Conditions: Pulmonary Arterial Hypertension
Keywords: PAH BIA 5-1058 Zamicastat Bial Bial - Portela & Ca, S.A. dopamine ß-hydroxylase (DßH) inhibitor vascular obstruction pulmonary arteries right-heart catheterisation (RHC) idiopathic rare lung disease
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 33
Healthy volunteers: no

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

Detailed description:
This is an open-label, multi-centre study in patients with PAH who are currently on stable treatment with at least one PAH medication. It is planned to evaluate the PK profile (24 hour profile and trough levels) and the safety, tolerability and efficacy of four different zamicastat doses. Each patient will start treatment with the lowest dose (50 mg zamicastat once daily) and the dose will be up-titrated to the individual highest tolerated dose (HTD) i.e. up to 200 mg zamicastat once daily.

A data safety monitoring board (DSMB) will periodically review the safety data and will issue a recommendation if the doses can be used as planned.

This study will consist of:

* A screening period, 5 to 12 days: visit V1
* Up to four dose finding periods, 14 days each:

  * Dose A (50 mg zamicastat once daily): visits A1, A2 and A3
  * Dose B (100 mg zamicastat once daily): visits B2 and B3
  * Dose C (150 mg zamicastat once daily): visits C2 and C3
  * Dose D (200 mg zamicastat once daily): visits D2 and D3
* Maintenance period, 42 days: maintenance period visit (MPV)1, MPV2 and MPV3
* Follow-up (FU) period, 14 to 28 days: visits FU (down-titration) and FU

Arms:
arm 1: 50 mg zamicastat once daily arm 2: 100 mg zamicastat once daily arm 3: 150 mg zamicastat once daily arm 4: 200 mg zamicastat once daily

Interventions: intervention 1: Oral zamicastat
Intervention descriptions: intervention 1: Tablets for oral administration under fed conditions containing 100 mg of zamicastat

Protocol document:
ICF_002.pdf: 
Bial - Portela & Ca, S.A. 
Protocol No.: BIA-51058-201, EudraCT Number: 2018-002448-10 
Patient Information Sheet/Informed Consent  
Final English Master Version 2.0, 18-JUN-2019 
 
 
Page 1 of 17 
Patient Information Sheet and Informed Consent Form 
 
Study title: 
An open-label, multicentre study to evaluate pharmacokinetics, safety and 
efficacy of zamicastat as adjunctive therapy in pulmonary arterial 
hypertension (PAH) 
Protocol no.: 
BIA-51058-201 
EudraCT-Number: 
2018-002448-10 
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 
 
 
Your study doctor: 
_________________________________________________ 
 
 
Your study site: 
(Institution, address, 
phone number) 
_________________________________________________ 
_________________________________________________ 
_________________________________________________ 
 
Your study nurse: 
_________________________________________________ 
 
(may not be permitted in some countries)Patient Number |__|__|__|__|__|__| 
Dear patient,  
You are being invited to take part in a clinical research study because you have pulmonary arterial 
hypertension (PAH).  
Clinical studies are necessary to obtain or increase knowledge on whether medications which have 
not yet been registered are effective and safe. According to the law, clinical studies must be carried 
out before a new medication is registered. This study is subject to international guidelines and 
regulations: The Declaration of Helsinki, the rules for Good Clinical Practice (GCP) and the national 
laws. Your rights as a volunteer in a clinical study are laid down in these regulations. The protocol for 
this study and this information sheet have been reviewed and approved by the national competent 
authority and by an Independent Ethics Committee. 
Before you decide if you participate in this study, it is important for you to understand why the 
research is being done and what it will involve. Please take time to read the following information 
carefully and discuss it with your friends or relatives if you wish. Ask the study doctor or nurse if 
there is something that is not clear or if you need more information. Take as much time as you need 
to decide whether you may take part or not. 


Bial - Portela & Ca, S.A. 
Protocol No.: BIA-51058-201, EudraCT Number: 2018-002448-10 
Patient Information Sheet/Informed Consent  
Final English Master Version 2.0, 18-JUN-2019 
 
 
Page 2 of 17 
Purpose of this study 
Zamicastat is a medication which was developed by Bial - Portela & Ca, S.A. for PAH treatment. 
Zamicastat works by reducing the drive of the sympathetic nervous system. The sympathetic nervous 
system is part of the autonomic nervous system. The sympathetic nervous system can increase heart 
rate, make passages of the airways wider, decrease movement of the large intestine, make blood 
vessels narrower, cause widening of the pupils, goose bumps and sweating and raise blood pressure. 
This clinical study is being conducted for research purposes. Zamicastat is an investigational 
medication for the treatment of PAH that will be used as adjunctive therapy (used along with other 
PAH medications). The word “investigational” means that zamicastat is still being tested and is not 
yet approved for sale. A total of 386 healthy volunteers received zamicastat in previous clinical 
studies. 
With this study, researchers want to investigate the pharmacokinetics (what your body makes with 
zamicastat) and pharmacodynamics (how zamicastat affects your body) of different zamicastat doses 
(50 mg, 100 mg, 150 mg and 200 mg). They also want to know which side effects it causes and if 
treatment with zamicastat can reduce PAH related symptoms.  
This study will be performed in about 15 hospitals in approximately nine European countries. It is 
planned to include approximately 32 patients who receive zamicastat. This clinical study will be 
organised and financed by Bial - Portela & Ca, S.A., the sponsor of this study. Please be informed that 
your study doctor and/or the study site will receive financial compensation for performing this study.  
Voluntary participation and withdrawal from the study 
It is entirely up to you if you will take part. If you decide to take part, you will be asked to sign a 
consent form before any study related procedures are performed.  
If you agree to take part, you are still free to withdraw from the study at any time, for any reason 
without penalty or loss of benefits to which you are otherwise entitled. If you do not wish to take 
part in this study or later withdraw from it, this will not affect your future care or your 
relationship with your study doctor in any way. 
In case of withdrawal, a final examination (early discontinuation visit [EDV]) within 10 days of 
discontinuation is recommended for your safety. However, you have the right to refuse additional 
examinations. 
Your participation can also be terminated by the investigator or the sponsor due to the following 
reasons:  
• Your health condition changes in a way that staying in the study is no longer medically justifiable. 
• The entire study will be discontinued by the sponsor, any regulatory authority or ethics committee 
for safety or other reasons. 
• Pregnancy. 
In this case, a medical examination concluding your participation is necessary, for safety purposes. In 
addition, your study doctor will explain the reasons and will arrange for your care to continue. 
In addition, at any time during or after withdrawal from the study, you will have the right to request 
the destruction of previously collected, stored and identifiable blood samples to prevent any further 
analysis. Please be informed that the data already collected until the time of withdrawal cannot be 
deleted with respect to the legal requirement to store the data. 


Bial - Portela & Ca, S.A. 
Protocol No.: BIA-51058-201, EudraCT Number: 2018-002448-10 
Patient Information Sheet/Informed Consent  
Final English Master Version 2.0, 18-JUN-2019 
 
 
Page 3 of 17 
Study medication 
In this study, all patients will receive zamicastat in addition to their current PAH treatment. The study 
medication are tablets containing 100 mg zamicastat. You will receive the following zamicastat doses 
in this study if you are fine with the treatment and have no intolerable side effects:  
• 50 mg zamicastat once daily (half a tablet of 100 mg) 
• 100 mg zamicastat once daily (one tablet of 100 mg) 
• 150 mg zamicastat once daily (one and a half tablet of 100 mg) 
• 200 mg zamicastat once daily (two tablets of 100 mg) 
The doses will be increased in sequential steps to your individual highest tolerated dose i.e. up to 
200 mg zamicastat once daily.  
You will start treatment with 50 mg zamicastat once daily and take the tablets for 14 days. If you 
should have intolerable side effects, you will be withdrawn from the study. If the study doctor 
confirms that you tolerate the dose, you will receive 100 mg zamicastat, 150 mg zamicastat and 
200 mg zamicastat, each for 14 days (dose finding period). Afterwards, you will receive your highest 
tolerated dose for further 42 days.  
A data monitoring board (a group of experts for PAH disease) will evaluate the safety of the used 
doses and will give a recommendation if the doses can be used as planned. 
If you do not tolerate any of the next doses (i.e.100 mg, 150 mg or 200 mg zamicastat) at any time 
during the 14-day dose finding period you will come immediately to the study site or call the study 
doctor and the dose will be decreased to the previous tolerated dose. Then you will receive this dose 
for 42 days (the maintenance period). In case you should have intolerable side effects during the 
maintenance period, you will be withdrawn from the study. 
You will take zamicastat for up to a maximum of 124 days.  
You will have to take your study medication once daily in the morning after breakfast, orally to be 
swallowed. If required, the tablet can be divided at the brake score into equal halves. The study 
medication should be kept in the original packaging until administration and should be stored at 
temperatures up to 25 ºC in a dry place, out of reach from children. Please do not take the study 
medication at home on the day of visit A3, B3, C3, D3, MPV1, MPV2 and MPV3 (for more 
information please see Section “Study visits and study procedures”) 
Please make sure that you are familiar with the intake schedule after having received the tablets and 
feel free to ask your study doctor if anything remains unclear.  
If you have forgotten to take the study medication after breakfast, you should take zamicastat after 
lunch and the next dose should be taken as scheduled. If you notice only later that you missed a dose, 
then you have to skip the dose for this day. Please report the missing dose to your study doctor on the 
next study visit. 
In case more tablets have been forgotten, your study doctor will advise you how to further proceed. 
Your study doctor will hand over the next bottles with study medication for administration during the 
course of the study. During the study you should bring the study medication with you at each on-site 
visit for inspection – also all empty bottles.  


Bial - Portela & Ca, S.A. 
Protocol No.: BIA-51058-201, EudraCT Number: 2018-002448-10 
Patient Information Sheet/Informed Consent  
Final English Master Version 2.0, 18-JUN-2019 
 
 
Page 4 of 17 
Study visits and Study Procedures 
Your participation in this study will be between 12 and 21 weeks and you will have the following 
visits. 
Visits 
V1 (on-site) 
Your first visit; 9 to 7 days before A1. 
Your study doctor will check whether there is any medical or other 
reason that you may not participate. 
Dose finding period 
A1 (on-site) 
Day 1 of the study treatment, you will receive 50 mg zamicastat. You 
will come to the site in the morning and you will stay overnight; i.e. until 
24 hours after zamicastat intake.  
A2 (phone call) 
8 days ±2 after A1 
A3 (on-site) 
14 days ±2 after A1  
If you tolerate 50 mg, you will receive 100 mg and continue with B2. 
B2 (phone call) 
8 days ±2 after A3 
B3 (on-site) 
14 days ±2 after A3  
If you tolerate 100 mg, you will receive 150 mg and continue with C2. 
C2 (phone call) 
8 days ±2 after B3 
C3 (on-site) 
14 days ±2 after B3 
If you tolerate 150 mg, you will receive 200 mg and continue with D2. 
D2 (phone call) 
8 days ±2 after C3 
D3 (on-site) 
14 days ±2 after C3  
 
NOTE: If you do not tolerate 100 mg, 150 mg or 200 mg zamicastat at 
any time during the dose finding period, your dose will be decreased to 
your previous tolerated dose. Please come immediately to the study site 
or call the study doctor, unless intolerance was detected during a 
scheduled visit.  
Maintenance period 
MPV1 (on-site) 
13 days ±2 after D3 (or after down-titration) 
MPV2 (on-site) 
27 days ±2 after D3 (or after down-titration) 
MPV3 (on-site) 
41 days ±2 after D3 (or after down-titration). You will come to the study 
site in the morning and you will stay overnight; i.e. until 24 hours after 
zamicastat intake.  
Follow-up period 
 
Follow-up (down-
titration) (phone call) 
14 days ±2 after MPV3, only if you have taken 150 mg or 200 mg 
zamicastat and will not participate in the extension study. 
Follow-up (on-site)  
14 days ±2 after last zamicastat intake, only if you will not participate in 
the extension study.  
In case you withdraw prematurely, an EDV will be performed. 
If considered necessary, the study doctor will ask you to come to additional visits or give you calls. 
Please contact the study doctor immediately if you experience side effects.   


Bial - Portela & Ca, S.A. 
Protocol No.: BIA-51058-201, EudraCT Number: 2018-002448-10 
Patient Information Sheet/Informed Consent  
Final English Master Version 2.0, 18-JUN-2019 
 
 
Page 5 of 17 
In case that you do not return for a scheduled visit and the site cannot contact you by telephone or 
certified letter, a family member or friend will be contacted. Please provide the name and telephone 
number in the consent form, at the end of this document. If you wish, you can change the contact 
person during the course of the study. Please inform the study doctor accordingly.  
During the course of the study (V1 to FU visit), your study doctor will perform the following 
procedures:  
Procedures 
Visit 
Discussion of your participation and asking for your consent. 
V1 
Documentation of your age, gender and race. 
V1 
Documentation of all illnesses, especially those related to PAH. 
V1 
Documentation of all medications/treatments you have been taking. 
All visits 
Measurement of your weight. 
V1, MPV3/EDV 
Measurement of your height. 
V1 
Your study doctor will rate the severity of your PAH.  
V1, MPV3/EDV 
Your study doctor will check if you fulfil all criteria for participation. 
V1, A1 
First intake of study medication. 
A1 
Please inform the study doctor about any changes in health condition or 
symptoms that occurred.  
All visits 
Blood samples up to a volume of 12 mL per visit and urine samples will 
be taken for standard assessments. A maximal total amount of 96 mL 
blood will be collected during the study for safety tests.  
V1, A3, B3, C3, D3, 
MPV1, MPV3/EDV, 
FU 
Blood pregnancy test if you are a woman able to become pregnant. 
V1 
Urine pregnancy test if you are a woman able to become pregnant. 
A1, A3, B3, C3, D3, 
MPV1, MPV2, 
MPV3/EDV, FU 
The amount of a certain protein (so-called biomarker) will be analysed 
from your blood plasma. A blood sample up to a volume of 6 mL per visit 
will be taken. 
V1, MPV3 
Blood gas analysis. The blood amount required to perform the blood gas 
analysis is approximately 1 drop.  
A1, MPV3 
Blood samples for pharmacokinetic and pharmacodynamic purposes.  
At A1 and MPV3 blood samples of 9 mL each will be taken before intake 
of zamicastat and 1 h, 2 h, 4 h, 8 h, 16 h and 24 h after intake.  
At A3, B3, C3, D3, MPV1 and MVPV2 one blood sample of 9 mL will 
be taken before intake of zamicastat.  
A1, A3, B3, C3, D3, 
MPV1, MPV2, MPV3 


Bial - Portela & Ca, S.A. 
Protocol No.: BIA-51058-201, EudraCT Number: 2018-002448-10 
Patient Information Sheet/Informed Consent  
Final English Master Version 2.0, 18-JUN-2019 
 
 
Page 6 of 17 
Procedures 
Visit 
24-hour urine samples for pharmacodynamic purposes. 
Collection of the 24-hour urine sample will start at home one day before 
the respective visit in the morning.  
A1, A3, B3, C3, D3, 
MPV3 
Measurement of heart rate, blood pressure and body temperature. Heart 
rate and blood pressure will be measured twice in a laying position 
(separated at least be one minute) and then one more time in a standing 
position. At A1 and MPV3 heart rate and blood pressure will be measured 
before zamicastat intake, 4, 8 and 24 hours afterwards. 
All on-site visits 
A recording of the electrical activity of the heart (electrocardiogram). At 
visits A1 and MPV3 three measurements will be performed before 
zamicastat intake, 4 and 8 hours afterwards, respectively.  
V1, A1, A3, B3, C3, 
D3, MPV1, MPV2 
MPV3/EDV, FU 
Ultrasound examination of your heart (echocardiography). 
V1, MPV3 
Routine physical examination e.g. listen to the heart, lungs etc. 
V1, A3, B3, C3, D3, 
MPV1, MPV2, 
MPV3/EDV 
Assessment for scars at the fingers and toes (in patients with scleroderma 
only). 
V1, A3, B3, C3, D3, 
MPV1, MPV2, 
MPV3/EDV 
Assessment of your skin (in patients with scleroderma only). 
V1, MPV3/EDV 
Measurement of the distance you can walk within 6 minutes. The 
measurement will be performed twice at visit V1. 
V1, MPV3 
A questionnaire rating your quality of life. 
V1, MPV3 
Right heart catheterisation 
A right-heart catheterisation will be performed to see how well or poorly 
your heart is pumping, and to measure the pressures in your heart and 
lungs. After injection of local anaesthetic into the skin, your study doctor 
guides a special catheter (a small, hollow tube) to the right side of your 
heart. He or she then passes the tube into your pulmonary artery. This is 
the main artery that carries blood to your lungs. Your study doctor 
observes blood flow through your heart and measures the pressures inside 
your heart and lungs. You may feel slight sensations as the catheter is 
moved about, but these are generally not uncomfortable. 
A1, MPV3 
It is not necessary to stop your previous PAH treatment but you should not start further PAH-specific 
or any other new treatment during the study without contacting your study doctor first.  
During the entire study, a total amount of approximately 288 mL blood will be collected over a period 
of approximately 12 to 21 weeks (as comparison, 450 to 500 mL of blood is taken at a typical blood 
donation). 


Bial - Portela & Ca, S.A. 
Protocol No.: BIA-51058-201, EudraCT Number: 2018-002448-10 
Patient Information Sheet/Informed Consent  
Final English Master Version 2.0, 18-JUN-2019 
 
 
Page 7 of 17 
What will happen at the end of this study? 
Your study doctor will invite you to take part in an extension study. If you agree to participate, you 
will be asked to sign a new informed consent form. In the extension study, the sponsor will continue 
to provide you with study medication.  
If you do not agree to take part in this extension study and you are taking 150 mg or 200 mg zamicastat 
at MPV3, you will decrease (down-titrate) your zamicastat dose by taking 100 mg for 14 days before 
stopping intake of zamicastat completely. The study doctor or another member of the study team will 
contact you by phone to ask you about any changes in health condition or symptoms that occurred 
and about all medications/treatments which you have taken. In case you are taking 100 mg or 50 mg 
zamicastat at MPV3, you will take the last tablet of zamicastat at MPV3.  
If you do not continue with the extension study, no additional care apart from your standard treatment 
will be necessary due to your participation in the study at the end of the study. However, your study 
doctor will contact you by phone as soon as the last patient in this study has completed his/her last 
visit to obtain information about your health status. 
Your responsibilities during your study participation 
During your study participation, you will need to: 
1. Follow the study doctor’s instructions; 
2. Provide your medical history and answer all questions truthfully; 
3. Come to the site for the scheduled visits and be available for the telephone calls; 
4. Stay overnight at the site at visits A1 and MPV3; 
5. Take the study medication following the study doctor’s instructions; 
6. Not take any other prescribed or over-the-counter medicines, herbal products or vaccinations or 
change the regimen or dosage of any currently agreed concomitant therapy without talking to the 
study doctor first (excluding emergencies); 
7. Return all unused study medication and empty bottles to the study doctor at each on-site visit; 
8. Inform the study doctor or a study team member immediately about any changes in your health 
condition during the study; 
9. Take your patient card with you at any time and show it in case a medical treatment at some other 
location may be necessary (e.g. in case of an accident); 
10. Not participate in any other clinical study at the same time; 
11. Not to eat grapefruits or to drink or eat products containing grapefruit; 
12. For women able to become pregnant: follow the study doctor’s instruction on contraception from 
the time of signing the informed consent until 30 days after the last zamicastat intake.  
13. For man sexually active with a woman able to become pregnant: follow the study doctor’s 
instruction on contraception from the time of signing the informed consent until 90 days after the 
last zamicastat intake. 
For women: In case you gave birth to a child recently, you can only participate if you are not 
breastfeeding. 


Bial - Portela & Ca, S.A. 
Protocol No.: BIA-51058-201, EudraCT Number: 2018-002448-10 
Patient Information Sheet/Informed Consent  
Final English Master Version 2.0, 18-JUN-2019 
 
 
Page 8 of 17 
Risks and special warnings 
Zamicastat is a new medication which is currently under investigation. Thus, even though proposed 
according to previous test results, it cannot be guaranteed to date that it will be as effective as other 
medications that are already on the market. 
Zamicastat has been tested in 386 healthy volunteers and was generally well tolerated. The reported 
side effects were usually mild to moderate in intensity. The highest exposure to zamicastat was 
1200 mg single-dose with food and 1200 mg once-daily for 10 days. 
Like all medicines, zamicastat can cause side effects, although not everybody gets them. In previous 
clinical studies, the following side effects that were judged to be at least possibly related to zamicastat 
treatment. 
In local versions, incidence in % can be deleted if not requested by national requirements. 
Reported in more than 1 in 100 people:   
Nervous system 
headache (11.9%), feeling dizzy or sleepy (dizziness, 2.8%), 
dizziness postural (2.1%) 
Gastrointestinal system 
feeling sick (nausea, 5.2%), abdominal pain (1.6%), diarrhoea, 
(1.3%) 
General: 
fatigue (4.1%) 
 
Blood vessels 
circulatory problems due to low blood pressure (orthostatic 
hypotension, 1.8%) 
 
Skin 
rash (rash papular, 1.8%) 
Reported in less than 1 in 100 people:  
Nervous system 
head discomfort (0.8%), numbness (hypoaesthesia, 0.5%), 
disturbance in attention, pricking (paraesthesia), and sleepiness 
(somnolence), 0.3% each 
Gastrointestinal system 
vomiting and abdominal discomfort, 0.5%, each, upper 
abdominal pain, impaired digestion (dyspepsia), soft faeces, 
stomach does not empty food as quickly as it should (impaired 
gastric emptying), toothache, flatulence and frequent bowel 
movements, 0.3% each 
General 
feeling drunk (0.8%), feeling abnormal (0.5%), weakness 
(asthenia), chest pain, feeling hot and discomfort (malaise), 
0.3% each 


Bial - Portela & Ca, S.A. 
Protocol No.: BIA-51058-201, EudraCT Number: 2018-002448-10 
Patient Information Sheet/Informed Consent  
Final English Master Version 2.0, 18-JUN-2019 
 
 
Page 9 of 17 
Skin 
inflammation of the skin due to allergens exposure (dermatitis 
contact) and increased sweating (hyperhidrosis), 0.5% each, 
sensitivity to light, itch (pruritus), redness of the skin or mucous 
membranes (rash erythematous) and irritation of the skin, 0.3% 
each 
Blood vessels 
hot flushes (0.5%) 
Infections and infestations 
cold (rhinitis) and inflammation of the gastrointestinal tract 
(gastroenteritis), 0.3% each 
Breathing and chest area 
sneezing (0.5%) 
Heart 
beating of the heart (palpitations, 0.5%) 
Eye 
Eye pain and blurred vision, 0.3% each 
Investigations 
blood tests showing high levels of creatine phosphokinase (an 
enzyme mainly found in the heart, brain, and skeletal muscle, 
0.3%) 
Metabolism 
and 
nutrition 
disorders 
decreased appetite (0.6%) 
Psychiatric 
difficulty in sleeping (insomnia) and depressed mood, 0.3% 
each 
Musculoskeletal 
muscle pain (myalgia, 0.3%) 
Kidney and urinary tract 
 abnormally frequent urination (pollakiuria, 0.3%) 
Sexual organs and breast 
irregular menstrual bleeding (0.3%) 
 
