Efficacy and Safety of Riociguat (MK-4836) in Incipient Pulmonary Vascular Disease as an Indicator for Early Pulmonary Arterial Hypertension Double-blind, Randomized, Multicenter, Multinational, Placebo-controlled Phase IIa Study (ESRA)
Phase: PHASE2
Conditions: Pulmonary Vascular Disorder, Primary Pulmonary Hypertension, Systemic Sclerosis, Other Systemic Involvement of Connective Tissue
Sponsor: Heidelberg University

Efficacy and safety of riociguat (MK-4836) in incipient pulmonary vascular 
disease as an indicator for early pulmonary arterial hypertension 
Double-blind, randomized, multicenter, multinational, placebo-controlled phase 
IIa study 
 
 
Clinical Trial Code: ESRA 
EudraCT No.: 2021-001633-40 
EU CT No.: 2023-509695-42-00 
NCT Number: NCT05339087 
Version: 1.7; 15.01.2025 
 

CONFIDENTIAL 
 
CLINICAL STUDY PROTOCOL 
Efficacy and safety of riociguat (MK-4836) in incipient pulmonary vascular disease as an 
indicator for early pulmonary arterial hypertension 
Double-blind, randomized, multicenter, multinational, placebo-controlled phase IIa study 
ESRA 
Local Project ID: 2020-01RCT 
Supplier’s Protocol No. (MSD): MK-4836-004 
 
 
 
Clinical Trial Code:  ESRA 
EudraCT No.:  
2021-001633-40 
EU CT No.:   
2023-509695-42-00 
Clinical Phase:  
IIa 
Version:  
 
1.7; 15.01.2025 
 
 
 
 
 
 
 
 
 
 
Confidential 
The recipient of this document agrees to keep it strictly confidential. The information 
contained in this document must not be communicated to a third party without prior 
written approval of Thoraxklinik Heidelberg gGmbH at Heidelberg University Hospital. 
 
 
 

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PRINCIPAL INVESTIGATOR/ 
COORDINATING INVESTIGATOR 
 
SPONSOR 
 
Commercial Hospital Director  
Prof. Dr. med. Ekkehard Gr nig 
Thoraxklinik-Heidelberg gGmbH  
at Heidelberg University Hospital 
Center for Pulmonary Hypertension 
Sebastian Frank  
Thoraxklinik-Heidelberg gGmbH  
at Heidelberg University Hospital 
Röntgenstraße 1 
69126 Heidelberg, Germany 
Röntgenstraße 1 
69126 Heidelberg, Germany 
Phone: 
Phone: 
Fax:
Fax: 
 
 
 
 
 
DEPUTY INVESTIGATOR 
Thoraxklinik-Heidelberg gGmbH  
at Heidelberg University Hospital 
Center for Pulmonary Hypertension 
Röntgenstraße 1 
69126 Heidelberg, Germany 
Phone:
Fax: 
INVESTIGATOR 
Thoraxklinik-Heidelberg gGmbH  
at Heidelberg University Hospital 
Center for Pulmonary Hypertension 
Röntgenstraße 1 
69126 Heidelberg, Germany 
Phone:
Fax: 
 
 
DATA MANAGEMENT AND BIOMETRY 
TRIAL COORDINATOR 
Thoraxklinik-Heidelberg gGmbH  
at Heidelberg University Hospital 
Center for Pulmonary Hypertension 
Röntgenstraße 1 
69126 Heidelberg, Germany 
Phone: 
Fax: 

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Table of contents 
1 
CLINICAL STUDY PROTOCOL SYNOPSIS .............................................................................................. 6 
2 
INTRODUCTION ........................................................................................................................................... 20 
2.1 
SCIENTIFIC BACKGROUND ............................................................................................................................ 20 
2.2 
TRIAL RATIONALE/ JUSTIFICATION ............................................................................................................... 22 
2.3 
STUDY COMMITTEES ..................................................................................................................................... 22 
3 
TRIAL OBJECTIVES AND ENDPOINTS .................................................................................................. 22 
3.1 
PRIMARY OBJECTIVE AND PRIMARY ENDPOINT ............................................................................................ 22 
3.2 
SECONDARY OBJECTIVES .............................................................................................................................. 23 
4 
TRIAL DESIGN .............................................................................................................................................. 24 
5 
TRIAL DURATION AND SCHEDULE ....................................................................................................... 25 
5.1 
STUDY PHASES .............................................................................................................................................. 25 
5.2 
TRIAL DURATION .......................................................................................................................................... 25 
5.3 
RECRUITMENT PLAN ..................................................................................................................................... 26 
6 
SELECTION OF SUBJECTS ........................................................................................................................ 27 
6.1 
NUMBER OF SUBJECTS .................................................................................................................................. 27 
6.2 
GENERAL CRITERIA FOR SUBJECTS’ SELECTION ........................................................................................... 27 
6.3 
INCLUSION CRITERIA .................................................................................................................................... 27 
6.4 
EXCLUSION CRITERIA ................................................................................................................................... 29 
6.5 
CRITERIA FOR REMOVAL OR WITHDRAWAL .................................................................................................. 31 
6.5.1 
Withdrawal of Subjects........................................................................................................................ 31 
6.5.2 
Replacement of Subjects ...................................................................................................................... 32 
6.5.3 
Premature Closure of the Clinical Trial ............................................................................................. 32 
6.6 
PRIOR AND CONCOMITANT ILLNESSES .......................................................................................................... 32 
6.7 
PRIOR AND CONCOMITANT TREATMENTS ..................................................................................................... 32 
7 
INVESTIGATIONAL MEDICINAL PRODUCT ........................................................................................ 33 
7.1 
GENERAL INFORMATION ABOUT THE INVESTIGATIONAL MEDICINAL PRODUCT ........................................... 33 
7.1.1 
Riociguat ............................................................................................................................................. 33 
7.1.2 
Placebo ................................................................................................................................................ 33 
7.2 
THERAPEUTIC EFFECTS ................................................................................................................................. 33 
7.3 
BENEFIT/ RISK ASSESSMENT ......................................................................................................................... 34 
7.4 
KNOWN SIDE EFFECTS .................................................................................................................................. 35 
7.5 
DOSAGE SCHEDULE, TITRATION AND ADMINISTRATION ............................................................................... 36 
7.6 
TREATMENT ASSIGNMENT ............................................................................................................................ 37 
7.7 
RANDOMIZATION AND BLINDING .................................................................................................................. 37 
7.8 
LABELLING AND SUPPLY ............................................................................................................................... 38 
7.9 
SUPPLIES AND ACCOUNTABILITY .................................................................................................................. 38 
7.10 COMPLIANCE ................................................................................................................................................ 39 
8 
TRIAL METHODS ......................................................................................................................................... 40 
8.1 
OVERVIEW OF VISITS AND ASSESSMENTS ...................................................................................................... 40 
8.2 
ASSESSMENTS ............................................................................................................................................... 41 
8.2.1 
Physical examination and demographic data ..................................................................................... 41 
8.2.2 
Hemodynamic parameters ................................................................................................................... 41 

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8.2.3 
Echocardiography ............................................................................................................................... 42 
8.2.4 
Determination of WHO functional class ............................................................................................. 42 
8.2.5 
Lung function tests and blood gas analysis ......................................................................................... 42 
8.2.6 
6-minute walking distance and Borg dyspnea Score (CR 10) ............................................................. 42 
8.2.7 
Quality of Life (QoL) ........................................................................................................................... 43 
8.2.8 
Vital signs ............................................................................................................................................ 43 
8.2.9 
Electrocardiography ........................................................................................................................... 44 
8.2.10 
Clinical laboratory investigations .................................................................................................. 44 
8.3 
STUDY PHASES AND VISITS ........................................................................................................................... 44 
8.3.1 
Screening Phase .................................................................................................................................. 44 
8.3.2 
Visit 1 Baseline / Randomization - Day 1 ............................................................................................ 45 
8.3.3 
Visit 1.1- Visit 1.4 - Titration phase (week 2, 4, 6, 8 ± 2 days) ........................................................... 45 
8.3.4 
Visit 2 - 12 weeks assessment (± 7 days) ............................................................................................. 46 
8.3.5 
Phone visit 2.1 and phone visit 2.2 – WOCBP only (week 16 and 20 ± 2 days) ................................. 46 
8.3.6 
Visit 3 – 24 weeks assessment ± 14 days (termination of double-blind study) .................................... 47 
8.3.7 
Visit 4 - Safety follow-up 30 days after last IMP intake ...................................................................... 47 
8.3.8 
Unscheduled visit ................................................................................................................................ 47 
8.4 
METHODS OF DATA COLLECTION ................................................................................................................. 47 
8.4.1 
Efficacy Parameters ............................................................................................................................ 47 
8.4.2 
Safety Parameters ............................................................................................................................... 49 
8.5 
END OF TRIAL ............................................................................................................................................... 49 
8.6 
PLAN FOR TREATMENT OF CARE AFTER THE TRIAL ...................................................................................... 49 
9 
ADVERSE EVENTS ....................................................................................................................................... 50 
9.1 
DEFINITIONS ................................................................................................................................................. 50 
9.1.1 
Adverse Event ...................................................................................................................................... 50 
9.1.2 
Serious Adverse Event ......................................................................................................................... 50 
9.1.3 
Expectedness ....................................................................................................................................... 51 
9.1.4 
Suspected Unexpected Serious Adverse Reaction (SUSAR) ................................................................ 51 
9.1.5 
Grading of AEs .................................................................................................................................... 52 
9.1.6 
Relationship and outcome of AEs, action taken .................................................................................. 52 
9.2 
PERIOD OF OBSERVATION AND DOCUMENTATION ........................................................................................ 54 
9.3 
REPORTING OF SERIOUS ADVERSE EVENTS BY THE INVESTIGATOR .............................................................. 54 
9.4 
EXPEDITED REPORTING ................................................................................................................................. 55 
9.5 
EMERGENCY UNBLINDING ............................................................................................................................ 57 
9.6 
EMERGENCY TREATMENT ............................................................................................................................. 57 
10 
STATISTICAL PROCEDURES .................................................................................................................... 57 
10.1 SAMPLE SIZE CALCULATION ......................................................................................................................... 57 
10.2 DEFINITION OF TRIAL POPULATION TO BE ANALYZED................................................................................... 59 
10.3 STATISTICAL METHODS ................................................................................................................................ 60 
10.3.1 
General ........................................................................................................................................... 60 
11 
DATA MANAGEMENT ................................................................................................................................. 64 
11.1 DATA COLLECTION ....................................................................................................................................... 64 
11.2 DATA HANDLING .......................................................................................................................................... 64 
11.3 STORAGE AND ARCHIVING OF DATA ............................................................................................................. 64 
12 
ETHICAL AND LEGAL ASPECTS ............................................................................................................. 64 
12.1 GOOD CLINICAL PRACTICE ........................................................................................................................... 64 
12.2 SUBJECT INFORMATION AND INFORMED CONSENT ....................................................................................... 65 
12.3 CONFIDENTIALITY ......................................................................................................................................... 65 
12.4 RESPONSIBILITIES OF THE INVESTIGATOR ..................................................................................................... 66 
12.5 APPROVAL OF TRIAL PROTOCOL AND AMENDMENTS ................................................................................... 66 
12.6 CONTINUOUS INFORMATION TO INDEPENDENT ETHICS COMMITTEE............................................................. 66 
12.7 NOTIFICATION OF REGULATORY AUTHORITIES ............................................................................................. 66 
12.8 REGISTRATION OF THE TRIAL ........................................................................................................................ 67 
12.9 INSURANCE ................................................................................................................................................... 67 
13 
QUALITY ASSURANCE ............................................................................................................................... 67 

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13.1 MONITORING................................................................................................................................................. 67 
13.2 QUALITY CHECKS .......................................................................................................................................... 68 
13.3 INSPECTIONS/ AUDITS ................................................................................................................................... 68 
14 
AGREEMENTS ............................................................................................................................................... 68 
14.1 FINANCING OF THE TRIAL ............................................................................................................................. 68 
14.2 FINANCIAL DISCLOSURE ............................................................................................................................... 68 
14.3 REPORTS ....................................................................................................................................................... 68 
14.4 PUBLICATION ................................................................................................................................................ 68 
15 
SPONSOR SIGNATURES ............................................................................................................................. 69 
16 
DECLARATION OF INVESTIGATOR ....................................................................................................... 70 
17 
REFERENCES ................................................................................................................................................ 71 
18 
APPENDICES ................................................................................................................................................. 74 
 
 
 

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1 
 Clinical study protocol synopsis 
Protocol title: 
Efficacy and safety of riociguat (MK-4836) in incipient pulmonary 
vascular disease as an indicator for early pulmonary arterial 
hypertension 
Double-blind, randomized, multicenter, multinational, placebo-
controlled phase IIa study   
Acronym 
ESRA 
Phase: 
Phase IIa 
Regulatory 
obligations: 
Pharmaceutical study under the applicable Pharmaceutical Drug Law; 
requires IRB approval / EC vote. 
Study location: 
Coordinating center: Heidelberg, Germany  
Other centers: London, Zurich, Graz, Linz, Lille, Naples, Dresden 
 
No. of study 
sites: 
8 
Principal 
investigator: 
 
Prof. Dr. Ekkehard Grünig 
Thoraxklinik Heidelberg gGmbH at Heidelberg University Hospital 
Center for pulmonary hypertension 
Röntgenstraße 1 
69126 Heidelber , German  
Phon
Fax:  
Mail: 
 
Study type: 
Randomized, controlled, clinical trial 
Study design: 
 
Investigator-Initiated-Trial (IIT)  
This is a randomized (1:1), double-blind, placebo-controlled, multicenter, 
multinational study investigating the effect of riociguat (MK-4836) in 
patients with early pulmonary vascular disease, defined as either  
a) mean pulmonary arterial pressure (mPAP) ≥25 mmHg with pulmonary 
vascular resistance (PVR) ≥2 to <3 WU and pulmonary arterial wedge 
pressure (PAWP) ≤15 mmHg or  
b) mPAP 21-<25 mmHg with PVR ≥2 WU, and PAWP ≤15 mmHg 
associated with connective tissue disease (CTD) or as idiopathic/heritable 
form. 
Patients in group b will likely represent the greatest proportion of trial 
participants based on epidemiological data and trial objectives.  

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The primary efficacy endpoint in this study is the change in PVR from 
baseline to 24 weeks. 
Patients who stop the study or discontinue medication prematurely will 
be asked to continue with the study and participate in study assessments 
and visits until the last follow-up as per protocol. Subjects will be taking 
three doses daily with each dose taken 6 to 8 hours apart. In the case of 
side effects (e.g. symptomatic hypotension), down-titration by 0.5 mg 
three times daily (tid) is allowed. 
 
Interventions 
 
After the pre-treatment phase, eligible subjects will be randomized at 
Visit 1 in a 1:1 ratio to the following 2 treatment groups: 
- riociguat (MK-4836) 1.0-2.5 mg group (titration between 1.0 mg and 2.5 
mg tid according to individual tolerability) 
- placebo group (placebo tid, sham-titration according to individual 
tolerability). 
 
