Open-label, Individual Dose Titration Study to Evaluate Safety, Tolerability and Pharmacokinetics of Riociguat in Children From 6 to Less Than 18 Years of Age With Pulmonary Arterial Hypertension (PAH)
Phase: PHASE3
Conditions: Hypertension, Pulmonary
Sponsor: Bayer

 
Document Type: Study Protocol 
Official Title: 
Open-label, individual dose titration study to evaluate safety, 
tolerability and pharmacokinetics of riociguat in children from 6 
to less than 18 years of age with pulmonary arterial hypertension 
(PAH) 
NCT Number: 
NCT02562235 
Document Date: 
20-JUL-2020 
 
 

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Cover Page of Integrated Study Protocol
Open-label, individual dose titration study to evaluate safety, tolerability and 
pharmacokinetics of riociguat in children from 6 to less than 18 years of age with 
pulmonary arterial hypertension (PAH)
This protocol version is an integration of the following documents / sections:

Original protocol, Version 1.0, dated 13 MAR 2015

Amendment 03 (global amendment described in Section 17.1) forming integrated 
protocol Version 2.0, dated 24 NOV 2015

Amendment 05 (global amendment described in Section 17.2) forming integrated 
protocol Version 3.0, dated 31 MAY 2016

Amendment 06 (global amendment described in Section 17.3) forming integrated 
protocol Version 4.0, dated 9 JAN 2017

Amendment 09 (global amendment described in Section 17.4) forming integrated 
protocol Version 5.0, dated 13 MAR 2018

Amendment 12 (global amendment described in Section 17.5) forming integrated 
protocol Version 6.0, dated 23 AUG 2019

Amendment 14 (global amendment described in Section 17.6) forming integrated 
protocol Version 7.0, dated 20 JUL 2020
Amendments not included in the consecutive numbering of amendments are local 
amendments not forming part of this integrated global protocol.

Amendment 01 dated 25 AUG 2015 (local amendment valid for UK only)

Amendment 02 dated 3 NOV 2015 (local amendment valid for Poland only)

Amendment 04 dated 8 MAR 2016 (local amendment valid for Japan only)

Amendment 07 dated 7 MAR 2017 (local amendment valid for Japan only)

Amendment 08 dated 3 NOV 2017 (local amendment valid for Germany only)

Amendment 10 dated 29 MAY 2018 (local amendment valid for Taiwan only)

Amendment 11 dated 05 APR 2019 (local amendment valid for Romania only)

Amendment 13 dated 17 OCT 2019 (local amendment valid for Germany only)
This document integrates the original protocol and all global amendments.

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Title page - amended
Open-label, individual dose titration study to evaluate safety, tolerability and 
pharmacokinetics of riociguat in children from 6 to less than 18 years of age with 
pulmonary arterial hypertension (PAH)
Riociguat in children with PAH
PATENT-CHILD
Test drug:
BAY 63-2521 / Riociguat
Study purpose:
Safety
Clinical study phase:
3
Date:
20 JUL 2020
Registration:
EudraCT: 2014-003952-29
Version no.:
7.0
Sponsor’s study no.:
BAY 63-2521 / 15681
Sponsor:
(Note: Sponsor info was 
updated according to 
Amendment 6, see Section 
17.3.1.10.)
Bayer AG, D-51368 Leverkusen, Germany
US territory: Bayer HealthCare Pharmaceuticals Inc., 100 
Bayer Boulevard, P.O. Box 915, Whippany NJ
07981-0915, USA
Sponsor’s medical expert:
(Note: Study medical expert 
was changed according to 
Amendment 3, see section 
17.1.1.16. The contact details 
were updated according to 
Amendment 5, see Section 
17.2.1.8. Study medical expert 
was changed according to 
Amendment 9, see Section 
17.4.1.13. Study medical expert 
was changed according to 
Amendment 14, see Section
17.6. )
 
Bayer U.S. LLC
Pharmaceuticals, Pharmaceuticals
Study Medical Experts
100 Bayer Boulevard
Whippany NJ  07981
United States
Tel:  
Cell: 
The study will be conducted in compliance with the protocol, ICH-GCP and any applicable 
regulatory requirements.
Confidential
The information provided in this document is strictly confidential and is intended solely for 
the guidance of the clinical investigation.  Reproduction or disclosure of this 
document - whether in part or in full - to parties not associated with the clinical 
investigation, or its use for any other purpose, without the prior written consent of the 
sponsor is not permitted.
Throughout this document, symbols indicating proprietary names (, TM) may not be displayed.  Hence, the 
appearance of product names without these symbols does not imply that these names are not protected.
PPD
PPD
PPD

20JVL2020 
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Signature of the sponsor's medically responsible person 
The signatory agrees to the content of the fmal clinical study protocol amendment as 
presented. 
Name: 
 
Role: 
GCL ( Global Clinical Lead) 
Signature: 
PPD
PPD

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Signature of principal investigator
The signatory agrees to the content of the final clinical study protocol amendment as 
presented.
Name:
Affiliation:
Date:
Signature:
Signed copies of this signature page are stored in the sponsor’s study file and in the respective 
center’s investigator site file.

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List of abbreviations - amended
6MWD
6-minutes-walking-distance
AE(s)
adverse event(s)
Alb
albumin
ALT
alanine aminotransferase (also known as SGPT)
APAH
associated PAH
ASD
atrial septal defect
AST
aspartate aminotransferase (also known as SGOT)
AUC
area under the curve
BCRP
breast cancer resistance protein
BP
blood pressure
BUN
BW
blood urea nitrogen
body weight
Ca
calcium
CBC
complete blood count
CCDS
Company Core Data Sheet
cGMP
cyclic guanosine monophosphate
CHD
congenital heart disease
CHMP
Committee for Medicinal Products for Human Use
Cmax
maximum concentration
CSR
Clinical Study Report
CTEPH
chronic thromboembolic pulmonary hypertension
CTS
clinical trials simulations 
CYP
DDI
cytochrome P450
drug-drug interaction
DMC
Data Monitoring Committee
ECG
Electrocardiogram
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
ERA
endothelin receptor antagonist
ESC
European Society of Cardiology
EU
European Union
EU-SmPC
Summary of Product Characteristics (EU)
FAS
Full analysis set
FC
Functional class
FPAH
Familial PAH
GCP
Good Clinical Practice
GGT
gamma-glutamyltransferase
GMP
Good Manufacturing Practice
HIV
human immunodeficiency virus
HPAH
Hereditable PAH
IB
investigator’s brochure
ICH
International Council on Harmonization
IDMS
isotope dilution mass spectrometry
IDT
individual dose titration
IEC(s)
Independent Ethics Committee(s)
INN
International non-proprietary name
IPAH
Idiopathic PAH
IRB(s)
Institutional Review Board(s)
IxRS
interactive voice / web response system
K
potassium
LTE
long-term extension
MedDRA
Medical Dictionary for Regulatory Activities
Na
sodium

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NO
nitric oxide
NT-proBNP
N-terminal pro–brain natriuretic peptide
P
phosphate
OS-ASD
ostium secundum atrial septal defect
PAH
pulmonary arterial hypertension
PAP
pulmonary artery pressure
PAPmean
mean pulmonary artery pressure
PASP
pulmonary arterial systolic pressure
PBPK
physiologically based pharmacokinetic
PCA
prostacyclin analogue
PD
pharmacodynamic
PDE
Phosphodiesterase
P-gp
P-glycoprotein
PFO
patent foramen ovale
PH
pulmonary hypertension
PIP
pediatric investigation plan
PK
Pharmacokinetic
PTC
Product Technical Compliant
PVR
pulmonary vascular resistance
QoL
quality of life
RHC
right heart catheter
SAE(s)
serious adverse event(s)
SAP
Statistical Analysis Plan
SBP
systolic blood pressure
SC
Steering Committee
SCr
serum creatinine
sGC
soluble guanylate cyclase
SUSARs
suspected unexpected serious adverse reaction(s)
TAPSE
tricuspid annular plane systolic excursion
T-Bil
total bilirubin
TEAE(s)
treatment-emergent adverse event(s)
TID
three times a day
TOPP
Tracking Outcomes and Practice in Pediatric Pulmonary Hypertension
TTCW
time to clinical worsening
UA
uric acid
WHO
World Health Organization
(Note: Changes to this section were applied according to Amendment 3, see Section
17.1.1.16. Changes to this section were applied according to Amendment 5, see Section
17.2.1.8. Changes to this section were applied according to Amendment 9, see Section 
17.4.1.13.)

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Synopsis - amended
Title
Open-label, individual dose titration study to evaluate safety, 
tolerability and pharmacokinetics of riociguat in children from 
6 to less than 18 years of age with pulmonary arterial 
hypertension (PAH)
Short title
Riociguat in children with PAH
Acronym
PATENT-CHILD
Clinical study phase
3
Study objective(s)
Primary objectives: 

To evaluate safety, tolerability and pharmacokinetics of 
oral riociguat treatment.
Secondary objectives: 

Exploratory efficacy.
Test drug(s)
Riociguat (BAY 63-2521)
Name of active ingredient Methyl-N-[4,6-diamino-2-[1-[(2-fluorphenyl)methyl]-1H-
pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl]-N-methyl-
carbaminate
Dose(s)
(Note: For ensuring the correct 
dosing, the text was clarified by 
Amendment 3, see Section 
17.1.1.6.)
For children with body-weight <50 kg at screening, body-
weight adjusted dose equivalent to the exposure of (0.5 mg) 
1.0 - 2.5 mg three times a day (TID), individual dose titration 
(IDT) in adults treated for PAH. Doses of 1.0 to 2.5 mg TID 
will be applied for children ≥50 kg at screening
The individual optimal (maintenance) dose is to be determined 
based on patients’ monitoring of systolic blood pressure, well-
being and clinical status.
Route of administration Oral
Duration of treatment Active treatment period: 24 weeks (titration phase: 8 weeks, 
maintenance phase: 16 weeks)
Reference drug(s)
N/A
Background treatment
(Note: the wording was modified 
according to Amendment 6, see 
Section 17.3.1.2.)
Patients must be on standard of care PAH medications, 
allowing Endothelin Receptor Antagonists (ERA) and/or 
Prostacyclin Analogues (PCA), for at least 12 weeks prior to 
baseline visit.
Indication
Pulmonary arterial hypertension 

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Diagnosis and main criteria 
for inclusion /exclusion
(Note: This part was modified 
according to Amendment 3, see 
Section 17.1.1.16.This part was 
modified according to Amendment 
6, see Sections 17.3.1.2 and
17.3.1.5.)
Children from 6 years to less than 18 years of age with PAH 
Main inclusion criteria:

PAH, diagnosed by right heart catheterization (RHC)
(for patients with closed shunts – RHC no less than 4 
months after surgery).

Patients must be on standard of care PAH medications, 
allowing ERA and/or PCA, for at least 12 weeks prior 
to baseline visit.

Two groups of patients will be included:
Prevalent: Patients currently on PAH medication 
(allowing ERA and/or PCA) who need additional 
treatment (discretion of the investigator)
Incident: Treatment naïve patients initiated on PAH 
medication (allowing ERA and/or PCA) and then 
riociguat added once patients are stable on standard of 
care. 

WHO functional class I-III.
Main exclusion criteria:

Concomitant use of the following medications: 
phosphodiesterase 5 inhibitors (such as sildenafil, 
tadalafil, vardenafil) and non-specific 
phosphodiesterase (PDE) inhibitors (theophylline, 
dipyridamole), nitrates or NO donors (such as amyl 
nitrite) in any form.

Pretreatment with NO donors (e.g. nitrates) within the 
last 2-weeks before visit1.

Active state of hemoptysis or pulmonary hemorrhage, 
including those events managed by bronchial artery 
embolization.
Study design
Open-label, single arm, individual dose titration
Methodology
(Note: For ensuring the correct 
dosing, the text was clarified by 
Amendment 3, see Section 
17.1.1.6.)
This study is designed to evaluate the safety, tolerability, 
pharmacodynamics and pharmacokinetics of riociguat in 
children from ≥6 to less than 18 years with pulmonary arterial
hypertension (PAH) group 1. For children with body weight < 
50 kg at screening, body weight adjusted doses of 1.0 mg, 
1.5mg, 2.0 mg, and 2.5 mg TID will be applied. For children 
with body weight ≥50 kg, doses of 1.0 mg, 1.5 mg, 2.0 mg,
and 2.5 mg TID will be applied. The study consists of two 
phases: titration phase up to 8 weeks and a maintenance phase 

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up to 16 weeks.
Type of control
N/A
Data Monitoring 
Committee
A Data Monitoring Committee will provide the Steering 
Committee and the sponsor with recommendations related to 
the protection of the children’s safety, including stopping 
recruitment and study treatment.
Number of subjects
(Note: the wording was modified 
according to Amendment 6, see 
Section 17.3.1.2.)
Children on treatment with ERAs and/or PCAs can be 
enrolled. At least 20 children on treatment with bosentan or 
other Endothelin Receptor Antagonists (ERA) must be 
enrolled.
Primary variable(s)
(Note: the wording was modified 
according to Amendment 9, see
Section 17.4.1.13)

Change from baseline to end of treatment (week 24) of 
safety and tolerability assessed by incidence of adverse 
events and serious adverse events, recording of vital signs 
and left-hand x-ray.

Pharmacokinetics/Pharmacodynamics analyses.
Blood samples will be taken for pharmacokinetic and 
pharmacodynamic measurements from all participants 
treated with riociguat. 
The number of pharmacokinetic (PK) blood samples to be 
taken will be determined using physiologically based 
pharmacokinetic (PBPK) modelling predictions. It is 
intended to collect the minimum amount of blood needed 
for adequate analysis (sparse sampling).

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Main secondary variable(s)
(Note: this part was modified 
according to Amendment 5, see 
Sections 17.2.1.3 and 17.2.1.7. 
This part was modified according 
to Amendment 6, see Section 
17.3.1.6 This part was modified 
according to Amendment 9, see 
Section 17.4.1.7 and 17.4.1.13.)
Change from baseline to end of treatment (week 24) of:

6-Minute Walking Distance (6MWD).

WHO functional class.

N-terminal prohormone brain-type natriuretic peptide or 
brain-type natriuretic peptide. When both tests are 
available, N-terminal pro–brain natriuretic peptide (NT-
proBNP) should be chosen over BNP and the same test 
should be performed at every required visit.

Quality of Life scores (parent questionnaire and in 
children able to understand questions).

Echocardiographic assessment of the following:
o
pulmonary arterial systolic pressure (PASP),
o
tricuspid annular plane systolic excursion (TAPSE),
o
pericardial effusion, 
o
left ventricular eccentricity index, 
o
estimated right atrial pressure,
o
right ventricular pressure by tricuspid regurgitant jet 
velocity,
o acceleration time of pulmonary flow,
o right heart dimensions, and
o cardiac output
Time to clinical worsening defined as:
o
hospitalization for right heart failure,
o
death,
o
lung transplantation, 
o
Pott’s anastomosis and atrioseptostomy, 
o
worsening of PAH symptoms, which must include 
either 

an increase in WHO functional class, 
                 OR

appearance/worsening symptoms of right heart 
failure 
                 AND
need for additional PAH therapy.

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Time point/frame of 
measurement for primary 
variable(s)
Timeframe of measurement for primary variable:
24 weeks
Time points of assessment:
Assessment of adverse events
o
at baseline, 
o
at all visits in the titration phase and maintenance 
phase, and 
o
every 3-4 months in the extension phase. 
Left hand x-ray 
o
at baseline
o
at end of study treatment period (week 24)
o
every 12 months in the extension phase until growth 
plates are closed.
Exploratory efficacy
o
at baseline
o
at end of study treatment period (week 24)
o
every 3 to 4 months in the extension phase.
Plan for statistical analysis
A descriptive analysis of the safety and efficacy parameters 
will be performed.

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Study flow chart - amended
Table 0–1: Flow chart - amended
Main study treatment period - 24 weeks
Screening
Individual titration 
phase
(8 weeks)
Maintenance phase
(16 weeks)
Unscheduled 
visit
End of 
treatment 
visit l
Safety 
follow-
up 
60 ± 8 
days
Optional 
Long-term 
extension 
phase
Safety 
follow up 
visit 
60 +8 days 
after 
optional 
LTE 
Visit
V0
V1 g
V2
V3
V4
V5
V6k
V7
V8k
V9
Every 3 
months 
(± 14 
days)
Week f
Day -14 
to -1
0
2
4
6
8
12
16
20
24
Informed 
consent/assent
•
In-/exclusion 
criteria
•
•
Demographics
• 
Medical history
• 
Concomitant 
medication
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Concomitant 
PAH specific 
medication
• 
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Physical 
examination m
• 
• d
•
•
•
•
•
•
•
•
•
•
•
•h
•
Obtain lab test
•i
•
•
•
Pregnancy test a
•
•
•
•
•
•
•
•
•
•
•
•
Dispense study 
medication
•
•
•
•
•
•
•
•
•
(•)
•
Instruct how to 
take study drug
•
•
•
•
•
•
•
•
•
(•)
•

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Table 0–1: Flow chart - amended
Main study treatment period - 24 weeks
Screening
Individual titration 
phase
(8 weeks)
Maintenance phase
(16 weeks)
Unscheduled 
visit
End of 
treatment 
visit l
Safety 
follow-
up 
60 ± 8 
days
Optional 
Long-term 
extension 
phase
Safety 
follow up 
visit 
60 +8 days 
after 
optional 
LTE 
Visit
V0
V1 g
V2
V3
V4
V5
V6k
V7
V8k
V9
Every 3 
months 
(± 14 
days)
Week f
Day -14 
to -1
0
2
4
6
8
12
16
20
24
Provide study 
guidelines
•
Vital signs 
• 
•d
•
•
•
•
•
•
•
•
•
•
•
•

ECG 
• 
•d
•
•
Echocardiogram
•
•
•
•
RHC data o
•o
WHO functional 
class
•
•
•
•
6MWD
•
•
•
•
NT-proBNP or 
BNPp
•
•
•
•
Left hand x-ray
• j
•
• e
Adverse events n
•
•
•
•
•
•
•
•
•
•
•
•
•
•

Drug 
accountability
•
•
•
•
•
•
•
•
•
•
PK blood sampleb
•
•
• 
Child Health 
Questionnaire 
(SF-10 and 
PedsQL)
• 
•
•
•

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Table 0–1: Flow chart - amended
Main study treatment period - 24 weeks
Screening
Individual titration 
phase
(8 weeks)
Maintenance phase
(16 weeks)
Unscheduled 
visit
End of 
treatment 
visit l
Safety 
follow-
up 
60 ± 8 
days
Optional 
Long-term 
extension 
phase
Safety 
follow up 
visit 
60 +8 days 
after 
optional 
LTE 
Visit
V0
V1 g
V2
V3
V4
V5
V6k
V7
V8k
V9
Every 3 
months 
(± 14 
days)
Week f
Day -14 
to -1
0
2
4
6
8
12
16
20
24
Check the systo-
lic BP monitoring 
form if applicable
•
•
•
•
•
•
•
•
Tanner scale c
• 
•
•
• e
Taste 
assessment 
questionnaire
•
•
•
Table 0-1: Flow chart - amended
a    Urine or serum pregnancy test for women of childbearing potential, in the LTE pregnancy testing is to be performed in 4-weekly interval;
also actively request the results of the home urinary pregnancy test as soon as this test is due
b
A minimum volume of 1.0 mL per sample is needed. Accurate adherence to time points is essential and has to be documented, 
      see Table 0–2
c
Scale of physical development in children and adolescents 
d
At Visit 1 blood pressure, heart rate and ECG pre-dose, 2 and 4 hours after first dose (see Table 0–2)
e
Every 12 months until growth velocity is plateauing and growth plates are closed (see section 6.1.6)
f
±2 days for Visits 1 to 4, ±4 days for Visit 5, ±5 days for Visits 6 to 9
g
Visit 1 is considered the baseline visit
h
Including monitoring of growth velocity
i
Obtain blood samples if AST and ALT, creatinine, BUN, GGT, UA, T-Bil, Alb, Na, K, Ca, P, and CBC are not available within 30 days prior to Visit 0. Record 
the same laboratory parameters to eCRF when obtained as medically required according to a local package insert of bosentan or other ERAs, or medical 
practice at the study site at any time.

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j
If no historical data (not older than 30 days) of x-ray is available
k
Home visits (only at week 12 and/or 20 of maintenance phase) at the discretion and responsibility of the investigator
l
For subjects dropping off the protocol at any time after V1 and before V9
m
Including height and weight
n
Including AEs of special interest
o
In case RHC has been performed for a study subject before enrollment, record most recent RHC parameters to the eCRF on V0 (timing of RHC not 
limited to the period of Day -14 to -1). Additionally, if RHC is conducted on medical reasons during the study, the RHC data should be recorded to the 
eCRF.
p
When both tests are available, NT-proBNP should be chosen over BNP and the same test should be performed at every required visit
(Note: The table was modified according to protocol Amendment 3, see Sections 17.1.1.1, 17.1.1.15. The table was modified according to 
Amendment 5, see Sections 17.2.1.1 and 17.2.1.2.The table and footnotes were modified according to Amendment 6, see Sections 17.3.1.2,
17.3.1.3, 17.3.1.6, 17.3.1.7, and 17.3.1.8. The table was modified according to Amendment 9, see Sections 17.4.1.8, 17.4.1.12, and 17.4.2.4.)

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Table 0–2: Visit details - amended
Visit 1 (Baseline visit)
Visit 3 and 5
Detailed study activities at pre-dose and after the first study 
medication dose intake
Study activities before first study 
medication dose intake
Order of 
procedures
Time interval (h)
pre-dose
0:00
0:30 to 1:30
2:00
2:30 to 4:00
4:00
-1:00 to 0:00
0:00
Pharmacokinetic blood 
sample
•
•
•
Blood sample for 
NT-proBNP or BNPb
•
Blood sample for safety 
laboratory
• a
Blood pressure, heart rate
•
•
•
ECG
•
•
•
WHO functional class
•
Left hand x-ray
•
Echocardiogram
•
Administration study drug
•
•
a.
Obtain blood sample for safety parameters on Visit 5 only. 
b.
When both tests are available, NT-proBNP should be chosen over BNP and the same test should be performed at every required visit
Abbreviations: ECG = electrocardiogram
(Note: Visit details were modified according to Amendment 3, see Section 17.1.1.16.The table for visit details was modified according to 
Amendment 5, see Section 17.2.1.8. The table for details was modified according to Amendment 6, see Section 17.3.1.6. The table for visit details 
was modified according to Amendment 9, see Section 17.4.1.12 and 17.4.2.4.)

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Protocol Amendment Summary of Changes Table
Amendment 14, forming integrated protocol Version 7.0 (20 JUL 2020)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union.
Overall Rationale for the Amendment
The purpose of this amendment is to modify the definition of End of Study. 
Section number and 
name
Description of (wording) change
Brief rationale
3.1 Study description  End of Study definition was modified
from LPLV of the main study to LPLV 
of the long-term extension (LTE). 
For clarification and to avoid interruption 
of the ongoing LTE
6.3 Efficacy/
Pharmacodynamic/
Other outcomes –
amended
Wording for time of assessment for 
Taste and texture of the pediatric 
formulation(s) was modified.
For consistency with the wording given 
in the protocol “Change from baseline to 
end of treatment (week 24)” and the 
timepoints indicated in the Study flow 
chart
6.1 Study visits
Wording describing study periods 
was modified. 
To align with wording in Study flow chart 
and other sections and keep consistent 
with PIP
Title page
Sponsor’s medical 
expert
The Study Medical Expert was 
changed.
Administrative change

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Table of contents
Cover Page of Integrated Study Protocol .............................................................................. 1
Title page - amended................................................................................................................ 2
Signature of the sponsor’s medically responsible person..................................................... 3
Signature of principal investigator......................................................................................... 4
List of abbreviations - amended.............................................................................................. 5
Synopsis - amended .................................................................................................................. 7
Study flow chart - amended................................................................................................... 12
Protocol Amendment Summary of Changes Table............................................................. 17
Table of contents..................................................................................................................... 18
Table of tables......................................................................................................................... 20
Table of figures....................................................................................................................... 21
1.
Introduction - amended .................................................................................................. 22
Riociguat........................................................................................................................ 24
1.1
Rationale of the study and risk-benefit assessment - amended...................................... 25
1.2
2.
Study objectives - amended............................................................................................ 28
3.
Study design..................................................................................................................... 28
Study description - amended.......................................................................................... 28
3.1
4.
Study population ............................................................................................................. 30
Planned number of subjects - amended ......................................................................... 30
4.1
Inclusion criteria – amended.......................................................................................... 30
4.2
Exclusion criteria - amended ......................................................................................... 31
4.3
Concomitant medication - amended .............................................................................. 34
4.4
5.
Treatment groups and regimens.................................................................................... 35
Method of treatment allocation...................................................................................... 35
5.1
5.1.1
Body-weight adjusted individual dose titration regimen - amended.......................... 35
Subject identification ..................................................................................................... 37
5.2
Duration of study treatment - amended ......................................................................... 38
5.3
Formulation and dose - amended................................................................................... 38
5.4
Packaging, labeling, and storage.................................................................................... 41
5.5
Treatment assignment - amended .................................................................................. 41
5.6
Study treatment delivery and compliance assessment................................................... 41
5.7
6.
Study procedures............................................................................................................. 41
Study visits - amended................................................................................................... 41
6.1
6.1.1
Pre-treatment phase (Visit 0, Day -14 to -1) - amended............................................. 42
6.1.2
Main study treatment period - amended..................................................................... 43
6.1.3
End-of-treatment visit - amended............................................................................... 45
6.1.4
Safety follow-up visit - amended ............................................................................... 45
6.1.5
Unscheduled visit - amended...................................................................................... 46

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6.1.6
Optional long-term extension phase (until adulthood or approval in the indication 
and commercial availability) - amended .................................................................... 46
Safety outcomes - amended ........................................................................................... 47
6.2
Efficacy/Pharmacodynamic/Other outcomes - amended............................................... 48
6.3
Pharmacokinetics/Pharmacodynamics analyses - amended .......................................... 50
6.4
Study guidelines for parents and children - amended.................................................... 50
6.5
Study committees........................................................................................................... 51
6.6
6.6.1
Steering Committee.................................................................................................... 51
6.6.2
Data Monitoring Committee....................................................................................... 51
7.
Statistical and analytical methods ................................................................................. 52
General considerations................................................................................................... 52
7.1
Analysis sets .................................................................................................................. 52
7.2
Demographic and other baseline characteristics............................................................ 52
7.3
Analyses......................................................................................................................... 52
7.4
7.4.1
Safety analysis - amended .......................................................................................... 52
7.4.2
Efficacy analysis - amended....................................................................................... 53
7.4.3
Pharmacokinetic analysis - amended.......................................................................... 54
7.4.4
Interim analyses.......................................................................................................... 54
7.4.5
Analyses - amended.................................................................................................... 54
Determination of sample size - amended....................................................................... 54
7.5
8.
Adverse events ................................................................................................................. 54
Definitions ..................................................................................................................... 55
8.1
8.1.1
Adverse event (AE) - amended .................................................................................. 55
8.1.2
Serious adverse event (SAE)...................................................................................... 55
8.1.3
Unexpected AEs ......................................................................................................... 55
Relationship of AE to study drug .................................................................................. 56
8.2
Causal relationship to protocol-required procedure....................................................... 56
8.3
Intensity of an AE, action taken and outcome............................................................... 56
8.4
Assessment and documentation of adverse events ........................................................ 56
8.5
Reporting of serious adverse events .............................................................................. 57
8.6
Expected AEs................................................................................................................. 57
8.7
Adverse events of special interest.................................................................................. 57
8.8
Premature discontinuation of study medication............................................................. 57
8.9
Pregnancies .................................................................................................................... 59
8.10
Appropriateness of procedures/measurements .............................................................. 59
8.11
Device malfunction or failure and medical device related events reporting - amended 59
8.12
9.
Data handling and quality assurance............................................................................ 61
Data processing.............................................................................................................. 61
9.1
Audit and inspection ...................................................................................................... 61
9.2
Archiving ....................................................................................................................... 62
9.3
10. Premature termination of the study .............................................................................. 62
11. Ethical and legal aspects................................................................................................. 62
Ethical and legal conduct of the study........................................................................... 62
11.1
Child information and consent....................................................................................... 63
11.2
12. Investigators and other study participants................................................................... 64

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13. Publication policy............................................................................................................ 64
14. Insurance for subjects..................................................................................................... 64
15. Confidentiality................................................................................................................. 64
16. Reference list – amended................................................................................................ 64
17. Protocol amendments...................................................................................................... 69
Amendment 3................................................................................................................. 69
17.1
17.1.1
Overview of changes to the study............................................................................... 69
Modification 10.................................................................................................... 72
17.1.1.10
17.1.2
Changes to the protocol text....................................................................................... 75
Amendment 5............................................................................................................... 109
17.2
17.2.1
Overview of changes ................................................................................................ 109
17.2.2
Changes to the protocol text..................................................................................... 111
Amendment 6............................................................................................................... 128
17.3
17.3.1
Overview of changes ................................................................................................ 128
17.3.2
Changes to the protocol text..................................................................................... 132
Amendment 9............................................................................................................... 156
17.4
17.4.1
Overview of changes ................................................................................................ 156
17.4.2
Changes to the protocol text..................................................................................... 161
Amendment 12............................................................................................................. 186
17.5
17.5.1
Overview of changes ................................................................................................ 186
Amendment 14............................................................................................................. 188
17.6
18. Appendices - amended .................................................................................................. 189
Appendix 1: Growth charts - amended........................................................................ 189
18.1
Appendix 2: Child Health Questionnaire (SF-10) - amended ..................................... 193
18.2
Appendix 3: Tanner scale ............................................................................................ 195
18.3
Appendix 4: Taste assessment - amended ................................................................... 196
18.4
Appendix 5: Blood pressure levels for children and adolescents by gender, age and 
18.5
height percentile according to the National High Blood Pressure Education Program 
Working Group............................................................................................................ 202
Appendix 6: Glomerular filtration rate: Calculation instructions by Schwartz formula -
18.6
amended....................................................................................................................... 203
Appendix 7: PedsQL Generic Core Scales.................................................................. 205
18.7
Table of tables
Table 0-1: Flow chart - amended ............................................................................................. 12
Table 0-2: Visit details - amended ........................................................................................... 16
Table 4-1: Age- and sex-adapted SBP (Boys) ......................................................................... 32
Table 4-2: Age- and sex-adapted SBP (Girls).......................................................................... 33
Table 5-1: Identity of investigational product.......................................................................... 39
Table 5-2 : Body weight-adjusted riociguat dosing schedule .................................................. 40
Table 17-1: Flow chart - amended ......................................................................................... 167
Table 17-2: Flow chart - amended ......................................................................................... 170
Table 17-3: Visit details - amended ....................................................................................... 174

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Table 17-4: Visit details - amended ....................................................................................... 175
Table of figures
Figure 1–1: Pediatric IPAH/FPAH treatment algorithm.......................................................... 23
Figure 5–1: Titration scheme for main study treatment phase................................................. 36

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1.
Introduction - amended
Pulmonary arterial hypertension (PAH) is a chronic disorder of the pulmonary vasculature, 
characterized by a progressive increase in pulmonary vascular resistance leading to right heart 
failure and death. Pulmonary Hypertension (PH) according to the current European Society of 
Cardiology (ESC) guidelines (Galie et al., 2009) is defined by a mean pulmonary artery 
pressure (PAP) ≥25 mmHg at rest, which is still consistent with the definition of the 5th 
World Symposium on Pulmonary Hypertension, which took place in Nice, 2013 (Simonneau 
et al., 2013). The definitions for adults have been applied to children without any modification 
of the values (Donti et al., 2007, Ivy et al., 2013, Widlitz and Barst, 2003, Park, 2008). 
Pulmonary hypertension (PH) can present at any age from infancy to adulthood. Data on 
pediatric epidemiology remain scarce and the exact incidence and prevalence of PH in 
children is not known. In the French registry, the estimated prevalence for PAH in children 
was 3.7 cases/million (Fraisse et al., 2010). The distribution of etiologies in children is quite 
different than that of adults, in children, idiopathic PAH (IPAH), heritable PAH, and APAH-
CHD (PAH associated with congenital heart disease) constitute the majority of cases, whereas 
cases of PAH associated with connective tissue disease are relatively rare (Fraisse et al., 2010, 
Barst et al., 2012, Barst et al., 2011, Berger et al., 2012, Takatsuki et al., 2011, Haworth and 
Hislop, 2009). Large registries of pediatric PH, including the TOPP (Tracking Outcomes and 
Practice in Pediatric Pulmonary Hypertension) registry (Berger et al., 2012) and the combined 
adult and pediatric U.S. REVEAL (Registry to Evaluate Early and Long- Term PAH Disease 
Management) registry, have been described (Barst et al., 2012).
Without appropriate treatments, median survival rate after diagnosis of children with IPAH 
appears worse when compared with that of adults with an estimate median survival in 
children of only 10 months (D'Alonzo et al., 1991, McLaughlin et al., 2002, Barst et al., 
1999). 
Although many treatment goals and endpoints for clinical trials are similar in adults and 
children, there are also important differences. As in adults, clinically meaningful endpoints 
include clinically relevant events such as death, transplantation, and hospitalization for PAH. 
Further parameters that directly measure how a patient feels, functions, and survive are 
meaningful and include functional class and exercise testing; however, there are no acceptable 
surrogates in children (Ivy et al., 2013). Although World Health Organization (WHO) 
functional class is not designed specifically for infants and children, it has been shown to 
correlate with 6-min walk distance and hemodynamic parameters (Fraisse et al., 2010, Barst 
et al., 2012, van Loon et al., 2011, Moledina et al., 2010, Haworth and Hislop, 2009).
The prognosis of children with PAH has improved in the past decade owing to new 
therapeutic agents and aggressive treatment strategies. However, the use of targeted PAH 
therapies in children is almost mainly based on experience and data from adult studies, rather 
than evidence from clinical trials in pediatric patients. Treating physicians propose a 
pragmatic treatment algorithm based on the strength of expert opinion that is most applicable 
to children with IPAH (Ivy et al., 2013) (Figure 1–1).

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Figure 1–1: Pediatric IPAH/FPAH treatment algorithm
Note: Use of all agents is considered off-label in children aside from sildenafil in Europe. **Dosing 
recommendations per European approved dosing for children
Abbreviations: CCB = calcium channel blocker; ERA = endothelin receptor antagonist; 
HPAH = hereditary pulmonary arterial hypertension; inh = inhalation; IPAH = idiopathic pulmonary 
arterial hypertension; IV = intravenous; PDE-5i = phosphodiesterase 5 inhibitor; 
SQ = subcutaneous, FPAH = Familial PAH
Source: (Ivy et al., 2013)
The recommended treatment scheme for pediatric populations is similar to that of adult 
populations and in general obtained by extrapolation of adult experience (Galie et al., 2004, 
Beghetti, 2009, Galie et al., 2009). In general, children will undergo a vasoreactivity test, 
which tests the acute response to short-acting vasodilators. Based on current literature 
children show a better response compared to adult patients permitting more children to be 
treated with calcium channel blockers and also translating into a better prognosis for those 
children who respond. On the other hand non-responders in pediatric age have a worse 
prognosis than adult patients with severe disease (Galie et al., 2004). The guideline of the 
European Society of Cardiology has been updated recently to reflect the recommendations of 
the World Conference on Pulmonary Hypertension in Nice (Simonneau et al., 2013). Thus, 
due to the rarity of the disease and the limited treatment data gained from pediatric 
populations (with the exception of STARTS 2) there is also paucity of internationally 
recommended treatment guidelines. The use of targeted pulmonary PAH therapies in children 
is almost exclusively based on experience and data from adult studies, rather than evidence 
from clinical trials in pediatric patients.
Revatio (sildenafil) and bosentan are PAH-specific drugs approved for children in European 
Union. The medical treatment recommendations of Tracleer (International non-proprietary 

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name [INN]: bosentan) in pediatric populations with PAH in the European Union (EU) are 
mainly based on extrapolation from experience in adult populations (EMA, 2012b). Data from 
clinical studies in pediatric patients are derived from retrospective cohort studies (without 
control-group) in mono-therapy and combination therapy, (Hislop et al., 2011, Ivy et al., 
2010, Maiya et al., 2006, Rosenzweig et al., 2005), from clinical studies in pediatric patients 
with PAH and focus on pharmacokinetics (PK) (without control group) (Beghetti, 2009, 
Barst et al., 2003), from a European non-interventional post-marketing surveillance database 
(Beghetti et al., 2008), and from a double-blind placebo controlled study in patients > 12 
years of age with Eisenmenger’s syndrome (Galie et al., 2006). These studies showed 
encouraging results for the benefit of the pediatric population but still indicate that 
improvement in medical treatment is needed. Recent expert guidelines suggest the use of 
endothelin receptor antagonists (ERA) or phosphodiesterase 5 (PDE5) inhibitors and, when 
children deteriorate on use of any of these medications, additional agents may be considered, 
either in an up-front approach or sequential add-on (Ivy et al., 2013). 
There is a paucity of combination therapy data in children with PAH. In the recent Nice 
guidelines, it is stated that combination therapy should be considered for children who 
deteriorate on either ERA or phosphodiesterase 5 (PDE5) inhibitors. Indeed, it is suggested 
that patients may benefit from early (up-front) combination therapy. At the international 
European Respiratory Society meeting 2014, the results of the randomized, double-blind 
AMBITION study were presented (Galie et al., 2014). This study investigated the first-line
treatment of PAH in adults with the combination of ambrisentan 10 mg and tadalafil 40 mg 
(compared to the pooled ambrisentan and tadalafil monotherapy arm). The combination 
therapy reduced the risk of clinical failure by 50% compared to pooled ambrisentan and 
tadalafil monotherapy arm (hazard ratio = 0.502; p=0.0002). This study may support the 
direct treatment of affected patients with combination therapy, which is recommended by Ivy 
et al. as primary approach for children with higher risk PAH (Galie et al., 2014). In addition, 
the study supports the concept to add another PAH specific drug when clinically necessitated 
as stated in the ESC adult guidelines (Galie et al., 2009) and in the treatment 
recommendations of the 5th World Symposium on Pulmonary Hypertension at Nice, 2013 
(Galie et al., 2013). The results of the AMBITION study corroborate the findings of the 
PATENT-1 study (Ghofrani et al., 2013), where the addition of riociguat to treatment with 
ERA or prostanoids resulted in further beneficial effects for adults with PAH.
Taking into account the current treatment options and the bad prognosis for the pediatric 
patients, a new medication with a novel mechanism of action may offer another treatment 
option to this population. This might be especially true of riociguat because of its different 
mode of action in the nitric oxide pathway and distinctive from currently used drugs, i.e. 
direct soluble guanylate cyclase (sGC) stimulation as it has been shown in adult PAH patients 
(Schermuly et al., 2008).
(Note: The text was modified according to the Amendment 3, see Section 17.1.1.10. The text 
was modified according to Amendment 5, see Section 17.2.1.5. The text was modified 
according to Amendment 6, see Section 17.3.1.10.)
Riociguat
1.1
Riociguat is the first of a new class of drugs, the soluble guanylate cyclase (sGC) stimulators 
that acts in the nitric oxide pathway and is being developed for the treatment of pulmonary 
hypertension (PH). Riociguat has a dual mode of action: it sensitizes sGC to the body’s own 

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nitric oxide (NO) and can also increase sGC activity in the absence of NO, causing 
vasorelaxation, anti-proliferation and anti-fibrotic effects. Riociguat is approved for adults in 
over 40 countries for the treatment of PAH and chronic thromboembolic pulmonary 
hypertension (CTEPH). Recent data presented has demonstrated long-term (2-year) safety and 
tolerability data in adult patients with PAH and CTEPH (Rubin et al., 2015, Simonneau et al., 
2014).
Rationale of the study and risk-benefit assessment - amended
1.2
There is an unmet medical need for children with group 1 PAH. Riociguat would be a new 
class of drugs tested in this patient population, and may provide a safe and effective drug for 
this life-threatening disease, as seen in adults.
sGC is an important regulator in the cardiovascular system and is present in vascular cells and 
platelets. The endogenous activator of sGC is endothelial cell-derived NO, which acts in 
paracrine fashion. In smooth muscle cells and in platelets NO activates sGC, resulting in an 
increased intracellular cyclic guanosine monophosphate (cGMP) level which induces 
vasorelaxation, and inhibition of cell proliferation and fibrotic effects. By increasing the sGC 
activity in the absence of NO, riociguat causes vasorelaxation, anti-proliferation and anti-
fibrotic effects.
PATENT-1 was the pivotal study that led to the approval of riociguat (Adempas) for adults 
with PAH. The PATENT-1 study was a phase 3, double-blind study where 443 adult subjects 
with symptomatic PAH were randomly assigned to treatment and actually received placebo, 
riociguat in individually adjusted doses of up to 2.5 mg three times daily (2.5 mg–maximum 
group), or riociguat in individually adjusted doses that were capped at 1.5 mg three times 
daily (1.5 mg–maximum group). The 1.5 mg–maximum group was included for exploratory 
purposes, and the data from that group were analyzed descriptively. Subjects who were 
receiving no other treatment for pulmonary arterial hypertension and subjects who were 
receiving endothelin-receptor antagonists or (non-intravenous) prostanoids were eligible. The 
primary end point was the change from baseline to the end of week 12 in the distance walked 
in 6 minutes. Secondary endpoints included the change in pulmonary vascular resistance, N-
terminal pro–brain natriuretic peptide (NT-proBNP) levels, World Health Organization 
(WHO) functional class, and time to clinical worsening, score on the Borg dyspnea scale, 
quality-of-life variables, and safety. By week 12, the 6-minute walk distance had increased by 
a mean of 30 m in the 2.5 mg–maximum group and had decreased by a mean of 6 m in the 
placebo group (least-squares mean difference, 36 m; 95% confidence interval, 20 to 52; 
P<0.001). Important for this current study, prespecified subgroup analyses showed that 
riociguat improved the 6-minute walk distance both in subjects who were receiving no other 
treatment for the disease AND in those who were receiving endothelin-receptor antagonists or 
prostanoids. There were significant improvements in pulmonary vascular resistance 
(P<0.001), NT-proBNP levels (P<0.001), WHO functional class (P = 0.003), time to clinical 
worsening (P = 0.005), and Borg dyspnea score (P = 0.002). The most common serious 
adverse event in the placebo group and the 2.5 mg–maximum group was syncope (4% and 
1%, respectively). In conclusion, riociguat significantly improved exercise capacity and 
secondary efficacy end points in subjects with pulmonary arterial hypertension (Ghofrani et 
al., 2013). In PATENT-1, riociguat improved the 6-minute walk distance in both patients who 
were receiving no therapy for the disease and patients who were receiving endothelin-receptor 
antagonists or prostanoids.

