Clinical trial NCT00863681
Conditions: Hypertension, Pulmonary
Keywords: Pulmonary arterial hypertension PH Stimulator
Sponsor: Bayer
Start date: 2009-03-12; Completion date: 2019-08-19
Enrollment: 396 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Patients who have completed the 12 weeks treatment of the PATENT-1 trial (study number 12934) will be asked to participate in this long term extension study with BAY63-2521.

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: Riociguat (BAY63-2521)
Intervention descriptions: intervention 1: BAY63-2521: 1mg tid -2.5 mg tid oral until end of study

Protocol documents:
Prot_000.pdf: 
Integrated Protocol /Study number BAY 63-2521/12935/
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Final Version 1.0/ 13 Dec 2012/AMD 11
Bayer
CLINICAL STUDY PROTOCOL
Title:
Long-term extension, multi-centre, multi-national study 
to evaluate the safety and tolerability of oral 
BAY 63-2521 (1 mg, 1.5 mg, 2 mg, or 2.5 mg tid) in 
patients with symptomatic Pulmonary Arterial 
Hypertension (PAH). PATENT-2 Study
Test Drug:
BAY 63-2521 (INN Riociguat)
Sponsor’s Name and Address:
Bayer HealthCare AG
D-51368 Leverkusen
Study Number/Version/Date:
12935 / Version 2.0/ 2008-Sep-11
The following Amendments have been incorporated into this Integrated Protocol.
AMENDMENT 
NUMBER
VERSION NUMBER
DATE
Amendment 5
1.0
10-June-2009
Amendment 6
1.0
22-March-2010
Amendment 8
1.0
15-Feb-2011
Amendment 11
1.0
13-Dec-2012


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Table of Contents
Table of Contents.......................................................................................................................2
Glossary and Abbreviations.......................................................................................................4
1.
INTRODUCTION..............................................................................................................6
2.
STUDY OBJECTIVES ......................................................................................................7
3.
INVESTIGATOR(S) AND OTHER STUDY PARTICIPANTS ......................................7
4.
INVESTIGATIONAL PLAN ............................................................................................8
4.1
Study Design and Plan ................................................................................................8
4.2
Selection of Study Population...................................................................................13
4.2.1
Inclusion Criteria ...............................................................................................13
4.2.2
Exclusion Criteria ..............................................................................................13
4.3
Removal of Patients from Study ...............................................................................14
4.4
Premature Termination of Study/Closure of Centre .................................................15
4.5
Treatments.................................................................................................................16
4.5.1
Treatments to be administered...........................................................................16
4.5.2
Identity of Investigational Product(s) ................................................................16
4.5.3
Method of Assigning Patients to Treatment Groups..........................................17
4.5.4
Selection of Doses in the Study .........................................................................17
4.5.5
Selection and Timing of Dose for Each Patient.................................................17
4.5.6
Blinding..............................................................................................................18
4.5.7
Concomitant Therapy.........................................................................................18
4.5.8
Treatment Compliance.......................................................................................21
4.6
Study Variables .........................................................................................................21
4.6.1
Safety Variables.................................................................................................21
4.6.2
Other Variables ..................................................................................................22
4.6.3
Assessment Periods............................................................................................22
4.6.4
Observations and Measurements .......................................................................30
4.6.5
Drug Concentration Measurements ...................................................................37
4.7
Data Quality ..............................................................................................................38
4.8
Documentation ..........................................................................................................38
5.
ETHICAL AND LEGAL ASPECTS ...............................................................................39
5.1
Ethics Committee (EC) or Institutional Review Board (IRB) ..................................39
5.2
Ethical Conduct of the Study ....................................................................................39
5.3
Regulatory Authority Approvals/Authorizations......................................................40
5.4
Patient Information and Consent...............................................................................40
5.5
Insurance ...................................................................................................................40
5.6
Confidentiality...........................................................................................................40
6.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ................41
6.1
Statistical and Analytical Plans.................................................................................41
6.2
Determination of Sample Size...................................................................................42
7.
ADVERSE EVENTS .......................................................................................................43
7.1
Contraindications/Warnings/Precautions/Interactions/Undesirable Effects .............43


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7.2
Adverse Event Monitoring........................................................................................46
7.3
Adverse Event Definitions ........................................................................................46
7.3.1
Adverse Event....................................................................................................46
7.3.2
Serious Adverse Event.......................................................................................47
7.3.3
Unexpected Adverse Event................................................................................49
7.3.4
Relationship of Adverse Event to Investigational Product................................49
7.3.5
Severity of the Adverse Event ...........................................................................50
7.3.6
Adverse Event Documentation ..........................................................................51
7.4
Reporting of Serious Adverse Events/Pregnancy .....................................................51
7.5
Reporting of Safety Related Events of Special Interest ............................................52
8.
USE OF DATA AND PUBLICATION...........................................................................52
9.
REFERENCES.................................................................................................................53
10.
APPENDICES ..............................................................................................................53
10.1
Study Flow Chart ......................................................................................................54
10.2
Pharmacokinetic Sampling........................................................................................61
10.3
Blood Gas Analysis...................................................................................................61
10.4
6 Min Walking Distance (6MWD) Test....................................................................62
10.5
Borg CR 10 Scale® or Modified Borg Dyspnoea Scale............................................64
10.5.1
Borg CR 10 scale and test instructions ..............................................................64
10.5.2
Modified Borg Dyspnoea Scale.........................................................................66
10.6
WHO functional class ...............................................................................................67
10.7
EQ-5D .......................................................................................................................67
10.8
Living with Pulmonary Hypertension questionnaire (LPH) .....................................72
10.9
Role of the Steering Committee (SC) .......................................................................74
10.10
Role of the Data Monitoring Committee (DMC) ..................................................74


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Glossary and Abbreviations
6MWD
6-minute walking distance
AE
adverse event or experience
ALT
alanine aminotransferase (also known as SGPT, qv)
ALP
alkaline phosphatase
AST
aspartate aminotransferase (also known as SGOT, qv)
CCW
concalc for Windows
cGMP
cyclic guanosine monophosphate
CHE
Cholinesterase
CK
creatine kinase
CRF
case report form
eCRF
electronic case report form
CT
computed tomography
CTEPH
chronic thromboembolic pulmonary hypertension
CYP3A4
cytochrome P450 isoenzyme 3A4 (etc)
d
Day
EC
ethical committee
ECG
Electrocardiogram
eg
exempli gratia, for example
EQ-5D
EuroQol questionnaire
g
standard acceleration due to gravity at the Earth's surface, by 
definition: g = 9.80665 m/sec2
GCP
Good Clinical Practice
GGT
gamma glutamyl transpeptidase
GLDH
glutamate dehydrogenase
h
Hour
H
Height
HDPE
High Density Polyethylen
HEOR
Health Economics, Outcomes and Reimbursement
HPLC
high pressure liquid chromatography
ie
id est, that is
IR
immediate release
INR
international normalized ratio (prothrombin time expressed in 
relation to normal value)
IRB
Institutional Review Board
iv
Intravenous
IVR / IVRS
interactive voice response system
LPH
Living with Pulmonary Hypertension questionnaire
M-1
metabolite M-1
mg
Milligram
mmHg
millimeter of mercury
MRR
Medical Research Report
NO
Nitric oxide
NT-proBNP
N-terminal pro-brain natriuretic peptide
O2
Oxygen


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PaCO2
arterial partial pressure of carbon dioxide
PaO2
arterial partial oxygen pressure
PEA
Pulmonary endarterectomy
PDE5
phosphodiesterase type-5
PH
pulmonary hypertension
PK
Pharmacokinetic
PTT
partial thromboplastin time
PvO2
venous oxygen pressure
PVOD
Pulmonary-veno-occlusive disease
QC
quality control
SAE
serious adverse event
SaO2
oxygen saturation
SAS
Statistical Analysis System
SBP
systolic blood pressure
tid
ter in die (3 times a day)
WHO
World Health Organization


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1. INTRODUCTION
Please see INTRODUCTION of the BAY 12394 (PATENT-1) protocol.
In addition, the following aspects should be considered with respect to the long-
term extension trial:
Based on the currently available scientific evidence, a large proportion of 
Pulmonary Artery Hypertension (PAH) patients cannot be cured. Therefore, it can 
be assumed that their disease will progress over the years, requiring a long-term 
medical treatment to maintain their quality of life and to increase their life 
expectancy.
Although the experiences with BAY 63-2521 with respect to the treatment of PAH 
are limited, in the light of the severity of the underlying disease it is justified to offer 
all patients who participated in the PATENT-1 trial a long-term treatment with 
BAY 63-2521 (until commercially available).
In this context, it should be highlighted that BAY 63-2521 revealed a positive 
benefit-risk ratio in the trials conducted in Pulmonary Hypertension (PH) patients to 
date (trials # 11874 and # 12166), allowing continuation of the development 
program. Moreover, in a first interim analysis of the extension phase of trial # 
12166 (includes 21 patients with a BAY 63-2521 treatment up to one year) the 
improvements in walking distance observed within the first 12 weeks of treatment 
were sustained without any significant safety concerns.
For further information refer to the Investigator Brochure. The Investigator’s 
Brochure will be updated at regular intervals during the conduct of the trial. New 
versions of the Investigator’s Brochure will be made available to the investigators 
without delay


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2. STUDY OBJECTIVES
To assess the long-term safety and tolerability of BAY 63-2521 in treatment naive 
patients and patients pretreated with an Endothelin Receptor Antagonist or a 
Prostacycline Analogue with symptomatic Pulmonary Arterial Hypertension (PAH).
The trial provides patients, who have completed 12 weeks of BAY 63-2521 double 
blind treatment (PATENT-1 trial, #12934), the option of long-term treatment with 
BAY 63-2521.
Efficacy assessments are included to provide an indication of maintenance of 
efficacy with long-term treatment.
3. INVESTIGATOR(S) AND OTHER STUDY PARTICIPANTS
Principal Investigator/Coordinating Investigator of the study
Name:
Address:
The Study Manager and the Medical Expert will appoint the coordinating 
investigator responsible for signing the MRR.
Information regarding additional key personnel involved in the conduct of the study, 
including names and contact details of participating investigators, monitors, clinical 
laboratories, technical departments and/or institutions, as well as information on 
members of additional study committees, will be found in the study files of the 
sponsor and on site if requested.
PPD
PPD
PPD
PPD
PPD


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4. INVESTIGATIONAL PLAN
4.1
Study Design and Plan
Multicentre, multinational, open label one arm study in patients with symptomatic 
PAH.
Study Phases:

Treatment Phase:

Titration Phase: 8 weeks

Main-Study Phase: Duration until BAY 63-2521 receives official 
approval and will be commercially available

Safety Follow Up Phase: 30 days
BAY 63-2521 will be administered orally as a tablet in doses of 0.5 mg, 1.0 mg, 1.5
mg, 2.0 mg, and 2.5 mg tid.
Titration Phase (8 weeks):
General aspects:
During the first eight weeks of the trial, patients from the Placebo Arm and from the 
BAY 63-2521 1.5 mg Dose Arm (applies only to patients who reached the 1.5 mg 
tid level) of PATENT-1 trial will be up-titrated, if tolerated, up to 2.5 mg 
BAY 63-2521 tid according to an individual dose titration scheme.
To maintain the blinding of PATENT-1, the PATENT-2 study medication 
(BAY 63-2521) is blinded with respect to the dose during the Titration Phase and
investigators will not know at which dose level a certain patient enters the
PATENT-2 trial.
Patients from the BAY 63-2521 Individual Dose Titration Arm
and the 
BAY 63-2521 1.5 mg Dose Arm will enter the extension trial on the same dose level 


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which they have received on the last day of PATENT-1, while patients from the 
Placebo Arm will start at Visit 1 with a BAY 63-2521 dose of 1.0 mg tid.
To allow a blinded individual dose titration, the titration will be performed with the 
aid of an IVR-System. At each Titration Visit (with the exception of Visit 1) the 
investigator needs to decide, based on the patient’s systolic blood pressure, if the 
study medication dose should be modified. The respective decision (increase, 
maintain or decrease dose) must be entered in the IVR-System that will 
automatically allocate the right dose in accordance with the respective titration 
scheme. Afterwards, the investigator will be informed by the system, which of the 
blinded medication bottles (blinded with respect to the dose) needs to be handed
over for the next titration period (starts always with the morning dose).
Independently from the patient’s allocation to a specific treatment arm in
PATENT-1, the investigators will apply the following blood pressure based titration 
rules for their dose decision in PATENT-2:
The individual study medication dose of the next titration step will be 
determined every 2 weeks according to the peripheral SBP measured at trough 
before intake of the morning dose 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 - 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 study treatment; restart after 24 hours with 
reduced dose (-0.5 mg tid).


