Conditions: Scleroderma, Systemic
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 121
Healthy volunteers: no

Brief summary:
To investigate if Riociguat is effective in the treatment of systemic sclerosis

Detailed description:

Arms:
arm 1: Main treatment phase of 52 weeks: participants received increasing doses of riociguat by 0.5 mg every 2 weeks up to 2.5 mg 3 times a day (TID) in a-titration period of up to 10 weeks and a maintenance period of up to 42 weeks. Long-term extension phase: starting after the completion of the Main Treatment Phase in Week 52, participants received sham-titration in a dose-titration period of up to 10 weeks followed by a maintenance period. arm 2: Main treatment phase of 52 weeks: participants received matching placebo tablets to riociguat as sham titration in a dose-titration period up to 10 weeks and a maintenance period of up to 42 weeks. Long-term extension phase: starting after the completion of the Main Treatment Phase in Week 52, participants received increasing doses of riociguat by 0.5 mg every 2 weeks up to 2.5 mg 3 times a day (TID) in a dose-titration period of up to 10 weeks followed by a maintenance period.

Interventions: intervention 1: Riociguat (Adempas, BAY63-2521) intervention 2: Placebo
Intervention descriptions: intervention 1: Starting dose 0.5 mg TID, increase by 0.5 mg every 2 weeks until highest possible dose of 2.5 mg TID intervention 2: Sham-titration

Protocol document:
SAP_002.pdf: 
 
 
 
Document Type: 
Statistical Analysis Plan  
Official Title: 
A Randomized, Double-Blind, Placebo-Controlled Phase II Study to 
Investigate the Efficacy and Safety of Riociguat in Patients With 
Diffuse Cutaneous Systemic Sclerosis (dcSSc) 
NCT Number: 
NCT02283762 
Document Date: 
06 MAR 2019 
 


Statistical Analysis Plan – Final report
Protocol No.: BAY 63-2521/16277
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A Randomized, Double-Blind, Placebo-Controlled Phase II Study 
to Investigate the Efficacy and Safety of Riociguat in Patients 
With Diffuse Cutaneous Systemic Sclerosis (dcSSc)
Riociguat in diffuse cutaneous systemic sclerosis (dcSSc)
Bayer study drug
BAY 63-2521 / Riociguat
Study purpose:
To evaluate exploratory outcomes and safety in subjects with diffuse 
cutaneous systemic sclerosis (dcSSc) treated with riociguat in the 
long-term extension phase
Clinical study 
phase:
II
Date:
06 MAR 2019
Study No.:
16277
Version:
Final 1.0
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


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Table of Contents
1.
Introduction ....................................................................................................................... 5
2.
Study Objectives................................................................................................................ 5
3.
Study Design ...................................................................................................................... 6
3.1
Design overview – Long term extension phase ............................................................... 6
3.1.1
Dose-Titration period (Visits 12 to 17; Week 52 to 62)............................................... 6
3.1.2
Open-label Extension period (Visit 18; Week 64 onward) .......................................... 6
3.1.3
Termination visit and Safety follow-up visit................................................................ 7
3.1.4
Definition of rescue therapy ......................................................................................... 7
3.2
End of study ..................................................................................................................... 7
4.
General Statistical Considerations .................................................................................. 8
4.1
General Principles............................................................................................................ 8
4.2
Handling of Dropouts ...................................................................................................... 8
4.3
Handling of Missing Data................................................................................................ 8
4.4
Interim Analyses and Data Monitoring............................................................................ 9
4.5
Data Rules........................................................................................................................ 9
4.5.1
Definition of baseline and handling of repeated measurements................................... 9
4.5.2
Definition of treatment-emergence............................................................................... 9
4.5.3
Definition of regions..................................................................................................... 9
4.6
Unblind Review ............................................................................................................... 9
5.
Analysis Sets..................................................................................................................... 10
5.1
Assignment of analysis sets ........................................................................................... 10
6.
Statistical Methodology................................................................................................... 10
6.1
Population characteristics .............................................................................................. 10
6.1.1
Demographics and baseline characteristics ................................................................ 10
6.1.2
Medical history and concomitant medication............................................................. 11
6.1.3
Study medication duration and exposure.................................................................... 11
6.2
Efficacy.......................................................................................................................... 12
6.2.1
mRSS.......................................................................................................................... 13
6.2.2
Pulmonary function testing......................................................................................... 13
6.2.3
PROs / HRQoL........................................................................................................... 13
6.2.4
Worsening of end-organ diseases............................................................................... 14
6.2.5
Subgroup analysis....................................................................................................... 14
6.3
Pharmacokinetics/pharmacodynamics........................................................................... 15
6.4
Safety ............................................................................................................................. 15
6.4.1
Adverse events and mortality ..................................................................................... 15
6.4.2
Laboratory data........................................................................................................... 16
6.4.3
Other safety parameters .............................................................................................. 16
6.4.4
Subgroup analysis....................................................................................................... 17
6.4.5
Possible changes of observations in main phase ........................................................ 17
7.
Document history and changes in the planned statistical analysis ............................. 18
8.
References ........................................................................................................................ 19
9.
Appendices ....................................................................................................................... 20


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Abbreviations
ACR
American College of Rheumatology
ADS
Analysis dataset
AE
Adverse event
ATC
Anatomical therapeutic chemical
BDG
Bayer Drug Grouping
BMI
Body mass index
CM
Concomitant medication
CRF
Case report form
CRP
C-reactive protein
CSR
Clinical study report
CTEPH
Chronic thromboembolic pulmonary hypertension
dcSSc
Diffuse cutaneous systemic sclerosis
DLCO
Diffusion capacity of the lung for carbon monoxide
DMC
Data Monitoring Committee
ECG
Electrocardiogram
EU
European Union
EULAR
European League Against Rheumatism
FAS
Full analysis set
FVC
Forced vital capacity
HAQ-DI
Health Assessment Questionnaire disability index
HRCT
High resolution computed tomography
HRQoL
Health-related quality of life
ILD
Interstitial lung disease
ITT
Intent-to-treat
IxRS
Telephone- or web-based response system
lcSSc
Limited cutaneous systemic sclerosis
LOQ
Limit of quantification
LTE
Long term extension
MedDRA
Medical Dictionary for Regulatory Activities
MH
Medical history
mRSS
modified Rodnan skin score
NSAID
Nonsteroidal anti-inflammatory drug
PAH
Pulmonary arterial hypertension
PROs
Patient-reported outcomes
PT
Preferred term
RAVE
Validated electronic system used for data collection
SAE
Serious adverse event
SAP
Statistical analysis plan
SAS
Statistical analysis system
SBP
Systolic blood pressure
SF-36
Short Form 36
SHAQ
Scleroderma Health Assessment Questionnaire
SOC
System organ class


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SSc
Systemic sclerosis
TEAE
Treatment-emergent adverse event
TLF
Tables, Listings and Figures
TID
ter in die, 3 times a day
VAS
Visual analog scale
WHO-DD
World Health Organization Drug Dictionary


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1.
Introduction
Systemic sclerosis (SSc) is a rare, orphan disease featuring chronic, fibrosing, autoimmune 
responses characterized by small vessel vasculopathy, autoantibody production, and fibroblast 
dysfunction leading to increased deposition of extracellular matrix.  Systemic sclerosis is 
further divided into 2 subtypes defined by the extent of skin involvement: limited cutaneous 
systemic sclerosis (lcSSc) and diffuse cutaneous systemic sclerosis (dcSSc).
Both dcSSc and lcSSc are associated with internal organ involvement; however, patients with 
dcSSc are at greater risk for clinically significant major organ dysfunction. Diffuse cutaneous 
SSc is one of the most fatal rheumatic diseases, and is associated with substantial morbidity 
and many detrimental effects on health-related quality of life (HRQoL).
Currently, no therapy has been proven to reverse the vascular and fibrotic damage in patients 
with scleroderma. However, due to the high medical need, a number of drugs, such as 
methotrexate, mycophenolate mofetil, cyclophosphamide, azathioprine, and cyclosporine, are 
used off-label in an attempt to slow the progression of fibrosis. Current treatment options only 
target various SSc-related symptoms. No disease-modifying drug is available for SSc. In the 
European Union (EU), only bosentan is approved “to reduce the number of new digital ulcers 
in patients with SSc and ongoing digital ulcer disease” thus addressing also only one aspect of 
the disease. 
Based on the positive results of riociguat in patients with PAH and chronic thromboembolic 
pulmonary hypertension (CTEPH) together with the compound’s known anti-proliferative and 
antifibrotic effects as seen in vitro and in animal models, patients with SSc may benefit from 
treatment with riociguat. The current study will be the first study testing riociguat in this 
indication. The efficacy and safety of riociguat in patients with dcSSc will be evaluated.
This Statistical Analysis Plan is based on the following document(s):
Integrated Clinical Study Protocol, Amendment 7, version 6.0 dated 17 APR 2018
The SAP for the main treatment phase of the study was finalized prior to unblinding to
describe the evaluation the efficacy and safety of 52-week treatment (plus 30-day safety 
follow-up, when applicable) with riociguat compared to the placebo (16277 Statistical 
Analysis Plan - Final Version 4_0). The SAP describing the interim benefit-risk evaluation for 
the long term extension (LTE) phase was finalized on 12 JUL 2018 (16277 Statistical 
Analysis Plan for Benefit-risk update version 1.0). This SAP describes the complete 
evaluation of the LTE phase. Results from the final LTE analyses will be presented in the
Addendum to the Clinical Study Report (CSR).  
2.
Study Objectives
The overall objective of the main phase of study 16277 was to evaluate the efficacy and safety 
of 52 weeks of treatment with riociguat versus placebo in subjects with dcSSc. For details on 
the primary and secondary objectives of the study, see the SAP of the main treatment phase. 
The main focus of the evaluation of the LTE phase described in this SAP was to allow a 
continued exploratory assessment of benefit risk profile of riociguat.


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3.
Study Design
3.1
Design overview – Long term extension phase
The study design consists of a main study treatment phase followed by a LTE phase. At Visit 
12 (Week 52), patients randomized to the placebo arm in the main treatment phase were 
initiated active treatment with riociguat, as part of the LTE phase. During the first 10 weeks, a 
titration/sham-titration was performed to maintain the study blind, after which the extension 
phase becomes open-label. During the LTE phase, clinical outcomes were continued to be 
measured for exploratory long-term treatment effects. Adverse event (AE) information was
continued to be collected throughout the LTE phase.
As defined in the protocol Section 4.1.3, the LTE phase was planned to continue up to 6 years 
after the last patient last visit (LPLV) in the main treatment phase. However, this study was
terminated (LPLV planned in MAR 2019), following the Sponsor´s decision to stop pursuing
the development of riociguat in dcSSc indication.
3.1.1
Dose-Titration period (Visits 12 to 17; Week 52 to 62)
At Visit 12 (Week 52), all patients were assigned in IxRS to treatment with riociguat. To
maintain the study blinding, neither the patients prior treatment assignment nor dose were
unblinded. During the first 10 weeks of LTE phase, patients previously on placebo were up-
titrated on riociguat according to the dose titration algorithm described below (Section 3.1.2). 
Patients randomized to riociguat in the main treatment phase underwent sham titration to 
maintain the blinding during this period.
3.1.2
Open-label Extension period (Visit 18; Week 64 onward)
After completing the double-blind dose-titration period, from Week 64 onwards the study was
open-label and the investigator and the patient were able to see the current treatment dose. All 
patients returned to the clinic for visits every 3 months ± 2 weeks. Ongoing titration of 
riociguat within the range of 0.5 mg to 2.5mg TID remained at the discretion of the 
investigator, and dose reductions for safety reasons were allowed.
Figure 3–1 - LTE phase design


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Dose Interruptions
Although not intended, patients could interrupt their intake of study medication for various 
reasons (e.g., hospitalization in a remote hospital without study medication access, safety
reasons or side effects). If treatment was interrupted, the following rules were applied:
LTE phase:

≤3 consecutive days without treatment (9 missing doses) in the dose-titration period:
restart at the same dose

>3 days but ≤14 consecutive days without treatment in the dose-titration period:
treatment can be restarted at the discretion of the investigator at 0.5 mg TID lower
than the last dose

>14 consecutive days without treatment in the dose-titration period: discontinue the
patient from study medication.

Interruptions in the open-label extension period:
o
>13 and ≤28 consecutive days: treatment can be restarted at the discretion of
the investigator at 0.5 mg TID lower than the last dose.
o
>28 consecutive days: discontinue the patient from study medication.
3.1.3
Termination visit and Safety follow-up visit
A termination visit should have been performed for patients who discontinued, per clinical 
study protocol, from study medication for any reason except death or lost to follow-up, and 
should have occurred as soon as possible after the patient received his/her last dose of study 
drug. In general, at the Termination Visit the same safety and efficacy relevant measurements 
and procedures should have been performed as at Visit 12. If the Termination Visit was
performed after Visit 12 (Week 52) the patient’s and physician’s global assessment, patient 
interference with skin assessment, and tender and swollen joint count assessment must not 
have been performed.
A safety follow-up visit (30 [+5] days after the last dose of study medication) were to be 
performed for all the patients.
3.1.4
Definition of rescue therapy
During the LTE phase (ie, after completion of all efficacy- and safety-related procedures at 
Visit 12), except for the contraindicated nitrates or NO donors and PDE5 inhibitors, the 
addition of any other concomitant medication was at the discretion of the investigator.
Use of rescue therapy agents (4 agents: methotrexate, mycophenolate mofetil, 
cyclophosphamide or azathioprine are counted as defined in the main SAP) will be tabulated 
by therapy from Week 52 to the end of the study date and overall by timepoint.
3.2
End of study
For each participating EU country, the end of the study according to the EU Clinical Trial 
Directive will be reached when the last visit of the last subject for all centers in the respective 
country has occurred.


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The end of the study as a whole will be reached as soon as the end of the study according to 
the above definition has been reached in all participating countries (EU and non-EU).
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).
The statistical analysis will conform to Bayer Global Standard Tables version 3.0, 
16 JAN 2017 with any riociguat project-specific options for these tables, and also any 
additional riociguat project-specific tables (Riociguat Standard Tables version 2.0, 
19 JUN 2013).  Subject data listings will conform to Bayer Global Standard Listings 
version 3.1, 16 JAN 2017.  Additional data summaries not contained within these standards 
will be study specific.
All variables will be analyzed by descriptive statistical methods. The number of data 
available and missing data, mean, standard deviation, minimum, median, quartiles (if data are 
clearly non-normal) and maximum will be calculated for continuous data. Frequency tables 
will be generated for categorical data.
All the analyses will be performed in patients valid for the full analysis set (FAS), who took
part in the LTE. This is the long-term safety analysis set.
4.2
Handling of Dropouts
The frequency of enrolled subjects not completing LTE phase and associated reasons will be 
summarized.
A patient who discontinues study participation prematurely for any reason is defined as a 
“dropout”, if the patient has already been entered to LTE phase.
Any patient, if entered to long-tem extension phase, removed from the trial should undergo 
the assessments at the termination visit.
4.3
Handling of Missing Data
All missing or partial data will be presented in the subject data listing as they are recorded on 
the Case Report Form (CRF). 
Kaplan-Meier plot for “Time to end of study treatment” will be provided.
General rules
When appropriate, the following rules will be implemented so as not to exclude subjects from 
descriptive analyses due to missing or incomplete data:

Safety Variables
When only partial dates are available, the following rules will be used for the 
derivation:
If either the day or month of the start date of the adverse event is missing, then a worst 
case assumption is made for the treatment-emergent flag. For example, if study 
medication starts on 15 JAN 2016 and the AE start date is recorded as JAN 2016, then 


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this is considered treatment-emergent, as it is possible the adverse event started while 
the patient is on study medication.
4.4
Interim Analyses and Data Monitoring
No formal interim analyses for LTE phase will be done. There will be no Data Monitoring 
Committees either. 
4.5
Data Rules
Analysis datasets (ADS) containing all derived variables needed for the statistical evaluation 
will be generated. The structure of the ADS and the contained variables will be described in a 
separate specification document. 
Efficacy analysis datasets will be created that include key data, such as demography, flag for 
use of rescue medication, baseline efficacy. Relative days and flags for treatment emergent 
events are included in the databases.  
The rules for data handling are described in detail in the Project Data Handling Rules, current 
version 1.2, dated 09 JAN 2014, and any updated versions becoming available during the 
course of this study.
4.5.1 Definition of baseline and handling of repeated measurements
Baseline for the main phase is defined as the last set of non-missing measurements taken prior 
to the first intake of study medication, called ‘baseline for main treatment phase’. 
In case of multiple measurements per post baseline visit, the last non-missing value per visit 
will be taken for analysis.
For LTE phase, Week 52 will serve as baseline measurement for LTE (‘baseline for LTE 
phase’) to be compared with measurements during the LTE phase.
4.5.2 Definition of treatment-emergence
Values will be considered treatment-emergent if they start within 2 calendar days after the last 
day of study drug administration, i.e. the treatment-emergent window will be 2 days. 
4.5.3 Definition of regions
The following regions are used for further subgroup analyses:

Europe and Australia/New Zealand: Belgium, Netherlands, Switzerland, Germany, 
Czech Republic, Hungary, Turkey, Spain, Italy, France, UK, Australia, and New 
Zealand 

North America: US and Canada

East Asia: Japan.
4.6
Unblind Review
The results of the unblinded validity review meeting will be documented in the Validity 
Review Report.


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5.
Analysis Sets
5.1
Assignment of analysis sets
Long term safety analysis set will be used in LTE phase. It will consist of all patients 
randomized and treated with study medication (FAS), who have continued treatment with 
study medication in the LTE phase of the study.
6.
Statistical Methodology
Although dose titration is in use, the descriptive analyses will be shown to the following 
treatment groups:

Patients randomized to riociguat in the main phase who stayed on riociguat in the 
LTE phase (called Riociguat-Riociguat in outputs)

Patients randomized to placebo in the main phase who switched to riociguat in the 
LTE phase (called Placebo-Riociguat in outputs)

Total of all patients.
Any comparison between the two treatment groups defined above should be done very 
carefully, since all patients received riociguat in the LTE phase (ie. initial randomization is 
not preserved). The decision whether or not a patient takes part in the LTE phase may depend 
on the treatment which was given in the main phase and thus the groups may not be 
comparable. All results are purely exploratory.
Number of decimal places for summary statistics will be the following:
Figure 6–1 - Decimal places for summary statistics
Statistic
Number of digits
Minimum, maximum
Same as original data
Mean, median
1 more than in original data
SD
2 more than in original data
Frequencies (%)
1 decimal place
6.1
Population characteristics
6.1.1
Demographics and baseline characteristics
Demographic variables and baseline characteristics will be summarized by treatment group 
and overall for long term safety analysis population.
The following demographic data will be recorded: 

Date of birth (month and year) (age)

Sex

Ethnicity


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
Smoking status, including number of cigarettes per day

Alcohol consumption
Summary statistics (number of data available and missing data, mean, standard deviation, 
minimum, median and maximum) will be presented for continuous variables. Frequency 
tables will be presented for categorical variables. Smoking history and status will be 
summarized. Age will be summarized as a continuous variable and as a categorical variable 
categorized into two groups (< 65 years, ≥65 years).
6.1.2
Medical history and concomitant medication
Medical history (MH) and concomitant medication (CM) will be summarized by treatment 
group and overall.
Medical history findings will be coded by Medical Dictionary for Regulatory Activities
(MedDRA) codes. System organ class (SOC) and preferred term (PT) will be used in 
tabulations.
Medical history findings (i.e., previous diagnoses, diseases or surgeries) meeting all criteria 
listed below will be collected:

Pertaining to the study indication

Started before signing of the informed consent

Considered relevant to the study

Medical history related to concomitant therapy
In the following differentiation between medical history and AEs, the term “condition” may 
include abnormal e.g., physical examination findings, symptoms, diseases, laboratory, ECG.

Conditions that started before signing of informed consent and for which no symptoms 
or treatment are present until signing of informed consent are recorded as medical 
history (e.g., seasonal allergy without acute complaints).

Conditions that started before signing of informed consent and for which symptoms or 
treatment are present after signing of informed consent, at unchanged intensity, are 
recorded as medical history (e.g., allergic pollinosis).

Conditions that started or deteriorated after signing of informed consent will be 
documented as AEs.
Prior and concomitant medications will be coded by Anatomical Therapeutic Chemical (ATC) 
classification system according to the World Health Organization Drug Dictionary (WHO-
DD).  The ATC class is taken from the WHO-DD code (first character) and the ATC subclass 
is taken from the WHO-DD code (first 3 characters). 
Bayer Drug Groupings (BDG) will be used to select concomitant medications of special 
interest. The selected concomitant medications will be summarized by parent BDG, BDG and 
substance name. See the main SAP section 6.1.2 for reference. 
6.1.3
Study medication duration and exposure
Study medication duration and exposure will be summarized by treatment group and overall.


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The duration of study medication (in days) is derived by calculating the study medication 
durations by the following formula: period (last dose date – first dose date + 1).  Descriptive 
statistics of treatment duration as well as frequency counts by treatment duration categories 
will be presented. Dose titration by visit, dose titration sequence and reasons for up- and 
down-titration by visit and dose will also be summarized using frequency counts from 
titration phase of LTE period.
The formula for compliance is:
(Total dispensed – total returned/ (Days between visits x dose[# of pills])  X 100 
= What was taken / What should've been taken
x 100 = % Compliance
6.2
Efficacy
In the LTE phase, the following endpoints will be described:

mRSS

Pulmonary function testing:
o
FVC% predicted
o
FVC (l)
o
DLco% predicted
o
DLco (mmol/min/kPa)

PROs / HRQoL:
o
Scleroderma Health Assessment Questionnaire (SHAQ)
o
Short Form 36 (SF-36)
o
Patient-Reported Outcomes Measurement Information System (PROMIS)-29
o
University of California, Los Angeles, Scleroderma Clinical Trial Consortium 
Gastrointestinal Scale (UCLA SCTC GIT) 2.0.

Worsening of end-organ disease (cardiac, renal, pulmonary, gastrointestinal & digital 
ischemia)

Digital ulcer net burden

Proportion of patients developing new digital ulcers

Evaluate digital ulcers for patients with and without DUs at baseline by line plots

All cause mortality

Composite endpoint will be assessed from Week 52 to the end of the study (in 
addition, each individual endpoint will be described separately):
o
mRSS progression (defined as an increase in mRSS by > 4 units or >=20%)
o
worsening of FVC (defined as an absolute change of FVC% predicted ≤ -10)


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o
new organ involvement (as defined in CRISS Step 1 main SAP).
Main study phase and LTE phase data will be shown in summary tables. Change from 
baseline and change from Week 52 (which is the baseline for the LTE analysis) will be 
shown. Progression/regression/improvement/worsening rates will be assessed from Week 52 
until the end of the study.
6.2.1
mRSS

Summary statistics for mRSS 

mRSS progression rate (defined as increase in mRSS by > 5 units and ≥ 25% )

mRSS regression rate (defined as decrease in mRSS by > 5 units and ≥ 25% )

mRSS progression rate (defined as increase in mRSS by > 4 units or ≥ 20% )

Percentage of subjects with ≥ 20%, 40%, or 60% improvement in mRSS

Percentage of subjects with ≥ 20%, 40%, or 60% worsening in mRSS
6.2.2
Pulmonary function testing

Summary statistics for pulmonary function testing (FVC (forced vital capacity)% 
predicted, FVC (l), DLco % predicted, DLco (mmol/min/kPa)

Number of subjects who experience worsening (absolute and relative decline) in 
FVC% predicted by 15% or more  

Number of subjects who experience worsening (absolute and relative decline) in
FVC% predicted by 10% or more  
6.2.3
PROs / HRQoL

SF-36 (Variables: Bodily Pain, General Health, Mental Health, Physical Functioning, 
Role Emotional, Role Physical, Social Functioning, Vitality, Mental Component 
Score, Physical Component Score, Mental Health Enhanced score and Health Utility 
Index) [1.] Norm-based scores in addition to scores 0-100 will be reported.

SHAQ (VAS variables: pain, intestinal problems, breathing problems, Raynaud’s 
symptoms, finger ulcers and overall severity). All the VAS scores will be converted to 
0-3 scale by multiplying results in mm by factor 0.03 and rounding by 0.1 decimals 
[2.]

Gastrointestinal involvement as assessed by University of California, Los Angeles, 
Scleroderma Clinical Trial Consortium Gastrointestinal Scale (UCLA SCTC GIT) 2.0 
instrument

Patient-Reported Outcomes Measurement Information System (PROMIS)-29 (subset 
of sites belonging to English-speaking countries) [3.]


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
Number and proportion of patients with HAQ-DI improvement (HAQ-DI≤-0.21) or
non-improvement (HAQ-DI>-0. 21)

Number and proportion of patients with HAQ-DI improvement (HAQ-DI≤-0.25) or 
non-improvement (HAQ-DI>-0.25)
6.2.4
Worsening of end-organ diseases
Possible worsened adverse events (cardiac, renal, pulmonary, gastrointestinal & digital 
ischemia) in the LTE phase identified by certain SOC and PT will be reviewed by an 
(internal) medical expert applying the definitions of “worsening of end-organ disease” as 
defined in the Adjudication Committee charter. After evaluation of medical expert, 
investiagtors will be asked to confirm the finding. Worsened events, which are confirmed by 
investigators, will be marked in Rave for reporting. In contrast, in the main phase, 
adjudication of clinical events was done by an (external) adjudication committee. Thus, only 
events from the LTE phase will be tabulated. Careful interpretation is necessary when 
comparing the results from the main phase and the LTE phase.
6.2.5
Subgroup analysis 
Descriptive analyses of the primary efficacy outcome measure (change in mRSS from 
baseline to the end of the study and change in mRSS from Week 52 to end of study) will be 
performed for the following subgroups:

region (North America, Europe and Australia/New Zealand, East Asia)

gender (males/females)

age (age < 65 years/age ≥ 65 years)

mRSS at baseline (10 - 16 units/17 - 22 units)

disease duration at baseline (0 - 6 months, 7 - 12 months, 13 - 18 months)

antibody at baseline:
o
SCL-70, RNA polymerase III; both positive, both negative, either one 
positive
o
Anti-centromere B; negative (< 10 U/mL) / positive (>= 10 U/mL)
o
Anti-centromere B positive + SCL-70 and RNA polymerase III negative
o
Anti-centromere B positive + either SCL-70 or RNA polymerase III 
positive

ILD (interstitial lung disease) per medical history (defined with preferred terms: 
interstitial lung disease and pulmonaryfibrosis) at baseline (yes/no)

FVC%, predicted at baseline (<50, 50-75, > 75)

FVC%, predicted at week 52 (<50, 50-75, > 75)

hsCRP elevated at baseline (≤ 3.0mg/L, > 3.0 mg/L; and ≤ 10.0 mg/L, > 10.0 
mg/L)

use of corticosteroids at baseline (yes/no)


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
tendon friction at baseline (yes/no)

mRSS at week 52 (<10 units/ 10 - 16 units/ 17 - 22 units/ >22 units)
6.3
Pharmacokinetics/pharmacodynamics
BAY 63-2521 and M1 trough concentrations will be summarized per visit, according to 
previous dose for trough concentrations. During LTE phase PK was assessed only through 
visits from V12 to V17. 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. Boxplot of concentration of BAY 63-2521 by visit 
will be created.
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.
6.4
Safety
The safety analysis will be performed in the population of patients valid for the long-term 
safety analysis set. All tabulations will be descriptive only. Data from LTE phase until end of 
study will be shown. Absolute values and changes from Week 52 (which is the baseline for
the LTE phase analysis) will be shown.
Adverse events starting in the main phase and continuing into the LTE phase will be included.
6.4.1
Adverse events and mortality
The incidence of AEs (includes incidence of TEAEs and incidence of post-treatment AEs)
will be summarized using MedDRA (version 21.1) preferred terms grouped by primary 
system organ class. The version number of MedDRA relevant for study evaluation will be 
stored in the study database.
The incidence of treatment-emergent AEs (TEAEs) occurring during the LTE phase will be 
tabulated by treatment groups defined for LTE phase. More specifically, AEs are considered 
to be treatment-emergent if they have started or worsened after first application of study drug 
up to 2 days after end of treatment with study drug. 
An overall summary of the number and percentage of patients with TEAEs will be presented 
by treatment groups for events from Week 52 to the end of the study. This summary will 
include the number and the percentage of patients with drug-related TEAEs, treatment 
emergent serious adverse events (TESAEs), drug-related TESAEs, maximum intensity, AEs 
leading to permanent discontinuation and AEs with outcome of death.
Incidences of subjects with TEAEs occurring during LTE phase will be summarized by 
treatment arm and MedDRA terms using frequency tables for the following AE types:


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
TEAEs

Drug-related TEAEs

TESAEs 

Drug-related TESAEs

TEAEs of special interests

Drug-related TEAEs of special interest
Tables for maximum intensity of TEAEs, TESAEs and drug-related TEAEs will be provided.
TEAEs which occurred during the main phase and were ongoing (i.e. not reported as 
“recovered/resolved” or “recovered/resolved with sequelae”) at the entry in LTE phase will 
be summarized.
Incidences of TEAEs and TESAEs per 100 person-years will be tabulated. The rate per
100 person-years is calculated as
Rate per 100 person-years = number of events / (total drug exposure in years / 100),
where 365.25 days are taken as one year.
The incidence of all post-treatment AEs (i.e., AEs occurring more than 2 days after end of 
treatment with study drug) will be tabulated separately.
AEs with outcome of death will be tabulated from Week 52 to the end of the study.
SAEs, deaths, AE leading to discontinuation and AEs of special interest (as defined in the 
protocol Section 7.5.1.6) will be listed. The date, relative day (to study medication) will be 
included.
Further summaries of AEs by intensity and outcome, may be provided, consistent with Bayer
Global Medical Standards.
Incidences of AEs of special interest will be tabulated. The protocol Section 7.5.1.6 specifies 
symptomatic hypotension and serious hemoptysis as AEs of special interest.
6.4.2
Laboratory data
The safety evaluation of laboratory data will include:

Incidence rates of treatment-emergent laboratory values outside of normal range.

Incidence rates of pre-specified laboratory data abnormalities.

Descriptive analysis of continuous laboratory parameters, and their changes from 
baseline (i.e. Week 52) by visit.

Categorical analysis of transitions from low, normal, high from baseline (i.e. Week 52)
to post baseline.
6.4.3
Other safety parameters
Descriptive analysis of weight and vital signs, pulse oximetry and their changes from Week 
52 (which is the baseline for the LTE analysis) until end of the study will be performed.
Number of subjects with low/normal/high vital signs, will be tabulated by treatment group and 


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visit. Assessments for orthostatic test will be listed. The number of subjects with abnormal 
ECG findings, as well as the number of subjects with treatment-emergent ECG abnormalities 
will be tabulated by treatment group from Week 52 to the end of the study.  
6.4.4
Subgroup analysis
A summary table (number and percentage of patients) of the following groups will be created
by treatment group:

Patients with ILD per MH (defined with PTs: interstitial lung disease and pulmonary 
fibrosis) by treatment group (already listed as subgroup analysis in section 6.2.5)

Patients with ILD confirmed by HRCT (confirmed, if interstitial fibrosis and /or 
ground glass found on HRCT) devided to sub-categories:

All patients with ILD per HRCT

All patients with ILD per HRCT done pre-therapy (HRCT prior 
randomization)

All patients with ILD per HRCT done post-baseline (HRCT after 
randomization)

Patients with ILD per MH and confirmed by HRCT (if a patient with ILD in MH has 
HRCT done pre-randomization with interstitial fibrosis and/or ground glass found)

Patients with worsening or new onset of ILD per AE (defined with PTs interstitial lung 
disease and pulmonary fibrosis in AE data)

Patients with worsening or new onset of ILD (defined with PTs interstitial lung 
disease and pulmonary fibrosis in AE data) confirmed by HRCT (Worsening is 
confirmed, when interstitial fibrosis and/or ground glass finding is defined as 
worsened on HRCT. New onset is confirmed, when interstitial fibrosis and/or ground 
glass found on HCRT. HRCT confirms AE in question, if it has been done 28 days 
before – 28 days after AE start date and fulfills the requirements defined before.)
Descriptive analyses by ILD (yes/no) per MH will be perfomed as follows:

TEAEs by treatment group

TESAEs by treatment group

Lung function tests (FVC%, FVC, DLco% predicted, DLco (mmol/min/kPa),) by 
treatment group

Discontinuations of study medication by treatment group
Obligatory HRCTs were performed at baseline or during the study to be able to confirm 
possible ILD finding in MH or AE.
6.4.5
Possible changes of observations in main phase
If there are corrected observations in AE, MH or CM domains after analysis of main treatment 
phase, those will be listed per domain by subject.


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7.
Document history and changes in the planned statistical analysis  
•
Approval of the SAP version 4.0 dated 22 Dec 2017.
•
Approval of the SAP for Benefit-risk update version 1.0 dated 12 Jul 2018.


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8.
References
1. SF-36v2® Advanced Scoring Guidelines: 
How to submit data, what you will receive back, and scoring timeline Final. 
Revised: VL, KM, MW, AY, 11/13/2014
2. IMACS Form 04a: Instructions for the Health Assessment Questionnaire
3. PROMIS ADULT PROFILE INSTRUMENTS


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9.
Appendices
NA

Prot_000.pdf: 
 
Document Type: Study Protocol  
Official Title: 
A Randomized, Double-Blind, Placebo-Controlled Phase II Study 
to Investigate the Efficacy and Safety of Riociguat in Patients 
With Diffuse Cutaneous Systemic Sclerosis (dcSSc) 
NCT Number: 
NCT02283762 
Document Date: 
17 Apr 2018 
 


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Version 6.0
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A Randomized, Double-Blind, Placebo-Controlled Phase II Study to 
Investigate the Efficacy and Safety of Riociguat in Patients With Diffuse 
Cutaneous Systemic Sclerosis (dcSSc)
This protocol version is an integration of the following documents / sections:
Original protocol, Version 1.0, dated 04 SEP 2014
Amendment no. 1 (described in Section 13.1)
forming integrated protocol Version 2.0, dated 04 FEB 2015
Amendment no. 4 (described in Section 13.2)
forming integrated protocol Version 3.0, dated 24 FEB 2016
Amendment no. 5 (described in Section 13.3)
forming integrated protocol Version 4.0, dated 31 AUG 2016
Amendment no. 6 (described in Section 13.4)
forming integrated protocol Version 5.0, dated 02 MAY 2017
Amendment no. 7 (described in Section13.5)
forming integrated protocol Version 6.0, dated 17 APR 2018
This protocol has also been amended for specific countries:
Amendment no 2 (UK), dated 29 JAN 2015 (not submitted).
Amendment no 3 (UK), dated 12 MAR 2015
These local amendments do not form part of this integrated global protocol.


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Title page - amended
A Randomized, Double-Blind, Placebo-Controlled Phase II Study to Investigate the 
Efficacy and Safety of Riociguat in Patients With Diffuse Cutaneous Systemic Sclerosis 
(dcSSc)
Riociguat in diffuse cutaneous systemic sclerosis (dcSSc)
Test drug:
BAY63-2521 / Riociguat 
Study purpose:
Safety and efficacy
Clinical study phase:
II
Date:
17 APR 2018
EudraCT no.:
2014-001353-16
Version no.:
6.0
Study no.:
BAY 63-2521 / 16277
Sponsor1:
Non-US: Bayer AG, D-51368 Leverkusen, Germany
US territory: Bayer Healthcare Pharmaceuticals Inc., 100 Bayer 
Boulevard, P.O. Box 915, Whippany NJ 07981-
0915, USA
Sponsor’s medical expert2:
Bayer Healthcare Company Ltd
Bayer Center, 
No.27, Dong San Huan North Road, Chaoyang District, 
Beijing, 100020 , China
Tel: 
Fax:
The study will be conducted in compliance with the protocol, ICH-GCP and any applicable 
regulatory requirements.
Confidential
The information provided in this document is strictly confidential and is intended solely for 
the guidance of the clinical investigation.  Reproduction or disclosure of this 
document - whether in part or in full - to parties not associated with the clinical 
investigation, or its use for any other purpose, without the prior written consent of the 
sponsor is not permitted.
Throughout this document, symbols indicating proprietary names (, TM) may not be displayed.  Hence, the 
appearance of product names without these symbols does not imply that these names are not protected.
                                                
1 Per Amendment 5
2 Per Amendment 1
PPD
PPD
PPD


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Signature of the sponsor’s medically responsible person
The signatory agrees to the content of the final clinical study protocol as presented.
Name:
Role:  
Global Clinical Lead
Date:
Signature:
PPD


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


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Synopsis - amended
Title
A Randomized, Double-Blind, Placebo-Controlled Phase II Study to 
Investigate the Efficacy and Safety of Riociguat  in Patients With Diffuse 
Cutaneous Systemic Sclerosis (dcSSc)
Short title
Riociguat in diffuse cutaneous systemic sclerosis (dcSSc)
Clinical study phase
II
Study objective(s)
To evaluate the efficacy and safety of 52 weeks of treatment with riociguat 
versus placebo in patients with diffuse cutaneous systemic sclerosis (dcSSc)
Test drug(s)
BAY 63-2521 / Riociguat
Name of active ingredient
BAY 63-2521 / Riociguat
Dose(s)
0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg administered 3 times a day (TID);
dose titration starting with 0.5 mg (planned up-titration every 2 weeks)
Route of administration
Oral
Duration of treatment
Total of 52 weeks, consisting of a 10-week titration period and 42 weeks of 
maintenance. 
Reference drug(s)
Placebo
Name of active ingredient
Not applicable
Dose(s)
Matching placebo tablets to BAY 63-2521 / Riociguat 0.5 mg, 1 mg, 1.5 mg, 
2 mg and 2.5 mg administered TID; dose titration starting with 0.5 mg 
matching placebo tablet.
Route of administration
Oral
Duration of treatment
52 weeks
Background treatment
Not applicable
Indication
dcSSc


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Diagnosis and main criteria for 
inclusion
Men or women aged 18 years and older
Disease duration of ≤ 18 months (defined as time from the first 
non−Raynaud’s phenomenon manifestation), SSc as defined by 2013 the 
American College of Rheumatology (ACR) / European League Against 
Rheumatism (EULAR) classification, and presence of dcSSc based on Leroy 
criteria
≥ 10 and ≤ 22 modified Rodnan skin score (mRSS) units at the screening 
visit
Forced vital capacity (FVC) ≥ 45% of predicted at screening
Diffusion capacity of the lung for carbon monoxide (DLCO) ≥40% 
(hemoglobin-corrected) of predicted at screening
Women of childbearing potential must have a negative serum pregnancy test 
at the screening visit.
Study design
Randomized (1:1), double-blind, placebo-controlled, parallel-group, 
multicenter, multinational study
Methodology
This study is designed to investigate the efficacy and safety of riociguat 
(0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg TID) in patients with dcSSc.  The 
study consists of 2 parts: a main treatment phase for efficacy and safety 
(placebo-controlled) and a long-term extension phase for collection of 
exploratory long-term outcomes.
Type of control
Placebo 
Number of patients
Up to approximately 130 randomized patients3
Primary variable
Change in mRSS from baseline to Week 52
Plan for statistical analysis
The change in mRSS from baseline to all assessments post baseline up to 
Week 52 will be analyzed using mixed model repeated measures (MMRM) 
with baseline mRSS as a covariate, fixed effects treatment arm and region, 
the interaction effect between study visit and treatment arm, and 
patient-specific random effects.  The main estimand of interest is the 
treatment difference between the riociguat and placebo treatment arms at 
Week 52.
                                                
3 Per Amendment 5


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Protocol amendment summary of changes table
Amendment no. 7 (17 APR 2018)
This amendment is considered to be non-substantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the European 
Union because it neither significantly impacts the safety or physical/mental integrity of 
participants nor the scientific value of the study.
Overall rationale for the amendment
Overall rationale: The protocol amendment 7 was prepared based on the main treatment phase 
results of the study to better characterize the enrolled patient population and their 
autoantibody profile.
This change does not affect the design or the overall concept of the study.
In addition, a change of responsible Global Clinical Lead was made. 
Section # and name
Description of change
Brief rationale
Signature of the sponsor’s 
medically responsible person 
The Global Clinical Lead was 
updated to 
Change of responsible Global 
Clinical Lead
7.6.4
Autoantibody screen
The addition of the anti-
centromere was included in the 
autoantibody screen.
Further autoantibodies will 
allow better characterization of 
the enrolled patient population 
and their autoantibody profile.
PPD


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Table of contents
Title page - amended................................................................................................................ 2
Signature of the sponsor’s medically responsible person..................................................... 3
Signature of principal investigator......................................................................................... 4
Synopsis - amended .................................................................................................................. 5
Protocol amendment summary of changes table................................................................... 7
Table of contents....................................................................................................................... 8
Table of in-text tables............................................................................................................. 12
Table of in-text figures........................................................................................................... 12
List of abbreviations............................................................................................................... 13
1.
Introduction..................................................................................................................... 16
1.1
Background.................................................................................................................... 16
1.1.1
Scleroderma (systemic sclerosis)................................................................................ 16
1.1.2
Riociguat..................................................................................................................... 17
1.1.2.1
Mechanism of Action.............................................................................................. 17
1.1.2.2
Preclinical Data - amended ..................................................................................... 18
1.1.2.3
Clinical Data............................................................................................................ 19
1.2
Rationale of the study .................................................................................................... 19
1.3
Benefit-risk assessment - amended................................................................................ 20
2.
Study objectives - amended............................................................................................ 21
3.
Investigators and other study personnel - amended.................................................... 22
4.
Study design..................................................................................................................... 24
4.1
Design overview -amended............................................................................................ 24
4.1.1
Screening phase (up to 2 weeks) ................................................................................ 26
4.1.2
Main treatment phase (Week 0 to Week 52) - amended ............................................ 26
4.1.3
Long-term extension phase......................................................................................... 27
4.1.4
Dose Interruptions - amended..................................................................................... 28
4.1.5
Termination visit and safety follow-up visit - amended............................................. 29
4.2
Primary variable............................................................................................................. 29
4.3
Justification of the design .............................................................................................. 29
4.4
End of study................................................................................................................... 30
5.
Study population ............................................................................................................. 30
5.1
Eligibility ....................................................................................................................... 30
5.1.1
Inclusion criteria - amended ....................................................................................... 30
5.1.2
Exclusion Criteria - amended ..................................................................................... 30
5.1.3
Justification of selection criteria................................................................................. 32
5.2
Withdrawal of patients from study - amended............................................................... 33
5.2.1
Withdrawal - amended................................................................................................ 33
5.2.1.1
Withdrawal from the study...................................................................................... 33
5.2.1.2
Discontinuation of study medication....................................................................... 33
5.2.1.3
Handling of withdrawals or discontinuations from study medication .................... 34
5.2.2
Replacement - amended.............................................................................................. 35