Estimated Study 
duration 
The study consists of a pre-treatment phase of up to 28 days followed by a 
24-week treatment phase. The treatment phase is divided into an 8-week 
titration phase, followed by a 16-week main study phase 
Background 
Chronic pulmonary arterial hypertension (PAH) is associated with 
impaired exercise capacity, quality of life (QoL) and right ventricular 
function.(Galiè et al. 2016) The disease is characterized by an increase of 
pulmonary vascular resistance (PVR) and pulmonary arterial pressure, 
leading to right heart insufficiency.(Galiè et al. 2016, Grünig et al. 2010) 
Riociguat is a soluble guanylate cyclase stimulator and the first drug that 
has been approved for the treatment of both PAH and chronic 
thromboembolic pulmonary hypertension (CTEPH).(Ghofrani et al. 
2013) The 12-week PATENT-1 study showed a significant improvement 
of the primary endpoint 6-minute walking distance (6MWD) and of 
secondary endpoints such as PVR, N-terminal pro brain natriuretic 
peptide (NT-proBNP) levels, World Health Organization functional class 
(WHO-FC), time to clinical worsening and Borg dyspnea score.(Ghofrani 
et al. 2013) An exploratory analysis of the first 12 weeks of the long-term 
extension study (PATENT-2) showed further significant improvement of 
6MWD in the 215 PAH-patients receiving up to 2.5 mg of riociguat three 
times daily (tid).(Rubin et al. 2015) In CTEPH-patients the 12-week 
CHEST-1 study revealed a statistically significant improvement of 
6MWD (primary end-point) and in PVR, NT-proBNP serum values, and 
in WHO-FC (secondary endpoints).(Ghofrani et al. 2013) Further studies 
investigating the effect of riociguat in an uncontrolled design were the 
early access study (EAS) in patients with CTEPH (McLaughlin et al. 

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2017) and PATENT plus in PAH.(Galiè et al. 2015) Recently, two 
retrospective studies of patients who participated in the phase III studies 
PATENT, CHEST, PATENT plus as well as the Phase II study and early 
access study in German centers have shown that riociguat treatment (1.0-
2.5 mg tid) was associated with a significant reduction of right ventricular 
(RV) and right atrial (RA) area after 3, 6 and 12 months compared to 
baseline.(Marra et al. 2015, Marra et al. 2018) RA area significantly 
decreased after 12 months and RV systolic function assessed with 
tricuspid annular plane systolic excursion (TAPSE) improved during 
riociguat therapy.(Marra et al. 2015, Marra et al. 2018) 
Early diagnosis of systemic sclerosis associated PAH (SSc-APAH) is of 
utmost importance, since it leads to significant improvement of survival 
rates through the implementation of PAH-targeted therapies.(Humbert et 
al. 2011) 
In order to enhance early diagnosis of patients with pulmonary vascular 
disease, a new hemodynamic definition of PAH was proposed at the 6th 
World Symposium of PH (Simonneau et al. 2019), which lowered the cut-
off for mPAP from ≥25 mmHg (as stated in the actual PH guidelines, Galiè 
et al. 2016) to >20 mmHg in combination with pulmonary arterial wedge 
pressure (PAWP) ≤15mmHg and PVR ≥3 Wood Units (WU). The change 
in the hemodynamic definition of pre-capillary PH represents a step 
towards the upper limit of physiological hemodynamic thresholds as 
shown in a systemic review of Kovacs et al. (Kovacs et al. 2009) including 
1187 healthy subjects presenting with an upper limit of normal for mPAP 
of 20.6 mmHg (mean + 2 standard deviations). Subsequent studies 
performed mainly in SSc patients reported that patients with mildly 
elevated mPAP (21-24 mmHg) had reduced exercise capacity, impaired 
QoL, decreased RV output reserve, abnormal pulmonary arterial 
compliance (PAC) and survival.(Valerio et al. 2013, Coghlan et al. 2018, 
Nagel et al. 2019) Recent data from cohorts in a US-PH-center (Jaafar et 
al. 2019), and from SSc-patients cohorts in Zurich and Heidelberg 
(Xanthouli  et al. 2020) have shown that the new PAH definition will most 
likely prevent an early PAH-diagnosis due to a too highly chosen threshold 
for PVR ≥3 WU.(Jaafar et al. 2019, Xanthouli et al. 2020) Patients with 
PVR ≥ 2 WU already had an early pulmonary vascular disease with 
reduced 6MWD, right heart function, PAC and survival.(Xanthouli et al. 
2020) Data on early treatment of patients with early PAH with mildly 
elevated pulmonary arterial pressures is still scarce. 
A recent double-blind-randomized controlled trial (EDITA) testing the 
effect of ambrisentan, an endothelin receptor antagonist, on mean 
pulmonary arterial pressure (primary endpoint) among SSc-patients with 
mildly elevated mPAP and/or exercise PH, without significant left heart 
or lung disease, failed to change the primary endpoint, however, showed 

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an improvement of PVR as secondary endpoint (Pan et al. 2019), which 
may be of prognostic relevance in this patient cohort. Further research in 
this field is needed.  
As PVR has a prognostic significance among patients with SSc-APAH, 
may be an indicator of early pulmonary vascular disease and previous 
studies proved the positive effects of riociguat on right heart size and PVR 
(secondary endpoint in phase III studies), PVR was chosen as primary 
endpoint of the current study.  
The aim of this study is to investigate the effect of riociguat (MK-4836) 
on PVR, clinical parameters, safety and tolerability in patients with early 
pulmonary vascular disease. 
References 
Coghlan JG, Wolf M, Distler O, Denton CP, Doelberg M, Harutyunova S, Marra AM, 
Benjamin N, Fischer C, Grünig E. Incidence of pulmonary hypertension and determining 
factors in patients with systemic sclerosis. Eur Respir J. 2018;51(4). 
Galiè N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, Simonneau G, Peacock 
A, Vonk Noordegraaf A, Beghetti M, Ghofrani A, Gomez Sanchez MA, Hansmann G, 
Klepetko W, Lancellotti P, Matucci M, McDonagh T, Pierard LA, Trindade PT, 
Zompatori M, Hoeper M. 2015 ESC/ERS Guidelines for the Diagnosis and Treatment 
of Pulmonary Hypertension. Rev Esp Cardiol (Engl Ed). 2016;69(2):177. 
Galiè N, Müller K, Scalise AV, Grünig E. PATENT PLUS: a blinded, randomised and 
extension study of riociguat plus sildenafil in pulmonary arterial hypertension. Eur 
Respir J. 2015;45(5):1314-22 
Ghofrani HA, Galiè N, Grimminger F, Grünig E, Humbert M, Jing ZC, Keogh AM, 
Langleben D, Kilama MO, Fritsch A, Neuser D, Rubin LJ; PATENT-1 Study Group. 
Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 
2013;369(4):330-40. 
Ghofrani HA, D'Armini AM, Grimminger F, Hoeper MM, Jansa P, Kim NH, Mayer E, 
Simonneau G, Wilkins MR, Fritsch A, Neuser D, Weimann G, Wang C; CHEST-1 Study 
Group. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. 
N Engl J Med. 2013;369(4):319-29 
Grünig E, Barner A, Bell M, Claussen M, Dandel M, Dumitrescu D, Gorenflo M, Holt 
S, Kovacs G, Ley S, Meyer JF, Pabst S, Riemekasten G, Saur J, Schwaiblmair M, Seck 
C, Sinn L, Sorichter S, Winkler J, Leuchte HH. Non-invasive diagnosis of pulmonary 
hypertension: ESC/ERS Guidelines with commentary of the Cologne Consensus 
Conference 2010. Dtsch Med Wochenschr. 2010;135 Suppl 3:S67-77.  
Humbert M, Yaici A, de Groote P, Montani D, Sitbon O, Launay D, Gressin V, Guillevin 
L, Clerson P, Simonneau G, Hachulla E. Screening for pulmonary arterial hypertension 
in patients with systemic sclerosis: clinical characteristics at diagnosis and long-term 
survival. Arthritis Rheum. 2011;63(11):3522-30. 
Jaafar S, Visovatti S, Young A, Huang S, Cronin P, Vummidi D, McLaughlin V, Khanna 
D. Impact of the revised haemodynamic definition on the diagnosis of pulmonary 
hypertension in patients with systemic sclerosis. Eur Respir J. 2019;54(2). 

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Kovacs G, Berghold A, Scheidl S, Olschewski H. Pulmonary arterial pressure during 
rest and exercise in healthy subjects: a systematic review. Eur Respir J. 2009;34(4):888-
94. 
Marra AM, Egenlauf B, Ehlken N, Fischer C, Eichstaedt C, Nagel C, Bossone E, 
Cittadini A, Halank M, Gall H, Olsson KM, Lange TJ, Grünig E. Change of right heart 
size and function by long-term therapy with riociguat in patients with pulmonary arterial 
hypertension and chronic thromboembolic pulmonary hypertension. Int J Cardiol. 
2015;195:19-26. 
Marra AM, Halank M, Benjamin N, Bossone E, Cittadini A, Eichstaedt CA, Egenlauf 
B, Harutyunova S, Fischer C, Gall H, Ghofrani HA, Hoeper MM, Lange TJ, Olsson KM, 
Klose H, Grünig E. Right ventricular size and function under riociguat in pulmonary 
arterial hypertension and chronic thromboembolic pulmonary hypertension (the RIVER 
study). Respir Res. 2018;19(1):258. 
McLaughlin VV, Jansa P, Nielsen-Kudsk JE, Halank M, Simonneau G, Grünig E, Ulrich 
S, Rosenkranz S, Gómez Sánchez MA, Pulido T, Pepke-Zaba J, Barberá JA, Hoeper 
MM, Vachiéry JL, Lang I, Carvalho F, Meier C, Mueller K, Nikkho S, D'Armini AM. 
Riociguat in patients with chronic thromboembolic pulmonary hypertension: results 
from an early access study. BMC Pulm Med. 2017;17(1):216. 
Nagel C, Marra AM, Benjamin N, Blank N, Cittadini A, Coghlan G, Distler O, Denton 
CP, Egenlauf B, Fiehn C, Fischer C, Harutyunova S, Hoeper MM, Lorenz HM, 
Xanthouli P, Bossone E, Grünig E. Reduced Right Ventricular Output Reserve in 
Patients With Systemic Sclerosis and Mildly Elevated Pulmonary Artery Pressure. 
Arthritis Rheumatol. 2019;71(5):805-816. 
Pan Z, Marra AM, Benjamin N, Eichstaedt CA, Blank N, Bossone E, Cittadini A, 
Coghlan G, Denton CP, Distler O, Egenlauf B, Fischer C, Harutyunova S, Xanthouli P, 
Lorenz HM, Grünig E. Early treatment with ambrisentan of mildly elevated mean 
pulmonary arterial pressure associated with systemic sclerosis: a randomized, controlled, 
double-blind, parallel group study (EDITA study). Arthritis Res Ther. 2019;21(1):217. 
Rubin LJ, Galiè N, Grimminger F, Grünig E, Humbert M, Jing ZC, Keogh A, Langleben 
D, Fritsch A, Menezes F, Davie N, Ghofrani HA. Riociguat for the treatment of 
pulmonary arterial hypertension: a long-term extension study (PATENT-2). Eur Respir 
J. 2015;45(5):1303-13. 
Simonneau G, Montani D, Celermajer DS, Denton CP, Gatzoulis MA, Krowka M, 
Williams PG, Souza R. Haemodynamic definitions and updated clinical classification of 
pulmonary hypertension. Eur Respir J. 2019;53(1). 
Valerio CJ, Schreiber BE, Handler CE, Denton CP, Coghlan JG. Borderline mean 
pulmonary artery pressure in patients with systemic sclerosis: transpulmonary gradient 
predicts risk of developing pulmonary hypertension. Arthritis Rheum. 2013;65(4):1074-
84. 
Xanthouli P, Jordan S, Milde N, Marra A, Blank N, Egenlauf B, Gorenflo M, 
Harutyunova S, Lorenz HM, Nagel C, Theobald V, Lichtblau M, Berlier C, Ulrich S, 
Grünig E, Benjamin N, Distler O. Haemodynamic phenotypes and survival in patients 

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with systemic sclerosis: the impact of the new definition of pulmonary arterial 
hypertension. Ann Rheum Dis. 2020;79(3):370-378.  
Materials & 
Supplies 
Investigator-Initiated-Trial (IIT) 
Riociguat (MK-4836) and placebo will be supplied by MSD 
SHARP&DOHME GmbH Germany. 
Trial population 
Adult male and female patients with CTD or idiopathic/heritable early 
pulmonary vascular disease.  
Both an elevated mean pulmonary arterial pressure >20 mmHg and an 
increase of PVR >2 WU have been shown to be above the upper limit of 
normal and are associated with development of manifest PAH and 
impaired survival in CTD. As a placebo-controlled study would seem 
unethical in patients, who are in clear indication of targeted treatment, 
patients with manifest PAH according to the current definition may not 
be included in this study (combination of both mPAP ≥25 mmHg and 
PVR ≥3 WU and PAWP ≤15 mmHg). 
Patients with early pulmonary vascular disease, indicated by either  
a) mPAP ≥25 mmHg with PVR ≥2 to <3 WU and PAWP ≤15 mmHg or 
b) mPAP 21-<25 mmHg with PVR ≥2 WU and PAWP ≤15 mmHg (see 
Group I / Nice Clinical Classification of Pulmonary Hypertension) (acc. 
to Simonneau et al. 2019) may therefore be included into this study. 
Both a) and b) represent one phenotype with early pulmonary vascular 
disease/pathology. Patients in group b will be mainly enrolled as long as 
patients in group a are not defined as having pulmonary arterial 
hypertension according to European pulmonary hypertension guidelines. 
 
Aims and 
Objectives 
The aim of this 24 weeks randomized, controlled study is to investigate 
the effect of riociguat (MK-4836) treatment on hemodynamics, clinical 
parameters, safety and tolerability in patients with early pulmonary 
vascular disease, defined as stated above.  
Primary objective 
1) To investigate the effect of riociguat (MK-4836) treatment on 
pulmonary vascular resistance, defined as change from baseline to 
24 weeks of treatment. 
Secondary objectives 
2) To investigate, whether treatment with riociguat (MK-4836) may 
improve further hemodynamic and clinical parameters, defined as 
change from baseline to 24 weeks of treatment. 
3) To assess safety and tolerability of riociguat (MK-4836) treatment  

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Investigational 
Medicinal 
Product(s) 
(IMPs) 
IMP: Test treatment  
Riociguat (MK-4836): 1 mg, 1.5 mg, 2 mg and 2.5 mg tid will start at 1.0 
mg tid in the beginning of the study. Dosage will be individually up-
titrated up to a maximum dosage of 2.5mg tid after 8 weeks according to 
systemic blood pressure, the physician’s and the patient’s estimation. 
Study medication will be taken orally with or without food. Subjects will 
be taking three doses daily with each dose taken 6 to 8 hours apart. In the 
case of side effects (e.g. symptomatic hypotension), down-titration by 0.5 
mg tid is allowed. 
IMP: Placebo 
Placebo tablets with the same treatment regimen (tid) as the verum 
therapy will be provided. Treatment effect will be controlled at each study 
visit and the sham dose will be adapted.  
Sample size 
N= 70 (35 patients randomized in each group) 
If the true treatment effect is at least a 30±34.5% reduction of PVR (effect 
size is 0.87), a sample size of 29 patients/group (total 58 patients) achieves 
a statistical power of 90.2% to reject the null hypothesis, according to the 
two-sample student’s t-test, with a type I error of 0.05 (two-sided). 
With the sample size of 70 patients and a dropout of 15% (valid sample 
size n=58), we achieve a 90.2% power, if the means of PVR differ by at 
least 30% and both groups have an equal standard deviation of 34.5%. A 
sample of 70 patients (35 patients in each group), allocated in a 1:1 ratio, 
will therefore be included.  
The primary endpoint will be analyzed by an analysis of covariance 
(ANCOVA) with baseline values as covariates, which has a power 
advantage over the student’s t-test, achieving a statistical power of 90.2% 
or more. If the preconditions for ANCOVA are not met, a student’s t-test 
assuming unequal variances (Welch-test) will be performed. 
 