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In general, if the investigator requests an increase or decrease of study medication 
dose via the IVR-System, the subsequent dose modification will not exceed 
plus/minus 0.5 mg study medication.
Although the individual dose titration scheme is solely based on the patient’s 
systolic blood pressure, investigators are obliged to consider in addition the 
patient’s well being. Therefore, it is allowed in case of study medication side 
effects, to suspend a foreseen up-titration step and to maintain the dose.
To request an increase of study medication dose is only possible at the planned 
study visits Visit 2, Visit 3 and Visit 4.
The Titration Phase ends at day 56 (Visit 5). At this visit the actual dose of the 
patients will be unblinded by the IVR-System.
Patients from the PATENT-1 Placebo Arm:
For patients from the PATENT-1 Placebo Arm the starting dose will be 1 mg 
BAY 63-2521 tid. The individual BAY 63-2521 dose will be titrated every 2 weeks 
according to the peripheral SBP measured at trough before intake of the next
morning dose. At the end of the Titration Phase (Visit 5) patients will have reached 
BAY 63-2521 doses between 0.5 mg tid and 2.5 mg tid.
2 weeks
2 weeks
2 weeks
2 weeks
2.0 mg tid
1.5 mg tid
1 mg tid
V2
V1
V3
V4
V5
Vn
Vn
Vn
Vn
Vn
0.5 mg tid
1.5 mg tid
1.0 mg tid
2.0 mg tid
2.5 mg tid
2.5 mg tid


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Patients from the PATENT-1 1.5 mg Dose Arm:
Patients from the PATENT-1 1.5 mg Dose Arm will enter the extension trial on the 
same dose which they have received on the last day of PATENT-1 (Visit 6).

In case that starting dose of PATENT-2 is 1.5 mg tid, the individual optimal 
BAY 63-2521 dose will be determined every 2 weeks according to the 
peripheral SBP measured at trough before intake of the next morning dose. At 
the end of the Titration Phase (Visit 5) respective patients will have reached 
BAY 63-2521 doses between 0.5 mg tid and 2.5 mg tid.

In case that starting dose of PATENT-2 is 1.0 mg tid or 0.5 mg tid, the dose
cannot be further increased until Visit 5. If the investigator requests a dose 
increase above that level via the IVR-System, the patient will undergo a sham 
titration. Nevertheless, in case that the investigator requests a dose decrease 
(eg for safety reason), dose modifications are possible (i.e. from 1.0 mg tid to 
0.5 mg tid), but without a subsequent re-increase before Visit 5. Patients who 
do not tolerate the lowest BAY 63-2521 (0.5 mg tid) must be withdrawn from 
the trial (see section 4.3)
Patients from the PATENT-1 Individual Dose Titration Arm:
Patients from the BAY 63-2521 Individual Dose Titration Arm of the PATENT-1 
study will enter the extension trial on the same dose which they have received on the 
last day of PATENT-1 (Visit 6). Although the investigator will apply during the 
2 weeks
2 weeks
2 weeks
2 weeks
1.5 mg tid
V5
Vn
Vn
Vn
Vn
Vn
0.5 mg tid
1.5 mg tid
1.0 mg tid
2.0 mg tid
2.5 mg tid
2.5 mg tid
V1
V2
V3
2.0 mg tid
V4


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Titration phase the same titration rules as for the PATENT-1 placebo patients, the 
individual dose cannot be increased above the dose received at last day of
PATENT-1. If the investigator requests a dose increase above that level via the IVR-
System, the patient will undergo a sham titration. Nevertheless, in case that the 
investigator requests a dose decrease (eg for safety reason), dose modifications are
possible, but without a subsequent re-increase before Visit 5.
Main-Study Phase (Duration until BAY 63-2521 receives official approval and 
will be commercially available):
From Visit 5 on (begin of the Main-Study Phase) investigators are allowed to 
modify the BAY 63-2521 dose in a dose range between 0.5 mg tid and 2.5 mg tid
according to the patient’s need. In contrast to the Titration Phase, patients may be 
up-titrated between regular scheduled visits. In this context, investigators have to 
consider the patient’s blood pressure (refer to the individual dose titration scheme), 
potential BAY 63-2521 side effects and the progression of the underlying
Pulmonary Hypertension.
Safety Follow Up Phase (30days)
For all patients stopping study treatment at any time a Safety Follow Up Visit 30 
days after stop of study medication intake should be performed.
General Note: Stop of study medication and dose reductions for safety reasons (eg 
patient suffers from severe symptomatic hypotension) are allowed at any point in 
time during the Titration and the Main-Study Phase. In case of intended dose 
reductions the investigator will contact the IVR-System, which can be done 
independently from any planned study visit, and request a dose reduction (- 0.5 mg 
study medication).


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4.2
Selection of Study Population
4.2.1
Inclusion Criteria

Patients who have completed 12 weeks of treatment in the double blind trial 
PATENT-1.

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.
4.2.2
Exclusion Criteria

Patient’s participating in another clinical trial 

Patients who have an ongoing serious adverse event from PATENT-1 that is 
assessed as related to BAY 63-2521 are not allowed to participate in the 
extension trial.

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.

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 or the sponsor.

Pertinent non compliance with the conditions for the trial or instructions by the 
investigator during PATENT-1 participation.

Patients with hypersensitivity to the investigational drug or inactive 
constituents.


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4.3
Removal of Patients from Study
A patient who withdraws is one who discontinued in a clinical study for any reason.
Patients may be withdrawn from the study for the following reasons:

At their own request.

At the specific request of the sponsor (eg detection of a new significant 
safety concern related to the study drug).

Occurrence of adverse events 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 trial or instructions by 
the investigator

Although not intended, patients may interrupt their intake of study 
medication due to various reasons (eg hospitalization in a remote hospital 
without study medication access, safety reasons, side effects).
- In case that an interruption took place during the Titration Phase and lasts 
longer than 3 days at a stretch (9 missing doses), it is not allowed to restart 
the study medication again (respective patients must be withdrawn from the 
trial). In case of shorter interruptions, it is at the discretion of the investigator 
if the study medication can be restarted.
- In case that an interruption took place during the Main Study Phase and lasts 
longer than 14 days at a stretch, it is not allowed to restart the study 


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medication again (respective patients must be withdrawn from the trial). In 
case of shorter interruptions, it is at the discretion of the investigator if the 
study medication can be restarted.

In case of pregnancy or breast feeding.

Participation in another clinical trial

In case that the patient fulfills one of the stopping criteria specified in 
Section 4.5.7“Prior and Concomitant Therapy”.

In case no further dose reduction is possible and patient does not tolerate the 
lowest possible BAY 63-2521 dose (0.5.mg tid).
Patients who withdraw should take part at the Termination Visit and the Safety 
Follow Up Visit (refer to Section 4.6.3). Moreover, it is the investigator’s 
responsibility, in case of permanent discontinuation of the study medication, to 
decide together with the patient about the initiation of an alternative treatment.
4.4
Premature Termination of Study/Closure of Centre
The sponsor has the right to close this study, and the investigator/sponsor has the 
right to close a centre, at any time, although this should occur only after 
consultation between involved parties. The EC/IRB must be informed. 
Reasons to close the study prematurely may be for example:

If patients can be transferred to another clinical study or treatment program 
with BAY 63-2521 that ensures that patients who benefit can be treated with 
the compound until the drug receives official approval and will be 
commercially available.

The occurrence of a new relevant safety related finding that has a negative 
impact on Risk-Benefit Ratio of the compound.


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Should the study/centre be closed prematurely, 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 given by the 
sponsor for destruction.
4.5
Treatments
4.5.1
Treatments to be administered
Test-Drug:
BAY 63-2521
Dosage:
1.0 - 2.5 mg (Individual Dose Titration) a
Route of administration: 
oral
Time and frequency of administration:
tidb
aIn case of side effects (eg symptomatic hypotension) doses of 0.5 mg tid are allowed
bThe respective single daily doses should be taken 6-8 hours apart.
(For the individual dose titration refer to Section 4.1.)
4.5.2
Identity of Investigational Product(s)
Study medication will be labeled according to the requirements of local law and 
legislation. Label text will be approved according to agreed Bayer procedures, and a 
copy of the labels will be made available to the study site upon request.
BAY 63-2521 will be provided by BAYER Clinical Drug Supplies as tablets at a 
dose of 0.5mg, 1mg, 1.5 mg, 2mg and 2.5mg. The 5 tablets strengths are identical in 
appearance.
BAY 63-2521 tablets will be packed in HDPE bottles.
Storage requirements
All investigational drugs used during the trial will be stored at the investigational 
sites in a place inaccessible to unauthorized personnel, ie a locked cabinet.


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4.5.3
Method of Assigning Patients to Treatment Groups
Not applicable
4.5.4
Selection of Doses in the Study
The dose selection for this study was based on the following rationale:
The dose range of 1.0 - 2.5 mg tid was tested in healthy volunteers in a multiple-
dose study (# 11260). The highest dose of 2.5 mg tid showed a clear increase in 
adverse events and further escalation was stopped. A dose of 0.5 mg was identified 
in healthy volunteers (study 11258) as the no-effect dose while 1.0 mg already 
showed clinically relevant hemodynamic effects in some patients in the proof of 
concept study 11874. In the same study a strong lowering of systemic bl ood 
pressure was observed in one patient at the highest dose level (5 mg). Therefore 1.0 
mg tid was selected as the minimal dose and 2.5 mg tid as the maximum dose for 
further studies in patients (for further details refer to the Investigator Brochure). In
an ongoing Phase II trial (12166) in patients with PAH and CTEPH the respective 
dose range is tested in combination with an individual dose titration scheme. Based 
on interim analyses dose between 1.0 mg tid and 2.5 mg tid are effective and safe.
4.5.5
Selection and Timing of Dose for Each Patient
BAY 63-2521 will be administered tid as IR tablets with or without food.
During the eight weeks lasting Titration Phase, patients from the Placebo Arm and 
from the BAY 63-2521 1.5 mg Dose Arm (applies only to patients who reached the 
1.5 mg tid level) of PATENT-1 trial will be up-titrated, if tolerated, up to 2.5 mg 
BAY 63-2521 tid according to the individual dose titration scheme. In contrast to 
that, patients from the PATENT-1 Individual Dose Titration Arm will remain on 
their “optimal dose” from PATENT-1 (for further details refer to Section 4.1).


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After an individual BAY 63-2521 dose has been determined  all patients will enter
the Main-Study Phase (Visit 5). During the Main-Study Phase investigators are 
allowed to modify the BAY 63-2521 dose according to the patients need. In contrast 
to the Titration Phase, patients may be up-titrated between regular scheduled visits.
The maximum allowed BAY 63-2521 dose is 2.5 mg tid, the minimum 0.5 mg tid
(for further details refer to Section 4.1).
4.5.6
Blinding
Titration Phase:
To ensure the blinding of the treatment regimen of PATENT-1 study, the dosing of 
BAY 63-2521 will be kept blinded during the Titration Phase of PATENT-2.
Main Study Phase:
During the Main-Study Phase the blinding of dosing will be removed and patients 
will be treated with “open label” medication.
4.5.7
Concomitant Therapy
The intake of the following concomitant medications is not allowed during the 
Titration Phase and the Main-Study Phase of the trial:

Specific (eg Sildenafil or Tadalafil) or unspecific Phosphodiesterase
Inhibitors (eg Dipyridamole, Theophylline)

NO donors (eg Nitrates)
Patients, who require respective medications, need to be withdrawn from the study 
(refer to Section 4.3“Removal of Patients from Study”).
Treatment naive patients from PATENT-1
It is not allowed to start a concomitant Endothelin Receptor Antagonists- / 
Prostacycline Analogues therapy during the Titration Phase of the trial (after Visit 5 


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concomitant treatment is allowed). Patients, who require a concomitant Endothelin 
Receptor Antagonists- / Prostacycline Analogues therapy during the Titration Phase
need be withdrawn from the study medication (refer to Section 4.3 “Removal of 
Patients from Study”).
Patients pre-treated with an Endothelin Receptor Antagonist or a 
Prostacycline Analogue from PATENT-1
It is not allowed to modify the concomitant Endothelin Receptor Antagonists- / 
Prostacycline Analogues therapy (eg dosage, type of medication) during the 
Titration Phase of the trial (After Visit 5 therapy modifications are allowed). 
Patients who require a modification of their Endothelin Receptor Antagonists- / 
Prostacycline Analogues therapy during the Titration Phase need to be withdrawn 
from the study medication (refer to Section 4.3“Removal of Patients from Study”).
Other concomitant therapy

Due to possible pharmacokinetic interactions between BAY 63-2521 and 
strong CYP3A4 inhibitors (eg Ketoconazol) concomitant treatment should 
be applied with caution (eg additional blood pressure monitoring). Such 
drugs may significantly increase BAY 63-2521 plasma concentrations. In 
this context, dose reduction of BAY 63-2521 should be considered (eg – 0.5 
mg tid), in particular if the patient suffers a clinical relevant decrease in 
blood pressure (eg systolic blood pressure <90 mmHg with clinical 
symptoms). For further information refer to the Investigator Brochure.

Antacids like aluminum hydroxide/magnesium hydroxide (eg Maaloxan ®) 
should not be taken simultaneously with BAY 63-2521, because a negative 
impact on the bioavailability of the study drug has been observed (please 
refer to the Investigator Brochure). To avoid such kind of interaction, 
antacids should be taken 1 hour after intake of BAY 63-2521 at the earliest.