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5.3
Patient identification...................................................................................................... 36
6.
Treatment......................................................................................................................... 36
6.1
Treatments to be administered....................................................................................... 36
6.2
Identity of study treatment............................................................................................. 36
6.3
Treatment assignment.................................................................................................... 37
6.4
Dosage and administration............................................................................................. 38
6.4.1
Selection of doses in the study - amended.................................................................. 38
6.5
Blinding - amended........................................................................................................ 38
6.6
Drug logistics and accountability................................................................................... 39
6.7
Treatment compliance.................................................................................................... 39
6.8
Post-study therapy.......................................................................................................... 40
6.9
Prior and concomitant therapy - amended ..................................................................... 40
7.
Procedures and variables ............................................................................................... 43
7.1
Schedule of procedures.................................................................................................. 43
7.1.1
Tabulated overview - amended................................................................................... 44
7.1.2
Timing of assessments................................................................................................ 49
7.1.2.1
Visit 0 Screening phase – Screening visit............................................................ 49
7.1.2.2
Visit 1 Main treatment phase - Baseline (Day 0, Week 0)................................... 50
7.1.2.3
Visits 2 through to 6 Main treatment phase – Dose-titration period - amended.. 51
7.1.2.4
Visits 7 through to 11 Main treatment phase - Maintenance period - amended .. 52
7.1.2.5
Visit 12 (Week 52) - amended ................................................................................ 53
7.1.2.6
Visits 13 through to 17 Long-term extension phase - Dose-titration period -
amended .................................................................................................................. 55
7.1.2.7
Visits 18 through Visit n (every 12 weeks) Long-term extension phase Open-
label extension period - amended............................................................................ 55
7.1.2.8
Termination Visit - amended................................................................................... 56
7.1.2.9
Safety follow-up visit - amended ............................................................................ 57
7.1.2.10
Premature discontinuation of study drug treatment - amended............................... 58
7.2
Population characteristics .............................................................................................. 58
7.2.1
Demographic .............................................................................................................. 58
7.2.2
Medical history........................................................................................................... 58
7.3
Efficacy - amended ........................................................................................................ 58
7.4
Pharmacokinetics / pharmacodynamics - amended....................................................... 60
7.5
Safety ............................................................................................................................. 62
7.5.1
Adverse events............................................................................................................ 62
7.5.1.1
Definitions - amended ............................................................................................. 62
7.5.1.2
Classifications for adverse event assessment.......................................................... 63
7.5.1.2.1
Seriousness........................................................................................................... 63
7.5.1.2.2
Intensity................................................................................................................ 63
7.5.1.2.3
Causal relationship............................................................................................... 63
7.5.1.2.4
Action taken with study treatment ....................................................................... 65
7.5.1.2.5
Other specific treatment(s) of adverse events...................................................... 65
7.5.1.2.6
Outcome............................................................................................................... 65
7.5.1.3
Assessments and documentation of adverse events ................................................ 65
7.5.1.4
Reporting of serious adverse events ........................................................................ 65
7.5.1.5
Expected adverse events.......................................................................................... 66
7.5.1.6
Adverse events of special safety interest................................................................. 67


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7.5.1.7
Overdose of Study Medication................................................................................ 67
7.5.2
Pregnancies................................................................................................................. 67
7.6
Other procedures and variables...................................................................................... 67
7.6.1
Pregnancy testing........................................................................................................ 67
7.6.2
Laboratory parameters - amended.............................................................................. 68
7.6.3
Exploratory Biomarkers - amended............................................................................ 69
7.6.4
Autoantibody screen................................................................................................... 70
7.6.5
Blood pressure and heart rate measurement - amended ............................................. 70
7.6.6
Modified Rodnan skin scoring (mRSS)...................................................................... 70
7.6.7
Electrocardiogram ...................................................................................................... 71
7.6.8
Pulmonary function testing......................................................................................... 71
7.6.9
Skin biopsy................................................................................................................. 71
7.6.10
Digital ulcer net burden.............................................................................................. 72
7.6.11
Digital gangrene ......................................................................................................... 72
7.6.12
Raynaud’s attacks assessment .................................................................................... 73
7.6.13
Patient-reported outcomes (PROs) / Health-related quality of life (HRQoL) 
questionnaires............................................................................................................. 73
7.6.14
Tender and swollen joint count .................................................................................. 74
7.6.15
Patient’s and physician’s global assessment - amended............................................. 74
7.6.16
Patient interference with skin assessment .................................................................. 75
7.6.17
Tendon friction rubs ................................................................................................... 75
7.6.18
Oxygen saturation measurement using forehead pulse oximetry............................... 75
7.7
Appropriateness of procedures / measurements ............................................................ 75
8.
Statistical methods and determination of sample size ................................................. 75
8.1
General considerations................................................................................................... 75
8.2
Analysis sets - amended................................................................................................. 76
8.3
Variables ........................................................................................................................ 76
8.4
Statistical and analytical plans....................................................................................... 76
8.4.1
Demographic and other baseline characteristics ........................................................ 76
8.4.2
Efficacy - amended..................................................................................................... 76
8.4.2.1
Primary endpoint..................................................................................................... 76
8.4.2.2
Secondary and exploratory endpoints ..................................................................... 78
8.4.3
Safety - amended ........................................................................................................ 80
8.4.4
Pharmacokinetics........................................................................................................ 81
8.5
Planned interim analyses - amended.............................................................................. 81
8.6
Determination of sample size - amended....................................................................... 81
9.
Data handling and quality assurance............................................................................ 83
9.1
Data recording................................................................................................................ 83
9.2
Monitoring ..................................................................................................................... 83
9.3
Data processing.............................................................................................................. 84
9.4
Audit and inspection ...................................................................................................... 84
9.5
Archiving ....................................................................................................................... 84
10. Premature termination of the study .............................................................................. 85
11. Ethical and legal aspects................................................................................................. 85
11.1
Ethical and legal conduct of the study........................................................................... 85
11.2
Patient information and consent .................................................................................... 86
11.3
Publication policy .......................................................................................................... 87


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11.4
Compensation for health damage of patients / insurance .............................................. 87
11.5
Confidentiality ............................................................................................................... 87
12. Reference list - amended,................................................................................................ 89
13. Protocol amendments...................................................................................................... 93
13.1
Amendment 1................................................................................................................. 93
13.1.1
Overview of changes to the study............................................................................... 93
13.1.2
Changes to the protocol text....................................................................................... 93
13.2
Amendment 4............................................................................................................... 117
13.2.1
Overview of changes to the study............................................................................. 117
13.2.2
Changes to the protocol text..................................................................................... 117
13.3
Amendment 5............................................................................................................... 132
13.3.1
Overview of changes to the study............................................................................. 132
13.3.2
Changes to the protocol text..................................................................................... 133
13.4
Amendment 6............................................................................................................... 146
13.4.1
Overview of changes to the study............................................................................. 146
13.4.2
Changes to the protocol text..................................................................................... 146
13.5
Amendment 7............................................................................................................... 164
14. Appendices..................................................................................................................... 165
14.1
Child-Pugh Classification of Liver Disease................................................................. 165
14.2
Definition of Systemic Sclerosis Renal Crisis - amended ........................................... 166
14.3
Tender and Swollen Joint Count Assessment Form .................................................... 167


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Table of in-text tables
Table 6–1 Identity of investigational product ........................................................................ 37
Table 6–2 Prohibited prior and concomitant therapy - amended ........................................... 41
Table 7–1 Schedule of evaluations - amended....................................................................... 44
Table 7–2 Profile Day PK Sampling (Visit 1 and Visit 12)................................................... 48
Table 7–3 PK Sampling (Visits 2 – 6 and Visits 13 – 17) ..................................................... 48
Table 7–4 PK Sampling (Visit 11)......................................................................................... 49
Table 8–1 References for estimate of variability ................................................................... 82
Table 8–2 Power calculations: power varying from 70% to 80% in 2% stages..................... 82
Table of in-text figures
Figure 4–1 Main treatment phase design................................................................................. 25
Figure 4–2 Long-term extension phase design........................................................................ 25


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List of abbreviations
ACR
American College of Rheumatology
ADMA
asymmetrical dimethylarginine
AE
adverse event
ALT
alanine aminotransferase (also known as SGPT, qv)
ANCOVA
analysis of covariance
AP
alkaline phosphatase
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase (also known as SGOT, qv) 
ATC
Anatomical Therapeutic Chemical
AUC
area under the plasma concentration versus time curve
BMI
body mass index
BP
blood pressure
BPM
beats per minute
cGMP
cyclic guanosine monophosphate
CK
creatine kinase
Cmax
maximum plasma concentration
COL1A1
collagen type 1 alpha 1
COL1A2
collagen type 1 alpha 2
COL3A1
collagen type 3 alpha 1
COMP
cartilage oligomeric matrix protein
CREST
calcinosis, Raynaud’s phenomenon, esophageal dysmotility, 
sclerodactyly, and telangiectasias
CRISS
(American College of Rheumatology) Composite Response Index for 
Clinical Trials
CRO
clinical research organization
CSRG
Canadian Scleroderma Research Group
CTEPH
chronic thromboembolic pulmonary hypertension
CXCL-4
platelet factor-4
CYP
cytochrome P450
DBP
diastolic blood pressure
dcSSc
diffuse cutaneous systemic sclerosis
dL
Deciliter
DLCO
diffusion capacity of the lung for carbon monoxide
DMC
data monitoring committee
EC
Ethics Committee  
ECG
Electrocardiogram
eCRF
electronic case report form
eg
exempli gratia, for example
eGFR
estimated glomerular filtration rate
EU
European Union
EULAR
European League Against Rheumatism
EUSTAR
EULAR Scleroderma Trials and Research
FAS
full analysis set
FDA
Food and Drug Administration
FVC
forced vital capacity
g
Gram


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GCP
Good Clinical Practice
GGT
gamma glutamyl transpeptidase
GLDH
Glutamate dehydrogenase
GMP
Good Manufacturing Practice
h
Hour
HAQ-DI
Health Assessment Questionnaire disability index
HDPE
high density polyethylene
HPF
High power field
HR
heart rate
HRCT
High resolution computed tomography
HRQoL
health-related quality of life
hsCRP
high-sensitivity C-reactive protein
IB
investigator’s brochure
ICH
International Conference on Harmonization
ie
id est, that is
IEC
independent ethics committee
IHC
Immunohistochemistry
ILD
Interstitial lung disease
IND
Investigational New Drug
INR
international normalized ratio (prothrombin time expressed in relation 
to normal value)
IRB
institutional review board
ITT
intent to treat
IxRS
telephone-based or web-based response system
L
Liter
lcSSc
limited cutaneous systemic sclerosis
LPLV
Last Patient Last Visit
m2
square meter
MCP
Metacarpophalangeal joint
MDRD
modification of diet in renal disease
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram
min
Minute
mL
Milliliter
mol
Molarity
mmHg
millimeters of mercury
MMRM
mixed model repeated measures
mRNA
messenger ribonucleic acid
mRSS
modified Rodnan skin score
NO
nitric oxide
NSAID
nonsteroidal anti-inflammatory drug
PAH
pulmonary arterial hypertension
PD
pharmacodynamics
PDE
Phosphodiesterase
PDE5
phosphodiesterase 5
p-ERK
phosphorylated extracellular regulated kinase
P-gp
P-glycoprotein
PIP
Proximal interphalangeal joint
PK
pharmacokinetic(s)


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popPK
population PK
PPS
per protocol set
PRO
patient-reported outcome(s)
PROMIS
Patient-Reported Outcomes Measurement Information System
p-VASP
phosphorylated vasodilator-stimulated phosphoprotein
RBC
red blood cells
s
Second
SAE
serious adverse event
SAP
statistical analysis plan
SAS
Statistical Analysis System
SBP
systolic blood pressure
SD
standard deviation
SDMA
symmetrical dimethylarginine
sE-Selectin
soluble E-selectin
SF-36
Short Form 36
SFU
safety follow-up
sGC
soluble guanylate cyclase
SHAQ
Scleroderma Health Assessment Questionnaire
SNAP
S-nitroso-N-acetyl-penicillamine
sPECAM-1
soluble platelet endothelial cell adhesion molecule
SpO2
peripheral oxygen saturation
SSc
systemic sclerosis
SUSAR
suspected unexpected serious adverse reaction
TEAEs
treatment-emergent AEs
TGF-
transforming growth factor-beta
TID
ter in die, 3 times a day
TSP1
thrombospondin 1
TV
termination visit
UCLA SCTC GIT 
University of California, Los Angeles, Scleroderma Clinical Trial 
Consortium Gastrointestinal Scale
UK
United Kingdom
ULN
Upper limit of normal
US/ USA
United States/ United States of America
VAS
visual analog scale
WBC
white blood cell
WHO-DD
World Health Organization Drug Dictionary


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1.
Introduction
1.1
Background
1.1.1
Scleroderma (systemic sclerosis)
Systemic sclerosis (SSc) is a rare, orphan disease featuring chronic, fibrosing, autoimmune 
responses characterized by small vessel vasculopathy, autoantibody production, and fibroblast 
dysfunction leading to increased deposition of extracellular matrix.[1] 
Systemic sclerosis is further divided into 2 subtypes defined by the extent of skin 
involvement: limited cutaneous systemic sclerosis (lcSSc) and diffuse cutaneous systemic 
sclerosis (dcSSc).[2]  According to LeRoy and colleagues, classification as limited or diffuse 
disease is based on the extent of skin tightening.[3]  In limited disease (formerly called 
CREST [calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, and 
telangiectasias] syndrome), skin tightening is confined to the fingers, hands, and forearms 
distal to the elbows, with or without tightening of skin of the feet and of the legs distal to the 
knees. Proximal extremities and the trunk are not involved.  In dcSSc, the skin of the 
proximal extremities and trunk is also involved.  Both dcSSc and lcSSc are associated with 
internal organ involvement; however, patients with dcSSc are at greater risk for clinically 
significant major organ dysfunction. Diffuse cutaneous SSc is one of the most fatal rheumatic 
diseases, and is associated with substantial morbidity and many detrimental effects on 
health-related quality of life (HRQoL).
Systemic sclerosis is an orphan disease with an estimated prevalence of 50,000 in Europe and
276/106 patients in the United States of America (USA).[4] With a 2010 USA census of 
309 million people, there are < 100,000 patients in the USA with SSc. Approximately 60% 
have limited SSc and 35 to 40% have diffuse SSc.
The tissue fibrosis in SSc is caused by an increased production of extracellular matrix 
components by activated fibroblasts [5] and affects the skin and various internal organs such 
as the heart, lungs, kidneys and gastrointestinal tract.  Tissue fibrosis contributes significantly 
to the high morbidity and the increased mortality of SSc.[6] The vascular alterations show a 
predilection for the small arteries and arterioles.  Vascular dysfunction (ie, Raynaud’s 
phenomenon) is one of the earliest alterations of SSc and may represent the initiating event in 
its pathogenesis.  Severe alterations in small blood vessels of skin and internal organs, 
including fibrosis and perivascular cellular infiltration with diverse inflammatory cells, are 
almost always present in SSc.
Survival in SSc is dependent on the extent of internal organ involvement and the disease 
course.[2]  Because internal organ and skin involvement are more extensive and progress 
faster in dcSSc compared to lcSSc, the average 6-year survival rate is 50% in lcSSc compared 
to 30% in dcSSc. Twelve-year survival is 50% for lcSSc and 15% for dcSSc.[3] Death is 
generally attributed to progressive pulmonary fibrosis, pulmonary hypertension, extensive 
gastrointestinal deterioration, and scleroderma heart disease.  Except when pulmonary 
hypertension develops, limited disease is associated with a better prognosis.
No definitive diagnostic test for SSc is available; therefore, several diagnostic classifications 
have been developed.  Until recently, the standard classification used for diagnosis was the 
1980 preliminary criteria for the classification of SSc, developed by the American College of 
Rheumatology (ACR).[7]  Due to concern regarding the sensitivity of the 1980 criteria, as 
well as advances in knowledge about SSc in the past 30+ years, the ACR and the European 


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League Against Rheumatism (EULAR) established a committee to provide a joint proposal 
for new classification criteria for SSc.  The goals of the committee were to develop criteria 
that 1) encompass a broader spectrum of SSc, including patients whose disease is in the early 
stage as well as those in the late stage; 2) include vascular, immunologic, and fibrotic 
manifestations; 3) are feasible to use in daily clinical practice; and 4) are in accordance with 
criteria used for diagnosis of SSc in clinical practice.  The updated classification criteria were 
published in 2013.[1]  Using consensus methods, the committee determined that skin 
thickening of the fingers extending proximal to the metacarpophalangeal joints is sufficient 
for the patient to be classified as having SSc; if that feature is not present, the following 
7 additive items can be used, with varying weights for each: skin thickening of the fingers, 
fingertip lesions, telangiectasia, abnormal nailfold capillaries, interstitial lung disease or 
pulmonary arterial hypertension (PAH), Raynaud’s phenomenon, and SSc-related 
autoantibodies.
Currently, no therapy has been proven to reverse the vascular and fibrotic damage in patients 
with scleroderma.[2]  However, due to the high medical need, a number of drugs, such as 
methotrexate, mycophenolate mofetil, cyclophosphamide, azathioprine, and cyclosporine, are 
used off-label in an attempt to slow the progression of fibrosis. Current treatment options only 
target various SSc-related symptoms. No disease-modifying drug is available for SSc. In the 
European Union (EU), only bosentan is approved “to reduce the number of new digital ulcers 
in patients with SSc and ongoing digital ulcer disease,” thus addressing also only one aspect 
of the disease. 
Based on the positive results of riociguat in patients with PAH and chronic thromboembolic 
pulmonary hypertension (CTEPH) together with the compound’s known anti-proliferative and 
antifibrotic effects as seen in vitro and in animal models, patients with SSc may benefit from 
treatment with riociguat.
The current study will be the first study testing riociguat in this indication.  The efficacy and 
safety of riociguat in patients with dcSSc will be evaluated.
1.1.2
Riociguat
1.1.2.1
Mechanism of Action
Riociguat is the first-in-class of a new group of compounds, soluble guanylate cyclase (sGC) 
stimulators. Riociguat directly stimulates sGC, thereby increasing levels of the signaling 
molecule cyclic guanosine monophosphate (cGMP). The cGMP molecule plays a pivotal role 
in regulating cellular processes, such as vascular tone, proliferation, fibrosis, and 
inflammation. Two key features of riociguat include: 1) it directly stimulates sGC 
independently of nitric oxide (NO), and 2) it sensitizes sGC to low levels of NO. Because of
the broad spectrum of cGMP actions and specific mode of action of riociguat, the efficacy of 
sGC stimulators for the treatment of patients with SSc was investigated. Both, the vascular 
effects of riociguat and the direct antifibrotic effects could be beneficial for the treatment of 
patients with SSc. More specifically, it was shown that sGC stimulators decrease collagen 
production in dermal fibroblasts from SSc patients.[8] In addition, sGC stimulators block 
fibroblast to myofibroblasts differentiation of dermal fibroblasts.[9] Thus, sGC stimulators 
could block production of collagen and extracellular matrix components, which may explain, 
at least in part, the antifibrotic effects of sGC stimulators.


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1.1.2.2
Preclinical Data - amended
To support the use of riociguat for treatment of SSc, in vitro and in vivo investigations were 
undertaken, providing ample evidence of beneficial effects of cGMP elevation and the 
potential of sGC stimulators in the treatment of fibrotic diseases.
In vitro evidence for antifibrotic effects of cGMP elevation in the skin, which is a prerequisite 
to the effects of sGC stimulators for the treatment of SSc, includes the following findings:

Collagen production was evaluated in human dermal fibroblasts derived from 
hypertrophic scars as well as from normal cells from the patient’s donor site.  
Collagen production in fibroblasts, regardless of source, was substantially stimulated 
by TGF-β1 (transforming growth factor-beta) exposure. Increase of cGMP by either 
the NO donor SNAP (S-nitroso-N-acetyl-penicillamine) or the cGMP analog 8-
Bromo-cGMP offset the stimulation of collagen production [10]

sGC stimulation dose-dependently inhibited collagen mRNA expression and collagen 
release in dermal fibroblasts from SSc patients.[8,9]
In vivo evidence for anti-fibrotic effects of cGMP elevation in fibrotic diseases includes the 
following:

In a mouse model of pulmonary fibrosis, daily administration of riociguat ameliorated 
pulmonary inflammation and fibrosis and improved survival [11]

In a rat model for hypertension and organ damage, riociguat significantly ameliorated 
fibrotic tissue remodeling and degeneration in hearts and kidneys.[12,13]
To further evaluate the treatment potential of riociguat for SSc, riociguat was tested in 2
widely accepted mouse models for SSc, namely the a) bleomycin-induced skin fibrosis model, 
which resembles an early, inflammatory-driven stage of SSc and b) in the TSK-1 model 
which resembles a later, non-inflammatory, stage of the SSc. 
As also the vascular effects of riociguat could be beneficial for the treatment of patients with 
SSc, especially with regard to prevention and healing of digital ulcers. To this end, wound 
healing was analyzed in the TSK-1 skin fibrosis mouse model. 
In summary, investigations of the anti-fibrotic efficacy of sGC stimulators riociguat and 
BAY 41-2272, another sGC compound4, showed that these agents act dose-dependently:

reduced collagen production in human dermal fibroblasts  

reduced fibroblast-to-myofibroblast differentiation of human dermal fibroblasts

prevented TGF-ß-induced skin fibrosis in vivo

prevented skin fibrosis in bleomycin model

reduced established skin fibrosis in genetic TSK-1 model

promoted wound healing in TSK-1 mice.
                                                
4 Per Amendment 1


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1.1.2.3
Clinical Data
Riociguat was recently approved in a number of regions / countries including the USA,
Canada, Switzerland, Australia, Europe, Turkey, South Korea and Japan, for the treatment of 
2 forms of pulmonary hypertension: PAH and/or CTEPH.
Further details can be found in the investigator's brochure (IB), which contains 
comprehensive information on the study drug.
1.2
Rationale of the study
Diffuse cutaneous SSc is one of the most severely incapacitating and life-threatening 
rheumatic diseases. Fibrosis of the skin and internal organs is a hallmark of the disease and 
the progression of the fibrosis disrupts tissue architecture and causes organ failure, resulting 
in high morbidity and mortality among patients with SSc.
Based on preclinical in vitro and in vivo data demonstrating that riociguat was safe and 
efficacious in different models of fibrotic diseases including scleroderma, the hypothesis is 
that riociguat may bring significant clinical benefit to patients with scleroderma by acting not 
only by improving vascular disease but, most importantly, by its inhibition of biochemical 
fibrotic pathways.[8] Based on the preclinical data, it is anticipated that riociguat may slow 
down the progression of the fibrotic disease by acting through TGF-mediated pathways and, 
by its vasoactive properties, decrease the number and severity of Raynaud’s attacks as well as 
decrease digital ulcer net burden.
This study aims to recruit patients with dcSSc.  The rationale is: a) there is a better 
understanding of the natural history of dcSSc than lcSSc, and b) dcSSc is a subset of SSc in 
which more rapid progression in disease occurs with worse prognosis, and where there is a 
high unmet need for effective treatment.
To better design this study with regard to the inclusion criteria, a recent study [14] was taken 
into consideration and predictive parameters were identified for the progression of skin 
fibrosis within 1 year in patients with dcSSc. An observational study using the EUSTAR 
(EULAR Scleroderma Trials and Research) database was assessed. Worsening of skin 
fibrosis was defined as increase in modified Rodnan skin score (mRSS) > 5 points and ≥25% 
from baseline to the second visit. Inclusion criteria were dcSSc, ACR criteria fulfilled, mRSS
≥7 at the baseline visit, valid data for mRSS at the second visit, and available follow up of 
12 (±2) months. In the univariate analysis, patients with progressive fibrosis were compared 
to non-progressors and predictive markers with p<0.2 were included in the logistic regression 
analysis. The prediction models were then validated in a second cohort.
A total of 637 dcSSc patients were eligible. Univariate analyses identified joint synovitis, 
short disease duration (≤15 months), short disease duration in females/patients without 
creatine kinase (CK) elevation, low baseline mRSS (≤22/51), and absence of esophageal 
symptoms as potential predictors for progressive skin fibrosis. In the multivariate analysis, by 
employing combinations of the predictors, 17 models with varying prediction success were 
generated, allowing cohort enrichment from 9.7% progressive patients in the whole cohort to 
44.4% in the optimized enrichment cohort. Using a second validation cohort of 188 dcSSc 
patients, short disease duration, low baseline mRSS, and joint synovitis were confirmed as 
independent predictors of progressive skin fibrosis within 1 year showing a 4.5-fold increased 
prediction success rate.


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From the 17 models generated by the multivariate analysis, the combination of 2 predictors, 
short disease duration, and low baseline mRSS, which allowed for a cohort enrichment of 
around 20%, was chosen.
1.3
Benefit-risk assessment - amended
Diffuse cutaneous systemic sclerosis is a progressive, rare, orphan disease characterized by 
vasculopathy (Raynaud’s phenomenon, digital ulcers) and progressive fibrosis of the skin and 
internal organs, ultimately leading to death.  There are currently no disease-specific 
pharmacotherapies approved, and therefore, there is a high unmet medical need in this 
indication. 
Considering the mechanism of action of riociguat and the results of the preclinical studies 
demonstrating beneficial effects of riociguat in a) decreasing collagen synthesis by dermal 
fibroblasts, b) inhibiting fibroblast to myofibroblast differentiation, c) decrease in skin 
thickness in in vivo models, and d) improving wound healing in the skin of an animal model, 
the hypothesis is that riociguat treatment may bring the following benefits to patients with 
dcSSc:

Antifibrotic effect, as measured by a treatment effect between verum and placebo, as 
measured by the mRSS and by change from baseline in skin thickness;

Decrease number and severity of Raynaud’s attacks;

Decrease digital ulcer net burden.
Additional benefits that may occur include reduction in arthralgia and joint tenderness and 
slowing the progression of internal organ fibrosis.
Relevant risks for the dcSSc population may be unmasking of pulmonary vascular occlusive 
disease, hypotension, gastrointestinal motility disorders, serious bleeds, and embryo-fetal 
toxicity.
During the pivotal riociguat PATENT-1 trial for PAH, patients with PAH-SSc were included 
and the overall benefit-risk profile was positive.
Taking into account the seriousness of the disease as well as the medical need for an effective 
and safe therapy, on balance the expected benefit to patients with this life-threatening 
condition outweighs potential risks.
Recently, a potential safety issue has been reported for patients with pulmonary hypertension 
associated with idiopathic interstitial pneumonias (PH-IIP) and, therefore, the benefit-risk 
assessment for this indication has changed from positive to unfavorable. Following the data 
monitoring committee (DMC) recommendation, the study treatment has been terminated. 
Also per DMC recommendation patients are continuing in a safety follow-up for 4 months 
after study drug discontinuation and the study is expected to close in September 2016. 
A careful review, assessment and analysis will be done by the sponsor with unblinded and 
clean data originating from clinical study 13605 (RISE-IIP; final clinical study report 
expected in 2017). Information of health care professionals (via Dear Healthcare Professional 
Letter), label updates and an update of the risk management plan have been initiated in 
July 2016 in collaboration with the European Medicines Agency as well as national 
competent authorities.


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The benefit-risk profile for conditions being studied in ongoing clinical studies also has been 
carefully re-evaluated. In the case of the present study in the dcSSc indication, 2 ad-hoc 
meetings of the DMC for this study took place, on 23 MAY 2016 and on 25 MAY 2016, 
followed by a third meeting on 15 AUG 2016. The DMC concluded that this study may 
continue without amendment or modification. Overall, the benefit-risk balance for this 
indication remains positive.5
2.
Study objectives - amended
The overall objectives of this study are to evaluate the efficacy and safety of 52 weeks of 
treatment with riociguat versus placebo in patients with dcSSc.
The primary objective of this study is:

To assess the efficacy of riociguat administered 3 times a day (TID) as compared with
placebo in terms of change in the mRSS from baseline to Week 52
The secondary objectives of this study are to assess the efficacy of treatment with riociguat 
administered TID as compared with placebo in terms of: 

Efficacy6:
o
Key secondary objective:

American College of Rheumatology Combined Response Index for 
Systemic Sclerosis (CRISS) at Week 52.7
o
Further secondary objectives:

Health Assessment Questionnaire disability index (HAQ-DI) domain 
(separately from the Scleroderma Health Assessment Questionnaire 
[SHAQ] as part of the calculation of the CRISS algorithm)

Patient’s global assessment

Physician’s global assessment

Change in FVC (forced vital capacity) % predicted 

Further clinical outcomes (to be adjudicated by an Independent Central Adjudication 
Committee):
o
New renal crisis
o
Worsening of cardiac disease, defined as new or worsened clinically 
symptomatic and significant heart disease, considered secondary to dcSSc, 
including congestive heart failure requiring hospitalization, new onset 
pulmonary hypertension requiring treatment, pericardial disease requiring 
intervention or exhibiting clinical decompensation, and arrhythmias and/or 
conduction defects requiring treatment
o
Worsening of gastrointestinal disease requiring hospitalization or new 
requirement for parenteral nutrition
                                                
5 Per Amendment 5
6 Per Amendment 4
7 Per Amendment 5


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o
Critical digital ischemia requiring hospitalization, or digital gangrene
Additional information regarding the events to be adjudicated may be requested to be sent to 
the Adjudication Committee.  All events listed above, in addition to all cases of death, 
regardless of causality or seriousness will be reviewed by the Adjudication Committee.
3.
Investigators and other study personnel - amended
Sponsor’s medical expert8:
Name:
Address:
Bayer Healthcare Company Ltd
Bayer Center, 
No.27, Dong San Huan North Road, Chaoyang District, 
Beijing, 100020, China
Tel: 
Fax:
Coordinating investigators:
Title/Name: 
Address: 
 USA 
Telephone No:
 
Fax No:
Title/Name: 
Address: 
Switzerland
Telephone No:
All other study personnel not included in this section are identified in a separate personnel list 
(not part of this clinical study protocol) as appropriate.  This list will be updated as needed; an 
abbreviated version with personnel relevant for the centers will be available in each center’s 
investigator site file.
                                                
8 Per Amendment 1
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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Whenever the term “investigator” is noted in the protocol text, it may refer to either the 
principal investigator at the site or an appropriately qualified, trained, and delegated 
individual of the investigative site.
The principal investigator of each center must sign the protocol signature sheet before patient 
recruitment may start at the respective center.  Likewise, all protocol amendments/integrated 
protocols must be signed and dated by the principal investigator before becoming effective at 
the respective center.
A complete list of all participating centers and their investigators, as well as all required 
signature documents, will be maintained in the sponsor study file.
External data evaluation bodies
The independent DMC will be involved in the review of data for safety.  Detailed information 
on the roles and responsibilities of the DMC will be described in the DMC Charter.
Blinded adjudication of further clinical outcomes as described in Section 2 will be performed 
by an independent Central Adjudication Committee as described in the Adjudication 
Committee charter. 


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4.
Study design
4.1
Design overview -amended
In this multinational, multicenter, randomized (1:1), double-blind, placebo-controlled,
parallel-group study, a total of approximately 200 patients are planned for enrollment in order 
to randomize up to9 approximately 130 patients to study drug treatment (approximately 65
patients to the riociguat group and 65 to the placebo group).
The study design consists of a main treatment phase followed by a long-term extension phase 
as follows (see Figure 4–1 and Figure 4–2):

Screening phase: up to 2 weeks

Main treatment phase:  52 weeks of double-blind treatment, consisting of:
o
Dose titration period of up to 10 weeks
o
Maintenance period of up to 42 weeks 

Long-term extension phase
o Dose-titration period of up to 10 weeks (double-blind)
o Open-label extension period

Termination visit and safety follow-up visit
                                                
9 Per Amendment 5


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Figure 4–1
Main treatment phase design
Abbreviations:  V = visit; R = randomization; TID = 3 times a day.
Figure 4–2
Long-term extension phase design
Abbreviations:  TID = 3 times a day; V = visit.


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4.1.1
Screening phase (up to 2 weeks)
After providing written informed consent, patients will undergo a screening evaluation to 
determine their eligibility (see Section 7.1 for a detailed schedule of assessments).  Patients 
will complete a diary including details on the number and duration of Raynaud’s attacks per 
day for a period of 7 consecutive days leading up to Visit 1 / Day 0.
4.1.2
Main treatment phase (Week 0 to Week 52) - amended
At the baseline visit, patients who have met all of the inclusion and none of the exclusion 
criteria will be randomized via a telephone-based or web-based response system (IxRS) to 
receive treatment with either active study drug (riociguat) or placebo (Day 0, Visit 1).
Dose-titration period (Visits 1 to 6)
During the first 10 weeks of the main treatment phase, patients will undergo dose titration.
The starting dosage is 0.5mg TID. The dose should be increased by 0.5 mg increments no 
sooner than 2 weeks apart to 1 mg, 1.5 mg, 2 mg, and 2.5 mg TID, resulting in a maximum
total daily dose of 7.5 mg.  Patients will be maintained on a lower dose if higher doses are not 
tolerated (minimum dosage of 0.5 mg TID, total daily dose 1.5 mg; see Section 5.2.1).
To maintain blinding of the treatment arms, patients randomized to the placebo group will 
undergo sham titration from Visit 1 onwards during the dose-titration period according to the 
rules of the dose titration scheme. At Visit 6, the last visit of the Titration Phase, no further 
increase in study medication will be possible (see Figure 4–1)10.
Dose titration algorithm
The study medication dose for the next titration step will be determined every 2 weeks 
according to the patient’s well-being and the peripheral systolic blood pressure (SBP) 
measured at trough before intake of the morning dose as well as based on any of the 
2 measurements (supine or sitting) performed 2 hours after dose intake to assess orthostatic 
changes 11according to the following algorithm (dose titration scheme):

If SBP is ≥95 mmHg and the patient has no signs or symptoms of hypotension, the
dosage should be increased by 0.5 mg TID.

If SBP is < 95 mmHg, the dosage should be maintained provided the patient does not
show any signs or symptoms of hypotension.

If SBP is < 95 mmHg, and the patient exhibits signs or symptoms of hypotension, the
current dosage should be decreased by 0.5 mg TID.
During the dose-titration period a dose reduction can be performed according to patient well-
being / safety concerns at investigator’s discretion irrespective of SBP. If the investigator 
requests an increase or decrease in study medication dose via IxRS, the subsequent dose 
modification will not exceed ± 0.5 mg TID. Dose increases are allowed after a down-titration 
provided it is not done sooner than two weeks apart.
                                                
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Maintenance period (Visits 7 to 12)
The overall duration of the main treatment phase is 52 weeks, including the dose titration 
period. At the end of the dose titration period (Week 10) the patient’s maintenance dose will 
be determined using the treatment algorithm above. No further increase in dose will be 
allowed.  The established dose will then be taken as the “optimal dose” to be administered for 
the remaining duration of the main treatment phase (up to Week 52).
Dose reductions for safety reasons (eg, in case of any treatment-emergent adverse event
[TEAE]) are allowed, but a subsequent dose increase during the maintenance period is not 
permitted.
From Week 26 (Visit 10), patients will have the opportunity to add “rescue12 therapy”, 
consisting of immunosuppressant drugs, to their randomized study medication if they meet
certain criteria for worsening skin or pulmonary disease.  Please refer to Section 6.9 for 
further details.
4.1.3
Long-term extension phase
At Visit 12 (Week 52), patients randomized to the placebo arm in the main treatment phase 
will initiate active treatment with riociguat, as part of the long-term extension phase. During 
the first 10 weeks, a titration/sham-titration will be performed to maintain the study blind, 
after which the extension phase becomes open-label. During the extension phase, clinical 
outcomes will continue to be measured for exploratory long-term treatment effects. Adverse 
event information will continue to be collected during the extension phase as well.
The long-term extension phase will continue up to 6 years after the Last Patient Last Visit 
(LPLV) in the main treatment phase. Subsequent treatment should be discussed between the 
patient and his/her doctor during the final visit at the end of the extension phase. At the end of 
this study, it is expected that the patient will receive standard treatment at the discretion of the 
physician.
Dose-Titration period (Visits 12 to 17; Week 52 to 62)
At Visit 12 (Week 52), all patients will be assigned in IxRS to treatment with riociguat. To 
maintain the study blinding, neither the patient’s prior treatment assignment nor dose will be 
unblinded. During the first 10 weeks of the long-term extension phase, patients previously on 
placebo will be up-titrated on riociguat according to the dose titration algorithm described 
above in the main treatment phase (Section 4.1.2). Patients randomized to riociguat in the 
main treatment phase will undergo sham titration to maintain the blinding during this period.
Open-label Extension period (Visit 18; Week 64 onward)
After completing the double-blind dose-titration period, from Week 64 onwards the study is 
open-label and the investigator will be able to see the current treatment dose. All patients will 
return to the clinic for visits every 3 months ± 2 weeks. Ongoing titration of riociguat within 
the range of 0.5 mg to 2.5mg TID will remain at the discretion of the investigator, and dose 
reductions for safety reasons are allowed. 
                                                
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4.1.4
Dose Interruptions - amended
Although not intended, patients may interrupt their intake of study medication for various 
reasons (eg, hospitalization in a remote hospital without study medication access, safety 
reasons or side effects). If treatment is interrupted, the following rules should be applied:
Main treatment phase:

≤3 consecutive days without treatment (9 missing doses) in the dose-titration period:  
restart at the same dose

>3 consecutive days in the dose-titration period: discontinue13 the patient from study 
medication

>3 days but ≤14 consecutive days without treatment during the maintenance phase: 
treatment can be restarted at the discretion of the investigator at 0.5 mg TID lower 
than the last dose 

>14 consecutive days without treatment in the maintenance phase: discontinue14 the 
patient from study medication.
Long-term extension phase:

≤3 consecutive days without treatment (9 missing doses) in the dose-titration period:  
restart at the same dose

>3 days but ≤14 consecutive days without treatment in the dose-titration period:
treatment can be restarted at the discretion of the investigator at 0.5 mg TID lower 
than the last dose 

>14 consecutive days without treatment in the dose-titration period: discontinue15 the 
patient from study medication.

Interruptions in the open-label extension period16: 
o
>13 and ≤28 consecutive days: treatment can be restarted at the discretion of 
the investigator at 0.5 mg TID lower than the last dose.
o
>28 consecutive days: discontinue the patient from study medication.
                                                
13 Per Amendment 4
14 Per Amendment 4
15 Per Amendment 4
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4.1.5
Termination visit and safety follow-up visit - amended
A termination visit should be performed for patients who discontinue17 from study medication 
for any reason except death or lost to follow-up, and should occur as soon as possible after the 
patient receives his/her last dose of study drug. In general, at the Termination Visit the same 
safety and efficacy relevant measurements and procedures should be performed as at Visit 12. 
If the discontinuation occurs before Visit 8 (Week 14), the skin biopsy and the blood samples
for biomarkers are to be collected. No blood samples for pharmacokinetics (PK) have to be 
taken and vital signs post dose are not needed because no new medication will be dispensed to 
the patient. If the Termination Visit will be performed after Visit 12 (Week 52) the patient’s 
and physician’s global assessment, patient interference with skin assessment, and tender and 
swollen joint count assessment must not be performed.
A safety follow-up visit (30 [+5] days after the last dose of study medication) will be 
performed for all patients.
If the patient discontinues study drug18 prematurely during the main treatment phase (Week 0 
– Week 52) he/she will be invited to come for limited assessments (mRSS, pulmonary 
function test [FVC and DLCO (diffusion capacity of the lung for carbon monoxide) including 
hemoglobin measurement at the local laboratory]19, patient-reported outcomes [PROs], and 
patient’s and physician’s global assessment20) at Week 12, Week 26, Week 39, and Week 52, 
depending on the timing of discontinuation21.  The collection of these assessments is
important for endpoint analysis which considers all assessments post baseline up to Week 52.
A detailed schedule of evaluations is presented in Section 7.1.1.
4.2
Primary variable
The primary efficacy outcome measure is the change in mRSS from baseline to Week 52.
4.3
Justification of the design
Riociguat has been safe and well tolerated in previous clinical studies at multiple doses 
between 0.5 and 2.5 mg TID in patients with PAH. Based on the positive results of riociguat 
in patients with PAH and CTEPH together with the compound’s known antifibrotic effects as 
seen in in vitro and in animal models, patients with symptomatic dcSSc may benefit from 
treatment with riociguat. Currently, there is no approved therapy for dcSSc and no suitable 
active comparator in this target population. Therefore, the purpose of this study is to evaluate 
the efficacy and safety of riociguat versus placebo in patients with symptomatic dcSSc. The 
follow up time of 12 months has been chosen for the primary endpoint since it is considered 
an appropriate observation period to detect significant changes in the modified Rodnan Skin 
Score (mRSS) and is therefore used in many clinical studies with skin fibrosis.[15,16,17]
Moreover, the 12-month trial duration is supported and validated by a 3-round Delphi 
consensus of measures for clinical trials of SSc [18]. See also Section 8.6 for further details.    
                                                
17 Per Amendment 4
18 Per Amendment 1
19 Per Amendment 4
20 Per Amendment 5
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4.4
End of study
For each participating EU country, the end of the study according to the EU Clinical Trial 
Directive will be reached when the last visit of the last patient for all centers in the respective 
country has occurred.
The end of the study as a whole will be reached as soon as the end of the study according to 
the above definition has been reached in all participating countries (EU and non-EU).
5.
Study population
5.1
Eligibility
5.1.1
Inclusion criteria - amended
Patients must meet the following criteria to be eligible for enrollment in the study:
1. Written informed consent
2. Men or women aged 18 years and older
3. Systemic sclerosis, as defined by ACR/EULAR 2013 criteria[1]
4. dcSSc according to the LeRoy criteria[3] ie, skin fibrosis proximal to the elbows and 
knees in addition to acral fibrosis22.
5. Disease duration of ≤18 months (defined as time from the first non−Raynaud’s
phenomenon manifestation)
6. ≥10 and ≤22 mRSS units at the screening visit
7. FVC ≥45% of predicted at screening
8. DLCO ≥40% of predicted (hemoglobin-corrected) at screening
9. Negative serum pregnancy test in a woman of childbearing potential at the screening
visit
10. Women of childbearing potential must agree to use adequate contraception when 
sexually active.  “Adequate contraception” is defined as any combination of at least 2 
effective methods of birth control, of which at least 1 is a physical barrier (eg, condom 
with hormonal contraception like implants or combined oral contraceptives, condom 
with intrauterine devices).  This applies since signing of the informed consent form 
until 30 (+5) days after the last study drug administration.
11. Ability to comply with the clinical visits schedule and the study-related procedures
5.1.2
Exclusion Criteria - amended
Patients who meet any of the following criteria will be excluded from enrollment in the study:
1. Medical and surgical history

Limited cutaneous SSc at screening

Major surgery (including joint surgery) within 8 weeks prior to screening
                                                
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
Patients with a history of malignancy in the last 5 years other than non-melanoma 
skin cell cancers cured by local resection or carcinoma in situ

Known hypersensitivity to the study drug (active substance or excipients)
2. Hepatic-related criteria

Hepatic insufficiency classified as Child-Pugh C (see Appendix 14.1 for 
classification table)
o
Patients with isolated aspartate aminotransferase (AST) or ALT >3xULN 
(upper limit normal) or bilirubin >2xULN can be included in the trial under 
the condition of additional monitoring during the trial (see section 7.6.2)23
3. Renal-related criteria

Estimated glomerular filtration rate (eGFR) < 15 mL/min/1.73m2 (Modification of 
Diet in Renal Disease [MDRD] formula) or on dialysis at the screening visit. 
Patients entering the trial with eGFR 15-29 mL/min/1.73m2 will be undergo 
additional monitoring of renal function (see section 7.6.2)24
o
Because the MDRD formula is thought to cause significant bias for 
Japanese patients, the equation for Japanese patients is: 
194 x serum creatinine (mg/dL) -1.094 x Age -0.287 x 0.739 (if female).