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Further details can be found in the latest available version of the investigator's brochure, 
which contains comprehensive information on the study drug.
Based on the positive results of riociguat in adult subjects with PAH, children with PAH may 
also benefit from treatment with riociguat, e.g. those pre-treated with bosentan.
As previously discussed, Revatio (INN: sildenafil) is approved in Europe and has now 
become standard of care. Riociguat and PDE5 inhibitors such as sildenafil act on the NO-
sGC-cGMP signaling pathway. Thus, an additive effect on pulmonary and systemic 
circulation may be expected. Non-clinical studies in animal models showed an additive 
systemic blood pressure lowering effect when riociguat was combined with either sildenafil or 
vardenafil. With increased doses, more than additive effects on systemic blood pressure were 
observed in some cases. The interaction of riociguat and PDE5i was investigated in a clinical 
study (PATENT-Plus; study 15096). PATENT-Plus was designed as an interaction study to 
evaluate changes in blood pressure following 1, 1.5, 2, and 2.5 mg riociguat TID (i.e., the IDT 
regimen) compared to placebo treatment on the background of stable sildenafil pre-treatment 
in subjects with symptomatic PAH. 
On the basis of the safety, tolerability and efficacy data available, and in particular the 
apparent high rate of discontinuations due to hypotension and a lack of overall clinical benefit 
in the patient population studied, a positive benefit risk assessment could not be established 
and therefore riociguat should not be used in combination with sildenafil. After a review of 
the above data, the long-term extension phase of Patent-Plus was discontinued. Based on 
these considerations and in agreement with the CHMP (Committee for Medicinal Products for 
Human Use) (Adempas_EMEAHC2737) riociguat on top of sildenafil (Revatio in Europe) is 
contraindicated in the EU-SmPC. Accordingly, use of PDE5 inhibitors is a key exclusion 
criterion in this current study.
In general, treatment with riociguat is expected to cause comparable mode of action related 
side effects in children and adolescents as in adults. In growing rats, morphological changes 
(widening of the growth plates, increase of bone mass) of the bones have been found as 
additional adverse effects related to mode of action. Although the regulation of bone 
homeostasis via the NO-sGC-cGMP-PKG pathway holds true for all species including 
humans, the effect of sGC stimulation on the growing bone is yet unclear. Considering the 
severity and prognosis of PAH and the fact that the bone findings in rats were seen at 3-4 fold 
of human exposure, and that the findings were reversible and can be monitored in the clinical 
setting, the preclinical bone findings are considered as not prohibitive for the initiation of a 
clinical study in children.
The protocol was developed in accordance with ICH Good Clinical Practice, and other 
ICH/EMA guidelines for conducting clinical trials in pediatric population, in particular the 
ICH Topic E 11 (Clinical Investigation of Medicinal Products in the Pediatric Population) and 
the guideline on Ethical Considerations for Clinical Trials on Medicinal Products Conducted 
with the Pediatric Population. 
The necessity of minimizing any possible burden and any potential risk for participating child 
and adolescent patients was taken into consideration and addressed during the development of 
this protocol. In order to provide guidance for investigators this protocol describes use of all 
study procedures, as well as outlines any potential related burden for participating patients, 
whenever applicable, in the respective chapters. In terms of the IMD administration the 
titration phase has been implemented (as described in the Section 5.1.1 “Body-weight 

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adjusted individual dose titration regimen”), as well as a dosing pipette for administration of 
oral suspension will be used. Educational material for training on the dosing pipette use and 
dose administration for study site staff, as well as for the patients and their caregivers, to 
ensure adequate dosing pipette use and treatment compliance will be distributed.
The study design includes standard procedures for pediatric PAH management, and only a 
few additional, study specific procedures have been included wherever absolutely necessary 
to ensure the study conduct, and monitoring of safety of enrolled patients. Study-specific 
procedures are: ECGs, Echocardiogram, urine or serum pregnancy testing for female patients 
of childbearing potential, selected blood sampling, and the left-hand X-ray for monitoring of 
bone growth. The above listed study specific procedures are non-invasive, standard medical 
care procedures. Laboratory samples will be restricted to the selected laboratory tests at 
screening (only if historical data is not available), visit 1, 5 and 9. Pharmacokinetic samples 
and blood sampling for study purposes will be aligned with clinically required blood tests 
whenever possible in order to avoid additional burden of a painful procedure and blood 
volume taken (see the subchapter “Laboratory parameters” in Section 6.2). Blood samples for 
pharmacokinetic analysis will have the blood volume minimized to 1 ml per sample. All 
blood samples collection will be performed by pediatric specialist staff and will be performed 
with the use of techniques like distraction and local anesthetic techniques, if applicable, to 
reduce the burden for patients. The left hand X-ray for monitoring of bone growth will be 
performed and assessed according to the established method. The rare periodicity of this X-
ray examination, as well as the standard precautions will ensure minimal and therefore 
acceptable exposure to radiation (Section 6.2 Safety outcomes).
Investigators are mandated and trained to report adverse events, and all the respective 
definitions, criteria for qualifying AEs, and their reporting, as well as a description of 
pharmacovigilance procedures are included in a separate section of this protocol (Section 8.8). 
The monitoring of safety of participating patients by investigators and the sponsor is ensured 
by adherence to pharmacovigilance regulations and implementation of study specific 
monitoring measures (e.g. observation and evaluation of potential AEs of special interest, 
patients’ growth and bone growth monitoring). Close monitoring and ongoing medical review 
will be performed by the sponsor. An independent Data Monitoring Committee (DMC, which 
will be acting according to a DMC Charter) will meet periodically to review the safety data of 
enrolled patients, as well as the scientific merit of the trial. In addition a Steering Committee 
(SC) will ensure a scientifically sound and safe conduct of the study. Both, the DMC and the 
SC, are described in a separate subsection of this protocol (6.6 Study committees”). 
The expected benefit-risk balance of riociguat is considered positive if used in adherence to 
this clinical trial protocol and in accordance with the recommendations and guidance given in 
the Investigator’s Brochure.
(Note: The section was widened according to Amendment 3, to better describe the 
minimization of burden degree of pediatric subjects, see Sections 17.1.1.5 and 17.1.1.16.The 
section was modified according to Amendment 6, see Section 17.3.1.8.)

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2.
Study objectives - amended
The primary objectives:

To evaluate safety, tolerability and pharmacokinetics of oral riociguat treatment 
Secondary objectives:

Exploratory efficacy. To characterize the pharmacodynamic profile of riociguat 
comprising the following exploratory parameters: time to clinical worsening (TTCW), 
exercise capacity (6MWD test), functional capacity (measured by WHO FC), 
laboratory biomarkers (NT-proBNP or BNP), Quality of Life (QoL) measurements 
(SF-10, PedsQL), echocardiographic variables 
Other objective is:

To assess taste and texture of the pediatric formulation(s) by use of a questionnaire
(Note: The text was modified according to Amendment 3, see Section 17.1.1.3.The text was 
modified according to Amendment 5, see Section 17.2.1.7.The section was modified according 
to Amendment 6, see Sections 17.3.1.2 and 17.3.1.6.)
3.
Study design
This is an international, multicenter, single-arm, open-label study to evaluate the safety, 
tolerability and pharmacokinetics of a body-weight adjusted riociguat regimen in subjects 
aged between ≥6 years old and <18 years old who have been diagnosed with idiopathic PAH, 
hereditable PAH, or PAH associated with connective tissue disease or congenital heart disease 
with shunt closure. These subjects must be on stable treatment with PAH medications (ERA 
and/or PCA) prior to receiving the first dose of riociguat (EMA, 2009, EMA, 2012a, eMC, 
2015a, eMC, 2015b).
(Note: The Section was modified according to Amendment 6, see Section 17.3.1.2.)
Study description - amended
3.1
After providing written informed consent and assent (if applicable) subjects will undergo a 
screening evaluation to determine their eligibility. Eligible subjects – once on stable 
background treatment with PAH medications (ERA and/or PCA) - will start body-weight 
adjusted individual dose titration (IDT) regimen as described in section 5.1.1. After the 
individual titration phase of maximum of 8 weeks, subjects will enter the 16-week 
maintenance phase. The last dose administered at Visit 4 will be regarded as individual 
optimal dose and subject will receive that treatment during the maintenance phase.
Subjects of the older age cohort (≥12 to <18 years) will be treated first. After 5 patients of this 
age cohort have reached their optimal dose and received this dose until assessment of their 
first control x-ray of left hand at week 24, an independent Data Monitoring Committee 
(DMC) will give recommendations to the Steering Committee (SC) whether to continue with 
enrolment in this age cohort and open enrollment in the subsequent lower age cohort (≥6 to 
<12 years).
Children who require treatment with riociguat for more than 24 weeks will be offered 
participation in an extension study and continuation until market approval of riociguat for the 

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pediatric population or until they are 18 years of age (whatever comes first). Subjects reaching 
adulthood can be transitioned to commercially-available Adempas.
The primary objective is the evaluation of safety and tolerability as well as the 
pharmacokinetic properties of riociguat in the pediatric population. The DMC will monitor 
the subjects’ safety on an ongoing basis and give recommendations to the SC.
For all subjects, visits are scheduled at regular time points (see Table 0–1). Subjects who 
prematurely discontinue study drug or do not consent to participate in the long-term extension 
phase will be seen at the safety follow-up visit. During all contacts, the treatment and clinical 
course of the subject will be evaluated. Subjects with suspected safety concerns (for safety 
outcomes see section 6.2) will undergo confirmatory testing as per standard of care. Blood 
samples for PK will be taken at defined time points (see Table 0–2).
The reason why subjects did not pass the screen of in- and exclusion criteria after obtaining 
informed consent/child assent will be documented.
Primary completion
The primary completion event for this study is when the last visit of the last subject for all 
centers has occurred after 24 weeks of treatment.
End of study
The end of the study will be reached as soon as the last visit of the last subject has been 
reached in all centers in all participating countries (EU and non-EU).
A clinical study report (CSR) will be written after the primary completion. A separate CSR
will be prepared after completion of the optional long-term extension (LTE).
(Note: The wording in Primary completion and in End of the study was modified according to 
Amendment 3, see Section 17.1.1.2.The Section was modified according to Amendment 6, see 
Section 17.3.1.2. The wording in End of the study was modified according to Amendment 14, 
see Section 17.6.)

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4.
Study population
Planned number of subjects - amended
4.1
Children on treatment with ERAs and/or PCAs can be enrolled. At least 20 children on 
treatment with bosentan or other Endothelin Receptor Antagonists (ERA) must be enrolled in 
the study.
The sponsor commits to put efforts in enrolling equal number of subjects in each of the ≥12 to 
<18 year and the ≥6 to <12 year age cohort overall. Enrolment will be started with children
from 12 to less than 18 years of age.
After 5 patients in the ≥12 to <18 years old group have reached their optimal dose, have been 
treated on their maintenance dose and obtained the control x-ray of left hand at week 24, their 
data will be evaluated by DMC. Only after obtaining positive safety and efficacy data in the 
first 5 patients, enrolment in the group from 6 to less than 12 years of age will be started.
The sponsor will make every effort to facilitate an equal distribution between the two age 
cohorts with a minimum of 5 patients in each age cohort. In case of inadequate availability of 
patients in the age group ≥6 to <12 years total enrolment will be stopped only if at least 5 
patients of this younger age group have been enrolled.
(Note: The Section was modified according to Amendment 6, see Section 17.3.1.2. The Section 
was modified according to Amendment 9, see Section 17.4.1.9)
Inclusion criteria – amended
4.2
1. Children from 6 years to less than 18 years of age with pulmonary arterial hypertension 
(PAH)
2. Diagnosed with PAH :

Idiopathic (IPAH)

Hereditable (HPAH)

PAH associated with (APAH)
o
Connective tissue disease 
o
Congenital heart disease with shunt closure more than 6 months ago (no open 
shunts, confirmed by RHC no less than 4 months after surgery)
Regardless of the type of PAH, the following findings are not exclusionary:
o
Patent foramen ovale (PFO) and asymptomatic, isolated, ostium secundum 
atrial septal defect (OS-ASD) ≤ 1 cm (both confirmed by echocardiogram) and 
not associated with hemodynamic alterations indicative of significant shunt, 
e.g. Qp/Qs ratio less <1.5:1 are not exclusionary
3. Pulmonary arterial hypertension (PAH), diagnosed by right heart catheterization (RHC) at 
any time prior to enrolment (for patients with closed shunts – RHC no less than 4 months 
after surgery)
4. Pulmonary arterial hypertension confirmed by a RHC at any time prior to start of study, 
with mean pulmonary artery pressure (PAPmean) ≥25 mmHg at rest, pulmonary capillary 

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wedge pressure (PCWP) or left ventricular end-diastolic pressure (LVEDP) ≤15 mmHg, 
and pulmonary vascular resistance (PVR) >240 dyn•sec•cm-5 (i.e., ≥3.0 wood units•m2)
5. Patients must be on standard of care PAH medications, allowing Endothelin Receptor 
Antagonists (ERA) and/or Prostacyclin Analogues (PCA), for at least 12 weeks prior to 
baseline visit.
Two groups of patients will be included:
o
Prevalent: Patients currently on PAH medication (allowing ERA and/or PCA) 
who need additional treatment (discretion of the investigator)
o
Incident: Treatment naïve patients initiated on PAH medication (allowing ERA 
and/or PCA) and then riociguat added once patients are stable on standard of 
care
6. WHO functional class I-III
7. Adolescent females of childbearing potential can only be included in the study if a 
pregnancy test is negative. Adolescent females of childbearing potential must agree to 
receive sexual counseling and use effective contraception as applicable. ‘Effective
contraception’ is defined as progestogen-only hormonal contraception associated with 
inhibition of ovulation (implant), intrauterine device (IUD), intrauterine hormone-
releasing system (IUS), or any combination of adequate methods of birth control (e.g. 
condoms with hormonal contraception). Agreement to use contraception is required from 
the signing of the informed consent form up until 4 weeks after the last study drug 
administration.
8. Young men must agree to use adequate contraception when sexually active.
9. Written inform consent provided and if applicable child assent provided
(Note: The text was modified according to Amendment 3, please see Section 17.1.1.16. The 
Section was modified according to Amendment 6, see Section 17.3.1.2. The Section was 
modified according to Amendment 9, see Section 17.4.1.1, 17.4.1.2, and 17.4.1.3)
Exclusion criteria - amended
4.3

Concomitant use of the following medications: phosphodiesterase (PDE) 5 inhibitors 
(such as sildenafil, tadalafil, vardenafil) and non-specific phosphodiesterase (PDE)
inhibitors (theophylline, dipyridamole), nitrates or NO donors (such as amyl nitrite) in 
any form a
                                                
a Pretreatment with the phosphodiesterase (PDE) 5 inhibitor Sildenafil is allowed up to 24 h prior to start of 
riociguat treatment (Visit 1). Pretreatment with the phosphodiesterase (PDE) 5 inhibitor tadalafil is allowed up 
to 3 days prior to start of riociguat treatment (Visit 1). Patients are not expected to be withdrawn from 
treatment with PDE5i for the purpose of entering into this trial. During the period without PDE5i, patients who 
received treatment with PDE5i are expected to be on stable clinical condition and receiving standard of care 
treatment with ERA and/or PCAs.
(Note: The footnote was added by Amendment 6, see Section 17.3.1.4. The footnote text was modified according 
to Amendment 9, see Section 17.4.1.4)

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
Pretreatment with NO donors (e.g. nitrates) within the last 2 weeks before visit 1. The 
use of any drug including NO acutely for testing during catheterization is not an 
exclusion criterion.

Active state of hemoptysis or pulmonary hemorrhage, including those events managed by 
bronchial artery embolization or any history of bronchial artery embolization or massive 
hemoptysis within 3 months prior to screening

Systolic blood pressure (SBP) more than 5 mmHg lower than the age-, sex- and height-
adapted level of the 50th SBP percentile (NHBPEP, 2004) see Table 4–1 and Table 4–2
and appendix 18.5.
Table 4–1: Age- and sex-adapted SBP (Boys)
Note: Age will be rounded down if age is x years and <6 months and rounded up if x years and ≥6 months.
* Rounding up does not apply for those subjects older than 17 years and 6 months.

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Table 4–2: Age- and sex-adapted SBP (Girls)
Note: Age will be rounded down if age is x years and <6 months and rounded up if x years and ≥6 months.
* Rounding up does not apply for those subjects older than 17 years and 6 months.

History of left-sided heart disease, including valvular disease or heart failure

Pulmonary hypertension related to conditions other than specified in the inclusion criteria

WHO functional class IV

Pulmonary veno-occlusive disease

Screening aspartate transaminase (AST) and/ or alanine transaminase (ALT) more than 3 
times the upper limit of normal (ULN)

Non-stable disease status, e.g., signs and symptoms of decompensated right heart failure

Severe bronchial asthma

Severe restrictive lung disease

Severe congenital abnormalities of the lung, thorax, and diaphragm

Clinically relevant hepatic dysfunction (especially Child Pugh C)

Renal insufficiency (estimated glomerular filtration rate <30 mL/min/1.73m2 e.g. 
calculated based on Schwartz formula, for detailed calculation instructions, see 18.6) 

Subject with hypersensitivity to the investigational drug or any of the excipients

Active smoking of tobacco of any type or quantity. Smoking marijuana is also not 
permitted.

Subjects with any other condition that is not recommended with riociguat 

Previous assignment to treatment during this study

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
Previous (within 30 days) or concomitant participation in another clinical study with 
investigational medicinal product(s)

Any condition that, according to treating physician, might jeopardize subject's 
participation and compliance with procedures indicated in this protocol.

PH associated with idiopathic interstitial pneumonia (PH-IIP)
(Note: The section was modified according to Amendment 3, see Sections 17.1.1.16 and 
17.1.1.9.The section was modified according to Amendment 5, see Section 17.2.1.6.The 
Section was modified according to Amendment 6, see Sections 17.3.1.1, 17.3.1.2, 17.3.1.4, 
and 17.3.1.5. The Section was modified according to Amendment 9, see Sections 17.4.1.4 and 
17.4.1.11.)
Concomitant medication - amended 
4.4
Concomitant medication includes either continuation of a treatment started before study entry 
or addition of a new treatment during the study. 
Co-administration of riociguat with the following concomitant medications is not allowed 
during the study:

PDE inhibitors: PDE5 inhibitors (such as sildenafil, tadalafil, vardenafil) and 
nonspecific PDE inhibitors (such as dipyridamole or theophylline) because of 
increased risk of hypotension

Nitrates: Nitrates or NO donors (such as amyl nitrite) in any form (e.g. nitrates, 
molsidomine, sodium nitroprusside) because of increased risk of hypotension
Other concomitant medication considerations:

Strong multi pathway cytochrome P450 (CYP) and P-glycoprotein 1(P-gp)/breast 
cancer resistance protein (BCRP) inhibitors: Concomitant use of riociguat with strong 
multi pathway CYP inhibitors and P-gp/BCRP inhibitors such as azole antimycotics 
(for example, ketoconazole, itraconazole) or HIV (human immunodeficiency virus) 
protease inhibitors (such as ritonavir) increase riociguat exposure and may result in 
hypotension. Consider a starting dose of 0.5 mg TID equivalent when initiating 
riociguat in subjects on stable doses of strong multi pathway CYP and P-gp/BCRP 
inhibitors and monitor for signs and symptoms of hypotension. A dose reduction 
should be considered in subjects who may not tolerate the hypotensive effect of 
riociguat.

Strong CYP1A1 inhibitors and strong P-gp inhibitors: The concomitant use of 
riociguat with strong CYP1A1 (CYP family 1, subfamily A, polypeptide 1) inhibitors, 
such as the tyrosine kinase inhibitor erlotinib or the reverse-transcriptase inhibitor 
abacavir, and strong P-gp inhibitors, such as the immunosuppressive agent 
cyclosporine A, may increase riociguat exposure. In vitro, abacavir, rilpivirine, 
efavirenz, ritonavir, cobicistat and elvitegravir inhibited CYP1A1 and the metabolism 
of riociguat in the order listed with abacavir as the strongest inhibitor. Concomitant 
administration of HAART combinations with the drugs listed before led to an increase in 
riociguat mean AUC of up to about 160%.  All these drugs should be used with caution. 
Blood pressure should be monitored and dose reduction of riociguat considered.

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
Strong CYP3A4 inducers: The concomitant use of riociguat with strong CYP3A4 
inducers (e.g. phenytoin, carbamazepine, phenobarbitone or St. John’s Wort) may lead 
to decreased riociguat plasma concentration.

Antacids: Co-administration of the antacid aluminum hydroxide / magnesium 
hydroxide reduced riociguat mean area under the curve (AUC) by 34% and mean 
maximum concentration (Cmax) by 56%. Antacids should be taken at least 1 hour after 
riociguat.

Omeprazole: Pre- and co-treatment with the proton pump inhibitor omeprazole (40 mg 
once daily) reduced riociguat mean AUC by 26% and mean Cmax by 35%. This is not 
considered clinically relevant.
Clarithromycin: Co-administration of clarithromycin (500 mg twice daily), classified as 
strong and selective CYP3A4 inhibitor and also reported to be a weak-to-moderate P-gp 
inhibitor, moderately increased riociguat mean area under the curve (AUC) by 41% without 
significant change in Cmax. This is not considered clinically relevant.
(Note: The Section was modified according to the Amendment 3, see Section 17.1.1.16.)
5.
Treatment groups and regimens
Method of treatment allocation
5.1
Allocation to treatment dose will be done centrally by an interactive voice / web response 
system (IxRS). All subjects will be allocated to riociguat body-weight adjusted, individual 
dose titration (IDT).
The investigator will provide the IxRS with study center identification, the subject’s date of 
birth (year) and age, gender, and weight. Further details are contained in the IxRS manual.
5.1.1
Body-weight adjusted individual dose titration regimen - amended
Riociguat must be provided to all patients using an individual dose titration scheme according 
to a body weight-adjusted dose to achieve a similar exposure as that observed in adults treated 
for PAH (Figure 5–1). The individual optimal (maintenance) dose is to be determined based 
on patient’s monitoring of systolic blood pressure, well-being and clinical status. For children 
with <50 kg body weight at baseline, a body weight adjusted dosing will be applied. Children 
with ≥ 50kg body weight will receive adult doses. 
In subjects with a body-weight below 50 kg at baseline, riociguat will be administered as oral 
suspension TID with or without food. Subjects with a body-weight ≥50 kg at baseline will 
receive riociguat as tablet formulation.
The body weight-adjusted riociguat dosing schedule is provided in Table 5–2.
The following tablet strengths will be available: 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, and 2.5 mg. 
An oral suspension formulation of 0.15 mg/mL will also be available.
The treatment administration of riociguat oral suspension requires the use of a 5 mL or 10 mL 
dosing pipette. These dosing pipettes will be calibrated to the required volume of the weight 
adjusted dose and are manually operated. Each subject will be provided with a new reusable 
dosing pipette at each drug dispense. 
Recommended study medication handling process must be followed.

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Educational material for training on the dosing pipette and dose administration for study site 
staff as well as for the subjects to ensure adequate dosing pipette use and treatment 
compliance will be distributed.
Subjects with <50 kg body weight will start with body-weight adjusted riociguat dose 
equivalent to the exposure of 1.0 mg TID in adults. Subjects with ≥ 50kg body weight will 
start with dose 1.0 mg TID. During the individual titration period, the dose will be up-titrated 
every 2 weeks (±2 days) at the discretion of the investigator, based on subject’s peripheral 
systolic blood pressure and general tolerability measured at trough before intake of the next 
higher dose of riociguat. The maximum dose is the dose equivalent to the exposure of 2.5 mg 
in adults TID. Dose reductions for safety reasons are allowed at any time. The individual dose 
titration period will not exceed 8 weeks.
Dosing steps and dose equivalents in adults are shown in Figure 5–1. 
Figure 5–1: Titration scheme for main study treatment phase
At each titration visit, the individual dose will be assigned based on the following algorithm 
where peripheral systolic blood pressure (SBP) will be measured (by oscillometry with the 
same calibrated oscillometry unit in each center) at trough before intake of the first dose of 
the day.
(Note: The description of the dosing of riociguat was clarified according to Amendment 3, see 
Sections 17.1.1.6, 17.1.1.13, and 17.1.1.16.The Section wording was modified according to 
Amendment 5, see Section 17.2.1.8.The Section was modified according to Amendment 6, see 
Section 17.3.1.2.)
Dose titration algorithm

If systolic blood pressure (SBP) is less than 5 mmHg lower than the age-, sex- and 
height-adapted level of the 50th SBP percentile (NHBPEP, 2004) (see appendix 18.5), 
increase riociguat dose (+0.5 mg dose-equivalent TID)

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
If SBP is ≥5 mmHg but less than 10 mmHg lower than the age-, sex- and height-
adapted level of the 50th blood pressure (BP) percentile, maintain dose of riociguat. 

If SBP is ≥10 mmHg lower than the age-, sex- and height-adapted level of the 50th BP 
percentile, reduce riociguat dose (- 0.5 mg dose-equivalent TID)

If any SBP is ≥5 mmHg lower than the age-, sex- and height-adapted level of the 50th
BP percentile, with clinical symptoms of hypotension such as dizziness or presyncope, 
stop study treatment; restart after 24 hours with reduced dose - 0.5 mg dose-equivalent 
TID).
Down-titration of riociguat is possible for safety reasons at any time point. If at any time, the 
subject has symptoms of hypotension, temporarily stop the medication and restart after 
24 hours with a reduced dose (decrease dosage by 0.5 mg dose-equivalent TID).
The sex- and age-adapted height percentile will be determined using standard height charts 
(see 18.1, Appendix 1). Age-, sex- and height-adapted levels of the 50th BP percentile will be 
determined according to Table 4–1 and Table 4–2.
If at any time, the subject has symptoms of hypotension, decrease the dosage by 0.5-mg dose 
equivalent TID. 
At the end of the individual titration period (Visit 4), the subjects should have reached their 
individually adjusted dose (maximum equivalent dose of 2.5 mg riociguat TID). The 
established individual equivalent dose will then be taken as optimal dose to be administered 
during the 16-week maintenance period. Dose reductions for safety reasons are allowed in the 
maintenance phase, but a subsequent re-increase is not possible. During the LTE phase the 
dose may be up-titrated at the investigator’s discretion. 
Subjects not tolerating the body-weight adjusted riociguat 0.5 mg TID will be withdrawn 
from study.
The respective decision (increase, maintain, decrease) will be entered into the IxRS system. 
The study medication for the next 2-4 weeks will be dispensed to the subjects. 
Dose interruptions
In the case an interruption takes place during the individual dose titration period and lasts 
longer than 3 consecutive days (9 doses missed), it is not allowed to restart the study 
medication again (respective subjects must be withdrawn from the trial).
In case an interruption takes place after completion of the titration period and lasts longer than 
14 consecutive days, it is not allowed to restart the study medication again. In case of shorter 
interruptions, study medication can be restarted at the discretion of the investigator. Dose 
interruptions will be communicated to the DMC and/or SC.
(Note: The dose titration algorithm, dose up-titration in the LTE phase, and wording under 
dose interruptions were clarified according to Amendment 9, see Sections 17.4.1.10, 17.4.1.6
and 17.4.1.9.)
Subject identification
5.2
At screening Visit 0 and after having obtained informed consent and, if applicable, child 
assent has been provided, each subject will be assigned a unique 9-digit subject identification 
(SID) number by IxRS for unambiguous identification. The first 2 digits represent the country 

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code, the next 3 digits represent the center code, and the last 4 digits represent a sequential 
number assigned to each subject.
Subject identification numbers must be used in sequence and no number should be skipped, 
substituted or re-used.
Duration of study treatment - amended
5.3
During the individual dose titration period with a maximum duration of 8 weeks, the 
individual maximum equivalent dose will be established. Subjects will be treated on this 
body-weight adjusted dose level during the 16-week maintenance period as long as well 
tolerated. Subjects who have completed 24 weeks of treatment will be offered participation in 
the Long Term Extension (LTE) phase.
(Note: Wording describing the LTE in this section was modified according to Amendment 3, 
see Section 17.1.1.1.)
Formulation and dose - amended
5.4
Riociguat will be provided by Bayer as film-coated tablets and granules for reconstitution in 
an oral suspension (0.15 mg/mL), see Table 5–1. The following tablet strength will be 
available: 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, and 2.5 mg. For the application of the oral 
suspension, two sizes of dosing pipettes, manufactured by Raumedic, which are considered 
medical devices (therefore also called LDD- Liquid Dosing Device), are available and 
certified. These dosing pipettes are designed to deliver between 1 mL and 5 mL with 0.25 mL 
dosing increments as well as 2 mL to 10 mL with 0.5 mL dosing increments. These
increments were chosen to enable accurate bodyweight-adjusted dosing. Further details on the 
dose-measuring pipettes for the oral suspension formulation are given in detail in the 
suspension manual.
Tablets and oral suspension will be administered orally in a TID regimen.
Subjects <50 kg at baseline will receive riociguat oral suspension during the initial 24-week 
treatment phase.
Subjects ≥50 kg at baseline will receive oral tablets. If the BW decreases below 50 kg, then 
the IXRS will deliver the oral suspension.
During the long-term extension phase, subjects receiving stable dose of 1.0 mg, 1.5 mg, 
2.0 mg, or 2.5 mg TID as oral suspension, can switch to the tablet formulation according to 
the discretion of the investigator provided the body weight is ≥50 kg (for details on tablet and 
suspension body-weight adjusted equivalent dosing, see Table 5–2.) 
(Note: The text was modified according to Amendment 3, see Section 17.1.1.13.)

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Table 5–1: Identity of investigational product
International non-
proprietary name (INN)
Riociguat 
Sponsor’s internal 
reference number
BAY 63-2521
Formulation
Film-coated tablets
Oral suspension
Galenical form
Round immediate-released tablets, 
diameter 6 mm
Granules
Composition
Active ingredient: Methyl-N-[4,6-diamino-2-[1-[(2-fluorphenyl)methyl]-1H-
pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl]-N-methyl-carbaminate
Empirical formula: C20H19FN8O2
Molar mass: 422.42 g/mol (molarity)
Excipients: lactose, 
microcrystalline cellulose, 
magnesium stearate, 
crospovidone, hypromellose, and 
sodium lauryl sulphate 
Coating: hydroxypropyl cellulose, 
hypromellose, propylene glycol, 
iron oxide (red and yellow), and 
titanium dioxide.
Excipients: mannitol, 
microcrystalline cellulose and 
carmellose sodium, hypromellose, 
sodium benzoate, citric acid, 
xanthan gum, sucralose, 
strawberry flavor 
Strength
0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, 
and 2.5 mg
0.15 mg/mL
Material numbers
83296470 BAY 63-2521 TABL 0.5 
mg 511 COAT
83296535 BAY 63-2521 TABL 1.0 
mg 512 COAT
83296543 BAY 63-2521 TABL 1.5 
mg 513 COAT
83296578 BAY 63-2521 TABL 2.0 
mg 504 COAT
83296608 BAY 63-2521 TABL 2.5 
mg 515 COAT
84367923 BAY 63-2521 GRAN 
SUSP 0.3%
Packaging
High-density polyethylene bottles
Brown glass bottles
Abbreviation: TABL = tablet
All subjects will receive body-weight-adjusted dose of riociguat. The starting dose will be the 
body weight-adjusted equivalent of the 1.0-mg dose in adults. Guidelines on how to prepare 
the oral suspension are provided to the subjects/parents.
The body-weight-adjusted riociguat dosing schedule is provided in Table 5–2.

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Table 5–2 : Body weight-adjusted riociguat dosing schedule
Body 
weight
(kg)
0.5 mg 
equivalent 
TID (mg)/
equivalent 
volume of 
suspension 
TID (mL)*
1.0 mg 
equivalent 
TID (mg)
equivalent 
volume of 
suspension 
TID (mL)*
1.5 mg 
equivalent 
TID (mg)
equivalent 
volume of 
suspension 
TID (mL)*
2.0 mg 
equivalent 
TID (mg)
equivalent 
volume of 
suspension 
TID (mL)*
2.5 mg 
equivalent 
TID (mg)
equivalent 
volume of 
suspension 
TID (mL)*
≥12<14
0.12
1.0
0.25
1.75
0.37
2.50
0.50
3.25
0.62
4.25
≥14 <16
0.14
1.0
0.28
1.75
0.42
2.75
0.56
3.75
0.70
4.75
≥16 <18
0.15
1.0
0.31
2.00
0.46
3.00
0.62
4.25
0.77
5.00
≥18 <20
0.17
1.0
0.33
2.25
0.50
3.25
0.67
4.50
0.83
5.50
≥20 <25 
0.19
1.25
0.38
2.50
0.57
3.75
0.75
5.00
0.94
6.50
≥25 <30
0.22
1.50
0.44
3.00
0.66
4.25
0.87
6.00
1.09
7.50
≥30 <35 
0.25
1.75
0.50
3.25
0.74
5.00
0.99
6.50
1.24
8.50
≥35 <40 
0.28
1.75
0.56
3.75
0.84
5.50
1.12
7.50
1.41
9.50
≥40 <50 
0.33
2.25
0.66
4.50
1.00
6.50
1.33
9.00
1.66
11.00
≥50
0.50
3.25
1.00
6.50
1.50
10.00
2.00**
13.50
2.50**
16.50
Abbreviations: TID = three times daily
* For facilitation of administration of a proper body-adjusted dose, the volumes of suspension are provided with increments of 0.25 mL (for 1-5 mL) 
and 0.5 ml (for over 5 ml)
** For change in weight category from 40-<50 kg to ≥ 50 kg, IXRS will administer intermediate dose to adjust to 0.5 mg increment (e.g. intermediate dose for 
2.0 mg equivalent is 1.50 mg /10.00 mL; for 2.5 mg equivalent is 2.00 mg / 13.50 mL).
(Note: The table was modified according to Amendment 3, see Section 17.1.1.6.)