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
Pre- and co-treatment with Omeprazole led to a  decrease in BAY 63-2521 
bioavailability, indicating a lower bioavailability of BAY 63-2521 in neutral 
versus acidic milieu (for further information refer to the Investigator 
Brochure).

Preliminary inspection of trough and peak plasma concentrations of 
BAY 63-2521 and BAY 60-4552 (Main BAY 63-2521 metabolite) in a 
cohort of patients treated with bosentan (n=6) compared to the patients not 
treated 
with 
bosentan 
(n=66) 
clearly 
indicate 
a 
decrease 
in 
BAY 63-2521/BAY 60-4552 plasma exposure, most probably due to the 
known CYP3A4 enzyme-inducing effects of concomitant bosentan. 
However, patients treated with bosentan profited in about the same 
magnitude in the 6 minute walk test as patients in the therapy naïve cohort 
did (for further information refer to the Investigator Brochure, trial 12166).

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 Titration Phase of the 
study. However, later on during the Main Study Phase participation at 
respective training program is allowed, but need to be documented in the 
electronic CRF.
Concomitant treatment in case of clinical deterioration
In case of a clinically relevant deterioration of the patient’s signs or symptoms of 
pulmonary hypertension the investigator may consider starting an alternative 
treatment with Endothelin Receptor Antagonists, and/or Prostacycline Analogues, 
and/or Phosphodiesterase Type-5 Inhibitors or to modify a preexisting Prostacycline
Analogues treatment (ie increase of number of daily Iloprost inhalations from 6 to 9, 
or increase of Iloprost dosage from 2.5 to 5.0 microgram per inhalation, or start of an 
iv Prostacycline Analogue) at any point in time.


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In case that the administration of the treatment is in conflict with the limitations 
mentioned above, the treatment with the study drug needs to be terminated (refer to 
Section 4.3“Removal of Patients from Study”).
Due to possible synergistic effects on blood pressure Phosphodiesterase Type-5 
Inhibitors should only be administered after an appropriate wash out time of 24 
hours after last intake of BAY 63-2521.
4.5.8
Treatment Compliance
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 calculated dose. 
Moreover, plasma concentrations will give additional information about patients' 
compliance.
4.6
Study Variables
The objective of the trial is to assess safety and tolerability of long-term treatment 
of BAY 63-2521 in patients with symptomatic PAH. In addition, efficacy 
assessments are included to provide an indication of maintenance of efficacy with 
long term treatment.
4.6.1
Safety Variables

Treatment emergent adverse events

Treatment emergent serious adverse events

Laboratory parameters

Blood pressure

Heart rate

ECG

Blood gas parameter


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4.6.2
Other Variables

Change from baseline in 6 Minute Walking Distance

Change from baseline in NT-pro BNP

Change from baseline in WHO functional class

Time To Clinical Worsening

Change from baseline in Borg CR 10 Scale or Modified Borg Dyspnoea 
Scale (if patients were enrolled in trial 12934 before amendment 4 approval 
in their countries) (measured at the end of the 6MWD Test)

Change from baseline in EQ-5D questionnaire

Change from baseline in LPH questionnaire

Change in use of healthcare resources
4.6.3
Assessment Periods
Visit 1 at Day 0
Patients who finalized at Visit 6 the PATENT-1 trial and underwent invasive 
hemodynamic measurements may remain in the clinic until the next day (optional 
hospital stay).
At the day after finalization of PATENT-1 trial (= Visit 1 of PATENT -2), patients 
who fulfill the in/exclusion criteria and signed the informed consent form will be 
included into PATENT -2.
Please Note: it is not permitted to include a patient into the extension study on the 
same day of V6 of PATENT -1 (applies even if Visit 6 investigations were 
performed at two consecutive days).


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On Visit 1 prior to first administration of PATENT-2 study medication, blood 
pressure and heart rate will be measured.
Subsequently, the patients will be allocated via the IVR-System to their individual 
BAY 63-2521 starting dose. In this context, the IVR-System will consider the 
patient’s treatment arm allocation from the PATENT-1 trial (for further details refer 
to Section 4.1).
Two to three hours after the first intake of study medication, blood pressure and 
heart rate measurement will be repeated (for further details about the order of the 
procedures and the temporal relationship refer to Section 10.1).
Between six to eight hours after first study medication intake, the patients should
take the second dose of study medication (second measurement cycle). One to zero 
hours before intake of second dose of study medication, blood pressure and heart 
rate will be measured, pharmacokinetic blood samples will be collected and a 12-
lead electrocardiogram will be recorded. 2-3 hours after intake of second dose of 
study medication the blood pressure and heart rate should be measured (for further 
details about the order of the procedures and the temporal relationship refer to 
Section 10.1).
In addition to the measurements related to the measurement cycles, Adverse Events 
will be questioned and documented. Adverse events that occur before intake of first 
dose of PATENT-2 medication will be allocated to PATENT-1.
The study medication should be taken six to eight hours apart. If during the profile 
visit the systolic blood pressure falls below 90 mmHg with clinical symptoms of 
hypotension such as dizziness or presyncope, the study medication should be 
reduced by 0.5 mg tid or if deemed necessary interrupted (see section 4.1).
If there are no medical objections, the patients will be discharged, after the second 
measurement cycle (blood pressure and heart rate are the main hemodynamic safety 
parameters that need to be considered). In this context, study medication for the 
next two weeks will be dispensed.


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In case of medical objections (e.g. low blood pressure) patients should be 
hospitalized until a stable status is achieved (optional hospital stay).
During out-patient treatment until Visit 5, the patients will document the intake of 
the study medication on a patient diary which they will receive at Visit 1. The 
patients will return the patient diary to the investigator at each study visit until Visit 
5. The exact time points of the last 3 preceding doses before the ambulatory visit 
will be documented in the CRF.
Note: All blood pressure, heart rate measurements and ECGs should be performed 
in supine position at rest (for more details refer to Section 4.6.4).
Visit 2 at Day 14 / Visit 3 at Day 28 / Visit 4 at Day 42a
adeviations from the scheduled visits of ±2 days are permissible
Patients will return to hospital for an ambulatory assessment every 2 weeks without 
taking their morning dose of study medication. Before the dose of the study 
medication will be adjusted according to the titration scheme (refer to Section 4.1), 
blood pressure and heart rate will be measured, blood samples for clinical 
chemistry, hematology, coagulation parameters, NT-pro BNP will be collected, and 
a 12-lead electrocardiogram will be recorded.
Subsequently, based on the patient’s SBP at trough, an individual decision with 
respect to a dose modification will be made (for further details refer to Section 4.1). 
The respective decision will be entered into the IVR-System. Afterwards, under 
consideration of the IVR-System’s reply, the study medication for the next 2 weeks 
will be dispensed to the patients.
Two to three hours after intake of the morning dose of study medication, blood 
pressure and heart rate measurement will be repeated (for further details about the 
order of the procedures and the temporal relationship refer to Section 10.1).
Four to five hours after the intake of the morning dose of study medication 6MWD 
Test and an evaluation of Borg CR 10 Scale or Modified Borg Dyspnoea Scale (if 


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applicable) will be performed (for further details about the order of the procedures 
and the temporal relationship refer to Section 10.1).
.
In case that the SBP drops after intake of the morning dose below 90 mmHg with 
clinical symptoms of hypotension such as dizziness or presyncope, the study 
medication should be reduced by 0.5 mg tid or if deemed necessary interrupted for 
safety reasons (see section 4.1).
In addition to the measurements related to the cycle of measurements, the patient’s 
concomitant medication will be updated, healthcare resource information will be 
collected, WHO functional class will be assessed,  smoking status and Events of 
Special Interest as well as Adverse Events will be questioned and documented in the 
CRF.
The patients will be asked to return all unused study medication and the patient 
diary from the former visit for a compliance check. 
Note: All blood pressure, heart rate measurements and ECGs should be performed 
in supine position at rest (for more details refer to Section 4.6.4).
Visit 5 at Day 56a
adeviations from the scheduled visit of ± 2 days are permissible
Patients will return to hospital for an ambulatory assessment without taking their 
morning dose of study medication. Before the dose of the study medication will be 
adjusted according to the titration scheme (refer to Section 4.1), blood pressure and 
heart rate will be measured, blood samples for clinical chemistry, hematology, 
coagulation parameters, NT-pro BNP, and pharmacokinetics will be collected, and a 
12-lead electrocardiogram will be recorded. In addition, the patients will be asked to 
complete the EQ-5D and the LPH questionnaires.


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Subsequently, based on the patient’s SBP at trough, an individual decision with 
respect to dose modifications will be made (for further details refer to Section 4.1). 
The respective decision will be entered into the IVR-System. Afterwards, under 
consideration of the IVR-System’s reply, the study medication for the next 4 weeks 
will be dispensed to the patients (Note: from that point in time on, the dose of the 
study medication will be unblinded).
Two to three hours after intake of the morning dose of study medication, blood 
pressure and heart rate measurement will be repeated (for further details about the 
order of the procedures and the temporal relationship refer to Section 10.1).
Four to five hours after the intake of the morning dose of study medication 6MWD 
Test and an evaluation of Borg CR 10 Scale or Modified Borg Dyspnoea Scale (if 
applicable) will be performed(for further details about the order of the procedures 
and the temporal relationship refer to Section 10.1).
.
In case that the SBP drops after intake of the morning dose below 90 mmHg with 
clinical symptoms of hypotension such as dizziness or presyncope, the study 
medication should be reduced by 0.5 mg tid or if deemed necessary interrupted for 
safety reasons (see section 4.1).
In addition to the measurements related to the cycle of measurements, the patient’s 
concomitant medication will be updated, healthcare resource information will be 
collected, WHO functional class will be assessed, smoking status and Events of 
Special Interest as well as Adverse Events will be questioned and documented in the 
CRF.
The patients will be asked to return all unused study medication and the patient 
diary from the former visit for a compliance check. The exact time points of the last 
3 preceding doses before the ambulatory visit will be documented in the CRF.


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Note: All blood pressure, heart rate measurements and ECGs should be performed 
in supine position at rest (for more details refer to Section 4.6.4).
Visit 6 a (changed with amendment 11)
a deviations from the scheduled visit of ± 2 days are permissible 
Patients will return to hospital for an ambulatory assessment at Visit 6 without 
taking their morning dose of study medication.
Before the patients take the morning dose of the study medication, a physical 
examination will be done and the patient’s weight recorded, blood pressure and 
heart rate will be measured, blood samples for clinical chemistry, hematology, 
coagulation parameters, blood gas analysis, NT-pro BNP will be collected, and a 
12-lead electrocardiogram will be recorded. In addition, the patients will be asked to 
complete the EQ-5D questionnaire.
Subsequently, the investigator will make a decision (needs to be entered into the 
IVR-System) with respect to the patient’s BAY 63-2521 dose for the next treatment 
period. In this context, the investigator will consider the patient’s blood pressure 
(refer to the individual dose titration scheme Section 4.1), potential BAY 63-2521 
side effects and the progression of the underlying Pulmonary Hypertension.
Two to three hours after intake of the morning dose of study medication, blood 
pressure and heart rate measurement will be repeated (for further details about the 
order of the procedures and the temporal relationship refer to Section 10.1).
Four to five hours after the intake of the morning dose of study medication 6MWD 
Test and an evaluation of Borg CR 10 Scale or Modified Borg Dyspnoea Scale (if 
applicable) will be performed (for further details about the order of the procedures 
and the temporal relationship refer to Section 10.1).
In case that the SBP drops after intake of the morning dose below 90 mmHg with 
clinical symptoms of hypotension such as dizziness or presyncope, the study 


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medication should be reduced by 0.5 mg tid or if deemed necessary interrupted for 
safety reasons (see section 4.1).
In addition to the measurements related to the cycle of measurements, the patient’s 
concomitant medication will be updated, healthcare resource information will be 
collected, WHO functional class will be assessed, smoking status and Events of 
Special Interest as well as Adverse Events will be questioned and documented in the 
CRF.
The patients will be asked to return all unused study medication.
For female patients with child bearing potential a pregnancy test will be performed.
Unblinded study medication will be dispensed for the next 90 days.
Note: All blood pressure, heart rate measurements and ECGs should be performed 
in supine position at rest (for more details refer to Section 4.6.4).
Visit 7 – Vn (every 90 days)a* (added with amendment 11)
a deviations from the scheduled visit of ± 14 days are permissible 
Patients will return to hospital for an ambulatory assessment without taking their 
morning dose of study medication.
Before the patients take the morning dose of the study medication, a physical 
examination will be done and the patient’s weight recorded, blood pressure and 
heart rate will be measured.
Subsequently, the investigator will make a decision (needs to be entered into the 
IVR-System) with respect to the patient’s BAY 63-2521 dose for the next treatment 
period. In this context, the investigator will consider the patient’s blood pressure 
(refer to the individual dose titration scheme Section 4.1), potential BAY 63-2521 
side effects and the progression of the underlying Pulmonary Hypertension.


