Clinical trial NCT02891850
Conditions: Pulmonary Arterial Hypertension
Sponsor: Bayer
Start date: 2017-01-11; Completion date: 2020-03-03
Enrollment: 225 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To demonstrate the effectiveness of riociguat as replacement of phosphodiesterase-5 inhibitors (PDE-5i) therapy in pulmonary arterial hypertension (PAH) patients

Detailed description:
Data from a previous single arm study (RESPITE) indicate that transition from PDE5i to riociguat may be feasible, safe and beneficial in patients not adequately responding to PDE5i.

REPLACE is a randomized controlled study to confirm the potential clinical benefit of transition from PDE5i to riociguat. Satisfactory clinical response in patients who are on a stable dose of phosphodiesterase-5inhibitors (PDE-5i) with or without endothelin receptor antagonist (ERA), but not at treatment goal will be compared between one group of patients randomized to maintain current treatment and another group where the PDE5i is replaced by riociguat.

Arms: arm 1: PDE5i treatment will be stopped and riociguat treatment initiated following a defined washout period with a starting dose of 1 mg riociguat TID followed by an 8 weeks dose adjustment phase according to the approved riociguat dose adjustment scheme. arm 2: Patients will continue to receive PDE5i treatment as well as other standard of care treatments at the discretion of the investigator up to Week 24. Patients in the experimental and active comparator treatment arms follow the same visit schedule.
Interventions: intervention 1: Riociguat (Adempas, BAY63-2521) intervention 2: Sildenafil intervention 3: Tadalafil
Intervention descriptions: intervention 1: Film-coated tablets will be used in this study at a dosage of 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg. Tablets will be administered orally.The starting dose is 1 mg TID; the intervals between drug intakes should be 6 to 8 hours. The dosage should be increased by 0.5 mg increments in 2 week intervals to 1.5 mg, 2.0 mg, and 2.5 mg TID (maximal total daily dose). intervention 2: Patients randomized to the control arm will continue to receive stable doses of tadalafil (daily dose 20 to 40 mg) or sildenafil (daily dose at least 60 mg) as well as other supportive treatments at the discretion of the investigator. intervention 3: Patients randomized to the control arm will continue to receive stable doses of tadalafil (daily dose 20 to 40 mg) or sildenafil (daily dose at least 60 mg) as well as other supportive treatments at the discretion of the investigator.

Protocol documents:
Prot_000.pdf: 
 
Document Type: 
Study Protocol 
Official Title: 
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 
NCT Number: 
NCT02891850 
Document Date: 
6 JAN 2017 
 


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Cover page of the integrated protocol
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
For this study, the protocol and subsequent amendments were released as follows:
Original protocol, Version 1.0, dated 31 MAY 2016
Amendment 01, (dated 06 OCT 2016)
(local amendment, valid for Japan only)
Amendment 02, (dated 16 NOV 2016)
(local amendment, valid for the United Kingdom only)
Amendment 03, (dated 16 NOV 2016)
(local amendment, valid for France only)
Amendment 04, (global amendment described in Section 15)
forming integrated protocol Version 2.0, dated 6 JAN 2017
This document integrates the original protocol and its global amendment.


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1.
Title page - amended
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.
Riociguat rEplacing PDE-5i therapy evaLuated Against Continued PDE-5i thErapy
REPLACE
Test drug:
BAY 63-2521/ riociguat / Adempas
Study purpose:
To demonstrate the effectiveness of riociguat as replacement of 
PDE-5i therapy in PAH patients
Clinical study phase:
4
Date:
6 JAN 2017
Registration:
2016-001067-36
Version no.:
2.0
Sponsor’s study no.:
18588
Sponsor:
Non-US territory: 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:
 
Bayer SA
Rua Domingos Jorge 1100 - Prédio 9301 - 2º andar
04779-900 São Paulo - SP Brasil
Tel: 
The study will be conducted in compliance with the protocol, International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use - Good Clinical 
Practice 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
PPD


6JAN2017 
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Signatore of the sponsor's medically responsible person 
The signatory agrees to the content of the final clinical study protocol as presented. 
Name: 
Role: 
Medical Affairs Responsihle 
(M
Date: 
Signature: 
PPD
PPD


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Signature of principal investigator
The signatory agrees to the content of the final clinical study protocol 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.
In the protocol document, this page may remain unsigned.


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2.
Synopsis – amended
This section was changed in Amendment 4, see Section 15.1.2.2.
Title
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.
Short title
Riociguat rEplacing PDE-5i therapy evaLuated Against Continued PDE-5i 
thErapy
Acronym
REPLACE
Clinical study phase
4
Study objectives
The primary objective is to assess the proportion of patients in each treatment 
arm with a satisfactory clinical response as defined by a composite primary 
endpoint at Week 24.
The secondary objective is to demonstrate safety and clinical effect at 
Week 24 indicated by change in 6-minute walking distance (6MWD), 
N-terminal pro-brain natriuretic peptide (NT-proBNP), World Health 
Organization Functional Class (WHO FC) and clinical worsening from 
baseline in each treatment arm.
Test drug
Riociguat (BAY 63-2521)
Name of active ingredient
Methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo [3,4 b]pyridine-3-yl]-
5-pyrimidinyl (methyl)carbamate
Doses
0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg (maximum dose) 3 times daily
(TID)
Route of administration
Oral
Duration of treatment
24 weeks (including initial 8 week dose adjustment period according to 
label).
Reference drug(s)
PDE-5i approved for treatment of PAH (tadalafil, sildenafil)
Name of active ingredients
Sildenafil: 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo [4,3-d] 
pyrimidin-5-yl)-4-ethoxyphenyl] sulfonyl]-4-methylpiperazine citrate 
Tadalafil: pyrazino[1´,2´:1,6]pyrido[3,4–b]indole-1,4-dione, 6-(1,3-
benzodioxol-5-yl)2,3,6,7,12,12a-hexahydro-2-methyl-, (6R,12aR) 
Dose(s)
Sildenafil dose at least 60 mg/day
Tadalafil dose range 20 to 40 mg/day 
at the discretion of the investigator.
Route of administration
Oral
Duration of treatment
24 weeks
Indication
PAH


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Diagnosis and main criteria for 
inclusion /exclusion
Adult patients (18 to 75 years) with symptomatic PAH who are treated with a 
stable dose of a PDE-5i with or without ERA, but are not at treatment goal
i.e., remaining at intermediate risk according to European Respiratory 
Society/European Society of Cardiology (ERS/ESC) guidelines, as indicated 
by their WHO FC and a 6MWD test.
Patients on combination therapy with ERAs may best represent the clinical 
situation in which transition would be considered, whereas for most patients 
on PDE-5i monotherapy, combination therapy may be the next appropriate 
step of treatment escalation. There may however be clinical conditions where 
a transition to riociguat from PDE-5i monotherapy appears to be appropriate 
at the discretion of the treating physician.
Patients with symptomatic PAH according to WHO FC III and 6MWD of 
165-440 m at screening and at randomization, with a pulmonary vascular 
resistance (PVR) of > 400 dyn*sec*cm-5, mean pulmonary artery pressure 
≥25 mmHg, and pulmonary capillary wedge pressure (PCWP) ≤15 mmHg 
as assessed by right heart catheterization in medical history prior to screening
to confirm the diagnosis. Alternatively, PCWP can be replaced by left 
ventricular end-diastolic pressure.
PAH of the following types: idiopathic, hereditary, drug/toxin induced, and 
associated PAH due to connective tissue disease or congenital heart disease 
(patients had to have undergone surgical repair more than 1 year before 
enrolment), and portal hypertension with liver cirrhosis (patients with clinical 
relevant hepatic dysfunction are excluded).
Patients who are on stable doses of a PDE-5i and ERA combination therapy 
or on stable PDE-5i monotherapy for at least 6 weeks prior to and at 
randomization (tadalafil daily dose 20 to 40 mg or sildenafil daily dose at 
least 60 mg). Stable is defined as no change in the type of the PDE-5i and the 
daily dose of PDE-5i and ERA during the 6-week period prior to and at 
randomization. 
Patients who signed informed consent and are able to follow the study 
instructions.
Study design
Prospective, randomized, international, multicenter, double-arm, controlled, 
24-week open-label study. Patients will be randomized to remain on their 
current PAH-specific treatment or to replace the PDE-5i treatment with 
riociguat.
Patients on specific combination therapy with PDE-5i and ERA need to
continue taking ERA at a stable dose in both treatment arms.
At Week 24 a composite endpoint of satisfactory clinical response will be 
assessed.


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Methodology
Patients who are not at treatment goal and at intermediate risk according to 
ERS/ESC guidelines will be randomized in a 1:1 ratio to remain on their 
current PAH-specific treatment or to replace the PDE-5i treatment with 
riociguat for 24 weeks.
Patients need to be pretreated with a stable dose of PDE-5i +/- ERA for 
6 weeks prior to and at randomization. 
Riociguat treatment will be started after a wash-out period of 24 hours with 
previous sildenafil therapy (daily dose at least 60 mg) and 48 hours after 
previous tadalafil therapy (daily dose 20 to 40 mg).
Type of control
A mandatory screening period of 2 weeks before randomization will be 
performed for all patients to ensure stability and similar starting conditions at 
baseline. Patients randomized to the control arm will continue to receive 
stable doses of tadalafil (daily dose 20 to 40 mg) or sildenafil (daily dose at 
least 60 mg) as well as other supportive treatments at the discretion of the 
investigator. 
Number of patients
218 patients in total (109 per arm)
Primary variable
The primary efficacy endpoint ‘satisfactory clinical response’ is defined as 
the composite endpoint comprising the following components (independent 
central adjudication):

2 of 3 must be fulfilled

6MWD increase by ≥10% or ≥30 m from baseline to 
Week 24

WHO FC I or II at Week 24

NT-proBNP reduction ≥ 30% from baseline to 
Week 24 (NT-proBNP Week 24/baseline ratio ≤0.7), 
AND

No clinical worsening (i.e, death of any cause, hospitalization 
due to worsening PAH, disease progression)
Time point/frame of 
measurement for primary 
variable
Week 24 


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Plan for statistical analysis
All demographic variables and baseline characteristics will be summarized 
for all analysis sets. Medical history findings and adverse events will be 
coded according to the Medical Dictionary for Regulatory Activities and 
medications by Anatomical Therapeutic Chemical class according to the 
World Health Organization-Drug Dictionary.
An efficacy analysis will be performed in patients valid for the Full Analysis 
Set (primary analysis set) and additionally in patients valid for the Per 
Protocol Set. Both groups (riociguat vs. active control) will be compared 
using a stratified Mantel-Haenzel test with a two-sided alpha level of 5%. 
Stratum is disease class. 
The null hypothesis tested for the primary endpoint of efficacy is that there is 
no difference in the satisfactory clinical response rates (odds ratio [OR]) 
when treated with riociguat compared to patients who remain on their 
previous therapy (i.e., H0: OR = 1). The two-sided alternative is that there is 
a difference (i.e., H1: OR ≠1).
For statistical analysis of the primary endpoint with missing data, the last 
observation carried forward (LOCF) will be utilized. For composite 
endpoints each single component is independently replaced with the last 
available observation.
To assess the influence of missing data, a supportive analysis without LOCF 
will be performed with a generalized estimating equations (GEE, binomial 
distribution) approach, utilizing all adequate investigations of all primary 
variable components at any time from including baseline up to Week 24.
To assess the influence of missing values not at random, a sensitivity analysis 
is planned. A multiple imputation with penalty will be performed where the 
penalty is given by crossed improvement rates in both arms. Additionally, a 
tipping point analysis is planned.
A multiplicity correction is not necessary for the primary endpoint because 
only one primary endpoint is defined. Secondary endpoints are tested 
hierarchically with an alpha level of 5%.


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Table of contents
Cover page of the integrated protocol.................................................................................... 1
1.
Title page - amended.......................................................................................................... 2
Signature of the sponsor’s medically responsible person..................................................... 3
Signature of principal investigator......................................................................................... 4
2.
Synopsis – amended........................................................................................................... 5
Table of contents....................................................................................................................... 9
Table of table .......................................................................................................................... 12
Table of figures....................................................................................................................... 12
List of abbreviations............................................................................................................... 13
3.
Introduction - amended................................................................................................... 15
4.
Study objectives............................................................................................................... 17
5.
Study design - amended................................................................................................... 17
6.
Study population ............................................................................................................. 22
Inclusion criteria - amended........................................................................................... 22
6.1
Exclusion criteria - amended ......................................................................................... 23
6.2
Withdrawal of patients from study ................................................................................ 26
6.3
6.3.1
Withdrawal – amended............................................................................................... 26
Discontinuation of study treatment - amended ....................................................... 26
6.3.1.1
Discontinuation of study - amended........................................................................ 27
6.3.1.2
6.3.2
Replacement ............................................................................................................... 28
Patient identification...................................................................................................... 28
6.4
7.
Treatments....................................................................................................................... 29
Treatments to be administered - amended ..................................................................... 29
7.1
Identity of study treatment - amended ........................................................................... 29
7.2
Treatment assignment - amended .................................................................................. 31
7.3
Dosage and administration............................................................................................. 31
7.4
Blinding ......................................................................................................................... 32
7.5
Drug logistics and accountability................................................................................... 32
7.6
Treatment compliance.................................................................................................... 33
7.7
8.
Non-study therapy........................................................................................................... 33
Prior and concomitant therapy - amended ..................................................................... 33
8.1
Post-study therapy - amended........................................................................................ 34
8.2
9.
Procedures and variables ............................................................................................... 35
Tabular schedule of evaluations .................................................................................... 35
9.1
Visit description............................................................................................................. 35
9.2
9.2.1
Mandatory screening period (Week -2 ± 2 days, Visit 0) - amended......................... 35


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9.2.2
Randomization (Baseline visit, Week 0, Visit 1) - amended ..................................... 36
9.2.3
Visit 2 (Week 8 ± 2 days) - amended ......................................................................... 38
9.2.4
Telephone Contact (Week 12 ± 2 days) - amended.................................................... 38
9.2.5
Visit 3 (Week 16 ± 2 days) - amended ....................................................................... 39
9.2.6
Telephone Contact (Week 20 ± 2 days) - amended.................................................... 39
9.2.7
Visit 4 / End of Treatment (EOT) (Week 24 ± 4 days) - amended ............................ 39
9.2.8
Safety follow-up visit (30 days ± 5 days) - amended................................................. 40
Population characteristics .............................................................................................. 40
9.3
9.3.1
Demographics............................................................................................................. 40
9.3.2
Medical history........................................................................................................... 41
Efficacy.......................................................................................................................... 41
9.4
Pharmacokinetics/pharmacodynamics........................................................................... 42
9.5
Safety ............................................................................................................................. 43
9.6
9.6.1
Adverse events............................................................................................................ 43
Definitions............................................................................................................... 43
9.6.1.1
Classifications for adverse event assessment.......................................................... 44
9.6.1.2
9.6.1.2.1
Seriousness........................................................................................................... 44
9.6.1.2.2
Intensity................................................................................................................ 44
9.6.1.2.3
Causal relationship............................................................................................... 44
9.6.1.2.4
Action taken with study treatment ....................................................................... 46
9.6.1.2.5
Other specific treatment(s) of adverse events...................................................... 46
9.6.1.2.6
Outcome............................................................................................................... 46
Assessments and documentation of adverse events - amended .............................. 46
9.6.1.3
Reporting of serious adverse events ........................................................................ 47
9.6.1.4
Expected adverse events - amended........................................................................ 48
9.6.1.5
Adverse events of special safety interest - amended............................................... 48
9.6.1.6
9.6.2
Pregnancies................................................................................................................. 49
9.6.3
Further safety.............................................................................................................. 49
Physical examination............................................................................................... 49
9.6.3.1
Vital signs................................................................................................................ 49
9.6.3.2
12-lead ECG............................................................................................................ 49
9.6.3.3
Laboratory assessments - amended......................................................................... 50
9.6.3.4
Other procedures and variables...................................................................................... 51
9.7
9.7.1
Pulse oximetry - amended .......................................................................................... 51
9.7.2
Lung function testing.................................................................................................. 51
9.7.3
6MWD test - amended................................................................................................ 52
9.7.4
Determination of WHO FC - amended ...................................................................... 52
9.7.5
cMRI........................................................................................................................... 53
Appropriateness of procedures/measurements .............................................................. 53
9.8
10. Statistical methods and determination of sample size ................................................. 53
General considerations................................................................................................... 53
10.1
Analysis sets .................................................................................................................. 53
10.2
Variables and planned statistical analyses..................................................................... 54
10.3
10.3.1
Demographic and baseline characteristics.................................................................. 54


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10.3.2
Efficacy endpoints...................................................................................................... 54
Primary efficacy endpoint - amended ..................................................................... 55
10.3.2.1
Secondary efficacy endpoints.................................................................................. 56
10.3.2.2
Exploratory endpoints ............................................................................................. 56
10.3.2.3
10.3.3
Safety endpoints ......................................................................................................... 57
10.3.4
Subgroups................................................................................................................... 57
Determination of sample size......................................................................................... 58
10.4
10.4.1
Sample size sensitivity ............................................................................................... 60
Planned interim analyses ............................................................................................... 60
10.5
11. Data handling and quality assurance............................................................................ 60
Data recording................................................................................................................ 60
11.1
Monitoring ..................................................................................................................... 61
11.2
Data processing.............................................................................................................. 61
11.3
Missing data - amended ................................................................................................. 62
11.4
Audit and inspection ...................................................................................................... 62
11.5
Archiving ....................................................................................................................... 62
11.6
12. Premature termination of the study .............................................................................. 63
13. Ethical and legal aspects................................................................................................. 63
Investigator(s) and other study personnel - amended .................................................... 63
13.1
Funding and financial disclosure ................................................................................... 64
13.2
Ethical and legal conduct of the study........................................................................... 65
13.3
Patient information and consent - amended................................................................... 65
13.4
Publication policy and use of data ................................................................................. 67
13.5
Compensation for health damage of patients/insurance ................................................ 67
13.6
Confidentiality ............................................................................................................... 67
13.7
14. Reference list.................................................................................................................... 68
15. Protocol amendments...................................................................................................... 70
Amendment 4................................................................................................................. 70
15.1
15.1.1
Overview of changes .................................................................................................. 70
15.1.2
Changes to the protocol text....................................................................................... 72
Section 1 Title page................................................................................................. 72
15.1.2.1
Section 2 Synopsis .................................................................................................. 73
15.1.2.2
Section 3 Introduction............................................................................................. 74
15.1.2.3
Section 5 Study design ............................................................................................ 75
15.1.2.4
Section 6.1 Inclusion criteria................................................................................... 80
15.1.2.5
Section 6.2 Exclusion criteria.................................................................................. 81
15.1.2.6
Section 6.3.1 Withdrawal........................................................................................ 83
15.1.2.7
Section 6.3.1.1 Discontinuation of study treatment ................................................ 83
15.1.2.8
Section 6.3.1.2 Discontinuation of study ................................................................ 86
15.1.2.9
Section 7.1 Treatments to be administered ............................................................. 87
15.1.2.10
Section 7.2 Identity of study treatment ................................................................... 87
15.1.2.11
Section 7.3 Treatment assignment .......................................................................... 89
15.1.2.12
Section 8.1 Prior and concomitant therapy ............................................................. 89
15.1.2.13


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Section 8.2 Post-study therapy................................................................................ 90
15.1.2.14
Section 9.2.1 Mandatory screening period (Week -2 ± 2 days, Visit 0) ................. 91
15.1.2.15
Section 9.2.2 Randomization (Baseline visit, Week 0, Visit 1 ............................... 91
15.1.2.16
Section 9.2.3 Visit 2 (Week 8 ± 2 days................................................................... 93
15.1.2.17
Section 9.2.4 Telephone Contact (Week 12 ± 2 days)............................................ 94
15.1.2.18
Section 9.2.5 Visit 3 (Week 16 ± 2 days................................................................. 94
15.1.2.19
Section 9.2.6 Telephone Contact (Week 20 ± 2 days)............................................ 95
15.1.2.20
Section 9.2.7 Visit 4 / End of Treatment (EOT) (Week 24 ± 4 days)..................... 95
15.1.2.21
Section 9.2.8 Safety follow-up visit (30 days ± 5 days) ......................................... 96
15.1.2.22
Section 9.6.1.3 Assessments and documentation of adverse events ....................... 96
15.1.2.23
Section 9.6.1.5 Expected adverse events................................................................. 97
15.1.2.24
Section 9.6.1.6 Adverse events of special safety interest........................................ 97
15.1.2.25
Section 9.6.3.4 Laboratory assessments.................................................................. 97
15.1.2.26
Section 9.7.1  Pulse oximetry.................................................................................. 99
15.1.2.27
Section 9.7.3 6MWD test........................................................................................ 99
15.1.2.28
Section 9.7.4 Determination of WHO FC............................................................. 101
15.1.2.29
Section 10.3.2.1 Primary efficacy endpoint .......................................................... 102
15.1.2.30
Section 10.3.2.3 Exploratory endpoints ................................................................ 103
15.1.2.31
Section 11.4 Missing data ..................................................................................... 103
15.1.2.32
Section 13.1 Investigator(s) and other study personnel ........................................ 104
15.1.2.33
Section 13.4 Patient information and consent....................................................... 104
15.1.2.34
Section 16.1 Schedule of procedures .................................................................... 105
15.1.2.35
Section 16.2 6 Minute Walking Distance (6MWD) Test...................................... 109
15.1.2.36
16. Appendices..................................................................................................................... 110
Schedule of procedures – amended ............................................................................. 110
16.1
6 Minute Walking Distance (6MWD) Test - amended................................................ 114
16.2
WHO FC...................................................................................................................... 115
16.3
Modified REVEAL Risk Score ................................................................................... 115
16.4
Living with Pulmonary Hypertension questionnaire (LPH [QoL])............................. 117
16.5
Table of table
Table 7–1: Identity of investigational product ........................................................................ 30
Table 10–1: Improvement of endpoints in PATENT-1/2 at Week 24 and RESPITE at 
Week 24 for all patients and the subgroup: pretreated and WHO FC III at baseline58
Table 10–2: Improvement of endpoints in PATENT-1/2 at Week 12 for all patients and the 
subgroup: pretreated and WHO FC III at baseline................................................ 59
Table 10–3: Sensitivity analysis............................................................................................... 60
Table of figures
Figure 5–1: Study Design Overview........................................................................................ 18
Figure 7–1: Titration Scheme................................................................................................... 32


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List of abbreviations
6MWD
6 minute walking distance 
AE
adverse event
ALT
alanine aminotransferase 
APAH
associated PAH
AST
aspartate aminotransferase 
AUC
area under the curve
BCRP
breast cancer resistance protein
BMI
Body Mass Index
BP
blood pressure
bpm
Beats per minute
CEC
Clinical Endpoint Committee
cGMP
cyclic guanosine monophosphate
Cmax
maximum observed concentration
cMRI
cardiac magnetic resonance imaging
CRF
case report forms
CRO
contract research organization
CTD
connective tissue disease
CTEPH
chronic thromboembolic pulmonary hypertension 
CYP
cytochrome P450
DLCO
Diffusing capacity of the lung for carbon monoxide
dyn
dyn [1 dyn = 1 g*cm*s-2 = 10-5 N (Newton)]
ECG
electrocardiogram
eCRF
electronic case report form
ERA
endothelin receptor antagonist(s)
ERS
European Respiratory Society
ESC
European Society of Cardiology
EU
European Union
FAS
full analysis set
FEV1/FVC
forced expiratory volume in one second/forced vital capacity
FPAH
familial PAH
FU
follow-up
GCP
Good Clinical Practice
GEE
generalized estimating equations
HIV
Human immunodeficiency virus
HPAH
heritable PAH
HR
heart rate
IB
Investigator’s Brochure
ICF
Informed consent form
IEC
independent ethics committee
INN
international non-proprietary name
INR
international normalized ratio
IPAH
idiopathic PAH


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IRB
institutional review board
IXRS
interactive voice response system
LVEF
left ventricular ejection fraction
LOCF
last observation carried forward 
LPH
living with pulmonary hypertension 
MedDRA
Medical Dictionary for Regulatory Activities
mRRS
modified REVEAL Risk Score
NO
nitric oxide
NT-proBNP
N-terminal pro-brain natriuretic peptide
OR
odds ratio
PAH
pulmonary arterial hypertension
PCA
prostacyclin analogues
PCWP
pulmonary capillary wedge pressure
PDE-5
phosphodiesterase 5
PDE-5i
phosphodiesterase 5 inhibitor
P-gp
p-glycoprotein
PH
pulmonary hypertension
PH-LVD
pulmonary hypertension due to left ventricular dysfunction
PoPH
portopulmonary PAH
PPS
per protocol set
PRA
Prostacyclin receptor agonist
PVR
pulmonary vascular resistance
QoL
Quality of Life
RHC(s)
right heart catheterization(s)
SAE
serious adverse event
SAP
statistical analysis plan
SAS
Statistical Analysis System
SBP
systolic blood pressure
sGC
soluble guanylate cyclase
SUSAR
suspected unexpected serious adverse reaction
TID
ter in die (3 times daily)
TLC
total lung capacity
ULN
upper limit of normal
V
visit
WHO-DD
World Health Organization-Drug Dictionary
WHO FC
World Health Organization Functional Class


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3.
Introduction - amended
This section was changed in Amendment 4, see Section 15.1.2.3.
Background
Riociguat (BAY 63-2521) is a direct stimulator of the soluble Guanylate Cyclase (sGC). The
randomized, double-blind, placebo-controlled clinical Phase 3 study (PATENT-1) 
investigated the efficacy and safety of riociguat in patients with pulmonary arterial 
hypertension (PAH). The study met the primary endpoint (placebo-corrected change from 
baseline in 6-minute walking distance [6MWD] by 35.8 m) and showed statistically 
significant improvements in secondary endpoints, including pulmonary vascular resistance, 
N- terminal pro-brain natriuretic peptide (NT-proBNP), World Health Organization 
Functional Class (WHO FC), clinical worsening, living with pulmonary hypertension (LPH) 
questionnaire, and Borg dyspnea score (1).
PAH is a devastating, life-threatening disease that is characterized by rapid progression and a 
high mortality (2).
Sequential combination therapy has been the most widely used clinical strategy of treatment 
escalation if the treatment effect reached by oral monotherapy alone is not sufficient (European 
Society of Cardiology [ESC]/European Respiratory Society [ERS] guidelines 2015) (3). 
Transition between pulmonary hypertension (PH)-specific drug therapies has not been 
investigated in controlled studies and treatment response in the individual patient cannot be 
predicted. Failure of phosphodiesterase-5 inhibitor (PDE-5i) treatment however may indicate 
impairment of the nitric oxide (NO)-sGC-cyclic guanosine monophosphate (cGMP) pathway (4). 
In contrast the treatment effect of sGC-stimulation is based on a NO-independent mode of action. 
Preliminary data from the open-label transition study RESPITE indicate that patients transitioned 
from PDE-5i to riociguat may benefit based on this principle of pathway optimization.
Rationale of the study
Oral monotherapy including PDE-5i is one recommended treatment approach for patients with 
PAH who are classified as WHO FC II or III (3,5). However, a significant proportion of PAH 
patients fail to reach or maintain treatment goals with PDE-5i monotherapy (6,7,8,9) indicating 
that the NO-sGC-cGMP pathway in these patients may be impaired (4). The clinical approach in 
patients demonstrating an insufficient clinical response on PDE-5i monotherapy is typically to 
add an endothelin receptor antagonist (ERA). Most PAH treatment guidelines, including 
ESC/ERS, suggest that sequential combination therapy is reasonable to be considered in patients 
with an inadequate clinical response, but the clinical evidence supporting this is weak (3,5).
An increasing body of evidence suggests that a goal directed therapy approach where a patient’s 
treatment regimen should be re-assessed if they fail to reach certain clinical or therapeutic
targets in a certain time frame may be the best approach for patients with PAH (10) as certain 
therapeutic targets such as WHO FC demonstrated to have prognostic implications (11,12,13). 
In the 2015 ESC/ERS guideline for treatment of PAH, it is stated that the overall treatment goal 
in patients with PAH is achieving a low risk status as defined by determinants of prognosis such 
as WHO FC, 6MWD, and biomarkers (NT-proBNP, imaging) reflecting right heart function.


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The RESPITE study was conducted to investigate whether it is safe, feasible, and beneficial to 
replace PDE-5i therapy with riociguat in PAH patients demonstrating insufficient response to 
PDE-5 inhibition. The final data of this hypothesis-generating single arm study showed that
patients failing to respond to PDE-5i could benefit from replacing a PDE-5i with riociguat by 
improving 6MWD, WHO FC, and NT-proBNP. The data indicate that transition of PDE-5i to 
riociguat may serve as a treatment strategy for PAH patients.
The rationale of the study is to confirm the potential clinical benefit of switch within the NO 
sGC-cGMP pathway in a randomized controlled study.
Benefit-risk assessment
Riociguat was overall considered to be safe and well tolerated in previous clinical studies at 
multiple doses between 1 and 2.5 mg 3 times daily (TID) in patients with PAH and other 
indications, e.g., chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary 
hypertension due to left ventricular dysfunction (PH-LVD).
Beneficial effects of riociguat with regard to exercise capacity, cardiopulmonary 
hemodynamics, and symptoms while being overall safe and well tolerated have been 
demonstrated recently in PAH as well as CTEPH in two independent clinical Phase 3 studies, 
the PATENT-1 and CHEST-1, as well as the long-term extension studies thereof.
The safety analysis of the clinical studies showed that most adverse drug effects were 
non-serious in nature, mainly linked to the mechanisms of action of riociguat, and with a low
number of permanent treatment discontinuation.
Epistaxis and hemoptysis are known events for the underlying disease with a high proportion 
of patients taking anti-coagulants. However, the observation of few serious and 
life-threatening/fatal cases of hemoptysis and pulmonary hemorrhage poses a potential risk 
since these events may also occur under riociguat treatment.
Recently, results of a study on efficacy and safety of riociguat in patients with pulmonary 
hypertension associated with idiopathic interstitial pneumonias (PH-IIP) showed an increased 
risk of mortality and serious adverse events among patients who received riociguat compared 
to those who received placebo, and an absence of apparent clinical benefit. The study was 
terminated early upon the advice of its data monitoring committee (DMC).  It was concluded 
that the benefit risk balance of riociguat in patients with PH-IIP is negative.  Riociguat is 
contraindicated in patients with PH-IIP.
The REPLACE study (18588) will only include patients with subtypes of Pulmonary Arterial 
Hypertension (PAH), Dana Point Group 1 (14). Patients with all other types of PH/ Dana 
Point Groups are excluded, also comprising patients with PH-IIP, according to the protocol.
The overall benefit-risk balance of riociguat is considered positive if used in adherence to this 
clinical study protocol and in accordance with the recommendations and guidance given in the 
Investigator’s Brochure (IB).