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Packaging, labeling, and storage
5.5
All study medication will be labeled according to local law and legislation. Also, a system of 
numbering in accordance with Good Manufacturing Practice (GMP) will be used, ensuring 
that each dose of study medication can be traced back to the respective bulk ware of the 
ingredients. Further details are provided in a separate manual.
A complete record of batch numbers and expiry dates of all study medication provided by 
Bayer, as well as the labels, will be maintained in the study file.
All study medication need to be stored at the site according to the labeled storage advice in 
accordance with Good Clinical Practice (GCP) and GMP requirements. 
The study drug is to be kept in a secure area. The responsible site personnel will confirm 
receipt of study medication via IxRS and will use the study medication only for this study and 
in accordance with this protocol. Receipt, distribution, return and destruction (if any) of the 
study medication must be properly documented according to specified procedures.
Treatment assignment - amended
5.6
After enrolment, the subject identification number will be recorded on the corresponding 
electronic case report form (eCRF). The subject identification number will also have to be 
recorded on the label of the study medication.
In case bosentan or other ERA and/or PCA is/are provided locally, the compound’s name, 
dose, quantity and batch number, or a copy of the prescription has to be included in the 
subject’s files.
(Note: The text was modified according to Amendment 3, see Section 17.1.1.11.The text was 
modified according to Amendment 6, see Section 17.3.1.9.)
Study treatment delivery and compliance assessment
5.7
All empty packaging and unused study drug will be returned at all study visits. All non-used 
study medication will be kept securely in a designated locked container. Tablets and 
suspension volumes will be counted for a compliance check. The investigator should ensure 
adequate subject compliance. 
6.
Study procedures
Study visits - amended
6.1
The main study part comprises 3 periods:

Pre-treatment period (Screening): up to 2 weeks. This period is to identify potential 
eligibility of subjects who have been diagnosed with PAH. This visit will take place 
up to 2 weeks before Visit 1 (baseline visit).

Main study (Active) treatment period: 24 weeks (titration phase: 8 weeks, 
maintenance phase: 16 weeks):
o
The individual titration phase comprises 4 visits 2 weeks (±2 days) apart.
o
The maintenance phase comprises 5 visits 4 weeks (±5 days) apart.

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
Follow-up period: at least 60 days for serious adverse events (SAEs). (Only for 
patients who do not enter the long-term extension study or who stop the study 
medication prematurely.) 
Subjects who have completed 24 weeks of treatment will be offered participation in an 
optional long term extension phase. Subjects not entering the LTE phase will perform the 
safety follow-up visit (see section 6.1.4). Subjects completing the optional LTE will also 
perform the safety follow up visit after 60 + 8 days after LTE. Subjects dropping-off the 
protocol any time after Visit 1 and before Visit 9 will perform an end-of-treatment visit (see 
section 6.1.3).
The titration visits have to be performed at the study site. Only visits at Week 12 and/or Week 
20 (Visit 6 and/or Visit 8) might be performed as home visits by an experienced nurse/ 
healthcare practitioner in close contact with the treating investigator, when no further titration 
is scheduled and subjects are on stable dose. The decision to delegate the responsibility to 
visit the subject is at the discretion of the investigator, must be consistent with regional 
medical practice, and in accordance with regional legal requirements. The responsibility must 
be documented on the delegation log and signed by the investigator. At the end of the titration 
phase (Week 8, Visit 5) patients will have reached riociguat doses between 0.5 mg TID and 
2.5 mg TID.
(Note: The wording describing LTE was modified according to the Amendment 3, see Section 
17.1.1.1.The Section was modified according to Amendment 6, see Section 17.3.1.2.)
6.1.1
Pre-treatment phase (Visit 0, Day -14 to -1) - amended
The parents/legal guardians and children will be given an explanation about the study and will 
be given sufficient time to consider their participation in the study and to ask any questions. 
Afterwards, informed consent and, if applicable, assent will be obtained (see section 11.2). 
Collection of AEs starts after informed consent is signed. If the subject passes the screen of 
inclusion and exclusion criteria, the subject will be eligible to enter the study. The following 
procedures will be performed if no historical data (not older than 30 days) are available:

Obtain demographics (incl. smoking status) and medical history

Record concomitant PAH specific medication

Perform physical examination (incl. height, weight, vital signs and pubertal 
assessment using Tanner scale [see section 18.3])

Obtain blood sample if AST, ALT, creatinine, blood urea nitrogen (BUN), gamma-
glutamyltransferase (GGT), uric acid (UA), total bilirubin (T-Bil), Albumin (Alb), 
Sodium (Na), potassium (K), Calcium (Ca), P and complete blood count (CBC) are 
not available within 30 days prior to screening visit

Perform ECG (electrocardiogram)

Pregnancy test for females of childbearing potential

Child Health Questionnaire (SF-10 and PedsQL Generic Core Scales self-report) 
(section 18.2 and 18.7)

In case RHC has been performed for a study subject before enrollment, record the 
most recent RHC parameters to the eCRF (timing of RHC not limited to the period of 
Day -14 to -1)

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(Note: The text was modified according to Amendment 3, see Sections 17.1.1.8 and 17.1.1.16.
The Section was modified according to Amendment 5, see Sections 17.2.1.1 and 17.2.1.2. The 
Section was modified according to Amendment 6, see Sections 17.3.1.2 and 17.3.1.3. The 
Section was modified according to Amendment 9, see Section 17.4.1.8.)
6.1.2
Main study treatment period - amended
Individual titration phase (Visit 1 – Visit 4) - amended
6.1.2.1
At Visit 1, subjects should come to the hospital for the riociguat morning dose. At Visits 2
and 4, subjects are allowed to take the riociguat morning dose up to midday. The following 
procedures will be performed during the titration period:

Procedures and assessments for the baseline visit (Visit 1) should be completed within 
the span of one day

Re-confirm in-/exclusion criteria (Visit 1 only, prior to study drug intake)

Record concomitant medication incl. concomitant PAH specific medication

Perform physical examination (incl. height, weight and vital signs)

Pregnancy test for females of childbearing potential (at Visit 1 and Visit 3)

Decide on the next dose based on the titration algorithm and dispense study 
medication
o
Instruct how to take study drug
o
Provide study guidelines for dosing/suspension (Visit 1 only)

Determine WHO functional class (Visit 1 only)

Perform echocardiogram (Visit 1 only)

Perform electrocardiogram (Visit 1 only)

X-ray of left hand for determination of bone age (Visit 1 only: if no historical data [not 
older than 30 days] are available)

Perform 6MWD test (Visit 1 only)

Collect PK sample (Visit 1 and 3), for details see Table 0–2

Collect NT-proBNP or BNP (Visit 1 only; when both tests are available, NT-proBNP 
should be chosen over BNP and the same test should be performed at every required 
visit)

Check adverse events including adverse events of special interest

Check the systolic BP monitoring form provided by the patients at the visit, if 
applicable (Visit 2 – 4)

Check drug accountability (Visit 2 – 4)

Taste assessment questionnaire (Visit 1 only) (section 18.4)

Record laboratory parameters (AST, ALT, BUN, creatinine, GGT, UA, T-Bil, Alb, 
Na, K, Ca, P, and CBC) to eCRF when obtained as medically required according to a 

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local package insert of bosentan or other ERA, or medical practice at the study site at 
any time.

In case RHC is conducted based on medical reasons during the study, record RHC 
parameters to eCRF
(Note: The Section was modified according to Amendment 3, see Sections 17.1.1.8 and 
17.1.1.16. The Section was modified according to Amendment 5, see Sections 17.2.1.1 and 
17.2.1.2.The section was modified according to Amendment 6, see Sections 17.3.1.2 and 
17.3.1.6. The section was modified according to Amendment 9, see Section 17.4.1.5.)
Maintenance phase (Visit 5 - Visit 9) - amended
6.1.2.2
Subject should take the riociguat morning dose at home as usual, except of Visit 5, where the 
morning dose will be taken at the hospital. The following procedures will be performed 
during the maintenance period:

Record concomitant medication incl. concomitant PAH specific medication

Perform physical examination (incl. height, weight, vital signs and at Visit 9 only, 
pubertal assessment using Tanner scale) 

Collect PK sample (Visit 5 only, for details see Table 0–2)

Pregnancy test for females of childbearing potential 

Dispense study medication
o
Instruct how to take study drug

Check adverse events including adverse events of special interest

Check the systolic BP monitoring form provided by the patients at the visit, if 
applicable

Check drug accountability

Determine WHO functional class (Visit 9 only)

Perform echocardiogram (Visit 9 only)

Perform electrocardiogram (Visit 9 only)

Perform 6MWD (Visit 9 only)

Collect NT-proBNP or BNP (Visit 9 only; when both tests are available, NT-proBNP 
should be chosen over BNP and the same test should be performed at every required 
visit)

X-ray of left hand for determination of bone age (Visit 9 only)

Child Health Questionnaire (SF-10 and PedsQL Generic Core Scales self-report)
(Visit 9 only)

Taste assessment questionnaire (Visit 9 only)

Obtain laboratory parameters (AST, ALT, BUN, creatinine, GGT, UA, T-Bil, Alb, Na, 
K, Ca, P, and CBC) at Visits 5 and 9 as well as record the same parameters when 

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obtained as medically required according to a local package insert of bosentan or other 
ERA, or medical practice at the study site at any time

In case RHC is conducted based on medical reasons during the study, record RHC 
parameters to eCRF
(Note: The Section was modified according to Amendment 3, see Sections 17.1.1.8, 17.1.1.14, 
and 17.1.1.16. The Section was modified according to Amendment 5, see Sections 17.2.1.1
and 17.2.1.2. The section was modified according to Amendment 6, see Sections 17.3.1.2,
17.3.1.3, and 17.3.1.6. This section was modified according to Amendment 9, see Section 
17.4.1.13.)
6.1.3
End-of-treatment visit - amended
For all subjects dropping-off the protocol at any time after V1 and before V9, an end-of-
treatment visit has to be performed.
The same procedures as at Visit 9 will be performed with the exception of the x-ray of left 
hand. 
In case RHC is conducted based on medical reasons during the study, record RHC parameters 
to eCRF.
(Note: The Section was modified according to Amendment 3, see Section 17.1.1.16. 
The Section was modified according to Amendment 5, see Section 17.2.1.2. This section was 
modified according to Amendment 9, see Section 17.4.1.13.)
6.1.4
Safety follow-up visit - amended
For all subjects stopping study medication either at the end of treatment or prematurely 
discontinuing the study at any time, a follow-up visit 60 days (±8 days) after last study 
medication intake has to be performed.
For subjects directly proceeding with treatment in the long-term extension phase, a safety 
follow-up visit 60 days (+8 days) will be scheduled either at the end of optional LTE phase, 
when patient’s transition to approved and commercially available riociguat in the respective 
country is possible, or when prematurely discontinuing LTE phase at any time. 
The following procedures will be performed:

Record concomitant medication incl. concomitant PAH specific medication

Perform physical examination (incl. height, weight and vital signs)

Pregnancy test for females of childbearing potential 

Check adverse events including adverse events of special interest

Record laboratory parameters (AST, ALT, BUN, creatinine, GGT, UA, T-Bil, Alb, 
Na, K, Ca, P, and CBC) to eCRF when obtained as medically required according to a 
local package insert of bosentan or other ERA, or medical practice at the study site at 
any time

In case RHC is conducted based on medical reasons during the study, record RHC 
parameters to eCRF
(Note: The safety follow up visit added to concern all subjects as well as the wording was 
changed according to Amendment 3, see Section 17.1.1.4. The Section was modified 

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according to Amendment 5, see Sections 17.2.1.1 and 17.2.1.2.The section was modified 
according to Amendment 6, see Section 17.3.1.2.)
6.1.5
Unscheduled visit - amended
If deemed necessary, it is at the investigator’s discretion to arrange additional visits. The 
following procedures will be performed:

Record concomitant medication incl. concomitant PAH specific medication

Perform physical examination (incl. height, weight and vital signs)

Dispense study medication (if required)
o
Instruct how to take study drug

Check adverse events including adverse events of special interest

Update eCRF

Record laboratory parameters (AST, ALT, BUN, creatinine, GGT, UA, T-Bil, Alb, 
Na, K, Ca, P, and CBC) to eCRF when obtained as medically required according to a 
local package insert of bosentan or other ERA, or medical practice at the study site at 
any time

In case RHC is conducted based on medical reasons during the study, record RHC 
parameters to eCRF
(Note: The Section was modified according to Amendment 5, see Sections 17.2.1.1 and 
17.2.1.2.The Section was modified according to Amendment 6, see Section 17.3.1.2.)
6.1.6
Optional long-term extension phase (until adulthood or approval in the 
indication and commercial availability) - amended
Children who require treatment with riociguat for more than 24 weeks will be offered 
participation in the optional extension phase. Subjects who become 18 years of age will 
continue to receive their individually optimal dose of riociguat (drug) from the clinical supply 
for up to 6 months to allow the transition to commercial product to complete as locally 
applicable.
The following procedures will be performed:
Every 3 (± 14 days) months

Record concomitant medication incl. concomitant PAH specific medication

Pregnancy test for females of childbearing potential
Pregnancy testing is to be performed in 4-weekly intervals starting at Visit 1 until 4 
weeks after the patient stops intake of study drug. If the interval falls on a visit date 
pregnancy testing is to be performed locally while at all other dates the patient is to 
perform a urine dipstick test at home. The results are to be documented in the eCRF 
and in the patient file.  The result of every home urine pregnancy test should be 
actively requested by the site as soon as the test is due. The patient must report a 
positive result to the site without delay. The results are to be documented in the eCRF 
and in the patient file in a timely manner. It is not acceptable to obtain the result only 
at the next scheduled visit at the site.

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
Perform physical examination (In the long term extension phase the physical 
examination includes monitoring of growth velocity in addition to the. height, weight 
and vital signs) 

Dispense study medication
o
Instruct how to take study drug

Check drug accountability

Check adverse events including adverse events of special interest

Exploratory efficacy (6MWD test, WHO FC, NT-proBNP or BNP[when both tests are 
available, NT-pro-BNP should be chosen over BNP and the same test should be 
performed at every required visit], QoL [SF-10 and PedsQL Generic Core Scales self-
report], echocardiography, TTCW)

If needed and to reduce burden, 6MWD test and echocardiography can be performed 
at every second visit in LTE at the discretion of the investigator

Record laboratory parameters (AST, ALT, BUN, creatinine, GGT, UA, T-Bil, Alb, 
Na, K, Ca, P, and CBC) to eCRF when obtained as medically required according to a 
local package insert of bosentan or other ERA, or medical practice at the study site at 
any time

In case RHC is conducted based on medical reasons during the study, record RHC 
parameters to eCRF

X-ray of the left hand will be performed every 12 months until growth plates are 
closed

Pubertal assessment using Tanner scale will be performed every 12 months

Perform the Child Health-related Questionnaire (SF-10) and PedsQL. The age version 
used must match with subject´s actual age at time of completing the questionnaire.
(Note: The wording was modified according to Amendment 3, see Sections 17.1.1.1 and 
17.1.1.14. The Section was modified according to Amendment 5, see Sections 17.2.1.1 and 
17.2.1.2.The Section was modified according to Amendment 6, see Sections 17.3.1.2,
17.3.1.3, and 17.3.1.6. The Section was modified according to Amendment 9, see 
Section.17.4.1.13.)
Safety outcomes - amended
6.2
During the course of the study treatment-emergent adverse events (TEAEs), ECGs, bone age 
x-ray of left hand, laboratory tests, vital signs, body weight and frequency of premature 
discontinuations will be assessed.
The primary safety outcome is described as:
-
The change from baseline (V1, Day 0) to the end of treatment (V9, week 24) of:

Heart rate

Blood pressure

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
Bone age x-ray of left hand 

Laboratory parameters (see description in respective section below)
-
The assessment of:

Incidence of treatment-emergent adverse event

Incidence of treatment-emergent serious adverse events
Other safety outcomes are the changes from baseline (V1, Day 0) to the end of treatment (V9, 
week 24) of:

ECG parameters
Bone monitoring
Skeletal development will be assessed throughout the study trial.
During the main study period, x-ray of left hand will be performed before study drug intake 
(Visit 1) and at week 24 (Visit 9). For those patients entering the extension phase, the x-ray of 
left hand will be performed every 12 months until growth velocity is plateauing and growth 
plates are closed. 
Bone age and also bone morphology will be determined centrally by a specialist. Every 12 
months until growth velocity is plateauing and growth plates are closed, the subject’s overall 
development will also be assessed by physical examination, growth chart evaluation and 
pubertal development using Tanner scale, and at the discretion of the investigator in case of 
clinical suspicion for bone and/or growth anomalies.
This data will be reviewed on an ongoing basis by the DMC.
Laboratory parameters
Laboratory parameters will be collected at V0 (if no historical data is available), V5 and V9. 
Hematology: CBC
General Chemistry: AST, ALT, Creatinine, BUN, GGT, UA, T-Bil, Alb, Na, K, Ca, 
and P
Afterwards; any additional collection of laboratory parameters will be obtained in case 
medically required according to a local package insert of bosentan, or other ERA, or medical 
practice at the site at any time point and will be captured in the eCRFs.
Echocardiograph 
Echocardiographic parameters will be evaluated centrally by a specialist during the main 
study phase and optional long term extension. Details are specified in the respective Imaging 
documents.
(Note: The paragraph Laboratory parameters was added by Amendment 3, see Section
17.1.1.7. The paragraph was modified according to Amendment 5, see Sections 17.2.1.1 and 
17.2.1.4.The Section was modified according to Amendment 6, see Section 17.3.1.2.)
Efficacy/Pharmacodynamic/Other outcomes - amended
6.3
Main secondary endpoints will be assessed as:

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Change from baseline to end of treatment (week 24) of:

6-Minute Walking Distance (6MWD)

WHO functional class

Lab N-terminal prohormone brain-type natriuretic peptide or brain-type natriuretic 
peptide (when both tests are available, NT-proBNP should be chosen over BNP and 
the same test should be performed at every required visit)

Quality of Life scores (parent questionnaire and in children able to understand 
questions): Child Health-related Questionnaire (SF-10) and PedsQL Generic Core 
scales self-report

Echocardiographic parameters including pulmonary arterial systolic pressure (PASP), 
right ventricular pressure by tricuspid regurgitant jet velocity, tricuspid annular plane 
systolic excursion (TAPSE), pericardial effusion, left ventricular eccentricity index, 
estimated right atrial pressure, acceleration time of the pulmonary flow, right heart 
dimensions, and computing of cardiac output.
Time to clinical worsening

Hospitalization for right heart failure

Death

Lung transplantation

Pott’s anastomosis and atrioseptostomy

Worsening of PAH symptoms, which must include either:
o
an increase in WHO FC 
OR
o
appearance/worsening symptoms of right heart failure
AND
need for additional PAH therapy.
Other endpoints assessed in the study will be: 

Taste and texture of the pediatric formulation(s) must be assessed by use of a 
questionnaire at the beginning and at the end of treatment (week 24).

Right heart catheterization
A change in RHC parameters (if available) obtained from RHC performed before 
study enrollment and during study conduct.
(Note: The paragraph was modified according to Amendment 5, see Sections 17.2.1.2, 
17.2.1.3 and 17.2.1.7.The Section was modified according to Amendment 6, see Sections
17.3.1.2, 17.3.1.3, and 17.3.1.6. This section was modified according to Amendment 9, see 
Sections 17.4.1.7 and 17.4.1.13.)

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Pharmacokinetics/Pharmacodynamics analyses - amended
6.4
Blood samples will be taken for pharmacokinetic and pharmacodynamic measurements from 
all participants treated with riociguat. 
The number of PK blood samples to be taken has been optimized using physiologically based 
pharmacokinetic (PBPK) modelling predictions in conjunction with clinical trials simulations 
(CTS) in order to only collect the minimum amount of blood needed for adequate analysis 
(sparse sampling).
Based on these evaluations the following measures to minimize pain and distress have been 
included: the number of blood samples in children from 6 to less than 18 years of age for PK 
analysis must not exceed four, and the minimum amount of blood needed for adequate 
analysis of each sample is 1.0mL of blood.
The following blood samples will be taken:
Visit 1: 2 PK samples will be taken: the first at 0.5 to 1.5 h and the second at 2.5 to 4 h post-
dose. Preferred proposal is to have both post-dose samples at the first visit. (To ensure having 
PK samples in case of drop-outs, both “early post-dose” samples should be collected at the 
first visit. If this is not feasible, the second post-dose sample can be taken at any visit.)
Visit 3 and Visit 5: Trough samples should be collected -1 to 0 hours before the morning 
dose at both visit 3 and visit 5, which is approx. 5 to 15h after the evening dose.
For all visits in the main study phase, the exact time of three riociguat dosings (current and 
the previous two doses) and time of PK blood sampling will be documented in the eCRF.
If, for any reason, PK samples are taken outside of the pre-specified time window, the exact 
time that the sample was taken should be recorded and not the pre-defined time window. If 
riociguat was temporarily stopped prior to a PK sample collection visit, sampling of blood for
PK analysis according to this visit's schedule should be postponed until riociguat treatment 
has been restarted and sustained for 3 days.
If PK samples are collected at an unscheduled visit or at a visit not foreseeing PK collection, 
the previous riociguat doses and the time of sampling should be documented like described 
above. Those samples may be included in the analysis.
Primary PK outcome measure:
Pre- and post-dose blood samples for PK characterization of riociguat and its active 
metabolite BAY 60-4552 will be collected during the titration and the maintenance phase of 
the study. For details, see section 7.4.3.
(Note: Wording in this Section was changed according to Amendment 3, see Section 
17.1.1.16. The wording was modified according to Amendment 6, see Section 17.3.1.2. This 
section was modified according to Amendment 9, see Section 17.4.1.13.)
Study guidelines for parents and children - amended
6.5
Parents/children will receive study guidelines, specifying:

The local medical contact person and local emergency telephone number

The dates of hospital visits and telephone calls, if applicable

Instructions to return empty medication packages and unused study medication  

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
Instructions on signs and symptoms of hypotension (systolic BP monitoring form).

How to take riociguat tablets or suspension

Calendar to track the date, time of study drug intake
(Note: This section was modified according to Amendment 9, see Section 17.4.1.13.)
Study committees
6.6
6.6.1
Steering Committee
The Steering Committee (SC) has the overall scientific responsibility of the study. Its tasks 
and responsibilities are:

To facilitate and approve the final protocol

To help select the investigators network

To support and organize the national logistics in the initiation and conduct of the 
study

To ensure a scientifically sound and safe conduct of the study

To consider the DMC recommendations

To monitor progress of study enrollment

To assist in the analysis and presentation of the results

To decide on the publication and presentation policy of final results.
6.6.2
Data Monitoring Committee
This independent committee has the responsibility to provide the SC and the sponsor with 
recommendations related to the protection of the subjects safety, including stopping 
recruitment and study treatment. For that purpose, the DMC will regularly review all 
incidences of serious adverse events and adverse events of special interest. Organizational 
aspects, responsibilities, and processes will be described in the DMC charter.
For all subjects reaching week 24 of the main study treatment phase and all subjects 
continuing in the LTE, the left hand x-rays will be evaluated by the DMC. The DMC will be 
provided with all relevant documentation on an ongoing basis. 
After 5 patients in the ≥12 to <18 years old group have reached their optimal dose, have been 
treated on their maintenance dose and obtained the control x-ray of left hand at week 24, their 
data will be evaluated by DMC. After agreement of the DMC, the enrolment of patients in the 
age group ≥6 to <12 years will start.
All cases of clinical worsening (as defined in protocol section 6.3) that occur after intake of 
first dose of study medication in the main study treatment phase - including the 60 day safety 
follow-up period (only for those patients not entering the LTE) - will be evaluated by the 
DMC. After the completion of the main study, the DMC will be provided with all relevant 
documentation related to the cases. 
Organizational aspects, responsibilities, and processes will be described in the DMC charter. 
DMC results will be included in the final analyses of the main study.

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7.
Statistical and analytical methods
General considerations
7.1
The plan described in the following sections will be detailed in a Statistical Analysis Plan 
(SAP). The SAP will accommodate protocol amendments. Any revision will be clearly 
identified in the final SAP, issued prior to data base lock. All efforts will be taken to avoid 
missing data in important baseline characteristics and post baseline data. Missing data 
proportions will be reported.
All variables will be analyzed descriptively with appropriate statistical methods: categorical 
variables using frequency tables and continuous variables by sample statistics, i.e. mean, 
standard deviation, minimum, median, quartiles and maximum.
Statistical analyses will be performed using SAS; the version used will be specified in the 
statistical analysis plan (SAP).
Analysis sets
7.2
Safety analysis set (full analysis set, FAS): this population will include all subjects assigned 
to receive study medication who received at least one dose of study medication.
Listing only set (LOS): this population includes all screening failures.
Demographic and other baseline characteristics
7.3
Demographic and baseline characteristics, medical history, concomitant PAH medications and 
patient disposition will be summarized for the FAS population. For continuous measurements, 
the mean, standard deviation, range and median will be computed; for categorical values, the 
frequency and percent will be provided. Medical history findings (i.e. previous diagnoses, 
diseases or surgeries) will be summarized using Medical Dictionary for Regulatory Activities 
(MedDRA) terms.
Analyses
7.4
A descriptive analysis of the safety and efficacy parameters will be performed.
(Note: The section was modified according to Amendment 6, see Section 17.3.1.2.)
7.4.1
Safety analysis - amended
The primary objective is to evaluate the safety and tolerability of riociguat in children with 
PAH. Primary endpoint of the study is: Change from baseline to end of treatment (week 24) 
of safety and tolerability assessed by incidence of adverse events and serious adverse events, 
recording of vital signs and left-hand X-ray and laboratory panel.
The safety evaluation of adverse event (AE) data will include:

The incidence of treatment-emergent AEs (TEAEs). Adverse events are considered to 
be treatment-emergent if they have started or worsened after first application of study 
drug up to 2 days after end of treatment with study drug. 

Tables of serious and/or drug-related treatment-emergent AEs, treatment-emergent 
AEs leading to discontinuation of study drug and AEs of special safety interest. 

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
The incidence of AEs during pre-treatment and during follow-up (i.e. AEs occurring 
more than 2 days after end of treatment with study drug). 

Listings of serious adverse events (SAEs), AEs leading to discontinuation of study 
drug and AEs of special safety interest.

Descriptive summaries of mortality in the study. 

Listing of deaths in the study period, including day of death relative to start and stop 
of study drug and cause of death.
The safety evaluation of laboratory data will include:

Incidence rates of treatment-emergent laboratory values outside of normal range

Incidence rates of pre-specified laboratory data abnormalities

Descriptive analysis of laboratory parameters (AST, ALT, BUN, creatinine, GGT, 
UA, T-Bil, Alb, Na, K, Ca, P, and CBC) and their corresponding changes from 
baseline
Other evaluations of safety data will include:

Descriptive analysis of body weight, vital signs, ECG parameters, left hand x-ray and 
their corresponding changes from baseline.

Tabulation of ECG status pre-dose, 2 and 4 hours post treatment-initiation.

Incidence rates of treatment-emergent ECG abnormalities. 
Time points of assessment: Assessment of adverse events at baseline, at all visits in the 
titration phase and maintenance phase, and every 3-4 months in the extension phase. Left 
hand x-ray at baseline, end of study treatment period (week 24) and every 12 months until 
growth plates are closed.
For details on safety variables, see section 6.2.
(Note: The wording in this section was modified according to the Amendment 3, see Section
17.1.1.8. The wording in this section was modified according to Amendment 5, see Section
17.2.1.1.The Section was modified according to Amendment 6, see Section 17.3.1.2.)
7.4.2
Efficacy analysis - amended
Other objectives are to characterize the pharmacodynamic profile of riociguat using the 
following parameters: time to clinical worsening (TTCW), exercise capacity (6MWD test), 
functional capacity (measured by WHO FC), laboratory biomarkers (NT-proBNP or BNP
[when both tests are available, NT-proBNP should be chosen over BNP and the same test 
should be performed at every required visit]), echocardiographic parameters and QoL 
measurements (SF-10 and PedsQL Generic Core Scales self-report).
Continuous efficacy parameters will be analyzed descriptively by sample summary statistics. 
Time points of efficacy assessment: Exploratory efficacy at baseline and week 24 and every 3 
to 4 months in the extension phase.
Categorical efficacy parameters will be analyzed descriptively by frequency tables.
RHC parameters (if available) will be analyzed descriptively by summary tables.
For details on the exploratory efficacy variables, see section 6.3.

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(Note: The section was modified according to Amendment 5, see Section 17.2.1.2. The Section 
was modified according to Amendment 6, see Sections 17.3.1.2, 17.3.1.3, and 17.3.1.6.)
7.4.3
Pharmacokinetic analysis - amended
The number of blood samples to be taken for the assessment of pharmacokinetic parameters 
was determined using clinical trial simulation (CTS) based on the physiology based PK 
(PBPK) modeling predictions. In order to minimize pain and distress for the patient 
population, the number of PK samples was kept to the minimum. The minimum amount of 
blood needed for adequate analysis for each sample 1.0 mL of blood. For investigation of 
exposure behavior, plasma concentrations of BAY63-2521 and its active metabolite M1 
(BAY 60-4552) will be analyzed descriptively.
PK analyses using population approaches will be used to describe the pharmacokinetics of 
riociguat, including potential influence relevant subject covariables (e.g. age, gender, serum 
creatinine, etc.) and to relate pharmacodynamic parameters with riociguat plasma 
concentrations (PK/PD evaluations). Details will be given in a separate detailed PK/PD 
evaluation plan and will be reported separately.
(Note: This section was modified according to Amendment 9, see Section 17.4.1.13.)
7.4.4
Interim analyses
There is no interim analysis planned for this study.
7.4.5
Analyses - amended
The study results will be reported once all the pediatric subjects have completed their main 
study treatment period of 24 weeks. Thereafter only descriptive summaries of study data from 
the ongoing subjects will be provided.
(Note: The text was modified according to the Amendment 3, see Section 17.1.1.2.)
Determination of sample size - amended
7.5
Children on treatment with ERAs and/or PCAs can be enrolled. At least 20 subjects on 
treatment with bosentan or other Endothelin Receptor Antagonists (ERA) must be enrolled in 
the study. The sample size does not originate from a formal sample size calculation, but is 
based on an evidence-based feasibility assessment. Based on the results of the evidence-based 
feasibility survey (Davie, 2014) and the proposed PK evaluation (see section 7.4.3), 20 
patients will permit an accurate PK evaluation and feasibility of the study in a reasonable time 
frame. Every effort will be made to enroll equal numbers of patients in both age cohorts (see 
section 4.1).
(Note: The Section was modified according to Amendment 6, see Section 17.3.1.2. This 
section was modified according to Amendment 9, see Section 17.4.1.13.)
8.
Adverse events
Individual listings of adverse events will be provided. The incidence of treatment-emergent 
adverse events will be summarized, using MedDRA preferred terms, grouped by primary 
system organ class.

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Definitions
8.1
8.1.1
Adverse event (AE) - amended
An AE, including AE in relation to a medical device (i.e. Raumedic dosing pipette), is any 
untoward medical occurrence in a subject administered with a pharmaceutical product and 
does not necessarily have to have a causal relationship with this treatment. An AE can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a drug, whether or not considered 
related to the drug. AE associated with the use of a drug, whether or not considered drug-
related, includes AE occurring in the course of the use of a drug, from an overdose whether 
accidental or intentional, from drug abuse, from drug withdrawal, or if there is a reasonable 
possibility that the event occurred purely as a result of participation in the study, even if it is 
not related to the drug. AEs were considered to be treatment-emergent if they had started or 
worsened after the first dose of study medication up to 2 days after end of treatment with 
study medication. The clinical manifestation of any failure of expected pharmacological 
action is not recorded as an AE, if it is already reflected as an outcome captured in the eCRF, 
except if the event fulfills the criteria for a “serious” AE.
A surgical procedure or intervention that was planned prior to the study should not be 
recorded as an AE. Conditions, including abnormal physical examination findings, symptoms, 
and diseases will be recorded as medical history, if they started before providing written 
informed consent/assent. If the condition started or deteriorated after providing written 
informed consent/assent, it will be documented as adverse event.
Medical device related event is any occurrence or information the investigator becomes aware 
of regarding a medical device used in the study. Typical examples are:

Malfunction, failure or deterioration in the characteristics or performance, 

An inaccuracy in the labeling or instructions for use, 

Use error. 
(Note: The text was modified according to the Amendment 3, See section 17.1.1.13.)
8.1.2
Serious adverse event (SAE)
An SAE is any untoward medical occurrence that at any dose is resulting in death, is life-
threatening (i.e. the subject was at risk of death at the time of the event), requires 
hospitalization or prolongation of existing hospitalization unless the admission results in a 
hospital stay of less than 12 hours, is pre-planned (e.g. to perform routine RHC), or is not 
associated with an AE (i.e. social hospitalization for purposes of respite care), results in 
persistent or significant disability/incapacity. In addition, SAE is a congenital anomaly or a 
birth defect or an important medical event, including associated invasive treatment, as judged 
by the investigator. For reporting of a SAE, local regulations take precedence if more 
stringent definitions are applicable.
8.1.3
Unexpected AEs
An unexpected AE is any adverse drug event whose specificity or severity is not consistent 
with the investigator brochure or package inserts for marketed products. Also, reports which 
add significant information on specificity or severity of an already documented AE constitute 
unexpected AEs, e.g. an event more specific or more severe than described in the investigator 

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brochure would be considered “unexpected”. Specific examples would be 1) acute renal 
failure as a labeled adverse event with a subsequent new report of interstitial nephritis and 2) 
hepatitis with a first report of fulminant hepatitis.
Relationship of AE to study drug
8.2
The assessment of the causal relationship between an AE and the use of study drug is a 
decision to be made by the investigator based on all available information at the time of the 
completion of the eCRF and is based on whether there was a "reasonable causal relationship" 
to the study drug. An assessment of "no" would include the existence of a clear alternative 
explanation, e.g. mechanical bleeding at surgical site, or non-plausibility, e.g. the subject
while on a bike is struck by an automobile when there is no indication that the study drug 
caused disorientation that may have caused the event. An assessment of "yes" indicates that 
there is a reasonable suspicion that the AE is associated with the use of the study drug. 
Factors in assessing the relationship of the AE to study drug include the temporal sequence 
from drug administration (the event should occur after the study drug is given) and the length 
of time from study drug exposure, recovery on study drug discontinuation (de-challenge), and 
recurrence on study drug re-introduction (re-challenge), underlying, concomitant, or 
intercurrent diseases should be evaluated in the context of the natural history and course of 
any disease the subject may have, concomitant medication or treatment and, finally, the 
pharmacology and pharmacokinetics of study drug. 
Causal relationship to protocol-required procedure
8.3
The assessment of a possible causal relationship between the AE and protocol-required 
procedure is based on the presence of a reasonable relationship.
Intensity of an AE, action taken and outcome
8.4
The intensity of an AE is assessed as mild (usually transient in nature and generally not 
interfering with normal activities), moderate (sufficiently discomforting to interfere with 
normal activities), and severe (prevents normal activities).
Any action on study drug to resolve the AE is to be documented as either: study drug 
withdrawn, interrupted, dose increased, dose not changed, dose reduced, not applicable or 
unknown. Other specific treatment(s) of AEs will be documented as: none, remedial drug 
therapy or other. The outcome of the AE is documented as: recovered/resolved, recovering/ 
resolving, recovered/resolved with sequelae, not recovered/not resolved, fatal or unknown.
Assessment and documentation of adverse events
8.5
After signing the informed consent, documentation of AEs including the AEs related to the 
medical device, must be supported by an entry in the subject’s file. A laboratory test 
abnormality considered clinically relevant, e.g. causing the subject to withdraw from the 
study, requiring treatment or causing apparent clinical manifestations, or judged relevant by 
the investigator, should be reported as an AE. Each event should be described in detail along 
with start and stop dates, severity, relationship to study drug, action taken and outcome. When 
assigning the cause of death, "death" should not be recorded as an AE on the AE page. 
Instead, "death" is the outcome of underlying AE(s).

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Reporting of serious adverse events
8.6
All investigators will be thoroughly instructed and trained on all relevant aspects of the 
reporting obligations for SAEs including the SAEs related to the medical device. This 
information, including all relevant contact details, is summarized in the investigator site file 
and will be updated as needed.
SAEs occurring after enrolment up to 30 days after the last study drug administration must be 
reported within 24 hours of the investigator’s awareness. Reports should be as complete as 
possible, and must be followed up until resolution or stabilization. When required, and 
according to local law and regulations, SAEs must be reported to the ethics committee and 
regulatory authorities. If reported, SAEs occurring after the protocol-defined observation 
period will be processed by Bayer according to all applicable regulations (i.e. notification of 
Independent Ethics Committees/Institutional Review Boards [IECs / IRBs] and other 
authorities).
Bayer will inform all investigational sites about the occurrence of suspected unexpected 
serious adverse reaction/s (SUSARs) according to all applicable regulations.
Expected AEs
8.7
The applicable reference document is the most current version of the investigator’s brochure 
(IB) / Company Core Data Sheet (CCDS). Overview listings of frequent events that have 
occurred so far in the clinical development are shown in the current IB. If relevant new safety 
information is identified, it will be integrated into an update of the IB and distributed. The 
expectedness of AEs will be determined by the sponsor according to the applicable reference 
document and according to all local regulations.
Adverse events of special interest
8.8
The following AEs are of special interest:

Symptomatic hypotension

Hemoptysis

Bone and/or growth anomalies
Symptomatic hypotension, hemoptysis as well as bone and/or growth anomalies have been 
defined as adverse events of special interest and must be documented accordingly in the 
corresponding adverse events of special safety interest pages in the electronic case report form 
(eCRF). Events of special interest should not automatically be upgraded by the reporting 
Investigator to serious. Declaration of an event as serious should only occur when one or 
more of the serious criterion (as defined in Section 8.1.2) is applicable.
Premature discontinuation of study medication
8.9
Subjects must be withdrawn from the study for the following reasons:

At their own request or at the request of their legally acceptable representative at any 
time during the study and without giving reasons, a subject may decline to participate 
further. The subject will not suffer any disadvantage as a result

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
If, in the investigator's opinion, continuation of the study would be harmful to the 
subject's well-being.

If any AE occurred which is not acceptable in the opinion of the investigator and / or 
participating parent(s)/legal representative(s) or subject

Occurrence of adverse drug reactions, which have from the investigator’s point of 
view, a negative impact on the subject’s individual risk-benefit ratio.

If treatment is interrupted for more than 3 days during any individual dose titration 
phase

If treatment is interrupted for more than 14 consecutive days during the maintenance 
phase.

In case a female subject of childbearing potential is not compliant with pregnancy 
testing

In case of lung transplantation

In case of pregnancy or breast feeding

In case that the subject fulfills one of the stopping criteria specified in Section 5.1.1

Subject does not tolerate the lowest possible riociguat dose (0.5 mg TID)

Patient with pulmonary hypertension associated with idiopathic interstitial 
pneumonias (PH-IIP)
Discontinuation of bosentan or other ERA treatment (i.e. due to elevated liver enzymes) 
during the course of the study does not mandate withdrawal of the subject from the study. 
Also, discontinuation PCA treatment, during the course of the study, does not mandate 
withdrawal of the subject from the study. The final decision of withdrawal will be the 
responsibility of the investigator.
The DMC may recommend stopping the trial due to an unfavorable risk benefit assessment 
during the course of the trial. The final decision to terminate will be the responsibility of the 
Sponsor.
If the subject or parent(s)/legal representative(s) withdraw(s) consent to treatment with study 
drug, the investigator will ask to continue with study visits as planned, only with the aim to 
collect potential study outcomes and AEs. If the subject/parent(s)/legal representative(s) state 
to the investigator that they no longer authorize to continue to obtain outcome data, this will 
be respected and documented in the source records, and no further study data will be 
collected.
In all subjects who prematurely discontinue study drug for other reasons than withdrawal of 
informed consent, study visits will take place as planned to collect potential study outcomes 
and AEs.
(Note the section was modified according to Amendment 6, see Sections 17.3.1.1 and 
17.3.1.2.)

