Pharmacokinetics, Safety and Efficacy of BIA 5-1058 in PAH

Study Overview
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Brief Summary
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This Study evaluates the pharmacokinetic (PK) profile of different zamicastat doses in Pulmonary arterial hypertension (PAH) patients to find the most promising therapeutic dosage range for the treatment of PAH disease

Detailed Description
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This is an open-label, multi-centre study in patients with PAH who are currently on stable treatment with at least one PAH medication. It is planned to evaluate the PK profile (24 hour profile and trough levels) and the safety, tolerability and efficacy of four different zamicastat doses. Each patient will start treatment with the lowest dose (50 mg zamicastat once daily) and the dose will be up-titrated to the individual highest tolerated dose (HTD) i.e. up to 200 mg zamicastat once daily. A data safety monitoring board (DSMB) will periodically review the safety data and will issue a recommendation if the doses can be used as planned. This study will consist of: A screening period, 5 to 12 days: visit V1 Up to four dose finding periods, 14 days each: Dose A: visits A1, A2 and A3 Dose B: visits B2 and B3 Dose C: visits C2 and C3 Dose D: visits D2 and D3 Maintenance period, 42 days: visits MPV1, MPV2 and MPV3 Follow-up period, 14 to 28 days: visits FU (down-titration) and FU

Official Title
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An Open-label, Multicentre Study to Evaluate Pharmacokinetics, Safety and Efficacy of Zamicastat as Adjunctive Therapy in Pulmonary Arterial Hypertension (PAH)

Conditions
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Pulmonary Arterial Hypertension

Intervention / Treatment
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* Drug: Zamicastat


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: For inclusion in the study, patients must fulfil all of the following criteria: Male or female patients aged 18 to 65 years. Able to comprehend and willing to sign an informed consent form. 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]: Idiopathic, in non-vasoreactive patients Heritable: Bone morphogenetic protein receptor type II (BMPR2) mutation and other mutations, in non-vasoreactive patients Drugs and toxin induced, in non-vasoreactive patients Associated with connective tissue disease Associated with simple congenital defects (atrial septal defect and/or ventricular septal defect) if closed > 12 months before inclusion. WHO functional class II or III as judged by the investigator. 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. Exclusion Criteria: Patients having or being any of the following are to be excluded from the study: Contraindication to zamicastat, i.e. known hypersensitivity to ingredients of zamicastat formulation. Two or more consecutive measurements of SBP < 95 mmHg or DBP < 50 mmHg. Uncontrolled diabetes mellitus with HbA1c ≥ 8.5% within the last three months or at screening. PAH WHO Group 1 due to portal hypertension, human immunodeficiency virus (HIV) infection and schistosomiasis. 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. Restrictive lung disease: Total Lung Capacity (TLC) < 70% of predicted value. 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 V1). 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. Current or previous (within the past year) alcohol or substance abuse excluding caffeine or nicotine. 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 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), non-hormonal 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). 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. Vulnerable patients according to Section 1.61 of the ICH guideline for Good Clinical Practice E6.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 50 mg zamicastat<br>50 mg zamicastat once daily (half a tablet of 100 mg) | Drug: Zamicastat<br>* Tablets for oral administration under fed conditions containing 100 mg of zamicastat (BIA 5-1058)<br>* Other names: BIA 5-1058;|
| Experimental: 100 mg zamicastat once daily<br>100 mg zamicastat once daily (one tablet of 100 mg) | Drug: Zamicastat<br>* Tablets for oral administration under fed conditions containing 100 mg of zamicastat (BIA 5-1058)<br>* Other names: BIA 5-1058;|
| Experimental: 150 mg zamicastat once daily<br>150 mg zamicastat once daily (one and a half tablet of 100 mg) | Drug: Zamicastat<br>* Tablets for oral administration under fed conditions containing 100 mg of zamicastat (BIA 5-1058)<br>* Other names: BIA 5-1058;|
| Experimental: 200 mg zamicastat once daily<br>200 mg zamicastat once daily (two tablets of 100 mg) | Drug: Zamicastat<br>* Tablets for oral administration under fed conditions containing 100 mg of zamicastat (BIA 5-1058)<br>* Other names: BIA 5-1058;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the curve 0-24h (AUC0-24h) - 50 mg | This PK parameters (24-hour profile) for zamicastat and its metabolites will be derived after a single dose of 50 mg zamicastat | Day 1 (0 hours and then 1, 2, 4, 8, 16 and 24 hours after IMP intake) | 
| Area under the curve 0-24h (AUC0-24h) - HTD | This PK parameter (24-hour profile) for zamicastat and its metabolites will be derived at steady-state at the individual highest tolerated dose (HTD) | 1, 2, 4, 8, 16 and 24 hours after IMP intake | 
| Maximum plasma concentration (Cmax) - 50 mg | This PK parameters (24-hour profile) for zamicastat and its metabolites will be derived after a single dose of 50 mg zamicastat | Day 1 (0 hours and then 1, 2, 4, 8, 16 and 24 hours after IMP intake) | 
| Maximum plasma concentration (Cmax) - HTD | This PK parameter (24-hour profile) for zamicastat and its metabolites will be derived at steady-state at the individual highest tolerated dose (HTD) | 1, 2, 4, 8, 16 and 24 hours after IMP intake | 
| Time until Cmax (tmax) - 50 mg | This PK parameters (24-hour profile) for zamicastat and its metabolites will be derived after a single dose of 50 mg zamicastat | Day 1 (0 hours and then 1, 2, 4, 8, 16 and 24 hours after IMP intake) | 
| Time until Cmax (tmax) - HTD | This PK parameter (24-hour profile) for zamicastat and its metabolites will be derived at steady-state at the individual highest tolerated dose (HTD) | 1, 2, 4, 8, 16 and 24 hours after IMP intake | 
| Minimum plasma concentration at the end of the dosing interval (Cmin,SS) - HTD | This PK parameter (24-hour profile) for zamicastat and its metabolites will be derived at steady-state at the individual highest tolerated dose (HTD) | 1, 2, 4, 8, 16 and 24 hours after IMP intake | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PAH, BIA 5-1058, Zamicastat, Bial, Bial - Portela & Ca, S.A., dopamine ß-hydroxylase (DßH) inhibitor, vascular obstruction, pulmonary arteries, right-heart catheterisation (RHC), idiopathic, rare lung disease