Since zamicastat increases dopamine exposure, the following effects may be increased: hallucinations, 
nausea, and abnormal, uncontrollable, involuntary movements (dyskinesia), orthostatic hypotension 
and a temporary loss of consciousness usually related to insufficient blood flow to the brain (syncope). 
Therefore, please do not rise rapidly after sitting or lying down. Do not drive or use any tools or 
machines if you feel dizzy or drowsy or if your vision is affected.  
Like other medicines also zamicastat may cause hypersensitivity/allergic reactions. If you have a rash, 
hives, itching, difficulty in breathing, swelling of the face, mouth, lips or tongue please contact your 
study doctor immediately. This can be a sign of an allergic reaction. Allergic reactions can happen 
immediately after the first intake of a medication or days or weeks after. If you have a rash, please 
take photos of the affected skin area(s) according the instruction provided on the photocard for rash 
and send the photos to the study site. In case the rash is noticed during an on-site visit, a member of 
the study team will take pictures of the affected skin area(s). All photos will be taken in a way that 
nobody will recognise you. 
Zamicastat can potentially interact with other medicines (e.g. central nervous system depressants, 
catechol-structured medications or cardiovascular medications) and may affect your condition. There 


Bial - Portela & Ca, S.A. 
Protocol No.: BIA-51058-201, EudraCT Number: 2018-002448-10 
Patient Information Sheet/Informed Consent  
Final English Master Version 2.0, 18-JUN-2019 
 
 
Page 10 of 17 
are some medications that you cannot take at the same time while taking zamicastat due to potential 
interactions. Your study doctor will inform you about such medications. 
If you do not understand the meaning of any of these side effects or if you wish to have a more detailed 
description of these conditions and the risks associated with each one, please ask your study doctor. 
As with any medication at any stage of development, there is always a risk of rare or previously 
unknown side effects developing from treatment which are not known at this time. 
If you experience any of the side effects listed above or any other signs or symptoms, please contact 
your study doctor to get medical help as required. All reported side effects will be noted and closely 
observed by your study doctor. He/she will also decide whether it is necessary to stop taking 
zamicastat. In case of unusual or severe symptoms please consult your study doctor immediately. 
Right heart catheterisation 
This assessment is considered as the only accurate way to measure the pressure in the pulmonary 
artery (vessel that conducts the blood from the heart to the lungs) and to diagnose PAH. It is also used 
to periodically monitor your disease during the treatment process. In this study it will be used to assess 
whether zamicastat reduced or not the pressure in your pulmonary artery and heart. 
As with many medical tests there are some risks, although a right heart catheterisation is generally 
considered to be a safe test.  
The following serious risks were reported in less than 1 in 100 people: low blood pressure (0.18%), 
bruising of the skin at the site where the catheter is inserted (0.14%), abnormal heart rhythms (e.g. 
fast heart rate in your lower heart chambers [0.14%]), partial collapse of your lung if your neck or 
chest veins are used to insert the catheter (0.07%), death (0.055%), and pulmonary artery rupture (a 
damage to the main artery in your lung, can result in serious bleeding, making it hard to breathe 
[0.03%]).  
In local versions, incidence in % can be deleted if not required by national requirements. 
The following risks have been reported with an unknown frequency: excessive bleeding because of 
puncture of the vein during catheter insertion, cardiac tamponade (fluid build-up around your heart 
that affects its ability to pump blood effectively), infection, air embolism (air leaking into your heart 
or chest area), and blood clots at the tip of the catheter that can block blood flow. 
For some people, having to lie still on the cardiac catheterisation table for the length of the procedure 
may cause some discomfort or back pain. There may be other risks, depending on your specific 
condition. Your study doctor will explain them to you. 
After the procedure, you will be under close monitoring for bleeding, blood pressure changes, heart 
rate and breathing changes. The following symptoms should also be reported immediately to your 
study doctor: 
• shortness of breath or trouble breathing 
• fever or chills 
• increased pain, redness, swelling, or bleeding or other drainage from the insertion site 
• coolness, numbness or tingling, or other changes in the affected extremity 
• chest pain or pressure, nausea or vomiting, profuse sweating, dizziness, or fainting 


Bial - Portela & Ca, S.A. 
Protocol No.: BIA-51058-201, EudraCT Number: 2018-002448-10 
Patient Information Sheet/Informed Consent  
Final English Master Version 2.0, 18-JUN-2019 
 
 
Page 11 of 17 
Pregnancy 
For women: If you become pregnant in the period from first study medication intake until 30 days 
after last study medication intake, there may be risks to the unborn child, which are currently 
unknown. If you become pregnant or you suspect that you are pregnant during this period, please 
inform your study doctor immediately. If the pregnancy is confirmed, you have to stop zamicastat 
immediately and your study doctor will follow-up your pregnancy, the birth and the condition of your 
child.  
For men: If your partner become pregnant in the period from first study medication intake until 
90 days after last study medication intake, there may be risks to the unborn child, which are currently 
unknown. If your partner become pregnant during this period, please inform your study doctor 
immediately. Your study doctor will follow-up the pregnancy, the birth and the condition of your 
child.  
Blood withdrawals 
Risks associated with drawing blood may include pain, bruising, light-headedness and, on rare 
occasion, infection.  
Benefits 
We hope that if you receive zamicastat, you may experience an improvement of PAH symptoms. 
However, because the efficacy of this new medication is not yet confirmed, this cannot be guaranteed 
and it may happen that your participation in this study will not result in any clinical benefit for you.  
Compensation for study participation 
You do not have to pay for your participation in the study and for any procedure performed within the 
study. Your travel expenses which may arise due to your participation in this study will be 
compensated up to XXX € per visit. Please provide all receipts regarding travel costs to your study 
doctor. If you travel by car, you will receive mileage allowance of YYY €/km. Please ask your study 
doctor for more information.  
In addition, for visits A1 and MPV3 you will receive a monetary compensation of ZZZ € per visit for 
the unproductive time while staying at the study site for more than 24 hours.  
Apart from the reimbursements mentioned above, you will not receive any monetary compensation 
for participation in this study. 
Alternative treatment 
If you decide that you will not participate in this study, alternative treatments for PAH may include 
other approved treatments like ambrisentan, bosentan, macitentan, riociguat, selexipag, sildenafil, 
tadalafil, epoprostenol, iloprost or treprostinil. 
The potential benefits of these treatments are an improvement of PAH symptoms. The potential risks 
are the side effects described in the package leaflet of these medications. 
All mentioned medications differ in their effectiveness, their risks and their advantages. Please ask 
your study doctor if you need more information. 


Bial - Portela & Ca, S.A. 
Protocol No.: BIA-51058-201, EudraCT Number: 2018-002448-10 
Patient Information Sheet/Informed Consent  
Final English Master Version 2.0, 18-JUN-2019 
 
 
Page 12 of 17 
Insurance 
Insurance coverage for all study participants has been taken out in accordance with the requirements 
in your country in the name of the sponsor. 
In the event that an injury occurs as a result of this research, compensation will be available from this 
insurance. In case of an injury please inform the insurance company directly or the study doctor 
(see first page for contact details), who then will inform the insurance company in your name and 
provide you with a copy of the notification. The insurance company has to be informed immediately, 
otherwise you may lose the insurance coverage.  
The insurance was taken out with: 
 <Company name> 
<Address> 
<Phone number or other contact details> 
Insurance number: <Number>  
In local versions, “if you wish,” should be deleted, if it is mandatory to provide insurance documents. 
If you wish, you will receive a copy of the insurance terms and conditions. Please pay special attention 
to the sections referring to insurance benefits, loss of coverage and obligations. 
Confidentiality, data protection and authorised use of medical information 
All information collected about you during the study will be kept strictly confidential in accordance 
to, Regulation (EU) 2016/679 of the European Parliament and of the Council of 27 April 2016 on the 
protection of natural persons with regard to the processing of personal data and on the free movement 
of such data, and repealing Directive 95/46/EC (General Data Protection Regulation, GDPR). 
The information collected about you for BIAL or its designee will be used for the purposes of the 
study. It will be stored, both on paper and computer records, without identifying you by name or date 
of birth.  
The data will be passed on in a pseudonymised (encrypted with a code number) form preventing your 
identification by the recipient: 
a) to the sponsor of the clinical study and entities appointed by sponsor for the conduct of the study 
and the scientific evaluation of collected data, 
b) in the event of an application for marketing authorisation: to the applicant and the competent 
authority for processing the application, 
c) in the event of adverse events: to the competent ethics committees and the competent authorities, 
and from there to the European Database. 
Your study doctor will keep a list which links the code number to your name. Regulatory authorities, 
members of the ethics committee, study site personnel and representatives of the sponsor or sponsor’s 
designees may access this list and review your medical records. This is necessary to check that the 
study is being performed correctly and that the information is accurate. All personnel having access 
to your records are required to respect your confidentiality also after the end of this study. 


Bial - Portela & Ca, S.A. 
Protocol No.: BIA-51058-201, EudraCT Number: 2018-002448-10 
Patient Information Sheet/Informed Consent  
Final English Master Version 2.0, 18-JUN-2019 
 
 
Page 13 of 17 
In accordance with GDPR you have the right to access your collected information via your study 
doctor, and ask to correct any errors in the information. To obtain detailed information on your 
personal data the study site has stored, you may contact the study site in writing or via email. You 
may also request the study site to transfer the data that have been collected about you as indicated 
above to you or to forward such data to a third party designated by you. If you find that any information 
stored about you is inaccurate or incomplete, you may request immediate correction or completion of 
such information at any time. Access to your information may be postponed if it would hinder the 
conduct of the study. If you do not want to be any longer in the study, your information collected so 
far may still be used by the sponsor or sponsor’s designee, if permitted by law. 
Your data will be retained for the period required in accordance with compulsory applicable law 
<study-specific retention periods, e.g. contractual periods, need to be specified here, if applicable>. 
At the expiration of such terms your personal data will be deleted. 
If you agree, your general practitioner will be informed about your participation in this study. 
This clinical study will only be performed by collecting and using data related to your health. National 
and international data protection regulations give you the right to control the use of your medical 
information. Therefore, by signing this form you specifically authorise your medical information to 
be checked, transferred and processed as follows: 
The authorised representatives of the sponsor, and its designees, study site personnel, the ethics 
committee and regulatory authorities’ inspectors in various countries may review your medical 
information by direct access to your medical records. 
Study data, including your medical information, and information on any medical samples taken, may 
be processed, which means it will be collected, entered into computer databases, verified, analysed, 
printed and reported as necessary for legitimate scientific purposes, as outlined above. 
A transfer of your personal encrypted data to countries outside the European Union or the European 
Economic Area ("third countries") may take place, incl. to such countries which do not guarantee an 
equivalent level of data protection as the European Union. 
Contact: 
In the event of questions about the processing of your personal data by the study site, you may contact 
the person responsible for data processing of the study site:  
 
 _______________________________________________________________________  
Name and telephone number of the employee responsible for the data processing, e. g. data protection 
officer  
 
If you do not agree with the data processing activities carried out by the study site or the information 
provided by it, you have the right to lodge a complaint with the competent supervisory authority 
<insert the specific competent supervisory authority, if possible; otherwise add “competent 
supervisory authority”> 


Bial - Portela & Ca, S.A. 
Protocol No.: BIA-51058-201, EudraCT Number: 2018-002448-10 
Patient Information Sheet/Informed Consent  
Final English Master Version 2.0, 18-JUN-2019 
 
 
Page 14 of 17 
Samples of biological material 
Blood and urine samples will be collected and used for purposes of this study only. Blood samples for 
safety analysis and biomarker assessment will be analysed centrally at LKF, Laboratory for Clinical 
Trials GmbH, Lise-Meitner-Strasse 25, 24223 Schwentinental, Germany. Blood samples for 
pharmacokinetic and pharmacodynamic purposes will be analysed centrally at SYNLAB Analytics & 
Services Switzerland AG, Sternenfeldstrasse 14, CH-4127 Birsfelden, Switzerland (pharmacokinetic 
samples) and at Anapharm, Encuny 22, 2nd floor, 08038 Barcelona, Spain (pharmacodynamic 
samples). Urine samples for pharmacodynamic analysis will be analysed at The Doctors Laboratory, 
Halo Building, 1 Mabledon Place, London WC1H 9AX, United Kingdom.  
Future scientific research may reveal further naturally occurring biological substances in the blood 
(biomarkers) that may help to better understand your disease PAH. By analysing stored plasma 
samples after the end of this study, new biological substances which allow to predict if a patient will 
benefit most from treatment with zamicastat, could be identified. You will be asked at the end of this 
document for your consent to store those plasma samples for a maximum of 10 years. 
The samples will be stored until 6 months after the study report is finalised and will be destroyed 
afterwards (apart from the biomarker samples). No genetic analyses will be performed on your 
samples. 
Identifiable samples can be destroyed at any time at your request in order to prevent any further 
analysis. 
New findings 
New information may become available during the course of the study that might affect your 
willingness to agree to your further study participation. If this happens, your study doctor will explain 
it to you in a timely manner and discuss with you your participation in the study.  
Publicly accessible information on this clinical study 
A description of this study and the results will be available on the internet, e.g. on 
http://www.clinicalstudysregister.eu, and may be published in specialised medical journals. A 
summary of the results of the study presented in terms understandable to a layperson will be made 
available in the EU database. For details please ask your study doctor. This will not include 
information (text or photo) that can identify you. 
Whom to contact with questions 
For questions concerning this study, please contact your study doctor (see first page). For further 
information regarding your rights as a study patient, or in case of study-related injury, you can contact: 
Name: 
Phone: <phone number> 
Address: <National contact, address> 
Email address: <email> 
 
 
Thank you for reading this information.  


Name of the patient: _____________________________________________________  
(This can be entered by the site or patient) 
Bial - Portela & Ca, S.A. 
Protocol No.: BIA-51058-201, EudraCT Number: 2018-002448-10 
Patient Information Sheet/Informed Consent  
Final English Master Version 2.0, 18-JUN-2019 
 
 
Page 15 of 17 
INFORMED CONSENT FORM 
Study title: 
An open-label, multicentre study to evaluate pharmacokinetics, 
safety and efficacy of zamicastat as adjunctive therapy in 
pulmonary arterial hypertension (PAH) 
Protocol no.: 
BIA-51058-201 
 
I,  _____________________________________________________________________   
(Print patient’s name. This can be entered by the site or patient) 
declare by signing this informed consent form that: 
1. I have read the patient information sheet for this study. I have received an explanation of the 
nature, purpose, duration, and foreseeable effects and risks of the study and what I will be expected 
to do. My questions have been answered satisfactorily. I have been given ample time and 
opportunity to enquire about details of the study and to make my decision.  
2. I agree to take part in this study. I agree to cooperate fully with the study doctor and will contact 
him/her immediately if I suffer any unexpected or unusual symptoms or ─ for female patients ─ 
if I think that I am pregnant during the study or ─ for male patients ─ if I think that my partner is 
pregnant during the study. For the duration of the study, I will notify the study doctor of any other 
medical treatments that may be necessary for me to undergo.  
3. I have informed the study doctor of all my previous or present illnesses and medication and of any 
consultation that I have had with any doctor in the last months. 
4. I have further informed the study doctor of any participation in other studies in the past months. 
5. I am aware that if I do not cooperate fully with the study doctor’s requests and directions, I may 
harm myself by participating in the study. 
6. I understand that my participation is voluntary. I understand if I do not sign this form, I will not 
be able to participate in this study. I also understand that I may withdraw from the study: 
• Whenever I wish 
• Without having to explain why 
• Without this affecting my medical care 
7. I further understand that any information that becomes available during the course of the study 
that may affect my willingness to take part will be disclosed to me in a timely manner. 
8. Also, I agree that authorised representatives of sponsor and competent regulatory authorities, 
bound by professional secrecy, may inspect my personal data held by the investigator, in particular 
my health records, to the extent necessary to verify the proper conduct of the study. For this 
purpose, I release the investigator from his/her duty of secrecy. 
9. I agree that my general practitioner  _____________________________________________  
(insert name) will be notified of my involvement in the clinical study (strike-through, if not 
desired). 
10. I agree that health data from attending physicians be collected to the extent necessary for the proper 
conduct and monitoring of the study. For this purpose, I release these physicians from their duty 
of secrecy. 


Name of the patient: _____________________________________________________  
(This can be entered by the site or patient) 
Bial - Portela & Ca, S.A. 
Protocol No.: BIA-51058-201, EudraCT Number: 2018-002448-10 
Patient Information Sheet/Informed Consent  
Final English Master Version 2.0, 18-JUN-2019 
 
 
Page 16 of 17 
11. I agree that my plasma samples will be stored for a maximum of 10 years for further analysis for 
other scientific purposes as specified above (outside this study).  
Yes 
 __ No 
 
12. I agree that the following person(s) may be contacted in case that I do not return for a scheduled 
visit and the site cannot contact me by telephone or certified letter (strike-through, if not desired). 
 
 _______________________________________________________________________  
(name and telephone number of the specified person) 
 
 _______________________________________________________________________  
(name and telephone number of the specified person) 
 
 
I have spoken to __________________________________________________________  
(print full name of the person who carried out the consent discussion) 
 
 
I hereby freely consent that I will take part in the study. 
 
Signature of the patient _________________________________ Date ______________  
(Personally signed and dated) 
 
 
 
 
 
 
(dd-mm-yyyy) 
 
Study doctor: 
I, the undersigned, have fully and carefully explained the details of the study to the patient and certify 
that to the best of my knowledge, the patient clearly understand the nature, objectives, benefits, 
implications, risks and inconveniences of participation in this study. 
I herewith declare that currently no financial or other ties to the sponsor currently exist other than 
receiving financial compensation for performing this study (this is also valid for any of my 
institutional affiliations). 
 
Signature of the study doctor  ____________________________ Date ______________  
(Personally signed and dated by the person who  
 
 
 
(dd-mm-yyyy) 
carried out the consent discussion) 


Name of the patient: _____________________________________________________  
(This can be entered by the site or patient) 
Bial - Portela & Ca, S.A. 
Protocol No.: BIA-51058-201, EudraCT Number: 2018-002448-10 
Patient Information Sheet/Informed Consent  
Final English Master Version 2.0, 18-JUN-2019 
 
 
Page 17 of 17 
If this consent form is read to the patient because the patient is unable to read the form, an impartial 
witness not affiliated with the research or study doctor must be present for the consent and sign the 
following statement: 
I confirm that the information in the consent form and any other written information was accurately 
explained to, and apparently understood by, the patient. The patient freely consented to be in the study. 
 
 _______________________________________________________________________  
(Print full name of the impartial witness) 
 
Signature of the impartial witness _________________________ Date ______________  
(Personally signed and dated) 
 
 
 
 
 
 
(dd-mm-yyyy) 
 
The signed patient information sheet and consent form must be stapled. A copy <replace “A 
copy” by “An original” as applicable acc. to local law> of the signed patient information sheet 
and consent form will be given to the patient. 

Prot_000.pdf: 
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  
Page 3 of 82 
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 
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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 
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Final Version 3.0, 11-MAY-2020 
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Page 7 of 82 
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 
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Final Version 3.0, 11-MAY-2020 
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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 


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Final Version 3.0, 11-MAY-2020 
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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.  


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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  


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Final Version 3.0, 11-MAY-2020 
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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) 


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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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Final Version 3.0, 11-MAY-2020 
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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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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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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  
⊗ 
⊗ 
 
⊗ 
⊗ 
⊗ 
⊗ 
 
⊗ 
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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Final Version 3.0, 11-MAY-2020 
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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. 


Clinical Study Protocol BIA-51058-201 
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Final Version 3.0, 11-MAY-2020 
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Figure 1: Overview of study design
 


Clinical Study Protocol BIA-51058-201 
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Final Version 3.0, 11-MAY-2020 
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Page 19 of 82 
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 
total amount of 96 mL at maximum. 


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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 
score 


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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 
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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 
Jul;23(7):685-713; 
quiz 
786-8. 
doi: 
10.1016/j.echo.2010.05.010. 
http://www.onlinejase.com/article/S0894-7317(10)00434-7/pdf 
7. Barst RJ et al. Diagnosis and differential assessment of pulmonary arterial hypertension. J 
Am Coll Cardiol. 2004 Jun 16;43(12 Suppl S):40S-47S. DOI: 0.1016/j.jacc.2004.02.032  
8. Galiè N, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary 
hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary 
Hypertension of the European Society of Cardiology (ESC) and the European Respiratory 
Society (ERS): Endorsed by: Association for European Paediatric and Congenital 
Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). 
Eur Heart J. 2016 Jan 1;37(1):67-119. doi: 10.1093/eurheartj/ehv317. Epub 2015 Aug 29  
9. Lau EMT et al, Epidemiology and treatment of pulmonary arterial hypertension. Nat Rev 
Cardiol. 2017 Oct;14(10):603-614. doi: 10.1038/nrcardio.2017.84. Epub 2017 Jun 8 
10. Khanna D et al. Standardization of the modified Rodnan skin score for use in clinical trials 
of systemic sclerosis. J Scleroderma Relat Disord. 2017 Jan-Apr; 2(1): 11–18. doi:  
10.5301/jsrd.5000231 
11. Holland AE et al. An official European Respiratory Society/American Thoracic Society 
technical standard: field walking tests in chronic respiratory disease. Eur Respir J. 2014 
Dec;44(6):1428-46. doi: 10.1183/09031936.00150314. Epub 2014 Oct 30. Available on:  
http://erj.ersjournals.com/content/erj/44/6/1428.full.pdf 
12. Borg GA. Psychophysical bases of perceived exertion. Med Sci Sports Exerc. 
1982;14(5):377-81 
13. Roth M, Tym E, Mountjoy CQ, Huppert FA, Hendrie H, Verma S, Goddard R., CAMDEX. 
A standardised instrument for the diagnosis of mental disorder in the elderly with special 
reference to the early detection of dementia. Br J Psychiatry. 1986 Dec;149:698-70 

SAP_001.pdf: 
 
 
An open-label, multicentre study to evaluate pharmacokinetics, safety and efficacy of 
zamicastat as adjunctive therapy in pulmonary arterial hypertension (PAH) 
 
 
 
 
Sponsor Project Code: BIA-51058-201 
Scope Project Code: 0223BI26.MPB 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
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 
 
Author: 
Lukas Pukys 
Statistician 
Scope International AG 
Kalvariju 300 
LT-08318 Vilnius, Lithuania 
E-mail: lpukys@scope-international.com 
Phone: +370 5 2361 833 
Fax: +370 5 2388 533 
 
 
Version: 
Final 1.0 (22-MAR-2022) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The information provided in this document is strictly confidential. No part of this document may be reproduced, 
transmitted or copied in any form nor its contents disclosed to the third parties without prior written consent of Bial - 
Portela & Ca, S.A. or a nominated representative. 