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Pregnancies
8.10
The investigator must report to the sponsor any pregnancy occurring in a study subject, or in 
the study subject's partner, during the subject's participation in this study. The report should 
be submitted within the same timelines as an SAE, although a pregnancy per se is not 
considered an SAE. The outcome of the pregnancy should be followed up carefully, and any 
outcome of the mother or child should be reported. For the pregnancy of a study subject's 
partner, all efforts should be made to obtain similar information on course and outcome, 
subject to the partner’s consent. For all reports, the forms provided are to be used.
Appropriateness of procedures/measurements
8.11
The diagnostic methods to document safety and efficacy outcomes are standard methods in 
clinical practice and are used and generally recognized as reliable, accurate and relevant.
Device malfunction or failure and medical device related events reporting -
8.12
amended
Any device malfunction or failure including use errors or inadequacy in the labeling will be 
recorded by the clinical/investigational site, including all relevant device information, using 
the Product Technical Compliant (PTC) form, and forwarded within 24 hours to the Sponsor 
or Sponsor’s designee for evaluation and investigation.
A PTC is any report about a potential or alleged failure of a product in its quality (including 
the identity, durability, reliability, safety, efficacy or performance) or suspect counterfeit. The 
complaint may or may not represent a potential risk to the patient. 
There are three different situations, in which a PTC form might need to be filled out by the 
investigator.
1. When an AE is recorded, the investigator needs to check if a device malfunction or 
failure might be associated with the recorded AE.
2. When a device malfunction or device failure occurs, the investigator needs to assess 
whether an AE might have occurred in relation to the device complaint.
3. When a device malfunction, device failure, or use error occurs, without any associated 
AE, this also needs to be captured in the form, especially if it classifies as a near 
incident, and immediately forwarded to the sponsor for product technical complaints 
(PTC) investigation.
There are three different categories of medical related events (specified in the PTC form).
Incident
Any malfunction or deterioration in the characteristics and / or performance of a device, as 
well as any inadequacy in the labeling or the instructions for use which, directly or indirectly, 
led, might lead to or might have led to the death of a patient, or user or of other persons or to a 
serious deterioration in their state of health.
Any event which meets all three basic reporting criteria (a-c) is considered an incident and 
must be reported to the relevant National Competent Authority. The criteria are that:
a) An event has occurred
b) The suspension dosing device is suspected to be a contributory cause of the Incident.

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c) The event led, or might have led, to death or serious deterioration in state of health of a 
patient, or user, or other person
Other Reportable Incident (Near Incident)
Any incident that did not lead to death or serious deterioration in health, but it might do if it 
occurred again under less fortunate circumstances or without intervention of healthcare 
personnel. This may include cases without any medical event reported. 
Non-Incident
Any device related case that does not fulfill all the three basic incident criteria a-c listed in the 
definition of an “Incident” above. This includes reports of:

Deficiencies of a device which are always detected prior to its use

Event is caused by the patient’s condition

Service life or shelf life of the device is expired

Events which did not lead to serious deterioration in state of health or death, because a 
design feature protected against a fault becoming a hazard.

Events where the risk of a death or serious deterioration in state of health has been 
quantified and found to be negligibly small.
In case of an incident and other reportable incident a technical complaint form always needs 
to be completed.
Serious deterioration in state of health (=serious injury) is any AE in relation to a medical 
device if it: 

Resulted in a life-threating illness or injury, or 

Resulted in a permanent impairment of a body structure or a body function, or 

Required in-patient hospitalization or prolongation of existing hospitalization, or 

Resulted in medical or surgical intervention to prevent life-threating illness, or 
permanent impairment of a body function or damage to a body structure, or 

Led to fetal distress, fetal death or congenital abnormality or birth defect.
The details of the malfunction and medical circumstances will be captured on a PTC form and 
the eCRF for device-related events by the investigator and then returned to the sponsor or 
sponsor’s designee. The processing and reporting of all reportable device events (incidents / 
other reportable incidents) to the authorities will be done by the sponsor according to all 
applicable regulations. The final determination of reportability is made by the sponsor and not 
the clinical/investigational site based on the medical circumstances surrounding the event. 
The device manufacturer may recommend reporting an incident based on investigations, but 
the final determination of reportability is made by the sponsor.
Incidents / Other reportable incidents occurring after the protocol-defined observation period 
will be processed by the sponsor according to all applicable regulations.
Investigator’s notification of the sponsor
All investigators will be thoroughly instructed and trained on all relevant aspects of the 
investigator’s reporting obligations for incidents and serious public health threats related to 

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the suspension dosing device. This information, including all relevant contact details, is 
summarized in the investigator site file. This information will be updated as needed.
The sponsor will inform the device manufacturer about any incident or trend report and the 
manufacturer will then perform further evaluation and investigation of the device, as 
necessary, and exchange any significant information with the sponsor. The device 
manufacturer will inform the sponsor about necessary trend reports and will provide the 
required documentation after completing the respective investigation and statistical analysis. 
The sponsor will then notify the authorities of any trend reports according to all applicable 
regulations.
All devices that have malfunctioned or failed will be inventoried and returned to the device 
manufacturer. The devices should be stored in a hermetically sealed bag and labeled with the 
respective case reference. In cases where an AE is recorded in connection with the device 
malfunction or failure, the device should be sent immediately per courier to the device 
manufacturer. If any of the devices need to be replaced, the reason(s) will be documented. 
Additional clinical devices are provided for this purpose.
(Note: The section was modified according to Amendment 5, see Section 17.2.1.8.)
9.
Data handling and quality assurance
For all data entered into the eCRF, source documentation should be available at the site. A 
source document checklist will be used to identify the source data for all data points collected. 
In accordance with GCP and Bayer's/CRO’s procedures, monitors will review the protocol, 
study requirements, and responsibilities with the site staff, including identification and 
documentation of source data items. Sponsor and designee personnel will monitor the site to 
verify that data are authentic, accurate, and complete and that the safety and rights of 
participating subjects are being protected. In addition, they will assess if the study is 
conducted in accordance with the latest version of the protocol and study agreements. The 
investigator and the head of the medical institution (where applicable) agrees to allow the 
monitor direct access to all relevant documents.
Data processing
9.1
The data collection tool for this study will be a validated electronic system called RAVE and 
data will be entered into a validated database or data system (Tools for Syntactic Corpus 
Analysis [TOSCA]). Study data management will be performed in accordance with applicable 
Bayer’s/CRO’s standards. This is applicable for data recorded on eCRF as well as for data 
from other study sources. Internationally recognized and accepted dictionaries will be used for 
data coding.
Audit and inspection
9.2
Bayer's (or a designated contract research organization’s) quality assurance unit may conduct 
an audit to ensure compliance with GCP and regulatory requirements. The 
investigator/institution will be informed of the audit outcome. In addition, inspections by 
regulatory health authority representatives, ethic committees, and/or institutional review 
boards might occur and the site will notify Bayer immediately. The investigator/institution 
agrees to allow the auditor or inspector direct access to all relevant documents and allocate 

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time to the auditor/inspector to discuss any findings. Audits and inspections may occur at any 
time during or after completion of the study.
Archiving
9.3
Study documents will be archived safely and securely in such a way that they are readily 
available upon authorities' request. Subject and related hospital files will be archived 
according to local regulations and in accordance with the maximum period of time permitted 
by the hospital, institution or private practice. If the archiving procedures do not meet the 
minimum timelines required by Bayer, alternative arrangements will be made to ensure the 
availability of the source documents for the required period. The investigator/institution will 
notify Bayer if a change in archival arrangements occurs. The investigator site file will not be 
destroyed without Bayer's approval. The investigator's institution contract will contain all 
regulations relevant for the study center.
10.
Premature termination of the study
The investigator has the right to terminate participation in the study at any time.
Bayer has the right to close this study or study sites at any time, which may be due but not 
limited to the following reasons:

If the risk-benefit ratio becomes unacceptable due to, for example,
o
safety or efficacy findings from this study
o
results of parallel clinical studies.

If study conduct (e.g. recruitment rate; dropout rate; data quality; protocol compliance) 
does not suggest a proper completion of the trial within a reasonable time frame.
For any of the above closures, the following applies:

Closures should occur only after consultation between involved parties

All affected institutions must be informed, as applicable, according to local law.
All study materials will be returned to Bayer, except documentation that has to remain stored 
at the site. This documentation can only be destructed with approval from Bayer.
11.
Ethical and legal aspects
Ethical and legal conduct of the study
11.1
The procedures set out in this protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that Bayer and investigator abide by GCP 
guidelines and under the guiding principles detailed in the Declaration of Helsinki. The study 
will also be carried out in keeping with applicable local law(s) and regulation(s).
Documented approval from appropriate Independent Ethics Committees (IECs)/Institutional 
Review Boards (IRBs) will be obtained for all participating centers/countries before start of 
the study, according to GCP, local laws, regulations and organizations. When necessary, an 
extension, amendment or renewal of the IEC/IRB approval must be obtained and also 
forwarded to Bayer. The responsible unit (e.g. IEC/IRB, head of the study center/medical 
institution) must supply Bayer, upon request, a list of the IEC/IRB members involved in the 

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vote and a statement to confirm that the IEC/IRB is organized and operates according to GCP 
and applicable laws and regulations.
Strict adherence to all specifications laid down in this protocol is required for all aspects of 
study conduct; the investigator may not modify or alter the procedures described in this 
protocol.
Modifications to the study protocol will not be implemented by either Bayer or the 
investigator without agreement by both parties. However, the investigator or Bayer may 
implement a deviation from, or a change of, the protocol to eliminate an immediate hazard to 
the trial subjects without prior IEC/IRB/Bayer approval/favorable opinion. As soon as 
possible, the implemented deviation or change, the reasons for it and if appropriate the 
proposed protocol amendment should be submitted to the IEC/IRB/head of medical 
institution/Bayer. Any deviations from the protocol must be explained and documented by the 
investigator.
Child information and consent
11.2
All relevant study information will be summarized in an integrated subject information sheet, 
an informed consent and an informed assent form provided by Bayer or the study center. A 
sample child information and informed consent and assent form are provided as documents 
separate to this protocol. Consent will be asked from the parent(s)/ legal representative(s) and, 
if appropriate as determined by local regulation, age and individual subject capability, will be 
asked from the subject, according to country-specific regulations.
The investigator or designee will explain all relevant aspects of the study to the parent(s)/legal 
representative(s) and the subject, if applicable, prior to entry into the study.
The parent(s)/legal representative(s) and the subject, if applicable, will have ample time and 
opportunity to ask questions and will be informed about the right to withdraw from the study 
at any time without any disadvantage and without having to provide reasons for their 
decision.
The subject can only enter the study if the parent(s)/legal representative(s) voluntarily agree to 
sign and date the informed consent and the subject provides informed consent or assent, as 
appropriate and determined by local regulation, age and individual subject capability, and 
have done so. Then the investigator or designee will sign and date the forms. The 
parent(s)/legal representative(s) and the subject, if applicable, will receive a copy of the 
signed and dated form(s).
The signed informed consent and the assent form will remain in the investigator site file or, if 
locally required, in the subject’s file.
The informed consent/assent form and any other written information provided to the 
subject/parent(s)/legal representative(s) will be revised whenever important new information 
becomes available that may be relevant to the subject's consent, or if there is an amendment to 
the protocol that necessitates a change to the content of the subject information and/or the 
written informed consent/assent form. The investigator will inform the subject/parent(s)/legal 
representative(s) of changes in a timely manner and will ask the parent(s)/legal 
representative(s) and the subject, if applicable, to confirm participation in the study by signing 
the revised informed consent, and, if applicable, will ask the subject to provide informed 
assent as documented on the revised assent form. Revised informed consent/assent form and 
the subject information sheet must receive the IEC's/IRB's approval before implementation.

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In the event that informed consent is obtained on the date that baseline study procedures are 
performed, the study record or subject’s clinical record must clearly show that informed 
consent was obtained prior to these procedures.
12.
Investigators and other study participants
The principal investigator of each site must sign the protocol signature sheet before 
recruitment may start at the respective center. Likewise, all protocol amendments/integrated 
protocols must be signed and dated by the principal investigator before coming into effect at 
the respective center. A complete list of all participating centers and their investigators, as 
well as all required signature documents, will be maintained in the Bayer study file. If 
required by local law, local co-sponsors will be nominated; they will be identified on the 
respective country-specific signature pages. 
13.
Publication policy
Bayer is committed to publication of the results of every study it performs. The SC will be 
responsible for the publication and presentation strategy. All publications will be based on 
data released or agreed by Bayer, verified by the SC. The study protocol has been made 
publicly available at www.clinicaltrials.gov.
14.
Insurance for subjects
The sponsor maintains clinical trial insurance coverage for this study in accordance with the 
laws and regulations of the country in which the study is performed.
15.
Confidentiality
All records identifying the subject will be kept confidential and, to the extent permitted by the 
applicable laws and/or regulations, will not be made publicly available.
Subject names will not be supplied to Bayer. Only the subject’s study number will be 
recorded in the eCRF. If the subject’s name appears on any other document, it will be 
anonymized. Study data stored in a computer will be handled in accordance with local data 
protection laws. As part of the informed consent process, the children/parents/legal guardians 
will be informed in writing that representatives of Bayer, IEC/IRB, or regulatory authorities 
may inspect their medical records to verify collected information and that all personal 
information made available for inspection will be handled in strictest confidence and in 
accordance with local data protection laws. If the results of the study are published, the 
subject’s identity will remain confidential. The investigator will maintain a list to enable 
subjects to be identified.
16.
Reference list – amended
BARST, R. J., ERTEL, S. I., BEGHETTI, M. & IVY, D. D. 2011. Pulmonary arterial 
hypertension: a comparison between children and adults. Eur Respir J, 37, 665-77.
BARST, R. J., IVY, D., DINGEMANSE, J., WIDLITZ, A., SCHMITT, K., DORAN, A., 
BINGAMAN, D., NGUYEN, N., GAITONDE, M. & VAN GIERSBERGEN, P. L. 
2003. Pharmacokinetics, safety, and efficacy of bosentan in pediatric patients with 
pulmonary arterial hypertension. Clin Pharmacol Ther, 73, 372-82.

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BARST, R. J., MAISLIN, G. & FISHMAN, A. P. 1999. Vasodilator therapy for primary 
pulmonary hypertension in children. Circulation, 99, 1197-208.
BARST, R. J., MCGOON, M. D., ELLIOTT, C. G., FOREMAN, A. J., MILLER, D. P. & 
IVY, D. D. 2012. Survival in childhood pulmonary arterial hypertension: insights 
from the registry to evaluate early and long-term pulmonary arterial hypertension 
disease management. Circulation, 125, 113-22.
BEGHETTI, M. 2009. Paediatric pulmonary hypertension: monitoring progress and 
identifying unmet needs. Eur Respir Rev, 18, 18-23.
BEGHETTI, M., HOEPER, M. M., KIELY, D. G., CARLSEN, J., SCHWIERIN, B., SEGAL, 
E. S. & HUMBERT, M. 2008. Safety experience with bosentan in 146 children 2-11 
years old with pulmonary arterial hypertension: results from the European 
Postmarketing Surveillance program. Pediatr Res, 64, 200-4.
BERGER, R. M., BEGHETTI, M., HUMPL, T., RASKOB, G. E., IVY, D. D., JING, Z. C., 
BONNET, D., SCHULZE-NEICK, I. & BARST, R. J. 2012. Clinical features of 
paediatric pulmonary hypertension: a registry study. Lancet, 379, 537-46.
CRONK C., C. A. C. P. S. M. 1988. Growth charts for children with Down syndrome: 1 
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D'ALONZO, G. E., BARST, R. J., AYRES, S. M., BERGOFSKY, E. H., BRUNDAGE, B. 
H., DETRE, K. M., FISHMAN, A. P., GOLDRING, R. M., GROVES, B. M., 
KERNIS, J. T. & ET AL. 1991. Survival in patients with primary pulmonary 
hypertension. Results from a national prospective registry. Ann Intern Med, 115, 343-
9.
DAVIE, N. 2014. Evidence Based Feasibility Report on Conduct of a Paediatric Study in 
PAH. Bayer HealthCare AG.
DONTI, A., FORMIGARI, R., RAGNI, L., MANES, A., GALIE, N. & PICCHIO, F. M. 
2007. Pulmonary arterial hypertension in the pediatric age. J Cardiovasc Med 
(Hagerstown), 8, 72-7.
EMA 2009. GUIDELINE ON THE CLINICAL INVESTIGATIONS OF MEDICINAL 
PRODUCTS FOR THE TREATMENT OF PULMONARY ARTERIAL 
HYPERTENSION. In: USE, C. F. M. P. F. H. (ed.) 
EMEA/CHMP/EWP/356954/2008.
EMA 2012a. Paediatric addendum clinical investigation of medicinal products for the 
treatment of pulmonary arterial hypertension. In: USE, C. F. M. P. F. H. (ed.) 
EMA/CHMP/213972/2010.
EMA 2012b. Product information - Tracleer - EMEA/H/C/000401 -II/0062. European 
Medicines Agency.
EMC 2015a. Traceleer (bosentan) 62.5mg film-coated tablets-Summary of Product 
Characteristics https://www.medicines.org.uk/emc/medicine/20422.
EMC 2015b. Traceleer (bosentan) 62.5mg film-coated tablets -Patient Information Leaflet 
https://www.medicines.org.uk/emc/medicine/20424.
FRAISSE, A., JAIS, X., SCHLEICH, J. M., DI FILIPPO, S., MARAGNES, P., BEGHETTI, 
M., GRESSIN, V., VOISIN, M., DAUPHIN, C., CLERSON, P., GODART, F. & 

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BONNET, D. 2010. Characteristics and prospective 2-year follow-up of children with 
pulmonary arterial hypertension in France. Arch Cardiovasc Dis, 103, 66-74.
GALIE, N., BARBERA, J. A., FROST, A., GHOFRANI, H. A., HOEPER, M., 
MCLAUGHLIN, V., PEACOCK, A., SIMONNEAU, G., VACHIERY, J. L., BLAIR , 
C., GILLIES, H., HARRIS, J., LANGLEY, J. & RUBIN, L. 2014. AMBITION: A 
randomised, multicenter study of first-line ambrisentan and tadalafil combination 
therapy in subjects with pulmonary arterial hypertension (PAH) Eur Respir J, 44.
GALIE, N., BEGHETTI, M., GATZOULIS, M. A., GRANTON, J., BERGER, R. M., 
LAUER, A., CHIOSSI, E. & LANDZBERG, M. 2006. Bosentan therapy in patients 
with Eisenmenger syndrome: a multicenter, double-blind, randomized, placebo-
controlled study. Circulation, 114, 48-54.
GALIE, N., CORRIS, P. A., FROST, A., GIRGIS, R. E., GRANTON, J., JING, Z. C., 
KLEPETKO, W., MCGOON, M. D., MCLAUGHLIN, V. V., PRESTON, I. R., 
RUBIN, L. J., SANDOVAL, J., SEEGER, W. & KEOGH, A. 2013. Updated 
treatment algorithm of pulmonary arterial hypertension. J Am Coll Cardiol, 62, D60-
72.
GALIE, N., HOEPER, M. M., HUMBERT, M., TORBICKI, A., VACHIERY, J. L., 
BARBERA, J. A., BEGHETTI, M., CORRIS, P., GAINE, S., GIBBS, J. S., GOMEZ-
SANCHEZ, M. A., JONDEAU, G., KLEPETKO, W., OPITZ, C., PEACOCK, A., 
RUBIN, L., ZELLWEGER, M. & SIMONNEAU, G. 2009. Guidelines for the 
diagnosis and treatment of pulmonary hypertension: the 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 the International 
Society of Heart and Lung Transplantation (ISHLT). Eur Heart J, 30, 2493-537.
GALIE, N., TORBICKI, A., BARST, R., DARTEVELLE, P., HAWORTH, S., 
HIGENBOTTAM, T., OLSCHEWSKI, H., PEACOCK, A., PIETRA, G., RUBIN, L. 
J., SIMONNEAU, G., PRIORI, S. G., GARCIA, M. A., BLANC, J. J., BUDAJ, A., 
COWIE, M., DEAN, V., DECKERS, J., BURGOS, E. F., LEKAKIS, J., LINDAHL, 
B., MAZZOTTA, G., MCGREGOR, K., MORAIS, J., OTO, A., SMISETH, O. A., 
BARBERA, J. A., GIBBS, S., HOEPER, M., HUMBERT, M., NAEIJE, R. & 
PEPKE-ZABA, J. 2004. Guidelines on diagnosis and treatment of pulmonary arterial 
hypertension. The Task Force on Diagnosis and Treatment of Pulmonary Arterial 
Hypertension of the European Society of Cardiology. Eur Heart J, 25, 2243-78.
GHOFRANI, H. A., GALIE, N., GRIMMINGER, F., GRUNIG, E., HUMBERT, M., JING, 
Z. C., KEOGH, A. M., LANGLEBEN, D., KILAMA, M. O., FRITSCH, A., 
NEUSER, D. & RUBIN, L. J. 2013. Riociguat for the treatment of pulmonary arterial 
hypertension. N Engl J Med, 369, 330-40.
HAWORTH, S. G. & HISLOP, A. A. 2009. Treatment and survival in children with 
pulmonary arterial hypertension: the UK Pulmonary Hypertension Service for 
Children 2001-2006. Heart, 95, 312-7.
HISLOP, A. A., MOLEDINA, S., FOSTER, H., SCHULZE-NEICK, I. & HAWORTH, S. G. 
2011. Long-term efficacy of bosentan in treatment of pulmonary arterial hypertension 
in children. Eur Respir J, 38, 70-7.

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IVY, D. D., ABMAN, S. H., BARST, R. J., BERGER, R. M., BONNET, D., FLEMING, T. 
R., HAWORTH, S. G., RAJ, J. U., ROSENZWEIG, E. B., SCHULZE NEICK, I., 
STEINHORN, R. H. & BEGHETTI, M. 2013. Pediatric pulmonary hypertension. J 
Am Coll Cardiol, 62, D117-26.
IVY, D. D., ROSENZWEIG, E. B., LEMARIE, J. C., BRAND, M., ROSENBERG, D. & 
BARST, R. J. 2010. Long-term outcomes in children with pulmonary arterial 
hypertension treated with bosentan in real-world clinical settings. Am J Cardiol, 106,
1332-8.
MAIYA, S., HISLOP, A. A., FLYNN, Y. & HAWORTH, S. G. 2006. Response to bosentan 
in children with pulmonary hypertension. Heart, 92, 664-70.
MCLAUGHLIN, V. V., SHILLINGTON, A. & RICH, S. 2002. Survival in primary 
pulmonary hypertension: the impact of epoprostenol therapy. Circulation, 106, 1477-
82.
MOLEDINA, S., HISLOP, A. A., FOSTER, H., SCHULZE-NEICK, I. & HAWORTH, S. G. 
2010. Childhood idiopathic pulmonary arterial hypertension: a national cohort study. 
Heart, 96, 1401-6.
NHBPEP 2004. The fourth report on the diagnosis, evaluation, and treatment of high blood 
pressure in children and adolescents. Pediatrics, 114, 555-76.
PARK, M. K. 2008. Pulmonary hypertension. In: MOSBY (ed.) Park's Pediatric Cardiology 
for Practitioners. 6th ed. Philadelphia, PA, USA: Elsevier.
ROSENZWEIG, E. B., IVY, D. D., WIDLITZ, A., DORAN, A., CLAUSSEN, L. R., YUNG, 
D., ABMAN, S. H., MORGANTI, A., NGUYEN, N. & BARST, R. J. 2005. Effects of 
long-term bosentan in children with pulmonary arterial hypertension. J Am Coll 
Cardiol, 46, 697-704.
RUBIN, L. J., GALIE, N., GRIMMINGER, F., GRUNIG, E., HUMBERT, M., JING, Z. C., 
KEOGH, A., LANGLEBEN, D., FRITSCH, A., MENEZES, F., DAVIE, N. & 
GHOFRANI, H. A. 2015. Riociguat for the treatment of pulmonary arterial 
hypertension: a long-term extension study (PATENT-2). Eur Respir J.
SCHERMULY, R. T., STASCH, J. P., PULLAMSETTI, S. S., MIDDENDORFF, R., 
MULLER, D., SCHLUTER, K. D., DINGENDORF, A., HACKEMACK, S., 
KOLOSIONEK, E., KAULEN, C., DUMITRASCU, R., WEISSMANN, N., 
MITTENDORF, J., KLEPETKO, W., SEEGER, W., GHOFRANI, H. A. & 
GRIMMINGER, F. 2008. Expression and function of soluble guanylate cyclase in 
pulmonary arterial hypertension. Eur Respir J, 32, 881-91.
SIMONNEAU, G., D'ARMINI, A. M., GHOFRANI, H. A., GRIMMINGER, F., HOEPER, 
M. M., JANSA, P., KIM, N. H., WANG, C., WILKINS, M., FRITSCH, A., DAVIE, 
N., COLORADO, P. & MAYER, E. 2014. Riociguat for the treatment of chronic 
thromboembolic pulmonary hypertension: a long-term extension study (CHEST-2). 
Eur Respir J.
SIMONNEAU, G., GATZOULIS, M. A., ADATIA, I., CELERMAJER, D., DENTON, C., 
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SOUZA, R. 2013. Updated clinical classification of pulmonary hypertension. J Am 
Coll Cardiol, 62, D34-41.
TAKATSUKI, S., SOEP, J. B., CALDERBANK, M. & IVY, D. D. 2011. Connective tissue 
disease presenting with signs and symptoms of pulmonary hypertension in children. 
Pediatr Cardiol, 32, 828-33.
VAN LOON, R. L., ROOFTHOOFT, M. T., HILLEGE, H. L., TEN HARKEL, A. D., VAN 
OSCH-GEVERS, M., DELHAAS, T., KAPUSTA, L., STRENGERS, J. L., 
RAMMELOO, L., CLUR, S. A., MULDER, B. J. & BERGER, R. M. 2011. Pediatric 
pulmonary hypertension in the Netherlands: epidemiology and characterization during 
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WEBER, M. & HAMM, C. 2006. Role of B-type natriuretic peptide (BNP) and NT-proBNP 
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(A reference Weber et al. for Modification 6 was added to the reference list according to 
Amendment 6, see Section 17.3.1.6).

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17.
Protocol amendments
Amendment 3
17.1
Amendment 3 is the first global amendment dated 24 NOV 2015.
In order to consider medical practice according to feedback from investigators, Health 
Authorities, and Ethical Committees as well as ensure consistency and clarity, the global 
amendment was generated. 
17.1.1
Overview of changes to the study
Modification 1: Change in the wording in describing the Long Term 
17.1.1.1
Extension part of the study
According to the original protocol, the subjects who completed the 24-week main study 
treatment phase, and require further treatment with riociguat, will be offered to participate in a 
long-term extension (LTE) study and continue until market approval of riociguat for the 
pediatric population or until they are ≥18 years of age (whatever comes first). The wording 
study is replaced with wording phase, and a word optional is added for the description of 
LTE. Modifications clarify that the subjects can volunteer to participate to the long-term 
extension, and that the LTE is a part of this study 15681.
Sections affected by this modification are:
Study flow chart
Section 5.3 Duration of study treatment
Section 6.1 Study visits
Section 6.1.6 Long-term extension phase (until adulthood or approval in the indication 
and commercial availability)
Modification 2: Clarification of primary completion and end of study
17.1.1.2
According to the original protocol, the primary completion event is when the last visit of the 
last subject for all centers has occurred. The wording in Primary completion is modified for 
clarification that primary completion day is the day, when last visit of the last subject for all 
centers has occurred after main study treatment phase, after 24 weeks of treatment.
End of the study is determined in original protocol to be reached as soon as the last visit of the 
last subject has been reached in all centers in all participating countries (EU and non-EU). 
The wording in End of the study is modified for clarification to describe that the end of the 
study will be reached as soon as the last visit of the subject has been reached in all centers of 
all participating countries after 24 weeks of treatment. In addition, wording in End of the 
study highlights that long term extension phase is not a part of the main study phase as well 
as gives timing for CSR writing.
Sections affected by this modification are:
Section 3.1 Study description
Section 7.4.5 Analyses

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Modification 3: Changes to the text describing primary objective
17.1.1.3
Original protocol described pharmacodynamics as a primary and secondary objective in 
section 2.0, but elsewhere in the protocol pharmacodynamics was described as 
secondary/other objective. To keep consistency, the pharmacodynamics is deleted from 
primary objective. Furthermore, with the limited blood sample volume, a throughout 
pharmacokinetics/pharmacodynamics (PK/PD) analysis might not be feasible. Therefore PK 
and PD will be addressed separately, and handled as separate objectives, not as one PK/PD.
Section affected by this change is:
Section 2 Study objectives
Modification 4: Addition of safety follow up visit for subjects 
17.1.1.4
participating to the long- term extension phase
Original protocol describes no safety follow up visit for subjects directly enrolling to the long-
term extension phase. As all subjects should end study properly, the correction for the 
description is made, and the safety follow up visit is added as well as the time is specified,
regardless of end of the study in main study phase, or in long-term extension phase. 
Sections affected by this modification are:
Study flow chart
Section 6.1.4 Safety follow up visit
Modification 5: Widening the Section 1.2 to better describe the 
17.1.1.5
minimization of burden degree of pediatric subjects
In order to response to the feedback received from German Federal institute for Drugs and 
medical devices (Bundesinstitut für Arzneimittel und Medizinprodukte, BfArm), the section 
1.2 Rationale of the study and risk-benefit assessment is widened. The new text address 
following points: the low burden and risk of study subjects, definitions of the burden degree, 
continuous monitoring as well as the description of how the burden degree and threshold of 
risks shall be continuously monitored. 
Section affected by this modification is:
Section 1.2 Rationale of the study and risk-benefit assessment
Modification 6: Clarification for the body weight adjusted dosing
17.1.1.6
For preventing potential riociguat dosing mistakes, a new, more accurate wording for body 
weight adjusted dosing is presented. In addition, two tabular descriptions (table 5-2 of original 
protocol and Appendix 1of original protocol) of riociguat dosing schedule are integrated. 
The integration would help the health care professionals (HCPs) to figure out which dose, as 
well as which corresponding volume of suspension should be administered. Providing all 
necessary data in one table would also help to prevent possible errors in prescribing a proper 
dose, which could occur if the two separate tables would be used (one for a dose calculation, 
and another one for a corresponding volume of the suspension). Such tables, although 
complex, are widely used by pediatricians. Clear graphic differentiation between doses in mg 
and volumes in ml should be used for preventing of potential dosing mistakes (however, the 

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doses in mg are in the majority of cases not as “round” as the volumes of suspension, as well 
as the units of a scale on the suspension dosing devices are 0.25 ml and 0.50 ml respectively, 
what would in fact prevent dosing mistakes from occurring).
Sections affected by this modification are:
Synopsis
Section 5.1.1 Body-weight adjusted individual dose titration regimen
Section 5.4 Formulation and dose
Appendix 18.1
Modification 7: Addition of a paragraph of Laboratory parameters 
17.1.1.7
A new paragraph is added to the section 6.2 to describe the laboratory tests obtained during 
screening and Visits 5 and 9 as well as in case medically required. 
New paragraph is added to:
Section 6.2 Safety outcomes
Modification 8: Addition of blood sampling in study visits 0, 5 and 9
17.1.1.8
Blood sampling is added to the study visits 0, 5, and 9. There is no indication for drug-
induced laboratory parameter changes attributable to riociguat in the adult studies. However, 
our study population will be in use of Bosentan for at least 12 weeks and this medication has 
been associated with cases of anemia and increases in liver enzymes. Therefore, an evaluation 
of results of historical laboratory tests, as well as a collection of blood samples for CBC, 
BUN, creatinine, AST, and ALT was introduced at Visit 0 (if historical values would not be 
available), and visits 5 and 9. Collection and evaluation of laboratory parameters is intended 
to confirm the safety profile of riociguat in the studied pediatric population.
Sections affected by this modification are:
Study flow chart
Section 6.1.1 pre-treatment phase (Visit 0, day -14 to -1)
Section 6.1.2.1 Individual titration phase (Visit 1- Visit 4)
Section 6.1.2.2 Maintenance phase (Visit 5- Visit 9)
Section 7.4.1 Safety analysis
Modification 9: Change of calculation formula for glomerular 
17.1.1.9
filtration rate
According to original protocol the glomerular filtration rate is calculated based on Cockroft 
formula. Since Schwartz formula is more appropriate for children in the age group this study 
is conducted, the calculation is changed to base on Schwartz formula. In addition, the wording 
is modified for this exclusion criteria.
Section affected by this modification is:
Section 4.3 Exclusion criteria

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Modification 10: Deleting sentences describing bosentan formulation 
17.1.1.10
and preclinical bone findings.
In order to respond to the feedback from French authorities, the sentence describing bosentan 
galenic formulation and its approval in EU is deleted since galenic formulation is not actually 
a pediatric formulation. 
Section affected by the modification is:
Section 1 Introduction
Modification 11: Deleting sentences about bosentan
17.1.1.11
Since bosentan is not provided by Sponsor, and compound name, dose, quantity and batch 
numbers are not collected for any concomitant medication, the sentence in Section 5.6 from 
original protocol is deleted. 
Section affected by this change:
Section 5.6 Treatment assignment
Modification 12: Changing the growth charts for boys and girls with 
17.1.1.12
Down syndrome
Original protocol growth charts for subjects (boys and girls) having Down syndrome are 
replaced with similar than presented for subjects without Down. New growth charts are 
having height scales with centimeters and inches, weight scales with kilograms and pounds, 
and are having easier readability.
Section affected by this change is:
Appendix 18.1 Growth chart
Modification 13: Clarifying the wording about dosing pipette
17.1.1.13
The terminology in original protocol for describing the dosing pipette, which will be used to 
administer the oral suspension to children, and which is considered a medical device, has been 
harmonized. Specific information about the manufacturer of the dosing pipette has been 
added. In addition, the clarification of the wording describing dosing increments is done.
Sections affected by this change are:
Section 5.1.1 Body-weight adjusted individual dose titration regimen
Section 5.4 Formulation and dose
Section 8.1.1 Adverse events
Modification 14: Deleting wording from study visits
17.1.1.14
Wording adjust study drug dose according to body weight is deleted from visit description of 
Main study treatment visit and Optional long-term extension phase. The study drug dose 
adjustment is based on systolic blood pressure, and the wording is misleading in original 
protocol. 
Sections affected by this change are:
Section 6.1.2.2 Maintenance phase (Visit 5- Visit 9)

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Section 6.1.6 Long-term extension phase (until adulthood or approval in the indication 
and commercial availability)
Modification 15: Adjustments for Flow chart
17.1.1.15
The superscript j is deleted from following Flow Chart points: demographics, medical history, 
concomitant PAH specific medication, physical examination, vital signs, ECG, Child health 
questionnaire, and tanner Scale. These procedures are done per protocol at Screening visit 
(V0).
Section affected by this change:
Study flow chart
Minor clarifications
17.1.1.16
Minor, consistency and logical clarifications were made throughout the document. The 
changes were made to ensure clear wording and consistency throughout the document. These 
changes do not affect the overall study concept.
Sections affected by the changes are:
Title page: The Study medical expert is changed.
List of abbreviations: Correction to the phrasing of one abbreviation is done and new 
abbreviations have been added due to the Amendment 3 modifications.
Flow chart, table for Study visits: Clarification of the wording in column headers 
and deleting one row of PK sampling. PK sampling was twice in the original 
protocol.
Section 1.2 Rationale of the study and risk benefit assessment: Clarification of the 
wording and correcting the numbers describing bone changes.
Section 4.2 Inclusion criteria: Correction of inclusion criteria numbering, as well as 
clarification for inclusion criteria 6. 
Section 4.3 Exclusion criteria: Clarification of wording in exclusion criteria 1. 
Wording in Synopsis is also changed due to the new sentence structures in 
Section 4.3.
Section 4.4 Concomitant medication: Word equivalent is added to the sentence 
describing the starting dose of riociguat.
Section 5.1.1Body weight adjusted dosing: Wording of the day is added for 
clarification to the sentence describing individual dosing at titration visits.
Section 6.1.1 Main study treatment period: For clarification that pregnancy test is 
mandatory at screening visit, the wording at the discretion of the investigator
is deleted. 
Section 6.1.2.1 Individual titration phase: For clarification that pregnancy test is 
mandatory at the visits mentioned, the wording at the discretion of the 
investigator is deleted.
Section 6.1.2.2 Maintenance phase: For clarification that pregnancy test is 
mandatory at the visits mentioned, the wording at the discretion of the 
investigator is deleted.

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Section 6.1.3 End-of-treatment: For clarification that each subject should have this 
visit, the following sentence ‘All patients will be encouraged to perform this 
visit.’ is deleted. 
Section 6.4 Pharmacokinetics: For clarification, wording peak and through is 
replaced by pre- and post-dose.
References: Three new references added.
Appendices: Replacement of the sample of SF-10 health survey with a final copy.