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Primary hypothesis
Replacement of PDE-5i by riociguat in patients who are not at treatment goal but on a stable 
dose of PDE-5i +/- ERA will lead to a significantly higher rate of satisfactory clinical response 
compared to patients who remain on PDE-5i +/- ERA because of the optimization of the
NO-sGC-cGMP pathway provided by riociguat and its NO-independent mechanism of action.
Stable is defined as no change in the type of the PDE-5i and the daily dose of PDE-5i and 
ERA during the 6-week period prior to and at randomization.
Secondary hypothesis
In the group comparison, transition to riociguat will significantly improve 6MWD, 
NT-proBNP, WHO FC, and will have a reduction in clinical worsening at Week 24 compared 
to continuation of PDE-5i +/- ERA therapy.
4.
Study objectives
The primary objective is to assess the proportion of patients in each treatment arm with a 
satisfactory clinical response as defined by a composite primary endpoint at Week 24.
The secondary objective is to demonstrate safety and clinical effect at Week 24 indicated by 
change in 6MWD, NT-proBNP, WHO FC and clinical worsening from baseline in each 
treatment arm.
5.
Study design - amended
This section was changed in Amendment 4, see Section 15.1.2.4.
Design overview
This is a prospective, randomized, international, multicenter, double-arm, 24-week, 
controlled, open-label study of riociguat in patients with PAH who are on a stable dose of
PDE-5i +/- ERA, but not at treatment goal. The decision for a randomized but not blinded 
study design was made in agreement with the advisory committee for feasibility reasons. As 
riociguat is available as an approved treatment in the majority of countries, recruitment was 
not considered feasible into a blinded Phase 4 study. Moreover, the open-label, randomized 
design with a fixed duration of 24 weeks and the composite endpoint of satisfactory clinical 
response is considered a pragmatic alternative to allow for meaningful results with reasonable 
effort and within a reasonable time frame.
A mandatory screening period of 2 weeks before randomization will be performed for all 
patients to ensure stability and similar starting conditions at baseline.
Eligible PAH patients will be randomized in a 1:1 ratio to remain on their current 
PAH-specific treatment (the control arm) or to replace the PDE-5i treatment with riociguat
(the riociguat arm).
Patients on specific combination therapy with PDE-5i and ERA need to continue taking ERA 
at a stable dose in both treatment arms.
At Week 24, a composite endpoint of satisfactory clinical response will be assessed.
An overview of the study design is shown in Figure 5–1.


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Figure 5–1: Study Design Overview
EOT
Abbreviations: EOT = End of Treatment; FU = Follow-up; N = number of patients; TID = three times daily.


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Patients in both treatment arms follow the same visit schedule (see also Section 16.1). 
At the discretion of the investigators and if applicable (e.g., short distance to study center) the 
home visits may also be performed at the study center.
For riociguat the initial home visits (H1-3) and V2 include the dose titration period, followed 
by the maintenance period with the established individual dose.
Treatment period (Duration: 24 weeks)
Patients randomized to the control arm at the baseline visit (Week 0) will continue on their 
current PAH-specific treatment for 24 weeks. 
Patients randomized to the riociguat arm, will have a wash-out period before starting the 
titration period of riociguat:
Riociguat treatment will be started after a wash-out period of 24 hours with previous 
sildenafil therapy (daily dose at least 60 mg) and 48 hours after previous tadalafil 
therapy (daily dose 20 to 40 mg).
Titration period (Riociguat arm, duration: 8 weeks)
The dose titration will be performed with the aid of an interactive voice response system 
(IXRS). The investigator decision regarding study medication must be clearly documented in 
the source documents prior to contacting IXRS.
The starting dose will be 1 mg riociguat TID. The individual riociguat dose will be titrated 
every 2 weeks according to the patient’s well-being and peripheral systolic blood pressure 
(SBP) measured at trough, preferably before intake of the next morning dose. At each titration 
visit for the riociguat arm (Weeks 2, 4, and 6), the investigator needs to decide, based on the 
patient’s SBP, whether the study medication dose should be modified.
The respective decision (increase, maintain, or decrease dose) must be entered in the IXRS
that will automatically allocate the right dose in accordance with the respective individual 
titration scheme. Afterwards, the investigator will be informed by the system which dosage 
needs to be dispensed to the patient for the next titration period (starts preferably with the 
morning dose). Blood pressure measurements and communication with the center for dose 
decision will be facilitated by experienced study nurses.
The investigators will apply the following blood pressure (BP) based titration rules for their 
dose decision and should follow the local riociguat label for detailed information as follows:
Dosage should be increased in 2-week intervals by 0.5 mg increments to a maximum of 
2.5 mg three times daily, if SBP is ≥95 mmHg and the patient has no signs or symptoms 
of hypotension. If SBP falls below 95 mmHg, dosage should be maintained provided 
the patient does not show any signs or symptoms of hypotension. If at any time during 
the up-titration phase systolic blood pressure decreases below 95 mmHg, and the patient 
shows signs or symptoms of hypotension, the current dose should be decreased by 
0.5 mg tid.


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General Note: While dose up-titration can only occur at the scheduled visits, a dose decrease 
can be performed at any time based on the patient’s SBP and well-being. In case of intended 
dose decrease which can be done independently from any planned study visit, the investigator 
will contact the IXRS and request a dose adjustment. This visit is to be declared as an 
unscheduled visit.
In general, if the investigator requests an increase or decrease in the riociguat dose via the 
IXRS, the subsequent dose modification will not exceed plus/minus 0.5 mg.
It is allowed in case of riociguat side effects to suspend a foreseen up-titration step and to 
maintain the dose (this should be entered into the IXRS).
During the titration period, a request of an increase of riociguat dose is only possible at the 
planned titration visits at Weeks 2, 4, and 6. The dose reached at the end of the titration period
at Week 8 is considered the patient’s optimal dose based on SBP and well-being. 
Maintenance period (Riociguat arm, duration: 16 weeks)
Riociguat should be continued at the optimal dose as determined at the end of the titration 
period (Week 8) throughout the maintenance period. 
Visits (for both arms) will take place at Week 16 and Week 24. The IXRS will automatically 
allocate the right riociguat dose at each visit. 
Dose reductions or discontinuation of riociguat for safety reasons are allowed at any time. 
Increases or re-increases in 0.5 mg steps (maximum dose 2.5 mg) are possible at the 
investigator’s discretion weighing the benefit with potential risks implied, e.g., hypotension.
Smoking status is assessed regularly during the study as plasma concentrations of riociguat in 
smokers are reduced compared to non-smokers, and dose adjustment may be necessary in 
patients who start or stop smoking during treatment with riociguat.
General Note: In case of intended dose adjustments, the investigator will contact the IXRS, 
which can be done independently from any planned study visit, and request a dose 
adjustment. This visit is to be declared as an unscheduled visit.
Premature discontinuation of study treatment
In case of premature discontinuation of study treatment, the process detailed in Section 6.3.1.1
should be followed.
Visit 4 / End of Treatment (EOT) (Week 24 ± 4 days)
All patients randomized to either treatment arm should perform Visit 4 / EOT.  This is the last 
visit of the maintenance period, when all relevant efficacy and safety measurements will be 
performed.


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Safety Follow-Up (FU) visit (30 days ± 5 days after last intake of study treatment)
A safety FU visit is to be performed 30 days (± 5 days) after the planned end of study 
treatment OR 30 days (± 5 days) after premature discontinuation of study treatment.
Primary endpoint (at Week 24)
The primary composite endpoint is to assess the proportion of patients in each treatment arm 
with a satisfactory clinical response at Week 24 defined as improvement in “2 of 3” (see 
Section 10.3.2.1).
Justification of the design
Riociguat was considered safe and well tolerated in previous clinical studies at multiple doses 
between 1.0 and 2.5 mg TID in patients with PAH. This study will be conducted to assess the 
effectiveness of replacing PDE-5i therapy with riociguat compared with maintaining PDE-5i 
therapy in PAH patients who are on a stable dose of PDE-5i +/- ERA, but not at treatment goal.
While it may appear inappropriate to randomize patients who are not “at treatment goal” to 
the control arm, where their current PAH-specific treatment regimen will just be continued, 
in the absence of a clear definition of treatment response, the definition for this study is 
inspired by the ESC/ ERS table for risk assessment (15) and based on 6MWD and WHO FC 
only. Other parameters of prognostic relevance including pulmonary hemodynamics may well 
be in the range of low risk/ at treatment goal according to guidelines. It can be assumed that a 
large number of patients on mono-or combination therapy with PAH-targeted drugs are in a 
stable clinical situation, but do not reach WHO FC I/II or a 6MWD > 440 m. Clinical stability 
at randomization will be ensured by requirements such as stable doses of PAH-therapy and 
diuretics, and the mandatory 14-day screening period. By this, the study design intends to
represent the real-life clinical situation of PAH patients, in which close follow-up of 
prognostically relevant parameters is required for the decision on a next step of treatment 
escalation. As there will be rater-blinded assessments and central adjudication, but no 
blinding of the study treatment arms, the investigator will at any time be able to decide about 
any necessary treatment escalation. Thus, even treatment of a patient randomized to the 
control or maintenance arm will stringently follow treatment guidelines.      
End of Study
The end of the study as a whole will be reached as soon as the last safety FU visit of the last 
patient according to the above definition has been reached in all participating countries 
(European Union [EU] and non-EU).
Primary completion
Primary completion will be upon reaching the primary endpoint at 24 weeks of treatment. 


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6.
Study population
The patient population that best reflects the clinical situation for transition is patients on 
ERA-combination therapy, as for most patients on PDE-5i monotherapy combination therapy 
may be the next appropriate step of treatment escalation. There may however be clinical 
conditions where a transition to riociguat from PDE-5i monotherapy appears to be appropriate 
at the discretion of the treating physician.
Inclusion criteria - amended
6.1
This section was changed in Amendment 4, see Section 15.1.2.5.
Patients who fulfill the following inclusion criteria are eligible to enter the study:
1. Male and female patients aged 18 to 75 years.
2. Patients with symptomatic PAH with a pulmonary vascular resistance (PVR) 
> 400 dyn*sec*cm-5, mean pulmonary artery pressure ≥25 mmHg, and pulmonary 
capillary wedge pressure (PCWP) ≤15 mmHg as assessed by the most recent right 
heart catheterization (RHC) from medical history prior to screening to confirm the 
diagnosis. Alternatively, PCWP can be replaced by left ventricular end-diastolic 
pressure (≤15 mmHg).

PAH of the following types:

a. Idiopathic 

b. Hereditary

c. Drug and toxin induced PAH

d. Associated with PAH due to:

Connective tissue disease (CTD)

Congenital heart disease, but only if the patient underwent surgical 
repair more than one year before enrolment 

Portal hypertension with liver cirrhosis (Note: patients with clinical 
relevant hepatic dysfunction are excluded; see exclusions related to 
disorders in organ function)
3. Patients who are on stable doses of a PDE-5i and ERA combination therapy or on 
stable PDE-5i monotherapy 6 weeks prior to and at randomization but not at treatment 
goal (tadalafil 20 to 40 mg once daily or sildenafil at least 60 mg daily dose).
4. WHO FC III at screening and at randomization.
5. 6MWD test between 165 m and 440 m at screening and at randomization.
6. Stable dose of diuretics, if used, for at least 30 days prior to and at randomization.
7. Patients who are able to understand and follow instructions and who are able to 
participate in the study for the entire study.


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8. Women 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 1 is a physical barrier (e.g. 
condom with hormonal contraception like implants or combined oral contraceptives, 
condom with intrauterine devices). This applies beginning with signing of the
informed consent form until 30 (+5) days after the last administration of study drug.
9. Patients must have given their written informed consent to participate in the study 
after having received adequate previous information and prior to any study-specific 
procedures.
Exclusion criteria - amended
6.2
This section was changed in Amendment 4, see Section 15.1.2.6.
Patients who fulfill any of the exclusion criteria are not eligible to enter the study:
1. Participation in another interventional clinical study within 30 days prior to screening.
2. Previous randomization to treatment during this study (no re-randomization).
3. Previous treatment with riociguat.
4. Pregnant women (i.e., positive serum ß-human-chorionic-gonadotropin test or other 
signs of pregnancy), or breast feeding women, or women with childbearing potential 
not using a combination of 2 effective contraception methods (as laid out in inclusion 
criterion no. 8) throughout the study.
5. Patients with a medical disorder, condition, or history of such that would impair the 
patient’s ability to participate or complete this study, in the opinion of the investigator.
6. Patients with substance abuse (e.g., alcohol or drug abuse) within the previous 
3 months prior to and at randomization.
7. Patients with underlying medical disorders with an anticipated life expectancy below 
2 years (e.g., active cancer disease with localized and/or metastasized tumor mass).
8. Patients with a history of severe allergies or multiple drug allergies.
9. Patients with hypersensitivity to the investigational drug or any of the excipients.
10. Patients unable to perform a valid 6MWD test (e.g., orthopedic disease, peripheral 
artery occlusive disease, which affects the patient’s ability to walk). Note: Patients, 
who require walking aids, may be included if in the opinion of the investigator the 
walking distance is not impaired. Patients with a variance of more than 15% between 
the screening and the randomization (i.e., baseline) 6MWD test. 
11. Participation at a supportive physical training program, defined as a structured 
exercise and rehabilitation program supervised by a physician and/or a physiotherapist
within 12 weeks prior to screening. Participants enrolled in an exercise program for 
pulmonary rehabilitation > 12 weeks prior to screening may enter the study if they 


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agree to maintain their current level of rehabilitation during the screening and the 
24 weeks of the study.
12. Excluded medication/treatment:
a. Patients who are screened for possible participation in the study must not be 
withdrawn from treatments which are medically required. If such treatments 
are not in-line with the entry criteria of this study, the patient must not be 
enrolled. Concomitant use with riociguat of the following specific medications 
for treatment of PAH is not allowed at any time during the study:

PDE-5i (e.g., sildenafil, tadalafil or vardenafil) must not be co-administered 
with riociguat

Non-specific PDE-inhibitors (e.g., dipyridamole, theophylline)

NO donors (e.g., nitrates, amyl nitrite)
b. Prostacyclin analogues (PCA) and prostacyclin-receptor agonists (PRA) by any 
administration route within 30 days prior to and at randomization (except for 
vasoreactivity testing).
13. Exclusion criteria related to pulmonary disease:
a. All types of PH (including PH-IIP) except subtypes of Dana Point Group I 
specified in the inclusion criteria.  
b. Evidence of clinically significant restrictive or obstructive parenchymal lung 
diseases in the judgment of the investigator (e.g., based on a clean computed 
tomography lung scan).
c. Severe congenital abnormalities of the lungs, thorax, and diaphragm.
d. Severe restrictive lung disease (total lung capacity [TLC] < 60%).
e. Moderate obstructive lung disease (forced expiratory volume in one 
second/forced vital capacity [FEV1/FVC] < 50%).
f. Confirmed obstructive sleep apnea
g. Severe diffusion impairment (diffusing capacity of the lung for carbon monoxide 
< 30% predicted).
h. History or active state of serious hemoptysis/pulmonary hemorrhage including 
those managed by bronchial artery embolization.
14. Exclusion criterion related to hypoxia (pulse oximeter at rest):
a. Peripheral capillary oxygen saturation (SpO2) < 88% despite supplemental 
oxygen therapy (≤4 L/min) at rest.
15. Cardiovascular exclusion criteria:
a. Uncontrolled arterial hypertension (SBP > 180 mmHg and/or diastolic 
BP > 110 mmHg).


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b. SBP < 95 mmHg prior to and at randomization.
c. Resting heart rate in the awake patient < 50 bpm or > 105 bpm.
d. Permanent atrial fibrillation and new onset of atrial fibrillation within the last 
3 months prior to screening.
e. Left ventricular systolic dysfunction by echocardiography (left ventricular 
ejection fraction [LVEF] < 40%, Simpson’s methodology).
f. Hypertrophic obstructive cardiomyopathy.
g. Severe proven or suspected coronary artery disease (patients with Canadian 
Cardiovascular Society Angina Classification class 2 to 4, and/or requiring 
nitrates, and/or acute coronary syndrome, or coronary interventions (PCI, 
CABG) within the last 3 months prior to and at randomization).
h. Clinical evidence of symptomatic atherosclerotic disease (e.g., peripheral artery 
disease with reduced walking distance, history of stroke with persistent 
neurological deficit etc.).
i. History of stroke within 3 months prior to and at randomization.
j. Congenital or acquired valvular or myocardial disease if clinically significant 
apart from tricuspid valvular insufficiency due to PAH.
k.Three or more of the following left ventricular disease/ dysfunction risk factors: 

Body Mass Index (BMI) ≥ 30 

History of Essential Hypertension 

Diabetes mellitus of any type

History of significant Coronary Disease 
16. Exclusion criteria related to disorders in organ function:
a. Clinical relevant hepatic dysfunction indicated by:

Bilirubin > 2 times upper limit of normal (ULN), and/or

Alanine aminotransferase (ALT) or aspartate aminotransferase (AST)
> 3 times ULN
b. Signs of severe hepatic insufficiency (Child Pugh C), and/or
c. Renal insufficiency (glomerular filtration rate < 30 mL/min (calculated based on 
the Cockcroft formula or Modification of Diet in Renal Disease formula).
17. Other exclusion criteria:
a. Other co-morbidities impairing exercise capacity.


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Withdrawal of patients from study
6.3
6.3.1
Withdrawal – amended
This section was changed in Amendment 4, see Section 15.1.2.7.
Discontinuation of study treatment - amended
6.3.1.1
Study treatment (riociguat or control) discontinuation for any reason does not represent 
withdrawal from the study and should not result in withdrawal of the patient from the study.
Please see definitions for premature discontinuation from the study in Section 6.3.1.2.
Patients who prematurely discontinue from the study treatment will still be followed up for 
collection of safety and efficacy data at Visit 4 / EOT at Week 24 (± 4 days) and should also 
perform the safety FU visit at 30 days (± 5 days) after the last intake of study drug.  Note that 
the safety FU visit may occur before Visit 4 / EOT if premature discontinuation from 
treatment occurs early during the study.
In all cases, the reason for study treatment discontinuation must be recorded in the electronic 
case report form (eCRF) and in the patient’s medical records.
Patients may decide to withdraw their consent to participate in the study and to no longer 
attend study visits and take the study treatment (if not already discontinued); they may object 
to generation and processing of post-study treatment discontinuation data. Patient decision
will be recorded in the eCRF. Patients who withdraw from the study will have the vital status
(alive or dead) reported in the eCRF at Visit 4 / EOT. The contact can be by visit, phone or e-
mail, and also by family members. Every effort should be made to contact the patient by 
telephone at the times the study visits were scheduled for the remaining duration of the study, 
to determine if any of the primary, secondary, or other endpoints have been reached. All 
attempts to retrieve information about the patients should be documented in the patient’s 
records. In addition to withdrawing their consent for attending the study visits, patients may 
also object to releasing any other information regarding their health status. For this, the 
patient must sign a corresponding declaration of objection; alternatively, the patient’s oral 
objection may be documented in the source data. In such cases, every effort should be made 
to obtain vital status (alive or dead) information through consultation of public databases, 
wherever allowed by local regulations.
Criteria for withdrawal from study treatment
Patients must be withdrawn from study treatment if any of the following occurs:

At their own request or at the request of their legally acceptable representative. At 
any time during the study and without giving reasons, a patient may decline to 
participate further. The patient will not suffer any disadvantage as a result.

If, in the investigator’s opinion, continuation of the study treatment would be 
harmful to the patient’s well-being.


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
Occurrence of adverse events (AEs) or intercurrent diseases which the investigator 
judges unacceptable for continuation of participation in the study.

Occurrence of adverse drug reactions, which have from the investigator’s point of 
view, a negative impact on the patient’s individual risk-benefit ratio. (Investigators 
are obliged to reassess the patient’s individual risk-benefit ratio on a continuous 
basis. Factors like anticipated treatment effect, progression of underlying disease, 
occurrence of side effects and alternative treatment options have to be considered).

In case a patient is diagnosed with pulmonary veno-occlusive disease (PVOD) 
while on treatment with study drug, the administration of riociguat has to be 
stopped immediately

Pertinent non-compliance with the conditions for the study or instructions by the 
investigator

In case of pregnancy or breast feeding

Participation in another clinical study

Patient does not tolerate the lowest possible riociguat dose (0.5 mg TID)
Patients may be withdrawn from the study treatment if any of the following occurs:

At the specific request of the sponsor and in liaison with the investigator (e.g.,
obvious non-compliance, safety concerns).
Although not preferred, patients may interrupt their intake of study treatment due to 
reasonable circumstances/reasons at any time (e.g., hospitalization in a remote hospital 
without study treatment access, safety reasons, side effects). If an interruption lasts longer 
than 14 days in a row, it is at the discretion of the investigator to discontinue the study 
participation, and the eCRF of the early termination visit must be completed.
In case of treatment interruptions for 3 days or more, treatment should be restarted at 1 mg 
TID for 2 weeks, and continued with the dose titration regimen as shown in Figure 7–1.
Discontinuation of study - amended
6.3.1.2
Depending on the time point of withdrawal, a withdrawn patient is referred to as either 
“screening failure” or “dropout” as specified below:
Screening failure
A patient who, for any reason (e.g., failure to satisfy the selection criteria), terminates the 
study before the time point used for the definition of “dropout” (see below) is regarded a 
“screening failure”.
Re-screening of a “screening failure” is allowed; thus, participation of an initial “screening
failure” patient at a later time point, provided he/she meets all selection criteria upon 
re-screening, is acceptable. Re-screening should be limited to situations preventing the patient 
from safely completing the study procedures (e.g., acute infections or diseases affecting the 


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patient`s ability to complete the 6MWD test, acute dysregulations of blood pressure). 
Re-screening due to fluctuating data around the upper or lower limit of reference, in order to 
achieve a value within the normal range, is not allowed.
The investigator has to ensure that the repeated screening procedures do not expose the patient 
to an unjustifiable health risk. Also, for re-screening, the patient has to re-sign the informed 
consent form (ICF), even if it was not changed after the patient’s previous screening.
Dropout
A patient who discontinues study participation prematurely for any reason after randomization
is defined as a “dropout”.  If a patient prematurely discontinues study treatment and does 
not wish to continue with the remaining scheduled visits, the investigator should take 
all possible effort to complete a final evaluation, and the patient should be asked for his 
agreement to schedule an early termination visit as soon as possible, at which time point 
all assessments scheduled for Visit 4 / EOT are to be performed.
General procedures
In all cases, the reason for withdrawal must be recorded in the eCRF and in the patient’s 
medical records. 
The patient may object to the generation and processing of post-withdrawal data as specified 
in Section 13.4.
Any patient removed from the study will remain under medical supervision until discharge or 
transfer is medically acceptable.
Details for the premature termination of the study as a whole (or components thereof) are 
provided in Section 12).
6.3.2
Replacement
Patients who discontinue the study during the mandatory screening period may be replaced.
There will be no replacement of dropouts during this study.
Patient identification
6.4
After a patient has signed the ICF, the patient identification number that has been assigned to 
the patient will be provided to the investigator by IXRS.
The patient number is a 9-digit number consisting of:

first 2 digits = country code

next 3 digits = center number within the country

last 4 digits = current patient number within the center.


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7.
Treatments
Treatments to be administered - amended
7.1
This section was changed in Amendment 4, see Section 15.1.2.10.
Riociguat/BAY 63-2521 film-coated tablets will be used in this study at a dosage of 0.5 mg, 
1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg.
Tablets will be administered orally.
Note that patients randomized to the riociguat arm will have a washout period before starting 
titration period of riociguat (see “wash-out period” in Section 5 for details). The starting dose 
is 1 mg TID; the intervals between drug intakes should be 6 to 8 hours. The dosage should be 
increased by 0.5 mg increments in 2 week intervals to 1.5 mg, 2.0 mg, and 2.5 mg TID 
(maximal total daily dose). Patients should be maintained on lower doses if higher doses are 
not tolerated (minimal dose of 0.5 mg TID). After the titration period (i.e., during the 
maintenance period) riociguat should be continued at the optimal individual dose as 
determined at the end of the titration period (Week 8; see Figure 7–1). Dose reductions or 
discontinuation of riociguat for safety reasons are allowed at any time, as well as dose 
increases in 0.5 mg increments (up to 2.5 mg) at the discretion of the investigator (see
Section 5).
Patients randomized to the control arm will continue to receive stable doses of tadalafil (daily 
dose 20 to 40 mg) or sildenafil (daily dose at least 60 mg) as well as other supportive 
treatments at the discretion of the investigator.
Concomitant treatment with ERA is not subject of the research of this study; therefore, ERA 
are not considered study drug. However, as these are effective specific PAH drugs, their doses
need to remain stable in combination with PDE-5i within 6 weeks prior to randomization and 
throughout the study. Any change in dose or application of ERA needs to be documented.
Identity of study treatment - amended
7.2
This section was changed in Amendment 4, see Section 15.1.2.11.
All study drugs (investigational medicinal products [IMP]) will be labeled according to the 
requirements of local law and legislation. Label text will be approved according to the 
sponsor’s agreed procedures, and a copy of the labels will be made available to the study site 
upon request.
A system of numbering in accordance with all requirements of Good Manufacturing Practice 
will be used, ensuring that each dose of riociguat can be traced back to the respective bulk 
batch of the ingredients. Lists linking all numbering levels will be maintained by the 
sponsor’s clinical supplies Quality Assurance group. 
A complete record of riociguat batch numbers and expiry dates as well as the labels will be 
maintained in the sponsor’s study file.


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See Table 7–1 for details on the study treatment.
Treatment administered in the control arm (tadalafil, sildenafil) is considered standard of care.
Storage requirements:
All investigational drugs used during the study will be stored at the investigational sites in a 
place inaccessible to unauthorized personnel, i.e., in a locked cabinet. 
No special storage conditions are required for Riociguat.   Please note that PDE5i must be 
stored below 30°C.
Table 7–1: Identity of investigational product
Riociguat arm
International non-proprietary 
name (INN)
Riociguat 
Sponsor’s internal reference 
number
BAY 63-2521
Formulation
Galenical form
Round immediate-released tablets, diameter 6 mm
Composition
Active ingredient: Methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-
pyrazolo [3,4 b]pyridine-3-yl]-5-pyrimidinyl (methyl)carbamate
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.
Strength
0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg
Material numbers
83296470 BAY 63-2521 tablet 0.5 mg 511 COAT
83296535 BAY 63-2521 tablet 1.0 mg 512 COAT
83296543 BAY 63-2521 tablet 1.5 mg 513 COAT
83296578 BAY 63-2521 tablet 2.0 mg 504 COAT
83296608 BAY 63-2521 tablet 2.5 mg 515 COAT
Packaging
High-density polyethylene bottles
Control arm
Tadalafil
Material name
ADCIRCA 20MG 56 TAB
Active substance
Tadalafil
Formulation
Film-coated tablets
Description
Amygdaloid, debossed with 4467 on one side
Strength
20mg, 40mg
Dosage unit
20mg/tablet
Mode of administration
Oral
Packaging
Wallet containing 5 blister, each blister containing 14 tablets 
(total of 70 tablets)


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Table 7–1: Identity of investigational product
Sildenafil
Material name
REVATIO 20MG TAB B90 GER
Active substance
Sildenafil citrate
Formulation
Film-coated tablets
Description
Round biconvex, debossed with RVT 20 on one side and Pfizer 
on the other
Strength
Daily doses of 60mg, 80mg, 100mg, 120mg, 140mg, 160mg, 
180mg, 200mg, 220mg, 240mg, 260mg, 280mg, 300mg
Dosage unit
20mg/tablet
Mode of administration
Oral
Packaging
Wallet containing 6 blister, each blister containing 15 tablets 
(total of 90 tablets)
Treatment assignment - amended
7.3
This section was changed in Amendment 4, see Section 15.1.2.12.
Patients will be randomized 1:1 to remain on current PAH-specific treatment (the control arm) 
or to replace the PDE-5i treatment with riociguat (the riociguat arm). Central randomization
(by IXRS) is planned, stratified by etiology of PAH by:
•
Idiopathic (I)PAH/ heritable (H)PAH/ PAH drug and toxin induced
•
PAH-CHD, PAH-portopulmonary PAH (PoPH)
•
PAH- CTD
Following washout (see “wash-out period” in Section 5 for details), all eligible patients 
randomized to the riociguat arm will receive a starting dose of riociguat of 1 mg TID in this 
open-label study. The starting dose of 1 mg may be down-titrated to 0.5 mg at the discretion 
of the investigator and at any point during the 8-week titration period.
Patients randomized to the control arm will remain on their current PAH-specific treatment.
Patients on combination therapy with ERA need to continue at a stable dose in both treatment 
arms.
Dosage and administration
7.4
Riociguat will be administered TID as film-coated immediate-release tablets with or without 
food. The starting dose will be 1 mg TID, followed by a dose adjustment period of 8 weeks 
(titration period), and an overall treatment duration of 24 weeks.
Dose increase or decrease criteria are described in Section 5 and the titration scheme is 
presented in Figure 7–1.


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Figure 7–1: Titration Scheme
T = Titration (visit); TID = three times daily.
Blinding
7.5
This is an open-label study. 
There will only be blinded assessments for the 6MWD test as described in Section 9.7.1 and 
for the determination of WHO FC as described in Section 9.7.4.
Drug logistics and accountability
7.6
All study treatments will be stored at the investigational site in accordance with Good Clinical 
Practice (GCP) and Good Manufacturing Practice requirements and the instructions given by 
the clinical supplies department of the sponsor (or its affiliate/contract research organization 
[CRO]), and will be inaccessible to unauthorized personnel. Special storage conditions and a 
complete record of batch numbers and expiry dates can be found in the sponsor’s study file; 
the site-relevant elements of this information will be available in the investigator site file. On 
the day of receipt, the responsible site personnel will confirm receipt of study treatment via 
IXRS. The personnel will use the study treatment only within the framework of this clinical 
study and in accordance with this protocol. Receipt, distribution, return, and destruction (if 
any) of the study treatment must be properly documented according to the sponsor’s agreed 
and specified procedures.
Written instructions on medication destruction will be made available to affected parties as 
applicable. 


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Treatment compliance
7.7
Any discrepancies between actual and expected amount of returned study treatment must be 
discussed with the patient at the time of the visit, and any explanation must be documented in 
the source records.
The packages of the investigational drug have to be brought back to the investigational site, 
and tablets will be counted for a compliance check. 
The respective compliance should be between 80% and 120% of the calculated dose, based on 
the information on tablet count and exposure for the entire period of study participation.
8.
Non-study therapy
Prior and concomitant therapy - amended
8.1
This section was changed in Amendment 4, see Section 15.1.2.13.
The intake of the following concomitant medication is not allowed at any time while a 
patient is on riociguat:

PDE-5i (e.g., sildenafil, tadalafil or vardenafil) must not be co-administered with 
riociguat

Non-specific PDE-inhibitors (e.g., dipyridamole, theophylline)

NO donors (e.g., nitrates, amyl nitrite)
The intake of the following concomitant medication is not allowed within 30 days prior 
to and at randomization:

PCA and PRA by any administration route within 30 days before randomization
(except for vasoreactivity testing).
Patients, who require respective medications (except for PCA) need to be withdrawn from the 
study drug (refer to Section 6.3.1).
Specific PAH medication:
Dose changes in PAH-specific medication (i.e., PDE-5i or ERA) should be avoided during the 
study. Dose changes considered clinically necessary by the investigator need to be 
documented. Notably hospitalization for initiation of intravenous or subcutaneous prostanoid 
therapy fulfills the criterion of clinical worsening, as may disease progression with a need for 
any additional specific PAH targeted medication (see also Section 10.3.2.1 for Definition of 
Clinical Worsening). The patient may remain in the study even if escalation of PAH therapy 
is required to maintain or improve the clinical status of the patient. The decision to keep the 
patient in the study is at the discretion of the investigator.
Other concomitant medication:

The concomitant use of riociguat with strong multi-pathway cytochrome P450 
(CYP) and P-glycoprotein 1 (P-gp)/breast cancer resistance protein (BCRP) 
inhibitors such as azole antimycotics (e.g., ketoconazole, itraconazole) or human 


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immunodeficiency virus (HIV) protease inhibitors (e.g., ritonavir) is not 
recommended, due to the pronounced increase in riociguat exposure (see also 
‘Interaction with other medicinal products and other forms of interaction’ in 
Section 4.5 of the current Company Core Data Sheet).