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Statistical 
methods 
Data will be pseudonymized and checked for plausibility. After database 
closure, data will be analyzed. All data will be listed and trial summary 
tables will be provided with means, medians, variances and respective 
confidence intervals and with frequency tables. 
Baseline parameters will be described and compared between study arms 
and study centers. The primary endpoint, change of PVR, will be 
compared by ANCOVA of the differences (baseline value to 24 weeks) 
between the two groups with the baseline value as covariate. Data will be 
primarily analyzed in the modified intention-to-treat analysis set. As 
sensitivity analysis, multiple imputation will be performed and analyzed 
for the primary endpoint.  
Secondary and exploratory parameters at baseline and during follow-up 
will be compared between groups comparing the difference between 
baseline and follow-up visits. Data will be displayed by means and 
standard deviations, medians and variances with respective 95% 
confidence intervals. 
 
Indication 
Clinical phenotype patients with early pulmonary vascular disease, 
indicated by either a) mPAP ≥25 mmHg with PVR ≥2 to <3 WU and 
PAWP ≤15 mmHg or b) mPAP 21-<25 mmHg with PVR ≥2 WU and 
PAWP ≤15 mmHg. 
I27.0 Primary pulmonary hypertension (PAH) 
M34.- Systemic sclerosis 
M35.- Other systemic involvement of connective tissue 
MedDRA (V. 12.0) 
Systemic Sclerosis ID 10042953, Level 4 
Connective tissue disorders (excl. congenital) ID 10010761, Level 4 
Pulmonary Hypertension ID 10037400, Level 4 
 
 
Efficacy and 
safety variables 
 
Efficacy Variables 
The primary efficacy variable is the change of PVR from baseline to 24 
weeks. 
Secondary efficacy endpoints will be tested hierarchically: 
• 
change of cardiac index at rest (baseline to 24 weeks) 
• 
change of total pulmonary resistance (baseline to 24 weeks) 
• 
change of diffusion capacity of the lung (baseline to 24 weeks) 
Exercise capacity 
• 
change of 6-minute walking distance (baseline to 24 weeks) 

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Symptoms and quality of life 
• 
change of WHO functional class (baseline to 24 weeks) 
• 
change in QoL (SF-36, physical summation score; baseline value to 
24 weeks) 
The following parameters will be assessed in every patient according to 
the visits schedule and analyzed as exploratory variables. Exploratory 
endpoints will be analyzed as change from baseline to 12 and 24 weeks 
as available per assessment schedule. 
QoL assessed by the SF-36 questionnaire  
• 
mental summation score as well as the 8 sub scores 
 
WHO functional class 
 
Lung function and lung diffusing capacity 
• 
FEV1 (forced expiratory volume in 1 second), TLC (total lung 
capacity), DLCO (diffusing capacity of the lung) 
 
Echocardiography 
• 
systolic pulmonary arterial pressure (sPAP, mmHg), right 
ventricular area (RV-area, cm2), and right atrial area (RA-area, cm2), 
tricuspid annular plane systolic excursion (TAPSE), left ventricular 
eccentricity index (LV-EI), RV-pump function and LV-pump function 
(LV-EF, %).   
 
Analyses of blood samples 
Venous blood will be analyzed to determine:  
• 
NT-pro BNP 
 
Blood for blood gas analyses 
• 
oxygen partial pressure, carbon dioxide partial pressure, oxygen 
saturation of the blood (SpO2), pH values, bicarbonates, base excess  
 
Pulmonary hemodynamics by right heart catheterization 
• 
sPAP, mPAP, diastolic pulmonary artery pressure (dPAP), 
pulmonary artery wedge pressure (PAWP), right atrial pressure (RAP), 
cardiac output and ejection fraction (CO), central venous saturation, via 
blood gas analysis from pulmonary artery (SvO2) 
 
Clinical worsening will be defined as time to first event out of: 
• 
worsening of WHO functional class 
• 
deterioration of 6MWD >15% compared to baseline 

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• 
need of initiation of targeted PAH treatment 
• 
hospitalization due to worsening of right heart function 
• 
all cause death or lung-transplantation 
• 
atrial septostomy 
 
Safety variables 
Laboratory, electrocardiogram (ECG), vital signs, assessment of adverse 
events and serious adverse events will serve as safety parameters. 
Patients with a serious adverse event occurring during the study treatment 
will be followed by the study team until the serious adverse event will 
have resolved to the pre-study level and/or will have been addressed 
according to best clinical practice. Patients withdrawing from the study 
prematurely will have a final physical examination.  
If a patient withdraws from study treatment and agrees to stay in the study, 
study related examinations will be performed and data will be obtained 
according to protocol. 

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Course of the 
study 
Screening phase (Day -28 till Day 0):  
Eligible patients will be asked to participate upon written informed 
consent. In case of agreement medical history will be taken and they will 
undergo screening examinations, according to the table of assessments as 
described in Section “8.1 
Overview of visits and assessments”. Right 
heart catheterization (RHC) at Screening will not be performed in patients 
with a RHC not older than 1 month at screening or not older than 6 months 
if the patient had no signs of clinical changes defined as change of 6MWD 
>10%, WHO-FC change or >30% change in NT-proBNP. RHC must have 
been measured in the participating center under standardized conditions. 
Baseline / Visit 1 (day 1) 
Baseline visit will be performed according to the table of assessments as 
described in Section “8.1 
Overview of visits and assessments”. 
Eligibility will be checked again and patients will be randomized.  
Study drug will be supplied after the patient has received information on 
titration and study drug intake.  
Titration phase / V 1.1 till 1.4 (week 2, 4, 6, 8) 
Riociguat (MK-4836) dose will be individually adjusted in accordance 
with the in-label titration regimen. Dose adjustment will be performed 
every two weeks by phone taking the systemic blood pressure of the 
patient, the subjects and physicians’ subjective estimation and occurrence 
of adverse reactions into account. At week 8 the maintenance dose will be 
established and furtherly continued for the rest of the study.  
Interim Visit / Visit 2 (week 12) 
At the interim visit in week 12 assessments from screening /baseline will 
be repeated (except RHC and medical history) as described in Section 
“8.1 Overview of visits and assessments”. Unused study drug will be 
collected and medication for the remaining 12 weeks at maintenance dose 
will be supplied. 
Termination visit / Visit 3 (week 24) 
At this visit in week 24 assessments will be conducted as described in 
Section “8.1 Overview of visits and assessments”.   
Follow-up / Visit 4 (30 days after last study drug intake)  
Phone call 30±14 days after last study drug intake to assess adverse events 
and record a final pregnancy test (WOCBP only). 
Excluded 
medication: 
Pirfenidon; nintedanib, prednisolone >10 mg/day, PAH specific treatment  

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Pre-treatment 
period: 
N/A 
Duration of 
observation 
Up to 28 days screening period, 24 weeks double-blind, controlled study 
phase, + 30 days follow-up  
Follow-up period 30 days after week 24 visit each patient performs a follow-up visit via 
phone. Clinical follow-up of all SAEs until they have been resolved or 
improved if possible. 
Clinic visits 
Double-blind: Screening visit, baseline visit, week 12 and week 24 
Additional titration visits every two weeks via phone in the double-blind 
study phase (week 2, 4, 6, 8), and phone follow-up 30 days after last study 
drug intake. 
 
Dosing regimen 
Individual adjustment during the 8 weeks titration period according to the 
in-label titration regimen 
 
Route of 
administration 
 
Oral riociguat (MK-4836) or respective placebo 
Endpoints 
Primary 
All endpoints will be compared riociguat (MK-4836) vs. placebo: 
Pulmonary vascular resistance, change from baseline to 24 weeks 
Secondary 
Endpoints will be analyzed as change / difference 
• 
baseline to 24 weeks riociguat (MK-4836) vs. placebo 
• 
if available according to visit schedule, exploratory endpoints will 
also be presented as changes from baseline to 12 weeks. 
For list of parameters see caption on efficacy and safety variables 
 
 

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Study diagram: 
 
Abbreviations 
6MWD 
 
6-Minute Walking Distance 
AE 
 
 
Adverse Event 
ANCOVA 
 
Analyses of Covariance 
APAH  
 
Associated Pulmonary Arterial Hypertension 
ATS 
 
 
American Thoracic Society 
BGA  
 
Blood Gas Analysis 
CI 
 
 
Cardiac Index 
CO 
 
 
Cardiac Output 
CRF 
 
 
Case Report Form 
CT 
 
 
Computed Tomography 
CTCAE 
 
Common Terminology Criteria for Adverse Events 
CTEPH 
 
Chronic thromboembolic pulmonary hypertension 
CV 
 
 
Curriculum Vitae 
DBL 
 
 
Data Base Lock 
DLCO  
 
Diffusion limited carbon monoxide 
dPAP  
 
Diastolic Pulmonary Artery Pressure 

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DSUR  
 
Development Safety Update Report 
EC 
 
 
Ethics Committee 
ECG  
 
Electrocardiogram 
ERS 
 
 
European Respiratory Society 
ESC 
 
 
European Society of Cardiology 
FEV1  
 
Forced expiratory volume in the first second 
FPI 
 
 
First Patient In 
FVC 
 
 
Forced Vital Capacity 
GCP  
 
Good Clinical Practice 
HDL  
 
High Density Lipoprotein 
HIV   
 
Human Immunodeficiency Virus 
HPAH  
 
Heritable PAH (Familial PAH) 
ICF 
 
 
Informed Consent Form 
ICH 
International Conference on Harmonization of Technical Requirements  
for Registration of Pharmaceuticals for Human Use 
IIT 
 
 
Investigator Initiated Trial 
IMP 
 
 
Investigational Medicinal Product 
INN 
 
 
International Nonproprietary Name 
IPAH  
 
Idiopathic Pulmonary Arterial Hypertension 
IRB 
 
 
Institutional Review Board 
ISF 
 
 
Investigator Site File 
ISRCTN 
 
International Standard Randomized Controlled Trial Number 
ITT 
 
 
Intention To Treat 
LSI 
 
 
Last Subject In 
LSO 
 
 
Last Subject Out 
LTOT  
 
Long-Term Oxygen Therapy 
LV-EI  
 
Left Ventricular Eccentricity Index 
mPAP  
 
Mean Pulmonary Artery Pressure 
mRAP  
 
Mean Right Arterial Pressure 
NCI 
 
 
National Cancer Institute 
NT-proBNP 
 
N-terminal prohormone of brain natriuretic peptide 
NYHA  
 
New York Heart Association 
O2 
 
 
Oxygen 
PAH  
 
Pulmonary Arterial Hypertension 
PAP 
 
 
Pulmonary Arterial Pressure 
PAWP  
 
Pulmonary Artery Wedge Pressure 
PH 
 
 
Pulmonary Hypertension 
pO2 
 
 
Partial Pressure of Oxygen 
PVR 
 
 
Pulmonary Vascular Resistance 
QoL 
 
 
Quality of Life 
RA(-area) 
 
Right Atrial (Area) 
RAP 
 
 
Right Atrial Pressure 

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RHC  
 
Right Heart Catheterization 
RV 
 
 
Residual Volume 
RV(-area) 
 
Right Ventricular (Area) 
SAE 
 
 
Serious Adverse Event 
SpO2  
 
Peripheral Oxygen Saturation 
SC 
 
 
Steering Committee 
SF-36  
 
36-Item Short Form Survey as part of the Medical Outcome Study 
SGPT  
 
Serum Glutamic-Pyruvate Transaminase, also known as ALAT 
SGOT  
 
Serum Glutamic-Oxaloacetic Transaminase, also known as ASAT 
sPAP  
 
Systolic Pulmonary Artery Pressure 
SmPC/SPC 
 
Summary of Product Characteristics 
SSc 
 
 
Systemic Sclerosis 
SSc-APAH  
 
Systemic Sclerosis Associated PAH  
SUSAR 
 
Suspected Unexpected Serious Adverse Reaction 
SvO2  
 
Venous Oxygen Saturation 
TAPSE 
 
Tricuspid Annular Plane Systolic Excursion 
TLC 
 
 
Total Lung Capacity 
USA 
 
 
United States of America 
WHO  
 
World Health Organization 
WHO-FC 
 
World Health Organization Functional Class 
WOCBP 
 
Women of childbearing potential 
 
2 
Introduction 
2.1 
Scientific Background 
Chronic pulmonary arterial hypertension (PAH) is associated with impaired exercise capacity, 
quality of life (QoL) and right ventricular function.(Galiè et al. 2016) The disease is characterized 
by an increase of pulmonary vascular resistance and pulmonary arterial pressure, leading to right 
heart insufficiency.(Galiè et al. 2016, Grünig et al. 2010) Riociguat is a soluble guanylate cyclase 
stimulator and the first drug that has been approved for the treatment of both PAH and chronic 
thromboembolic pulmonary hypertension (CTEPH).(Ghofrani et al. 2013) The 12-week 
PATENT-1 study showed a significant improvement of the primary endpoint 6-minute walking 
distance (6MWD) and of secondary end-points as PVR, N-terminal prohormone brain natriuretic 
peptide (NT-proBNP) levels, World Health Organization functional class (WHO-FC), time to 
clinical worsening and Borg dyspnea score.(Ghofrani et al. 2013) An exploratory analysis of the 
first 12 weeks of the long-term extension study (PATENT-2) showed further significant 
improvement of 6MWD in the 215 PAH-patients receiving up to 2.5 mg of riociguat three times 
daily.(Rubin et al. 2015) In CTEPH-patients the 12-week CHEST-1 study revealed a statistically 
significant improvement of 6MWD (primary end-point) and in PVR, NT-proBNP serum values, 

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and in WHO-FC (secondary end points).(Ghofrani et al. 2013) Further studies investigating the 
effect of riociguat in an uncontrolled design were the early access study (EAS) in patients with 
CTEPH (McLaughlin et al. 2017) and PATENT plus in PAH.(Galiè et al. 2015) Recently, two 
retrospective studies of patients who participated in the phase III studies PATENT, CHEST, 
PATENT plus as well as the Phase II study and early access study in German centers have shown 
that riociguat treatment (1.0-2.5 mg tid) was associated with a significant reduction of right 
ventricular (RV) and right atrial (RA) area after 3, 6 and 12 months compared to baseline.(Marra 
et al. 2015, Marra et al. 2018) RA area significantly decreased after 12 months and RV systolic 
function assessed with tricuspid annular plane systolic excursion (TAPSE) improved during 
riociguat therapy.(Marra et al. 2015, Marra et al. 2018) 
Early diagnosis of systemic sclerosis associated pulmonary arterial hypertension (SSc-APAH) is 
of utmost importance, since it leads to significant improvement of survival rates through the 
implementation of PAH-targeted therapies.(Humbert et al. 2011) 
Therefore, a new hemodynamic definition of PAH was proposed at the 6th World Symposium of 
PH (Simonneau et al. 2019), which lowered the cut-off for mean pulmonary arterial pressure 
(mPAP) from ≥25 mmHg (as stated in the actual PH guidelines, Galiè et al. 2016) to >20 mmHg 
in combination with pulmonary arterial wedge pressure (PAWP) ≤15mmHg and PVR ≥3 Wood 
Units (WU). The change in the hemodynamic definition of pre-capillary PH represents a step 
towards the upper limit of physiological hemodynamic thresholds as shown in a systemic review 
of Kovacs et al. (Kovacs et al. 2009) including 1187 healthy subjects presenting with an upper 
limit of normal for mPAP of 20.6mmHg (mean + 2 standard deviations). Subsequent studies 
performed mainly in SSc patients reported that patients with mildly elevated mPAP (21-24 
mmHg) had reduced exercise capacity, impaired QoL, decreased RV output reserve, abnormal 
pulmonary arterial compliance (PAC) and survival.(Valerio et al. 2013, Coghlan et al. 2018, Nagel 
et al. 2019) Recent data from cohorts in a US-PH-center (Jaafar et al. 2019), and from SSc-patients 
cohorts in Zurich and Heidelberg (Xanthouli et al. 2020) have shown, that the new PAH-definition 
will most likely prevent from an early PAH-diagnosis due to a too high threshold for PVR 
≥3WU.(Jaafar et al. 2019, Xanthouli et al. 2020) Patients with PVR > 2 WU already had an early 
pulmonary vascular disease with reduced 6MWD, right heart function, PAC and survival 
(Xanthouli et al. 2020). Data on early treatment of patients with early PAH with mildly elevated 
pulmonary arterial pressures is still scarce. 
A recent double-blind-randomized controlled trial (EDITA) testing the effect of ambrisentan, an 
endothelin receptor antagonist, on mean pulmonary arterial pressure (primary endpoint) among 

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SSc-patients with mildly elevated mPAP and/or exercise PH, without significant left heart or lung 
disease, failed to change the primary endpoint, however, showed an improvement of PVR as 
secondary endpoint (Pan et al. 2019), which may be of prognostic relevance in this patient cohort. 
Further research in this field is needed.  
As PVR has a prognostic significance among patients with SSc-APAH and previous studies 
proved the positive effects of riociguat on right heart size and PVR (secondary endpoint in phase 
III studies), PVR was chosen as primary endpoint of the current study.  
The aim of this study is to investigate the effect of riociguat (MK-4836) on PVR, clinical 
parameters, safety and tolerability in patients with early pulmonary vascular disease. 
 