Any prior history of renal crisis (see Appendix 14.2 for definition)
4. Cardiovascular-related criteria

Sitting SBP <95 mmHg at the screening visit

Sitting heart rate <50 beats per minute (BPM) at the screening visit

Left ventricular ejection fraction <40% prior to screening
5. Pulmonary-related criteria

Any form of pulmonary hypertension25 as determined by right heart catheterization 

Pulmonary disease with FVC <45% of predicted or DLCO (hemoglobin-corrected) 
<40% of predicted at screening

Active state of hemoptysis or pulmonary hemorrhage, including those events 
managed by bronchial artery embolization

Any history of bronchial artery embolization or massive hemoptysis within 
3 months before screening. (Massive hemoptysis is defined as acute bleeding 
>240 mL in a 24-hour period or recurrent bleeding >100 mL/day over consecutive 
days)
6. Laboratory examinations

Patients with: hemoglobin <9.0 g/dL, white blood cell (WBC) count <3000/mm3
(<3 × 109/L), platelet count <100,000/mm3 (<100 × 109/L)26
                                                
23 Per Amendment 1
24 Per Amendment 1
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7. Prior and concomitant therapy

Concomitant use of nitrates or NO donors (such as amyl nitrate) in any form, 
including topical; phosphodiesterase (PDE) 5 (PDE5) inhibitors (such as sildenafil, 
tadalafil, vardenafil); and nonspecific PDE5 inhibitors (theophylline, 
dipyridamole)

Concomitant therapy with prostacyclin analogs. Oral beraprost for the treatment of 
digital ulcers / Raynaud’s disease, and short-term / intermittent therapy of up to 21 
days with intravenous prostacyclin analogs for digital / vascular lesions is allowed

Treatment with methotrexate, cyclophosphamide, hydroxychloroquine, 
cyclosporine A, azathioprine, mycophenolate mofetil, rapamycin, colchicine, 
D-penicillamine, tacrolimus27, mizoribine28 or intravenous immunoglobulin within 
4 weeks before the screening visit

Treatment with etanercept within 2 weeks; infliximab, leflunomide, certolizumab, 
golimumab, adalimumab, abatacept or tocilizumab within 8 weeks; or anakinra 
within 1 week prior to the screening visit

Previous treatment with chlorambucil, bone marrow transplantation, or total 
lymphoid irradiation

Treatment with rituximab or other anti-CD20 antibodies within the last 6 months 
before screening
8. Other

Pregnant women or breast feeding women

Women of childbearing potential not willing to use adequate contraception (as 
defined in the aforementioned inclusion criteria, Section 5.1.1) and not willing to 
agree to 4-weekly pregnancy testing from Visit 1 (first administration of study 
drug) onwards until 30 (+5) days after last study drug intake.

Any other condition or therapy that would make the patient unsuitable for this 
study and will not allow participation for the full planned study period

Previous assignment to treatment during this study

Participation in another clinical study with an investigational drug or medical 
device within 30 days prior to randomization (phases IIII clinical studies)
5.1.3
Justification of selection criteria
The selection criteria were carefully selected to exclude patients from the study who may 
potentially be exposed to specific risks after administering the study drug as well as patients 
with conditions that may have an impact on the aims of this study.
                                                                                                                                                        
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27 Per Amendment 1
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5.2
Withdrawal of patients from study - amended
5.2.1
Withdrawal29 - amended
5.2.1.1
Withdrawal from the study 30
Patients must be withdrawn from the study for the following reasons:

At their own request or at the request of their legally acceptable representative at any 
time during the study and without giving reasons, a patient may decline to participate 
further (withdrawal from study).  The patient will not suffer any disadvantage as a 
result.

Participation in another clinical trial after Visit 12.  Participation in observational 
registries is allowed.
5.2.1.2
Discontinuation of study medication31
Patients must be discontinued from the study medication32 for the following reasons:

If, in the investigator's opinion, continuation of the study would be harmful to the 
patient's well-being

Occurrence of AEs or intercurrent diseases which the investigator judges unacceptable 
for continuation of participation in the study

Occurrence of adverse drug reactions, which in the investigator’s opinion have 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 such as anticipated treatment effect, progression of underlying disease, 
occurrence of side effects, and alternative treatment options must be considered.)

If a subject, during the course of the study, develops 
a) renal disease that leads to eGFR <15/mL/min/1.73m2, 
b) hepatic insufficiency classified as Child-Pugh C 33.

Non-compliance with the conditions for the trial or instructions by the investigator

If treatment is interrupted for >3 consecutive days (9 doses)34 during the dose titration 
period of the main treatment phase

If treatment is interrupted for >14 consecutive days during the maintenance period of 
the main treatment phase or the dose-titration period of the long-term extension phase

If treatment is interrupted for >28 consecutive days during the open-label extension 
period (of the long-term extension phase)35

In case of pregnancy or breast feeding.
                                                
29 Per Amendment 4
30 Per Amendment 4
31 Per Amendment 4
32 Per Amendment 4
33 Per Amendment 5
34 Per Amendment 1
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
In case a female patient of childbearing potential is not compliant with 4-weekly 
pregnancy testing or with contraceptive measures.

In case no further dose reduction is possible and the patient does not tolerate the 
lowest possible dosage (0.5 mg TID) of study drug
Patients may be discontinued from the study medication36 for the following reasons:

At the specific request of the sponsor and in liaison with the investigator (eg, safety 
concerns)

A relative decline in FVC % predicted by ≥10% (eg, a change of FVC from 60% to 
54%) or a relative decline in FVC % predicted between 5 to < 10% with associated 
relative decline in DLCO % predicted by ≥15%, provided that the decline in FVC 
results in FVC <75% of predicted (confirmed by repeat pulmonary function testing 
within 1 month). Please refer to Section 6.9 for the option of adding rescue37 therapy.

An absolute increase in mRSS by > 5 units and ≥ 25% (Please refer to Section 6.9 for 
the option of adding rescue38 therapy), life-threatening or organ-threatening event 
attributable to SSc (such as renal crisis, digital gangrene, development of new PAH on 
right heart catheterization) or not attributable to SSc.
5.2.1.3
Handling of withdrawals or discontinuations from study medication39
A patient who, for any reason (eg, failure to satisfy the selection criteria), terminates the study 
before the time point used for the definition of “dropout” (see below) is regarded a “screening 
failure”.  Restarting the defined set of screening procedures to enable the “screening failure” 
patient’s participation at a later time point is not allowed.
One re-assessment of laboratory parameters is allowed during the screening phase to re-assess 
the eligibility of patients.
A patient who discontinues study participation prematurely for any reason is defined as a 
“dropout” if the patient has already been randomized.
Any randomized patient removed from the trial should undergo the assessments at the 
termination visit.  The patient will remain under medical supervision until discharge or 
transfer is medically acceptable and will complete the 30-day safety follow-up period.
If the patient discontinues study drug40 prematurely during the main treatment phase (Week 0 
– Week 52) he/she will be invited to come for limited assessments (mRSS, pulmonary 
function test [FVC and DLCO including hemoglobin measurement at the local laboratory]41, 
PROs, and patient’s and physician’s global assessment)42 at Week 12, Week 26, Week 39,
and Week 52, depending on the timing of discontinuation43. This will be in addition to the 
termination visit assessments (see Section 7.1.2.8), provided that the patient does not object to 
                                                
36 Per Amendment 4
37 Per Amendment 1
38 Per Amendment 1
39 Per Amendment 4
40 Per Amendment 1
41 Per Amendment 4
42 Per Amendment 5
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collection of study data after withdrawal of consent.  If the discontinuation occurs before Visit 
8 (Week 14), the skin biopsy and blood samples for biomarkers are to be collected.
All reasons for discontinuation44 (including lost to follow up), will be recorded in the
electronic case report from (eCRF) and site medical record. Study medication assigned to the 
discontinued45 patient may not be assigned to another patient. 
In the event that a patient is lost to follow-up, every possible effort must be made by study 
site personnel to contact the patient to obtain complete data and determine the reason for 
discontinuation46.
A patient may withdraw from further participation in the study and, unless he/she objects to 
further data collection, the following information should be obtained and documented in the 
eCRF47:

Vital status (at Week 52)

Outcome of serious adverse events (SAEs)

Efficacy endpoints at Weeks 12, 26, 39, and 52 (depending on timing of 
discontinuation of study medication)
The information should be collected in the eCRF until the safety follow-up visit 30 (+5) days 
after the last intake of study drug. Serious adverse events that occur within 30 (+5) days after 
the last dose of study drug will be followed up until resolution, if possible.
If patients refuse to be contacted via telephone (eg, patient objects to further release of 
information or are lost to follow-up), every effort should be made to obtain vital status (dead 
or alive) information at Week 52 through consultation of public databases, wherever allowed 
by local regulations48. 
The measures taken for follow up must be documented in the site medical record. Follow-up 
data will be collected for all randomized patients except those who specifically withdraw 
consent for release of such information, except as noted above. Thus, it is imperative to 
obtain complete data for all randomized patients, including information on efficacy and safety 
endpoint events, whether or not they receive study drug, or discontinue study drug 
prematurely.
Details for the premature termination of the study as a whole (or components thereof 
[eg, centers, treatment arms, dose steps]) are provided in Section 10.
5.2.2
Replacement - amended
There will be no replacement of randomized patients who withdraw from the study or 
prematurely discontinue study medication49.
                                                
44 Per Amendment 4
45 Per Amendment 4
46 Per Amendment 4
47 Per Amendment 4
48 Per Amendment 4
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5.3
Patient identification
After a patient signs the informed consent form, the patient identification number for each 
patient will be provided to the investigators via IxRS. Patients will be identified by a unique 
9-digit number consisting of the following: 

First 2 digits = Unique country code

Next 3 digits = Unique study center number within the country

Last 4 digits = Unique current patient number within the study center of a given 
country; sequential number reflecting the order in which the patients signed the 
informed consent form at the center (4 digits)
Patient identification numbers must be used in sequence and no number should be skipped, 
substituted, or reused.
6.
Treatment
6.1
Treatments to be administered
Test drug:
Riociguat
Dosage:
0.5 mg, 1 mg, 1.5 mg, 2 mg, and 2.5 mg ( dose 
titration)
Route of administration:
Oral
Time and frequency of administration:
TID
The optimal dose should be determined during the initial 10-week dose titration period based 
on monitoring of the patient’s SBP and well-being.
The recommended starting dose is 0.5 mg TID. The intervals between drug intake should be 
68 hours. The dosage should be increased by 0.5 mg increments no sooner than 2 weeks 
apart to 1 mg, 1.5 mg, 2 mg, and 2.5 mg TID, resulting in a maximum total daily dose of 
7.5 mg. Patients should be maintained on lower doses if higher doses are not tolerated 
(minimum dose of 0.5 mg TID, see Section 5.2.1). After the dose titration period, riociguat 
should be continued at the optimal dose for the duration of the maintenance period.
6.2
Identity of study treatment
Riociguat
Riociguat is supplied in various strengths as film-coated, immediate-release tablets (see 
Table 6–1). Riociguat and placebo tablets will have similar appearance at all dose strengths.
All study drugs will be labelled according to the requirements of local law and legislation. 
Label text will be approved according to the sponsor’s agreed procedures, and a copy of the 
labels will be made available to the study site upon request.
For all study drugs, a system of numbering in accordance with all requirements of Good 
Manufacturing Practice (GMP) will be used, ensuring that each dose of study drug can be 
traced back to the respective bulk ware of the ingredients. Lists linking all numbering levels 
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A complete record of batch numbers and expiry dates of all study treatment, as well as the 
labels, will be maintained in the sponsor study file.
Table 6–1
Identity of investigational product
International non-proprietary name (INN)
Riociguat 
Sponsor’s internal reference number
BAY 63-2521
Formulation
Film-coated tablets
Galenical form
Round immediate-release tablets, diameter 6 mm
Composition
Active ingredient: Methyl 4,6-diamino-2-[1-(2-
fluorobenzyl)-1H-pyrazolo [3,4 b]pyridine-3-yl]-5-
pyrimidinyl (methyl)carbamate
Empirical formula: C20H19FN8O2
Molar mass: 422.42 g/mol (molarity)
Excipients: lactose, microcrystalline cellulose, 
magnesium stearate, crospovidone* , hypromellose*, 
and sodium lauryl sulphate*
Coating: hydroxypropyl cellulose, hypromellose, 
propylene glycol, iron oxide (red and yellow), and 
titanium dioxide.
Strength
0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg
Material numbers
83296470 BAY 63-2521 TABL 0.5 mg 511 COAT
83296535 BAY 63-2521 TABL 1 mg 512 COAT
83296543 BAY 63-2521 TABL 1.5 mg 513 COAT
83296578 BAY 63-2521 TABL 2 mg 504 COAT
83296608 BAY 63-2521 TABL 2.5 mg 515 COAT
Packaging
High-density polyethylene (HDPE) bottles
Abbreviation: TABL = tablet
*Not in placebo tablets 
Matching placebo
Matching placebo tablets will appear identical to active riociguat tablets but will not contain 
active study drug product (riociguat) or any of the excipients marked with an asterisk as 
outlined in Table 6–1.
Storage requirements
All investigational drugs used during the trial will be stored at the investigational sites at 
room temperature in a place inaccessible to unauthorized personnel, ie, in a locked cabinet.
No special storage conditions are required.
6.3
Treatment assignment
This is a randomized, double-blind, placebo-controlled, parallel-group, multinational, 
multicenter study. Patients who complete all screening procedures and meet all eligibility 
criteria are to be randomized via IxRS in a 1:1 ratio to receive either riociguat or placebo.
The patient randomization scheme will use permutated blocks sized as a multiple of 2.  Each 
block will be allocated to a country or group of nearby countries within a region.  No other 
stratification is planned.
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6.4
Dosage and administration
6.4.1
Selection of doses in the study - amended
Riociguat has been safe and well tolerated in previous clinical studies at multiple doses 
between 0.5 and 2.5 mg TID in patients with various forms of pulmonary hypertension, 
including PAH, CTEPH, and, in a small patient population, SSc-related pulmonary 
hypertension. The intervals between drug intake should be 6 to 8 hours50.
Data from the phase III clinical program for riociguat in patients with pulmonary hypertension 
(PATENT and CHEST studies) showed that a starting dose of 1 mg TID was safe and 
effective. Because a few patients in both studies had their dosage reduced to 0.5 mg TID, the 
sponsor recognized that the 0.5 mg TID dosage may offer additional tolerability for some 
patients and adopted this additional dose recommendation. In the present study, the titration 
will start at 0.5 mg TID.
For further details refer to the IB.
6.5
Blinding - amended
Apart from the open-label extension period in the long-term extension phase, the study will be 
conducted in a double-blind fashion. Active riociguat and placebo tablet formulations will be 
identical in appearance (size, shape, color) and smell. The packaging and labeling will be 
designed to maintain blinded conditions for the investigator’s team and the patients. The 
study data will remain blinded until database lock and authorization of data release according 
to standard operating procedures.
Appropriate measures will be taken to maintain blinding of the study team while PK and 
biomarker analysis is ongoing. Data with a potential to unblind (eg, plasma concentrations) 
are not to be handled by or shown to the study team members and will only be uploaded into 
the clinical database after official unblinding. The process of data flow will be documented 
separately (see also Section 7.4 and Section 7.6.3.).51
Statistical analysis as described in the SAP (Statistical Analysis Plan) will be done after 
database lock and authorization of data release according to standard operating procedures. 52
Unblinding by drug safety personnel of the sponsor
For regulatory reporting purposes, drug safety personnel of the sponsor are permitted to 
unblind individual cases.
In compliance with applicable regulations, in the event of a suspected unexpected serious 
adverse reaction (SUSAR) (see Section 7.5.1.5), the patient’s treatment code will usually be 
unblinded before reporting to the health authorities, Independent Ethics Committees (IECs)/ 
Institutional Review Boards (IRBs), and investigators (see Section 7.5.1.4) if the SUSAR was 
related to the blinded treatment.
                                                
50 Per Amendment 4
51 Per Amendment 5
52 Per Amendment 5 


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Emergency unblinding by the investigator
In case of emergency, investigators are permitted to unblind individual cases via the IxRS.  
However, investigators are obligated to restrict such unblinding to cases of emergency where 
the unblinding result is of importance for the acute treatment strategy. 
Investigators should note that the occurrence of a serious adverse event (SAE) should not 
routinely precipitate the immediate unblinding of the label.  
Date, time, and reason for unblinding must be captured in the relevant eCRF.  Please refer to 
the IxRS and eCRF completion guideline for instructions.
Any patient who discontinues study medication will remain under medical supervision until 
discharge or transfer is medically acceptable.  Patients who withdraw from the study or 
discontinue study medication should take part at the termination visit (refer to Section 7.1.2.8) 
and the safety follow-up visit (refer to Section 7.1.2.9)53.  Further therapy is at the discretion 
of the investigational site.
Unblinding for ongoing safety monitoring
In order to allow ongoing safety monitoring during the conduct of the study by an external 
DMC, members of the committee will receive unblinded safety data.  The involvement of an 
external statistical analysis center in this process will ensure that unblinded information is not 
available for third parties.  Details of the process are described in the DMC charter.
6.6
Drug logistics and accountability
All study drugs will be stored at the investigational site in accordance with Good Clinical 
Practice (GCP) and GMP requirements and the instructions given by the clinical supplies 
department of the sponsor, and will be inaccessible to unauthorized personnel.  Special 
storage conditions and a complete record of batch numbers and expiry dates can be found in 
the sponsor study file; the site-relevant elements of this information will be available in the 
investigator site file.  The responsible site personnel will confirm receipt of study drug via 
IxRS and will use the study drug only within the framework of this clinical study and in 
accordance with this protocol.  Receipt, distribution, return and destruction (if any) of the 
study drug must be properly documented according to the sponsor’s agreed and specified 
procedures.
Written instructions on medication destruction will be made available to affected parties as 
applicable.
6.7
Treatment compliance
A drug dispensing log will be completed for each patient.  The overall compliance with study 
drug intake should be between 80% and 120% of the calculated dose. The date of dispensing 
the study drug to the patient will be documented. 
Patients will receive study medication dispensed per visit schedule (see Section 7.1.1).
To record treatment compliance, patients will be instructed to bring all study drug packaging, 
including unused study drug and empty packaging, to the investigative site at each study visit.  
Tablets will be counted for a compliance check.
                                                
53 Per Amendment 4


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If a dose of study drug is missed, the patient should take a dose immediately and continue 
with the TID intake as recommended on the following day. The dose should not be doubled to 
make up for a missed dose within the same day. 
6.8
Post-study therapy
In case patients discontinue study drug treatment during this study, further therapy is at the 
discretion of the investigator.
6.9
Prior and concomitant therapy - amended
A summary of the prohibited prior and concomitant therapy, outlined in the exclusion criteria 
(Section 5.1.2), is provided in Table 6–2.  During the trial, concomitant treatment is allowed 
with oral corticosteroids (≤10 mg/day of prednisone or equivalent), non-steroidal anti-
inflammatory drugs (NSAIDs), angiotensin converting enzyme (ACE) inhibitors, or calcium 
channel blockers if stable for ≥2 weeks before and including at baseline. These treatments 
will also be allowed as new-onset during the study at the discretion of the investigator to treat 
SSc-specific adverse events (eg, Raynaud’s phenomena, joint inflammation, new onset renal 
crisis).
During the long-term extension phase (ie, after completion of all efficacy- and safety-related 
procedures at Visit 12), except for the contraindicated nitrates or NO donors and PDE5 
inhibitors, the addition of any other concomitant medication is at the discretion of the 
investigator. 54
                                                
54 Per Amendment 5


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Table 6–2
Prohibited prior and concomitant therapy - amended
Therapy
Timeframe 
Chlorambucil, bone marrow transplantation, or total lymphoid irradiation
Any previous therapya, b
Rituximab or other anti-CD20 antibodies
Within 6 months prior to 
the screening visita, b
Infliximab, certolizumab, golimumab, adalimumab, abatacept,
leflunomide or tocilizumab
Within 8 weeks prior to the 
screening visita, b
Methotrexate, cyclophosphamide, hydroxychloroquine, cyclosporine A, 
azathioprine, mycophenolate mofetil, rapamycin, colchicine, D 
penicillamine, tacrolimus55, mizoribine56 or intravenous immunoglobulin
Within 4 weeks prior to the 
screening visita, b
Etanercept
Within 2 weeks prior to the 
screening visita,b 
Anakinra
Within 1 week prior to the 
screening visita,b 
Nitrates or NO donors (such as amyl nitrate) in any form, including 
topical; phosphodiesterase (PDE) 5 (PDE5) inhibitors (such as 
sildenafil, tadalafil, vardenafil); and nonspecific PDE5 inhibitors 
(theophylline, dipyridamole)
Concomitant therapy with 
study drug
Prostacyclin analogs (oral beraprost for digital ulcers / Raynaud’s 
disease and short-term / intermittent therapy of up to 21 days 
with intravenous prostacyclin analogs for digital / vascular lesions is 
allowed)
Concomitant therapy with 
study drug
a
Concomitant use of these treatments with study medication is also prohibited, except for certain 
agents from Week 26 onwards; please see “Rescue57 Therapy” below. 
b
Concomitant use of these medications will be allowed during the long-term extension phase58
In addition, as described in Section 8.4.1 of the IB, “Interaction with other medicinal products 
and other forms of interaction”, caution is advised during the intake of any of the following 
concomitant medications:

The concomitant use of riociguat with strong multi-pathway cytochrome P450 (CYP) 
and P-glycoprotein 1 (P-gp)/breast cancer resistance protein inhibitors such as azole 
antimycotics (eg, ketoconazole, itraconazole) or human immunodeficiency virus 
protease inhibitors (eg, ritonavir) is not recommended, due to the pronounced increase 
in riociguat exposure.

The concomitant use of riociguat with strong CYP1A1 (CYP family 1, subfamily A, 
polypeptide 1) inhibitors, such as the tyrosine kinase inhibitor erlotinib, and strong 
P-gp inhibitors, such as the immunosuppressive agent cyclosporine A, may increase 
                                                
55 Per Amendment 1
56 Per Amendment 1
57 Per Amendment 1
58 Per Amendment 5


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riociguat exposure. These drugs should be used with caution. Blood pressure should 
be monitored and dose reduction of riociguat considered.
Other medications and considerations (detailed information can be found in the current IB)

Pre- and concomitant treatment with the proton pump inhibitor omeprazole (40 mg 
once daily) reduced riociguat mean area under the plasma concentration versus time 
curve (AUC) by 26% and mean maximum plasma concentration (Cmax) by 35%. This 
is not considered clinically relevant.

Co-administration of the antacid aluminum hydroxide / magnesium hydroxide reduced 
riociguat mean AUC by 34% and mean Cmax by 56%. Antacids should be taken at 
least 1 hour after riociguat.

Plasma concentrations in smokers are reduced by 5060% compared with 
nonsmokers. For this reason, it is highly recommended to strongly advise patients to 
stop smoking while taking this medication59. A dose reduction should be considered 
in patients who stop smoking whilst participating in the study.
Rescue60 therapy
From Week 26 (Visit 10), patients with the following will have the opportunity to add rescue 
therapy to their randomized study medication. “Rescue therapy” is defined as treatment with 
an immunosuppressant drug, under the following situations:

Worsening of skin disease (defined as >5 units and ≥25% increase in mRSS), or

Relative decline in FVC % predicted by ≥10%, or relative decline in FVC % predicted 
between ≥5% and <10% with associated relative decline in DLCO % predicted by 
≥15%, provided that the decline in FVC results in FVC <75% of predicted  (confirmed 
by repeat pulmonary function testing within 1 month).
The decision to initiate rescue therapy is based on investigator discretion in eligible patients.  
Rescue therapy may include any of the following 4 agents: methotrexate, mycophenolate 
mofetil, cyclophosphamide, or azathioprine.

Worsening of inflammatory joint disease or myositis.61
Rescue therapy can be initiated at investigator’s discretion in eligible patients. In addition to 
the 4 agents methotrexate, mycophenolate mofetil, cyclophosphamide, or azathioprine, 
hydroxychloroquine will be allowed for the treatment of inflammatory joint disease and 
myositis. 62
These treatments are not provided by the Sponsor.
A survey conducted by the Scleroderma Clinical Trials Consortium (SCTC) and Canadian 
Scleroderma Research Group (CSRG) to gain a consensus from SSc experts worldwide 
recommended these agents in the management of SSc after failure of first-line therapy.[19]
                                                
59 Per Amendment 1
60 Per Amendment 1– this footnote covers all changes in the section from escape to rescue
61 Per Amendment 5
62 Per Amendment 5


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These agents also are featured in EULAR recommendations for the treatment of SSc[20] and 
in a recently published review of old and new therapies for SSc used in clinical practice.[21]
7.
Procedures and variables
7.1
Schedule of procedures
The study will be divided into the following phases:  screening phase, main treatment phase
and long-term extension phase.  Please refer to Table 7–1 for a schedule of evaluations.


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7.1.1
Tabulated overview - amended
Table 7–1
Schedule of evaluations - amended63
Scr
Main Treatment Phase  (Double-blind) v
Long-term Extension Phase  
Scr 
Phase
Dose-Titration Period 
Maintenance Period
Dose-Titration Period
Open-label 
Extension Period
Safety Follow-
up
Visit
V0
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12a
V13
V14
V15
V16
V17
V18 – Vn
(q 12 wk)
TVb
SFU
Week
-2
0
2
4
6
8
10
12
14
20
26
39
52
54
56
58
60
62
64 – n 
Day
-14
to
-1
0
14 
± 2
28 
± 2
42 
± 2
56 
± 2
70 
± 2
84 
± 2
98 
± 2
140 
± 2
182 
± 2
273 
± 14
364
-14
to +2
378 
± 2
392 
± 2
406 
± 2
420 
± 2
434 
± 2
448 – (n + 84)
V18 ± 2
Vn ± 14
30 + 5
Written informed consent
X
Inclusion / exclusion criteria
X
X
Demographic data
X
Medical and surgical history
X
X
Other history (alcohol)
X
Smoking history
X
X
X
X
X
X
Height and weightc
X
X
X
X
X
X
X
X
Physical examination
X
X
X
X
X
X
X
X
mRSS
X
X
X
X
X
X
X
Assessment of Raynaud’s 
attacks
Xd
Xe
Xf
Xe
Digital ulcer net burden
assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
                                                
63 Visit window for V12 changed per Amendment 4; visit window for V18 changed per Amendment 5


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Table 7–1
Schedule of evaluations - amended63
Scr
Main Treatment Phase  (Double-blind) v
Long-term Extension Phase  
Scr 
Phase
Dose-Titration Period 
Maintenance Period
Dose-Titration Period
Open-label 
Extension Period
Safety Follow-
up
Visit
V0
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12a
V13
V14
V15
V16
V17
V18 – Vn
(q 12 wk)
TVb
SFU
Week
-2
0
2
4
6
8
10
12
14
20
26
39
52
54
56
58
60
62
64 – n 
Day
-14
to
-1
0
14 
± 2
28 
± 2
42 
± 2
56 
± 2
70 
± 2
84 
± 2
98 
± 2
140 
± 2
182 
± 2
273 
± 14
364
-14
to +2
378 
± 2
392 
± 2
406 
± 2
420 
± 2
434 
± 2
448 – (n + 84)
V18 ± 2
Vn ± 14
30 + 5
Tender & swollen joint count
X
X
Xg
Oximetryw, 64
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs (BP, HR)h
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs post-dose 
(BP, HR)i,j
Xi
Xj
Xi
BP and HR for assessment 
of orthostatic changesx, 65
X
X
X
X
X
X
X
Blood sample for safetyk, u
X
X
Xu
Xu
Xu
Xu
X
X66
X
X
X
X
X
X
Blood sample for PK
Xl
Xm
Xm
Xm
Xm
Xm
Xn
Xl
Xm
Xm
Xm
Xm
Xm
Blood sample for biomarkers 
X
X
Xr
Blood sample for 
Autoantibody screen
X
Pregnancy test (if 
applicable)o
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECGp
X
X
X
X
X
X
X
X
X
                                                
64 Per Amendment 6
65 Per Amendment 6
66 Per Amendment 1


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Table 7–1
Schedule of evaluations - amended63
Scr
Main Treatment Phase  (Double-blind) v
Long-term Extension Phase  
Scr 
Phase
Dose-Titration Period 
Maintenance Period
Dose-Titration Period
Open-label 
Extension Period
Safety Follow-
up
Visit
V0
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12a
V13
V14
V15
V16
V17
V18 – Vn
(q 12 wk)
TVb
SFU
Week
-2
0
2
4
6
8
10
12
14
20
26
39
52
54
56
58
60
62
64 – n 
Day
-14
to
-1
0
14 
± 2
28 
± 2
42 
± 2
56 
± 2
70 
± 2
84 
± 2
98 
± 2
140 
± 2
182 
± 2
273 
± 14
364
-14
to +2
378 
± 2
392 
± 2
406 
± 2
420 
± 2
434 
± 2
448 – (n + 84)
V18 ± 2
Vn ± 14
30 + 5
Pulmonary function testsq
X
X
X
X
X
X
X
Skin biopsy
X
X
Xr
Questionnairess
X
X
X
X
X
X
X
Patient’s and physician’s 
global assessment
X
X
X
Xg
Patient interference with skin 
X
X
X
Xg
Tendon Friction Rubst
X
X
Randomization (IxRS)
X
Dispensation of study drug
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Drug accountability
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events recording
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Prior and concomitant 
therapy
X
X 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Survival status
X
Abbreviations:  BP = blood pressure; ECG = electrocardiogram; TV = Termination Visit; SFU = 30-Day Safety Follow-up (30 [+5] days after the last dose of study drug); HR = heart rate; IxRS = 
telephone-based or web-based response system; mRSS = modified Rodnan skin score; PK = pharmacokinetics; q 12 wk = every 12 weeks; Scr = Screening.
Note:  Day 0 (Visit 1) is the baseline visit.
a
Visit 12 (Week 52) is the last visit in the Maintenance Period of the Main Treatment phase and the first (baseline) visit in the Long-term Extension phase.


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b
To be performed as soon as possible after discontinuation67 of study medication.  
c
Height to be measured only at the screening visit
d
Patient to be provided with 7-day diary, to complete daily for 7 consecutive days leading up to Visit 1 
e
Patient and physician assessment of Raynaud’s disease (see Section 7.6.12)
f
Patient to be provided with 7-day diary, to complete daily for 7 consecutive days leading up to Visit 8.
g
Must not be performed if TV is after V12.
h
Blood pressure and heart rate will be measured at all visits with the patient in a sitting position, after the patient has been at rest for at least 5 minutes.  The same arm is always used for these 
measurements (see Section 7.6.5).
i
Vital signs to be measured within 20 minutes prior to each post-dose PK sampling (see Table 7–2)
j
Vital signs to be measured within 20 minutes prior to PK sampling (see Table 7–2)
k
Coagulation tests to be performed at a local laboratory
l
Samples for PK to be taken 1 – 2 hours and 3 – 4 hours after the morning dose of study medication (see Table 7–2)
m
Sample for PK to be taken up to 1 hour before the morning dose of study medication (trough) (see Table 7–3)
n
Samples for PK to be taken up to 1 hour before the morning dose of study medication (trough) and 2 – 3 hours after the morning dose of study medication (peak) 
(see Table 7–4)
o
For women of childbearing potential only. Serum pregnancy test is required only at screening; pregnancy testing (urine) will be done every 4 weeks and should continue until 30 days after the 
last dose of study drug. When pregnancy testing coincides with a visit, the test should be performed at the site, but otherwise should be performed at home. 
p
Standard ECG (12-lead ECG) will be recorded with the patient in the supine position, after the patient has been at rest for at least 5 minutes (see Section 7.6.7).
q
Pulmonary function tests include forced vital capacity (FVC) and diffusion capacity of the lung for carbon monoxide (DLCO).
r
Must be done at a TV if this visit occurs before Visit 8.
s
Questionnaires include Scleroderma Health Assessment Questionnaire (SHAQ), Short Form 36 (SF-36), Patient-Reported Outcomes Measurement Information System (PROMIS)-29, and 
University of California, Los Angeles, Scleroderma Clinical Trial Consortium Gastrointestinal Scale (UCLA SCTC GIT) 2.0.
t
Assessment of the presence or absence of tendon friction rubs
u     Additional monitoring may apply for patients with impaired renal and liver function at Visit 2, 3, 4, 5 as needed (see Section 7.6.2)68
v
All patients who discontinue study drug prematurely during the main treatment phase (Week 0 – Week 52) will be invited to come for limited assessments (see Sections 7.1.2.10 and 7.6.2).69
w
Oxygen saturation will be measured using forehead pulse oximetry. At visits with blood samples for PK and blood pressure measurements for the assessment of orthostatic changes, post-dose 
measurements will be performed in addition to pre-dose measurements (see Section 7.6.18, Table 7–2, Table 7–3, Table 7–4)70
x
Measure supine and sitting blood pressure and heart rate to check for orthostatic changes approximately 2 hours after intake of study medication. (see Section 7.6.5, Table 7–2, Table 7–3, 
Table 7–4).71
                                                
67 Per Amendment 4
68 Per Amendment 1
69 Per Amendment 4
70 Per Amendment 6
71 Per Amendment 6


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Pharmacokinetics sampling flow charts - amended
Profile day (Visit 1 and Visit 12)

2 hours after administration of the morning dose of study medication72

3 – 4 hours after administration of the morning dose of study medication
Table 7–2
Profile Day PK Sampling (Visit 1 and Visit 12)73
Visit 1 and Visit 12 (profile days)
Cycle of procedures
Order of 
procedures
Starting point of procedures
Time interval (h)
00
00
1:45 – 2 h 2h
3 – 4 h
At Visit 12 only: oxygen saturation using 
forehead pulse oximetry
X
Blood pressure, heart rate 
X
Administration of morning dose of study 
medication 
X
At Visit 12 only: oxygen saturation using 
forehead pulse oximetry
Xa
Blood pressure, heart rate; at Visit 12 only: 
supine and sitting position
Xa
Blood sample for PK
X
Blood pressure, heart rate (within 20 minutes 
prior to PK sample)
X
Blood sample for PK
X
a
At Visit 12 only: measure oxygen saturation, blood pressure and heart rate in supine and sitting 
position (see Section 7.6.5 and Section 7.6.18).
Abbreviations:  h = hours; PK = pharmacokinetic.
Visits 2 to 6 and Visits 13 to 17

Up to 1 hour before administration of the morning dose of study medication (trough)
Table 7–3
PK Sampling (Visits 2 – 6 and Visits 13 – 17)74
Visit 2 to Visit 6 and Visit 13 to Visit 17
Cycle of procedures
Order of 
procedures
Starting point of procedures
Time interval (h)
1 h 00
00
00
2h
Blood sample for PK
X
Visit 13-17 only: oxygen saturation using forehead 
pulse oximetry
X
Blood pressure, heart rate
X
Administration of morning dose of study medication 
X
Visit 13-17 only: oxygen saturation using forehead 
pulse oximetry
X
Visits 13-17 only: Blood pressure, heart rate in 
supine and sitting position
X
                                                
72 Per Amendment 6
73 Per Amendment 6
74 Per Amendment 6


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Abbreviations:  h = hours; PK = pharmacokinetic.
Visit 11

Up to 1 hour before administration of morning dose of study medication (trough)

2 hours after administration of morning dose of study medication (peak)75
Table 7–4
PK Sampling (Visit 11)76
Visit 11
Cycle of procedures
Order of 
procedures
Starting point of procedures
Time interval (h)
1 h 00
00
00
1:45-2 h
2 h
Blood sample for PK
X
Oxygen saturation using forehead pulse 
oximetry
X
Blood pressure, heart rate
X
Administration of morning dose of study 
medication 
X
Oxygen saturation using forehead pulse 
oximetry
Xa
Blood pressure, heart rate in supine and sitting 
position 
Xa
Blood sample for PK
X
a
Measure oxygen saturation, blood pressure and heart rate in supine and sitting position (see 
Section 7.6.5 and Section 7.6.18).
Abbreviations:  h = hour; PK = pharmacokinetics.
7.1.2
Timing of assessments
If not stated otherwise, all assessments and procedures will be performed by or under the 
supervision of an investigator.
For timing of assessments and procedures, please refer to Section 7.1.1.
7.1.2.1
Visit 0 Screening phase – Screening visit
Screening evaluations will be performed only after the patient has provided written informed 
consent.  The following evaluations will be performed and information obtained up to 14 days 
(but not less than 8 days) before randomization and the start of study drug treatment:

Patient information and obtaining of written informed consent

Eligibility: Assessment of inclusion and exclusion criteria (see Section 5.1)

Demographic data, including sex, ethnicity, date of birth, smoking history and alcohol 
consumption (See Section 7.2.1)

Medical and surgical history (see Section 7.2.2)

Prior and concomitant therapy (see Section 6.9 for prohibited medication)
                                                
75 Per Amendment 6
76 Per Amendment 6


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
Physical examination, including height and weight (Note: body mass index [BMI]
will be calculated automatically in the eCRF)

Vital signs (blood pressure and heart rate).  Blood pressure and heart rate will be 
measured at all visits with the patient in a sitting position, after the patient has been at 
rest for at least 5 minutes. The same arm is always used for these measurements (See 
Section 7.6.5)

mRSS (see Section 7.6.6)

Provision of 7-day diary to patients which they will complete daily for 7 consecutive 
days leading up to Visit 1 (see Section 7.6.12)

Digital ulcer net burden assessment (see Section 7.6.10)

Tender and swollen joint count assessment (see Section 7.6.14)

Blood samples for safety (see Section 7.6.2)

Blood sample for autoantibody screen (see Section 7.6.4)

Pregnancy test (serum) for all women of childbearing potential (see Section 7.6.1)

12-lead electrocardiogram (ECG) for centralized reading.  A standard 12-lead ECG 
will be obtained with the patient in the supine position after resting for at least 
5 minutes (see Section 7.6.7)

Pulmonary function tests (FVC and DLCO) (see Section 7.6.8)

Continuous assessment of AEs will start immediately after signing the informed 
consent form (see Section 7.5.1)
7.1.2.2
Visit 1 Main treatment phase - Baseline (Day 0, Week 0)
The following assessments will be performed at Visit 1 (Day 0 of study drug treatment):
Before intake of study medication

Reconfirmation of eligibility (assessment of inclusion/exclusion criteria; Section 5.1)

Questionnaires (see Section 7.6.13)

Update of medical and surgical history, if needed (see Section 7.2.2)

Smoking history

Physical examination, including weight

Vital signs (blood pressure and heart rate).  Blood pressure and heart rate will be 
measured at all visits with the patient in a sitting position, after the patient has been at 
rest for at least 5 minutes. The same arm is always used for these measurements (see 
Section 7.6.5).

Patient and physician assessments of Raynaud’s attacks, and patient to return 
completed 7-day diary (see Section 7.6.12)

Digital ulcer net burden assessment (see Section 7.6.10)

Patient’s and physician’s global assessment (see Section 7.6.15)

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
Assessment for the presence or absence of tendon friction rubs (see Section 7.6.17)

Blood samples for safety (see Section 7.6.2)

Blood sample for biomarkers to be obtained before the start of study drug treatment
(see Section 7.6.3)

Pregnancy test (urine) for all women of childbearing potential (see Section 7.6.1)

12-lead ECG for centralized reading.  A standard 12-lead ECG will be obtained with 
the patient in the supine position after resting for at least 5 minutes (See Section 7.6.7)

Skin biopsy to be obtained before the start of study drug treatment (see Section 7.6.9)

Recording and assessment of AEs (see Section 7.5.1)

Concomitant therapy

Randomization (IxRS) to study drug treatment with either riociguat or placebo (see 
Section 6)

Dispensation of study drug and first intake by patient
After intake of study medication

Blood sample for PK (see Section 7.4)
o
PK blood sample between 1 – 2 hours after administration of the morning dose 
of study medication
o
PK blood sample between 3 – 4 hours after administration of the morning dose 
of study medication

Vital signs (blood pressure and heart rate) should be measured within 20 minutes prior 
to each post-dose PK sampling with the patient in a sitting position and after the 
patient has been at rest for at least 5 minutes.  The same arm is always used for these 
measurements (see Section 7.6.5).
7.1.2.3
Visits 2 through to 6 Main treatment phase – Dose-titration period -
amended
At these study visits, the patient should attend the clinic without having taken the morning 
dose of study medication.
During the dose titration period of the main treatment phase, the following assessments will 
be performed according to the Schedule of evaluations (Section 7.1.1):

Vital signs (blood pressure and heart rate).  Blood pressure and heart rate will be 
measured at all visits with the patient in a sitting position, after the patient has been at 
rest for at least 5 minutes. The same arm is always used for these measurements (see 
Section 7.6.5).