Sponsor: Bial - Portela & Ca, S.A.  
Protocol no. BIA-51058-201 
Statistical Analysis Plan, Version Final 1.0  
22-MAR-2022 
 
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Effective date: 15.09.2020 
DOCUMENT REVISION HISTORY 
 
Version Draft 0.1 (09-JUL-2021): Document was created. 
Version Draft 0.2 (07-SEP-2021): Document updated after sponsor’s review. Notable changes: 
• 
Added table 15.2.5.1 (section 5.5.5) 
• 
Removed the original SF-6D score from analysis (section 5.5.6) 
• 
Added figures 15.2.1 and 15.2.2 (section 5.5.6) 
• 
Added the definition of TEAEs leading to down-titration and table 15.3.1.7 (section 5.6.1) 
• 
Added table 15.3.5.4.2 (section 5.6.5) 
Version Draft 0.3 (24-NOV-2021): Document updated after sponsor’s review. Notable changes: 
• 
Added specification that the definition of PAH medications will be reviewed during the DRM 
(section 5.3) 
• 
Updated the range of nominal compliance to 90%-110% (section 5.4.2) 
• 
Added within-visit shift table for ECG abnormalities (section 5.6.5) 
Version Draft 0.4 (06-JAN-2022): Document updated after the Data Review meeting and the 
sponsor’s review. Notable changes: 
• 
Changed definition of FAS to only include patients with non-missing efficacy assessments at 
MPV3 (Section 3.1) 
• 
Added definition of mFAS (Section 3.1). Efficacy analyses will be performed for both the 
FAS and MFAS (Section 5.5). 
• 
Added definitions for TAPSE subgroups (Section 3.2). TAPSE subgroup analyses will be 
performed for selected efficacy parameters (Sections 5.5.1, 5.5.2, 5.5.4) 
• 
Safety data will no longer be summarised at derived visit V3. Actual visits will be used 
(Section 4.4) 
• 
Added definition of PAH-approved medications and corresponding tables (Section 5.3) 
• 
Right heart catheterisation clinical significance assessments will not be used in statistical 
analysis (Section 5.5.1) 
• 
Added specification that in case the distance covered during both 6MWT attempts is equal, 
the first attempt will be considered as baseline (Section 5.5.2) 
• 
Changed unit for biomarket NT-proBNP from pg/mL to ng/L (Section 5.5.3) 
• 
Added specification for interpreting normal, NCS abnormal, and CS abnormal findings for 
arterial blood gas analysis (Section 5.6.3) and ECG (Section 5.6.5) 
Version Draft 0.5 (08-FEB-2022): Document updated after sponsor’s review. Notable changes: 
• 
Added the coefficient of variance to standard summary statistics (Section 4.1) 
Version Draft 0.6 (17-MAR-2022): Document updated after sponsor’s review. Notable changes: 
• 
Amended the definition of PAH-approved medications to include diuretics (Sections 3.1, 5.3) 
Version Final 1.0 (22-MAR-2022): Document finalised.  
 


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Protocol no. BIA-51058-201 
Statistical Analysis Plan, Version Final 1.0  
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND KEY TERMS ............................................................................ 5 
INTRODUCTION ................................................................................................................................. 7 
1 
FLOW CHART AND VISIT SCHEDULE ................................................................................ 8 
1.1 
FLOW CHART ......................................................................................................................... 8 
1.2 
SCHEDULE OF STUDY PROCEDURES ...................................................................................... 9 
2 
OBJECTIVES AND DESIGN................................................................................................... 12 
2.1 
STUDY OBJECTIVES ............................................................................................................. 12 
2.1.1 
Primary Objective ....................................................................................................... 12 
2.1.2 
Secondary Objectives .................................................................................................. 12 
2.2 
STUDY ENDPOINTS .............................................................................................................. 12 
2.2.1 
Primary Endpoint ....................................................................................................... 12 
2.2.2 
Secondary Endpoints .................................................................................................. 13 
2.2.2.1 
Safety Endpoints ................................................................................................ 13 
2.2.2.2 
Efficacy Endpoints ............................................................................................. 13 
2.2.2.3 
Pharmacokinetic Endpoints ................................................................................ 13 
2.2.2.4 
Pharmacodynamic Endpoints ............................................................................. 14 
2.3 
OVERALL STUDY DESIGN .................................................................................................... 14 
2.4 
RANDOMISATION ................................................................................................................. 15 
2.5 
TREATMENT ......................................................................................................................... 15 
2.6 
SAMPLE SIZE ........................................................................................................................ 15 
2.7 
BLINDING ............................................................................................................................. 16 
3 
ANALYSIS SETS AND SUBGROUPS .................................................................................... 17 
3.1 
ANALYSIS SETS .................................................................................................................... 17 
3.2 
SUBGROUP ANALYSIS .......................................................................................................... 17 
4 
GENERAL DEFINITIONS AND NAMING CONVENTIONS ............................................ 18 
4.1 
GENERAL METHODOLOGY AND PRESENTATION OF THE RESULTS...................................... 18 
4.2 
STATISTICAL OUTPUT LAYOUT ........................................................................................... 18 
4.3 
DOSE GROUP NAMES AND LABELS ..................................................................................... 18 
4.4 
VISIT NAMES AND LABELS .................................................................................................. 19 
4.5 
DAY NUMBERING ................................................................................................................ 20 
4.6 
STUDY PERIODS ................................................................................................................... 20 
4.7 
BASELINE VALUE ................................................................................................................ 21 
4.8 
VISIT WINDOWS ................................................................................................................... 21 
4.9 
CODING SYSTEMS AND CONVENTIONS ................................................................................ 21 
4.9.1 
Coding of adverse events and medical history............................................................ 21 
4.9.2 
Coding of medications ................................................................................................ 21 
4.10 
HANDLING OF MISSING DATA ............................................................................................. 21 
5 
STATISTICAL ANALYSIS: DEFINITIONS, DERIVATIONS, CALCULATIONS AND 
METHODOLOGY ..................................................................................................................... 22 
5.1 
PATIENT DISPOSITION .......................................................................................................... 22 
5.1.1 
Disposition and Withdrawals ...................................................................................... 22 
5.1.2 
Protocol Deviations .................................................................................................... 23 
5.1.3 
Inclusion/Exclusion ..................................................................................................... 23 
5.2 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ................................................ 24 
5.2.1 
Demographics ............................................................................................................. 24 
5.2.2 
Disease Characteristics .............................................................................................. 24 
5.2.3 
Medical History .......................................................................................................... 25 
5.3 
PRIOR AND CONCOMITANT MEDICATIONS .......................................................................... 25 


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5.4 
EXPOSURE TO IMP AND COMPLIANCE ................................................................................ 27 
5.4.1 
Exposure to IMP ......................................................................................................... 27 
5.4.2 
Compliance ................................................................................................................. 28 
5.5 
ANALYSIS OF EFFICACY ENDPOINTS ................................................................................... 29 
5.5.1 
Right Heart Catheterisation ........................................................................................ 29 
5.5.2 
6-Min Walk Test (6-MWT) .......................................................................................... 31 
5.5.3 
Biomarker ................................................................................................................... 32 
5.5.4 
Echocardiography ...................................................................................................... 32 
5.5.5 
New York Heart Association/Word Health Organisation Functional Class 
(NYHA/WHO) ..................................................................................................... 33 
5.5.6 
Quality of Life (SF-36v2) ............................................................................................ 33 
5.6 
ANALYSIS OF SAFETY ENDPOINTS ...................................................................................... 35 
5.6.1 
Adverse Events ............................................................................................................ 35 
5.6.2 
Clinical Laboratory Evaluation .................................................................................. 37 
5.6.3 
Arterial Blood Gas Analysis ....................................................................................... 39 
5.6.4 
Vital Signs ................................................................................................................... 39 
5.6.5 
12-Lead Electrocardiogram (ECG) Data ................................................................... 40 
5.6.6 
Physical Examination Findings .................................................................................. 42 
5.6.7 
Number of Digital Scars ............................................................................................. 42 
5.6.8 
Modified Rodnan Skin Score (mRSS) .......................................................................... 42 
6 
DATA REVIEW ......................................................................................................................... 44 
7 
INTERIM ANALYSIS ............................................................................................................... 48 
8 
CHANGES TO THE ANALYSIS AS LAID DOWN IN THE PROTOCOL AND 
AMENDMENTS ........................................................................................................................ 49 
9 
REFERENCES ........................................................................................................................... 50 
10 
APPENDICES ............................................................................................................................ 51 
10.1 
TABLES ................................................................................................................................ 51 
10.2 
LISTINGS .............................................................................................................................. 56 
10.3 
FIGURES ............................................................................................................................... 58 
SIGNATURES..................................................................................................................................... 59 


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LIST OF ABBREVIATIONS AND KEY TERMS 
Abbreviations 
Description of abbreviations 
6-MWT  
6-minute walk test  
λz 
Terminal rate constant 
AE  
Adverse event  
ALT  
Alanine transaminase  
AST  
Aspartate transaminase  
AUC  
Area under the curve  
AUEC  
Area under the effect-time curve  
CI  
Cardiac index  
CL/f  
Apparent total clearance  
Cmax  
Maximum plasma concentration  
Cmin  
Minimum plasma concentration  
CO 
Cardiac output 
CPK  
Creatine phosphokinase  
CS 
Clinically significant 
CV 
Coefficient of variation 
DßH  
Dopamine ß-hydroxylase  
DBP  
Diastolic blood pressure  
DPG 
Diastolic pressure gradient 
DR(M) 
Data review (meeting) 
DSMB  
Data safety monitoring board  
ECG  
Electrocardiogram  
eCRF  
Electronic case report form  
EDV  
Early discontinuation visit  
Emax  
Maximum observed effect on DβH activity  
ES  
Enrolled set  
FAS  
Full analysis set  
GGT  
Gamma-glutamyl transferase  
HbA1c  
Haemoglobin A1c  
HCG  
Human chorionic gonadotropin  
HTD 
Highest tolerated dose 
ICF  
Informed consent form  
IMP  
Investigational medicinal product  
LDH  
Lactate dehydrogenase  
LLOQ  
Lower limit of quantification  
LPLV  
Last patient’s last visit  
MedDRA  
Medical Dictionary for Regulatory Activities  
mPAP  
Mean pulmonary artery pressure  
mRSS  
Modified Rodnan skin score  
NCS 
Not clinically significant 
NT-proBNP  
N-terminal pro brain natriuretic peptide  
NYHA/WHO  
New York Heart Association/Word Health Organisation  
PAC 
Pulmonary arterial compliance 
PAH  
Pulmonary arterial hypertension  
PAPs 
Pulmonary artery pressure systolic 
PAPd 
Pulmonary artery pressure diastolic 
PAWP 
Pulmonary artery wedge pressure 
PD  
Pharmacodynamic 
PK  
Pharmacokinetic 
PKS 
Pharmacokinetic analysis set 


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PT  
Preferred term 
PVR  
Pulmonary vascular resistance 
RAP  
Right atrial pressure 
RBC  
Red blood cell count 
RHC 
Right heart catheterisation 
SAE  
Serious adverse event 
SAP  
Statistical analysis plan  
SAS  
Statistical Analysis System  
SBP  
Systolic blood pressure  
SF-36  
Short Form - 36  
SvO2 
Mixed venous oxygen saturation  
SOC  
System organ class  
SS  
Safety set  
SVR 
Systemic ventricular resistance 
t1/2  
Terminal half-life  
TAPSE  
Tricuspid annular plane systolic excursion  
TEAE  
Treatment emergent adverse event  
TEmax  
Time to occurrence of Emax  
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  
ZMC 
Zamicastat 
 
 


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INTRODUCTION 
This statistical analysis plan (SAP) contains a more technical and detailed elaboration of the principal 
features of the statistical analyses as described in the clinical study protocol versions: 
Document, Version 
Date 
Protocol, Final 1.0 
22-JUN-2018 
Protocol, Final 2.0 
18-JUN-2019 
Protocol, Final 2.0 UK 
08-JUL-2019 
Protocol, Final 2.0 DE 
23-SEP-2019 
Protocol, Final 3.0 
12-MAY-2020 
This SAP is written assuming the latest version (Final 3.0, 12-MAY-2020). Relevant differences 
between the protocol versions will be listed in the corresponding subsections of the SAP. 
This SAP includes detailed procedures for executing the statistical analysis of the secondary safety, 
tolerability and efficacy variables and other data, and it is structured according to different data types. 
The SAP is finalised and signed-off before analysis begins in an open-label study. This SAP supersedes 
statistical considerations previously defined in the clinical study protocol. Analysis of the primary 
endpoint (pharmacokinetics (PK)) as well as secondary PK and pharmacodynamics (PD) endpoints is 
covered in a separate reporting and analysis plan prepared by Quotient Sciences Ltd (Appendix 4). 
All analysis data sets and statistical output related to the secondary safety, tolerability and efficacy 
endpoints will be produced by the statistics department of Scope International AG using SAS® for 
Windows (SAS Institute Inc., Cary, NC, USA) [1] version 9.4 or higher. The actual version used will 
be documented in the Validation Plan for Statistical Programming. 
 


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1 
FLOW CHART AND VISIT SCHEDULE 
1.1 
Flow Chart 
 


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1.2 
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 
 
 
Urinalysis (dopamine and 
norepinephrine levels, 24h 
urine collection)15 
 
⚫ 
 
⚫ 
 
 
⚫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  
 
 
 
 
 
 
 
 
 
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 
 
 
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.  


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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).  
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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2 
OBJECTIVES AND DESIGN 
2.1 
Study Objectives 
2.1.1 
Primary Objective 
The primary objective of this study is to evaluate the PK profile of different zamicastat doses in 
pulmonary arterial hypertension (PAH) patients to find the most promising therapeutic dosage range 
for the treatment of PAH disease. This SAP does not cover the analysis of the primary objective. 
2.1.2 
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 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  
* Covered in a reporting and analysis plan prepared by Quotient Sciences Ltd. (Appendix 4). 
2.2 
Study Endpoints 
2.2.1 
Primary Endpoint 
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 (visits A3, B3, 
C3, D3, MPV1, MPV2, MPV3). 
8. 
Minimum plasma concentration at the end of the dosing interval (Cmin,SS) 
 


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The analysis of PK parameters is covered in a reporting and analysis plan prepared by Quotient Sciences 
Ltd. (Appendix 4). 
 
2.2.2 
Secondary Endpoints 
2.2.2.1 
Safety Endpoints 
The safety endpoints of this study are: 
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 physical examination 
5. 
Clinically relevant changes in ECG 
6. 
Number of digital scars (only in patients with scleroderma) 
7. 
Skin score (only in patients with scleroderma) 
2.2.2.2 
Efficacy Endpoints 
The secondary efficacy endpoints of this study are the change from baseline to visit MPV3 in: 
8. 
Pulmonary vascular resistance (PVR), right atrial pressure (RAP), mean pulmonary artery 
pressure (mPAP), cardiac index (CI) and mixed venous oxygen saturation (SvO2). Further 
haemodynamic parameters may also be calculated if considered appropriate. 
9. 
6-MWT, including Borg dyspnoea score 
10. Biomarker (NT-proBNP) 
11. Echocardiogram parameters: 
• Tricuspid regurgitation, classified as absent, mild, moderate or severe 
• Right ventricular contractibility, 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 
12. WHO functional class 
13. Quality of life (SF-36v2) 
2.2.2.3 
Pharmacokinetic Endpoints 
14. Apparent total clearance (CL/f) 
15. Terminal half-life (t1/2) 
16. Apparent volume of distribution (Vz/f) 
The analysis of PK parameters is covered in a reporting and analysis plan prepared by Quotient Sciences 
Ltd. (Appendix 4). 


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2.2.2.4 
Pharmacodynamic Endpoints 
17. 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) 
18. 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 
19. 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. 
The analysis of pharmacodynamic parameters is covered in a reporting and analysis plan prepared by 
Quotient Sciences Ltd. (Appendix 4). 
2.3 
Overall 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.  
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, the patient 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.  
After a positive safety evaluation at visit B3, the patient 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, he/she 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. 


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At the end of the maintenance period, the patient will have the opportunity to continue treatment in an 
extension study (BIA-51058-202), which is described in a separate protocol.  
Patients not tolerating their individual HTD during the maintenance period have to be withdrawn from 
the study. 
2.4 
Randomisation 
No randomisation will be performed in this study. 
2.5 
Treatment 
The study medication is zamicastat (BIA 5-1058). One tablet of the IMP contains 100 mg of zamicastat. 
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. 
Table 1: 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)  
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 study. 
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). 
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 study early due to the occurrence of an AE, down-titration is not 
mandatory, but at the investigator’s discretion. 
2.6 
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 constraints. 


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2.7 
Blinding 
Blinding is not applicable to this study. 
 
 


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3 
ANALYSIS SETS AND SUBGROUPS 
3.1 
Analysis Sets 
Within the framework of this study, the following analysis sets are defined and analysed: 
The Enrolled Set (ES) will be defined as all patients who provided informed consent. 
The Safety Set (SS) will be defined as all patients who belong to ES with at least one IMP 
administration. 
The Full Analysis Set (FAS) will be defined as all patients who belong to SS with at least one efficacy 
assessment at visit MPV3. 
The modified Full Analysis Set (mFAS) will be defined as all patients who belong to FAS with no 
substantial changes to their regimen of PAH-approved medications (including diuretics) between visits 
A1 and MPV3. These patients were defined during Data Review (see Data Review Report, Final 1.0, 
10-MAR-2022). 
The Pharmacokinetic Analysis Set (PKS) and the Pharmacodynamic (PD) Analysis Set, as well as 
all corresponding analyses, are described in the reporting and analysis plan prepared by Quotient 
Sciences Ltd. 
Efficacy analyses will be performed on the FAS and mFAS, and the SS will be used for the analysis of 
the safety endpoints. 
3.2 
Subgroup Analysis 
Subgroups will be formed to explore the effects of right ventricular dysfunction at baseline on selected 
efficacy parameters based on echocardiography results at V1. The subgroups are described in Table 2 
below. 
Statistical analyses using subgroups will be conducted when specifically referred to in relevant 
subsections of Section 5, as not every endpoint might need further evaluation using subgroups. 
Table 2: Subgroup Labels 
Number 
Description 
Label in TLFs 
1 
Right ventricular contractility (TAPSE) ≤ 17 mm 
TAPSE ≤ 17 mm 
2 
Right ventricular contractility (TAPSE) > 17 mm 
TAPSE > 17 mm 
 
 


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4 
GENERAL DEFINITIONS AND NAMING CONVENTIONS   
In order to avoid ambiguity during the analysis, a number of definitions and conventions for data 
handling are described here. 
4.1 
General Methodology and Presentation of the Results 
The default summary statistics for quantitative (continuous) variables will be  
- 
the number of patients (n),  
- 
mean,  
- 
standard deviation (SD),  
- 
coefficient of variation (%CV), 
- 
median,  
- 
minimum (min) and maximum (max)  
for patients with data. 
Mean and median will be presented to one more decimal place than the raw value. The minimum and 
maximum values will be presented with the same decimal precision as the raw value. SD will be 
reported to two decimal places greater than the original value, however no more than 3 decimal places 
will be presented. CV will be reported to one decimal place. 
For qualitative (categorical) variables, the frequency count (n) and percentage (%) of patients with non-
missing data per category will be the default frequency tabulations. Where appropriate and present, the 
number of missing values will be displayed as “Missing” category. 
Percentage values are to be presented to one decimal place, for example, 52.3%. 
The denominator used for calculation of the percentages will be specified in a footnote to the tables for 
clarification. 
4.2 
Statistical Output Layout 
All titles and column headers (consisting of one or several words) will be capitalised; articles, 
prepositions, and conjunctions, and “To” in infinitives will not be capitalised, except they are at the 
beginning of titles or headers. 
All pages will be numbered according to the table/listing/figure to which the page belongs to. Every 
table/listing/figure will be numbered from page 1, “Page X of Y” at the bottom of each page. 
The definition of baseline value will be described in a footnote in every TLF where applicable. Other 
important definitions will also be presented if necessary. 
Dates will be listed in the format: yyyy-mm-dd (e.g. 2003-11-20). Times will be listed in the format: 
hh:mm (e.g. 09:15) or in the format hh:mm:ss if seconds are collected. When date and time are collected, 
these are listed in the format: yyyy-mm-ddThh:mm (e.g. 2003-11-20T09:15), yyyy-mm-ddThh, or 
yyyy-mm-ddThh:mm:ss.  
Partial missing dates will be listed in the format yyyy-mm (e.g. 2013-11) if only day is missing or in 
the format yyyy (e.g. 2013) if month and day are missing. 
Missing data including missing dates or times will be displayed in listings as blank fields, unless 
otherwise specified. 
Listings will be sorted by patient’s number and visit number where applicable, unless specified 
otherwise. 
4.3 
Dose Group Names and Labels 
Statistical output for baseline characteristics, as well as visit-based safety and efficacy evaluations, will 
be presented by dose groups. Patients will be allocated to a particular dose group based on their 
individual HTD, while patients that do not tolerate the 50 mg dose will be allocated to the “No HTD” 
group for analysis by HTD. 


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Adverse events and concomitant medications will be summarised based on the concurrent IMP dose, 
without allocating patients to separate dose groups. Details of assignment of concurrent IMP doses will 
be further described in the Sections 5.3 and 5.6.1. 
The labels to be used in the tables, listings and figures are defined in the table below. 
Table 3: Dose Group Labels 
Description 
Label in TLFs 
By Concurrent Dose By HTD 
Dose A: 50 mg zamicastat once daily  
(half a tablet of 100 mg) 
ZMC 50 mg 
No HTD 
HTD 50 mg 
Dose B: 100 mg zamicastat once daily  
(one tablet of 100 mg) 
ZMC 100 mg 
HTD 100 mg 
Dose C: 150 mg zamicastat once daily  
(one and a half tablet of 100 mg) 
ZMC 150 mg 
HTD 150 mg 
Dose D: 200 mg zamicastat once daily  
(two tablets of 100 mg) 
ZMC 200 mg 
HTD 200 mg 
 
4.4 
Visit Names and Labels 
This SAP covers only visits which are part of the core study. The extension study (BIA-51058-202) 
will be covered in a dedicated SAP. The names to be used in the analysis datasets and the labels to be 
used in the tables, listings and figures for the different study visits are defined below. 
Table 4: Visit Names and Labels 
Period 
Number Name 
Description 
Label in 
TLFs 
Screening 
100 
Visit 1 
Screening visit. Day -12 to -5  
V1 
Dose finding 
110 
Visit A1 
Day 1 
A1 
120 
Visit A2 
8 days ±2 after A1 (phone call) 
A2 
130 
Visit A3 
14 days ±2 after A1 
A3 
220 
Visit B2 
8 days ±2 after A3 (phone call) 
B2 
230 
Visit B3 
14 days ±2 after A3 
B3 
320 
Visit C2 
8 days ±2 after B3 (phone call) 
C2 
330 
Visit C3 
14 days ±2 after B3 
C3 
420 
Visit D2 
8 days ±2 after C3 (phone call) 
D2 
430 
Visit D3 
14 days ±2 after C3 
D3 
Maintenance   
510 
Visit MPV1 
13 days ±2 after D3/UV for down-
titration 
MPV1 
520 
Visit MPV2 
27 days ±2 after D3/UV for down-
titration 
MPV2 
530 
Visit MPV3 
41 days ±2 after D3/UV for down-
titration 
MPV3 
Dose finding/ 
Maintenance  
600 
Early Discontinua-
tion Visit 
Within 10 days of early 
discontinuation 
EDV 
Follow-up 
610 
Follow-up visit 
[down-titration] 
14 days ±2 after MPV3/EDV (phone 
call) 
FUV1 
620 
Follow-up visit 
14 days ±2 after last IMP intake 
FUV2 
Unscheduled visits (UV) will be numbered and labelled based on the preceding scheduled visit, e.g. 
“UV A1.1” for the first unscheduled visit after the scheduled visit A1. Multiple unscheduled visits after 
the same scheduled visit will be numbered and labelled sequentially. 
For patients attending the extension study, adverse events and concomitant medications will only be 
displayed up to the end date of visit MPV3. 