2.2 
Trial Rationale/ Justification 
The aim of this 24 weeks randomized, controlled multicenter, multinational study is to investigate 
the effect of riociguat (MK-4836) treatment on pulmonary vascular resistance in patients with 
early pulmonary vascular disease, indicated by either a) mPAP ≥25 mmHg with PVR ≥2 to <3 
WU and PAWP ≤15 mmHg or b) mPAP 21-<25 mmHg with PVR ≥2 WU and PAWP ≤15 mmHg. 
 
2.3 
Study Committees 
The following study committees will be established, each governed by a separate charter:  
• 
Independent Steering Committee (SC) - to advise on the study protocol, oversee the 
conduct of the study, contribute to interpretation of the results, and support 
publications.  
Any suspension or premature termination of the study must be discussed with the SC. 
3 
Trial Objectives and Endpoints 
3.1 
Primary Objective and Primary Endpoint 
1) To investigate the effect of treatment with riociguat (MK-4836) in patients with early 
pulmonary vascular disease, defined as either a) mean pulmonary arterial pressure (mPAP) 
≥25 mmHg with pulmonary vascular resistance (PVR) ≥2 to <3 WU and pulmonary arterial 
wedge pressure (PAWP) ≤15 mmHg or b) mPAP 21-<25 mmHg with PVR ≥2 WU, and 
PAWP ≤15 mmHg associated with connective tissue disease (CTD) or as 
idiopathic/heritable form. 

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3.2 
Secondary Objectives 
1) To investigate, whether treatment with riociguat (MK-4836) may improve further 
hemodynamic and clinical parameters in patients with early pulmonary vascular disease, 
defined as stated above. 
2) To assess safety and tolerability of riociguat (MK-4836) treatment in patients with early 
pulmonary vascular disease, defined as stated above. 
 
Secondary efficacy endpoints will be tested hierarchically: 
• 
change of cardiac index at rest (baseline to 24 weeks) 
• 
change of total pulmonary resistance (baseline to 24 weeks) 
• 
change of diffusion capacity of the lung (baseline to 24 weeks) 
• 
change of 6-minute walking distance (baseline to 24 weeks) 
• 
change of WHO functional class (baseline to 24 weeks) 
• 
change in QoL (SF-36, physical summation score; baseline to 24 weeks) 
 
Exploratory endpoints 
The following parameters will be assessed in every patient according to the visits schedule and 
analyzed as exploratory variables. Secondary endpoints will be analyzed as change from baseline 
to 12 and to 24 weeks as exploratory variables if available according to assessment schedule. 
QoL assessed by the SF-36 questionnaire  
• 
mental summation score as well as the 8 sub scores 
 
WHO functional class 
 
Lung function and lung diffusing capacity 
• 
FEV1 (forced expiratory volume in 1 second), TLC (total lung capacity), DLCO (diffusing 
capacity of the lung) 
 
Echocardiography 
• 
systolic pulmonary arterial pressure (sPAP, mmHg), right ventricular area (RV-area, cm2), 
and right atrial area (RA-area, cm2), tricuspid annular plane systolic excursion (TAPSE), left 
ventricular eccentricity index (LV-EI), RV-pump function and LV-pump function (LV-EF, %).   
 
Analyses of blood samples 
Venous blood will be analyzed to determine:  
• 
NT-pro BNP 
 

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Blood for blood gas analyses 
• 
oxygen partial pressure, carbon dioxide partial pressure, oxygen saturation of the blood 
(SpO2), pH values, bicarbonates, base excess  
 
Pulmonary hemodynamics by right heart catheterization 
• 
sPAP, mPAP, diastolic pulmonary artery pressure (dPAP), pulmonary artery wedge 
pressure (PAWP), right atrial pressure (RAP), cardiac output and ejection fraction (CO), central 
venous saturation, via blood gas analysis from pulmonary artery (SvO2) 
 
Clinical worsening will be defined as time to first event out of: 
• 
worsening of WHO functional class 
• 
deterioration of 6MWD >15% compared to baseline 
• 
need of initiation of targeted PAH treatment 
• 
hospitalization due to worsening of right heart function 
• 
all cause death or lung-transplantation 
• 
atrial septostomy 
 
Safety variables 
Laboratory, electrocardiogram, vital signs, assessment of adverse events and serious adverse 
events will serve as safety parameters. 
Patients with a serious adverse event occurring during the study treatment will be followed by the 
study team until the serious adverse event will have resolved to the pre-study level and/or will 
have been addressed according to best clinical practice.  
If a patient withdraws from study treatment and agrees to stay in the study, study related 
examinations will be performed and data will be obtained according to protocol. 
 
4 
Trial Design 
Investigator-Initiated-Trial (IIT)  
This is a prospective, randomized, controlled, parallel-group, double-blind multicenter 
multinational clinical trial, which investigates the effect of riociguat (MK-4836) in patients with 
early pulmonary vascular disease, defined as either a) mean pulmonary arterial pressure (mPAP) 
≥25 mmHg with pulmonary vascular resistance (PVR) ≥2 to <3 WU and pulmonary arterial wedge 
pressure (PAWP) ≤15 mmHg or b) mPAP 21-<25 mmHg with PVR ≥2 WU, and PAWP ≤15 
mmHg associated with connective tissue disease (CTD) or as idiopathic/heritable form. Patients 
in group b will be mainly enrolled as long as patients in group a are not defined as having 
pulmonary arterial hypertension according to European pulmonary hypertension guidelines. 

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The primary efficacy endpoint in this study is the change in PVR from baseline to 24 weeks. The 
study consists of a pre-treatment phase of up to 28 days followed by a 24-week treatment phase. 
The treatment phase is divided into an 8-week titration phase, followed by a 16-week main study 
phase. 
The patients who discontinue medication prematurely will be asked to continue with study 
assessments and perform study visits as outlined in the protocol. Subjects will be taking three doses 
daily with each dose taken 6 to 8 hours apart. In the case of side effects (e.g. symptomatic 
hypotension), down-titration by 0.5 mg tid is allowed. The maintenance dose achieved after 8 
weeks should be at least 1.5 mg tid. 
Medical examinations comprise of medical history, physical examination, electrocardiogram 
(ECG), blood gas analyses, lung function tests, DLCO, WHO-FC, 6MWD, quality of life 
questionnaires, laboratory testing (including NT-proBNP), echocardiography at rest, and right 
heart catheterization (RHC) according to clinical practice. If patients fulfil the inclusion criteria 
they will be invited to join the study. The prospective period of data collection will comprise of a 
24-week study period and a follow-up phase of about 30±14 days. 
After the pre-treatment phase, eligible subjects will be randomized at Visit 1 in a1:1 ratio to the 
following 2 treatment groups 
- 
Riociguat (MK-4836) 1.0-2.5 mg group (titration between 1.0 mg and 2.5 mg tid based on 
an individual dose titration scheme) 
- 
placebo group (placebo tid) 
 
5 
Trial Duration and Schedule 
5.1 
Study Phases 
• 
Screening Phase: up to 28 days before treatment start 
• 
Treatment phase: 24 weeks ± 14 days including 8 weeks titration phase and 16 weeks 
continuation phase. 
• 
Safety Follow-up: patient’s well-being will be monitored by phone after 30 ± 14 days after 
last intake of study drug. 
 
5.2 
Trial Duration 
The overall duration of the trial is expected to be approximately 4 ½ years. The actual overall 
duration or recruitment may vary.  

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Total trial duration: 
[4 ½ years] 
Duration of the double-blind phase: 
[24 weeks ± 14 days]   
Safety follow-up: 
[30 ± 14 days] 
 
5.3 
Recruitment plan 
Study sites will be activated to enroll the needed patient number for this study. 
 
 

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Case payments will be provided according to performed visits. Sites will be regularly informed 
about the screening process.  
 
6 
Selection of Subjects 
6.1 
Number of Subjects 
As calculated in section 10.1, 70 subjects will be enrolled in the clinical trial, 35 subjects per 
treatment group. 
 
6.2 
General Criteria for Subjects’ Selection 
Adult male and female patients with early pulmonary vascular disease will be included.  
Both an elevated mean pulmonary arterial pressure >20 mmHg and an increase of PVR >2 WU 
have been shown to be above the upper limit of normal and are associated with development of 
manifest PAH and impaired survival in CTD. As a placebo-controlled study would seem unethical 
in patients, who are in clear indication of targeted treatment, patients with manifest PAH according 
to the current definition may not be included in this study (combination of both mPAP ≥25 mmHg 
and PVR ≥3 WU and PAWP ≤15 mmHg).  
It is assumed that for any patient, considered for inclusion, a regular diagnostic workup in 
accordance with international guidelines (ESC/ERS Guidelines) was performed. Hemodynamics 
will be assessed by right heart catheterization at the screening visit, up to 1 month prior to 
screening or up to 6 months prior to screening if the patient had no signs of clinical changes defined 
as change of 6MWD >10%, WHO-FC change or >30% change in NT-proBNP. RHC must have 
been measured in the participating center under standardized conditions. For statistical 
considerations see section 10.  
 
6.3 
Inclusion Criteria 
1. ≥18 years of age at time of inclusion. 
2. Male and female patients with early pulmonary vascular disease, defined as either  
a) mean pulmonary arterial pressure (mPAP) ≥25 mmHg with pulmonary vascular 
resistance (PVR) ≥2 to <3 WU and pulmonary arterial wedge pressure (PAWP) ≤15 mmHg 
(group I PAH according to 2022 ERS/ESC guidelines) or  

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b) mPAP 21-<25 mmHg with PVR ≥2 WU, and PAWP ≤15 mmHg associated with 
connective tissue disease (CTD) or as idiopathic/heritable form (see Group I / Nice Clinical 
Classification of Pulmonary Hypertension) (acc. to Simonneau et al. 2019; Humbert et al. 
2022). Patients with rheumatoid arthritis or connective tissue disease of any kind, except 
systemic lupus erythematosus, may also be included. Patients in group b will be mainly 
enrolled as long as patients in group a are not defined as having pulmonary arterial 
hypertension according to European pulmonary hypertension guidelines. 
3. Treatment naïve patients (with respect to PAH specific medication) 
4. Unspecific treatments which may also be used for the treatment of pulmonary hypertension 
such as oral anticoagulants, diuretics, digitalis, calcium channel blockers or oxygen 
supplementation are permitted. Permitted are also treatments of the rheumatologic disease. 
However, these drugs must have been started at least 1 month before right heart 
catheterization. 
5. Right-heart catheterization results must not be older than 1 month at Visit 1 (will be 
considered as baseline values, the time frame can be prolonged up to 6 months, if the patient 
has had no signs of clinical changes defined as >20% change of 6MWD, WHO FC, > 30% 
change in NT-proBNP) and must have been measured in the participating center under 
standardized conditions (refer to the study specific Swan Ganz catheterization manual). If 
the respective measurements have not been performed in context with the patient’s regular 
diagnostic work up, they have to be performed as a part of the study during the pre-study 
phase (after the patient signed the informed consent). 
6. Women without childbearing potential defined as postmenopausal women with amenorrhea 
for at least 12 consecutive months and a serum FSH level within the laboratory’s reference 
range for postmenopausal females, women with bilateral tubal ligation, women with 
bilateral ovariectomy, and women with hysterectomy can be included in the study.  
7. Women of childbearing potential can only be included in the study if all of the following 
applies (listed below):  
a. Negative serum pregnancy test at screening and at study start (visit 1).  
b. Agreement to undertake monthly urine pregnancy tests during the study and up to at 
least 30 days after study treatment discontinuation. These tests should be performed 
by the patient at home.  
c. Agreement to use a highly effective contraception method from screening until at least 
30 days after last dose of study medication.  

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Option 1 or 
Option 2 
One method from this 
list 
or 
Option 3 
or 
Option 4 
Tubal 
sterilization 
(occlusion or 
ligation 
of 
tubes 
at least 6 
weeks 
prior to 
Screening) 
 Oral*, 
Implantable*, 
Transdermal*, or 
Injectable* 
hormonal 
contraceptives 
Intrauterine 
Devices 
 
 Sterilization of the 
male partner with 
documented post-
vasectomy 
confirmation of the 
absence of sperm 
in the ejaculate 
PLUS one 
method from this 
list 
Oral*, 
Implantable*, 
Transdermal*, or 
Injectable* 
hormonal 
contraceptives 
Intrauterine 
devices 
Diaphragm, 
female condom 
cervical cap, 
partner’s use of a 
condom 
 True abstinence 
from intercourse 
with a male 
partner only when 
this is in line with 
the preferred 
lifestyle of the 
subject. 
* If a hormonal contraceptive is chosen from this group, it must have been taken for at least 28 days prior to study start (visit 1). 
8. Patients who are able to understand and follow instructions and who are able to participate 
in the study for the entire period. 
9. Patients must have given their written informed consent to participate in the study after 
having received adequate previous information and prior to any study-specific procedures. 
 