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17.1.2
Changes to the protocol text
All affected protocol sections are detailed; the sequence of the sections follows the structure 
of the original protocol. In the display of modifications, the “old text” refers to the original
protocol. Deletions are crossed out in the “old text”. Additions are underlined in the “new 
text”. Minor editorial changes or corrections are not listed. 
Title page
17.1.2.1
Old text:
[…]
Sponsor:
Bayer HealthCare AG, D-51368 Leverkusen, Germany
Sponsor’s medical expert:
 
Bayer HealthCare Pharmaceuticals
Av. Domingos Jorge 1100, 04779-900 São Paulo-SP Brasil 
Phone: 
[...]
New text:
[…]
Sponsor:
Bayer HealthCare AG, D-51368 Leverkusen, Germany
Sponsor’s medical expert:
 
Bayer HealthCare Pharmaceuticals
BPH-GD-P&O
Aprather Weg, Bd 402
42113, Wuppertal, Germany
Phone:
[…]
PPD
PPD
PPD
PPD
PPD

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List of abbreviations
17.1.2.2
Old text:
[…]
BCRP
BP
breast cancer related protein
blood pressure
CCDS
Company Core Data Sheet
[…]
New text:
[…]
BCRP
BP
BUN
CBC
breast cancer resistance protein
blood pressure
blood urea nitrogen
complete blood count
CCDS
Company Core Data Sheet
[…]
Synopsis
17.1.2.3
Old text:
[…]
Dose(s) Body-weight adjusted dose equivalent to the exposure of 
(0.5mg) 1.0 - 2.5 mg three times a day (TID), individual dose 
titration (IDT) in adults treated for PAH.
The individual optimal (maintenance) dose is to be determined 
based on patients’ monitoring of systolic blood pressure, well-
being and clinical status.
[…]
New text:
[…]
Dose(s) For children with body-weight <50 kg at screening, body-
weight adjusted dose equivalent to the exposure of (0.5 mg) 
1.0 - 2.5 mg three times a day (TID), individual dose titration 
(IDT) in adults treated for PAH. Doses of 1.0 to 2.5 mg TID 
will be applied for children ≥50 kg at screening.
The individual optimal (maintenance) dose is to be determined 
based on patients’ monitoring of systolic blood pressure, well-
being and clinical status.
[…]

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Old text:
[…]
Diagnosis and main criteria 
for inclusion /exclusion

Concomitant use of the following medication: 
phosphodiesterase 5 inhibitors (such as sildenafil, 
tadalafil, vardenafil) and non-specific phosphodiesterase 
(PDE) inhibitors (theophylline, dipyridamole), nitrates or 
NO donors (such as amyl nitrite) in any form or pre-
treatment within the last 2-weeks before Visit 1 with NO 
donors (e.g. nitrates).
[…]
New text:
[…]
Diagnosis and main criteria 
for inclusion /exclusion

Concomitant use of the following medications: 
phosphodiesterase 5 inhibitors (such as sildenafil, 
tadalafil, vardenafil) and non-specific phosphodiesterase 
(PDE) inhibitors (theophylline, dipyridamole) in any form 
or pretreatment are not allowed. Concomitant use of 
nitrates or NO donors are allowed up to two weeks before 
Visit 1.
[…]
Old text:
[…]
Methodology
This study is designed to evaluate the safety, tolerability, 
pharmacodynamics and pharmacokinetics of riociguat at age-, 
sex- and body-weight-adjusted doses of 0.5 mg, 1.0 mg, 
1.5 mg, 2.0 mg and 2.5 mg TID in children from ≥6 to less 
than 18 years with pulmonary arterial hypertension (PAH) 
group 1. The study consists of two phases: titration phase up to 
8 weeks and a maintenance phase up to 16 weeks.
[…]
New text:
[…]
Methodology
This study is designed to evaluate the safety, tolerability, 
pharmacodynamics and pharmacokinetics of riociguat in 
children from ≥6 to less than 18 years with pulmonary arterial 
hypertension (PAH) group 1. For children with body weight < 
50 kg at screening, body weight adjusted doses of 1.0 mg, 
1.5mg, 2.0 mg, and 2.5 mg TID will be applied. For children 
with body weight ≥50 kg, doses of 1.0 mg, 1.5 mg, 2.0 mg,

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and 2.5 mg TID will be applied. The study consists of two 
phases: titration phase up to 8 weeks and a maintenance phase 
up to 16 weeks.
[…]

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Study flow chart
17.1.2.4
Old text:
Table 0-1: Flow chart
Main study treatment period - 24 weeks
Screening
Individual titration phase
(8 weeks)
Maintenance phase
(16 weeks)
Unscheduled 
visit
End of 
treatment 
visit l
Safety 
follow-
up 
60 ± 8 
days
Long-term 
extension 
phase
Visit
V0
V1 g
V2
V3
V4
V5
V6k
V7
V8k
V9
Every 3 
months 
(± 14 
days)
Week f
Day -14 to 
-1
0
2
4
6
8
12
16
20
24
Informed 
consent/assent
•
In-/exclusion 
criteria
•
•
Demographics
• j
Medical history
• j
•
Concomitant 
medication
•
•
•
•
•
•
•
•
•
•
•
•
•
Concomitant 
PAH specific 
medication
• j
•
•
•
•
•
•
•
•
•
•
•
•
•
Physical 
examination m
• j
• d
•
•
•
•
•
•
•
•
•
•
•
• h
Obtain lab test i
•
Check lab test
•
•
Pregnancy test a
•
•
•
•
•
•
•
•
•
•
•
Dispense study 
medication
•
•
•
•
•
•
•
•
•
(•)
•

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Instruct how to 
take study drug
•
•
•
•
•
•
•
•
•
•
•
Provide booklet
•
Vital signs d
• j
•
•
•
•
•
•
•
•
•
•
•
•
•
ECG d
• j
•
•
•
Echocardiogram
•
•
•
•
WHO functional 
class
•
•
•
•
6MWD
•
•
•
•
NT-proBNP
•
•
•
•
Left hand x-ray
• j
•
• e
Adverse events n
•
•
•
•
•
•
•
•
•
•
•
•
•
Update eCRF
•
•
•
•
•
•
•
•
•
•
•
Drug 
accountability
•
•
•
•
•
•
•
•
•
•
PK blood sample 
b
•
•
• 
Child Health 
Questionnaire 
(SF-10) 
• j
•
•
•
Tanner scale c
• j
•
•
• e
Taste 
assessment 
questionnaire
•
•
•

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Abbreviation: eCRF = electronic case report form
a
Urine pregnancy test for women of childbearing potential at the discretion of the investigator (mandatory at screening).
b
A volume of 1.0 mL per sample is needed. Accurate adherence to time points is essential and has to be documented, see Table 0-2
c
Scale of physical development in children and adolescents 
d
Blood pressure, heart rate and ECG pre-dose, 2 and 4 hours after first dose (see Table 0-2)
e
Every 12 months until growth velocity is plateauing and growth plates are closed (see section 6.1.6)
f
±2 days for Visits 1 to 4, ±5 days for Visits 5 to 9
g
Visit 1 is considered the baseline visit.
h
Incl. height, growth velocity and weight
i
Obtain blood sample if AST and or ALT are not available within 30 days prior to Visit 1
j
If no historical data (≤30 days) is available
k
Home visits (only at week 12 and/or 20 of maintenance phase) at the discretion and responsibility of the investigator
l
For subjects dropping off the protocol at any time after V1 and before V9
m
Including height and weight
n
Including AEs of special interest

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New text:
Table 0–1: Flow chart - amended
Main study treatment period - 24 weeks
Screening
Individual titration 
phase
(8 weeks)
Maintenance phase
(16 weeks)
Unscheduled 
visit
End of 
treatment 
visit l
Safety 
follow-
up 
60 ± 8 
days
Optional
Long-term 
extension 
phase
Safety 
follow up 
visit 
60 +8 days 
after 
optional 
LTE
Visit
V0
V1 g
V2
V3
V4
V5
V6k
V7
V8k
V9
Every 3 
months 
(± 14 
days)
Week f
Day -14 to -
1
0
2
4
6
8
12
16
20
24
Informed 
consent/assent
•
In-/exclusion 
criteria
•
•
Demographics
• 
Medical history
• 
•
Concomitant 
medication
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Concomitant 
PAH specific 
medication
• 
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Physical 
examination m
• 
• d
•
•
•
•
•
•
•
•
•
•
•
• h
•
Obtain lab test 
•i
•
•
•
Pregnancy test 
a
•
•
•
•
•
•
•
•
•
•
•
•
Dispense study 
medication
•
•
•
•
•
•
•
•
•
(•)
•

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Instruct how to 
take study drug
•
•
•
•
•
•
•
•
•
•
•
Provide booklet
•
Vital signs d
• 
•
•
•
•
•
•
•
•
•
•
•
•
•
•
ECG d
• 
•
•
•
Echocardiogra
m
•
•
•
•
WHO functional 
class
•
•
•
•
6MWD
•
•
•
•
NT-proBNP
•
•
•
•
Left hand x-ray
• j
•
• e
Adverse events 
n
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Drug 
accountability
•
•
•
•
•
•
•
•
•
•
PK blood 
sample b
•
•
• 
Child Health 
Questionnaire 
(SF-10) 
•
•
•
•
Tanner scale c
• 
•
•
• e
Taste 
assessment 
questionnaire
•
•
•
a
Urine pregnancy test for women of childbearing potential 
b
A volume of 1.0 mL per sample is needed. Accurate adherence to time points is essential and has to be documented, see 
Table 0-2
c
Scale of physical development in children and adolescents 
d
Blood pressure, heart rate and ECG pre-dose, 2 and 4 hours after first dose (see Table 0-2)
e
Every 12 months until growth velocity is plateauing and growth plates are closed (see section 6.1.6)
f
±2 days for Visits 1 to 4, ±5 days for Visits 5 to 9
g
Visit 1 is considered the baseline visit.
h
Incl. height, growth velocity and weight
i
Obtain blood samples if AST and ALT, creatinine, BUN, and CBC are not available within 30 days prior to Visit0

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j
If no historical data (≤30 days) of x-ray is available
k
Home visits (only at week 12 and/or 20 of maintenance phase) at the discretion and responsibility of the investigator
l
For subjects dropping off the protocol at any time after V1 and before V9
m
Including height and weight
n
Including AEs of special interest

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Old text:
Table 0–2: Visit details
Visit 1 (Baseline visit)
Visit 3 and 5
First study medication dose intake 
Second study medication dose intake
First study medication dose intake
Order of procedures
Time interval (h)pre-dose0:000:30 to 1:302:002:30 to 4:004:00
-1:00 to 0:00
0:00
Pharmacokinetic blood sample
•
•
•
Blood sample for safety laboratory (incl. NT-proBNP)
•
Blood pressure, heart rate
•
•
•
ECG
•
•
•
WHO functional class
•
Left hand x-ray
•
Administration study drug
•
•
Pharmacokinetic blood sample
•
•
Echocardiogram
•
Abbreviations: ECG = electrocardiogram, PK = pharmacokinetic

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New text: 
Table 0–2: Visit details
Visit 1 (Baseline visit)
Visit 3 and 5
Detailed study activities at pre-dose and after the 
first study medication dose intake
Study activities before first study 
medication dose intake
Order of 
procedures
Time interval (h) pre-dose
0:00
0:30 to 1:30
2:00
2:30 to 4:00
4:00
-1:00 to 0:00
0:00
Pharmacokinetic blood sample
•
•
•
Blood sample for safety laboratory 
(incl. NT-proBNP)
•
Blood pressure, heart rate
•
•
•
ECG
•
•
•
WHO functional class
•
Left hand x-ray
•
Administration study drug
•
•
Echocardiogram
•
Abbreviations: ECG = electrocardiogram

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Section 1 Introduction
17.1.2.5
Old text:
[…]
The only PAH-specific drug approved for children is Revatio (sildenafil), and this approval is 
restricted to the European Union only. Bosentan is widely used in children with PAH. The 
medical treatment recommendations of Tracleer (International non-proprietary name [INN]: 
bosentan) in pediatric populations with PAH in the European Union (EU) are mainly based on 
extrapolation from experience in adult populations. For bosentan a pediatric galenic 
formulation is approved in the EU.
[…]
New text:
[…]
The only PAH-specific drug approved for children is Revatio (sildenafil), and this approval is 
restricted to the European Union only. Bosentan is widely used in children with PAH. The 
medical treatment recommendations of Tracleer (International non-proprietary name [INN]: 
bosentan) in pediatric populations with PAH in the European Union (EU) are mainly based on 
extrapolation from experience in adult populations. 
[…]
Section 1.2 Rationale of the study and risk-benefit assessment 
17.1.2.6
Old text:
[…]
Considering the severity and prognosis of PAH and the fact that the bone findings in rats were 
only seen at high multiples of exposure (≥ 66-fold of human exposure in adults at the 
maximum clinical dose of 10 mg) and that the findings were reversible and can be monitored 
in the clinical setting, the preclinical bone findings are not considered as critical for the 
initiation of a clinical study in children.
The expected benefit-risk balance of riociguat is considered positive if used in adherence to 
this clinical trial protocol and in accordance with the recommendations and guidance given in 
the Investigator’s Brochure.
[…]
New text:
[…]
Considering the severity and prognosis of PAH and the fact that the bone findings in rats were 
seen 3-4 fold of human exposure and that the findings were reversible and can be monitored 
in the clinical setting, the preclinical findings are considered as not prohibitive for the 
initiation of a clinical study in children.
The protocol was developed in accordance with ICH Good Clinical Practice, and other 
ICH/EMA guidelines for conducting clinical trials in pediatric population, in particular the 
ICH Topic E 11 (Clinical Investigation of Medicinal Products in the Pediatric Population) and 

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the guideline on Ethical Considerations for Clinical Trials on Medicinal Products Conducted 
with the Pediatric Population. 
The necessity of minimizing any possible burden and any potential risk for participating child 
and adolescent patients was taken into consideration and addressed during the development of 
this protocol. In order to provide guidance for investigators this protocol describes use of all 
study procedures, as well as outlines any potential related burden for participating patients, 
whenever applicable, in the respective chapters. In terms of the IMD administration the 
titration phase has been implemented (as described in the section 5.1.1. “Body-weight 
adjusted individual dose titration regimen”), as well as a dosing pipette for administration of 
oral suspension will be used. Educational material for training on the dosing pipette use and 
dose administration for study site staff, as well as for the patients and their caregivers, to 
ensure adequate dosing pipette use and treatment compliance will be distributed.
The study design includes standard procedures for pediatric PAH management, and only a 
few additional, study specific procedures have been included wherever absolutely necessary 
to ensure the study conduct, and monitoring of safety of enrolled patients. Study-specific 
procedures are: ECGs, Echocardiogram, serum or urine pregnancy testing for female patients 
of childbearing potential, selected blood sampling, and the left-hand X-ray for monitoring of 
bone growth. The above listed study specific procedures are non-invasive, standard medical 
care procedures. Laboratory samples will be restricted to the selected laboratory tests at 
screening (only if historical data is not available), visit 1, 5, and 9. Pharmacokinetic samples 
and blood sampling for study purposes will be aligned with clinically required blood tests 
whenever possible in order to avoid additional burden of a painful procedure and blood 
volume taken (see the subchapter “Laboratory parameters” in Section 6.2). Blood samples for 
pharmacokinetic analysis will have the blood volume minimized to 1 ml per sample. All 
blood samples collection will be performed by pediatric specialist staff and will be performed 
with the use of techniques like distraction and local anesthetic techniques, if applicable, to 
reduce the burden for patients. The left hand X-ray for monitoring of bone growth will be 
performed and assessed according to the established method. The rare periodicity of this X-
ray examination, as well as the standard precautions will ensure minimal and therefore 
acceptable exposure to radiation (Section 6.2 Safety outcomes). 
Investigators are mandated and trained to report adverse events, and all the respective 
definitions, criteria for qualifying AEs, and their reporting, as well as a description of 
pharmacovigilance procedures are included in a separate section of this protocol (Section 8.8). 
The monitoring of safety of participating patients by investigators and the sponsor is ensured 
by adherence to pharmacovigilance regulations and implementation of study specific 
monitoring measures (e.g. observation and evaluation of potential AEs of special interest, 
patients’ growth and bone growth monitoring). Close monitoring and ongoing medical review 
will be performed by the sponsor. An independent Data Monitoring Committee (DMC, which 
will be acting according to a DMC Charter) will meet periodically to review the safety data of 
enrolled patients, as well as the scientific merit of the trial. In addition a Steering Committee 
(SC) will ensure a scientifically sound and safe conduct of the study. Both, the DMC and the 
SC, are described in a separate subsection of this protocol (6.6 Study committees).
The expected benefit-risk balance of riociguat is considered positive if used in adherence to 
this clinical trial protocol and in accordance with the recommendations and guidance given in 
the Investigator’s Brochure.
[…]

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Section 2 Study objectives
17.1.2.7
Old text:
[…]

To evaluate safety, tolerability, and pharmacokinetics/pharmacodynamics body-
weight adjusted riociguat treatment in children with PAH
[…]
New text:
[…]

To evaluate safety, tolerability and pharmacokinetics of body-weight adjusted 
riociguat treatment in children with PAH
[…]
Section 3.1 Study description
17.1.2.8
Old text:
[…]
Primary completion
The primary completion event for this study is when the last visit of the last subject for all
centers has occurred.
End of study
The end of the study as a whole will be reached as soon as the last visit of the last subject has 
been reached in all centers in all participating countries (EU and non-EU).
[…]
New text:
[…]
Primary completion
The primary completion event for this study is when the last visit of the last subject for all 
centers has occurred after 24 weeks of treatment.
End of study
In accordance to the EU guideline 2009/c28/01 the end of the study will be reached as soon as 
the last visit of the last subject has been reached in all centers in all participating countries 
(EU and non-EU) after 24 weeks of treatment. A clinical study report (CSR) will be written 
after the completion of the main study.
The LTE is not considered part of the main study and the results will be reported separately.
[…]

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Section 4.2 Inclusion criteria
17.1.2.9
Old text:
[…]
5.
WHO functional class I-III
[…]
New text:
[…]
5.
WHO functional class I, II, and III
[…]
Section 4.3 Exclusion criteria
17.1.2.10
Old text:
[…]
1. 
Concomitant use of the following medication: phosphodiesterase (PDE) 5 inhibitors 
(such as sildenafil, tadalafil, vardenafil) and non-specific PDE inhibitors (theophylline, 
dipyridamole), nitrates or NO donors (such as amyl nitrite) in any form, or pre-
treatment within the last 2-weeks before Visit 1: NO donors (e.g. nitrates)
[…]
14.
Renal insufficiency (glomerular filtration rate <30 mL/min e.g. calculated based on 
Cockroft formula) 
[…]
New text:
[…]
1.
Concomitant use of the following medications: phosphodiesterase (PDE) 5 inhibitors 
(such as sildenafil, tadalafil, vardenafil) and non-specific PDE inhibitors (theophylline, 
dipyridamole) in any form or pretreatment are not allowed. Concomitant use of nitrates 
or NO donors are allowed up to two weeks before Visit 1.
[…]
14.
Renal insufficiency (estimated glomerular filtration rate <30 mL/min/1.73m2 e.g. 
calculated based on Schwartz formula) 
[…]
Section 4.4 Concomitant medication
17.1.2.11
Old text:
[…]

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
Strong cytochrome P450 (CYP) and P-glycoprotein 1(P-gp)/breast cancer related 
protein (BCRP) inhibitors: Concomitant use of riociguat with strong cytochrome CYP 
inhibitors and P-gp/BCRP inhibitors such as azole antimycotics (for example, 
ketoconazole, itraconazole) or HIV protease inhibitors (such as ritonavir) increase 
riociguat exposure and may result in hypotension. Consider a starting dose of 0.5 mg 
TID when initiating riociguat in subjects receiving strong CYP and P-gp/BCRP 
inhibitors and monitor for signs and symptoms of hypotension. A dose reduction 
should be considered in subjects who may not tolerate the hypotensive effect of 
riociguat.
[…]
New text:
[…]

Strong cytochrome P450 (CYP) and P-glycoprotein 1(P-gp)/breast cancer related 
protein (BCRP) inhibitors: Concomitant use of riociguat with strong cytochrome CYP 
inhibitors and P-gp/BCRP inhibitors such as azole antimycotics (for example, 
ketoconazole, itraconazole) or HIV protease inhibitors (such as ritonavir) increase 
riociguat exposure and may result in hypotension. Consider a starting dose of 0.5 mg 
TID equivalent when initiating riociguat in subjects receiving strong CYP and P-
gp/BCRP inhibitors and monitor for signs and symptoms of hypotension. A dose 
reduction should be considered in subjects who may not tolerate the hypotensive effect 
of riociguat.
[…]
Section 5.1.1 Body-weight adjusted individual dose titration regimen
17.1.2.12
Old text:
Riociguat will be provided to all subjects using an individual dose titration scheme according 
to a body weight- adjusted dose of riociguat to achieve a similar exposure as that observed in 
adults treated for PAH (Figure 5-1). The individual optimal dose will be determined based on 
subject's monitoring of systolic blood pressure, well-being and clinical status. 
In subjects with a body-weight below 50 kg at baseline, riociguat will be administered as oral 
suspension TID with or without food. Subjects with a body-weight ≥50 kg at baseline will 
receive riociguat as tablet formulation.
Riociguat will be dosed according to the dosing calculations given in Appendix 1 (see section 
18.1 Appendix 1). The body weight-adjusted riociguat dosing schedule is provided in Table 
5-2.
[…]
Educational material for training on the device and dose administration for study site staff as 
well as for the subjects to ensure adequate device use and treatment compliance will be 
distributed.
All subjects will start with body-weight adjusted riociguat dose equivalent to the exposure of 
1.0 mg TID in adults. During the individual titration period, the dose will be uptitrated every 
2 weeks (±2 days) at the discretion of the investigator, based on subject’s peripheral systolic 

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blood pressure and general tolerability measured at trough before intake of the next higher 
dose of riociguat.
[…]
At each titration visit, the individual dose will be assigned based on the following algorithm 
where peripheral systolic blood pressure (SBP) will be measured (by oscillometry with the 
same calibrated device in each center) at trough before intake of the first dose.
[…]
New text:
Riociguat will be provided to all subjects using an individual dose titration scheme to achieve 
a similar exposure as that observed in adults treated for PAH (Figure 5-1). For children with 
<50 kg body weight at baseline, a body weight adjusted dosing will be applied. Children with 
≥ 50kg body weight will receive adult doses. The individual optimal dose will be determined 
based on subject's monitoring of systolic blood pressure, well-being and clinical status. 
In subjects with a body-weight below 50 kg at baseline, riociguat will be administered as oral 
suspension TID with or without food. Subjects with a body-weight ≥50 kg at baseline will 
receive riociguat as tablet formulation.
The body weight-adjusted riociguat dosing schedule is provided in Table 5-2.
[…]
Educational material for training on the dosing pipette and dose administration for study site 
staff as well as for the subjects to ensure adequate dosing pipette use and treatment 
compliance will be distributed.
Subjects with <50 kg body weight will start with body-weight adjusted riociguat dose
equivalent to the exposure of 1.0 mg TID in adults. Subjects with ≥ 50kg body weight will 
start with dose 1.0 mg TID. During the individual titration period, the dose will be up-titrated 
every 2 weeks (±2 days) at the discretion of the investigator, based on subject’s peripheral 
systolic blood pressure and general tolerability measured at trough before intake of the next 
higher dose of riociguat.
[…]
At each titration visit, the individual dose will be assigned based on the following algorithm 
where peripheral systolic blood pressure (SBP) will be measured (by oscillometry with the 
same calibrated device in each center) at trough before intake of the first dose of the day.
[…]
Section 5.3 Duration of study treatment
17.1.2.13
Old text:
During the individual dose titration period with a maximum duration of 8 weeks, the 
individual maximum equivalent dose will be established. Subjects will be treated on this 
body-weight adjusted dose level during the 16-week maintenance period as long as well 
tolerated. Subjects who have completed 24 weeks of treatment will be offered participation in 
an extension study.

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New text:
During the individual dose titration period with a maximum duration of 8 weeks, the 
individual maximum equivalent dose will be established. Subjects will be treated on this 
body-weight adjusted dose level during the 16-week maintenance period as long as well 
tolerated. Subjects who have completed 24 weeks of treatment will be offered participation in 
the Long Term Extension (LTE) phase.
Section 5.4 Formulation and dose
17.1.2.14
Old text:
Riociguat will be provided by Bayer as film-coated tablets and granules for reconstitution in 
an oral suspension (0.15 mg/mL), see Table 5-1. The following tablet strength will be 
available: 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, and 2.5 mg. For the application of the oral 
formulation two medical devices (LDD- Liquid Dosing Device) are available and certificated. 
The devices are able to deliver between 1 mL and 5 mL with 0.25 mL dosing increments as 
well as 2 mL to 10 mL with 0.5 mL dosing increments. This incrementation was chosen to 
enable accurate bodyweight-related adjustment of subject dosing.
[…]
Table 5-2: Body weight-adjusted riociguat dosing schedule 
Body weight 
(kg)
0.5 mg 
equivalent TID 
(mg)
1.0 mg 
equivalent 
TID (mg)
1.5 mg 
equivalent 
TID (mg)
2.0 mg 
equivalent 
TID (mg)
2.5 mg 
equivalent 
TID (mg)
≥14 <16
0.14
0.28
0.42
0.56
0.70
≥16 <18
0.15
0.31
0.46
0.62
0.77
≥18 <20
0.17
0.33
0.50
0.67
0.83
≥20 <25 
0.19
0.38
0.57
0.75
0.94
≥25 <30
0.22
0.44
0.66
0.87
1.09
≥30 <35 
0.25
0.50
0.74
0.99
1.24
≥35 <40 
0.28
0.56
0.84
1.12
1.41
≥40 <50 
0.33
0.66
1.00
1.33
1.66
≥50
0.50
1.00
1.50
2.00
2.50
Abbreviations: TID = three times daily

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New text:
Riociguat will be provided by Bayer as film-coated tablets and granules for reconstitution in an oral suspension (0.15 mg/mL), see Table 5–1. 
The following tablet strength will be available: 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, and 2.5 mg. For the application of the oral formulation two sizes 
of dosing pipettes, manufactured by Raumedic, which are considered medical devices (therefore also called LDD- Liquid Dosing Device) are 
available and certificated. These dosing pipettes are designed to deliver between 1 mL and 5 mL with 0.25 mL dosing increments as well as 2 mL 
to 10 mL with 0.5 mL dosing increments. These increments were chosen to enable accurate bodyweight-related adjustment of subject dosing. 
[…]
Table 5-2: Body weight-adjusted riociguat dosing schedule
Body 
weight
(kg)
0.5 mg 
equivalent 
TID (mg)/
equivalent 
volume of 
suspension 
TID (mL)*
1.0 mg 
equivalent 
TID (mg)
equivalent 
volume of 
suspension 
TID (mL)*
1.5 mg 
equivalent 
TID (mg)
equivalent 
volume of 
suspension 
TID (mL)*
2.0 mg 
equivalent 
TID (mg)
equivalent 
volume of 
suspension 
TID (mL)*
2.5 mg 
equivalent 
TID (mg)
equivalent 
volume of 
suspension 
TID (mL)*
≥14 <16
0.14
1.0
0.28
1.75
0.42
2.75
0.56
3.75
0.70
4.75
≥16 <18
0.15
1.0
0.31
2.00
0.46
3.00
0.62
4.25
0.77
5.00
≥18 <20
0.17
1.0
0.33
2.25
0.50
3.25
0.67
4.50
0.83
5.50
≥20 <25 
0.19
1.25
0.38
2.50
0.57
3.75
0.75
5.00
0.94
6.50
≥25 <30
0.22
1.50
0.44
3.00
0.66
4.25
0.87
6.00
1.09
7.50
≥30 <35 
0.25
1.75
0.50
3.25
0.74
5.00
0.99
6.50
1.24
8.50
≥35 <40 
0.28
1.75
0.56
3.75
0.84
5.50
1.12
7.00
1.41
9.50
≥40 <50 
0.33
2.25
0.66
4.50
1.00
6.50
1.33
9.00
1.66
11.00
≥50
0.50
3.25
1.00
6.50
1.50
10.00
2.00
13.50
2.50
16.50
Abbreviations: TID = three times daily
*For facilitation of administration of a proper body-adjusted dose, the volumes of suspension are provided with increments of 0.25 mL (for 1-5 
mL) and 0.5 ml (for over 5 ml)

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Section 5.6 Treatment assignment
17.1.2.15
Old text:
After enrolment, the subject identification number will be recorded on the corresponding 
electronic case report form (eCRF). The subject identification number will also have to be 
recorded on the label of the study medication.
In case bosentan is provided locally, the compound’s name, dose, quantity and batch number, 
or a copy of the prescription has to be included in the subject’s files.
New text:
After enrolment, the subject identification number will be recorded on the corresponding 
electronic case report form (eCRF). The subject identification number will also have to be 
recorded on the label of the study medication.
Section 6.1 Study visits
17.1.2.16
Old text:
[…]
Subjects who have completed 24 weeks of treatment will be offered participation in an 
extension study. Subjects not entering the LTE phase will perform the safety follow-up visit 
(see section 6.1.4). Subjects dropping-off the protocol any time after Visit 1 and before Visit 9 
will perform an end-of-treatment visit (see section 6.1.3).
[…]
New text:
[…]
Subjects who have completed 24 weeks of treatment will be offered participation in an
optional long term extension phase. Subjects not entering the LTE phase will perform the 
safety follow-up visit (see section 6.1.4). Subjects dropping-off the protocol any time after 
Visit 1 and before Visit 9 will perform an end-of-treatment visit (see section 6.1.3).
[…]
Section 6.1.1 pre-treatment phase (Visit 0, day -14 to -1)
17.1.2.17
Old text:
[…]
Obtain blood sample if AST and or ALT are not available within 30 days prior to 
screening visit
[…]
New text:
[…]

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
Obtain blood sample if AST, ALT, creatinine, BUN and CBC are not available within 
30 days prior to screening visit
[…]
Section 6.1.2.1 Individual titration phase (Visit 1- Visit 4)
17.1.2.18
Old text:
[…]

Pregnancy test for females of childbearing potential (at the discretion of the 
investigator at Visit 1 and 3)

Update eCRF
[…]
New text:
[…]

Pregnancy test for females of childbearing potential (at Visit 1 and Visit 3)
[…]
Section 6.1.2.2 Maintenance phase (Visit 5- Visit 9)
17.1.2.19
Old text:
[…]

Perform physical examination (incl. height, weight, vital signs and at Visit 9 only, 
pubertal assessment using Tanner scale) – adjust study drug dose according to body 
weight
[…]

Pregnancy test for females of childbearing potential (at the discretion of the 
investigator)
[…]

Update eCRF
[…]
New text:
[…]

Perform physical examination (incl. height, weight, vital signs and at Visit 9 only, 
pubertal assessment using Tanner scale) 
[…]

Pregnancy test for females of childbearing potential 

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
Obtain laboratory parameters (AST, ALT, BUN, creatinine, and CBC) at Visits 5 and 
9 as well as when medically required according to medical practice at the study site at 
any time
Section 6.1.3 End of treatment visit
17.1.2.20
Old text:
For all subjects dropping-off the protocol at any time after V1 and before V9, an end-of-
treatment has to be performed. All patients will be encouraged to perform this visit.
The same procedures as at Visit 9 will be performed with the exception of the x-ray of left 
hand.
New text:
For all subjects dropping-off the protocol at any time after V1 and before V9, an end-of-
treatment has to be performed. 
The same procedures as at Visit 9 will be performed with the exception of the x-ray of left 
hand. 
Section 6.1.4 Safety follow up visit
17.1.2.21
Old text:
For all subjects stopping study medication either at the end of treatment or prematurely 
discontinuing the study at any time, a follow-up visit 60 days (±8 days) after last study 
medication intake has to be performed. For subjects directly proceeding with treatment in the 
long-term extension phase no safety follow-up visit will be scheduled. 
[…]

Pregnancy test for females of childbearing potential (at the discretion of the 
investigator)
[…]
New text:
For all subjects stopping study medication either at the end of treatment or prematurely 
discontinuing the study at any time, a follow-up visit 60 days (±8 days) after last study 
medication intake has to be performed. For subjects directly proceeding with treatment in the 
long-term extension phase, a safety follow-up visit 60 days (+8 days) will be scheduled either 
at the end of optional LTE phase, when patient’s transition to approved and commercially 
available riociguat in the respective country is possible, or when prematurely discontinuing 
LTE phase at any time.
[…]
Pregnancy test for females of childbearing potential 
[…]

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Section 6.1.6 Long-term extension phase (until adulthood or approval 
17.1.2.22
in the indication and commercial availability)
Old text:
6.1.6 Long-term extension phase (until adulthood or approval in the indication and 
commercial availability) 
Subjects who require treatment with riociguat for more than 24 weeks will be offered 
participation in an optional extension study. Subjects will receive riociguat until they can be 
transitioned to approved Adempas.
[…]

Pregnancy test for females of childbearing potential (at the discretion of the 
investigator)

Perform physical examination (incl. height, weight and vital signs) – adjust study drug 
dose according to body weight
[…]
New text:
6.1.6 Optional long-term extension phase (until adulthood or approval in the indication 
and commercial availability) 
Subjects who require treatment with riociguat for more than 24 weeks will be offered 
participation in an optional extension phase. Subjects will receive riociguat until they can be 
transitioned to approved Adempas.
[…]

Pregnancy test for females of childbearing potential 

Perform physical examination (incl. height, weight and vital signs)
[…]

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Section 6.2 Safety outcomes
17.1.2.23
Old text:
Not applicable.
New text:
Laboratory parameters
Laboratory parameters will be collected at V0 (if no historical data is available), V5 and V9. 
Hematology: CBC 
General Chemistry: AST,ALT, Creatinine and BUN
Afterwards; any additional collection of laboratory parameters will be obtained in case 
medically required and according to medical practice at the site at any time point and will be 
captured in the eCRFs.
Section 6.4 Pharmacokinetics
17.1.2.24
Old text:
Primary PK outcome measure:
Peak and trough blood samples for PK characterization of riociguat and its active metabolite 
BAY 60-4552 will be collected during the titration and the maintenance phase of the study.
New text:
Primary PK outcome measure:
Pre- and post-dose blood samples for PK characterization of riociguat and its active 
metabolite BAY 60-4552 will be collected during the titration and the maintenance phase of 
the study.
Section 7.4.1 Safety analysis
17.1.2.25
Old text:
[…]

Descriptive analysis of continuous laboratory parameters and their corresponding 
changes from baseline
[…]
New text:
[…]

Descriptive analysis of laboratory parameters (AST, ALT, BUN, creatinine, and CBC)
and their corresponding changes from baseline
[…]

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Section 7.4.5 Analyses
17.1.2.26
Old text:
The study results will be reported once all the pediatric subjects have completed their main 
study treatment period. Thereafter only descriptive summaries of study data from the ongoing 
subjects will be provided.
New text:
The study results will be reported once all the pediatric subjects have completed their main 
study treatment period of 24 weeks. Thereafter only descriptive summaries of study data from 
the ongoing subjects will be provided.
Section 8.1.1 Adverse events 
17.1.2.27
Old text:
An AE, including AE in relation to a medical device, is any untoward medical occurrence in a 
subject administered with a pharmaceutical product and does not necessarily have to have a 
causal relationship with this treatment.
[…]
New text:
An AE, including AE in relation to a medical device (i.e. Raumedic dosing pipette), is any 
untoward medical occurrence in a subject administered with a pharmaceutical product and 
does not necessarily have to have a causal relationship with this treatment.
[…]

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Appendix 18.1 Body-weight adjusted dosing of riociguat
17.1.2.28
Old text:
18.1 Appendix 1: Body-weight adjusted dosing of riociguat 
New text:
Not applicable! 
Appendix 1 deleted, and the numbering of Appendices is changed accordingly.

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Appendix 18.1 Growth charts
17.1.2.29
Old text:

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Growth charts for boys and girls with Down syndrome from (CRONK C., 1988)

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Appendix 18.3 Child health Questionnaire (SF-10)
17.1.2.30
Old text:

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New text:

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Amendment 5
17.2
Amendment 5 is the second global amendment dated 31 MAY 2016.
17.2.1
Overview of changes
Modification 1: An addition of following laboratory parameters: 
17.2.1.1
GGT, UA, T-Bil, Alb, Na, K, Ca, and P 
There is no signal for drug-induced laboratory parameter changes attributable to riociguat in 
the adult studies. However, considering that riociguat was never administered in this patient 
population and the fact that patients will be in use of Bosentan, the sponsor decided to add the 
collection of the following parameters: GGT, UA, T-Bil, Alb, Na, K, Ca, and P at visit 0, 5 
and 9 for safety reasons. Furthermore, all laboratory parameters are recorded to electronic 
case report form (eCRF) when obtained as medically required according to a local package 
insert of bosentan or medical practice at any time. The protocol sections affected by this 
modification are:
Study flow chart - amended
6.1.1 Pre-treatment phase (Visit 0, Day -14 to -1) - amended
6.1.2.1 Individual titration phase (Visit 1 – Visit 4) - amended
6.1.2.2 Maintenance phase (Visit 5 - Visit 9) - amended
6.1.4 Safety follow-up visit - amended
6.1.5 Unscheduled visit - amended
6.1.6 Optional long-term extension phase (until adulthood or approval in the indication and 
commercial availability) - amended
6.2 Safety outcomes - amended
7.4.1 Safety analysis - amended
Modification 2: An addition of collection of right heart catheterization 
17.2.1.2
parameters to eCRF
The collection of RHC parameters in the eCRF was included in order to have access to 
hemodynamics data at baseline and at any time during the study, in case a RHC will be
performed. This will allow us the possibility of analyzing hemodynamics response to 
riociguat (in case patient has more than one RHC).
The protocol sections affected by this modification are:
Study flow chart - amended
6.1.1 Pre-treatment phase (Visit 0, Day -14 to -1) - amended
6.1.2.1 Individual titration phase (Visit 1 – Visit 4) - amended
6.1.2.2 Maintenance phase (Visit 5 - Visit 9) - amended
6.1.3 End-of-treatment visit - amended
6.1.4 Safety follow-up visit - amended
6.1.5 Unscheduled visit - amended

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6.1.6 Optional long-term extension phase (until adulthood or approval in the indication and 
commercial availability) - amended
6.3 Efficacy/Pharmacodynamic/Other outcomes - amended
7.4.2 Efficacy analysis - amended
Modification 3: Addition of right heart dimensions Echo parameters: 
17.2.1.3
right atrial and right ventricular dimensions
It has been demonstrated that right atrial and right ventricular dimensions correlate with 
disease severity and outcome in children with pulmonary arterial hypertension (PAH) and a 
recent study in adults has shown that long term treatment with riociguat significantly reduced 
right heart size and improved right ventricular function in PAH. Taking these facts in 
consideration, the echocardiography parameter of right heart dimensions was introduced in 
the study. Furthermore, all Echo parameters were listed as secondary main variables. 
The protocol sections affected by this modification are:
Synopsis - amended
6.3 Efficacy/Pharmacodynamic/Other outcomes - amended
Modification 4: Echocardiography central reading
17.2.1.4
Echocardiographic parameters are one of our main secondary variables which will be 
analyzed in our study. Considering that it is an open label study, with a low number of 
patients, and the fact that echocardiogram is an operator dependent exam, the sponsor decided 
to include central reading in order to have a more reliable data.
The protocol section affected by this modification is:
6.2 Safety outcomes - amended
Modification 5: Modification of the wording which describes 
17.2.1.5
approved drugs for children with PAH, as well as modification 
regarding to the expert guidelines was done in Introduction.
Since both drugs Revatio (sildenafil) and bosentan are approved to be used in children with 
PAH in EU, the sentences describing the Revatio and bosentan in Introduction were not 
accurate and were modified. Furthermore, according to recent expert guidelines not only 
endothelin receptor antagonists (ERA) but also phosphodiesterase 5(PDE5) inhibitors are 
suggested to be used, and for accuracy the wording for expert guidelines was modified.
The protocol section affected by these modifications is:
1. Introduction - amended
Modification 6: Addition Appendix 6; calculation instructions for 
17.2.1.6
eGFR by Schwartz formula
Since there are two Schwartz formulas which are based on the creatinine assessment method 
used, the calculation instructions for estimated glomerular filtration rate (eGFR) calculation 
by Schwartz formula was added to ensure the sites have easy access to correct calculation 
formula. 
The protocol sections affected by this modification are:

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4.3 Exclusion criteria - amended
18.6 Appendix 6.
Modification 7: Changes regarding to taste and texture questionnaire 
17.2.1.7
Taste and texture of the pediatric formulation will be assessed by use of a questionnaire at the 
beginning and at the end of the study. The questionnaire is not considered to be a main 
secondary variable nor affect to the pharmacodynamic profile of riociguat, and the protocol is 
modified to clarify the use of taste and texture questionnaire. 
The protocol sections affected by this modification are:
Synopsis - amended
2. Study objectives - amended
6.3 Efficacy/Pharmacodynamic/Other outcomes - amended
Modification 8: Minor clarifications
17.2.1.8
Minor, consistency and logical clarifications were made throughout the document. The 
changes were made to ensure clear wording and consistency throughout the document. These 
changes do not affect the overall study concept.
Sections affected by the changes are:

Title page: Sponsor name and medical expert contact details were updated.