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4.5 
Day Numbering 
All assessment dates will be related to the date of first IMP intake. The date of first IMP intake is 
referred to as Day 1. Day –1 is the day preceding Day 1 and Day 0 will not be defined. The numbering 
is such that Day –2 is the day before Day -1, Day 2 is the day after the first IMP intake, etc.  
Treatment days may alternatively be numbered with reference to the ongoing study period using the 
following rules: 
- 
Dates prior to the first IMP intake will be numbered with reference to the date of first IMP 
intake as described above. 
- 
Dates after the first IMP intake will be numbered with reference to the first day of the ongoing 
study period using the same rules as described above. Study days during the dose-finding period 
will be prefixed with the corresponding dose letter (e.g. C-11 for day 11 on the 150 mg dose), 
study days in the maintenance period will be prefixed with the letter M, and study days in the 
post-maintenance periods will be prefixed with “DT” and “FU” for the down-titration period 
and the follow-up period respectively. 
For definitions of the study periods, see section 4.6. 
4.6 
Study Periods 
Screening period 
The Screening period will be defined as the period from informed consent signature date to the first 
IMP intake date. 
Dose finding period 
The dose finding period will be defined as the period from the date of the first IMP intake to the day 
before visit D3 or the day before IMP down-titration. 
The dose finding period will be split into dose toleration periods for each dose prescribed for that 
period. The period will start from the date of the IMP taken at the site at visit A1/A3/B3/C3 to the day 
before visit A3/B3/C3/D3 or the day before IMP down-titration. 
Maintenance period 
The maintenance period will be defined as the period between visit D3 or the date of IMP down-titration 
and the date of the last IMP intake until MPV3 (including the first day of visit). For patients participating 
in the extension study, the end of the maintenance period will be the end date of visit MPV3. 
Down-titration period 
The down-titration period is only applicable to patients not participating in the extension study and with 
an IMP dispensation at visit MPV3/EDV. 
The down-titration period will be defined as the period starting on the second day of MPV3 or one day 
after visit EDV until the date of the follow-up visit for down titration (FUV1). 
Follow-up period 
The follow-up period is only applicable to patients not participating in the extension study. 
The follow-up period will be defined as the period between the day after the last IMP intake until the 
date of study termination. 
Early discontinuation 
For patients who discontinue the study early, the EDV date will be the end date of any ongoing study 
period. 
 
 


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4.7 
Baseline Value 
Baseline value 
The baseline value for a variable is defined as the last non-missing value collected before the first IMP 
intake, unless otherwise specified. 
See section 5.4.1 Exposure to IMP for definition of first IMP intake. 
Absolute change from baseline will be calculated as 
𝐴𝑏𝑠𝑜𝑙𝑢𝑡𝑒 𝐶ℎ𝑎𝑛𝑔𝑒 𝑓𝑟𝑜𝑚 𝐵𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝑎𝑡 𝑉𝑖𝑠𝑖𝑡 𝑋= 𝑉𝑎𝑙𝑢𝑒 𝑎𝑡 𝑉𝑖𝑠𝑖𝑡 𝑋−𝐵𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝑉𝑎𝑙𝑢𝑒 
4.8 
Visit Windows 
Data will be analysed with the nominal visit number. 
4.9 
Coding Systems and Conventions 
4.9.1 
Coding of adverse events and medical history 
Adverse event and medical history investigator terms are assigned to a lowest level term (LLT) and a 
preferred term (PT) and will be classified by high level term (HLT), high level group term (HLGT) and 
system organ class (SOC) according to the Medical Dictionary for Regulatory Activities (MedDRA), 
Version 22.0 or higher. 
4.9.2 
Coding of medications 
Medications are classified according to active drug substance using the WHO Drug Global dictionary, 
version 2019, March, or higher. The WHO drug code has 11 digits. The generic name is defined by the 
first 6 of the 11 digits. In addition, the Anatomical Therapeutic Chemical (ATC) classes are assigned to 
the drug code. In this study, ATC codes are defined to the 4th level. 
4.10 Handling of Missing Data 
No imputations of missing data are planned for this study.  


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5 
STATISTICAL ANALYSIS: DEFINITIONS, DERIVATIONS, CALCULATIONS AND 
METHODOLOGY 
5.1 
Patient Disposition 
5.1.1 
Disposition and Withdrawals 
The following disposition data will be collected in the electronic case report form (eCRF): 
- 
date of informed consent 
- 
date of study termination 
- 
did the patient complete the study as scheduled (yes, no) 
- 
will the patient participate in the extension study (yes, no) 
- 
reason for premature study termination 
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 (withdrew consent, 
did not fulfil eligibility criteria, decision of investigator, etc.). 
Withdrawals will be all patients who have been enrolled and, for whatever reason, discontinue the 
study after the first IMP intake at visit A1. Patients may withdraw or may be withdrawn from the study 
for the following reasons: 
-  
At their own request (withdrawal of consent) 
-  
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 or inclusion criterion no longer fulfilled  
-  
Intolerable adverse event(s)  
-  
At the specific request of the sponsor 
-  
Major protocol deviations 
-  
Patient non-compliance 
-  
Lost to follow up 
-  
Other reasons 
Study completion status will be determined by patient’s decision to participate in the extension study. 
If the question “Will the patient participate in the extension study?” in the eCRF is answered as “Yes”, 
the patient will be considered as a completer. If the patient does not participate in the extension study, 
then the completion status will be based on the Study Termination page in the eCRF. 
The following statistical output will be provided: 
Table 15.1.1.1 Analysis Sets – Enrolled Set 
Number and percentage of patients included into the enrolled, safety, full analysis, modified full 
analysis, pharmacokinetic, and pharmacodynamic analysis sets will be provided. 
Table 15.1.1.2 Reasons for Exclusions from Analysis Sets – Safety Set 
Number and percentage of patients excluded from the full analysis, modified full analysis, 
pharmacokinetic, and pharmacodynamic analysis sets will be provided. Percentages will be based on 
the number of patients in the safety set. The reasons of exclusion from the analysis sets will be 
incorporated into the table. 
Table 15.1.2 Screening Failures – Enrolled Set 
Counts and percentages of patients who discontinued the study during the screening phase prior to 
enrolment to the treatment period will be summarised by reasons associated with the discontinuation. 
Percentage will be based on the number of patients in the enrolled set. 
Table 15.1.4 Patient Disposition – Safety Set 
Counts and percentages of patients who completed the treatment period as scheduled, withdrawals 
during the treatment period will be summarised by HTD and overall. Reasons associated with the 
termination will be included. Percentage will be based on the number of patients in the safety set. 


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Table 15.1.5.1.1 Number of Patients by Country and Site – Enrolled Set 
Table 15.1.5.1.2 Number of Patients by Country and Site – Safety Set 
Counts and percentages of patients will be presented by country and by site. Percentage will be based 
on the number of patients in the specified set. 
Table 15.1.5.2 Number of Patients by Visit – Safety Set 
Counts and percentages of patients who continue the study will be presented by visit. Percentage will 
be based on the number of patients in the safety set. 
Listing 16.2.1.1.1 Patient Disposition – Safety Set 
Patients who enter the treatment period and complete the study as scheduled or as withdrawals will be 
listed. Reasons for premature study termination will be displayed for withdrawals. 
Listing 16.2.1.1.2 Screening Failures – Enrolled Set 
Patients who discontinued the study during the screening phase prior to enrolment to the treatment 
period will be listed. Reasons associated with the discontinuation will be displayed. 
Listing 16.2.1.2 Patient Visits – Enrolled Set 
All visit dates will be listed by patient. 
Listing 16.2.1.4 Exclusions from Analysis Sets – Enrolled Set 
Patients excluded from any analysis set and corresponding reasons for exclusion will be listed. 
Figure 15.1.1 Flow Chart of Patient Disposition – Enrolled Set 
Number of  patients will be displayed in flow chart by their disposition. 
Figure 15.1.2 Flow Chart of Analysis Sets – Enrolled Set 
Number of patients will be displayed in flow chart by analysis sets. 
5.1.2 
Protocol Deviations 
Protocol deviations are deviations from the procedures outlined in the clinical study protocol or from 
subsequent protocol-related instructions like missed evaluations, incorrect timing of evaluations, non-
compliance with IMP and intake of prohibited medications or any non-adherence to the clinical study 
protocol that impacts patient’s rights, safety or welfare. Protocol deviations that may affect the 
pharmacokinetic and pharmacodynamic outcomes will be discussed during the Data Review Meeting 
(DRM). 
In addition, the study disruption due to the COVID-19 pandemic will be assessed in terms protocol 
deviations and discussed during the DRM. A separate listing for patients affected by the COVID-19 
related study disruption will be provided. 
Details regarding the DRM will be provided in Section 6.  
The following statistical output will be provided: 
Table 15.1.3 Major Protocol Deviations – Safety Set 
Number and percentage of patients with major protocol deviations will be summarised by HTD and 
overall. Protocol deviations will be summarised during the dose finding and maintenance periods and 
overall. Percentage will be based on the number of patients in the safety set. 
Listing 16.2.1.3.1 Major Protocol Deviations – Safety Set 
Patients with major protocol deviations will be listed. 
Listing 16.2.1.3.2 Patients Affected by the COVID-19 Pandemic – Safety Set 
Patients that were affected by the COVID-19 pandemic as well as the details of the deviation will be 
listed. 
5.1.3 
Inclusion/Exclusion 
The study specific Inclusion/Exclusion Criteria are presented in Section 9.2 and 9.3 of the Clinical 
Study Protocol. 


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For each criterion, as appropriate, a response of “Yes/No” is to be obtained at Screening and checked 
again prior to the first IMP administration, at visit A1. 
The following statistical output will be provided: 
Listing 16.2.1.3.3 Inclusion Criteria Not Met and Exclusion Criteria Met – Enrolled Set 
Listing of inclusion criteria which were not met and exclusion criteria which were met will be presented 
per patient. 
5.2 
Demographic and Other Baseline Characteristics 
5.2.1 
Demographics 
The following demographic characteristics will be presented: 
-  
Age (years) 
-  
Gender (Male, Female) 
-  
Race (White, Black or African American, Asian, American Indian or Alaska Native, Native 
Hawaiian or Other Pacific Islander, Unknown) 
- 
Women of childbearing potential (Yes, No) 
Also, the following physical characteristics at baseline will be presented:  
-  
Height (cm) 
-  
Weight (kg) 
- 
Body mass index BMI (kg/m2) 
Body mass index (BMI) will be calculated as follows: 
𝐵𝑀𝐼 𝑎𝑡 𝑉𝑖𝑠𝑖𝑡 𝑋 (𝑘𝑔/𝑚2) = 𝐵𝑜𝑑𝑦 𝑤𝑒𝑖𝑔ℎ𝑡 𝑎𝑡 𝑉𝑖𝑠𝑖𝑡 𝑋 (𝑘𝑔)
[𝐵𝑜𝑑𝑦 ℎ𝑒𝑖𝑔ℎ𝑡 𝑎𝑡 𝑉𝑖𝑠𝑖𝑡 1 (𝑚)]2  
The following statistical output will be provided:  
Table 15.1.6.1.1 Demographics – Safety Set 
Table 15.1.6.1.2 Demographics – Full Analysis Set 
Table 15.1.6.1.3 Demographics – Pharmacokinetic Analysis Set 
Demographic data will be summarised by HTD and overall in the respective set. Percentage for 
categorical variables will be based on the respective set. 
Table 15.1.6.2.1 Baseline Characteristics – Safety Set 
Table 15.1.6.2.2 Baseline Characteristics – Full Analysis Set 
Table 15.1.6.2.3 Baseline Characteristics – Pharmacokinetic Analysis Set 
Weight, height and BMI data will be summarised by HTD and overall in the respective set. 
Listing 16.2.1.5 Demographics and Baseline Characteristics – Enrolled Set 
Demographic and baseline characteristic data will be listed for the patients in the enrolled set. 
5.2.2 
Disease Characteristics 
The following information on patient PAH status at baseline will be presented: 
- 
WHO functional class at baseline (see Section 5.5.5) 
- 
The cause of PAH: 
• 
Idiopathic, in non-vasoreactive patients  
• 
Heritable: Bone morphogenetic protein receptor type II (BMPR2) mutation and other 
mutations, in non-vasoreactive patients 
• 
Drugs and toxin induced, in non-vasoreactive patients 
• 
Associated with connective tissue disease 
• 
Associated with simple congenital defects (atrial septal defect and/or ventricular septal 
defect) if closed > 12 months before inclusion 
- 
Does the patient suffer from scleroderma? (yes, no) 


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The following statistical output will be provided:  
Table 15.1.6.3.1 Disease Characteristics – Safety Set 
Table 15.1.6.3.2 Disease Characteristics – Full Analysis Set 
Table 15.1.6.3.3 Disease Characteristics – Pharmacokinetic Analysis Set 
Disease characteristics data will be presented by HTD and overall in the respective set. Percentage for 
categorical variables will be based on the number of patients in the respective analysis set. 
Listing 16.2.1.6 Disease Characteristics – Enrolled Set 
Disease characteristics data will be listed for the patients in the enrolled set. 
5.2.3 
Medical History  
Medical history encompasses relevant prior or ongoing relevant diseases, conditions, hospitalisation 
and surgical procedures. Medical history records are collected at Visit 1. 
Medical history of the patients includes: 
- 
Medical condition/procedure 
- 
Start date  
- 
Stop date  
- 
Ongoing 
- 
Treatment used (yes, no) 
Medical history is classified as: 
- 
Prior medical conditions are the conditions which started and ended prior to Visit 1. 
- 
Ongoing medical conditions are the conditions which are marked as ongoing at Visit 1 or with 
a stop date at or after Visit 1 
In case of partial missing stop dates, a disease will be considered as ongoing at Visit 1, unless the partial 
date information clearly indicates that the condition stopped prior to Visit 1. 
The following statistical output will be provided:  
Table 15.1.7.1.1 Prior Medical Conditions – Safety Set 
Table 15.1.7.1.2 Prior Medical Conditions – Full Analysis Set 
Table 15.1.7.1.3 Prior Medical Conditions – Pharmacokinetic Analysis Set 
Table 15.1.7.2.1 Ongoing Medical Conditions – Safety Set 
Table 15.1.7.2.2 Ongoing Medical Conditions – Full Analysis Set 
Table 15.1.7.2.3 Ongoing Medical Conditions – Pharmacokinetic Analysis Set 
Medical history will be summarised displaying counts and percentages of patients having at least one 
medical condition and will be presented by Primary System Organ Class (SOC) and by Preferred Term 
(PT) within SOC. SOCs and PT within SOC are to be sorted by descending order of overall incidence. 
Patients with two or more occurrences of the same condition (as qualified by its PTs) will be counted 
only once for the respective PT. Percentage will be based on the number of patients in the corresponding 
analysis set.  
Listing 16.2.1.7 Medical History – Enrolled Set 
Medical history conditions will be listed for the patients from the enrolled set 
5.3 
Prior and Concomitant Medications 
Prior and concomitant medications and therapies are documented in the eCRF.  
The following information is collected: 
- 
Medication / therapy  
- 
Indication (Medical history condition, Adverse event, Other) 
- 
Total daily dose 
- 
Units 
- 
Route 


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- 
Frequency 
- 
Start date of medication 
- 
Stop date of medication 
- 
Ongoing (yes, no) 
Medications and therapies will be classified as ‘prior’, ‘concomitant’ or ‘post-treatment’ based on 
start/stop dates: 
- 
Prior medications/therapies are defined as those medications/therapies starting and ending 
prior to the first IMP intake. 
- 
Concomitant medications/therapies are defined as medications/therapies started at or after 
first IMP intake and include medications/therapies started prior to the first IMP intake but 
continued during the study. 
- 
Post-treatment medications/therapies are defined as medications/therapies which started 
after the last IMP intake. 
If the start or stop date of a medication/therapy is incomplete or missing, it will be assumed to be 
concomitant except if the incomplete start or stop date indicates that the medication/therapy started and 
ended prior to the first IMP intake or started after the last IMP intake. 
PAH medications will be defined as medications where the preferred term for the indication is 
“pulmonary arterial hypertension”, “congenital pulmonary hypertension”, or “pulmonary 
hypertension”, as well as any other medications taken for a condition related to PAH. These medications 
were selected manually during the Data Review (see Data Review Report, Final 1.0, 10-MAR-2022). 
In addition, PAH-approved medications will be defined as those medications described in the protocol 
as being an approved PAH therapy (Ambrisentan, Bosentan, Macitentan, Riociguat, Selexipag, 
Sildenafil, Tadalafil, Epoprostenol intravenous, Iloprost inhaled or Treprostinil intravenous or 
subcutaneous) and diuretics. PAH-approved medications were selected manually during the Data 
Review (see Data Review Report, Final 1.0, 10-MAR-2022). 
PAH-approved medications will be combined into groups of monotherapy, double therapy, triple 
therapy, etc., based on the number of PAH-approved medications taken at a given timepoint. 
Concomitant medications will be assigned to IMP dose groups based on the prescribed IMP dose at the 
time of medication intake. If the start or end date indicates that the medication was taken concurrently 
with multiple doses, it will be assigned to every corresponding dose. If the start or end date is incomplete 
such that it could belong to more than one dose, the concomitant medication will be assigned to all such 
doses. 
The following statistical output will be provided:  
Table 15.1.8.1.1 Prior Medications – Safety Set  
Table 15.1.8.1.2 Prior Medications – Full Analysis Set  
Table 15.1.8.1.3 Prior Medications – Pharmacokinetic Analysis Set 
Table 15.1.8.2.1 Concomitant Medications – Safety Set 
Table 15.1.8.2.2 Concomitant Medications – Full Analysis Set 
Table 15.1.8.2.3 Concomitant Medications – Pharmacokinetic Analysis Set 
The number and percentage of patients with at least one medication within each ATC 2nd level 
subgroup. Substance name (or combination of substances) will be presented by HTD for prior 
medication, by dose for concomitant medications and overall in the corresponding analysis set. The 
ATC 2nd level subgroups and substance drug name within ATC 2nd level subgroup will be ordered by 
descending overall incidence. Medications that differ at the substance drug name level but belong to the 
same therapeutic category will be combined. 


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Table 15.1.8.3.1 Prior PAH Medications – Safety Set  
Table 15.1.8.3.2 Prior PAH Medications –Full Analysis Set  
Table 15.1.8.3.3 Prior PAH Medications – Pharmacokinetic Analysis Set 
Table 15.1.8.4.1 Concomitant PAH Medications – Safety Set 
Table 15.1.8.4.2 Concomitant PAH Medications – Full Analysis Set 
Table 15.1.8.4.3 Concomitant PAH Medications – Pharmacokinetic Analysis Set 
Medications for pulmonary arterial hypertension will be summarised as above. 
Table 15.1.8.5.1 PAH-Approved Therapy by Visit – Safety Set 
Table 15.1.8.5.2 PAH-Approved Therapy by Visit – Full Analysis Set 
Table 15.1.8.5.3 PAH-Approved Therapy by Visit – Pharmacokinetic Analysis Set 
The number and percentage of patients with PAH-approved monotherapy, double therapy, and triple 
therapy will be summarised at visits A1 and MPV3. The substance names for each therapy combination 
will be presented by HTD and overall in the corresponding analysis set. 
Listing 16.2.1.8 Medications and Therapies – Enrolled Set  
All medications, prior, concomitant and subsequent, will be listed for the patients from the enrolled set. 
5.4 
Exposure to IMP and Compliance 
5.4.1 
Exposure to IMP 
Exposure data from the eCRF include: 
- 
First IMP intake  
- 
Last IMP intake before the visit (except unscheduled visits) 
- 
IMP intake at the site (except unscheduled visits) 
- 
Last IMP intake (for withdrawals and patients that do not participate in the extension study) 
- 
Date of IMP down-titration 
The overall treatment duration in days will be calculated as follows:  
𝑂𝑣𝑒𝑟𝑎𝑙𝑙 𝑡𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡 𝑑𝑢𝑟𝑎𝑡𝑖𝑜𝑛 (𝑑𝑎𝑦𝑠) = 𝑙𝑎𝑠𝑡 𝐼𝑀𝑃 𝑖𝑛𝑡𝑎𝑘𝑒 𝑑𝑎𝑡𝑒−𝑓𝑖𝑟𝑠𝑡 𝐼𝑀𝑃 𝑖𝑛𝑡𝑎𝑘𝑒 𝑑𝑎𝑡𝑒+ 1 
The following definitions will be used to calculate the overall treatment duration: 
• 
The date of the first IMP intake is the date of the IMP intake as recorded at visit A1. 
• 
The date of the last IMP intake depends on the patient’s decision to participate in the 
extension study. If the patient is not participating in the extension study, then the last IMP intake 
is the date of the last intake recorded at the study termination page. If the patient is participating 
in the extension study, then the on-site IMP intake at MPV3 will be the date of the last IMP 
intake. 
The duration of the study periods in days will be calculated as follows: 
𝑇𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡 𝑝𝑒𝑟𝑖𝑜𝑑 𝑑𝑢𝑟𝑎𝑡𝑖𝑜𝑛 (𝑑𝑎𝑦𝑠)
= 𝑡𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡 𝑝𝑒𝑟𝑖𝑜𝑑 𝑒𝑛𝑑 𝑑𝑎𝑡𝑒 −𝑡𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡 𝑝𝑒𝑟𝑖𝑜𝑑 𝑠𝑡𝑎𝑟𝑡 𝑑𝑎𝑡𝑒+ 1 
See Section 4.6 for definitions of study periods. 
Overall and by-period treatment duration will be adjusted in the case of occurrence of adverse events 
with associated IMP interruption periods. The calendar days between and including start and stop dates 
of IMP interruptions will not count towards treatment duration. 
The following statistical output will be provided:  
Table 15.1.9.1.1 Treatment Duration (days) – Safety Set  
Table 15.1.9.1.2 Treatment Duration (days) – Full Analysis Set  
Table 15.1.9.1.3 Treatment Duration (days) – Pharmacokinetic Analysis Set 
The default summary statistics of treatment duration will be presented by HTD and overall. 