6.4 
Exclusion Criteria 
1. Patients with systemic lupus erythematosus. 
2. Concomitant PAH-targeted treatment is not allowed during the study. Accordingly, 
patients scheduled to receive another investigational drug during the course of this study 
cannot participate (see exclusion criterion 12). Patients already receiving or having 
received any PAH targeted therapy will therefore not be included into the study. Such 
treatment may not be discontinued to enable inclusion into the study. 
3. Concomitant treatment with phosphodiesterase 5 inhibitors, endothelin receptor 
antagonists and prostacyclin analogues due to digital ulcers is contraindicated and must not 

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be taken during the study period. Such drugs must have a washout-phase of 3 days at the 
time of right heart catheterization at screening. Intravenous treatment with prostacyclin 
analogues should not be performed within 1 week of right heart catheterization. Any 
decision to discontinue above-mentioned drugs will be made by the clinicians and the 
patient at screening, which takes part during the patients’ regular routine visit. The 
discontinuation of above-mentioned drugs will be evaluated by considering the presence 
or absence of digital ulcers and their frequency of appearance in the patient’s medical 
history. 
4. Pulmonary hypertension explained by other cause including group 2, 3, 4 and 5 PH 
according to the current guidelines. 
5. Cardiac comorbidity, defined with three or more of the following conditions: uncontrolled 
arterial hypertension, diabetes mellitus, body mass index >35, left atrial enlargement >20 
cm², atrial fibrillation, left ventricular ejection fraction <50%. 
6. Pulmonary comorbidity, defined as forced vital capacity (FVC) ≤70; forced expiratory 
volume in 1 second (FEV1) ≤50%; diffusion capacity of the lung (DLCO) ≤30%.  
7. Patients with a medical disorder, condition, or history of such that would impair the 
patient's ability to participate or complete this study in the opinion of the investigator. 
8. Patients with underlying medical disorders with an anticipated life expectancy below 2 
years (e.g. active cancer disease with localized and/or metastasized tumor mass). 
9. Patients with a history of severe or multiple drug allergies (defined as allergic reactions to 
three or more structurally unrelated drugs). 
10. Patients with hypersensitivity to the investigational drug or any of the excipients. 
11. Contraindications according to summary of product characteristics of riociguat (e.g. 
arterial hypotension with systolic blood pressure <95 mmHg; nitrates or nitric oxide donors 
(such as amyl nitrite) in any form including recreational drugs) 
12. Participation in any clinical drug trial within 4 weeks prior or 5 half-lives, whichever 
longer, to screening of this study and/or patient, who is scheduled to receive an 
investigational medicinal product (IMP) during the course of this study 
13. Background therapy with highly anti-fibrotic drugs (pirfenidone) or nintedanib, 
prednisolone >10 mg/day  
 

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6.5 
Criteria for Removal or Withdrawal 
6.5.1 Withdrawal of Subjects  
A subject will be withdrawn from the trial treatment for the following reasons: 
1. at their own request or at request of their legal representative 
2. if, in the investigator's opinion, continuation of the trial would be detrimental to the 
subject's well-being 
3. occurrence of a severe serious adverse event (SAE) caused by the IMP 
4. The participant has a medical condition or personal circumstance which, in the opinion 
of the investigator placed the participant at unnecessary risk from continued 
administration of study treatment. This includes progression or aggravation of the 
pulmonary hypertension, so that appropriate PAH targeted therapy may be introduced 
without delay. 
5. The participant has a confirmed positive serum pregnancy test. 
The Coordinating Investigator decides about withdrawal of subjects from trial treatment in case of 
occurrence of criteria mentioned above.  
Patients with a serious adverse event occurring during the study treatment will be followed by the 
study team until the serious adverse event will have resolved to the pre-study level and/or will 
have been addressed according to best clinical practice. The patient, either willingly withdrawn 
from the study or due to premature termination, will be asked thoroughly to complete all 
examinations scheduled for the final trial day, and these will be performed as far as possible and 
documented.  
In all cases, the reason for withdrawal must be recorded in the CRF and in the subject’s medical 
records. 
In case of withdrawal of a subject at his/ her own request, the reason should be asked for as 
extensively as possible and documented. 
All efforts will be made to follow up the subject.  
A subject may/ will be withdrawn from all trial related procedures (including follow-up visits) for 
the following reasons: 
- at his/her own request or at request of his/her legal representative 
- non-adherence to the trial-related requirements, which may (have) influence(d) the validity 
of the trial data 
 

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6.5.2 Replacement of Subjects 
Per treatment arm, 35 subjects will be enrolled and included into the modified intention to treat 
(ITT) and safety analysis (SA) (total n=70). Subjects who terminate the study prematurely will not 
be replaced as a 15% drop-out rate is included in this sample size calculation.  
 
6.5.3 Premature Closure of the Clinical Trial 
The trial can be prematurely closed or suspended by the Coordinating Investigator in case if new 
serious risks for subjects become known. The Ethics Committee (EC) and the competent 
regulatory authorities must then be informed. Furthermore, the Ethics Committee(s) and 
competent regulatory authorities themselves may decide to stop or suspend the trial.  
Should the trial be closed prematurely, all trial material (completed, partially completed, and blank 
CRF, randomization envelopes, IMP, etc.) must be returned to and/or kept within the files of the 
Coordinating Investigator.  
All involved investigators have to be informed immediately about a cessation/ suspension of the 
trial. The decision is binding to all trial centers and investigators.  
 
6.6 
Prior and Concomitant Illnesses 
Relevant additional illnesses present at the time of informed consent are regarded as concomitant 
illnesses and will be documented on the appropriate pages of the CRF as medical history. Included 
are conditions that are seasonal, cyclic, or intermittent (e.g. seasonal allergies; intermittent 
headache). 
Abnormalities which appear for the first time or worsen (intensity, frequency) during the trial are 
adverse events (AEs) and must be documented on the appropriate pages of the CRF. 
 
6.7 
Prior and Concomitant Treatments 
Any prior or concomitant therapy must be assessed in terms of potential interactions with the study 
drug as listed in the most current version of the riociguat summary of product characteristics. 
Relevant additional treatments administered to the subjects on entry to the trial or at any time 
during the trial are regarded as concomitant treatments and must be documented on the appropriate 
pages of the CRF. 
In case of clinical worsening and if clinically indicated additional PAH-targeted rescue medication 
will be initiated at the discretion of the investigators. If patients present with manifest PAH after 
24 weeks at the end of the double-blind phase, patients will be offered targeted treatment according 
to current PH guidelines. Participants will not be included if scheduled to receive another 
investigational drug during the course of this study. 

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Patients receiving highly anti-fibrotic drugs (pirfenidon), nintedanib, prednisolone >10 mg/day or 
any other PAH specific treatment may not participate in this study. Sildenafil and tadalafil must 
be discontinued at least 24 hours and at least 48 hours respectively prior to first administration of 
riociguat. Moreover, administration of concomitant drugs that may decrease riociguat plasma 
concentration as listed in the current summary of product characteristics should be avoided (e.g. 
strong CYP3A4 inducers). 
 
7 
Investigational Medicinal Product 
7.1 
General Information about the Investigational Medicinal Product 
7.1.1 Riociguat  
International Nonproprietary Name (INN): riociguat  
Investigational medicinal product code of MSD: MK-4836 
ATC code: C02KX05 
Chemical formula: C20H19FN8O2 
Pharmaceutical form: film-coated tablet 
Route of administration: oral 
Time and frequency of administration: tid 
Dosage: individual titration starting at 1.0 mg with maximum dosage of 2.5 mg three 
times/day 
Storage conditions: 15-30°C  
Clinical drugs supplied by MSD SHARP&DOHME GmbH, Germany 
Devices: none 
 
7.1.2 Placebo 
Placebo medication consists of tablets indistinguishable from the riociguat (MK-4836) 
tablets supplied by MSD SHARP&DOHME GmbH, Germany 
 
7.2 
Therapeutic Effects 
Pulmonary arterial hypertension is defined by an increased mean pulmonary arterial pressure and 
pulmonary vascular resistance. Patients with systemic sclerosis or other forms of connective tissue 
disease have an increased risk to develop pulmonary arterial hypertension which significantly 
impairs their prognosis. 
Riociguat is the first drug that has been approved for the treatment of both PAH and CTEPH 
(Ghofrani et al. 2013). The 12-week PATENT-1 study showed a significant improvement of the 

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primary endpoint 6MWD and of secondary endpoints such as PVR, NT-proBNP levels, WHO-
FC, time to clinical worsening and Borg dyspnea score (Ghofrani et al. 2013). An exploratory 
analysis of the first 12 weeks of the long-term extension study (PATENT-2) showed further 
significant improvement of 6MWD in the 215 PAH-patients receiving up to 2.5 mg of riociguat 
tid (Rubin et al. 2015).  
In CTEPH-patients the 12-week CHEST-1 study revealed a statistically significant improvement 
of 6MWD (primary endpoint) and in PVR, NT-proBNP serum values, and in WHO-FC (secondary 
end points) (Ghofrani, et al. 2013). Further studies investigating the effect of riociguat in an 
uncontrolled design were the early access study (EAS) in patients with CTEPH (McLaughlin et 
al. 2017) and PATENT plus in PAH (Galiè et al. 2015).  
In a retrospective analysis of patients with CTD-APAH receiving riociguat in PATENT-1 and 
PATENT-2, mean improvement of PVR after 12 weeks was 132±140 dynes*sec*cm-5 in patients 
with SSc (equals 1.65±1.75 WU).  
Up to now, it is not known, whether targeted treatment for PAH provides a benefit in patients with 
early pulmonary vascular disease. 
 
7.3 
Benefit/ Risk Assessment 
An early detection and treatment of CTD-PAH is especially important, as patients tend to have a 
poor prognosis with a median survival rate of one year after diagnosis if left untreated.  
Patients with SSc and mildly elevated mPAP of 21-24 mmHg have been shown to be more likely 
to develop PH than patients with mPAP <21 mmHg (p <0.001 by log rank test, hazard ratio 3.7). 
A TPG >11 mmHg at baseline also predicted PH (p <0.001 by log rank test, hazard ratio 7.9), 
yielding a sensitivity of 87% and a specificity of 70% (Valerio et al. 2013). Development of PH 
was associated with a mortality of 18% within 3 years in this cohort. Early treatment with riociguat 
might have a beneficial impact on pulmonary vascular disease, hemodynamics and thus improve 
prognosis. 
Early diagnosis of SSc-APAH is of utmost importance, since it leads to significant improvement 
of survival rates through the implementation of PAH-targeted therapies. (Humbert et al. 2011) 
Therefore, a new hemodynamic definition of PAH was proposed at the 6th World Symposium of 
PH (Simonneau et al. 2019), which lowered the cut-off for mPAP from ≥25 mmHg (as stated in 
the actual PH guidelines, Galiè et al. 2016) to >20 mmHg in combination with PAWP ≤15mmHg 
and PVR ≥3WU. The change in the hemodynamic definition of pre-capillary PH represents a step 

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towards the upper limit of physiological hemodynamic thresholds as shown in a systemic review 
of Kovacs et al. (Kovacs et al. 2009) including 1187 healthy subjects presenting with an upper 
limit of normal for mPAP of 20.6mmHg (mean + 2 standard deviations). 
The effects of an early treatment have already been indicated by a study of Kovacs et al. (2012). 
In a small cohort of ten patients with SSc, which were observed for a period of 12 months without 
treatment and then treated with bosentan for six months, bosentan treatment led to a reduction of 
mPAP and PVR. During the observation period patient’s hemodynamic values worsened. Thus, a 
beneficial effect is expected to be demonstrable after a period of 6 months.  
Risks of treatment with riociguat (MK-4836) include the known side effects listed below. 
 
7.4 
Known Side Effects 
Treatment with riociguat (MK-4836) may cause side effects. Side effects are summarized in the 
most recent summary of product characteristics.  
The currently known most serious side effects are 
• coughing up blood (hemoptysis) (common side effect, may affect up to 1 in 10 people), 
• acute bleeding from the lungs (pulmonary hemorrhage) may result in coughing up blood, 
cases with fatal outcomes were observed (uncommon side effect, may affect up to 1 in 100 
people). 
Overall list of possible side effects: 
Very common: may affect more than 1 in 10 people 
• headache, dizziness, indigestion (dyspepsia), swelling of limbs (edema peripheral), 
diarrhea, feeling or being sick (nausea and vomiting) 
Common: may affect up to 1 in 10 people 
• inflammation of the stomach (gastritis), inflammation in the digestive system 
(gastroenteritis), reduction of red blood cells (anemia) seen as pale skin, weakness or 
breathlessness, awareness of an irregular, hard, or rapid heartbeat (palpitation), low blood 
pressure (hypotension), nose bleed (epistaxis), difficulty breathing through your nose 
(nasal congestion), pain in the stomach, intestine or abdomen (gastrointestinal and 
abdominal pain), heartburn (gastro-esophageal reflux disease), difficulty in swallowing 
(dysphagia), constipation, bloating (abdominal distension) 

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According to the current summary of product characteristics, smoking may lead to a reduced 
response to riociguat. Therefore, participating current smokers will be advised to stop smoking. 
 
7.5 
Dosage Schedule, Titration and Administration 
Dose titration 
The recommended starting dose is 1.0 mg three times daily for 2 weeks. Tablets should be taken 
three times daily approximately 6 to 8 hours apart. 
Dose should be increased by 0.5 mg three times daily every two weeks to a maximum of 2.5 mg 
three times daily, if systolic blood pressure is ≥95 mmHg and the patient has no signs or symptoms 
of hypotension. If systolic blood pressure falls below 95 mmHg, the dose should be maintained 
provided the patient does not show any signs or symptoms of hypotension. If at any time during 
the up-titration phase systolic blood pressure decreases below 95 mmHg and the patient shows 
signs or symptoms of hypotension the current dose should be decreased by 0.5 mg three times 
daily. The maintenance dose should be at least 1.5 mg tid after the titration phase. 
If a participant does not tolerate the study medication, the investigator may down-titrate the dose 
by 0.5 mg. If down-titration occurs during the titration period, re-uptitration may be attempted 
until the end of week 12. Re-uptitration may be performed via titration phone-call. Re-uptitration 
can be done using originally assigned medication doses from the most recent study treatment 
dispensing visit (baseline). No dose adjustment is allowed during the maintenance period after 
week 12, except for safety reasons. 
Study treatment may be temporarily interrupted in response to an AE, a diagnostic or therapeutic 
procedure, a laboratory abnormality, or for administrative reasons. 
If study treatment is interrupted by the participant for any reason, they must immediately inform 
the investigator. Interruptions of study treatment must be kept as short as possible. Treatment 
should be restarted according to the instructions in the most recent summary of product 
characteristics of riociguat, i.e. in case treatment has to be interrupted for 3 days or more, it should 
be restarted with 1 mg three times daily for 2 weeks and continued with the dose titration regimen 
as described. 
If treatment is stopped for more than 14 consecutive days, re-introduction is not permitted, and 
treatment must be permanently discontinued. Study treatment dose adjustments / interruptions 
must be recorded in the eCRF. 

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If a patient does not tolerate a dose of 1.5 mg three times daily after reasonable attempt, he/she has 
to stop study treatment. 
 
Maintenance dose 
The established individual dose should be maintained unless signs and symptoms of hypotension 
occur. The maximum total daily dose is 7.5 mg i.e., 2.5 mg 3 times daily. If a dose is missed, 
treatment should be continued with the next dose as planned. If not tolerated, dose reduction should 
be considered at any time.  
Administration 
Tablets are for oral use and can generally be taken with or without food. For patients prone to 
hypotension, as a precautionary measure, switches between fed and fasted riociguat (MK-4836) 
intake are not recommended because of increased peak plasma levels of riociguat (MK-4836) in 
the fasting compared to the fed state. 
 
7.6 
Treatment Assignment 
Patients who have signed the consent form will be given a unique screening number including 
center number (e.g. 01, 02…) and patient ID (001, 002, …). Screening number will ascend, starting 
with 001, 002, etc. If the patient is eligible for the prospective drug trial, a 1:1 randomization will 
be performed into riociguat (MK-4836) and placebo group and a consecutive randomization 
number will be allocated to the patient.  
The trial medication will be administered to subjects only after confirming their eligibility after 
the initial screening. Study drug will be supplied at baseline and consecutive visits.  
Subjects withdrawn from the trial retain their identification codes (e.g. randomization number, if 
already given). New subjects must always be allotted a new identification code. 
 