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One hour after the intake of the morning dose of study medication 6MWD Test will 
be performed. 
In case that the SBP drops below 90 mmHg with clinical symptoms of hypotension 
such as dizziness or presyncope, the study medication should be reduced by 0.5 mg 
tid or if deemed necessary interrupted for safety reasons (see section 4.1).
In addition to the measurements related to the cycle of measurements, the patient’s 
concomitant medication will be updated, WHO functional class will be assessed and 
Events of Special Interest as well as Adverse Events will be questioned and 
documented in the CRF.
The patients will be asked to return all unused study medication.
For female patients with child bearing potential a pregnancy test  must be performed 
locally.
Unblinded study medication will be dispensed for the next 90 days.
Note: All blood pressure, heart rate measurements should be performed in supine 
position at rest (for more details refer to Section 4.6.4).
Termination Visit
In case the decision has been made to stop the study medication prematurely or if 
the sponsor announces the official end of the study, a Termination Visit should be 
performed at the respective point in time or as soon as possible after stop of 
medication. In general, at the Termination Visit the same efficacy and safety 
relevant measurements should be performed as at Visit n (Exception: no pregnancy 
test needs to be performed). In particular, every effort should be made to perform 
the 6MWD Test. Deviations need to be documented in the electronic CRF.


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Safety Follow Up Visit 30 days after stop of study medication a
a deviations from the scheduled visit of +5 days are permissible
For all patients who stopped the study medication either at the official end of the 
trial or prematurely, a Safety Follow-Up Visit 30 days after last study medication 
intake has to be performed.
At the Safety Follow Up Visit the following assessments should be performed: 
physical examination including determination of patient’s weight, blood pressure 
and heart rate measurement (changed with amendment 11).
For female patients with child bearing potential a pregnancy test must be performed
locally. Moreover, adverse events will be questioned and the concomitant 
medication pages in the electronic CRF will be updated.
Note: All blood pressure and heart rate measurements should be performed in 
supine position at rest (for more details refer to Section 4.6.4).
4.6.4
Observations and Measurements
(Visits and numbering updated with amendment 11)
Laboratory Parameters
All blood samples will be analyzed in a central laboratory until V6.
Laboratory procedures will be described in a separate laboratory manual.
At the latest at the end of the study when all planned analyses are completed, all 
blood samples will be destroyed.

Hematology, clinical chemistry, coagulation test
Hematology (white blood cell differential count, erythrocytes, hemoglobin, 
hematocrit, platelets)
Coagulation tests (PTT, INR)


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Clinical chemistry (AST, ALT, ALP, GGT, GLDH, CK, lipase, CHE, creatinine, 
urea, uric acid, total bilirubin, total protein, serum albumin, sodium, potassium, 
calcium, phosphate)
Note: Calcium and phosphate will only be analyzed for patients who were included 
under amendment 8 of study 12934.
Frequency: At every visit until V6 (except Visit 1)

NT-proBNP
Frequency: At every visit until V6 with the exception of Visit 1 and Safety Follow 
Up Visit
Changes from baseline NT-proBNP will be considered as a secondary efficacy 
endpoint in PATENT-1. To ensure the blinding of the treatment regime of 
PATENT-1, the results of the NT-pro BNP determinations at PATENT -2 Visits 2-5 
will not be forwarded to the investigators before lock of the PATENT-1 database. In 
contrast to that the results of the NT-pro BNP determination at PATENT-2, Visit 6 
will be forwarded to the investigators.

Pregnancy testing
Methodology: Determination of ß- human chorionic gonadotropin in blood serum or 
urine
Frequency: Will be performed centrally at Visit 6 and locally at least at every Main-
Study Phase Visit (V7-Vn) and at Safety Follow Up Visit. Based on country 
specific regulations further measurements might be performed.
In addition to the above mentioned serum ß- human chorionic gonadotropin tests, a 
urine test will be performed at Visit 6 of PATENT-1 study if the patient will 


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participate in the extension study. Female patients with childbearing potential can 
be enrolled into the extension study based on the result of this test.
Blood gas analysis
SaO2(%)
PaO2(mmHg
PaCO2(mmHg)
Supplemental oxygen  “yes” or “no” (If the patient receives supplemental oxygen 
the amount will be recorded in the electronic CRF in liter per minute)
Methodology: Capillary or arterial blood gas analysis
Frequency: At V6 
Blood pressure and heart rate measurement
Blood pressure and heart rate will be measured after the patient has been at rest for 
10 minutes in a supine position. The same arm is always used for these 
measurements.
Methodology: 
Non 
invasive 
measurement 
preferably 
with 
a 
mercury 
sphygmomanometer or a validated electronic device in accordance with published 
guidelines (eg American Heart Association. Recommendations for Blood Pressure 
Measurement in Humans and Experimental Animals. Hypertension 2005;45;142-
161)
Frequency: At every visit
Point in time: For details refer to appendix 10.1
Electrocardiography
For deriving the ECGs the patient should always be in supine position. The ECGs 
should be derived after a resting period of 15 min. The ECGs for the study will be 


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transferred electronically and assessed centrally. In addition, the investigator will 
print-out the ECGs locally and review the ECGs for potential AEs.
ECG procedures will be described in a separate manual.
Methodology: 12 lead ECG
Frequency: Every visit until V6
Point in time: For details refer to appendix 10.1
Exercise Testing / 6 Min Walking Distance (6MWD) Test
The 6 Min Walking Distance Test will be performed in accordance with the
American Thoracic Society Guideline. 
Methodology: During the Titration Phase the test 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 blood pressure and heart rate after dosing. 
This person will enter the test results on a separate work sheet and a different person
(could be the same person as involved in titration) will enter them into the electronic 
CRF.
Frequency: At every visit with the exception of Visit 1 and Safety Follow-Up Visit
Point in time: For details refer to section 4.6.3and appendix 10.1For further details 
refer to Section 10.4.
Borg CR 10 Scale® or Modified Borg Dyspnoea Scale 
The Borg CR 10 Scale or Modified Borg Dyspnoea Scale (if patient was enrolled 
before 12934 Amendment 4 approval in their country) will be measured together 
with 6MWD Test. 
Methodology: The test will be explained to the patients before starting the 6MWD 
test. The patients will be asked to rank their exertion at the end of the 6MWD test.
During the Titration Phase the test has to be performed by a person who is not 
involved in the process of study drug titration and is unaware of the immediate 
reaction of the patient’s blood pressure and heart rate after dosing. This person will 


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enter the test results on a separate work sheet and a different person(could be the 
same person as involved in titration) will enter them into the electronic CRF.
In context with 12934 protocol amendment 4 the “Modified Borg Dyspnoea Scale” 
was replaced by the Borg CR 10 Scale®. For consistency reason, patients who were 
enrolled before approval of 12934 protocol amendment 4 in their country must use 
the “Modified Borg Dyspnoea Scale” throughout the main and the extension study.
Frequency: At every visit until V6 with the exception of Visit 1 and Safety Follow
Up Visit
Point in time: Immediately after the 6MWD Test
For further details refer to section 4.6.3and Section 10.5.
Determination of WHO Functional Class
The patient’s functional class will be determined according to the WHO 
classification.
Methodology: During the Titration Phase the evaluation has to be performed by a 
second physician who is not involved in the process of study drug titration and is 
unaware of the immediate reaction of the patient’s blood pressure and heart rate 
after dosing. This physician will enter the test results on a separate work sheet and a 
different person(could be the same person as involved in titration) will enter them 
into the electronic CRF.
Frequency: At every visit with the exception of Visit 1 and Safety Follow-Up Visit
For further details refer to Section 10.6.


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Events of Special Interest
Time To Clinical Worsening
The first occurrence of the following events of special interest need to be 
documented in the electronic CRF and will be considered for the calculation of the 
combined endpoint “Time To Clinical Worsening”:

Death (all-cause mortality)

Heart/lung transplantation

Atrial septostomy (AS)

Hospitalization due to persistent worsening of Pulmonary Hypertensiona,b

Start of new PH specific treatment (Endothelin Receptor Antagonists, 
Prostacycline
Analogues, 
Phosphodiesterase 
Type-5 
Inhibitors) 
or 
modification of a preexisting Prostacycline Analogues treatment (ie increase of 
number of daily Iloprost inhalations from 6 to 9, or increase of Iloprost dosage 
from 2.5 to 5.0 microgram per inhalation, or start of an iv Prostacycline
Analogue) due to worsening Pulmonary Hypertension.

Persistent decrease of more than 15 % from baseline or more than 30% 
compared to the last study related measurement in 6MWD due to worsening 
pulmonary hypertensionb.
The persistence of the decrease has to be confirmed by a second measurement 
performed after 14 days. In case that the period between first occurrence of the 
event and the Termination Visit is less than 14 days, the decrease needs to be 
confirmed at the Termination Visit.

Persistent worsening of functional class due to deterioration of Pulmonary 
Hypertensionb:


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Patients who deteriorate from class II or III to class IV: The persistence of 
worsening has to be confirmed by a second measurement performed after 14 
days. In case that the period between first occurrence of the event and the 
Termination Visit is less than 14 days, the decrease needs to be confirmed at 
the Termination Visit.
Other Events of Special Interest
The first occurrence of the following event of special interest needs to be 
documented in the electronic CRF, but will not be considered for the calculation of 
the combined end point “Time To Clinical Worsening”:

Initiation of a supplemental long-term oxygen therapy (= oxygen application 
for more than 30 days at a stretch) or persistent modification of a pre-existing 
supplemental long term oxygen therapy (ie need for a persistent increase of the 
amount of delivered oxygen for more than 30 days) due to worsening 
pulmonary hypertension.b
aTransient deteriorations of clinical status requiring hospitalization, treatable by eg short time 
application of iv diuretics, positive inotropic agents or non-invasive ventilation and allowing patients 
discharge within 48 hours are not considered as persistent with respect to the event of special interest 
definition.
bIn case of clinical deterioration the investigator has to assess carefully if the deterioration of the 
patient’s condition (eg worsening functional class) is related to the underlying pulmonary 
hypertension or can be explained by an alternative cause (eg transient infection, musculoskeletal 
disease, surgical or medical intervention other than PH related, exacerbation of a concomitant lung 
disease, lacking compliance of medication intake). Only persistent clinical deteriorations caused by 
the underlying pulmonary hypertension will be considered as events of special interest.
Frequency: At every visit with the exception of Visit 1 and Safety Follow-Up Visit 
the investigator must check if an event of special interest has occurred in the period 
between start and termination of the study drug treatment. With respect to each 
subcategory (eg “hospitalization due to persistent worsening of pulmonary 


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hypertension”) it is only necessary to document the first occurrence of such an event 
in the electronic CRF.
HEOR measurements
EQ-5D, LPH
EQ-5D and LPH are health questionnaires that evaluate the patient’s health status 
and quality of life.
Methodology: Questionnaires need to be self-completed by the patients
EQ-5D Frequency: V5 and V6 only
LPH Frequency: Visit 5 only.
For further details refer to Section 10.7and Section 10.8.
Use of healthcare resources
For health economic calculations (see section 4.6.2) investigators need to collect 
information about the use of healthcare resources. This includes information about:

Visits at healthcare professionals (eg type of healthcare professional visited)

Hospitalizations and rehabilitation procedures (eg start and stop date of 
hospitalization)

Diagnostic and therapeutic procedures (eg type of diagnostic procedure)
Frequency: From Visit 2 until Visit 6 investigators need to collect on an ongoing 
basis information about health care resources that the patient uses since intake of the 
first dose of PATENT-2 study medication. The respective information will be 
recorded in the electronic CRF.
4.6.5
Drug Concentration Measurements
For investigation of drug exposure and potential relationships to drug effects,
plasma concentrations of BAY 63-2521 (and its main metabolite BAY 60-4552) 


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will be determined at the times given in the Trial Flow Chart (see Section 10.1) and 
in the Appendix 10.2using a sparse sampling approach in all participating patients.
Frequency: Visit 1 and Visit 5
BAY 63-2521 and metabolite M-1 (BAY 60-4552) concentrations in plasma will be 
measured by a validated HPLC-MS/MS method. Quality control (QC) and 
calibration samples will be analyzed concurrently with study samples. The results of 
QC samples will be reported together with concentrations in unknown samples in 
the MRR of this study.
Drug concentrations are calculated from the 
chromatographic raw data in accordance with current Bayer guidelines (see Section 
9). The data are evaluated using CCW software in its most recently released 
version.
4.7
Data Quality
Monitoring and auditing procedures defined/agreed by the sponsor will be followed, 
in order to comply with GCP guidelines. Each centre will be visited at regular 
intervals by a monitor to ensure compliance with the study protocol, GCP and legal 
aspects. This will include on-site checking of the case report forms (CRF) for 
completeness and clarity, cross-checking with source documents, and clarification 
of administrative matters.
4.8
Documentation
An electronic data capture system will be used in this study (e-CRF). All entries 
made in the e-CRF must be verifiable against source documents.  The source data 
parameter to be verified and the identification of the source document must be 
documented. The study file and all source data should be retained until notification 
given by the sponsor for destruction.