List of Abbreviations: New abbreviations were added due to the Amendment 5 
modifications. Additionally, the abbreviation DSMB was deleted since not found from 
the document.

Study flow chart, table 0-2: For better readability the line describing blood sampling 
for NT-proBNP and safety laboratory was divided to two individual lines, and a 
missing dot for safety laboratory was added.

Section1. Introduction: The symbol > was corrected as ≥ in the sentence describing
the guidelines for definition of the pulmonary hypertension (the mean pulmonary 
artery pressure should be ≥25 mmHg instead of > 25mmHg).

Section 5.1.1 Body-weight adjusted individual dose titration regimen: For clarity
the word device has been replaced with wording oscillometry unit in the paragraph 
describing individual dose assignment.

Section 8.12 Device malfunction failure and medical device related events 
reporting: Correction of wording regarding to reporting of dosing device malfunction 
or device related events was done. Furthermore, to ensure clarity the wording under 
Incident and Investigators notification of the sponsor was modified to highlight that 
word device means suspension dosing device.
17.2.2
Changes to the protocol text
All affected protocol sections are detailed; the sequence of the sections follows the structure 
of the original protocol. In the display of modifications, the “old text” refers to the original 

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protocol. Deletions are crossed out in the “old text”. Additions are underlined in the “new 
text”. Minor editorial changes or corrections are not listed.
Title page
17.2.2.1
Old text:
Sponsor:
Bayer HealthCare AG, D-51368 Leverkusen, Germany
Sponsor’s medical expert:
 
Bayer HealthCare Pharmaceuticals
BPH-GD-P&O
Aprather Weg, Bd 402
42113, Wuppertal, Germany
Phone: 
New text: 
Sponsor:
Bayer AG, D-51368 Leverkusen, Germany
Sponsor’s medical expert:
 
Bayer Pharma AG
BPH-GD-P&O
Aprather Weg, Bd 402
42113, Wuppertal, Germany
Phone:
Abbreviations - amended:
17.2.2.2
Old text:
DSMB
data safety monitoring board
New text:
[…]
Alb
albumin
Ca
calcium
eGFR
estimated glomerular filtration rate
GGT
gamma-glutamyltransferase
IDMS
isotope dilution mass spectrometry
K
potassium
Na
sodium
P
phosphate
SCr
serum creatinine
PPD
PPD
PPD
PPD

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T-Bil
total bilirubin
UA
uric acid
[…]

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Synopsis - amended
17.2.2.3
Old text:
Main secondary variable(s) […]

Echocardiographic parameters including 
o
pulmonary arterial systolic pressure (PASP),
o
tricuspid annular plane systolic excursion (TAPSE),
o
pericardial effusion, 
o
left ventricular eccentricity index, 
o
estimated inferior vena cava pressure.
[…]

Taste and texture of the pediatric formulation(s) must be 
assessed by use of a questionnaire.
New text:
Main secondary variable(s) […]

Echocardiographic parameters including 
o
pulmonary arterial systolic pressure (PASP),
o
tricuspid annular plane systolic excursion (TAPSE),
o
pericardial effusion, 
o
left ventricular eccentricity index, 
o
estimated inferior vena cava pressure.
o
right ventricular pressure by tricuspid regurgitant jet 
velocity
o
acceleration time of pulmonary flow and
o
right heart dimensions 
[…]
Not applicable.

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Study flow chart - amended
17.2.2.4
Old text:
Table 0-1: Flow chart - amended
Main study treatment period - 24 weeks
Screening
Individual titration 
phase
(8 weeks)
Maintenance phase
(16 weeks)
Unscheduled 
visit
End of 
treatment 
visit l
Safety 
follow-
up 
60 ± 8 
days
Optional 
Long-term 
extension 
phase
Safety 
follow up 
visit
60 +8 days
after 
optional 
LTE
Visit
V0
V1 g
V2
V3
V4
V5
V6k
V7
V8k
V9
Every 3 
months 
(± 14 
days)
Week f
Day -14 to -
1
0
2
4
6
8
12
16
20
24
[…]
Obtain lab test i
•i
•
•
•
[…]
i.
Obtain blood samples if AST and ALT, creatinine, BUN and CBC are not available within 30 days prior to Visit 0

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New text:
Table 0-1: Flow chart - amended
Main study treatment period - 24 weeks
Screening
Individual titration 
phase
(8 weeks)
Maintenance phase
(16 weeks)
Unscheduled 
visit
End of 
treatment 
visit l
Safety 
follow-
up 
60 ± 8 
days
Optional 
Long-term 
extension 
phase
Safety 
follow up 
visit
60 +8 days
after 
optional 
LTE
Visit
V0
V1 g
V2
V3
V4
V5
V6k
V7
V8k
V9
Every 3 
months 
(± 14 
days)
Week f
Day -14 
to -1
0
2
4
6
8
12
16
20
24
[…]
Obtain lab test i
•i
•
•
•
[…]
RHC data o
•o
[…]
i.
Obtain blood samples if AST, ALT, creatinine, BUN, GGT, UA, T-Bil, Alb, Na, K, Ca, P, and CBC are not available within 30 
days prior to Visit 0. Record the same laboratory parameters to eCRF when obtained as medically required according to a 
local package insert of bosentan or medical practice at the study site at any time.
o.    In case RHC has been performed for a study subject before enrollment, record most recent RHC parameters to the eCRF 
on V0 (timing of RHC not limited to the period of Day -14 to -1). Additionally, if RHC is conducted on medical reasons during 
the study, the RHC data should be recorded to the eCRF.

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Old text:
Table 0–2: Visit details - amended
Visit 1 (Baseline visit)
Visit 3 and 5
Detailed study activities at pre-dose and after the first 
study medication dose intake
Study activities before first study 
medication dose intake
Order of 
procedures
Time interval (h) pre-dose
0:00
0:30 to 1:30
2:00
2:30 to 4:00
4:00
-1:00 to 0:00
0:00
Pharmacokinetic blood sample
•
•
•
Blood sample for safety laboratory
(incl. NT-proBNP)
•
Blood pressure, heart rate
•
•
•
ECG
•
•
•
WHO functional class
•
Left hand x-ray
•
Administration study drug
•
•
Echocardiogram
•
Abbreviations: ECG = electrocardiogram

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New text:
Table 0–2: Visit details - amended
Visit 1 (Baseline visit)
Visit 3 and 5
Detailed study activities at pre-dose and after the first study 
medication dose intake
Study activities before first study 
medication dose intake
Order of 
procedures
Time interval (h)
pre-dose
0:00
0:30 to 1:30
2:00
2:30 to 4:00
4:00
-1:00 to 0:00
0:00
Pharmacokinetic blood 
sample
•
•
•
Blood sample for 
NT-proBNP
•
Blood sample for safety 
laboratory
• a
Blood pressure, heart rate
•
•
•
ECG
•
•
•
WHO functional class
•
Left hand x-ray
•
Administration study drug
•
•
Echocardiogram
•
a.
Obtain blood sample for safety parameters on Visit 5 only. 
       Abbreviations: ECG = electrocardiogram

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1. Introduction - amended
17.2.2.5
Old text:
[…]
Pulmonary Hypertension (PH) according to the current European Society of Cardiology 
(ESC) guidelines (Galie et al., 2009) is defined by a mean pulmonary artery pressure (PAP) 
>25 mmHg at rest, which is still consistent with the definition of the 5th World Symposium 
on Pulmonary Hypertension, which took place in Nice, 2013 (Simonneau et al., 2013).
[…]
The only PAH-specific drug approved for children is Revatio (sildenafil), and this approval is 
restricted to the European Union only. Bosentan is widely used in children with PAH. The 
medical treatment recommendations of Tracleer (International non-proprietary name [INN]: 
bosentan) in pediatric populations with PAH in the European Union (EU) are mainly based on 
extrapolation from experience in adult populations (EMA, 2012b). Data from clinical studies 
in pediatric patients are derived from retrospective cohort studies (without control-group) in 
mono-therapy and combination therapy, (Hislop et al., 2011, Ivy et al., 2010, Maiya et al., 
2006, Rosenzweig et al., 2005), from clinical studies in pediatric patients with PAH and focus 
on pharmacokinetics (without control group) (Beghetti, 2009, Barst et al., 2003), from a 
European non-interventional post-marketing surveillance database (Beghetti et al., 2008), and 
from a double-blind placebo controlled study in patients > 12 years of age with 
Eisenmenger’s syndrome (Galie et al., 2006). These studies showed encouraging results for 
the benefit of the pediatric population but still indicate that improvement in medical treatment 
is needed. Recent expert guidelines suggest the use of endothelin receptor antagonists (ERA)
and, when children deteriorate on this medication, additional agents may be considered, either 
in an up-front approach or sequential add-on (Ivy et al., 2013).
[…]
New text:
[…]
Pulmonary Hypertension (PH) according to the current European Society of Cardiology 
(ESC) guidelines (Galie et al., 2009) is defined by a mean pulmonary artery pressure (PAP) 
≥25 mmHg at rest, which is still consistent with the definition of the 5th World Symposium 
on Pulmonary Hypertension, which took place in Nice, 2013 (Simonneau et al., 2013).
[…]
Revatio (sildenafil) and bosentan are PAH-specific drugs approved for children in European 
Union. The medical treatment recommendations of Tracleer (International non-proprietary 
name [INN]: bosentan) in pediatric populations with PAH in the European Union (EU) are 
mainly based on extrapolation from experience in adult populations (EMA, 2012b). Data from 
clinical studies in pediatric patients are derived from retrospective cohort studies (without 
control-group) in mono-therapy and combination therapy, (Hislop et al., 2011, Ivy et al., 
2010, Maiya et al., 2006, Rosenzweig et al., 2005), from clinical studies in pediatric patients 
with PAH and focus on pharmacokinetics (without control group) (Beghetti, 2009, Barst et 
al., 2003), from a European non-interventional post-marketing surveillance database (Beghetti 
et al., 2008), and from a double-blind placebo controlled study in patients > 12 years of age 

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with Eisenmenger’s syndrome (Galie et al., 2006). These studies showed encouraging results 
for the benefit of the pediatric population but still indicate that improvement in medical 
treatment is needed. Recent expert guidelines suggest the use of endothelin receptor 
antagonists (ERA) or phosphodiesterase 5 (PDE5) inhibitor and, when children deteriorate on 
use of any of these medications, additional agents may be considered, either in an up-front 
approach or sequential add-on (Ivy et al., 2013).
[…]
2. Study objectives - amended
17.2.2.6
Old text:
[…]
Secondary exploratory objectives are:

To characterize the pharmacodynamic profile of riociguat comprising the following 
exploratory parameters: time to clinical worsening (TTCW), exercise capacity 
(6MWD test), functional capacity (measured by WHO FC), laboratory biomarkers 
(NT-proBNP), QoL measurements (SF-10), echocardiographic variables and taste 
assessment (questionnaire).
New text:
[…]
Secondary exploratory objectives are:

To characterize the pharmacodynamic profile of riociguat comprising the following 
exploratory parameters: time to clinical worsening (TTCW), exercise capacity 
(6MWD test), functional capacity (measured by WHO FC), laboratory biomarkers 
(NT-proBNP), QoL measurements (SF-10), echocardiographic variables 
Other objective is:

To assess taste and texture of the pediatric formulation(s) by use of a questionnaire
4.3 Exclusion criteria - amended
17.2.2.7
Old text:
[…]
14.
Renal insufficiency (estimated glomerular filtration rate <30 mL/min/1.73m2 e.g. 
calculated based on Schwartz formula)
[…]
New text:
[…]
14.
Renal insufficiency (estimated glomerular filtration rate <30 mL/min/1.73m2 e.g. 
calculated based on Schwartz formula, for detailed calculation instructions, see 18.6)
[…]

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5.1.1 Body weight adjusted individual dose titration regimen -
17.2.2.8
amended
Old text:
[…]
At each titration visit, the individual dose will be assigned based on the following algorithm 
where peripheral systolic blood pressure (SBP) will be measured (by oscillometry with the 
same calibrated device in each center) at trough before intake of the first dose of the day.
[…]
New text:
[…]
At each titration visit, the individual dose will be assigned based on the following algorithm 
where peripheral systolic blood pressure (SBP) will be measured (by oscillometry with the 
same calibrated oscillometry unit in each center) at trough before intake of the first dose of 
the day.
[…]
6.1.1 Pre-treatment phase (Visit 0, Day -14 to -1) - amended
17.2.2.9
Old text:
[…]

Obtain blood sample if AST, ALT, creatinine, BUN, and CBC are not available within 
30 days prior to screening visit
[…]

Not applicable.
[…]
New text:
[…]

Obtain blood sample if AST, ALT, creatinine, BUN, GGT, UA, T-Bil, Alb, Na, K, Ca, 
P, and CBC are not available within 30 days prior to screening visit
[…]

In a case RHC has been performed for a study subject before enrollment, record the 
most recent RHC parameters to the eCRF (timing of RHC not limited to the period of 
Day -14 to -1).
[…]

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6.1.2.1 Individual titration phase (Visit 1 – Visit 4) - amended
17.2.2.10
Old text:
Not applicable.
New text:
[…]

Record laboratory parameters (AST, ALT, BUN, creatinine, GGT, UA, T-Bil, Alb, 
Na, K, Ca, P, and CBC) to eCRF when obtained as medically required according to a 
local package insert of bosentan or medical practice at the study site at any time

In a case RHC is conducted based on medical reasons during the study, record RHC 
parameters to eCRF
6.1.2.2 Maintenance phase (Visit 5 - Visit 9) - amended
17.2.2.11
Old text:
[…]

Obtain laboratory parameters (AST, ALT, BUN, creatinine, and CBC) at Visits 5 and 
9 as well as when medically required according to medical practice at the study site at 
any time
New text:
[…]

Obtain laboratory parameters (AST, ALT, BUN, creatinine, GGT, UA, T-Bil, Alb, Na, 
K, Ca, P, and CBC) at Visits 5 and 9 as well as record the same parameters when 
obtained as medically required according to a local package insert of bosentan or
medical practice at the study site at any time

In a case RHC is conducted based on medical reasons during the study, record RHC 
parameters to eCRF
6.1.3 End-of-treatment visit - amended
17.2.2.12
Old text:
Not applicable.
New text:
[…]
In a case RHC is conducted based on medical reasons during the study, record RHC 
parameters to eCRF.

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6.1.4 Safety follow-up visit - amended
17.2.2.13
Old text:
Not applicable.
New text:
[…]

Record laboratory parameters (AST, ALT, BUN, creatinine, GGT, UA, T-Bil, Alb, 
Na, K, Ca, P, and CBC) to eCRF when obtained as medically required according to a 
local package insert of bosentan or medical practice at the study site at any time

In a case RHC is conducted based on medical reasons during the study, record RHC 
parameters to eCRF
6.1.5 Unscheduled visit - amended
17.2.2.14
Old text:
Not applicable.
New text:
[…]

Record laboratory parameters (AST, ALT, BUN, creatinine, GGT, UA, T-Bil, Alb, 
Na, K, Ca, P, and CBC) to eCRF when obtained as medically required according to a 
local package insert of bosentan or medical practice at the study site at any time

In a case RHC is conducted based on medical reasons during the study, record RHC 
parameters to eCRF
6.1.6 Optional long-term extension phase (until adulthood or approval 
17.2.2.15
in the indication and commercial availability) - amended
Old text:
Not applicable.
New text:
[…]

Record laboratory parameters (AST, ALT, BUN, creatinine, GGT, UA, T-Bil, Alb, 
Na, K, Ca, P, and CBC) to eCRF when obtained as medically required according to a 
local package insert of bosentan or medical practice at the study site at any time

In a case RHC is conducted based on medical reasons during the study, record RHC 
parameters to eCRF
[…]

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6.2 Safety outcomes - amended
17.2.2.16
Old text:
Laboratory parameters
Laboratory parameters will be collected at V0 (if no historical data is available), V5 and V9. 

Hematology: CBC 

General Chemistry: AST,ALT, Creatinine and BUN
Afterwards; any additional collection of laboratory parameters will be obtained in case 
medically required and according to medical practice at the site at any time point and will be 
captured in the eCRFs.
New text:
Laboratory parameters
Laboratory parameters will be collected at V0 (if no historical data is available), V5 and V9. 

Hematology: CBC 

General Chemistry: AST,ALT, Creatinine, BUN, GGT, UA, T-Bil, Alb, Na, K, Ca
and P
Afterwards; any additional collection of laboratory parameters will be obtained in case 
medically required according to a local package insert of bosentan or medical practice at the 
site at any time point and will be captured in the eCRFs.
Echocardiograph 
Echocardiographic parameters will be evaluated centrally by a specialist during the main 
study phase and optional long term extension. Details are specified in the respective Imaging 
documents.
6.3 Efficacy/Pharmacodynamic/Other outcomes - amended
17.2.2.17
Old text:
6.3 Efficacy/Pharmacodynamic outcomes
Secondary pharmacodynamic outcomes (descriptive analysis) are the change from baseline 
(Day 0) to end of treatment (week 24) of:
[…]
•
Echocardiographic parameters including pulmonary arterial systolic pressure (PASP), 
right ventricular pressure by tricuspid regurgitant jet velocity, tricuspid annular plane 
systolic excursion (TAPSE), pericardial effusion, left ventricular eccentricity index, 
estimated inferior vena cava pressure, acceleration time of the pulmonary flow
[…]
Not applicable.
New text:
6.3 Efficacy/Pharmacodynamic/Other outcomes

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Secondary efficacy, pharmacodynamic, and other outcomes (descriptive analysis) are the 
change from baseline (Day 0) to end of treatment (week 24) of:
[…]
•
Echocardiographic parameters including pulmonary arterial systolic pressure (PASP), 
right ventricular pressure by tricuspid regurgitant jet velocity, tricuspid annular plane 
systolic excursion (TAPSE), pericardial effusion, left ventricular eccentricity index, 
estimated inferior vena cava pressure, acceleration time of the pulmonary flow and 
right heart dimensions 
[…]
Right heart catheterization
A change in RHC parameters (if available) obtained from RHC performed before study 
enrollment and during the study conduct.
7.4.1 Safety analysis - amended
17.2.2.18
Old text:
[…]
-
Descriptive analysis of laboratory parameters (AST, ALT, BUN, creatinine, and CBC) 
and their corresponding changes from baseline
[…]
New text:
[…]
-
Descriptive analysis of laboratory parameters (AST, ALT, BUN, creatinine, GGT, 
UA, T-Bil, Alb, Na, K, Ca, P, and CBC) and their corresponding changes from 
baseline
[…]
7.4.2 Efficacy analysis - amended
17.2.2.19
Old text:
Not applicable.
New text:
[…]
RHC parameters (if available) will be analyzed descriptively by summary tables.
[…]

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8.12 Device malfunction or failure and medical device related events
17.2.2.20
reporting - amended
Old text:
Any device malfunction or failure including use errors or inadequacy in the labeling will be 
recorded by the clinical/investigational site, including all relevant device information, using 
the Product Technical Compliant (PTC) form, medical clinical investigations device 
complaint form and the eCRF for device-related events, and forwarded within 24 hours to the 
Sponsor or Sponsor’s designee for evaluation and investigation.
[…]
Any event which meets all three basic reporting criteria (a-c) is considered an incident and 
must be reported to the relevant National Competent Authority. The criteria are that:
a)
An event has occurred
b)
The device is suspected to be a contributory cause of the Incident.
[…]
Investigator’s notification of the sponsor
All investigators will be thoroughly instructed and trained on all relevant aspects of the 
investigator’s reporting obligations for incidents and serious public health threats related to 
the investigational device.
[…]
New text:
Any device malfunction or failure including use errors or inadequacy in the labeling will be 
recorded by the clinical/investigational site, including all relevant device information, using 
the Product Technical Compliant (PTC) form, and forwarded within 24 hours to the Sponsor 
or Sponsor’s designee for evaluation and investigation.
[…]
Any event which meets all three basic reporting criteria (a-c) is considered an incident and 
must be reported to the relevant National Competent Authority. The criteria are that:
a)
An event has occurred
b)
The suspension dosing device is suspected to be a contributory cause of the Incident
[…]
Investigator’s notification of the sponsor
All investigators will be thoroughly instructed and trained on all relevant aspects of the 
investigator’s reporting obligations for incidents and serious public health threats related to 
the suspension dosing device.
[…]

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18.6 Appendix 6. Glomerular filtration rate: Calculation instructions 
17.2.2.21
by Schwartz formula
Old text:
Not applicable, the Appendix 6 was applied in Amendment 5.
New text:
18.6
Appendix 6: Glomerular filtration rate: Calculation instructions by 
Schwartz formula 
If serum creatinine (SCr) is measured with routine methods that have not been recalibrated to 
be traceable to isotope dilution mass spectrometry (IDMS) (e.g. the traditional Jaffé reaction), 
the eGFR should be obtained from the original Schwartz formula: 
eGFR (mL/min/1.73 m2) = k * height (cm) / SCr (mg/dL)
Where k is proportionality constant:
k = 0.55 in children up to 13 years of age
k = 0.70 in boys >13 years and <18 years of age (not in girls; because of the
presumed increase in male muscle mass, the constant remains 0.55 for girls)
If SCr is measured by an enzymatic creatinine method that has been calibrated to be traceable 
to IDMS, the updated Schwartz formula should be used to obtain the eGFR: 
eGFR (mL/min/1.73 m2) = 0.413 * height (cm) / SCr (mg/dL)
Note: To express SCr in micromoles per liter, the value should be multiplied by 88.4 
(1 mg/dL = 88.4 µmol/L).

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Amendment 6
17.3
Amendment 6 is the third global amendment dated 9 JAN 2017.
17.3.1
Overview of changes
Modification 1: An exclusion criterion related to patients with 
17.3.1.1
pulmonary hypertension associated with idiopathic interstitial 
pneumonia was added
A new exclusion criterion “patients with pulmonary hypertension associated with idiopathic 
interstitial pneumonia (PH-IIP)" was added to the protocol as according to the new updated 
CCDS, riociguat is now contraindicated in patients with PH-IIP.
Study RISE-IIP was recently terminated early on the recommendation of DMC. RISE-IIP 
study was a randomized, double-blind, placebo-controlled, multicenter phase II study to 
investigate the efficacy and safety of riociguat in patients with symptomatic pulmonary 
hypertension associated with idiopathic interstitial pneumonias (PH-IIP). An evaluation of the 
interim results by European Medicinal Agency concluded that the benefit risk balance of 
riociguat in patients with PH-IIP is negative and thus patients with PH-IIP should not be 
treated with riociguat. The protocol section affected by this modification is:
4.3 Exclusion criteria
8.9 Premature discontinuation of study medication
Modification 2: Broadening of the study population and wording 
17.3.1.2
adaptation to keep compliance with pediatric investigation plan (PIP)
The agreed study population was broadened to include patients treated with PAH medications 
including endothelin receptor antagonists (ERA) (besides bosentan), prostacycling analogues 
(PCAs) or combination of these. The protocol was modified according to positive opinion of 
the Paediatric Committee, EMEA. Furthermore, several wording adaptations were made to 
keep consistency and compliance with the PIP.
The protocol sections affected by this modification are:
Synopsis
Study Flow chart
2. Study objectives
3. Study design
3.1 Study description
4.1 Planned number of subjects
4.2 Inclusion criteria
4.3 Exclusion criteria

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5.1.1 Body-weight adjusted individual dose titration regimen
6.1 Study visits
6.1.1 Pre-treatment phase (Visit 0, Day -14 to -1)
6.1.2.1 Individual titration phase (Visit 1- Visit 4)
6.1.2.2 Maintenance phase (Visit 5 - Visit 9)
6.1.4 Safety follow-up visit
6.1.5 Unscheduled visit
6.1.6 Optional long-term extension phase (until adulthood or approval in the indication and 
commercial availability)
6.2 Safety outcomes
6.3 Efficacy/Pharmacodynamic/Other outcomes
6.4 Pharmacokinetics/Pharmacodynamics analyses
7.4 Analyses
7.4.1 Safety analysis
7.4.2 Efficacy analysis
7.5 Determination of sample size
8.9 Premature discontinuation of study medication
Modification 3: New Quality of Life questionnaire
17.3.1.3
The quality of life questionnaire currently used in the protocol is a parent questionnaire. 
Studies have shown that there is a discrepancy between parents and patients perceptions of 
psychosocial quality of life scores, indicating that parents and patients questionnaires should 
be applied in order to have more accurate results.
The protocol sections affected by this modification are:
Study Flow chart
6.1.1 Pre-treatment phase (Visit 0, Day -14 to -1)
6.1.2.2 Maintenance phase (Visit 5 - Visit 9)
6.1.6 Optional long-term extension phase (until adulthood or approval in the indication and 
commercial availability)
6.3 Efficacy/Pharmacodynamic/Other outcomes
7.4.2 Efficacy analysis
Modification 4: Pretreatment with PDE5 inhibitors
17.3.1.4
Patients are not expected to be withdrawn from treatment with PDE5i for the purpose of 
entering into this trial.
Guidelines for management of PAH in pediatric patients recommend use of PDE5 inhibitors. 
In fact, most pediatric patients are being treated with PDE5i as monotherapy or as a 

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component of a combination therapy, including with PCAs or ERAs. Furthermore, some 
patients may have a degree of intolerance to PDE5i and could require a treatment change in 
the future. The inclusion of patients previously treated with PDE5i takes into consideration 
these elements. However, pretreatment with PDE5i is now allowed but up to 3 three days 
prior to start of riociguat treatment (Visit 1), considered as washout period. 
Acknowledgement of treatment practice of PDE5i use, before entering into the trial, is also 
relevant as sequential modification of treatment is a potential management approach in real 
life. This criterion is consistent with study participation criteria in trials of riociguat in adults 
with PAH. In these trials riociguat showed consistent efficacy across multiple endpoints, with 
an acceptable safety profile. Finally, addressing the NO pathway with an alternative to PDE5i, 
such as riociguat, can provide benefits to the pediatric population as it did in adults. During 
the treatment period, the contraindication of co-treatment with PDE5i will stay.
Section affected by this modification:
4.3 Exclusion criteria
Modification 5: Exclusion criterion 1 divided to two criteria
17.3.1.5
Exclusion criterion 1 converted into two criteria to assure that the wording “last 2 weeks
period” applies to NO donors only. 
Note: The overall criteria numbering in Section 4.3 was changed due to this modification.
Sections affected by this change are:
Synopsis
4.3 Exclusion criteria
Modification 6: Brain natriuretic peptide added as an alternative for 
17.3.1.6
N-terminal natriuretic peptide
Both biomarkers provide prognostic information in various cardiovascular diseases and there 
is no meaningful clinical difference between them (Weber and Hamm, 2006). This is a global 
clinical trial with sites in different continents, therefore each laboratory may have different 
capabilities in relation to which one of biomarkers can be collected. As a percentage change 
from baseline for NT pro-BNP and BNP can be done separately, brain natriuretic peptide was 
added as an alternative for the NT-proBNP collection.
Sections affected by this change are:
Synopsis
Study Flow chart
2. Study objectives
6.1.2.1 Individual titration phase (Visit 1- Visit 4)
6.1.2.2 Maintenance phase (Visit 5 - Visit 9)
6.1.6 Optional long-term extension phase (until adulthood or approval in the indication and 
commercial availability)

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6.3 Efficacy/Pharmacodynamic/Other outcomes
7.4.2 Efficacy analysis
Modification 7: Visit window for Visit 5 adjusted
17.3.1.7
The time window between visit 4 and visit 5 was adapted due to the number of tablets in the 
bottle supplied to the patients. Bottles supplied to patients have a total of 54 tablets, which 
allows up to a maximum of 18 days of time window between the visits 4 and 5.
Sections affected by this change are:
Study Flow chart
Modification 8: Urine or Serum pregnancy test
17.3.1.8
Pregnancy test is done in almost every visit. As in some of the visits patient has blood 
sampling done, an option of serum pregnancy test was added in order to facilitate the process 
of having the test performed. 
Sections affected by this change are:
Study Flow chart
1.2 Rationale of the study and risk-benefit assessment
Modification 9: Wording related to bosentan reinserted
17.3.1.9
The respective wording referent to bosentan was reinserted due to a request from Health
Authority in Germany in order to improve clarity of the text. As PAH specific medications 
also include other ERAs and PCA, these two classes of medications were also added in the 
sentence.
Section affected by this change:
5.6 Treatment assignment
Modification 10: Minor clarifications
17.3.1.10
Minor, consistency and logical clarifications were made throughout the document. The 
changes were made to ensure clear wording and consistency throughout the document. These 
changes do not affect the overall study concept.
Sections affected by the changes are:

Title page: Sponsor information for USA was added

Introduction: The wording clarification and a reference added to point describing 
European Respiratory Society meeting and AMBITION study

Reference list: A reference for Amendment 6, Modification 6 was added.

Appendix 4: The logo in the Taste and texture assessment was changed 

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17.3.2
Changes to the protocol text
All affected protocol sections are detailed; the sequence of the sections follows the structure 
of the original protocol. In the display of modifications, the “old text” refers to the original 
protocol. Deletions are crossed out in the “old text”. Additions are underlined in the “new 
text”. Minor editorial changes or corrections are not listed.
Title page
17.3.2.1
Old text:
[…]
Sponsor:
[…]
Bayer AG, D-51368 Leverkusen, Germany
New text:
[…]
Sponsor:
Bayer AG, D-51368 Leverkusen, Germany
US territory: Bayer HealthCare Pharmaceuticals Inc., 100 
Bayer Boulevard, P.O. Box 915, Whippany NJ
07981-0915, USA
[…]
Synopsis
17.3.2.2
Old text:
[…]
Background treatment
Patients must be treated with standard of care comprising 
background therapy and stable dose of bosentan (> 12 weeks 
with stable doses).
[…]

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Diagnosis and main criteria 
for inclusion /exclusion
Children from 6 years to less than 18 years of age with 
pulmonary arterial hypertension (PAH).
Main inclusion criteria:
•
Pulmonary arterial hypertension (PAH), diagnosed by 
right heart catheterization (RHC) (for patients with closed 
shunts – RHC no less than 4 months after surgery).
•
Patients must be treated with standard of care comprising 
background therapy and stable dose of bosentan (at least 
12 weeks with stable doses).
•
Two groups of patients will be included:
Prevalent: Patients currently on monotherapy with 
bosentan who need additional treatment (discretion of the 
investigator)
Incident: Treatment naïve patients initiated on bosentan
then riociguat added once bosentan dose is stable for at 
least 12 weeks.
•
WHO functional class I-III.
Main exclusion criteria:

Concomitant use of the following medications: 
phosphodiesterase 5 inhibitors (such as sildenafil, 
tadalafil, vardenafil) and non-specific phosphodiesterase 
(PDE) inhibitors (theophylline, dipyridamole) in any form 
or pretreatment are not allowed. Concomitant use of 
nitrates or NO donors are allowed up to two weeks before 
Visit 1.

[…]
[…]
Number of subjects
At least 20 children must be enrolled.
Main secondary variable(s) Change from baseline to end of treatment (week 24) of:

6-Minute Walking Distance (6MWD).

WHO functional class.

N-terminal prohormone brain-type natriuretic peptide 
[…]
[…]
New text:
[…]

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Background treatment
Patients must be on standard of care PAH medications, 
allowing Endothelin Receptor Antagonists (ERA) and/or 
Prostacyclin Analogues (PCA), for at least 12 weeks prior to 
baseline visit
[…]
Diagnosis and main criteria 
for inclusion /exclusion
Children from 6 years to less than 18 years of age with 
pulmonary arterial hypertension (PAH). 
Main inclusion criteria:

Pulmonary arterial hypertension (PAH), diagnosed by 
right heart catheterization (RHC) (for patients with 
closed shunts – RHC no less than 4 months after 
surgery).

Patients must be on standard of care PAH medications, 
allowing Endothelin Receptor Antagonists (ERA) 
and/or Prostacyclin Analogues (PCA), for at least 12 
weeks prior to baseline visit

Two groups of patients will be included:
Prevalent: Patients currently on PAH medication 
(allowing ERA and/or PCA) who need additional 
treatment (discretion of the investigator)
Incident: Treatment naïve patients initiated on PAH 
medication (allowing ERA and/or PCA) and then 
riociguat added once patients are stable on standard of 
care. 

WHO functional class I-III.
Main exclusion criteria:

Concomitant use of the following medications: 
phosphodiesterase 5 inhibitors (such as sildenafil, 
tadalafil, vardenafil) and non-specific 
phosphodiesterase (PDE) inhibitors (theophylline, 
dipyridamole), nitrates or NO donors (such as amyl 
nitrite) in any form 

Pretreatment with NO donors (e.g. nitrates) within the 
last 2-weeks before visit1 
[…]
[…]

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Number of subjects
Children on treatment with ERAs and/or PCAs can be 
enrolled. At least 20 children on treatment with bosentan or 
other Endothelin Receptor Antagonists (ERA) must be 
enrolled.
[…]
Main secondary variable(s) Change from baseline to end of treatment (week 24) of:

6-Minute Walking Distance (6MWD).

WHO functional class.

N-terminal prohormone brain-type natriuretic peptide or 
brain-type natriuretic peptide. When both tests are 
available, NT-proBNP should be chosen over BNP and 
the same test should be performed at every required visit.
       […]
[…]

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Study Flow chart
17.3.2.3
Old text:
[…]
Main study treatment period - 24 weeks
Screening
Individual titration 
phase
(8 weeks)
Maintenance phase
(16 weeks)
Unscheduled 
visit
End of 
treatment 
visit l
Safety 
follow-
up 
60 ± 8 
days
Optional 
Long-term 
extension 
phase
Safety 
follow up 
visit 
60 +8 days 
after 
optional 
LTE 
Visit
V0
V1 g
V2
V3
V4
V5
V6k
V7
V8k
V9
Every 3 
months 
(± 14 
days)
Week f
Day -14 
to -1
0
2
4
6
8
12
16
20
24
[…]
NT-proBNP 
•
•
•
•
[…]
Child Health 
Questionnaire 
(SF-10) 
• 
•
•
•
[…]
[…]
a
Urine pregnancy test for women of childbearing potential 
b
A volume of 1.0 mL per sample is needed. Accurate adherence to time points is essential and has to be documented, see Table 0-2
[…]
f
±2 days for Visits 1 to 4, ±5 days for Visits 5 to 9
[…]

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i
Obtain blood samples if AST and ALT, creatinine, BUN, GGT, UA, T-Bil, Alb, Na, K, Ca, P, and CBC are not available within 30 days prior to Visit 0. 
Record the same laboratory parameters to eCRF when obtained as medically required according to a local package insert of bosentan or medical practice 
at the study site at any time.
[…]
Table 0–2: Visit details - amended
Visit 1 (Baseline visit)
Visit 3 and 5
Detailed study activities at pre-dose and after the first study 
medication dose intake
Study activities before first study medication 
dose intake
Order of 
procedures
Time interval 
(h)
pre-dose
0:00
0:30 to 1:30
2:00
2:30 to 4:00
4:00
-1:00 to 0:00
0:00
[…]
Blood sample 
for 
NT-proBNP 
•
[…]

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New text:
[…]
Main study treatment period - 24 weeks
Screening
Individual titration 
phase
(8 weeks)
Maintenance phase
(16 weeks)
Unscheduled 
visit
End of 
treatment 
visit l
Safety 
follow-
up 
60 ± 8 
days
Optional 
Long-term 
extension 
phase
Safety 
follow up 
visit 
60 +8 days 
after 
optional 
LTE 
Visit
V0
V1 g
V2
V3
V4
V5
V6k
V7
V8k
V9
Every 3 
months 
(± 14 
days)
Week f
Day -14 
to -1
0
2
4
6
8
12
16
20
24
[…]
NT-proBNP or 
BNPp
•
•
•
•
[…]
Child Health 
Questionnaire 
(SF-10 and 
PedsQL) 
• 
•
•
•
[…]
[…]
a
Urine or serum pregnancy test for women of childbearing potential 
b
A minimum volume of 1.0 mL per sample is needed.  Accurate adherence to time points is essential and has to be documented, see Table 0-2
[…]
f
±2 days for Visits 1 to 4, ±4 days for Visit 5, ±5 days for Visits 6 to 9
[…]

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i
Obtain blood samples if AST and ALT, creatinine, BUN, GGT, UA, T-Bil, Alb, Na, K, Ca, P, and CBC are not available within 30 days prior to Visit 0. Record 
the same laboratory parameters to eCRF when obtained as medically required according to a local package insert of bosentan or other ERAs, or medical 
practice at the study site at any time.
[…]
p
When both tests are available, NT-proBNP should be chosen over BNP and the same test should be performed at every required visit
[…]
Table 0–2: Visit details - amended
Visit 1 (Baseline visit)
Visit 3 and 5
Detailed study activities at pre-dose and after the first study 
medication dose intake
Study activities before first study medication 
dose intake
Order of 
procedures
Time interval (h)
pre-dose
0:00
0:30 to 1:30
2:00
2:30 to 4:00
4:00
-1:00 to 0:00
0:00
[…]
Blood sample for 
NT-proBNP or 
BNPb
•
[…]
[…]
b When both tests are available, NT-proBNP should be chosen over BNP and the same test should be performed at every required visit

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1. Introduction
17.3.2.4
Old text:
[…]
At the recent European Society of Respirology, the results of the randomized, double-blind 
AMBITION study were presented.
[…]
New text:
[…]
At the international European Respiratory Society meeting 2014, the results of the 
randomized, double-blind AMBITION study were presented (Galie et al., 2014).
[…]
1.2 Rationale of the study and risk-benefit assessment
17.3.2.5
Old text:
[…]
Study-specific procedures are: ECGs, Echocardiogram, urine pregnancy testing for female 
patients of childbearing potential, selected blood sampling, and the left-hand X-ray for 
monitoring of bone growth.
[…]
New text:
[…]
Study-specific procedures are: ECGs, Echocardiogram, urine or serum pregnancy testing for 
female patients of childbearing potential, selected blood sampling, and the left-hand X-ray for 
monitoring of bone growth.
[…]
2. Study objectives
17.3.2.6
Old text:
The primary objective is:

To evaluate safety, tolerability and pharmacokinetics of body-weight adjusted 
riociguat treatment in children with PAH
Secondary exploratory objectives are:

To characterize the pharmacodynamic profile of riociguat comprising the following 
exploratory parameters: time to clinical worsening (TTCW), exercise capacity
(6MWD test), functional capacity (measured by WHO FC), laboratory biomarkers 
(NT-proBNP), QoL measurements (SF-10), echocardiographic variables

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[…]
New text:
The primary objectives:

To evaluate safety, tolerability and pharmacokinetics of oral riociguat treatment
Secondary objectives: 

Exploratory efficacy. To characterize the pharmacodynamic profile of riociguat 
comprising the following exploratory parameters: time to clinical worsening (TTCW), 
exercise capacity (6MWD test), functional capacity (measured by WHO FC), 
laboratory biomarkers (NT-proBNP or BNP), QoL measurements (SF-10, PedsQL), 
echocardiographic variables
[…]
3. Study design
17.3.2.7
Old text:
This is an international, multicenter, single-arm, open-label study to evaluate the safety, 
tolerability and pharmacokinetics of a body-weight adjusted riociguat regimen in subjects 
aged between ≥6 years old and <18 years old who have been diagnosed with idiopathic PAH, 
hereditable PAH, or PAH associated with connective tissue disease or congenital heart disease 
with shunt closure. These subjects must be on stable treatment with bosentan prior to 
receiving the first dose of riociguat.
New text:
This is an international, multicenter, single-arm, open-label study to evaluate the safety, 
tolerability and pharmacokinetics of a body-weight adjusted riociguat regimen in subjects 
aged between ≥6 years old and <18 years old who have been diagnosed with idiopathic PAH, 
hereditable PAH, or PAH associated with connective tissue disease or congenital heart disease 
with shunt closure. These subjects must be on stable treatment with PAH medications (ERA 
and/or PCA) prior to receiving the first dose of riociguat.
3.1 Study description
17.3.2.8
Old text:
After providing written informed consent and assent (if applicable), subjects will undergo a 
screening evaluation, to determine their eligibility. Eligible subjects – once on stable 
background treatment with bosentan - will start body-weight adjusted individual dose titration 
(IDT) regimen as described in section 5.1.1.
[…]
Subjects who completed the 24-week main study treatment phase and require further 
treatment with riociguat will be offered to participate in a long-term extension phase and 
continue until market approval of riociguat for the pediatric population or until they are ≥18
years of age (whatever comes first). Subjects reaching adulthood can be transitioned to 
commercially-available Adempas.

