An Open-label, Multicentre Study to Evaluate Pharmacokinetics, Safety and Efficacy of Zamicastat as Adjunctive Therapy in Pulmonary Arterial Hypertension (PAH)
Phase: PHASE2
Conditions: Pulmonary Arterial Hypertension
Sponsor: Bial - Portela C S.A.

Clinical Study Protocol BIA-51058-201 
Bial - Portela & Ca, S.A. 
Final Version 3.0, 11-MAY-2020 
CONFIDENTIAL  
Page 1 of 82 
Bial - Portela & Ca, S.A 
 
CLINICAL STUDY PROTOCOL 
 
An open-label, multicentre study to evaluate pharmacokinetics, safety and efficacy of 
zamicastat as adjunctive therapy in pulmonary arterial hypertension (PAH) 
 
Protocol Short Title 
Pharmacokinetics, safety and efficacy of 
BIA 5-1058 in PAH 
Protocol Number 
BIA-51058-201 
EudraCT Number 
2018-002448-10 
Phase 
II 
Version 
Final Version 3.0 
Date 
11-MAY-2020 
Product Name 
Zamicastat (BIA 5-1058) 
Indication 
 Pulmonary arterial hypertension 
Sponsor 
Bial - Portela & Ca, S.A. 
À Av. da Siderurgia Nacional  
4745-457 Coronado (S. Romão e S. Mamede), 
Portugal 
Phone: +351 229866100 
Fax:     +351 229866192 
http://www.bial.com 
24/7 Medical Contact 
SCOPE International Medical Monitoring 
Phone: +370 52 360 336 
 
The information contained in this document is the property of Bial and may not be 
disclosed to parties not associated with the clinical investigation or used for any purpose 
without prior written consent of Bial. 
Throughout this document, symbols indicating proprietary names (®, ™) are not 
displayed. Hence the appearance of product names without these symbols does not imply 
that these names are not protected. 
This study will be performed in compliance with the protocol, Good Clinical Practices 
(GCP) and applicable regulatory requirements, including the archiving of essential 
documents. 
 
 

Clinical Study Protocol BIA-51058-201 
Bial - Portela & Ca, S.A. 
Final Version 3.0, 11-MAY-2020 
CONFIDENTIAL  
Page 2 of 82 
Protocol Version History 
This protocol, Final version 3.0, 11-MAY-2020 supersedes the following protocol versions: 
 
 
Protocol version 
Countries 
Final Version 2.0, 18-JUN-2019 
Austria, Italy, Portugal, Spain, Ukraine 
Final Version 2.0_UK, 08-JUL-2019 
United Kingdom 
Final Version 2.0_DE, 23-SEP-2019 
Germany 
Summary of Changes from Final Protocol Version 2.0, 18-JUN-2019 
This protocol Final version 3.0 was prepared to increase the age limit provided in inclusion 
criterion no. 1, to potentially reduce the number of right heart catheterisations (RHCs) and to 
implement minor updates.  
 
Section* 
Change 
5 
The drug safety manager changed. 
6.2 
This section was updated according to Investigator’s Brochure edition no 
6.2. 
9.1, 9.2 
Inclusion criterion no. 1 was amended to increase the age limit from 65 to 75 
years, inclusive.  
9.2, 11.4.4, 
11.6.2 
Right heart catheterisation results which were measured at the study site from 
within 90 days before V1 will be accepted as baseline value (new inclusion 
criterion no. 4). 
9.2 
Inclusion criterion 7 was introduced; women must agree not to donate ova 
from the time of informed consent until 30 days after the last IMP intake und 
men must agree not to donate sperm from the time of informed consent until 
90 days after the last IMP intake. 
9.3 
Relevant previous spirometry data must be available in the medical history 
for checking exclusion criteria no. 6 and 7. 
9.3 
Exclusion criterion no 13 was updated; women of childbearing potential 
have to use highly effective contraceptive measures in combination with a 
barrier method.   
 
Please note that minor clarifications and corrections of typing errors are not listed above. 
*In addition, all changes have also been implemented in the protocol synopsis (Section 2). 
 
 

Clinical Study Protocol BIA-51058-201 
Bial - Portela & Ca, S.A. 
Final Version 3.0, 11-MAY-2020 
CONFIDENTIAL  
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1. 
SIGNATURE PAGES 
1.1 
Sponsor Signatures 
 
PROTOCOL TITLE: 
An 
open-label, 
multicentre 
study 
to 
evaluate 
pharmacokinetics, safety and efficacy of zamicastat as 
adjunctive therapy in pulmonary arterial hypertension (PAH) 
 
PROTOCOL NUMBER: 
BIA-51058-201 
 
PROTOCOL VERSION: 
Final Version 3.0 
 
PROTOCOL DATE: 
11-MAY-2020 
 
Protocol approved by: 
 
SIGNATURE: 
 
DATE: 
 
 
 
Patrício Soares-da-Silva, MD, PhD  
 
Research and Development General Manager 
Research & Development Area 
Bial - Portela & Ca, S.A. 
À Av. da Siderurgia Nacional 
4745-457 Coronado (S. Romão e S. Mamede), Portugal 
Phone: +351 229866100 
Fax:     +351 229866192 
psoares.silva@bial.com 
 
 
 
 
 

Clinical Study Protocol BIA-51058-201 
Bial - Portela & Ca, S.A. 
Final Version 3.0, 11-MAY-2020 
CONFIDENTIAL  
Page 4 of 82 
1.2 
Coordinating Investigator’s Declaration 
 
PROTOCOL TITLE: 
An 
open-label, 
multicentre 
study 
to 
evaluate 
pharmacokinetics, safety and efficacy of zamicastat as 
adjunctive therapy in pulmonary arterial hypertension (PAH) 
 
PROTOCOL NUMBER: 
BIA-51058-201 
 
PROTOCOL VERSION: 
Final Version 3.0 
 
PROTOCOL DATE: 
11-MAY-2020 
 
I have read and understand the protocol and agree to conduct the study in compliance 
with this protocol, Good Clinical Practice, designated Standard Operating Procedures, 
applicable regulatory requirements and within the principles of the Declaration of 
Helsinki (adopted Version, Fortaleza, Brazil, 2013). 
 
SIGNATURE: 
 
DATE: 
 
 
 
Prof. Dr. med. Marius Hoeper 
 
Medizinische Hochschule Hannover 
Klinik für Pneumologie 
Carl-Neuberg-Straße 1 
30623 Hannover, Germany 
 
 

Clinical Study Protocol BIA-51058-201 
Bial - Portela & Ca, S.A. 
Final Version 3.0, 11-MAY-2020 
CONFIDENTIAL  
Page 5 of 82 
1.3 
Principal Investigator’s Declaration 
 
PROTOCOL TITLE: 
An 
open-label, 
multicentre 
study 
to 
evaluate 
pharmacokinetics, safety and efficacy of zamicastat as 
adjunctive therapy in pulmonary arterial hypertension (PAH) 
 
PROTOCOL NUMBER: 
BIA-51058-201 
 
PROTOCOL VERSION: 
Final Version 3.0 
 
PROTOCOL DATE: 
11-MAY-2020 
 
I have read and understand the protocol and agree to conduct the clinical study in 
compliance with this protocol, Good Clinical Practice, designated Standard Operating 
Procedures, applicable regulatory requirements and within the principles of the 
Declaration of Helsinki (adopted Version, Fortaleza, Brazil, 2013). 
 
SIGNATURE: 
 
DATE: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Print principal investigator name and address 
 

Clinical Study Protocol BIA-51058-201 
Bial - Portela & Ca, S.A. 
Final Version 3.0, 11-MAY-2020 
CONFIDENTIAL  
Page 6 of 82 
2. 
PROTOCOL SYNOPSIS 
Name of sponsor/company: Bial - Portela & Ca, S.A., À Av. da Siderurgia Nacional, 
4745-457 Coronado (S. Romão e S. Mamede), Portugal  
Name of active ingredient: Zamicastat (BIA 5-1058) 
Title of study: An open-label, multicentre study to evaluate pharmacokinetics, safety and 
efficacy of zamicastat as adjunctive therapy in pulmonary arterial hypertension (PAH) 
Study number: BIA-51058-201 
EudraCT number: 2018-002448-10 
Coordinating investigator: Prof. Dr. med. Marius Hoeper, Medizinische Hochschule
Hannover, Klinik für Pneumologie, Carl-Neuberg-Straße 1, 30623 Hannover, Germany  
Study centre(s): Approximately 15 sites in 9 countries. Other sites and countries may be 
added as needed. 
Planned duration of the study: 
First patient first visit: May 2019 
Last patient last visit:  Nov 2020 
Phase of development: II 
Objectives:  
Primary:  
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: 
1. To assess further PK parameters including apparent total clearance, terminal half-life and 
apparent volume of distribution 
2. To assess the safety and tolerability of different zamicastat doses 
3. To investigate the effect of different zamicastat doses on plasma dopamine β hydroxylase 
(DβH) activity 
4. To investigate the effect of different zamicastat doses on urinary catecholamine levels 
(norepinephrine and dopamine) 
5. To investigate the change in pulmonary haemodynamic parameters  
6. To investigate the change in the 6-minute walk test (6-MWT) 
7. To investigate the change in biomarkers 
8. To investigate the change in cardiac structure and contractibility, assessed by 
echocardiography 
9. To investigate the change in quality of life, assessed by SF-36v2 
Methods / study design:  
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. 

Clinical Study Protocol BIA-51058-201 
Bial - Portela & Ca, S.A. 
Final Version 3.0, 11-MAY-2020 
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This study will consist of: 
• A screening period, 5 to 12 days: visit V1 
• Up to four dose finding periods, 14 days each: 
o Dose A: visits A1, A2 and A3 
o Dose B: visits B2 and B3 
o Dose C: visits C2 and C3 
o 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 
After confirmed eligibility, patients will initiate treatment with Dose A (50 mg zamicastat 
once daily) at visit A1 and will be treated with this dose level for 14 days. If Dose A was 
considered safe by the investigator, it will be up-titrated to Dose B (100 mg zamicastat once 
daily) at visit A3 and the patient will continue with this dosage for 14 days. Patients not 
tolerating Dose A have to be withdrawn from the study.  
The up-titration is based on safety criteria, including but not limited to: 
• Absence of symptomatic and/or clinically relevant orthostatic hypotension 
• Systolic blood pressure (SBP) > 95 mmHg or diastolic blood pressure (DBP) > 50 mmHg 
• Absence of clinically significant changes in electrocardiogram (ECG) parameters (heart 
rate, P-R interval, QRS duration, QT and QTc interval) 
• Absence of clinically significant hypersensitivity/skin allergic reactions 
After a positive safety evaluation at visit B3, the dose will be up-titrated to Dose C (150 mg 
zamicastat once daily) and the patient will continue on this dose level for a further 14 days. 
If Dose C was tolerated by the patient, it will be up-titrated at visit C3 to Dose D (200 mg 
zamicastat once daily) where the patient will remain for 56 days (14 days dose finding period 
+ 42 days maintenance period).  
Patients not tolerating their next dose at any time during the 14-days dose finding period will 
come immediately to the site or call the investigator (unscheduled visit), unless intolerance 
was detected during a scheduled visit and the dose will be down-titrated to the patient’s 
previous tolerated dose. Then they will continue this treatment for 42 days during the 
maintenance period.  
The dose which will be taken during the maintenance period will be considered as an 
individual HTD. 
At the end of the maintenance period, the patient will have the opportunity to continue 
treatment in an extension study (BIA-51058-202), which will be described in a separate 
protocol.  
Patients not tolerating the individual HTD during the maintenance period have to be 
withdrawn from the study. An overview of the study design is provided in Figure 1. 
Number of patients (planned): 
It is planned to allocate approximately 32 patients to treatment to meet the objectives of the 
study. 

Clinical Study Protocol BIA-51058-201 
Bial - Portela & Ca, S.A. 
Final Version 3.0, 11-MAY-2020 
CONFIDENTIAL  
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Diagnosis and main criteria for inclusion and exclusion: 
Diagnosis: Pulmonary arterial hypertension (PAH) 
Inclusion criteria: 
For inclusion in the study, patients must fulfil all of the following 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. 
Exclusion criteria: 
Patients having or being any of the following are to be excluded from the study: 
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 

Clinical Study Protocol BIA-51058-201 
Bial - Portela & Ca, S.A. 
Final Version 3.0, 11-MAY-2020 
CONFIDENTIAL  
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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 DβH e.g. rimiterole, 
isoprenaline, dopamine, dopexamine or dobutamide or α- and/or β-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, 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. 
Duration of treatment for the individual patient: Maximum treatment duration will 
depend on the individual HTD. Patients tolerating Dose D (200 mg zamicastat) will take 
zamicastat for up to 124 days.  

Clinical Study Protocol BIA-51058-201 
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Final Version 3.0, 11-MAY-2020 
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Test product, dose and mode of administration:  Tablets for oral administration under fed 
conditions containing 100 mg of zamicastat (BIA 5-1058) each. It is planned to use the 
following doses: 
Dose A 
50 mg zamicastat once daily (half a tablet of 100 mg) 
Dose B 
100 mg zamicastat once daily (one tablet of 100 mg) 
Dose C 
150 mg zamicastat once daily (one and a half tablet of 100 mg) 
Dose D 
200 mg zamicastat once daily (two tablets of 100 mg) 
Reference therapy, dose and mode of administration: NA  

Clinical Study Protocol BIA-51058-201 
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Final Version 3.0, 11-MAY-2020 
CONFIDENTIAL  
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Criteria for evaluation:  
Primary endpoint; pharmacokinetics:  
The following PK parameters (24-hour profile) for zamicastat and its metabolites will be 
derived after a single dose of 50 mg zamicastat at visit A1 (Day 1): 
1. Area under the curve 0-24h (AUC0-24h) 
2. Maximum plasma concentration (Cmax) 
3. Time until Cmax (tmax) 
The following PK parameters (24-hour profile) for zamicastat and its metabolites will be 
derived at steady-state at the individual HTD and will be taken at visit MPV3. 
4. Area under the curve 0-24h (AUC0-24h,SS) 
5. Maximum plasma concentration (Cmax,SS) 
6. Time until Cmax,SS (tmax,SS) 
7. Minimum plasma concentration at the end of the dosing interval (Cmin,SS) 
The following PK parameter (trough level) will be derived for each dose at steady-state. 
8. Minimum plasma concentration at the end of the dosing interval (Cmin,SS) 
Additional PK parameters may also be calculated if considered appropriate. 
Secondary endpoints: 
Safety and tolerability endpoints: 
1. Adverse events 
2. Clinically relevant changes in laboratory parameters (haematology, biochemistry, 
coagulation, urinalysis, arterial blood gas analysis) 
3. Clinically relevant changes in vital signs 
4. Clinically relevant changes in ECG 
5. Number of digital scars (only in patients with scleroderma) 
6. Skin score (only in patients with scleroderma) 
Efficacy endpoints: 
Change from baseline to MPV3 in: 
7. PVR, right atrial pressure (RAP), mPAP, cardiac index (CI) and mixed venous oxygen 
saturation (SvO2). Further haemodynamic parameters may also be calculated if 
considered appropriate. 
8. 6-MWT, including Borg dyspnoea score  
9. Biomarker (N-terminal pro brain natriuretic peptide [NT-proBNP]) 
10. Echocardiogram parameters: 
• Tricuspid regurgitation, classified as absent, mild, moderate or severe 
• Right ventricular contractility, measured via tricuspid annular plane systolic 
excursion (TAPSE) 
• Pericardial effusion, classified as absent, traces or present 
• Right atrial area (end-systolic), right ventricular end-diastolic area 
11. WHO functional class 
12. Quality of life 
Pharmacokinetic endpoints: 
13. Apparent total clearance (CL/f) 

Clinical Study Protocol BIA-51058-201 
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Final Version 3.0, 11-MAY-2020 
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14. Terminal half-life (t1/2) 
15. Apparent volume of distribution (Vz/f) 
Pharmacodynamic endpoints: 
16. Percent inhibition in plasma DβH activity (i.e. % change from baseline of DβH activity) 
on visits A3/B3/C3/D3, MPV1 and MPV2 (trough samples) and to visits A1 and MPV3 
(24-hour profiles)  
17. Maximal and minimal observed effect on DβH activity and time to occurrence of Emax 
(TEmax) and Emin (TEmin) on visit A1 (Day 1) and MPV3 
18. Area under the effect-time curve (AUEC24) for % DβH inhibition on visit A1 (Day 1) 
and MPV3 
19. Change from baseline 24-hour urinary catecholamine levels (norepinephrine and 
dopamine) on visits A3/B3/C3/D3 and MPV3 
Additional parameters may be calculated if considered appropriate. 
Statistical methods: 
Analysis populations: 
The enrolled set (ES) includes all patients who provided informed consent. 
The full analysis set (FAS) includes all patients with at least one IMP administration. 
The pharmacokinetic analysis set (PKS) will include all patients with an evaluable 24-hour 
PK profile and no major protocol deviations with an impact on PK analysis. 
The safety set (SS) includes all patients with at least one IMP administration. The FAS and 
the SS are identical. 
Sample size: 
The clinical study BIA-51058-201 was designed to explore for the first time the 
pharmacokinetics, safety and efficacy of zamicastat in PAH patients in its potential 
therapeutic dose range (50 mg to 200 mg). Since this is an exploratory and descriptive study 
and no powered comparative statistical analysis is planned, study sample size was not 
formally calculated. Thus, it was considered that 32 patients constitute an appropriate sample 
size to meet the objectives of the study, considering the low prevalence of the disease and 
the consequent recruitment constrains.  
Pharmacokinetic analysis: 
The primary analysis of this study will be the analysis of the PK parameters derived by non-
compartmental analysis from the plasma drug concentration-time data. Actual sampling 
times will be used. The area under the plasma concentration-time curve from time zero to 
24-hour post-dose will be calculated using the linear trapezoidal rule. 
Summary statistics will be reported, as appropriate, using the geometric mean, arithmetic 
mean, standard deviation, coefficient of variation, median, minimum, and maximum. 
PK analysis will be based on the PKS. 
Pharmacodynamic analysis: 
Maximum observed effect on plasma DβH activity (Emax), time to occurrence of Emax (TEmax), 
area under the effect-time curve (AUEC24) and urinary catecholamine levels 
(norepinephrine and dopamine) including changes from baseline will be described using 
summary statistics by each dose group. Pharmacodynamic analysis will be based on the PKS. 
Safety analysis: 
Treatment-emergent adverse events (TEAEs) will be summarised by MedDRA primary 
system organ class (SOC) and preferred term (PT). TEAEs will be summarised by severity 

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and drug relationship. TEAEs leading to discontinuation from the study, adverse events 
(AEs) of special interest and serious TEAEs will be summarised separately. All AEs will be 
listed. 
Laboratory, vital signs and ECG parameters will be described using summary statistics. 
The number of digital scars and skin score in patients with scleroderma will be analysed 
using standard summary statistics. 
All safety analyses will be based on the SS. 
Efficacy analysis: 
Efficacy data will be analysed exploratively. Continuous measures will be summarised using 
summary statistics: mean, standard deviation, median, minimum and maximum, in addition 
for the changes from baseline a 95% confidence interval will be provided. Categorical 
variables will be summarised by using frequency counts and percentages.  
The scores of each SF-36v2 subscale, as well as the physical and mental component summary 
scores (PCS and MCS), will be described using summary statistics. 
Efficacy analyses will be based on the FAS. 
Interim analyses: 
No interim analyses are planned in this study. 