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5. ETHICAL AND LEGAL ASPECTS
5.1
Ethics Committee (EC) or Institutional Review Board (IRB)
Documented approval from appropriate Ethics Committee(s)/IRBs will be obtained 
for all participating centers/countries prior to study start, according to GCP, local 
laws, regulations and organizations. When necessary, an extension, amendment or 
renewal of the Ethics Committee approval must be obtained and also forwarded to 
the sponsor. The Ethics Committees must supply to the sponsor, upon request, a list 
of the Ethics Committee members involved in the vote and a statement to confirm 
that the Ethics Committee is organized and operates according to GCP and 
applicable laws and regulations.
5.2
Ethical Conduct of the Study
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 Good Clinical Practice Guidelines and under the guiding principles 
detailed in the Declaration of Helsinki. The study will also be carried out in keeping 
with applicable local law(s) and regulation(s). This may include an inspection by 
the sponsor representatives and/or Regulatory Authority representatives at any time.  
The investigator must agree to the inspection of study-related records by the 
Regulatory Authority/sponsor representatives, and must allow direct access to 
source documents to the Regulatory Authority/sponsor representatives. 
Modifications to the study protocol will not be implemented by either the sponsor or 
the investigator without agreement by both parties. However, the investigator may 
implement a deviation form, or a change of, the protocol to eliminate an immediate 
hazard(s) to the trial patients without prior EC/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 
EC/IRB/Sponsor. Any deviations from the protocol must be fully explained and 
documented by the investigator.


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5.3
Regulatory Authority Approvals/Authorizations
Regulatory Authority approvals/authorizations/ notifications, where required, must 
be in place and fully documented prior to study start.
5.4
Patient Information and Consent
A core Information and Informed Consent Form will be provided. Prior to the 
beginning of the study, the investigator must have the ECs/IRB written 
approval/favorable opinion of the written Informed Consent Form and any other 
written information to be provided to patients. The written approval of the EC/IRB 
together with the approved Patient Information/Informed Consent Forms must be 
filed in the study files.
Written informed consent must be obtained before any study specific procedure 
takes place. Participation in the study and date of informed consent given by the 
patient should be documented appropriately in the patient’s files.
5.5
Insurance
All patients participating in the study will have insurance coverage by the sponsor, 
which is in line with applicable laws and/or regulations.
5.6
Confidentiality
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 case report form, and if the patient name appears on any other 
document (eg, 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.  The patients will be informed 
in writing that representatives of the sponsor, EC/IRB, or Regulatory Authorities 


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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’ records to be identified.
6. STATISTICAL METHODS AND DETERMINATION OF SAMPLE 
SIZE
6.1
Statistical and Analytical Plans
The aim of this long-term extension study is primarily the assessment of safety and 
tolerability, so no single primary variable has been identified. Patient numbers will 
be determined by those completing the PATENT-1 study and willing to enter the 
PATENT-2 study. As the extension is of an open label design with no comparator 
group, all statistical analyses will be descriptive. The summary tables will be 
presented for the overall group of patients, and also split by previous treatment 
groups in PATENT-1. Baseline will be week 0 in PATENT-1 (changed with 
amendment 11). 
Statistical analysis of safety variables
For the analysis of safety, all patients entering PATENT-2 and receiving 
BAY 63-2521 will be included. For treatment-emergent adverse events, ECG and 
laboratory test abnormalities, frequency counts of incidence rates during the 
extension period (changed with amendment 11) and incidence per 100 patient years 
at risk will be presented. For ECG and laboratory test measurements, vital signs, 
changes from baseline will also be summarized using descriptive methods (mean, 
standard deviation, median, minimum, maximum).


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Statistical analyses of other variables
Patients will be included in these analyses if they are included in the safety analysis 
and have both baseline and post-baseline data available for the variable being 
analyzed. For Time To Clinical Worsening, incidence tables of the overall rate and 
the particular event leading to clinical worsening will be presented, together with 
the Kaplan-Meier survival curve. Change in Borg CR 10 Scale or Modified Borg 
Dyspnoea Scale and functional class at each visit will be summarized by frequency 
counts. Patients with data on the Borg CR10 Scale and patients with data on the 
Modified Borg Dyspnoea Scale will be combined in the statistical analysis. Change 
in 6MWD, NT pro-BNP, EQ-5D and LPH at each visit will be summarized using 
descriptive methods.
The study endpoints related to health care resource utilization will be summarized 
using appropriate statistical methods: categorical variables by frequency tables and 
continuous variables by sample statistics.  It is envisaged that all endpoints will be 
measured either on a semi-continuous scale or have ordered categories, and so 
exploratory statistical tests will be ANCOVA or the stratified Wilcoxon test, 
depending on the distribution.
Statistical summaries (changed with amendment 11)
It is planned to produce two formal statistical summaries.  The first will be when all 
patients enrolled in the long-term extension at Last Patient First Treatment of the 
PATENT-1 study have reached Visit 5 and the PATENT-1 study has been 
unblinded. The second will be at the conclusion of this extension study. Additional 
summaries will be performed, at least on a yearly basis, to monitor long-term safety.
6.2
Determination of Sample Size
Not applicable


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7. ADVERSE EVENTS
7.1
Contraindications/Warnings/Precautions/Interactions/Undesirable 
Effects
The potential for drug-drug pharmacodynamic interactions, leading to an 
exaggerated vasodilatation and excess blood pressure drop should always be 
considered if patients are treated concomitantly with other drugs with vasoactive 
properties.
Concomitant treatment with specific or unspecific Phosphodiesterase Inhibitors 
leading to higher production and decreased degradation of cGMP is not allowed 
during the trial (refer to Section 4.5.7“concomitant therapy”).
Due to possible pharmacodynamic interactions, BAY 63-2521 must not be 
administered together with NO donors/nitrates (refer to Section 4.5.7 “concomitant 
therapy”).
Due to possible pharmacokinetic interactions between BAY 63-2521 and strong 
CYP3A4 inhibitors (eg Ketoconazol) concomitant treatment should be applied with 
caution (eg additional blood pressure monitoring). Such drugs may significantly 
increase BAY 63-2521 plasma concentrations. In this context, dose reduction of 
BAY 63-2521 should be considered (eg – 0.5 mg tid), in particular if the patient 
suffers a clinical relevant decrease in blood pressure (eg systolic blood pressure <90 
mmHg with clinical symptoms). For further information refer to the Investigator 
Brochure.
Antacids like aluminum hydroxide/magnesium hydroxide (eg Maaloxan ®) should 
not be taken simultaneously with BAY 63-2521, because a negative impact on the 
bioavailability of the study drug has been observed (please refer to the Investigator 
Brochure). To avoid such kind of interaction, antacids should be taken 1 hour after 
intake of BAY 63-2521 at the earliest.


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Pre- and co-treatment with Omeprazole led to a decrease in BAY 63-2521 
bioavailability, indicating a lower bioavailability of BAY 63-2521 in neutral versus 
acidic milieu (for further information refer to the Investigator Brochure).
Preliminary inspection of trough and peak plasma concentrations of BAY 63-2521 
and BAY 60-4552 (Main BAY 63-2521 metabolite) in a cohort of patients treated 
with bosentan (n=6) compared to the patients not treated with bosentan (n=66) 
clearly indicate a decrease in BAY 63-2521/BAY 60-4552 plasma exposure, most 
probably due to the known CYP3A4 enzyme-inducing effects of concomitant 
bosentan. However, patients treated with bosentan profited in about the same 
magnitude in the 6 minute walk test as patients in the therapy naïve cohort did (for 
further information refer to the Investigator Brochure, trial 12166).
The BAY 63-2521 clearance was increased in smokers compared to non-smokers in 
a previous trial in patients with pulmonary hypertension (IMP 12166; see IB for 
more information). Therefore, patients should report their smoking status to the 
investigator.
Due to the pharmacological mode of action of a guanylate cyclase stimulator, 
treatment with BAY 63-2521 may unmask existing Pulmonary Veno-Occlusive 
disease (PVOD), leading to pulmonary congestion and subsequent pulmonary 
edema. Given the severity of the underlying disease this effect may be life-
threatening. Clinical symptoms of uncovering of a PVOD may occur weeks to 
months after start of treatment with BAY 63-2521. Should signs of pulmonary 
edema occur when BAY 63-2521 is administered, the possibility of associated 
PVOD should be considered and BAY 63-2521
should be discontinued 
immediately.
The following undesirable effects of the compound have been observed in clinical 
trials: decrease in blood pressure (in healthy volunteers mainly diastolic blood 
pressure), postural hypotension, dizziness, syncope, increase in heart rate, nasal 
congestion, feeling hot, headache, dyspepsia, nausea, vomiting, gastritis, flushing, 
and hyperhidrosis (refer to the Investigator Brochure). Most of the undesirable 


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effects are caused by the vasodilators mode of action of the drug. The effects of the 
compound on smooth muscles may lead to gastrointestinal symptoms (eg dilation of 
the esophageal sphincter with heartburn, esophagitis and dysphagia; diarrhea; 
constipation).
In addition, the possibility of hitherto unforeseen side effects and allergic reactions 
to drugs, which can result in severe damage and even death, must always be 
considered.
Any new, relevant information about adverse drug reactions of BAY 63-2521 will 
be given to the patients (verbally and in writing).
Inadvertent overdosing with total daily BAY 63-2521 doses of 9 mg (13 and 
32 days), 22.5 mg (14 and 15 days), and 25 mg (2 days) was reported for 5 subjects, 
which was tolerated without any adverse events (for further information refer to the 
Investigator Brochure).
Overdosage following administration of BAY 63-2521 should be treated as 
clinically indicated. There is no known antidote to BAY 63-2521.
Due to the pharmacological profile of BAY 63-2521, cardiovascular effects as 
described in the Investigator Brochure (Section 5.3.3.3) may be expected in case of 
overdose.
If symptoms develop after the investigational drug has been administered, any 
therapy that becomes necessary has to be guided by the predominant symptoms. 
Patients have to remain under medical supervision until all relevant adverse effects 
have subsided. If adverse events occur, the investigator has to decide whether or not 
to remove the patient from the trial (refer to Section 4.3). Emergency drugs and 
equipment has to be available to provide any treatment, which may become 
necessary.
In case of overdose, general measures to prevent absorption (eg, gastric lavage, 
activated charcoal) should to be taken.


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Note: To keep the investigators up-to-date regarding any kind of safety relevant 
information the Development Core Safety Information (DCSI), which is an 
appendix of the Investigators’ brochure, will be updated at regular intervals during 
the conduct of the trial. New versions of the investigator’s brochure will be made 
available to the investigators without delay.
7.2
Adverse Event Monitoring
Patients must be carefully monitored for adverse events. Adverse events should be 
assessed in terms of their seriousness, severity, and relationship to the study drug.
7.3
Adverse Event Definitions
7.3.1
Adverse Event
An adverse event is any untoward medical occurrence in a patient or clinical 
investigation patient administered with a pharmaceutical product. The adverse event 
does not necessarily have to have a causal relationship with this treatment. An 
adverse event can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the 
use of an investigational product, whether or not considered related to the medicinal 
product.
Adverse events associated with the use of a drug in humans, whether or not 
considered drug related, include the following: 

An adverse event occurring in the course of the use of a drug product in 
professional practice.

An adverse event occurring from an overdose whether accidental or intentional.

An adverse event occurring from drug abuse.

An adverse event occurring from drug withdrawal. 


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
An adverse events where there is a reasonable possibility that the event occurred 
purely as a result of the patients participation in the study (eg adverse event or 
serious adverse event due to discontinuation of anti-hypertensive drugs during 
Wash-Out Phase) must also be reported as an adverse event even if it is not 
related to the investigational product.
The clinical manifestation of any failure of expected pharmacological action is not 
recorded as an adverse event if it is already reflected as a data point captured in the 
electronic CRF (adapted with amendment 11).  If, however, the event fulfills any of 
the criteria for a “serious” adverse event, it must be recorded and reported as such.
7.3.2
Serious Adverse Event
A serious adverse event is any untoward medical occurrence that at any dose: 

Results in death.

Is life-threatening.

Requires in-patient hospitalization or prolongation of existing hospitalization.

Results in persistent or significant disability or incapacity.

Is a congenital anomaly or birth defect.

Is an important medical event.
Life-threatening: The term “life-threatening” in the definition of “serious” refers to 
an adverse event in which the patient was at risk of death at the time of the event. It
does not refer to an adverse event which hypothetically might have caused death if 
it were more severe.
Hospitalization: Any adverse event leading to hospitalization or prolongation of 
hospitalization will be considered as Serious, UNLESS at least one of the following 
exceptions are met:

The admission results in a hospital stay of less than 12 hours.
OR


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
The admission is pre-planned (ie, elective or scheduled surgery arranged prior to 
the start of the study). 
OR

The admission is not associated with an adverse event (eg, social hospitalization 
for purposes of respite care).
However it should be noted that invasive treatment during any hospitalization may 
fulfill the criteria of ‘medically important’ and as such may be reportable as a 
serious adverse event dependant on clinical judgment. In addition where local 
regulatory authorities specifically require a more stringent definition, the local 
regulation takes precedent.
Any hospitalization required for carrying out a routine right heart catheterization 
(RHC) procedure for conducting diagnostic invasive hemodynamic measurements 
to evaluate a patient’s underlying disease (without taking into account any clinical 
suspicion or finding with regard to the worsening of the underlying disease) will not 
be considered as a serious adverse event. In this context, a RHC procedure is 
considered as a procedure and not as an adverse event (changed with amendment 
11).
Disability means a substantial disruption of a person’s ability to conduct normal 
life’s functions.
Important medical event: Any adverse event may be considered serious because it 
may jeopardize the patient and may require intervention to prevent another serious 
condition. As guidance for determination of important medical events refer to the 
“WHO Adverse Reaction Terminology – Critical Terms List. These terms either 
refer to or might be indicative of a serious disease state. 
Such reported events warrant special attention because of their possible association 
with a serious disease state and may lead to more decisive action than reports on 
other terms. 