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New text:
After providing written informed consent and assent (if applicable) subjects will undergo a
screening evaluation to determine their eligibility. Eligible subjects – once on stable 
background treatment with PAH medications (ERA and/or PCA) - will start body-weight 
adjusted individual dose titration (IDT) regimen as described in section 5.1.1.
[…]
Children who require treatment with riociguat for more than 24 weeks will be offered 
participation in an extension study and continuation until market approval of riociguat for the 
pediatric population or until they are ≥18 years of age (whatever comes first). Subjects 
reaching adulthood can be transitioned to commercially-available Adempas.
[…]
4.1 Planned number of subjects
17.3.2.9
Old text:
At least 20 subjects must be enrolled in the study. 
[…]
After 5 patients in the ≥12 to <18 years old group have reached their optimal dose, have been 
treated on their maintenance dose and obtained the control x-ray of left hand at week 24, their 
data will be evaluated by DMC. After agreement of the DMC, the enrolment of patients in the 
age group ≥6 to <12 years will start.
[…]
New text:
Children on treatment with ERAs and/or PCAs can be enrolled. At least 20 children on 
treatment with bosentan or other Endothelin Receptor Antagonists (ERA) must be enrolled in 
the study. 
[…]
After 5 patients in the ≥12 to <18 years old group have reached their optimal dose, have been 
treated on their maintenance dose and obtained the control x-ray of left hand at week 24, their 
data will be evaluated by DMC. Only after obtaining positive safety and efficacy data in the 
first 5 patients, enrolment in the group from 6 to less than 12 years of age will be started.
[…]
4.2 Inclusion criteria
17.3.2.10
Old text:
[…]
1. Children aged ≥6 to <18 years
[…]

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3. Diagnosis of PAH confirmed by right heart catheterization (RHC) at any time prior to 
enrolment (for patients with closed shunts – RHC no less than 4 months after surgery)
[…]
5. Patients must be treated with standard of care comprising background therapy and stable 
dose of bosentan (at least 12 weeks with stable doses).
Two groups of patients will be included:
o
Prevalent: Patients currently on monotherapy with bosentan who need additional 
treatment (discretion of the investigator)
o
Incident: Treatment naïve patients initiated on bosentan then riociguat added once 
bosentan dose is stable for at least 12 weeks.
6. WHO functional class I, II, and -III
[…]
New text:
[…]
1. Children from 6 years to less than 18 years of age with pulmonary arterial hypertension 
(PAH)
[…]
3. Pulmonary arterial hypertension (PAH), diagnosed by right heart catheterization (RHC) at 
any time prior to enrolment (for patients with closed shunts – RHC no less than 4 months 
after surgery)
[…]
5. Patients must be on standard of care PAH medications, allowing Endothelin Receptor 
Antagonists (ERA) and/or Prostacyclin Analogues (PCA), for at least 12 weeks prior to 
baseline visit. 
Two groups of patients will be included:
o
Prevalent: Patients currently on PAH medication (allowing ERA and/or PCA) who
need additional treatment (discretion of the investigator)
o
Incident: Treatment naïve patients initiated on PAH medication (allowing ERA and/or 
PCA) and then riociguat added once patients are stable on standard of care.
6.
WHO functional class I-III
[…]
4.3 Exclusion criteria
17.3.2.11
Old text:
1. Concomitant use of the following medications: phosphodiesterase (PDE) 5 inhibitors 
(such as sildenafil, tadalafil, vardenafil) and non-specific PDE inhibitors (theophylline, 
dipyridamole) in any form or pretreatment are not allowed. Concomitant use of nitrates 
or NO donors are allowed up to two weeks before Visit 1.

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[…]
New text:
Please note that criteria numbering was changed in this section due to the modification
1. Concomitant use of the following medications: phosphodiesterase (PDE) 5 inhibitors 
(such as sildenafil, tadalafil, vardenafil) and non-specific phosphodiesterase (PDE)
inhibitors (theophylline, dipyridamole), nitrates or NO donors (such as amyl nitrite) in 
any form a
2. Pretreatment with NO donors (e.g. nitrates) within the last 2-weeks before visit 1
a Pretreatment with phosphodiesterase (PDE) 5 inhibitors is allowed up to 3 three days prior to start of riociguat 
treatment (Visit 1). Patients are not expected to be withdrawn from treatment with PDE5i for the purpose of 
entering into this trial. During the 3 days period without PDE5i, patients who received treatment with PDE5i 
are expected to be on stable clinical condition and receiving standard of care treatment with ERA and/or 
PCAs.
[…]
22. PH associated with idiopathic interstitial pneumonia (PH-IIP)
5.1.1 Body-weight adjusted individual dose titration regimen
17.3.2.12
Old text:
Riociguat will be provided to all subjects using an individual dose titration scheme to achieve 
a similar exposure as that observed in adults treated for PAH (Figure 5-1). For children with 
<50 kg body weight at baseline, a body weight adjusted dosing will be applied. Children with 
≥ 50kg body weight will receive adult doses. The individual optimal dose will be determined 
based on subject's monitoring of systolic blood pressure, well-being and clinical status. 
[…]
New text:
Riociguat must be provided to all patients using an individual dose titration scheme according 
to a body weight-adjusted dose to achieve a similar exposure as that observed in adults treated 
for PAH (Figure 5-1). The individual optimal (maintenance) dose is to be determined based 
on patient’s monitoring of systolic blood pressure, well-being and clinical status. For children 
with <50 kg body weight at baseline, a body weight adjusted dosing will be applied. Children 
with ≥ 50kg body weight will receive adult doses. 
[…]
5.6 Treatment assignment
17.3.2.13
Old text:
After enrolment, the subject identification number will be recorded on the corresponding 
electronic case report form (eCRF). The subject identification number will also have to be 
recorded on the label of the study medication.
New text:

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After enrolment, the subject identification number will be recorded on the corresponding 
electronic case report form (eCRF). The subject identification number will also have to be 
recorded on the label of the study medication.
In case bosentan or other ERA and/or PCA is/are provided locally, the compound’s name, 
dose, quantity and batch number, or a copy of the prescription has to be included in the 
subject’s files
6.1 Study visits
17.3.2.14
Old text:
The main study comprises 3 phases:

Pre-treatment phase: this phase is to identify potential eligibility of subjects who have 
been diagnosed with PAH. This visit will take place up to 2 weeks before Visit 1 
(baseline visit).

Main study treatment period is divided into 2 periods:
o
The individual titration phase compromises 4 visits 2 weeks (±2 days) apart.
o
The maintenance phase compromises 5 visits 4 weeks (±5 days) apart.

Safety follow-up phase (60±8days)
Subjects who have completed 24 weeks of treatment will be offered participation in an 
optional long term extension phase. Subjects not entering the LTE phase will perform the
safety follow-up visit (see section 6.1.4). Subjects dropping-off the protocol any time after 
Visit 1 and before Visit 9 will perform an end-of-treatment visit (see section 6.1.3).
[…]
New text:
The main study comprises 3 periods:

Pre-treatment period: up to 2 weeks. This period is to identify potential eligibility of 
subjects who have been diagnosed with PAH. This visit will take place up to 2 weeks 
before Visit 1 (baseline visit).

Active treatment period: 24 weeks (titration phase: 8 weeks, maintenance phase: 16 
weeks.) (Main study treatment period):
o
The individual titration phase comprises 4 visits 2 weeks (±2 days) apart.
o
The maintenance phase comprises 5 visits 4 weeks (±5 days) apart.

Follow-up period: at least 60 days for serious adverse events (SAEs). (Only for 
patients who do not enter the long term extension study or who stop the study 
medication prematurely.)
Subjects who have completed 24 weeks of treatment will be offered participation in an
optional long term extension phase. Subjects not entering the LTE will perform the safety 
follow-up visit (see section 6.1.4). Subjects completing the optional LTE will also perform the 

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safety follow up visit after 60 ± 8 days after LTE. Subjects dropping-off the protocol any time 
after Visit 1 and before Visit 9 will perform an end-of-treatment visit (see section 6.1.3).
[…]
6.1.1 Pre-treatment phase (Visit 0, Day -14 to -1)
17.3.2.15
Old text:
[…]

Pregnancy test for females of childbearing potential

Child Health Questionnaire (SF-10) (section 18.2)
[…]
New text:
[…]

Pregnancy test for females of childbearing potential

Child Health Questionnaire (SF-10 and PedsQL Generic Core Scales self-report) 
(section 18.2 and 18.7)
[…]
6.1.2.1 Individual titration phase (Visit 1- Visit 4)
17.3.2.16
Old text:
[…]

Collect NT-proBNP (Visit 1 only)
[…]

Record laboratory parameters (AST, ALT, BUN, creatinine, GGT, UA, T-Bil, Alb, 
Na, K, Ca, P, and CBC) to eCRF when obtained as medically required according to a 
local package insert of bosentan or medical practice at the study site at any time.
[…]
New text:
[…]

Collect NT-proBNP or BNP (Visit 1 only; when both tests are available, NT-proBNP 
should be chosen over BNP and the same test should be performed at every required 
visit)
[…]

Record laboratory parameters (AST, ALT, BUN, creatinine, GGT, UA, T-Bil, Alb, 
Na, K, Ca, P, and CBC) to eCRF when obtained as medically required according to a 
local package insert of bosentan or other ERA, or medical practice at the study site at 
any time.

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[…]
6.1.2.2 Maintenance phase (Visit 5 - Visit 9) 
17.3.2.17
Old text:
[…]

Collect NT-proBNP (Visit 9 only)
[…]

Child Health Questionnaire (SF-10) (Visit 9 only)
[…]

Obtain laboratory parameters (AST, ALT, BUN, creatinine, GGT, UA, T-Bil, Alb, Na, 
K, Ca, P, and CBC) at Visits 5 and 9 as well as record the same parameters when
obtained as medically required according to a local package insert of bosentan or 
medical practice at the study site at any time
[…]
New text:
[…]

Collect NT-proBNP or BNP (Visit 9 only; when both tests are available, NT-proBNP 
should be chosen over BNP and the same test should be performed at every required 
visit)
[…]

Child Health Questionnaire (SF-10 and PedsQL Generic Core Scales self-report) 
(Visit 9 only)
[…]

Obtain laboratory parameters (AST, ALT, BUN, creatinine, GGT, UA, T-Bil, Alb, Na, 
K, Ca, P, and CBC) at Visits 5 and 9 as well as record the same parameters when 
obtained as medically required according to a local package insert of bosentan or other 
ERA, or medical practice at the study site at any time
[…]
6.1.4 Safety follow-up visit
17.3.2.18
Old text:
[…]

Record laboratory parameters (AST, ALT, BUN, creatinine, GGT, UA, T-Bil, Alb, 
Na, K, Ca, P, and CBC) to eCRF when obtained as medically required according to a 
local package insert of bosentan or medical practice at the study site at any time.

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[…]
New text:
[…]

Record laboratory parameters (AST, ALT, BUN, creatinine, GGT, UA, T-Bil, Alb,
Na, K, Ca, P, and CBC) to eCRF when obtained as medically required according to a 
local package insert of bosentan or other ERA, or medical practice at the study site at 
any time.
[…]
6.1.5 Unscheduled visit
17.3.2.19
Old text:
[…]

Record laboratory parameters (AST, ALT, BUN, creatinine, GGT, UA, T-Bil, Alb, 
Na, K, Ca, P, and CBC) to eCRF when obtained as medically required according to a 
local package insert of bosentan or medical practice at the study site at any time.
[…]
New text:
[…]

Record laboratory parameters (AST, ALT, BUN, creatinine, GGT, UA, T-Bil, Alb,
Na, K, Ca, P, and CBC) to eCRF when obtained as medically required according to a 
local package insert of bosentan or other ERA, or medical practice at the study site at 
any time.
[…]
6.1.6 Optional long-term extension phase (until adulthood or approval 
17.3.2.20
in the indication and commercial availability)
Old text:
Subjects who require treatment with riociguat for more than 24 weeks will be offered 
participation in an optional extension phase. Subjects will receive riociguat until they can be 
transitioned to approved Adempas.
The following procedures will be performed:
Every 3 (± 14 days) months
[…]

Exploratory efficacy (6MWD test, WHO FC, NT-proBNP, QoL [SF-10], 
echocardiography, TTCW)

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
Record laboratory parameters (AST, ALT, BUN, creatinine, GGT, UA, T-Bil, Alb, 
Na, K, Ca, P, and CBC) to eCRF when obtained as medically required according to a 
local package insert of bosentan or medical practice at the study site at any time
[…]
Bone-age x-ray of the left hand and pubertal assessment using Tanner scale will be performed 
every 12 months until growth velocity is plateauing and growth plates are closed and at the
discretion of the investigator in case of clinical suspicion for bone and/or growth anomalies.
New text:
Children who require treatment with riociguat for more than 24 weeks will be offered 
participation in an extension study (optional extension phase). Subjects will receive riociguat 
until they can be transitioned to approved Adempas.
The following procedures will be performed:
Every 3 (± 14 days) months
[…]

Exploratory efficacy (6MWD test, WHO FC, NT-proBNP or BNP [when both tests 
are available, NT-proBNP should be chosen over BNP and the same test should be 
performed at every required visit], QoL [SF-10 and PedsQL Generic Core Scales self-
report], echocardiography, TTCW)

Record laboratory parameters (AST, ALT, BUN, creatinine, GGT, UA, T-Bil, Alb,
Na, K, Ca, P, and CBC) to eCRF when obtained as medically required according to a 
local package insert of bosentan or other ERA, or medical practice at the study site at 
any time
[…]

X-ray of the left hand will be performed every 12 months until growth plates are 
closed

Pubertal assessment using Tanner scale will be performed every 12 months
[…]
6.2 Safety outcomes
17.3.2.21
Old text:
[…]
Bone age and also bone morphology will be determined centrally by a specialist. Every 12 
months until growth velocity is plateauing and growth plates are closed, the subject’s overall 
development will also be assessed by physical examination, growth chart evaluation and 
pubertal development using Tanner scale.
[…]
Afterwards; any additional collection of laboratory parameters will be obtained in case 
medically required according to a local package insert of bosentan or medical practice at the 
site at any time point and will be captured in the eCRFs.

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New text:
[…]
Bone age and also bone morphology will be determined centrally by a specialist. Every 12 
months until growth velocity is plateauing and growth plates are closed, the subject’s overall 
development will also be assessed by physical examination, growth chart evaluation and 
pubertal development using Tanner scale, and at the discretion of the investigator in case of 
clinical suspicion for bone and/or growth anomalies.
[…]
Afterwards; any additional collection of laboratory parameters will be obtained in case 
medically required according to a local package insert of bosentan, or other ERA, or medical 
practice at the site at any time point and will be captured in the eCRFs.
[…]
6.3 Efficacy/Pharmacodynamic/Other outcomes
17.3.2.22
Old text:
Secondary efficacy, pharmacodynamic, and other outcomes (descriptive analysis) are the
change from baseline to end of treatment (week 24) of:

Functional capacity measured by a 6MWD test 

Functional status measured by WHO FC assessment

Laboratory biomarker: NT-proBNP

Quality of life: Child Health-related Questionnaire (SF-10)
[…]

Taste and texture of the pediatric formulation(s) by use of a questionnaire at the 
beginning and at the end of the study.
[…]
New text:
Main secondary endpoints will be assessed as: Change from baseline to end of treatment 
(week 24) of:

6-Minute Walking Distance (6MWD)

WHO functional class

Lab N-terminal prohormone brain-type natriuretic peptide or brain-type natriuretic 
peptide (when both tests are available, NT-proBNP should be chosen over BNP and 
the same test should be performed at every required visit)

Quality of Life scores (parent questionnaire and in children able to understand 
questions): Child Health-related Questionnaire (SF-10) and PedsQL Generic Core 
scales self-report
[…]

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
Taste and texture of the pediatric formulation(s) must be assessed by use of a
questionnaire at the beginning and at the end of the study.
[…]
6.4 Pharmacokinetics/Pharmacodynamics analyses
17.3.2.23
Old text:
6.4 Pharmacokinetics - amended
Primary PK outcome measure:
[…]
New text:
6.4 Pharmacokinetics/Pharmacodynamics analyses
Blood samples will be taken for pharmacokinetic and pharmacodynamic measurements from 
all participants treated with riociguat. The number of blood samples to be taken has been 
optimized using physiologically based pharmacokinetic (PBPK) modelling predictions in 
conjunction with clinical trials simulations (CTS) in order to only collect the minimum 
amount of blood needed for adequate analysis (sparse sampling).
Based on these evaluations the following measures to minimize pain and distress have been 
included: the number of blood samples in children from 6 to less than 18 years of age for PK 
analysis must not exceed four, and the minimum amount of blood needed for adequate 
analysis of each sample is 1.0mL of blood.
Primary PK outcome measure:
[…]
7.4 Analyses
17.3.2.24
Old text:
Not applicable.
New text:
A descriptive analysis of the safety and efficacy parameters will be performed.
7.4.1 Safety analysis
17.3.2.25
Old text:
The primary objective is to evaluate the safety and tolerability of riociguat in children with 
PAH. Safety and tolerability will be assessed by adverse event recording, vital signs, left hand 
x-ray and laboratory panel.
[…]

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New text:
The primary objective is to evaluate the safety and tolerability of riociguat in children with 
PAH. Primary endpoint of the study is: Change from baseline to end of treatment (week 24) 
of safety and tolerability assessed by incidence of adverse events and serious adverse events, 
recording of vital signs and left-hand X-ray and laboratory panel.
[…]
7.4.2 Efficacy analysis
17.3.2.26
Old text:
Other objectives are to characterize the pharmacodynamic profile of riociguat using the 
following parameters: time to clinical worsening (TTCW), exercise capacity (6MWD test), 
functional capacity (measured by WHO FC), laboratory biomarkers (NT-proBNP), 
echocardiographic parameters and QoL measurements (SF-10).
Continuous efficacy parameters, and their corresponding changes from baseline to the end of 
treatment (week 24), will be analyzed descriptively by sample summary statistics. 
[…]
New text:
Other objectives are to characterize the pharmacodynamic profile of riociguat using the 
following parameters: time to clinical worsening (TTCW), exercise capacity (6MWD test),
functional capacity (measured by WHO FC), laboratory biomarkers (NT-proBNP or BNP
[when both tests are available, NT-proBNP should be chosen over BNP and the same test 
should be performed at every required visit]), echocardiographic parameters and QoL 
measurements (SF-10 and PedsQL Generic Core Scales self-report).
Continuous efficacy parameters will be analyzed descriptively by sample summary statistics. 
Time points of efficacy assessment: Exploratory efficacy at baseline and week 24 and every 3 
to 4 months in the extension phase.
[…]
7.5 Determination of sample size
17.3.2.27
Old text:
At least 20 subjects will be enrolled in the study. 
[…]
New text:
Children on treatment with ERAs and/or PCAs can be enrolled. At least 20 subjects on 
treatment with bosentan or other Endothelin Receptor Antagonists (ERA) must be enrolled in 
the study.
[…]

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8.9 Premature discontinuation of study medication
17.3.2.28
Old text:
[…]

Subject does not tolerate the lowest possible riociguat dose (0.5 mg TID)
Discontinuation of bosentan treatment (i.e. due to elevated liver enzymes) during the course
of the study does not mandate withdrawal of the subject from the study. The final decision of 
withdrawal will be the responsibility of the investigator.
[…]
New text:
[…]

Subject does not tolerate the lowest possible riociguat dose (0.5 mg TID)

Patient with pulmonary hypertension associated with idiopathic interstitial 
pneumonias (PH-IIP) 
Discontinuation of bosentan or other ERA treatment (i.e. due to elevated liver enzymes) 
during the course of the study does not mandate withdrawal of the subject from the study.
Also, discontinuation PCA treatment, during the course of the study, does not mandate 
withdrawal of the subject from the study. The final decision of withdrawal will be the 
responsibility of the investigator.
[…]
16. Reference list
17.3.2.29
Old text:
Not applicable
New text:
Weber M, Hamm C. Role of B-Type natriuretic peptide (BNP) and NT-proBNP in clinical 
routine. Heart 2006; 92 (6):843-849

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18.4 Appendix 4: Taste assessment
17.3.2.30
Old text:
[…]

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[…]
18.7 Appendix 7: PedsQL Generic Core Scales
17.3.2.31
Old text:
Not applicable.
New text:
New Pediatric Quality of Life questionnaire: PedsQL Generic Core Scales self-report was 
added as Appendix 7

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Amendment 9
17.4
Amendment 9 is the fourth global amendment dated 13 MAR 2018.
17.4.1
Overview of changes
Modification 1: Change to allow the inclusion of patients with ostium 
17.4.1.1
secundum atrial septal defect ≤ 1 cm without hemodynamic alterations
In the current protocol, inclusion criterion 2 states that children from 6 to < 18 years with 
PAH associated with congenital heart disease (CHD) should only be enrolled if the CHD is
associated with shunt closure more than 6 months ago. Taking into account: (i) the high 
prevalence of atrial septal defects (ASD), which account for approximately 6%–10% of all 
congenital heart diseases; (ii) the fact that ostium secundum ASD (OS-ASD) is the most 
common form of ASD (75% of cases); (iii) that OS-ASD generally presents as an isolated 
defect; and (iv) that OS-ASD ≤ 1 cm of effective diameter assessed by echocardiogram 
usually remains asymptomatic and itself does not account for the development of PAH; the 
inclusion of such patients into the study was discussed with the Steering Committee and was
allowed.
The protocol sections affected by this modification are:
4.2 Inclusion criteria
Modification 2: Change to allow the inclusion of patients with patent 
17.4.1.2
foramen ovale ≤ 1 cm
In the current protocol, inclusion criterion 2 states that children from 6 to < 18 years with 
PAH associated with CHD should only be enrolled if the CHD is associated with shunt 
closure more than 6 months ago. Taking into account: (i) the fact that PFO is considered a 
physiological connection rather than a congenital heart disease; (ii) the high prevalence (25 to 
30% of the general population) of PFO; (iii) that PFO ≤ 1 cm is not associated with significant 
shunt through the defect and itself does not account for the development of PAH, the 
inclusion of such patients into the study was discussed with the Steering Committee and was
allowed.
The protocol sections affected by this modification are:
4.2 Inclusion criteria

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Modification 3: Change of text in the inclusion criterion of pediatric 
17.4.1.3
female patients of child bearing potential not agreeing to use effective 
contraception
The inclusion criterion 7 was adjusted according to applicable guidelines on contraception 
during clinical trials to clarify that all adolescent females of childbearing potential must agree 
to use an “effective” contraception method to be allowed to be enrolled in the study. The 
inclusion criterion text was adjusted to include the definition of “effective” methods, covering 
combination of methods, some of which to be applied when sexually active, and to receive 
sexual counseling as applicable.
The protocol sections affected by this modification are:
4.2 Inclusion criteria
Modification 4: Change of the washout period for Sildenafil (24h 
17.4.1.4
instead of 3 days), to align with current label and ongoing studies
As the concomitant use of PDE5i and riociguat is contraindicated, a washout period needs to 
be considered when switching between these classes.
The Adempas label has been updated to provide guidance on the required time before 
stopping sildenafil and starting riociguat therapy. Patients switching to riociguat from 
sildenafil should discontinue sildenafil treatment at least 24 hours prior to riociguat 
administration.
Since the elimination half-life of sildenafil is short, about 4 hours, sildenafil concentration in 
the bloodstream after 24 hours is negligible. Differing from nitrates, riociguat has not been 
found to act synergistically with PDE5i, although similarities in the mode of action suggest 
this as a possibility. Considering the lack of synergistic hypotension, and a 24-hour washout 
period that is effective in reducing the interaction with nitrates, initiating riociguat 24 hours 
after discontinuation of sildenafil is recommended. 
The washout time of 24 hours is consistent with ongoing randomized riociguat study 
REPLACE (A prospective, randomized, international, multicenter, double-arm, controlled, 
open-label study of Riociguat in patients with pulmonary arterial hypertension (PAH) who 
are on a stable dose of phosphodiesterase-5 inhibitors (PDE-5i) with or without endothelin 
receptor antagonist (ERA), but not at treatment goal).
The protocol sections affected by this modification are:
4.3 Exclusion criteria
Modification 5: Change to allow dose to be taken at midday during the 
17.4.1.5
visits without PK sampling
Since, as per in the protocol, PK samples are not required to be taken at Visit 2 and 4, subjects 
were allowed to take the morning dose of the study drug until midday.

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After Visit 1, PK blood sampling occurs at Visits 3 and 5, for which patients are required to 
come to the hospital without having taken the riociguat morning dose.
It has been noticed that the same requirement is kept in the study protocol at Visits 2 and 4 
although no PK sampling takes place. In the amendment this requirement only applies to 
Visits 3 and 5, where in the visits without PK sampling it is allowed to take the morning dose 
until midday.
The protocol sections affected by this modification are:
6.1.2.1 Individual titration phase (Visit 1 – Visit 4)
Modification 6: Change to allow up-titration during the LTE phase at 
17.4.1.6
the discretion of the investigator
According to the protocol: “At the end of the individual titration period, the subjects should 
have reached their individually adjusted dose. The established individual equivalent dose will 
then be taken as optimal dose to be administered during the 16 week maintenance period… 
and a subsequent re-increase is not possible…”.
Taking into consideration the feedback received so far from some investigators requesting up-
titration of the dose of riociguat during LTE phase and preliminary PK data available to the 
DMC, the study protocol is amended to allow up-titration in the LTE phase at the discretion 
of the investigator. 
The protocol sections affected by this modification are:
5.1.1 Body-weight adjusted individual dose titration regimen
Modification 7: Addition of computing cardiac output to the 
17.4.1.7
echocardiographic assessment
There is a direct relationship between riociguat plasma concentration and hemodynamic 
parameters such as systemic vascular resistance, systolic blood pressure, pulmonary vascular 
resistance (PVR), and cardiac output (IB BAY 63-2521).
The current study protocol includes exploratory echocardiographic assessments; and by 
means of the amendment it will be included the computing of cardiac output as part of the 
exploratory efficacy measurements.
The protocol sections affected by this modification are:
Synopsis
6.3 Efficacy/Pharmacodynamic/Other outcomes
Modification 8: Change to specify that collection of AEs starts after 
17.4.1.8
informed consent is signed
To clarify the procedure during the pre-treatment phase, it is specified that the collection 
period for AEs will begin after informed consent is obtained consistent with safety reporting 
rules in clinical trials.
The protocol sections affected by this modification are:

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Study Flow chart
6.1.1 Pre-treatment phase (Visit 0, Day -14 to -1)
Modification 9: Clarification of the planned number of patients 
17.4.1.9
For clarity and compliance with the PIP, this statement regarding the number of patients,
which does not fall under the PIP commitment, was removed: “At least 20 subjects are 
planned to be enrolled into this study. Every effort is made to enroll equal numbers (i.e. 
approximately 10 subjects each) in both age cohorts.”
“…In case of inadequate availability of patients in the age group ≥6 to <12 years total 
enrolment will be stopped only if at least 5 patients of this younger age group have completed 
their 24-week initial treatment period.”, was modified to “if at least 5 patients of this younger 
age group have been enrolled”.
Sections affected by this change are:
4.1 Planned number of subjects
5.1.1 Body-weight adjusted individual dose titration regimen
Modification 10: Clarification of the study algorithm for dose titration, 
17.4.1.10
for completeness
The symbol equal was missing. Therefore, the ≥ symbol was added as applicable in the 
following bullet points:

If SBP is ≥5 mmHg but less than 10 mmHg lower than the age-, sex- and height-
adapted level of the 50th blood pressure (BP) percentile, maintain dose of riociguat. 

If SBP is ≥10 mmHg lower than the age-, sex- and height-adapted level of the 50th BP 
percentile, reduce riociguat dose (- 0.5 mg dose-equivalent TID)

If any SBP is ≥ 5 mmHg lower than the age-, sex- and height-adapted level of the 50th
BP percentile, with clinical symptoms of hypotension such as dizziness or 
presyncope, stop study treatment; restart after 24 hours with reduced dose - 0.5 mg 
dose-equivalent TID). 
The protocol sections affected by this modification are:
5.1.1 Body-weight adjusted individual dose titration regimen
Modification 11: Change to exclusion criteria to cover any condition 
17.4.1.11
that is not recommended with riociguat
Rewording of exclusion criteria 18 was updated to cover any conditions that are not 
recommended with riociguat according to the reference safety information
The protocol sections affected by this modification are:
4.3 Exclusion criteria

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Modification 12: Adjustments to the Flow chart and visit detail table
17.4.1.12
For clarification, the collection of AEs was added at screening. The term study booklet was 
replaced with study guidelines. Medical history at Visit 1 was removed. The footnote “i” was 
removed from the position after ‘Obtain lab test’. Under instruct how to take study drug, 
brackets were added at the unscheduled visit. Footnote “d” positioned directly after Vital 
signs and in ECG was shifted to Visit 1.
In the visit detail table (Table 0-2), “At pre-dose, blood sample safety laboratory” was shaded 
out. In the order of procedures, the administration study drug was placed at the end.
The protocol sections affected by this modification are:
Study Flow chart
Modification 13: Minor editing corrections
17.4.1.13
Minor, consistency and logical clarifications were made throughout the document. The 
changes were made to ensure clear wording and consistency throughout the document. These 
changes do not affect the overall study concept.
Sections affected by the changes are:

Title page: The Study medical expert was changed.

Signature of the sponsor’s medically responsible person: The Global Clinical Lead 
was changed.

List of Abbreviations: New abbreviations were added due to the Amendment 9, 
Modifications 1 and 2. The spelling of calcium was corrected. Additional 
abbreviations were added.

Synopsis: Under primary variables, the paragraph describing 
pharmacokinetics/pharmacodynamics analyses was split into two separate lines, and 
PK was specified to the number of blood samples. Under main secondary variables:
inferior vena cava pressure was replaced with right atrial pressure, the word both was 
removed from the definition of worsening of PAH symptoms, and the spelling of 
tricuspide to tricuspid was corrected.

Section 6.1.2.2 Maintenance phase (Visit 5 - Visit 9): For clarification Visit 5 was 
added to the sentence. The bullet points were reordered according to the procedures to 
be performed starting at Visit 5 to 9.

Section 6.1.3 End-of-treatment visit: For completeness the word Visit was added.

Section 6.1.1 Optional long-term extension phase (until adulthood or approval in 
the indication and commercial availability): In the LTE phase the physical 
examination includes monitoring of growth velocity was included for consistency with 
the flow chart.

Section 6.3 Efficacy/Pharmacodynamic/Other outcomes: Inferior vena cava 
pressure was replaced with right atrial pressure. Under the bullet point “Worsening of 
PAH symptoms, the word both was removed from the definition of worsening of PAH 

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symptoms and the bullet point at the position of “need for additional PAH therapy” 
was removed.

Section 6.4 Pharmacokinetics/Pharmacodynamics analyses: For correctness, the 
word PK was added. Section 7.4.3 paragraph describing blood sampling at each visit 
was moved to Section 6.4. For clarity, “For all visits in the main study phase, the exact 
time of three riociguat dosing (current and the previous two doses) and time of PK/PD 
blood sampling will be documented in the eCRF”, was added.

6.5 Study guidelines for parents and children: For correctness the term study 
guidelines was added to replace study booklet.

Section 7.4.3 Pharmacokinetic analysis: For completeness the sentence For 
investigation of exposure behavior, plasma concentrations of BAY63-2521 and its 
metabolite (M1) will be analyzed descriptively, the cross-reference to Section 6.4, and 
term PK/PD evaluations were added.

Section 7.5 Determination of sample size: For clarity and compliance with the PIP, 
(i.e. 10 subjects each) was removed, and the word patient was added.
17.4.2
Changes to the protocol text
All affected protocol sections are detailed; the sequence of the sections follows the structure 
of the original protocol. In the display of modifications, the “old text” refers to the original 
protocol. Deletions are crossed out in the “old text”. Additions are underlined in the “new 
text”. Minor editorial changes or corrections are not listed.

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Title page
17.4.2.1
Old text:
[…]
Sponsor’s medical expert:
(Note: Study medical expert 
was changed according to 
Amendment 3, see section 
17.1.1.16. The contact details 
were updated according to 
Amendment 5, see Section 
17.2.1.8.)
 
Bayer Pharma AG
BPH-GD-P&O
Aprather Weg, Bd 402
42113, Wuppertal, Germany
Phone: 
[…]
New text:
[…]
Sponsor’s medical expert:
(Note: Study medical expert 
was changed according to 
Amendment 3, see section 
17.1.1.16. The contact details 
were updated according to 
Amendment 5, see Section 
17.2.1.8.)
 
Study Medical Expert - TA Cardiology & Coagulation 
Global Development-Portfolio & Operations
Bayer SA
Rua Cancioneiro de Évora 255 - Prédio E1 - 1º andar
04708-010 São Paulo - SP Brasil
Tel: 
Signature of the sponsor’s medically responsible person
17.4.2.2
Old text:
[…]
Name:
Role: 
GCL (Global Clinical Lead)
Date:
Signature:
[…]
PPD
PPD
PPD
PPD
PPD

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New text:
[…]
Name:
Role: 
GCL (Global Clinical Lead)
Date:
Signature:
PPD

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Synopsis
17.4.2.3
Old text:
[…]
Primary variable(s)

Change from baseline to end of treatment (week 24) of 
safety and tolerability assessed by incidence of adverse 
events and serious adverse events, recording of vital signs 
and left-hand x-ray.

Pharmacokinetics/Pharmacodynamics analyses.
Blood samples will be taken for pharmacokinetic and 
pharmacodynamic measurements from all participants 
treated with riociguat. The number of blood samples to be 
taken will be determined using physiologically based 
pharmacokinetic (PBPK) modelling predictions. It is 
intended to collect the minimum amount of blood needed 
for adequate analysis (sparse sampling).
New text:
[…]
Primary variable(s)

Change from baseline to end of treatment (week 24) of 
safety and tolerability assessed by incidence of adverse 
events and serious adverse events, recording of vital signs 
and left-hand x-ray.

Pharmacokinetics/Pharmacodynamics analyses.
Blood samples will be taken for pharmacokinetic and 
pharmacodynamic measurements from all participants 
treated with riociguat.
The number of pharmacokinetic (PK) blood samples to be 
taken will be determined using physiologically based 
pharmacokinetic (PBPK) modelling predictions. It is 
intended to collect the minimum amount of blood needed 
for adequate analysis (sparse sampling).

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Old text:
Main secondary variable(s)
(Note: this part was modified 
according to Amendment 5, see 
Sections 17.2.1.3 and 17.2.1.7. 
This part was modified according 
to Amendment 6, see Section 
17.3.1.6.)
Change from baseline to end of treatment (week 24) of:

6-Minute Walking Distance (6MWD).

WHO functional class.

N-terminal prohormone brain-type natriuretic peptide or 
brain-type natriuretic peptide. When both tests are 
available, NT-proBNP should be chosen over BNP and 
the same test should be performed at every required visit.

Quality of Life scores (parent questionnaire and in 
children able to understand questions).

Echocardiographic parameters including 
o
pulmonary arterial systolic pressure (PASP),
o
tricuspid annular plane systolic excursion (TAPSE),
o
pericardial effusion, 
o
left ventricular eccentricity index, 
o
estimated inferior vena cava pressure,
o
right ventricular pressure by tricuspide regurgitant jet 
velocity,
o acceleration time of pulmonary flow, and
o right heart dimensions. 

Time to clinical worsening defined as
o
hospitalization for right heart failure,
o
death,
o
lung transplantation, 
o
Pott’s anastomosis and atrioseptostomy, 
o
worsening of PAH symptoms, which must include 
either 

an increase in WHO functional class, 
OR 

both appearance/worsening symptoms of right 
heart failure 
AND

need for additional PAH therapy.