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Final Version 3.0, 11-MAY-2020 
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Schedule of study procedures 
 
Screening 
Dose finding period 
42-days Maintenance period 
Follow-up 
Visit no.  
V1 
A12 
A2/B2/C2/D2 
A3/B3/C3/D35 
MPV15 
MPV25 
MPV32,5/ 
EDV1 
Follow-up 
down-
titration7 
FU17 
 
Day -12 to -5 
Day 1 
8 days ±2 after  
A1/A3/B3/C3 
14 days ±2 after 
A1/A3/B3/C3 
13 days ±2 
after 
D3/down-
titration19   
27 days ±2 
after 
D3/down-
titration19 
41 days ±2 
after 
D3/down-
titration19 
14 days ±2 
after 
MPV3/EDV 
14 days ±2 
after last IMP 
intake 
on-site visit ⊗ / 
telephone contact  
⊗ 
⊗ 
 
⊗ 
⊗ 
⊗ 
⊗ 
 
⊗ 
Initiation procedures 
 
 
 
 
 
 
 
 
 
Informed consent  
 
 
 
 
 
 
 
 
 
Demographics 
 
 
 
 
 
 
 
 
 
Height 
 
 
 
 
 
 
 
 
 
Weight 
 
 
 
 
 
 
 
 
 
Medical history 
 
 
 
 
 
 
 
 
 
Prior medication 
 
 
 
 
 
 
 
 
 
Concomitant medication 
 
 
 
 
 
 
 
 
 
WHO functional class 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
 
 
 
 
 
 
 
 
 
Medication 
 
 
 
 
 
 
 
 
 
First IMP administration 
 
 
 
 
 
 
 
 
 
Dose increase 
 
 
 
3 
 
 
 
 
 
Dispense IMP 
 
 
 
 
 
 
7 
 
 
IMP accountability 
 
 
 
 
 
 
 
 
7 
Pharmacokinetics/ 
Pharmacodynamics 
 
 
 
 
 
 
 
 
 
Blood withdrawal (24h profile) 
 
4 
 
 
 
 
4,8 
 
 
Blood withdrawal (trough level) 
 
 
 
14 
14 
14 
 
 
 
Blood withdrawal (DβH 
activity) 
 
4 
 
14 
14 
14 
4,8 
 
 

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Final Version 3.0, 11-MAY-2020 
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Screening 
Dose finding period 
42-days Maintenance period 
Follow-up 
Visit no.  
V1 
A12 
A2/B2/C2/D2 
A3/B3/C3/D35 
MPV15 
MPV25 
MPV32,5/ 
EDV1 
Follow-up 
down-
titration7 
FU17 
 
Day -12 to -5 
Day 1 
8 days ±2 after  
A1/A3/B3/C3 
14 days ±2 after 
A1/A3/B3/C3 
13 days ±2 
after 
D3/down-
titration19   
27 days ±2 
after 
D3/down-
titration19 
41 days ±2 
after 
D3/down-
titration19 
14 days ±2 
after 
MPV3/EDV 
14 days ±2 
after last IMP 
intake 
on-site visit ⊗ / 
telephone contact  
⊗ 
⊗ 
 
⊗ 
⊗ 
⊗ 
⊗ 
 
⊗ 
Urinalysis (dopamine and 
norepinephrine levels, 24h 
urine collection)15 
 
 
 
 
 
 
8 
 
 
Safety 
 
 
 
 
 
 
 
 
 
Adverse events 
 
 
 
 
 
 
 
 
 
Vital signs11 (blood pressure, 
heart rate, tympanic body 
temperature)  
 
12 
 
 
 
 
12 
 
 
Blood withdrawal 
(haematology, biochemistry 
and coagulation) 
 
 
 
 
 
 
 
 
 
Urinalysis 
 
 
 
 
 
 
 
 
 
Physical examination 
 
 
 
 
 
 
 
 
 
12-lead electrocardiogram 
 
18 
 
 
 
 
18 
 
 
Number of digital scars10 
 
 
 
 
 
 
 
 
 
Modified Rodnan Skin Score10 
 
 
 
 
 
 
 
 
 
Blood pregnancy test6 
 
 
 
 
 
 
 
 
 
Urine pregnancy test6 
 
 
 
 
 
 
 
 
 
Arterial blood gas analysis16,21 
 
 
 
 
 
 
8 
 
 
Efficacy 
 
 
 
 
 
 
 
 
 
SF-36v2 
 
 
 
 
 
 
8 
 
 
6-min walk test/Borg dyspnoea 
score 
13 
 
 
 
 
 
8,20 
 
 
Echocardiography 
 
 
 
 
 
 
8 
 
 

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Screening 
Dose finding period 
42-days Maintenance period 
Follow-up 
Visit no.  
V1 
A12 
A2/B2/C2/D2 
A3/B3/C3/D35 
MPV15 
MPV25 
MPV32,5/ 
EDV1 
Follow-up 
down-
titration7 
FU17 
 
Day -12 to -5 
Day 1 
8 days ±2 after  
A1/A3/B3/C3 
14 days ±2 after 
A1/A3/B3/C3 
13 days ±2 
after 
D3/down-
titration19   
27 days ±2 
after 
D3/down-
titration19 
41 days ±2 
after 
D3/down-
titration19 
14 days ±2 
after 
MPV3/EDV 
14 days ±2 
after last IMP 
intake 
on-site visit ⊗ / 
telephone contact  
⊗ 
⊗ 
 
⊗ 
⊗ 
⊗ 
⊗ 
 
⊗ 
Right heart catheterisation16,22 
 
 
 
 
 
 
8 
 
 
Blood withdrawal biomarker 
 
 
 
 
 
 
8 
 
 
 
1. EDV = early discontinuation visit. An EDV has to be performed within 10 days of early discontinuation. Additionally, patients who will not participate in 
the extension study will be contacted by phone at the time of last patient’s last visit (LPLV) to document their vital status.  
2. Patients will be hospitalised for 24 hours. 
3. The dose will be increased if the previous dose was considered safe by the investigator according to safety criteria (at A3, B3 and C3). 
4. Blood samples for PK and PD to be taken prior to IMP intake as well as 1, 2, 4, 8, 16 and 24 hours after IMP intake (but still prior to next IMP intake). 
5. The patient has to be advised not to take the IMP at home on the day of A3, B3, C3, D3, MPV1, MPV2 and MPV3. 
6. Only in women of childbearing potential.  
7. Only applicable in patients taking 150 mg or 200 mg zamicastat and who will not participate in the extension study. In case a patient will discontinue the 
study early due to the occurrence of an AE, down-titration is not mandatory, but at the investigator’s discretion.  
8. Not applicable at EDV. 
9. Visits during the Dose-finding period:  
Dose A (50 mg zamicastat): visits A1, A2 and A3 
Dose B (100 mg zamicastat): visits B2 and B3. These visits will only be performed if the patient was up-titrated to 100 mg zamicastat at A3. 
Dose C (150 mg zamicastat): C2 and C3. These visits will only be performed if the patient was up-titrated to 150 mg zamicastat at B3. 
Dose D (200 mg zamicastat): D2 and D3. These visits will only be performed if the patient was up-titrated to 200 mg zamicastat at C3. 
If the patient’s next dose will not be tolerated, the patient will be asked to come to an unscheduled visit (UV) and he/she will be down-titrated to his/her 
previous dose.  
10. In scleroderma patients only. 
11. Blood pressure and heart rate will be measured in supine position (two measurements) and afterwards in standing position (one measurement).  

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12. At A1 and MPV3 blood pressure and heart rate (two measurements in supine and one measurement in standing position) will be measured before IMP 
intake as well as 4, 8 and 24 hours after IMP intake.  
13. Two baseline tests, separated by an interval of at least 30 minutes. 
14. Blood samples will be taken prior to IMP intake. 
15. 24-hour urine collection will start on the day before the respective visit.  
16. Right heart catheterisation and arterial blood gas analysis have to be performed before IMP intake. 
17. Applicable in all patients who will not participate in the extension study as well as in patients who discontinued early.   
18. At A1 and MPV3 triplicate ECGs recordings will be performed before IMP intake, 4 and 8 hours after IMP intake. At EDV only one ECG recording will 
be performed.  
19. Down-titration can be performed at a scheduled visit or an unscheduled visit (on-site visit or telephone contact) during the dose finding period.  
20. 6-MWT has to be performed after arterial blood gas analysis but before right heart catheterisation and IMP intake. 
21. Arterial blood gas analysis has to be performed before right heart catheterisation. 
22. Right heart catheterisation will only be performed if no results which were measured at the study site from within 90 days before V1 are available. 

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Figure 1: Overview of study design
 

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3. 
TABLE OF CONTENTS 
 
1. 
SIGNATURE PAGES ......................................................................................3 
1.1 
Sponsor Signatures ...........................................................................................3 
1.2 
Coordinating Investigator’s Declaration ...........................................................4 
1.3 
Principal Investigator’s Declaration .................................................................5 
2. 
PROTOCOL SYNOPSIS .................................................................................6 
3. 
TABLE OF CONTENTS ................................................................................19 
3.1 
List of Tables ..................................................................................................24 
3.2 
List of Figures .................................................................................................24 
4. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ...................25 
4.1 
List of Abbreviations ......................................................................................25 
4.2 
Definition of Terms ........................................................................................28 
5. 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE .....29 
6. 
INTRODUCTION ..........................................................................................34 
6.1 
Background .....................................................................................................34 
6.2 
Investigational Medicinal Product ..................................................................34 
6.2.1 
Non-clinical aspects ........................................................................................34 
6.2.2 
Experience in humans .....................................................................................37 
6.3 
Rationale .........................................................................................................39 
6.4 
Benefit-Risk Considerations ...........................................................................40 
7. 
STUDY OBJECTIVES ...................................................................................41 
7.1 
Primary Objective ...........................................................................................41 
7.2 
Secondary Objectives .....................................................................................41 
8. 
STUDY DESIGN ...........................................................................................42 
8.1 
Overall Study Design and Plan .......................................................................42 
8.2 
Discussion of Study Design ............................................................................43 
8.3 
Duration of the Study ......................................................................................43 
9. 
STUDY POPULATION .................................................................................44 
9.1 
Selection of Study Population and Diagnosis .................................................44 
9.2 
Inclusion Criteria ............................................................................................44 
9.3 
Exclusion Criteria ...........................................................................................44 
9.4 
Screening Failures and Withdrawals ..............................................................46 
9.4.1 
Screening failures ...........................................................................................46 

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9.4.2 
Withdrawals ....................................................................................................46 
9.5 
Termination of Study ......................................................................................47 
9.5.1 
Regular termination of study ..........................................................................47 
9.5.2 
Premature termination of study .......................................................................47 
9.5.3 
Premature termination of the study in a study centre .....................................47 
10. 
TREATMENTS ..............................................................................................49 
10.1 
Identity of Investigational Medicinal Product(s) ............................................49 
10.2 
Identity of Non-Investigational/Auxiliary Medicinal Product(s) ...................49 
10.3 
Selection of Doses in the Study ......................................................................49 
10.3.1 
Selection and timing of dose for each patient .................................................49 
10.3.2 
Dose adjustment criteria .................................................................................50 
10.4 
Method of Assigning Patients to Treatment Groups ......................................50 
10.4.1 
Randomisation ................................................................................................50 
10.4.2 
Blinding ..........................................................................................................50 
10.5 
Labelling and Packaging .................................................................................50 
10.6 
Supply, Storage, Dispensing and Return ........................................................51 
10.7 
Treatment Compliance and Drug Accountability ...........................................51 
10.8 
Prior and Concomitant Therapy ......................................................................52 
10.8.1 
Previous therapy .............................................................................................52 
10.8.2 
Concomitant medication .................................................................................52 
10.8.3 
Other restrictions .............................................................................................52 
10.9 
Further Treatment after the End of the Study .................................................52 
11. 
ASSESSMENTS .............................................................................................53 
11.1 
Baseline Characteristics ..................................................................................53 
11.1.1 
Demographic data, medical history and concomitant diseases .......................53 
11.1.2 
New York Heart Association/Word Health Organisation functional class 
(NYHA/WHO) ................................................................................................53 
11.2 
Pharmacokinetic and Pharmacodynamic Assessment Criteria .......................53 
11.2.1 
Pharmacokinetics ............................................................................................53 
11.2.2 
Pharmacodynamics .........................................................................................54 
11.3 
Safety Assessment Criteria .............................................................................54 
11.3.1 
Adverse events ................................................................................................54 
11.3.2 
Clinical laboratory evaluations .......................................................................54 
11.3.3 
Physical examinations .....................................................................................56 
11.3.4 
Vital signs .......................................................................................................56 

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11.3.5 
Electrocardiogram ...........................................................................................56 
11.3.6 
Number of digital scars ...................................................................................56 
11.3.7 
Modified Rodnan skin score (mRSS) .............................................................56 
11.4 
Efficacy Assessment Criteria ..........................................................................56 
11.4.1 
36-item Short Form Survey version2 (SF-36v2) ............................................56 
11.4.2 
Echocardiography ...........................................................................................57 
11.4.3 
6-min walk test (6-MWT) ...............................................................................57 
11.4.4 
Right heart catheterisation ..............................................................................57 
11.4.5 
Biomarker .......................................................................................................58 
11.5 
Appropriateness of Measurements ..................................................................58 
11.6 
Description of Study Visits .............................................................................58 
11.6.1 
Visit 1 (V1, Screening visit, Day -12 to -5) ....................................................58 
11.6.2 
Visit A1 (Day 1) .............................................................................................59 
11.6.3 
Visit A2/B2/C2/D2 (8 days ±2 after A1/A3/B3/C3) ......................................59 
11.6.4 
Visit A3/B3/C3/D3 (14 days ±2 after A1/A3/B3/C3) ....................................59 
11.6.5 
Visit MPV1 (13 days ±2 after D3/down-titration during the dose-finding 
period) .............................................................................................................60 
11.6.6 
Visit MPV2 (27 days ±2 after D3/UV) ...........................................................60 
11.6.7 
Visit MPV3 (41 days ±2 after D3/UV)/ EDV ................................................61 
11.6.8 
Follow-up visit (FU [down-titration], 14 days ±2 after MPV3/EDV) ............62 
11.6.9 
Follow-up visit (FU, 14 days ±2 after last IMP intake) ..................................62 
11.7 
Unscheduled Visits .........................................................................................62 
12. 
ADVERSE EVENTS ......................................................................................64 
12.1 
Definitions ......................................................................................................64 
12.1.1 
Adverse event .................................................................................................64 
12.1.2 
Adverse drug reaction .....................................................................................64 
12.1.3 
Unexpected adverse drug reaction ..................................................................64 
12.1.4 
Serious adverse event ......................................................................................64 
12.1.5 
Treatment emergent adverse event .................................................................65 
12.1.6 
Suspected unexpected serious adverse reaction ..............................................65 
12.1.7 
Severity of adverse events ..............................................................................65 
12.1.8 
Drug relationship of adverse events ................................................................65 
12.1.9 
Adverse event outcome ...................................................................................66 
12.1.10 
Adverse events of special interest ...................................................................66 
12.2 
Documentation and Treatment of Adverse Events by the Investigator ..........67 

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12.3 
Reporting of Serious Adverse Events .............................................................67 
12.3.1 
Reporting of serious adverse events to the sponsor ........................................67 
12.3.2 
Reporting of serious adverse events and other relevant safety information to 
the health authorities, ethics committees, study investigators ........................68 
12.4 
Pregnancy ........................................................................................................68 
12.4.1 
Patient’s pregnancy .........................................................................................68 
12.4.2 
Pregnancy of male patient’s partner ...............................................................69 
12.5 
Overdose .........................................................................................................69 
13. 
STATISTICS ..................................................................................................70 
13.1 
Variables .........................................................................................................70 
13.1.1 
Primary endpoint; pharmacokinetics ..............................................................70 
13.1.2 
Secondary endpoints .......................................................................................70 
13.2 
Analysis Populations .......................................................................................71 
13.2.1 
Enrolled Set .....................................................................................................71 
13.2.2 
Full Analysis Set .............................................................................................71 
13.2.3 
Pharmacokinetic Analysis Set ........................................................................71 
13.2.4 
Safety Set ........................................................................................................71 
13.2.5 
Procedures for accounting for missing, unused and spurious data .................71 
13.3 
Determination of Sample Size ........................................................................71 
13.4 
Statistical Methods ..........................................................................................72 
13.4.1 
Analysis of primary pharmacokinetic endpoints ............................................72 
13.4.2 
Analysis of secondary efficacy endpoints ......................................................72 
13.4.3 
Analysis of secondary safety endpoints ..........................................................72 
13.4.4 
Analysis of secondary pharmacokinetic endpoints .........................................72 
13.4.5 
Analysis of secondary pharmacodynamic endpoints ......................................72 
13.4.6 
Interim analyses and criteria for the termination of the study ........................73 
13.5 
Deviations from the Original Statistical Analysis Plan ..................................73 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .............................74 
14.1 
Source Data .....................................................................................................74 
14.2 
Source Documents ..........................................................................................74 
14.3 
Direct Access ..................................................................................................74 
15. 
DATA HANDLING AND RECORD KEEPING ..........................................75 
15.1 
Completion of Case Report Forms .................................................................75 
15.2 
Patient Diary ...................................................................................................75 
15.3 
Monitoring ......................................................................................................75 

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15.4 
Data Processing ...............................................................................................75 
15.5 
Archiving ........................................................................................................76 
15.6 
Data protection ................................................................................................76 
16. 
QUALITY ASSURANCE/AUDITS ..............................................................77 
17. 
ETHICAL CONSIDERATIONS ....................................................................78 
17.1 
Informed Consent ...........................................................................................78 
18. 
FINANCING AND INSURANCE .................................................................80 
19. 
PUBLICATION POLICY ..............................................................................81 
20. 
REFERENCE LIST ........................................................................................82 
 