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7.3.3
Unexpected Adverse Event
An unexpected adverse event is any adverse drug event, the specificity or severity 
of which is not consistent with the current Investigator Brochure (refer to Section
8.1. “Development Core Safety Information” of the Investigator Brochure). Also, 
reports which add significant information on specificity or severity of a known, 
already documented adverse event constitute unexpected adverse events. For 
example, an event more specific or more severe than described in the Investigator 
Brochure would be considered “unexpected”. Specific examples would be; (a) acute 
renal failure as a labeled adverse event with a subsequent new report of interstitial 
nephritis and (b) hepatitis with a first report of fulminant hepatitis.
7.3.4
Relationship of Adverse Event to Investigational Product
The assessment of the relationship of an adverse event to the administration of study 
drug is a clinical decision based on all available information at the time of the 
completion of the case report form.
An assessment of ‘No’ would include:
1. The existence of a clear alternative explanation eg, mechanical bleeding at 
surgical site.
OR
2. Non-Plausibility eg, 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 there is a reasonable suspicion that the 
adverse event is associated with the use of the investigational drug.
Factors to be considered in assessing the relationship of the adverse event to study 
drug include: 


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
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 discontinuation (de-challenge), recurrence on reintroduction (re-
challenge): Patient’s response after drug discontinuation (de-challenge) or 
patients response after drug re-introduction (re-challenge) should be considered 
in the view of the usual clinical course of the event in question.

Underlying, concomitant, intercurrent diseases: Each report 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 may be suspected to cause the event in question.

The pharmacology and pharmacokinetics of the test drug: The pharmacokinetic 
properties (absorption, distribution, metabolism and excretion) of the test 
drug(s), coupled with the individual patient’s pharmacodynamics should be 
considered.
7.3.5
Severity of the Adverse Event
The following classification should be used:
The severity of adverse events should be graded as follows:
Mild – usually transient in nature and generally not interfering with normal 
activities.
Moderate –
sufficiently discomforting to interfere with normal activities
Severe – prevents normal activities.


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7.3.6
Adverse Event Documentation
All adverse events occurring in the period between the patient has signed the 
informed consent and until 30 days after definite stop of study medication must be 
fully recorded in the patient’s case record form. However, in case that more than 30 
days after stop of study medication an adverse event occurred that has been 
considered as related by the investigator, this needs to be documented too.
Documentation must be supported by an entry in the patient’s file.  A laboratory test 
abnormality considered clinically relevant, eg, causing the patient to withdraw from 
the study, requiring treatment or causing apparent clinical manifestations, or judged 
relevant by the investigator, should be reported as an adverse event.  Each event 
should be described in detail along with start and stop dates, severity, relationship to 
investigational product, action taken and outcome.
7.4
Reporting of Serious Adverse Events/Pregnancy
Serious adverse events (SAEs), including laboratory test abnormalities fulfilling the 
definition of serious, that occurred in the period between the patient signed the 
informed consent and until 30 days after definite stop of study medication must 
immediately (within 24 hours of the investigator’s awareness) be reported to the 
person detailed in the study file. A serious adverse event form must also be 
completed within 24 hours of the investigator’s awareness and forwarded to the 
designated person as detailed in the study file. For reporting of serious adverse 
events an electronic adverse event as provided in the electronic CRF shall be used. 
If the electronic CRFis not available due to technical problems (eg information 
cannot be entered into the electronic CRF) serious adverse events need to be 
reported within 24 hours of the investigator’s awareness by using print out forms 
(e.g. via fax). Each serious adverse event must be followed up until resolution or 
stabilization by submission of updated reports to the designated person.
If Global Pharmacovigilance requests supportive documents in context with a 
serious adverse event report (eg autopsy report, hospital report) these documents 
shall be forwarded to the person detailed in the study file (eg via fax).


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The same rules apply to serious adverse events that occurred more than 30 days 
after definite stop of study medication, if the investigator considers them as related 
to the study medication.
When required, and according to local law and regulations, serious adverse events 
must be reported to the Ethics Committee and Regulatory Authorities.
Pregnancy occurring during a clinical investigation, although not considered a 
serious adverse event, must be reported to Bayer within the same timelines as a 
serious adverse event on a Pregnancy Monitoring Form. The outcome of a 
pregnancy should be followed up carefully and any abnormal outcome of the 
mother or the child should be reported. This also applies to pregnancies following 
the administration of the investigational product to the father prior to sexual 
intercourse.
7.5
Reporting of Safety Related Events of Special Interest
For this trial the following safety related event of special interest has been defined:

Syncope
Any syncope has to be reported as “important medical event” (see section 7.3.2) and 
therefore as Serious Adverse Event (SAE) to the sponsor within 24 hours of 
becoming aware of the event.
8. USE OF DATA AND PUBLICATION
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 the data in 
various ways, such as for submission to government regulatory authorities or 
disclosure to other investigators. The investigator, whilst free to utilize data derived 
from the study for scientific purposes, must discuss any publication with the 
sponsor prior to release and obtain written consent of the sponsor on the intended 
publication. The sponsor recognizes the right of the investigator to publish the 


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results upon completion of the study. However, the investigator must send a draft 
manuscript of the publication or abstract to the sponsor thirty days in advance of 
submission in order to obtain approval prior to submission of the final version for 
publication. This will be reviewed promptly and approval will not be withheld 
unreasonably. In case of a difference of opinion between the sponsor and the 
investigator(s), the contents of the publication will be discussed in order to find a 
solution which satisfies both parties.
9. REFERENCES
Investigator Brochure: BAY 63-2521
American College of Chest Physicians. Diagnosis and Management of Pulmonary 
Arterial Hypertension: ACCP Evidence-Based Clinical Practice Guidelines. Chest 
2004; 126; 7-10s
American Heart Association. Recommendations for Blood Pressure Measurement in 
Humans and Experimental Animals. Hypertension 2005;45;142-161
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
10.APPENDICES


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10.1 Study Flow Chart
Tabular Schedule of Study Procedures
Study Phase
PATENT-1
PATENT-2
Treatment Phase (Duration until BAY 63-2521 receives official approval and will be commercially available)
Safety- Follow-Up Phase 
                          (30 days + 5 )
Titration Phase (8 weeks)
Main-Study Phase
Blinding of study medication
Blinded 
treatment
Blinded with respect to the BAY 63-2521 dose
Unblinded
Visit
V 6 of 
PATENT-1
V 1 g
V 2
V 3
V 4
V 5
V6
V7- V n
(every 90 days)
Termination 
Visitc
Safety-Follow 
Up-Visit 
Day
- 1
0
14±2
28±2
42±2
56±2
84±2
174±14
Vn+14
-
30 + 5
Week
-
0
2
4
6
8
12
24- n
-
-
In-patient hospitalization - optional
Xa
Xb
-
-
-
-
-
-
-
Informed consent
X
Patient’s Weight
X
X
X
X
X
Concomitant Medication
X
X
X
X
X
X
X
X
X
Collection of smoking statush
X
X
X
X
X
X
Physical examination
X
X
X
X
X
Blood pressure, heart rate
X
X
X
X
X
X
X
X
X
X


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Tabular Schedule of Study Procedures
Study Phase
PATENT-1
PATENT-2
Treatment Phase (Duration until BAY 63-2521 receives official approval and will be commercially available)
Safety- Follow-Up Phase 
                          (30 days + 5 )
Titration Phase (8 weeks)
Main-Study Phase
Blinding of study medication
Blinded 
treatment
Blinded with respect to the BAY 63-2521 dose
Unblinded
Visit
V 6 of 
PATENT-1
V 1 g
V 2
V 3
V 4
V 5
V6
V7- V n
(every 90 days)
Termination 
Visitc
Safety-Follow 
Up-Visit 
Day
- 1
0
14±2
28±2
42±2
56±2
84±2
174±14
Vn+14
-
30 + 5
Week
-
0
2
4
6
8
12
24- n
-
-
Blood gas analysis
X
X
WHO functional classd
X
X
X
X
X
X
X
X
6 MWD Testd
X
X
X
X
X
X
X
X
Borg CR 10 Scaledor Modified 
Borg Scalef
X
X
X
X
X
X
EQ-5D Questionnaire
X
X
X
LPH Questionnaire
X
X
Use of healthcare resources
X
X
X
X
X
X
Standard lab. blood sampling
X
X
X
X
X
X


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Tabular Schedule of Study Procedures
Study Phase
PATENT-1
PATENT-2
Treatment Phase (Duration until BAY 63-2521 receives official approval and will be commercially available)
Safety- Follow-Up Phase 
                          (30 days + 5 )
Titration Phase (8 weeks)
Main-Study Phase
Blinding of study medication
Blinded 
treatment
Blinded with respect to the BAY 63-2521 dose
Unblinded
Visit
V 6 of 
PATENT-1
V 1 g
V 2
V 3
V 4
V 5
V6
V7- V n
(every 90 days)
Termination 
Visitc
Safety-Follow 
Up-Visit 
Day
- 1
0
14±2
28±2
42±2
56±2
84±2
174±14
Vn+14
-
30 + 5
Week
-
0
2
4
6
8
12
24- n
-
-
NT-pro BNP
X
X
X
X
X
X
PK blood sampling
X
X
X
12-lead electrocardiogram
X
X
X
X
X
X
X
Pregnancy test (if applicable)
Xe
X
Xi
Xi
Dispense study medication
X
X
X
X
X
X
X
Drug accountability
X
X
X
X
X
X
X
X
Collection of patient Diary
X
X
X
X
Event of special interest evaluation
X
X
X
X
X
X
X
X
X
Adverse event reporting
Xf
Xf
X
X
X
X
X
X
X
X


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Flowchart updated (last with amendment 11)
Indexes:
aAccording to hospital routine, patients may be hospitalized for one day after the performance of invasive hemodynamic measurements.
bPatients will be discharged if there is no medical objection. Blood pressure monitoring and heart rate are the main hemodynamic safety 
parameters that need to be considered.
cA Termination Visit will only be performed in case of premature stop of study medication or if the sponsor announces the official end of the 
study. In such case, generally the same measurements and procedures should be performed as at Main-Study Visits (V7 – Vn). In particular, 
every effort should be made to perform the 6MWD Test. Deviations, particularly from the scheduled points in time need to be documented in 
the electronic CRF.
dDuring the Titration Phase these test have to be performed by a second person (for WHO functional class assessment a second physician) 
who is not involved in the process of study drug titration and is unaware of the immediate reaction of the patient’s blood pressure and heart 
rate after dosing. This person will record the test results on a separate work sheet and a different person (could be the same person as involved 
in titration) will enter them into the electronic CRF
For consistency reason, patients who were enrolled in trial 12934 before approval of protocol amendment 4 in their country must use the 
“Modified Borg Dyspnoea Scale” throughout the main and the extension study   (for further details see section 4.6.4).
eAt Visit 6 of PATENT-1 a urine ( if the patient will participate in the extension study) and a serum pregnancy test should be performed. 
Female patients with childbearing potential can be enrolled into the extension study based on the results of the urine test
fAdverse events that occur before intake of first dose of PATENT-2 medication will be allocated to PATENT-1.
gIt is not permitted to include a patient into the extension study on the same day of V6 of PATENT-1 study (applies even if Visit 6 
investigations were performed at two consecutive days).


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hPatients will be asked if their smoking habits has changed since the previous visit and the results will be recorded in the electronic CRF
i Test to be done locally
Visit Details
Day
Day 0
Visit 1
First cycle of 
measurements c
First study medication 
dose intake
Second cycle of 
measurements c
Second study medication 
dose intake
Order of 
procedures
Starting point of 
procedures
Time interval (h)
00
>-01
<00
00
00c
00
>02
<03
00
>-01
<00
00
00c
00
>02
<03
Blood pressure, heart rateb
X
X
12-lead ECGa,b
X
Pharmacokinetic blood sampleb
X
Administration of BAY 63-2521b
X
X
Blood pressure, heart rateb
X
X
Discharge from ward
X
aSingle ECG
bThe point in time when the respective procedures are performed will be documented in the case report form.
cThe respective single daily doses of study medication should be taken 6-8 hours apart.