The concomitant use of riociguat with strong CYP1A1 (CYP family 1, subfamily 
A, polypeptide 1) inhibitors, such as the tyrosine kinase inhibitor erlotinib, and 
strong P-gp/BCRP inhibitors, such as the immunosuppressive agent cyclosporine 
A, may increase riociguat exposure (see Section ‘Interaction with other medicinal 
products and other forms of interaction’ in Section 4.5 of the current Company 
Core Data Sheet). These drugs should be used with caution. BP should be 
monitored and dose reduction of riociguat considered.
Other medications considerations (detailed information can be found in the current IB):

Pre- and comedication with the proton pump inhibitor omeprazole (40 mg once 
daily) reduced riociguat mean area under the curve (AUC) by 26% and mean 
maximum observed concentration (Cmax) by 35%. This is not considered clinically 
relevant. 

Co-administration of the antacid aluminum hydroxide/magnesium hydroxide 
reduced riociguat mean AUC by 34% and mean Cmax by 56%. Antacids should be 
taken at least 1 hour after riociguat.
Other treatments considerations:

Supportive treatments which may also be used for the treatment of PAH such as 
oral anticoagulants, diuretics, digitalis, calcium channel blockers or oxygen 
supplementation are permitted. However, treatment with diuretics should be stable 
for at least 30 days before randomization. 

Patients with supplemental long-term oxygen therapy may be included.
Concomitant treatment in case of clinical deterioration:

In case of a clinically relevant deterioration of the patient’s signs or symptoms of 
PAH, it is at the discretion of the investigator to perform additional invasive 
hemodynamic measurements according to practice guidelines; this needs to be 
documented in the eCRF.
Post-study therapy - amended
8.2
This section was changed in Amendment 4, see Section 15.1.2.14.
Further medical treatment of patients at the end of the study will be decided by the 
investigator at Visit 4 / EOT.  In case riociguat is indicated for further treatment, patients will 
be prescribed riociguat / Adempas. The sponsor is going to ensure that patients will receive 
riociguat treatment after completion of the study in countries where riociguat is not 
reimbursed/commercially available. Based on the local regulations, the sponsor is going to 
identify and take appropriate measures, in agreement with the center/treating physician, such 


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as allowing the patient access to a drug supply study, to a compassionate use, or other drug 
supply programs.
9.
Procedures and variables
Tabular schedule of evaluations
9.1
See schedule of procedures in Section 16.1.
Patients will be contacted via telephone every 4 weeks, if there is no scheduled visit to the 
study center.
Visit description
9.2
9.2.1
Mandatory screening period (Week -2 ± 2 days, Visit 0) - amended
This section was changed in Amendment 4, see Section 15.1.2.15.
The mandatory screening period starts 2 weeks prior to randomization (baseline visit) and 
includes primary diagnostic procedures and the verification of the following eligibility 
criteria:

Signed ICF.
Patients who sign the ICF will undergo the following investigations:

Check for inclusion/exclusion criteria (see Sections 6.1 and 6.2)

Lung function test (see exclusion criterion 13 in Sections 6.2 and 9.7.2)

Pulse oximetry (see exclusion criterion 14 in Sections 6.2 and 9.7.1)

Echocardiography (LVEF) (see exclusion criterion 15 in Section 6.2)

Medical history (see Section 9.3.2)

Smoking status, including number of cigarettes per day 

Specific PAH medication (see Section 8.1)

Patient’s demographics (see Section 9.3.1)

Pregnancy test (women of childbearing potential only; see Section 9.6.2)

Physical examination (see Section 9.6.3.1)

Weight and height

6MWD test (blinded assessment, see Section 9.7.1)

WHO FC (blinded assessment, see Section 9.7.4)

Safety laboratory measurements (see Section 9.6.3.4)


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
Vital signs, including sitting BP and pulse rate (see Section 9.6.3.2)

Electrocardiogram (ECG) (see Section 9.6.3.3)

Concomitant medication (see Section 8.1)

Adverse event (AE) assessment and reporting (see Section 9.6.1). The recording 
period of AEs begins with the signature of the ICF.
9.2.2
Randomization (Baseline visit, Week 0, Visit 1) - amended
This section was changed in Amendment 4, see Section 15.1.2.16.
Patients need to be pretreated with a stable dose of PDE-5i +/- a stable dose of ERA for 
6 weeks prior to and at randomization.
The following procedures will be performed at baseline prior to randomization:

Inclusion/exclusion criteria (see Sections 6.1 and 6.2)

Pulse oximetry (see exclusion criterion 14 in Section 6.2 and Section 9.7.1)

Smoking status, including number of cigarettes per day 

Specific PAH medication (see Section 8.1)

Pregnancy test (women of childbearing potential only, see Section 9.6.2)

6MWD test (blinded assessment, see Section 9.7.1)

Biomarkers (central laboratory; see Section 9.6.3.4)

WHO FC (blinded assessment, see Section 9.7.4)

mRRS (see Section 16.4)

LPH (QoL) questionnaire (see Section 16.5)

Vital signs, including sitting BP and pulse rate (see Section 9.6.3.2)

Concomitant medication (see Section 8.1)

AE assessment and reporting (see Section 9.6.1)

Cardiac magnetic resonance imaging (cMRI; exploratory, reported separately)

Randomization – via IXRS (see Section 7.3).
Patients will be randomized 1:1 to either the control arm (standard of care) or the riociguat 
arm on the same day.
Patients randomized to the control arm
Patients will continue to receive tadalafil (dose range between 20 and 40 mg/day) or sildenafil 
(dose at least 60 mg/day) as well as other standard of care treatments at the discretion of the 
investigator up to Week 24.


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Patients randomized to the riociguat arm
Riociguat will be dispensed (note the dose titration scheme for riociguat arm, see Figure 7–1).
Date and time of the last PDE-5i dose will be documented by the investigator. Patients will 
have the following wash-out periods:

Patients pretreated with a stable dose of sildenafil (dose at least 60 mg/day) will be
switched to riociguat after a wash-out period of 24 hours following the last dose of 
sildenafil

Patients pretreated with a stable dose of tadalafil (dose range 20 to 40 mg/day) will be 
switched to riociguat after a wash-out period of 48 hours following the last dose of 
tadalafil.
Riociguat dosing start
Based on the time of the last PDE-5i dose, date and time of the first dose of riociguat after the 
wash-out period will be determined by the investigator and communicated to the patient. 
Before the first dose of riociguat, BP measurements need to be performed to ensure that SBP 
is ≥95 mmHg. If the BP is below this value, riociguat must not be administered (BP 
measurement may be repeated within the next 24 hours). Measurement of BP and 
application of first riociguat dose may be performed at the study center or by an experienced 
nurse at home (see Section 9.6.3.2).
Date and time of intake of the first dose of riociguat need to be documented by the investigator.
The nurse will contact the center for this purpose via phone. The dosage will then be 
individually adjusted during the titration period (H 1 to V 2). 
Home Visits 1, 2, 3 (Weeks 2, 4, 6 ± 2 days)
Home visits may be facilitated by experienced nurses, measuring BP and agreeing on the next 
dose in phone contact with the treating investigator at the center. Prior to start of any 
study-related activities, the experienced nurse needs to be trained on the Study Protocol. The 
training needs to be documented in the investigator site file. The nurse will follow the 
instructions given by the treating investigator.
The experienced nurse is responsible for the Drug Accountability, and dispensing riociguat 
medication. When performing home visits, the experienced nurse will collect the following 
information and report to treating investigator at the site.
The following procedures will be performed:

Dispense of study medication (see Section 7.4) 

Drug accountability (see treatment compliance in Section 7.7)

Dose of riociguat (see Section 7.4)

Vital signs, including sitting BP and pulse rate (see Section 9.6.3.2)

Change in concomitant medication (see Section 8.1)

AE assessment and reporting (see Section 9.6.1)


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
At Week 4 only: smoking status, including number of cigarettes per day 

At Week 4 only: pregnancy test (women of childbearing potential only see 
Section 9.6.3.4).
In the riociguat arm, the investigator will decide about the dose adjustment of riociguat based 
on the vital signs and wellbeing of the patient, enter it into the IXRS and retrieve a new dose 
box number (initial dose adjustment period, see Section 7.4). 
The procedures of home nurse service and drug delivery must be in agreement with local 
medical practice and local legal requirements.
At the discretion of the investigators and if applicable (e.g., short distance to study center) 
these visits may also be performed at the study center.
9.2.3
Visit 2 (Week 8 ± 2 days) - amended
This section was changed in Amendment 4, see Section 15.1.2.17.
Titration step 4 takes place at Visit 2.
The following procedures will be performed:

Smoking status, including number of cigarettes per day 

Pregnancy test (women of childbearing potential only see Section 9.6.3.4)

Dispense of study medication (see Section 7.4)

Drug accountability (see treatment compliance in Section 7.7)

Dose of riociguat (see Section 7.4)

6MWD (blinded assessment, see Section 9.7.1)

Biomarkers (central laboratory; see Section 9.6.3.4)

WHO FC (blinded assessment, see Section 9.7.4)

Vital signs, including sitting BP and pulse rate (see Section 9.6.3.2)

Change in concomitant medication (see Section 8.1)

AE assessment and reporting (see Section 9.6.1).
9.2.4
Telephone Contact (Week 12 ± 2 days) - amended
This section was changed in Amendment 4, see Section 15.1.2.18.
The following will be recorded:

Smoking status, including number of cigarettes per day 

Pregnancy test (women of childbearing potential only, see Section 9.6.2)

Change in concomitant medication (see Section 8.1)

AE assessment and reporting (see Section 9.6.1).


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9.2.5
Visit 3 (Week 16 ± 2 days) - amended
This section was changed in Amendment 4, see Section 15.1.2.19.
The following procedures will be performed:

Smoking status, including number of cigarettes per day 

Pregnancy test (women of childbearing potential only, see Section 9.6.2)

Dispense of study medication (see Section 7.4)

Drug accountability (see treatment compliance in Section 7.7)

Dose of riociguat (see Section 7.4)

6MWD (blinded assessment, see Section 9.7.1)

Biomarkers (central laboratory; see Section 9.6.3.4)

WHO FC (blinded assessment, see Section 9.7.4)

mRRS (see Section 16.4)

Safety laboratory measurements (local laboratory; Section 9.6.3.4)

Vital signs, including sitting BP and pulse rate (see Section 9.6.3.2)

Change in concomitant medication (see Section 8.1)

AE assessment and reporting (see Section 9.6.1).
9.2.6
Telephone Contact (Week 20 ± 2 days) - amended
This section was changed in Amendment 4, see Section 15.1.2.20.
The following will be recorded:

Smoking status, including number of cigarettes per day 

Pregnancy test (women of childbearing potential only, see Section 9.6.2)

Change in concomitant medication (see Section 8.1)

AE assessment and reporting (see Section 9.6.1).
9.2.7
Visit 4 / End of Treatment (EOT) (Week 24 ± 4 days) - amended
This section was changed in Amendment 4, see Section 15.1.2.21.
The Visit 4 / EOT visit will be performed at Week 24 ± 4 days after the last dose of riociguat, 
sildenafil or tadalafil, and a decision on further treatment will be made.
The following procedures will be performed:

Smoking status, including number of cigarettes per day 

Pregnancy test (women of childbearing potential only, see Section 9.6.2)


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
Physical examination (see Section 9.6.3.1)

Drug accountability (see treatment compliance in Section 7.7)

6MWD (blinded assessment, see Section 9.7.1)

Biomarkers (central laboratory; see Section 9.6.3.4)

WHO FC (blinded assessment, see Section 9.7.4)

mRRS (see Section 16.4)

LPH (QoL) questionnaire (see Section 16.5)

Safety laboratory measurements (local laboratory; see Section 9.6.3.4)

Vital signs, including sitting BP and pulse rate (see Section 9.6.3.2)

Change in concomitant medication (see Section 8.1)

AE assessment and reporting (see Section 9.6.1)

cMRI (exploratory, reported separately).
9.2.8
Safety follow-up visit (30 days ± 5 days) - amended
This section was changed in Amendment 4, see Section 15.1.2.22.
The following assessments will be performed and documented in the eCRF:

Smoking status, including number of cigarettes per day

Pregnancy test (women of childbearing potential only, see Section 9.6.2)

Vital signs, including sitting BP and pulse rate (see Section 9.6.3.2)

AE assessment and reporting (see Section 9.6.1).
Population characteristics
9.3
9.3.1
Demographics
The following demographic data will be recorded:

Age

Sex

Ethnicity

Weight and height (screening only)

Smoking status including number of cigarettes per day.


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9.3.2
Medical history
Medical history findings (i.e., previous diagnoses, diseases or surgeries) meeting all criteria 
listed below will be collected as available to the investigator:

Start before signing of the informed consent 

Considered relevant for the patient’s study eligibility

Time of first diagnosis of PAH

Date of most recent RHC

Time of first PAH specific treatment.
Detailed instructions on the differentiation between (i) medical history and (ii) AEs can be 
found in Section 9.6.1.1.
Efficacy
9.4
A complete list of variables to be analyzed for this study and the methods of analysis will be 
provided in the statistical analysis plan (SAP). 
Standard efficacy outcomes at Week 24:

Change from baseline in 6MWD (blinded assessment, see Section 9.7.1)

Change from baseline in NT-proBNP

Change from baseline in WHO FC (blinded assessment, see Section 9.7.4)

Clinical worsening (for definition, see Section 10.3.2.1)

Change from baseline in QoL: LPH (see Section 16.5)

Change from baseline in mRRS and mRRS category (see Section 16.4).
Approach to the analysis
Oral monotherapy or upfront combination therapy is recommended by the ERS/ESC 
guidelines for treatment of PAH patients with a low or intermediate risk according to their 
prognostic evaluation. There is increasing evidence that the concept of combining different 
signaling pathways in PAH-specific combination therapy may provide additional benefit to 
patients. 
The general treatment goal is to achieve a low risk status for the individual PAH patient as 
defined by determinants of prognosis such as WHO FC, 6MWD, or NT-proBNP.
Interim results from the uncontrolled open-label RESPITE study showed that transition of 
PDE-5i to riociguat in patients not reaching treatment goals results in improvements in these 
clinically and prognostic relevant parameters. To the widely accepted concept of combination 
therapy, this adds the concept of optimizing a pathway by transition to a more effective drug. 


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It has been agreed by key experts that a randomized study would be needed to confirm the 
concept. The study design of REPLACE comes as close as possible in matching the real 
clinical situation in which a patient in on stable PDE-5i and ERA–combination therapy, or on 
PDE-5i monotherapy and does not reach treatment goals. Treatment escalation may not be 
imminent but would be the next step. Patients will be randomized to remain on their stable 
treatment or to transition their PDE-5i treatment component to riociguat.
Recent studies in PAH as AMBITION applied an event-driven design with a clinical 
worsening endpoint. Due to the low event rate on active treatment these studies would require 
large patient numbers and lengthy studies until results are available. In recent expert 
discussions moving away from the rather defensive strategy of counting deterioration to a 
composite endpoint of clinical improvement has been discussed as a pragmatic necessity. This 
is supported by the fact that mortality never made a difference between treatment groups in 
these studies. The REPLACE composite endpoint reflects the concept of clinical 
improvement in the absence of events of clinical worsening. This reflects what the clinician 
and the treatment guidelines define as treatment goals: improvement in parameters relevant 
clinically and for prognosis and thus reducing the risk of deterioration in the individual 
patient.
Similar endpoints were applied successfully in the AIR-study with inhaled iloprost and as 
secondary endpoint in AMBITION. The criteria when applied to our data from PATENT1/2 
or RESPITE showed that improvement with riociguat treatment can nicely be demonstrated.
This also holds true when the component of NT-proBNP improvement was added to the 
composite endpoint. This has been recommended by the Study Core Advisory Committee 
considering the more objective nature of this parameter in an unblinded randomized study.
Baseline Demographics
A prevalent patient population similar to the one in RESPITE is expected, with the difference 
that also PAH associated with CTD will be included, and expected to form up to 20% of the 
overall study population. Mean age: 54 years, slight female predominance of 60%; 75% 
IPAH/HPAH; mean time on PDE-5i treatment 2 years; 80% on ERA-PDE-5i combination at 
baseline; mean 6MWD at baseline 370 m; all patients WHO FC III.
Pharmacokinetics/pharmacodynamics
9.5
Not applicable.


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Safety
9.6
9.6.1
Adverse events
Definitions
9.6.1.1
Definition of adverse event
In a clinical study, an AE is any untoward medical occurrence (i.e., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a patient or 
clinical investigation patient after providing written informed consent for participation in the 
study. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
A surgical procedure that was planned prior to the start of the study by any physician treating 
the patient should not be recorded as an AE (however, the condition for which the surgery is 
required may be an AE).
In the following differentiation between medical history and AEs, the term “condition” may 
include abnormal e.g., physical examination findings, symptoms, diseases, laboratory.

Conditions that started before signing of informed consent and for which no 
symptoms or treatment are present until signing of informed consent are recorded 
as medical history (e.g., seasonal allergy without acute complaints).

Conditions that started before signing of informed consent and for which 
symptoms or treatment are present after signing of informed consent, at unchanged 
intensity, are recorded as medical history (e.g., allergic pollinosis).

Conditions that started or deteriorated after signing of informed consent will be 
documented as AEs. This includes intercurrent illnesses.
Definition of serious adverse event 
A serious adverse event (SAE) is classified as any untoward medical occurrence that, at any 
dose, meets any of the following criteria (a – f):
a.
Results in death
b. Is life-threatening
The term ‘life-threatening’ in the definition refers to an event in which the patient was 
at risk of death at the time of the event, it does not refer to an event which 
hypothetically might have caused death if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization 
A hospitalization or prolongation of hospitalization will not be regarded as an SAE if 
at least one of the following exceptions is met:

The admission results in a hospital stay of less than 12 hours


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
The admission is preplanned (e.g., elective or scheduled surgery arranged prior to 
the start of the study; admission is part of the study procedures as described in 
Section 9.2)

The admission is not associated with an AE (e.g., social hospitalization for
purposes of respite care).
However, it should be noted that invasive treatment during any hospitalization may 
fulfill the criterion of ‘medically important’ and as such may be reportable as an SAE 
dependent on clinical judgment. In addition, where local regulatory authorities 
specifically require a more stringent definition, the local regulation takes precedence.
d. Results in persistent or significant disability/incapacity.
Disability means a substantial disruption of a person’s ability to conduct normal life’s 
functions.
e.
Is a congenital anomaly/birth defect
f.
Is another serious or important medical event as judged by the investigator.
Classifications for adverse event assessment
9.6.1.2
All AEs will be assessed and documented by the investigator according to the categories 
detailed below.
9.6.1.2.1
Seriousness
For each AE, the seriousness must be determined according to the criteria given in 
Section 9.6.1.1.
9.6.1.2.2
Intensity
The intensity of an AE is classified according to the following categories:

Mild

Moderate

Severe.
9.6.1.2.3
Causal relationship
The assessment of the causal relationship between an AE and the administration of study 
treatment is a decision to be made by the investigator, who is a qualified physician, based on 
all information available at the time of the completion of the case report form (CRF).
Causality should be assessed separately for each study treatment as detailed in the CRF. If the 
investigator feels that the event cannot be firmly attributed to one of the study treatments 
(e.g., owing to a suspected underlying interaction), the same assessment will be documented 
for each study treatment.


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The assessment is based on the question whether there was a “reasonable causal relationship” 
to the study treatment in question.
Possible answers are “yes” or “no”.
An assessment of “no” would include:
1. The existence of a clear alternative explanation, e.g., mechanical bleeding at surgical 
site.
or
2. Non-plausibility, e.g., the patient is struck by an automobile when there is no 
indication that the drug caused disorientation that may have caused the event; cancer 
developing a few days after the first drug administration.
An assessment of “yes” indicates that the AE is reasonably associated with the use of the 
study treatment.
Important factors to be considered in assessing the relationship of the AE to study treatment 
include:

The temporal sequence from drug administration: The event should occur after the 
drug is given. The length of time from drug exposure to event should be evaluated 
in the clinical context of the event.

Recovery on drug discontinuation (de-challenge), recurrence on drug 
re-introduction (re-challenge): Patient’s response after de-challenge or re-
challenge should be considered in view of the usual clinical course of the event in 
question.

Underlying, concomitant, intercurrent diseases:
Each event should be evaluated in the context of the natural history and course of 
the disease being treated and any other disease the patient may have.

Concomitant medication or treatment: 
The other drugs the patient is taking or the treatment the patient receives should be 
examined to determine whether any of them might have caused the event in 
question.

The pharmacology and pharmacokinetics of the study treatment: 
The pharmacokinetic properties (absorption, distribution, metabolism, and 
excretion) of the study treatment, coupled with the individual patient’s 
pharmacodynamics should be considered.
Causal relationship to protocol-required procedure(s)
The assessment of a possible causal relationship between the AE and protocol-required 
procedure(s) is based on the question whether there was a “reasonable causal relationship” to 
protocol-required procedure(s).
Possible answers are “yes” or “no”.


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9.6.1.2.4
Action taken with study treatment 
Any action on study treatment to resolve the AE is to be documented using the categories 
listed below.

Drug withdrawn

Drug interrupted

Dose reduced

Dose not changed

Dose increased

Not applicable

Unknown.
9.6.1.2.5
Other specific treatment(s) of adverse events

None

Remedial drug therapy

Other.
9.6.1.2.6
Outcome
The outcome of the AE is to be documented as follows: 

Recovered/resolved

Recovering/resolving

Recovered/resolved with sequelae

Not recovered/not resolved

Fatal

Unknown.
Assessments and documentation of adverse events - amended
9.6.1.3
This section was changed in Amendment 4, see Section 15.1.2.23.
The investigator has to record on the respective eCRF pages (additionally to the source data) 
all AEs occurring in the period between the signing of the informed consent and the safety FU 
visit at 30 days (± 5 days) after last intake of study treatment (for details, please also refer to
Sections 5 and 16.1 ); after that, there is no requirement to actively collect AEs, including 
deaths. The type of information that should be assessed and recorded by the investigator for 
each AE is listed in Section 9.6.1.2.
“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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For all SAEs the sponsor has to carry out a separate assessment for expectedness, seriousness,
and causal relationship to study treatment.
Reporting of serious adverse events
9.6.1.4
The definition of SAEs is given in Section 9.6.1.1.
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 SAEs. This information, including all relevant contact 
details, is summarized in the investigator site file. This information will be updated as needed.
The investigator must report immediately (within 24 hours of the investigator’s awareness) all 
SAEs occurring during the observation period defined in Section 9.6.1.3 to the recipient 
detailed in the instructions for SAE reporting included in the Investigator File. For this, an AE 
page in the eCRF as well as the complementary pages provided in the Investigator File must 
be completed for each SAE.
Each SAE must be followed up until resolution or stabilization by submission of updated 
reports to the designated recipient.
SAEs occurring after the protocol-defined observation period will be processed by the 
sponsor according to all applicable regulations.
Notification of the IECs/IRBs
Notification of the independent ethics committees (IECs)/institutional review boards (IRBs)
about all relevant events (e.g., SAEs, suspected, unexpected, serious adverse reactions 
[SUSARs]) will be performed by the sponsor and/or by the investigator according to all 
applicable regulations.
Notification of the authorities
The processing and reporting of all relevant events (e.g., SAEs, SUSARs) to the authorities 
will be done by the sponsor according to all applicable regulations.
Sponsor’s notification of the investigational site
The sponsor will inform all investigational sites about reported relevant events (e.g.,
SUSARs) according to all applicable regulations.


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Expected adverse events - amended
9.6.1.5
This section was changed in Amendment 4, see Section 15.1.2.24.
For this study, the applicable reference document is the most current version of the IB for 
Adempas and the EU SmPC / local SPC for Revatio (sildenafil) and Adcirca (tadalafil).
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, the information will 
be integrated into an update of the IB and distributed to all participating sites.
The expectedness of AEs will be determined by the sponsor according to the applicable 
reference document and according to all local regulations.
In this study, the events of disease progression based on the definition given in 
Section 10.3.2.1, will be part of the adjudication as efficacy endpoints, e.g.,:
Disease progression (adjudicated):

6MWD decrease ≥15% from baseline (2 measurements on 2 separate days), and

Worsening in WHO FC.
OR

6MWD decrease ≥15% (2 measurements on 2 separate days), and

Need of new PAH-targeted medication or decompensated right sided heart 
failure.
For the purposes of this trial, these events will be considered expected and will not be subject 
to expedited reporting process, if reported as serious adverse drug reactions. They will be 
captured in the Global Pharmacovigilance database, in the eCRF and undergo adjudication 
and review.
Adverse events of special safety interest - amended
9.6.1.6
This section was changed in Amendment 4, see Section 15.1.2.25.
Symptomatic hypotension and serious hemoptysis (which includes pulmonary hemorrhage) 
are considered AEs of special interest and must be reported to Bayer within the same 
timelines as an SAE by reporting them on the AE page of the eCRF. Events of symptomatic 
hypotension and non-serious hemoptysis should not automatically be upgraded by the reporting 
investigator to serious. Declaration of an event as serious should only occur where the 
seriousness criterion (as defined in Section 9.6.1.1) is applicable.


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9.6.2
Pregnancies
The investigator must report to the sponsor any pregnancy occurring in a female study patient 
during her 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.
For the patient, the outcome of the pregnancy should be followed up carefully, and any 
outcome of the mother or the child should be reported.
Bayer usually does not gather information of drug exposure via the father, however, if those 
cases are reported, all efforts will 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.
For female patients of reproductive potential, in addition to the tests during the scheduled 
visits, monthly pregnancy tests are required, which can be performed at home. The results will 
be followed up during telephone contacts and home visits.
Pregnancy tests during the scheduled visits will be performed in urine or blood, locally, at the 
time points specified in the Schedule of Procedures in Section 16.1.
9.6.3
Further safety
Physical examination
9.6.3.1
Physical examination will be performed as per schedule of procedures (see Section 16.1).
Abnormal physical examination findings are recorded either as medical history or as AEs (see 
Section 9.6.1.1).
Vital signs
9.6.3.2
Pulse rate and BP will be assessed according to the schedule of procedures (Section 16.1). 
Any clinically relevant measurements or changes are to be reported as AEs.
BP and pulse rate will be measured after the patient has been at rest for 15 minutes in a sitting 
position, and the same arm should be used for every examination.
12-lead ECG
9.6.3.3
12-lead ECGs will be performed at screening and at any other time during the study at the 
investigator’s discretion and should be reported in the unscheduled procedure page (see 
Section 16.1). 
For deriving the ECGs, a supine position of the patient and a resting period of 10 minutes are 
recommended. In addition, the investigator will print out the ECGs locally and review the 
ECGs for potential AEs.


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Laboratory assessments - amended
9.6.3.4
This section was changed in Amendment 4, see Section 15.1.2.26.
The following safety laboratory parameters will be measured in the local laboratory:

Hematology: white blood cell differential count, erythrocytes, hemoglobin, hematocrit, 
platelets

Coagulation tests: prothrombin time (INR), only for patients under anticoagulation 
therapy

Clinical chemistry: AST, ALT, total bilirubin, serum albumin, creatinine, potassium.
The following biomarkers will be analyzed in the central laboratory:

NT-proBNP

ADMA

cGMP (from plasma)

GDF-15

ST-2.
All time points for collection of safety laboratory parameters and biomarker are provided in 
Section 16.1.
In the event of implausible results, the laboratory may measure additional parameters to 
assess the quality of the sample (e.g., clotted or hemolyzed) and to verify the results. The 
results from such additional analyses may neither be included in the clinical database of this 
study nor evaluated further. If the results are relevant, the investigator will be informed to 
determine follow-up activities outside of this protocol.
In women of childbearing potential, pregnancy tests in urine or blood will be performed at the 
local laboratory, at the time points specified in Section 16.1.


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Other procedures and variables
9.7
9.7.1
Pulse oximetry - amended
This section was changed in Amendment 4, see Section 15.1.2.27.
The patient’s oxygen saturation will be measured with a noninvasive method expressing the 
SpO2 (peripheral oxygen saturation) percentage.
If the patient receives supplemental oxygen, the amount [L/min] will be recorded in the 
eCRF.
9.7.2
Lung function testing
The FEV1 [L/s] and FEV1, % of predicted and TLC [L] should preferably be analyzed by 
body plethysmography or alternatively by inert gas dilution (helium, argon, neon) or nitrogen 
washout at screening.
Available lung function testing results will be considered as baseline if they are not older than 
180 days at V1 and analyzed by one of the below mentioned methods. Diffusing capacity of 
the lung for carbon monoxide (DLCO) must be newly determined. In case that the respective 
lung function test results are not available, measurements need to be performed during the 
pre-treatment phase.
The measured values have to be transferred into the eCRF.
Lung function measurement:

Actual time

Date

FEV1[L/s]

FEV1 % of predicted

TLC [L]

TLC, % of predicted.
The predicted forced expiratory volume in one second (FEV1) is a calculated value. For the 
calculation the following formulas need to be applied:

Predicted forced expiratory volume (FEV) (women) = 3.95 * height [m] – 0.025 * 
age [years] – 2.60.

Predicted FEV (man) = 4.30 * height [m] – 0.029 * age [years] – 2.49.
The predicted TLC is a calculated value. For the calculation the following formulas need to be 
applied:

Predicted TLC (women) = 6.60 * height [m] - 5.79.

Predicted TLC (man) = 7.99 * height [m] – 7.08.


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DLCO predicted will be newly determined by the single breath technique according to the 
standards recommended by the American Thoracic Society (and the European Respiratory 
Society) (16).
9.7.3
6MWD test - amended
This section was changed in Amendment 4, see Section 15.1.2.28.
The 6MWD test will be performed in accordance with the American Thoracic Society 
Guideline without assessing Borg-Dyspnoea-Index (17). Test results will be recorded on the 
eCRF. 
To ensure a blinded assessment from the randomization visit (baseline), adequate measures 
need to be taken at the study center when performing the 6MWD:

The test has to be performed by a physician or study nurse who is blinded to the 
study treatment of the patient.

The person performing the test must not be involved in the process of study drug 
administration.

The person performing the test should record the results on a separate work sheet 
and, where possible, a different person (could be the person who is involved in the 
study treatment administration) should enter them into the eCRF.
For details on time points refer to Section 16.1, for further details on assessment refer to 
Section 16.2.
9.7.4
Determination of WHO FC - amended
This section was changed in Amendment 4, see Section 15.1.2.29.
The patients’ WHO FC will be determined according to the WHO classification. Test results 
will be recorded on the eCRF. 
The person assessing the WHO FC must be suitably trained (referred to as “assessor” below).  
To ensure blinded assessment of the WHO FC from the randomization visit (baseline), the 
following adequate measures also need to be taken at the study center:

The assessor must be blinded to the study treatment of the patient

The assessor must not be involved in the process of study drug administration.

The assessor should record the test results on a separate work sheet and, where 
possible, a different person (could be the same person who is involved in the 
treatment administration) should enter them into the eCRF.
Ideally, the WHO FC assessment should always be performed by the same person.
For details on time points refer to Section 16.1, for further details on the assessment refer to 
Section 16.3.