 

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3.1 
List of Tables 
Table 1: Extent of exposure of zamicastat and its metabolites .......................................36 
Table 2: Dosage regimen ................................................................................................49 
Table 3: Functional classification of pulmonary hypertension modified after the NYHA 
functional classification according to the WHO 1998 ...................................53 
 
3.2 
List of Figures 
Figure 1: Overview of study design ................................................................................18 
 

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4. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
4.1 
List of Abbreviations 
ABBREVIATION 
EXPLANATION 
6-MWT 
6-minute walk test 
AE 
adverse event 
AESI 
adverse events of special interest 
ADR 
adverse drug reaction 
ALP 
alkaline phosphatase 
ALT 
alanine transaminase 
AoR 
acknowledgment of receipt form 
APD90 
action potential duration at 90% repolarisation 
APT 
action potential triangulation 
AST 
aspartate transaminase 
AUC 
area under the curve 
AUEC 
area under the effect-time curve 
BMPR2 
bone morphogenetic protein receptor type II 
CCB 
calcium channel blocker 
CI 
cardiac index 
CL/f 
apparent total clearance 
CLR 
renal clearance 
Cmax 
maximum plasma concentration 
Cmin 
minimum plasma concentration 
CNS 
central nervous system 
CO 
cardiac output 
CPK 
creatine phosphokinase 
CRA 
clinical research associate 
CRO 
contract research organisation 
DßH 
dopamine ß-hydroxylase 
DA 
dopamine 
DMP 
Data Management Plan 
DBP 
diastolic blood pressure 
DOPAC 
3,4-dihydroxyphenylacetic acid 
DPG 
diastolic pressure gradient 
DSMB 
data safety monitoring board 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EDV 
early discontinuation visit 
eGFR 
estimated glomerular filtration rate 
Emax 
maximum observed effect on DβH activity 
ES 
enrolled set 
FAS 
full analysis set 

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ABBREVIATION 
EXPLANATION 
FEV1 
Forced Expiratory Volume in 1 second 
FVC 
Forced Vital Capacity 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GI 
gastrointestinal 
GMP 
Good Manufacturing Practices 
HbA1c 
haemoglobin A1c 
HCG 
human chorionic gonadotropin 
HEK 
human embryonic kidney 
hERG 
human-ether-à-go-go related gene 
HIV 
human immunodeficiency virus 
HTD 
highest tolerated dose 
HVA 
homovanillic acid 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals 
for Human Use 
IEC 
Independent Ethics Committee 
IMP 
investigational medicinal product 
INR 
International normalised ratio 
ISF 
investigator site file 
LDH 
lactate dehydrogenase 
LLOQ 
lower limit of quantification 
LPLV 
last patient’s last visit 
MAD 
multiple ascending dose 
MCT 
monocrotaline 
MedDRA 
Medical Dictionary for Regulatory Activities 
mPAP 
mean pulmonary artery pressure 
mRSS 
modified Rodnan skin score 
NE 
norepinephrine 
NOAEL 
no-observed adverse effect level 
NT-proBNP 
N-terminal pro brain natriuretic peptide 
NYHA/WHO 
New York Heart Association/Word Health 
Organization 
PAC 
pulmonary arterial compliance 
PAH 
pulmonary arterial hypertension 
PAP 
pulmonary artery pressure 
PAWP 
pulmonary artery wedge pressure 
PCWP 
pulmonary capillary wedge pressure 
PD 
pharmacodynamic 
PK 
pharmacokinetic 

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ABBREVIATION 
EXPLANATION 
PKS 
pharmacokinetic analysis set 
PT 
preferred term 
PVR 
pulmonary vascular resistance 
RAP 
right atrial pressure 
RBC 
red blood cell count 
RHC 
right-heart catheterisation 
RV 
right ventricular 
RVP 
right ventricular pressure 
SAD 
single ascending dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS 
Statistical Analysis System 
SBP 
systolic blood pressure 
SCr 
standardised serum creatinine 
SDV 
source document verification 
SF-36v2 
Short Form – 36 version 2 
SHR 
spontaneously hypertensive rat 
SNS 
sympathetic nervous system 
SvO2 
mixed venous oxygen saturation 
SOC 
system organ class 
SS 
safety set 
SUSAR 
suspected unexpected serious adverse reaction 
SVR 
systemic vascular resistance 
t1/2 
terminal half-life 
TAPSE 
tricuspid annular plane systolic excursion 
TEAE 
treatment emergent adverse event 
TEmax 
time to occurrence of Emax 
TLC 
Total Lung Capacity 
TMF 
Trial Master File 
tmax 
time until Cmax 
TPG 
transpulmonary pressure gradient 
UV 
unscheduled visit 
V 
visit 
Vz/f 
apparent volume of distribution 
WBC 
white blood cell count 
WHO 
World Health Organization 
WKY 
Wistar-Kyoto rats 
WU 
Wood unit 
 

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4.2 
Definition of Terms 
Woman of childbearing 
potential 
A woman is considered of childbearing potential, i.e. fertile, 
following menarche and until becoming post-menopausal unless 
permanently sterile. Permanent sterilisation methods include 
hysterectomy, 
bilateral 
salpingectomy 
and 
bilateral 
oophorectomy. 
A postmenopausal state is defined as no menses for 12 months 
without an alternative medical cause. [1] 
 

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5. 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE 
This study will be conducted in approximately 15 sites in nine European countries. Other sites 
and other countries may be added as needed. A list of principal investigators and their 
affiliations will be kept in the Trial Master File (TMF). 
The sponsor, Bial, will contract planning, conduct, data management, medical monitoring 
support, pharmacovigilance, statistical analysis (except pharmacokinetic [PK] and 
pharmacodynamic [PD] analysis) and medical writing to the contract research organisation 
(CRO) given below. 
SPONSOR: 
Bial - Portela & Ca, S.A. (further Bial) 
À Av. da Siderurgia Nacional 
4745-457 Coronado (S. Romão e S. Mamede), Portugal 
Phone: +351 229866100 
Fax:     +351 229866192 
www.bial.com 
Research and Development General Manager: 
Patrício Soares-da-Silva, MD, PhD 
Research & Development Area 
psoares.silva@bial.com 
Project Managers: 
Ana Santos, BSc, MBA  
Department of Development 
ana.santos@bial.com  
 
Andreia Guimarães, BSc, PhD 
Department of Development 
andreia.guimaraes@bial.com 

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SPONSOR: 
Drug Safety Managers: 
Helena Gama, MD, MSc 
Head of Pharmacovigilance and Drug Safety, EU QPPV 
Av. Da Siderurgia Nacional, 4745-457 Coronado (S. Romão e S. Mamede) 
Phone: +351 229866100 (working hours) 
Phone: +351 966633353 (nights, weekends and holidays) 
Fax: +351 229866198 
e-mail: helena.gama@bial.com 
 
Mariana Vieira, PharmD, MSc 
Senior Pharmacovigilance and Drug Safety Manager (Deputy EU QPPV) 
Av. Da Siderurgia Nacional, 4745-457 Coronado (S. Romão e S. Mamede) 
Phone: +351 22 9866100 (working hours) 
Phone: +351 963469988 (nights, weekends and holidays) 
Fax: +351 229866198 
e-mail: mariana.vieira@bial.com 
Medical Monitors: 
Luís Magalhães, MD, PhD, PharmD  
Department of Development 
luis.magalhaes@bial.com  
 
Fábio Ikedo, MD, MSc (back-up) 
Department of Development 
fabio.ikedo@bial.com 
 
CONTRACT RESEARCH ORGANISATION 
Scope International AG (further SCOPE) 
Konrad-Zuse-Ring 18 
68163 Mannheim, Germany 
Phone: +49 621 429 39 0 
Fax: 
+49 621 429 39 40 
 
COORDINATING PRINCIPAL INVESTIGATOR 
Prof. Dr. med. Marius Hoeper 
Medizinische Hochschule Hannover 
Klinik für Pneumologie 
Carl-Neuberg-Straße 1 
30623 Hannover, Germany 
 

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DATA SAFETY MONITORING BOARD (DSMB) 
The DSMB will independently safeguard the interests of patients in this study and will 
enhance the data integrity and credibility of this study. The primary responsibilities of the 
DSMB, its relationship with other study components, and the purpose and timing of its 
meetings are described in the DSMB Charter. The DSMB membership includes three 
specialists with experience in cardiology and in pulmonary hypertension, one expert with 
experience in dermatology as well as one statistician.  
 
ELECTRONIC DATA CAPTURE (EDC) SYSTEM PROVIDERS 
Electronic data capture (EDC) system provider 
Oracle America, Inc. 
500 Oracle Parkway 
Redwood Shores, CA 94065, USA 
 
Phone: +44 (0) 118 9249 766 
Fax: 
+44 (0) 118 9249 766 
http://www.oracle.com/us/products/applications/health-sciences/e-
clinical/inform/index.html 
Electronic case report form:  
Oracle Health Sciences InForm 
 
 
LABORATORY 
Safety laboratory assessments (blood), blood pregnancy testing and biomarker (blood 
samples) assessments will be performed by: 
LKF Laboratorium für Klinische Forschung GmbH 
Lise-Meitner-Str. 25 
D- 24223 Schwentinental, Germany 
Phone: 
+49 4307 82760 
Fax: 
+49 4307 827679 
www.lkf-kiel.de 
Octopamine level assessments will be performed by: 
Anapharm 
Encuny 22, 2nd floor 
08038 Barcelona, Spain 
Phone: 
+34 93 223 86 36 
Email 
info@anapharmbioanalytics.com 
www.anapharmbioanalytics.com 

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LABORATORY 
PK assessments will be performed by:  
SYNLAB Analytics & Services Switzerland AG  
Sternenfeldstrasse 14 CH-4127 Birsfelden, Switzerland 
Phone: +41 61 317 9010  
Fax: +41 61 317 2310  
Email: Anette.Orjuela@synlab.com 
https://www.synlab.de/de/home/ 
 
Catecholamine (norepinephrine and dopamine) level assessment will be performed by: 
The Doctors Laboratory Ltd 
The Halo Building, 1 Mabledon Place 
London WC1H 9AX, United Kingdom 
Phone: + 44 (0)20 7307 7373 
Fax: + 44 (0)20 7307 7374 
Email: tdl@tdlpathology.com 
https://tdlpathology.com/ 
CENTRAL CLINICAL STUDY SUPPLY MANAGEMENT 
Bial - Portela & Ca, S.A. 
À Av. da Siderurgia Nacional 
4745-457 Coronado (S. Romão e S. Mamede), Portugal 
Phone: +351 229866100 
Fax:     +351 229866192 
www.bial.com 
 
STATISTICAL ANALYSIS 
Pharmacokinetic and pharmacodynamic analysis will be performed by: 
Quotient Science 
Mere Way, Ruddington 
Nottingham, NG11 6JS, United Kingdom 
https://www.quotientsciences.com 
Project Manager:  
Claire Swann, Senior Project Manager 
Phone: +44 15 931 5505 
Email: Claire.Swann@quotientsciences.com 
 
Note: Labelling and shipping of the study drug might be subcontracted to a contract 
manufacturing organisation.  

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All other study personnel not included in this section is identified in a separate personnel list 
as appropriate. This list will be regularly updated as needed. Its most current version will be 
available in each centre’s Investigator Site File (ISF) and/or in the TMF. 

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6. 
INTRODUCTION 
6.1 
Background 
Pulmonary arterial hypertension (PAH) is a chronic and progressive disease which affects 
small pulmonary arteries. It is characterised by vascular obstruction leading to progressive 
increase in vascular resistance. This increases right ventricular (RV) afterload and 
consequently results in RV failure. Intima and media proliferation and its consequent 
pulmonary vascular obstruction are considered to be the key elements in the pathogenesis of 
PAH. Vasoconstriction, vascular remodelling and thrombosis are factors that increase 
pulmonary vascular resistance (PVR) in PAH. These processes involve a multitude of cellular 
and molecular elements. [2] 
PAH is diagnosed by right-heart catheterisation (RHC) showing precapillary pulmonary 
hypertension with a mean pulmonary artery pressure (mPAP) of ≥ 25 mmHg and a normal 
pulmonary artery wedge pressure (PAWP) of ≤ 15 mmHg and increased pulmonary vascular 
resistance (PVR > 3 Wood units [WU]). [3] 
6.2 
Investigational Medicinal Product 
Zamicastat (also known as BIA 5-1058; 1-[(3R)-6,8-difluoro-3,4-dihydro-2H-1-benzopyran-
3-yl]-1,3- dihydro-5-[2-[(phenylmethyl)amino]ethyl]-2H-Imidazole-2-thione) is currently 
being developed by BIAL - Portela & Cª, S.A. for the treatment of cardiovascular diseases.  
Zamicastat is a reversible dopamine ß-hydroxylase (DßH) inhibitor that prevents the 
conversion of dopamine (DA) to norepinephrine (NE) in sympathetically innervated tissues 
and reduces the drive of the sympathetic nervous system (SNS). Zamicastat is a peripherally-
selective inhibitor as a result of its reduced ability to cross the blood-brain barrier. In contrast 
to what was found in peripheral tissues, zamicastat failed to affect brain levels of NE and had 
minimal impact on DA tissue levels in the brain, which is unique among DßH inhibitors 
previously tested for the treatment of cardiovascular disorders. The PD and PK profiles of 
zamicastat envisage a long duration of DßH inhibition, which may allow a once-daily 
administration. [4] 
6.2.1 
Non-clinical aspects 
Zamicastat, BIA 5-453 - a metabolite of zamicastat and its N-acetylated metabolite BIA 5-961, 
produced concentration-dependent decreases in DβH activity in human neuroblastoma 
SK-N-SH cells. In mice, zamicastat produced significant decreases in NE levels and increases 
in DA levels in the heart but no marked effect on NE tissue levels in the parietal and frontal 
cortex of the brain. Zamicastat (30 mg/kg) reduced to a similar extent the urinary excretion of 
NE in normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR), 
accompanied by a significant increase in the urinary excretion of DA, and metabolites 
3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). The effects of 
zamicastat have been explored in various animal models of disease. In the SHR model, 
zamicastat reduced systolic and diastolic blood pressure with no changes in heart rate. In the 
monocrotaline (MCT) rat model of PAH, zamicastat treatment, initiated on day 12 post MCT, 
significantly improved the survival rate, decreased the frequency of arrhythmic beats and the 
number of arrhythmic episodes, and reduced the incidence of lung plexiform lesions. There 
was no effect on the deteriorated hemodynamics and cardiac contractility. Safety 
pharmacology studies demonstrated that zamicastat had no significant effects on the gross 
behavioural state and gastrointestinal transit in the rat. Some effects on renal function were 
observed at 100 or 300 mg/kg (p.o.) in the rat; small increases in urinary volume, pH and 
sodium excretion with a more marked effect on potassium excretion. In conscious dogs 
monitored by telemetry, single administration of zamicastat (20, 60 or 120 mg/kg) had no 

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substantial effect on arterial blood pressure, heart rate, and on the PR, QRS, QT and the QTc 
intervals as compared with the vehicle control animals. 
Zamicastat had no or only slight effects on the action potential parameters in the dog Purkinje 
fiber at 0.222 μg/ml (measured concentration) and higher pro-arrhythmic potential related to 
lengthened action potential duration at 90% repolarization (APD90) and enhanced action 
potential triangulation (APT) at the measured concentration of 1.930 µg/ml. In a study that 
evaluated the effects of zamicastat on hERG potassium channel the IC50 was determined to be 
113.84 ng/mL, and no difference from the vehicle group was observed up to 39.2 ng/mL of 
zamicastat. These concentrations (up to 39.2 ng/ml) exceed by 22 times the free maximum 
observed plasma concentration at steady state (Cmax) of zamicastat in human plasma at 
zamicastat doses of 200 mg/day after repeated administration for 10 days under fed conditions 
and micronized API (BIA-51058-116). In a chronic toxicity study in non-rodents, zamicastat 
was administered by oral capsule to beagle dogs for 6 months at dose levels of 30, 60 or 
90 mg/kg/day in Week 1 and 10, 30 or 60 mg/kg/day thereafter followed by a 7-week recovery 
period. Electrocardiogram measurements showed decreases in heart rate for treated groups only 
during Week 13 when compared with control and pretreatment. Increases in QT and QTc 
interval were observed during Weeks 13 and 26 for all treated groups. These alterations did not 
result in any clinically detectable evidence of cardiac malfunction in the dogs. There was less 
of an effect at end of recovery phase, indicating partial recovery, and as no heart lesions were 
seen during the histopathological examination, in the context of this study the changes were 
considered non-adverse. Zamicastat has undergone a comprehensive toxicological evaluation 
in studies of appropriate design consistent with ICH requirements in the mouse, rat and dog. 
Embryofetal development studies have been conducted in rats and rabbits and fertility studies 
and pre- and post-natal development toxicity have been conducted in rats. Administration of 
zamicastat was associated with dose-dependent increases in zamicastat plasma levels. Table 1 
indicates the extent of exposure [area under the plasma concentration-time curve up to the last 
measurable concentration (AUC0-t)] of zamicastat and its metabolite BIA 5-453 corresponding 
to the no-observed adverse effect level (NOAEL) at the end of treatment with zamicastat in 
toxicity studies. 