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Ambulatory Visits 
Visit 2 – Visit 5
Cycle of measurements
Order of 
procedures
Starting point of 
procedures
Time interval (h)
00
>-01
<00
00
00
00
>02
<03
00
>04
<05
Blood pressure, heart ratec
X
12-lead ECGa,c
X
Pharmacokinetic blood samplec, d
X
Administration of BAY 63-2521c
X
Blood pressure, heart ratec
X
6 MWD testb,c
X
Borg CR 10 Scale(or Modified Borg 
Dyspnoea Scale)b,c
X
aSingle ECG
bDuring the Titration Phase these test have 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 blood pressure and heart rate after dosing. This person will record the test results on a 
separate work sheet and a different person (could be the same person as involved in titration) will enter them into the electronic CRF.
cThe point in time when the respective procedures are performed will be documented in the case report form.
dPharmacokinetic blood sample will only be collected at Visit 5


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Ambulatory visits V6
Cycle of measurements
Order of 
procedures
Starting point of 
procedures
Time interval (h)
00
>-01
<00
00
00
00
>02
<03
00
>04
<05
Blood pressure, heart rate b
X
12-lead ECG a, b
X
Administration of BAY 63-2521 b
X
Blood pressure, heart rate b
X
6 MWD test b
X
Borg CR 10 Scale (or Modified Borg 
Dyspnoea Scale) b
X
a Single ECG (updated with amendment 11)
b The point in time when the respective procedures are performed will be documented in the case report form.
a The point in time when the respective procedures are performed will be documented in the case report form
(updated with amendment 11).
Ambulatory visits V7 – Vn, Termination Visit
Cycle of 
measurements
Order of 
procedures
Starting point of 
procedures
Time interval (h)
00
>-01
<00
00
00
00
>00
<01
Blood pressure, heart ratea
X
Administration of BAY 63-2521a
X
6 MWD testa
X


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10.2
Pharmacokinetic Sampling
The number of samples taken for the assessment of pharmacokinetics 
has been optimized to take the minimum amount of blood.
PK samples will be analyzed under the responsibility of the Institute of 
Clinical Pharmacology, BAYER AG, Wuppertal, Germany.
Visit 1
Point in time: -01-00 hours before administration of the second dose of 
BAY 63-2521 (Day 1)
V 5
At this study visit the patients should present themselves to the hospital 
without taking the morning dose of BAY 63-2521. During the visit the 
pharmacokinetic sample should always be taken at trough before 
administration of the morning dose of study medication.
Point in time: -01-00 hours before administration of BAY 63-2521 
morning dose
Sample collection, processing and storage
The blood samples will be collected in specific tubes which will be 
provided by the central laboratory. Further details on collection, 
labeling, storage and shipping of samples are provided in a separate 
laboratory manual.
At the latest at the end of the study when all planned analyses are 
completed, all PK samples will be destroyed.
10.3
Blood Gas Analysis
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 


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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. Printouts from 
the analyzer have to be stored in the patient file and the measured values 
have to be transferred into the electronic CRF.
Blood gas measurement
Actual time
Date
SaO2 (%)
PaO2 (mmHg)
PaCO2 (mmHg)
Supplemental oxygen “Yes” or “No”
If “Yes”,amount of supplemental O2 (l/min)
10.4
6 Min Walking Distance (6MWD) Test
The 6MWD Test must be performed in accordance with the American 
Thoracic Society Guideline (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)
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 meters (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 min.
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.


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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 (truncated with amendment 11):

Patients, who used walking aids already at the eligibility-test 
and the baseline-test (eg 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 
CRF.
In case that a patient has never performed a 6MWD Test, a 
familiarization test should be performed during the Pre-Treatment Phase. 
To avoid any interactions, it is not permitted to perform the 
familiarization test on the same day as the eligibility 6MWD Test.


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10.5 Borg CR 10 Scale® or Modified Borg Dyspnoea Scale 
In context with 12934 protocol amendment 4 the “Modified Borg 
Dyspnoea Scale” was replaced by the Borg CR 10 Scale®. For 
consistency reason, patients who were enrolled before approval of 12934  
protocol amendment 4 in their country must use the “Modified Borg 
Dyspnoea Scale” throughout the main and the extension study.
The Borg CR 10 Scale or the Modified Borg Dyspnoea Scale will 
always be measured in conjunction with the 6MWD Test.
The Borg CR 10 Scale or the Modified Borg Dyspnoea Scale will be 
explained to the patients before starting the 6MWD Test (questionnaires 
and instructions will be provided in local language). Patients will be 
asked to rank their exertion at the end of the 6MWD Test. If a patient 
has problems to understand the principles of rating, an attempt should be 
made to explain the principles in a neutral and unpersuasive manner.
The test result will be entered on same work sheet as the 6MWD Test 
result Later on the results will be transferred into the electronic CRF.
10.5.1
Borg CR 10 scale and test instructions
 
 
 
 
 
 
 
 
 
 
CCI


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CCI
CCI


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10.5.2
Modified Borg Dyspnoea Scale
 
CCI
CCI
CCI


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10.6
WHO functional class
The patient’s functional class will be determined by using the WHO 
classification (Class I- IV / refer to American College of Chest 
Physicians. Diagnosis and Management of Pulmonary Arterial 
Hypertension: ACCP Evidence-Based Clinical Practice Guidelines. 
Chest 2004; 126; 7-10s):
I: Patients with PH but without resulting limitation of physical activity. 
Ordinary physical activity does not cause undue dyspnoea 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 
dyspnoea 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 
dyspnoea 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. 
Dyspnoea and/or fatigue may even be present at rest. Discomfort is 
increased by any physical activity.
10.7
EQ-5D
 
 
 The EQ-5D is a self-report questionnaire and needs to 
CCI
CCI


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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 
electronic CRF.


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CCI


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CCI


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CCI


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10.8
Living with Pulmonary Hypertension questionnaire (LPH)
 
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
electronic CRF.
 
 
 
CCI
CCI


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CCI


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10.9
Role of the Steering Committee (SC)
The Steering Committee has the overall scientific responsibility of the 
study. It will guide the trial in all aspects of safety and efficacy and has 
to assure that all relevant information coming from the sponsor (e.g. 
from the Global Pharmacovigilance department), from other study 
committees (e.g. from the Data Monitoring Committee) and from the 
investigators will thoroughly be reviewed and all relevant decisions with 
regard to the conduct will be taken in due time. In particular the Steering 
committee has the following responsibilities:

Primary responsibility for designing the study

Primary responsibility for the content of protocol amendments

To ensure a scientifically sound and safe conduct of the study

To decide on Data Monitoring Committee recommendations 
together with the sponsor

Primary responsibility for the final study report
10.10
Role of the Data Monitoring Committee (DMC)
It is the main responsibility of the Data Monitoring Committee (DMC) 
to protect the safety of the patients participating in the BAY 63-2521 
phase III program. In this context, the DMC will regularly review 
accumulating study data with the responsibility to provide an 
independent recommendation on the advisability of continuing the study 
as planned.
The DMC will conduct its reviews based on unblinded data summaries. 
During the course of the trial the DMC and the SC should closely 
interact and alert each other in order to assess all safety relevant 
information. The DMC should also closely interact with the sponsor´s 
Global Pharmacovigilance department.


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In case of unacceptable safety profile, the DMC can recommend to stop 
the trial. However, the final decision will be made by the SC together 
with the sponsor.
DMC will stop when all patients are on open label dose of Riociguat
(changed with amendment 11).
For further details refer to the DMC Charter.

SAP_001.pdf: 
Statistical Analysis Plan
Protocol No.: BAY 63-2521 / 12935
Page: 1 of 11
Reference Number: RD-OI-0119
Supplement Version: 8
Title page
Long-term extension, multi-center, multi-national study to 
evaluate the safety and tolerability of oral BAY 63-2521 (1 mg, 
1.5 mg, 2 mg, or 2.5 mg TID) in patients with symptomatic 
Pulmonary Arterial Hypertension (PAH), PATENT-2 study
PATENT-2 study
Bayer study drug
BAY 63-2521/Riociguat/Adempas
Study purpose:
Long-term extension 
Clinical study 
phase:
III
Date:
25 JUL 2019
Study No.:
12935
Version:
5.0
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


Statistical Analysis Plan
Protocol No.: BAY 63-2521 / 12935
Page: 2 of 11
Reference Number: RD-OI-0119
Supplement Version: 8
Table of Contents
Title page................................................................................................................................... 1
Abbreviations............................................................................................................................ 3
1.
Introduction....................................................................................................................... 3
2.
Study Objectives................................................................................................................ 4
3.
Study Design ...................................................................................................................... 4
4.
General Statistical Considerations .................................................................................. 5
4.1
General Principles............................................................................................................ 5
4.2
Handling of Dropouts ...................................................................................................... 5
4.3
Handling of Missing Data................................................................................................ 5
4.4
Interim Analyses and Data Monitoring ........................................................................... 6
4.5
Data Rules........................................................................................................................ 6
4.6
Blind Review ................................................................................................................... 6
5.
Analysis Sets ...................................................................................................................... 6
5.1
Assignment of analysis sets ............................................................................................. 6
6.
Statistical Methodology .................................................................................................... 6
6.1
Population characteristics ................................................................................................ 7
6.2
Efficacy............................................................................................................................ 8
6.3
Pharmacokinetics/pharmacodynamics........................................................................... 10
6.4
Safety ............................................................................................................................. 10
7.
Document history and changes in the planned statistical analysis............................. 11
8.
References ........................................................................................................................ 11


Statistical Analysis Plan
Protocol No.: BAY 63-2521 / 12935
Page: 3 of 11
Reference Number: RD-OI-0119
Supplement Version: 8
Abbreviations
6MWD
6 minute walking distance
6MWT
6 minute walking test
AS
Atrial septostomy
ATC
Anatomical Therapeutic Chemical Classification System
BP
Blood pressure
CCB
Calcium channel blocker
ECG
Electrocardiogram
EQ-5D
EuroQol Questionnaire
ERA
Endothelin Receptor Antagonist
FC
Functional Class
HEOR
Health Economics and Outcomes Research
ICH
International Conference on Harmonisation
i.e.
id est (that is) 
ITT
Intent to treat
LPFT
Last patient first treatment
LPH
Living with Pulmonary Hypertension Questionnaire
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
NT pro-BNP
N-terminal pro-brain natriuretic peptide
PAH
Pulmonary arterial hypertension
PAP
Pulmonary artery pressure
PDE5I
Phosphodiesterase type 5 inhibitors
PH
Pulmonary Hypertension
PPI
Proton pump inhibitor
PVR
Pulmonary vascular resistance
SAS
Statistical Analysis System
TID
ter in die (3 times a day)
WHO
World Health Organization
WHO-DD
World Health Organization – Drug Dictionary
1.
Introduction
This SAP for the final analysis is based on the following study protocol versions:

12935 / version 2.0, 11 September 2008

Amendment 1 (Japan) / Version 1.0 / 01 Oct 2008

Amendment 2 (UK) / Version 1.0 / 08 Jan 2009

Amendment 3 (NZ) / Version 1.0 / 18 Mar 2009

Amendment 4 (Spain) / Version 1.0 / 09 Jun 2009

Amendment 5/ Version 1.0 / 10 Jun 2009

Amendment 6/ Version 1.0 / 22 Mar 2010

Amendment 7 (Japan) / Version 1.0 / 23 Mar 2010

Amendment 8 / Version 1.0 / 15 Feb 2011

Amendment 9 (US, CAN) / Version 1.0 / 28 Feb 2011

Amendment 10 / Version 1.0 / 30 Nov 2011


Statistical Analysis Plan
Protocol No.: BAY 63-2521 / 12935
Page: 4 of 11
Reference Number: RD-OI-0119
Supplement Version: 8

Amendment 11/ Version 1.0/ 13 DEC 2012

Amendment 12 (Korea)/ Version 1.0 / 03 APR 2013

Amendment 13 (China)/Version 1.0/ 08 JUL 2014

Amendment 14 (France)/ Version 1.0/ 28 OCT2015
There is a set of global and project standard tables. References are given in the TLF 
specifications document associated with this SAP. 
2.
Study Objectives
To assess the long-term safety and tolerability of riociguat in treatment naive patients and 
patients pretreated with an Endothelin Receptor Antagonist or a Prostacyclin Analogue with 
symptomatic Pulmonary Arterial Hypertension (PAH). The trial provides patients, who have 
completed 12 weeks of riocigua double blind treatment (PATENT-1, study 12934), the option 
of long-term treatment with riociguat.
For this study it is planned to enroll subjects in the following countries:
United States of America, Canada, Sweden, Denmark, Norway, China, Singapore, Taiwan, 
South Korea, Austria, Germany, Switzerland, Netherlands, Belgium, France, Italy, Spain, 
Ireland, South Africa, United Kingdom, Argentina, Brazil, Mexico, Australia, New Zealand, 
Japan, Czech Republic, Poland.
A list of countries that actually enrolled patients will be given.
3.
Study Design
This is an open-label, multicenter, multinational, long-term extension (blinded with respect to 
dose up to Visit 5 [end of titration phase], in order to maintain the blinding of the PATENT-1 
study).
All subjects entering the extension study first participated in a blinded 8-week titration phase. 
The dose of riociguat was increased, maintained, or decreased depending on whether 
peripheral systolic blood pressure (SBP) was ≥95 mmHg, 90 – 94 mmHg, or <90 mmHg, in 
accordance with the following rules:
Subjects from the former placebo group of the PATENT-1 study started at Visit 1 with a 
riociguat dose of 1.0 mg tid. The individual riociguat dose was up-titrated in steps of 
0.5 mg tid every 2 weeks up to a maximum of 2.5 mg tid.
Subjects from the former riociguat 1.0–1.5 mg tid capped dose titration group of 
PATENT-1 entered the extension trial on the same dose level as they received on the last 
day of PATENT-1. Subjects whose last dose in PATENT-1 was 1.0–1.5 mg tid were up-
titrated in steps of 0.5 mg tid every 2 weeks up to a maximum of 2.5 mg tid. Subjects 
whose last dose in PATENT-1 was 1.0 mg or 0.5 mg tid underwent sham titration, with no 
increase in dose of study drug before the end of the titration phase. 
(titration approach modified by protocol amendment 5)
Subjects from the former riociguat 1.0-2.5 mg tid group of PATENT-1 entered the 
extension trial on the same dose level as they received on the last day of PATENT-1.
Subjects underwent sham titration, with no increase in dose of study drug before the end of 
the titration phase.