7.7 
Randomization and blinding 
After the pre-treatment phase, eligible subjects will be randomized at Visit 1 in a1:1 ratio to the 
following 2 treatment groups: 
• Riociguat (MK-4836) 1.0-2.5 mg group (titration between 1.0 mg and 2.5 mg tid based on 
an individual dose titration scheme) (35 subjects planned) 
• Placebo group (placebo tid) (35 subjects planned) 
Investigator, sponsor, study personnel, monitor, biometrician, and the patient will be blinded to 
treatment. The sponsor will engage an independent qualified external service (e.g. pharmacy) to 

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centrally generate the randomization envelopes and emergency envelopes for each participating 
center. 
Earlier screening failures may be rescreened once for possible study entry. Patients who dropped 
out of the study are not allowed to re-enter or to be enrolled again. 
Randomization to one of the groups will be performed by permuted block randomization. Blocks 
will be stratified according to centre. Randomization lists will be created by the above-mentioned 
unblinded independent, central external service designated by the sponsor. The randomization list 
will be kept centrally in safe and confidential custody at the external service in compliance with 
applicable local laws/regulations.  
 
Emergency Envelopes: In addition to the trial medication the investigator will receive a set of 
sealed envelopes, one for each randomization number. These envelopes will be created by the 
unblinded independent, central external service (e.g. pharmacy) in charge of randomization  and 
provided according to the random number with the study medication. An identical set of sealed 
envelopes will be held at Pharmacovigilance Safety Officer. These envelopes contain information 
on the subject’s trial medication and are to be opened only under circumstances in which it is 
medically imperative to know what the subject is receiving. Date and reason for opening a sealed 
envelope must be documented. If possible, the investigator will confer with the Coordinating 
Investigator before unblinding. The randomization envelopes are not to be opened by the 
investigator at the end of the trial. All envelopes will be collected by the monitor at the end of the 
trial. 
 
7.8 
Labelling and Supply 
Study medication will be labelled according to the requirements of local law and legislation by 
MSD SHARP&DOHME GmbH Germany and provided to the only single site in a country or a 
central pharmacy in case there are several sites in a country as determined by the principle 
investigator/sponsor. Each center will receive the study medication in a blinded fashion.  
Medication of the maintenance phase will be packed in bottles containing medication for 12 weeks 
± 14 days. At the week 12 visit, the bottle number will be allocated to the respective patient 
according to the dosage selected during the visit. 
 
7.9 
Supplies and Accountability 
The investigator will keep an account of the trial medication and acknowledge the receipt of all 
shipments of the trial medication. All investigational drugs used during the trial will be stored at 

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the investigational sites in a place inaccessible to unauthorized personnel. The study drug must be 
stored between 15°C and 30°C. The investigator will also keep accurate records of the quantities 
of trial medication dispensed, used, and returned by each subject. The documentation has to 
include date of dispensing, subject identification, batch number and medication number of trial 
medication. The site monitor will periodically check the supplies of trial medication held by the 
investigator to ensure the correct accountability of all trial medication used. At the end of the trial, 
any unused drug supply will be documented by the study site and destroyed in compliance with 
the institution’s procedures and applicable local laws/regulations. Unused trial medication 
returned by patients will be sealed during monitoring visits and destroyed at the end of the study. 
The procedure will be documented and archived. It will be assured that a final report of the drug 
accountability is prepared and maintained by the investigator. 
 
7.10 Compliance 
Trial medication will be dispensed to the subjects by the investigator. Subjects will be instructed 
to bring all trial medication to the trial site at every visit. Compliance will be assessed by tablet 
count. Details will be recorded in the CRF. Treatment effects will be assessed and the dosage will 
be discussed at each visit.  
The patient will adapt the dose from 1.0 mg to 2.5 mg three times/day during the 8-week titration 
phase according to tolerability and after consultation (by phone or personally) with one of the 
investigators as to common practice of the clinic. 
Furthermore, the patients will receive a patient diary recording medication intake and time points. 
The patient diary will be checked for compliance at each study visit. 
 

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8 
Trial Methods 
8.1 
Overview of visits and assessments 
 
 
Double-blind 
Assessments 
Screening  
Visit 1 
Baseline 
V 1.1-1.4 
Phone 
Visits  
Titration 
Visit 2 
Interim 
visit 
V 2.1-2.2 
Phone 
Visits  
Only WOCBP 
Visit 3 
Terminatio
n visit 
 
Visit 4 
Safety FU 
  
Day 1 
Week 2, 4, 
6 and 8 
Week 12 
Week 16 
and 20 
Week 24 
30 days after 
last IMP intake 
 -28 days 
 
±2 days 
±7 days 
±2 days 
±14 days 
±14 days 
Informed Consent 
1 
- 
- 
- 
- 
- 
- 
Inclusion / exclusion 
criteria 
1 
1 
- 
- 
- 
- 
- 
Patient diary(handing out 
/ compliance check) 
- 
1 
- 
1 
- 
1 
- 
Prior and concomitant 
medication 
1 
1° 
4 
1 
2 
1 
1 
Demography, height and 
medical history 
1 
- 
- 
- 
- 
- 
- 
PAH classification, 
etiology, diagnosis date  
1 
- 
- 
- 
- 
- 
- 
WHO-FC 
- 
1 
- 
1 
- 
1 
- 
Vital signs, incl. heart 
rate, SpO2 (%) 
1 
1 
- 
1 
- 
1 
- 
6MWD, Borg Dyspnea 
Score 
- 
1 
- 
1 
- 
1 
- 
Weight 
1 
1° 
- 
1 
- 
1 
- 
ECG 
1 
1° 
- 
1 
- 
1 
- 
Blood gas analysis 
1 
1° 
- 
- 
- 
1 
- 
Lung function testing 
(Plethysmography)  
1 
1° 
- 
- 
- 
1 
- 
Diffusing capacity of the 
lung 
1 
1° 
- 
- 
- 
1 
- 
Right heart catheter  
   1* 
- 
- 
- 
- 
1 
- 
Physical examination 
1 
1° 
- 
1 
- 
1 
- 
Laboratory Hematology, 
Chemistry,  
Hemostaseology, 
NT-proBNP 
1 
1° 
- 
1 
- 
1 
- 
Pregnancy test (only 
WOCBP) 
1 
1°¶ 
2+ (week 4 
and 8) 
1 
2+ (week 16 
and 20) 
1 
1+ 
Echocardiography 
-# 
1# 
- 
- 
- 
1 
- 
Quality of life (SF-36) 
- 
1 
- 
- 
- 
1 
- 
Adverse Events 
1 
1 
4 
1 
2 
1 
1 
Systolic blood pressure 
and dose adjustment 
- 
- 
4 
- 
- 
- 
- 
Drug dispensed 
- 
1 
- 
1 
- 
 
- 
Drug collected 
- 
- 
- 
1 
- 
1 
- 
Drug compliance 
- 
- 
- 
1 
- 
1 
- 
Phone visits 
- 
- 
4 
- 
2 
- 
1 
* RHC at screening will only be performed in patients who have not had a RHC within the preceding 1 month at screening. A preceding RHC from the last 6 months can be used if the patient had 
no signs of clinical changes defined as change of 6MWD >10%, WHO-FC change or >30% change in NT-proBNP. RHC must have been measured in the participating center under standardized 
conditions. 
+ Pregnancy test at home.  
¶ Handing out pregnancy tests for home use 
° Will not be performed if already performed at Screening AND if Screening and Baseline are conducted during same hospital stay. 
† Optional during the SARS-CoV2-pandemic. 
# If, due to organisational reasons, echocardiography cannot be performed at Baseline, it can be performed during Screening period and it can be used as baseline value. Echocardiography cannot 
be performed after baseline. 

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8.2 
Assessments 
8.2.1 Physical examination and demographic data 
The physical examination comprises measurement of body weight and height (height will be 
measured only once) and a routine internal medical examination. Physical examinations will be 
performed to ensure suitability according to the inclusion and exclusion criteria and to document 
the health status before and following treatment with the IMP. 
Connective tissue disease will be diagnosed by rheumatologists based on the current classification 
criteria for connective tissue diseases (van den Hoogen et al. 2013, Anger et al. 2019, Shiboski et 
al. 2017).  
Underlying causes of pulmonary vascular disease will be ruled out according to the guidelines 
(Galiè et al. 2015). 
 
8.2.2 Hemodynamic parameters 
Hemodynamic parameters will be determined by right heart catheterization according to current 
guidelines (Opitz et al. 2011). The right heart catheterization (RHC) will be performed at screening 
only in patients who have not performed a RHC within the preceding 1 month or in the last 6 
months if the patient had no signs of clinical changes defined as change of 6MWD >10%, WHO-
FC change or >30% change in NT-proBNP. RHC must have been measured in the participating 
center under standardized conditions. RHC may involve exposure to ionising radiation only if 
clinically indicated. 
Directly, invasively measured parameters are: CI, sPAP, mPAP, dPAP, PAWP, RAP, PVR, CO, 
SvO2. During the right heart catheterization, a continuous ECG will be performed. The values will 
be based on three measurements at one time point. The three values of CO should not differ by 
more than 10% from each other. Optionally, arterial blood gas saturation can be measured in wedge 
position.  
Directly non-invasive measured parameters: heart rate, blood pressure 
Methodology: Swan-Ganz catheterization and thermodilution methodology 
The primary endpoint PVR (in WU) will be calculated by the formula PVR = (mPAP-
PAWP)/CO*80. CI (in l/min/m2) will be calculated by CO/Body mass area. 
The data will be directly measured in the participating centers and will be transferred to the CRF. 
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to study treatment. Original RHC data will be submitted for central reading with pseudonymized 
pressure curves and data of thermodilution.  
 
8.2.3 Echocardiography  
Echocardiography will be performed according to current guidelines (Rudski et al. 2010). 
Following parameters will be assessed: sPAP, RV-area and RA-area, TAPSE, LV-EI, RV-pump 
function and LV-EF. 
 
8.2.4 Determination of WHO functional class  
Functional assessment of pulmonary hypertension will be performed according to the WHO-
Functional Class, i.e. the Evian Symposium, 1998, modified New York Heart Association 
(NYHA) Classification: 
Class I: Patients with PH but without resulting limitation of physical activity. Ordinary physical 
activity does not cause undue dyspnea of fatigue, chest pain or near syncope. 
Class II: Patients with PH resulting in slight limitation of physical activity. They are comfortable 
at rest. Ordinary physical activity causes undue dyspnea or fatigue, chest pain or near syncope. 
Class III: Patients with PH resulting in marked limitation of physical activity. They are 
comfortable at rest. Less than ordinary activity causes undue dyspnea or fatigue, chest pain or near 
syncope. 
Class IV: Patients with pulmonary hypertension with inability to carry out any physical activity 
without symptoms. These patients manifest signs of right heart failure. Dyspnea and/or fatigue 
may even be present at rest. Discomfort is increased by any physical activity. 
 
8.2.5 Lung function tests and blood gas analysis 
Lung function test: Body plethysmography including forced vital capacity (FVC), forced 
expiratory volume in one second (FEV1), total lung capacity (TLC), residual volume (RV), and 
diffusion capacity diffusion-limited carbon monoxide (DLCO), DLCO/VA (Krogh index).  
Blood gas analysis: capillary or arterial blood gas analysis; partial pressure of oxygen and carbon 
dioxide, SpO2, pH values, bicarbonates, base excess. 
If the patient receives oxygen the amount will be recorded in the CRF in liters/minute. 
 
8.2.6 6-minute walking distance and Borg dyspnea Score (CR 10)  
6-minute walking test will be performed according to ATS guidelines (ATS 2002). The patient is 
asked to walk along a prescribed path as far as possible during a 6-minute interval of time. The 
patient may walk at whatever pace he/she feels comfortable with the goal of walking the most 

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distance he/she feels possible. If the patient feels the need to rest, he/she may do this. Blood 
pressure, heart rate and oxygen saturation will be measured before and after the test.  
The Borg Scale (Breathlessness Scale) is commonly used to measure shortness of breath of patients 
or in sports medicine. In this study, the Borg Scale will be applied to record dyspnea immediately 
following the 6-minute walk test. 
The Borg Scale comprises the following parameters according to the ATS guidelines (ATS 2002): 
0  
Nothing at All 
0.5 
Very, very slight (just noticeable) 
1 
Very slight 
2 
Slight 
3 
Moderate 
4 
Somewhat Moderate 
5 
Severe 
6 
 
7 
Very Severe 
8 
 
9 
Very, very severe (almost maximal) 
10 
Maximal 
 
8.2.7 Quality of Life (QoL) 
QoL will be assessed using the SF 36-questionnaire (see Appendix) that will be handed out to the 
patients. Scoring will be carried out according to the test manual. 
The SF-36 consists of eight scaled scores, which are the weighted sums of the questions in their 
section. Each scale is directly transformed into a 0-100 scale, i.e. a score of zero is equivalent to 
maximum disability and a score of 100 is equivalent to no disability. The eight sections are: 
vitality; physical functioning; bodily pain; general health perceptions; physical role functioning; 
emotional role functioning; social role functioning; mental health. Two summation scores, 
physical summation score and mental summation score, will be calculated. 
 
8.2.8 Vital signs 
Blood pressure, heart rate and oxygen saturation will be measured after the patient has been at rest 
for at least 5 minutes.  
Blood pressure (systolic and diastolic) will be measured by means of a standard manual or an 
automatic blood pressure measuring device (cuff method) in sitting or supine position. 
Nevertheless, the same method and body posture should be used during the entire study period 
(the type of device has to be recorded into the CRF). The same upper arm will be used for each 

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measurement of blood pressure, preferably the left arm. Heart rate and SpO2 will be measured by 
pulse oximetry. 
 
8.2.9 Electrocardiography 
A 12-lead electrocardiogram (ECG) will be performed. For deriving the 12-lead ECGs the patients 
should always be in supine position. The 12-lead ECGs should be derived after a resting period of 
at least 10 minutes. The investigator will review the ECGs for potential AEs. 
A continuous 12-lead ECG monitoring will be applied during right heart catheterization. 
 
8.2.10 Clinical laboratory investigations  
Clinical laboratory investigations will comprise: 
Hematology 
Leucocytes, erythrocytes, hemoglobin, hematocrit, platelets 
Substrates 
Bilirubin, cholesterol, triglycerides, creatinine, uric acid, urea, total protein, glucose 
Electrolytes 
Sodium, potassium, calcium, chloride 
Enzymes 
SGOT/ASAT, SGPT/ALAT, Gamma-GT, AP, LDH, CK 
Others 
INR, PTT, β-HCG test or urine dipstick for WOCBP  
Biomarkers 
CRP, NT-proBNP 
All laboratory assessments will be determined locally on-site. Any leftover biomaterials will be 
destroyed in line with local regulations.  
 
8.3 
Study Phases and Visits 
8.3.1 Screening Phase 
Patients who sign the informed consent form to participate in the medical trial will undergo the 
screening examinations: medical history, demographics, checking of in- and exclusion criteria, 
physical and weight examination, vital signs (blood pressure, heart rate, SpO2), lung function test 
(body plethysmography and diffusion capacity), blood gas analysis (BGA), echocardiography at 
rest, right heart catheterization with continuous 12-lead ECG at rest, clinical laboratory, including 
pregnancy test (only WOCBP), survey of concomitant medication and diseases and recording of 
adverse events. Measurements/assessments taken during screening visit will be recorded as 
baseline values for study assessment of endpoints unless described otherwise. 
The right heart catheterization should not be older than 1 month at screening or not older than 6 
months if the patient had no signs of clinical changes defined as change of 6MWD >10%, WHO-
FC change or >30% change in NT-proBNP. RHC must have been measured in the participating 

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center under standardized conditions. Patients without recent RHC fulfilling the above-mentioned 
criteria, will receive a RHC at screening, be before the beginning of the intervention. Baseline will 
be within 28 days after screening. 
If, due to organisational reasons, echocardiography cannot be performed at Baseline, it can be 
performed during Screening period and it can be used as baseline value. Echocardiography cannot 
be performed after baseline. 
 