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9.7.5
cMRI
cMRI will be performed on a subset of patients participating in this study. A separate manual 
will be produced and provided to the site.
Objective measurements of pulmonary hemodynamics assessed by RHC have been applied in 
PAH studies using primary endpoints, in which parameters of subjective nature were the main 
components (e.g., 6MWD or WHO FC). For the feasibility of this Phase 4 study, RHC 
investigation was not considered. Instead, as an alternative, cMRI was recommended because 
it is well standardized and provides an accurate and objective assessment of parameters of 
right ventricular function with established prognostic relevance. Based on the characteristics 
of this method, assessment will even be possible if a subset of patients from centers with 
expertise and technical requirements is to be included. The assessment of cMRI parameters is 
considered an important element of this study as it will provide essential complementary 
information on right ventricular function and remodeling; both of which are closely related to
the major study objectives and will therefore be relevant for supporting the interpretation of 
the clinical endpoints.
Appropriateness of procedures/measurements
9.8
All procedures and measurements are standard variables/methods in clinical studies and/or 
clinical practice. They are widely used and generally recognized as reliable, accurate and 
relevant.
10.
Statistical methods and determination of sample size
General considerations
10.1
All variables will be analyzed descriptively with appropriate statistical methods: categorical 
variables by frequency tables and continuous variables by sample statistics (mean, standard 
deviation, minimum, median, quartiles, and maximum). If not mentioned otherwise, all 
statistical tests will be performed with a type I two-sided error rate of 5%.
Statistical analyses will be performed using Statistical Analysis System (SAS) version 9.2 or 
later.
Analysis sets
10.2
Analyses will be performed for three analysis sets: full analysis set (FAS), per protocol set 
(PPS) and safety analysis set. The FAS will be the primary analysis set. 
All patients randomized and treated (at least one treatment after randomization) will be valid 
for the FAS, hence the number of patients in the safety and FAS will be identical. 
A patient is valid for the per protocol analysis, if the patient is valid for the safety analysis 
set/FAS, has an adequate investigation of all primary variable components at baseline and 


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shows no major protocol deviations (refer to the SAP for details on major protocol 
deviations).
Primary endpoint components are: assessments of clinical worsening (as defined in
Section 10.3.2.1), 6MWD, WHO FC, and NT-proBNP.
Final decisions regarding validity will be made during the Validity Review Meeting and 
documented in the Validity Review Report.
Variables and planned statistical analyses
10.3
10.3.1
Demographic and baseline characteristics
All demographic variables and baseline characteristics will be summarized for all analysis 
sets. Medical history findings and AEs will be coded according to the Medical Dictionary for 
Regulatory Activities (MedDRA) codes and medications by Anatomical Therapeutic 
Chemical class according to the WHO-Drug Dictionary (WHO-DD).
10.3.2
Efficacy endpoints
An efficacy analysis will be performed in patients valid for FAS (primary analysis) and PPS. 
Both groups (riociguat vs. active control) will be compared using a stratified Mantel-Haenzel 
test with a two-sided alpha level of 5%. Stratum is the disease class (definition see 
Section 7.3). 
The null hypothesis tested for the primary endpoint of efficacy is that there is no difference in 
the satisfactory clinical response rates (OR) when treated with riociguat compared to patients 
that remain on their previous therapy (i.e., H0: OR = 1). The two-sided alternative is that there 
is a difference (i.e., H1: OR ≠1). 
For statistical analysis of the primary endpoint with missing endpoint data, the last 
observation carried forward (LOCF) will be utilized. The reason for LOCF is given in the 
following: the primary endpoint measures improvements, thus, using LOCF will (a) not yield 
favorable results in the riociguat arm and (b) yield favorable results in the active control arm. 
Because of the inclusion criterion “stable on PDE5-i one expects the first case (a) to be much 
more frequent. Thus, LOCF is not in favor for the whole study. For composite endpoints each 
single component is independently replaced with the last available observation, respectively.
To assess the influence of missing data, a supportive analysis without LOCF will be 
performed with a generalized estimating equations approach (binomial distribution) utilizing 
all adequate investigations of all primary variable components at any time from including 
baseline up to Week 24. 


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Both methods above cover missing values of type ‘missing completely at random’. In this 
open-label study there might also be missing values of type ‘missing not at random’. To 
assess the influence of these missing values a sensitivity analysis is planned. A multiple 
imputation with penalty will be performed where the penalty is given by crossed 
improvement rates in both arms.

Riociguat arm: imputation with a clinical improvement rate observed in active 
control arm

Control arm: imputation with a clinical improvement rate observed in riociguat
arm
Thus, the highest sensible rate of clinical improvement is the rate in the riociguat arm and this 
is applied to the control arm in the imputation process. Further, the lowest sensible rate of 
clinical improvement is the rate in the control arm and this is applied to the riociguat arm in 
the imputation process.
Additionally, a tipping point analysis is performed (a detailed definition will be given in the 
SAP).
A multiplicity correction is not necessary for the primary endpoint because only one primary 
endpoint is defined. Secondary endpoints are tested hierarchically. An alpha level of 5% is 
used for secondary endpoints (each) as well as for exploratory endpoints.
The null hypothesis tested for the secondary efficacy endpoints is that there is no difference 
when treated with riociguat compared to patients who remain on their previous therapy. The 
two-sided alternative is that there is a difference, respectively (details are given in the SAP).
Primary efficacy endpoint - amended
10.3.2.1
This section was changed in Amendment 4, see Section 15.1.2.30.
The primary efficacy endpoint ‘satisfactory clinical response’ is defined as the composite 
endpoint comprising the following components (independent central adjudication):

2 of 3 must be fulfilled

6MWD increase by ≥10% or ≥30 m from baseline to Week 24

WHO FC I or II at Week 24

NT-proBNP reduction ≥30% from baseline to Week 24 (NT-proBNP ratio 
Week 24/baseline ≤0.7), AND

No clinical worsening (for definition, see below)
‘Satisfactory clinical response’ is defined as ‘YES’ only if the 2 major composites (‘2 of 3’ 
and ‘No clinical worsening’) are both ’YES’. The component ‘2 of 3’ is ‘YES’ if at least 2 of 
its 3 sub-components are ‘YES’. In all other cases ‘satisfactory clinical response’ is defined as 
‘NO’. The biomarker is given the same importance as the clinical parameters to introduce 
more objectivity to the endpoint and reduce possible open-label bias. 


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Definition of Clinical Worsening:

Death of any cause

Hospitalization due to worsening PAH (adjudicated)

Non-elective hospitalization due to PAH, or

Initiation of intravenous/subcutaneous prostanoid therapy.

Disease progression (adjudicated)

6MWD decrease ≥15% from baseline (2 measurements on 2 separate 
days), and

Worsening in WHO FC.
OR

6MWD decrease ≥15% (2 measurements on 2 separate days), and

Need of new PAH-targeted medication or decompensated right sided heart 
failure 1.
Secondary efficacy endpoints
10.3.2.2
Standard efficacy outcomes (hierarchical testing in the order specified below) at 
Week 24:

Change from baseline in 6MWD (blinded assessment, see Section 9.7.1)

Change from baseline in NT-proBNP

Change from baseline in WHO FC (blinded assessment, see Section 9.7.4)

Clinical worsening (for definition, see Section 10.3.2.1).
Exploratory endpoints
10.3.2.3
A complete list of variables to be analyzed for this study and the methods of analysis will be 
provided in the SAP. 

cMRI (core laboratory, reported separately)

Change from baseline in QoL: LPH (see Section 16.5)

Change from baseline in mRRS and mRRS category (see Section 16.4)

Change in other biomarkers (ADMA, cGMP, GDF-15 [plasma], ST-2).
                                                
1
Decompensated right-sided heart failure is defined as the appearance or worsening of signs/symptoms of 
right heart failure that did not respond to optimized oral diuretic therapy (need for intravenous diuretic 
therapy and/or inotropic drugs).


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10.3.3
Safety endpoints
Adverse events
The safety analysis will be performed in the population of patients valid for FAS. All 
tabulations will be descriptive only.
The incidence of treatment-emergent AEs will be tabulated overall. AEs are considered to be 
treatment-emergent if they have started or worsened after the first treatment administration up 
to 2 days after end of treatment. Further tables will be produced for serious and/or 
drug-related treatment-emergent AEs. The incidence of AEs during pre-treatment and during 
follow-up (i.e., AEs occurring more than 2 days after the end of treatment) will be tabulated 
separately.
Other safety parameters
Mortality in the study will be summarized descriptively. Any deaths in the study period will 
be listed, with 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 continuous laboratory parameters, and their changes from 
baseline by visit.
Descriptive analysis of vital signs, and their changes from baseline, will be performed by visit.
10.3.4
Subgroups
Subgroup analyses will be performed for following subgroups:

PAH class as defined in randomization strata

Pre-treatment with combination therapy with ERAs and PDE-5i versus 
pre-treatment with PDE-5i monotherapy

Gender 

6MWD at baseline

Pre-treatment with tadalafil or sildenafil.
Subgroup analyses will be applied on primary and secondary endpoints. Further details (e.g.,
thresholds) will be defined in the SAP.


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Determination of sample size
10.4
Sample size is determined based on results of Studies 12934/12935/16719 (PATENT-1/2, 
RESPITE) for riociguat. The estimate for the ‘satisfactory clinical response’ rate at Week 24 
is 40% for the riociguat arm. Assuming a treatment effect of 50% (relative reduction, see next 
subsections) to the active control the estimate for a ‘satisfactory clinical response’ in the active 
control arm is 20%. The sample size of 218 patients is calculated using SAS Version 9.2 (proc 
power, two-sample-frequency, χ2-test, two-sided alpha = 5%, power = 90%). 
The screening failure rate is estimated at 15% and therefore a screening number of 
257 patients is required. As it is planned to use LOCF for the primary analysis, no adjustment 
for dropouts is needed.
Estimate riociguat arm
The estimate for the ‘satisfactory clinical response’ rate at Week 24 is 40% for the riociguat 
arm. 
Table 10–1 presents the patient level analyses of Bayer’s PATENT-1/2 and RESPITE studies 
for Week 24. A satisfactory clinical outcome of 48.1% was observed on 231 patients of the 
individual titration arm. For the subset of pretreated patients with WHO FC III at baseline, the 
satisfactory clinical outcome was 41.6%. The latter subset was the closest PATENT-1/2 
subset to REPLACE. The RESPITE data, closest set to REPLACE, are in the same range with 
a focus in NT-proBNP; however, the number of patients is low. Given the fact that a slightly 
lower net effect due to the more effective treatment than in PATENT-1/2 is expected and a 
lower NT-proBNP reduction due to another baseline definition in RESPITE is expected, an 
assumption of 40% satisfactory clinical response is reasonable.
Table 10–1: Improvement of endpoints in PATENT-1/2 at Week 24 and RESPITE at Week 24 for 
all patients and the subgroup: pretreated and WHO FC III at baseline
Week 24 
PATENT-2
Week 24 PATENT-2
WHO FC III
Pre-treated = TRUE
Week 24 
RESPITE
Endpoint
Riociguat 
(N=231)
Riociguat (N=77)
Riociguat 
(N=30)
WHO
35.5
50.6
43.3
6MWD
64.1
53.2
43.3
NT-proBNP
42.9
23.4
66.7
Clinical worsening
3.0
3.9
13.3
Satisfactory Clinical 
Outcome
48.1
41.6
53.3
Abbreviations: 6MWD = 6-minute walking distance; N = number of patients; NT-proBNP 
= N-terminal pro-brain natriuretic peptide; WHO FC = World Health 
Organization Functional Class.
The numbers are the percentages of improvements in the categories. For example 
NT-proBNP: percentage of patients with a proBNP-reduction of 30% from baseline to 
follow-up. Placebo was skipped because patients were shifted to riociguat therapy. The 
pretreated subset of RESPITE is not shown due to the low number of patients.


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Estimate active control arm
For the active control arm, no reliable patient-level data for Week 24 exist, but endpoint-
related analyses for Week 12 are available based on PATENT-1 (Table 10–2). The 
satisfactory clinical response rates for the placebo patients in Week 12 are 8.3% for the total 
number (109 patients) and 3.3% (30 patients) for the subgroup, whereas the rates of the 
treatment arm are comparable to the Week 24 results. The placebo arm rates of the single 
endpoints are in the range of 15% to 30%. Thus, the low numbers of the satisfactory clinical 
response are due to a poor association of the single endpoints. Whether this low association is 
observed just by chance or is a systematical feature cannot be judged by this data solely. From 
a medical point of view a complete missing of association seems to be unrealistic. Therefore,
a conservative 20% satisfactory clinical response for the active control arm is assumed, 
postulating a higher association of the sub-endpoints in the REPLACE study. The high-level 
data given in AMBITION, GRIPHON, SERAPHIN and COMPASS-2 indicate a reasonable 
similarity to PATENT-1/2 data. The 50% reduction (100% improvement) assumed in this 
study (40% to >20%) is at the upper range of the observed effects in these studies, most of 
which analysed clinical worsening.
Table 10–2: Improvement of endpoints in PATENT-1/2 at Week 12 for all patients and the 
subgroup: pretreated and WHO FC III at baseline
Week 12
Week 12
WHO FC III
Pre-treated = TRUE
Endpoint
Riociguat 
(N=231)
Placebo 
(N=109)
Riociguat 
(N=77)
Placebo 
(N=30)
WHO
21.6
17.4
36.4
23.3
6MWD
50.6
31.2
44.3
23.3
NT-proBNP
42.9
14.7
26.0
16.7
Clinical worsening
0,0
0.0
0.0
0.0
Satisfactory Clinical Outcome
34.6
8.3
32.5
3.3
Abbreviations: 6MWD = 6-minute walking distance; N = number of patients; NT-proBNP = 
N-terminal pro-brain natriuretic peptide; WHO FC = World Health 
Organization Functional Class.
The numbers are the percentages of improvements in the categories. For example 
NT-ProBNP: percentage of patients with a proBNP-reduction of 30% from baseline to follow-
up. The data base is the subset which continued in the long term study Patent-2, which was 
required for the 24-week data. (Therefore, no clinical worsening was counted. The rates in 
PATENT-1 were very low, thus this endpoint has a very small impact in this analysis.)


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10.4.1
Sample size sensitivity
Additionally, a sensitivity analysis for the power has been performed where the rate of the 
active control arm is varied. The results are presented in Table 10–3 (assuming a sample size 
of 218 patients, 2-sided alpha = 5%, SAS 9.2, proc power, two-sample-frequency, χ2-test). 
Table 10–3: Sensitivity analysis
Planned interim analyses
10.5
No interim analysis is planned.
11.
Data handling and quality assurance
Data recording
11.1
It is the expectation of the sponsor that all data entered into the eCRF has source 
documentation available at the site. The site must implement processes to ensure this happens. 
A source document checklist will be used at the site to identify the source data for all data 
points collected and the monitor will work with the site to complete this.
Data recorded from screening failures
At a minimum, the following data should be recorded in the eCRF:

Demographic information (patient number; year of birth/age; sex; if applicable 
race/ethnicity)

Date of informed consent

Relevant inclusion/exclusion criteria

Reason for premature discontinuation

Date of last visit.
24-week satisfactory clinical 
response rate [%]
Relative improvement [%]
Approximate Power [%]
Riociguat
Active control
40
18
122.2
95.2
40
19
110.5
93.0
40
20
100.0
90.2
40
21
90.5
86.7
40
22
81.8
82.4
40
23
73.9
77.5
40
24
66.7
71.9
40
29
37.9
40.0


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These data will be transferred to the respective database.
For screening failures with an SAE, the following data should be collected in the eCRF in 
addition to the data specified above:

All information related to the SAE such as: 

The SAE itself

Concomitant medication

Medical history

Other information needed for SAE complementary page.
Monitoring
11.2
In accordance with applicable regulations, GCP, and sponsor’s/CRO’s procedures, monitors 
will contact the site prior to the start of the study to review with the site staff the protocol, 
study requirements, and their responsibilities to satisfy regulatory, ethical, and sponsor’s 
requirements. When reviewing data collection procedures, the discussion will also include 
identification and documentation of source data items.
The sponsor/designee will monitor the site activity to verify that the:

Data are authentic, accurate and complete.
Supporting data may be requested (example: blood glucose readings to support a 
diagnosis of diabetes)

Safety and rights of patients are being protected

Study is conducted in accordance with the currently approved protocol 
(including study treatment being used in accordance with the protocol)

Any other study agreements, GCP, and all applicable regulatory requirements are 
met.
The investigator and the head of the medical institution (where applicable) agrees to allow the 
monitor direct access to all relevant documents.
Data processing
11.3
Data will be collected as described in Section 11.1. Clinical data management will be 
performed in accordance with applicable sponsor’s/CRO’s standards and data cleaning 
procedures. This is applicable for data recorded in the eCRF as well as for data from other 
sources (e.g., IXRS, laboratory, ECG, adjudication committees).
For data coding (e.g., AEs, medication), internationally recognized and accepted dictionaries 
will be used.


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Missing data - amended
11.4
This section was changed in Amendment 4, see Section 15.1.2.31.
Due to the short period of the study, it is expected that the amount of missing data will only 
be minor. Every effort will be made to collect data until the EOT visit for all patients unless a 
patient withdraws consent and collection of further information is not allowed.
Audit and inspection
11.5
To ensure compliance with GCP and regulatory requirements, a member of the sponsor’s (or a 
designated CRO’s) quality assurance unit may arrange to conduct an audit to assess the 
performance of the study at the study site and of the study documents originating there. The 
investigator/institution will be informed of the audit outcome.
In addition, inspections by regulatory health authority representatives and IECs/IRBs are 
possible. The investigator should notify the sponsor immediately of any such inspection.
The investigator/institution agrees to allow the auditor or inspector direct access to all relevant 
documents and allocate his/her time and the time of his/her staff to the auditor/inspector to 
discuss findings and any issues. Audits and inspections may occur at any time during or after 
completion of the study.
Archiving
11.6
Essential documents shall be archived safely and securely in such a way that ensures that they 
are readily available upon authorities’ request.
Patient (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. Where 
the archiving procedures do not meet the minimum timelines required by the sponsor, 
alternative arrangements must be made to ensure the availability of the source documents for 
the required period.
The investigator/institution notifies the sponsor if the archival arrangements change 
(e.g., relocation or transfer of ownership).
The investigator site file is not to be destroyed without the sponsor’s approval.
The contract with the investigator/institution will contain all regulations relevant for the study 
center.


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12.
Premature termination of the study
The sponsor has the right to close this study (or, if applicable, individual segments thereof 
[e.g., treatment arms; dose steps; centers]) at any time, which may be due but not limited to 
the following reasons: 

If risk-benefit ratio becomes unacceptable owing to, for example,

Safety findings from this study (e.g., SAEs)

Results of parallel clinical studies

Results of parallel animal studies 
(on e.g., toxicity, teratogenicity, carcinogenicity or reproduction toxicity).

If the study conduct (e.g., recruitment rate; dropout rate; data quality; protocol 
compliance) does not suggest a proper completion of the study within a reasonable 
time frame.
The investigator has the right to close his/her center at any time.
For any of the above closures, the following applies:

Closures should occur only after consultation between involved parties. Final 
decision on the closure must be in writing.

All affected institutions (e.g., IECs/IRBs; competent authority(ies); study center; 
head of study center) must be informed as applicable according to local law.

All study materials (except documentation that has to remain stored at site) must 
be returned to the sponsor. The investigator will retain all other documents until 
notification is given by the sponsor for destruction.

In the event of a partial study closure, ongoing patients must be taken care of in an 
ethical manner.
Details for individual patient’s withdrawal can be found in Section 6.3.1.
13.
Ethical and legal aspects
Investigator(s) and other study personnel - amended
13.1
This section was changed in Amendment 4, see Section 15.1.2.33.
All other study personnel not included in this section are identified in a separate personnel list 
(not part of this clinical study protocol) as appropriate. This list will be updated as needed; an 
abbreviated version with personnel relevant for the centers will be available in each center’s 
investigator site file.
Whenever the term ‘investigator’ is noted in the protocol text, it may refer to either the 
principal investigator at the site, or an appropriately qualified, trained and delegated 
individual of the investigational site.


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The principal investigator of each center must sign the protocol signature page and must 
receive all required external approvals (e.g., health authority, IEC/IRB, sponsor) before 
patient recruitment may start at the respective center. Likewise, all amendments to the 
protocol must be signed by the principal investigator and must have received all required 
external approvals 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 sponsor’s study file.
The global sponsor of this study is identified on the title page of this protocol. If required by 
local law, local co-sponsors will be nominated; they will be identified on the respective 
country-specific signature pages.
External data evaluation bodies
Advisory Committee
The Advisory Committee has guided the development of the study concept and protocol. It 
will also provide feedback and expert advice on any modification/amendment of the protocol 
as well as on the conduct of the study. It will be kept updated on all new relevant information 
during study conduct and all relevant information on riociguat safety and efficacy that may 
influence the study.
The Advisory Committee is composed of experts in PH.
Clinical Endpoint Committee 
An independent Clinical Endpoint Committee (CEC) will review and confirm the correctness 
of the assessments of clinical worsening (see Section 10.3.2.1) as well as of the other 
components of the primary endpoint in a blinded fashion. In the situation where despite all 
efforts to ensure protocol compliance, a second 6MWD could not be performed as 
confirmation of clinical worsening of PAH, the CEC will adjudicate on the clinical 
worsening. 
Details of the CEC will be provided in a separate charter.
Central Laboratory
Analyses of biomarkers will be performed centrally by the sponsor. For details please refer to 
the Laboratory Manual.
Funding and financial disclosure
13.2
Funding
This study will be funded by its sponsor.
Financial disclosure 
Each investigator (including principal and/or any sub investigators) who is directly involved 
in the treatment or evaluation of research patients has to provide a financial disclosure 


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according to all applicable legal requirements. All relevant documentation will be filed in the 
study master file.
Ethical and legal conduct of the study
13.3
The procedures set out in this protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the sponsor and investigator abide by 
GCP guidelines and 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 IECs/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 the sponsor. The responsible unit (e.g., IEC/IRB, head 
of the study center/medical institution) must supply to the sponsor, upon request, a list of the 
IEC/IRB members involved in the 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 the sponsor or the 
investigator without agreement by both parties. However, the investigator or the sponsor may 
implement a deviation from, or a change of, the protocol to eliminate an immediate hazard(s) 
to the patients without prior IEC/IRB/sponsor 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/sponsor. Any deviations from the protocol must be explained and documented by 
the investigator.
Details on discontinuation of the entire study or parts thereof can be found in Section 12.
Patient information and consent - amended
13.4
This section was changed in Amendment 4, see Section 15.1.2.34.
All relevant information on the study will be summarized in an integrated patient information 
sheet and ICF provided by the sponsor or the study center. A sample patient information and 
ICF is provided as a document separate to this protocol.
Based on this patient information sheet, the investigator or designee will explain all relevant 
aspects of the study to each patient, prior to his/her entry into the study (i.e., before any 
examinations and procedures associated with the selection for the study are performed or any 
study-specific data is recorded on study-specific forms).
The investigator will also mention that written approval of the IRB/IEC has been obtained.


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Each patient will be informed about the following aspects of premature withdrawal:
Each patient has the right to withdraw from the study at any time without any 
disadvantage and without having to provide reasons for this decision.
The patient’s consent covers EOT assessments as specified in the visit description 
described in Section 9.2.7 to be conducted after withdrawal of consent.
The patient’s data that have been collected until the time of withdrawal will be retained 
and statistically analyzed in accordance with the SAP. 
Patient-specific data on the basis of material obtained before withdrawal may be generated 
after withdrawal (e.g., image reading, analysis of biological specimen such as blood, urine 
or tissues); these data would also be retained and statistically analyzed in accordance with 
the SAP. The patient has the right to object to the generation and processing of this post-
withdrawal data. The patient’s oral objection may be documented in the patient’s source 
data.
Each patient will have ample time and opportunity to ask questions.
Only if the patient voluntarily agrees to sign the ICF and has done so, may he/she enter the 
study. Additionally, the investigator will personally sign and date the form. The patient/legal 
representative or proxy consenter will receive a copy of the signed and dated form.
The signed ICF is to remain in the investigator site file or, if locally required, in the patient’s 
note/file of the medical institution.
In the event that informed consent is obtained on the date that screening study procedures are 
performed, the study record or patient’s clinical record must clearly show that informed 
consent was obtained prior to these procedures. 
If the patient is not capable of providing a signature, a verbal statement of consent can also be 
given in the presence of an impartial witness (independent of the sponsor and the 
investigator). This is to be documented by a signature from the informing physician as well as 
by a signature from the witness.
The ICF and any other written information provided to the patients will be revised whenever 
important new information becomes available that may be relevant to the patient’s consent, or 
there is an amendment to the protocol that necessitates a change to the content of the patient 
information and/or the written ICF. The investigator will inform the patient/legal 
representative or proxy consenter of changes in a timely manner and will ask the patient to 
confirm his/her participation in the study by signing the revised informed consent form. Any 
revised written informed consent form and written information must receive the IEC/IRB’s 
approval/favorable opinion in advance of use.


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Publication policy and use of data
13.5
The sponsor has made the information regarding the study protocol publicly available on the 
internet at www.clinicaltrials.gov. 
All data and results and all intellectual property rights in the data and results derived from the 
study will be the property of the sponsor who may utilize them in various ways, such as for 
submission to government regulatory authorities or disclosure to other investigators.
Regarding public disclosure of study results, the sponsor will fulfill its obligations according 
to all applicable laws and regulations. The sponsor is interested in the publication of the 
results of every study it performs.
The sponsor recognizes the right of the investigator to publish the results upon completion of 
the study. However, the investigator, whilst free to utilize study data derived from his/her 
center for scientific purposes, must obtain written consent of the sponsor on the intended 
publication manuscript before its submission. To this end, the investigator must send a draft 
of the publication manuscript to the sponsor within a time period specified in the contract.
The sponsor will review the manuscript promptly and will discuss its content with the 
investigator to reach a mutually agreeable final manuscript.
Compensation for health damage of patients/insurance
13.6
The sponsor maintains clinical study insurance coverage for this study in accordance with the 
laws and regulations of the country in which the study is performed.
Confidentiality
13.7
All records identifying the patient will be kept confidential and, to the extent permitted by the 
applicable laws and/or regulations, will not be made publicly available.
Patient names will not be supplied to the sponsor. Only the patient number will be recorded in 
the eCRF, and if the patient name appears on any other document (e.g., pathologist report), it 
must be obliterated before a copy of the document is supplied to the sponsor. Study findings 
stored on a computer will be stored in accordance with local data protection laws. As part of 
the informed consent process, the patients will be informed in writing that representatives of 
the sponsor, IEC/IRB, or regulatory authorities may inspect their medical records to verify the 
information collected, 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 patient’s identity will remain confidential.
The investigator will maintain a list to enable patients to be identified.


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14.
Reference list
1.
Ghofrani HA, Galiè N, Grimminger F, Grünig E, Humbert M, Jing ZC, Keogh AM, 
Langleben D, Kilama MO, Fritsch A, Neuser D, Rubin LJ; PATENT-1 Study Group. 
Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013 Jul 
25;369(4):330-40.
2.
Vachiéry JL, Simonneau G. Management of severe pulmonary arterial hypertension. Eur 
Respir Rev. 2010 Dec;19(118):279-87.
3.
Task Force for Diagnosis and Treatment of Pulmonary Hypertension of European Society 
of Cardiology (ESC); European Respiratory Society (ERS); International Society of Heart 
and Lung Transplantation (ISHLT), Galiè N, Hoeper MM, Humbert M, Torbicki A, 
Vachiery JL, Barbera JA, Beghetti M, Corris P, Gaine S, Gibbs JS, Gomez-Sanchez MA, 
Jondeau G, Klepetko W, Opitz C, Peacock A, Rubin L, Zellweger M, Simonneau G. 
Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J. 2009 
Dec;34(6):1219-63.
4.
Stasch JP, Pacher P, Evgenov OV. Soluble guanylate cyclase as an emerging therapeutic 
target in cardiopulmonary disease. Circulation. 2011 May 24;123(20):2263-73.
5.
McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, Mathier 
MA, McGoon MD, Park MH, Rosenson RS, Rubin LJ, Tapson VF, Varga J; American 
College of Cardiology Foundation Task Force on Expert Consensus Documents; 
American Heart Association; American College of Chest Physicians; American Thoracic
Society, Inc; Pulmonary Hypertension Association. ACCF/AHA 2009 expert consensus 
document on pulmonary hypertension a report of the American College of Cardiology 
Foundation Task Force on Expert Consensus Documents and the American Heart 
Association developed in collaboration with the American College of Chest Physicians; 
American Thoracic Society, Inc.; and the Pulmonary Hypertension Association. J Am 
Coll Cardiol. 2009 Apr 28;53(17):1573-619.
6.
Leuchte HH, Schwaiblmair M, Baumgartner RA, Neurohr CF, Kolbe T, Behr J. 
Hemodynamic response to sildenafil, nitric oxide, and iloprost in primary pulmonary 
hypertension. Chest. 2004 Feb;125(2):580-6.
7.
Chockalingam A, Gnanavelu G, Venkatesan S, Elangovan S, Jagannathan V, 
Subramaniam T, Alagesan R, Dorairajan S. Efficacy and optimal dose of sildenafil in 
primary pulmonary hypertension. Int J Cardiol. 2005 Mar 10;99(1):91-5.
8.
Oudiz R, Shapiro S, Torres F, Feldman J, Frost A, Allard M, Blair C, Gillies H. 
ATHENA-1: Hemodynamic Improvements Following the Addition of Ambrisentan to 
Background PDE-5i Therapy in Patients With Pulmonary Arterial Hypertension. CHEST. 
October 2011;140(4_MeetingAbstracts):905A-905A.
9.
Badesch DB, Raskob GE, Elliott CG, Krichman AM, Farber HW, Frost AE, Barst RJ, 
Benza RL, Liou TG, Turner M, Giles S, Feldkircher K, Miller DP, McGoon MD. 
Pulmonary arterial hypertension: baseline characteristics from the REVEAL Registry. 
Chest. 2010 Feb;137(2):376-87.


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10. Hoeper MM, Markevych I, Spiekerkoetter E, Welte T, Niedermeyer J. Goal-oriented 
treatment and combination therapy for pulmonary arterial hypertension. Eur Respir J. 
2005 Nov;26(5):858-63.
11. Sitbon O, Humbert M, Nunes H, Parent F, Garcia G, Hervé P, Rainisio M, Simonneau G. 
Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: 
prognostic factors and survival. J Am Coll Cardiol 2002;40:780e788.
12. Benza RL, Miller DP, Gomberg-Maitland M, Frantz RP, Foreman AJ, Coffey CS, Frost 
A, Barst RJ, Badesch DB, Elliott CG, Liou TG, McGoon MD. Predicting survival in 
pulmonary arterial hypertension: insights from the Registry to Evaluate Early and Long-
Term Pulmonary Arterial Hypertension Disease Management (REVEAL). Circulation. 
2010 Jul 13;122(2):164-72.
13. Nickel N, Golpon H, Greer M, Knudsen L, Olsson K, Westerkamp V, Welte T, Hoeper 
MM. The prognostic impact of follow-up assessments in patients with idiopathic 
pulmonary arterial hypertension. Eur Respir J. 2012 Mar; 39(3):589-96.
14. Simonneau G, Gatzoulis MA, Adatia I, Celermajer D, Denton C, Ghofrani A, et al. 
Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2013 Dec 
24;62(25 Suppl):D34-41.
15. Galie N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, Simonneau G, 
Peacock A, Noordegraaf AV, Beghetti M, Ghofrani A, Sanchez MAG , Hansmann G, 
Klepetko W, Lancellotti P, Matucci M, McDonagh T, Pierard LA, Trindade PT, 
Zompatori M, Hoeper M.  2015 ESC/ERS Guidelines for the diagnosis and treatment of 
pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of 
Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European 
Respiratory Society (ERS). Eur Respir J. 2015; 46: 903-975.
16. Macintyre N, Crapo RO, Viegi G, Johnson DC, van der Grinten CP, Brusasco V, Burgos 
F, Casaburi R, Coates A, Enright P, Gustafsson P, Hankinson J, Jensen R, McKay R, 
Miller MR, Navajas D, Pedersen OF, Pellegrino R, Wanger J. Standardisation of the 
single-breath determination of carbon monoxide uptake in the lung. Eur Respir J. 2005;
26(4):720-35.
17. American Thoracic Society. ATS Statement: Guidelines for Six-Minute Walk Test. 
American Journal of Respiratory and Critical Care Medicine 2002; Vol 166. pp 111-117.
18. American College of Chest Physicians. Diagnosis and Management of Pulmonary 
Arterial Hypertension: ACCP Evidence-Based Clinical Practice Guidelines. Chest 2004; 
126; 7-10s.