Digital ulcer net burden assessment (see Section 7.6.10)

Recording and assessment of AEs (see Section 7.5)


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
Blood samples for additional safety for patients with impaired renal and liver function 
at Visit 2, 3, 4, 5 as needed77 (see Section 7.6.2)

Blood samples for safety Visit 6 (see Section 7.6.2)

Blood sample for PK up to 1 hour before the morning dose of study medication (see 
Section 7.4)

Pregnancy test (urine) for all women of childbearing potential (Visit 3 and Visit 5)
(see Section 7.6.1)

Concomitant therapy

Dose titration according to the titration algorithm (see Section 4.1.2)

Dispensation of study drug and drug accountability
7.1.2.4
Visits 7 through to 11 Main treatment phase - Maintenance period -
amended
At these visits, the patient should attend the clinic without having taken the morning dose of 
riociguat or placebo.
During the maintenance period of the main treatment phase, the following assessments will be 
performed according to the Schedule of evaluations (Section 7.1.1):

Questionnaires (Visit 8, 10, and 11) (see Section 7.6.13)

Smoking history (Visit 10)

Physical examination, including weight (at Visit 7 and Visit 10) (Note: BMI will be 
calculated automatically in the eCRF)

Oxygen saturation measurement using forehead pulse oximetry at Visit 9 only. At 
Visits 10 and 11 only, oxygen saturation will be measured before and after intake of 
study drug (see Section 7.6.18, Table 7–2, Table 7–3, and Table 7–4)78

Vital signs (blood pressure and heart rate).  Blood pressure and heart rate will be 
measured at all visits with the patient in a sitting position, after the patient has been at 
rest for at least 5 minutes. The same arm is always used for these measurements (see 
Section 7.6.5) 

Assessment of orthostatic changes: measure blood pressure and heart rate in supine 
position and sitting position approximately 2 h after intake of study drug (Visit 11 
only, see Section 7.6.5).79

mRSS (Visits 7, 10 and 11) (see Section 7.6.6)

Digital ulcer net burden assessment (see Section 7.6.10)

Provision of 7-day diary to patients at Visit 7, which they will complete daily for 
7 consecutive days leading up to Visit 8 (see Section 7.6.12)
                                                
77 Per Amendment 1
78 Per Amendment 6
79 Per Amendment 6


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
Patient and physician assessment of Raynaud’s attacks, and patient to return 
completed 7-day diary (Visit 8) (see Section 7.6.12)

Patient’s and physician’s global assessment (Visit 10) (see Section 7.6.15)

Patient interference with skin assessment (Visit 10) (see Section 7.6.16)

Assessment for the presence or absence of tendon friction rubs (Visit 8) (see Section 
7.6.17)

Blood samples for safety (Visit 10 and 11) (see Section 7.6.2)

Blood sample for PK at Visit 11 up to 1 hour before the morning dose of study 
medication (see Section 7.4)

Blood sample for biomarkers (Visit 8) (see Section 7.6.3)

Pregnancy test (urine) for all women of childbearing potential (Visits 7 and 9) (see 
Section 7.6.1) and every 4 weeks in between as required

12-lead ECG for centralized reading (Visits 7, 10 and11).  A standard 12-lead ECG 
will be obtained with the patient in the supine position after resting for at least 
5 minutes (see Section 7.6.7)

Pulmonary function tests (FVC and DLCO) (Visits 7, 10 and 11) (see Section 7.6.8)

Skin biopsy (Visit 8) (see Section 7.6.9)

Recording and assessment of AEs (see Section 7.5)

Concomitant therapy

Dispensation of study drug and drug accountability
After intake of study medication (at Visit 11 only):

Blood sample for PK: between 2 3 hours after administration of the morning dose 
of study medication (see Section 7.4)

Vital signs (blood pressure and heart rate) within 20 minutes prior to the PK sampling 
with the patient in a sitting position and after the patient has been at rest for at least 
5 minutes.  The same arm is always used for these measurements (see Section 7.6.5).
7.1.2.5
Visit 12 (Week 52) - amended
This is the last visit of the main treatment phase, and the first visit of the long-term extension 
phase. At this visit, the patient should attend the clinic without having taken the morning dose 
of riociguat or placebo.
Before intake of study medication:

Questionnaires (see Section 7.6.13)

Smoking history 

Physical examination, including weight (Note: BMI will be calculated automatically 
in the eCRF)


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
Oxygen saturation will be measured before and after intake of study drug (see Section 
7.6.18, Table 7–2, Table 7–3, and Table 7–4).80

Vital signs (blood pressure and heart rate).  Blood pressure and heart rate will be 
measured at all visits with the patient in a sitting position, after the patient has been at 
rest for at least 5 minutes.  The same arm is always used for these measurements (see 
Section 7.6.5) 

Assessment of orthostatic changes: measure blood pressure and heart rate in supine 
position and sitting position approximately 2 h after intake of study drug (see 
Section 7.6.5).81

mRSS (see Section 7.6.6)

Digital ulcer net burden assessment (see Section 7.6.9)

Patient’s and physician’s global assessment (see Section 7.6.15)

Patient interference with skin assessment (see Section 7.6.16)

Tender and swollen joint count assessment (see Section 7.6.14)

Blood samples for safety (see Section 7.6.2)

Pregnancy test (urine) for all women of childbearing potential (see Section 7.6.1)

12-lead ECG for centralized reading.  A standard 12-lead ECG will be obtained with 
the patient in the supine position after resting for at least 5 minutes (see Section 7.6.7)

Pulmonary function tests (FVC and DLCO) (see Section 7.6.8)

Recording and assessment of AEs (see Section 7.5)

Concomitant therapy

Drug accountability

Start of long-term extension phase

Assignment of patients to treatment with riociguat via IxRS, dispensation of study 
drug and intake by patient
After intake of study medication:

Blood sample for PK (see Section 7.4)
o
PK blood sample between 1 – 2 hours after administration of the morning 
(first) dose of study medication 
o
PK blood sample between 3 – 4 hours after administration of the morning
(first) dose of study medication

Vital signs (blood pressure and heart rate) should be measured within 20 minutes prior 
to each PK sampling with the patient in a sitting position and after the patient has been 
at rest for at least 5 minutes.  The same arm is always used for these measurements 
(see Section 7.6.5).
                                                
80 Per Amendment 6
81 Per Amendment 6


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7.1.2.6
Visits 13 through to 17 Long-term extension phase - Dose-titration 
period - amended
At these study visits, the patient should attend the clinic without having taken the morning 
dose of riociguat.
During the double-blind dose-titration period of the long-term extension phase, the following 
assessments will be performed according to the Schedule of evaluations (Section 7.1.1):

Oxygen saturation will be measured before and after intake of study drug (see Section 
7.6.18, Table 7–2, Table 7–3, and Table 7–4)82

Vital signs (blood pressure and heart rate).  Blood pressure and heart rate will be 
measured at all visits with the patient in a sitting position, after the patient has been at 
rest for at least 5 minutes. The same arm is always used for these measurements (see 
Section 7.6.5)

Assessment of orthostatic changes: measure blood pressure and heart rate in supine 
position and sitting position approximately 2 h after intake of study drug (see 
Section 7.6.5).83

Digital ulcer net burden assessment (see Section 7.6.10)

Blood samples for safety (Visit 17; see Section 7.6.2)

Blood sample for PK up to 1 hour before the morning dose of study drug (see 
Section 7.4)

Pregnancy test (urine) for all women of childbearing potential (on-site at Visits 14 and 
16) (see Section 7.6.1)

Recording and assessment of AEs (see Section 7.5)

Concomitant therapy

Dose titration according to the titration algorithm (see Section 4.1.2)

Dispensation of study drug and drug accountability
7.1.2.7
Visits 18 through Visit n (every 12 weeks) Long-term extension 
phase Open-label extension period - amended
At these study visits, the patient should attend the clinic without having taken the morning 
dose of riociguat. 
During the open-label extension period, the following assessments and procedures will be 
performed according to the Schedule of evaluations (Section 7.1.1):

Questionnaires (see Section 7.6.13)

Smoking history

Physical examination, including weight
                                                
82 Per Amendment 6
83 Per Amendment 6


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
Oxygen saturation measurement using forehead pulse oximetry (see Section 7.6.18).84

Vital signs (blood pressure and heart rate).  Blood pressure and heart rate will be 
measured at all visits with the patient in a sitting position, after the patient has been at 
rest for at least 5 minutes. The same arm is always used for these measurements (see 
Section 7.6.5)

mRSS (see Section 7.6.6)

Digital ulcer net burden assessment (see Section 7.6.10)

Blood samples for safety (see Section 7.6.2)

Pregnancy test (urine) for all women of childbearing potential (every 4 weeks) (see 
Section 7.6.1). When pregnancy testing coincides with a visit, the test should be 
performed at the site, but otherwise should be performed at home.

12-lead ECG for centralized reading.  A standard 12-lead ECG will be obtained with 
the patient in the supine position after resting for at least 5 minutes (see Section 7.6.7)

Pulmonary function tests (FVC and DLCO) (see Section 7.6.8)

Recording and assessment of AEs (see Section 7.5)

Concomitant therapy

Dispensation of study drug and drug accountability
7.1.2.8
Termination Visit - amended
The termination visit will be performed if the patient is discontinued85 from study medication 
for any reason except death or lost to follow-up, and should occur as soon as possible after the 
patient receives his/her last dose of study drug.  Assessments and procedures at this visit 
include the following:

Questionnaires (see Section 7.6.13)

Smoking history

Physical examination, including weight

Oxygen saturation measurement using forehead pulse oximetry (see Section 7.6.18).86

Vital signs (blood pressure and heart rate).  Blood pressure and heart rate will be 
measured at all visits with the patient in a sitting position, after the patient has been at 
rest for at least 5 minutes. The same arm is always used for these measurements (see 
Section 7.6.5)

mRSS (see Section 7.6.6)

Digital ulcer net burden assessment (see Section 7.6.10)

Tender and swollen joint count assessment (not needed after V12, see Section 
7.6.14)87
                                                
84 Per Amendment 6
85 Per Amendment 4
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
Patient’s and physician’s global assessment (not needed after V1288, see Section 
7.6.15)

Patient interference with skin assessment (not needed after V1289, see Section 7.6.16)

Blood samples for safety (see Section 7.6.2)

Pulmonary function tests (FVC and DLCO) (see Section 7.6.8)

Blood sample for biomarkers (if TV occurs before Visit 8) (see Section 7.6.3)

Skin biopsy (if TV occurs before Visit 8) (see Section 7.6.9)

Pregnancy test (urine) for all women of childbearing potential (if 4 weeks since the 
previous visit) (see Section 7.6.1)

12-lead ECG for centralized reading.  A standard 12-lead ECG will be obtained with 
the patient in the supine position after resting for at least 5 minutes (see Section 7.6.7)

Recording and assessment of AEs (see Section 7.5)

Drug accountability

Concomitant therapy
See also Section 7.1.2.10 for further planned assessments.
7.1.2.9
Safety follow-up visit - amended
Patients must be evaluated for safety 30 (+ 5) days after the last dose intake of study 
medication.  Assessments will include the following:

Physical examination, including weight

Oxygen saturation measurement using forehead pulse oximetry (see Section 7.6.18).90

Vital signs (blood pressure and heart rate).  Blood pressure and heart rate will be 
measured at all visits with the patient in a sitting position, after the patient has been at
rest for at least 5 minutes.  The same arm is always used for these measurements (see 
Section 7.6.5)

Recording and assessment of AEs (see Section 7.5)

Blood samples for safety (see Section 7.6.2)

Pregnancy test (urine) for all women of childbearing potential

12-lead ECG for centralized reading.  A standard 12-lead ECG will be obtained with 
the patient in the supine position after resting for at least 5 minutes (see Section 7.6.7)

Concomitant therapy

Survival status (see Section 5.2.1)
                                                                                                                                                        
87 Per Amendment 1
88 Per Amendment 1
89 Per Amendment 1
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7.1.2.10
Premature discontinuation of study drug treatment - amended
In the event of premature discontinuation of study drug treatment, patients must undergo the 
same procedures as outlined for the termination visit (Section 7.1.2.8) and then undergo 
evaluation at the safety follow-up visit, 30 (+5) days later (Section 7.1.2.9).
The reason for premature discontinuation of study drug treatment or early withdrawal from 
the study must be recorded in the eCRF (please refer to Section 5.2).
If the patient discontinues study drug91 prematurely during the main treatment phase (Week 0 
– Week 52) he/she will be invited to come for limited assessments (mRSS, pulmonary 
function test [FVC and DLCO including hemoglobin measurement at the local laboratory]92,
PROs, and patient’s and physician’s global assessment)93 at Week 12, Week 26, Week 39 and 
Week 52, depending on the timing of discontinuation94. This will be in addition to the 
termination visit assessments (see Section 7.1.2.8), provided that the patient does not object to 
collection of study data after withdrawal of consent.  If the discontinuation occurs before Visit 
8 (Week 14), a skin biopsy will also be performed.
7.2
Population characteristics
7.2.1
Demographic
The following demographic data will be recorded: 

Date of birth (month and year) (age)

Sex

Ethnicity

Smoking status, including number of cigarettes per day

Alcohol consumption
7.2.2
Medical history
Medical history findings (ie, previous diagnoses, diseases or surgeries) meeting all criteria 
listed below will be collected:

Pertaining to the study indication

Started before signing of the informed consent 

Considered relevant to the study

Medical history related to concomitant therapy
Detailed instructions on the differentiation between (i) medical history and (ii) AEs can be 
found in Section 7.5.1.1.
7.3
Efficacy - amended
Primary efficacy outcome measure
                                                
91 Per Amendment 1
92 Per Amendment 4
93 Per Amendment 5
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
Change in mRSS from baseline to Week 52
Secondary efficacy outcome95 measures96
Key secondary endpoint:

CRISS at Week 5297, consisting of five variables: mRSS, FVC % predicted, physician 
and patient global assessments, and HAQ-DI score (from SHAQ patient reported 
outcome)
Further secondary endpoints:

HAQ-DI domain (separately from the SHAQ as part of the calculation of the CRISS 
algorithm).

Patient’s global assessment

Physician’s global assessment

Change in FVC (forced vital capacity) % predicted 
Further clinical outcomes (to be adjudicated by an Independent Central Adjudication 
Committee)

New renal crisis

Worsening of cardiac disease, defined as new or worsened clinically symptomatic and 
significant heart disease, considered secondary to dcSSc, including congestive heart 
failure requiring hospitalization, new onset pulmonary hypertension requiring 
treatment, pericardial disease requiring intervention or exhibiting clinical 
decompensation, and arrhythmias and/or conduction defects requiring treatment.

Worsening of gastrointestinal disease requiring hospitalization or new requirement for 
parenteral nutrition

Critical digital ischemia requiring hospitalization, or digital gangrene
Additional information regarding the events to be adjudicated may be requested to be sent to 
the Adjudication Committee.  All events listed above, in addition to all cases of death, 
regardless of causality or seriousness will be reviewed by the Adjudication Committee.
Other exploratory measures:98

mRSS progression rate (defined as increase in mRSS by > 5 units and > 25% from 
baseline) and mRSS regression rate (defined as decrease in mRSS by > 5 units and 
> 25% from baseline)

HRQoL using SF-36 and the SHAQ.

Digital ulcer net burden (defined as total number of ulcers at time point minus number 
of ulcers at baseline) and proportion of patients who do not develop new ulcers
                                                
95 Per Amendment 1
96 Per Amendment 4
97 Per Amendment 5
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
Change in DLCO (carbon monoxide diffusing capacity) % predicted

Need for Rescue99 Therapy (see definition in Section 6.9)

All-cause Mortality

Gastrointestinal involvement as assessed by University of California, Los Angeles, 
Scleroderma Clinical Trial Consortium Gastrointestinal Scale (UCLA SCTC GIT) 2.0 
instrument

Patient-Reported Outcomes Measurement Information System (PROMIS)-29 (subset 
of patients)

Patient interference with skin 

Presence or absence of tendon friction rubs

Pain visual analog scale (VAS)

Change in BMI

Joint involvement using tender and swollen joint counts

New items for Raynaud’s response index excluding items included in secondary 
outcome measures
o Patient and physician assessment of Raynaud's phenomenon; pain, numbness, 
and tingling during a Raynaud's phenomenon attack; Raynaud’s condition 
score, average number of attacks/day; and duration of attacks
Endpoints long-term extension phase (Week 52 to study completion)

mRSS

Pulmonary function testing

PROs / HRQoL

Worsening end-organ disease (cardiac, renal, pulmonary, gastrointestinal & digital 
ischemia)
7.4
Pharmacokinetics / pharmacodynamics - amended
At these study visits the patients should present themselves to the hospital without taking the 
morning dose of study medication. The trough PK sample should always be obtained at up to 
1 hour before administration of the morning dose of study medication and approximately 5 to 
15 hours after the evening dose100.
It is essential that the exact time of blood sampling and time of dose administration of the 
3 preceding doses of study medication are documented accurately in the eCRF. For samples 
taken before riociguat administration, also the time of the first dose taken at the visit needs to 
be documented101.
                                                
99 Per Amendment 1
100 Per Amendment 5
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For investigation of exposure behavior, plasma concentrations of BAY63-2521 and its 
metabolite (M1) will be determined at the times given below using a sparse sampling 
approach in all participating patients. If the investigator decides to take additional PK 
samples, those may be used for PK analysis as well.102
Blood samples for PK will be taken at the following times:
Profile day (Visit 1 and Visit 12)

2 hours after administration of the morning dose of study medication103

3 – 4 hours after administration of the morning dose of study medication
Visits 2 through to 6 and Visits 13 through to 17

Up to 1 hour before administration of morning dose of study medication (trough)
Visit 11

Up to 1 hour before administration of morning dose of study medication (trough)

2 hours after administration of morning dose of study medication (peak)104
For details regarding the timing of PK sampling and flow charts detailing the order of 
procedures at these visits, please refer to Section 7.1.1.
Plasma concentration time points will be compared to the available plasma concentration 
profiles in healthy volunteers and selected patient populations. Pharmacokinetic and 
exposure-response analysis might be performed using population approaches (popPK
(population PK) and popPK/pharmacodynamic (PD), eg, by non-linear mixed effect 
modeling). Analysis and report will be done under separate cover. This evaluation might be 
started prior to database lock. If this is applicable, appropriate measures will be taken to 
maintain blinding of the study team, eg, data will be stored separately, and members of the 
study team will neither have access to the randomization list nor to individual data.105
Sample collection, processing and storage
Further details on collection, labeling, storage and shipping of samples are provided in a 
separate laboratory manual.
Pharmacokinetic (PK) samples will be analyzed under the responsibility of the Bayer 
HealthCare Bioanalytics Laboratory, Bayer Pharma AG, GDD-GED-DMPK Bioanalytics, 
42096 Wuppertal, Germany. The bioanalyst will be unblinded and have access to the 
randomization list.106
Any residual PK samples will be destroyed at end of study.
                                                
102 Per Amendment 5
103 Per Amendment 6
104 Per Amendment 6
105 Per Amendment 5
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7.5
Safety
7.5.1
Adverse events
7.5.1.1
Definitions - amended
Definition of adverse event (AE)
In a clinical study, an AE is any untoward medical occurrence (ie, any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a 
patient or clinical investigation subject after providing written informed consent for 
participation in the study.  Therefore, an AE may or may not be temporally or causally 
associated with the use of a medicinal (investigational) product.
A surgical procedure that was planned prior to the start of the study by any physician treating 
the patient should not be recorded as AE (however, the condition for which the surgery is 
required may be an AE).
In the following differentiation between medical history and AEs, the term “condition” may 
include abnormal eg, physical examination findings, symptoms, diseases, laboratory, ECG.

Conditions that started before signing of informed consent and for which no symptoms 
or treatment are present until signing of informed consent are recorded as medical 
history (eg, seasonal allergy without acute complaints).

Conditions that started before signing of informed consent and for which symptoms or 
treatment are present after signing of informed consent, at unchanged intensity, are 
recorded as medical history (eg, allergic pollinosis).

Conditions that started or deteriorated after signing of informed consent will be 
documented as AEs. This includes any conditions related to the underlying disease107.
Definition of serious adverse event (SAE)
An SAE is classified as any untoward medical occurrence that, at any dose, meets any of the 
following criteria (a – f):
a. Results in death
b. Is life-threatening
The term ‘life-threatening’ in the definition refers to an event in which the subject 
was at risk of death at the time of the event, it does not refer to an event which 
hypothetically might have caused death if it were more severe.
                                                
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c. Requires inpatient hospitalization or prolongation of existing hospitalization
A hospitalization or prolongation of hospitalization will not be regarded as an SAE if 
at least one of the following exceptions is met:
- The admission results in a hospital stay of less than 12 hours
- The admission is pre-planned 
(ie, elective or scheduled surgery arranged prior to the start of the study)
- The admission is not associated with an AE 
(eg, social hospitalization for purposes of respite care).
However, it should be noted that invasive treatment during any hospitalization may 
fulfill the criterion of ‘medically important’ and as such may be reportable as an SAE 
dependent on clinical judgment.  In addition, where local regulatory authorities 
specifically require a more stringent definition, the local regulation takes precedence.
d. Results in persistent or significant disability / incapacity
Disability means a substantial disruption of a person’s ability to conduct normal life’s 
functions.
e.
Is a congenital anomaly / birth defect
f.
Is another medically important serious event as judged by the investigator
7.5.1.2
Classifications for adverse event assessment
All AEs will be assessed and documented by the investigator according to the categories 
detailed below. 
7.5.1.2.1
Seriousness
For each AE, the seriousness must be determined according to the criteria given in 
Section 7.5.1.1.
7.5.1.2.2
Intensity
The intensity of an AE is classified according to the following categories:
- Mild
- Moderate
- Severe
7.5.1.2.3
Causal relationship 
The assessment of the causal relationship between an AE and the administration of treatment 
is a clinical decision based on all available information at the time of the completion of the 
eCRF.
The assessment is based on the question whether there was a “reasonable causal relationship” 
to the study treatment in question.
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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 subject 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 AE is associated 
with the use of the study treatment.
Important factors to be considered in assessing the relationship of the AE to study treatment 
include:
- The temporal sequence from drug administration:  The event should occur after the drug 
is given.  The length of time from drug exposure to event should be evaluated in the 
clinical context of the event.
- Recovery on drug discontinuation (de-challenge), recurrence on drug re-introduction (re-
challenge):
- Subject’s response after de-challenge or subjects response after re-challenge should be 
considered in the view of the usual clinical course of the event in question.
- Underlying, concomitant, intercurrent diseases:  
Each event should be evaluated in the context of the natural history and course of the 
disease being treated and any other disease the subject may have.
- Concomitant medication or treatment: 
The other drugs the subject is taking or the treatment the subject receives should be 
examined to determine whether any of them may be suspected to cause the event in 
question.
- The pharmacology and PK of the study treatment: 
The PK properties (absorption, distribution, metabolism and excretion) of the study 
treatment, coupled with the individual subject’s pharmacodynamics should be considered.
Causal relationship to protocol-required procedure(s)
The assessment of a possible causal relationship between the AE and protocol-required 
procedure(s) is based on the question whether there was a “reasonable causal relationship” to 
protocol-required procedure(s).
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7.5.1.2.4
Action taken with study treatment 
Any action on study treatment to resolve the AE is to be documented using the categories 
listed below.
- Drug withdrawn
- Drug interrupted
- Dose reduced
- Dose not changed
- Dose increased
- Not applicable
- Unknown
7.5.1.2.5
Other specific treatment(s) of adverse events
- None
- Remedial drug therapy
- Other
7.5.1.2.6
Outcome
The outcome of the AE is to be documented as follows: 
- Recovered/resolved
- Recovering/resolving
- Recovered/resolved with sequelae
- Not recovered/not resolved
- Fatal
- Unknown
7.5.1.3
Assessments and documentation of adverse events
The investigator has the obligation to report AEs. All non-serious events will be assessed and 
recorded during the specified observational phase (from signing the informed consent form up 
to the follow-up visit 30 (+5) days after last study medication intake), whether believed to be 
related or unrelated to the treatment. AE forms will be included in the eCRFs. The record will 
include clinical symptoms or final diagnosis when available, date of appearance, duration, 
severity and relationship to treatment. A record will also be kept of the action taken and the 
follow-up until resolution of the AE.
7.5.1.4
Reporting of serious adverse events
The definition of SAEs is given in Section 7.5.1.1.
Investigator’s notification of the sponsor
All investigators will be thoroughly instructed and trained on all relevant aspects of the 
investigator’s reporting obligations for SAEs.  This information, including all relevant contact 


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details, is summarized in the investigator site file.  This information will be updated as 
needed.
All SAEs occurring during the observation period defined in Section 7.5.1.3 must 
immediately (within 24 hours of the investigator’s awareness) be reported to the recipient 
detailed in the manual.  An SAE form must also be completed within 24 hours of the 
investigator awareness and forwarded to the designated recipient.  Each SAE must be 
followed up until resolution or stabilization by submission of updated reports to the 
designated recipient.
SAEs occurring after the protocol-defined observation period will be processed by the 
sponsor according to all applicable regulations.
Notification of the IECs / IRBs
Notification of the IECs / IRBs about all relevant events (eg, SAEs, suspected, unexpected, 
serious adverse reactions [SUSARs]) will be performed by the sponsor and/or by the 
investigator according to all applicable regulations.
Notification of the authorities
The processing and reporting of all relevant events (eg, SAEs, SUSARs) to the authorities 
will be done by the sponsor according to all applicable regulations.
Sponsor’s notification of the investigational site
The sponsor will inform all investigational sites about reported relevant events (eg, SUSARs) 
according to all applicable regulations.
7.5.1.5
Expected adverse events
For this study, the applicable reference document is the most current version of the 
IB/summary of product characteristics.
Overview listings of frequent events that have occurred so far in the clinical development are 
shown in the current IB.  If relevant new safety information is identified, the information will 
be integrated into an update of the IB and distributed to all participating sites.
The expectedness of AEs will be determined by the sponsor according to the applicable 
reference document and according to all local regulations.
In this study, the following events are outcome events and/or consistent with the underlying 
condition and will be considered as disease related in the defined study population:  

New renal crisis

Worsening of cardiac disease considered secondary to dcSSc

Worsening of gastrointestinal disease requiring hospitalization or new requirement for 
parenteral nutrition

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For the purposes of this trial, these events will not be subject to systematic unblinding and 
expedited reporting process, if reported as serious adverse drug reactions. They will be 
captured in the Global Pharmacovigilance database, in the eCRF and undergo regular central 
adjudication and unblinded DMC review.
7.5.1.6
Adverse events of special safety interest
Symptomatic hypotension and serious hemoptysis have been defined as AEs of special 
interest and must be documented accordingly in the corresponding AEs of special safety 
interest pages in the eCRF. Events of asymptomatic hypotension and non-serious hemoptysis 
should not automatically be upgraded by the reporting investigator to serious. Declaration of 
an event as serious should only occur when 1 or more of the serious criteria (as defined in 
Section 7.5.1.1) are applicable.
7.5.1.7
Overdose of Study Medication
In case of overdose, standard supportive measures should be adopted as required.  In case of 
pronounced hypotension, active cardiovascular support may be required.  If symptoms 
develop after the investigational drug has been administered, any therapy that becomes 
necessary has to be guided by the predominant symptoms.  Patients must remain under 
medical supervision until all relevant adverse effects have resolved in the event of overdose; 
patient continuation remains at the discretion of the investigator.
7.5.2
Pregnancies
The investigator must report to the sponsor any pregnancy occurring in a study subject or his 
female partner during the subject’s participation in this study.  The report should be submitted 
within the same timelines as an SAE, although a pregnancy per se is not considered an SAE.  
For a study subject, the outcome of the pregnancy should be followed up carefully, and any 
outcome of the mother or the child should be reported.
Bayer usually does not gather information of drug exposure via the father, however, if those 
cases are reported, all efforts should be made to obtain similar information on course and 
outcome, subject to the partner’s consent.
For all reports, the forms provided are to be used.
7.6
Other procedures and variables
7.6.1
Pregnancy testing
Pregnancy testing is to be performed at the screening visit (serum only), Visit 1 (Day 0; urine) 
and at 4-weekly intervals thereafter (urine), at a termination visit, and until 30 (+ 5) days after 
the patient stops intake of study drug. If the interval falls on a visit date, pregnancy testing is 
to be performed locally at the site, while at all other dates the patient is to perform a urine 
dipstick test at home. The results are to be documented in the eCRF and in the patient file.
The result of every home urine pregnancy test should be actively requested by the site as soon 
as the test is due. The patient must report a positive result to the site without delay. The 
results are to be documented in the eCRF and in the patient file in a timely manner. It is not 
acceptable to obtain the result only at the next scheduled visit at the site. In the event of 
pregnancy, a referral to a gynecologist for confirmation of pregnancy must be organized as 
soon as possible. In addition, the pregnancy must be reported to the sponsor as described in 
Section 7.5.2 and further consequences with regard to ongoing participation in the study must 


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be discussed with the patient. In the event uncertainties about a pregnancy test outcome exist, 
the patient should contact the site immediately to discuss further steps (eg, exclusion of 
pregnancy by serum pregnancy test).
Based on country-specific regulations, further measurements may be performed.
Women of childbearing potential must agree to use adequate contraception when sexually 
active.
“Adequate contraception” is defined as any combination of at least 2 effective methods of 
birth control, of which at least 1 is a physical barrier (eg, condom with hormonal 
contraception like implants or combined oral contraceptives, condom with intrauterine 
devices).  Patients must agree to utilize 2 methods of contraception simultaneously, of which 
at least 1 should be a physical barrier (eg, condom, diaphragm or cervical cap).
7.6.2
Laboratory parameters - amended
The following safety laboratory parameters will be analyzed in a central laboratory (apart 
from coagulation tests, which will be analyzed at a local laboratory) at the screening visit
(Visit 0), Visit 1 (Day 0), Visit 6 (Week 10), Visit 10 (Week 26)108, Visit 11 (Week 39), Visit 
12 (Week 52), Visit 17 (Week 62), every 12 weeks during the Open-label extension period, 
termination visit, and safety follow-up visit:

Hematology: WBC differential count, erythrocytes, hemoglobin, hematocrit and
platelets
The hemoglobin value required for the pulmonary function tests performed at visits 
with limited assessments (see Section 7.1.2.10) will be measured at the local 
laboratory. The hemoglobin value will be entered in the eCRF and used for the 
calculation of predicted DLCO only. 109

Coagulation tests: activated partial thromboplastin time (aPTT) and international 
normalized ratio (INR) (to be performed at a local laboratory)

Clinical chemistry: aspartate aminotransferase (AST), alanine aminotransferase 
(ALT), alkaline phosphatase (AP), gamma glutamyl transferase (GGT), CK, sodium, 
potassium, magnesium, calcium, phosphate, creatinine, urea, uric acid, total bilirubin, 
total protein, serum albumin.
Patients with isolated AST or ALT >3xULN or bilirubin >2xULN at screening and/or
baseline will have additional analysis of coagulation tests, AST, ALT, AP, GGT, total 
bilirubin and serum albumin until normalization and/ or stabilization at Visit 2 (Day 14), Visit 
3 (Day 28), Visit 4 (Day 42), Visit 5 (Day 56), as needed. Worsening of the parameters in the 
order of 2-fold from baseline values will be considered clinically significant [22] and 
additional diagnostic procedures may be requested110. See Section 5.2.1.2 for discontinuation 
criteria related to liver function.111
Patients entering the trial with eGFR 15-29 mL/min/1.73m2 will be undergo additional serum 
creatinine and eGFR calculation until normalization and/ or stabilization at Visit 2 (Day 14), 
Visit 3 (Day 28), Visit 4 (Day 42), and Visit 5 (Day 56), as needed. A decrease in eGFR 
                                                
108 Per Amendment 1
109 Per Amendment 4
110 Per Amendment 1
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equal or greater than 5ml/min/1.73m2 in these patients (eGFR 15-29 ml/min/1.73m2) during 
the study or a reduction of 25% or more in 12 months will be considered clinically 
significant112 [23,24]. See Section 5.2.1.2 for discontinuation criteria related to eGFR 
values.113
At latest, at the end of the study when all planned analyses are completed, all blood samples 
will be destroyed. The name and address for the central laboratory service provider can be 
found in the documentation supplied by the vendor.
Note:  One re-assessment of laboratory parameters is allowed during the screening phase to 
re-assess the eligibility of patients.
7.6.3
Exploratory Biomarkers - amended
Exploratory biomarkers will be evaluated at Visit 1 (Day 0) and Visit 8 (Week 14) and at a 
termination visit if this visit occurs before Visit 8.  Skin biopsy and blood samples (serum and 
plasma) will be collected and processed to measure the following biomarkers (see 
Section 7.6.9 for details of skin biopsy):

Skin biomarkers:
o
 
 
 
 

Serum/plasma biomarkers: 
o
 
 
 
Blood samples for inflammatory, vascular, and fibrosis as well as skin samples will be 
analyzed by an external central laboratory; details will be provided in the Laboratory Manual. 
The evaluation of biomarkers might be started prior to database lock; if this is applicable, 
appropriate measures will be taken to maintain blinding of the study team (see also 
Section 6.5 and Section 7.4). 114
The results of the biomarker analysis will be reported separately to the clinical study report.115
                                                
112 Per Amendment 1
113 Per Amendment 5
114 Per Amendment 5
115 Per Amendment 5
CCI
CCI


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7.6.4
Autoantibody screen
Blood samples will be sent to the central laboratory at the Screening Visit (Visit 0) for 
anti-nuclear antibody immunofluorescence and to detect the presence of SSc-associated anti-
nuclear autoantibodies, such as anti-Scl-70 (anti-topoisomerase 1), anti-RNA polymerase III, 
and anti-centromere.
7.6.5
Blood pressure and heart rate measurement - amended
Blood pressure and heart rate will be measured at all visits with the patient in a sitting 
position, after the patient has been at rest for 5 minutes. The same arm is always used for 
these measurements.
At certain visits where a blood sample for PK is scheduled after the morning dose of study 
medication, an additional vital signs measurement (blood pressure and heart rate) will be 
taken within 20 minutes prior to PK sampling. Please refer to Section 7.1.1.
Methodology: Noninvasive measurement preferably with a validated electronic device in 
accordance with published guidelines (eg, American Heart Association Recommendations for 
Blood Pressure Measurement in Humans and Experimental Animals [25]).
Assessment of orthostatic changes116
To assess orthostatic changes, blood pressure and heart rate will be measured with the patient 
in a supine position, after the patient has rested for 5 minutes. Immediately thereafter, the 
patient should sit up and blood pressure and heart rate will be measured after the patient has 
rested for 2 minutes. 
These measurements should be performed approximately 2 hours after study medication 
intake.
Frequency: Visit 11 (Week 39), Visit 12 (Week 52), during the Dose-Titration Period of the 
Long-Term Extension Phase (Visits 13 to 17).
7.6.6
Modified Rodnan skin scoring (mRSS) 
The mRSS is a validated physical examination method for estimating skin induration. It
correlates with biopsy measures of skin thickness and reflects prognosis and visceral 
involvement, especially in early disease. It is scored on 0 (normal) to 3+ (severe induration) 
ordinal scales over 17 body areas, with a maximum score of 51 and is used to categorize 
severity of SSc.[26] It has been extensively used as a primary and secondary outcome 
measure in randomized clinical trials.[27,28]
This assessment should be performed by a physician who is experienced and trained in skin 
scoring. To prevent inter-observer variability, the same physician must perform skin scoring 
for the same patient throughout the entire study.
Frequency: Screening Visit (Visit 0), Visit 7 (Week 12), Visit 10 (Week 26), Visit 11 (Week 
39), Visit 12 (Week 52), and every 3 months thereafter in the long-term extension phase and 
termination visit. 
                                                
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7.6.7
Electrocardiogram
Standard ECGs (12-lead ECG) will be recorded with the patient in the supine position after 
the patient has rested for at least 5 minutes.
All ECG printouts will be identified with the patient identification as well as date and time of 
recording and will be attached to the patient’s file. All ECG printouts will be examined 
locally by the investigator on the day of recording for safety and quality. Any clinically 
relevant abnormality will be documented as an AE. 
Electrocardiograms will then be transferred electronically and assessed centrally by an expert 
in cardiology who will provide expert assessment and interpretation of all ECGs obtained. 
The name and address for the ECG service provider can be found in the documentation
supplied by the vendor. Electrocardiogram procedures will be described in a separate manual. 
Frequency: screening visit (Visit 0), Visit 1 (Day 0), Visit 7 (Week 12), Visit 10 (Week 26), 
Visit 11 (Week 39), Visit 12 (Week 52), every 3 months (12 weeks) in the long-term 
extension phase, termination visit and safety follow-up visit.
7.6.8
Pulmonary function testing
The following lung function measurements will be performed locally: 

FVC and % of predicted

DLCO (mmol/min/kPa) and % of predicted (hemoglobin-corrected)
Printouts from the analyzer must be stored in the patient file and the measured values 
transferred to the eCRF.
The hemoglobin value required for the pulmonary function tests performed at visits with 
limited assessments (see Section 7.1.2.10) will be measured at the local laboratory. The 
hemoglobin value will be entered in the eCRF and used for the calculation of predicted DLCO
only.117.
Frequency: screening visit (Visit 0), Visit 7 (Week 12), Visit 10 (Week 26), Visit 11 (Week 
39), Visit 12 (Week 52), and every 3 months (12 weeks) in the long-term extension phase and 
termination visit.
7.6.9
Skin biopsy
As stated in Section 7.6.3 above, biomarker analysis will be performed using skin and blood
samples.
Skin biopsies will be obtained from the mid dorsal surface of the forearm (150 ± 20 mm 
proximal to the ulnar styloid) at Visit 1 (Day 0) and at Visit 8 (Week 14) and at a termination 
visit if this visit occurs before Visit 8.
If affected skin is located in that area, then the affected skin should be used. A biopsy should 
be performed regardless of whether or not affected skin is present. The skin biopsy obtained 
after treatment should be taken from the same arm, approximately 25 mm distance away from 
the initial biopsy, so as to avoid healing of the initial biopsy interfering with mRNA 
measurement. The location of the biopsy (right or left forearm) and distance from the ulnar 
                                                
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styloid will be documented. If in the opinion of the investigator the mid dorsal forearm is not 
appropriate, another location can be chosen. The alternative site and the reason for changing 
the site will be documented.
At each time point (Visit 1 and Visit 8), two 4-mm skin punch biopsies next to each other will 
be obtained (one for RNA extraction and the other for histology/immunohistochemistry). The 
skin to be biopsied will be cleaned before biopsy and the remainder of the procedure will be 
performed using clean technique, per standard dermatological practice. The skin at the biopsy 
site will be marked by drawing a circle of about 10 mm diameter using a dermatological ink 
skin marker. 
Skin will be biopsied with a 4-mm Baker style skin punch, provided by the Sponsor.  The 
punch will be centered at the 10-mm diameter circle.  The biopsy site will be closed by Steri-
strips or sutures (at the discretion of the investigator) to provide hemostasis and ensure proper 
healing.
At the discretion of the investigator, patients may be instructed to apply a small amount of 
antibiotic ointment and a sterile bandage to the site daily; these supplies will be provided by 
the investigator. At the discretion of the investigator the biopsy site can be dressed with an 
appropriate dressing. If sutures are used the sutures will be removed after 5 to 14 days.
7.6.10
Digital ulcer net burden
Digital ulcers are defined as a full thickness skin lesion with loss of epithelium including 
lesions covered by eschar. Ulcers should be > 3mm in maximal diameter. Healing is defined 
by re-epithelialization with loss of pain and exudate. Pitting scars and hyperkeratotic lesions 
are always excluded.
Digital ulcer net burden will be assessed by the following methods:

Ulcer count – this ideally will be performed by the same healthcare professional at 
every visit: 
o
Total ulcer counts
o
Distal counts: distal (fingertip) – any ulcer including skin area distal to proximal 
interphalangeal (PIP) joint

Ulcer burden:
o
Number of ulcers at time point minus baseline number of ulcers

Visual analog score (VAS) for patient-reported severity of digital ulcers as part of the 
SHAQ (see section 7.6.13)
Frequency: Digital ulcer net burden assessment at every visit. VAS as part of SHAQ: Visit 1 
(Day 0), Visit 8 (Week 14), Visit 10 (Week 26), Visit 11 (Week 39), Visit 12 (Week 52), 
Visit 18 (week 64), and every 3 months thereafter in the long-term extension phase and 
termination visit.
7.6.11
Digital gangrene
Digital gangrene will be recorded as a separate event and may co-exist with digital ulcers that 
affect the same digit and fulfil the criteria in section 7.6.10 above. 
Gangrene is defined as diffuse necrosis (pathologic death of deeper, eg, subcutaneous 
structures) due to obstruction, loss, or diminution of blood supply; it is of black color and 


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painful, and may be localized to parts of the finger or involve an entire finger. It may be wet 
or dry, reflecting a degree of adjacent tissue perfusion, time course of necrosis and presence 
or type of associated secondary infection. 
7.6.12
Raynaud’s attacks assessment
Raynaud’s attacks will be assessed using the composite of the following 6 individual outcome 
measures in order to minimize the measurement variability and placebo response: Raynaud’s 
condition score, patient assessment of Raynaud’s phenomenon, physician assessment of 
Raynaud’s phenomenon, attack symptoms, duration of attacks, and average number of attacks 
per day.[29]
The Raynaud’s condition score is a daily patient self-assessment of Raynaud’s phenomenon 
activity using a 0-10 ordinal scale from ‘no difficulty’ to ‘extreme difficulty’. It incorporates 
the cumulative frequency, duration, severity and impact of Raynaud’s phenomenon attacks, 
reflecting the overall degree that Raynaud’s has affected use of the patient’s hands.[30] 
The Raynaud’s condition score, details of the frequency and duration of Raynaud’s attacks, 
and attack symptoms of pain, numbness and tingling, each represented by a 0 – 100 VAS, will 
be incorporated into the daily diary that patients will be asked to complete for 7 days at the 
time points detailed below. 
The patient and physician assessment measures the severity of Raynaud’s phenomenon in the 
past week using a 0100 VAS and will be assessed at the clinic visits outlined below.
Frequency: Daily diary to be completed by patient for 7 consecutive days leading up to Visit 
1 (Day 0), and 7 consecutive days leading up to Visit 8 (Week 14). The patient and physician 
assessments of Raynaud’s phenomenon will be performed at Visit 1 and Visit 8. 
7.6.13
Patient-reported outcomes (PROs) / Health-related quality of life 
(HRQoL) questionnaires
Three PROs—the SF-36 v2.0, SHAQ, and UCLA SCTC GIT 2.0—will be completed by all 
patients in the study. The PROMIS-29 PRO will be completed by patients in a subset of sites 
belonging to English-speaking countries as this instrument has not yet undergone translation 
into multiple languages. To minimize bias, patients will be assured that all data will be 
treated confidentially, will not be reported to their patient files, and that the answers will not 
have any influence on study drug treatment.  In addition, patients will complete the 
questionnaires on their own, or with the help of relatives, friends or study staff if restricted by 
digital lesions, before being seen by the clinician at the respective visit. Subsequently, a 
member of the site investigator’s team will enter the responses into the eCRF.
Short Form 36 (SF-36) Questionnaire v2.0
The SF-36 is a multi-purpose, generic, HRQoL instrument that is composed of 1 multi-item 
scale that assesses 8 health concepts: physical function, physical role limitations, bodily pain, 
general health perceptions, vitality, social functioning, role limitations due to emotional 
problems, and emotional well-being.[31] The instrument has 36 items and requires
approximately 5 minutes to complete.