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Table 1: Extent of exposure of zamicastat and its metabolites 
Study 
 
Study 
number 
NOAEL 
(mg/kg/day) 
AUC0-t (ng.h/mL) 
Zamicastat 
BIA 5-453 
Males 
Females 
Males 
Females 
4-week oral repeat 
administration in the mouse 
C64635 
100 
15100 
15000 
1580 
2240 
3-month oral repeat administration in 
the mouse 
C75007 
80 
11800 
6000 
1350 
1130 
4-week oral repeat administration in 
the rat 
C64657 
100 
60200 
112000 
5120 
7410 
3-month oral repeat administration 
in the rat 
C75018 
20 
4890 
10100 
50
4 
786 
6-month oral repeat administration 
in the rat 
D35961 
20 
9940 
8660 
1170 
313 
4-week oral repeat 
administration in the dog 
C77922 
180 
12400 
29400 
15800 
25500 
3-month oral repeat administration 
in the dog 
S31096 
80 
7730 
2510 
3360 
2640 
6-month oral repeat administration 
in the dog 
WJ02C
V 
60 
6860 
7890 
4850 
7630 
Studies to evaluate the genotoxic potential of zamicastat included in vitro bacterial assay, in 
vitro chromosomal aberration assay and in vivo mouse bone marrow micronucleus assay. 
Overall, there was no indication of mutagenicity, clastogenicity or aneugenicity for zamicastat. 
Pharmacokinetic studies in male Wistar rats demonstrated that following a single oral 
(30 mg/kg) and intravenous (2.5 mg/kg) administration of [14C]-zamicastat, Cmax of total 
radioactivity were observed (tmax) at 6-8 hours and 0.083 hours post-dose, respectively. 
Following single oral administration of 30 mg/kg [ 14C]- zamicastat to the male Beagle dog, 
Cmax of total radioactivity were observed between 1-4 hours post-dose (tmax). Following 
intravenous administration, plasma concentrations of total radioactivity were quantifiable up 
to 72 hours post-dose. Following a single oral administration of [14C]-zamicastat in male rats, 
radioactivity was quickly distributed in the tissues achieving the maximum concentration of 
radioactivity at the initial sampling point of 8 hours post-dose, and the majority of tissues were 
observed to have levels BLQ at the final sampling point of 168 hours post-dose. No evidence 
of concentration-dependent blood cell binding for [14C]-zamicastat was observed. The 
zamicastat binding interaction studies with warfarin, diazepam, digoxin or tolbutamide 
indicated that the plasma protein binding site of zamicastat differs from that of the interactants. 
The intrinsic clearance (CLint) values for zamicastat were estimated at 40.3, 32.6, 13.6, 44.2 
and 6.29 µL/min/106 cells in mouse, rat, dog, monkey and human hepatocytes, respectively. 
In general, the metabolites observed in hepatocytes across species were formed as a result of 
multiple (2 or more) biotransformation processes such as potential oxidation which include 
potential hydroxylation, epoxidation or oxide formation and N-dealkylated. BIA 5-453, a 
zamicastat N-dealkylated metabolite was identified as an active metabolite. Zamicastat is 
metabolised by CYP1A2, CYP2C8, CYP2C19, CYP2D6 and CYP3A4 recombinant enzymes 
with CYP2D6 with the highest metabolic clearance followed by CYP1A2, CYP2C19, CYP2C8 
and CYP3A4, respectively. In human hepatic microsomes, zamicastat inhibited CYP2B6, 
CYP2C8, CYP2C9, CYP2D6 and CYP3A4 activity. Faecal excretion was the primary route of 
excretion of total radioactivity, following both oral and intravenous administration of [ 14C]-
zamicastat. 

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6.2.2 
Experience in humans 
Clinical experience with zamicastat in humans includes 11 completed phase I studies [4]:  
• a combined rising single-dose and multiple-dose study, including food interaction 
(BIA-51058-101), to investigate the safety, tolerability, PK and PD profile of zamicastat, 
in healthy male young subjects; 
• a food interaction study (BIA-51058-102), to investigate the effect of food (different meals 
and time of food intake) on the PK of zamicastat, in healthy male and female young 
subjects;  
• an open-label study to assess the absorption, distribution, metabolism and excretion, 
including the mass balance, of [14C]-labelled BIA 5-1058 and metabolites following a 
single oral dose administration in healthy male subjects (BIA-51058-104);  
• a 10-day multiple-dose study (BIA-51058-105) to investigate the effect of age-gender on 
the PK and PD profiles of zamicastat, in healthy male and female young and elderly 
subjects.  
• an open-label, three period, fixed sequence study to assess the effect of a single dose of 
BIA 5-1058 200 mg on the steady state pharmacokinetics of treprostinil in healthy subjects 
under fed conditions (BIA-51058-106); 
• an open-label, three period, fixed sequence study to assess the effect of a single dose of 
BIA 5-1058 400 mg on the steady state pharmacokinetics of bosentan in healthy subjects 
under fasting conditions (BIA-51058-107); 
• an open-label, three period, fixed sequence study to assess the effect of a single dose of 
BIA 5-1058 400 mg on the steady state pharmacokinetics of sildenafil in healthy subjects 
under fasting conditions (BIA-51058-108); 
• an open-label, three period, fixed sequence study to assess the effect of a single dose of 
BIA 5-1058 400 mg on warfarin pharmacokinetics in healthy subjects under fasting 
conditions (BIA-51058-109);  
• an open-label, three period, fixed sequence study to assess the pharmacokinetics, safety and 
tolerability of concurrent doses of BIA 5-1058 and furosemide in healthy subjects under 
fasting conditions (BIA-51058-111); 
• a randomised, double-blind, placebo-controlled and open-label, active-controlled, 4-period 
crossover trial to evaluate the effect of BIA 5-1058 on cardiac repolarisation in healthy adult 
males and females under fed conditions (BIA-51058-115); 
• a double-blind, randomised, placebo-controlled, parallel-group study to investigate the 
safety, tolerability, pharmacokinetics and pharmacodynamics of multiple doses of 
BIA 5-1058 in healthy volunteers (BIA-51058-116). 
Clinical experience with zamicastat in humans also includes three ongoing phase I clinical 
studies: 
• an open-label, sequential group, multiple-dose study to evaluate the PK, safety, and 
tolerability of zamicastat in subjects with hepatic impairment and normal hepatic function 
(BIA-51058-113); 
• an open-label, sequential group, multiple-dose study to evaluate the pharmacokinetics, 
safety, and tolerability of zamicastat in subjects with renal impairment and normal renal 
function (BIA-51058-114); 

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• an open-label study to assess the absorption, distribution, metabolism and excretion, 
including the mass balance recovery, metabolite profiling and identification, of [14C] 
labelled BIA 5-1058 following a single oral dose administration in healthy male subjects 
(BIA-51058-119). 
Overall, 571 healthy subjects aged 18 to 73 years, have been enrolled in the completed phase I 
studies and 512 have been exposed to zamicastat. The highest doses of zamicastat administered 
in the clinical studies were 2400 mg under single-dose conditions (study BIA-51058-101) and 
1200 mg under multiple-dose conditions (studies BIA-51058-101, and 105). On the other hand, 
the highest single and multiple-dose exposure to zamicastat were achieved with the 1200 mg, 
micronized API, under fed conditions (BIA-51058-102) and 1200 mg, micronized API, under 
fasted conditions (BIA-51058-105), respectively. 
Pharmacokinetic properties 
Systemic plasma exposure of zamicastat increases in a dose-dependent manner and 
pharmacokinetics indicates to be dose-linear over the dose range of 25 to 400 mg in fed and 
micronized conditions (BIA-51058-116), despite the moderate to high variability between 
subjects.  
The AUC0-t of total radioactivity in plasma was 91-fold higher than the cumulative 
concentration of zamicastat and its metabolites (BIA 5-453 and BIA 5-961) in plasma 
suggesting that other metabolites than BIA 5-453 and BIA 5-961 may be formed during 
metabolism of zamicastat which have not yet been identified (BIA-51058-104). Moreover, 
zamicastat and its metabolites demonstrated to be excreted both by faeces and urine, with 
faeces as the major route (65.3%). Overall, zamicastat plasma exposure is higher in multiple-
dose than in single-dose conditions (time-dependent pharmacokinetics), with the mean 
accumulation ratios (Cmax and AUC) ranging from 0.963 to 2.597 and 1.095 to 3.462. 
Zamicastat steady-state is reached between Day 3 and Day 5 following once-daily 
administration (BIA-51058-104).  
Peak exposures (Cmax) of zamicastat at steady state (Day 10) in fed conditions were 60% higher 
than those in the fasted state at 400 mg, but there were no other statistically significant 
differences in Cmax or in overall exposure (AUC0-t) at any dose level examined (50 mg, 100 mg, 
200 mg, 400 mg), indicating the lack of a meaningful food effect for zamicastat following 
repeated dosing (BIA-5-1058-116).  
Also, the micronization step performed on the API before the beginning of the BIA-51058-102 
study was found to increase the plasma exposure of zamicastat at 400, 800 and 1200 mg 
(BIA-51058-102).  
In turn, age appeared to have a positive effect on the PK of zamicastat, despite the reduced 
number of subjects included in the study (BIA-51058-105). Specifically, plasma exposure of 
zamicastat was found to be higher in elderly subjects compared to young subjects following 
multiple oral dose administration of 400 mg and 1200 mg of micronized zamicastat for 10 days 
(BIA-51058-105).  
Pharmacodynamic properties 
Zamicastat showed a dose-dependent and a long-lasting plasma DβH inhibition, with Emax 
ranging from 11% to 62% following once-daily doses. In line with the accumulation effect 
observed in the pharmacokinetics, the overall extent of DβH inhibition was found to be higher 
on Day 10 than Day 1, following multiple-dose administration of zamicastat.  
Doses of zamicastat that achieved 30-40% inhibition of plasma DβH activity in phase I studies 
serve as the basis for establishing its likely therapeutic dose (BIA-51058-101, -105, 116).  

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Drug-drug interactions 
The single-dose PK of zamicastat (400 mg) is affected by the co-administration of multiple 
oral doses of treprostinil (BIA-51058-106) and by multiple oral doses of bosentan 
(BIA-51058-107). Treprostinil increased the peak (Cmax) and total exposure (AUC0-t) of 
zamicastat, whilst co-administration of bosentan increased the peak exposure and decreased 
the total exposure of zamicastat. On the other hand, single-dose PK of zamicastat (400 mg) is 
not affected by the co-administration of multiple oral doses of sildenafil (BIA-51058-108), 
single-dose of warfarin (BIA-51058-109) or single-dose of furosemide (BIA-51058-111).  
Zamicastat did not significantly affect the steady-state PK of bosentan and sildenafil, neither 
the single-dose PK and PD (International Normalized Ratio of prothrombin time) of warfarin 
(S- and R-warfarin), when co-administered with these drugs in single dose of 400 mg under 
fasting conditions (BIA-51058-107, BIA-510158-108 and BIA-51058-109, respectively). On 
the other hand, single-dose of zamicastat (200 mg) decreased the total exposure of treprostinil 
in steady-state conditions, whilst single-dose of zamicastat (400 mg) reduced the peak and total 
exposure of single-dose of furosemide. 
Tolerability and safety 
Overall, no serious or severe adverse events were reported. Eight out of 512 (1.6%) subjects 
exposed to zamicastat reported skin and subcutaneous tissue disorders assessed as at least 
possibly related to zamicastat (5 cases of moderate diffuse erythemato papulous cutaneous 
eruption from study BIA-51058-105, one case of mild rash erythematous from study 
BIA-51058-106, one case of mild papular rash from study BIA-51058-109 and one case of 
mild rash pruritic from study BIA-51058-111); these TEAEs were considered to be of special 
interest. All 8 cases were assessed as non-serious, were self-limited and subjects recovered 
completely. The potential maximum therapeutic exposure of zamicastat (400 mg, single-dose, 
fed conditions, micronized API) did not have a clinically significant effect on cardiac 
repolarization, whilst a supratherapeutic exposure (1200 mg, single-dose, fed conditions, 
micronized API) had a minimal effect. The 400 mg and 1200 mg doses of zamicastat did not 
have a clinically relevant effect on heart rate, PR interval, or QRS duration, and there were no 
new clinically significant ECG morphology events (BIA-51058-115). There was no clear trend 
or effect with respect to tolerability of zamicastat through dose escalation or administration 
with food and no clear indication that food status influenced a subject’s dose tolerability 
(BIA-51058-116). Overall, zamicastat was well tolerated in all the completed clinical trials till 
date. 
 Further details are provided in the current Investigator’s Brochure (IB). [4] 
6.3 
Rationale 
The currently licensed therapies for PAH – prostacyclin‐cAMP, nitric oxide‐soluble guanylate 
cyclase‐phosphodiesterase type 5 (cGMP‐PDE5) and endothelin – target the three main 
vasoactive pathways. Despite improvement in patient symptoms and well‐being with these 
agents, mortality rates remain high (~65% survival at 5 years) and there is a need for therapies 
targeting alternative pathways that can reverse pulmonary vascular remodelling, inhibit disease 
progression and improve survival. [3] 
Experimental and clinical evidence supports a relation between PAH and the SNS, indicating 
that PAH can be mediated, at least partly, by SNS hyperactivation. A strategy for the 
modulation of sympathetic nerve function is to reduce the biosynthesis of NE DβH, the enzyme 
that catalyses the conversion of DA to NE in sympathetic nerves. In the monocrotaline (MCT)-
induced pulmonary hypertension model in the rat oral treatment with the DβH inhibitor 

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zamicastat prevented the MCT-induced increase in mean right ventricular pressure (RVP) and 
decrease in pulse rate was significantly attenuated. [5]  
Based on these promising experimental results and the need of new therapies with different 
mechanism of action for the treatment of PAH, the effect of zamicastat as adjunctive therapy 
will be investigated in PAH patients. Moreover, this study is particularly planned to evaluate 
the PK profile, safety and tolerability of different zamicastat doses in order to define the 
suitable dosage window for the treatment of PAH disease, considering that the PK profile of 
zamicastat may be different in PAH patients due to the known haemodynamic changes.   
6.4 
Benefit-Risk Considerations 
Zamicastat is a newly developed reversible DßH inhibitor. Preclinical results suggest that PAH 
patients potentially benefit from zamicastat treatment.  
Potential risks of study participation are experiencing an ADR to treatment with zamicastat. A 
detailed description of preclinical and clinical experience with zamicastat and of all treatment 
emergent adverse events (TEAEs) is provided in the IB. All reported related TEAEs were of 
mild or moderate intensity and resolved without sequelae. [4] No deaths and SAEs were 
reported. The safety of the patients will be monitored by a data safety monitoring board 
(DSMB). 
In case of unusual symptoms or questions the patients can always contact the investigator and 
arrange an unscheduled visit (UV). The planned study procedures, standard examinations and 
questionnaires, will not pose a risk to the patients other than those associated with assessments 
in general common clinical practice.  
This study will be performed in PAH specialised centres. The study will be conducted in 
compliance with this protocol, by study personnel who are qualified by education, training, and 
experience in their roles, with adherence to Good Clinical Practice (GCP), the applicable 
regulatory requirements, and ethical principles based on the Declaration of Helsinki. 
 

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7. 
STUDY OBJECTIVES 
7.1 
Primary 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. 
7.2 
Secondary Objectives 
The secondary objectives of this study are: 
1. To assess further PK parameters including apparent total clearance, terminal half-life and 
apparent volume of distribution 
2. To assess the safety and tolerability of different zamicastat doses 
3. To investigate the effect of different zamicastat doses on plasma DβH activity 
4. To investigate the effect of different zamicastat doses on urinary catecholamine levels 
(norepinephrine and dopamine) 
5. To investigate the change in pulmonary haemodynamic parameters  
6. To investigate the change in the 6-minute walk test (6-MWT) 
7. To investigate the change in biomarkers  
8. To investigate the change in cardiac structure and contractibility, assessed by 
echocardiography 
9. To investigate the change in quality of life, assessed by SF-36v2 

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8. 
STUDY DESIGN 
8.1 
Overall Study Design and Plan 
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 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: 
o Dose A: visits A1, A2 and A3 
o Dose B: visits B2 and B3 
o Dose C: visits C2 and C3 
o Dose D: visits D2 and D3 
• Maintenance period, 42 days: visits MPV1, MPV2 and MPV3 
• Follow-up period: 
o Visit FU (down-titration): 14 days after MPV3 (only for patients taking 150 mg or 
200 mg zamicastat who will not participate in the 
extension study)  
o Visit FU: 14 days after last IMP intake 
After confirmed eligibility, patients will initiate treatment with Dose A (50 mg zamicastat once 
daily) at visit A1 and will be treated with this dose level for 14 days. If Dose A was considered 
safe by the investigator, it will be up-titrated to Dose B (100 mg zamicastat once daily) at visit 
A3 and the patient will continue with this dosage for 14 days. Patients not tolerating Dose A 
have to be withdrawn from the study.  
The up-titration is based on safety criteria, including but not limited to: 
• Absence of symptomatic and/or clinically relevant orthostatic hypotension 
• Systolic blood pressure (SBP) > 95 mmHg or diastolic blood pressure (DBP) > 50 mmHg 
• Absence of clinically significant changes in ECG parameters (heart rate, P-R interval, 
QRS duration, QT and QTc interval) 
• Absence of clinically significant hypersensitivity/skin allergic reactions 
After a positive safety evaluation at visit B3, the dose will be up-titrated to Dose C (150 mg 
zamicastat once daily) and the patient will continue on this dose level for a further 14 days. If 
Dose C was tolerated by the patient, it will be up-titrated at visit C3 to Dose D (200 mg 
zamicastat once daily) where the patient will remain for 56 days (14 days dose finding period 
+ 42 days maintenance period).  
Patients not tolerating their next dose at any time during the 14-days dose finding period will 
come immediately to the site or call the investigator (unscheduled visit), unless intolerance was 
detected during a scheduled visit and the dose will be down-titrated to the patient’s previous 

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tolerated dose. Then they will continue this treatment for 42 days during the maintenance 
period.  
The dose which will be taken during the maintenance period will be considered as an individual 
HTD. 
At the end of the maintenance period, the patient will have the opportunity to continue 
treatment in an extension study (BIA-51058-202), which will be described in a separate 
protocol.  
Patients not tolerating their individual HTD during the maintenance period have to be 
withdrawn from the study. An overview of the study design is provided in Figure 1. 
8.2 
Discussion of Study Design 
Zamicastat is currently being developed for the treatment of cardiovascular disorders, including 
PAH. At this level, previous clinical experience with zamicastat includes phase I clinical 
studies in healthy volunteers in a wide doses range (5 mg to 2400 mg in single-dose conditions 
and 50 mg to 1200 mg in multiple-dose conditions), which were found to be well tolerated. 
Nevertheless, patients with PAH frequently present an altered haemodynamic, as well as other 
individual factors, which may change the drug pharmacokinetics in relation to healthy 
volunteers. 
Thus, in this study, PAH patients on stable treatment with at least one approved PAH therapy 
will be included and treated with the individual HTD zamicastat dose for 42 days during the 
maintenance period.  
In a clinical study with healthy subjects, PK and PD analysis demonstrated that the dose range 
between 50 mg and 200 mg zamicastat once daily is the most promising therapeutic dose range, 
considering a DβH inhibition of 30-40% as the target pharmacodynamic effect. Moreover, it is 
expected that this dose range is considerably conservative to account for potential 
pharmacokinetic differences between PAH patients and healthy volunteers. Noteworthy, the 
maximum dose planned for PAH patients in the present clinical study (200 mg) is 6-fold lower 
than the maximum multiple-dose tested in healthy volunteers (1200 mg, study 
BIA-51058-105). 
Bearing in mind the exploratory character of the study, the zamicastat dose will be increased 
in steps of 50 mg every 14 days up to the maximum dose of 200 mg zamicastat. Thereby, the 
dose increase is based on safety criteria to guaranty the safety of the patients. Additionally, the 
patient’s safety will be supervised by a DSMB. 
The treatment duration of 42 days at the individual HTD will be sufficient to investigate PK/PD 
parameters and safety aspects of zamicastat. Patients benefiting from treatment with zamicastat 
will be offered to participate in a subsequent extension study which will be described in a 
separate protocol.  
8.3 
Duration of the Study 
First patient first visit (start date): 
May 2019 
Last patient last visit (end of study): Nov 2020 