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15.
Protocol amendments
Amendment 4
15.1
Amendment 4 is the first global amendment dated 6 JAN 2017. The following is an overview 
of the changes made to the original Protocol Version 1.0.
15.1.1
Overview of changes
The original protocol was amended for the following reasons:
1). Administrative changes (e.g. addition of sponsor for US territory [Bayer HealthCare 
Pharmaceuticals Inc.], which is and has been sponsor for US territory for this study as set 
forth in FDA Investigational New Drug (IND) form 1571; the reference on the protocol 
was incomplete in this regard)
2). To reiterate that the benefit-risk balance for the population in this study (i.e. pulmonary 
arterial hypertension [PAH], Dana Point Group 1) is positive, despite the potential safety 
issue in Study 13605 in patients with PH-IIP (Dana Point Group 3) which had led to its 
early termination
3). To add the requirement for adequate use of effective contraceptive methods during this 
study
4). To include other  biomarkers (in addition to NT-proBNP) at the request of the advisory 
committee, to further elucidate the value of selected NO-pathway related biomarkers for 
treatment decision in this controlled study and in comparison with biomarker results from 
the previous, uncontrolled RESPITE study
5). To include details for consistency with the Company Core Data Sheet (e.g. titration rules) 
and other studies using riociguat (e.g. extending the time for collecting AE information) 
6). To improve clarity and correct typographical errors, inconsistencies and unintended 
omissions.
Sections affected include:

Section 1
Title page

Section 2
Synopsis

Section 3
Introduction

Section 5
Study design

Section 6.1
Inclusion criteria

Section 6.2
Exclusion criteria

Section 6.3.1 Withdrawal

Section 6.3.1.1
Discontinuation of study treatment


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
Section 6.3.1.2
Discontinuation of study

Section 7.1
Treatments to be administered

Section 7.2
Identity of study treatment

Section 7.3
Treatment assignment

Section 8.1
Prior and concomitant therapy

Section 8.2
Post-study therapy

Section 9.2.1 Mandatory screening period (Week -2 ± 2 days, Visit 0)

Section 9.2.2 Randomization (Baseline visit, Week 0, Visit 1

Section 9.2.3 Visit 2 (Week 8 ± 2 days

Section 9.2.4 Telephone Contact (Week 12 ± 2 days)

Section 9.2.5 Visit 3 (Week 16 ± 2 days

Section 9.2.6 Telephone Contact (Week 20 ± 2 days)

Section 9.2.7 Visit 4 / End of Treatment (EOT) (Week 24 ± 4 days

Section 9.2.8 Safety follow-up visit (30 days ± 5 days)

Section 9.6.1.3
Assessments and documentation of adverse events

Section 9.6.1.5
Expected adverse events

Section 9.6.1.6
Adverse events of special safety interest

Section 9.6.3.4
Laboratory assessments

Section 9.7.1 Pulse oximetry

Section 9.7.3 6MWD test

Section 9.7.4 Determination of WHO FC

Section 10.3.2.1 Primary efficacy endpoint

Section 11.4
Missing data

Section 13.1
Investigator(s) and other study personnel

Section 13.4
Patient information and consent

Section 16.1
Schedule of procedures

Section 16.2
6 Minute Walking Distance (6MWD) Test.


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15.1.2
Changes to the protocol text
In this section, 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 protocol version preceding this 
amendment.
Deletions are crossed out in the “old text”. Additions are underlined in the “new text”.
Corrections of typographical errors or omissions are not highlighted in this amendment.
Section 1
Title page
15.1.2.1
Old text:
Study title: 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.
Short title: Riociguat rEplacing PDE-5i therapy evaLuated Against Continued PDE-5i 
thErapy
Acronym: REPLACE
Test drug:
BAY 63-2521/ riociguat / Adempas
Study purpose:
To demonstrate the effectiveness of riociguat as replacement of 
PDE-5i therapy in PAH patients
Clinical study phase:
4
Date:
31 MAY 2016
Registration:
EudraCT: no. 2016-001067-36 Version no.:
1.0
Sponsor’s study no.:
IMPACT no. 18588
Sponsor:
Bayer AG, D-51368 Leverkusen, Germany
[…]


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New text:
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.
Riociguat rEplacing PDE-5i therapy evaLuated Against Continued PDE-5i thErapy
REPLACE
Test drug:
BAY 63-2521/ riociguat / Adempas
Study purpose:
To demonstrate the effectiveness of riociguat as replacement of 
PDE-5i therapy in PAH patients
Clinical study phase:
4
Date:
6 JAN 2017
Registration:
EudraCT: no. 2016-001067-36 Version no.:
2.0
Sponsor’s study no.:
18588
Sponsor:
Non- US territory: Bayer AG, D-51368 Leverkusen, Germany
US territory: Bayer HealthCare Pharmaceuticals Inc.,
100 Bayer Boulevard, P.O. Box 915, Whippany 
NJ 07981-0915, USA
[…]
Section 2
Synopsis
15.1.2.2
Old text:
Diagnosis and main criteria for 
inclusion /exclusion
[…]
Patients with symptomatic PAH according to WHO FC III and 6MWD of 
165-440 m at screening and at randomization, with a pulmonary vascular 
resistance (PVR) of > 400 dyn*sec*cm-5, mean pulmonary artery pressure 
≥25 mmHg, and pulmonary capillary wedge pressure (PCWP) ≤15 mmHg 
as assessed by right heart catheterization within 12 months prior to screening. 
Alternatively, PCWP can be replaced by left ventricular end-diastolic 
pressure.
[…]
New text:
Diagnosis and main criteria for 
inclusion /exclusion
[…]
Patients with symptomatic PAH according to WHO FC III and 6MWD of 
165-440 m at screening and at randomization, with a pulmonary vascular 
resistance (PVR) of > 400 dyn*sec*cm-5, mean pulmonary artery pressure 
≥25 mmHg, and pulmonary capillary wedge pressure (PCWP) ≤15 mmHg 
as assessed by right heart catheterization in medical history prior to screening 
to confirm the diagnosis. Alternatively, PCWP can be replaced by left 
ventricular end-diastolic pressure.
[…]


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Section 3
Introduction
15.1.2.3
Old text:
[…]
The RESPITE study was conducted to investigate whether it is safe, feasible, and beneficial to 
replace PDE-5i therapy with riociguat in PAH patients demonstrating insufficient response to 
PDE-5 inhibition. Interim analysis data of this hypothesis-generating single arm study showed 
that patients failing to respond to PDE-5i could benefit from replacing a PDE-5i with 
riociguat by improving 6MWD, WHO FC, and NT-proBNP. The data indicate that transition 
of PDE-5i to riociguat may serve as a treatment strategy for PAH patients.
However, a randomized controlled study is required to confirm the potential clinical benefit of 
transition.
Benefit-risk assessment
[…]
The overall benefit-risk balance of riociguat is considered positive if used in adherence to this 
clinical study protocol and in accordance with the recommendations and guidance given in the 
Investigator’s Brochure (IB). […]
New text:
[…]
The RESPITE study was conducted to investigate whether it is safe, feasible, and beneficial to 
replace PDE-5i therapy with riociguat in PAH patients demonstrating insufficient response to
PDE-5 inhibition. The final data of this hypothesis-generating single arm study showed that
patients failing to respond to PDE-5i could benefit from replacing a PDE-5i with riociguat by 
improving 6MWD, WHO FC, and NT-proBNP. The data indicate that transition of PDE-5i to 
riociguat may serve as a treatment strategy for PAH patients.
The rationale of the study is to confirm the potential clinical benefit of switch within the 
NO-sGC-cGMP pathway in a randomized controlled study.
Benefit-risk assessment
[…]
Recently, results of a study on efficacy and safety of riociguat in patients with pulmonary 
hypertension associated with idiopathic interstitial pneumonias (PH-IIP) showed an increased 
risk of mortality and serious adverse events among patients who received riociguat compared 
to those who received placebo, and an absence of apparent clinical benefit.  The study was 
terminated early upon the advice of its data monitoring committee (DMC).  It was concluded 
that the benefit risk balance of riociguat in patients with PH-IIP is negative.  Riociguat is 
contraindicated in patients with PH-IIP.


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The REPLACE study (18588) will only include patients with subtypes of Pulmonary Arterial 
Hypertension (PAH), Dana Point Group 1 (14). Patients with all other types of PH/ Dana 
Point Groups are excluded, also comprising patients with PH-IIP, according to the protocol.
The overall benefit-risk balance of riociguat is considered positive if used in adherence to this 
clinical study protocol and in accordance with the recommendations and guidance given in the 
Investigator’s Brochure (IB). […]
Section 5
Study design
15.1.2.4
Old text:
[…]


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Figure 5-1: Study Design Overview
EOS
Abbreviations: EOS = End of Study; FU = Follow-up; N = number of patients; TID = three times daily.


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[…]
Titration period (Riociguat arm, duration: 8 weeks)
[…]
The investigators will apply the following blood pressure (BP) based titration rules for their 
dose decision:
The individual riociguat dose will be titrated under consideration of the following algorithm 
(= individual dose titration scheme):

If trough SBP 95 mmHg, increase dose (+ 0.5 mg TID)

If trough SBP 90 to 94 mmHg, maintain dose

If trough SBP < 90 mmHg without symptoms of hypotension, reduce dose (- 0.5 mg 
TID)

If any SBP < 90 mmHg with clinical symptoms of hypotension such as dizziness or 
presyncope, stop treatment; restart after 24 hours with reduced dose (- 0.5 mg TID).
[…]
Premature discontinuation of study treatment
In case of premature discontinuation of study treatment, the process detailed in Section 6.3.1
should be followed.
End of Study (Week 24 ± 2 days)
At the last visit of the maintenance period, i.e., at the EOS visit, all relevant efficacy and 
safety measurements will be performed.
Safety follow-up phase (30 days ± 5 days)
A safety follow-up (FU) visit 30 days (± 5 days) after discontinuation of treatment intake 
should be performed for both arms.
[…]
Justification of the design
[…]
End of Study
The end of the study as a whole will be reached as soon as the end of the study according to 
the above definition has been reached in all participating countries (European Union [EU] and 
non-EU).
[…]
New text:
[…]


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Figure 5-1: Study Design Overview
EOT 
Abbreviations: EOT = End of Treatment; FU = Follow-up; N = number of patients; TID = three times daily.


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[…]
Titration period (Riociguat arm, duration: 8 weeks)
[…]
The investigators will apply the following blood pressure (BP) based titration rules for their 
dose decision:
Dosage should be increased in 2-week intervals by 0.5 mg increments to a 
maximum of 2.5 mg three times daily, if SBP is ≥95 mmHg and the patient has 
no signs or symptoms of hypotension. If SBP falls below 95 mmHg, dosage should be 
maintained provided the patient does not show any signs or symptoms of hypotension. 
If at any time during the up-titration phase systolic blood pressure decreases below 
95 mmHg, and the patient shows signs or symptoms of hypotension, the current dose 
should be decreased by 0.5 mg tid.
[…]
Premature discontinuation of study treatment
In case of premature discontinuation of study treatment, the process detailed in Section 6.3.1.1
should be followed.
Visit 4 / End of Treatment (EOT) (Week 24 ± 4 days)
All patients randomized to either treatment arm should perform Visit 4 / EOT.  This is the last 
visit of the maintenance period, when all relevant efficacy and safety measurements will be 
performed.
Safety Follow-Up (FU) visit (30 days ± 5 days after last intake of study treatment)
A safety FU visit is to be performed 30 days (± 5 days) after the planned end of study 
treatment OR 30 days (± 5 days) after premature discontinuation of study treatment.
Justification of the design
[…]
While it may appear inappropriate to randomize patients who are not “at treatment goal” to 
the control arm, where their current PAH-specific treatment regimen will just be continued, 
in the absence of a clear definition of treatment response, the definition for this study is 
inspired by the ESC/ ERS table for assessment (15) and based on 6MWD and WHO FC only.  
Other parameters of prognostic relevance including pulmonary hemodynamics may well be in 
the range of low risk/ at treatment goal according to guidelines. It can be assumed that a large 
number of patients on mono-or combination therapy with PAH-targeted drugs are in a stable 
clinical situation, but do not reach WHO FC I/II or a 6MWD > 440 m. Clinical stability at 
randomization will be ensured by requirements such as stable doses of PAH-therapy and 


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diuretics, and the mandatory 14-day screening period. By this, the study design intends to 
represent the real-life clinical situation of PAH patients, in which close follow-up of 
prognostically relevant parameters is required for the decision on a next step of treatment 
escalation. As there will be rater-blinded assessments and central adjudication, but no 
blinding of the study treatment arms, the investigator will at any time be able to decide about 
any necessary treatment escalation. Thus, even treatment of a patient randomized to the 
control or maintenance arm will stringently follow treatment guidelines.      
End of Study
The end of the study as a whole will be reached as soon as the last safety FU visit of the last 
patient according to the above definition has been reached in all participating countries 
(European Union [EU] and non-EU).
[…]
Section 6.1
Inclusion criteria
15.1.2.5
Old text:
2. Patients with symptomatic PAH with a pulmonary vascular resistance (PVR) 
> 400 dyn*sec*cm-5, mean pulmonary artery pressure ≥25 mmHg, and pulmonary 
capillary wedge pressure (PCWP) ≤15 mmHg as assessed by the most recent right 
heart catheterization (RHC) within 12 months prior to screening. Alternatively, PCWP 
can be replaced by left ventricular end-diastolic pressure (≤15 mmHg).
[…]
7. Patients who are able to understand and follow instructions and who are able to 
participate in the study for the entire study.
8. Patients must have given their written informed consent to participate in the study 
after having received adequate previous information and prior to any study-specific 
procedures.
New text:
2. Patients with symptomatic PAH with a pulmonary vascular resistance (PVR) 
> 400 dyn*sec*cm-5, mean pulmonary artery pressure ≥25 mmHg, and pulmonary 
capillary wedge pressure (PCWP) ≤15 mmHg as assessed by the most recent right 
heart catheterization (RHC) from medical history prior to screening to confirm the 
diagnosis. Alternatively, PCWP can be replaced by left ventricular end-diastolic 
pressure (≤15 mmHg).
[…]


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7. Patients who are able to understand and follow instructions and who are able to 
participate in the study for the entire study.
8. Women 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 1 is a physical barrier (e.g. 
condom with hormonal contraception like implants or combined oral contraceptives, 
condom with intrauterine devices). This applies beginning with signing of the 
informed consent form until 30 (+5) days after the last administration of study drug.
9. Patients must have given their written informed consent to participate in the study 
after having received adequate previous information and prior to any study-specific 
procedures.
Section 6.2
Exclusion criteria
15.1.2.6
Old text:
[…]
4. Pregnant women (i.e., positive serum ß-human-chorionic-gonadotropin test or other
signs of pregnancy), or breast feeding women, or women with childbearing potential 
not using a combination of safe contraception methods.
[…]
11. Participation at a supportive physical training program, defined as a structured 
exercise and rehabilitation program supervised by a physician and/or a physiotherapist 
is not allowed during the pretreatment and the treatment phase of the study (up to the 
EOS visit).
[…]
13. Exclusion criteria related to pulmonary disease:
a.
All types of PH except subtypes of Dana Point Group I specified in the inclusion 
criteria.  
[…]
14. Exclusion criterion related to hypoxia (pulse oximeter at rest):
a.
Peripheral capillary oxygen saturation (SpO2) < 88% despite supplemental 
oxygen therapy (< 4 L/min) at rest.
[…]
16. Exclusion criteria related to disorders in organ function:
[…]
b.
Signs of severe hepatic insufficiency (e.g., impaired albumin synthesis, with an 
albumin < 25 g/L, hepatic encephalopathy > Grade 3), and/or
[…]


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New text:
[…]
4. Pregnant women (i.e., positive serum ß-human-chorionic-gonadotropin test or other 
signs of pregnancy), or breast feeding women, or women with childbearing potential 
not using a combination of 2 effective contraception methods (as laid out in inclusion 
criterion no. 8) throughout the study.
[…]
11. Participation at a supportive physical training program, defined as a structured 
exercise and rehabilitation program supervised by a physician and/or a physiotherapist 
within 12 weeks prior to screening. Participants enrolled in an exercise program for 
pulmonary rehabilitation > 12 weeks prior to screening may enter the study if they 
agree to maintain their current level of rehabilitation during the screening and the 
24 weeks of the study.
[…]
13. Exclusion criteria related to pulmonary disease:
a.
All types of PH (including PH-IIP) except subtypes of Dana Point Group I 
specified in the inclusion criteria.  
[…]
14. Exclusion criterion related to hypoxia (pulse oximeter at rest):
a.
Peripheral capillary oxygen saturation (SpO2) < 88% despite supplemental 
oxygen therapy (<= 4 L/min) at rest.
[…]
16. Exclusion criteria related to disorders in organ function:
[…]
c.
Signs of severe hepatic insufficiency (Child Pugh C), and/or
[…]


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Section 6.3.1
Withdrawal
15.1.2.7
Old text:
Study treatment (riociguat or control) discontinuation for any reason does not represent 
withdrawal from the study and should not result in withdrawal of the patient from the study.
[…]
Depending on the time point of withdrawal, a withdrawn patient is referred to as either 
“screening failure” or “dropout” as specified below:
[…]
New text:
6.3.1.1
Discontinuation of study treatment
Study treatment (riociguat or control) discontinuation for any reason does not represent 
withdrawal from the study and should not result in withdrawal of the patient from the study.
[…]
6.3.1.2
Discontinuation of study
Depending on the time point of withdrawal, a withdrawn patient is referred to as either 
“screening failure” or “dropout” as specified below:
[…]
Section 6.3.1.1 Discontinuation of study treatment
15.1.2.8
Old text:
Study treatment (riociguat or control) discontinuation for any reason does not represent 
withdrawal from the study and should not result in withdrawal of the patient from the study. 
Patients who prematurely discontinue from the study treatment will still be followed up for 
collection of safety and efficacy data until the EOS visit. If a patient refuses to continue with 
the remaining visits, the EOS visit will be performed as soon as the study treatment was 
discontinued. This will include all efficacy and safety relevant measurements that would have 
been performed at the EOS visit (at Week 24).
In all cases, the reason for temporary or permanent study treatment discontinuation must be 
recorded in the electronic case report form (eCRF) and in the patient’s medical records.
Patients may decide to withdraw their consent to participate in the study and to no longer 
attend study visits and take the study treatment (if not already discontinued); they may object 
to generation and processing of post-study treatment discontinuation data. Patient decision 
will be recorded in the eCRF. Patients who withdraw from the study will have the vital status 
(alive or dead) reported in the eCRF at EOS (Week 24). The contact can be by visit, phone or 
e-mail, and also by family members. Every effort should be made to contact the patient by 
telephone at the times the study visits were scheduled for the remaining duration of the study, 


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to determine if any of the primary, secondary, or other endpoints have been reached. All 
attempts to retrieve information about the patients should be documented in the subject’s 
records. In addition to withdrawing their consent for attending the study visits, patients may 
also object to releasing any other information regarding their health status. For this, the 
patient must sign a corresponding declaration of objection; alternatively, the patient’s oral 
objection may be documented in the source data. In such cases, every effort should be made 
to obtain vital status (alive or dead) information through consultation of public databases, 
wherever allowed by local regulations.
Withdrawal criteria
Patients must be withdrawn from study treatment if any of the following occurs:

At their own request or at the request of their legally acceptable representative. At 
any time during the study and without giving reasons, a patient may decline to 
participate further. The patient will not suffer any disadvantage as a result.

If, in the investigator’s opinion, continuation of the study treatment would be 
harmful to the patient’s well-being.

Occurrence of adverse events (AEs) or intercurrent diseases which the investigator 
judges unacceptable for continuation of participation in the study.

Occurrence of adverse drug reactions, which have from the investigator’s point of 
view, a negative impact on the patient’s individual risk-benefit ratio. (Investigators 
are obliged to reassess the patient’s individual risk-benefit ratio on a continuous 
basis. Factors like anticipated treatment effect, progression of underlying disease, 
occurrence of side effects and alternative treatment options have to be considered).

Pertinent non-compliance with the conditions for the study or instructions by the 
investigator
[…]
Although not preferred, patients may interrupt their intake of study treatment due to 
reasonable circumstances/reasons at any time (e.g., hospitalization in a remote hospital 
without study treatment access, safety reasons, side effects). If an interruption lasts longer 
than 14 days in a row, it is at the discretion of the investigator to discontinue the study 
participation, and the eCRF of the termination visit /EOS visit must be completed.
[…]


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New text:
6.3.1.1
Discontinuation of study treatment
Study treatment (riociguat or control) discontinuation for any reason does not represent 
withdrawal from the study and should not result in withdrawal of the patient from the study.  
Please see definitions for premature discontinuation from the study in Section 6.3.1.2.
Patients who prematurely discontinue from the study treatment will still be followed up for 
collection of safety and efficacy data at Visit 4 / EOT at Week 24 (± 4 days) and should also 
perform the safety FU visit at 30 days (± 5 days) after the last intake of study drug.  Note that 
the safety FU visit may occur before Visit 4 / EOT if premature discontinuation from 
treatment occurs early during the study.
In all cases, the reason for study treatment discontinuation must be recorded in the electronic 
case report form (eCRF) and in the patient’s medical records.
Patients may decide to withdraw their consent to participate in the study and to no longer 
attend study visits and take the study treatment (if not already discontinued); they may object 
to generation and processing of post-study treatment discontinuation data. Patient decision 
will be recorded in the eCRF. Patients who withdraw from the study will have the vital status 
(alive or dead) reported in the eCRF at Visit 4 / EOT. The contact can be by visit, phone or 
e-mail, and also by family members. Every effort should be made to contact the patient by 
telephone at the times the study visits were scheduled for the remaining duration of the study, 
to determine if any of the primary, secondary, or other endpoints have been reached. All 
attempts to retrieve information about the patients should be documented in the patient’s 
records. In addition to withdrawing their consent for attending the study visits, patients may 
also object to releasing any other information regarding their health status. For this, the 
patient must sign a corresponding declaration of objection; alternatively, the patient’s oral 
objection may be documented in the source data. In such cases, every effort should be made 
to obtain vital status (alive or dead) information through consultation of public databases, 
wherever allowed by local regulations.
Criteria for withdrawal from study treatment
Patients must be withdrawn from study treatment if any of the following occurs:

At their own request or at the request of their legally acceptable representative. At 
any time during the study and without giving reasons, a patient may decline to 
participate further. The patient will not suffer any disadvantage as a result.

If, in the investigator’s opinion, continuation of the study treatment would be 
harmful to the patient’s well-being.

Occurrence of adverse events (AEs) or intercurrent diseases which the investigator 
judges unacceptable for continuation of participation in the study.

Occurrence of adverse drug reactions, which have from the investigator’s point of 
view, a negative impact on the patient’s individual risk-benefit ratio. (Investigators 
are obliged to reassess the patient’s individual risk-benefit ratio on a continuous 


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basis. Factors like anticipated treatment effect, progression of underlying disease, 
occurrence of side effects and alternative treatment options have to be considered).

In case a patient is diagnosed with pulmonary veno-occlusive disease (PVOD) 
while on treatment with study drug, the administration of riociguat has to be 
stopped immediately

Pertinent non-compliance with the conditions for the study or instructions by the 
investigator
[…]
Although not preferred, patients may interrupt their intake of study treatment due to 
reasonable circumstances/reasons at any time (e.g., hospitalization in a remote hospital 
without study treatment access, safety reasons, side effects). If an interruption lasts longer 
than 14 days in a row, it is at the discretion of the investigator to discontinue the study 
participation, and the eCRF of the early termination visit must be completed.
[…]
Section 6.3.1.2 Discontinuation of study
15.1.2.9
Old text:
[…]
Dropout
A patient who discontinues study participation prematurely for any reason after randomization 
is defined as a “dropout”.
New text:
[…]
Dropout
A patient who discontinues study participation prematurely for any reason after randomization 
is defined as a “dropout”.  If a patient prematurely discontinues study treatment and does 
not wish to continue with the remaining scheduled visits, the investigator should take 
all possible effort to complete a final evaluation, and the patient should be asked for his 
agreement to schedule an early termination visit as soon as possible, at which time point 
all assessments scheduled for Visit 4 / EOT are to be performed.


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Section 7.1
Treatments to be administered
15.1.2.10
Old text:
[…]
The starting dose is 1 mg TID; the intervals between drug intakes should be 6 to 8 hours.
[…]
New text:
[…]
Note that patients randomized to the riociguat arm will have a washout period before starting 
titration period of riociguat (see “wash-out period” in Section 5 for details). The starting dose 
is 1 mg TID; the intervals between drug intakes should be 6 to 8 hours.
[…]
Section 7.2
Identity of study treatment
15.1.2.11
Old text:
Riociguat will be labeled according to the requirements of local law and legislation. Label text 
will be approved according to the sponsor’s agreed procedures, and a copy of the labels will 
be made available to the study site upon request.  
[…]
See Table 7-1 for details on the study treatment.
Treatment administered in the control arm is considered standard of care.
Table 7-1:
Identity of investigational product
International non-proprietary 
name (INN)
Riociguat 
[…]
[…]
[…]
Storage requirements:
[…]
No special storage conditions are required. 
New text:
All study drugs (investigational medicinal products [IMP]) will be labeled according to the 
requirements of local law and legislation. Label text will be approved according to the 


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sponsor’s agreed procedures, and a copy of the labels will be made available to the study site 
upon request.
[…]
See Table 7-1 for details on the study treatment.
Treatment administered in the control arm (tadalafil, sildenafil) is considered standard of care.
Table 7-1:
Identity of investigational products
Riogicuat arm
International non-proprietary 
name (INN)
Riociguat 
[…]
[…]
Control arm
Tadalafil
Material name
ADCIRCA 20MG 56 TAB
Active substance
Tadalafil
Formulation
Film-coated tablets
Description
Amygdaloid, debossed with 4467 on one side
Strength
20mg, 40mg
Dosage unit
20mg/tablet
Mode of administration
Oral
Packaging
Wallet containing 5 blister, each blister containing 14 tablets 
(total of 70 tablets)
Sildenafil
Material name
REVATIO 20MG TAB B90 GER
Active substance
Sildenafil citrate
Formulation
Film-coated tablets
Description
Round biconvex, debossed with RVT 20 on one side and Pfizer 
on the other
Strength
Daily doses of 60mg, 80mg, 100mg, 120mg, 140mg, 160mg, 
180mg, 200mg, 220mg, 240mg, 260mg, 280mg, 300mg
Dosage unit
20mg/tablet
Mode of administration
Oral
Packaging
Wallet containing 6 blister, each blister containing 15 tablets 
(total of 90 tablets)
[…]
Storage requirements:
[…]
No special storage conditions are required for Riociguat.   Please note that PDE5i must be 
stored below 30°C.


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Section 7.3
Treatment assignment
15.1.2.12
Old text:
[…]
All eligible patients randomized to the riociguat arm will receive a starting dose of riociguat 
of 1 mg TID in this open-label study. The starting dose of 1 mg may be down-titrated to 
0.5 mg at the discretion of the investigator and at any point during the 8-week titration period.
Patients randomized to the control arm will remain on their current PAH-specific treatment. 
Patients on specific combination therapy with PDE-5i and ERA need to continue taking ERA
at a stable dose in both treatment arms.
New text:
[…]
Following washout (see “wash-out period” in Section 5 for details), all eligible patients 
randomized to the riociguat arm will receive a starting dose of riociguat of 1 mg TID in this 
open-label study. The starting dose of 1 mg may be down-titrated to 0.5 mg at the discretion 
of the investigator and at any point during the 8-week titration period.
Patients randomized to the control arm will remain on their current PAH-specific treatment. 
Patients on combination therapy with ERA need to continue at a stable dose in both treatment 
arms.
Section 8.1
Prior and concomitant therapy
15.1.2.13
Old text:
[…]
The intake of the following concomitant medication is not allowed within 30 days prior 
to and at randomization:

PCA by any administration route within 30 days before randomization (except for 
vasoreactivity testing).
Patients, who require respective medications (except for PCA) need to be withdrawn from the 
study drug (refer to Section 6.3.1).
Specific PAH medication:
Dose changes in PAH-specific medication (i.e., PDE-5i or ERA) should be avoided during the 
study. Dose changes considered clinically necessary by the investigator need to be 
documented. Notably hospitalization for initiation of intravenous or subcutaneous prostanoid 
therapy fulfills the criterion of clinical worsening, as does disease progression with a need for 
any additional specific PAH targeted medication. If possible, the patient should remain in the 


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study for follow-up of vital status even if escalation of PAH therapy is required to maintain or 
improve the clinical status of the patient. The decision to keep the patient in the study is at the 
discretion of the investigator.
[…]
New text:
[…]
The intake of the following concomitant medication is not allowed within 30 days prior 
to and at randomization:

PCA and PRA by any administration route within 30 days before randomization 
(except for vasoreactivity testing).
Specific PAH medication:
Dose changes in PAH-specific medication (i.e., PDE-5i or ERA) should be avoided during the 
study. Dose changes considered clinically necessary by the investigator need to be 
documented. Notably hospitalization for initiation of intravenous or subcutaneous prostanoid 
therapy fulfills the criterion of clinical worsening, as may disease progression with a need for 
any additional specific PAH targeted medication (see also Section 10.3.2.1 for Definition of 
Clinical Worsening). The patient may remain in the study even if escalation of PAH therapy 
is required to maintain or improve the clinical status of the patient. The decision to keep the 
patient in the study is at the discretion of the investigator
[…]
Section 8.2
Post-study therapy
15.1.2.14
Old text:
After treatment with riociguat, further treatment and dosage will be decided by the 
investigator at the EOS visit.  In case riociguat is indicated for further treatment, patients will 
be prescribed Adempas.
[…]
New text:
Further medical treatment of patients at the end of the study will be decided by the 
investigator at Visit 4 / EOT.  In case riociguat is indicated for further treatment, patients will 
be prescribed riociguat / Adempas.
[…]


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Section 9.2.1
Mandatory screening period (Week -2 ± 2 days, Visit 0)
15.1.2.15
Old text:

[…]

Lung function test (see exclusion criterion 13 in Section 6.2)

Blood gases (see exclusion criterion 14 in Section 6.2)

[…]

Pregnancy test (women of childbearing potential only; see Section 9.6.3.4)

[…]
New text:

[…]

Lung function test (see exclusion criterion 13 in Sections 6.2 and 9.7.2)

Pulse oximetry (see exclusion criterion 14 in Sections 6.2 and 9.7.1)

[…]

Pregnancy test (women of childbearing potential only; see Section 9.6.2)

[…]
Section 9.2.2
Randomization (Baseline visit, Week 0, Visit 1
15.1.2.16
Old text:

Inclusion/exclusion criteria (see Sections 6.1 and 6.2)

Smoking status, including number of cigarettes per day 

Specific PAH medication (see Section 8.1)

Pregnancy test (women of childbearing potential only, see Section 9.6.3.4)

6MWD test (blinded assessment, see Section 9.7.1)

Biomarker NT-proBNP (central laboratory; see Section 9.6.3.4)

WHO FC (blinded assessment, see Section 9.7.4)

mRRS (see Section 16.4)

LPH (QoL) questionnaire, provided at start of each visit (see Section 16.5)

[…]
[…]