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Scleroderma Health Assessment Questionnaire (SHAQ)
The SHAQ consists of 8 domains from the HAQ-DI, a HRQoL instrument that measures self-
reported function in 8 domains of activity in 20 weighted responses and a VAS of pain 
experienced in the past week. It additionally measures 5 domains specific to scleroderma 
using a continuous VAS: Raynaud’s phenomenon, digital tip ulcers, lung symptoms, 
gastrointestinal symptoms, and a global patient assessment.[32] The VAS subscales of the 
SHAQ were shown to be significantly correlated with objective parameters,[32] and was 
responsive to change in a cohort and in a Raynaud’s phenomenon trial in SSc.[30, 32] The 
SHAQ requires approximately 5 minutes to complete.
University of California, Los Angeles, Scleroderma Clinical Trial Consortium 
Gastrointestinal Scale (UCLA SCTC GIT) 2.0
The UCLA SCTC GIT 2.0 instrument is a self-reported PRO consisting of 34 items, which 
are revised from the 52-item instrument SSC-GIT version 1.0, and 7 multi-item scales that 
include reflux, distension/bloating, diarrhea, fecal soilage, constipation, emotional well-being,
and social functioning. The validity and reliability of this tool has been supported in a study 
performed in individuals with SSc, which also demonstrated good symptom correlation with 
gastrointestinal diagnoses.[33] The UCLA SCTC GIT 2.0 requires approximately 2 minutes 
to complete.
Patient-Reported Outcomes Measurement Information System (PROMIS)-29
The PROMIS-29 is a validated instrument to measure the health status of SSc patients, 
demonstrating moderate to high correlation with other instruments validated in SSc, including 
the SF-36 physical component score and HAQ-DI.[34] It incorporates 7 core domains from 
the PROMIS questionnaire, which specifically relate to physical, mental, and social health 
aspects of chronic illness: pain, fatigue, depression, anxiety, sleep, and physical function, as 
well as one 11-point rating scale for pain intensity.[34] It contains 8 items with 29 weighted 
responses in total, and requires approximately 5 minutes to complete. 
Frequency of all PROs: Visit 1 (Day 0), Visit 8 (Week 14), Visit 10 (Week 26), Visit 11 
(Week 39), Visit 12 (Week 52), Visit 18 (week 64), and every 3 months thereafter in the main 
treatment phase and long-term extension phase and at a termination visit.
7.6.14
Tender and swollen joint count
This physician-reported tool evaluates 28 joints for swelling and tenderness. This outcome 
measure should be performed by the same physician to assess the burden of joint disease from 
SSc-associated polyarthritis and myopathy. 
A sample form is shown in Appendix 14.3
Frequency: Screening Visit (Visit 0) and Visit 12 (Week 52) and termination visit (not 
needed after V12).
7.6.15
Patient’s and physician’s global assessment - amended
This tool incorporates a self-assessment and physician assessment on the patient’s overall 
health in the prior 1 week using a 010 ordinal scale and a rating of overall SSc-related health 
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Frequency: Visit 1 (Day 0), Visit 10 (Week 26) and Visit 12 (Week 52), termination visit (not 
needed after V12), and visits with limited assessments.118
7.6.16
Patient interference with skin assessment
This self-assessment evaluates the degree in which skin involvement has interfered with the 
patient’s daily activities over the last month on an ordinal scale of 0 (does not limit activity) 
to 10 (very severe limitation). 
Frequency: Visit 1 (Day 0), Visit 10 (Week 26) and Visit 12 (Week 52) and termination visit 
(not needed after V12). 
7.6.17
Tendon friction rubs
Anatomical sites including the hands, wrists, elbows, shoulders, knees and ankles will be 
examined for the presence or absence of tendon friction rubs at the two time points detailed 
below. 
Frequency: Visit 1 (Day 0) and Visit 8 (Week 14). 
7.6.18
Oxygen saturation measurement using forehead pulse oximetry119
Oxygen saturation measurements will be performed in all subjects using non-invasive 
forehead pulse oximetry expressing the SpO2 (peripheral oxygen saturation) percentage. At 
visits with blood pressure measurements to assess orthostatic changes, oxygen saturation will 
be measured pre-dose and post-dose (see Table 7–2, Table 7–3, and Table 7–4). At all other 
visits, oxygen saturation will be measured pre-dose only. 
If the patient receives supplemental oxygen, the amount [L/min] will be recorded in the 
eCRF.
Frequency: Visit 9 (Week 20), Visit 10 (Week 26), Visit 11 (Week 39), Visit 12 (Week 52), 
Visits 13 to 17 (Week 54 to 62), Visit 18 to Visit n (Open-label Extension Period), 
Termination Visit, and 30-day Safety Follow-up.
7.7
Appropriateness of procedures / measurements
All safety and efficacy variables, as well as the methods to measure them, are standard 
variables/ methods in clinical studies and/ or clinical practice.  They are widely used and 
generally recognized as reliable, accurate and relevant.
8.
Statistical methods and determination of sample size
8.1
General considerations
All variables will be analyzed descriptively with appropriate statistical methods: categorical 
variables by frequency tables and continuous variables by sample statistics, ie, mean, standard 
deviation, minimum, median, quartiles (if data are clearly non-normal) and maximum.
If not mentioned otherwise, all statistical tests will be performed with a type I two-sided error 
rate of =5%.
                                                
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Statistical analyses will be performed using SAS (Statistical Analysis System); the version 
used will be specified in the statistical analysis plan (SAP).
8.2
Analysis sets - amended
Efficacy and safety analyses will be performed in patients valid for the full analysis set (FAS).  
This is defined as all patients randomized and treated with study medication.  Investigators 
will be instructed not to make the call to the IxRS system until they are certain the patient is 
valid to be treated with study medication, on the day that study medication is to start.  In that 
way, we expect all patients who are randomized also to be treated, so the FAS population 
would then be consistent with the full intent-to-treat (ITT) definition.
For the primary and secondary exploratory efficacy and safety endpoints, as a supportive 
analysis, a per protocol set (PPS) will also be defined, including patients who meet the major 
inclusion and exclusion criteria at randomization that may affect efficacy, who are not taking 
excluded concomitant medications during the study that could have an effect on efficacy (not 
including rescue120 medication after Week 26), have the mRSS assessed at baseline and at 
least once during the main treatment phase and who are at least 80% compliant with study 
medication.  A full definition of valid for PPS will be given in the SAP.
8.3
Variables
Efficacy variables are provided in Section 7.3 and safety variables are described in 
Section 7.5.
8.4
Statistical and analytical plans
8.4.1
Demographic and other baseline characteristics
Demographic variables and baseline characteristics will be summarized by treatment group 
for both analysis populations, that is, the FAS and PPS.
Medical history findings and AEs will be coded by Medical Dictionary for Regulatory 
Activities (MedDRA) codes and medications by Anatomical Therapeutic Chemical (ATC)
codes (World Health Organization Drug Dictionary [WHO-DD]).
8.4.2
Efficacy - amended
In the efficacy analyses, countries and centers will be clustered by geographic region. The 
decision on country pooling will be made before unblinding. Statistical analyses will be 
adjusted for these countries / geographic regions.
8.4.2.1
Primary endpoint121
The primary analysis will be the change in mRSS from baseline to all assessments post 
baseline up to Week 52 using mixed model repeated measures (MMRM) with baseline mRSS 
as a covariate, fixed effects treatment arm and region, the interaction effect between study 
visit and treatment arm, and patient specific random effects to account for both heterogeneity 
among patients and correlation among measurements taken on the same patient with an 
unstructured covariance assumption.  The main estimand of interest is the treatment difference 
                                                
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between the riociguat and placebo treatment arms at Week 52. The null hypothesis to be 
tested is no difference between riociguat and placebo at this visit.
The model statement is:
Yij = μ + βXi + tk + rl + vj+ (tv)jk + si + εi j
where Yij  is the change from baseline in mRSS to visit j for subject i that is in 
treatment group k and region l; μ is the intercept, β is the baseline covariate effect, Xi
is the baseline mRSS for subject i, tk is the fixed effect of treatment k, rl is the fixed 
effect of region l, vj is the fixed effect of visit j, (tv)jk is the interaction effect of 
treatment k by visit j, si is the random effect of subject i and εi j  ~ Normal(0, σ2) 
represents the residual variance component with corr(ε i j, ε i j’) = ρjj’,  j ≠ j’
As a sensitivity analysis, the MMRM using the above model will also be applied to 
assessments post-baseline up to termination of study medication or initiation of rescue 
medication.  In addition, the MMRM on all assessments will be repeated including additional 
effects time on rescue medication and time on study medication.  MMRM assumes missing at 
random; mRSS by time of patient discontinuation from study medication122 will be 
summarized and further methods using multiple imputation that allow for missing data not at 
random will be investigated.  Details of such methods will be described in the SAP.
An additional univariate sensitivity analysis will look at change in mRSS from baseline to 
Week 52 / last visit using analysis of covariance (ANCOVA) with baseline mRSS as a 
covariate, treatment arm and region as main effects.  Last visit is defined as the last visit on 
treatment which in the case of premature termination of study medication is the termination 
visit.  In the case of rescue123 medication, the last visit is the visit where the decision is made 
to start rescue124 medication with efficacy being assessed prior to escape medication starting.
As a robustness analysis, a stratified (by region) non-parametric Wilcoxon test comparing 
riociguat and placebo will also be performed.  In addition, and consistent with the primary 
analysis, a further ITT sensitivity endpoint analysis of change in mRSS to Week 52 / last visit 
will include all measurements recorded up to Week 52 or the termination visit, including 
those while rescue125 medication was taken or if the patient returned after termination for a 
later visit up to Week 52.
Rules for the imputation of missing values where the patient discontinues the study 
(withdrawal of consent or death) or the study medication126 for the univariate analysis, null / 
alternative hypothesis statements, and model statements in mathematical notation will be 
specified in the SAP.  Two-sided 95% confidence intervals of treatment (riociguat compared 
to placebo) differences will be calculated in addition to the statistical significance testing.
                                                
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8.4.2.2
Secondary and exploratory endpoints127
General aspects
The other secondary and exploratory efficacy variables measured on a continuous or semi-
continuous scale will analyzed using the MMRM, ANCOVA, and stratified Wilcoxon test, as 
for the mRSS above.
The time to first mRSS progression and regression and clinical outcome parameters will be 
analyzed using the log-rank test comparing between treatment groups.
Any binary outcomes, such as the predicted CRISS outcome, will be analyzed using Mantel-
Haenzel weights, stratified by region.  Also as a sensitivity analysis in addition to the time to 
event analysis, the occurrence of the events mRSS progression and regression and clinical 
outcome parameters will be analyzed using this method.
Details on any descriptive subgroup analyses will be specified in the SAP.  These will include 
gender and region.
Hierarchical testing of secondary endpoints128
The following secondary endpoints will be tested in a hierarchical fashion at a 2-sided 5% 
level, only if the primary endpoint of mRSS is shown to be statistically significant at a 2-sided 
5% level.
The following order of testing will be applied:

CRISS

HAQ-DI (health assessment questionnaire-disability index)

Patient's global assessment

Physician's global assessment

FVC % predicted
For example, if CRISS is statistically significant at a 2-sided 5% level, then the HAQ-DI will 
be tested, if not the testing procedure will be stopped. This step is repeated further down the 
list of the 5 secondary endpoints until a non-statistically significant endpoint is reached. 
These particular secondary endpoints were chosen to be tested in this hierarchical fashion, 
because the mRSS and the above additional, secondary variables were considered to have the 
greatest face validity when designing the CRISS [41].
                                                
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American College of Rheumatology Combined Response Index for Systemic Sclerosis129
The key secondary endpoint will be the CRISS at Week 52.130
Application of CRISS algorithm in a randomized clinical trial is a 2-step process. Firstly, 
evaluate if patients have met the criterion for not-improved. If yes, these patients are assigned 
a probability score of 0.0. For the remaining patients, calculate the probability based on 
change in 5 measures: mRSS, FVC %, HAQ-DI, patient’s global assessment, and physician's 
global assessment, where each measure has a probability score between 0 and 1 [41]. 
In Step 1, a patient is clinically evaluated to determine whether the patient has improved or 
not.  Expert consensus on the definition of a patient who is not improved during a trial is the 
following:
A patient is considered not improved and is assigned a probability score of improving equal to 
0.0, irrespective of improvement on other core items, if he/she develops: 
1. New scleroderma renal crisis, 
2. Decline in FVC % predicted ≥15% (relative), confirmed by another FVC % within a 
month, high resolution computed tomography (HRCT) to confirm interstitial lung 
disease (if previous HRCT did not show interstitial lung disease) and FVC % 
predicted below 80% predicted (attributable to SSc), 
3. New onset of left ventricular failure (defined as ejection fraction ≤45%) or new onset 
of pulmonary arterial hypertension requiring treatment (attributable to SSc).
If the patient is determined to exhibit improvement in Step 1 (ie, not assigned a 0.0), Step 2 
involves computing the predicted probability of improving (a score between 0.0 and 1.0, 
inclusive) for each patient using the equation:
	.	.∗∆.∗∆%.∗∆ .∗∆! ".∗∆#$%!&'
	.	.∗∆.∗∆%.∗∆ .∗∆! ".∗∆#$%!&'
where ∆MRSS indicates the change in mRSS from baseline to Week 52, ∆FVC denotes the 
change in FVC % predicted from baseline to Week 52, ∆Pt-glob indicates the change in patient 
global assessment, ∆MD-glob denotes the change in physician global assessment, and ∆HAQ-DI is 
the change in HAQ-DI131. Note that all changes are absolute changes (Time2 – Timebaseline) 
and that the physician’s and patient’s global assessment was measured on the Likert scale 
ranging from 0 to 10, where 0 = excellent, and 10 = extremely poor.
Hence, the CRISS is comprised of 5 variables: mRSS, FVC % predicted, patient’s global 
assessment, physician’s global assessment, and HAQ-DI from the SHAQ patient reported 
outcome. Combined, the 5 variables explained 89.3% of the variability in the data. 
Individually, when used in a single-variable logistic regression model, mRSS explained 
66.3% of the variation, FVC % predicted explained 36.1% of the variation, physician global 
assessment explained 24.5% of the variation, patient global assessment explained 23.7% of 
the variation, and HAQ-DI explained 28.5% of the variation. A change in mRSS, FVC % 
predicted and HAQ-DI are strong indicators of whether a patient is likely to be improved or 
not. In each scenario, a decrease of mRSS or HAQ-DI from baseline to Week 52132and an 
                                                
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increase in FVC % predicted corresponds to very high probabilities of improving. For 
patient’s global and physician’s global assessment, the association between probability of 
improving and change in these 2 core components is less evident. Subjects for which the 
predicted probability is greater or equal to 0.60 are considered improved, while subjects for 
which the predicted probability is below 0.60 are considered not improved. The 2 groups 
(riociguat vs. placebo) can then be compared in a 2x2 table using appropriate significance 
tests. The predicted probabilities obtained using the CRISS can also be assessed as a 
continuous variable and the distributions of the probability of improving for patients on drug 
vs. placebo can be compared using non-parametric tests [41]. In this study, the CRISS 
outcome will be analyzed using Mantel-Haenzel weights, stratified by region, and 
additionally, the stratified Wilcoxon test will be used as non-parametric test.
However, Step 2 assumes that there is complete data; ie, all 5 components of the CRISS are 
fully recorded at Week 52. If the subject discontinues from study drug before Week 52, or 
has one or more missing components of the CRISS at this visit, then a mixed model repeated 
measures (MMRM) analysis will be implemented to estimate the value or values for those 
components at Week 52. These estimates will then we used to calculate the CRISS score at 
Week 52 as given in Step 2. Subjects for which the predicted probability is greater or equal to 
0.60 are considered improved, while subjects for which the predicted probability is below 
0.60 are considered not improved. [41] Further details will be provided in the statistical 
analysis plan.
8.4.3
Safety - amended
The incidence of treatment-emergent AEs (TEAEs) 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 drug up to 2 days after end of treatment with study drug.  Further 
tables will be produced for serious and/or drug-related treatment-emergent AEs, also 
treatment-emergent AEs leading to discontinuation of study drug and of special safety 
interest.  The incidence of AEs during pre-treatment and during follow-up (ie, AEs occurring 
more than 2 days after end of treatment with study drug) will be tabulated separately. In 
addition to the summary tables of AEs, listings of SAEs, AEs leading to discontinuation of 
study drug and AEs of special safety interest will be provided.
Mortality in the study will be summarized descriptively. Any deaths in the study period will 
be listed, with day of death relative to start and stop of study drug and cause of death.
Mortality is also defined as an exploratory efficacy parameter, and so being a binary outcome 
the difference in occurrence between treatment groups will be analyzed as described in 
Section 8.4.2.
The safety evaluation of laboratory data will include:

Incidence rates of treatment-emergent laboratory values outside of normal range

Incidence rates of pre-specified laboratory data abnormalities

Descriptive analysis of continuous laboratory parameters and their changes from 
baseline by treatment group and visit.
Descriptive analysis of vital signs and their changes from baseline will be performed by 
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rate measurements for the assessment of orthostatic changes will be performed by treatment 
group and visit.133
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 treatment group and visit will also be presented.
8.4.4
Pharmacokinetics
For the investigation of PK, the plasma concentrations of riociguat and its main metabolite 
M-1 (BAY 60-4552) will be determined at the times given in Section 7.4 using a sparse 
sampling approach.
The data processing and the statistical analysis will be performed in accordance with the 
sponsor’s current guidelines.
Riociguat and its main metabolite M-1 (BAY 60-4552) peak and trough concentrations will 
be summarized by visit, separated according to actual dose.
8.5
Planned interim analyses - amended
A formal interim analysis of the main treatment phase is not planned.  The main treatment 
phase will be unblinded for data analysis when the last patient completes the main treatment 
phase (Visit 12)134 and the database for the main treatment phase is declared clean, whichever 
occurs last.
The first safety update will be performed on the long-term extension phase when the last 
patient completes 24 weeks of treatment (Visit 19)135.  Safety updates then will be performed 
at least yearly until the last patient completes the entire study, when a final analysis will be 
conducted.
8.6
Determination of sample size - amended
There is lack of positive trials in dcSSc.  Most trials have used change in mRSS to Month 6 or 
Month 12 as the primary endpoint, and 4 published articles are referenced for the estimate of 
variability in this study (Table 8–1).
                                                
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Table 8–1
References for estimate of variability
Reference
Trial treatment
Active arm SD
Placebo arm SD
Postlethwaite (2008)[35]
Collagen 0 – 12 months
7.6
7.7
Khanna (2009)[26]
Relaxin 0 – 24 weeks
7.0
7.0
Merkel (2012)[36]
0 – 6 month meta-analysis
7.2
0 – 12 month meta-analysis
8.4
Amjadi (2009)[37]
D-Pen
8.6
Relaxin
7.0
Collagen
7.1
Abbreviations:  D-Pen = D-penicillamine; SD = standard deviation.
Taking these sources into account, a reasonable upper bound for the estimate of the standard 
deviation to be used in the sample size calculation of this study has been taken as 8.0.
One of the components of exploratory efficacy measure136 mRSS progression is a 5 point or 
more deterioration from baseline to any assessment in the 12 month study period, this being 
considered a clinically meaningful change [14].  For the primary sample size calculation 
based on change in mRSS from baseline to Week 52, a slightly more conservative 4-point 
difference between riociguat and placebo has been taken, given that the trials referenced 
above never achieved a 5-point, or even a 4-point, superiority of active over placebo.
The primary efficacy estimand in this study will be change in mRSS from baseline to 
Week 52. Assuming a standard deviation of 8 points, a power of between 70% and 80% and a 
two-sided significance level of 5%, with a 1:1 randomization, then to detect a 
placebo-adjusted difference of 4 points, between 51 and 64 patients in each treatment group, a 
total of 102 to 128 patients, would be required to be valid for the ITT analysis (see Table 8–
2). Allowing for up to two patients randomized and not treated, approximately 130 
randomized patients are planned.137
Table 8–2
Power calculations: power varying from 70% to 80% in 2% stages138
N per group
51
53
56
58
61
64
Total N
102
106
112
116
122
128
Power (%)
70
72
74
76
78
80
N = number of patients
Sources of these sample size and power calculations are nQuery version 7.0, module 
MTT0-1.139
                                                
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9.
Data handling and quality assurance
9.1
Data recording
It is the expectation of the sponsor that all data entered into the eCRF has source 
documentation available at the site.  The site must implement processes to ensure this 
happens.  A source document checklist will be used at the site to identify the source data for 
all data points collected and the monitor will work with the site to complete this.
Specific data may be entered directly into the eCRF according to instructions provided in the 
eCRF completion manual. 
Data recorded from “only screened patients (screening failures)”
Data of 'only screened patients' will be recorded at least as source data, as far as the reason for 
the premature discontinuation is identifiable.  At minimum, data to be recorded in the eCRF
are demographic information (patient number, date of birth/age, sex and ethnicity), inclusion 
and exclusion criteria, the reason for premature discontinuation and date of last visit.  These 
data will be transferred to the respective database.
For screening failures with an SAE, the following additional data should be collected in the 
eCRF, in addition to demographic information, primary reason for discontinuation and date of 
last visit:
All information about the SAE
All information related to the SAE such as: 

Concomitant medication

Medical history

Other information needed for SAE complementary page
9.2
Monitoring
In accordance with applicable regulations, GCP, and sponsor’s/clinical research 
organization’s (CRO’s) procedures, monitors will contact the site prior to the start of the 
study to review with the site staff the protocol, study requirements, and their responsibilities 
to satisfy regulatory, ethical, and sponsor’s requirements. When reviewing data collection 
procedures, the discussion will also include identification and documentation of source data 
items.
The sponsor/designee will monitor the site activity to verify that the:

Data are authentic, accurate and complete

Safety and rights of patients are being protected

Study is conducted in accordance with the currently approved protocol 
(including study treatment being used in accordance with the protocol)

Any other study agreements, GCP, and all applicable regulatory requirements are met.
The investigator and the head of the medical institution (where applicable) agrees to allow the 
monitor direct access to all relevant documents.


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9.3
Data processing
The data collection tool for this study will be a validated electronic system called Medidata 
Rave. Patient data necessary for analysis and reporting will be entered/ transmitted into a 
validated database or data system (eg, TOSCA V4 3_1_1; SAS 9.2).  Clinical data 
management will be performed in accordance with applicable sponsor’s standards and data 
cleaning procedures. This is applicable for data recorded on eCRF as well as for data from 
other sources (eg, IxRS, laboratory, ECG).
For data coding (eg, AEs, medication), internationally recognized and accepted dictionaries 
will be used. After its initial release for biometrical analysis, the clinical database is planned 
to be re-opened for the inclusion of the following additional data: eg, PK data, biomarker140
data.
9.4
Audit and inspection
To ensure compliance with GCP and regulatory requirements, a member of the sponsor’s (or a 
designated CRO’s) quality assurance unit may arrange to conduct an audit to assess the 
performance of the study at the study site and of the study documents originating there.  The 
investigator/institution will be informed of the audit outcome.
In addition, inspections by regulatory health authority representatives and IEC(s)/IRB(s) are 
possible.  The investigator should notify the sponsor immediately of any such inspection.
The investigator/institution agrees to allow the auditor or inspector direct access to all relevant 
documents and allocate his/her time and the time of his/her staff to the auditor/inspector to 
discuss findings and any issues.  Audits and inspections may occur at any time during or after 
completion of the study.
9.5
Archiving
Essential documents shall be archived safely and securely in such a way that ensures that they 
are readily available upon authorities’ request.
Patient (hospital) files will be archived according to local regulations and in accordance with 
the maximum period of time permitted by the hospital, institution or private practice.  Where 
the archiving procedures do not meet the minimum timelines required by the sponsor, 
alternative arrangements must be made to ensure the availability of the source documents for 
the required period.
The investigator/institution notifies the sponsor if the archival arrangements change 
(eg, relocation or transfer of ownership).
The investigator site file is not to be destroyed without the sponsor’s approval.
The contract with the investigator/institution will contain all regulations relevant for the study 
center.
                                                
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10.
Premature termination of the study
The sponsor has the right to close this study (or, if applicable, individual segments thereof 
[eg, treatment arms; dose steps; centers]) at any time, which may be due but not limited to the 
following reasons: 

If risk-benefit ratio becomes unacceptable owing to, for example,
- Safety findings from this study (eg, SAEs)
- Results of any interim analysis
- Evaluation of risk-benefit at any time in the study where a lack of substantial 
treatment benefit is shown
- Results of parallel clinical studies
- Results of parallel animal studies 
(on eg, toxicity, teratogenicity, carcinogenicity or reproduction toxicity).

If the study conduct (eg, recruitment rate; drop-out rate; data quality; protocol 
compliance) does not suggest a proper completion of the trial within a reasonable time 
frame.
The investigator has the right to close his/her center at any time.
For any of the above closures, the following applies:

Closures should occur only after consultation between involved parties.  Final decision 
on the closure must be in writing.

All affected institutions (eg, IEC(s)/IRB(s); competent authority(ies); study center; 
head of study center) must be informed as applicable according to local law.

All study materials (except documentation that has to remain stored at site) must be 
returned to the sponsor.  The investigator will retain all other documents until 
notification given by the sponsor for destruction.

In case of a partial study closure, ongoing patients, including those in post study 
follow-up, must be taken care of in an ethical manner.
Details for individual patient's discontinuation141 can be found in Section 5.2.1.
11.
Ethical and legal aspects
11.1
Ethical and legal 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 
GCP guidelines and under the guiding principles detailed in the Declaration of Helsinki.  The 
study will also be carried out in keeping with applicable local law(s) and regulation(s).
Documented approval from appropriate IEC(s)/IRBs will be obtained for all participating 
centers/countries before start of the study, according to GCP, local laws, regulations and 
organizations.  When necessary, an extension, amendment or renewal of the Ethics 
                                                
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Committee (EC)/IRB approval must be obtained and also forwarded to the sponsor.  The 
responsible unit (eg, EC/IRB, head of the study center/medical institution) must supply to the 
sponsor, upon request, a list of the EC/IRB members involved in the vote and a statement to 
confirm that the EC/IRB is organized and operates according to GCP and applicable laws and 
regulations.
Strict adherence to all specifications laid down in this protocol is required for all aspects of 
study conduct; the investigator may not modify or alter the procedures described in this 
protocol.  
Modifications to the study protocol will not be implemented by either the sponsor or the 
investigator without agreement by both parties.  However, the investigator or the sponsor may 
implement a deviation from, or a change of, the protocol to eliminate an immediate hazard(s) 
to the trial subjects without prior IEC/IRB/sponsor approval/favorable opinion.  As soon as 
possible, the implemented deviation or change, the reasons for it and if appropriate the 
proposed protocol amendment should be submitted to the IEC/IRB/head of medical 
institution/sponsor.  Any deviations from the protocol must be explained and documented by 
the investigator.
Details on discontinuation of the entire study or parts thereof can be found in Section 10.
11.2
Patient information and consent
All relevant information on the study will be summarized in an integrated patient information 
sheet and informed consent form provided by the sponsor or the study center.  A sample 
patient information and informed consent form is provided as a document separate to this 
protocol.
In addition there will be a Declaration of Objection to the Collection of Study Data after 
Withdrawal of Consent and the Information Sheet & Informed Consent Form for Collection 
of Data on Pregnancy and Birth.
Based on this patient information sheet, the investigator or designee will explain all relevant 
aspects of the study to each patient / legal representative or proxy consenter (if the patient is 
under legal protection), prior to his/her entry into the study (ie, before any examinations and 
procedures associated with the selection for the study are performed or any study-specific data 
is recorded on study-specific forms).
The investigator or designee will also mention that written approval of the IRB/IEC has been 
obtained.
Each patient / legal representative or proxy consenter will have ample time and opportunity to 
ask questions and will be informed about the right to withdraw from the study at any time 
without any disadvantage and without having to provide reasons for this decision.
Only if the patient / legal representative or proxy consenter voluntarily agrees to sign the 
informed consent form and has done so, may he/she enter the study.  Additionally, the 
investigator and other information provider (if any) will personally sign and date the form.  
The patient / legal representative or proxy consenter will receive a copy of the signed and 
dated form.
The signed informed consent statement is to remain in the investigator site file or, if locally 
required, in the patient’s note/file of the medical institution.


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In the event that informed consent is obtained on the date that baseline study procedures are 
performed, the study record or patient’s clinical record must clearly show that informed 
consent was obtained prior to these procedures.
1. If the patient is not capable of providing a signature, a verbal statement of consent can 
also be given in the presence of an impartial witness (independent of the sponsor and the 
investigator).  This is to be documented by a signature from the informing physician as 
well as by a signature from the witness.
2. For adults under legal protection, consent shall be given by the legal guardian(s).  The 
consent of an adult under legal protection shall also be requested where such a person is 
able to express his/her own will.  His/her refusal or the withdrawal of his/her consent may 
not be disregarded.
The informed consent form and any other written information provided to patients / legal 
representatives or proxy consenters will be revised whenever important new information 
becomes available that may be relevant to the patient’s consent, or there is an amendment to 
the protocol that necessitates a change to the content of the patient information and / or the 
written informed consent form.  The investigator will inform the patient / legal representative 
or proxy consenter of changes in a timely manner and will ask the patient to confirm his/her 
participation in the study by signing the revised informed consent form.  Any revised written 
informed consent form and written information must receive the IEC/IRB`s approval / 
favorable opinion in advance of use.
11.3
Publication policy
The sponsor is interested in the publication of the results of every study it performs.  
All relevant aspects regarding publication will be part of the contract between the sponsor and 
the investigator/institution.
The sponsor has made the information regarding the study protocol publicly available on the 
internet at www.clinicaltrials.gov.  
11.4
Compensation for health damage of patients / insurance
The sponsor maintains clinical trial insurance coverage for this study in accordance with the 
laws and regulations of the country in which the study is performed.
11.5
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 eCRF, 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.  As part of 
the informed consent process, the patients will be informed in writing that representatives of 
the sponsor, IEC/IRB, or regulatory authorities may inspect their medical records to verify the 
information collected, and that all personal information made available for inspection will be 
handled in strictest confidence and in accordance with local data protection laws.
If the results of the study are published, the patient’s identity will remain confidential.


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The investigator will maintain a list to enable patients to be identified.


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12.
Reference list - amended142,143
1. Van den Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall A, et al. 
2013 Classification criteria for systemic sclerosis. Arthritis Rheum. 2013; 65:2737-
2747.
2. Chatterjee S. Systemic scleroderma. Cleveland Clinic Center for Continuing 
Education. 
http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/rheumatolog
y/systemic-sclerosis/. Accessed on 29 Dec 2013.
3. LeRoy EC, Black C, Fleischmajer R, et al: Scleroderma (systemic sclerosis): 
Classification, subsets and pathogenesis. J Rheumatol. 1988; 15: 202-205.
4. Mayes MD, Lacey JV, Beebe-Dimmer K, Gillespie BW, Cooper B, Laing TK, 
Schottenfeld D. Prevalence, incidence, survival, and disease characteristics of 
systemic sclerosis in a large US population. Arthritis Rheum. 2003; 48(8):2246-2255.
5. Varga J, Bashey RI. Regulation of connective tissue synthesis in systemic sclerosis. 
Int Rev Immunol. 1995;12:187-199.
6. Hesselstrand R, Scheja A, Akesson A. Mortality and causes of death in a Swedish 
series of systemic sclerosis patients. Ann Rheum Dis. 1998; 57:682-686.
7. Subcommittee for Scleroderma Criteria of the American Rheumatism Association 
Diagnostic and Therapeutic Criteria Committee. Preliminary criteria for the 
classification of systemic sclerosis (scleroderma). Arthritis Rheum. 1980;23:581–590.
8. Beyer C, Reich N, Schindler SC, Akhmetshina A, Dees C, Tomcik M, et al. 
Stimulation of soluble guanylate cyclase reduces experimental dermal fibrosis. Ann 
Rheum Dis. 2012; 71:1019-1026.
9. Beyer C, Zenzmaier C, Palumbo-Zerr K, Mancuso R, Distler A, Dees C, Zerr P, et al. 
Stimulation of the soluble guanylate cyclase (sGC) inhibits fibrosis by blocking non-
canonical TGFβ signalling. Ann Rheum Dis. 2014 Feb 23 [Epub ahead of print].
10. Chu AJ, Prasad JK. Up-regulation by human recombinant transforming growth factor 
β-1 of collagen production in cultured dermal fibroblasts is mediated by the inhibition 
of nitric oxide signaling. J Am Coll Surg. 1999; 188:271-280.
11. Evgenov OV, Zou L, Zhang M, Mino-Kenudson M, Mark EJ, Buys ES, et al. Nitric 
oxide-independent stimulation of soluble guanylate cyclase attenuates pulmonary 
fibrosis. BMC Pharmacol. 2011;11(Suppl 1):O9 (abstract).
12. Geschka S, Kretschmer A, Sharkovska Y, Evgenov O, Lawrenz B, Hucke A et al. 
Soluble guanylate cyclase stimulation prevents fibrotic tissue remodeling and 
improves survival in salt-sensitive Dahl rats. PLoD One. 2011;6(7):e21853.
13. Sharkovska Y, Kalk P, Lawrenz B, Godes M, Hoffman LS, Wellkisch K et al. Nitric 
oxide-independent stimulation of soluble guanylate cyclase reduces organ damage in 
experimental low-renin and high-renin models. J Hypertens. 2010 Aug;28(8):1666-
1675.
                                                
142 References 22, 23, 24, 39, and 40 were added per Amendment 1
143 References 41 and 40 were added per Amendment 4


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14. Maurer B, Graf N, Michel BA, Müller-Ladner U, Czirják L, Denton CP, Tyndall A, 
Metzig C, Lanius V, Khanna D, Distler O. Prediction of worsening of skin fibrosis in 
patients with diffuse cutaneous systemic sclerosis using the EUSTAR database. Ann 
Rheum Dis, 2014 - http://ard.bmj.com/content/early/2014/06/30/annrheumdis-2014-
205226.full.
15. Khanna. Recombinant human relaxin in the treatment of systemic sclerosis with 
diffuse cutaneous involvement: a randomized, double-blind, placebo-controlled trial. 
Arthritis Rheum. 2009, 60(4):1102-11.
16. Pope JE, Bellamy N, Seibold JR, Baron M, Ellman M, Carette S, Smith CD, Chalmers 
IM, Hong P, O'Hanlon D, Kaminska E, Markland J, Sibley J, Catoggio L, Furst DE. A 
randomized, controlled trial of methotrexate versus placebo in early diffuse 
scleroderma. Arthritis Rheum. 2001, 44:1351-8.
17. Amjadi S, Maranian P, Furst DE, Clements PJ, Wong WK, Postlethwaite AE, Khanna 
PP, Khanna D. Course of the modified Rodnan skin thickness score in systemic 
sclerosis clinical trials: analysis of three large multicenter, double-blind, randomized 
controlled trials. Arthritis Rheum. 2009, 60(8):2490-8.
18. Khanna D, Lovell DJ, Giannini E, Clements PJ, Merkel PA, Seibold JR, Matucci-
Cerinic M, Denton CP, Mayes MD, Steen VD, Varga J, Furst DE. Development of a 
provisional core set of response measures for clinical trials of systemic sclerosis. Ann
Rheum Dis 2008;67:703–709.
19. Walker KM, Pope J, participating members of the Scleroderma Clinical Trials 
Consortium (SCTC) and Canadian Scleroderma Research Group (CSRG). Treatment 
of systemic sclerosis complications: what to use when first-line treatment fails—a 
consensus of systemic sclerosis experts. Semin Arthritis Rheum. 2012;42:42-55.
20. Kowal-Bielecka, Landewe R, Avouac J, et al. EULAR recommendations for the 
treatment of systemic sclerosis: a report from the EULAR Scleroderma Trials and 
Research group (EUSTAR). Ann Rheum Dis 2009;68:620-628.
21. Nagaraja V, Denton CP, Khanna D. Old medications and new targeted therapies in 
systemic sclerosis. Rheumatology. 2014 July 26 [Epub ahead of print].
22. Regev A, Seeff LB, Merz M, Ormarsdottir S, Aithal GP, Gallivan J, Watkins PB. 
Causality Assessment for Suspected DILI During Clinical Phases of Drug 
Development. Drug Saf (2014) 37 (Suppl 1):S47–S56.
23. NICE clinical guideline 182 “Chronic kidney disease: early identification and 
management of chronic kidney disease in adults in primary and secondary care”, 
issued in July 2014 (guidance.nice.org.uk/cg182). 
24. MacGregor MS and Taal MW. Clinical Practice Guidelines - Detection, Monitoring 
and Care of Patients with CKD. UK renal association, 5th edition, 2011 
(www.renal.org/guidelines).
25. Thomas G. Pickering, J.E.H., Lawrence J. Appel, Bonita E. Falkner, John Graves, 
Martha N. Hill, Daniel W. Jones, Theodore Kurtz, Sheldon G. Sheps, Edward J. 
Roccella, AHA Scientific Statement: Recommendations for Blood Pressure 
Measurement in Humans and Experimental Animals. Hypertension. 2005;(45):142-
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26. Khanna D, Merkel PA. Outcome measures in systemic sclerosis: an update on 
instruments and current research. Curr Rheumatol Rep. 2007;9:151-157.
27. Khanna D, Clements PJ, Furst DE, Korn JH, Ellman M, Rothfield N, et al. A 
randomized, double-blind, placebo-controlled trial of recombinant human relaxin in 
the treatment of systemic sclerosis with diffuse scleroderma. Arthritis Rheum 
2009;60(4):1102-1111.
28. Denton C, Merkel PA, Furst DE, Khanna K, Emery P, et al. Recombinant human anti-
transforming growth factor β1 antibody therapy in systemic sclerosis: a multicenter, 
randomized, placebo-controlled phase I/II trial of CAT-192. Arthritis Rheum
2007;56:323-333.
29. Gladue H, Maranian P, Paulus H, Khanna D. Evaluation of test characteristics for 
outcome measures used in Raynaud’s phenomenon clinical trials. Arthritis Care & 
Res. 2013;65(4):630-636.
30. Merkel PA, Herlyn K, Martin RW, Anderson JJ, Mayes MD, Bell P, et al. 
Scleroderma Clinical Trials Consortium. Measuring Disease Activity and Functional 
Status in Patients with Scleroderma and Raynaud’s Phenomenon. Arthritis Rheum 
2002;46:2410-2420.
31. Ware JE, Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. 
Conceptual Framework and Item Selection. Med Care. 1992;30(6):473-483.
32. Steen VD, Medsger TA. The value of the Health Assessment Questionnaire and 
Special Patient-Generated Scales to Demonstrate Change in Systemic Sclerosis 
Patients Over Time. Arthritis Rheum 1997;40:1984-1991.
33. Khanna D, Hays RD, Maranian P, Seibold JR, Impens A, Mayes MD, et al. Reliability 
and validity of the University of California, Los Angeles Scleroderma Clinical Trial 
Consortium Gastrointestinal Tract Instrument. Arthritis Rheum 2009;61(9):1257-
1263.
34. Hinchcliff M, Beaumont JL, Thavarajah K, Varga J, Chung A, Podulsky S, et al. 
Validity of two new patient-reported outcome measures in systemic sclerosis:  Patient-
Reported Outcomes Measurement Information System 29-Item Health Profile and 
Functional Assessment of Chronic Illness Therapy–Dyspnea Short Form. Arthritis 
Care & Res 2011;63(11):1620-1628.
35. Postlethwaite AE, Wong WK, Clements P, Chatterjee S, Fessler BJ, Kang AH, et al. A 
multicenter, randomized, double-blind, placebo-controlled trial of oral type I collagen 
treatment in patients with diffuse cutaneous systemic sclerosis:  I. Oral type I collagen 
does not improve skin in all patients, but may improve skin in late-phase disease. 
Arthritis Rheum 2008;58 (6):1810-1822.
36. Merkel PA, Silliman NP, Clements PJ, Denton CP, Furst DE, Mayes MD, et al. 
Patterns and predictors of change in outcome measures in clinical trials in scleroderma 
an individual patient meta-analysis of 629 subjects with diffuse scleroderma. Arthritis 
Rheum 2012;64(10): 3420-3429.
37. Amjadi S, Maranian P, Furst DE, Clements PJ, Wong WK, Postlethwaite AE, et al. for 
the investigators of the D-Penicillamine, human recombinant relaxin, and oral bovine 
type I collagen clinical trials. Course of modified Rodnan skin score in systemic 


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sclerosis clinical trials:  analysis of 3 large multicenter, randomized clinical trials. 
Arthritis Rheum 2009;60(8):2490-2498.
38. Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the 
oesophagus for bleeding oesophageal varices. Br J Surg.1973;60:646-649.
39. Steen VD and Medsger TA. Long-Term Outcomes of Scleroderma Renal Crisis. Ann 
Intern Med. 2000;133:600-603.
40. Shanmugam VK and Steen VD. Renal disease in scleroderma: an update on 
evaluation, risk stratification, pathogenesis and management. Curr Opin Rheumatol. 
2012 November ; 24(6): 669–676.
41. Khanna D, Berrocal VJ, Giannini EH, Seibold JR, Merkel PA, Mayes MD, et al. The 
American College of Rheumatology Provisional Composite Response Index for 
Clinical Trials in Early Diffuse Cutaneous Systemic Sclerosis. Arthritis Rheumatol. 
2016; 68(2):299-311.
42. Khanna D, Lovell DJ, Giannini E, Clements PJ, Merkel PA, Seibold JR, et al. 
Development of a provisional core set of response measures for clinical trials of 
systemic sclerosis. Ann.Rheum Dis. 2008;67(5):703-709.


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13.
Protocol amendments
13.1
Amendment 1
Amendment 1 was approved on 4 FEB 2015.
13.1.1
Overview of changes to the study
Due to regulatory feedback, additional safety laboratory monitoring is being included for 
patients entering the study with elevated liver transaminases or bilirubin, or with eGFR 
between 15-29 mL/min/1.73 m2.  These patients were not included in the riociguat pivotal 
trials in pulmonary hypertension.  While there is no evidence of liver or renal toxicity with 
riociguat, there is an increased risk for adverse events related to the mechanism of action of 
the drug, such as hypotension, due to a higher plasma concentration caused by impaired 
riociguat metabolism/elimination by liver and kidneys.
The list of immunosuppressant therapies requiring washout before inclusion in the study was 
also expanded to account for standard of care treatment among the participating countries.
Safety laboratory tests were added at Visit 10, along with other safety assessments such as 
ECG and lung function tests to be performed.  Measurement of glutamate dehydrogenase 
(GLDH) will be deleted from the list of standard safety parameters because the review of data 
from previous studies and the ongoing long-term studies did not show any clinically 
significant changes of this parameter in patients treated with riociguat.
Typos and inconsistencies were also corrected, as well as re-wording to make the protocol 
clearer.
13.1.2
Changes to the protocol text
Section – Title page
Old text:
Sponsor’s medical expert:
 
Bayer Healthcare UK
Strawberry Hill
Newbury, RG14 1JA
United Kingdom
Phone: 
New text:
Sponsor’s medical expert:
Bayer Healthcare Company Ltd
Bayer Center,
No.27, Dong San Huan North Road, Chaoyang District, 
Beijing, 100020 , China
Tel: 
Fax:
 
PPD
PPD
PPD
PPD
PPD


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1.1.2.2
Preclinical Data
Old text:
In summary, investigations of the anti-fibrotic efficacy of sGC stimulators riociguat and 
BAY 41-2272 showed that these agents act dose-dependently:

reduced collagen production in human dermal fibroblasts  

reduced fibroblast-to-myofibroblast differentiation of human dermal fibroblasts

prevented TGF-ß-induced skin fibrosis in vivo

prevented skin fibrosis in bleomycin model

reduced established skin fibrosis in genetic TSK-1 model

promoted wound healing in TSK-1 mice.
New text:
In summary, investigations of the anti-fibrotic efficacy of sGC stimulators riociguat and 
BAY 41-2272, another sGC compound, showed that these agents act dose-dependently:

reduced collagen production in human dermal fibroblasts  

reduced fibroblast-to-myofibroblast differentiation of human dermal fibroblasts

prevented TGF-ß-induced skin fibrosis in vivo

prevented skin fibrosis in bleomycin model

reduced established skin fibrosis in genetic TSK-1 model

promoted wound healing in TSK-1 mice.
2
Study objectives
Old text:
The secondary objectives of this study are to assess the efficacy of treatment with riociguat 
administered TID as compared with placebo in terms of: 

Efficacy:
o
Need for Escape Therapy (see definition in Section 6.9)
New text:
The secondary objectives of this study are to assess the efficacy of treatment with riociguat 
administered TID as compared with placebo in terms of: 

Efficacy:
o
Need for Rescue Therapy (see definition in Section 6.9)


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3.
Investigators and other study personnel
Old text:
Sponsor’s medical expert:
Name:
 
Address:
Bayer Healthcare UK
Strawberry Hill
Newbury, RG14 1JA
United Kingdom
Phone: 
New text:
Sponsor’s medical expert:
Name:
Address:
Bayer Healthcare Company Ltd
Bayer Center, 
No.27, Dong San Huan North Road, Chaoyang District, 
Beijing, 100020, China
Tel: 
Fax: 
4.1.2 Main treatment phase (Week 0 - Week 52)
Old text:
Maintenance period (Visits 7 to 12)
The overall duration of the main treatment phase is 52 weeks, including the dose titration 
period.  At the end of the dose titration period (Week 10) the patient’s maintenance dose will 
be determined using the treatment algorithm above.  No further increase in dose will be 
allowed.  The established dose will then be taken as the “optimal dose” to be administered for 
the remaining duration of the main treatment phase (up to Week 52).
Dose reductions for safety reasons (eg, in case of any treatment-emergent adverse event [AE]) 
are allowed, but a subsequent dose increase during the maintenance period is not permitted.
From Week 26 (Visit 10), patients will have the opportunity to add “escape therapy”, 
consisting of immunosuppressant drugs, to their randomized study medication if they meet 
certain criteria for worsening skin or pulmonary disease.  Please refer to Section 6.9 for 
further details.
New text:
Maintenance period (Visits 7 to 12)
The overall duration of the main treatment phase is 52 weeks, including the dose titration 
period.  At the end of the dose titration period (Week 10) the patient’s maintenance dose will 
be determined using the treatment algorithm above.  No further increase in dose will be 
PPD
PPD
PPD
PPD
PPD


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allowed.  The established dose will then be taken as the “optimal dose” to be administered for 
the remaining duration of the main treatment phase (up to Week 52).
Dose reductions for safety reasons (eg, in case of any treatment-emergent adverse event [AE]) 
are allowed, but a subsequent dose increase during the maintenance period is not permitted.
From Week 26 (Visit 10), patients will have the opportunity to add “rescue therapy”, 
consisting of immunosuppressant drugs, to their randomized study medication if they meet 
certain criteria for worsening skin or pulmonary disease.  Please refer to Section 6.9 for 
further details.
4.1.4 Termination visit and safety follow-up 
Old text:
....
If the patient discontinues study participation prematurely during the main treatment phase 
(Week 0 – Week 52) he/she will be invited to come for limited assessments (mRSS, FVC, 
DLCO and patient-reported outcomes [PROs]) at Week 12, Week 26, Week 39, and Week 52, 
depending on the timing of withdrawal.  The collection of these assessments is important for 
endpoint analysis which considers all assessments post baseline up to Week 52.
New text:
...
If the patient discontinues study drug prematurely during the main treatment phase (Week 0 –
Week 52) he/she will be invited to come for limited assessments (mRSS, FVC, DLCO and 
patient-reported outcomes [PROs]) at Week 12, Week 26, Week 39, and Week 52, depending 
on the timing of withdrawal.  The collection of these assessments is important for endpoint 
analysis which considers all assessments post baseline up to Week 52.
5.1.2 Exclusion criteria
Old text:
2. Hepatic-related criteria

Hepatic insufficiency classified as Child-Pugh C (see Appendix 14.1 for 
classification table)
3. Renal-related criteria

Estimated glomerular filtration rate (eGFR) < 15 mL/min/1.73m2 (Modification of 
Diet in Renal Disease [MDRD] formula) or on dialysis at the screening visit
o
Because the MDRD formula is thought to cause significant bias for 
Japanese patients, the equation for Japanese patients is: 
194 x serum creatinine (mg/dL) -1.094 x Age -0.287 x 0.739 (if female).
7. Prior and concomitant therapy

Treatment with methotrexate, cyclophosphamide, hydroxychloroquine, 
cyclosporine A, azathioprine, mycophenolate mofetil, rapamycin, colchicine, 


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D-penicillamine, or intravenous immunoglobulin within 4 weeks before the 
screening visit
New text:
2. Hepatic-related criteria

Hepatic insufficiency classified as Child-Pugh C (see Appendix 14.1 for 
classification table)
o
Patients with isolated AST or ALT >3xULN or bilirubin >2xULN can be 
included in the trial under the condition of additional monitoring during the 
trial (see section 7.6.2)
3. Renal-related criteria

Estimated glomerular filtration rate (eGFR) < 15 mL/min/1.73m2 (Modification of 
Diet in Renal Disease [MDRD] formula) or on dialysis at the screening visit. 
Patients entering the trial with eGFR 15-29 mL/min/1.73m2 will be undergo 
additional monitoring of renal function (see section 7.6.2)
o
Because the MDRD formula is thought to cause significant bias for 
Japanese patients, the equation for Japanese patients is: 
194 x serum creatinine (mg/dL) -1.094 x Age -0.287 x 0.739 (if female).
7. Prior and concomitant therapy

Treatment with methotrexate, cyclophosphamide, hydroxychloroquine, 
cyclosporine A, azathioprine, mycophenolate mofetil, rapamycin, colchicine, 
D-penicillamine, tacrolimus, mizoribine or intravenous immunoglobulin within 
4 weeks before the screening visit
5.2.1 Withdrawal
Old text:
Patients must be withdrawn from the study for the following reasons:

If treatment is interrupted for > 3 consecutive days during the dose titration period of 
the main treatment phase
Patients may be withdrawn from the study for the following reasons:

At the specific request of the sponsor and in liaison with the investigator (eg, safety 
concerns)

A relative decline in FVC % predicted by ≥10% (eg, a change of FVC from 60% to 
54%) or a relative decline in FVC % predicted between 5 to < 10% with associated 
relative decline in DLCO % predicted by ≥15%, provided that the decline in FVC 
results in FVC <75% of predicted (confirmed by repeat pulmonary function testing 
within 1 month). Please refer to Section 6.9 for the option of adding escape therapy.