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5.4.2 
Compliance 
The following compliance-related data will be collected in the eCRF: 
- 
date of IMP dispensation 
- 
prescribed IMP dose 
- 
number of tablets dispensed  
- 
dispensed IMP bottle number 
- 
toleration of IMP dose (Yes, No) 
- 
date of IMP down-titration 
- 
date of IMP return 
- 
number of tablets returned  
- 
returned IMP bottle number 
The calculation of the compliance will be based on the total number of tablets prescribed, dispensed 
and returned overall or during particular study period (for definitions of study periods, see Section 4.6).  
The total number of tablets prescribed will be calculated as the prescribed daily number of tablets based 
on the dose (see Section 2.5) multiplied by the length of the dose prescription in calendar days. The 
total number of prescribed tablets will be adjusted in the case of occurrence of adverse events with 
associated IMP interruption periods.  
The total number of tablets dispensed and returned will be calculated as the sum of all tablets dispensed 
and all tablets returned during the corresponding study period. The total number of tablets returned will 
be considered as missing if not all dispensed bottles are returned in the same corresponding period or 
the returned bottle(s) is from the previous period. 
The overall compliance and compliance during each treatment period will be calculated as: 
𝐶𝑜𝑚𝑝𝑙𝑖𝑎𝑛𝑐𝑒  (%) = 100 × (𝑡𝑎𝑏𝑙𝑒𝑡𝑠 𝑑𝑖𝑠𝑝𝑒𝑛𝑠𝑒𝑑−𝑡𝑎𝑏𝑙𝑒𝑡𝑠 𝑟𝑒𝑡𝑢𝑟𝑛𝑒𝑑)
𝑡𝑎𝑏𝑙𝑒𝑡𝑠 𝑝𝑟𝑒𝑠𝑐𝑟𝑖𝑏𝑒𝑑
 
In case an IMP bottle is not returned, the overall compliance will be considered as missing. 
The following statistical output will be provided: 
Table 15.1.9.2.1 Compliance (%) – Safety Set 
Table 15.1.9.2.2 Compliance (%) – Full Analysis Set 
Table 15.1.9.2.3 Compliance (%) – Pharmacokinetic Analysis Set 
The default summary statistics of compliance will be presented by HTD and overall for the respective 
analysis set. Number and percentage of patients will also be summarised by compliance categories 
(< 90%, ≥ 90% and ≤ 110%, >110%) for the respective analysis set. 
Listing 16.2.2.1 Drug Accountability – Safety Set 
Information related drug accountability will be listed for the patients from the safety set. 
Listing 16.2.2.2 Exposure to IMP and Compliance – Safety Set 
Information related exposure to IMP and compliance will be listed for the patients from the safety set. 
 
 


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5.5 
Analysis of Efficacy Endpoints  
The following efficacy related secondary endpoints will be calculated and analysed: 
- 
Right heart catheterisation parameters 
- 
6-MWT, including Borg dyspnoea score 
- 
Biomarker (NT-proBNT) 
- 
Echocardiogram parameters 
- 
NYHA/WHO functional class 
- 
Quality of life (SF-36v2) 
Efficacy data will be analysed exploratively. Continuous measures will be summarised using summary 
statistics, 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. 
5.5.1 
Right Heart Catheterisation 
Right heart catheterisation (RHC) will be performed at visit A1 and at visit MPV3 before IMP intake 
to determine the change of haemodynamic parameters in the patients. If available, results from a right 
heart catheterisation within 90 days before V1 may be used in place of the V1 measurement. The 
following haemodynamic parameters will be collected: 
- 
Cardiac output (L/min) (CO) 
- 
Mixed venous oxygen saturation (%) (SvO2) 
- 
Pulmonary artery pressure systolic (mmHg) (PAPs) 
- 
Pulmonary artery pressure diastolic (mmHg) (PAPd) 
- 
Mean pulmonary artery pressure (mmHg) (mPAP) 
- 
Pulmonary artery wedge pressure (mmHg) (PAWP) 
- 
Right atrial pressure (mmHg) (RAP) 
- 
Transpulmonary pressure gradient (mmHg) (TPG) 
- 
Diastolic pressure gradient (mmHg) (DPG) 
- 
Pulmonary vascular resistance (dyn*s/cm5) (PVR) 
- 
Systemic ventricular resistance (dyn*s/cm5) (SVR) 
- 
Cardiac index (L/min/m2) (CI) 
- 
Pulmonary arterial compliance (mL/mmHg) (PAC, SV/PP) 
- 
Heart rate (bpm) 
- 
Stroke volume (mL/beat) (SV) 
- 
Stroke volume index (mL/m2/beat) (SVI) 
The derived parameters mPAP, TPG, DPG, PVR, PAC, SV, and SVI will be recalculated from other 
parameters using standardised formulae below. 
𝑚𝑃𝐴𝑃= 𝑃𝐴𝑃𝑑+ (𝑃𝐴𝑃𝑠−𝑃𝐴𝑃𝑑) 3
⁄  
𝑇𝑃𝐺= 𝑚𝑃𝐴𝑃−𝑃𝐴𝑊𝑃 
𝐷𝑃𝐺= 𝑃𝐴𝑃𝑑−𝑃𝐴𝑊𝑃 
𝑃𝑉𝑅= (𝑚𝑃𝐴𝑃−𝑃𝐴𝑊𝑃) 𝐶𝑂
⁄
∙80 
𝑃𝐴𝐶= 𝑆𝑉(𝑃𝐴𝑃𝑠−𝑃𝐴𝑃𝑑)
⁄
 
𝑆𝑉= 𝐶𝑂𝐻𝑅
⁄
∙1000 
𝑆𝑉𝐼= 𝐶𝐼𝐻𝑅
⁄
∙1000 
The recalculated parameter values will be used in summaries and listings. 
The clinical significance (yes/no) of any abnormal right heart catheterisation findings will be assessed 
by the investigator. 
Post-DR note: Clinical significance as assessed by the investigator will not be used for statistical 
analyses (see Data Review Report, Final 1.0, 10-MAR-2022). Instead, right heart catheterisation results 


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will be assigned a “Low”, “Normal” or “High” value according to ranges defined by Table 4. The ranges 
are based on the Data Validation Plan (Final 3.0, 21-JUL-2020).  
Table 5: Right Heart Catheterisation Normal Ranges 
Parameter 
Normal Range 
Cardiac output (L/min) (CO) 
2.5-8.0 
Mixed venous oxygen saturation (%) (SvO2) 
60-80 
Pulmonary artery pressure systolic (mmHg) (PAPs) 
25-80 
Pulmonary artery pressure diastolic (mmHg) (PAPd) 
8-16 
Mean pulmonary artery pressure (mmHg) (mPAP) 
≥25 
Pulmonary artery wedge pressure (mmHg) (PAWP) 
≤15 
Right atrial pressure (mmHg) (RAP) 
<14 
Transpulmonary pressure gradient (mmHg) (TPG) 
>12 
Diastolic pressure gradient (mmHg) (DPG) 
>6 
Pulmonary vascular resistance (dyn*s/cm5) (PVR) 
250-1000 
Systemic vascular resistance (dyn*s/cm5) (SVR) 
800-1200 
Cardiac index (L/min/m2) (CI) 
>2 
Pulmonary arterial compliance (mL/mmHg) (PAC; SV/PP) 
0.4-3.8 
Heart rate (bpm) 
50-100 
Stroke volume (mL/beat) (SV) 
>50 
Stroke volume index (mL/m2/beat) (SVI) 
>30 
Recalculated results will be used for applicable parameters. 
The following statistical output will be provided:  
Table 15.2.1.1.1 Summary of Right Heart Catheterisation Parameters by HTD – Full Analysis Set 
Table 15.2.1.1.2 Summary of Right Heart Catheterization Parameters – Full Analysis Set 
Table 15.2.1.1.3 Summary of Right Heart Catheterisation Parameters by HTD – Modified Full 
Analysis Set 
Table 15.2.1.1.4 Summary of Right Heart Catheterization Parameters – Modified Full Analysis Set 
The default summary statistics of RHC test results will be presented by HTD and overall at visits A1 
and MPV3. The absolute change from baseline will be presented as well. For the changes from baseline 
a 95% confidence interval will be provided. 
Table 15.2.1.1.5 Summary of Right Heart Catheterization Parameters – Modified Full Analysis Set 
(TAPSE Subgroups) 
The default summary statistics of RHC parameters PVR, mPAP, RAP, and CI will be presented by 
TAPSE subgroup and overall at visits A1 and MPV3. The absolute change from baseline will be 
presented as well. For the changes from baseline a 95% confidence interval will be provided. 
Table 15.2.1.2.1 Incidence of Right Heart Catheterisation Abnormalities – Full Analysis Set 
Table 15.2.1.2.2 Incidence of Right Heart Catheterisation Abnormalities – Modified Full Analysis Set 
Number and percentage of patients with abnormal values will be displayed by HTD and overall in not 
CS abnormal and CS abnormal categories. Percentage will be based on the number of patients at 
specified visit. 
Table 15.2.1.3.1 Shift Table of Right Heart Catheterisation Results – Full Analysis Set 
Table 15.2.1.3.2 Shift Table of Right Heart Catheterisation Results – Modified Full Analysis Set 
Shift tables showing changes in the number and frequency of patients in not CS abnormal and CS 
abnormal categories between baseline and MPV3 will be provided. 
Listing 16.2.3.1 Right Heart Catheterisation Parameters – Enrolled Set 
Values of parameters of right heart catheterisation will be listed. 


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5.5.2 
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 test will be performed at visit V1 before IMP intake and at visit MPV3 before right heart 
catheterisation. 
At screening, two attempts must be performed, separated by at least 30 minutes. The attempt in which 
the longer distance was covered will be considered as baseline. In case the distance covered during both 
attempts is equal, the first attempt will be considered as baseline. 
The following parameters will be collected: 
-  
SpO2 (%) – before and after the test 
-  
Borg Dyspnoea score – before and after the test 
-  
Heart rate (bpm) – before and after the test 
- 
Lap length (m) 
- 
Number of laps completed 
-  
Distance covered (m) 
-  
Time walking (min) 
-  
Oxygen flow rate (L/min) 
-  
Number of stops 
-  
Time stopped (min) 
The Borg Dyspnoea score is a patient-reported measure for assessing breathlessness. Symptoms of 
breathlessness are rated on a scale of 0-10, where 0 indicates no symptoms and 10 indicates the most 
severe breathlessness.  
The differences in SpO2, the Borg Dyspnoea score, and heart rate between after and before the test will 
be calculated. These differences will be displayed as additional parameters in summaries. 
The following statistical output will be provided: 
Table 15.2.2.1 Summary of 6-MWT by HTD – Full Analysis Set 
Table 15.2.2.2 Summary of 6-MWT – Full Analysis Set 
Table 15.2.2.3 Summary of 6-MWT by HTD – Modified Full Analysis Set 
Table 15.2.2.4 Summary of 6-MWT – Modified Full Analysis Set 
The default summary statistics of 6-MWT test results will be presented by HTD and overall at visits V1 
and MPV3. The absolute change from baseline will be presented as well. For the changes from baseline 
a 95% confidence interval will be provided. 
Table 15.2.2.5 Summary of 6-MWT Distance – Modified Full Analysis Set (TAPSE Subgroups) 
The default summary statistics of 6-MWT distance travelled will be summarised by TAPSE subgroup 
and overall at visits V1 and MPV3. The absolute change from baseline will be presented as well. For 
the changes from baseline a 95% confidence interval will be provided. 
 
Listing 16.2.3.2-Min Walk Test – Enrolled Set 
Values of parameters of 6-Min walk test will be listed. 


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5.5.3 
Biomarker 
Blood samples will be collected for biomarker NT-proBNP (pg/mL) evaluation at visits V1 and MPV3. 
NT-proBNP will be summarized in the unit ng/L for statistical output. No derivations are needed as the 
conversion factor between these units is 1. 
The following statistical output will be provided:  
Table 15.2.3.1.1 Summary of Biomarker NT-proBNP (ng/L) by HTD – Full Analysis Set 
Table 15.2.3.1.2 Summary of Biomarker NT-proBNP (ng/L) – Full Analysis Set 
Table 15.2.3.1.3 Summary of Biomarker NT-proBNP (ng/L) by HTD – Modified Full Analysis Set 
Table 15.2.3.1.4 Summary of Biomarker NT-proBNP (ng/L) – Modified Full Analysis Set 
The default summary statistics of biomarker NT-proBNP will be presented by HTD and overall at visits 
V1 and MPV3. The absolute change from baseline will be presented as well. For the changes from 
baseline a 95% confidence interval will be provided. 
Table 15.2.3.2.1 Summary of Biomarker NT-proBNP (ng/L) by Pooled HTD –Full Analysis Set 
Table 15.2.3.2.2 Summary of Biomarker NT-proBNP (ng/L) by Pooled HTD – Modified Full Analysis 
Set 
Biomarker NT-proBNP will be summarised as above, with HTD pooled into “HTD < 200 mg” and 
“HTD 200 mg” groups. 
Figure 15.2.1.1 Box-Whisker Plot of NT-proBNP by Pooled HTD – Full Analysis Set 
Figure 15.2.1.2 Box-Whisker Plot of NT-proBNP by Pooled HTD – Modified Full Analysis Set 
Box-whisker plots of NT-proBNP will be displayed by HTD at visits V1 and MPV3. The HTD will be 
pooled into “HTD < 200 mg” and “HTD 200 mg” groups. Summary statistics will be displayed below 
each box. 
Listing 16.2.3.3 Biomarker NT-proBNP – Enrolled Set 
Values of biomarker NT-proBNP will be listed. 
5.5.4 
Echocardiography 
Transthoracic echocardiography is used to image the effects of PAH on the heart. An echocardiogram 
(ECHO) will be performed at Visit 1 and MPV3.  
The following parameters will be determined:  
- 
Tricuspid regurgitation (absent, mild, moderate or severe) 
- 
Right ventricular contractility (TAPSE) (mm) 
- 
Pericardial effusion (absent, traces or present) 
- 
Right atrial area (end-systolic) (cm2) 
- 
Right ventricular end-diastolic area (cm2) 
The clinical significance (yes/no) of any abnormal ECHO findings will be assessed by the investigator. 
The following statistical output will be provided:  
Table 15.2.4.1.1 Summary of Categorical Echocardiography Parameters – Full Analysis Set 
Table 15.2.4.1.2 Summary of Categorical Echocardiography Parameters – Modified Full Analysis Set 
Number and percentage of patients will be displayed by HTD and overall at visits V1 and MPV3. 
Percentage will be based on the number of patients at the specified visit. 
Table 15.2.4.2.1 Summary of Numerical Echocardiography Parameters by HTD – Full Analysis Set 
Table 15.2.4.2.2 Summary of Numerical Echocardiography Parameters – Full Analysis Set 
Table 15.2.4.2.3 Summary of Numerical Echocardiography Parameters by HTD – Modified Full 
Analysis Set 
Table 15.2.4.2.4 Summary of Numerical Echocardiography Parameters – Modified Full Analysis Set 
The default summary statistics of ECHO parameters will be presented by HTD and overall at visits V1 
and MPV3. The absolute change from baseline will be presented as well. For the changes from baseline 
a 95% confidence interval will be provided. 


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Table 15.2.4.2.5 Summary of Numerical Echocardiography Parameters – Modified Full Analysis Set 
(TAPSE Subgroups) 
The default summary statistics of ECHO parameters will be presented by TAPSE subgroup and overall 
at visits V1 and MPV3. The absolute change from baseline will be presented as well. For the changes 
from baseline a 95% confidence interval will be provided. 
Table 15.2.4.3.1 Incidence of Echocardiography Abnormalities – Full Analysis Set 
Table 15.2.4.3.2 Incidence of Echocardiography Abnormalities – Modified Full Analysis Set 
Number and percentage of patients will be displayed by HTD and overall in Not CS abnormal and CS 
abnormal categories. Percentage will be based on the number of patients at the specified visit. 
Table 15.2.4.4.1 Shift Table of Echocardiography Results – Full Analysis Set 
Table 15.2.4.4.2 Shift Table of Echocardiography Results – Modified Full Analysis Set 
Shift tables showing changes in the number and frequency of patients in Not CS abnormal and CS 
abnormal categories between V1 and MPV3 visits will be provided. 
Listing 16.2.3.4 Echocardiography – Enrolled Set 
Values of echocardiography tests will be listed. 
5.5.5 
New York Heart Association/Word Health Organisation Functional Class 
(NYHA/WHO) 
Classification of functional status of patients will be performed at Visit 1 and at visit MPV3/EDV by 
the investigator by using the NYHA/WHO classification system defined below. 
Table 6:NYHA/WHO Classes 
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  
The following statistical output will be provided:  
Table 15.2.5.1.1 Summary of NYHA/WHO Functional Class – Full Analysis Set 
Table 15.2.5.1.2 Summary of NYHA/WHO Functional Class – Modified Full Analysis Set 
Number and percentage of patients will be displayed by HTD and overall in each NYHA/WHO 
functional class. Percentage will be based on the number of patients at the specified visit. 
Table 15.2.5.2.1 Shift Table of NYHA/WHO Functional Class – Full Analysis Set 
Table 15.2.5.2.2 Shift Table of NYHA/WHO Functional Class – Modified Full Analysis Set 
Shift tables showing changes in the number and frequency of patients with respect to the NYHA/WHO 
functional class between V1 and MPV3/EDV will be provided. 
Listing 16.2.3.5 NYHA/WHO Functional Class – Enrolled Set 
NYHA/WHO functional class data will be listed by visit. 
5.5.6 
Quality of Life (SF-36v2) 
The 36-item Short Form Survey version 2 (SF-36v2) is used to assess the quality of life. The 
questionnaire will be completed by the patient at Visit 1 and at MPV3. 


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SF-36v2 asks 36 questions (items) to measure functional health and well-being from the patient's point 
of view. All but one (question 2) of the 36 items will be used to score the eight SF-36v2 health domains: 
- 
Physical Functioning (PF) 
- 
Role Limitations due to Physical Health (RP) 
- 
Bodily Pain (BP) 
- 
General Health (GH) 
- 
Vitality (VT) 
- 
Social Functioning (SF) 
- 
Role Limitations due to Emotional Health (RE) 
- 
Mental Health (MH). 
A total score will be calculated for each SF-36v2 health domain by taking the sum of the corresponding 
responses and rescaling it to a range of 0 to 100, where 100 represents the best possible result. Each 
domain will then be standardised using a general population norm. 
The scores of the eight health domains will be used to calculate a physical component summary (PCS) 
and mental component summary (MCS) score using coefficients based on a principal components 
analysis of the SF-36v2 domain scores in the general population. The PCS and MCS are summary 
measures that represent the overall physical and mental health of the patient, with higher scores 
representing better outcomes. 
A subset of items from six domains (PF, RE, SF, BP, MH, VT) will be used to calculate a Utility Index 
Score, which rates the overall health state from 0.0 (worst health state) to 1.0 (best health state). The 
updated (SF-6D R2) Utility Index Score will be summarised. 
Optum PRO CoRE will be used to generate the following scores: 
- 
SF-36v2 domain scores (0-100 scale) 
- 
SF-36v2 domain scores based on the 2009 US general population norms 
- 
PCS and MCS scores based on the 2009 US general population norms 
- 
SF-6D R2 
In addition, interpretations for the norm-based SF-36v2 health domains and PCS and MCS scores will 
be provided based on benchmarks from the general population cardiac patients: 
- 
“Well Below”, if the norm-based score is 10 points or more below the benchmark; 
- 
“Below”, if the norm-based score is from 5 to 9 points below the benchmark; 
- 
“Same or Better”, if the norm-based score is less than 5 points below the benchmark. 
The following statistical output will be provided: 
Table 15.2.6.1.1 Summary of SF-36v2 Domain Scores by HTD – Full Analysis Set 
Table 15.2.6.1.2 Summary of SF-36v2 Domain Scores – Full Analysis Set 
Table 15.2.6.1.3 Summary of SF-36v2 Domain Scores by HTD – Modified Full Analysis Set 
Table 15.2.6.1.4 Summary of SF-36v2 Domain Scores – Modified Full Analysis Set 
The default summary statistics of SF-36v2 results will be presented by HTD and overall at visits V1 
and MPV3. The absolute change from baseline will be presented as well. For the changes from baseline 
a 95% confidence interval will be provided. 
Table 15.2.6.2.1 Summary of Norm-Based SF-36v2 Domain Scores by HTD – Full Analysis Set 
Table 15.2.6.2.2 Summary of Norm-Based SF-36v2 Domain Scores– Full Analysis Set 
Table 15.2.6.2.3 Summary of Norm-Based SF-36v2 Domain Scores by HTD – Modified Full Analysis 
Set 
Table 15.2.6.2.4 Summary of Norm-Based SF-36v2 Domain Scores – Modified Full Analysis Set 
The default summary statistics of SF-36v2 results based on 2009 US norms will be presented by HTD 
and overall at visits V1 and MPV3. The absolute change from baseline will be presented as well. For 
the changes from baseline a 95% confidence interval will be provided. 


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Table 15.2.6.3.1 Summary of SF-36v2 Utility Index Scores by HTD – Full Analysis Set 
Table 15.2.6.3.2 Summary of SF-36v2 Utility Index Scores – Full Analysis Set 
Table 15.2.6.3.3 Summary of SF-36v2 Utility Index Scores by HTD – Modified Full Analysis Set 
Table 15.2.6.3.4 Summary of SF-36v2 Utility Index Scores – Modified Full Analysis Set 
The default summary statistics of Utility Index scores will be presented by HTD and overall at visits 
V1 and MPV3. The absolute change from baseline will be presented as well. For the changes from 
baseline a 95% confidence interval will be provided. 
Table 15.2.6.4.1 Summary of SF-36v2 Cardio Benchmark Interpretation – Full Analysis Set 
Table 15.2.6.4.2 Summary of SF-36v2 Cardio Benchmark Interpretation – Modified Full Analysis Set 
Number and percentage of patients will be displayed by HTD at visits V1 and MPV3. Percentage will 
be based on the number of patients at the specified visit. 
Table 15.2.6.5.1 Shift Table of SF-36v2 Cardio Benchmark Interpretation – Full Analysis Set 
Table 15.2.6.5.2 Shift Table of SF-36v2 Cardio Benchmark Interpretation – Modified Full Analysis Set 
Shift tables showing changes in the number and frequency of patients with respect to the Cardio 
benchmark interpretation between V1 and MPV3 will be provided. 
Figure 15.2.2.1 Norm-Based SF-36v2 Domain Scores by Visit – Full Analysis Set 
Figure 15.2.2.2 Norm-Based SF-36v2 Domain Scores by Visit – Modified Full Analysis Set 
The means of norm-based SF-36v2 domain scores will be presented by HTD at visits V1 and MPV3 
using a bar chart. A reference line will be included for the average score in the general population. 
Figure 15.2.3.1 SF-36v2 Cardio Benchmark Interpretation by Visit – Full Analysis Set 
Figure 15.2.3.2 SF-36v2 Cardio Benchmark Interpretation by Visit – Modified Full Analysis Set 
The numbers of patients in each cardio benchmark interpretation category will be displayed by HTD 
for each domain at visits V1 and MPV3 using a stacked bar chart. 
Listing 16.2.3.6 SF-36v2 – Enrolled Set 
Summary scores based on the SF-36v2 survey results will be listed. 
 