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Patients randomized to the riociguat arm
Riociguat will be dispensed (note the wash-out period for riociguat arm, see Section 7.4).
[…]
Riociguat dosing start
Based on the time of the last PDE-5i dose, date and time of the first dose of riociguat after the 
wash-out period will be determined by the investigator and communicated to the patient. 
Before the first dose of riociguat, BP measurements need to be performed to ensure that SBP 
is ≥95 mmHg. If the BP is below this value, riociguat must not be administered (BP 
measurement may be repeated within the next 24 hours). Measurement of BP and 
application of first riociguat dose may be performed at the study center, or by an experienced 
nurse in the outpatient setting (see Section 9.6.3.2).
[…]
Home Visits 1, 2, 3 (Weeks 2, 4, 6 ± 2 days)
[…]
Based on the vital signs and wellbeing of the patient, the investigator will decide about the 
dose adjustment of riociguat, and enter it into IXRS and retrieve a new dose box number. 
[…]
New text:

Inclusion/exclusion criteria (see Sections 6.1 and 6.2)

Pulse oximetry (see exclusion criterion 14 in Section 6.2 and Section 9.7.1) 

Smoking status, including number of cigarettes per day 

Specific PAH medication (see Section 8.1)

Pregnancy test (women of childbearing potential only, see Section 9.6.2)

6MWD test (blinded assessment, see Section 9.7.1)

Biomarkers (central laboratory; see Section 9.6.3.4)

WHO FC (blinded assessment, see Section 9.7.4)

mRRS (see Section 16.4)

LPH (QoL) questionnaire (see Section 16.5)

[…]
[…]
Patients randomized to the riociguat arm
Riociguat will be dispensed (note the dose titration scheme for riociguat arm, see Figure 7–1).
[…]


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Riociguat dosing start
Based on the time of the last PDE-5i dose, date and time of the first dose of riociguat after the 
wash-out period will be determined by the investigator and communicated to the patient. 
Before the first dose of riociguat, BP measurements need to be performed to ensure that SBP 
is ≥95 mmHg. If the BP is below this value, riociguat must not be administered (BP 
measurement may be repeated within the next 24 hours). Measurement of BP and 
application of first riociguat dose may be performed at the study center or by an experienced 
nurse at home (see Section 9.6.3.2).
[…]
Home Visits 1, 2, 3 (Weeks 2, 4, 6 ± 2 days)
[…]
In the riociguat arm, the investigator will decide about the dose adjustment of riociguat based 
on the vital signs and wellbeing of the patient, enter it into the IXRS and retrieve a new dose 
box number (initial dose adjustment period, see Section 7.4). 
[…]
Section 9.2.3
Visit 2 (Week 8 ± 2 days
15.1.2.17
Old text:

[…]

Drug accountability (see treatment compliance in Section 7.7)

6MWD (blinded assessment, see Section 9.7.1)

NT-proBNP (central laboratory; see Section 9.6.3.4)

[…]
New text:

[…]

Drug accountability (see treatment compliance in Section 7.7)

Dose of riociguat (see Section 7.4)

6MWD (blinded assessment, see Section 9.7.1)

Biomarkers (central laboratory; see Section 9.6.3.4)

[…]


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Section 9.2.4
Telephone Contact (Week 12 ± 2 days)
15.1.2.18
Old text:

[…]

Pregnancy test (women of childbearing potential only; see Section 9.6.3.4)

[…]
New text:

[…]

Pregnancy test (women of childbearing potential only; see Section 9.6.2)

[…]
Section 9.2.5
Visit 3 (Week 16 ± 2 days
15.1.2.19
Old text:

[…]

Pregnancy test (women of childbearing potential only; see Section 9.6.3.4)

Dispense of study medication (see Section 7.4)

Drug accountability (see treatment compliance in Section 7.7)

6MWD (blinded assessment, see Section 9.7.1)

NT-proBNP (Central lab; see Section 9.6.3.4) 

WHO FC (blinded assessment, see Section 9.7.4)

mRRS (see Section 16.4)

Safety laboratory measurements (Local lab; Section 9.6.3.4)

[…]
New text:

[…]

Pregnancy test (women of childbearing potential only; see Section 9.6.2)

Dispense of study medication (see Section 7.4)

Drug accountability (see treatment compliance in Section 7.7)

Dose of riociguat (see Section 7.4)

6MWD (blinded assessment, see Section 9.7.1)

Biomarkers (central laboratory; see Section 9.6.3.4)

WHO FC (blinded assessment, see Section 9.7.4)


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
mRRS (see Section 16.4)

Safety laboratory measurements (local laboratory; Section 9.6.3.4)

[…]
Section 9.2.6
Telephone Contact (Week 20 ± 2 days)
15.1.2.20
Old text:

[…]

Pregnancy test (women of childbearing potential only; see Section 9.6.3.4)

[…]
New text:

[…]

Pregnancy test (women of childbearing potential only; see Section 9.6.2)

[…]
Section 9.2.7
Visit 4 / End of Treatment (EOT) (Week 24 ± 4 days)
15.1.2.21
Old text:
9.2.7
End of Study (Week 24 ± 5 days)
The EOS visit will be performed at Week 24 ± 5 days after the last dose of riociguat, 
sildenafil or tadalafil, and a decision on further treatment will be made.
The following procedures will be performed:

[…]

Pregnancy test (women of childbearing potential only; see Section 9.6.3.4)

[…]

NT-proBNP (Central lab; see Section 9.6.3.4)

WHO FC (blinded assessment, see Section 9.7.4)

mRRS (see Section 16.4)

LPH (QoL) questionnaire, provided at start of each visit (see Section 16.5)

[…]


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New text:
9.2.7
Visit 4 / End of Treatment (EOT) (Week 24 ± 4 days)
The Visit 4 / EOT visit will be performed at Week 24 ± 4 days after the last dose of riociguat, 
sildenafil or tadalafil, and a decision on further treatment will be made.
The following procedures will be performed:

[…]

Pregnancy test (women of childbearing potential only; see Section 9.6.2)

[…]

Biomarkers (central laboratory; see Section 9.6.3.4)

WHO FC (blinded assessment, see Section 9.7.4)

mRRS (see Section 16.4)

LPH (QoL) questionnaire (see Section 16.5)

[…]
Section 9.2.8
Safety follow-up visit (30 days ± 5 days)
15.1.2.22
Old text:

[…]

Pregnancy test (women of childbearing potential only; see Section 9.6.3.4)

[…]
New text:

[…]

Pregnancy test (women of childbearing potential only; see Section 9.6.2)

[…]
Section 9.6.1.3 Assessments and documentation of adverse events
15.1.2.23
Old text:
The investigator has to record on the respective eCRF pages (additionally to the source data) 
all AEs occurring in the period between the signing of the informed consent and at the end of 
study visit; after the end of study visit, there is no requirement to actively collect AEs, 
including deaths. The type of information that should be assessed and recorded by the 
investigator for each AE is listed in Section 9.6.1.2. 
[…]


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New text:
The investigator has to record on the respective eCRF pages (additionally to the source data) 
all AEs occurring in the period between the signing of the informed consent and the safety FU 
visit at 30 days (± 5 days) after last intake of study treatment (for details, please also refer to 
Sections 5 and 16.1); after that, there is no requirement to actively collect AEs, including 
deaths. The type of information that should be assessed and recorded by the investigator for 
each AE is listed in Section 9.6.1.2.
[…]
Section 9.6.1.5 Expected adverse events
15.1.2.24
Old text:
For this study, the applicable reference document is the most current version of the IB.
[…]
New text:
For this study, the applicable reference document is the most current version of the IB 
for Adempas and the EU SmPC / local SPC for Revatio (sildenafil) and Adcirca (tadalafil).  
[…]
Section 9.6.1.6 Adverse events of special safety interest
15.1.2.25
Old text:
Symptomatic hypotension and serious hemoptysis are considered AEs of special interest and 
must be reported to Bayer within the same timelines as an SAE by reporting them on the AE 
page of the eCRF. […]
New text:
Symptomatic hypotension and serious hemoptysis (which includes pulmonary hemorrhage)
are considered AEs of special interest and must be reported to Bayer within the same 
timelines as an SAE by reporting them on the AE page of the eCRF.  […]
Section 9.6.3.4 Laboratory assessments
15.1.2.26
Old text:
The following parameters may be included:

Hematology: white blood cell differential count, erythrocytes, hemoglobin, hematocrit, 
platelets

Coagulation tests: prothrombin time, only for patients under anticoagulation therapy

Clinical chemistry: AST, ALT, total bilirubin, serum albumin, creatinine, potassium.


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NT-proBNP

NT-proBNP will be analyzed centrally at the time points specified in Section 16.1.
[…]
New text:
The following safety laboratory parameters will be measured in the local laboratory:

Hematology: white blood cell differential count, erythrocytes, hemoglobin, hematocrit, 
platelets

Coagulation tests: prothrombin time (INR), only for patients under anticoagulation 
therapy

Clinical chemistry: AST, ALT, total bilirubin, serum albumin, creatinine, potassium. 
The following biomarkers will be analyzed in the central laboratory:

NT-proBNP

ADMA

cGMP (from plasma)

GDF-15

ST-2.
All time points for collection of safety laboratory parameters and biomarker are provided in 
Section 16.1.
[…]
In women of childbearing potential, pregnancy tests in urine or blood will be performed at the 
local laboratory, at the time points specified in Section 16.1.


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Section 9.7.1
Pulse oximetry
15.1.2.27
Old text:
9.7.1
Blood gas analysis
SaO2 (%), PaO2 (mmHg), PaCO2 (mmHg) will be measured by capillary or arterial blood gas 
analysis at screening.
If the patient receives supplemental oxygen, the amount [L/min] will be recorded in the eCRF.
Blood gases are to be obtained from the arterial blood or from arterialized capillary blood. All 
samples should be obtained with the patient resting in a sitting or supine position for at least 
10 min. If possible no supplementary oxygen should be given during the resting period and 
while blood samples are drawn. If the patient requires oxygen, care should be taken that all 
samples are drawn with the same flow of oxygen throughout the study whenever possible. 
The measured values have to be transferred into the eCRF.
Blood gas measurement:

Actual time

Date

SaO2 [%]

PaO2 [mmHg]

PaCO2 [mmHg].
New text:
9.7.1
Pulse oximetry
The patient’s oxygen saturation will be measured with a noninvasive method expressing the 
SpO2 (peripheral oxygen saturation) percentage.
If the patient receives supplemental oxygen, the amount [L/min] will be recorded in the 
eCRF.
Section 9.7.3
6MWD test
15.1.2.28
Old text:
The 6MWD test will be performed in accordance with the American Thoracic Society 
Guideline (17). The test will be performed 4 hours after the previous dose. Test results will be 
recorded on the eCRF. 
To ensure a blinded assessment from the randomization visit (baseline), adequate measures 
need to be taken at the study center when performing the 6MWD:

The test has to be performed by a physician or study nurse who is blinded to the 
study treatment of the patient.


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
The person performing the test must not be involved in the process of study drug 
administration, and must be unaware of the immediate reaction of the patient’s BP 
and heart rate after dosing.

The person performing the test should record the results on a separate work sheet 
and, where possible, a different person (could be the person who is involved in the 
study treatment administration) should enter them into the eCRF.
For details on time points refer to Section 16.1, for further details on assessment refer to 
Section 16.2.
New text:
The 6MWD test will be performed in accordance with the American Thoracic Society 
Guideline without assessing Borg-Dyspnoea-Index (17).  Test results will be recorded on the 
eCRF. 
To ensure a blinded assessment from the randomization visit (baseline), adequate measures 
need to be taken at the study center when performing the 6MWD:

The test has to be performed by a physician or study nurse who is blinded to the 
study treatment of the patient.

The person performing the test must not be involved in the process of study drug 
administration.

The person performing the test should record the results on a separate work sheet 
and, where possible, a different person (could be the person who is involved in the 
study treatment administration) should enter them into the eCRF.
For details on time points refer to Section 16.1, for further details on assessment refer to 
Section 16.2.


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Section 9.7.4
Determination of WHO FC
15.1.2.29
Old text:
The patients’ WHO FC will be determined according to the WHO classification. Test results 
will be recorded on the eCRF. 
To ensure blinded assessment of the WHO FC from the randomization visit (baseline), 
adequate measures need to be taken at the study center:

The physician must be blinded to the study treatment of the patient.

The physician must not be involved in the process of study drug administration 
and be unaware of the immediate reaction of the patient’s BP and heart rate after 
dosing.

The physician should record the test results on a separate work sheet and, where 
possible, a different person (could be the same person who is involved in the 
treatment administration) should enter them into the eCRF.
Ideally, the WHO FC assessment should always be performed by the same person.
For details on time points refer to Section 16.1, for further details on the assessment refer to 
Section 16.3.
New text:
The patients’ WHO FC will be determined according to the WHO classification. Test results 
will be recorded on the eCRF. 
The person assessing the WHO FC must be suitably trained (referred to as “assessor” below).  
To ensure blinded assessment of the WHO FC from the randomization visit (baseline), the 
following adequate measures also need to be taken at the study center:

The assessor must be blinded to the study treatment of the patient

The assessor must not be involved in the process of study drug administration.

The assessor should record the test results on a separate work sheet and, where 
possible, a different person (could be the same person who is involved in the 
treatment administration) should enter them into the eCRF.
Ideally, the WHO FC assessment should always be performed by the same person.
For details on time points refer to Section 16.1, for further details on the assessment refer to 
Section 16.3.


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Section 10.3.2.1
Primary efficacy endpoint
15.1.2.30
Old text:
Definition of Clinical Worsening:

….

Disease progression (adjudicated)

6MWD decrease ≥15% from baseline (2 measurements on 2 separate 
days), and

Worsening in WHO FC.
OR

6MWD decrease ≥15% (2 measurements on 2 separate days), and

Need of new PAH-targeted medication or decompensated right sided heart 
failure.
New text:
Definition of Clinical Worsening:

….

Disease progression (adjudicated)

6MWD decrease ≥15% from baseline (2 measurements on 2 separate 
days), and

Worsening in WHO FC.
OR

6MWD decrease ≥15% (2 measurements on 2 separate days), and

Need of new PAH-targeted medication or decompensated right sided heart 
failure 1.
Footnote 1 added: Decompensated right-sided heart failure is defined as the appearance or 
worsening of signs/symptoms of right heart failure that did not respond to 
optimized oral diuretic therapy (need for intravenous diuretic therapy and/or 
inotropic drugs)


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Section 10.3.2.3
Exploratory endpoints
15.1.2.31
Old text:
A complete list of variables to be analyzed for this study and the methods of analysis will be 
provided in the SAP. 

cMRI (core laboratory, reported separately)

Change from baseline in QoL: LPH (see Section 16.5)

Change from baseline in mRRS and mRRS category (see Section 16.4).
New text:
A complete list of variables to be analyzed for this study and the methods of analysis will be 
provided in the SAP. 

cMRI (core laboratory, reported separately)

Change from baseline in QoL: LPH (see Section 16.5)

Change from baseline in mRRS and mRRS category (see Section 16.4)

Change in other biomarkers (ADMA, cGMP, GDF-15 [plasma], ST-2).
Section 11.4
Missing data
15.1.2.32
Old text:
Due to the short period of the study, it is expected that the amount of missing data will only 
be minor. Every effort will be made to collect data until the EOS visit for all patients unless a 
patient withdraws consent and collection of further information is not allowed.
New text:
Due to the short period of the study, it is expected that the amount of missing data will only 
be minor. Every effort will be made to collect data until the EOT visit for all patients unless a 
patient withdraws consent and collection of further information is not allowed.


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Section 13.1
Investigator(s) and other study personnel
15.1.2.33
Old text:
[…]
Central Laboratory
Analyses of NT-proBNP will be performed centrally by the sponsor. For details please refer 
to the Laboratory Manual. 
New text:
[…]
Central Laboratory
Analyses of biomarkers will be performed centrally by the sponsor. For details please refer to 
the Laboratory Manual. 
Section 13.4
Patient information and consent
15.1.2.34
Old text:
[…]
Each patient will be informed about the following aspects of premature withdrawal:
Each patient has the right to withdraw from the study at any time without any 
disadvantage and without having to provide reasons for this decision. 
The patient’s consent covers EOS assessments as specified in the visit description 
described in Section 9.2.7 to be conducted after withdrawal of consent.
[…]
New text:
[…]
Each patient will be informed about the following aspects of premature withdrawal:
Each patient has the right to withdraw from the study at any time without any 
disadvantage and without having to provide reasons for this decision. 
The patient’s consent covers EOT assessments as specified in the visit description 
described in Section 9.2.7 to be conducted after withdrawal of consent.
[…]


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Section 16.1
Schedule of procedures
15.1.2.35
Old text:
Measurement
Mandatory
Screening 
period
(2 weeks) 
Rando-
mization
(baseline)
Overall treatment period (24 weeks) 
Follow-up 
phase
Visit
V 0
V 1 a
H 1 b
H 2 b
H 3 b
V 2 c
Tele-
phone 
contact d
V 3
Tele-
phone 
contact d
EOS
Safety 
FU e
Week/Days
W -2
(± 2 D)
W 0
(± 2 D)
W 2
(± 2 D)
W 4
(± 2 D)
W 6
(± 2 D)
W 8
(± 2 D)
W 12
(± 2 D)
W 16
(± 2 D)
W 20
(± 2 D)
W 24
(± 5 D)
30 D
(± 5 D)
[…]
Echocardiography 
(LVEF)
X
[…]
Dispense of riociguat
medication g
X
X
X
X
X
X
[…]
NT-proBNP (central 
lab)
X
X
X
X
[…]
LPH (QoL) l
X
X
Abbreviations: 6MWD = 6-minute walking distance; AE = adverse event; cMRI = cardiac magnetic resonance imaging; D = Days; ECG = 
electrocardiogram; EOS = end of study; FU = Follow-up; LVEF = left ventricular ejection fraction; mRRS = modified Reveal Risk 
Score; NT-proBNP = N-terminal pro-brain natriuretic peptide; LPH =Living with Pulmonary Hypertension Questionnaire; PAH = 
Pulmonary Arterial Hypertension; QoL = Quality of Life; W = Week; WHO FC = World Health Organization Functional Class.
[…]


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e Safety Follow-up visit after last dose of study drug. 
[…]
g For the riociguat arm IXRS consultation IXRS consultation will be performed to supply drug.
[…]
k This will be performed by the core laboratory and reported separately.
l To be performed if not available within last 6 months. 


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New text:
Measurement
Mandatory
Screening 
period
(2 weeks) 
Rando-
mization
(baseline)
Overall treatment period (24 weeks) 
Follow-up 
visit
Visit
V 0
V 1 a
H 1 b
H 2 b
H 3 b
V 2 c
Tele-
phone 
contact d
V 3
Tele-
phone 
contact d
V4
/ EOT
e
Safety 
FU e
Week/Days
W -2
(± 2 D)
W 0
(± 2 D)
W 2
(± 2 D)
W 4
(± 2 D)
W 6
(± 2 D)
W 8
(± 2 D)
W 12
(± 2 D)
W 16
(± 2 D)
W 20
(± 2 D)
W 24
(± 4 D)
30 D
(± 5 D)
[…]
Echocardiography 
(LVEF) l
X
[…]
Dispense study 
medication g
X
X
X
X
X
X
[…]
Biomarkers
(central laboratory);
see Section 9.6.3.4)
X
X
X
X
[…]
LPH (QoL)
X
X
Abbreviations: 6MWD = 6-minute walking distance; AE = adverse event; cMRI = cardiac magnetic resonance imaging; D = Days; ECG = 
electrocardiogram; EOT = end of treatment; FU = Follow-up; LVEF = left ventricular ejection fraction; mRRS = modified Reveal 
Risk Score; NT-proBNP = N-terminal pro-brain natriuretic peptide; LPH =Living with Pulmonary Hypertension Questionnaire; PAH 
= Pulmonary Arterial Hypertension; QoL = Quality of Life; W = Week; WHO FC = World Health Organization Functional Class.
[…]


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e Safety FU visit at 30 days (±5 days) after last dose of study drug.  Note that although the safety FU visit is depicted above as occurring after 
Visit 4 / EOT, the safety FU visit may be performed before Visit 4 / EOT if a patient prematurely discontinues study treatment early in the 
study. If a patient prematurely discontinues study treatment and does not wish to continue with the remaining scheduled visits, an early 
termination visit should be agreed upon as soon as possible, and all activities scheduled for Visit 4 / EOT should be performed during this 
visit.
[…]
g For the riociguat arm IXRS consultation will be performed at every visit that involves dispense of study medication (V1, H1, H2, H3, V2 and V3).
  For the control arm, IXRS consultation will only be performed by sites which source the comparator centrally at V1, V2 and V3.
[…]
k This will be performed by the core laboratory and reported separately, only at selected sites.  The cMRI should be performed at V1 or 
within 5 days before randomization.
[…]
l To be performed if not available within last 6 months from screening. 


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Section 16.2
6 Minute Walking Distance (6MWD) Test
15.1.2.36
Old text:
The 6MWD test must be performed in accordance with the American Thoracic Society 
Guideline (17).
To ensure a blinded assessment, it has to be performed by a second person who is not 
involved in the process of study drug titration and is unaware of the immediate reaction of the 
patient’s BP and heart rate after dosing.
[…]
New text:
The 6MWD test must be performed in accordance with the American Thoracic Society 
Guideline without assessing Borg-Dyspnoea-Index (17).
To ensure a blinded assessment, it has to be performed by a second person who is not 
involved in the process of study drug dispensation or is unaware of the treatment arm.
[…]


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16.
Appendices
Schedule of procedures – amended
16.1
This section was changed in Amendment 4, see Section 15.1.2.35.
Measurement
Mandatory
Screening 
period
(2 weeks) 
Rando-
mization
(baseline)
Overall treatment period (24 weeks) 
Follow-up 
visit
Visit
V 0
V 1 a
H 1 b
H 2 b
H 3 b
V 2 c
Tele-
phone 
contact d
V 3
Tele-
phone 
contact d
V4
/ EOT
e
Safety 
FU e
Week/Days
W -2
(± 2 D)
W 0
(± 2 D)
W 2
(± 2 D)
W 4
(± 2 D)
W 6
(± 2 D)
W 8
(± 2 D)
W 12
(± 2 D)
W 16
(± 2 D)
W 20
(± 2 D)
W 24
(± 4 D)
30 D
(± 5 D)
Rio 
Start 
Informed consent
X
Check of inclusion/
exclusion criteria
X
X
Lung function test
X
Pulse oximetry
X
X
Echocardiography 
(LVEF) l
X
Medical history
X
Smoking status
X
X
X
X
X
X
X
X
X
Specific PAH 
medication
X
X
Demographics
X
Pregnancy test f
X
X
X
X
X
X
X
X
X
Physical 
examination
X
X
Weight and height
X
Dispense study 
X
X
X
X
X
X


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Measurement
Mandatory
Screening 
period
(2 weeks) 
Rando-
mization
(baseline)
Overall treatment period (24 weeks) 
Follow-up 
visit
Visit
V 0
V 1 a
H 1 b
H 2 b
H 3 b
V 2 c
Tele-
phone 
contact d
V 3
Tele-
phone 
contact d
V4
/ EOT
e
Safety 
FU e
Week/Days
W -2
(± 2 D)
W 0
(± 2 D)
W 2
(± 2 D)
W 4
(± 2 D)
W 6
(± 2 D)
W 8
(± 2 D)
W 12
(± 2 D)
W 16
(± 2 D)
W 20
(± 2 D)
W 24
(± 4 D)
30 D
(± 5 D)
Rio 
Start 
medication g
Drug accountability
X
X
X
X
X
X
6MWD (blinded) h
X i
X
X
X
X
Biomarkers
(central laboratory);
see Section 9.6.3.4)
X
X
X
X
WHO FC (blinded) h
X i
X
X
X
X
mRRS
X
X
X
LPH (QoL)
X
X
Safety laboratory
(local laboratory)
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
ECG j
X
Change in 
concomitant 
medication h
X
X
X
X
X
X
X
X
X
X
AE assessment and 
reporting h
X
X
X
X
X
X
X
X
X
X
X
X
cMRI (exploratory, 
reported separately) k
X
X
Abbreviations: 6MWD = 6-minute walking distance; AE = adverse event; cMRI = cardiac magnetic resonance imaging; D = Days; ECG = 
electrocardiogram; EOT = end of treatment; FU = Follow-up; LVEF = left ventricular ejection fraction; mRRS = modified Reveal Risk Score; 
NT-proBNP = N-terminal pro-brain natriuretic peptide; LPH =Living with Pulmonary Hypertension Questionnaire; PAH = Pulmonary Arterial 
Hypertension; QoL = Quality of Life; W = Week; WHO FC = World Health Organization Functional Class.


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a Riociguat wash-out, first dose and dose titration: 
Patients in the riociguat arm will have a wash-out period between discontinuation of PDE-5i and the first dose of riociguat: 24-hour 
wash-out following last dose of sildenafil and 48-hour wash-out following last dose of tadalafil.
Based on the time of the last PDE-5i dose, date and time of the first dose of riociguat after the wash-out period will be determined by the 
investigator and communicated to the patient. Before the first dose of riociguat a blood pressure measurement needs to be performed to 
ensure that systolic blood pressure is ≥95 mmHg. If the blood pressure is below this value, it can be measured again within 24 hours and if 
still below 95 mmHg, riociguat must not be administered. Measurement of blood pressure and application of first riociguat dose may be 
performed at the study center, or by an experienced nurse in the outpatient setting. Date and time of intake of the first dose of riociguat need 
to be documented by the investigator. The nurse will contact the center for this purpose via phone.
Patients in the control arm will continue their current specific PAH treatment (PDE-5i +/-ERA).
b Home Visits (H1, H2, H3):
These visits will be conducted by an experienced nurse at the patient’s (both treatment arms) home. At the discretion of the investigators and 
if applicable (e.g., short distance to study center) these visits may also be performed at the study center.
For the riociguat arm, these visits are part of the titration period that will be performed according to the titration scheme (until Week 8, Visit 2). 
While in the titration period dose increase can only occur at the scheduled visits, a dose decrease (-0.5 mg) can be performed at any time 
based on the patient’s systolic blood pressure and well-being. In both arms blood pressure will be measured; in the riociguat arm the next 
riociguat dose will be decided in phone contact with the center according to the titration scheme.
c Visit 2, Week 8: This is the first regular visit at the center after randomization. For the riociguat arm it will also be the last visit of the titration 
period. Following the titration period, patients will continue to receive riociguat TID at the optimal dose achieved at Week 8 (start of 
maintenance period). 
d Patients will be contacted via telephone every 4 weeks, if there is no scheduled visit to the study center.
e Safety FU visit at 30 days (±5 days) after last dose of study drug.  Note that although the safety FU visit is depicted above as occurring after 
Visit 4 / EOT, the safety FU visit may be performed before Visit 4 / EOT if a patient prematurely discontinues study treatment early in the 
study. If a patient prematurely discontinues study treatment and does not wish to continue with the remaining scheduled visits, an early 
termination visit should be agreed upon as soon as possible, and all activities scheduled for Visit 4 / EOT should be performed during this 
visit.
f Only women of childbearing potential will have a urine or serum test, depending on local routine at each study site. If the test is performed 
> 48 hours before randomization, the test will need to be repeated.
g For the riociguat arm IXRS consultation will be performed at every visit that involves dispense of study medication (V1, H1, H2, H3, V2 and V3).
  For the control arm, IXRS consultation will only be performed by sites which source the comparator centrally at V1, V2 and V3.
h Forms part of the clinical worsening assessment.
i Blinded assessment starts at randomization.
j An ECG can be done at any time during the study, at the discretion of the investigator. It should be reported in the unscheduled procedure page.


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k This will be performed by the core laboratory and reported separately, only at selected sites.  The cMRI should be performed at V1 or 
within 5 days before randomization.
l To be performed if not available within 6 months from screening.


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6 Minute Walking Distance (6MWD) Test - amended
16.2
This section was changed in Amendment 4, see Section 15.1.2.36.
The 6MWD test must be performed in accordance with the American Thoracic Society
Guideline without assessing Borg-Dyspnoea-Index (17).
To ensure a blinded assessment, it has to be performed by a second person who is not 
involved in the process of study drug dispensation or is not aware of the treatment arm. Test 
results should be recorded on a separate work sheet and, where possible, should be entered by 
a different person into the eCRF. 
According to the guideline, the 6MWD test should be carried out indoors, along a long, flat,
straight, enclosed corridor with hard surface that is seldom traveled. The walking course
should be preferably 30 m in length, but not less than 25 m (longer walking courses should be
shortened to 30 m). The length of the corridor and turnaround points should be marked.
Patients will be instructed to walk alone, not run, from one end to the other end of the walking
course, at their own pace, while attempting to cover as much ground as possible in 6 minutes.
During the walk, patients are allowed to stop, lean against the wall and rest, but should
resume walking as soon as they feel able to do so.
A “warm-up” period before the test should not be performed. The patients should sit at rest in
a chair, located near the starting position, for at least 10 minutes before the test starts.
Investigators should not walk with the patients. Moreover, only standardized phrases for
encouragement must be used during the test. To allow reproducibility, standardized phrases
should be used every minute according to the following pattern:

After the first minute, tell the patient the following (in even tones): “You are doing
well. You have 5 minutes to go.”

When the timer shows 4 minutes remaining, tell the patient the following: “Keep 
up the good work. You have 4 minutes to go.”

When the timer shows 3 minutes remaining, tell the patient the following: “You 
are doing well. You are halfway done.”

When the timer shows 2 minutes remaining, tell the patient the following: “Keep 
up the good work. You have only 2 minutes left.”

When the timer shows only 1 minute remaining, tell the patient: “You are doing 
well. You have only 1 minute to go.”
To reduce the variability of the 6MWD tests, it is of utmost importance that the eligibility test,
the baseline-test and all following tests are performed under the same conditions:

If a supplemental oxygen therapy was implemented already at baseline, all 
subsequent 6MWD tests have to be performed under the same “baseline” 


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conditions (same flow of oxygen, same application route, and same way of 
carrying the oxygen bottle).

Even if a supplemental oxygen therapy is implemented or modified during the 
study (e.g., increase of oxygen flow), it is not permitted to perform the subsequent 
6MWD tests under conditions other than the baseline conditions.

Patients, who used walking aids already at the eligibility-test and the baseline-test 
(e.g., cane, walker), need to use the same walking aids at every subsequent 6MWD 
test.
For quality reasons, the inhalation of supplemental oxygen and the use of walking aids during
the 6MWD tests must be documented in the eCRF.
In case a patient has never performed a 6MWD test, a familiarization test should be
performed during the pretreatment phase. To avoid any interactions, it is not permitted to
perform the familiarization test on the same day as the eligibility 6MWD test.
WHO FC
16.3
The patient’s functional class will be determined by using the WHO classification (Class I to 
IV) (18):

I: Patients with PH but without resulting limitation of physical activity. Ordinary 
physical activity does not cause undue dyspnea or fatigue, chest pain, or near 
syncope.

II: Patients with PH resulting in slight limitation of physical activity. They are 
comfortable at rest. Ordinary physical activity causes undue dyspnea or fatigue, 
chest pain, or near syncope.

III: Patients with PH resulting in marked limitation of physical activity. They are 
comfortable at rest. Less than ordinary activity causes undue dyspnea or fatigue, 
chest pain, or near syncope.