An absolute increase in mRSS by > 5 units and ≥ 25% (Please refer to Section 6.9 for 
the option of adding escape therapy), life-threatening or organ-threatening event 
attributable to SSc (such as renal crisis, digital gangrene, development of new PAH on 
right heart catheterization) or not attributable to SSc.


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A patient who, for any reason (eg, failure to satisfy the selection criteria), terminates the study 
before the time point used for the definition of “dropout” (see below) is regarded a “screening 
failure”.  Restarting the defined set of screening procedures to enable the “screening failure” 
patient’s participation at a later time point is not allowed.
One re-assessment of laboratory parameters is allowed during the screening phase to re-assess 
the eligibility of patients.
A patient who discontinues study participation prematurely for any reason is defined as a 
“dropout” if the patient has already been randomized.
Any randomized patient removed from the trial should undergo the assessments at the 
termination visit.  The patient will remain under medical supervision until discharge or 
transfer is medically acceptable and will complete the 30-day safety follow-up period.
If the patient discontinues study participation prematurely during the main treatment phase 
(Week 0 – Week 52) he/she will be invited to come for limited assessments (mRSS, FVC, 
DLCO and patient-reported outcomes [PROs]) at Week 12, Week 26, Week 39, and Week 52, 
depending on the timing of withdrawal.  This will be in addition to the termination visit 
assessments (see Section 7.1.2.8), provided that the patient does not object to collection of 
study data after withdrawal of consent.  If the discontinuation occurs before Visit 8 
(Week 14), the skin biopsy and blood samples for biomarkers are to be collected.
New text:
Patients must be withdrawn from the study for the following reasons:

If treatment is interrupted for > 3 consecutive days (9 doses) during the dose titration 
period of the main treatment phase
Patients may be withdrawn from the study for the following reasons:

At the specific request of the sponsor and in liaison with the investigator (eg, safety 
concerns)

A relative decline in FVC % predicted by ≥10% (eg, a change of FVC from 60% to 
54%) or a relative decline in FVC % predicted between 5 to < 10% with associated 
relative decline in DLCO % predicted by ≥15%, provided that the decline in FVC 
results in FVC <75% of predicted (confirmed by repeat pulmonary function testing 
within 1 month). Please refer to Section 6.9 for the option of adding rescue therapy.

An absolute increase in mRSS by > 5 units and ≥ 25% (Please refer to Section 6.9 for 
the option of adding rescue therapy), life-threatening or organ-threatening event 
attributable to SSc (such as renal crisis, digital gangrene, development of new PAH on 
right heart catheterization) or not attributable to SSc.
A patient who, for any reason (eg, failure to satisfy the selection criteria), terminates the study 
before the time point used for the definition of “dropout” (see below) is regarded a “screening 
failure”.  Restarting the defined set of screening procedures to enable the “screening failure” 
patient’s participation at a later time point is not allowed.
One re-assessment of laboratory parameters is allowed during the screening phase to re-assess 
the eligibility of patients.
A patient who discontinues study participation prematurely for any reason is defined as a 
“dropout” if the patient has already been randomized.


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Any randomized patient removed from the trial should undergo the assessments at the 
termination visit.  The patient will remain under medical supervision until discharge or 
transfer is medically acceptable and will complete the 30-day safety follow-up period.
If the patient discontinues study drug prematurely during the main treatment phase (Week 0 –
Week 52) he/she will be invited to come for limited assessments (mRSS, FVC, DLCO and 
patient-reported outcomes [PROs]) at Week 12, Week 26, Week 39, and Week 52, depending 
on the timing of withdrawal.  This will be in addition to the termination visit assessments (see 
Section 7.1.2.8), provided that the patient does not object to collection of study data after 
withdrawal of consent.  If the discontinuation occurs before Visit 8 (Week 14), the skin 
biopsy and blood samples for biomarkers are to be collected.


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6.9
Prior and concomitant medications
Old text:
Table 6-2 Prohibited prior and concomitant therapy
Therapy
Timeframe 
Chlorambucil, bone marrow transplantation, or total lymphoid irradiation
Any previous therapya
Rituximab or other anti-CD20 antibodies
Within 6 months prior to 
the screening visita
Infliximab, certolizumab, golimumab, adalimumab, abatacept, 
leflunomide or tocilizumab
Within 8 weeks prior to the 
screening visita
Methotrexate, cyclophosphamide, hydroxychloroquine, cyclosporine A, 
azathioprine, mycophenolate mofetil, rapamycin, colchicine, D 
penicillamine, or intravenous immunoglobulin
Within 4 weeks prior to the 
screening visita
Etanercept
Within 2 weeks prior to the 
screening visita
Anakinra
Within 1 week prior to the 
screening visita
Nitrates or NO donors (such as amyl nitrate) in any form, including 
topical; phosphodiesterase (PDE) 5 (PDE5) inhibitors (such as 
sildenafil, tadalafil, vardenafil); and nonspecific PDE5 inhibitors 
(theophylline, dipyridamole)
Concomitant therapy with 
study drug
Prostacyclin analogs (oral beraprost for digital ulcers / Raynaud’s 
disease and short-term / intermittent therapy of up to 21 days 
with intravenous prostacyclin analogs for digital / vascular lesions is 
allowed)
Concomitant therapy with 
study drug
a
Concomitant use of these treatments with study medication is also prohibited, except for certain 
agents from Week 26 onwards; please see “Escape Therapy” below.  
Other medications and considerations (detailed information can be found in the current IB)

Pre- and concomitant treatment with the proton pump inhibitor omeprazole (40 mg 
once daily) reduced riociguat mean area under the plasma concentration versus time 
curve (AUC) by 26% and mean maximum plasma concentration (Cmax) by 35%.  This 
is not considered clinically relevant.

Co-administration of the antacid aluminum hydroxide / magnesium hydroxide reduced 
riociguat mean AUC by 34% and mean Cmax by 56%.  Antacids should be taken at 
least 1 hour after riociguat.

Plasma concentrations in smokers are reduced by 5060% compared with 
nonsmokers.  A dose reduction should be considered in patients who stop smoking 
whilst participating in the study.


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Escape therapy
From Week 26 (Visit 10), patients with the following will have the opportunity to add rescue 
therapy to their randomized study medication.  “Escape therapy” is defined as treatment with 
an immunosuppressant drug, under the following situations:

Worsening of skin disease (defined as > 5 units and ≥ 25% increase in mRSS), or

Relative decline in FVC % predicted by ≥ 10%, or relative decline in FVC % 
predicted between ≥5% and < 10% with associated relative decline in DLCO % 
predicted by ≥ 15%, provided that the decline in FVC results in FVC <75% of 
predicted  (confirmed by repeat pulmonary function testing within 1 month).
The decision to initiate rescue therapy is based on investigator discretion in eligible patients.  
Rescue therapy may include any of the following 4 agents:  methotrexate, mycophenolate 
mofetil, cyclophosphamide, or azathioprine. These treatments are not provided by the 
Sponsor.
New text:
Table 6-2 Prohibited prior and concomitant therapy - amended
Therapy
Timeframe 
Chlorambucil, bone marrow transplantation, or total lymphoid irradiation
Any previous therapya
Rituximab or other anti-CD20 antibodies
Within 6 months prior to 
the screening visita
Infliximab, certolizumab, golimumab, adalimumab, abatacept, 
leflunomide or tocilizumab
Within 8 weeks prior to the 
screening visita
Methotrexate, cyclophosphamide, hydroxychloroquine, cyclosporine A, 
azathioprine, mycophenolate mofetil, rapamycin, colchicine, D 
penicillamine, tacrolimus, mizoribine or intravenous immunoglobulin
Within 4 weeks prior to the 
screening visita
Etanercept
Within 2 weeks prior to the 
screening visita
Anakinra
Within 1 week prior to the 
screening visita
Nitrates or NO donors (such as amyl nitrate) in any form, including 
topical; phosphodiesterase (PDE) 5 (PDE5) inhibitors (such as 
sildenafil, tadalafil, vardenafil); and nonspecific PDE5 inhibitors 
(theophylline, dipyridamole)
Concomitant therapy with 
study drug
Prostacyclin analogs (oral beraprost for digital ulcers / Raynaud’s 
disease and short-term / intermittent therapy of up to 21 days 
with intravenous prostacyclin analogs for digital / vascular lesions is 
allowed)
Concomitant therapy with 
study drug
a
Concomitant use of these treatments with study medication is also prohibited, except for certain 
agents from Week 26 onwards; please see “Rescue Therapy” below.  


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Other medications and considerations (detailed information can be found in the current IB)

Pre- and concomitant treatment with the proton pump inhibitor omeprazole (40 mg 
once daily) reduced riociguat mean area under the plasma concentration versus time 
curve (AUC) by 26% and mean maximum plasma concentration (Cmax) by 35%.  This 
is not considered clinically relevant.

Co-administration of the antacid aluminum hydroxide / magnesium hydroxide reduced 
riociguat mean AUC by 34% and mean Cmax by 56%.  Antacids should be taken at 
least 1 hour after riociguat.

Plasma concentrations in smokers are reduced by 5060% compared with 
nonsmokers.  For this reason, it is highly recommended to strongly advise patients to 
stop smoking while taking this medication.  A dose reduction should be considered in 
patients who stop smoking whilst participating in the study.
Rescue therapy
From Week 26 (Visit 10), patients with the following will have the opportunity to add rescue 
therapy to their randomized study medication. “Rescue therapy” is defined as treatment with 
an immunosuppressant drug, under the following situations:

Worsening of skin disease (defined as > 5 units and ≥ 25% increase in mRSS), or

Relative decline in FVC % predicted by ≥ 10%, or relative decline in FVC % 
predicted between ≥5% and < 10% with associated relative decline in DLCO % 
predicted by ≥ 15%, provided that the decline in FVC results in FVC <75% of 
predicted  (confirmed by repeat pulmonary function testing within 1 month).
The decision to initiate rescue therapy is based on investigator discretion in eligible patients.  
Rescue therapy may include any of the following 4 agents:  methotrexate, mycophenolate 
mofetil, cyclophosphamide, or azathioprine. These treatments are not provided by the 
Sponsor.


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7.1.1 Tabulated overview
Old text:
Table 7-1
Schedule of evaluations
Scr
Main Treatment Phase  (Double-blind)
Long-term Extension Phase  
Scr 
Phase
Dose-Titration Period 
Maintenance Period
Dose-Titration Period
Open-label 
Extension 
Period
Safety 
Follow-up
Visit
V0
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11 V12a V13
V14
V15
V16
V17
V18 – Vn
(q 12 wk)
TVb
SFU
Week
-2
0
2
4
6
8
10
12
14
20
26
39
52
54
56
58
60
62
64 – n 
Day
-14
to
-1
0
14 
± 2
28 
± 2
42 
± 2
56 
± 2
70 
± 2
84 
± 2
98 
± 2
140 
± 2
182 
± 2
273 
± 14
364 
± 14
378 
± 2
392 
± 2
406 
± 2
420 
± 2
434 
± 2
448 – (n + 84)
± 14
30 + 5
Written informed consent
X
Inclusion / exclusion criteria
X
X
Demographic data
X
Medical and surgical history
X
X
Other history (alcohol)
X
Smoking history
X
X
X
X
X
X
Height and weightc
X
X
X
X
X
X
X
X
Physical examination
X
X
X
X
X
X
X
X
mRSS
X
X
X
X
X
X
X
Assessment of Raynaud’s 
attacks
Xd
Xe
Xf
Xe
Digital ulcer net burden
assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Tender & swollen joint count
X
X
Xg


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Table 7-1
Schedule of evaluations
Scr
Main Treatment Phase  (Double-blind)
Long-term Extension Phase  
Scr 
Phase
Dose-Titration Period 
Maintenance Period
Dose-Titration Period
Open-label 
Extension 
Period
Safety 
Follow-up
Visit
V0
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11 V12a V13
V14
V15
V16
V17
V18 – Vn
(q 12 wk)
TVb
SFU
Week
-2
0
2
4
6
8
10
12
14
20
26
39
52
54
56
58
60
62
64 – n 
Day
-14
to
-1
0
14 
± 2
28 
± 2
42 
± 2
56 
± 2
70 
± 2
84 
± 2
98 
± 2
140 
± 2
182 
± 2
273 
± 14
364 
± 14
378 
± 2
392 
± 2
406 
± 2
420 
± 2
434 
± 2
448 – (n + 84)
± 14
30 + 5
Vital signs (BP, HR)h
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs post-dose 
(BP, HR)i,j
Xi
Xj
Xi
Blood sample for safetyk
X
X
X
X
X
X
X
X
X
Blood sample for PK
Xl
Xm
Xm
Xm
Xm
Xm
Xn
Xl
Xm
Xm
Xm
Xm
Xm
Blood sample for biomarkers 
X
X
Xr
Blood sample for 
Autoantibody screen
X
Pregnancy test (if 
applicable)o
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECGp
X
X
X
X
X
X
X
X
X
Pulmonary function testsq
X
X
X
X
X
X
X
Skin biopsy
X
X
Xr
Questionnairess
X
X
X
X
X
X
X
Patient’s and physician’s 
global assessment
X
X
X
Xg
Patient interference with skin 
X
X
X
Xg
Tendon Friction Rubst
X
X


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Table 7-1
Schedule of evaluations
Scr
Main Treatment Phase  (Double-blind)
Long-term Extension Phase  
Scr 
Phase
Dose-Titration Period 
Maintenance Period
Dose-Titration Period
Open-label 
Extension 
Period
Safety 
Follow-up
Visit
V0
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11 V12a V13
V14
V15
V16
V17
V18 – Vn
(q 12 wk)
TVb
SFU
Week
-2
0
2
4
6
8
10
12
14
20
26
39
52
54
56
58
60
62
64 – n 
Day
-14
to
-1
0
14 
± 2
28 
± 2
42 
± 2
56 
± 2
70 
± 2
84 
± 2
98 
± 2
140 
± 2
182 
± 2
273 
± 14
364 
± 14
378 
± 2
392 
± 2
406 
± 2
420 
± 2
434 
± 2
448 – (n + 84)
± 14
30 + 5
Randomization (IxRS)
X
Dispensation of study drug
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Drug accountability
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events recording
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Prior and concomitant 
therapy
X
X 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Survival status
X
Abbreviations:  BP = blood pressure; ECG = electrocardiogram; TV = Termination Visit; SFU = 30-Day Safety Follow-up (30 [+5] days after the last 
dose of study drug); HR = heart rate; IxRS = telephone-based or web-based response system; mRSS = modified Rodnan skin score; 
PK = pharmacokinetics; q 12 wk = every 12 weeks; Scr = Screening.
Note:  Day 0 (Visit 1) is the baseline visit.
a
Visit 12 (Week 52) is the last visit in the Maintenance Period of the Main Treatment phase and the first (baseline) visit in the Long-term Extension 
phase.
b
To be performed as soon as possible after withdrawal of study medication.  
c
Height to be measured only at the screening visit
d
Patient to be provided with 7-day diary, to complete daily for 7 consecutive days leading up to Visit 1 
e
Patient and physician assessment of Raynaud’s disease (see Section 7.6.12)
f
Patient to be provided with 7-day diary, to complete daily for 7 consecutive days leading up to Visit 8.
g
Must not be performed if TV is after V12.
h
Blood pressure and heart rate will be measured at all visits with the patient in a sitting position, after the patient has been at rest for at least 5 
minutes.  The same arm is always used for these measurements (see Section 7.6.5).
i
Vital signs to be measured within 20 minutes prior to each post-dose PK sampling (see Table 7–2)


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Table 7-1
Schedule of evaluations
Scr
Main Treatment Phase  (Double-blind)
Long-term Extension Phase  
Scr 
Phase
Dose-Titration Period 
Maintenance Period
Dose-Titration Period
Open-label 
Extension 
Period
Safety 
Follow-up
Visit
V0
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11 V12a V13
V14
V15
V16
V17
V18 – Vn
(q 12 wk)
TVb
SFU
Week
-2
0
2
4
6
8
10
12
14
20
26
39
52
54
56
58
60
62
64 – n 
Day
-14
to
-1
0
14 
± 2
28 
± 2
42 
± 2
56 
± 2
70 
± 2
84 
± 2
98 
± 2
140 
± 2
182 
± 2
273 
± 14
364 
± 14
378 
± 2
392 
± 2
406 
± 2
420 
± 2
434 
± 2
448 – (n + 84)
± 14
30 + 5
j
Vital signs to be measured within 20 minutes prior to PK sampling (see Table 7–2)
k
Coagulation tests to be performed at a local laboratory
l
Samples for PK to be taken 1 – 2 hours and 3 – 4 hours after the morning dose of study medication (see Table 7–2)
m
Sample for PK to be taken up to 1 hour before the morning dose of study medication (trough) (see Table 7–3)
n
Samples for PK to be taken up to 1 hour before the morning dose of study medication (trough) and 2 – 3 hours after the morning dose of study 
medication (peak) (see Table 7–4)
o
For women of childbearing potential only. Serum pregnancy test is required only at screening; pregnancy testing (urine) will be done every 
4 weeks and should continue until 30 days after the last dose of study drug. When pregnancy testing coincides with a visit, the test should be 
performed at the site, but otherwise should be performed at home. 
p
Standard ECG (12-lead ECG) will be recorded with the patient in the supine position, after the patient has been at rest for at least 5 minutes (see 
Section 7.6.7).
q
Pulmonary function tests include forced vital capacity (FVC) and diffusion capacity of the lung for carbon monoxide (DLCO).
r
Must be done at a TV if this visit occurs before Visit 8.
s
Questionnaires include Scleroderma Health Assessment Questionnaire (SHAQ), Short Form 36 (SF-36), Patient-Reported Outcomes 
Measurement Information System (PROMIS)-29, and University of California, Los Angeles, Scleroderma Clinical Trial Consortium 
Gastrointestinal Scale (UCLA SCTC GIT) 2.0.
t
Assessment of the presence or absence of tendon friction rubs


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New text:
Table 7-1
Schedule of evaluations - amended
Scr
Main Treatment Phase  (Double-blind)
Long-term Extension Phase  
Scr 
Phase
Dose-Titration Period 
Maintenance Period
Dose-Titration Period
Open-label 
Extension 
Period
Safety 
Follow-up
Visit
V0
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11 V12a V13
V14
V15
V16
V17
V18 – Vn
(q 12 wk)
TVb
SFU
Week
-2
0
2
4
6
8
10
12
14
20
26
39
52
54
56
58
60
62
64 – n 
Day
-14
to
-1
0
14 
± 2
28 
± 2
42 
± 2
56 
± 2
70 
± 2
84 
± 2
98 
± 2
140 
± 2
182 
± 2
273 
± 14
364 
± 14
378 
± 2
392 
± 2
406 
± 2
420 
± 2
434 
± 2
448 – (n + 84)
± 14
30 + 5
Written informed consent
X
Inclusion / exclusion criteria
X
X
Demographic data
X
Medical and surgical history
X
X
Other history (alcohol)
X
Smoking history
X
X
X
X
X
X
Height and weightc
X
X
X
X
X
X
X
X
Physical examination
X
X
X
X
X
X
X
X
mRSS
X
X
X
X
X
X
X
Assessment of Raynaud’s 
attacks
Xd
Xe
Xf
Xe
Digital ulcer net burden
assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Tender & swollen joint count
X
X
Xg
Vital signs (BP, HR)h
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Table 7-1
Schedule of evaluations - amended
Scr
Main Treatment Phase  (Double-blind)
Long-term Extension Phase  
Scr 
Phase
Dose-Titration Period 
Maintenance Period
Dose-Titration Period
Open-label 
Extension 
Period
Safety 
Follow-up
Visit
V0
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11 V12a V13
V14
V15
V16
V17
V18 – Vn
(q 12 wk)
TVb
SFU
Week
-2
0
2
4
6
8
10
12
14
20
26
39
52
54
56
58
60
62
64 – n 
Day
-14
to
-1
0
14 
± 2
28 
± 2
42 
± 2
56 
± 2
70 
± 2
84 
± 2
98 
± 2
140 
± 2
182 
± 2
273 
± 14
364 
± 14
378 
± 2
392 
± 2
406 
± 2
420 
± 2
434 
± 2
448 – (n + 84)
± 14
30 + 5
Vital signs post-dose 
(BP, HR)i,j
Xi
Xj
Xi
Blood sample for safetyk, u
X
X
Xu
Xu
Xu
Xu
X
X
X
X
X
X
X
X
Blood sample for PK
Xl
Xm
Xm
Xm
Xm
Xm
Xn
Xl
Xm
Xm
Xm
Xm
Xm
Blood sample for biomarkers 
X
X
Xr
Blood sample for 
Autoantibody screen
X
Pregnancy test (if 
applicable)o
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECGp
X
X
X
X
X
X
X
X
X
Pulmonary function testsq
X
X
X
X
X
X
X
Skin biopsy
X
X
Xr
Questionnairess
X
X
X
X
X
X
X
Patient’s and physician’s 
global assessment
X
X
X
Xg
Patient interference with skin 
X
X
X
Xg
Tendon Friction Rubst
X
X
Randomization (IxRS)
X


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Version 6.0
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Table 7-1
Schedule of evaluations - amended
Scr
Main Treatment Phase  (Double-blind)
Long-term Extension Phase  
Scr 
Phase
Dose-Titration Period 
Maintenance Period
Dose-Titration Period
Open-label 
Extension 
Period
Safety 
Follow-up
Visit
V0
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11 V12a V13
V14
V15
V16
V17
V18 – Vn
(q 12 wk)
TVb
SFU
Week
-2
0
2
4
6
8
10
12
14
20
26
39
52
54
56
58
60
62
64 – n 
Day
-14
to
-1
0
14 
± 2
28 
± 2
42 
± 2
56 
± 2
70 
± 2
84 
± 2
98 
± 2
140 
± 2
182 
± 2
273 
± 14
364 
± 14
378 
± 2
392 
± 2
406 
± 2
420 
± 2
434 
± 2
448 – (n + 84)
± 14
30 + 5
Dispensation of study drug
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Drug accountability
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events recording
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Prior and concomitant 
therapy
X
X 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Survival status
X
Abbreviations:  BP = blood pressure; ECG = electrocardiogram; TV = Termination Visit; SFU = 30-Day Safety Follow-up (30 [+5] days after the last 
dose of study drug); HR = heart rate; IxRS = telephone-based or web-based response system; mRSS = modified Rodnan skin score; 
PK = pharmacokinetics; q 12 wk = every 12 weeks; Scr = Screening.
Note:  Day 0 (Visit 1) is the baseline visit.
a
Visit 12 (Week 52) is the last visit in the Maintenance Period of the Main Treatment phase and the first (baseline) visit in the Long-term Extension 
phase.
b
To be performed as soon as possible after withdrawal of study medication.  
c
Height to be measured only at the screening visit
d
Patient to be provided with 7-day diary, to complete daily for 7 consecutive days leading up to Visit 1 
e
Patient and physician assessment of Raynaud’s disease (see Section 7.6.12)
f
Patient to be provided with 7-day diary, to complete daily for 7 consecutive days leading up to Visit 8.
g
Must not be performed if TV is after V12.
h
Blood pressure and heart rate will be measured at all visits with the patient in a sitting position, after the patient has been at rest for at least 5 
minutes.  The same arm is always used for these measurements (see Section 7.6.5).
i
Vital signs to be measured within 20 minutes prior to each post-dose PK sampling (see Table 7–2)
j
Vital signs to be measured within 20 minutes prior to PK sampling (see Table 7–2)


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Table 7-1
Schedule of evaluations - amended
Scr
Main Treatment Phase  (Double-blind)
Long-term Extension Phase  
Scr 
Phase
Dose-Titration Period 
Maintenance Period
Dose-Titration Period
Open-label 
Extension 
Period
Safety 
Follow-up
Visit
V0
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11 V12a V13
V14
V15
V16
V17
V18 – Vn
(q 12 wk)
TVb
SFU
Week
-2
0
2
4
6
8
10
12
14
20
26
39
52
54
56
58
60
62
64 – n 
Day
-14
to
-1
0
14 
± 2
28 
± 2
42 
± 2
56 
± 2
70 
± 2
84 
± 2
98 
± 2
140 
± 2
182 
± 2
273 
± 14
364 
± 14
378 
± 2
392 
± 2
406 
± 2
420 
± 2
434 
± 2
448 – (n + 84)
± 14
30 + 5
k
Coagulation tests to be performed at a local laboratory
l
Samples for PK to be taken 1 – 2 hours and 3 – 4 hours after the morning dose of study medication (see Table 7–2)
m
Sample for PK to be taken up to 1 hour before the morning dose of study medication (trough) (see Table 7–3)
n
Samples for PK to be taken up to 1 hour before the morning dose of study medication (trough) and 2 – 3 hours after the morning dose of study 
medication (peak) (see Table 7–4)
o
For women of childbearing potential only. Serum pregnancy test is required only at screening; pregnancy testing (urine) will be done every 
4 weeks and should continue until 30 days after the last dose of study drug. When pregnancy testing coincides with a visit, the test should be 
performed at the site, but otherwise should be performed at home. 
p
Standard ECG (12-lead ECG) will be recorded with the patient in the supine position, after the patient has been at rest for at least 5 minutes (see 
Section 7.6.7).
q
Pulmonary function tests include forced vital capacity (FVC) and diffusion capacity of the lung for carbon monoxide (DLCO).
r
Must be done at a TV if this visit occurs before Visit 8.
s
Questionnaires include Scleroderma Health Assessment Questionnaire (SHAQ), Short Form 36 (SF-36), Patient-Reported Outcomes 
Measurement Information System (PROMIS)-29, and University of California, Los Angeles, Scleroderma Clinical Trial Consortium 
Gastrointestinal Scale (UCLA SCTC GIT) 2.0.
t
Assessment of the presence or absence of tendon friction rubs
u     Additional monitoring may apply for patients with impaired renal and liver function at Visit 2, 3, 4, 5 as needed (see section 7.6.2)


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7.1.2.3
Visits 2 through to 6 - Main treatment phase – Dose-titration period 
Old text:
At these study visits, the patient should attend the clinic without having taken the morning 
dose of study medication.
During the dose titration period of the main treatment phase, the following assessments will 
be performed according to the Schedule of evaluations (Section 7.1.1):

Vital signs (blood pressure and heart rate).  Blood pressure and heart rate will be 
measured at all visits with the patient in a sitting position, after the patient has been at 
rest for at least 5 minutes.  The same arm is always used for these measurements (see 
Section 7.6.5).

Digital ulcer net burden assessment (see Section 7.6.10)

Recording and assessment of AEs (see Section 7.5)

Blood samples for safety Visit 6 (see Section 7.6.2)

Blood sample for PK up to 1 hour before the morning dose of study medication (see 
Section 7.4)

Pregnancy test (urine) for all women of childbearing potential (Visit 3 and Visit 5) 
(see Section 7.6.1)

Concomitant therapy

Dose titration according to the titration algorithm (see Section 4.1.2)

Dispensation of study drug and drug accountability
New text:
At these study visits, the patient should attend the clinic without having taken the morning 
dose of study medication.
During the dose titration period of the main treatment phase, the following assessments will 
be performed according to the Schedule of evaluations (Section 7.1.1):

Vital signs (blood pressure and heart rate).  Blood pressure and heart rate will be 
measured at all visits with the patient in a sitting position, after the patient has been at 
rest for at least 5 minutes.  The same arm is always used for these measurements (see 
Section 7.6.5).

Digital ulcer net burden assessment (see Section 7.6.10)

Recording and assessment of AEs (see Section 7.5)

Blood samples for additional safety for patients with impaired renal and liver function 
at Visit 2, 3, 4, 5 as needed (see Section 7.6.2)

Blood samples for safety Visit 6 (see Section 7.6.2)

Blood sample for PK up to 1 hour before the morning dose of study medication (see 
Section 7.4)


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
Pregnancy test (urine) for all women of childbearing potential (Visit 3 and Visit 5) 
(see Section 7.6.1)

Concomitant therapy

Dose titration according to the titration algorithm (see Section 4.1.2)

Dispensation of study drug and drug accountability
7.1.2.8
Termination visit
Old text:
The termination visit will be performed if the patient is withdrawn from study medication for 
any reason except death or lost to follow-up, and should occur as soon as possible after the 
patient receives his/her last dose of study drug.  Assessments and procedures at this visit 
include the following:

Questionnaires (see Section 7.6.13)

Smoking history

Physical examination, including weight

Vital signs (blood pressure and heart rate).  Blood pressure and heart rate will be 
measured at all visits with the patient in a sitting position, after the patient has been at 
rest for at least 5 minutes.  The same arm is always used for these measurements (see 
Section 7.6.5)

mRSS (see Section 7.6.6)

Digital ulcer net burden assessment (see Section 7.6.10)

Patient’s and physician’s global assessment (see Section 7.6.15)

Patient interference with skin assessment (see Section 7.6.16)

Assessment for the presence or absence of tendon friction rubs (see Section 7.6.17)
New text:
The termination visit will be performed if the patient is withdrawn from study medication for 
any reason except death or lost to follow-up, and should occur as soon as possible after the 
patient receives his/her last dose of study drug.  Assessments and procedures at this visit 
include the following:

Questionnaires (see Section 7.6.13)

Smoking history

Physical examination, including weight

Vital signs (blood pressure and heart rate).  Blood pressure and heart rate will be 
measured at all visits with the patient in a sitting position, after the patient has been at 
rest for at least 5 minutes.  The same arm is always used for these measurements (see 
Section 7.6.5)


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
mRSS (see Section 7.6.6)

Digital ulcer net burden assessment (see Section 7.6.10)

Tender and swollen joint count assessment (not needed after V12, see Section 7.6.14)

Patient’s and physician’s global assessment (not needed after V12, see Section 7.6.15)

Patient interference with skin assessment (not needed after V12, see Section 7.6.16)
7.1.2.10
Premature discontinuation of study drug treatment
Old text:
In the event of premature discontinuation of study drug treatment, patients must undergo the 
same procedures as outlined for the termination visit (Section 7.1.2.8) and then undergo 
evaluation at the safety follow-up visit, 30 (+5) days later (Section 7.1.2.9).
The reason for premature discontinuation of study drug treatment or early withdrawal from 
the study must be recorded in the eCRF (please refer to Section 5.2).
If the patient discontinues study participation prematurely during the main treatment phase 
(Week 0 – Week 52) he/she will be invited to come for limited assessments (mRSS, FVC, 
DLCO and PROs) at Week 12, Week 26, Week 39 and Week 52, depending on the timing of 
withdrawal.  This will be in addition to the termination visit assessments (see Section 7.1.2.8), 
provided that the patient does not object to collection of study data after withdrawal of 
consent.  If the discontinuation occurs before Visit 8 (Week 14), a skin biopsy will also be 
performed.
New text:
In the event of premature discontinuation of study drug treatment, patients must undergo the 
same procedures as outlined for the termination visit (Section 7.1.2.8) and then undergo 
evaluation at the safety follow-up visit, 30 (+5) days later (Section 7.1.2.9).
The reason for premature discontinuation of study drug treatment or early withdrawal from 
the study must be recorded in the eCRF (please refer to Section 5.2).
If the patient discontinues study drug prematurely during the main treatment phase (Week 0 –
Week 52) he/she will be invited to come for limited assessments (mRSS, FVC, DLCO and 
PROs) at Week 12, Week 26, Week 39 and Week 52, depending on the timing of withdrawal.  
This will be in addition to the termination visit assessments (see Section 7.1.2.8), provided 
that the patient does not object to collection of study data after withdrawal of consent.  If the 
discontinuation occurs before Visit 8 (Week 14), a skin biopsy will also be performed.
7.6.2 Laboratory parameters
Old text:
The following safety laboratory parameters will be analyzed in a central laboratory (apart 
from coagulation tests, which will be analyzed at a local laboratory) at the screening visit 
(Visit 0), Visit 1 (Day 0), Visit 6 (Week 10), Visit 11 (Week 39), Visit 12 (Week 52), Visit 17 
(Week 62), every 12 weeks during the Open-label extension period, termination visit, and 
safety follow-up visit:


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
Hematology: WBC differential count, erythrocytes, hemoglobin, hematocrit and 
platelets

Coagulation tests: activated partial thromboplastin time (aPTT) and international 
normalized ratio (INR) (to be performed at a local laboratory)

Clinical chemistry: aspartate aminotransferase (AST), alanine aminotransferase 
(ALT), alkaline phosphatase (AP), gamma glutamyl transferase (GGT), glutamate 
dehydrogenase (GLDH), CK, sodium, potassium, magnesium, calcium, phosphate, 
creatinine, urea, uric acid, total bilirubin, total protein, serum albumin.
At latest, at the end of the study when all planned analyses are completed, all blood samples 
will be destroyed.  The name and address for the central laboratory service provider can be 
found in the documentation supplied by the vendor.
Note:  One re-assessment of laboratory parameters is allowed during the screening phase to 
re-assess the eligibility of patients.
New text:
The following safety laboratory parameters will be analyzed in a central laboratory (apart 
from coagulation tests, which will be analyzed at a local laboratory) at the screening visit 
(Visit 0), Visit 1 (Day 0), Visit 6 (Week 10), Visit 10 (Week 26), Visit 11 (Week 39), Visit 12 
(Week 52), Visit 17 (Week 62), every 12 weeks during the Open-label extension period, 
termination visit, and safety follow-up visit:

Hematology: WBC differential count, erythrocytes, hemoglobin, hematocrit and 
platelets

Coagulation tests: activated partial thromboplastin time (aPTT) and international 
normalized ratio (INR) (to be performed at a local laboratory)

Clinical chemistry: aspartate aminotransferase (AST), alanine aminotransferase 
(ALT), alkaline phosphatase (AP), gamma glutamyl transferase (GGT), CK, sodium, 
potassium, magnesium, calcium, phosphate, creatinine, urea, uric acid, total bilirubin, 
total protein, serum albumin.
Patients with isolated AST or ALT >3xULN or bilirubin >2xULN at screening and/or
baseline will have additional analysis of coagulation tests, AST, ALT, AP, GGT, total 
bilirubin and serum albumin until normalization and/ or stabilization at Visit 2 (Day 14), Visit 
3 (Day 28), Visit 4 (Day 42), Visit 5 (Day 56), as needed.  Worsening of the parameters in the 
order of 2-fold from baseline values will be considered clinically significant [22] and 
additional diagnostic procedures may be requested.
Patients entering the trial with eGFR 15-29 mL/min/1.73m2 will be undergo additional serum 
creatinine and eGFR calculation until normalization and/ or stabilization at Visit 2 (Day 14), 
Visit 3 (Day 28), Visit 4 (Day 42), and Visit 5 (Day 56), as needed.  A decrease in eGFR 
equal or greater than 5ml/min/1.73m2 in these patients (eGFR 15-29 ml/min/1.73m2) during 
the study or a reduction of 25% or more in 12 months will be considered clinically significant 
[23,24].
At latest, at the end of the study when all planned analyses are completed, all blood samples 
will be destroyed.  The name and address for the central laboratory service provider can be 
found in the documentation supplied by the vendor.


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Note:  One re-assessment of laboratory parameters is allowed during the screening phase to 
re-assess the eligibility of patients.
8.2
Analysis sets
Old text:
Efficacy and safety analyses will be performed in patients valid for the full analysis set (FAS).  
This is defined as all patients randomized and treated with study medication.  Investigators 
will be instructed not to make the call to the IxRS system until they are certain the patient is 
valid to be treated with study medication, on the day that study medication is to start.  In that 
way, we expect all patients who are randomized also to be treated, so the FAS population 
would then be consistent with the full intent-to-treat (ITT) definition.
For the primary and secondary exploratory efficacy and safety endpoints, as a supportive 
analysis, a per protocol set (PPS) will also be defined, including patients who meet the major 
inclusion and exclusion criteria at randomization that may affect efficacy, who are not taking 
excluded concomitant medications during the study that could have an effect on efficacy (not 
including escape medication after Week 26), have the mRSS assessed at baseline and at least 
once during the main treatment phase and who are at least 80% compliant with study 
medication.  A full definition of valid for PPS will be given in the SAP.
New text:
Efficacy and safety analyses will be performed in patients valid for the full analysis set (FAS).  
This is defined as all patients randomized and treated with study medication.  Investigators 
will be instructed not to make the call to the IxRS system until they are certain the patient is 
valid to be treated with study medication, on the day that study medication is to start.  In that 
way, we expect all patients who are randomized also to be treated, so the FAS population 
would then be consistent with the full intent-to-treat (ITT) definition.
For the primary and secondary exploratory efficacy and safety endpoints, as a supportive 
analysis, a per protocol set (PPS) will also be defined, including patients who meet the major 
inclusion and exclusion criteria at randomization that may affect efficacy, who are not taking 
excluded concomitant medications during the study that could have an effect on efficacy (not 
including rescue medication after Week 26), have the mRSS assessed at baseline and at least 
once during the main treatment phase and who are at least 80% compliant with study 
medication.  A full definition of valid for PPS will be given in the SAP.
12
Reference list
New text:
22.
Regev A, Seeff LB, Merz M, Ormarsdottir S, Aithal GP, Gallivan J, Watkins PB. 
Causality Assessment for Suspected DILI During Clinical Phases of Drug 
Development. Drug Saf (2014) 37 (Suppl 1):S47–S56.
23.
NICE clinical guideline 182 “Chronic kidney disease: early identification and 
management of chronic kidney disease in adults in primary and secondary care”, 
issued in July 2014 (guidance.nice.org.uk/cg182).
24.
MacGregor MS and Taal MW. Clinical Practice Guidelines - Detection, Monitoring 
and Care of Patients with CKD. UK renal association, 5th edition, 2011 
(www.renal.org/guidelines).


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39.
Steen VD and Medsger TA. Long-Term Outcomes of Scleroderma Renal Crisis. Ann 
Intern Med. 2000;133:600-603.
40.
Shanmugam VK and Steen VD. Renal disease in scleroderma: an update on 
evaluation, risk stratification, pathogenesis and management. Curr Opin Rheumatol. 
2012 November ; 24(6): 669–676.
14.2
Definition of Systemic Sclerosis Renal Crisis
Old text:
The definition of systemic sclerosis hypertensive renal crisis is independent of whether or not 
concomitant antihypertensive medications are used.
...
At least 1 of the following 5 features:
1. Serum Creatinine: increase of ≥ 50% above baseline*
2. Proteinuria: ≥ 2+ by dipstick confirmed by protein: creatinine ratio > ULN
3. Hematuria: ≥ 2+ by dipstick or > 10 RBCs (red blood cells) /HPF (high power field)
(without menstruation)
4. Thrombocytopenia: < 100,000 platelets/mm3
5. Hemolysis: by blood smear or increased reticulocyte count
*Historical baseline creatinine of the patient
New text:
Scleroderma renal crisis is defined as the new onset of severe hypertension associated with a 
rapid increase in serum creatinine concentration, microangiopathic hemolytic anemia, or both 
[39]. Systemic sclerosis renal crisis usually manifests with acute onset of moderate-to-severe 
‘accelerated’ hypertension and oliguric renal failure [40].
The definition of systemic sclerosis hypertensive renal crisis is independent of whether or not 
concomitant antihypertensive medications are used.
...
At least 1 of the following 5 features:
1. Serum Creatinine: increase of ≥ 50% above baseline*
2. Proteinuria: ≥ 2+ by dipstick confirmed by protein: creatinine ratio > ULN
3. Hematuria: ≥ 2+ by dipstick or > 10 RBCs/High Power Field [HPF] (without 
menstruation)
4. Thrombocytopenia: < 100,000 platelets/mm3
5. Hemolysis: by blood smear or increased reticulocyte count
*Historical baseline creatinine of the patient


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13.2
Amendment 4
Amendment 4 was approved on 24 FEB 2016.
13.2.1
Overview of changes to the study
With this amendment, the list of secondary endpoints was changed to include a hierarchy of
testing. The chosen key secondary endpoint is the CRISS and the other endpoints in the 
hierarchy are components of this endpoint. Since 2008, researchers at 4 scleroderma centers in 
the US (United States) with the participation of the Scleroderma Clinical Trial Consortium 
(SCTC) have been developing a combined response index known as CRISS based on 
prospective, data-driven, consensus building techniques [42]. The result of this effort was 
given approval by the American Colleague of Rheumatology (ACR [41]). The use of CRISS 
in clinical trials is believed to greatly facilitate the interpretation of results and assess the 
impact of a pharmacological agent on overall disease activity or severity.
Based on feedback from the US Food and Drug Administration, the protocol was adjusted to 
clearly differentiate between withdrawal from the study (ie, withdrawal of informed consent) 
or discontinuation of study treatment (with continued data collection). This change mainly 
affected Section 5.2, but wording was also adapted in several other sections.
Further changes to the protocol, eg, based on feedback from investigators, included:

Clarification that at Visit 6 no further dose increase is possible.

Addition of a clearer definition for dcSSc disease criterion to inclusion criterion 4.

Addition of local hemoglobin measurements to visits with limited assessments.

Clarification of the timing of the vital status check for patients who prematurely 
discontinue study medication before Week 52.