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9. 
STUDY POPULATION 
9.1 
Selection of Study Population and Diagnosis 
This study will be performed in male and female PAH patients (WHO Group 1) aged 18 to 
75 years, inclusive. The patients have to be on stable treatment with at least one approved PAH 
therapy within the 3 months before V1 (for details see Section 10.8.1). Additionally, patients 
have to be classified by the investigator as WHO functional class II or III according to 
ESC/ERS guidelines. [8] The sample size rationale is given in Section 13.3.   
Patients will be enrolled in approximately 15 sites in 9 European countries. Other sites and 
other countries may be added as needed. 
9.2 
Inclusion Criteria  
At Visit 1 (Screening), patients must meet ALL of the following criteria: 
1. Male or female patients aged 18 to 75 years, inclusive. 
2. Able to comprehend and willing to sign an informed consent form (ICF).  
3. Diagnosis of PAH (pulmonary arterial hypertension WHO Group 1) documented by RHC 
with a mPAP ≥ 25 mmHg, a PAWP ≤ 15 mmHg and a PVR > 3 WU [8,9]: 
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. 
9.3 
Exclusion Criteria 
Patients are to be excluded from the study for ANY ONE of the following reasons: 
Criterion: 
Rationale: 
1. Contraindication to zamicastat, i.e. known hypersensitivity to 
ingredients of zamicastat formulation. 
Lack of suitability 
2. Two or more consecutive measurements of SBP < 95 mmHg or 
DBP < 50 mmHg measured at V1. 
Safety 

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3. Uncontrolled diabetes mellitus with HbA1c ≥ 8.5% within the last 
three months or at screening.  
Safety 
4. PAH WHO Group 1 due to portal hypertension, human 
immunodeficiency virus (HIV) infection and schistosomiasis. 
Lack of suitability 
5. Any disease known to cause pulmonary hypertension other than 
PAH WHO Group 1.  
Lack of suitability 
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. 
Safety 
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. 
Safety 
8. History of moderate to severe hepatic impairment (Child-Pugh B 
and C). 
Safety 
9. Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 
(measured at V1). 
Safety 
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 DβH e.g. rimiterole, 
isoprenaline, dopamine, dopexamine or dobutamide or α- and/or β-
blockers. 
Safety 
11. Current or previous (within the past year) alcohol or substance 
abuse excluding caffeine or nicotine. 
Lack of suitability 
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. 
Safety 
13. For women: Pregnancy or breast-feeding. Women of childbearing 
potential (as defined in Section 4.2) 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. 
Safety 

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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. 
Lack of suitability 
15. Vulnerable patients according to Section 1.61 of the ICH guideline 
for Good Clinical Practice E6 
Vulnerable patients 
according to GCP 
1.61 
9.4 
Screening Failures and Withdrawals 
9.4.1 
Screening failures 
Screening failures will be all patients who have been enrolled in the study (i.e. ICF signed), but 
discontinue the study before the first IMP intake at visit A1 due to whatever reason (withdrawn 
consent, do not fulfil criteria, by decision of investigator, etc.). 
One additional attempt at screening may be permitted within 4 weeks.  
In addition to their records of performed assessments, screening failures have to be documented 
on the termination page of the electronic case report form (eCRF). 
9.4.2 
Withdrawals 
Patients who have been enrolled and, for whatever reason, discontinue the study after first IMP 
intake at visit A1 are classified as withdrawals. Patients may withdraw from the study at any 
time, either on their own request or at the discretion of the investigator.  
Reasons for withdrawal must be documented carefully in the patient’s medical records and in 
the eCRF. Investigators must attempt to contact patients who fail to attend scheduled visits by 
telephone, letter, visit, etc., to exclude the possibility of an AE being the cause. Should this be 
the case, the AE must be documented, reported and followed up as described in Section 12. 
Attempts to contact the patient must be documented in the patient’s medical records. The 
project leader and the medical monitor of the study at Bial will be informed of each withdrawal 
and the reason for it. To minimize the loss to follow-up, the specified patient’s family 
member/friend (if available) will be contacted. An early discontinuation visit (EDV) (see 
Section 11.6.7) should be performed within 10 days, if possible, on each withdrawal. However, 
in case of early discontinuation due to withdrawal of consent, the patient will have the right to 
refuse this additional visit and phone calls and no further data will be collected for this patient 
apart from the reason for discontinuation. The investigator should attempt to retrieve all IMPs 
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Patients may withdraw or may be withdrawn from the study for the following reasons: 
• At their own request (withdrawal of consent) 
• If in the investigator’s opinion, for reasons of safety or ethics, continuation in the study 
would be detrimental to the patient’s well-being 
• Pregnancy 
• Ineligibility/development of an exclusion criterion 
• In case of an intolerable adverse event(s) 
• At the specific request of the sponsor 
• Lost to follow up 
• Other reasons 
Patients who are withdrawn are not to be replaced. 
9.5 
Termination of Study 
9.5.1 
Regular termination of study 
The end of this study is defined as the date of last patient’s last visit (LPLV) undergoing this 
study. Within 90 days of the end of a clinical study SCOPE will notify Independent Ethics 
Committees (IECs) and regulatory authorities about the regular termination of the study as 
required according to national laws and regulations. If the study has to be terminated early, this 
period shall be reduced to 15 days and the reasons must be clearly explained. 
9.5.2 
Premature termination of study 
The study may be terminated prematurely for any reason and at any time by Bial, IECs, or 
regulatory authorities. A decision to prematurely terminate the study is binding to all 
investigators of all study centres. IECs and regulatory authorities will be informed about reason 
and time of termination according to the applicable laws and regulations. 
Once dosing has begun, the study will be completed as planned unless the following criteria 
are satisfied that require temporary suspension or early termination of the study. 
• One SAE in one patient considered at least possibly related to the IMP administration will 
imply an urgent benefit-risk assessment and might result in a premature study termination 
in favour of patients’ well-being. 
• New information regarding the safety of the IMP becomes available, reviewed by the 
DSMB, and indicating a change in the risk/benefit profile for the compound, such that the 
risk/benefit is no longer acceptable for patients participating in the study. The DSMB will 
also periodically review the safety data and is empowered to recommend modifications of 
the protocol (dosage levels) or temporary suspension or early termination of the study, if 
major concerns arise about patient safety at any time during the course of the study. 
• Significant violation of Good Clinical Practice (GCP) that compromises the ability to 
achieve the primary study objectives or compromises patient safety. 
If the study is terminated prematurely, all investigators have to inform their patients in writing 
and take care of appropriate follow-up and further treatment of the patients. 
9.5.3 
Premature termination of the study in a study centre 
The sponsor reserves the right to discontinue the study at a specific study site any time. The 
reasons will be discussed with the principal investigator. A study site may also be discontinued 

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by the sponsor for major deviations from the protocol or due to difficulties experienced in 
running the study at that centre. 
Bial may terminate this study in one particular or several study centre(s) for one of the 
following reasons: 
• Non-compliance with GCP and/or regulatory requirements 
• Centre cannot recruit an adequate number of patients 
• False documentation in the eCRF due to carelessness or deliberately 
• Inadequate co-operation with Bial or its representatives 
• The principal investigator requests closure of his/her study centre 
If the study is prematurely terminated in one (or more) study centre(s), all investigators in this 
study centre (in these study centres) have to inform their patients and take care of appropriate 
follow-up and further treatment of the patients. IEC and regulatory authorities will be informed 
about reason and time of termination according to the applicable laws and regulations. 

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10. TREATMENTS 
10.1 
Identity of Investigational Medicinal Product(s) 
Name(s): 
Zamicastat (BIA 5-1058) 
Dosage form: 
Tablet 
Active ingredient: 
Zamicastat; 1-[(3R)-6,8-difluoro-3,4-dihydro-2H-1-
benzopyran-3-yl]- 1,3-dihydro-5-[2-
[(phenylmethyl)amino]ethyl]-2H- imidazole-2-thione 
Strength: 
100 mg of zamicastat 
Excipients: 
Microcrystalline cellulose (Avicel PH 101®), lactose 
200M, povidone K-30, croscarmelose sodium, magnesium 
stearate, OPADRY® II 85F205017 blue and purified water 
(does not appear in the final product) 
Presentation: 
Blue oblong tablets, grooved on both sides, without further 
engravings 
Pharmaceutical Manufacturer: 
BIAL - Portela & Cª, S.A., À Av. da Siderurgia Nacional, 
4745-457 Coronado (S. Romão e S. Mamede), Portugal 
 
A complete record of batch numbers and expiry dates of all IMP will be maintained in the 
TMF. 
This is an open-label study. IMP will be manufactured, packed and labelled according to 
current Good Manufacturing Practice (GMP) and GCP guidelines, and national legal 
requirements. 
10.2 
Identity of Non-Investigational/Auxiliary Medicinal Product(s) 
Not applicable 
10.3 
Selection of Doses in the Study 
10.3.1 Selection and timing of dose for each patient 
Each patient will start treatment with 50 mg zamicastat once daily (Dose A) at visit A1 and 
will be up-titrated step by step to the individual HTD i.e. up to 200 mg zamicastat once daily. 
The 100 mg tablet has to be split at the break score in two equal halves using a pill splitter. 
Table 2: Dosage regimen  
 
Daily dose 
Dose A 
50 mg (half a tablet of 100 mg) 
Dose B 
100 mg (one tablet of 100 mg) 
Dose C 
150 mg (one and a half tablet of 100 mg) 
Dose D 
200 mg (two tablets of 100 mg) 

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Each next dose will start after 14 days of treatment if the previous dose was considered safe by 
the investigator. The up-titration is based on the following safety criteria, including but not 
limited to: 
• Absence of symptomatic and/or clinically relevant orthostatic hypotension 
• SBP > 95 mmHg or DBP > 50 mmHg 
• Absence of clinically significant changes in ECG parameters (heart rate, P-R interval, 
QRS duration, QT and QTc interval) 
• Absence of clinically significant hypersensitivity/skin allergic reactions 
Patients not fulfilling the criteria for up-titration after 14 days of treatment with 50 mg 
zamicastat have to be withdrawn from the trial.  
If the patient’s next dose will not be tolerated by the patient, the dose has to be down-titrated 
to his/her previous dose and this dose will be considered as the individual HTD, if tolerated by 
the patient. Treatment at the individual HTD will be for 42 days during the maintenance period. 
Zamicastat has to be taken in the morning after breakfast. The patient must not take the tablet 
at home on visit days (A3/B3/C3/D3, MPV1, MPV2 and MPV3). 
In case a patient missed to take the dose after breakfast, (s)he should take the dose after lunch. 
The next dose should be taken as scheduled. If the dose was missed after lunch too, the dose 
for this day has to be skipped.  
Patients taking 150 mg or 200 mg of zamicastat and who will not participate in the extension 
study will take 100 mg zamicastat for 14 days. 
In case a patient will discontinue the trial early due to the occurrence of an AE, down-titration 
is not mandatory, but at the investigator’s discretion. In case down-titration is recommended 
by the investigator, it should follow the same procedure as described above. 
10.3.2 Dose adjustment criteria 
For dose adjustment please refer to Section 10.3.1. 
10.4 
Method of Assigning Patients to Treatment Groups 
10.4.1 Randomisation 
Not applicable to this study. 
10.4.2 Blinding 
Not applicable to this study. 
10.5 
Labelling and Packaging 
Packaging of study medication will be performed by Bial - Portela & Cª, S.A., 4745-457 
Coronado (S. Romão e S. Mamede), Portugal. Labelling and shipping of the study medication 
might be subcontracted to a contract manufacturing organisation. 
Zamicastat (BIA 5-1058) tablets will be provided in HDPE bottles, labelled specifically for 
this clinical study. The labels for the IMP will be in accordance with the GMP, more 
specifically with the annex 13, and with local regulations i.e. label terminology may vary 
according to local regulations, and country-specific remarks will be added as needed. Adequate 
labels with the relevant information will be affixed to each bottle. Each bottle label will bear 
the following information: name, address and phone number of sponsor, name of principal 
investigator (information to be added/completed by the site), protocol code, patient number 
(information to be added/completed by the site), batch number, bottle number, open expiry 

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date, storage conditions, pharmaceutical dosage form and strength, route of administration, 
dosing instructions, number of tablets (content), and the following statements: “For clinical 
trial use only”,” Do not store above 25°C” and “Keep out of the sight and reach of children”. 
Sample labels will be filed in the TMF. 
Each patient will be supplied with IMP sufficient for periods of 14 days, including additional 
medication for visit windows, taking also into account the highest daily dose of 200 mg 
zamicastat (i.e. two tablets of 100 mg daily).  
10.6 
Supply, Storage, Dispensing and Return 
The IMP is to be used exclusively in the clinical study according to the instructions of this 
protocol. 
The investigator must confirm the receipt by completing an acknowledgment of receipt form 
(AoR) of the IMP with his/her signature.  
A USB temperature monitor will be included in the shipments. Once the shipment arrives at 
the site, the staff must download the temperature data immediately and print out the PDF report. 
This report should be filled together with the shipment documentation in the study file. In case 
of excursions, the Sponsor must be contacted to decide on the IMP final disposition. 
A copy of all the documentation, including AoR must be kept by the investigator and another 
copy will be stored at SCOPE. 
IMP must be stored in securely locked areas not generally accessible until dispensed to the 
patients. 
The investigator/institution and/or a pharmacist or other appropriate individual, who is 
designated by the investigator/institution, will maintain records of the IMPs’ delivery to the 
study site, the inventory at the site, the use by each patient, and the return to the sponsor or 
alternative disposition of unused study medication(s). These records will include dates, 
quantities, batch/serial numbers, expiration dates, and any unique code numbers assigned to 
the IMP(s) (kit number) and study patient (subject number). The investigator will maintain 
records that document adequately that the patients were provided the doses specified by the 
protocol and reconcile all IMP received from the sponsor. 
Zamicastat should be kept out of the reach and sight of children and at temperatures up to 25 ºC. 
Additionally, it should be kept in the original container. The storage temperature should be 
recorded continuously and documented, e.g. by system print-outs or by documenting 
minimum/maximum temperature on logs. Temperature logs should be completed once daily 
on each working day. 
The investigator or an authorised delegate is responsible for the dispensing of medication 
according to the dosage scheme (see Section 10.3). 
At the end of the study, or as directed during the course of the study, all IMP supplies (including 
partial and empty packaging) will be returned to the study medication supplier with the 
accountability sheets. However, before IMP will be returned to the study medication supplier, 
accountability has to be performed by the site. 
10.7 
Treatment Compliance and Drug Accountability 
At each study visit, the patient will be reminded of the importance of taking the IMP exactly 
as prescribed. IMP is to be taken by study patients only, during the course of the study. Study 
staff will dispense the appropriate amount of IMP for each patient and for each treatment 
interval plus additional medication. At each on-site visit, patients must bring back the IMP 

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(including empty and partially empty containers) and drug accountability must be performed 
and documented. 
10.8 
Prior and Concomitant Therapy 
10.8.1 Previous therapy 
Patients must be on stable treatment with at least one of the following approved PAH therapies 
for at least 90 days prior to V1: 
• Ambrisentan 
• Bosentan 
• Epoprostenol intravenous 
• Iloprost inhaled  
• Macitentan 
• Riociguat 
• Selexipag 
• Sildenafil 
• Tadalafil 
• Treprostinil intravenous or subcutaneous 
10.8.2 Concomitant medication 
Treatment with the following medications and therapies is prohibited: 
• CCBs, if taken 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 
• α- and/or β-blockers 
The potential for drug interactions has not yet been assessed. Therefore, the use of concomitant 
medications should be cautiously evaluated and avoided whenever possible. 
10.8.3 Other restrictions 
There are no study restrictions with respect to caffeine and smoking. Grapefruits as well as 
foods or drinks containing grapefruit are not permitted during entire study participation (from 
V1 to FU). 
Since zamicastat increases dopamine exposure, dopaminergic effects associated with 
dopaminergic therapy, such as hallucinations, nausea, dyskinesia, orthostatic hypotension and 
syncope, may be potentiated. Patients should be informed about the possible occurrence of 
such effects and cautioned against rising rapidly after sitting or lying down. Patients should be 
advised not to drive or operate dangerous machinery. Because of potential additive sedative 
effects, caution should be used when taking central nervous system (CNS) depressants.  
Additional information regarding contraindications, precautions and warnings concerning 
zamicastat are provided in the current version of the IB. [4] 
10.9 
Further Treatment after the End of the Study 
After the end of the study, patients will be offered to take part in the subsequent extension study 
which is described in a separate protocol. 