IV: Patients with PH with inability to carry out any physical activity without 
symptoms. These patients manifest signs of right-heart failure. Dyspnea and/or 
fatigue may even be present at rest. Discomfort is increased by any physical 
activity.
Modified REVEAL Risk Score
16.4
The Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL®) risk 
score calculator is a validated assessment tool that has been developed to predict the 1-year 
survival of patients with PAH. Calculated risk scores can range from 0 (lowest risk) to
22 (highest risk).
For the study a modified version of the REVEAL risk score calculator will be used, since 
echocardiographic and hemodynamic data, as well as diffusing capacity of the lung for carbon 


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monoxide will not be available. The mRRS algorithm will incorporate the following 
parameters: WHO Group I subgroup, renal insufficiency, age/sex, WHO FC, resting SBP, 
heart rate, 6MWD, NT-proBNP. In this mRRS algorithm, calculated risk score could range 
from 1 (lowest risk) to 15 (highest risk).
WHO Group I
Subgroup
(APAH CTD)
(APAH-PoPH a)
FPAH
Score
+1
+2
+2
Demographics
and comorbidities
Renal insufficiency
Males age >60 years
+1
+2
NYHA/WHO FC
I
III
IV
-2
+1
+2
Vital signs
SBP <110 mmHg
HR>92 bpm
+1
+1
6MWD
≥440 m
<165 m
-1
+1
NT-proBNP
<300 pg/mL
>1500 pg/mL
-2
+1
Sum of above
+
6
= REVEAL Risk Score
a Excluded from study
Abbreviations: APAH = associated PAH, BP = blood pressure, bpm = beats per minute,
CTD = connective tissue disease, DLCO = diffusing capacity of the lung for carbon monoxide,
FPAH = familial PAH, HR = heart rate, 6MWD = 6 minute walking distance, mRAP = mean right
atrial pressure, NT-proBNP = N-terminal pro-brain natriuretic peptide, NYHA = New York Heart 
Association, PAH = pulmonary arterial hypertension, PoPH = portopulmonary PAH,
PVR = pulmonary vascular resistance, RHC = right heart catheterization, SBP = systolic blood 
pressure, WHO = World Health Organization, WHO FC = World Health Organization Functional 
Class
Risk scores and predicted 1-year survival for 5 specified risk strata:
Risk score ranges
Risk group
Predicted 1-year survival
1 – 7
low-risk
95% to 100%
8
average-risk
90% to <95%
9
moderately high-risk
85% to <90%
10 – 11
high-risk
70% to <85
≥12
very high-risk
<70%


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6 JAN 2017
Version no. 2.0
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Living with Pulmonary Hypertension questionnaire (LPH [QoL])
16.5
The LPH questionnaire is designed to measure the effects of PH and PH specific treatments 
on an individual’s quality of life. The LPH is a self-report questionnaire and needs to be 
completed by the patient (questionnaires will be provided in local language). However, if the 
patient has problems completing the questionnaire, an attempt should be made to explain the 
questions in a neutral and unpersuasive manner.
After the patient has filled in the questionnaire, the questionnaire is transferred to the study 
personnel, who will enter the content into the eCRF.
To measure the effects of symptoms, functional limitations, psychological distress on an 
individual’s quality of life, the LPH asks patients to indicate using a 6-point, zero to five, 
Likert scale how much each of 21 facets prevented them from living as they desired.
LIVING WITH PULMONARY HYPERTENSION
The following questions ask how much your pulmonary hypertension affected your life 
during the past 7 days. After each question, circle the 0, 1, 2, 3, 4 or 5 to show how much 
your life was affected. If a question does not apply to you, circle the 0 after that question.
Did your pulmonary hypertension prevent you
from living as you wanted during the past 7 days 
by-
No
Very 
Little
Very 
Much
1.
causing swelling in your ankles, legs?
0
1
2
3
4
5
2.
making you sit or lie down to rest during
0
1
2
3
4
5
3.
making it difficult to walk about or climb
0
1
2
3
4
5
4.
making it difficult to work around the
0
1
2
3
4
5
5.
making it difficult to go anywhere away
0
1
2
3
4
5
6.
making it difficult to sleep well at night?
0
1
2
3
4
5
7.
making it difficult to have relationships
0
1
2
3
4
5
8.
making it difficult to work to earn a
0
1
2
3
4
5
9.
making your recreational pastimes,
0
1
2
3
4
5
10.
making your sexual activities difficult?
0
1
2
3
4
5
11.
making you eat less of the foods you like?
0
1
2
3
4
5
12.
making you short of breath?
0
1
2
3
4
5
13.
making you tired, fatigued, or lacking in 
0
1
2
3
4
5
14.
making you stay in hospital?
0
1
2
3
4
5


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Did your pulmonary hypertension prevent you
from living as you wanted during the past 7 days 
by-
No
Very 
Little
Very 
Much
15.
costing you money for medical care?
0
1
2
3
4
5
16.
giving you side effects from treatments?
0
1
2
3
4
5
17.
making you feel you are a burden to your 
family or friends?
0
1
2
3
4
5
18.
making you feel a loss of self-control
in your life?
0
1
2
3
4
5
19.
making you worry?
0
1
2
3
4
5
20.
making it difficult for you to concentrate or
0
1
2
3
4
5
21.
making you feel depressed?
0
1
2
3
4
5
Derived from copyrighted materials under a license agreement with the University of Minnesota.

SAP_001.pdf: 
 
Document Type: 
Statistical Analysis Plan 
Official Title: 
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 
NCT Number: 
NCT02891850 
Document Date: 
09 April 2020 
 


 
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1 of 
33
 
 
Statistical Analysis Plan Final Version 3.0 
BAY 63-2521 IMPACT no. 18588.  Document Date:   09 April 2020 
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. 
Riociguat rEplacing PDE-5i therapy evaLuated Against Continued PDE-5i thErapy 
BSP study drug 
BAY 63-2521/Adempas/Riociguat 
Study purpose: 
To demonstrate the effectiveness of riociguat as replacement of PDE-
5i therapy in PAH patients 
Clinical study 
phase: 
IV 
Date: 
09 April 2020 
Study No.: 
 
IMPACT no. 18588 
Version: 
Final 3.0 
Author: 
 
 
 
 
 
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) are not displayed.  Hence, the 
appearance of product names without these symbols does not imply that these names are not protected. 
 
This Statistical Analysis Plan is produced on a word-processing system and bears no signatures. 
The approval of the Statistical Analysis Plan is documented in a separate Signature Document.
PPD


Reference Number: RD-SOP-1119 
Supplement Version: 7 
Statistical Analysis Plan (Amendment/Supplement) 
Approval Fo nn 
Study Number (Bay No./lMP no.)* 
Statistical Analysis Plan (SAP) 
Version and Date 
BAY 63-2521 / IMPACT no. 18588 
Final v3.0 09-April-2020 
• if no IM PACT number is available, refer to the approved Study Concept 
I have read and approve the SAP/ SAP Amendment referred above. 
Name 
Signature 
Author: 
Study Statistician 
Approved by: 
Project Statistician 
 
 
Datu 
Study Medical Expert 
 
Medical Writer 
Date 
: 2020.04.09 14:37:05 +0l'00' 
Page 1 of 1 
PPD
PPD
PPD
PPD
PPD
PPD


Reference Number: RD-SOP-1119 
Supplement Version: 7 
Statistical Analysis Plan (Amendment/Supplement) 
Approval Form 
Study Number (Bay No./lMP no.)* 
Statistical Analysis Plan (SAP) 
Version and Date 
BAY 63-2521 I IMPACT no. 18588 
Final v3.0 09-April-2020 
• if no IMPACT number is available, refer to the approved Study Concept 
I have read and approve the SAP / SAP Amendment referred above. 
Name 
Signature 
Author: 
Study Statistician 
Approved by: 
Project Statistician 
Study Medical Expert 
O.t" 
Medical Writer 
 
Date 
C)q -tl\',:..2® 
2020 04.09 14:31 08 +01'00' 
. 
Page 1 of 1 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


 
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Statistical Analysis Plan Final Version 3.0 
BAY 63-2521 IMPACT no. 18588.  Document Date:   09 April 2020 
Table of Contents 
 
1. 
Introduction ......................................................................................................................... 5 
2. 
Study Objectives ................................................................................................................. 5 
3. 
Study Design ....................................................................................................................... 6 
3.1 
General Consideration ................................................................................................. 6 
3.2 
Sample size .................................................................................................................. 8 
4. 
General Statistical Considerations ...................................................................................... 8 
4.1 
General Principles ........................................................................................................ 8 
4.2 
Handling of Dropouts .................................................................................................. 8 
4.3 
Handling of Missing Data ............................................................................................ 9 
4.3.1 
Handling of missing efficacy endpoint ............................................................. 9 
4.3.2 
Safety variables ................................................................................................. 9 
4.3.3 
Laboratory values ........................................................................................... 10 
4.4 
Interim Analyses and Data Monitoring ..................................................................... 11 
4.5 
Data Rules .................................................................................................................. 11 
4.6 
Protocol Deviation ..................................................................................................... 11 
4.7 
Analysis definitions, variables and subgroups ........................................................... 12 
4.7.1 
Analysis definitions and variables .................................................................. 12 
4.7.2 
Subgroups ....................................................................................................... 13 
5. 
Analysis Sets ..................................................................................................................... 13 
6. 
Statistical Methodology .................................................................................................... 14 
6.1 
Population characteristics .......................................................................................... 14 
6.1.1 
Disposition of subjects .................................................................................... 14 
6.1.2 
Demographic and baseline characteristics ...................................................... 15 
6.1.3 
Medical history ............................................................................................... 15 
6.1.4 
Prior and concomitant medications ................................................................ 15 
6.2 
Efficacy ...................................................................................................................... 16 
6.2.1 
Primary efficacy variable ............................................................................. 16 
6.2.2 
Secondary efficacy variable ............................................................................ 20 
6.2.3 
Exploratory variable ....................................................................................... 22 
6.3 
Pharmacokinetics / pharmacodynamics ..................................................................... 23 
6.4 
Safety ......................................................................................................................... 23 
6.4.1 
Extent of exposure .......................................................................................... 23 
6.4.2 
Adverse events ................................................................................................ 24 
6.4.3 
Adverse events of special safety interest ........................................................ 26 
6.4.4 
Safety laboratory assessments ........................................................................ 26 
6.4.5 
Vital signs ....................................................................................................... 27 
6.4.6 
12-lead electrocardiogram .............................................................................. 27 
6.4.7 
Pregnancy test ................................................................................................. 27 
6.4.8 
Other procedures and variables ...................................................................... 27 
7. 
Document history and changes in the planned statistical analysis ................................... 28 
8. 
References ......................................................................................................................... 28 


 
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Statistical Analysis Plan Final Version 3.0 
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9. 
Appendix ........................................................................................................................... 29 
9.1 
Study schedule of procedures .................................................................................... 29 
9.2 
Sample SAS code ...................................................................................................... 32 
 
Abbreviations 
 
6MWD 
6 minute walking distance  
AE 
adverse event 
ALT 
alanine aminotransferase  
AST 
aspartate aminotransferase  
AUC 
area under the curve 
BP 
blood pressure 
cGMP 
cyclic guanosine monophosphate 
cMRI 
cardiac magnetic resonance imaging 
CRO 
contract research organization 
CTEPH 
chronic thromboembolic pulmonary hypertension  
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EOS 
End of Study 
ERA 
endothelin receptor antagonist 
EU 
European Union 
FEV1/FVC 
forced expiratory volume in one second/forced vital capacity 
FAS 
full analysis set 
FU 
follow-up 
GCP 
Good Clinical Practice 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
IEC 
independent ethics committee 
IRB 
institutional review board 
IXRS 
interactive voice response system 
LOCF 
last observation carried forward  
LPH 
living with pulmonary hypertension  
MedDRA 
Medical Dictionary for Regulatory Activities 
mRAP 
mean right atrial pressure 
mRRS 
modified REVEAL Risk Score 
NT-proBNP 
N-terminal pro-brain natriuretic peptide 
NYHA 
New York Heart Association 
OR 
odds ratio 
PAH 
pulmonary arterial hypertension 
PCA 
prostacyclin analogues 
PDE-5 
phosphodiesterase 5 
PDE-5i 
phosphodiesterase 5 inhibitor 
PH 
pulmonary hypertension 


 
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PH-LVD 
pulmonary hypertension due to left ventricular dysfunction 
PoPH 
portopulmonary PAH 
PPS 
per protocol set 
PVR 
pulmonary vascular resistance 
QoL 
Quality of Life 
RHC(s) 
right heart catheterization(s) 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS 
Statistical Analysis System 
SBP 
systolic blood pressure 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
TLC 
total lung capacity 
TID 
ter in die (3 times daily) 
ULN 
upper limit of normal 
WHO-DD 
World Health Organization-Drug Dictionary 
WHO FC 
World Health Organization Functional Class 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Statistical Analysis Plan Final Version 3.0 
BAY 63-2521 IMPACT no. 18588.  Document Date:   09 April 2020 
1. Introduction 
Riociguat rEplacing PDE-5i therapy evaLuated Against Continued PDE-5i thErapy 
(REPLACE) is 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. 
This statistical analysis plan (SAP) describes the study objective, study design, study 
population, safety and efficacy variables, statistical methods, and study tables to be used in 
REPLACE study. It is based on study protocol version 4.0, dated 06 Jan 2017and eCRF 
version 1.0, dated 19 April 2017. 
Pulmonary arterial hypertension (PAH) is a devastating, life-threatening disease that is 
characterized by rapid progression and a high mortality. Traditionally, oral monotherapy 
including PDE-5i is one recommended treatment approach for patients with PAH who are 
classified as World Health Organization Functional Class (WHO FC) II or III. However, a 
significant proportion of PAH patients fail to reach or maintain treatment goals with PDE-5i 
monotherapy indicating that the NO-sGC-cGMP pathway in these patients may be impaired. 
The clinical approach in patients demonstrating an insufficient clinical response on PDE-5i 
monotherapy is typically to add an endothelin receptor antagonist (ERA).  
Riociguat (BAY 63-2521) is a direct stimulator of the soluble Guanylate Cyclase. The 
randomized, double-blind, placebo-controlled clinical Phase III study (PATENT-1) 
investigated the efficacy and safety of riociguat in patients with pulmonary arterial 
hypertension (PAH). The study met the primary endpoint and showed statistically significant 
improvements in several secondary endpoints. Riocigut was overall considered to be 
beneficial with regard to exercise capacity, cardiopulmonary hemodynamics, and symptoms 
and well tolerated also in previous clinical studies at multiple doses in patients with PAH and 
other indications, e.g., chronic thromboembolic pulmonary hypertension (CTEPH) and 
pulmonary hypertension due to left ventricular dysfunction (PH-LVD). 
The REPLACE study was designed to examine whether the replacement of PDE-5i by 
riociguat in patients who are not at treatment goal but on a stable dose of PDE-5i +/- ERA will 
lead to a significantly higher rate of satisfactory clinical response compared to patients who 
remain on PDE-5i +/- ERA because of the optimization of the NO sGC-cGMP pathway 
provided by riociguat and its NO-independent mechanism of action. 
2. Study Objectives 
The primary objective is to assess the proportion of patients in each treatment arm with a 
satisfactory clinical response as defined by a composite primary endpoint at Week 24.  


 
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The secondary objective is to demonstrate safety and clinical effect at Week 24 indicated by 
change in 6 minute walking distance (6MWD), N terminal pro-brain natriuretic peptide (NT-
proBNP), World Health Organization Functional Class (WHO FC) and clinical worsening 
from baseline in each treatment arm. 
3. Study Design 
3.1 General Consideration 
This is a prospective, randomized, international, multicenter, double-arm, 24 week, 
controlled, open-label study of riociguat in patients with PAH who are on a stable dose of 
PDE-5i +/- ERA, but not at treatment goal. The planned sample size is 218 (109 per arm). 
Central randomization is planned, stratified by etiology of PAH: 
• IPAH/ HPAH/ PAH drug and toxin induced 
• PAH-CHD, PAH-portopulmonary PAH (PoPH)  
• PAH- CTD 
At Week 24 a composite endpoint of satisfactory clinical response will be assessed. 
Treatment period (Duration: 24 weeks) 
Patients randomized to the control arm at the baseline visit (Week 0) will continue on their 
current PAH-specific treatment for 24 weeks.  
Patients randomized to the riociguat arm, will have a wash-out period before starting the 
titration period of riociguat. The wash-out period is 24 hours with previous sildenafil therapy 
(daily dose 60 to 300 mg) and 48 hours after previous tadalafil therapy (daily dose 20 to 40 
mg). Riociguat will be administered according to the established and approved dose 
adjustment/ titration scheme over 8 weeks. The starting dose will be 1 mg riociguat TID. The 
individual riociguat dose will be adjusted every 2 weeks according to the patient’s well-being 
and peripheral systolic blood pressure (SBP) measured at trough, preferably before intake of 
the next morning dose. At each titration visit for the riociguat arm (Weeks 2, 4, and 6), the 
investigator needs to decide, based on the patient’s SBP, whether the study medication dose 
should be modified. 
Titration period (Duration: 8 weeks) 
Patients randomized to the riociguat arm will have an 8-week titration period. The dose 
titration will be performed with the aid of an interactive voice response system (IXRS). The 
individual riociguat dose will be adjusted every 2 weeks as described above. While dose up-
titration can only occur at the scheduled visits, a dose decrease can be performed at any time 


 
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based on the patient’s SBP and well-being. In case of intended dose decrease which can be 
done independently from any planned study visit, the investigator will contact the IXRS and 
request a dose adjustment. This visit is to be declared as an unscheduled visit. 
During the titration period, a request of an increase of riociguat dose is only possible at the 
planned titration visits at Weeks 2, 4, and 6. The dose reached at the end of the titration period 
at Week 8 is considered the patient’s optimal dose based on SBP and well being.  
Patients in the control arm will also have home visits at Weeks 2, 4, and 6 and will attend the 
Week 8 visit. At the discretion of the investigators and if applicable (e.g., short distance to 
study center) the home visits may also be performed at the study center. 
Maintenance period (Duration: 16 weeks) 
Riociguat should be continued at the optimal dose as determined at the end of the titration 
period (Week 8) throughout the maintenance period.  
Visits (for both arms) will take place at Week 16 and Week 24. The IXRS will automatically 
allocate the right riociguat dose at each visit.  
Dose reductions or discontinuation of riociguat for safety reasons are allowed at any time. 
Increases or re-increases in 0.5 mg steps (maximum dose 2.5 mg) are possible at the 
investigator’s discretion weighing the benefit with potential risks implied, e.g., hypotension 
during the maintenance period.   
End of Treatment (Week 24 ± 4 days) 
 All patients randomized to either treatment arm should perform Visit 4 / end of treatment 
(EOT).  This is the last visit of the maintenance period, when all relevant efficacy and safety 
measurements will be performed. 
Safety follow-up Visit (30 days ± 5 days) 
A safety follow-up (FU) visit 30 days (± 5 days) after discontinuation of treatment intake 
should be performed for both arms. 
End of Study 
The end of the study as a whole will be reached as soon as the last safety FU visit of the last 
patient according to the above definition has been reached in all participating countries 
(European Union [EU] and non EU). 


 
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3.2 Sample size  
Sample size is determined based on results of Studies 12934/12935/16719 (PATENT-1/2, 
RESPITE) for riociguat. The estimate for the ‘satisfactory clinical response’ rate at Week 24 
is 40% for the riociguat arm. Assuming a treatment effect of 50% (relative reduction, see next 
subsections) to the active control the estimate for a ‘satisfactory clinical response’ in the 
active control arm is 20%. The sample size of 218 patients is calculated using SAS Version 
9.2 (proc power, two-sample-frequency, χ2-test, two-sided alpha = 5%, power = 90%). 
The screening failure rate is estimated at 15% and therefore a screening number of 257 
patients is required. As it is planned to use LOCF for the primary analysis, no adjustment for 
dropouts is needed. 
4. General Statistical Considerations 
4.1 General Principles 
The statistical evaluation will be performed by using the software package SAS release 9.3 or 
higher (SAS Institute Inc., Cary, NC, USA).  
Unless otherwise noted, data will be analyzed by descriptive statistical methods: the number 
of data available, means, standard deviations, minimums, quartiles, medians, and maximums 
will be calculated for continuous data. Frequency tables will be generated for categorical data 
including number and percentage of subjects.  
Definition of efficacy and safety endpoints, analyses strategies, structure of analyses datasets, 
and layout of analyses data displays are following Bayer Biostatistics and Statistical 
Programming standards. 
4.2 Handling of Dropouts 
A patient who discontinues study participation prematurely for any reason after randomization 
is defined as a “dropout”. Subjects who drop out will not be replaced. 
A subject who, for any reason (e.g., failure to satisfy the selection criteria), terminates the 
study before the time point used for the definition of “dropout” in this study is regarded a 
“screening failure” (which literally means usually before randomisation). 
In all cases, the reason for withdrawal must be entered in the electronic case report form 
(eCRF) and in the subject’s medical records. 


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4.3 Handling of Missing Data 
In order to achieve the goal of a well conducted clinical trial according to International 
Council on Harmonisation Good Clinical Practice, every effort should be made to collect all 
data (i.e., if a subject misses a scheduled assessment, the site personnel should contact the 
subject and request him/her to come to the clinic for the visit). However, despite best efforts, 
it may be inevitable that missing or incomplete data are reported. All missing or partial data 
will be presented in the subject data listings, as they were recorded on the eCRF. 
For efficacy and safety variables analyzed by visits, the values at scheduled visits will be used 
if available. If values at scheduled visits are missing but values are available at an associated 
unscheduled visit (within the analysis phase), the value from the closest unscheduled visit will 
be used to the scheduled visit.  
If there are no values at scheduled or unscheduled visits, missing data are not imputed in 
statistical analyses, except as noted below (Section 4.3.1 - 4.3.3). 
A value from the termination visit (for discontinued subjects) will be assigned to the next 
scheduled visit (for the particular assessment per protocol) after the last visit the subject has 
completed. 
4.3.1 
Handling of missing efficacy endpoint 
The primary efficacy endpoint ‘satisfactory clinical response’ is defined as the composite 
endpoint comprising 2 major components. It is defined as ‘YES’ only if the 2 major 
composites (‘2 of 3 items for the first component’ and ‘No clinical worsening for the second 
component’) are both ’YES’. The component ‘2 of 3’ is ‘YES’ if at least 2 of its 3 sub-
components are ‘YES’.  
For the primary efficacy endpoint with missing data, the last observation carried forward 
(LOCF) will be utilized for each individual component for subjects who are still alive during 
the study. The composite outcome is then derived based on the LOCF imputed individual 
component. Where a subject dies with no termination visit, the following rules will be used: 
6MWD worst possible score (0m), Modified REVEAL with worst risk score (22), LPH worst 
possible score (105), WHO functional class, in case of death before visit 4 the worst possible 
score value plus 1 (V). NT pro-BNP is the efficacy measures designed to the direct effect of 
study treatment on biomarker, so it is not appropriate to use imputation rule for those in case 
of death or missing post-baseline data.  
4.3.2 
Safety variables 
Incomplete adverse event start or stop dates and concomitant medication start or stop dates 
will be imputed to determine treatment emergent AE and concomitant medication as 


 
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described in Table 1. Missing or partial dates will be presented in the subject data listings as 
they were recorded on the CRFs. 
Table 1.  Imputation Rules for Incomplete Dates for AE and Concomitant Medication 
 
  
Missing 
Scenario 
Imputation 
Start date  
(AE, 
concomitant 
medication) 
Day 
Event month&year < 
month&year of first dose 
last day of the month 
Event month&year = 
month&year of first dose 
first dose date 
Event month&year > 
month&year of first dose 
first day of the month 
Day / 
Month 
Event year < year of first dose 
December 31 
Event year = year of first dose 
first dose date 
Event year > year of first dose 
January 01 
Complete 
missing 
  
AE: first dose date 
Conmed: no imputation 
Stop date  
(AE, 
concomitant 
medication) 
Day 
Event month&year < 
month&year of last known 
assessment date (LKAD) 
last day of the month 
Event month&year = 
month&year of LKAD 
date of LKAD 
Event month&year > 
month&year of LKAD 
no imputation 
Day / 
Month 
Event year < year of LKAD 
December 31 
Event year = year of LKAD 
date of LKAD 
Event year > year of LKAD 
no imputation 
Complete 
missing 
  
date of LKAD 
 
 Note: If first dose date is missing, use enrollment date for the imputation. 
           If the imputed start date is after the stop date, the start date will be imputed to equal the stop date. 
           If the imputed stop date is before the start date, the stop date will be imputed to equal the start date. 
4.3.3 
Laboratory values 
For laboratory values below the lower limit of quantification (LLOQ) like “<xxx” or “≤xxx”, 
or above the upper limit of quantification (ULOQ) like “>xxx” or “≥xxx”, LLOQ or ULOQ 
(xxx) will be used for calculation of descriptive statistics. The original laboratory values 
(“<xxx”, “≤xxx”, “>xxx” or “≥xxx”) are presented in the listing. 


 
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4.4 Interim Analyses and Data Monitoring 
No interim analysis is planned for this study. 
4.5 Data Rules 
Generally, for each date stored in database a set of organizational variables will be derived to 
describe the temporal context of that date in the specific study: phase of treatment (pre-, 
during or post study treatment), the day relative to the start of study treatment, the day relative 
to the end of study treatment. 
Refer to Section 4.3 for handling of missing data, as well as to Section 4.7, for specific 
endpoints data rules, for example: definition of treatment-emergent adverse events (TEAEs). 
4.6 Protocol Deviation 
The subjects who meet the criteria below will be flagged as having an important protocol 
deviation that leads to exclusion from per-protocol set.  
Important protocol deviations leading to exclusion for per-protocol set are as follows:  
• Subjects did not sign informed consent 
• Subject was randomized but never received any study medication 
• Subjects subsequently found not to satisfy the definition of PAH, including 
hemodynamic definition in RHC from medical history 
• Baseline 6MWT less than 165 m or greater than 440 m 
• Age less than 18 years at visit 1 
• Concomitant use with riociguat of the following specific medications for treatment of 
PAH during the study: (1) PDE 5i (e.g., sildenafil, tadalafil or vardenafil) with 
riociguat; (2) Non-specific PDE-inhibitors (e.g., dipyridamole, theophylline) and (3) 
NO donors (e.g., nitrates, amyl nitrite); 
• Prostacyclin analogues (PCA) and prostacyclin-receptor agonists (PRA) by any 
administration route within 30 days prior to and at randomization (except for 
vasoreactivity testing). 
In addition to the deviations listed above, subjects will be excluded from analysis sets based 
on team review prior to database lock. 


 
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4.7 Analysis definitions, variables and subgroups   
4.7.1 
 Analysis definitions and variables 
A summary of the planned study analysis definitions and variables is provided in Table 2. 
Table 2 - Summary of Analysis Definitions/Variables 
Terms 
Definition 
Study Day 1 
Day 1 is defined as randomization date. If an Adempas therapy 
is postponed, the day at start of wash-out is Day 1. 
 
Study Day 
Study Day = Measurement Date - Day 1 + 1, if measurement 
date is on or after Day 1. 
 
Study Day = Day 1 - Measurement Date, if measurement date is 
before Day 1. 
 
Treatment Exposure 
Treatment exposure is defined as duration of study treatment, 
calculated as last study treatment dose date - first study 
treatment dose date + 1. 
 
Baseline 
Baseline is defined as the value taken at randomization. If this is 
missing, the latest value before will be taken. 
 
Change from Baseline 
Change from baseline is defined as the difference between the 
post-baseline measurement and the baseline.  
 
Titration Period 
Patients randomized to the riociguat arm, will have a wash-out 
period of 24 hours with previous sildenafil therapy and 48 hours 
after previous tadalafil therapy before starting the 8-week 
titration period of riociguat. The dose titration will be performed 
with the aid of IXRS. 
Maintenance Period 
Once the subject completes titration period, he/she is entering 
maintenance period till the end of study. 
 
Treatment Emergent 
Adverse Event (TEAE) 
Treatment emergent adverse event is defined as having started or 
worsened after the first treatment administration up to 2 days 
after end of treatment.  
 
 


 
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End of Treatment 
All patients randomized to either treatment arm should perform 
Visit 4 / EOT.  This is the last visit of the maintenance period, 
when all relevant efficacy and safety measurements will be 
performed. 
Safety follow-up phase 
A safety follow-up (FU) visit is 30 days (± 5 days) after 
discontinuation of treatment intake. 
 
End of Study 
The end of the study as a whole will be reached as soon as the 
last safety FU visit of the last patient according to the above 
definition has been reached in all participating countries 
(European Union [EU] and non EU). 
4.7.2 
Subgroups 
The following subgroups are defined in support of efficacy and safety analysis : 
•   PAH class as defined in randomization strata:  
o IPAH/ HPAH/ PAH drug and toxin induced 
o PAH-CHD, PAH-portopulmonary PAH (PoPH)  
o PAH- CTD 
•   Pre treatment: combination therapy with ERAs and PDE-5i vs. PDE-5i monotherapy 
•   ERA pre-treatment subgroups (Bosentan, Ambrisentan and Macitentan) 
•   Sex: male vs. female 
•   6MWD at baseline: (<320 m vs. >=320 m) 
•   Pre treatment:  tadalafil vs. sildenafil 
•   Age group:  <65 years old vs. >= 65 years old 
•   Smoking status:  current and former vs. never 
•   cMRI (subjects who performed cMRI vs. not) 
5. Analysis Sets 
Three analysis sets are defined as below. 
Full Analysis Set (FAS) 


 
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The subjects who are randomized and take at least 1 medication will be considered for 
“FAS”. Subjects will be analyzed as randomized.  
Safety Analysis Set (SAF) 
The population for safety analysis will be comprised of all subjects who received at 
least 1 dose of study drug. SAF set will be analyzed as treated. 
All patients randomized and treated (at least 1 treatment after randomization) will be valid for 
the FAS, hence the number of patients in the safety and FAS will be identical. The actual 
treatment is defined as the majority study drug the subject received. 
Per Protocol Set (PPS) 
The PPS is defined as all FAS subjects who have no important protocol deviations that lead to 
exclusion in per-protocol set. The important protocol deviations are those protocol deviations 
that are considered to affect subject efficacy evaluations and subjects with such deviations 
should be excluded from the efficacy analysis. These important protocol deviations are 
defined in Section 4.6. 
In addition to the criteria listed above, subjects will be excluded from analysis sets based on 
team review prior to database lock. 
6. Statistical Methodology 
The formal statistical analysis will be both descriptive and inferential. Summaries will be 
provided for each of the treatment groups. 
6.1 Population characteristics 
For this analysis, only descriptive statistics will be provided (no testing performed). The 
results will be displayed by treatment group as well as the total study population for FAS, 
SAF and PPS. 
6.1.1 
Disposition of subjects 
Summary tables will be presented for the following subject populations:  
• Subjects screened (subjects who signed informed consent) 
• Screening failures (subjects who terminated the study before randomization) 
• Subjects in FAS/ SAF 
• Subjects in PPS 
• Premature termination of treatment 


 
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• Subjects who completed the study  
• Subjects who prematurely withdrawn from study medication in the study 
 
In addition, detailed reasons for subjects who prematurely withdraw from the study or 
discontinue the study drug will be tabulated by treatment group. 
 
6.1.2 
Demographic and baseline characteristics  
Standard descriptive statistics will be presented for the following variables of:  
• Age 
• Sex 
• Race 
• Ethnicity 
• Weight and height (screening only) 
• Body Mass Index 
• Smoking status  
• Pre treatment: combination therapy with ERAs and PDE-5i vs. PDE-5i monotherapy  
• ERA pre-treatment subgroups (Bosentan, Ambrisentan and Macitentan)  
• 6MWD at baseline: (<320 m vs. >=320 m)  
• Pre treatment:  tadalafil vs. sildenafil  
• cMRI (subjects who performed cMRI vs. not) 
 
Descriptive analysis will also be provided for baseline Dana Point classification of PH, time 
of first diagnosis of PAH to randomization, time from the confirmatory RHC to 
randomization and PAH classes at baseline.   
6.1.3 
Medical history 
The dictionary for coding is the Medical Dictionary for Regulatory Activities (MedDRA) 
(version 17.1 or higher). By treatment group summary statistics (frequency and percentage) 
will be provided by system organ class and preferred term. 
6.1.4 
Prior and concomitant medications  
Medications received prior to or concomitantly with treatment will be coded using the WHO 
Drug Dictionary Version Q3 2015, or later if updated during the study, and the Anatomical 
Therapeutic Chemical (ATC) Classification codes. 
 