Correction of inconsistencies.
Correction of typographical errors and minor editorial changes are not specified in the list of 
changes below. New text is displayed as underlined; text that was deleted is presented as 
strike-through text.
13.2.2
Changes to the protocol text
General change
In several sections of the protocol, the term “withdrawal” was replaced by “discontinuation/
discontinuation of study medication” if it did not refer to withdrawal of informed consent.
Individual changes are marked by footnotes in the body of the protocol, but due to the high 
number of changes, not all are provided in the list of changes below.
2.
Study objectives - amended
Old text:

Efficacy:
o
mRSS progression rate (defined as increase in mRSS by > 5 units and ≥ 25% 
from baseline) and mRSS regression rate (defined as decrease in mRSS by 
> 5 units and ≥25% from baseline)
o
Patient’s and physician’s global assessment 


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o
HRQoL using Short Form 36 (SF-36) and the Scleroderma Health Assessment 
Questionnaire (SHAQ)
o
Digital ulcer net burden (defined as total number of ulcers at time point minus 
number of ulcers at baseline) and proportion of patients who do not develop 
new ulcers
o
Change in FVC (forced vital capacity) % predicted and percent DLCO (carbon 
monoxide diffusing capacity) % predicted
o
Combined Response Index for Systemic Sclerosis (CRISS) 
o
Need for Rescue Therapy (see definition in Section 6.9)
New text:

Efficacy:
o
Key secondary objective

American College of Rheumatology Combined Response Index for 
Systemic Sclerosis (CRISS)
o
Further secondary objectives

Health Assessment Questionnaire disability index (HAQ-DI) domain 
(separately from the Scleroderma Health Assessment Questionnaire 
[SHAQ] as part of the calculation of the CRISS algorithm)

Patient’s global assessment 

Physician’s global assessment

Change in FVC (forced vital capacity) % predicted
4.1.2 Main treatment phase (Week 0 to Week 52) – amended
Old text:
To maintain blinding of the treatment arms, patients randomized to the placebo group will 
undergo sham titration from Visit 1 onwards during the dose-titration period according to the 
rules of the dose titration scheme.
New text:
To maintain blinding of the treatment arms, patients randomized to the placebo group will 
undergo sham titration from Visit 1 onwards during the dose-titration period according to the 
rules of the dose titration scheme. At Visit 6, the last visit of the Titration Phase, no further 
increase in study medication will be possible (see Figure 4-1).
4.1.4
Dose Interruptions
Old text:

Interruptions of any length in the open-label extension period: treatment can be 
restarted at the discretion of the investigator at 0.5 mg TID lower than the last dose.
New text:

Interruptions in the open-label extension period: 


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o
≤28 days: treatment can be restarted at the discretion of the investigator at 
0.5 mg TID lower than the last dose.
o
>28 days: discontinue the patient from study medication.
4.1.5
Termination visit and safety follow-up visit - amended
Old text:
If the patient discontinues study drug prematurely during the main treatment phase (Week 0 –
Week 52) he/she will be invited to come for limited assessments (mRSS, FVC, DLCO and 
PROs) at Week 12, Week 26, Week 39 and Week 52, depending on the timing of withdrawal.
New text:
If the patient discontinues study drug prematurely during the main treatment phase (Week 0 –
Week 52) he/she will be invited to come for limited assessments (mRSS, pulmonary function 
test [FVC and DLCO including hemoglobin measurement at the local laboratory], and patient 
reported outcome [PROs]) at Week 12, Week 26, Week 39 and Week 52, depending on the 
timing of discontinuation.
5.1.1 Inclusion criteria
Old text:
4.
dcSSc according to the LeRoy criteria[3]
New text:
4.
dcSSc according to the LeRoy criteria[3], ie, skin fibrosis proximal to the elbows and 
knees in addition to acral fibrosis
5.1.2 Exclusion Criteria - amended
Old text:
5.
Pulmonary-related criteria

Diagnosed PAH as determined by right heart catheterization
New text:
5.
Pulmonary-related criteria

Diagnosed pulmonary hypertension as determined by right heart catheterization


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5.2.1
Withdrawal - amended
Old text:
Patients must be withdrawn from the study for the following reasons:

At their own request or at the request of their legally acceptable representative at any 
time during the study and without giving reasons, a patient may decline to participate 
further.  The patient will not suffer any disadvantage as a result.

If, in the investigator's opinion, continuation of the study would be harmful to the 
patient's well-being

Occurrence of AEs or intercurrent diseases which the investigator judges unacceptable 
for continuation of participation in the study

Occurrence of adverse drug reactions, which in the investigator’s opinion have 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 such as anticipated treatment effect, progression of underlying disease, 
occurrence of side effects, and alternative treatment options must be considered.)

Non-compliance with the conditions for the trial or instructions by the investigator

If treatment is interrupted for > 3 consecutive days (9 doses)144 during the dose 
titration period of the main treatment phase

If treatment is interrupted for > 14 consecutive days during the maintenance period of 
the main treatment phase or the dose-titration period of the long-term extension phase

In case of pregnancy or breast feeding.

In case a female patient of childbearing potential is not compliant with 4-weekly 
pregnancy testing or with contraceptive measures.

Participation in another clinical trial.  Participation in observational registries is 
allowed.

In case no further dose reduction is possible and the patient does not tolerate the 
lowest possible dosage (0.5 mg TID) of study drug
Patients may be withdrawn from the study for the following reasons:

At the specific request of the sponsor and in liaison with the investigator (eg, safety 
concerns)

A relative decline in FVC % predicted by ≥10% (eg, a change of FVC from 60% to 
54%) or a relative decline in FVC % predicted between 5 to < 10% with associated 
relative decline in DLCO % predicted by ≥15%, provided that the decline in FVC 
results in FVC <75% of predicted (confirmed by repeat pulmonary function testing 
within 1 month). Please refer to Section 6.9 for the option of adding rescue145 therapy.
                                                
144 Per Amendment 1
145 Per Amendment 1


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
An absolute increase in mRSS by > 5 units and ≥ 25% (Please refer to Section 6.9 for 
the option of adding rescue146 therapy), life-threatening or organ-threatening event 
attributable to SSc (such as renal crisis, digital gangrene, development of new PAH on 
right heart catheterization) or not attributable to SSc.
A patient who, for any reason (eg, failure to satisfy the selection criteria), terminates the study 
before the time point used for the definition of “dropout” (see below) is regarded a “screening 
failure”.  Restarting the defined set of screening procedures to enable the “screening failure” 
patient’s participation at a later time point is not allowed.
[…]
If the patient discontinues study drug147 prematurely during the main treatment phase (Week 0 
– Week 52) he/she will be invited to come for limited assessments (mRSS, FVC, DLCO and 
patient-reported outcomes [PROs]) at Week 12, Week 26, Week 39, and Week 52, depending 
on the timing of withdrawal.  
[…]
A patient may withdraw from further participation in the study and, unless he/she signs an 
objection form, the following information should be obtained and documented in the eCRF:

Vital status

Outcome of SAEs

Efficacy endpoints at Weeks 12, 26, 39, and 52 (depending on timing of withdrawal)
The information should be collected in the eCRF until the safety follow-up visit 30 (+5) days 
after the last intake of study drug.  Serious adverse events that occur within 30 (+5) days after 
the last dose of study drug will be followed up until resolution, if possible.
For patients who object to further release of information, vital status only should be obtained.  
The measures taken for follow up must be documented in the site medical record.  
New text:
5.2.1.1 Withdrawal from the study
Patients must be withdrawn from the study for the following reasons: 

At their own request or at the request of their legally acceptable representative at any 
time during the study and without giving reasons, a patient may decline to participate 
further (withdrawal from study).  The patient will not suffer any disadvantage as a 
result. 

Participation in another clinical trial after Visit 12.  Participation in observational 
registries is allowed.
5.2.1.2 Discontinuation of study medication
                                                
146 Per Amendment 1
147 Per Amendment 1


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Patients must be discontinued from the study medication for the following reasons:

If, in the investigator's opinion, continuation of the study would be harmful to the 
patient's well-being

Occurrence of AEs or intercurrent diseases which the investigator judges unacceptable 
for continuation of participation in the study

Occurrence of adverse drug reactions, which in the investigator’s opinion have 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 such as anticipated treatment effect, progression of underlying disease, 
occurrence of side effects, and alternative treatment options must be considered.)

Non-compliance with the conditions for the trial or instructions by the investigator

If treatment is interrupted for >3 consecutive days (9 doses) during the dose titration 
period of the main treatment phase

If treatment is interrupted for >14 consecutive days during the maintenance period of 
the main treatment phase or the dose-titration period of the long-term extension phase

If treatment is interrupted for >28 days during the open-label extension period (of the 
long-term extension phase)

In case of pregnancy or breast feeding.

In case a female patient of childbearing potential is not compliant with 4-weekly 
pregnancy testing or with contraceptive measures.

Participation in another clinical trial.  Participation in observational registries is 
allowed.

In case no further dose reduction is possible and the patient does not tolerate the 
lowest possible dosage (0.5 mg TID) of study drug
Patients may be discontinued from the study medication for the following reasons:

At the specific request of the sponsor and in liaison with the investigator (eg, safety 
concerns)

A relative decline in FVC % predicted by ≥10% (eg, a change of FVC from 60% to 
54%) or a relative decline in FVC % predicted between 5 to < 10% with associated 
relative decline in DLCO % predicted by ≥15%, provided that the decline in FVC 
results in FVC <75% of predicted (confirmed by repeat pulmonary function testing 
within 1 month). Please refer to Section 6.9 for the option of adding rescue therapy.

An absolute increase in mRSS by > 5 units and ≥ 25% (Please refer to Section 6.9 for 
the option of adding rescue therapy), life-threatening or organ-threatening event 
attributable to SSc (such as renal crisis, digital gangrene, development of new PAH on 
right heart catheterization) or not attributable to SSc.
5.2.1.3 Handling of withdrawals or discontinuations from study medication
A patient who, for any reason (eg, failure to satisfy the selection criteria), terminates the study 
before the time point used for the definition of “dropout” (see below) is regarded a “screening 


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failure”.  Restarting the defined set of screening procedures to enable the “screening failure” 
patient’s participation at a later time point is not allowed.
[…]
If the patient discontinues study drug  prematurely during the main treatment phase (Week 0 –
Week 52) he/she will be invited to come for limited assessments (mRSS, pulmonary function 
test [FVC and DLCO including hemoglobin measurement at the local laboratory], and PROs) 
at Week 12, Week 26, Week 39 and Week 52, depending on the timing of discontinuation.
[…]
A patient may withdraw from further participation in the study and, unless he/she objects to 
further data collection, the following information should be obtained and documented in the 
eCRF:

Vital status (at Week 52)

Outcome of SAEs

Efficacy endpoints at Weeks 12, 26, 39, and 52 (depending on timing of 
discontinuation of study medication)
The information should be collected in the eCRF until the safety follow-up visit 30 (+5) days 
after the last intake of study drug.  Serious adverse events that occur within 30 (+5) days after 
the last dose of study drug will be followed up until resolution, if possible.
If patients refuse to be contacted via telephone (eg, patient objects to further release of 
information or are lost to follow-up), every effort should be made to obtain vital status (dead 
or alive) information at Week 52 through consultation of public databases, wherever allowed 
by local regulations. 
5.2.2
Replacement
Old text:
There will be no replacement of randomized patients who withdraw from the study.
New text:
There will be no replacement of randomized patients who withdraw from the study or 
prematurely discontinue study medication.
6.4.1
Selection of doses in the study
Old text:
The respective single doses of riociguat should be taken at least 6 hours apart. 
New text:
The intervals between drug intake should be 6 to 8 hours.


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6.5
Blinding - amended
Old text:
Any patient withdrawn from the trial will remain under medical supervision until discharge or 
transfer is medically acceptable.  Patients who withdraw should take part at the termination 
visit (refer to Section 7.1.2.8) and the safety follow-up visit (refer to Section 7.1.2.9).
New text:
Any patient who discontinues study medication will remain under medical supervision until 
discharge or transfer is medically acceptable.  Patients who withdraw from the study or 
discontinue study medication should take part at the termination visit (refer to Section 7.1.2.8) 
and the safety follow-up visit (refer to Section 7.1.2.9).
7.1.1
Tabulated overview - amended
Old text:
Not applicable. A new footnote was added for the Main Treatment Phase to the schedule of 
events in Table 7.1.
The visit window for V12 was changed. Original visit window: ±14 days. 
New text:
v
All patients who discontinue study drug prematurely during the Main Treatment Phase 
(Week 0 – Week 52) will be invited to come for limited assessments (see Sections 
7.1.2.10 and 7.6.2).
New visit window for V12: -14 to +2 days.
7.1.2.10
Premature discontinuation of study drug treatment - amended
Old text:
If the patient discontinues study drug prematurely during the main treatment phase (Week 0 –
Week 52) he/she will be invited to come for limited assessments (mRSS, FVC, DLCO and 
PROs) at Week 12, Week 26, Week 39 and Week 52, depending on the timing of withdrawal.
New text:
If the patient discontinues study drug  prematurely during the main treatment phase (Week 0 –
Week 52) he/she will be invited to come for limited assessments (mRSS, pulmonary function 
test [FVC and DLCO including hemoglobin measurement at the local laboratory], and PROs) 
at Week 12, Week 26, Week 39 and Week 52, depending on the timing of discontinuation.
7.3
Efficacy - amended
Old text:
Secondary efficacy outcome measures

mRSS progression rate (defined as increase in mRSS by > 5 units and > 25% from 
baseline) and mRSS regression rate (defined as decrease in mRSS by > 5 units and 
> 25% from baseline)


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
Patient’s and physician’s global assessment 

HRQoL using SF-36 and the SHAQ

Digital ulcer net burden (defined as total number of ulcers at time point minus number 
of ulcers at baseline) and proportion of patients who do not develop new ulcers

Change in FVC (forced vital capacity) % predicted and DLCO (carbon monoxide 
diffusing capacity) % predicted

Combined Response Index for Systemic Sclerosis (CRISS), consisting of five 
variables: mRSS, FVC % predicted, physician and patient global assessments, and 
HAQ-DI score (from SHAQ patient reported outcome)

Need for Rescue Therapy (see definition in Section 6.9)
[…]
Other exploratory measures:

All-cause Mortality

Gastrointestinal involvement as assessed by University of California, Los Angeles, 
Scleroderma Clinical Trial Consortium Gastrointestinal Scale (UCLA SCTC GIT) 2.0 
instrument

Patient-Reported Outcomes Measurement Information System (PROMIS)-29 (subset 
of patients)

Patient interference with skin 

Presence or absence of tendon friction rubs

Pain VAS

Change in BMI

Joint involvement using tender and swollen joint counts

New items for Raynaud’s response index excluding items included in secondary 
outcome measures
o Patient and physician assessment of Raynaud's phenomenon; pain, numbness, 
and tingling during a Raynaud's phenomenon attack; Raynaud’s condition 
score, average number of attacks/day; and duration of attacks
New text:
Secondary efficacy outcome measures
Key secondary endpoint:

CRISS, consisting of five variables: mRSS, FVC % predicted, physician and patient 
global assessments, and HAQ-DI score (from SHAQ patient reported outcome)
Further secondary endpoints:

HAQ-DI domain (separately from the SHAQ as part of the calculation of the CRISS 
algorithm).

Patient’s global assessment


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
Physician’s global assessment

Change in FVC (forced vital capacity) % predicted
[…]
Other exploratory measures148:

mRSS progression rate (defined as increase in mRSS by > 5 units and > 25% from 
baseline) and mRSS regression rate (defined as decrease in mRSS by > 5 units and 
> 25% from baseline)

HRQoL using SF-36 and the SHAQ.

Digital ulcer net burden (defined as total number of ulcers at time point minus number 
of ulcers at baseline) and proportion of patients who do not develop new ulcers

Change in DLCO (carbon monoxide diffusing capacity) % predicted

Need for Rescue Therapy (see definition in Section 6.9)

All-cause Mortality

Gastrointestinal involvement as assessed by University of California, Los Angeles, 
Scleroderma Clinical Trial Consortium Gastrointestinal Scale (UCLA SCTC GIT) 2.0 
instrument

Patient-Reported Outcomes Measurement Information System (PROMIS)-29 (subset 
of patients)

Patient interference with skin 

Presence or absence of tendon friction rubs

Pain VAS

Change in BMI

Joint involvement using tender and swollen joint counts

New items for Raynaud’s response index excluding items included in secondary 
outcome measures
o Patient and physician assessment of Raynaud's phenomenon; pain, numbness, 
and tingling during a Raynaud's phenomenon attack; Raynaud’s condition 
score, average number of attacks/day; and duration of attacks
7.6.2 Laboratory parameters - amended
Old text:

Hematology: WBC differential count, erythrocytes, hemoglobin, hematocrit and 
platelets
                                                
148 Per Amendment 4


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New text:

Hematology: WBC differential count, erythrocytes, hemoglobin, hematocrit and 
platelets
The hemoglobin value required for the pulmonary function tests performed at visits 
with limited assessments (see Section 7.1.2.10) will be measured at the local 
laboratory. The hemoglobin value will be entered in the eCRF and used for the 
calculation of predicted DLCO only.
7.6.8
Pulmonary function testing
Old text:
Printouts from the analyzer must be stored in the patient file and the measured values
transferred to the eCRF.
New text:
Printouts from the analyzer must be stored in the patient file and the measured values 
transferred to the eCRF.
The hemoglobin value required for the pulmonary function tests performed at visits with 
limited assessments (see Section 7.1.2.10) will be measured at the local laboratory. The 
hemoglobin value will be entered in the eCRF and used for the calculation of predicted DLCO
only.
8.4.2 Efficacy - amended
Old text:
In the efficacy analyses, countries and centers will be clustered by geographic region.  The 
decision on country pooling will be made before unblinding.  Statistical analyses will be 
adjusted for these countries / geographic regions.
The primary analysis will be the change in mRSS from baseline to all assessments post 
baseline up to Week 52 using mixed model repeated measures (MMRM) with baseline mRSS 
as a covariate, fixed effects treatment arm and region, the interaction effect between study 
visit and treatment arm, and patient specific random effects to account for both heterogeneity 
among patients and correlation among measurements taken on the same patient with an 
unstructured covariance assumption.  
[…]
As a sensitivity analysis, the MMRM using the above model will also be applied to 
assessments post-baseline up to termination of study medication or initiation of rescue 
medication.  In addition, the MMRM on all assessments will be repeated including additional 
effects time on rescue medication and time on study medication.  MMRM assumes missing at 
random; mRSS by time of patient withdrawal will be summarized and further methods using 
multiple imputation that allow for missing data not at random will be investigated.  Details of 
such methods will be described in the SAP.
[…]


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Rules for the imputation of missing values where the patient withdraws or dies for the 
univariate analysis, null / alternative hypothesis statements, and model statements in 
mathematical notation will be specified in the SAP.  Two-sided 95% confidence intervals of 
treatment (riociguat compared to placebo) differences will be calculated in addition to the 
statistical significance testing.
The other secondary and exploratory efficacy variables measured on a continuous or semi-
continuous scale will analyzed using the MMRM, ANCOVA, and stratified Wilcoxon test, as 
for the mRSS above.
The time to first mRSS progression and regression and clinical outcome parameters will be 
analyzed using the log-rank test comparing between treatment groups.
Any binary outcomes, such as the predicted CRISS outcome will be analyzed using Mantel-
Haenzel weights, stratified by region.  Also as a sensitivity analysis in addition to the time to 
event analysis, the occurrence of the events mRSS progression and regression and clinical 
outcome parameters will be analyzed using this method.
Details on any descriptive subgroup analyses will be specified in the SAP.  These will include 
gender and region.
New text:
In the efficacy analyses, countries and centers will be clustered by geographic region.  The 
decision on country pooling will be made before unblinding.  Statistical analyses will be 
adjusted for these countries / geographic regions.
8.4.2.1 Primary endpoint
The primary analysis will be the change in mRSS from baseline to all assessments post 
baseline up to Week 52 using mixed model repeated measures (MMRM) with baseline mRSS 
as a covariate, fixed effects treatment arm and region, the interaction effect between study 
visit and treatment arm, and patient specific random effects to account for both heterogeneity 
among patients and correlation among measurements taken on the same patient with an 
unstructured covariance assumption.
[…]
As a sensitivity analysis, the MMRM using the above model will also be applied to 
assessments post-baseline up to termination of study medication or initiation of rescue 
medication.  In addition, the MMRM on all assessments will be repeated including additional 
effects time on rescue medication and time on study medication.  MMRM assumes missing at 
random; mRSS by time of patient discontinuation from study medication will be summarized 
and further methods using multiple imputation that allow for missing data not at random will 
be investigated.  Details of such methods will be described in the SAP.
[…]
Rules for the imputation of missing values where the patient discontinues the study (eg, 
withdrawal of consent or death) or study medication for the univariate analysis, null / 
alternative hypothesis statements, and model statements in mathematical notation will be 
specified in the SAP.  Two-sided 95% confidence intervals of treatment (riociguat compared 
to placebo) differences will be calculated in addition to the statistical significance testing.


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8.4.2.2 Secondary and exploratory endpoints
General aspects
The other secondary and exploratory efficacy variables measured on a continuous or semi-
continuous scale will analyzed using the MMRM, ANCOVA, and stratified Wilcoxon test, as 
for the mRSS above.
The time to first mRSS progression and regression and clinical outcome parameters will be 
analyzed using the log-rank test comparing between treatment groups.
Any binary outcomes, such as the predicted CRISS outcome will be analyzed using Mantel-
Haenzel weights, stratified by region.  Also as a sensitivity analysis in addition to the time to 
event analysis, the occurrence of the events mRSS progression and regression and clinical 
outcome parameters will be analyzed using this method.
Details on any descriptive subgroup analyses will be specified in the SAP.  These will include 
gender and region.
Hierarchical testing of secondary endpoints
The following secondary endpoints will be tested in a hierarchical fashion at a 2-sided 5% 
level, only if the primary endpoint of mRSS is shown to be statistically significant at a 2-sided 
5% level.
The following order of testing will be applied:

CRISS

HAQ-DI (health assessment questionnaire-disability index)

Patient's global assessment

Physician's global assessment

FVC % predicted
For example, if CRISS is statistically significant at a 2-sided 5% level, then the HAQ-DI will 
be tested, if not the testing procedure will be stopped.  This step is repeated further down the 
list of the 5 secondary endpoints until a non-statistically significant endpoint is reached. 
These particular secondary endpoints were chosen to be tested in this hierarchical fashion, 
because the mRSS and the above additional, secondary variables were considered to have the 
greatest face validity when designing the CRISS [41].
American College of Rheumatology Combined Response Index for Systemic Sclerosis
Application of CRISS algorithm in a randomized clinical trial is a 2-step process.  Firstly, 
evaluate if patients have met the criterion for not-improved.  If yes, these patients are assigned 
a probability score of 0.0.  For the remaining patients, calculate the probability based on 
change in 5 measures: mRSS, FVC %, HAQ-DI, patient’s global assessment, and physician's 
global assessment, where each measure has a probability score between 0 and 1 [41].
In Step 1, a patient is clinically evaluated to determine whether the patient has improved or 
not.  Expert consensus on the definition of a patient who is not improved during a trial is the 
following:


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A patient is considered not improved and is assigned a probability score of improving equal to 
0.0, irrespective of improvement on other core items, if he/she develops: 
1. New scleroderma renal crisis, 
2. Decline in FVC % predicted ≥15% (relative), confirmed by another FVC % within a 
month, high resolution computed tomography (HRCT) to confirm interstitial lung 
disease (if previous HRCT did not show interstitial lung disease) and FVC % 
predicted below 80% predicted (attributable to SSc), 
3. New onset of left ventricular failure (defined as ejection fraction ≤45%) or new onset 
of pulmonary arterial hypertension requiring treatment (attributable to SSc).
If the patient is determined to exhibit improvement in Step 1 (ie, not assigned a 0.0), Step 2 
involves computing the predicted probability of improving (a score between 0.0 and 1.0, 
inclusive) for each patient using the equation:
	.	.∗∆.∗∆%.∗∆ .∗∆! ".∗∆#$%!&'
	.	.∗∆.∗∆%.∗∆ .∗∆! ".∗∆#$%!&'
where ∆MRSS indicates the change in mRSS from baseline to follow-up, ∆FVC denotes the 
change in FVC % predicted from baseline to follow-up, ∆Pt-glob indicates the change in patient 
global assessment, ∆MD-glob denotes the change in physician global assessment, and ∆HAQ-DI is 
the change in HAQ-DI.  Note that all changes are absolute changes (Time2 – Timebaseline) and 
that the physician’s and patient’s global assessment was measured on the Likert scale ranging 
from 0 to 10, where 0 = excellent, and 10 = extremely poor.
Hence, the CRISS is comprised of 5 variables: mRSS, FVC % predicted, patient’s global 
assessment, physician’s global assessment, and HAQ-DI from the SHAQ patient reported 
outcome.  Combined, the 5 variables explained 89.3% of the variability in the data.  
Individually, when used in a single-variable logistic regression model, mRSS explained 
66.3% of the variation, FVC % predicted explained 36.1% of the variation, physician global 
assessment explained 24.5% of the variation, patient global assessment explained 23.7% of 
the variation, and HAQ-DI explained 28.5% of the variation.  A change in mRSS, FVC % 
predicted and HAQ-DI are strong indicators of whether a patient is likely to be improved or 
not. In each scenario, a decrease of mRSS or HAQ-DI from baseline to follow-up and an 
increase in FVC % predicted corresponds to very high probabilities of improving.  For 
patient’s global and physician’s global assessment, the association between probability of 
improving and change in these 2 core components is less evident.  Subjects for which the 
predicted probability is greater or equal to 0.60 are considered improved, while subjects for 
which the predicted probability is below 0.60 are considered not improved.  The 2 groups 
(riociguat vs. placebo) can then be compared in a 2x2 table using appropriate significance 
tests.  The predicted probabilities obtained using the CRISS can also be assessed as a 
continuous variable and the distributions of the probability of improving for patients on drug 
vs. placebo can be compared using non-parametric tests [41]. In this study, the CRISS 
outcome will be analyzed using Mantel-Haenzel weights, stratified by region, and 
additionally, the stratified Wilcoxon test will be used as non-parametric test.
However, Step 2 assumes that there is complete data; ie, all 5 components of the CRISS are 
fully recorded at Week 52.  If the subject discontinues from study drug from the study before 
Week 52, or has one or more missing components of the CRISS at this visit, then a mixed 
model repeated measures (MMRM) analysis will be implemented to estimate the value or 
values for those components at Week 52. These estimates will then we used to calculate the 


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CRISS score at Week 52 as given in Step 2.  Subjects for which the predicted probability is 
greater or equal to 0.60 are considered improved, while subjects for which the predicted 
probability is below 0.60 are considered not improved. [41] Further details will be provided in 
the statistical analysis plan.
8.6
Determination of sample size
Old text:
One of the components of secondary efficacy measure mRSS progression is a 5 point or more 
deterioration from baseline to any assessment in the 12 month study period, this being 
considered a clinically meaningful change [14].  
New text:
One of the components of exploratory efficacy measure mRSS progression is a 5 point or 
more deterioration from baseline to any assessment in the 12 month study period, this being 
considered a clinically meaningful change [14].  
12.
Reference list - amended
New text:
41.
Khanna D, Berrocal VJ, Giannini EH, Seibold JR, Merkel PA, Mayes MD, et al. The 
American College of Rheumatology Provisional Composite Response Index for Clinical 
Trials in Early Diffuse Cutaneous Systemic Sclerosis. Arthritis Rheumatol. 2016; 68(2):299-
311.
42.
Khanna D, Lovell DJ, Giannini E, Clements PJ, Merkel PA, Seibold JR, et al. 
Development of a provisional core set of response measures for clinical trials of systemic 
sclerosis. Ann.Rheum Dis. 2008;67(5):703-709.


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13.3
Amendment 5
Amendment 5 was approved on 18 Aug 2016.
13.3.1
Overview of changes to the study
This amendment was implemented to clarify that the benefit-risk balance for the population in 
this study (patients with dcSSc) remains positive, despite the potential safety issue that has 
been reported in a study in patients with PH-IIP leading to early termination of the concerned
study. The benefit-risk assessment for patients with dcSSc was re-evaluated by the DMC in 
3 meetings and was confirmed to remain positive. 
Furthermore, the sample size determination in Section 8.6 was adapted to reflect 

The change in key secondary efficacy endpoint to CRISS (implemented with 
amendment 4).

Appropriate ranges for the significance levels and number of patients required. 
When scientific advice was initially sought from the Food and Drug Administration (FDA)
and European Medicines Agency (EMA) during the set-up of this study, a one-sided 
significance level of 5%, equivalent to a two-sided significance level of 10%, was proposed, 
resulting in a total sample size of 102 patients. If such a significance level was achieved, 
together with a clinically significant effect on the mRSS, then this was considered a potential 
criterion for efficacy to proceed with the drug to Phase III studies. To make the study more 
robust, the final protocol specified a two-sided significance level of 5%, resulting in a total 
sample size of 128 patients. 
Additionally, the time point of the CRISS assessment was clarified to be Week 52. The 
original term “follow-up”, as mentioned in Section 8.4.2.2, was taken from the paper 
describing the derivation of the CRISS score [41]. This was not referring to a specific visit, 
but a post-baseline follow-up assessment of a patient to be able to calculate the CRISS. 
Week 52 has now been specified, this being the planned final visit in the main treatment 
phase, and to avoid the interpretation that this might have been the post-treatment Safety 
Follow-up visit.
As of 01 July 2016, Bayer HealthCare AG merged with Bayer AG. Thereby, Bayer 
HealthCare AG ceased to exist and Bayer AG became its legal successor and automatically 
took over all of the Bayer HealthCare AG’s rights, obligations and liabilities by law, 
including the sponsorship for clinical studies currently sponsored by Bayer HealthCare AG.

The sponsorship information for this study was changed on the title page.

Additionally, the sponsor for US territory was added. Bayer HealthCare 
Pharmaceuticals Inc. is and has been the sponsor for the US territory for this study as 
set forth in FDA Investigational New Drug (IND) form 1571. The reference on the 
protocol was incomplete in this regard.
Further changes to the protocol included the following clarifications and additions:

Update of permitted concomitant medication during the long-term extension phase.

Update of allowed rescue therapy.

Clarification that biomarker analyses will be reported separately.

Addition of description of unblinding process for biomarker and PK analysis.


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
Clarification of sampling time points for blood samples for PK analysis and 
documentation requirements.

Addition of analysis of PK data in relationship of exposure parameters with treatment 
effects.

Change in time point for first data cleaning and reporting.

Clarification for adverse event reporting regarding conditions of SSc.

Clarification of the wording for exclusion criterion 5.

Addition of one criterion for discontinuation of the study medication in case patients 
develop renal disease and hepatic insufficiency in alignment with exclusion criteria 2 
and 3.

Addition of the patient’s and physician’s global assessment to the visits with limited 
assessments to ensure that all required variables are available at Week 52 for the 
analysis of the CRISS.

Correction of visit window for Visit 18.

Clarification of allowed dose interruptions in the open-label extension period.
Correction of typographical errors and minor editorial changes are not specified in the list of 
changes below. New text is displayed as underlined; text that was deleted is presented as 
strike-through text.
13.3.2
Changes to the protocol text
General change
Due to the change in the sponsor details, the header was adapted in the whole document: the 
old logo was deleted and replaced by the new logo.
Title page - amended
Old text:
Sponsor:
Bayer HealthCare AG,  D-51368 Leverkusen,  Germany
New text:
Sponsor:
Non-US: Bayer AG,  D-51368 Leverkusen,  Germany
US territory: Bayer Healthcare Pharmaceuticals Inc., 
100 Bayer Boulevard, P.O. Box 915, 
Whippany NJ 07981-0915, USA
Synopsis – Number of patients
Old text:
130 randomized patients.
New text:


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Up to approximately 130 randomized patients.
1.3
Benefit-risk assessment – amended
Old text:
[Not applicable. New text added in the end of the section.]
New text:
Recently, a potential safety issue has been reported for patients with pulmonary hypertension 
associated with idiopathic interstitial pneumonias (PH-IIP) and, therefore, the benefit-risk 
assessment for this indication has changed from positive to unfavorable. Following the data 
monitoring committee (DMC) recommendation, the study treatment has been terminated. 
Also per DMC recommendation patients are continuing in a safety follow-up for 4 months 
after study drug discontinuation and the study is expected to close in September 2016. 
A careful review, assessment and analysis will be done by the sponsor with unblinded and 
clean data originating from clinical study 13605 (RISE-IIP; final clinical study report 
expected in 2017). Information of health care professionals (via Dear Healthcare Professional 
Letter), label updates and an update of the risk management plan have been initiated in 
July 2016 in collaboration with the European Medicines Agency as well as national 
competent authorities.
The benefit-risk profile for conditions being studied in ongoing clinical studies also has been 
carefully re-evaluated. In the case of the present study in the dcSSc indication, 2 ad-hoc 
meetings of the DMC for this study took place, on 23 MAY 2016 and on 25 MAY 2016, 
followed by a third meeting on 15 AUG 2016. The DMC concluded that this study may 
continue without amendment or modification. Overall, the benefit-risk balance for this 
indication remains positive.
2.
Study objectives - amended
Old text:
o
Key secondary objective:

American College of Rheumatology Combined Response Index for 
Systemic Sclerosis (CRISS)
New text:
o
Key secondary objective:

American College of Rheumatology Combined Response Index for 
Systemic Sclerosis (CRISS) at Week 52.
4.1
Design overview
Old text:
In this multinational, multicenter, randomized (1:1), double-blind, placebo-controlled, 
parallel-group study, a total of approximately 200 patients are planned for enrollment in order 


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to randomize approximately 130 patients to study drug treatment (approximately 65 patients 
to the riociguat group and 65 to the placebo group).
New text:
In this multinational, multicenter, randomized (1:1), double-blind, placebo-controlled, 
parallel-group study, a total of approximately 200 patients are planned for enrollment in order 
to randomize up to approximately 130 patients to study drug treatment (approximately 65 
patients to the riociguat group and 65 to the placebo group).
4.1.4 Dose Interruptions - amended
Old text:
o
≤28 days: treatment can be restarted at the discretion of the investigator at 
0.5 mg TID lower than the last dose.
o
>28 days: discontinue the patient from study medication.
New text:
o
>13 and ≤28 consecutive days: treatment can be restarted at the discretion of 
the investigator at 0.5 mg TID lower than the last dose.
o
>28 consecutive days: discontinue the patient from study medication.
4.1.5 Termination visit and safety follow-up visit - amended
Old text:
If the patient discontinues study drug  prematurely during the main treatment phase (Week 0 –
Week 52) he/she will be invited to come for limited assessments (mRSS, pulmonary function 
test [FVC and DLCO including hemoglobin measurement at the local laboratory], and patient-
reported outcomes [PROs]) at Week 12, Week 26, Week 39, and Week 52, depending on the 
timing of discontinuation .  
New text:
If the patient discontinues study drug prematurely during the main treatment phase (Week 0 –
Week 52) he/she will be invited to come for limited assessments (mRSS, pulmonary function 
test [FVC and DLCO including hemoglobin measurement at the local laboratory], patient-
reported outcomes [PROs], and patient’s and physician’s global assessment) at Week 12, 
Week 26, Week 39, and Week 52, depending on the timing of discontinuation.  
5.1.2 Exclusion Criteria - amended
Old text:
5.
Pulmonary-related criteria
•
Diagnosed pulmonary hypertension  as determined by right heart 
catheterization  
New text:


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Pulmonary-related criteria
•
Any form of pulmonary hypertension as determined by right heart 
catheterization  
5.2.1.2
Discontinuation of study medication 
Old text:
Patients must be discontinued from the study medication for the following reasons:
[…]

Occurrence of adverse drug reactions, which in the investigator’s opinion have 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 such as anticipated treatment effect, progression of underlying disease, 
occurrence of side effects, and alternative treatment options must be considered.)

[…]

If treatment is interrupted for >28 days during the open-label extension period (of the 
long-term extension phase)
New text:
Patients must be discontinued from the study medication for the following reasons:
[…]

Occurrence of adverse drug reactions, which in the investigator’s opinion have 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 such as anticipated treatment effect, progression of underlying disease, 
occurrence of side effects, and alternative treatment options must be considered.)

If a subject, during the course of the study, develops 
a) renal disease that leads to eGFR <15/mL/min/1.73m2, 
b) hepatic insufficiency classified as Child-Pugh C.  

[…]

If treatment is interrupted for >28 consecutive days during the open-label extension 
period (of the long-term extension phase)
5.2.1.3
Handling of withdrawals or discontinuations from study medication
Old text:
If the patient discontinues study drug prematurely during the main treatment phase (Week 0 –
Week 52) he/she will be invited to come for limited assessments (mRSS, pulmonary function 
test [FVC and DLCO including hemoglobin measurement at the local laboratory] , and PROs) 
at Week 12, Week 26, Week 39, and Week 52, depending on the timing of discontinuation.  


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New text:
If the patient discontinues study drug prematurely during the main treatment phase (Week 0 –
Week 52) he/she will be invited to come for limited assessments (mRSS, pulmonary function 
test [FVC and DLCO including hemoglobin measurement at the local laboratory], PROs, and 
patient’s and physician’s global assessment) at Week 12, Week 26, Week 39, and Week 52, 
depending on the timing of discontinuation.  
6.5
Blinding - amended
Old text:
[Not applicable. New text added.]
New text:
Appropriate measures will be taken to maintain blinding of the study team while PK and 
biomarker analyses are ongoing. Data with a potential to unblind (eg, plasma concentrations) 
are not to be handled by or shown to the study team members and will only be uploaded into 
the clinical database after official unblinding. The process of data flow will be documented 
separately (see also Section 7.4 and Section 7.6.3.).
Statistical analysis as described in the SAP will be done after database lock and authorization 
of data release according to standard operating procedures.
6.9
Prior and concomitant therapy – amended
Old text:
[…] These treatments will also be allowed as new-onset during the study at the discretion of 
the investigator to treat SSc-specific adverse events (eg, Raynaud’s phenomena, joint 
inflammation, new onset renal crisis).
[…]
Table 6-2
Prohibited prior and concomitant therapy - amended


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Therapy
Timeframe 
Chlorambucil, bone marrow transplantation, or total lymphoid irradiation
Any previous therapya
Rituximab or other anti-CD20 antibodies
Within 6 months prior to 
the screening visita
Infliximab, certolizumab, golimumab, adalimumab, abatacept, 
leflunomide or tocilizumab
Within 8 weeks prior to the 
screening visita,
Methotrexate, cyclophosphamide, hydroxychloroquine, cyclosporine A, 
azathioprine, mycophenolate mofetil, rapamycin, colchicine, D 
penicillamine, tacrolimus, mizoribine or intravenous immunoglobulin
Within 4 weeks prior to the 
screening visita,
Etanercept
Within 2 weeks prior to the 
screening visita,
Anakinra
Within 1 week prior to the 
screening visita
Nitrates or NO donors (such as amyl nitrate) in any form, including 
topical; phosphodiesterase (PDE) 5 (PDE5) inhibitors (such as 
sildenafil, tadalafil, vardenafil); and nonspecific PDE5 inhibitors 
(theophylline, dipyridamole)
Concomitant therapy with 
study drug
Prostacyclin analogs (oral beraprost for digital ulcers / Raynaud’s 
disease and short-term / intermittent therapy of up to 21 days 
with intravenous prostacyclin analogs for digital / vascular lesions is 
allowed)
Concomitant therapy with 
study drug 
a
Concomitant use of these treatments with study medication is also prohibited, except for certain 
agents from Week 26 onwards; please see “Rescue Therapy” below.  
Rescue therapy
[…] The decision to initiate rescue therapy is based on investigator discretion in eligible 
patients.  Rescue therapy may include any of the following 4 agents:  methotrexate, 
mycophenolate mofetil, cyclophosphamide, or azathioprine. These treatments are not 
provided by the Sponsor.
New text:
[…] These treatments will also be allowed as new-onset during the study at the discretion of 
the investigator to treat SSc-specific adverse events (eg, Raynaud’s phenomena, joint 
inflammation, new onset renal crisis).
During the long-term extension phase (ie, after completion of all efficacy- and safety-related 
procedures at Visit 12), except for the contraindicated nitrates or NO donors and PDE5 
inhibitors, the addition of any other concomitant medication is at the discretion of the 
investigator.
[….]
Table 6-2
Prohibited prior and concomitant therapy - amended


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Therapy
Timeframe 
Chlorambucil, bone marrow transplantation, or total lymphoid irradiation
Any previous therapya, b
Rituximab or other anti-CD20 antibodies
Within 6 months prior to 
the screening visita, b
Infliximab, certolizumab, golimumab, adalimumab, abatacept, 
leflunomide or tocilizumab
Within 8 weeks prior to the 
screening visita, b
Methotrexate, cyclophosphamide, hydroxychloroquine, cyclosporine A, 
azathioprine, mycophenolate mofetil, rapamycin, colchicine, D 
penicillamine, tacrolimus, mizoribine or intravenous immunoglobulin
Within 4 weeks prior to the 
screening visita, b
Etanercept
Within 2 weeks prior to the 
screening visita,b
Anakinra
Within 1 week prior to the 
screening visita,b
Nitrates or NO donors (such as amyl nitrate) in any form, including 
topical; phosphodiesterase (PDE) 5 (PDE5) inhibitors (such as 
sildenafil, tadalafil, vardenafil); and nonspecific PDE5 inhibitors 
(theophylline, dipyridamole)
Concomitant therapy with 
study drug
Prostacyclin analogs (oral beraprost for digital ulcers / Raynaud’s 
disease and short-term / intermittent therapy of up to 21 days 
with intravenous prostacyclin analogs for digital / vascular lesions is 
allowed)
Concomitant therapy with 
study drug 
a
Concomitant use of these treatments with study medication is also prohibited, except for certain 
agents from Week 26 onwards; please see “Rescue Therapy” below.  
b
Concomitant use of these medications will be allowed during the long-term extension phase
Rescue therapy
[…] The decision to initiate rescue therapy is based on investigator discretion in eligible 
patients.  Rescue therapy may include any of the following 4 agents:  methotrexate, 
mycophenolate mofetil, cyclophosphamide, or azathioprine.

Worsening of inflammatory joint disease or myositis.  
Rescue therapy can be initiated at investigator’s discretion in eligible patients. In addition to 
the 4 agents methotrexate, mycophenolate mofetil, cyclophosphamide, or azathioprine, 
hydroxychloroquine will be allowed for the treatment of inflammatory joint disease and 
myositis.
These treatments are not provided by the Sponsor.
7.1.1 Tabulated overview - amended
The visit window for Visit 18 was changed from ±14 days to ±2 days in the schedule of events 
(Table 7-1). The visit windows for all following visits (Vn) remains unchanged.


