA-51058-201 will also be the first visit (V1) of this extension study (BIA-51058-202). Their treatment with zamicastat will be continued at their individual highest tolerated dose (HTD) for an additional 12 weeks (50 mg, 100 mg, 150 mg or 200 mg). Further visits will be performed 20 ±3 days (V2, telephone), 41 ±3 days (V3, on-site), 62 ±3 days (V4, telephone) and 83 ±3 days (V5, on-site) after V1. At V5, patients will have the opportunity to continue treatment with zamicastat in a compassionate use program. Patients who will not participate in this compassionate use program will come to the following follow-up visit(s): * Follow-up (FU) down-titration (telephone, 14 ±2 days after V5); only applicable in patients taking 150 mg or 200 mg zamicastat * FU visit (on-site, 14 ±2 days after last investigational medicinal product (IMP) intake). The data and safety monitoring board (DSMB) will periodically review the safety data and will issue a recommendation if the study can be continued as planned.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Pulmonary Arterial Hypertension

Interventions

Oral zamicastatDRUG

Tablets for oral administration under fed conditions containing 100 mg of zamicastat. Zamicastat has to be taken in the morning after breakfast.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 70 Years

Medical Language ↔ Plain English

Inclusion Criteria: For inclusion in the extension study, patients had to fulfil all of the following criteria at visit V1 (Day 1, start of the extension study): * Have performed MPV3 of the preceding study BIA-51058-201. * Able to comprehend and willing to sign an informed consent form (ICF). * For women: Agreed not to donate ova from the time of informed consent until 30 days after the last IMP intake. * For men: Agreed not to donate sperm from the time of informed consent until 90 days after the last IMP intake Exclusion Criteria: Patients were to be excluded for any one of the following reasons: * Significant non-compliance with the protocol during the preceding study BIA-51058-201 which may have an impact on this extension study. * WHO functional class IV as judged by the investigator (reference 1) * Two or more consecutive measurements of systolic blood pressure (SBP) \< 95 mmHg or diastolic blood pressure (DBP) \< 50 mmHg measured at visit V1. * Uncontrolled diabetes mellitus with HbA1c ≥ 8.5% within the last three months or at visit V1. * Occurrence of an AE during the preceding study which is judged by the investigator as contraindicative to further participation in the extension study. * Any disease known to cause pulmonary hypertension other than PAH WHO Group 1. * 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 visit V1. * 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 visit V1. * History of moderate to severe hepatic impairment (Child-Pugh B and C). * Estimated glomerular filtration rate (eGFR) \< 30 mL/min/1.73 m2 (measured at Maintenance period visit 1 (MPV1) of study BIA-51058-201). * 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 DβH (e.g. rimiterole, isoprenaline, dopamine, dopexamine or dobutamide) or α- and/or β-blockers. * 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. * 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 the 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, 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). * Concurrent participation in any other drug investigational study except BIA-51058-201. * Vulnerable patients according to Section 1.61 of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guideline for Good Clinical Practice E6.

Locations (11)

Ordensklinikum Linz Elisabethinen, Interne 2 - Kardiologie, Angiologie & Interne Intensivmedizin Fadingerstraße 1

Linz, Austria

Universitätsklinikum Carl Gustav Carus Dresden, Medizinische Klinik und Poliklinik I, Pneumologie Fetscherstraße 74

Dresden, Germany

Outcomes

Primary Outcomes

Number of participants with adverse events (AEs)

The number of participants with AEs will be presented. An AE is any untoward medical occurrence in a patient to whom a medicinal product is administered and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease occurring during the course of the study.

Time frame: Up to 12 weeks

Clinically relevant changes in laboratory parameters: coagulation

Based on coagulation analysis measurements of prothrombin time test (international normalized ratio). The prothrombin time (PT) test measures how long it takes for a clot to form in a blood sample. The International Normalized Ratio is a type of calculation based on PT test results. Baseline values will be obtained from V1/A1 of study BIA-51058-201.

Time frame: From baseline to week 6 and week 12, and from day -1 to week 6 and week 12

Incidence of clinically relevant changes (abnormalities) in laboratory parameters: biochemistry

Based on biochemistry analysis measurements (mmol/L) of Sodium, Potassium, Chloride, Calcium, Phosphate . Baseline values will be obtained from V1/A1 of study BIA-51058-201.

Time frame: From baseline to week 6 and week 12, and from day -1 to week 6 and week 12

Incidence of clinically relevant changes (abnormalities) in laboratory parameters: haematology

Based on haematology analysis measurement haemoglobin (g/dL). Baseline values will be obtained from V1/A1 of study BIA-51058-201.

Time frame: From baseline to week 6 and week 12, and from day -1 to week 6 and week 12

Clinically relevant changes in laboratory parameters: urinalysis

Based on urinalysis analysis measurements of the potential of hydrogen (pH). The pH scale is used to determine the degree of acidity of a substance. The basic pH scale extends from 0 (strong acid) to 7 (neutral, pure water) to 14 (strong caustic). Urine has the widest range of pH compared to other bodily fluids. Baseline values will be obtained from V1/A1 of study BIA-51058-201.

Data from ClinicalTrials.gov

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Secondary Outcomes

Changes in haemodynamic parameters: pulmonary vascular resistance (PVR)

Pulmonary vascular resistance (measured in dyn\*s/cm\^5) is determined by right heart catheterization to be performed before IMP intake. Baseline values will be obtained from V1/A1 of study BIA-51058-201.

Time frame: From Baseline to week 12, and from Day -1 to week 12

Changes in haemodynamic parameters: right atrial pressure (RAP)

Right atrial pressure (RAP), measured in mmHg units, is a robust predictor of the pulmonary hypertension severity. Baseline values will be obtained from V1/A1 of study BIA-51058-201.

Time frame: From Baseline to week 12, and from Day -1 to week 12

Changes in haemodynamic parameters: mean pulmonary artery pressure (mPAP)

Haemodynamic parameter mean pulmonary artery pressure (mPAP) is measured in mmHg units. Baseline values will be obtained from V1/A1 of study BIA-51058-201.

Time frame: From Baseline to week 12, and from Day -1 to week 12

Changes in haemodynamic parameters: Cardiac index (CI)

Cardiac index (CI) is a haemodynamic parameter that relates the cardiac output from left ventricle in one minute to body surface area, thus relating heart performance to the size of the individual. The unit of measurement is liters per minute per square meter (L/min/m2). Baseline values will be obtained from V1/A1 of study BIA-51058-201.

Time frame: From Baseline to week 12, and from Day -1 to week 12

Changes in haemodynamic parameters: mixed venous oxygen saturation (SvO2)

SvO2 is the percentage (%) of oxygen bound to hemoglobin in blood returning to the right side of the heart. Baseline values will be obtained from V1/A1 of study BIA-51058-201.

Time frame: From Baseline to week 12, and from Day -1 to week 12

Changes in the New York Heart Association / World Health Organization (NYHA/WHO) functional class

The NYHA/WHO Classification system is a tool that classifies patients with heart failure into one of four classes according to their degree of symptoms at rest and with activity: Class I, patients with pulmonary hypertension but without resulting limitation of physical activity; Class II, patients with pulmonary hypertension resulting in a slight limitation of physical activity; Class III, patients with pulmonary hypertension resulting in marked limitation of physical activity; Class IV: patients with pulmonary hypertension with inability to carry out any physical activity without symptoms. These patients manifest signs of right heart failure. Dyspnoea and/or fatigue may even be present at rest. Discomfort is increased by any physical activity. Baseline values will be obtained from V1/A1 of study BIA-51058-201.