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11. ASSESSMENTS 
The assessments and procedures will be performed at the timepoints indicated in the schedule 
of study procedures (page 14). 
11.1 
Baseline Characteristics 
11.1.1 Demographic data, medical history and concomitant diseases 
Demographic data (age, gender and race), relevant medical history for former 6 months (longer 
in case of PAH relevance) and concomitant diseases or interventions are to be documented.  
Additionally, height and weight will be documented.  
11.1.2 New York Heart Association/Word Health Organisation functional class 
(NYHA/WHO) 
Classification of functional status of patients will be performed by the investigator by using the 
NYHA/WHO classification system. [7]  
Table 3: Functional classification of pulmonary hypertension modified after the NYHA 
functional classification according to the WHO 1998 
Class 
Description 
Class I 
Patients with pulmonary hypertension but without resulting limitation of 
physical activity. Ordinary physical activity does not cause undue 
dyspnoea or fatigue, chest pain or near syncope. 
Class II 
Patients with pulmonary hypertension resulting in a slight limitation of 
physical activity. They are comfortable at rest. Ordinary physical activity 
causes undue dyspnoea or fatigue, chest pain or near syncope. 
Class III 
Patients with pulmonary hypertension resulting in marked limitation of 
physical activity. They are comfortable at rest. Less than ordinary activity 
causes undue dyspnoea or fatigue, chest pain or near syncope. 
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. 
11.2 
Pharmacokinetic and Pharmacodynamic Assessment Criteria 
It has to be ensured that PK/PD blood sampling will be performed at the indicated time points. 
11.2.1 Pharmacokinetics  
24-hour profile 
Blood sampling for PK assessments will be performed at the following time points, preferably 
using an in-dwelling catheter: 
• 
Prior to IMP intake (0 hours) 
• 
1, 2, 4, 8 and 16 hours after IMP intake  
• 
24 hours after IMP intake, but still prior to next IMP intake (i.e. at the end of one dosing 
interval) 
Blood samples of approximately 8-9 mL have to be taken at each sampling time point (includes 
the sample for PK and plasma DβH activity). Blood samples from central catheters or port 

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systems should be withdrawn according to respective clinic standards, safeguarding that blood 
samples will not be diluted and no residual amounts of other drugs are included. 
Trough level assessment 
A blood sample of approximately 8-9 mL will be taken immediately before the intake of the 
next zamicastat dose (includes the sample for PK and plasma DβH activity).  
The site will instruct the patients not to take the tablet at home on the day of an on-site visit.  
If the tablet was already taken by the patient on the day of the visit before blood withdrawal or 
if the tablet of the day before this visit was not taken by the patient, the blood sample should 
be taken on the next day. 
A total blood volume of 180 mL at maximum will be collected together for PK and PD analysis 
(24-hour profile and trough level assessment). The time of the previous dose of IMP (not at 
visit A1) and time of sampling must be recorded in the eCRF. Plasma concentrations of 
zamicastat and its metabolites will be determined by a central laboratory for PK analyses 
(SYNLAB Analytics & Services Switzerland AG, Birsfelden, Switzerland). Details regarding 
the collection, storage and shipment of samples and reporting of results will be outlined in a 
laboratory manual, which will be supplied to all sites.  
Plasma concentrations of zamicastat and its metabolites will be used for evaluation/calculation 
of PK parameters as outlined in detail in Section 13.4.1 and Section 13.4.4. 
For diet restrictions please refer to Section 10.8.3. 
11.2.2 Pharmacodynamics 
The assessment of plasma DβH activity (octopamine levels) will be performed centrally by 
Anapharm, Barcelona, Spain. Blood sampling for the assessment of DβH activity will be 
performed together with the PK blood sampling (see Section 11.2.1).  
Catecholamine levels (norepinephrine and dopamine) will also be assessed centrally by The 
Doctors Laboratory Ltd, London, United Kingdom. For the assessment of catecholamines, a 
24-hour urine collection will start on the day before the respective visit. 
Details regarding the collection, storage and shipment of samples and reporting of results will 
be outlined in a laboratory manual, which will be supplied to all sites. 
Urine catecholamine levels (24-hour collection) and determination of plasma DβH activity by 
measuring octopamine levels will be used for the evaluation/calculation of PD parameters as 
outlined in detail in Section 13.4.5.  
11.3 
Safety Assessment Criteria 
11.3.1 Adverse events 
For adverse events see Section 12. 
11.3.2 Clinical laboratory evaluations 
A central laboratory (LKF Laboratorium für Klinische Forschung GmbH, Schwentinental, 
Germany) will be used for all safety laboratory analyses and the blood pregnancy test. Details 
regarding the collection, shipment of samples, reporting of results, and alerting of abnormal 
values will be outlined in a laboratory manual, which will be supplied to all sites. For these 
tests, approximately 12 mL of blood will be collected at each blood withdrawal, resulting in a 
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Urine safety analysis and urine pregnancy tests will be performed on-site. Microscopy and 
other appropriate tests (as needed) will be performed by the central laboratory if dipstick 
indicates any clinically relevant abnormality, as judged by the investigator. 
All laboratory reports must be reviewed for clinical relevance, signed and dated by the 
investigator. A copy of all reports must be filed in patient’s medical record (source document) 
for that visit. Urinalysis results will be recorded in patient’s medical record (source document) 
for that visit. 
Haematology: haemoglobin, haematocrit, red blood cell count (RBC), white blood cell count 
(WBC), differential - neutrophils, eosinophils, lymphocytes, monocytes and basophils, and 
platelet count 
Coagulation: prothrombin time test (International normalised ratio [INR]) 
Biochemistry: sodium, potassium, chloride, calcium, phosphate, blood urea nitrogen, aspartate 
transaminase (AST), alanine transaminase (ALT), gamma-glutamyl transferase (GGT), lactate 
dehydrogenase (LDH), alkaline phosphatase (ALP), creatine phosphokinase (CPK), creatinine, 
glucose, C-reactive protein, albumin, total protein, total cholesterol, low-density lipoprotein-
cholesterol, high-density lipoprotein-cholesterol, triglycerides, total bilirubin (bilirubin will be 
fractionated direct/indirect if elevated) and haemoglobin A1c (HbA1c) 
eGFR [13] will be estimated at V1 and MPV1 based on serum creatinine value using the 
according CKD-EPI formula using age, sex and race as follows:  
eGFR [mL/min/1.73 m2]  
= 141 x Min (SCr/κ, 1)α x Max (SCr /κ, 1)-1.209 x 0.993Age x 1.018 [if female] x 1.159 [if 
Black] 
Using the following abbreviations / units:  
SCr (standardised serum creatinine) = [mg/dL] 
κ = 0.7 (females) or 0.9 (males) 
α = -0.329 (females) or -0.411 (males) 
Min = indicates the minimum of SCr/κ or 1 
Max = indicates the maximum of SCr/κ or 1 
age = [years]. 
Arterial blood gas analysis: pH, oxygen partial pressure (pO2), carbon dioxide partial pressure 
(pCO2), bicarbonate, base excess (BE), arterial oxygen saturation (SaO2), electrolytes (Na+ and 
K+), and lactate.   
The blood gas analysis should be performed from arterial or arterialised capillary blood; this 
analysis may be replaced by peripheral oxygen saturation in stable patients or if a blood gas 
analysis cannot be performed. Blood sampling has to be performed before right heart 
catheterisation and IMP intake. Blood gas analysis will be performed on-site.  
Urinalysis: pH, specific gravity, protein, blood, glucose, ketones, bilirubin, urobilinogen, 
leucocytes and nitrites (local dipstick). Microscopy and other appropriate tests (as needed) will 
be performed if dipstick indicates any relevant abnormality, as judged by the investigator. 
Blood pregnancy test: human chorionic gonadotropin (HCG), in females of childbearing 
potential 
Urine pregnancy test: in females of childbearing potential. 

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11.3.3 Physical examinations 
Physical examination will be performed for relevant body systems (appearance, skin, eyes, 
ears-nose-throat, lungs-chest, heart, abdomen, extremities, other). 
11.3.4 Vital signs 
Vital signs (systolic and diastolic blood pressure and heart rate) will be measured after the 
patient has rested for at least 5 minutes in supine position (first measurement) and at least one 
minute after the first measurement, again in supine position (second measurement). 
Afterwards, vital signs will be measured again in standing position after the patient has been 
standing for at least 3 minutes (third measurement).  
At A1 and MPV3, blood pressure and heart rate will be measured before IMP intake as well as 
4, 8 and 24 hours after IMP intake. Painful procedures, like drawing blood, should always be 
performed after vital signs measurements (not before).   
Tympanic body temperature will be assessed once at all on-site visits. 
11.3.5 Electrocardiogram 
After each recording of a simultaneous 12-lead resting ECG, a copy will be printed and 
assessed by an investigator for at least the following parameters: heart rate, heart rhythm, P 
pulmonale, right axis deviation, RV hypertrophy, RV strain, right bundle branch block, P-R 
interval, QRS duration, QT interval and QTc interval. [8] 
At visits A1 and MPV3 triplicate ECG recordings will be performed before IMP intake as well 
as 4 and 8 hours after IMP intake. Painful procedures, like drawing blood, should always be 
performed after ECG recordings (not before).   
11.3.6 Number of digital scars 
At screening the investigator will document the number of existing digital scars at the fingers 
and toes. At subsequent on-site visits the investigator will examine fingers and toes of the 
patient for digital scars and will document the number of digital scars. Additionally, the clinical 
examination will be supported by interviewing the patient. This assessment will be performed 
in scleroderma patients only. 
11.3.7 Modified Rodnan skin score (mRSS) 
The mRSS is a measure of skin thickness and is used as an outcome measure for systemic 
sclerosis (scleroderma).  
This score consists of an evaluation of patient’s skin thickness rated by clinical palpation using 
a scale from 0 to 3 (0=normal skin; 1=mild thickness; 2=moderate thickness; 3=severe 
thickness with inability to pinch the skin into a fold) for each of 17 surface anatomic areas of 
the body: face, anterior chest, abdomen, (right and left separately) fingers, forearms, upper 
arms, tights, lower legs, dorsum of hands and feet. These individual values are added and the 
sum is defined as the total skin score. [9]  
11.4 
Efficacy Assessment Criteria 
11.4.1 36-item Short Form Survey version2 (SF-36v2) 
The SF-36v2 asks 36 questions to measure functional health and well-being from the patient's 
point of view in eight health concepts: physical functioning, bodily pain, role limitations due 
to physical health problems, role limitations due to personal or emotional problems, emotional 
well-being, social functioning, energy/fatigue, and general health perceptions. 
The questionnaire will be completed by the patient at the beginning of the visit.  

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11.4.2 Echocardiography 
Transthoracic echocardiography is used to image the effects of PAH on the heart. The 
following parameters will be determined [6].:  
• Tricuspid regurgitation, classified as absent, mild, moderate or severe 
• Right ventricular contractility, measured via tricuspid annular plane systolic excursion 
([TAPSE]; mm or cm) 
• Pericardial effusion, classified as absent, traces or present 
• Right atrial area (end-systolic), right ventricular end-diastolic area (cm2) 
A cardiologist will evaluate the echocardiography records.  
11.4.3 6-min walk test (6-MWT) 
The 6-MWT is a self-paced test of walking capacity used to assess aerobic capacity and 
endurance. It plays a key role in evaluation functional exercise capacity, assessing prognosis 
and evaluating response to treatment across a wide range of respiratory diseases. The distance 
covered over a time of 6 minutes is used as the outcome by which to compare changes in 
performance capacity. The 6-MWT will be performed according to the Technical Standard 
described by Holland et. al. [11].  
At screening (V1) two tests must be completed, separated by at least 30 minutes. Additionally, 
heart rate and arterial oxygen saturation measured by pulse oximetry (SpO2) must have returned 
to baseline prior to the second test. At visit MPV3 only one test will be performed after arterial 
blood gas analysis but before IMP intake.   
11.4.4 Right heart catheterisation 
Right heart catheterisation will be performed at visit A1, unless an RHC was performed within 
90 days before visit V1 at the study site and the result of the following parameters is available: 
PVR, right atrial pressure (RAP), mPAP, cardiac index (CI) and mixed venous oxygen 
saturation (SvO2%). Additionally, an RHC will be performed at MPV3 to determine the change 
of haemodynamic parameters in the patients. The RHC has to be performed before IMP intake. 
The following haemodynamic parameters will be determined:  
• Cardiac output (CO, L/min) 
• Mixed venous oxygen saturation (SvO2,%) 
• Pulmonary artery pressure systolic, diastolic and mean (PAPs, PAPd and mPAP, mmHg) 
• Pulmonary artery wedge pressure (PAWP, mmHg) 
• Right atrial pressure (RAP, mmHg) 
• Transpulmonary pressure gradient (TPG, mean PAP – mean PCWP) 
• Diastolic pressure gradient (DPG, diastolic PAP – mean PCWP)   
• Pulmonary vascular resistance (PVR; dyn x s xcm-5) 
• Systemic vascular resistance (SVR, dyn · s/cm5) 
• Cardiac index (CI, L/min/m2) 
• Pulmonary arterial compliance (PAC; SV/PP, mL/mmHg) 
• Heart rate (bpm) 
• Stroke volume (mL/beat) 
• Stroke volume index (mL/m2) 

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RHC will be performed according to the standard procedures provided in the 2015 ESC/ERS 
Guidelines for the diagnosis and treatment of pulmonary hypertension. [8] 
If data from an RHC within 90 days before visit V1 are available, which were measured at the 
study site, the available data points will be transcribed to the eCRF and the procedure will not 
be repeated at visit A1. 
11.4.5 Biomarker 
For biomarker laboratory tests an additional amount of approximately 6 mL blood will be 
collected twice. The blood samples for biomarker assessment will be analysed by a central 
laboratory. Details regarding the collection, storage and shipment of samples and reporting of 
results will be outlined in a laboratory manual, which will be supplied to all sites. 
The following biomarker will be analysed: 
• N-terminal pro brain natriuretic peptide (NT-proBNP) 
For possible further analyses of PAH biomarkers, remaining samples will be stored for a 
maximum of 10 years. 
11.5 
Appropriateness of Measurements 
All measurements performed in this study are recognised standard methods. Therefore, no 
further details concerning reliability or relevance will be discussed here. 
11.6 
Description of Study Visits 
For the schedule of study procedures, see Page 14. 
11.6.1 Visit 1 (V1, Screening visit, Day -12 to -5) 
The following assessments will be performed: 
• Informed consent 
• Demographics, including height and weight 
• Medical history 
• Prior and concomitant medication 
• WHO functional class 
• Inclusion/exclusion criteria 
• SF-36v2 
• AEs 
• Vital signs* (blood pressure, heart rate and tympanic body temperature; blood pressure and 
heart rate will be measured twice in supine position and afterwards once in standing 
position) 
• 12-lead ECG* 
• Blood withdrawal (haematology, coagulation and biochemistry, including hCG [in women 
of childbearing potential]) 
• Urinalysis 
• Physical examination 
• Number of digital scars, in scleroderma patients only 
• mRSS, in scleroderma patients only 
• 6-MWT, two baseline tests, separated by an interval of at least 30 minutes/Borg dyspnoea 
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• Echocardiography 
• Blood withdrawal (biomarker) 
*Painful procedures should be performed only afterwards. 
11.6.2 Visit A1 (Day 1) 
The following assessments will be performed: 
• Concomitant medication 
• Vital signs* (blood pressure, heart rate and tympanic body temperature). Blood pressure 
and heart rate will be measured twice in supine position and afterwards once in standing 
position before IMP intake as well as 4, 8 and 24 hours after IMP intake. 
• Triplicate 12-lead ECG*, before IMP intake, 4 and 8 hours after IMP intake 
• Urine pregnancy test, in women of childbearing potential 
• Inclusion/exclusion criteria 
• Arterial blood gas analysis (to be performed before first IMP intake and right heart 
catheterisation) 
• Right heart catheterisation (unless RHC results which were measured at the study site from 
within 90 days before V1 are available), to be performed before first IMP intake 
• Pharmacokinetic blood withdrawal (blood samples will be taken prior to IMP intake as well 
as 1, 2, 4, 8, 16 and 24 hours after IMP intake [but still prior to next IMP intake]) 
• Plasma DβH activity (blood samples will be taken prior to IMP intake as well as 1, 2, 4, 8, 
16 and 24 hours after IMP intake [but still prior to next IMP intake]) 
• First IMP administration 
• Urinalysis (dopamine and norepinephrine levels, 24-hour urine collection [from Day -1 to 
Day 1]) 
• Dispense IMP 
• AEs 
*Painful procedures should be performed only afterwards. 
11.6.3 Visit A2/B2/C2/D2 (8 days ±2 after A1/A3/B3/C3) 
This is a telephone visit. The following assessments will be performed: 
• Concomitant medication 
• AEs 
11.6.4 Visit A3/B3/C3/D3 (14 days ±2 after A1/A3/B3/C3) 
The following assessments will be performed: 
• Concomitant medication 
• Urine pregnancy test, in women of childbearing potential 
• Vital signs* (blood pressure, heart rate and tympanic body temperature; blood pressure and 
heart rate will be measured twice in supine position and afterwards once in standing 
position) 
• 12-lead ECG* 
• Pharmacokinetic blood withdrawal (trough level), blood sample will be taken prior to IMP 
intake 

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• Plasma DβH activity (trough level), blood sample will be taken prior to IMP intake 
• Dose increase, if applicable 
• Dispense IMP 
• IMP accountability 
• Urinalysis (dopamine and norepinephrine levels, 24-hour urine collection on the day before 
the visit) 
• AEs 
• Blood withdrawal (haematology, coagulation and biochemistry) 
• Urinalysis 
• Physical examination 
• Number of digital scars, in scleroderma patients only 
*Painful procedures should be performed only afterwards. 
11.6.5 Visit MPV1 (13 days ±2 after D3/down-titration during the dose-finding period) 
The following assessments will be performed: 
• Concomitant medication 
• Vital signs* (blood pressure, heart rate and tympanic body temperature; blood pressure and 
heart rate will be measured twice in supine position and afterwards once in standing 
position) 
• 12-lead ECG* 
• Pharmacokinetic blood withdrawal (trough level), blood sample will be taken prior to IMP 
intake 
• Plasma DβH activity (trough level), blood sample will be taken prior to IMP intake 
• Urine pregnancy test, in women of childbearing potential 
• Dispense IMP 
• IMP accountability 
• AEs 
• Blood withdrawal (haematology, coagulation and biochemistry) 
• Urinalysis 
• Physical examination 
• Number of digital scars, in scleroderma patients only 
*Painful procedures should be performed only afterwards. 
11.6.6 Visit MPV2 (27 days ±2 after D3/UV) 
The following assessments will be performed: 
• Concomitant medication 
• Vital signs* (blood pressure, heart rate and tympanic body temperature; blood pressure and 
heart rate will be measured twice in supine position and afterwards once in standing 
position) 
• 12-lead ECG* 
• Urine pregnancy test, in women of childbearing potential 