Statistical Analysis Plan
Protocol No.: BAY 63-2521 / 12935
Page: 5 of 11
Reference Number: RD-OI-0119
Supplement Version: 8
During the main study phase, investigators (unblinded to dose) could modify the riociguat 
dose in a range between 0.5 mg tid and 2.5 mg tid according to the subject’s need.
Dose reductions for safety reasons were allowed at any time.
For further details see integrated study protocol, amendment 11, version 1.0, Section 4.1.
4.
General Statistical Considerations
4.1
General Principles
The statistical evaluation will be performed by using the software package SAS release 9.2 or 
higher (SAS Institute Inc., Cary, NC, USA). All variables will be analyzed by descriptive 
statistical methods. The number of data available and missing data, mean, standard deviation, 
minimum, quartiles, median, and maximum will be calculated for metric data. Frequency 
tables will be generated for categorical data.
4.2
Handling of Dropouts
There is no definition of dropouts in the CSP.
4.3
Handling of Missing Data
Although efficacy variables will be summarized in a purely descriptive manner, imputation 
for missing values will still be made, for comparability of the results with study 12934, at 
week 12 and end of study. The imputation to the end of the study will only be done at the 
conclusion of the extension study.
For subjects completing the study as planned, the measurements taken at the end of study will 
be used.  However, should a subject stop the study medication prematurely, the values 
recorded at the termination visit will be used.
Where a subject dies or withdraws due to clinical worsening with no subsequent visit, the 
following rules will be used:  6MWD worst possible value (0 m), Borg CR 10 Scale® worst 
possible value (10), EQ-5D and LPH worst possible score.  Death or withdrawal due to 
clinical worsening are components of time to clinical worsening, so will be included as an 
event by definition. For WHO functional class, in the case of withdrawal due to clinical 
worsening with no termination visit, the worst possible score (IV) will be used, in the case of 
death the worst possible value plus one (V).
In the case of withdrawal for other reasons with no post-baseline measurements, the baseline 
will be taken.  If the subject completes the study as planned, but there is no efficacy 
measurement at the end of the study, the last post-baseline value will be used.
PVR and NT pro-BNP are efficacy measures designed to show the direct effects of study 
treatment on biomarkers, and so it would not be appropriate to use an imputation rule in the 
case of death or missing post-baseline data.  In the case of premature stop of study 
medication, measurements taken at the termination visit or last visit post-baseline will be 
used.


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4.4
Interim Analyses and Data Monitoring
It is planned to produce two formal statistical summaries.  The first will be when all patients 
enrolled in the long-term extension at LPFT of the PATENT-1 study have reached Visit 5 and 
the PATENT-1 study has been unblinded. The second will be at the conclusion of this 
extension study.  Additional summaries will be performed, at least on a yearly basis, to 
monitor long-term safety.
4.5
Data Rules
Efficacy analysis datasets will be created that include key demographic data that will be used 
for the descriptive subgroup analyses. These datasets will also include results from the 
imputations of missing values in the period up to week 12 and end of study, such that the 
descriptive efficacy analyses can be performed without the need for major pre-processing 
within the statistical analysis programs.
4.6
Blind Review
All subjects receiving treatment in the long-term extension will be valid for the descriptive 
safety and efficacy analyses.  Hence, there will be no formal validity assignment.
5.
Analysis Sets
The safety and efficacy analyses will be performed in subjects entering and treated in the 
long-term extension. Formally, these can be considered the long-term safety population.
A subject is valid for the long-term safety and efficacy analysis, if at least one dose of study 
medication in the extension period was administered.
5.1
Assignment of analysis sets
A subject is valid for the long-term safety and efficacy analysis, if at least one dose of study 
medication in the extension period was administered.
6.
Statistical Methodology
The statistical evaluation will be performed according to the company Global Standards for 
demography and safety analyses when these have been published (see section 1 for table 
templates), the statistical methods given in the protocol and, if applicable, any relevant 
protocol amendments.
For all descriptive analyses, unless otherwise specified, it is planned to summarize the group 
of subjects as a whole (“all subjects”) and by the following groups:


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
Patients randomized to riociguat individual titration in the main phase who stayed 
on riociguat in the LTE phase, referred to as "riociguat individual titration"

Patients randomized to placebo in the main phase who switched to riociguat in the 
LTE phase, referred to as "placebo-riociguat"
By week 8 of the extension, all subjects should be receiving riociguat at the optimized dose, 
but prior to this there may be some differences between the treatment groups as those subjects 
in the placebo group will be receiving active medication for the first time, or those in the 1.5 
mg group will be up-titrated above 1.5 mg for the first time. 
6.1
Population characteristics
Demographic variables and baseline characteristics will be summarized by former treatment 
group for the long-term safety population.
New (“treatment-emergent”) and current concomitant medication received during the long-
term extension will be summarized, coded by ATC codes (WHO-DD).
Specific concomitant medications will also be summarized by class and corrected generic 
name:
1. PH specific medication (note, for the PAH indication PDE5Is are excluded entirely until 
after stop of riociguat):
- ERAs (bosentan, ambrisentan, sitaxsentan)
- Prostacycline (iloprost, epoprostenol, treprostinil)
- PDE5I (sildenafil, vardenafil, tadalafil)
2. Background therapy
- CCB
- diuretics
- digoxin
- oral anticoagulation
- oxygen
3. Safety relevant medication
- PPI (omeprazol, pantoprazol, rabeprazol, esomeprazol, etc)
- antacids (e.g. aluminum hydroxide, magnesium hydroxide)
- strong CYP3A4 inhibitors
- CYP3A4 inductors
- vasodilative drugs (e.g. antihypertensive medication)
Duration of study medication (in days), in total and by dose, will be summarized descriptively 
and by three-monthly intervals using frequency counts.  Compliance (taken as a percentage of 
planned), over the first 12 weeks of the study and for the first four weeks after the titration, 


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will be summarized descriptively and in 10% intervals.  Dose titration by visit, dose titration 
sequence and reasons for up- and down-titration by visit and dose (after titration) will also be 
summarized using frequency counts.  Formally, the dose titration information should just be 
needed for the former riociguat 1.5 mg and placebo groups, but as the investigators and 
subjects remain fully blinded during the 8 week (sham) titration phase, in theory those 
subjects randomized to the riociguat Individual Dose Titration group, despite actually being 
on a stable dose of study medication, could also have a sham dose adjustment.
6.2
Efficacy
Efficacy variables are:

6 minute walking distance from the 6MWT

PVR (no RHC required at any time during study, PVR only measured if RHC performed 
as part of regular diagnostic work up)

NT pro-BNP 

WHO functional class

Time to clinical worsening

Borg CR 10 Scale®

EQ-5D questionnaire

LPH questionnaire
In the efficacy analyses, countries and centres will be clustered by geographic region, 
consistent with the pooling in study 12934.
All analyses will be descriptive.  For non-categorical data, absolute values and changes from 
baseline will be summarized.  Baseline will be week 0 of study 12934.
It is envisaged that WHO functional class will either remain the same, improve by one or two 
categories, or deteriorate by one category in most cases. A change score (end of study minus 
baseline) will be calculated, which could go from -3 (class IV at baseline and class I at end of 
study) to +4 (class I at baseline, death at end of study), but in practice for those patients still 
alive at the end of the study it will most likely range from -2 to +1
Time to clinical worsening is made up of several components:
1) all-cause mortality
2) heart/lung transplantation
3) Atrial septostomy (AS)
4) hospitalization due to persistent worsening of pulmonary hypertension
5) start of new PH-specific treatment
6) persistent decrease in 6MWD
7) persistent worsening of functional class
as defined in the protocol section 4.6.4.


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The occurrence of the event of clinical worsening during the long-term extension will be 
summarized using categorical methods, but as an additional summary, the time to event will 
also be described. In determining whether an event is considered to be an event of clinical 
worsening the same rules as in study 12934 will be applied.  
Change in the Borg CR 10 Scale® will be summarized using frequency counts.  
The exploratory efficacy variables described in the Supplementary SAP of study 12934 will 
be summarized descriptively. This includes the subscales of the EQ5D and LPH and the 
additional haemodynamic variables. Also the sensitivity analysis of clinical worsening and the 
categorical analyses described in the Supplementary SAP of study 12934 will be performed.
The primary and secondary efficacy variables, except PVR,  will be summarized descriptively 
for the following subgroups:

therapy-naïve

pre-treated

pre-treated with Endothelin Receptor Antagonist

pre-treated with Prostacyclin Analogue

region

idiopathic/familial PAH

connective tissue disease

associated (other forms) PAH

WHO FC I/II at baseline

WHO FC III/IV at baseline

therapy-naïve and WHO FC I/II at baseline

therapy-naïve and WHO FC III/IV at baseline

pre-treated and WHO FC I/II at baseline

pre-treated and WHO FC III/IV at baseline

< 320m 6MWD at baseline

≥320m 6MWD at baseline

< 380m 6MWD at baseline

≥ 380m 6MWD at baseline

males

females

age < 65 years


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
age ≥ 65 years

race.
6.3
Pharmacokinetics/pharmacodynamics
BAY 63-2521 and BAY 60-4552 trough concentrations will be summarized per visit, 
separated according to actual dose. The analyses will be focused on descriptive statistics. The 
following statistics will be calculated for each of the sampling points: arithmetic mean, 
standard deviation and coefficient of variation (CV), geometric mean, geometric standard 
deviation (re-transformed standard deviation of the logarithms), and CV, minimum, median, 
maximum value and the number of measurements. Means at any time will only be calculated 
if at least 2/3 of the individual data were measured and were above the limit of quantification 
(LOQ). For the calculation of the mean value a data point below LOQ will be substituted by 
one half of the limit. In tables showing mean values, this means will be marked. Tables will 
be split by scheduled/ unscheduled visits.
Boxplots of plasma concentrations of BAY 63-2521 and BAY 60-4552 at each visit will be 
given for scheduled extension visits and the last visit of the main study 12934. Separate plots 
will be given for each of the former treatment groups (“Riociguat Individual Dose Titration”, 
“Riociguat 1.5 mg Dose”, “Placebo”). The plots will be restricted to patients that, while 
receiving riociguat, have been uptitrated at all planned times and have not been down-titrated 
until visit 5 of the extension study.  
6.4
Safety
Safety variables are:

Adverse events

Mortality

Laboratory parameters

Vital signs

ECG parameters

Blood gas analysis
Baseline for continuous safety variables will be week 0 of study 12934.
The incidence of treatment-emergent adverse events during the extension will be tabulated by 
treatment group. Adverse events are considered to be treatment-emergent if they have started 
or worsened after first application of study medication up to 2 days after end of treatment with 
study medication. Further tables will be produced for serious and/or drug-related treatment-
emergent adverse events. The incidence of adverse events during follow-up (that is, adverse 
events occurring more than 2 days after end of treatment with study medication) will be 


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tabulated separately. The incidence of adverse events that started in the main study 12934 and 
continue into study 12935 will also be tabulated separately.
In addition, given the varying length of time subjects are in the long-term study, the incidence 
of treatment-emergent adverse events will also be give per 100 subject years.
Mortality 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

listings of laboratory data out of normal range

incidence rates of treatment-emergent laboratory values outside of normal range by 
treatment group

incidence rates of pre-specified laboratory data abnormalities by treatment group

descriptive analysis of continuous laboratory parameters, and their changes from baseline 
by visit and treatment group 
The specific laboratory data abnormalities are consistent with those requested by the Data 
Monitoring Committee or as part of the company medical safety review, and include hepatic 
transaminases, bilirubin and creatinine (and calculated eGFR).
With global amendment 11, a laboratory value testing was completely removed from the 
study protocol.
Vital signs (systolic BP, diastolic BP, heart rate and weight) and blood gas analysis will be 
summarised by visit and treatment group for the population of subjects valid for safety.
For ECGs, the status pre-treatment and post treatment-initiation will be tabulated.  The 
incidence rates of treatment-emergent ECG abnormalities will be tabulated by treatment 
group.  A descriptive analysis of continuous ECG parameters and their changes from baseline 
by visit and treatment group will also be presented.
7.
Document history and changes in the planned statistical analysis
SAP version 2.0 dated 30 Sep 2009
SAP version 3.0 dated 15 Mar 2012
SAP version 4.0 dated 29 May 2012
SAP version 5.0 dated 25 Jul 2019, Update to new template
8.
References
Not applicable.