8.3.2 Visit 1 Baseline / Randomization - Day 1 
Baseline visit may be performed according to the hospital’s routine practice as in-hospital stay. 
The baseline visit includes the following assessments/measurements: physical examination, SSc 
characteristics including the WHO-FC, vital signs (blood pressure, heart rate, SpO2), weight, 12-
lead ECG, clinical laboratory (including pregnancy test only for WOCBP), echocardiography, 
6MWD including Borg Dyspnea Score, QoL questionnaire (SF-36), concomitant medications, 
diseases/clinical symptoms and adverse events. If it is not possible to perform all requested 
assessments for visit 1 at one day, it is allowed to split the visit and to conduct the required 
measurements at two consecutive days. If screening and baseline are conducted during the same 
hospital stay following assessments will only be performed once, otherwise at screening and 
baseline: 12-lead ECG, physical examination, concomitant medication, lung function testing, 
DLCO, blood gas analysis pregnancy test (WOCBP only), hematology, chemistry and NT-
proBNP.  
If, due to organisational reasons, echocardiography cannot be performed at Baseline, it can be 
performed during Screening period and it can be used as baseline value. Echocardiography cannot 
be performed after baseline. 
Patient’s eligibility to participate in the trial will be confirmed. Subsequently, patients will be 
randomized. After the explanation of intake and titration, study medication (riociguat (MK-4836) 
or placebo) and the patient diary will be handed out to patients.  
 
8.3.3 Visit 1.1- Visit 1.4 - Titration phase (week 2, 4, 6, 8 ± 2 days) 
Double-blind riociguat (MK-4836) vs. placebo treatment will be initiated and individually adjusted 
according to systolic blood pressure and tolerability. During the titration phase, each patient will 
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per day and document the values in the patient diary. The results will be examined by the 
investigator during each visit/phone call-visit. The patient will be handed out a diary to document 
the blood-pressure at study start (see Appendices). Provided that the systolic blood pressure is ≥ 
95 mmHg measured at trough before intake of each dose and the patient has no signs or symptoms 
of hypotension, the dose of study medication will be titrated by +0.5 mg tid every 2 weeks until 
the maximal tolerated dosage with a maximal permitted dosage of 2.5 mg tid under consideration 
of the titration algorithm (= individual dose titration scheme). After the titration period, blood 
pressure should be measured upon signs or symptoms of hypotension. WOCBP have to perform 
pregnancy tests at home in week 4 (visit 1.2) and 8 (visit 1.4). Adverse events and concomitant 
medication will be recorded. 
To ensure blinding, subjects allocated to the placebo group undergo a sham titration from Visit 1 
onwards that follows the rules of the individual dose titration scheme. Independently of the 
investigator’s decision to increase, maintain or decrease the dose of the study medication blinded 
placebo medication will be allocated. 
 
8.3.4 Visit 2 - 12 weeks assessment (± 7 days) 
During the main study phase (weeks 9-24), all subjects are to remain on their optimal dose of 
riociguat (MK-4836) or placebo. Dose reductions for safety reasons are allowed, but a subsequent 
re-increase during the main study phase is not possible. In case of dose delays, patients may be 
further titrated according to tolerability up to week 12. Clinical evaluations and phone visits are to 
be scheduled according to the physician’s estimation and patient safety.  
Visit 2 procedures/assessments include the following: WHO-FC, vital signs, physical examination, 
laboratory, 6MWD and Borg dyspnea score will be assessed and concomitant medications, weight, 
ECG, drug compliance, adverse events and diseases/clinical symptoms will be recorded. The 
patient dairy will be examined. Unused study drug will be collected and medication for the 
remaining 12 weeks at maintenance dose will be dispensed. 
 
8.3.5 Phone visit 2.1 and phone visit 2.2 – WOCBP only (week 16 and 20 ± 2 days) 
WOCBP have to perform pregnancy tests at home in week 16 (visit 2.1) and 20 (visit 2.2) and the 
results will be assessed by phone.  
 

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8.3.6 Visit 3 – 24 weeks assessment ± 14 days (termination of double-blind study) 
After 24 weeks ± 14 days, patients will be assessed by clinical evaluation. 
Visit 3 procedures/assessments include the following: physical examination, WHO-FC, vital signs, 
laboratory (including pregnancy test only for WOCBP), weight, ECG, lung function test 
(plethysmography and diffusion capacity test), BGA, QoL (SF-36 questionnaire), 6MWD and 
Borg dyspnea score, echocardiogram, right heart catheterization, drug compliance, concomitant 
medications, adverse events and diseases/clinical symptoms will be recorded. Unused study drug 
will be collected and the patient diary examined. 
 
8.3.7 Visit 4 - Safety follow-up 30 days after last IMP intake 
Patients will be contacted via phone 30 days after their last intake of study drug (±14 days). The 
assessment will serve to monitor adverse events, concomitant medication, safety and tolerability, 
and in case of WOCBP pregnancy test results. Clinical follow-up of all SAEs will be performed 
until they have been resolved, if possible. 
8.3.8 Unscheduled visit 
Unscheduled visits may be performed at any time during the study. Depending on the reason for 
the unscheduled visit (e.g., AE), appropriate assessments will be performed based on the judgment 
of the investigator, and the AEs will be recorded in the eCRF. After an unscheduled visit, the 
regular scheduled study visits must continue according to the planned visit and assessment 
schedule as originally planned. 
 
8.4 
Methods of Data Collection 
Data will be entered by the center’s study nurses. The data entered in the CRFs will be checked by 
the clinical monitor for data quality and integrity. All data will be entered into one database and 
signed by the principal investigator or study physician. Data management will perform data 
cleaning (e.g. range checks), pose queries and prepare the data for data analysis.  
 
8.4.1 Efficacy Parameters 
The primary efficacy variable is the change in pulmonary vascular resistance from baseline to 
week 24. 
Secondary efficacy endpoints will be tested hierarchically: 

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• 
change of cardiac index at rest (baseline to 24 weeks) 
• 
change of total pulmonary resistance (baseline to 24 weeks) 
• 
change of diffusion capacity of the lung (baseline to 24 weeks) 
• 
change of 6-minute walking distance (baseline to 24 weeks) 
• 
change of WHO functional class (baseline to 24 weeks) 
• 
change in QoL (SF-36, physical summation score; baseline to 24 weeks) 
 
Exploratory endpoints 
The following parameters will be assessed in every patient according to the visits schedule and 
analyzed as exploratory variables. Exploratory endpoints will be analyzed as change from 
baseline to 12 and to 24 weeks as available according to assessment schedule. 
QoL assessed by the SF-36 questionnaire  
• 
mental summation score as well as the 8 sub scores 
 
WHO functional class 
 
Echocardiography 
• 
systolic pulmonary arterial pressure (sPAP, mmHg), right ventricular area (RV-area, cm2), 
and right atrial area (RA-area, cm2), tricuspid annular plane systolic excursion (TAPSE), left 
ventricular eccentricity index (LV-EI), RV-pump function and LV-pump function (LV-EF, %).   
 
Lung function  
• 
FEV1 (forced expiratory volume in 1 second), TLC (total lung capacity), DLCO (diffusing 
capacity of the lung) 
 
Analyses of blood samples 
Venous blood will be analyzed to determine:  
• 
NT-pro BNP 
 
Blood for blood gas analyses 
• 
oxygen partial pressure, carbon dioxide partial pressure, oxygen saturation of the blood 
(SpO2), pH values, bicarbonates, base excess  
 
Pulmonary hemodynamics by right heart catheterization 
• 
sPAP, mPAP, diastolic pulmonary artery pressure (dPAP), pulmonary artery wedge 
pressure (PAWP), right atrial pressure (RAP), cardiac output and ejection fraction (CO), central 
venous saturation, via blood gas analysis from pulmonary artery (SvO2) 
 
 

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8.4.2 Safety Parameters 
Safety variables include and will be determined: 
1. Electrocardiogram (ECG) 
2. Vital signs: Blood pressure, heart rate/pulse, oxygen saturation 
3. Hemodynamics: Cardiac Output, SvO2 (during RHC) 
4. Echocardiography 
5. Clinical laboratory investigations 
6. Concomitant medication 
7. Concomitant diseases 
8. Adverse events 
 
Clinical worsening will be defined as time to first event out of: 
• 
worsening of WHO functional class 
• 
deterioration of 6MWD >15% compared to baseline 
• 
need of initiation of targeted PAH treatment 
• 
hospitalization due to worsening of right heart function 
• 
all cause death or lung-transplantation 
• 
atrial septostomy 
 
Safety variables 
Laboratory, electrocardiogram, vital signs, assessment of adverse events and serious adverse 
events will serve as safety parameters. 
Patients with a serious adverse event occurring during the study treatment will be followed by the 
study team until the serious adverse event will have resolved to the pre-study level and/or will 
have been addressed according to best clinical practice. Patients withdrawing from the study 
prematurely will have a final examination.  
If a patient withdraws from study treatment and agrees to stay in the study, study related 
examinations will be performed and data will be obtained according to protocol. 
 
8.5 
End of Trial 
The trial will end once the last patient has had their safety follow-up visit by phone 30 ± 14 days 
after last intake of study drug. 
 
8.6 
Plan for Treatment of Care after the Trial 
 Riociguat (MK-4836) is not approved for the indications studied and therefore cannot be further 
prescribed after the end of the study. In case of development of manifest PAH, measured by RHC 

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during Visit 3, a targeted PAH therapy will be initiated according to the guidelines. Otherwise the 
study medication will be discontinued. Patients will be offered a follow-up for 6 more months in 
terms of early detection any clinical deterioration.  
9 
Adverse Events 
9.1 
Definitions 
9.1.1 Adverse Event 
An AE is any unfavorable and unintentional change in the body temporally associated with the use 
of a drug whether or not considered related to the use of the product. A clinically significant 
worsening of a pre-existing condition is also assumed to be an adverse event. AEs may also occur 
subsequent to overdose, improper use, or due to premature withdrawal of a product. 
An AE may be: 
- New symptoms/ medical conditions 
- New diagnosis 
- Significant changes of laboratory parameters 
- Intercurrent diseases and accidents 
- Worsening (change in nature, severity or frequency) of medical conditions/ diseases 
existing before clinical trial start 
- Recurrence of disease 
- Increase of frequency or intensity of episodical diseases. 
- Events related or possibly related to concomitant medications 
A pre-existing disease or symptom will not be considered an adverse event unless there will be an 
untoward change in its intensity, frequency or quality. This change will be documented by an 
investigator. 
Surgical procedures themselves are not AEs; they are therapeutic measures for conditions that 
require surgery. The condition for which the surgery is required may be an AE. Planned surgical 
measures permitted by the clinical trial protocol and the condition(s) leading to these measures are 
not AEs, if the condition leading to the measure was present prior to inclusion into the trial. 
AEs are classified as "non-serious" or "serious". 
All AEs need to be documented in data entry forms and sent to the sponsor. 
 
9.1.2 Serious Adverse Event 
A serious adverse event (SAE) is one that at any dose: 
- Results in death 

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- Is life-threatening (the term life-threatening refers to an event in which the subject was at 
risk of death at the time of event and not to an event which hypothetically might have 
caused death if it was more severe)  
- Requires subject hospitalization or prolongation of existing hospitalization (unless the 
admission results in a stay of less than 12 hours or the admission is pre-planned or the 
admission is not associated with an adverse event) 
- Results in persistent or significant disability/ incapacity or is a congenital anomaly/ birth 
defect. 
- Is another important medical event which may not fulfil the aforementioned criteria but 
may jeopardize the patient based upon appropriate medical judgment. Medical and 
scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations. These should also usually be considered serious (e.g. 
treatment at home for allergic bronchospasm). 
 
The following events don’t need to be reported as an SAE: 
- Planned hospitalization due to scheduled elective catheterization (e.g. scheduled re-
evaluation of pulmonary disease), scheduled hospitalization for further diagnostics or 
therapeutic measures. 
 
9.1.3 Expectedness 
An ‘unexpected’ adverse event is one the nature or severity of which is not consistent with the 
applicable “Summary of Product Characteristics” (SmPC) or scientific literature. Furthermore, 
reports which add significant information on specificity or severity of a known adverse reaction 
constitute ‘unexpected’ events. 
 
9.1.4 Suspected Unexpected Serious Adverse Reaction (SUSAR) 
SAEs that are both suspected, i.e. possibly related to IMP and ‘unexpected’, i.e. the nature and/ or 
severity of which is not consistent with the applicable product information are to be classified as 
Suspected Unexpected Serious Adverse Reactions (SUSARs). The definition covers also 
medication errors and uses outside what is foreseen in the protocol, including misuse and abuse of 
the product. 
In case, either the investigator who primarily reported the SAE or the second assessor classify the 
SAE as ‘suspected’ (i.e. either related or probably or possibly related to the IMP or not assessable) 
and the SAE is unexpected it will be categorized as a SUSAR.  

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All SUSARs are subject to an expedited reporting to the responsible IRB / EC and to all 
participating investigators.  
 
9.1.5 Grading of AEs 
The grading of an AE should be assessed by the investigator according to the 5-grade scale as 
follows: 
Grade 1: 
mild AE, temporary event which is tolerated well by the subject 
Grade 2:  
moderate AE; event which results in discomfort for the subject and impairs his/ her 
normal activity 
Grade 3:  
severe AE; event which results in substantial impairment of normal activities of 
subject 
Grade 4: 
life-threatening AE or AE causing disablement 
Grade 5:  
death related to AE 
 
9.1.6 Relationship and outcome of AEs, action taken 
Causality assessment of an AE/SAE regarding an investigational product (causality) is determined 
and documented by the investigator based on the following criteria: 
definite: 
There is a definite relationship. 
probable: 
An AE that has a reasonable possibility that the event is likely to have been 
caused by IMP. The AE has a timely relationship and follows a known 
pattern of response, but a potential alternative cause may be present. 
possible: 
An AE that has a reasonable possibility that the event may have been 
caused by IMP. The AE has a timely relationship to the IMP; however, 
the pattern of response is untypical, and an alternative cause seems more 
likely, or there is significant uncertainty about the cause of the event. 
unlikely: 
Only a remote connection exists between the IMP and the reported adverse 
event. Other conditions including concurrent illness, progression or 
expression of the disease state or reaction of the concomitant medication 
appear to explain the reported adverse event. 
Definitely not: 
No relationship. An AE that does not follow a reasonable temporal 
sequence related to IMP and is likely to have been produced by the 
subject’s clinical state, other modes of therapy or other known etiology. 
not assessable: 
There is insufficient or incomplete evidence to make a clinical judgement 
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An AE/SAE will be classified as drug-related if the relationship determined by the investigator is 
possible, probable, or definite (causal relationship). 
 