5.6 
Analysis of Safety Endpoints 
Safety will be assessed by evaluation of the following variables: 
- 
Adverse events 
- 
Clinically relevant changes in laboratory parameters (haematology, biochemistry, coagulation, 
urinalysis, arterial blood gas analysis)  
- 
Clinically relevant changes in vital signs  
- 
Clinically relevant changes in ECG 
- 
Physical examination findings 
- 
Number of digital scars (only in patients with scleroderma)  
- 
Modified Rodnan Skin score (only in patients with scleroderma)  
5.6.1 
Adverse Events 
AEs will be coded according to latest Medical Dictionary for Regulatory Activities (MedDRA®) 
Version 22.0. 
Adverse events’ data include:  
- 
adverse event name 
- 
start/stop dates 
- 
ongoing 
- 
severity (mild, moderate, severe) 
- 
relationship (not related, unlikely, possible, probable, definite) 
- 
action taken with study medication (dose not changed, dose reduced, drug interrupted, drug 
withdrawn, not applicable, unknown) 
- 
other actions (none, medication required, tests required, withdrawn from the study, 
hospitalisation required or prolonged, other specification) 


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- 
outcome of event (recovered/resolved, recovering/resolving, not recovered/not resolved, 
recovered/resolved with sequelae, fatal, unknown) 
- 
AE of special interest (yes or no) 
- 
seriousness (yes or no) 
- 
start/stop dates of drug interruption 
All AEs will be presented in listings. 
Summaries of adverse events will include AEs defined as treatment-emergent adverse events 
(TEAEs), defined as AEs with the first onset or worsening after the first IMP intake and not more than 
14 days after the last IMP intake.  
If the start date of an AE is incomplete or missing, it will be assumed to be treatment-emergent except 
if the incomplete start date or the stop date indicates that the event started or ended prior to the first IMP 
intake or started later than 14 days after last IMP intake. 
AEs will be further assigned to the following categories: 
- 
Serious Adverse Events (SAEs): defined as AEs considered by the investigator as serious. 
- 
Adverse Event of Special Interest (AESIs): defined as AEs assessed by the investigator as 
being of special interest. 
- 
Related TEAEs: defined as AEs assessed as being “Possible”, “Probable” or “Definite” to IMP 
and include the events with missing IMP relationship assessment. 
- 
Unrelated TEAEs: defined as AEs assessed as being “Not related” or “Unlikely” to be related 
to IMP.  
- 
Severe TEAEs: defined as AEs assessed as being “Severe” in intensity and include the events 
with missing severity assessment. 
- 
TEAEs leading to down-titration: defined as AEs where “Action taken with study 
medication” is indicated as “dose reduced”. 
- 
TEAEs leading to discontinuation: selected as those events where “Action taken with study 
medication” is indicated as “drug withdrawn” or “other actions” is “discontinued from study”. 
- 
TEAEs leading to death: selected as those events where outcome of event is indicated as 
“fatal”. 
Adverse events will be assigned to IMP dose groups based on the prescribed IMP dose at the date of 
AE onset. AEs with an onset date on the same day as a down-titration will be assigned to the previous 
dose. If the AE onset date is incomplete such that it could belong to more than one prescribed dose, the 
AE will be assigned to all such doses. 
The following statistical output will be provided: 
Table 15.3.1.1 Overall Summary of TEAEs – Safety Set 
An overview of TEAEs:  
- 
TEAE  
- 
Non-serious TEAE 
- 
Serious TEAE  
- 
TEAEs of special interest 
- 
Related TEAE 
- 
Related serious TEAE 
- 
Mild TEAE 
- 
Moderate TEAE 
- 
Severe TEAE 
- 
TEAE leading to down-titration 
- 
TEAE leading to discontinuation 
- 
Serious TEAE leading to discontinuation 


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- 
Related TEAE leading to discontinuation 
- 
TEAE leading to death  
will be displayed during the trial as well as the dose finding, maintenance, and down-titration periods 
by dose and overall for the patients in the safety set. 
Table 15.3.1.2 Incidence of TEAEs – Safety Set 
Table 15.3.1.3 Incidence of Serious TEAEs – Safety Set 
Table 15.3.1.4 Incidence of TEAEs of Special Interest – Safety Set 
Table 15.3.1.5 Incidence of Related TEAEs – Safety Set 
Table 15.3.1.6 Incidence of Related Serious TEAEs – Safety Set 
Table 15.3.1.7 Incidence of TEAEs Leading to Down-Titration – Safety Set 
Table 15.3.1.8 Incidence of TEAEs Leading to Discontinuation – Safety Set 
Table 15.3.1.9 Incidence of TEAEs Leading to Death – Safety Set 
TEAEs occurring during the trial as well as the dose finding, maintenance, and down-titration periods 
will be summarised by concurrent dose and overall via the numbers of adverse events, as well as counts 
and percentages of patients having experienced adverse events during the dose finding and maintenance 
periods and overall. Percentages will be based on the number of patients in the safety set. Here and in 
the tables below the SOCs and PTs within each SOC will be ordered by descending overall incidence. 
In addition, the following will be provided summarised by SOC and PT for the safety set for each dose 
and overall: 
Table 15.3.1.10 Incidence of TEAEs by Severity – Safety Set 
Table 15.3.1.11 Incidence of TEAEs by Relationship to IMP – Safety Set 
All adverse event data will be listed as follows: 
Listing 16.2.4.1.1 Adverse Events: MedDRA Coding 
Listing 16.2.4.1.2 Adverse Events: General – Enrolled Set 
Listing 16.2.4.1.3 Non-Serious Adverse Events – Safety Set 
Listing 16.2.4.1.4 Serious Adverse Events – Safety Set 
Listing 16.2.4.1.5 TEAEs of Special Interest – Safety Set 
Listing 16.2.4.1.6 AEs Leading to Discontinuation – Safety Set 
Listing 16.2.4.1.7 AEs Leading to Death – Safety Set 
All AEs will be displayed by patient including the PT of an AE, start and stop dates, duration and other 
characteristics of AEs. 
5.6.2 
Clinical Laboratory Evaluation 
Clinical laboratory values for haematology, coagulation, biochemistry and urinalysis will be collected 
at screening (V1), visits A3/B3/C3/D3, MPV1, MPV3/EDV and FUV2 for each laboratory parameter. 
Blood pregnancy test values will be collected only for women with childbearing potential at screening 
(V1) and urine pregnancy test will be collected at visits A1, A3/B3/C3/D3, MPV1, MPV2, MPV3/EDV 
and FUV2. For patients enrolled under protocol version final 1.0, urine pregnancy test will be evaluated 
at visits A1, A3/B3/C3/D3, MPV1, MPV2, MPV3/EDV. 
The following parameters will be collected:  
- 
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 (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, and total bilirubin (bilirubin will 
be fractionated direct/indirect if elevated), haemoglobin A1c (HbA1c).  


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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. 
Haematology, coagulation and biochemistry test results will be assigned an LNH classification 
according to whether the value is lower than (L), within (N) or higher than (H) the reference range for 
that parameter as provided by the corresponding laboratory.  
For urinalysis shift tables, all parameters except pH and specific gravity will be assigned a 
“normal”/”abnormal” category based on the recorded result. “Negative” and “normal” results will be 
considered as normal, and any positive results will be considered as abnormal. 
Clinical significance of laboratory values will be evaluated by the investigator. 
The following statistical output will be provided:  
Table 15.3.2.1.1.1 Summary of Clinical Laboratory Tests: Haematology by HTD– Safety Set 
Table 15.3.2.1.1.2 Summary of Clinical Laboratory Tests: Haematology – Safety Set 
Table 15.3.2.1.2.1 Summary of Clinical Laboratory Tests: Biochemistry by HTD – Safety Set 
Table 15.3.2.1.2.2 Summary of Clinical Laboratory Tests: Biochemistry – Safety Set 
Table 15.3.2.1.3.1 Summary of Clinical Laboratory Tests: Coagulation by HTD – Safety Set 
Table 15.3.2.1.3.2 Summary of Clinical Laboratory Tests: Coagulation – Safety Set 
The default summary statistics of clinical laboratory test results will be presented by HTD and overall 
at V1, A3/B3/C3/D3, MPV1, MPV3/EDV and FUV2. The absolute change from baseline will be 
presented as well. 
Table 15.3.2.1.4 Summary of Clinical Laboratory Tests: Urinalysis – Safety Set 
Number and percentage of patients will be displayed by HTD and overall at V1, A3/B3/C3/D3, MPV1, 
MPV3/EDV and FUV2. Percentage will be based on the number of patients at the specified visit. 
Table 15.3.2.2.1 Clinical Laboratory Tests: Incidence of Haematology Abnormalities – Safety Set 
Table 15.3.2.2.2 Clinical Laboratory Tests: Incidence of Biochemistry Abnormalities – Safety Set 
Table 15.3.2.2.3 Clinical Laboratory Tests: Incidence of Coagulation Abnormalities – Safety Set 
Number and percentage of patients for each laboratory parameter will be displayed by HTD and overall 
in Low, CS Low, Normal, High and CS High categories. Percentage will be based on the number of 
patients at specified visit. 
Table 15.3.2.2.4 Clinical Laboratory Tests: Incidence of Urinalysis Abnormalities – Safety Set 
Number and percentage of patients for each laboratory parameter will be displayed by HTD and overall 
in Normal, Abnormal and CS abnormal categories. Percentage will be based on the number of patients 
at specified visit. 
Table 15.3.2.3.1 Clinical Laboratory Tests: Shift Table of Haematology Results – Safety Set 
Table 15.3.2.3.2 Clinical Laboratory Tests: Shift Table of Biochemistry Results – Safety Set 
Table 15.3.2.3.3 Clinical Laboratory Tests: Shift Table of Coagulation Results – Safety Set 
Shift tables showing changes in the number and frequency of patients with respect to the normal range 
between baseline and MPV3/EDV will be provided. 
Table 15.3.2.3.4 Clinical Laboratory Tests: Shift Table of Urinalysis Results – Safety Set 
Shift tables showing changes in the number and frequency of patients in Normal, Abnormal and CS 
abnormal categories between baseline and MPV3/EDV will be provided. 
Listing 16.2.4.2.1 Laboratory Data: Haematology – Enrolled Set 
Listing 16.2.4.2.2 Laboratory Data: Biochemistry – Enrolled Set 
Listing 16.2.4.2.3 Laboratory Data: Coagulation – Enrolled Set 
Values of laboratory tests will be listed. 
Listing 16.2.4.2.4 Laboratory Data: Urinalysis – Enrolled Set 
All urinalysis (dipstick) data will be listed.  
Listing 16.2.4.2.5 Laboratory Data: Microscopy – Enrolled Set 
All microscopy data will be listed. 


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Listing 16.2.4.2.6 Laboratory Data: Pregnancy Tests – Enrolled Set 
Data of pregnancy tests will be listed. 
5.6.3 
Arterial Blood Gas Analysis 
Arterial blood gas analysis will be performed at visit A1 and MPV3 before first IMP intake. 
The following parameters of Arterial blood gas analysis will be collected:  
- 
Fraction of inspired oxygen (%) (FiO2) 
- 
pH 
- 
oxygen partial pressure (mmHg) (pO2) 
- 
carbon dioxide partial pressure (mmHg) (pCO2) 
- 
bicarbonate (mEq/L) 
- 
base excess (mEq/L) (BE) 
- 
arterial oxygen saturation (%) (SaO2)* 
- 
sodium (mEq/L) 
- 
potassium (mEq/L) 
- 
lactate (mEq/L) 
* - Collected as “O2 content (%)” in earlier eCRF versions. 
If arterial blood gas analysis is not performed, then peripheral oxygen saturation (%) will be collected. 
The clinical significance (yes/no) of any abnormal Arterial blood gas analysis findings will be assessed 
by the investigator. Parameter values without a clinical significance evaluation will be considered as 
“Normal”, and values with “No” or “Yes” clinical significance evaluations will be considered as “NCS 
Abnormal” and “CS Abnormal”, respectively. 
The following statistical output will be provided:  
Table 15.3.3.1.1 Summary of Arterial Blood Gas Analysis by HTD – Safety Set 
Table 15.3.3.1.2 Summary of Arterial Blood Gas Analysis – Safety Set 
The default summary statistics of Arterial blood gas analysis parameters will be presented by HTD and 
overall at visits A1 and MPV3. The absolute change from baseline will be presented as well. For the 
changes from baseline a 95% confidence interval will be provided. 
Table 15.3.3.2 Incidence of Arterial Blood Gas Analysis Abnormalities – Safety Set 
Number and percentage of patients with abnormal values will be displayed by HTD and overall in Not 
CS abnormal and CS abnormal categories. Percentage will be based on the number of patients at 
specified visit. 
Table 15.3.3.3 Shift Table of Arterial Blood Gas Analysis Results – Safety Set 
Shift tables showing changes in the number and frequency of patients in Not CS abnormal and CS 
abnormal categories between baseline and MPV3/EDV will be provided. 
Table 15.3.3.4.1 Summary of Peripheral Oxygen Saturation (%) by HTD – Safety Set 
Table 15.3.3.4.2 Summary of Peripheral Oxygen Saturation (%) – Safety Set 
The default summary statistics of peripheral oxygen saturation (%) will be presented by HTD and 
overall at visits A1 and MPV3. The absolute change from baseline will be presented as well. For the 
changes from baseline a 95% confidence interval will be provided. 
Listing 16.2.4.3 Arterial blood gas analysis – Enrolled Set 
Values of arterial blood gas analysis and peripheral oxygen saturation (%) will be listed. 
5.6.4 
Vital Signs 
Vital signs will be collected at screening (V1), visits A1, A3/B3/C3/D3, MPV1, MPV2, MPV3/EDV 
and FUV2. Blood pressure and heart rate will be measured in supine position (two measurements) and 
afterwards in standing position (one measurement). Tympanic body temperature will also be assessed. 


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At visits 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. For patients enrolled under protocol version final 1.0, vital signs were 
only evaluated before IMP intake. 
Systolic and diastolic blood pressure and pulse rate will be summarised by measurement position. The 
mean value of measurements in the supine position at a given timepoint will be used in summaries. 
Orthostatic changes in vital sign parameters will also be calculated as the difference between the 
measurement in the standing position and the mean of the supine measurements. The orthostatic changes 
will be displayed after each corresponding parameter’s standing position results in summaries. 
To evaluate the short-term effects of the IMP on vital sign parameters, the absolute change from the 
pre-dose value within the corresponding visit will be calculated for each parameter at visits A1 and 
MPV3. Additionally, the difference in the within-visit changes will be evaluated for each corresponding 
timepoint between visits MPV3 and A1. 
Physical measurements – height and weight will be assessed at visit V1. Weight will also be measured 
at MPV3/EDV. BMI will be calculated from available data (see Section 5.2.1 for calculation). 
The following statistical output will be provided:  
Table 15.3.4.1.1 Summary of Vital Signs by HTD– Safety Set 
Table 15.3.4.1.2 Summary of Vital Signs – Safety Set 
Vital sign parameters will be summarised including change from baseline at each timepoint by HTD 
and overall.  
Table 15.3.4.2 Summary of Vital Signs by Pooled HTD – Safety Set 
Vital sign parameters will be summarised as above, with HTD pooled into “HTD < 200 mg” and “HTD 
200 mg” groups. 
Table 15.3.4.3.1 Summary of Short-Term IMP Effect on Vital Signs by HTD – Safety Set 
Table 15.3.4.3.2 Summary of Short-Term IMP Effect on Vital Signs – Safety Set 
The observed values and absolute changes from the pre-dose value will be summarised for each vital 
sign parameter at each timepoint by HTD and overall. 
Table 15.3.4.4.1 Summary of Change in Short-Term IMP Effect on Vital Signs by HTD – Safety Set 
Table 15.3.4.4.2 Summary of Change in Short-Term IMP Effect on Vital Signs – Safety Set 
The changes from pre-dose values and the differences in changes from pre-dose values will be 
summarised between corresponding timepoints at visits A1 and MPV3 by HTD and overall. 
Table 15.3.4.5.1 Summary of Physical Measurements by HTD – Safety Set 
Table 15.3.4.5.2 Summary of Physical Measurements – Safety Set 
Physical measurements will be summarised including change from baseline at each timepoint by HTD 
and overall.  
Figure 15.3.1 Vital Signs Median Change from Baseline – Safety Set 
The median changes from baseline of vital signs parameters at each post-baseline timepoint will be 
displayed by will be displayed by HTD. The HTD will be pooled into “HTD < 200 mg” and “HTD 200 
mg” groups. 
Listing 16.2.4.4 Vital Signs and Physical Measurements – Enrolled Set 
Values of vital signs and physical measurements will be listed. 
5.6.5 
12-Lead Electrocardiogram (ECG) Data 
A simultaneous 12-lead resting electrocardiogram (ECG) will be collected at screening (V1), A1, 
A3/B3/C3/D3, MPV1, MPV2, MPV3/EDV and FUV2. At visits A1 and MPV3 triplicate ECG 
recordings will be performed at following time points - before IMP intake as well as 4 and 8 hours after 
IMP intake. At EDV only one ECG recording will be performed. For patients enrolled under protocol 
version final 1.0, ECG assessments were only collected once at visits V1, A3/B3/C3/D3, MPV1, 
MPV3/EDV. 
Following parameters will be assessed:  


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- 
Heart rate (bpm) 
- 
P-R interval (msec) 
- 
QRS duration (msec) 
- 
QTcF interval (msec) 
- 
QT interval (msec) 
- 
P pulmonale 
- 
Right axis deviation 
- 
RV hypertrophy 
- 
RV strain 
- 
Right bundle branch block 
- 
Heart rhythm (normal, abnormal) 
For patients enrolled under protocol version final 1.0, heart rhythm was not collected. 
Clinical significance (yes/no) of any abnormal ECG data findings will be assessed by the investigator. 
Parameter values without a clinical significance evaluation will be considered as “Normal”, and values 
with “No” or “Yes” clinical significance evaluations will be considered as “NCS Abnormal” and “CS 
Abnormal”, respectively. 
Where multiple ECG recordings are performed within a visit or timepoint, ECG parameters will be 
summarised as follows. For numeric parameters, the mean of collected values will be used in 
summaries. For abnormality assessments, the worst value within the visit/timepoint will be used. 
To evaluate the short-term effects of the IMP on ECG parameters, the absolute change from the pre-
dose value within the corresponding visit will be calculated for each parameter at visits A1 and MPV3. 
Additionally, the difference in the within-visit changes will be evaluated for each corresponding 
timepoint between visits MPV3 and A1. 
The following statistical output will be provided: 
Table 15.3.5.1.1 Summary of ECG Assessments by HTD – Safety Set 
Table 15.3.5.1.2 Summary of ECG Assessments – Safety Set 
ECG parameters will be summarised including change from baseline at each visit by HTD and overall.  
Table 15.3.5.2.1 Summary of Short-Term IMP Effect on ECG Assessments by HTD – Safety Set 
Table 15.3.5.2.2 Summary of Short-Term IMP Effect on ECG Assessments – Safety Set 
The observed values and absolute changes from the pre-dose value will be summarised for each vital 
sign parameter at each timepoint by HTD and overall. 
Table 15.3.5.3.1 Summary of Change in Short-Term IMP Effect on ECG Assessements by HTD – 
Safety Set 
Table 15.3.5.3.2 Summary of Change in Short-Term IMP Effect on ECG Assessements – Safety Set 
The changes from pre-dose values and the differences in changes from pre-dose values will be 
summarised between corresponding timepoints at visits A1 and MPV3 by HTD and overall.  
Table 15.3.5.4.1 Incidence of ECG Abnormalities – Safety Set 
Number and percentage of patients with Not CS abnormal and CS abnormal ECG parameters 
assessments will be displayed by HTD and overall. Percentage will be based on the number of patients 
at specified visit. 
Table 15.3.5.4.2 Shift Table of ECG Abnormalities – Safety Set 
Shift tables showing changes in the number and frequency of patients in not CS abnormal and CS 
abnormal categories between baseline and MPV3/EDV will be provided. The worst abnormality 
assessment collected during MPV3/EDV will be selected for each patient. Percentage will be based on 
the number of patients in the safety set. 
Table 15.3.5.4.3 Shift Table of Within-Visit ECG Abnormalities – Safety Set 
Shift tables showing changes in the number and frequency of patients in not CS abnormal and CS 
abnormal categories between the pre-dose measurement and each post-dose measurement at each visit. 


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The worst abnormality assessment collected during the corresponding timepoint will be selected for 
each patient. Percentage will be based on the number of patients in the safety set. 
Listing 16.2.4.5 Electrocardiogram – Enrolled Set  
Values of simultaneous 12-lead resting electrocardiogram tests will be listed. 
5.6.6 
Physical Examination Findings 
Physical examinations will be performed at Visit 1, visits A3/B3/C3/D3, MPV1, MPV2, MPV3/EDV 
on relevant body systems (appearance, skin, eyes, ears-nose-throat, lungs-chest, heart, abdomen, 
extremities, other). Clinical significance (yes/no) of any abnormal physical examination findings and 
specification of clinically significant abnormality findings will be assessed by the investigator.  
The following statistical output will be provided: 
Table 15.3.6 Summary of Physical Examination Findings – Safety Set 
Number and percentage of patients with not CS abnormal and CS abnormal physical examinations 
findings will be displayed at each visit by HTD and overall. Percentage will be based on the number of 
patients at the specified visit. 
Listing 16.2.4.6 Physical Examinations – Enrolled Set 
Values of physical examination will be listed. 
5.6.7 
Number of Digital Scars 
Number of digital scars will be documented in patients with scleroderma only. 
At Visit 1 the investigator will document the number of existing digital scars at the fingers and toes. At 
visits A3/B3/C3/D3, MPV1, MPV2 and MPV3/EDV the investigator will examine fingers and toes of 
the patient and will document the number of digital scars. Additionally, the clinical examination will 
be supported by interviewing the patient. 
For patients enrolled with protocol version 1.0 the investigator documented only the number of new 
scars at post-baseline visits, therefore the total number of scars will be derived adding number of scars 
at baseline and new scars. 
The following statistical output will be provided: 
Table 15.3.7.1 Summary of Scleroderma Scarring by HTD – Safety Set 
Table 15.3.7.2 Summary of Scleroderma Scarring – Safety Set 
The default summary statistics of number of digital scars will be presented by HTD and overall at each 
visit. The absolute change from baseline will be presented as well. 
Listing 16.2.4.7 Number of Digital Scars – Enrolled Set 
Number of scars will be listed by visit. 
5.6.8 
Modified Rodnan Skin Score (mRSS) 
The mRSS is a measure of skin thickness and is used as an outcome measure for scleroderma. 
The 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) 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. 
The investigator will document the total skin score at Visit 1 and visit MPV3/EDV. 


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The following statistical output will be provided: 
Table 15.3.8.1 Summary of mRSS by HTD – Safety Set 
Table 15.3.8.2 Summary of mRSS – Safety Set 
The default summary statistics of modified Rodnan score will be presented by HTD and overall at each 
visit. The absolute change from baseline will be presented as well. 
Listing 16.2.4.8 Modified Rodnan Skin Score – Enrolled Set 
Values of mRSS will be listed. 
 