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7.1.2.10
Premature discontinuation of study drug treatment - amended
Old text:
If the patient discontinues study drug prematurely during the main treatment phase (Week 0 –
Week 52) he/she will be invited to come for limited assessments (mRSS, pulmonary function 
test [FVC and DLCO including hemoglobin measurement at the local laboratory] , and PROs) 
at Week 12, Week 26, Week 39, and Week 52, depending on the timing of discontinuation.  
New text:
If the patient discontinues study drug prematurely during the main treatment phase (Week 0 –
Week 52) he/she will be invited to come for limited assessments (mRSS, pulmonary function 
test [FVC and DLCO including hemoglobin measurement at the local laboratory], PROs, and 
patient’s and physician’s global assessment) at Week 12, Week 26, Week 39, and Week 52, 
depending on the timing of discontinuation.  
7.3
Efficacy - amended
Old text:
Key secondary endpoint:

CRISS, consisting of five variables: mRSS, FVC % predicted, physician and patient 
global assessments, and HAQ-DI score (from SHAQ patient reported outcome)
New text:
Key secondary endpoint:

CRISS at Week 52, consisting of five variables: mRSS, FVC % predicted, physician 
and patient global assessments, and HAQ-DI score (from SHAQ patient reported 
outcome)
7.4
Pharmacokinetics / pharmacodynamics
Old text:
At these study visits the patients should present themselves to the hospital without taking the 
morning dose of study medication. The trough PK sample should always be obtained at up to 
1 hour before administration of the morning dose of study medication.
It is essential that the exact time of blood sampling and time of dose administration of the 3 
preceding doses of study medication are documented accurately in the eCRF.
For investigation of exposure behavior, plasma concentrations of BAY63-2521 and its 
metabolite (M1) will be determined at the times given below using a sparse sampling 
approach in all participating patients. 
[…]
Plasma concentration time points will be compared to the available plasma concentration 
profiles in healthy volunteers and selected patient populations.
[…]


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Pharmacokinetic (PK) samples will be analyzed under the responsibility of the Bayer 
HealthCare Bioanalytics Laboratory, Bayer Pharma AG, GDD-GED-DMPK Bioanalytics, 
42096 Wuppertal, Germany.
New text:
At these study visits the patients should present themselves to the hospital without taking the 
morning dose of study medication. The trough PK sample should always be obtained at up to 
1 hour before administration of the morning dose of study medication and approximately 5 to 
15 hours after the evening dose.
It is essential that the exact time of blood sampling and time of dose administration of the 
3 preceding doses of study medication are documented accurately in the eCRF. For samples 
taken before riociguat administration, also the time of the first dose taken at the visit needs to 
be documented.
For investigation of exposure behavior, plasma concentrations of BAY63-2521 and its 
metabolite (M1) will be determined at the times given below using a sparse sampling 
approach in all participating patients. If the investigator decides to take additional PK 
samples, those may be used for PK analysis as well.
[…]
Plasma concentration time points will be compared to the available plasma concentration 
profiles in healthy volunteers and selected patient populations. Pharmacokinetic and 
exposure-response analysis might be performed using population approaches (popPK and 
popPK/PD, eg, by non-linear mixed effect modeling). Analysis and report will be done under 
separate cover. This evaluation might be started prior to database lock. If this is applicable, 
appropriate measures will be taken to maintain blinding of the study team, eg, data will be 
stored separately, and members of the study team will neither have access to the 
randomization list nor to individual data.
[…]
Pharmacokinetic (PK) samples will be analyzed under the responsibility of the Bayer 
HealthCare Bioanalytics Laboratory, Bayer Pharma AG, GDD-GED-DMPK Bioanalytics, 
42096 Wuppertal, Germany. The bioanalyst will be unblinded and have access to the 
randomization list. 
7.5.1.1
Definitions 
Old text:

Conditions that started or deteriorated after signing of informed consent will be 
documented as AEs.
New text:

Conditions that started or deteriorated after signing of informed consent will be 
documented as AEs. This includes any conditions related to the underlying disease.


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7.6.2 Laboratory parameters - amended
Old text:
Patients with isolated AST or ALT >3xULN or bilirubin >2xULN at screening and/or 
baseline will have additional analysis of coagulation tests, AST, ALT, AP, GGT, total 
bilirubin and serum albumin until normalization and/ or stabilization at Visit 2 (Day 14), Visit 
3 (Day 28), Visit 4 (Day 42), Visit 5 (Day 56), as needed.  Worsening of the parameters in the 
order of 2-fold from baseline values will be considered clinically significant [22] and 
additional diagnostic procedures may be requested.
Patients entering the trial with eGFR 15-29 mL/min/1.73m2 will be undergo additional serum 
creatinine and eGFR calculation until normalization and/ or stabilization at Visit 2 (Day 14), 
Visit 3 (Day 28), Visit 4 (Day 42), and Visit 5 (Day 56), as needed.  A decrease in eGFR 
equal or greater than 5ml/min/1.73m2 in these patients (eGFR 15-29 ml/min/1.73m2) during 
the study or a reduction of 25% or more in 12 months will be considered clinically significant 
[23,24].
New text:
Patients with isolated AST or ALT >3xULN or bilirubin >2xULN at screening and/or 
baseline will have additional analysis of coagulation tests, AST, ALT, AP, GGT, total 
bilirubin and serum albumin until normalization and/ or stabilization at Visit 2 (Day 14), Visit 
3 (Day 28), Visit 4 (Day 42), Visit 5 (Day 56), as needed. Worsening of the parameters in the 
order of 2-fold from baseline values will be considered clinically significant [22] and 
additional diagnostic procedures may be requested. See Section 5.2.1.2 for discontinuation 
criteria related to liver function.
Patients entering the trial with eGFR 15-29 mL/min/1.73m2 will be undergo additional serum 
creatinine and eGFR calculation until normalization and/ or stabilization at Visit 2 (Day 14), 
Visit 3 (Day 28), Visit 4 (Day 42), and Visit 5 (Day 56), as needed.  A decrease in eGFR 
equal or greater than 5ml/min/1.73m2 in these patients (eGFR 15-29 ml/min/1.73m2) during 
the study or a reduction of 25% or more in 12 months will be considered clinically significant 
[23,24]. See Section 5.2.1.2 for discontinuation criteria related to eGFR values.
7.6.3 Exploratory Biomarkers 
Old text:
[Not applicable. New text added in the end of the section.]
New text:
The evaluation of biomarkers might be started prior to database lock; if this is applicable, 
appropriate measures will be taken to maintain blinding of the study team (see also Section 
6.5 and Section 7.4).  
The results of the biomarker analysis will be reported separately to the clinical study report.


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7.6.15 Patient’s and physician’s global assessment
Old text:
Frequency: Visit 1 (Day 0), Visit 10 (Week 26) and Visit 12 (Week 52) and termination visit 
(not needed after V12).
New text:
Frequency: Visit 1 (Day 0), Visit 10 (Week 26) and Visit 12 (Week 52), termination visit (not 
needed after V12), and visits with limited assessments.
8.4.2.2
Secondary and exploratory endpoints
Old text:
American College of Rheumatology Combined Response Index for Systemic Sclerosis
Application of CRISS algorithm in a randomized clinical trial is a 2-step process.  
[…]
If the patient is determined to exhibit improvement in Step 1 (ie, not assigned a 0.0), Step 2 
involves computing the predicted probability of improving (a score between 0.0 and 1.0, 
inclusive) for each patient using the equation:
	.	.∗∆.∗∆%.∗∆ .∗∆! ".∗∆#$%!&'
	.	.∗∆.∗∆%.∗∆ .∗∆! ".∗∆#$%!&'
where ∆MRSS indicates the change in mRSS from baseline to follow-up, ∆FVC denotes the 
change in FVC % predicted from baseline to follow-up, ∆Pt-glob indicates the change in patient 
global assessment, ∆MD-glob denotes the change in physician global assessment, and ∆HAQ-DI is 
the change in HAQ-DI.
[…]
In each scenario, a decrease of mRSS or HAQ-DI from baseline to follow-up and an increase 
in FVC % predicted corresponds to very high probabilities of improving.
New text:
American College of Rheumatology Combined Response Index for Systemic Sclerosis
The key secondary endpoint will be the CRISS at Week 52.
Application of CRISS algorithm in a randomized clinical trial is a 2-step process.  
[…]
If the patient is determined to exhibit improvement in Step 1 (ie, not assigned a 0.0), Step 2 
involves computing the predicted probability of improving (a score between 0.0 and 1.0, 
inclusive) for each patient using the equation:
	.	.∗∆.∗∆%.∗∆ .∗∆! ".∗∆#$%!&'
	.	.∗∆.∗∆%.∗∆ .∗∆! ".∗∆#$%!&'
where ∆MRSS indicates the change in mRSS from baseline to Week 52, ∆FVC denotes the 
change in FVC % predicted from baseline to Week 52, ∆Pt-glob indicates the change in patient 
global assessment, ∆MD-glob denotes the change in physician global assessment, and ∆HAQ-DI is 
the change in HAQ-DI.


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[…]
In each scenario, a decrease of mRSS or HAQ-DI from baseline to Week 52 and an increase 
in FVC % predicted corresponds to very high probabilities of improving.
8.5
Planned interim analyses
Old text:
The main treatment phase will be unblinded for data analysis when the last patient completes 
the dose-titration period of the long-term extension phase and the database for the main 
treatment phase is declared clean, whichever occurs last.
The first safety update will be performed on the long-term extension phase when the last 
patient completes the dose-titration period after the first 10 weeks of this phase.  
New text:
The main treatment phase will be unblinded for data analysis when the last patient completes 
the main treatment phase (Visit 12) and the database for the main treatment phase is declared 
clean, whichever occurs last.
The first safety update will be performed on the long-term extension phase when the last 
patient completes 24 weeks of treatment (Visit 19).
8.6
Determination of sample size 
Old text:
The primary efficacy estimand in this study will be change in mRSS from baseline to 
Week 52.  Assuming a standard deviation of 8 points, a power of 80% and a two-sided 
significance level of 5%, with a 1:1 randomization, then to detect a placebo-adjusted 
difference of 4 points, 64 patients in each treatment group, a total of 128 patients, would be 
required to be valid for the ITT analysis.  Allowing for up to two patients randomized and not 
treated, a total of 130 randomized patients are planned.
For the secondary efficacy measure based on the mRSS progression rate, if the sample size is 
fixed at 128 patients with a 1:1 randomization, then with an event rate on placebo of 20% and 
on riociguat of 4% (a relative risk reduction of 80%), the study has a power of 71% to detect 
this as statistically significant at a two-sided p ≤ 0.05.
Sources of these sample size and power calculations are nQuery version 7.0, modules
MTT0-1 and PTT2-1.
New text:
The primary efficacy estimand in this study will be change in mRSS from baseline to 
Week 52. Assuming a standard deviation of 8 points, a power between 70% and 80% and a 
two-sided significance level of 5% with a 1:1 randomization, then to detect a placebo-adjusted 
difference of 4 points, between 51 and 64 patients in each treatment group, a total of 102 to
128 patients, would be required to be valid for the ITT analysis (see Table 8–2). Allowing for 
up to two patients randomized and not treated, approximately 130 randomized patients are 
planned.


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Table 8-2
Power calculations: power varying from 70% to 80% in 2% stages
N per group
51
53
56
58
61
64
Total N
102
106
112
116
122
128
Power (%)
70
72
74
76
78
80
N = number of patients
Sources of these sample size and power calculations are nQuery version 7.0, module MTT0-1.
9.3
Data processing
Old text:
For data coding (eg, AEs, medication), internationally recognized and accepted dictionaries 
will be used. After its initial release for biometrical analysis, the clinical database is planned 
to be re-opened for the inclusion of the following additional data: eg, PK data, antibody data.
New text:
For data coding (eg, AEs, medication), internationally recognized and accepted dictionaries 
will be used. After its initial release for biometrical analysis, the clinical database is planned 
to be re-opened for the inclusion of the following additional data: eg, PK data, biomarker
data.


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13.4
Amendment 6
Amendment 6 was approved on 02 MAY 2017.
13.4.1
Overview of changes to the study
This amendment was implemented based on the recommendation of the data monitoring 
committee (DMC) after review of the safety analysis on 01 MAR 2017. Due to increased 
complaints of both palpitations and dizziness in subjects with interstitial lung disease (ILD) 
noted by the DMC, the assessment of orthostatic changes in blood pressure and heart rate as 
well as the measurement of oxygen saturation (using forehead pulse oximetry) were added to 
the protocol assessments for all subjects. As recruitment for this study was already completed, 
the new assessments will not be implemented starting with the screening visit, but only for 
study visits, which will be performed after implementation of this amendment.
Additionally, an error in the description of the units provided in exclusion criterion 6 was 
corrected.
Correction of typographical errors and minor editorial changes are not specified in the list of 
changes below. New text is displayed as underlined; text that was deleted is presented as 
strike-through text.
13.4.2
Changes to the protocol text
4.1.2 Main treatment phase (Week 0 to Week 52) – amended
Old text:
Dose titration algorithm
The study medication dose for the next titration step will be determined every 2 weeks 
according to the patient’s well-being and the peripheral systolic blood pressure (SBP) 
measured at trough before intake of the morning according to the following algorithm (dose 
titration scheme):

If SBP is ≥95 mmHg and the patient has no signs or symptoms of hypotension, the 
dosage should be increased by 0.5 mg TID. 

If SBP is < 95 mmHg, the dosage should be maintained provided the patient does not 
show any signs or symptoms of hypotension.

If SBP is < 95 mmHg, and the patient exhibits signs or symptoms of hypotension, the 
current dosage should be decreased by 0.5 mg TID.


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New text:
Dose titration algorithm
The study medication dose for the next titration step will be determined every 2 weeks 
according to the patient’s well-being and the peripheral systolic blood pressure (SBP) 
measured at trough before intake of the morning dose as well as based on any of the 
2 measurements (supine or sitting) performed 2 hours after dose intake to assess orthostatic 
changes according to the following algorithm (dose titration scheme):

If SBP is ≥95 mmHg and the patient has no signs or symptoms of hypotension, the 
dosage should be increased by 0.5 mg TID. 

If SBP is < 95 mmHg, the dosage should be maintained provided the patient does not 
show any signs or symptoms of hypotension.

If SBP is < 95 mmHg, and the patient exhibits signs or symptoms of hypotension, the 
current dosage should be decreased by 0.5 mg TID.
5.1.2 Exclusion Criteria - amended
Old text:
6.
Laboratory examinations

Patients with:  hemoglobin <9.0 g/dL, white blood cell (WBC) count <3000/mm3
(<3 × 109/L), platelet count <100,000/mm3 (<3 × 109/L)
New text:
6.
Laboratory examinations

Patients with:  hemoglobin <9.0 g/dL, white blood cell (WBC) count <3000/mm3
(<3 × 109/L), platelet count <100,000/mm3 (<100 × 109/L)


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7.1.1 Tabulated overview - amended
Old text:
Table 7–1
Schedule of evaluations - amended
Scr
Main Treatment Phase  (Double-blind) v
Long-term Extension Phase  
Scr 
Phase
Dose-Titration Period 
Maintenance Period
Dose-Titration Period
Open-label 
Extension Period
Safety Follow-
up
Visit
V0
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12a
V13
V14
V15
V16
V17
V18 – Vn
(q 12 wk)
TVb
SFU
Week
-2
0
2
4
6
8
10
12
14
20
26
39
52
54
56
58
60
62
64 – n 
Day
-14
to
-1
0
14 
± 2
28 
± 2
42 
± 2
56 
± 2
70 
± 2
84 
± 2
98 
± 2
140 
± 2
182 
± 2
273 
± 14
364
-14
to +2
378 
± 2
392 
± 2
406 
± 2
420 
± 2
434 
± 2
448 – (n + 84)
V18 ± 2
Vn ± 14
30 + 5
Written informed consent
X
Inclusion / exclusion criteria
X
X
Demographic data
X
Medical and surgical history
X
X
Other history (alcohol)
X
Smoking history
X
X
X
X
X
X
Height and weightc
X
X
X
X
X
X
X
X
Physical examination
X
X
X
X
X
X
X
X
mRSS
X
X
X
X
X
X
X
Assessment of Raynaud’s 
attacks
Xd
Xe
Xf
Xe
Digital ulcer net burden
assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Tender & swollen joint count
X
X
Xg


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17 APR 2018
Version 6.0
Page:  149 of 167
Table 7–1
Schedule of evaluations - amended
Scr
Main Treatment Phase  (Double-blind) v
Long-term Extension Phase  
Scr 
Phase
Dose-Titration Period 
Maintenance Period
Dose-Titration Period
Open-label 
Extension Period
Safety Follow-
up
Visit
V0
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12a
V13
V14
V15
V16
V17
V18 – Vn
(q 12 wk)
TVb
SFU
Week
-2
0
2
4
6
8
10
12
14
20
26
39
52
54
56
58
60
62
64 – n 
Day
-14
to
-1
0
14 
± 2
28 
± 2
42 
± 2
56 
± 2
70 
± 2
84 
± 2
98 
± 2
140 
± 2
182 
± 2
273 
± 14
364
-14
to +2
378 
± 2
392 
± 2
406 
± 2
420 
± 2
434 
± 2
448 – (n + 84)
V18 ± 2
Vn ± 14
30 + 5
Vital signs (BP, HR)h
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs post-dose 
(BP, HR)i,j
Xi
Xj
Xi
Blood sample for safetyk, u
X
X
Xu
Xu
Xu
Xu
X
X
X
X
X
X
X
X
Blood sample for PK
Xl
Xm
Xm
Xm
Xm
Xm
Xn
Xl
Xm
Xm
Xm
Xm
Xm
Blood sample for biomarkers 
X
X
Xr
Blood sample for 
Autoantibody screen
X
Pregnancy test (if 
applicable)o
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECGp
X
X
X
X
X
X
X
X
X
Pulmonary function testsq
X
X
X
X
X
X
X
Skin biopsy
X
X
Xr
Questionnairess
X
X
X
X
X
X
X
Patient’s and physician’s 
global assessment
X
X
X
Xg
Patient interference with skin 
X
X
X
Xg
Tendon Friction Rubst
X
X


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17 APR 2018
Version 6.0
Page:  150 of 167
Table 7–1
Schedule of evaluations - amended
Scr
Main Treatment Phase  (Double-blind) v
Long-term Extension Phase  
Scr 
Phase
Dose-Titration Period 
Maintenance Period
Dose-Titration Period
Open-label 
Extension Period
Safety Follow-
up
Visit
V0
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12a
V13
V14
V15
V16
V17
V18 – Vn
(q 12 wk)
TVb
SFU
Week
-2
0
2
4
6
8
10
12
14
20
26
39
52
54
56
58
60
62
64 – n 
Day
-14
to
-1
0
14 
± 2
28 
± 2
42 
± 2
56 
± 2
70 
± 2
84 
± 2
98 
± 2
140 
± 2
182 
± 2
273 
± 14
364
-14
to +2
378 
± 2
392 
± 2
406 
± 2
420 
± 2
434 
± 2
448 – (n + 84)
V18 ± 2
Vn ± 14
30 + 5
Randomization (IxRS)
X
Dispensation of study drug
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Drug accountability
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events recording
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Prior and concomitant 
therapy
X
X 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Survival status
X
Abbreviations:  BP = blood pressure; ECG = electrocardiogram; TV = Termination Visit; SFU = 30-Day Safety Follow-up (30 [+5] days after the last dose of study drug); HR = heart rate; IxRS = 
telephone-based or web-based response system; mRSS = modified Rodnan skin score; PK = pharmacokinetics; q 12 wk = every 12 weeks; Scr = Screening.
Note:  Day 0 (Visit 1) is the baseline visit.
a
Visit 12 (Week 52) is the last visit in the Maintenance Period of the Main Treatment phase and the first (baseline) visit in the Long-term Extension phase.
b
To be performed as soon as possible after discontinuation of study medication.  
c
Height to be measured only at the screening visit
d
Patient to be provided with 7-day diary, to complete daily for 7 consecutive days leading up to Visit 1 
e
Patient and physician assessment of Raynaud’s disease (see Section 7.6.12)
f
Patient to be provided with 7-day diary, to complete daily for 7 consecutive days leading up to Visit 8.
g
Must not be performed if TV is after V12.
h
Blood pressure and heart rate will be measured at all visits with the patient in a sitting position, after the patient has been at rest for at least 5 minutes.  The same arm is always used for these 
measurements (see Section 7.6.5).
i
Vital signs to be measured within 20 minutes prior to each post-dose PK sampling (see Table 7–2)
j
Vital signs to be measured within 20 minutes prior to PK sampling (see Table 7–2)
k
Coagulation tests to be performed at a local laboratory
l
Samples for PK to be taken 1 – 2 hours and 3 – 4 hours after the morning dose of study medication (see Table 7–2)


Integrated Clinical Study Protocol
No. BAY 63-2521 / 16277
17 APR 2018
Version 6.0
Page:  151 of 167
m
Sample for PK to be taken up to 1 hour before the morning dose of study medication (trough) (see Table 7–3)
n
Samples for PK to be taken up to 1 hour before the morning dose of study medication (trough) and 2 – 3 hours after the morning dose of study medication (peak) 
(see Table 7–4)
o
For women of childbearing potential only. Serum pregnancy test is required only at screening; pregnancy testing (urine) will be done every 4 weeks and should continue until 30 days after the 
last dose of study drug. When pregnancy testing coincides with a visit, the test should be performed at the site, but otherwise should be performed at home. 
p
Standard ECG (12-lead ECG) will be recorded with the patient in the supine position, after the patient has been at rest for at least 5 minutes (see Section 7.6.7).
q
Pulmonary function tests include forced vital capacity (FVC) and diffusion capacity of the lung for carbon monoxide (DLCO).
r
Must be done at a TV if this visit occurs before Visit 8.
s
Questionnaires include Scleroderma Health Assessment Questionnaire (SHAQ), Short Form 36 (SF-36), Patient-Reported Outcomes Measurement Information System (PROMIS)-29, and 
University of California, Los Angeles, Scleroderma Clinical Trial Consortium Gastrointestinal Scale (UCLA SCTC GIT) 2.0.
t
Assessment of the presence or absence of tendon friction rubs
u     Additional monitoring may apply for patients with impaired renal and liver function at Visit 2, 3, 4, 5 as needed (see Section 7.6.2)149
v
All patients who discontinue study drug prematurely during the main treatment phase (Week 0 – Week 52) will be invited to come for limited assessments (see Sections 7.1.2.10 and 7.6.2).150
                                                
149 Per Amendment 1
150 Per Amendment 4


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No. BAY 63-2521 / 16277
17 APR 2018
Version 6.0
Page:  152 of 167
New text:
Table 7–1
Schedule of evaluations - amended
Scr
Main Treatment Phase  (Double-blind) v
Long-term Extension Phase  
Scr 
Phase
Dose-Titration Period 
Maintenance Period
Dose-Titration Period
Open-label 
Extension Period
Safety Follow-
up
Visit
V0
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12a
V13
V14
V15
V16
V17
V18 – Vn
(q 12 wk)
TVb
SFU
Week
-2
0
2
4
6
8
10
12
14
20
26
39
52
54
56
58
60
62
64 – n 
Day
-14
to
-1
0
14 
± 2
28 
± 2
42 
± 2
56 
± 2
70 
± 2
84 
± 2
98 
± 2
140 
± 2
182 
± 2
273 
± 14
364
-14
to +2
378 
± 2
392 
± 2
406 
± 2
420 
± 2
434 
± 2
448 – (n + 84)
V18 ± 2
Vn ± 14
30 + 5
Written informed consent
X
Inclusion / exclusion criteria
X
X
Demographic data
X
Medical and surgical history
X
X
Other history (alcohol)
X
Smoking history
X
X
X
X
X
X
Height and weightc
X
X
X
X
X
X
X
X
Physical examination
X
X
X
X
X
X
X
X
mRSS
X
X
X
X
X
X
X
Assessment of Raynaud’s 
attacks
Xd
Xe
Xf
Xe
Digital ulcer net burden
assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Tender & swollen joint count
X
X
Xg
Oximetryw
X
X
X
X
X
X
X
X
X
X
X
X


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Version 6.0
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Table 7–1
Schedule of evaluations - amended
Scr
Main Treatment Phase  (Double-blind) v
Long-term Extension Phase  
Scr 
Phase
Dose-Titration Period 
Maintenance Period
Dose-Titration Period
Open-label 
Extension Period
Safety Follow-
up
Visit
V0
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12a
V13
V14
V15
V16
V17
V18 – Vn
(q 12 wk)
TVb
SFU
Week
-2
0
2
4
6
8
10
12
14
20
26
39
52
54
56
58
60
62
64 – n 
Day
-14
to
-1
0
14 
± 2
28 
± 2
42 
± 2
56 
± 2
70 
± 2
84 
± 2
98 
± 2
140 
± 2
182 
± 2
273 
± 14
364
-14
to +2
378 
± 2
392 
± 2
406 
± 2
420 
± 2
434 
± 2
448 – (n + 84)
V18 ± 2
Vn ± 14
30 + 5
Vital signs (BP, HR)h
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs post-dose 
(BP, HR)i,j
Xi
Xj
Xi
BP and HR for assessment 
of orthostatic changesx
X
X
X
X
X
X
X
Blood sample for safetyk, u
X
X
Xu
Xu
Xu
Xu
X
X
X
X
X
X
X
X
Blood sample for PK
Xl
Xm
Xm
Xm
Xm
Xm
Xn
Xl
Xm
Xm
Xm
Xm
Xm
Blood sample for biomarkers 
X
X
Xr
Blood sample for 
Autoantibody screen
X
Pregnancy test (if 
applicable)o
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECGp
X
X
X
X
X
X
X
X
X
Pulmonary function testsq
X
X
X
X
X
X
X
Skin biopsy
X
X
Xr
Questionnairess
X
X
X
X
X
X
X
Patient’s and physician’s 
global assessment
X
X
X
Xg
Patient interference with skin 
X
X
X
Xg


Integrated Clinical Study Protocol
No. BAY 63-2521 / 16277
17 APR 2018
Version 6.0
Page:  154 of 167
Table 7–1
Schedule of evaluations - amended
Scr
Main Treatment Phase  (Double-blind) v
Long-term Extension Phase  
Scr 
Phase
Dose-Titration Period 
Maintenance Period
Dose-Titration Period
Open-label 
Extension Period
Safety Follow-
up
Visit
V0
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12a
V13
V14
V15
V16
V17
V18 – Vn
(q 12 wk)
TVb
SFU
Week
-2
0
2
4
6
8
10
12
14
20
26
39
52
54
56
58
60
62
64 – n 
Day
-14
to
-1
0
14 
± 2
28 
± 2
42 
± 2
56 
± 2
70 
± 2
84 
± 2
98 
± 2
140 
± 2
182 
± 2
273 
± 14
364
-14
to +2
378 
± 2
392 
± 2
406 
± 2
420 
± 2
434 
± 2
448 – (n + 84)
V18 ± 2
Vn ± 14
30 + 5
Tendon Friction Rubst
X
X
Randomization (IxRS)
X
Dispensation of study drug
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Drug accountability
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events recording
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Prior and concomitant 
therapy
X
X 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Survival status
X
Abbreviations:  BP = blood pressure; ECG = electrocardiogram; TV = Termination Visit; SFU = 30-Day Safety Follow-up (30 [+5] days after the last dose of study drug); HR = heart rate; IxRS = 
telephone-based or web-based response system; mRSS = modified Rodnan skin score; PK = pharmacokinetics; q 12 wk = every 12 weeks; Scr = Screening.
Note:  Day 0 (Visit 1) is the baseline visit.
a
Visit 12 (Week 52) is the last visit in the Maintenance Period of the Main Treatment phase and the first (baseline) visit in the Long-term Extension phase.
b
To be performed as soon as possible after discontinuation of study medication.  
c
Height to be measured only at the screening visit
d
Patient to be provided with 7-day diary, to complete daily for 7 consecutive days leading up to Visit 1 
e
Patient and physician assessment of Raynaud’s disease (see Section 7.6.12)
f
Patient to be provided with 7-day diary, to complete daily for 7 consecutive days leading up to Visit 8.
g
Must not be performed if TV is after V12.
h
Blood pressure and heart rate will be measured at all visits with the patient in a sitting position, after the patient has been at rest for at least 5 minutes.  The same arm is always used for these 
measurements (see Section 7.6.5).
i
Vital signs to be measured within 20 minutes prior to each post-dose PK sampling (see Table 7–2)
j
Vital signs to be measured within 20 minutes prior to PK sampling (see Table 7–2)


Integrated Clinical Study Protocol
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Version 6.0
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k
Coagulation tests to be performed at a local laboratory
l
Samples for PK to be taken 1 – 2 hours and 3 – 4 hours after the morning dose of study medication (see Table 7–2)
m
Sample for PK to be taken up to 1 hour before the morning dose of study medication (trough) (see Table 7–3)
n
Samples for PK to be taken up to 1 hour before the morning dose of study medication (trough) and 2 – 3 hours after the morning dose of study medication (peak) 
(see Table 7–4)
o
For women of childbearing potential only. Serum pregnancy test is required only at screening; pregnancy testing (urine) will be done every 4 weeks and should continue until 30 days after the 
last dose of study drug. When pregnancy testing coincides with a visit, the test should be performed at the site, but otherwise should be performed at home. 
p
Standard ECG (12-lead ECG) will be recorded with the patient in the supine position, after the patient has been at rest for at least 5 minutes (see Section 7.6.7).
q
Pulmonary function tests include forced vital capacity (FVC) and diffusion capacity of the lung for carbon monoxide (DLCO).
r
Must be done at a TV if this visit occurs before Visit 8.
s
Questionnaires include Scleroderma Health Assessment Questionnaire (SHAQ), Short Form 36 (SF-36), Patient-Reported Outcomes Measurement Information System (PROMIS)-29, and 
University of California, Los Angeles, Scleroderma Clinical Trial Consortium Gastrointestinal Scale (UCLA SCTC GIT) 2.0.
t
Assessment of the presence or absence of tendon friction rubs
u     Additional monitoring may apply for patients with impaired renal and liver function at Visit 2, 3, 4, 5 as needed (see Section 7.6.2)151
v
All patients who discontinue study drug prematurely during the main treatment phase (Week 0 – Week 52) will be invited to come for limited assessments (see Sections 7.1.2.10 and 7.6.2).152
w
Oxygen saturation will be measured using forehead pulse oximetry. At visits with blood samples for PK and blood pressure measurements for the assessment of orthostatic changes, post-dose 
measurements will be performed in addition to pre-dose measurements (see Section 7.6.18, Table 7–2, Table 7–3, Table 7–4)
x
Measure supine and sitting blood pressure and heart rate to check for orthostatic changes approximately 2 hours after intake of study medication. (see Section 7.6.5, Table 7–2, Table 7–3, 
Table 7–4).
                                                
151 Per Amendment 1
152 Per Amendment 4


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7.1.1 Tabulated overview - amended
Old text:
Pharmacokinetics sampling flow charts
Profile day (Visit 1 and Visit 12)

1 2 hours after administration of the morning dose of study medication

3 – 4 hours after administration of the morning dose of study medication
Table 7–2:  Profile Day PK Sampling (Visit 1 and Visit 12)
Visit 1 and Visit 12 (profile days)
Cycle of procedures
Order of 
procedures
Starting point of procedures
Time interval (h)
00
00
1 – 2 h
3 – 4 h
Blood pressure, heart rate 
X
Administration of morning dose of study 
medication 
X
Blood pressure, heart rate (within 20 minutes 
prior to PK sample)
X
Blood sample for PK
X
Blood pressure, heart rate (within 20 minutes 
prior to PK sample)
X
Blood sample for PK
X
Abbreviations:  h = hours; PK = pharmacokinetic.
Visits 2 to 6 and Visits 13 to 17

Up to 1 hour before administration of the morning dose of study medication (trough)
Table 7–3:  PK Sampling (Visits 2 – 6 and Visits 13 – 17)
Visit 2 to Visit 6 and Visit 13 to Visit 17
Cycle of procedures
Order of 
procedures
Starting point of procedures
Time interval (h)
1 h 00
00
00
Blood sample for PK
X
Blood pressure, heart rate
X
Administration of morning dose of study medication 
X
Abbreviations:  h = hours; PK = pharmacokinetic.
Visit 11

Up to 1 hour before administration of morning dose of study medication (trough)

2 3 hours after administration of morning dose of study medication (peak)


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Table 7–4
PK Sampling (Visit 11)
Visit 11
Cycle of procedures
Order of 
procedures
Starting point of procedures
Time interval (h)
1 h 00
00
00
2 – 3 h
Blood sample for PK
X
Blood pressure, heart rate
X
Administration of morning dose of study 
medication 
X
Blood pressure, heart rate (within 20 minutes 
prior to PK sampling)
X
Blood sample for PK
X
Abbreviations:  h = hour; PK = pharmacokinetics.
New text:
Pharmacokinetics sampling flow charts
Profile day (Visit 1 and Visit 12)

2 hours after administration of the morning dose of study medication

3 – 4 hours after administration of the morning dose of study medication
Table 7–2
Profile Day PK Sampling (Visit 1 and Visit 12)153
Visit 1 and Visit 12 (profile days)
Cycle of procedures
Order of 
procedures
Starting point of procedures
Time interval (h)
00
00
1:45 – 2 h 2h
3 – 4 h
At Visit 12 only: oxygen saturation using 
forehead pulse oximetry
X
Blood pressure, heart rate 
X
Administration of morning dose of study 
medication 
X
At Visit 12 only: oxygen saturation using 
forehead pulse oximetry
Xa
Blood pressure, heart rate; at Visit 12 only: 
supine and sitting position
Xa
Blood sample for PK
X
Blood pressure, heart rate (within 20 minutes 
prior to PK sample)
X
Blood sample for PK
X
a
At Visit 12 only: measure oxygen saturation, blood pressure and heart rate in supine and sitting 
position (see Section 7.6.5 and Section 7.6.18).
Abbreviations:  h = hours; PK = pharmacokinetic.
Visits 2 to 6 and Visits 13 to 17

Up to 1 hour before administration of the morning dose of study medication (trough)
                                                
153 Per Amendment 6


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Table 7-3
PK Sampling (Visits 2 – 6 and Visits 13 – 17)
Visit 2 to Visit 6 and Visit 13 to Visit 17
Cycle of procedures
Order of 
procedures
Starting point of procedures
Time interval (h)
1 h 00
00
00
2h
Blood sample for PK
X
Visit 13-17 only: oxygen saturation using forehead 
pulse oximetry
X
Blood pressure, heart rate
X
Administration of morning dose of study medication 
X
Visit 13-17 only: oxygen saturation using forehead 
pulse oximetry
X
Visits 13-17 only: Blood pressure, heart rate in 
supine and sitting position
X
Abbreviations:  h = hours; PK = pharmacokinetic.
Visit 11

Up to 1 hour before administration of morning dose of study medication (trough)

2 hours after administration of morning dose of study medication (peak)
Table 7–4
PK Sampling (Visit 11)154
Visit 11
Cycle of procedures
Order of 
procedures
Starting point of procedures
Time interval (h)
1 h 00
00
00
1:45-2 h
2 h
Blood sample for PK
X
Oxygen saturation using forehead pulse 
oximetry
X
Blood pressure, heart rate
X
Administration of morning dose of study 
medication 
X
Oxygen saturation using forehead pulse 
oximetry 
Xa
Blood pressure, heart rate in supine and sitting 
position 
Xa
Blood sample for PK
X
a
Measure oxygen saturation, blood pressure and heart rate in supine and sitting position (see 
Section 7.6.5 and Section 7.6.18).
Abbreviations:  h = hour; PK = pharmacokinetics.
                                                
154 Per Amendment 6


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7.1.2.4
Visits 7 through to 11 – Main treatment phase - Maintenance period
Old text:
[…]

Vital signs (blood pressure and heart rate).  Blood pressure and heart rate will be 
measured at all visits with the patient in a sitting position, after the patient has been at 
rest for at least 5 minutes.  The same arm is always used for these measurements (See 
Section 7.6.5)
[…]
New text:
[…]

Oxygen saturation measurement using forehead pulse oximetry at Visits 9 and 10 
only. At Visit 11 only, oxygen saturation will be measured before and after intake of 
study drug (see Section 7.6.18, Table 7–2, Table 7–3, and Table 7–4)

Vital signs (blood pressure and heart rate).  Blood pressure and heart rate will be 
measured at all visits with the patient in a sitting position, after the patient has been at 
rest for at least 5 minutes.  The same arm is always used for these measurements (See 
Section 7.6.5)

Assessment of orthostatic changes: measure blood pressure and heart rate in supine 
position and sitting position approximately 2 h after intake of study drug (Visit 11 
only, see Section 7.6.5).
[…]
7.1.2.5
Visit 12 (Week 52)
Old text:
[…]

Vital signs (blood pressure and heart rate).  Blood pressure and heart rate will be 
measured at all visits with the patient in a sitting position, after the patient has been at 
rest for at least 5 minutes.  The same arm is always used for these measurements (See
Section 7.6.5)
[…]


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New text:
[…]

Oxygen saturation will be measured before and after intake of study drug (see 
Section 7.6.18, Table 7–2, Table 7–3, and Table 7–4)

Vital signs (blood pressure and heart rate).  Blood pressure and heart rate will be 
measured at all visits with the patient in a sitting position, after the patient has been at 
rest for at least 5 minutes.  The same arm is always used for these measurements (See 
Section 7.6.5)

Assessment of orthostatic changes: measure blood pressure and heart rate in supine 
position and sitting position approximately 2 h after intake of study drug (see 
Section 7.6.5).
[…]
7.1.2.6
Visits 13 through to 17 – Long-term extension phase - Dose-titration 
period 
Old text:
[…]

Vital signs (blood pressure and heart rate).  Blood pressure and heart rate will be 
measured at all visits with the patient in a sitting position, after the patient has been at 
rest for at least 5 minutes.  The same arm is always used for these measurements (See 
Section 7.6.5)
[…]
New text:
[…]

Oxygen saturation will be measured before and after intake of study drug (see Section 
7.6.18, Table 7–2, Table 7–3, and Table 7–4)

Vital signs (blood pressure and heart rate).  Blood pressure and heart rate will be 
measured at all visits with the patient in a sitting position, after the patient has been at 
rest for at least 5 minutes.  The same arm is always used for these measurements (See 
Section 7.6.5)

Assessment of orthostatic changes: measure blood pressure and heart rate in supine 
position and sitting position approximately 2 h after intake of study drug (see 
Section 7.6.5).
[…]


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7.1.2.7
Visits 18 through Visit n (every 12 weeks) – Long-term extension 
phase – Open-label extension period 
7.1.2.8
Termination Visit
7.1.2.9
Safety follow-up visit 
The following change applies to all sections mentioned above.
Old text:
[…]

Vital signs (blood pressure and heart rate).  Blood pressure and heart rate will be 
measured at all visits with the patient in a sitting position, after the patient has been at 
rest for at least 5 minutes.  The same arm is always used for these measurements (See 
Section 7.6.5)
[…]
New text:
[…]

Oxygen saturation measurement using forehead pulse oximetry (see Section 7.6.18).

Vital signs (blood pressure and heart rate).  Blood pressure and heart rate will be 
measured at all visits with the patient in a sitting position, after the patient has been at 
rest for at least 5 minutes.  The same arm is always used for these measurements (See 
Section 7.6.5)
[…]
7.4
Pharmacokinetics / pharmacodynamics – amended
Old text:
Profile day (Visit 1 and Visit 12)

1 2 hours after administration of the morning dose of study medication

3 – 4 hours after administration of the morning dose of study medication
Visits 2 through to 6 and Visits 13 through to 17

Up to 1 hour before administration of morning dose of study medication (trough)
Visit 11

Up to 1 hour before administration of morning dose of study medication (trough)

2 3 hours after administration of morning dose of study medication (peak)
New text:
Profile day (Visit 1 and Visit 12)

2 hours after administration of the morning dose of study medication


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
3 – 4 hours after administration of the morning dose of study medication
Visits 2 through to 6 and Visits 13 through to 17

Up to 1 hour before administration of morning dose of study medication (trough)
Visit 11

Up to 1 hour before administration of morning dose of study medication (trough)

2 hours after administration of morning dose of study medication (peak)
7.6.5 Blood pressure and heart rate measurement
New text was added in the end of the section.
New text:
Assessment of orthostatic changes 
To assess orthostatic changes, blood pressure and heart rate will be measured with the patient 
in a supine position, after the patient has rested for 5 minutes. Immediately thereafter, the 
patient should sit up and blood pressure and heart rate will be measured after the patient has 
rested for 2 minutes.
These measurements should be performed approximately 2 hours after study medication 
intake.
Frequency: Visit 11 (Week 39), Visit 12 (Week 52), during the dose-titration period of the 
long-term extension phase (Visits 13 to 17).
7.6.18 Oxygen saturation measurement using forehead pulse oximetry 
Section was newly inserted with Amendment 6.
New text:
Oxygen saturation measurements will be performed in all subjects using non-invasive 
forehead pulse oximetry expressing the SpO2 (peripheral oxygen saturation) percentage. At 
visits with blood pressure measurements to assess orthostatic changes, oxygen saturation will 
be measured pre-dose and post-dose (see Table 7–2, Table 7–3, and Table 7–4). At all other 
visits, oxygen saturation will be measured pre-dose only. 
If the patient receives supplemental oxygen, the amount [L/min] will be recorded in the 
eCRF.
Frequency: Visit 9 (Week 20), Visit 10 (Week 26), Visit 11 (Week 39), Visit 12 (Week 52), 
Visits 13 to 17 (Week 54 to 62), Visit 18 to Visit n (Open-label Extension Period), 
Termination Visit, and 30-day Safety Follow-up.
8.4.3 Safety 
Old text:
[…]


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Descriptive analysis of vital and their changes from baseline will be performed by treatment 
group and visit.
New text:
[…]
Descriptive analysis of vital signs and their changes from baseline will be performed by 
treatment group and visit. Descriptive statistics of pulse oximetry and blood pressure/heart 
rate measurements for the assessment of orthostatic changes will be performed by treatment 
group and visit.


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13.5
Amendment 7
Amendment 7 is presented using a different approach to the previous amendments of this 
protocol. The rationale for changes in this amendment and all affected sections are provided 
in the “Protocol Amendment Summary of Changes Table” at the beginning of this document 
directly before the Table of Contents. The old/new text section detailing the changes 
compared to the last global CSP version has been replaced with a document edited in track 
change mode showing all changes, this document is available on request.


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14.
Appendices
14.1
Child-Pugh Classification of Liver Disease
Factor
+1
+2
+3
Bilirubin (mg/dL)
< 2
2 – 3
> 3
Albumin (g/dL)
> 3.5
2.8 – 3.5
< 2.8
International Normalized 
Ratio
< 1.7
1.7 – 2.3
> 2.3
Ascites
None
Mild
Moderate / Severe
Encephalopathy
None
Grade I – II or 
medically controlled
Grade III – IV or 
poorly controlled
Child-Pugh Class
A
B
C
Points
5 6
7 – 9
10 15
Source:  Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the 
oesophagus for bleeding oesophageal varices. Br J Surg 1973;60:646-649.[38]


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14.2
Definition of Systemic Sclerosis Renal Crisis - amended
Scleroderma renal crisis is defined as the new onset of severe hypertension associated with a 
rapid increase in serum creatinine concentration, microangiopathic hemolytic anemia, or both 
[39]155. Systemic sclerosis renal crisis usually manifests with acute onset of moderate-to-
severe ‘accelerated’ hypertension and oliguric renal failure [40].
The definition of systemic sclerosis hypertensive renal crisis is independent of whether or not 
concomitant antihypertensive medications are used.
History of new-onset hypertension, based on any of the following (measurements repeated 
and confirmed at least 2 hours apart within 3 days of first event-associated observation, with a 
change from baseline*). As a reminder, renal crisis is defined as meeting the first 4 signs:
1. Systolic blood pressure (SBP) ≥ 140 mmHg
2. Diastolic blood pressure (DBP) ≥ 90 mmHg
3. Rise in SBP ≥ 30 mmHg compared to baseline
4. Rise in DBP ≥ 20 mmHg compared to baseline
*Historical baseline blood pressure of the patient
AND
At least 1 of the following 5 features:
1. Serum Creatinine: increase of ≥ 50% above baseline*
2. Proteinuria: ≥ 2+ by dipstick confirmed by protein: creatinine ratio > ULN
3. Hematuria: ≥ 2+ by dipstick or > 10 RBCs/High Power Field (HPF) (without 
menstruation)
4. Thrombocytopenia: < 100,000 platelets/mm3
5. Hemolysis: by blood smear or increased reticulocyte count
*Historical baseline creatinine of the patient
                                                
155 References 39 and 40 added per Amendment 1


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14.3
Tender and Swollen Joint Count Assessment Form
TENDER & SWOLLEN JOINT COUNT ASSESSMENTS
Left
Right
Swollen
Tender
Swollen
Tender
Shoulder
Elbow
Wrist
MCP 1
         2
         3
         4
         5
PIP   1
         2
         3
         4
         5
Knee
Subtotal
TOTAL
Swollen
Tender
0 = Absent     1 = Present     9 = Replaced/N.A.*
*Injected joints will not be assessed for a period of one month (30 days) and will be documented as 
“Replaced/N.A.”