 
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Prior medications are those with a stop date before the first dose date of study treatment. 
Concomitant medications are those with a start date on or after the first dose date of study 
treatment, or those with a start date before the first dose date of treatment and a stop date on 
or after the first dose date of study treatment.  
 
To handle classification of medications in the event of missing or partial dates, please refer to 
Section 4.3.2 for imputation rules. 
 
Prior and concomitant medications will be tabulated by treatment group using ATC codes. 
Frequencies of subjects having received medication from each drug category (ATC-level 2 
and generic term) will be provided. 
6.2 Efficacy 
6.2.1 Primary efficacy variable  
6.2.1.1 
Definition of ‘satisfactory clinical response’ 
The primary efficacy endpoint ‘satisfactory clinical response’ is defined as the composite 
endpoint comprising the following major components (independent central adjudication): 
• 2 of 3 must be fulfilled 
• 6MWD increase by ≥ 10% or ≥ 30 m from baseline to Week 24 
• WHO FC I or II at Week 24 
• NT-proBNP reduction ≥ 30% from baseline to Week 24 (NT-proBNP ratio Week 
24/baseline ≤ 0.7),  
AND 
• No clinical worsening (Defined in the protocol Section10.3.2.1 ) 
‘Satisfactory clinical response’, also referred to as improvement rate, is defined as ‘YES’ only 
if the 2 major composites (‘2 of 3’ and ‘No clinical worsening’) are both ’YES’. The 
component ‘2 of 3’ is ‘YES’ if at least 2 of its 3 sub-components are ‘YES’. The biomarker is 
given the same importance as the clinical parameters to introduce more objectivity to the 
endpoint and reduce possible open-label bias.  
6.2.1.2 
Final analysis of primary efficacy variable  
The null hypothesis tested for the primary endpoint of efficacy is that there is no difference in 
the satisfactory clinical response rates in terms of odds ratio (OR) when treated with riociguat 


 
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compared to patients that remain on their previous therapy (i.e., H0: OR = 1). The two-sided 
alternative is that there is a difference (i.e., H1: OR ≠ 1). 
For statistical analysis of the primary endpoint with missing data, the LOCF will be utilized. 
The reason for LOCF is given in the following: the primary endpoint measures improvements, 
thus, using LOCF will (a) not yield favorable results in the riociguat arm and (b) yield 
favorable results in the active control arm. Because of the inclusion criterion “stable on PDE5i 
” one expects the first case (a) to be much more frequent. Thus, LOCF is conservative with 
respect to the null hypothesis. For composite endpoints each single component is 
independently replaced with the last available observation, respectively. The composite 
outcomes will then be derived based on the imputed individual items. 
Both groups (riociguat vs. active control) will be compared using a stratified Mantel-Haenzel 
test with a two-sided alpha level of 5%. Stratification factor is the PAH classes at baseline 
based on eCRF. The point estimate and 95% CI for odds ratio (OR) will be derived. Both FAS 
and PPS will be used for this analysis.  Hypothesis testing is based on p-value.  In some cases 
MH confidence intervals might not fit to p-value due to non-continuos variable. 
6.2.1.3 
Sensitivity analysis of primary efficacy variable  
The sensitivity analysis for the primary efficacy variable will be conducted utilizing the 
following 3 approaches. The first approach is to consider the data is missing completely at 
random and the other two approaches will consider the data is not missing at random.  
The primary efficacy outcome will be considered as missing at a given visit if (1) the clinical 
worsening status is unknown; or (2) 2 of 3 (6MWD, WHOC FC and NT-proBNP reduction) 
are missing or (3) 1 of 3 (6MWD, WHOC FC and NT-proBNP reduction) is missing and the 
other two known items with one outcome of yes and one outcome of no. 
6.2.1.3.1 Missing completely at random 
To assess the influence of missing data, a supportive analysis without LOCF will be 
performed with a generalized estimating equations approach (GEE, binomial distribution) 
utilizing all adequate investigations of all primary variable components at any time from 
baseline up to Week 24.  
This method covers missing values of type ‘missing completely at random’. Data from all 
assessed time points (i.e., Week 8, Week 16 and Week 24) will be included as the dependent 
variable in the model.  PAH class, treatment group, visit and interaction between treatment 
and visit will be included as the predictors in the model, with visit as a continuous variable.  
The alternating  logistic regression method will be used with exchangeable log odds ratios. . 
The 95% CIs will be constructed for OR of improvement rate between riociguat and PDE-5i 
at Week 8, Week 16 and Week 24.   


 
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6.2.1.3.2  Missing not at random 
In this open-label study there might also be missing values of type ‘missing not at random’. 
To assess the influence of these missing values a sensitivity analysis is planned, multiple 
imputation with penalty and tipping point analysis will also be performed for the 
improvement rate at Week 24. 
 
Imputation with penalty 
A multiple imputation with penalty will be performed where the penalty is given by crossed 
improvement rates in both arms. 
• Riociguat arm: imputation with a clinical improvement rate observed in active control arm 
• Control arm: imputation with a clinical improvement rate observed in riociguat arm 
Thus, the highest sensible rate of clinical improvement is the rate in the riociguat arm and this 
is applied to the control arm in the imputation process. Further, the lowest sensible rate of 
clinical improvement is the rate in the control arm and this is applied to the riociguat arm in 
the imputation process. 
To be more specific, the multiple imputations will be carried out 10 times for missing data. 
Each time, the penalty is given by the crossed improvement rates in the other group using 
SAS procedure, (i.e., Proc MI). Each of these imputed datasets (which contains identical 
values for the non-missing data but different values for missing data) is analyzed using the 
logistic regression with covariates of PAH baseline class and treatment. If convergence 
problems were encountered during the logistic regression, the PAH category will be removed. 
The results from all these 10 imputed datasets are then combined together for overall 
inference using Proc MIANALYZE. 
Tipping point analysis 
In this analysis, all the observed data will be included as non-missing. The analysis will be 
performed using a general 3 steps approach for each given shift (pre-specified value used for 
imputation). 
First, multiple imputation will be conducted using PROC MI to generate 10 imputed datasets 
by imputing missing data using a pre-specified shift assuming monotone missing pattern. The 
missing values for clinical improvement rate in each treatment group will be imputed 
independently.  


 
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Secondly, each of the imputed datasets that contained identical values of non-missing data but 
different values of imputed data for missing data is analyzed using logistic regression 
controlling for PAH baseline class and treatment.  
Last, the results from all these 10 analysis are then combined together for overall inference 
using PROC MIANALYZE by considering within and between variances. 
More specifically, control group will be imputed with an improvement rate ranging from 1% 
to 99% with a step of 1% to identify the tipping point while the missing data in the treatment 
group will be imputed using the same rate as others in the treatment group.  Note, the tipping 
point is defined as the data point where the conclusion based on p-value is changed. It may or 
may not exist depending on the amount of missing data. Due to the MCMC nature, the first p-
value where the conclusion is changed will be defined as the tipping point. For example, if the 
treatment vs. control has a p-value of 0.001, then the tipping point will be the one where the 
first p-value is bigger or equal to 0.05. The analysis results will demonstrate the robustness of 
the primary outcome when missing data is imputed independently for two groups. 
The main difference between the imputation with penalty and tipping point is that imputation 
with penalty will impute missing data with only 1 given improvement rate from the other 
group, while tipping point will impute data many times with different values and demonstrate 
the robustness of the results while the missing data were imputed with all the plausible values.  
6.2.1.4 
Subgroup analysis of primary efficacy variable  
Subgroup analyses will be performed for the primary efficacy variable for the following 
subgroups: 
• 
PAH categories at baseline based on eCRF 
o IPAH/ HPAH/ PAH drug and toxin induced 
o PAH-CHD, PAH-portopulmonary PAH (PoPH)  
o PAH- CTD 
• 
Pre treatment with combination therapy with ERAs and PDE-5i versus pre treatment with 
PDE-5i monotherapy 
• 
ERA pre-treatment subgroups (Bosentan, Ambrisentan and Macitentan) 
• 
Gender  
• 
6MWD at baseline (<320m vs. >=320m) 
• 
Pre treatment with tadalafil or sildenafil 


 
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• 
Age group:  <65 years old vs. >= 65 years old 
• 
Smoking status:  current and former vs. never 
• 
cMRI: Subjects who conducted cMRI vs. not 
Categorization of stratification factors (PAH) will use the values from eCRF. Subgroups may 
be collapsed or revised due to sparse data at a level prior to database lock.  
In each subgroup analysis, both groups (riociguat vs. active control) will be compared for the 
primary efficacy endpoint ‘satisfactory clinical response’ using a Cochrane Mantel-Haenzel 
test with a two-sided alpha level of 5%. The point estimate and 95% CI for odds ratio (OR) 
will be derived. 
Besides all the subgroup analysis, a forest plot will also be presented to illustrate the OR and 
its 95% CI for each subgroup. 
6.2.2 
Secondary efficacy variable  
 
The following secondary efficacy variables will be examined at Week 8, 16 and 24. The null 
hypothesis tested for the secondary efficacy endpoints is that there is no difference when 
treated with riociguat compared to patients who remain on their previous therapy. The two-
sided alternative is that there is a difference, respectively.  
6.2.2.1 
Change from baseline in 6MWD    
 
The mean change and percentage change of 6MWD from baseline at each time point will be 
calculated for each group and total. The categories for 6MWD increase by ≥10% or ≥30m 
will also be displayed.  
 
Especially, the change of 6WMD at Week 24 from baseline will be compared between 
riociguat and active control group using stratified Wilcoxon test with a two-sided alpha level 
of 5%. Mean difference and 95% CI for the mean difference obtained using tt test. The 
stratification factor will be PAH class at baseline. The analysis will be performed with and 
without missing data imputed using LOCF. 
6.2.2.2 
Change from baseline in NT-proBNP    
The mean change and percent change of NT-proBNP from baseline at each time point will be 
calculated for each group and total. The number and percentage for the subjects wheather for 
NT-proBNP reduction by ≥30% (NT-proBNP Week 24/baseline ratio ≤ 0.7) will also be 
displayed.  


 
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Especially, the change of NT-proBNP at Week 24 from baseline will be compared between 
riociguat and PDE5i group using stratified Wilcoxon test and the stratification factor will be 
PAH classes at baseline. Mean difference and 95% CI for the mean difference obtained using 
tt test. The analysis will be performed with and without missing data imputed using LOCF. 
6.2.2.3 
Change from baseline in WHO FC    
The status for WHO FC will be described at each time point. It is envisaged that WHO 
functional class will either remain the same, improve by 1 or 2 categories or deteriorate by 1 
or 2 categories. A change score from baseline could go from -2 (class III at baseline and class 
I at the end of study) and +2 (class III at baseline and class V, death at the end of study).  The 
change from baseline in WHO FC between two groups and total will be analyzed using 
Wilcoxon test stratified by PAH classes at baseline. Mean difference and 95% CI for the mean 
difference obtained using tt test. The analysis will be performed with and without missing 
data imputed using LOCF. 
6.2.2.4 
Clinical worsening   
The adjudicated outcome for clinical worsening at Week 24 will be analyzed descriptively.  
Stratified Mantel-Haenzel test with a two-sided alpha level of 5% will be used to compare 
these two groups. Stratification factor is the PAH classes at baseline based on eCRF. The 
point estimate and 95% CI for OR will be presented. 
The distribution of time from date of first dose of study drug to clinical worsening for each 
treatment group will be generated using Kaplan-Meier (KM) estimate.  Subjects who do not 
have clinical worsening reported will be censored at the EOS. For each percentile (25th, 50th, 
75th) if reached, an estimate of time of clinical worsening from date of first dose and its 
associated 95% CI using Brookmeyer-Crowley methodology will be presented for each 
treatment group. The survival rates at Week 8, 16 and 24 for each treatment group will also be 
presented. 
6.2.2.5 
Multiplicity 
A multiplicity correction is not necessary for the primary endpoint because only one primary 
endpoint is defined. Secondary endpoints are tested hierarchically strictly according to the 
order listed in Table 3. An alpha adjustment is therefore not necessary for secondary and 
exploratory endpoints. 
Table 3: Hypothesis testing order 


 
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Order 
Endpoints 
1 
Satisfactory clinical response at Week 24  
2 
Change from baseline in 6MWD    
3 
Change from baseline in NT-proBNP    
4 
Change from baseline in WHO FC    
5 
Clinical worsening   
 
6.2.3 
Exploratory variable  
Summary tables will be provided for the exploratory variables at each visit (number and 
percentage of subjects for categorical variables and descriptive statistics of absolute values, as 
well as the change from baseline values for continuous variables): 
6.2.3.1 
cMRI (core laboratory, reported separately) 
cMRI is performed on a subset of patients. Descriptive analysis will be provided for the 
information including right ventricular function and all the other variables included in cMRI.  
6.2.3.2 
Living with Pulmonary Hypertension questionnaire (LPH)  
The LPH questionnaire is designed to measure the effects of Pulmonary Hypertension (PH) 
and PH specific treatments on an individual’s quality of life. The questionnaire and scoring 
method for LPH is defined in the protocol Section 16.5. In order to minimize the missing 
value for the total score, if the answer for a subquestion is missing, the LOCF for that 
particular question will be utilized to derive the total score if the previous score exists. 
Otherwise, the worst score, 5 will be used in order to derive the total score. The descriptive 
analysis for LPH total score at each time point and the change from baseline will be presented. 
A stratified Wilcoxon test for the change of LPH score at Week 24 from baseline will be used 
to determine if there is a difference between two treatment groups.  
6.2.3.3 
Modified REVEAL Risk Score (mRRS) and mRRS category  
The Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) risk 
score calculator is a validated assessment tool that has been developed to predict the 1-year 
survival of patients with PAH. The scoring method for mRRS is defined in protocol Section 
16.4 with a range from 0 (lowest risk) to 22 (highest risk). In order to minimize the missing 
value for the total score, if the answer for a subquestion is missing,  the LOCF for that 
particular question will be utilized to derive the total score if the previous score exists. 
Otherwise, the worst score for that particular question will be used in order to derive the total 
score.  
There are 5 risk groups defined for mRRS in Table 4: 


 
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Table 4. Risk scores and predicted 1-year survival for 5 specified risk strata for mRRS: 
 
Risk score ranges 
Risk group 
Predicted 1-year survival 
1 – 7 
low-risk 
95% to 100% 
8 
average-risk 
90% to <95% 
9 
moderately high-risk 
85% to <90% 
10 – 11 
high-risk 
70% to <85 
≥ 12 
very high-risk 
<70% 
The descriptive analysis will be presented for total mRRS score, change and percentage 
change from baseline and mRRS risk group at each time point. A stratified Wilcoxon test for 
the change from baseline of the mRRS score at Week 16 and Week 24 from baseline will be 
used to compare if there is a difference between the two treatment groups. A shift table will be 
also presented to demonstrate the change of risk category from baseline to Week 24. 
All the efficacy analyses will be performed on both FAS and PPS. During the analysis, if 
convergence problem is encountered, the stratification factor PAH category will be removed 
from the model. 
6.2.3.4 
Change in other biomarkers (ADMA, cGMP, GDF 15 [plasma], ST 2). 
The descriptive analysis will be presented for all the other biomarkers parameters (AMDA, 
cGMP, cGMP, GDF-15 and DT-2), including change and percentage change from baseline at 
each time point.  
6.3 Pharmacokinetics / pharmacodynamics 
Not applicable. 
6.4 Safety 
Analyses of safety variables will be performed on the SAF, unless otherwise specified.  The 
summaries will be provided by treatment group and overall. No statistical comparison will be 
performed between the two treatment groups. 
6.4.1 
Extent of exposure 
Descriptive statistical summaries will be provided for the SAF, FAS and PPS by treatment 
group for the following variables:  
• treatment duration (calculated from the first dose of study medication to the date the 
last dose of study medication was ingested)  


 
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• number of tablets received during titration period (first 8 weeks), maintenance period 
and overall study 
• average daily dose during titration period, maintenance period and overall study period 
• treatment compliance (calculated as total number of administered doses / total number 
of scheduled doses*100) during titration period, maintenance period and overall study 
period 
• number of subjects requiring dose up-titration, down-titration and without titration at 
each visit for riociguat group during titration period 
6.4.2 
Adverse events 
All adverse events (AEs) will be coded using the most updated version of MedDRA. 
AEs will be considered treatment-emergent if the events occurred or worsened on or after the 
date of the first dose of study drug and up to the 2 days after the end of treatment. Missing or 
partial data will be handled using the rules listed in section 4.3.2 in order to determine 
whether the AE is treatment-emergent.  
AEs that occur before the first study dose will be considered AEs before first study dose and 
AEs that occur more than 2 days after the end of treatment will be considered AEs during the 
follow-up period. 
All AE data including wash-out period for Adempas arm will be listed, including, onset 
relative to start of treatment, duration, intensity, relationship to study drug/protocol required 
procedure, action taken, outcome, and the coded terms. In addition, deaths, serious adverse 
events (SAEs), severe AEs, and AEs leading to study drug discontinuation or withdrawal 
from the study will be listed separately (if applicable). 
An overview table will summarize by treatment and overall the number of events and the 
number and percentage of subjects with at least one of the following AEs: 
• any AE before first study dose  
• any AE during the follow-up period 
• any TEAE  
• any serious TEAE 
• any severe TEAE 
• TEAE leading to dose reduction 
• TEAE leading to drug interruption 
• TEAE leading to discontinuation of the study drug 
• AE with the outcome of death  


 
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• any study drug-related TEAE 
• any study drug-related serious TEAE 
• any protocol-required procedure related TEAE 
• TEAEs starting prior to week 8 visit 
• TEAEs starting on or after week 8 visit  
The number and percentage of subjects reporting each AE will be summarized by SOC and 
Preferred Term (PT). Tables will be sorted alphabetically by SOC. PTs will be sorted by 
descending overall total frequency within an SOC. The following summaries will be 
produced: 
• TEAEs, by SOC and PT 
• TEAEs starting prior to week 8 visit, by SOC and PT 
• TEAEs starting on or after week 8 visit, by SOC and PT 
• AEs during the pre-treatment period, by SOC and PT 
• AEs during the follow-up period, by SOC and PT 
• TEAEs that occurred in more than 5% of the subjects, by SOC and PT 
• TEAEs, by SOC and PT and by intensity 
• TEAEs, by SOC and PT and by relationship to the study drug 
• serious TEAEs, by SOC and PT 
• serious TEAEs that occurred in more than 5% of the subjects, by SOC and PT 
• serious TEAEs, by SOC and PT and by intensity 
• serious TEAEs, by SOC and PT and by relationship to the study drug 
• TEAE leading to dose reduction by SOC and PT 
• TEAE leading to dose interruption by SOC and PT 
• TEAE leading to discontinuation of the study drug by SOC and PT 
• AEs with the outcome of death, by SOC and PT   
In the above summaries, subjects with more than one AE within a particular SOC are counted 
only once for that SOC.  Similarly, subjects with more than one AE within a particular PT are 
counted only once for that PT. In case a subject has events with different intensities , the 
maximum reported intensity will be used. If intensity is missing, the event will be considered 
as severe. Similarly, if the same event is reported as both unrelated and related to the study 
drug in one subject, the event will be reported as related to study drug. If the drug relationship 
is missing, the event will be considered as being related to the study drug. 
The exposure adjusted subject incidence per 100-person year will be produced for the 
following tables. The risk period is defined as from the first dose date to the end of treatment 
and all the events, including the recurrent ones will be counted for exposure adjusted subject 
incidence.  


 
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• TEAEs, by SOC and PT 
• serious TEAEs, by SOC and PT 
6.4.3 
Adverse events of special safety interest 
Symptomatic hypotension and serious hemoptysis (which includes pulmonary hemorrhage) 
are considered AEs of special interest and will be tableted for each group. The following 
tables will be produced by treatment group: 
• Treatment emergent hypotension, by SOC and PT 
• Treatment emergent hypotension, by PT and by intensity 
• Treatment emergent hypotension, by PT and by relationship to the study drug 
• Treatment emergent hemoptysis, by SOC and PT 
• Treatment emergent hemoptysis, by PT and by intensity 
• Treatment emergent hemoptysis, by PT and by relationship to the study drug 
 
The exposure adjusted subject incidence per 100-person year will be also produced for the 
symptomatic hypotension and serious hemoptysis/ pulmonary hemorrhage. 
6.4.4 
Safety laboratory assessments 
The following lab parameters will be summarized by treatment group and visit.  If data for 
any additional analytes are also recorded, these will be listed only. 
• Hematology: white blood cell differential count, erythrocytes, hemoglobin, 
hematocrit, platelets 
• Coagulation tests: prothrombin time, only for patients under anticoagulation therapy 
• Clinical chemistry: AST, ALT, total bilirubin, serum albumin, creatinine, potassium 
Biomarkers will be analyzed centrally according to the time points  given in the protocol. 
Out-of-reference-range laboratory values will be flagged as high (H) or low (L) in the listings.  
Descriptive summaries will be provided by treatment group for laboratory test for both by-
visit measures and change from baseline measures. Incidence rates of high lab abnormalities 
and low lab abnormalities will be reported. Shift tables presenting abnormal changes from 
baseline will be tabulated. 
Additionally, the following pre-specified abnormalities/changes will be displayed in 
frequency table. It will also summarize a combined elevation of AST or  ALT≥ 3 times ULN 
and bilirubin ≥ 2 times ULN at the same visit. 


 
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Statistical Analysis Plan Final Version 3.0 
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ALT (U/L) 
≥ 3 times ULN 
AST (U/L) 
≥ 3 times ULN 
Total Bilirubin (mg/dl) 
≥ 2 times ULN   
6.4.5 
Vital signs 
Vital signs including systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart 
rate (HR), measured at scheduled visits, will be summarized by treatment group and visit. 
Descriptive summaries will be provided for baseline values, post-baseline values and change 
from baseline. 
6.4.6 
12-lead electrocardiogram  
The following quantitative electrocardiogram (ECG) measurements will be taken during the 
study: 
• heart rate (beats/min) 
• PR interval (msec) 
• QRS interval (msec) 
• QT& QTcB/QTcF interval (msec)  
An overall Investigator assessment of ECG will be provided (categories “normal”, “abnormal, 
not clinically significant” and “abnormal, clinically significant”). Abnormal findings on 12-
lead ECG will be summarized by treatment group by visit using descriptive statistics. 
The ECG measurements in ECG will be summarized by treatment group using standard 
descriptive statistics. QT corrected for heart rate will additionally be described using Bazett’s 
formula (QTcB), Fridericia’s formula (QTcF) and Linear Correction Formula (QTcLC) .  
6.4.7 
Pregnancy test 
Pregnancy tests with positive result for women at scheduled visits will be displayed in a 
listing.  
6.4.8 
Other procedures and variables 
The descriptive analysis for pulse oximetry at baseline, including SaO2 (%),will be reported. 
The descriptive analysis for lung function testing at baseline including FEV1[L/s], FEV1 % of 
predicted, TLC [L] and TLC, % of predicted will also be reported. 
 


 
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7. Document history and changes in the planned statistical analysis 
Changes from SAP Final v2 (26-Mar-2020) to SAP Final v3 (09-Apr-2020): 
No change was made to the SAP. However, listing numbers were updated in the mocks. 
Changes from SAP Final v1 (09-June-2017) to SAP Final v2 (26-Mar-2020): 
Protocol deviations updated to reflect important deviations rather than major. Detail added 
regarding analysis sets being based on team review prior to database lock. 
Subgroup analysis for Race has been removed.   
Baseline characteristics updated to include subgroup analysis parameters. 
Tipping point analysis updated to include an imputation with improvement range ranging 
from 1%-99% in control group whilst the treatment group is imputed at the observed rate. 
Analysis on AEs updated to include TEAEs prior to week 8 visit and post week 8 visit. AEs 
leading to discontinuation of study by SOC and PT has been removed. 
 
8. References 
 


 
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9. Appendix 
9.1 Study schedule of procedures 
 
Mandatory 
Screening 
period 
(2 weeks)  
Rando-
mization 
(baseline) 
Overall treatment period (24 weeks)  
Follow-up 
period 
Visit 
V 0 
V 1 a 
H 1 b 
H 2 b 
H 3 b 
V 2 c 
Tele-
phone 
contact d  
V 3 
Tele-
phone 
contact d  
EOT 
Safety 
FU e 
Week/Days 
W -2 
(± 2 D) 
W 0 
(± 2 D) 
W 2 
(± 2 D) 
W 4 
(± 2 D) 
W 6 
(± 2 D) 
W 8 
(± 2 D) 
W 12 
(± 2 D) 
W 16 
(± 2 D) 
W 20 
(± 2 D) 
W 24 
(± 5 D) 
30 D 
(± 5 D) 
 
 
 
Rio 
Start  
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Check of inclusion/ 
exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
Lung function test 
X 
 
 
 
 
 
 
 
 
 
 
 
Pulse oximetry 
X 
X 
 
 
 
 
 
 
 
 
 
 
Echocardiography 
(LVEF) 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
Smoking status 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
Specific PAH 
medication 
X 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test f 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
Physical 
examination 
X 
 
 
 
 
 
 
 
 
 
X 
 
Weight and height 
X 
 
 
 
 
 
 
 
 
 
 
 
Dispense of riociguat 
 
 
X 
X 
X 
X 
X 
 
X 
 
 
 


 
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Mandatory 
Screening 
period 
(2 weeks)  
Rando-
mization 
(baseline) 
Overall treatment period (24 weeks)  
Follow-up 
period 
Visit 
V 0 
V 1 a 
H 1 b 
H 2 b 
H 3 b 
V 2 c 
Tele-
phone 
contact d  
V 3 
Tele-
phone 
contact d  
EOT 
Safety 
FU e 
Week/Days 
W -2 
(± 2 D) 
W 0 
(± 2 D) 
W 2 
(± 2 D) 
W 4 
(± 2 D) 
W 6 
(± 2 D) 
W 8 
(± 2 D) 
W 12 
(± 2 D) 
W 16 
(± 2 D) 
W 20 
(± 2 D) 
W 24 
(± 5 D) 
30 D 
(± 5 D) 
 
 
 
Rio 
Start  
 
 
 
 
 
 
 
 
 
medication g 
Drug accountability 
 
 
 
X 
X 
X 
X 
 
X 
 
X 
 
6MWD (blinded) h 
X i 
X 
 
 
 
 
X 
 
X 
 
X 
 
Biomarkers (central 
lab) 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
WHO FC (blinded) h 
X i 
X 
 
 
 
 
X 
 
X 
 
X 
 
mRRS 
 
X 
 
 
 
 
 
 
X 
 
X 
 
LPH (QoL) l 
 
X 
 
 
 
 
 
 
 
 
X 
 
Safety laboratory 
(local laboratory) 
X 
 
 
 
 
 
 
 
X 
 
X 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
ECG j 
X 
 
 
 
 
 
 
 
 
 
 
 
Change in 
concomitant 
medication h 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
AE assessment and 
reporting h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
cMRI (exploratory, 
reported separately) k 
 
X 
 
 
 
 
 
 
 
 
X 
 
Abbreviations: 6MWD = 6-minute walking distance; AE = adverse event; cMRI = cardiac magnetic resonance imaging; D = Days; ECG = 
electrocardiogram; EOS = end of study; FU = Follow-up; LVEF = left ventricular ejection fraction; mRRS = modified Reveal Risk Score; NT-
proBNP = N-terminal pro-brain natriuretic peptide; LPH =Living with Pulmonary Hypertension Questionnaire; PAH = Pulmonary Arterial 
Hypertension; QoL = Quality of Life; W = Week; WHO FC = World Health Organization Functional Class. 


 
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a Riociguat wash-out, first dose and dose titration:  
Patients in the riociguat arm will have a wash-out period between discontinuation of PDE-5i and the first dose of riociguat: 24-hour 
wash-out following last dose of sildenafil and 48-hour wash-out following last dose of tadalafil. 
Based on the time of the last PDE-5i dose, date and time of the first dose of riociguat after the wash-out period will be determined by the 
investigator and communicated to the patient. Before the first dose of riociguat a blood pressure measurement needs to be performed to 
ensure that systolic blood pressure is ≥ 95 mmHg. If the blood pressure is below this value, it can be measured again within 24 hours and if 
still below 95 mmHg, riociguat must not be administered. Measurement of blood pressure and application of first riociguat dose may be 
performed at the study center, or by an experienced nurse in the outpatient setting. Date and time of intake of the first dose of riociguat need 
to be documented by the investigator. The nurse will contact the center for this purpose via phone. 
Patients in the control arm will continue their current specific PAH treatment (PDE-5i +/-ERA). 
b Home Visits (H1, H2, H3):  
These visits will be conducted by an experienced nurse at the patient’s (both treatment arms) home. At the discretion of the investigators and 
if applicable (e.g., short distance to study center) these visits may also be performed at the study center. 
For the riociguat arm these visit are part of the titration period that will be performed according to the titration scheme (until Week 8, Visit 2). 
While in the titration period dose increase can only occur at the scheduled visits, a dose decrease (-0.5 mg) can be performed at any time 
based on the patient’s systolic blood pressure and well-being. In both arms blood pressure will be measured; in the riociguat arm the next 
riociguat dose will be decided in phone contact with the center according to the titration scheme. 
c Visit 2, Week 8: This is the first regular visit at the center after randomization. For the riociguat arm it will also be the last visit of the titration 
period. Following the titration period, patients will continue to receive riociguat TID at the optimal dose achieved at Week 8 (start of 
maintenance period).  
d Patients will be contacted via telephone every 4 weeks, if there is no scheduled visit to the study center. 
e Safety Follow-up visit after last dose of study drug. 
f Only women of childbearing potential will have a urine or serum test, depending on local routine at each study site. If test is performed 
> 48 hours before randomization, the test will need to be repeated. 
g For the riociguat arm IXRS consultation will be performed to supply drug. 
h Forms part of the clinical worsening assessment. 
i Blinded assessment starts at randomization 
j An ECG can be done at any time during the study, at the discretion of the investigator. It should be reported in the unscheduled procedure page. 
k This will be performed by core laboratory and reported separately. 
l To be performed if not available within last 6 months. 
 


 
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9.2 Sample SAS code 
General Estimation Equation: 
PROC GENMOD data=dataset descend; 
     CLASS subjectid treatment  PAH ; 
     MODEL outcome=treatment PAH visit visit*treatment / dist=bin; 
     REPEATED subject=subjectid / logor=exch; 
RUN; 
Tipping point analysis 
Step 1: Impute data with specified value: 
PROC MI data=dataset seed=12345 nimpute=10 out=outmi; 
            CLASS treatment PAH improvement; 
             MONOTNE logistic; 
             MNAR adjust (improvement(event=’1’)/shift=<log odds (shift1 + completer response 
rate) – log odds of completer response rate>     adjustobs(TRTP=’Riociguat’); 
                 adjust (improvement(event=’1’)/shift=<log odds (shift2 + completer response rate) 
– log odds of completer response rate>  adjustobs(TRTP=’PDE-5i’); 
                 VAR treatment PAH improvement; 
RUN; 
Step 2: Analyze the data with imputed datasets: (sort the data first before BY statement) 
PROC LOGISTIC data=outmi descending; 
           BY <_imputation_>; 
            CLASS treatment PAH; 
            MODEL improvement=treatment PAH / dist=binomial link=logit; 
            ESTIMATE ‘Week 24 Improvement rate difference for riociguat vs. PDE5i’ TRTP 1 -
1 /exp alpha=0.05; 


 
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            ODS OUTPUT ParameterEstimates=lgsparms CovB=lgscovb; 
RUN; 
Step 3: Combine results for inference: 
  PROC MIANALYZE parms=lgsparms  covb=lgscovb; 
             MODEL EFFECTS TREATMENT; 
   RUN;