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6 
DATA REVIEW 
The aims of the Data Review (DR) are: 
- 
to identify major/minor protocol deviations, that may affect the pharmacokinetic or 
pharmacodynamic outcomes, or the treatment of the patients 
- 
to identify impacts of the COVID-19 pandemic on the study conduct 
- 
to solve any outstanding issues in the SAP 
- 
to discuss any open data issues 
The DR will be performed after data entry and following a database lock. All decisions made during 
the DR will be documented in the DR report before the closure of the database. 
An appropriate clinical study team, including a physician, will review potential protocol deviations and 
relevant information regarding those deviations to determine a possible impact on pharmacokinetic 
endpoints. The status, major or minor, of each protocol deviation will be documented in the DR report. 
A patient may have one or more major protocol deviations resulting in the exclusion of that patient from 
the PKS set. 
Protocol deviations will, if possible, be validated against data recorded in the eCRF. Where an answer 
for an inclusion/exclusion tick box differs from the algorithmic check of the criteria, the algorithmic 
check will overrule the tick box. 
Additionally, protocol deviations will be reviewed by the medical monitor and will be categorized 
according to their impact on the PK analysis into following groups: major, minor and case by case 
decision. 
Protocol deviations of the following categories and respective data listings will be reviewed during the 
DR. 
Inclusion Criteria 
No. 
Inclusion Criteria Deviation 
Major/ 
Minor/ 
Case by 
case review 
PD#01.  Male or female patients aged 18 to 75 years, inclusive. 
 
Protocol Versions Final 1.0 and 2.0: 
Male or female patients aged 18 to 65 years. 
Case by case 
PD#02.  Able to comprehend and willing to sign an informed consent form (ICF). 
Major 
PD#03.  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. 
Case by case 
PD#04.  Added in Protocol Version Final 3.0: 
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. 
Minor 


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No. 
Inclusion Criteria Deviation 
Major/ 
Minor/ 
Case by 
case review 
PD#05.  WHO functional class II or III as judged by the investigator. 
Case by case 
PD#06.  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. 
 
Protocol Version Final 1.0: 
Stable treatment with at least one of the following approved oral PAH 
therapies within 3 months before V1: Ambrisentan, Bosentan, Macitentan, 
Riociguat, Selexipag, Sildenafil or Tadalafil. 
Case by case 
PD#07.  Added in Protocol Version Final 3.0: 
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. 
Minor 
 
Exclusion Criteria 
No. 
Exclusion Criteria Deviation 
Major/ 
Minor/ 
Case by 
case review 
PD#08.  Contraindication to zamicastat, i.e. known hypersensitivity to ingredients of 
zamicastat formulation. 
Minor 
PD#09.  Two or more consecutive measurements of SBP < 95 mmHg or DBP < 50 
mmHg measured at V1. 
 
Protocol Version Final 2.0 
Two or more consecutive measurements of SBP < 95 mmHg or DBP < 50 
mmHg. 
 
Protocol Version Final 1.0: 
Persistent hypotension defined as SBP < 95 mmHg or DBP < 50 mmHg. 
Minor 
PD#10.  Uncontrolled diabetes mellitus with HbA1c ≥ 8.5% within the last three 
months or at screening. 
 
Protocol Version Final 1.0: 
Uncontrolled diabetes mellitus. 
Minor 
PD#11.  PAH WHO Group 1 due to portal hypertension, human immunodeficiency 
virus (HIV) infection and schistosomiasis. 
Case by case 
PD#12.  Any disease known to cause pulmonary hypertension other than PAH WHO 
Group 1. 
 
Protocol Version Final 1.0: 
Any disease known to cause pulmonary hypertension other than PAH 
WHO Group 1 e.g. obstructive lung diseases, parasitic disease affecting 
the pulmonary system, sickle cell anaemia, left heart disease. 
Case by case 
PD#13.  Added in Protocol Version Final 2.0: 
Case by case 


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No. 
Exclusion Criteria Deviation 
Major/ 
Minor/ 
Case by 
case review 
Obstructive lung disease: Forced Expiratory Volume in 1 second/Forced 
Vital Capacity (FEV1/FVC) < 60% and FEV1 < 60% of predicted value 
after bronchodilator administration. 
PD#14. 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. 
 
Added in Protocol Version Final 2.0: 
Restrictive lung disease: Total Lung Capacity (TLC) < 70% of predicted 
value. 
Case by case 
PD#15. History of moderate to severe hepatic impairment (Child-Pugh B and C). 
Case by case 
PD#16. Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 
(measured at V1). 
Case by case 
PD#17. 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. 
Case by case 
PD#18. Current or previous (within the past year) alcohol or substance abuse 
excluding caffeine or nicotine. 
Minor 
PD#19. 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. 
Case by case 
PD#20. 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. 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, 
Minor 


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No. 
Exclusion Criteria Deviation 
Major/ 
Minor/ 
Case by 
case review 
intrauterine hormone-releasing system); partner’s use of implantable 
intrauterine device; surgical sterilisation (for example, vasectomy or 
bilateral tubal occlusion). 
 
Protocol Version Final 2.0: 
For women: Pregnancy or breast-feeding. Women of childbearing potential 
unable or unwilling to undergo pregnancy tests and practice acceptable 
contraceptive measures from the time of informed consent until 30 days 
after last IMP intake. Acceptable methods for women are surgical 
intervention (e.g. bilateral tubal occlusion), non-hormonal implantable 
intrauterine device, double-barrier methods, true sexual abstinence (i.e. 
when this is in line with the preferred and usual lifestyle of the patient) and 
vasectomised partner (provided that the partner is the sole sexual partner of 
the patient and the partner has received medical assessment of the surgical 
success). Periodic abstinence (e.g., calendar, ovulation, symptothermal, 
post-ovulation methods), hormonal contraceptives and withdrawal are not 
acceptable methods of contraception. 
For men: Male patients who are sexually active with a partner of 
childbearing potential must use, with their partner, a condom plus an 
approved acceptable contraceptive measure from the time of informed 
consent until 90 days after the last IMP intake. The following methods are 
acceptable methods of contraception: partner’s use of combined (oestrogen 
and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation (oral, intravaginal, transdermal); partner’s use of 
progestogen-only hormonal contraception (oral, injectable/implantable, 
intrauterine hormone-releasing system); partner’s use of implantable 
intrauterine device; surgical sterilisation (for example, vasectomy or 
bilateral tubal occlusion). 
 
Protocol Version Final 1.0: 
For women: Pregnancy or breast-feeding. Women of childbearing potential 
unable or unwilling to undergo pregnancy tests and practice acceptable 
contraceptive measures. Acceptable methods for women are surgical 
intervention (e.g. bilateral tubal occlusion), intrauterine device, double-
barrier methods and true sexual abstinence (i.e. when this is in line with the 
preferred and usual lifestyle of the patient). Periodic abstinence (e.g., 
calendar, ovulation, symptothermal, post-ovulation methods) and 
withdrawal are not acceptable methods of contraception.  
PD#21. 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. 
Case by case 
PD#22. Vulnerable patients according to Section 1.61 of the ICH guideline for 
Good Clinical Practice E6 
Minor 
 


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Additional Study Conduct Deviations 
No. 
Deviation 
Major/ 
Minor/ 
Case by 
case review 
PD#23.  Down-titration dose not according to the protocol. 
Case by 
case 
PD#24.  Up-titration safety criteria deviations 
Minor 
PD#25.  IMP compliance <90% or >110% by period or overall 
Case by 
case 
PD#26.  Schedule deviations of visits with scheduled IMP dispensations 
Case by 
case 
PD#27.  Time deviations of scheduled assessments (ECG, Vital signs, blood 
withdrawal for PK/PD) at A1 and MPV3 
Case by 
case 
PD#28.  Deviations in sequences of assessments/tests/procedures 
Minor 
PD#29.  Prohibited medications/therapies 
Case by 
case 
PD#30.  Adverse events with possible impact on primary endpoint. 
Case by 
case 
PD#31.  Missing/incomplete blood withdrawal for PK, blood and urinalysis 
sampling for PD 
Case by 
case 
PD#32.  Missing/incomplete test/examination assessments: 
vital signs, physical measurements, NYHA/WHO functional class, 
laboratory tests, physical examination, ECG, number of digital scars, 
modified Rodnan Skin Score, SF-36v2, 6-min walk test, echocardiography, 
right heart catheterisation, blood withdrawal biomarker 
Minor 
PD#33.  Protocol deviations documented by CRAs and selected by medical 
monitors for discussion during DR 
Case by 
case 
Reference listings will be made available to help with the review of the protocol deviations. The specific 
content and format of listings to be reviewed during the DR meeting (including any additional 
requirements that may be necessary to aid in review) will be determined outside the scope of this SAP. 
7 
INTERIM ANALYSIS 
No interim analysis is planned for this study. 


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8 
CHANGES TO THE ANALYSIS AS LAID DOWN IN THE PROTOCOL AND 
AMENDMENTS 
No changes to the analysis as laid down in the clinical study protocol and protocol amendment(s) were 
made. 


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Effective date: 15.09.2020 
9 
REFERENCES 
 
1. SAS® Institute Inc., Cary, North Carolina, United States of America, Version 9.4. 
2. MedDRA – Medical Dictionary for Regulated Activities. International Federation of 
Pharmaceutical Manufacturers Associations (IFPMA), c/o TRW, VAR1/8A/MSSO, 12011 
Sunset Hills Road, Reston, VA 20190-3285, USA, Version 22.0, 1 March 2019. 
3. WHODrug Global dictionary. World Health Organization Collaborating Center for 
International Drug Monitoring, P.O. Box 26, S-751 03 Uppsala, Sweden, version 2019, 
March. 
4. Optum, Inc 1301 Atwood Avenue, Suite 311 N Johnston, R.I. 02919, U.S.A, Pro Core 
Version 1.4 


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Effective date: 15.09.2020 
10 APPENDICES 
The following documents are attached as appendices to the SAP: 
1. 0223_TableShells_1.0_20220322.docx 
2. 0223_ListingShells_1.0_20220322.docx 
3. 0223_FigureShells_1.0_20220322.docx 
4. QSC202579 (BIA-51058-201) RAP_20Feb2020_Finalv1.0.pdf 
10.1 Tables 
Appendix tables defined below will be provided in separate .rtf files for each output. 
No 
Table Identifier, Title 
Output file 
Demographic and Study Population Data 
1 
Table 15.1.1.1 Analysis Sets – Enrolled Set   
BIA-T-150101010000-anlset-enr.rtf 
2 
Table 15.1.1.2 Reasons for Exclusion from Analysis 
Sets – Safety Set   
BIA-T-150101020000-reas-excl-ss.rtf 
3 
Table 15.1.2 Screening Failures – Enrolled Set   
BIA-T-150102000000-scrfail-enr.rtf 
4 
Table 15.1.3 Major Protocol Deviations – Safety Set 
BIA-T-150103000000-protdev-ss.rtf 
5 
Table 15.1.4 Patient Disposition – Safety Set 
BIA-T-150104000000-disp-ss.rtf 
6 
Table 15.1.5.1.1 Number of Patients by Country and 
Site – Enrolled Set 
BIA-T-150105010100-countrysite-enr.rtf 
7 
Table 15.1.5.1.2 Number of Patients by Country and 
Site – Safety Set 
BIA-T-150105010200-countrysite-ss.rtf 
8 
Table 15.1.5.2 Number of Patients by Visit – Safety 
Set 
BIA-T-150105020000-visits-ss.rtf 
9 
Table 15.1.6.1.1 Demographics – Safety Set 
BIA-T-150106010100-dm-ss.rtf 
10 
Table 15.1.6.1.2 Demographics – Full Analysis Set 
BIA-T-150106010200-dm-fas.rtf 
11 
Table 15.1.6.1.3 Demographics – Pharmacokinetic 
Analysis Set 
BIA-T-150106010300-dm-pks.rtf 
12 
Table 15.1.6.2.1 Baseline Characteristics – Safety Set 
BIA-T-150106020100-basechar-ss.rtf 
13 
Table 15.1.6.2.2 Baseline Physical Characteristics – 
Full Analysis Set 
BIA-T-150106020200-basechar-fas.rtf 
14 
Table 15.1.6.2.3 Baseline Physical Characteristics – 
Pharmacokinetic Analysis Set 
BIA-T-150106020300-basechar-pks.rtf 
15 
Table 15.1.6.3.1 Disease Characteristics – Safety Set 
BIA-T-150106030100-diseasechar-ss.rtf 
16 
Table 15.1.6.3.2 Disease Characteristics – Full 
Analysis Set 
BIA-T-150106030200-diseasechar-fas.rtf 
17 
Table 15.1.6.3.3 Disease Characteristics – 
Pharmacokinetic Analysis Set 
BIA-T-150106030300-diseasechar-pks.rtf 
18 
Table 15.1.7.1.1 Prior Medical Conditions – Safety Set 
BIA-T-150107010100-mh-prior-ss.rtf 
19 
Table 15.1.7.1.2 Prior Medical Conditions – Full 
Analysis Set 
BIA-T-150107010200-mh-prior-fas.rtf 
20 
Table 15.1.7.1.3 Prior Medical Conditions – 
Pharmacokinetic Analysis Set 
BIA-T-150107010300-mh-prior-pks.rtf 
21 
Table 15.1.7.2.1 Ongoing Medical Conditions – Safety 
Set 
BIA-T-150107020100-mh-ongoing-ss.rtf 
22 
Table 15.1.7.2.2 Ongoing Medical Conditions – Full 
Analysis Set 
BIA-T-150107020200-mh-ongoing-fas.rtf 
23 
Table 15.1.7.2.3 Ongoing Medical Conditions – 
Pharmacokinetic Analysis Set 
BIA-T-150107020300-mh-ongoing-pks.rtf 
24 
Table 15.1.8.1.1 Prior Medications – Safety Set 
BIA-T-150108010100-priormed-ss.rtf 
25 
Table 15.1.8.1.2 Prior Medications – Full Analysis Set 
BIA-T-150108010200-priormed-fas.rtf 
26 
Table 15.1.8.1.3 Prior Medications – Pharmacokinetic 
Analysis Set 
BIA-T-150108010300-priormed-pks.rtf 
27 
Table 15.1.8.2.1 Concomitant Medications – Safety Set 
BIA-T-150108020100-conmed-ss.rtf 


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28 
Table 15.1.8.2.2 Concomitant Medications – Full 
Analysis Set 
BIA-T-150108020200-conmed-fas.rtf 
29 
Table 15.1.8.2.3 Concomitant Medications – 
Pharmacokinetic Analysis Set 
BIA-T-150108020300-conmed-pks.rtf 
30 
Table 15.1.8.3.1 Prior PAH Medications – Safety Set 
BIA-T-150108030100-priormed-pah-ss.rtf 
31 
Table 15.1.8.3.2 Prior PAH Medications – Full 
Analysis Set 
BIA-T-150108030200-priormed-pah-fas.rtf 
32 
Table 15.1.8.3.3 Prior PAH Medications – 
Pharmacokinetic Analysis Set 
BIA-T-150108030300-priormed-pah-pks.rtf 
33 
Table 15.1.8.4.1 Concomitant PAH Medications – 
Safety Set 
BIA-T-150108040100-conmed-pah-ss.rtf 
34 
Table 15.1.8.4.2 Concomitant PAH Medications – Full 
Analysis Set 
BIA-T-150108040200-conmed-pah-fas.rtf 
35 
Table 15.1.8.4.3 Concomitant PAH Medications – 
Pharmacokinetic Analysis Set 
BIA-T-150108040300-conmed-pah-pks.rtf 
36 
Table 15.1.8.5.1 PAH-Approved Therapy by Visit – 
Safety Set 
BIA-T-150108050100-pahappr-byvis-ss.rtf 
37 
Table 15.1.8.5.2 PAH-Approved Therapy by Visit – 
Full Analysis Set 
BIA-T-150108050200-pahappr-byvis-fas.rtf 
38 
Table 15.1.8.5.3 PAH-Approved Therapy by Visit – 
Pharmacokinetic Analysis Set 
BIA-T-150108050300-pahappr-byvis-
pks.rtf 
39 
Table 15.1.9.1.1 Treatment Duration (days) – Safety 
Set  
BIA-T-150109010100-trtdur-ss.rtf 
40 
Table 15.1.9.1.2 Treatment Duration (days) – Full 
Analysis Set 
BIA-T-150109010200-trtdur-fas.rtf 
41 
Table 15.1.9.1.3 Treatment Duration (days) – 
Pharmacokinetic Analysis Set 
BIA-T-150109010300-trtdur-pks.rtf 
42 
Table 15.1.9.2.1 Compliance (%) – Safety Set 
BIA-T-150109020100-compl-ss.rtf 
43 
Table 15.1.9.2.2 Compliance (%) – Full Analysis Set 
BIA-T-150109020200-compl-fas.rtf 
44 
Table 15.1.9.2.3 Compliance (%) – Pharmacokinetic 
Analysis Set 
BIA-T-150109020300-compl-pks.rtf 
Efficacy Data 
45 
Table 15.2.1.1.1 Summary of Right Heart 
Catheterisation Parameters by HTD – Full Analysis Set 
BIA-T-150201010100-rhc-htd-fas.rtf 
46 
Table 15.2.1.1.2 Summary of Right Heart 
Catheterization Parameters – Full Analysis Set  
BIA-T-150201010200-rhc-tot-fas.rtf 
47 
Table 15.2.1.1.3 Summary of Right Heart 
Catheterisation Parameters by HTD – Modified Full 
Analysis Set 
BIA-T-150201010300-rhc-htd-mfas.rtf 
48 
Table 15.2.1.1.4 Summary of Right Heart 
Catheterization Parameters – Modified Full Analysis 
Set 
BIA-T-150201010400-rhc-tot-mfas.rtf 
49 
Table 15.2.1.1.5 Summary of Right Heart 
Catheterization Parameters – Modified Full Analysis 
Set (TAPSE Subgroups) 
BIA-T-150201010500-rhc-tapse-mfas.rtf 
50 
Table 15.2.1.2.1 Incidence of Right Heart 
Catheterisation Abnormalities – Full Analysis Set 
BIA-T-150201020100-rhc-abnorm-fas.rtf 
51 
Table 15.2.1.2.2 Incidence of Right Heart 
Catheterisation Abnormalities – Modified Full 
Analysis Set 
BIA-T-150201020200-rhc-abnorm-mfas.rtf 
52 
Table 15.2.1.3.1 Shift Table of Right Heart 
Catheterisation Results – Full Analysis Set 
BIA-T-150201030100-rhc-shift-fas.rtf 
53 
Table 15.2.1.3.2 Shift Table of Right Heart 
Catheterisation Results – Modified Full Analysis Set 
BIA-T-150201030200-rhc-shift-mfas.rtf 
54 
Table 15.2.2.1 Summary of 6-MWT by HTD – Full 
Analysis Set 
BIA-T-150202010000-6mwt-htd-fas.rtf 
55 
Table 15.2.2.2 Summary of 6-MWT – Full Analysis 
Set 
BIA-T-150202020000-6mwt-tot-fas.rtf 
56 
Table 15.2.2.3 Summary of 6-MWT by HTD – 
Modified Full Analysis Set 
BIA-T-150202030000-6mwt-htd-mfas.rtf 
57 
Table 15.2.2.4 Summary of 6-MWT – Modified Full 
Analysis Set 
BIA-T-150202040000-6mwt-tot-mfas.rtf 


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58 
Table 15.2.2.5 Summary of 6-MWT Distance – 
Modified Full Analysis Set (TAPSE Subgroups) 
BIA-T-150202050000-6mwt-tapse-mfas.rtf 
59 
Table 15.2.3.1.1 Summary of Biomarker NT-proBNP 
(ng/L) by HTD – Full Analysis Set 
BIA-T-150203010100-biomarker-htd-fas.rtf 
60 
Table 15.2.3.1.2 Summary of Biomarker NT-proBNP 
(ng/L) – Full Analysis Set 
BIA-T-150203010200-biomarker-tot-fas.rtf 
61 
Table 15.2.3.1.3 Summary of Biomarker NT-proBNP 
(ng/L) by HTD – Modified Full Analysis Set 
BIA-T-150203010300-biomarker-htd-
mfas.rtf 
62 
Table 15.2.3.1.4 Summary of Biomarker NT-proBNP 
(ng/L) – Modified Full Analysis Set 
BIA-T-150203010400-biomarker-tot-
mfas.rtf 
63 
Table 15.2.3.2.1 Summary of Biomarker NT-proBNP 
(ng/L) by Pooled HTD –Full Analysis Set 
BIA-T-150203020100-biomarker-htdpool-
fas.rtf 
64 
Table 15.2.3.2.2 Summary of Biomarker NT-proBNP 
(ng/L) by Pooled HTD – Modified Full Analysis Set 
BIA-T-150203020200-biomarker-htdpool-
mfas.rtf 
65 
Table 15.2.4.1.1 Summary of Categorical 
Echocardiography Parameters– Full Analysis Set 
BIA-T-150204010100-echo-cat-fas.rtf 
66 
Table 15.2.4.1.2 Summary of Categorical 
Echocardiography Parameters – Modified Full 
Analysis Set 
BIA-T-150204010200-echo-cat-mfas.rtf 
67 
Table 15.2.4.2.1 Summary of Numerical 
Echocardiography Parameters by HTD – Full Analysis 
Set 
BIA-T-150204020100-echo-num-htd-fas.rtf 
68 
Table 15.2.4.2.2 Summary of Numerical 
Echocardiography Parameters – Full Analysis Set  
BIA-T-150204020200-echo-num-tot-fas.rtf 
69 
Table 15.2.4.2.3 Summary of Numerical 
Echocardiography Parameters by HTD – Modified Full 
Analysis Set 
BIA-T-150204020300-echo-num-htd-
mfas.rtf 
70 
Table 15.2.4.2.4 Summary of Numerical 
Echocardiography Parameters – Modified Full 
Analysis Set 
BIA-T-150204020400-echo-num-tot-
mfas.rtf 
71 
Table 15.2.4.2.5 Summary of Numerical 
Echocardiography Parameters – Modified Full 
Analysis Set (TAPSE Subgroups) 
BIA-T-150204020500-echo-num-tapse-
mfas.rtf 
72 
Table 15.2.4.3.1 Incidence of Echocardiography 
Abnormalities – Full Analysis Set 
BIA-T-150204030100-echo-abnorm-fas.rtf 
73 
Table 15.2.4.3.2 Incidence of Echocardiography 
Abnormalities – Modified Full Analysis Set 
BIA-T-150204030200-echo-abnorm-
mfas.rtf 
74 
Table 15.2.4.4.1 Shift Table of Echocardiography 
Results – Full Analysis Set 
BIA-T-150204040100-echo-shift-fas.rtf 
75 
Table 15.2.4.4.2 Shift Table of Echocardiography 
Results – Modified Full Analysis Set 
BIA-T-150204040200-echo-shift-mfas.rtf 
76 
Table 15.2.5.1.1 Summary of NYHA/WHO Functional 
Class – Full Analysis Set 
BIA-T-150205010100-whofc-fas.rtf 
77 
Table 15.2.5.1.2 Summary of NYHA/WHO Functional 
Class – Modified Full Analysis Set 
BIA-T-150205010200-whofc-mfas.rtf 
78 
Table 15.2.5.2.1 Shift Table of NYHA/WHO 
Functional Class – Full Analysis Set 
BIA-T-150205020100-whofc-shift-fas.rtf 
79 
Table 15.2.5.2.2 Shift Table of NYHA/WHO 
Functional Class – Modified Full Analysis Set 
BIA-T-150205020200-whofc-shift-mfas.rtf 
80 
Table 15.2.6.1.1 Summary of SF-36v2 Domain Scores 
by HTD – Full Analysis Set 
BIA-T-150206010100-sf36-htd-fas.rtf 
81 
Table 15.2.6.1.2 Summary of SF-36v2 Domain Scores 
– Full Analysis Set 
BIA-T-150206010200-sf36-tot-fas.rtf 
82 
Table 15.2.6.1.3 Summary of SF-36v2 Domain Scores 
by HTD – Modified Full Analysis Set 
BIA-T-150206010300-sf36-htd-mfas.rtf 
83 
Table 15.2.6.1.4 Summary of SF-36v2 Domain Scores 
– Modified Full Analysis Set 
BIA-T-150206010400-sf36-tot-mfas.rtf 
84 
Table 15.2.6.2.1 Summary of Norm-Based SF-36v2 
Scores by HTD – Full Analysis Set 
BIA-T-150206020100-sf36-norm-htd-fas.rtf 
85 
Table 15.2.6.2.2 Summary of Norm-Based SF-36v2 
Scores – Full Analysis Set 
BIA-T-150206020200-sf36-norm-tot-fas.rtf 
86 
Table 15.2.6.2.3 Summary of Norm-Based SF-36v2 
Domain Scores by HTD – Modified Full Analysis Set 
BIA-T-150206020300-sf36-norm-htd-
mfas.rtf 
87 
Table 15.2.6.2.4 Summary of Norm-Based SF-36v2 
Domain Scores – Modified Full Analysis Set 
BIA-T-150206020400-sf36-norm-tot-
mfas.rtf 