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• Pharmacokinetic blood withdrawal (trough level), blood sample will be taken prior to IMP 
intake 
• Plasma DβH activity (trough level), blood sample will be taken prior to IMP intake 
• Dispense IMP 
• IMP accountability 
• AEs 
• Physical examination 
• Number of digital scars, in scleroderma patients only 
*Painful procedures should be performed only afterwards. 
11.6.7 Visit MPV3 (41 days ±2 after D3/UV)/ EDV 
In case of a patient’s premature discontinuation, this visit should be performed as an EDV. The 
following assessments will be performed: 
• Weight 
• Concomitant medication 
• WHO functional class 
• Dispense IMP, only applicable in patients taking 150 mg or 200 mg zamicastat and who will not 
participate in the extension study 
• IMP accountability 
• Vital signs* (blood pressure, heart rate and tympanic body temperature). Blood pressure 
and heart rate will be measured twice in supine position and afterwards once in standing 
position before IMP intake as well as 4, 8 and 24 hours after IMP intake. 
• Triplicate 12-lead ECG*, before IMP intake, 4 and 8 hours after IMP intake. At EDV only 
one ECG recording will be performed. 
• SF-36v2 (not applicable at EDV) 
• Pharmacokinetic blood withdrawal (24-hour profile, not applicable at EDV), blood samples 
will be taken prior to IMP intake as well as 1, 2, 4, 8, 16 and 24 hours after IMP intake (but 
still prior to next IMP intake) 
• Plasma DβH activity (24-hour profile, not applicable at EDV), blood sample will be taken 
prior to IMP intake as well as 1, 2, 4, 8, 16 and 24 hours after IMP intake (but still prior to 
next IMP intake 
• Urinalysis (dopamine and norepinephrine levels, 24-hour urine collection on the day before 
the visit) (not applicable at EDV) 
• AEs 
• Blood withdrawal (haematology, coagulation and biochemistry) 
• Urinalysis 
• Physical examination 
• Number of digital scars, in scleroderma patients only 
• mRSS, in scleroderma patients only 
• Urine pregnancy test, in women of childbearing potential 
• 6-MWT, including Borg dyspnoea score (to be performed after arterial blood gas analysis 
but before right heart catheterisation and IMP intake [not applicable at EDV]) 

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• Echocardiography (not applicable at EDV) 
• Right heart catheterisation, to be performed before IMP intake (not applicable at EDV) 
• Arterial blood gas analysis; blood sampling has to be performed before right heart 
catheterisation and IMP intake (not applicable at EDV) 
• Blood withdrawal (biomarker), (not applicable at EDV) 
*Painful procedures should be performed only afterwards. 
11.6.8 Follow-up visit (FU [down-titration], 14 days ±2 after MPV3/EDV) 
This is a telephone visit and will be performed in patients who will be down-titrated (see 
Section 10.3.1). The following assessments will be performed: 
• Concomitant medication 
• AEs 
11.6.9 Follow-up visit (FU, 14 days ±2 after last IMP intake) 
This visit will be performed in all patients who will not participate in the extension study as 
well as in patients who discontinued early. The following assessments will be performed:  
• Concomitant medication 
• IMP accountability, only applicable in patients who were down-titrated 
• AEs 
• Vital signs* (blood pressure, heart rate and tympanic body temperature; blood pressure and 
heart rate will be measured twice in supine position and afterwards once in standing 
position) 
• 12-lead ECG* 
• Urine pregnancy test, in women of childbearing potential 
• Blood withdrawal (haematology, coagulation and biochemistry) 
• Urinalysis 
*Painful procedures should be performed only afterwards. 
11.7 
Unscheduled Visits 
Unscheduled visits can be performed as on-site visit or as telephone contact at any time during 
the trial for any reason. If a visit outside of the protocol evaluation time points is performed, 
the eCRF form for unscheduled visits will be completed. 
The following assessments will be at least performed: 
• Concomitant medication 
• AEs 
Additional examinations and blood sampling may be performed as deemed necessary by the 
investigator. 
If the patient’s next dose will not be tolerated, the patient will be asked to come immediately 
to an on-site visit or call the investigator and the dose will be down-titrated to the patient’s 
previous tolerated dose. The reason for down-titration has to be documented in the source data 
and eCRF.  
Patients who will not continue in the extension study will be contacted by phone at the time of 
LPLV to document their vital status. If it is not possible to contact the patient, the specified 

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patient’s family member/friend (if available) will be contacted. If a patient died the date of 
death has to be documented in the source data and eCRF.  

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12. ADVERSE EVENTS 
12.1 
Definitions 
12.1.1 Adverse event 
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 unfavourable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease occurring during the course of the study. 
Laboratory/ECG/vital signs abnormalities should not be documented as AEs unless they are 
considered clinically significant, require treatment, fulfil any SAE criterion, or cause the patient 
to change the study schedule. 
In the case of laboratory/ECG abnormalities that are a sign of a medical condition, the condition 
should be reported as an AE and not the sign. 
Events occurring in patients in the course of a clinical study during treatment free periods are 
also to be considered AEs. 
12.1.2 Adverse drug reaction 
All untoward and unintended responses to an IMP related to any dose administered should be 
considered ADRs. 
All AEs judged by either the reporting investigator or the sponsor as having a reasonable causal 
relationship (“possible” or “probable” or “definite”) to a medicinal product qualify as an ADR. 
12.1.3 Unexpected adverse drug reaction 
An unexpected ADR is defined as an adverse reaction, the nature, severity, or outcome of which 
is not consistent with the applicable product information e.g, IB for an unapproved IMP or 
Summary of Product Characteristics for an approved drug. [4] 
The term “expected” in pharmacovigilance, is not used to describe an event which might be 
anticipated from knowledge of the pharmacological properties of a substance. An event is also 
not to be described as “expected,” merely because it was foreseeable due to the health status 
(e.g., age, medical history) of the study patient. It refers strictly to the event being mentioned 
or listed in the applicable product information. 
In determining whether an AE is unexpected, consideration shall be given to whether the event 
adds significant information on the specificity, increase of occurrence, or severity of a known, 
already documented ADR. 
12.1.4 Serious adverse event 
An SAE is any untoward medical occurrence or effect that at any dose: 
• results in death, 
• is life-threatening, 
NOTE: The term “life-threatening” in the definition of “serious” refers to an event in which 
the patient was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe. 

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• requires hospitalisation or prolongation of existing hospitalisation*, 
• results in persistent or significant disability or incapacity,  
• is a congenital anomaly or birth defect, 
• is an important medical event that requires intervention to prevent one of the above. 
NOTE: Medical and scientific judgement should be exercised in deciding whether an event is 
“serious” in accordance with these criteria. Some medical events may jeopardise the patient or 
may require intervention to prevent one of the above characteristics/consequences. Such 
“important medical events” should also be considered as “serious” in accordance with the 
definition. 
* “Hospitalisation” is to be considered only as an overnight admission. 
EXCEPTION(S): 
1) The hospitalisation or prolongation of hospitalisation needed for a procedure required by 
the protocol. 
2) The hospitalisation or prolongation of hospitalisation as a part of a routine procedure 
followed by the centre (e.g. stent removal after surgery). 
3) The hospitalisation for a survey visit, annual physicals, or social reasons. 
4) Elective hospitalisations for pre-existing condition that had not worsened (e.g. elective 
hospitalisation for a total knee replacement due to a pre-existing condition of osteoarthritis 
of the knee that had not worsened during the course of the study). 
12.1.5 Treatment emergent adverse event 
An event that emerges during treatment having been absent prior to treatment or worsens 
relative to the pre-treatment state is defined as TEAE. In this clinical study, all AEs with onset 
or worsening after first intake of IMP until 14 days after last intake of IMP are defined as 
treatment emergent. For medical conditions diagnosed at screening also see Section 12.2. 
12.1.6 Suspected unexpected serious adverse reaction 
A suspected unexpected serious adverse reaction (SUSAR) is an adverse reaction that is both 
unexpected and serious. 
12.1.7 Severity of adverse events 
The maximum severity (intensity) of the AE will be categorised by the investigator as follows: 
Mild: a type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities of daily 
living. 
Moderate: a type of AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing discomfort but 
possess no significant or permanent risk of harm to the research participant. 
Severe: a type of AE that requires intensive therapeutic intervention. The event interrupts usual 
activities of daily living, or significantly affects clinical status. The event possesses a 
significant risk of harm to the research participant and hospitalisation may be required. 
12.1.8 Drug relationship of adverse events 
The relationship of an AE to the IMP is a clinical decision by the investigator based on all 
available information and is graded as follows: 

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Not related: A clinical event with no evidence of any causal relationship. 
Unlikely: A clinical event, including laboratory test abnormality, with a temporal relationship 
to drug administration which makes a causal relationship improbable, and in which other drugs, 
chemicals or underlying disease provide plausible explanations. 
Possible: A clinical event, including laboratory test abnormality, with a reasonable time 
sequence to administration of the drug, but which could also be explained by concurrent disease 
or other drugs or chemicals. Information on drug withdrawal may be lacking or unclear. 
Probable: A clinical event, including laboratory test abnormality, with a reasonable time 
sequence to administration of the drug, unlikely to be attributed to concurrent disease or other 
drugs or chemicals, and which follows a clinically reasonable response on withdrawal 
(dechallenge). Rechallenge information is not required to fulfil this definition. 
Definite: A clinical event, including laboratory test abnormality, occurring in a plausible time 
relationship to drug administration, and which cannot be explained by concurrent disease or 
other drugs or chemicals. The response to withdrawal of the drug (dechallenge) should be 
clinically plausible. The event must be definitive pharmacologically or phenomenologically, 
using a satisfactory rechallenge procedure if necessary. 
Mapping to the two categories “related” and “unrelated”: 
The categories “not related” and “unlikely” will be mapped to “unrelated”, the categories 
“possible”, “probable” and “definite” will be mapped to “related”. 
12.1.9 Adverse event outcome 
The outcome will be classified as follows: 
Recovered/Resolved: The patient has fully recovered from the event or the condition has 
returned to the level observed at baseline. 
Recovering/Resolving: The patient is improving but is still not fully recovered. 
Not recovered/Not resolved: As a final outcome, the condition is still present after appropriate 
follow-up. Improvement has not been observed and is no longer expected. 
Recovered/Resolved with sequelae: As a result of the AE, the patient suffers persistent and 
significant disability/incapacity (e.g., became blind, deaf or paralyzed). 
Fatal: The patient died due to the event.  
Unknown: If outcome is not known or not reported. 
12.1.10 Adverse events of special interest 
Adverse 
events 
of 
special 
interest 
(AESI) 
are 
AEs 
that 
may 
constitute 
a 
hypersensitivity/allergic reaction (cutaneous and/or non-cutaneous presentation) assessed by 
the investigator as moderate or severe and at least possibly related to IMP.  
The investigator will complete a Hypersensitivity/Allergic Reaction Adverse Event Report 
Form and (s)he will send this form to the SCOPE Safety Manager. Adverse events of special 
interest should be reported to the SCOPE Safety Manager following the SAE notification 
timelines (see Section 12.3.1). 
Whenever available, photographs of the affected skin area(s) should be provided to the SCOPE 
Safety Manager for assessment of individual events by the DSMB. In case an AESI is ongoing 
during a patient visit at the site, the site should take photographs of the affected skin area(s). 
Patients will also be advised to take photographs of the affected skin area(s) when a 

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hypersensitivity/allergic reaction occurs while not being at the site and to send these 
photographs to the site.  
Further details on procedure regarding AESI will be described in the Safety Management Plan 
(SMP). 
12.2 
Documentation and Treatment of Adverse Events by the Investigator 
All AEs, including SAEs, occurring within the period of observation for the clinical study must 
be recorded. The period of observation for the collection of AEs extends from the time when 
the patient gives informed consent until the date of final visit.  
Medical conditions that are diagnosed at the screening visit will only be documented as AEs, 
if they are known to have started or are suspected to have started after the ICF has been signed. 
All other medical findings at the medical examination at the screening visit will be documented 
as medical history. Medical judgement should be exercised to estimate if a condition is likely 
to have started between the signing of the informed consent and the date/time of the medical 
examination. 
Any AE that is still ongoing after final visit will be left as ongoing in the eCRF. However, the 
investigator will continue to follow up ongoing SAEs and record information in the source 
documents and on the Follow-Up SAE Form, until resolution or no further improvement can 
be expected. 
There is no time limit on collection of SAEs that are considered related to study drug. If the 
investigator detects a SAE of a study patients after the last visit, and considers the event 
possibly related to prior study treatment or procedures, he/she should contact one of the Bial 
safety managers to determine how the event should be documented and reported. 
At each visit, the investigator should ask the study patient in a non-leading manner about the 
state of his/her health in order to elicit information on AEs which may have occurred since the 
last visit. Any clinically significant observations made during the visit itself also constitute 
AEs. 
The AEs must be documented as soon and as completely as possible on the “Adverse Events” 
pages in the eCRF. Follow up information must be entered as soon as available. 
The following will also be specified: 
• Action taken with IMP: dose not changed, dose reduced, drug interrupted, drug withdrawn, 
not applicable, unknown. 
• Other actions (none, medication required, tests required, hospitalisation required or 
prolonged, withdrawn from the trial, other – please specify). 
• Outcome 
of 
event 
(fatal, 
not 
recovered/not 
resolved, 
recovered/resolved, 
recovered/resolved with sequelae, recovering/resolving, unknown) and date of outcome. 
• Seriousness: yes or no (criteria for SAE see above). 
• Severity. 
• Causal relationship to IMP 
Adverse events which occur during the study should be treated by established standards of care 
that will protect the life and health of the patient.  
12.3 
Reporting of Serious Adverse Events 
12.3.1 Reporting of serious adverse events to the sponsor 
See Section 12.1.4 for the definition of an SAE and also for study-specific exceptions. 

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As soon as the investigator learns of the occurrence of an SAE he/she must: 
• Ensure appropriate medical treatment. 
• Decide whether to withdraw the patient. 
• Immediately notify the SCOPE Safety Manager for the study (see below) by telephone, e-
mail or fax, of the event, providing the following information: suspect medicinal product, 
clinical study, reporter (study centre, investigator), study patient identification and AE with 
reason for seriousness and causal relationship. If the initial SAE notification was done by 
phone, the SCOPE Safety Manager must have received, within 24 hours, the respective 
form. The “Adverse Events” pages in the eCRF must also then be filled out as always. 
• Follow up as for all AEs. Basic follow up information must also be documented on the 
respective form and in the eCRF. On a revised version of the SAE Report Form, the box 
“Follow Up” must be ticked and it must be sent to the recipients of the initial information. 
• If requested, ensure that further information about the event is supplied to the SCOPE 
Safety Manager (see below) as soon as available (e.g., autopsy/biopsy reports, hospital 
admissions or discharge summaries, summaries of laboratory tests and other diagnostic 
examinations). 
SCOPE International Pharmacovigilance 
E-Mail: safety@scope-international.com 
Tel: +370 52 360 349 
Fax: +370 52 327 903 
The SCOPE Safety Manager must report the SAEs to Bial Pharmacovigilance within one 
working day of receipt. 
12.3.2 Reporting of serious adverse events and other relevant safety information to the health 
authorities, ethics committees, study investigators 
Expedited and periodic reporting required by the functionaries and institutions mentioned 
above will be fulfilled according to current local laws and guidance. The detailed reporting 
duties and division of responsibilities between the sponsor and the CRO will be detailed in the 
SMP. 
12.4 
Pregnancy 
12.4.1 Patient’s pregnancy 
Pregnancy discovered during the clinical study must lead immediately to exclusion (if at 
Screening) or withdrawal of the patient. 
A pregnancy with a calculated conception date after first IMP intake until 30 days after last 
IMP intake, should be documented on the corresponding form. The case must be reported 
within 24 hours of knowledge to SCOPE Safety manager. The investigator must follow up on 
pregnancies discovered after IMP administration until the end of pregnancy to document the 
outcome on the corresponding form. The event fulfils the criterion for an SAE in case of a 
congenital anomaly (birth defect), foetus death or spontaneous abortion, or adverse events in 
the neonate that are classified as serious. 

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12.4.2 Pregnancy of male patient’s partner 
A pregnancy with a calculated conception date after first IMP intake until 90 days after last 
IMP intake in the partner of a patient should be documented on the corresponding form. The 
case must be reported within 24 hours of knowledge to SCOPE Safety manager. 
12.5 
Overdose 
There is no human overdose experience. There is no known specific antidote. Symptomatic 
and supportive treatment should be administered as appropriate. Removal of the drug by gastric 
lavage and/or inactivation by administering activated charcoal should be considered. 

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13. STATISTICS 
This section presents a summary of the planned statistical analyses. All details of the statistical 
analyses and methods will be contained in a separate statistical analysis plan (SAP). 
13.1 
Variables 
13.1.1 Primary endpoint; pharmacokinetics 
The following PK parameters (24-hour profile) for zamicastat and its metabolites will be 
derived after a single dose of 50 mg zamicastat at visit A1 (Day 1): 
1. Area under the curve 0-24 h (AUC0-24h) 
2. Maximum plasma concentration (Cmax) 
3. Time until Cmax (tmax) 
The following PK parameter (24-hour profile) for zamicastat and its metabolites will be derived 
at steady-state at the individual HTD and will be taken at visit MPV3. 
4. Area under the curve 0-24 h (AUC0-24h,SS) 
5. Maximum plasma concentration (Cmax,SS) 
6. Time until Cmax,SS (tmax,SS) 
7. Minimum plasma concentration at the end of the dosing interval (Cmin,SS) 
The following PK parameter (trough level) will be derived for each dose at steady-state. 
8. Minimum plasma concentration at the end of the dosing interval (Cmin,SS) 
Additional PK parameters may also be calculated if considered appropriate. 
13.1.2 Secondary endpoints 
13.1.2.1 
Safety and tolerability endpoints 
1. Adverse events 
2. Clinically relevant changes in laboratory parameters (haematology, biochemistry, 
coagulation, urinalysis, arterial blood gas analysis) 
3. Clinically relevant changes in vital signs 
4. Clinically relevant changes in ECG 
5. Number of digital scars (only in patients with scleroderma) 
6. Skin score (only in patients with scleroderma) 
13.1.2.2 
Efficacy endpoints 
Change from baseline to MPV3 in:  
7. PVR, RAP, mPAP, CI and SvO2. Further haemodynamic parameters may also be calculated 
if considered appropriate. 
8. 6-MWT, including Borg dyspnoea score  
9. Biomarker (NT-proBNP) 
10. Echocardiogram parameters: 
• Tricuspid regurgitation, classified as absent, mild, moderate or severe 
• Right ventricular contractibility, measured via TAPSE 
• Pericardial effusion, classified as absent, traces or present 
• Right atrial area (end-systolic), right ventricular end-diastolic area 
11. WHO functional class 

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12. Quality of life (SF-36v2) 
13.1.2.3 
Pharmacokinetic endpoints 
13. Apparent total clearance (CL/f) 
14. Terminal half-life (t1/2) 
15. Apparent volume of distribution (Vz/f) 
13.1.2.4 
Pharmacodynamic endpoints 
16. Percent inhibition in plasma DβH activity (i.e. % change from baseline of DβH activity) on 
visits A3/B3/C3/D3, MPV1 and MPV2 (trough samples) and to visits A1 and MPV3 
(24-hour profiles)  
17. Maximal and minimal observed effect on DβH activity and time to occurrence of Emax 
(TEmax) and Emin (TEmin) on visit A1 (Day 1) and MPV3 
18. Area under the effect-time curve (AUEC24) for % DβH inhibition on visit A1 (Day 1) and 
MPV3 
20. Change from baseline 24-hour urinary catecholamine levels (norepinephrine and 
dopamine) on visits A3/B3/C3/D3 and MPV3. 
Additional parameters may be calculated if considered appropriate. 
13.2 
Analysis Populations 
Analysis will be based on the following populations: 
13.2.1 Enrolled Set 
The enrolled set (ES) includes all patients who provided informed consent. 
13.2.2 Full Analysis Set  
The full analysis set (FAS) includes all patients with at least one IMP administration. 
13.2.3 Pharmacokinetic Analysis Set 
The pharmacokinetic analysis set (PKS) will include all patients with an evaluable 24-hour PK 
profile and no major protocol deviations with an impact on PK analysis. 
13.2.4 Safety Set 
The safety set (SS) includes all patients with at least one IMP administration. The FAS and the 
SS are identical. 
13.2.5 Procedures for accounting for missing, unused and spurious data 
All data will be summarised descriptively using the observed cases; no data imputation other 
than imputation of missing dates is required. 
Imputation rules for partially or completely missing dates will be specified in the SAP. 
13.3 
Determination of Sample Size 
The clinical study BIA-51058-201 was designed to explore for the first time the 
pharmacokinetics, safety and efficacy of zamicastat in PAH patients in its potential therapeutic 
dose range (50 mg to 200 mg). Since this is an exploratory and descriptive study and no 
powered comparative statistical analysis is planned, study sample size was not formally 
calculated. Thus, it was considered that 32 patients constitute an appropriate sample to meet 
the objectives of the study, considering the low prevalence of the disease and the consequent 
recruitment constrains. 