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New text:
Main secondary variable(s)
(Note: this part was modified 
according to Amendment 5, see 
Sections 17.2.1.3 and 17.2.1.7. 
This part was modified according 
to Amendment 6, see Section 
17.3.1.6 This part was modified 
according to Amendment 9, see 
Section 17.4.1.7 and 17.4.1.13.)
Change from baseline to end of treatment (week 24) of:

6-Minute Walking Distance (6MWD).

WHO functional class.

N-terminal prohormone brain-type natriuretic peptide or 
brain-type natriuretic peptide. When both tests are 
available, NT-proBNP should be chosen over BNP and 
the same test should be performed at every required visit.

Quality of Life scores (parent questionnaire and in 
children able to understand questions).

Echocardiographic assessment of the following:
o
pulmonary arterial systolic pressure (PASP),
o
tricuspid annular plane systolic excursion (TAPSE),
o
pericardial effusion, 
o
left ventricular eccentricity index, 
o
estimated right atrial pressure,
o
right ventricular pressure by tricuspid regurgitant jet 
velocity,
o acceleration time of pulmonary flow
o right heart dimensions, and
o
cardiac output 
Time to clinical worsening defined as:
o
hospitalization for right heart failure,
o
death,
o
lung transplantation, 
o
Pott’s anastomosis and atrioseptostomy, 
o
worsening of PAH symptoms, which must include 
either 

an increase in WHO functional class, 
       OR 

appearance/worsening symptoms of right heart 
failure 
       AND
need for additional PAH therapy.

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Study Flow chart
17.4.2.4
Old text:
[…]
Table 17–1: Flow chart - amended
Main study treatment period - 24 weeks
Screening
Individual titration 
phase
(8 weeks)
Maintenance phase
(16 weeks)
Unscheduled 
visit
End of 
treatment 
visit l
Safety 
follow-
up 
60 ± 8 
days
Optional 
Long-term 
extension 
phase
Safety 
follow up 
visit 
60 +8 days 
after 
optional 
LTE 
Visit
V0
V1 g
V2
V3
V4
V5
V6k
V7
V8k
V9
Every 3 
months 
(± 14 
days)
Week f
Day -14 
to -1
0
2
4
6
8
12
16
20
24
Informed 
consent/assent
•
In-/exclusion 
criteria
•
•
Demographics
• 
Medical history
• 
•
Concomitant 
medication
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Concomitant 
PAH specific 
medication
• 
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Physical 
examination m
• 
• d
•
•
•
•
•
•
•
•
•
•
•
• h
•
Obtain lab test i
•i
•
•
•
Pregnancy test a
•
•
•
•
•
•
•
•
•
•
•
•

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20 JUL 2020
Version 7.0
Page: 168 of 211
Table 17–1: Flow chart - amended
Main study treatment period - 24 weeks
Screening
Individual titration 
phase
(8 weeks)
Maintenance phase
(16 weeks)
Unscheduled 
visit
End of 
treatment 
visit l
Safety 
follow-
up 
60 ± 8 
days
Optional 
Long-term 
extension 
phase
Safety 
follow up 
visit 
60 +8 days 
after 
optional 
LTE 
Visit
V0
V1 g
V2
V3
V4
V5
V6k
V7
V8k
V9
Every 3 
months 
(± 14 
days)
Week f
Day -14 
to -1
0
2
4
6
8
12
16
20
24
Dispense study 
medication
•
•
•
•
•
•
•
•
•
(•)
•
Instruct how to 
take study drug
•
•
•
•
•
•
•
•
•
•
•
Provide booklet
•
Vital signs d
• 
•
•
•
•
•
•
•
•
•
•
•
•
•

ECG d
• 
•
•
•
Echocardiogram
•
•
•
•
RHC data o
•o
WHO functional 
class
•
•
•
•
6MWD
•
•
•
•
NT-proBNP or 
BNPp
•
•
•
•
Left hand x-ray
• j
•
• e
Adverse events n
•
•
•
•
•
•
•
•
•
•
•
•
•

Drug 
accountability
•
•
•
•
•
•
•
•
•
•
PK blood sampleb
•
•
• 

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Table 17–1: Flow chart - amended
Main study treatment period - 24 weeks
Screening
Individual titration 
phase
(8 weeks)
Maintenance phase
(16 weeks)
Unscheduled 
visit
End of 
treatment 
visit l
Safety 
follow-
up 
60 ± 8 
days
Optional 
Long-term 
extension 
phase
Safety 
follow up 
visit 
60 +8 days 
after 
optional 
LTE 
Visit
V0
V1 g
V2
V3
V4
V5
V6k
V7
V8k
V9
Every 3 
months 
(± 14 
days)
Week f
Day -14 
to -1
0
2
4
6
8
12
16
20
24
Child Health 
Questionnaire 
(SF-10 and 
PedsQL)
• 
•
•
•
Tanner scale c
• 
•
•
• e
Taste 
assessment 
questionnaire
•
•
•
Table 17-1: Flow chart - amended
a
Urine or serum pregnancy test for women of childbearing potential 
b
A minimum volume of 1.0 mL per sample is needed. Accurate adherence to time points is essential and has to be documented, 
      see Table 0–2
c
Scale of physical development in children and adolescents 
d
Blood pressure, heart rate and ECG pre-dose, 2 and 4 hours after first dose (see Table 0–2)
e
Every 12 months until growth velocity is plateauing and growth plates are closed (see section 6.1.6)
f
±2 days for Visits 1 to 4, ±4 days for Visit 5, ±5 days for Visits 6 to 9
g
Visit 1 is considered the baseline visit
h
Incl. height, growth velocity and weight
i
Obtain blood samples if AST and ALT, creatinine, BUN, GGT, UA, T-Bil, Alb, Na, K, Ca, P, and CBC are not available within 30 days prior to Visit 0. Record 
the same laboratory parameters to eCRF when obtained as medically required according to a local package insert of bosentan or other ERAs, or medical 
practice at the study site at any time.

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j
If no historical data (≤30 days) of x-ray is available
k
Home visits (only at week 12 and/or 20 of maintenance phase) at the discretion and responsibility of the investigator
l
For subjects dropping off the protocol at any time after V1 and before V9
m
Including height and weight
n
Including AEs of special interest
o
In case RHC has been performed for a study subject before enrollment, record most recent RHC parameters to the eCRF on V0 (timing of RHC not 
limited to the period of Day -14 to -1). Additionally, if RHC is conducted on medical reasons during the study, the RHC data should be recorded to the 
eCRF.
p 
When both tests are available, NT-proBNP should be chosen over BNP and the same test should be performed at every required visit
New text:
[…]
Table 17–2: Flow chart - amended
Main study treatment period - 24 weeks
Screening
Individual titration 
phase
(8 weeks)
Maintenance phase
(16 weeks)
Unscheduled 
visit
End of 
treatment 
visit l
Safety 
follow-
up 
60 ± 8 
days
Optional 
Long-term 
extension 
phase
Safety 
follow up 
visit 
60 +8 days 
after 
optional 
LTE 
Visit
V0
V1 g
V2
V3
V4
V5
V6k
V7
V8k
V9
Every 3 
months 
(± 14 
days)
Week f
Day -14 
to -1
0
2
4
6
8
12
16
20
24
Informed 
consent/assent
•
In-/exclusion 
criteria
•
•
Demographics
• 
Medical history
• 

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Version 7.0
Page: 171 of 211
Table 17–2: Flow chart - amended
Main study treatment period - 24 weeks
Screening
Individual titration 
phase
(8 weeks)
Maintenance phase
(16 weeks)
Unscheduled 
visit
End of 
treatment 
visit l
Safety 
follow-
up 
60 ± 8 
days
Optional 
Long-term 
extension 
phase
Safety 
follow up 
visit 
60 +8 days 
after 
optional 
LTE 
Visit
V0
V1 g
V2
V3
V4
V5
V6k
V7
V8k
V9
Every 3 
months 
(± 14 
days)
Week f
Day -14 
to -1
0
2
4
6
8
12
16
20
24
Concomitant 
medication
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Concomitant 
PAH specific 
medication
• 
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Physical 
examination m
• 
• d
•
•
•
•
•
•
•
•
•
•
•
•h
•
Obtain lab test
•i
•
•
•
Pregnancy test a
•
•
•
•
•
•
•
•
•
•
•
•
Dispense study 
medication
•
•
•
•
•
•
•
•
•
(•)
•
Instruct how to 
take study drug
•
•
•
•
•
•
•
•
•
(•)
•
Provide study 
guidelines
•
Vital signs 
• 
•d
•
•
•
•
•
•
•
•
•
•
•
•

ECG 
• 
•d
•
•
Echocardiogram
•
•
•
•
RHC data o
•o
WHO functional 
class
•
•
•
•

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Version 7.0
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Table 17–2: Flow chart - amended
Main study treatment period - 24 weeks
Screening
Individual titration 
phase
(8 weeks)
Maintenance phase
(16 weeks)
Unscheduled 
visit
End of 
treatment 
visit l
Safety 
follow-
up 
60 ± 8 
days
Optional 
Long-term 
extension 
phase
Safety 
follow up 
visit 
60 +8 days 
after 
optional 
LTE 
Visit
V0
V1 g
V2
V3
V4
V5
V6k
V7
V8k
V9
Every 3 
months 
(± 14 
days)
Week f
Day -14 
to -1
0
2
4
6
8
12
16
20
24
6MWD
•
•
•
•
NT-proBNP or 
BNPp
•
•
•
•
Left hand x-ray
• j
•
• e
Adverse events n
•
•
•
•
•
•
•
•
•
•
•
•
•
•

Drug 
accountability
•
•
•
•
•
•
•
•
•
•
PK blood sampleb
•
•
• 
Child Health 
Questionnaire 
(SF-10 and 
PedsQL)
• 
•
•
•
Tanner scale c
• 
•
•
• e
Taste 
assessment 
questionnaire
•
•
•
Table 0-1: Flow chart - amended
a
Urine or serum pregnancy test for women of childbearing potential 
b
A minimum volume of 1.0 mL per sample is needed. Accurate adherence to time points is essential and has to be documented, 
      see Table 0–2
c
Scale of physical development in children and adolescents 

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d
At Visit 1 blood pressure, heart rate and ECG pre-dose, 2 and 4 hours after first dose (see Table 0–2)
e
Every 12 months until growth velocity is plateauing and growth plates are closed (see section 6.1.6)
f
±2 days for Visits 1 to 4, ±4 days for Visit 5, ±5 days for Visits 6 to 9
g
Visit 1 is considered the baseline visit
h
Including monitoring of growth velocity.
i
Obtain blood samples if AST and ALT, creatinine, BUN, GGT, UA, T-Bil, Alb, Na, K, Ca, P, and CBC are not available within 30 days prior to Visit 0. Record 
the same laboratory parameters to eCRF when obtained as medically required according to a local package insert of bosentan or other ERAs, or medical 
practice at the study site at any time.
j
If no historical data (not older than 30 days) of x-ray is available
k
Home visits (only at week 12 and/or 20 of maintenance phase) at the discretion and responsibility of the investigator
l
For subjects dropping off the protocol at any time after V1 and before V9
m
Including height and weight
n
Including AEs of special interest
o
In case RHC has been performed for a study subject before enrollment, record most recent RHC parameters to the eCRF on V0 (timing of RHC not 
limited to the period of Day -14 to -1). Additionally, if RHC is conducted on medical reasons during the study, the RHC data should be recorded to the 
eCRF.
p 
When both tests are available, NT-proBNP should be chosen over BNP and the same test should be performed at every required visit

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Version 7.0
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Old text:
Table 17–3: Visit details - amended
Visit 1 (Baseline visit)
Visit 3 and 5
Detailed study activities at pre-dose and after the first study 
medication dose intake
Study activities before first study 
medication dose intake
Order of 
procedures
Time interval (h)
pre-dose
0:00
0:30 to 1:30
2:00
2:30 to 4:00
4:00
-1:00 to 0:00
0:00
Pharmacokinetic blood 
sample
•
•
•
Blood sample for 
NT-proBNP or BNPb
•
Blood sample for safety 
laboratory
• a
Blood pressure, heart rate
•
•
•
ECG
•
•
•
WHO functional class
•
Left hand x-ray
•
Administration study drug
•
•
Echocardiogram
•
1.
Obtain blood sample for safety parameters on Visit 5 only. 
2.
When both tests are available, NT-proBNP should be chosen over BNP and the same test should be performed at every required visit
Abbreviations: ECG = electrocardiogram
(Note: Visit details were modified according to Amendment 3, see Section 17.1.1.16.The table for visit details was modified according to 
Amendment 5, see Section 17.2.1.8. The table for details was modified according to Amendment 6, see Section 17.3.1.6.)

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Page: 175 of 211
New text:
Table 17–4: Visit details - amended
Visit 1 (Baseline visit)
Visit 3 and 5
Detailed study activities at pre-dose and after the first study 
medication dose intake
Study activities before first study 
medication dose intake
Order of 
procedures
Time interval (h)
pre-dose
0:00
0:30 to 1:30
2:00
2:30 to 4:00
4:00
-1:00 to 0:00
0:00
Pharmacokinetic blood 
sample
•
•
•
Blood sample for 
NT-proBNP or BNPb
•
Blood sample for safety 
laboratory
• a
Blood pressure, heart rate
•
•
•
ECG
•
•
•
WHO functional class
•
Left hand x-ray
•
Echocardiogram
•
Administration study drug
•
•
a.
Obtain blood sample for safety parameters on Visit 5 only. 
b.
When both tests are available, NT-proBNP should be chosen over BNP and the same test should be performed at every required visit
Abbreviations: ECG = electrocardiogram
(Note: Visit details were modified according to Amendment 3, see Section 17.1.1.16.The table for visit details was modified according to 
Amendment 5, see Section 17.2.1.8. The table for details was modified according to Amendment 6, see Section 17.3.1.6.)

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4.1 Planned number of subjects
17.4.2.5
[…]
Old text:
[…]
The sponsor will make every effort to facilitate an equal distribution between the two age 
cohorts with a minimum of 5 patients in each age cohort. In case of inadequate availability of 
patients in the age group ≥6 to <12 years total enrolment will be stopped only if at least 5 
patients of this younger age group have been enrolled have completed their 24-week initial 
treatment period.
[…]
New text:
[…]
The sponsor will make every effort to facilitate an equal distribution between the two age 
cohorts with a minimum of 5 patients in each age cohort. In case of inadequate availability of 
patients in the age group ≥6 to <12 years total enrolment will be stopped only if at least 5 
patients of this younger age group have been enrolled.
4.2 Inclusion criteria
17.4.2.6
Old text:
[…]
2. Diagnosed with PAH :

Idiopathic (IPAH)

Hereditable (HPAH)

PAH associated with (APAH)
o
Connective tissue disease 
o
Congenital heart disease with shunt closure more than 6 months ago (no open 
shunts, confirmed by RHC no less than 4 months after surgery)
[…]
New text:
[…]

PAH associated with (APAH)
o
Connective tissue disease 
o
Congenital heart disease with shunt closure more than 6 months ago (no open 
shunts, confirmed by RHC no less than 4 months after surgery)
Regardless of the type of PAH, the following findings are not exclusionary:

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o
Patent foramen ovale (PFO) ≤ 1 cm (confirmed by echocardiogram) is not 
exclusionary
o
Asymptomatic, isolated, ostium secundum atrial septal defect (OS-ASD) ≤ 1 
cm (confirmed by echocardiogram) and not associated with hemodynamic 
alterations indicative of significant shunt, e.g. Qp/Qs ratio less <1.5:1 is not 
exclusionary
[…]
Old text:
[…]
10.
Adolescent females of childbearing potential can only be included in the study if a 
pregnancy test is negative. Adolescent females of childbearing potential must agree to use 
adequate contraception when sexually active. ‘Adequate contraception’ is defined as any
combination of at least 2 effective methods of birth control, of which at least one is a physical 
barrier (e.g. condoms with hormonal contraception or implants or combined oral 
contraceptives, certain intrauterine devices). Adequate contraception is required from the
signing of the informed consent form up until 6 weeks after the last study drug administration.
New text:
[…]
10.
Adolescent females of childbearing potential can only be included in the study if a 
pregnancy test is negative. Adolescent females of childbearing potential must agree to use 
adequate contraception when sexually active. ‘Effective contraception’ is defined as
progestogen-only hormonal contraception associated with inhibition of ovulation (implant), 
intrauterine device (IUD), intrauterine hormone-releasing system (IUS), or combination of 
adequate methods of birth control (e.g. condoms with hormonal contraception). Agreement to 
use effective contraception is required from the signing of the informed consent form up until 
4 weeks after the last study drug administration.
4.3 Exclusion criteria
17.4.2.7
Old text:
a Pretreatment with phosphodiesterase (PDE) 5 inhibitors is allowed up to 3 three days prior to start of 
riociguat treatment (Visit 1). Patients are not expected to be withdrawn from treatment with PDE5i 
for the purpose of entering into this trial. During the 3 days period without PDE5i, patients who 
received treatment with PDE5i are expected to be on stable clinical condition and receiving 
standard of care treatment with ERA and/or PCAs. 
New text:
a Pretreatment with the phosphodiesterase (PDE) 5 inhibitor Sildenafil is allowed up to 24 h prior to 
start of riociguat treatment (Visit 1). Pretreatment with the phosphodiesterase (PDE) 5 inhibitor 
tadalafil is allowed up to 3 days prior to start of riociguat treatment (Visit 1). Patients are not 
expected to be withdrawn from treatment with PDE5i for the purpose of entering into this trial. 
During the period without PDE5i, patients who received treatment with PDE5i are expected to be 
on stable clinical condition and receiving standard of care treatment with ERA and/or PCAs.
Old text:

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[…]
18.
Subjects with known HIV infection (evaluated by medical history)
New text:
[…]
18.  Subjects with any other condition that is not recommended with riociguat
5.1.1 Body-weight adjusted individual dose titration regimen
17.4.2.8
Old text:
[…]
At the end of the individual titration period (Visit 4), the subjects should have reached their 
individually adjusted dose (maximum equivalent dose of 2.5 mg riociguat TID). The 
established individual equivalent dose will then be taken as optimal dose to be administered 
during the 16-week maintenance period. Dose reductions for safety reasons are allowed in the 
maintenance phase, but a subsequent re-increase is not possible.
[…]
New text:
[…]
At the end of the individual titration period (Visit 4), the subjects should have reached their 
individually adjusted dose (maximum equivalent dose of 2.5 mg riociguat TID). The 
established individual equivalent dose will then be taken as optimal dose to be administered 
during the 16-week maintenance period. Dose reductions for safety reasons are allowed in the 
maintenance phase, but a subsequent re-increase is not possible. During the LTE phase the 
dose may be up-titrated at the investigator’s discretion.
[…]
Old text:
[…]
In case an interruption takes place after completion of the titration period and lasts longer than 
14 consecutive days, it is not allowed to restart the study medication again. In case of shorter 
interruptions, study medication can be restarted at the discretion of the investigator. Dose 
interruptions will be communicated to the DMC and/or SC.
At least 20 subjects are planned to be enrolled into this study. Every effort is made to enroll 
equal numbers (i.e. approximately 10 subjects each) in both age cohorts.
New text:
[…]
In case an interruption takes place after completion of the titration period and lasts longer than 
14 consecutive days, it is not allowed to restart the study medication again. In case of shorter 
interruptions, study medication can be restarted at the discretion of the investigator. Dose 
interruptions will be communicated to the DMC and/or SC.

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Old text:
[…]
Dose titration algorithm

If systolic blood pressure (SBP) is less than 5 mmHg lower than the age-, sex- and 
height-adapted level of the 50th SBP percentile (NHBPEP, 2004) (see appendix 18.5), 
increase riociguat dose (+0.5 mg dose-equivalent TID)

If SBP is more than 5 mmHg but less than 10 mmHg lower than the age-, sex- and 
height-adapted level of the 50th blood pressure (BP) percentile, maintain dose of 
riociguat. 

If SBP is more than 10 mmHg lower than the age-, sex- and height-adapted level of 
the 50th BP percentile, reduce riociguat dose (- 0.5 mg dose-equivalent TID)

If any SBP is more than 5 mmHg lower than the age-, sex- and height-adapted level of 
the 50th BP percentile, with clinical symptoms of hypotension such as dizziness or 
presyncope, stop study treatment; restart after 24 hours with reduced dose - 0.5 mg 
dose-equivalent TID). 
New text:
[…]
Dose titration algorithm

If systolic blood pressure (SBP) is less than 5 mmHg lower than the age-, sex- and 
height-adapted level of the 50th SBP percentile (NHBPEP, 2004) (see appendix 18.5), 
increase riociguat dose (+0.5 mg dose-equivalent TID)

If SBP is ≥5 mmHg but less than 10 mmHg lower than the age-, sex- and height-
adapted level of the 50th blood pressure (BP) percentile, maintain dose of riociguat. 

If SBP is ≥10 mmHg lower than the age-, sex- and height-adapted level of the 50th BP 
percentile, reduce riociguat dose (- 0.5 mg dose-equivalent TID)

If any SBP is ≥5 mmHg lower than the age-, sex- and height-adapted level of the 50th
BP percentile, with clinical symptoms of hypotension such as dizziness or presyncope, 
stop study treatment; restart after 24 hours with reduced dose - 0.5 mg dose-equivalent 
TID).
6.1.1 Pre-treatment phase (Visit 0, Day -14 to -1)
17.4.2.9
Old text:
The parents/legal guardians and children will be given an explanation about the study and will 
be given sufficient time to consider their participation in the study and to ask any questions. 
Afterwards, informed consent and, if applicable, assent will be obtained (see section 11.2).
[…]
New text:
The parents/legal guardians and children will be given an explanation about the study and will 
be given sufficient time to consider their participation in the study and to ask any questions. 
Afterwards, informed consent and, if applicable, assent will be obtained (see section 11.2). 
Collection of AEs starts after informed consent is signed.

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[…]
6.1.2.1 Individual titration phase (Visit 1 – Visit 4)
17.4.2.10
Old text:
At Visit 2 - 4, subjects should come to the hospital without having taken the riociguat 
morning dose. The following procedures will be performed during the titration period:

Re-confirm in-/exclusion criteria (Visit 1 only, prior to study drug intake)

Obtain medical history (Visit 1 only)

Record concomitant medication incl. concomitant PAH specific medication

Perform physical examination (incl. height, weight and vital signs)

Pregnancy test for females of childbearing potential (at Visit 1 and Visit 3)

Decide on the next dose based on the titration algorithm and dispense study 
medication
o
Instruct how to take study drug
o
Provide booklet/guidelines for dosing/suspension (Visit 1 only)

Determine WHO functional class (Visit 1 only)

Perform echocardiogram (Visit 1 only)

Perform electrocardiogram (Visit 1 only)

X-ray of left hand for determination of bone age (Visit 1 only [if no historical data 
(≤30 days) are available])
[…]
New text:
At Visit 1, subjects should come to the hospital for the riociguat morning dose. At Visits 2 
and 4, subjects are allowed to take the riociguat morning dose up to midday. The following 
procedures will be performed during the titration period. The following procedures will be 
performed during the titration period:

Procedures and assessments for the baseline visit (Visit 1) should be completed within 
the span of one day

Re-confirm in-/exclusion criteria (Visit 1 only, prior to study drug intake)

Record concomitant medication incl. concomitant PAH specific medication

Perform physical examination (incl. height, weight and vital signs)

Pregnancy test for females of childbearing potential (at Visit 1 and Visit 3)

Decide on the next dose based on the titration algorithm and dispense study 
medication
o
Instruct how to take study drug

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o
Provide study guidelines for dosing/suspension (Visit 1 only)

Determine WHO functional class (Visit 1 only)

Perform echocardiogram (Visit 1 only)

Perform electrocardiogram (Visit 1 only)

X-ray of left hand for determination of bone age (Visit 1 only: if no historical data [not 
older than 30 days] are available)
[…]
6.1.6 Optional long-term extension phase (until adulthood or approval 
17.4.2.11
in the indication and commercial availability)
Old text:
[…]
Every 3 (± 14 days) months

Record concomitant medication incl. concomitant PAH specific medication

Pregnancy test for females of childbearing potential 

Perform physical examination (incl. height, weight and vital signs) 
New text:
Every 3 (± 14 days) months

Record concomitant medication incl. concomitant PAH specific medication

Pregnancy test for females of childbearing potential 

Perform physical examination (In the long term extension phase the physical 
examination includes monitoring of growth velocity in addition to the. height, weight 
and vital signs) 
6.1.2.2 Maintenance phase (Visit 5 - Visit 9)
17.4.2.12
Old text:
Subjects should come to the hospital without having taken the riociguat morning dose. The 
following procedures will be performed during the maintenance period:
[…]
New text:
Subject should take the riociguat morning dose at home as usual, except of Visit 5, where the 
morning dose will be taken at the hospital. The following procedures will be performed 
during the maintenance period:
[…]

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6.1.3 End-of-treatment visit
17.4.2.13
Old text:
For all subjects dropping-off the protocol at any time after V1 and before V9, an end-of-
treatment has to be performed.
[…]
New text:
For all subjects dropping-off the protocol at any time after V1 and before V9, an end-of-
treatment visit has to be performed.
[…]
6.3 Efficacy/Pharmacodynamic/Other outcomes
17.4.2.14
Old text:
[…]

Echocardiographic parameters including pulmonary arterial systolic pressure (PASP), 
right ventricular pressure by tricuspid regurgitant jet velocity, tricuspid annular plane 
systolic excursion (TAPSE), pericardial effusion, left ventricular eccentricity index, 
estimated inferior vena cava pressure, acceleration time of the pulmonary flow and 
right heart dimensions.

Time to clinical worsening 

Hospitalization for right heart failure

Death

Lung transplantation

Pott’s anastomosis and atrioseptostomy

Worsening of PAH symptoms, which must include either:
o
an increase in WHO FC 
OR
o
both appearance/worsening symptoms of right heart failure
AND
o
need for additional PAH therapy
[…]
New text:
[…]

Echocardiographic parameters including pulmonary arterial systolic pressure (PASP), 
right ventricular pressure by tricuspid regurgitant jet velocity, tricuspid annular plane 
systolic excursion (TAPSE), pericardial effusion, left ventricular eccentricity index, 

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estimated right atrial pressure acceleration time of the pulmonary flow and right heart 
dimensions, and computing of cardiac output.

Time to clinical worsening 

Hospitalization for right heart failure

Death

Lung transplantation

Pott’s anastomosis and atrioseptostomy

Worsening of PAH symptoms, which must include either:
o
an increase in WHO FC 
                 OR
o
appearance/worsening symptoms of right heart failure
                 AND
need for additional PAH therapy
[…]
6.4 Pharmacokinetics/Pharmacodynamics analyses
17.4.2.15
Old text:
[…]
Blood samples will be taken for pharmacokinetic and pharmacodynamic measurements from 
all participants treated with riociguat. The number of blood samples to be taken has been 
optimized using physiologically based pharmacokinetic (PBPK) modelling predictions in 
conjunction with clinical trials simulations (CTS) in order to only collect the minimum 
amount of blood needed for adequate analysis (sparse sampling).
Based on these evaluations the following measures to minimize pain and distress have been 
included: the number of blood samples in children from 6 to less than 18 years of age for PK 
analysis must not exceed four, and the minimum amount of blood needed for adequate 
analysis of each sample is 1.0mL of blood.
Primary PK outcome measure:
Pre- and post-dose blood samples for PK characterization of riociguat and its active 
metabolite BAY 60-4552 will be collected during the titration and the maintenance phase of 
the study. For details, see section 7.4.3.
New text:
[…]
Blood samples will be taken for pharmacokinetic and pharmacodynamic measurements from 
all participants treated with riociguat. 
The number of PK blood samples to be taken has been optimized using physiologically based 
pharmacokinetic (PBPK) modelling predictions in conjunction with clinical trials simulations 

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(CTS) in order to only collect the minimum amount of blood needed for adequate analysis 
(sparse sampling).
Based on these evaluations the following measures to minimize pain and distress have been 
included: the number of blood samples in children from 6 to less than 18 years of age for PK 
analysis must not exceed four, and the minimum amount of blood needed for adequate 
analysis of each sample is 1.0mL of blood.
The following blood samples will be taken:
Visit 1: 2 PK samples will be taken: the first at 0.5 to 1.5 h and the second at 2.5 to 4 h post-
dose (Preferred proposal is to have both peak samples at the first visit. (To ensure having PK 
samples in case of drop-outs, both “peak” samples should be collected at the first visit. If this 
is not feasible, the second peak sample can be taken at any visit.)
Visit 3 and Visit 5: Trough samples should be collected -1 to 0 hours before the morning 
dose at both visit 3 and visit 5
For all visits in the main study phase, the exact time of three riociguat dosing (current and the 
previous two doses) and time of PK/PD blood sampling will be documented in the eCRF.
If, for any reason, PK samples are taken outside of the pre-specified time window, the exact 
time of the sample was taken should be recorded and not the pre-defined time window. If 
riociguat was temporarily stopped prior to a PK sample collection visit, sampling of blood for 
PK analysis according to this visit's schedule should be postponed until riociguat treatment 
has been restarted and sustained for 3 days. 
Primary PK outcome measure:
Pre- and post-dose blood samples for PK characterization of riociguat and its active 
metabolite BAY 60-4552 will be collected during the titration and the maintenance phase of 
the study. For details, see section 7.4.3.
6.5 Study booklet (Study guidelines for parents and children)
17.4.2.16
Old text:
Study booklet (Study guidelines for parents and children)
Parents/children will receive a booklet, specifying:

The local medical contact person and local emergency telephone number

The dates of hospital visits and telephone calls, if applicable

Instructions to return empty medication packages and unused study medication

Instructions on signs and symptoms of hypotension.

How to take riociguat tablets or suspension

Calendar to track the date, time of study drug intake
New text:
Study guidelines for parents and children
Parents/children will receive study guidelines, specifying:

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
The local medical contact person and local emergency telephone number

The dates of hospital visits and telephone calls, if applicable

Instructions to return empty medication packages and unused study medication

Instructions on signs and symptoms of hypotension.

How to take riociguat tablets or suspension

Calendar to track the date, time of study drug intake
7.4.3 Pharmacokinetic analysis
17.4.2.17
Old text:
[…]
The number of blood samples to be taken for the assessment of pharmacokinetic parameters 
was determined using clinical trial simulation (CTS) based on the physiology based PK 
(PBPK) modeling predictions. In order to minimize pain and distress for the patient 
population, the number of PK samples was kept to the minimum. The minimum amount of 
blood needed for adequate analysis for each sample 1.0 mL of blood.
New text:
[…]
The number of blood samples to be taken for the assessment of pharmacokinetic parameters 
was determined using clinical trial simulation (CTS) based on the physiology based PK 
(PBPK) modeling predictions. In order to minimize pain and distress for the patient 
population, the number of PK samples was kept to the minimum. The minimum amount of 
blood needed for adequate analysis for each sample 1.0 mL of blood.
For investigation of exposure behavior, plasma concentrations of BAY63-2521 and its active 
metabolite M1 (BAY 60-4552) will be analyzed descriptively.
7.5 Determination of sample size
17.4.2.18
Old text:
[…]
Children on treatment with ERAs and/or PCAs can be enrolled. At least 20 subjects on 
treatment with bosentan or other Endothelin Receptor Antagonists (ERA) must be enrolled in 
the study. The sample size does not originate from a formal sample size calculation, but is 
based on an evidence-based feasibility assessment. Based on the results of the evidence-based 
feasibility survey (Davie, 2014) and the proposed PK evaluation (see section 7.4.3), 20 
patients will permit an accurate PK evaluation and feasibility of the study in a reasonable time 
frame. Every effort will be made to enroll equal numbers (i.e. 10 subjects each) in both age 
cohorts (see section 4.1).

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New text:
[…]
Children on treatment with ERAs and/or PCAs can be enrolled. At least 20 subjects on 
treatment with bosentan or other Endothelin Receptor Antagonists (ERA) must be enrolled in 
the study. The sample size does not originate from a formal sample size calculation, but is 
based on an evidence-based feasibility assessment. Based on the results of the evidence-based 
feasibility survey (Davie, 2014) and the proposed PK evaluation (see section 7.4.3), 20 
patients will permit an accurate PK evaluation and feasibility of the study in a reasonable time 
frame. Every effort will be made to enroll equal number of patients in both age cohorts (see 
section 4.1).
Amendment 12
17.5
Amendment 12 is the fifth global amendment dated 23 AUG 2019.
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union.
Overall rationale for the amendment
The protocol amendment 12 was prepared to clarify several details for the long-term 
extension (LTE) phase of the study (i.e. 4-weekly intervals for pregnancy testing, the 
conditions for transitioning into the optional LTE phase and that 6MWD test and 
echocardiography can be performed at every second visit in LTE at the discretion of the 
investigator).
17.5.1
Overview of changes
The most relevant changes and the rationale for changes in Amendment 12 and the affected 
sections are provided as follows. A separate file with tracked changes against the last 
integrated protocol version is available upon request.
Section number and 
name
Description of (wording) change
Brief rationale
4.2 Inclusion criteria
Wording for criterion #2 (regarding 
PFO ≤1 cm confirmed by 
echocardiogram) was changed
To address redundancy.
4.3 Exclusion criteria
4.4 Concomitant 
medication
Specification that the use of any drug 
including NO acutely for testing 
during catheterization is not an 
exclusion criterion.
Further specification that this common 
medical practice is allowed.
4.3 Exclusion criteria
A specification was added prohibiting 
the smoking of marijuana during the 
study.
Clarification that smoking marijuana is 
not permitted.
4.4 Concomitant 
medication
The reverse-transcriptase inhibitor 
abacavir may increase the riociguat 
A recently conducted DDI study with 
riociguat in HIV patients revealed an 

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exposure, and should be used with 
caution.
increase in exposure when riociguat was 
administered on top of Triumeq®. In vitro 
investigations identified abacavir as 
CYP1A1 inhibitor reducing riociguat 
clearance.
5.4 Formulation and 
dose
Table 5-2
To correct the volume of 7.0 mL to 
7.5 mL for the body weight category 
of ≥35 <40 kg on 2.0 mg equivalent 
dose 
The correct volume of suspension to 
administer 1.12 mg is 7.5 mL. 
5.4 Formulation and 
dose
Table 5-2
Dosing recommendation for patients 
with body weight ≥12 <14 kg added
Dosing recommendation required for 
children with body weight <14 kg. 
According to in-/exclusion criteria 
patients with <14 kg may be enrolled.
With the minimum age criteria of 6 years 
BW < 12 kg otherwise matching all other 
eligibility criteria is not expected. With 
the given formulations and dosing 
devices dosing of patients <12 kg is not 
feasible.
6.1.6 Optional long-
term extension phase
Pregnancy testing is to be performed 
in 4-weekly intervals starting at Visit 1 
until 4 weeks after the patient stops 
intake of study drug
Frequency of pregnancy tests requested 
by HA
6.1.6 Optional long-
term extension phase
To clarify the conditions for 
transitioning into the optional LTE 
phase.
Transition must have time frame -
especially for subject who becomes 18 
years old in main study phase in order to 
allow them to enter the LTE
6.1.6 Optional long-
term extension phase
Clarified that 6MWD test and 
echocardiography can be performed 
at every second visit in LTE at the 
discretion of the investigator
Clarification
6.1.6 Optional long-
term extension phase
Child Health-related Questionnaire 
(SF-10) and PedsQ: The age version 
used must match with subject´s 
actual age at time of completing the 
questionnaire.
Clarification
6.4 Pharmacokinetics 
– amended
Name of the peak sample is changed 
to post-dose sample
Samples are taken after dosing and not 
exactly at peak plasma concentrations, 
therefore the name of PK sampling was 
clarified
6.5 Study guidelines 
for parents and 
children
To explicitly describe one investigator 
task at visits: to check the patient´s 
home SBP monitoring form.
For completeness 

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Amendment 14
17.6
Amendment 14 is the sixth global amendment dated 20 JUL 2020. The Protocol Amendment 
Summary of Changes Table for the current amendment is located directly before the Table of 
Contents. A separate file with tracked changes against the last integrated protocol version is 
available upon request.

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18.
Appendices - amended
Appendix 1: Growth charts - amended
18.1

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Growth charts for boys and girls with Down syndrome from: (CRONK C., 1988)
(Note: This section was modified according to Amendment 3, see Section 17.1.1.12.)

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Appendix 2: Child Health Questionnaire (SF-10) - amended
18.2
The SF-10, a parent-completed health survey for children will be performed during study 
visits as specified in Table 0–1.

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(Note: This section was modified according to Amendment 3, see Sections 17.1.1.12 and 
17.1.1.16.)

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Appendix 3: Tanner scale
18.3
Tanner scale
Pubic hair (both male and female)
I
no pubic hair at all (prepuberal state) [typically age 10 and younger]
II
small amount of long, downy hair with slight pigmentation at the base of the penis 
and scrotum (males) or on the labia majora (females) [10–11.5]
III
hair becomes more coarse and curly, and begins to extend laterally [11.5–13]
IV
adult-like hair quality, extending across pubis but sparing medial thighs [13–15]
V
hair extends to medial surface of the thighs [15+]

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Appendix 4: Taste assessment - amended
18.4

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(Note: The new logo was updated to the Taste and Texture Questionnaire front page 
according to Amendment 6, see Section 17.3.1.10.)

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Appendix 5: Blood pressure levels for children and adolescents by 
18.5
gender, age and height percentile according to the National High Blood 
Pressure Education Program Working Group

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Source: (NHBPEP, 2004)
Appendix 6: Glomerular filtration rate: Calculation instructions by 
18.6
Schwartz formula - amended

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If serum creatinine (SCr) is measured with routine methods that have not been recalibrated to 
be traceable to isotope dilution mass spectrometry (IDMS) (e.g. the traditional Jaffé reaction), 
the eGFR should be obtained from the original Schwartz formula: 
eGFR (mL/min/1.73 m2) = k * height (cm) / SCr (mg/dL)
Where k is proportionality constant:
k = 0.55 in children up to 13 years of age
k = 0.70 in boys >13 years and <18 years of age (not in girls; because of the
presumed increase in male muscle mass, the constant remains 0.55 for girls)
If SCr is measured by an enzymatic creatinine method that has been calibrated to be traceable 
to IDMS, the updated Schwartz formula should be used to obtain the eGFR: 
eGFR (mL/min/1.73 m2) = 0.413 * height (cm) / SCr (mg/dL)
Note: To express SCr in micromoles per liter, the value should be multiplied by 88.4 
(1 mg/dL = 88.4 µmol/L).
(Note: The Appendix 6 was applied to Amendment 5, see Section 17.2.1.6.)

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Appendix 7: PedsQL Generic Core Scales
18.7

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