Sponsor: Bial - Portela & Ca, S.A.  
Protocol no. BIA-51058-201 
Statistical Analysis Plan, Version Final 1.0  
22-MAR-2022 
 
I-DM-011SAP 
Page 54 of 59 
Effective date: 15.09.2020 
88 
Table 15.2.6.3.1 Summary of SF-36v2 Utility Index 
Scores by HTD – Full Analysis Set 
BIA-T-150206030100-sf36-util-htd-fas.rtf 
89 
Table 15.2.6.3.2 Summary of SF-36v2 Utility Index 
Scores – Full Analysis Set 
BIA-T-150206030200-sf36-util-tot-fas.rtf 
90 
Table 15.2.6.3.3 Summary of SF-36v2 Utility Index 
Scores by HTD – Modified Full Analysis Set 
BIA-T-150206030300-sf36-util-htd-mfas.rtf 
91 
Table 15.2.6.3.4 Summary of SF-36v2 Utility Index 
Scores – Modified Full Analysis Set 
BIA-T-150206030400-sf36-util-tot-mfas.rtf 
92 
Table 15.2.6.4.1 Summary of SF-36v2 Cardio 
Benchmark Interpretation – Full Analysis Set 
BIA-T-150206040100-sf36-cardio-fas.rtf 
93 
Table 15.2.6.4.2 Summary of SF-36v2 Cardio 
Benchmark Interpretation – Modified Full Analysis Set 
BIA-T-150206040200-sf36-cardio-mfas.rtf 
94 
Table 15.2.6.5.1 Shift Table of SF-36v2 Cardio 
Benchmark Interpretation – Full Analysis Set 
BIA-T-150206050100-sf36-cardio-shift-
fas.rtf 
95 
Table 15.2.6.5.2 Shift Table of SF-36v2 Cardio 
Benchmark Interpretation – Modified Full Analysis Set 
BIA-T-150206050200-sf36-cardio-shift-
mfas.rtf 
Safety Data 
96 
Table 15.3.1.1 Overall Summary of TEAEs – Safety 
Set 
BIA-T-150301010000-teae-sum-ss.rtf 
97 
Table 15.3.1.2 Incidence of TEAEs – Safety Set 
BIA-T-150301020000-teae-ss.rtf 
98 
Table 15.3.1.3 Incidence of Serious TEAEs – Safety 
Set 
BIA-T-150301030000-tesae-ss.rtf 
99 
Table 15.3.1.4 Incidence of TEAEs of Special Interest 
– Safety Set 
BIA-T-150301040000-teae-si-ss.rtf 
100 
Table 15.3.1.5 Incidence of Related TEAEs – Safety 
Set 
BIA-T-150301050000-teae-rel-ss.rtf 
101 
Table 15.3.1.6 Incidence of Related Serious TEAEs – 
Safety Set 
BIA-T-150301060000-tesae-rel-ss.rtf 
102 
Table 15.3.1.7 Incidence of TEAEs Leading to Down-
Titration – Safety Set 
BIA-T-150301070000-teae-dt-ss.rtf 
103 
Table 15.3.1.8 Incidence of TEAEs Leading to 
Discontinuation – Safety Set 
BIA-T-150301080000-teae-disc-ss.rtf 
104 
Table 15.3.1.9 Incidence of TEAEs Leading to Death – 
Safety Set 
BIA-T-150301090000-teae-death-ss.rtf 
105 
Table 15.3.1.10 Incidence of TEAEs by Severity – 
Safety Set 
BIA-T-150301100000-teae-bysev-ss.rtf 
106 
Table 15.3.1.11 Incidence of TEAEs by Relationship 
to IMP – Safety Set 
BIA-T-150301110000-teae-byrel-ss.rtf 
107 
Table 15.3.2.1.1.1 Summary of Clinical Laboratory 
Tests: Haematology by HTD– Safety Set 
BIA-T-150302010101-lbh-htd-ss.rtf 
108 
Table 15.3.2.1.1.2 Summary of Clinical Laboratory 
Tests: Haematology– Safety Set 
BIA-T-150302010102-lbh-tot-ss.rtf 
109 
Table 15.3.2.1.2.1 Summary of Clinical Laboratory 
Tests: Biochemistry by HTD – Safety Set 
BIA-T-150302010201-lbb-htd-ss.rtf 
110 
Table 15.3.2.1.2.2 Summary of Clinical Laboratory 
Tests: Biochemistry – Safety Set 
BIA-T-150302010202-lbb-tot-ss.rtf 
111 
SetTable 15.3.2.1.3.1 Summary of Clinical Laboratory 
Tests: Coagulation by HTD – Safety Set 
BIA-T-150302010301-lbco-htd-ss.rtf 
112 
Table 15.3.2.1.3.2 Summary of Clinical Laboratory 
Tests: Coagulation – Safety Set 
BIA-T-150302010302-lbco-tot-ss.rtf 
113 
Table 15.3.2.1.4 Summary of Clinical Laboratory 
Tests: Urinalysis – Safety Set 
BIA-T-150302010400-lbu-ss.rtf 
114 
Table 15.3.2.2.1 Clinical Laboratory Tests: Incidence 
of Haematology Abnormalities – Safety Set 
BIA-T-150302020100-lbh-abnorm-ss.rtf 
115 
Table 15.3.2.2.2 Clinical Laboratory Tests: Incidence 
of Biochemistry Abnormalities – Safety Set 
BIA-T-150302020200-lbb-abnorm-ss.rtf 
116 
Table 15.3.2.2.3 Clinical Laboratory Tests: Incidence 
of Coagulation Abnormalities – Safety Set 
BIA-T-150302020300-lbco-abnorm-ss.rtf 
117 
Table 15.3.2.2.4 Clinical Laboratory Tests: Incidence 
of Urinalysis Abnormalities – Safety Set 
BIA-T-150302020400-lbu-abnorm-ss.rtf 
118 
Table 15.3.2.3.1 Clinical Laboratory Tests: Shift Table 
of Haematology Results – Safety Set 
BIA-T-150302030100-lbh-shift-ss.rtf 
119 
Table 15.3.2.3.2 Clinical Laboratory Tests: Shift Table 
of Biochemistry Results – Safety Set 
BIA-T-150302030200-lbb-shift-ss.rtf 


Sponsor: Bial - Portela & Ca, S.A.  
Protocol no. BIA-51058-201 
Statistical Analysis Plan, Version Final 1.0  
22-MAR-2022 
 
I-DM-011SAP 
Page 55 of 59 
Effective date: 15.09.2020 
120 
Table 15.3.2.3.3 Clinical Laboratory Tests: Shift Table 
of Coagulation Results – Safety Set 
BIA-T-150302030300-lbco-shift-ss.rtf 
121 
Table 15.3.2.3.4 Clinical Laboratory Tests: Shift Table 
of Urinalysis Results – Safety Set 
BIA-T-150302030400-lbu-shift-ss.rtf 
122 
Table 15.3.3.1.1 Summary of Arterial Blood Gas 
Analysis by HTD– Safety Set 
BIA-T-150303010100-artbg-htd-ss.rtf 
123 
Table 15.3.3.1.2 Summary of Arterial Blood Gas 
Analysis – Safety Set 
BIA-T-150303010200-artbg-tot-ss.rtf 
124 
Table 15.3.3.2 Incidence of Arterial Blood Gas 
Analysis Abnormalities – Safety Set 
BIA-T-150303020000-artbg-abnorm-ss.rtf 
125 
Table 15.3.3.3 Shift Table of Arterial Blood Gas 
Analysis Results – Safety Set 
BIA-T-150303030000-artbg-shift-ss.rtf 
126 
Table 15.3.3.4.1 Summary of Peripheral Oxygen 
Saturation (%) by HTD– Safety Set 
BIA-T-150303040100-po2-htd-ss.rtf 
127 
Table 15.3.3.4.2 Summary of Peripheral Oxygen 
Saturation (%) – Safety Set 
BIA-T-150303040200-po2-tot-ss.rtf 
128 
Table 15.3.4.1.1 Summary of Vital Signs by HTD – 
Safety Set 
BIA-T-150304010100-vs-htd-ss.rtf 
129 
Table 15.3.4.1.2 Summary of Vital Signs – Safety Set 
BIA-T-150304010200-vs-tot-ss.rtf 
130 
Table 15.3.4.2 Summary of Vital Signs by Pooled 
HTD – Safety Set 
BIA-T-150304020000-vs-htdpool-ss.rtf 
131 
Table 15.3.4.3.1 Summary of Short-Term IMP Effect 
on Vital Signs by HTD – Safety Set 
BIA-T-150304030100-vs-visitchg-htd-ss.rtf 
132 
Table 15.3.4.3.2 Summary of Short-Term IMP Effect 
on Vital Signs – Safety Set 
BIA-T-150304030200-vs-visitchg-tot-ss.rtf 
133 
Table 15.3.4.4.1 Summary of Change in Short-Term 
IMP Effect on Vital Signs by HTD – Safety Set 
BIA-T-150304040100-vs-effchg-htd-ss.rtf 
134 
Table 15.3.4.4.2 Summary of Change in Short-Term 
IMP Effect on Vital Signs – Safety Set 
BIA-T-150304040200-vs-effchg-tot-ss.rtf 
135 
Table 15.3.4.5.1 Summary of Physical Measurements 
by HTD – Safety Set 
BIA-T-150304050100-physmeas-htd-ss.rtf 
136 
Table 15.3.4.5.2 Summary of Physical Measurements – 
Safety Set 
BIA-T-150304050200-physmeas-tot-ss.rtf 
137 
Table 15.3.5.1.1 Summary of ECG Assessments by 
HTD – Safety Set 
BIA-T-150305010100-ecg-htd-ss.rtf 
138 
Table 15.3.5.1.2 Summary of ECG Assessments – 
Safety Set 
BIA-T-150305010200-ecg-tot-ss.rtf 
139 
Table 15.3.5.2.1 Summary of Short-Term IMP Effect 
on ECG Assessments by HTD – Safety Set 
BIA-T-150305020100-ecg-visitchg-htd-
ss.rtf 
140 
Table 15.3.5.2.2 Summary of Short-Term IMP Effect 
on ECG Assessments – Safety Set 
BIA-T-150305020200-ecg-visitchg-tot-
ss.rtf 
141 
Table 15.3.5.3.1 Summary of Change in Short-Term 
IMP Effect on ECG Assessements by HTD – Safety 
Set 
BIA-T-150305030100-ecg-effchg-htd-ss.rtf 
142 
Table 15.3.5.3.2 Summary of Change in Short-Term 
IMP Effect on ECG Assessements – Safety Set 
BIA-T-150305030200-ecg-effchg-tot-ss.rtf 
143 
Table 15.3.5.4.1 Incidence of ECG Abnormalities – 
Safety Set 
BIA-T-150305040100-ecg-abnorm-ss.rtf 
144 
Table 15.3.5.4.2 Shift Table of ECG Abnormalities – 
Safety Set 
BIA-T-150305040200-ecg-shift-ss.rtf 
145 
Table 15.3.5.4.3 Shift Table of Within-Visit ECG 
Abnormalities – Safety Set 
BIA-T-150305040300-ecg-shift-visit-ss.rtf 
146 
Table 15.3.6 Summary of Physical Examination 
Findings – Safety Set 
BIA-T-150306000000-pe-ss.rtf 
147 
Table 15.3.7.1 Summary of Scleroderma Scarring by 
HTD – Safety Set 
BIA-T-150307010000-sclero-htd-ss.rtf 
148 
Table 15.3.7.2 Summary of Scleroderma Scarring – 
Safety Set 
BIA-T-150307020000-sclero-tot-ss.rtf 
149 
Table 15.3.8.1 Summary of mRSS by HTD – Safety 
Set 
BIA-T-150308010000-mrss-htd-ss.rtf 
150 
Table 15.3.8.2 Summary of mRSS – Safety Set 
BIA-T-150308020000-mrss-tot-ss.rtf 
 


Sponsor: Bial - Portela & Ca, S.A.  
Protocol no. BIA-51058-201 
Statistical Analysis Plan, Version Final 1.0  
22-MAR-2022 
 
I-DM-011SAP 
Page 56 of 59 
Effective date: 15.09.2020 
10.2 Listings 
Appendix listings defined below will be provided to the sponsor in separate .rtf files for each output.  
No 
Listing Identifier, Title 
Output file 
Demographic and Study Population Data 
1 
Listing 16.2.1.1.1 Patient Disposition – Safety Set   
BIA-L-1602010101-disp-ss.rtf 
2 
Listing 16.2.1.1.2 Screening Failures – Enrolled Set   
BIA-L-1602010102-scrfail-enr.rtf 
3 
Listing 16.2.1.2 Patient Visits – Enrolled Set   
BIA-L-1602010200-visits-enr.rtf 
4 
Listing 16.2.1.3.1 Major Protocol Deviations – Safety 
Set   
BIA-L-1602010301-protdev-ss.rtf 
5 
Listing 16.2.1.3.2 Patients Affected by the COVID-19 
Pandemic – Safety Set   
BIA-L-1602010302-protdev-covid-ss.rtf 
6 
Listing 16.2.1.3.3 Inclusion Criteria Not Met and 
Exclusion Criteria Met – Enrolled Set   
BIA-L-1602010303-ie-enr.rtf 
7 
Listing 16.2.1.4 Exclusions from Analysis Sets – 
Enrolled Set   
BIA-L-1602010400-anlset-excl-enr.rtf 
8 
Listing 16.2.1.5 Demographics and Baseline 
Characteristics – Enrolled Set   
BIA-L-1602010500-demo-enr.rtf 
9 
Listing 16.2.1.6 Disease Characteristics – Enrolled Set   
BIA-L-1602010600-diseasechar-enr.rtf 
10 
Listing 16.2.1.7 Medical History – Enrolled Set   
BIA-L-1602010700-mh-enr.rtf 
11 
Listing 16.2.1.8 Medications and Therapies – Enrolled 
Set   
BIA-L-1602010800-conmed-enr.rtf 
12 
Listing 16.2.2.1 Drug Accountability– Safety Set   
BIA-L-1602020100-da-ss.rtf 
13 
Listing 16.2.2.2 Exposure to IMP and Compliance – 
Safety Set   
BIA-L-1602020200-imp-compl-ss.rtf 
Efficacy Data 
14 
Listing 16.2.3.1 Right Heart Catheterization 
Parameters – Enrolled Set   
BIA-L-1602030100-rhc-enr.rtf 
15 
Listing 16.2.3.2 6-Min Walking Test – Enrolled Set   
BIA-L-1602030200-6mwt-enr.rtf 
16 
Listing 16.2.3.3 Biomarker NT-proBNP – Enrolled Set   BIA-L-1602030300-biomarker-enr.rtf 
17 
Listing 16.2.3.4 Echocardiography – Enrolled Set   
BIA-L-1602030400-echo-enr.rtf 
18 
Listing 16.2.3.5 NYHA/WHO Functional Class – 
Enrolled Set   
BIA-L-1602030500-whofc-enr.rtf 
19 
Listing 16.2.3.6 SF-36v2 – Enrolled Set   
BIA-L-1602030600-sf36-enr.rtf 
Safety Data 
20 
Listing 16.2.4.1.1 Adverse Events: MedDRA Coding   
BIA-L-1602040101-aecod.rtf 
21 
Listing 16.2.4.1.2 Adverse Events: General – Enrolled 
Set   
BIA-L-1602040102-ae-enr.rtf 
22 
Listing 16.2.4.1.3 Non-Serious Adverse Events – 
Safety Set   
BIA-L-1602040103-nsae-ss.rtf 
23 
Listing 16.2.4.1.4 Serious Adverse Events – Safety Set   BIA-L-1602040104-sae-ss.rtf 
24 
Listing 16.2.4.1.5 TEAEs of Special Interest - Safety 
Set   
BIA-L-1602040105-teae-si-ss.rtf 
25 
Listing 16.2.4.1.6 AEs Leading to Discontinuation – 
Safety Set   
BIA-L-1602040106-ae-disc-ss.rtf 
26 
Listing 16.2.4.1.7 AEs Leading to Death – Safety Set   
BIA-L-1602040107-ae-death-ss.rtf 
27 
Listing 16.2.4.2.1 Laboratory Data: Haematology – 
Enrolled Set   
BIA-L-1602040201-lbh-enr.rtf 
28 
Listing 16.2.4.2.2 Laboratory Data: Biochemistry – 
Enrolled Set   
BIA-L-1602040202-lbb-enr.rtf 
29 
Listing 16.2.4.2.3 Laboratory Data: Coagulation – 
Enrolled Set   
BIA-L-1602040203-lbco-enr.rtf 
30 
Listing 16.2.4.2.4 Laboratory Data: Urinalysis – 
Enrolled Set   
BIA-L-1602040204-lbu-enr.rtf 


Sponsor: Bial - Portela & Ca, S.A.  
Protocol no. BIA-51058-201 
Statistical Analysis Plan, Version Final 1.0  
22-MAR-2022 
 
I-DM-011SAP 
Page 57 of 59 
Effective date: 15.09.2020 
31 
Listing 16.2.4.2.5 Laboratory Data: Microscopy – 
Enrolled Set 
BIA-L-1602040205-lbmicro-enr.rtf 
32 
Listing 16.2.4.2.6 Laboratory Data: Pregnancy Tests – 
Enrolled Set 
BIA-L-1602040206-lbpreg-enr.rtf 
33 
Listing 16.2.4.3 Arterial Blood Gas Analysis – 
Enrolled Set   
BIA-L-1602040300-artbg-enr.rtf 
34 
Listing 16.2.4.4 Vital Signs – Enrolled Set   
BIA-L-1602040400-vs-enr.rtf 
35 
Listing 16.2.4.5 Electrocardiogram – Enrolled Set   
BIA-L-1602040500-ecg-enr.rtf 
36 
Listing 16.2.4.6 Physical Examinations – Enrolled Set   
BIA-L-1602040600-pe-enr.rtf 
37 
Listing 16.2.4.7 Number of Digital Scars – Enrolled 
Set   
BIA-L-1602040700-scars-enr.rtf 
38 
Listing 16.2.4.8 Modified Rodnan Skin Score – 
Enrolled Set   
BIA-L-1602040800-mrss-enr.rtf 
 
 


Sponsor: Bial - Portela & Ca, S.A.  
Protocol no. BIA-51058-201 
Statistical Analysis Plan, Version Final 1.0  
22-MAR-2022 
 
I-DM-011SAP 
Page 58 of 59 
Effective date: 15.09.2020 
10.3 Figures 
Appendix figures defined below will be provided to the sponsor in separate .rtf files for each output.  
 
No 
Figure Identifier, Title 
Output file 
Demographic and Study Population Data 
1 
Figure 15.1.1 Flow Chart of Patient Disposition – Enrolled Set 
BIA-F-15010100-disp-enr.rtf 
2 
Figure 15.1.2 Flow Chart of Analysis Sets – Enrolled Set   
BIA-F-15010200-anlset-enr.rtf 
Efficacy Data 
3 
Figure 15.2.1.1 Box-Whisker Plot of NT-proBNP by Pooled HTD 
– Full Analysis Set 
BIA-F-15020101-biomarker-htdpool-
fas.rtf 
4 
Figure 15.2.1.2 Box-Whisker Plot of NT-proBNP by Pooled HTD 
– Modified Full Analysis Set 
BIA-F-15020102-biomarker-htdpool-
mfas.rtf 
5 
Figure 15.2.2.1 Norm-Based SF-36v2 Domain Scores by Visit – 
Full Analysis Set 
BIA-F-15020201-sf36-norm-fas.rtf 
6 
Figure 15.2.2.2 Norm-Based SF-36v2 Domain Scores by Visit – 
Modified Full Analysis Set 
BIA-F-15020202-sf36-norm-mfas.rtf 
7 
Figure 15.2.3.1 SF-36v2 Cardio Benchmark Interpretation by 
Visit – Full Analysis Set 
BIA-F-15020301-sf36-cardio-fas.rtf 
8 
Figure 15.2.3.2 SF-36v2 Cardio Benchmark Interpretation by 
Visit – Modified Full Analysis Set 
BIA-F-15020302-sf36-cardio-mfas.rtf 
Safety Data 
9 
Figure 15.3.1 Vital Signs Median Change from Baseline – Safety 
Set 
BIA-F-15030100-vs-med-ss.rtf 
 


Sponsor: Bial - Portela & Ca, S.A.  
Protocol no. BIA-51058-201 
Statistical Analysis Plan, Version Final 1.0  
22-MAR-2022 
 
I-DM-011SAP 
Page 59 of 59 
Effective date: 15.09.2020 
SIGNATURES 
 
 
 
 
_______________________________  ______________________ 
Signature 
 
 
 
 
Date 
Author: 
Lukas Pukys 
Statistician, Scope International AG 
Vilnius, Lithuania 
 
 
 
 
_______________________________  ______________________ 
Signature 
 
 
 
 
Date 
Reviewer: 
Giedrius Vilutis 
Statistician, Scope International AG 
Vilnius, Lithuania 
 
 
 
 
______________________________  
______________________ 
Signature  
 
 
 
 
Date 
Sponsor: 
Ana Santos 
Clinical Operations Manager ($OC2), Bial - Portela & Ca, S.A. 
Coronado, Portugal 
 
 
 
 
______________________________  
______________________ 
Signature  
 
 
 
 
Date 
Sponsor: 
Luís Magalhães 
Head of Clinical Research, Bial - Portela & Ca, S.A. 
Coronado, Portugal 
 
 
 
 
______________________________  
______________________ 
Signature  
 
 
 
 
Date 
Sponsor: 
Guillermo Castilla 
Biostatistician, Bial - Portela & Ca, S.A. 
Coronado, Portugal