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13.4 
Statistical Methods 
13.4.1 Analysis of primary pharmacokinetic endpoints 
The primary analysis of this study will be the analysis of the PK parameters derived by non-
compartmental analysis from the plasma drug concentration versus time using 
Phoenix WinNonlin v8.0 or a more recent version (Certara USA, Inc., USA). Actual sampling 
times will be used. The area under the plasma concentration-time curve from time zero to 24 
hours post-dose will be calculated using the linear trapezoidal rule. 
Summary statistics will be reported, as appropriate, using the geometric mean, arithmetic mean, 
standard deviation, coefficient of variation, median, minimum, and maximum. 
Further details of the statistical analysis and reporting of the pharmacokinetic endpoints, such 
as, assessment of dose proportionality (e.g. CmaxSS and AUC0-24hSS) and time to steady state 
using concentration trough levels, will be included in a separate SAP. 
13.4.2 Analysis of secondary efficacy endpoints 
Efficacy data will be analysed exploratively and will be based on the FAS. Continuous 
measures will be summarised using summary statistics: mean, standard deviation, median, 
minimum and maximum, in addition for the changes from baseline a 95% confidence interval 
will be provided. Categorical variables will be summarised by using frequency counts and 
percentages.  
The scores of each SF-36v2 subscale, as well as the Physical and mental Component summary 
scores (PCS and MCS), will be described using summary statistics. The derivation of PCS and 
MCS will be defined in the SAP. 
13.4.3 Analysis of secondary safety endpoints 
All safety analyses will be based on the SS. Treatment-emergent AEs will be summarised by 
Medical Dictionary for Regulatory Activities (MedDRA) primary system organ class (SOC) 
and preferred term (PT). 
In addition, TEAEs will be summarised by severity and drug relationship. TEAEs leading to 
discontinuation from the study, AEs of special interest and serious TEAEs will be summarised 
sin addition. All AEs will be listed. 
Laboratory, vital signs and ECG parameters will be described using summary statistics. The 
incidence of clinically relevant abnormalities in laboratory and ECG results will be described 
using frequency counts and percentages. 
The number of digital scars and skin score in patients with scleroderma will be analysed using 
summary statistics. 
13.4.4 Analysis of secondary pharmacokinetic endpoints 
Apparent total clearance (CL/f), terminal half-life (t1/2) and apparent volume of distribution 
(Vz/f) will be described using summary statistics by each dose group. PK analysis will be based 
on the PKS.  
In the PK analysis all concentrations below the limit of quantitation or missing data will be 
labelled as such in the concentration data listings.  
13.4.5 Analysis of secondary pharmacodynamic endpoints 
Maximum observed effect on plasma DβH activity (Emax), minimal observed effect on plasma 
DβH activity (Emin), time to occurrence of Emax (TEmax), time to occurrence of Emin (TEmin) and 
area under the effect-time curve (AUEC24) will be calculated using % inhibition of DβH 

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activity using Phoenix WinNonlin v8.0 or a more recent version (Certara USA, Inc., USA). 
Percent inhibition of DβH activity, PD parameter estimates and urinary catecholamine levels 
(norepinephrine and dopamine) including changes from baseline will be described using 
summary statistics by each dose group. Pharmacodynamic analysis will be based on the PKS. 
Further details of the statistical analysis and reporting of the pharmacodynamic endpoints, such 
as, dose response modelling for % DβH inhibition and exposure response modelling to assess 
relationship between drug plasma concentrations and corresponding % DβH inhibition, will be 
included in a separate Statistical Analysis Plan. 
13.4.6 Interim analyses and criteria for the termination of the study 
No interim analyses are planned in this study. 
The DSMB will periodically review the safety data and is empowered to recommend 
modifications of the protocol (dosage levels) or to recommend temporary suspension or early 
termination of the study, if major concerns arise about patient safety at any time during the 
course of the study. 
13.5 
Deviations from the Original Statistical Analysis Plan 
Any deviation from the original SAP will be described and justified in the final report. 

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14. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
The investigator/institution will give the clinical research associate(s) (CRAs) direct access to 
primary patient data (i.e. source data) which support the data on the eCRFs for the study, i.e. 
general practice charts, hospital notes, appointment books, original laboratory records, 
electronic patient files etc. Other authorised persons such as auditors, IEC members and 
regulatory inspectors will be provided direct access to these source data, too. 
14.1 
Source Data 
Source data is defined as all information in original records and certified copies of original 
records of clinical findings, observations or other activities in a clinical study necessary for the 
reconstruction and evaluation of the study. Source data are contained in source documents 
(original records or certified copies). 
14.2 
Source Documents 
Source documents are defined as original documents, data and records (e.g. hospital records, 
clinical and office charts, laboratory notes, memoranda, patient diaries or evaluation check 
lists, pharmacy dispensing records, recorded data from automated instruments, copies or 
manuscripts certified after verification as being accurate copies, microfiches, photographic 
negatives, microfilm or magnetic media, x-rays, patient files, records kept at pharmacy, at the 
laboratories and at medico technical departments involved in clinical study). Source documents 
comprise documents in paper and electronic format. 
14.3 
Direct Access 
Direct access is defined as the permission to examine, analyse, verify and reproduce any 
records and reports that are important to evaluation of a clinical study. Any party (e.g. domestic 
and foreign regulatory authorities, Bial/SCOPE CRAs, IEC members and auditors) with direct 
access should take all reasonable precautions within the constraints of the applicable regulatory 
requirements to maintain the confidentiality of patient identities and sponsor proprietary 
information. 
 

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15. DATA HANDLING AND RECORD KEEPING 
15.1 
Completion of Case Report Forms 
Data reported on the eCRF that are derived from source documents should be consistent with 
the source documents. 
All clinical information requested in this protocol will be recorded by the principal investigator 
or his/her authorised staff in the eCRF in accordance with the study-specific data entry rules. 
Entries in the eCRFs must be reviewed and verified for accuracy by the principal investigator 
and signed off with electronic signature.  
Periodically, a CRA will review the accuracy, completeness and timeliness of all the data 
entered in the eCRF against source documents. 
No direct entries on the eCRFs (i.e. entries with no prior written or electronic record of data) 
will be allowed. 
15.2 
Patient Diary 
Not applicable in this study. 
15.3 
Monitoring 
On site monitoring visits will be made before the study begins and at regular intervals during 
the study. Other forms of communication (by telephone, mail, fax, etc.) may be used as needed 
to supplement (but not substitute) visits. The following will be reviewed at these visits: 
• Compliance with the protocol. 
• Patient enrolment and consent procedure. 
• Completeness, exactness and plausibility of data entered in the eCRF. 
• Source document verification (SDV, see below). 
• Occurrence of AEs and AE procedures. 
• Storage and accountability of materials. 
The purpose of SDV is to verify, so far as is possible, that the information in the eCRF reflects 
the data recorded in the patient’s medical records. Source document verification will be 
performed with due regard for patient confidentiality. Source document verification will be 
undertaken on an ongoing basis as part of the monitoring visits. Direct access to the source 
documents will be required (see Section 14.3). The CRA will make a direct comparison with 
data entered in the eCRFs. 
The principal investigator (or deputy) agrees to assist the CRA in resolving any problem that 
may be detected during the monitoring visit. 
It is the responsibility of the CRA to ensure that the principal investigator (or deputy) has 
correctly documented the dispensing and return of IMP. The CRA will arrange the collection 
of unused IMP returned by the patient. The CRA will verify the drug accountability in the 
course of the clinical study and also at the close-out visit. All discrepancies must be accounted 
for and documented. 
15.4 
Data Processing 
All data management procedures will be described in the Data Management Plan (DMP). The 
data will be captured in the eCRF and will be transferred from the eCRFs to SCOPE for 
processing (i.e. medical review, coding, statistical analysis, etc.) as defined in the DMP. 

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Automated checks will be implemented and manual checks will be done against the data to 
ensure completeness and consistency as defined in the Data Validation Plan. The database and 
check programming will be validated prior to implementation. 
Data identified as erroneous or inconsistent, or key data that are missing, will be referred to the 
CRA and to the principal investigator for clarification. The principal investigator or his/her 
authorised staff will correct the data as required. All modifications to the data will be logged 
in the audit trail. 
For data coding, the following thesauri will be used: 
• Adverse Events, concomitant diseases and medical history: MedDRA, in the version as 
specified in the DMP. 
• Concomitant medication: WHO Drug Dictionary, in the version as specified in the DMP. 
Visual and computerised methods of data validation will be applied in order to ensure accurate, 
consistent and reliable data for the subsequent statistical analysis. These procedures aim to 
detect out of range values, contradictory data, abnormal evolutions over time, and possible 
protocol deviations (eligibility criteria, time and medication compliance, etc.). 
The database will be closed in order to protect write access after the following preconditions 
are fulfilled: 
• All data are entered in the database 
• SAP is finalised 
• Decisions have been made and agreed as to the identities of all protocol deviations 
• Written authorisation to close the database from the project manager of the study at Bial is 
obtained. 
Statistical analysis will be performed by SCOPE, using the SAS for Windows (SAS Institute 
Inc., Cary, NC, USA) in the actual available version as specified in the DMP. 
15.5 
Archiving 
The principal investigator through his/her clinical study site shall retain and preserve one copy 
only of all data generated in the course of the clinical study for the period of 15 years after the 
end of the clinical study, or such longer period in accordance with relevant regulatory 
requirements. 
15.6 
Data protection 
All clinical study information will be recorded, processed, handled, and stored without 
disclosing personal information of the patients so that it can be accurately reported, interpreted 
and verified while the confidentiality of records and the personal data of the patients remain 
protected in accordance with the applicable law on personal data protection. 
Appropriate technical and organisational measures shall be implemented to protect processed 
information and personal data against unauthorised or unlawful access, disclosure, 
dissemination, alteration, or destruction or accidental loss, in particular where the processing 
involves the transmission over a network. 
 
 

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16. QUALITY ASSURANCE/AUDITS 
This study may be subject to audit by the sponsor or their representatives. The audits will be 
undertaken to check compliance with the requirements of GCP.  
In addition, the sponsor or their representatives may conduct additional audits on a selection of 
investigator sites, requiring access to patient notes, study documentation and facilities or 
laboratories used for the study. 
The investigator’s site, facilities and all data (including source data) and documentation will 
be made available for audit by an independent quality assurance unit and for IEC or regulatory 
authorities according to the ICH-GCP-guideline. The principal investigator agrees to cooperate 
with the auditor during his/her visit and will be available to give the auditor access to eCRFs 
or other files necessary to conduct that audit. Any findings will be strictly confidential. 
In the event that a regulatory authority informs the principal investigator that it intends to 
conduct an inspection, Bial shall be notified immediately. 
 

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17. ETHICAL CONSIDERATIONS 
The study will be conducted in accordance with the Declaration of Helsinki on Ethical 
Principles for Medical Research Involving Human Patients, adopted by the General Assembly 
of the World Medical Association, Fortaleza, Brazil 2013, as well as with the valid national 
law(s) of the participating countries, with the International Council on Harmonisation (ICH) 
Harmonised Tripartite Guideline for Good Clinical Practice (E6), and with the Commission 
Directives 2001/20/EC and 2005/28/EC. 
The CRO will submit the protocol to the responsible IEC(s) and their written unconditional 
approval must be obtained and submitted to the sponsor before the start of the study. 
Verification of the IEC unconditional approval of the protocol will be transmitted to the 
sponsor prior to the start of the study. A copy of the written approval of the IEC must be 
available before dispensing any study medication to study patients. 
The responsible IEC will be informed by the CRO of all subsequent protocol amendments and 
of unexpected SADRs occurring during the study that are likely to affect the safety of the 
patients or the conduct of the study. 
Protocol amendments referring to logistical or administrative changes (non-substantial) may 
be implemented with notification of the IEC and competent authority only. 
A list of the IEC members with names and qualifications plus a statement that it is organised 
according to GCP and the applicable laws should be provided to the investigator or Scope. 
17.1 
Informed Consent 
Patients must give their informed consent prior to admission to a clinical study and before any 
protocol specified procedures are carried out. Patients must therefore declare their consent in 
written form even before the first study-related visit by personally dating and signing the ICF. 
The written consent document will embody the elements of informed consent as described in 
the Declaration of Helsinki and will also comply with local regulations. 
Each patient should be made aware by the investigator of the nature of the study (aims, methods 
and potential hazards and benefits) and the procedures involved, using the information on the 
consent form. Information should be given in both oral and written form whenever possible 
and deemed appropriate by the IEC. Patients must be given ample opportunity to inquire about 
details of the study. 
Patient information and the consent form must be in a language fully comprehensible to the 
prospective patient. The written information must be handed over to the patient to give him/her 
sufficient time to understand the information provided and to prepare questions before being 
asked for his/her consent. The investigator must confirm that the text was understood by the 
patient. The patient will then sign and date the IEC approved consent form indicating that 
he/she has given his/her consent to participate in the study. The signature confirms the consent 
is based on information that has been understood. The form will also be signed by the 
investigator obtaining the consent and annotated with the study patient’s name or individual 
patient number, as applicable. Each patient’s signed ICF must be kept on file by the investigator 
for possible inspection by regulatory authorities, Bial and/or SCOPE personnel. It will be 
documented on the eCRF that informed consent has been obtained. A signed copy of the 
informed consent and any additional patient information must be given to each patient. 
Should a protocol amendment become necessary, the ICF and patient information may need to 
be revised. Bial/SCOPE is responsible that an amended ICF has received approval from the 
respective IECs and competent authorities before being used.  

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Furthermore, the patient will be informed that if he/she wishes to withdraw (for definition see 
Section 9.4) at any time during the study, this will not have any negative consequences. Patients 
may be withdrawn by the investigator if any change related to safety or ethics precludes further 
participation in the study. Patients will be asked to agree to a final assessment in the event of 
an early termination of the study. 
Patients will be informed that data from their case may be stored in a computer without 
inclusion of their name and such data will not be revealed to any unauthorised third party. 
Patients will also be informed that data will be reviewed by the CRA, an independent auditor 
and possibly by representatives of regulatory authorities and/or ethics committees. The terms 
of the local data protection legislation will be applied as appropriate. 

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18. FINANCING AND INSURANCE 
Details on financing will be outlined in a separate agreement between the investigators and the 
sponsor/CRO. 
Each investigator (including principal investigator and any sub-investigators) who is directly 
involved in the treatment or evaluation of patients has to provide a financial disclosure 
according to all applicable legal requirements. 
The sponsor will take out insurance for each patient against any health impairment occurring 
as a result of participation in the study in accordance with the laws and regulations of each 
country where the study is performed. The investigator has to inform the patients about the 
procedures and conditions for compensation and will provide them with a copy of the study 
specific insurance certificate and the terms of insurance. 
All relevant information regarding financial disclosure and insurance will be filed in the TMF 
and the ISF. 

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19. PUBLICATION POLICY 
The information generated by this study is the property of Bial. It is agreed that the results of 
the study will not be submitted for presentation, abstract, poster exhibition or publication by 
the investigator until Bial has reviewed and commented on such a presentation or manuscript 
for publication. 
The sponsor will publish the results of this study. 
 

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20. REFERENCE LIST 
1. Clinical Trail Facilitation Group (CTFG), Recommendation related to contraception and 
pregnancy testing in clinical trials, Final Version – 2014-09-15 
2. Montani D, et.al. Pulmonary arterial hypertension. Orphanet J Rare Dis. 2013 Jul 6;8:97. 
doi: 10.1186/1750-1172-8-97. Available at: 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3750932/pdf/1750-1172-8-97.pdf 
3. Ghataorhe P, Rhodes CJ, Harbaum L, Attard M, Wharton J, Wilkins MR. Pulmonary 
arterial hypertension - progress in understanding the disease and prioritizing strategies for 
drug development. J Intern Med. 2017 Aug;282(2):129-141. doi: 10.1111/joim.12623. 
Epub 2017 May 19. Available at: 
https://onlinelibrary.wiley.com/doi/epdf/10.1111/joim.12623 
4. BIAL Zamicastat (development code BIA 5-1058) Investigator’s Brochure. Edition 
No. 6.2, 2020.04.14 
5. Igreja B, Pires N, Moser P, and Soares-da-Silva P. Effect of Chronic Treatment With 
Zamicastat on Right Ventricle Pressure Overload in the Rat Monocrotaline Lung Injury 
Model of Pulmonary Hypertension. FASEB, No. 1_supplenment April 2017, Abstract 
number 1070.7  
6. Rudski LG et al. Guidelines for the echocardiographic assessment of the right heart in 
adults: a report from the American Society of Echocardiography endorsed by the European 
Association of Echocardiography, a registered branch of the European Society of 
Cardiology, and the Canadian Society of Echocardiography. J Am Soc Echocardiogr. 2010 
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quiz 
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