The outcome of an AE at the time of the last observation will be classified as: 
Recovered/ resolved 
all signs and symptoms of an AE disappeared without any sequels at 
the time of the last interrogation 
Recovering/ resolving the intensity of signs and symptoms has been diminishing and/ or 
their clinical pattern has been changing up to the time of the last 
interrogation in a way typical for its resolution 
Not recovered/ 
not resolved 
signs and symptoms of an AE are mostly unchanged at the time of the 
last interrogation 
Recovered/ 
resolved with sequel 
actual signs and symptoms of an AE disappeared but there are sequels 
related to the AE 
Fatal 
resulting in death. If there is more than one adverse event only the 
adverse event leading to death (possibly related) will be characterized 
as ‘fatal‘ 
Unknown 
the outcome is unknown or implausible and the information cannot be 
supplemented or verified 
 
The action taken with the IMP will be assigned to one of the following categories: 
‘Dose not changed’:  no change in the dose of IMP. 
‘Dose reduced’:  
reduction in the dose of IMP. 
‘Dose increased’:  
increase in the dose of IMP. 
‘Drug withdrawn’: 
discontinuation of IMP. 
‘Unknown’:  
the information is unknown or implausible and it cannot be supplemented 
or verified. 
‘Not applicable’:  
the question is implausible (e.g. the subject is dead). 
The term ‘Countermeasures’ refers to the specific actions taken to treat or alleviate adverse events 
or to avoid their sequels. The following categories will be used to categorize the countermeasures 
to adverse events: 
None: 
no action taken 
Drug treatment: 
newly-prescribed medication or change in dose of a medication 
 

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Others: 
other countermeasures, e.g. an operative procedure 
 
9.2 
Period of Observation and Documentation 
All AEs reported by the subject or detected by the investigator, will be collected during the trial 
and must be documented on the appropriate pages of the CRF. AEs must also be documented in 
the subject’s medical records. 
In this trial, all AEs that occur after first administration of the IMP up to the last visit (i.e. follow-
up visit) will be documented on the pages provided in the CRF. AEs will be assessed by the 
investigator using no-leading questions or observed during any visit during the whole study. The 
patient should be motivated to report any AEs by phone to the investigator occurring in between 
study visits. All subjects who have AEs, whether considered associated with the use of the trial 
medication or not, must be monitored to determine the outcome. The clinical course of the AE will 
be followed up until resolution or normalization of changed laboratory parameters or until it has 
changed to a stable condition. 
Each event should be described in detail along with start and stop dates, severity, relationship to 
investigational product, action taken and outcome. 
 
9.3 
 Reporting of Serious Adverse Events by the Investigator 
All SAEs must be reported by the investigator to the responsible Pharmacovigilance Safety Officer 
immediately without exceeding 24 hours after the SAE becomes known to the study team using 
the "Serious Adverse Event" form. The initial report must be as complete as possible, including 
details of the current illness and (serious) adverse event, information regarding onset, end date, 
severity, outcome and action taken with the IMP, an assessment of the causal relationship between 
the event and the trial medication. 
 
All facts which require a benefit-risk reassessment of the study drug have to be reported promptly 
(that is within 15 days at latest) to IRB / EC. This includes particularly: expected SAE with 
unexpected outcome, increase in frequency of clinically relevant SAEs, unexpected SAE with 
assumed causal relationship after finalization of the investigator sponsored study and events which 
probably may harm the safety of the study patients. In the event of premature termination of the 
trial for safety reasons, the sponsor will inform the competent authority and IRB / EC without 
delay within a maximum period of 15 days. 
 

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If measures to protect study patients from immediate danger are taken IRB / EC have to be notified 
immediately. 
 
At the time of the initial report, the investigator will fill in a SAE form comprising the following 
information: 
- 
Patient/subject demographics 
- 
Start and end date of treatment with the IMP 
- 
Nature of the SAE including date of onset, severity and treatment (including 
hospitalization) 
- 
Action taken with respect to the IMP 
- 
Relationship to the IMP in the opinion of the investigator 
- 
Relevant concomitant drug therapy, relevant medical history, relevant test and diagnostic 
procedures  
- 
Outcome (clinical state at time of current observation) 
- 
Recovery date (if available) 
- 
In the case of death, the cause and post-mortem findings (if available). 
 
 
9.4 
Expedited Reporting 
Unexpected SAE with assumed causal relationship (SUSARS) have to be promptly (that is within 
15 days at latest; in case of SAEs, that lead to death or are life threatening: within 7 days and a 
follow up report within further 8 days) reported to all involved investigators and competent IRB / 
EC.  
 
Investigators participating in this trial will report all SAEs to the responsible Pharmacovigilance 
Safety Officer by fax or e-mail using the SAE form as soon as possible but not later than 24 
hours after their notification. 
 
 
Additionally, all serious events as well as all other relevant safety information (e.g. pregnancy) 
have to be reported within one (1) working day following notice to  
MSD SHARP & DOHME GmbH, department of Pharmacovigilance  
Fax No. +49 89 / 4561-1352 or e-mail to Arzneimittelsicherheit@msd.de  
 

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Any requested supporting documentation (e.g. ECG, laboratory results, autopsy report) should be  
sent to the same address stated above. This documentation may only be sent in pseudonymized 
form. The original SAE-reports and all other reports will be kept by the investigator. 
Additionally, a list of all SAEs as well as a report about the safety of the study patients’ needs to 
be submitted annually (or on demand) to the competent IRB / EC during the investigator sponsored 
study. 
 
All initial reports and follow-up information (as many as required) will be pseudonymized and 
sent by fax or via e-mail.  
At the time of the initial report, the investigator will fill in a SAE form comprising the following 
information: 
- Patient/subject demographics 
- Protocol number 
- Start and end date of treatment with the IMP 
- Nature of the SAE including date of onset, severity, chronicity and treatment 
 (including hospitalization) 
- Action taken with respect to test drug 
- Relationship to test drug in the opinion of the investigator 
- Concomitant drug therapy at the time of the adverse event 
- Outcome (if available) 
- Recovery date (if available) 
- In the case of death, the cause and post-mortem findings (if available). 
 
The assessor will fill out a ‘Narrative Second Assessment Form’ for each SAE containing at least 
the following information:  
i) 
Assessment of relationship between SAE and IMP;  
ii) 
Assessment of expectedness of SAE (derived from SmPC);  
iii) 
Assessment of relationship between SAE and underlying disease  
iv) 
Statement if the benefit/ risk assessment for the trial did change as a result of the SAE. 
The expedited reporting (to IRB / EC and investigators) will be carried out by the responsible 
Safety Officer.  
The expedited reporting will be carried out after unblinding. Only SUSARs/SAEs occurring after 
administration of the IMP will undergo expedited reporting. In case of a SUSAR after 

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administration of placebo a decision regarding the need of expedited reporting will be taken after 
deliberation between the assessor and the Principal Investigator. 
 
9.5 
 Emergency Unblinding 
If it is medically imperative to know which trial medication the subject has received, the 
investigator or authorized person should open the emergency envelope. The investigator or the 
person who breaks the blind must record the date and the reasons for doing so in the CRF, in the 
subject’s medical record, and on the emergency envelope. Whenever possible, the Coordinating 
Investigator should be contacted before the blind is broken. 
 
9.6 
Emergency Treatment 
During and following a subject’s participation in the trial, the investigator should ensure that 
adequate medical care is provided to a subject for any AE including clinically significant 
laboratory values. The investigator should inform a subject when medical care is needed for 
intercurrent illness(es) of which the investigator becomes aware. 
In case of clinical worsening and if clinically indicated additional PAH-targeted rescue medication 
will be initiated. 
10 Statistical Procedures 
10.1 Sample Size Calculation 
In this randomized study patients with early pulmonary vascular disease, indicated by either a) 
mPAP ≥25 mmHg with PVR ≥2 to <3 WU and PAWP ≤15 mmHg or b) mPAP 21-<25 mmHg 
with PVR ≥2 WU and PAWP ≤15 mmHg will be randomized into two groups: one group receiving 
riociguat (MK-4836) and one placebo group.  
In the EDITA study (Pan et al. 2019) SSc patients with mildly elevated mPAP 21-24 mmHg 
showed a significant reduction of PVR after 6 months of treatment (control-group 0.02±0.76 vs. 
intervention group -0.59±0.79 WU; effect size 0.77). The changes in PVR were equal to a 
23.87±35.68% reduction in the intervention group and increase by 5.44±36.61% in the control 
group (effect size 0.81).  
A meta-analysis showed an effect size of 0.88 in both PAH and CTEPH (Zhao et al. 2019). 
In the retrospective analysis of patients with CTD-APAH receiving riociguat in PATENT-1 and 
PATENT-2, mean improvement of PVR after 12 weeks was 132±140 dynes*sec*cm-5 in patients 
with SSc (equals 1.65±1.75WU; effect size 0.94; Humbert et al. 2017). Patients with SSc-PAH 
had an effect size of 0.97 (Humbert et al. 2017). 

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In this study, patients with PVR ≥2WU will be included. The use of the effect size of the EDITA 
study for sample size calculation leads most likely to an underestimation of the effect, as in this 
study with ambrisentan most patients showed a PVR <2 WU at baseline. Furthermore, all studies 
reported in the table below had a study duration of 12 weeks. A study duration of 24 weeks will 
lead to a higher effect and reduction of PVR. Therefore, we assume an effect size of 0.87 of 
riociguat (MK-4836) treatment in this study. A comparable effect size for both included subgroups 
is anticipated for this study. 
 
Reference 
Change / difference in PVR 
Effect size Power 
Sample 
size 
without 
dropout 
Pan 2019; 
EDITA 
SSc: 0.61±0.79 WU (Ambrisentan) 
0.77 
80% 
56 
Pan 2019; 
EDITA 
SSc: -23.87±35.68% (n=17) in the 
intervention group and increase by 
5.44±36.61% (n=15) in the control 
(Ambrisentan)  
0.81 
90% 
66 
Zhao 2019 
Meta-analysis 
Riociguat 
PH (PAH and CTEPH): n=695 
(Riociguat) 
0.88 
85% 
50 
Humbert 2017 
CTD-APAH 
from 
PATENT-1 and 2 
SSc: 1.65±1.75 WU 
Other CTD: 3.45±3.54 WU 
(Riociguat) 
0.94 
0.97 
90% 
90% 
50 
48 
A sample size of 58 will lead to n=70 with dropout of 15%. 
 
If the true treatment effect is at least a 30% reduction of PVR (effect size is 0.87), a sample size 
of 29 patients/group (total 58 patients) achieves a statistical power of 90.2% to reject the null 
hypothesis, according to the two-sample student’s t-test, with a type I error of 0.05 (two-sided).  
With the sample size of 70 patients and a dropout of 15% (valid sample size n=58), we achieve a 
90.2% power, if the means of PVR differ by at least 30% and both groups have an equal standard 
deviation of 34.5%. A sample of 70 patients (35 patients in each group), allocated in a 1:1 ratio, 
will therefore be included.  
The primary endpoint will be analyzed by an analysis of covariance (ANCOVA) with baseline 
values as covariates, which has a power advantage over the student’s t-test, achieving a statistical 
power of 90.2% or more. If the preconditions for ANCOVA are not met, a student’s t-test assuming 
unequal variances (Welch-test) will be performed. 
 

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10.2 Definition of Trial Population to be analyzed 
All patients randomized and treated will be valid for the modified intention-to-treat population, 
hence the numbers of patients in the safety and modified intention-to-treat populations will be 
identical. In the modified intention-to-treat analysis set, patients will be analyzed according to the 
group allocation they were randomized into. The primary endpoint will be analyzed in a complete 
case analysis. 
As patients with only mild changes of hemodynamics will be included in this study, it is not 
assumed that the severity of pulmonary vascular disease will affect the participation in the follow-
up examination. A complete case analysis is considered as valid, as participation of the follow-up 
examination is assumed to be completely at random. 
As sensitivity analysis, multiple imputation for the primary endpoint will be performed and 
analyzed.  
A randomized patient is valid for safety / modified intention-to-treat analysis, if at least one dose 
of study medication was administered. 
A patient is valid for the per protocol analysis, if the patient is valid for the safety / modified 
intention-to-treat analysis, has an adequate PVR investigation at baseline and at week 24 or if 
withdrawn due to lack of efficacy has an adequate PVR investigation at any time post-baseline up 
to week 24, and shows no major protocol deviations. 
Major protocol deviations are: 
1. 
Patients who do not meet the inclusion criteria 
2. 
Administration of IMP not according to protocol (e.g. compliance less than 80% or greater 
than 120% (corresponding to an overdose)) 
The above specifications of the analysis populations are in accordance with the recommendations 
given in the ICH-E9 Guideline “Note for guidance on statistical principles for clinical trials”.  
 
 

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10.3 Statistical Methods 
10.3.1 General 
Descriptive statistics 
All variables will be analyzed descriptively with appropriate statistical methods: data 
(demographic and other baseline characteristics, continuous data at each visit and their change to 
baseline) will be listed and trial summary tables will be provided.  
Descriptive statistics will be displayed by treatment, including the usual location and scale 
statistics (mean, median, standard deviation, standard error, first and third quartiles, minimum and 
maximum) and 95% confidence limits of mean and median. 
Frequency tables for qualitative data will be provided. 
Demographic variables and baseline characteristics will be summarized by treatment group for 
both analysis populations (i.e. valid for safety / modified intent to treat analysis (ITT), valid for 
per protocol analysis). Wherever possible (i.e. sufficient sample size), centres will be considered 
for the analyses. 
 
Hypotheses and statistical interference 
Null-Hypothesis (H0):  
 
The means of the changes of the primary endpoint from baseline to follow-up after 24 weeks in 
the treatment and control group are the same. 
Alternative hypothesis (H1):  
The mean change of the primary endpoint from baseline to follow-up after 24 weeks in the 
treatment group differs from the mean change in the control group. 
 
Type I error   
If not mentioned otherwise, all statistical tests will be performed with a type I two-sided error rate 
of α= 0.05  
Efficacy analysis 
The primary efficacy analysis will be performed in patients valid for modified intention-to-treat 
analysis. The per-protocol analysis will be supportive. 
 
 
 

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Primary endpoint  
The evaluation of the primary efficacy endpoint will be the change from baseline to 24 weeks in 
pulmonary vascular resistance. The primary analysis set will be a complete case analysis of the 
modified intention to treat set. 
The main comparison will be the difference in treatment effect between riociguat (MK-4836) and 
placebo. 95% confidence intervals of treatment difference will also be calculated. The primary 
comparison will be an ANCOVA model including baseline scores as covariate.  
If the preconditions for an ANCOVA analysis are not met, the primary endpoint will be analyzed 
by robust, two-sided t-test (Welch-test). 
 
Secondary efficacy variables  
All secondary analyses will be exploratory and will be considered descriptively. Secondary 
parameters at baseline and during follow-up will be compared between groups comparing the 
difference between baseline and follow-up visits. Data will be displayed by means and standard 
deviations, medians and variances with respective 95% confidence intervals. p-values <0.05 will 
be considered as statistically significant.  
Secondary endpoints will be statistically analyzed by a hierarchical testing strategy using the two-
sided student’s t-test with comparison of the differences between riociguat (MK-4836) and 
placebo. 
The sequential testing procedure will be performed for these six secondary efficacy variables, 
strictly in the order listed 
• change of cardiac index at rest (baseline to 24 weeks) 
• change of total pulmonary resistance (baseline to 24 weeks) 
• change of diffusion capacity of the lung (baseline to 24 weeks) 
• change of 6-minute walking distance (baseline to 24 weeks) 
• change of WHO functional class (baseline to 24 weeks) 
• change in QoL (SF-36, physical summation score; baseline to 24 weeks) 
It is assumed that WHO functional class will either remain the same, improve by one or two 
categories, or deteriorate by one category in most cases. A change score (baseline minus end of 
study) will be calculated, which could go from -3 (class IV at baseline and class I at end of study) 
to +4 (class I at baseline, death at end of study), but in practice for those patients still alive at the 
end of the study it will most likely range from -2 to +1. 
 

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Exploratory endpoints  
Further outcome parameters will be tested exploratory and reported with 95% confidence intervals 
of the difference between changes in the intervention and placebo group, mean and standard 
deviation of the mean. Parameters will be analyzed as change from baseline to 24 weeks riociguat 
(MK-4836) vs. placebo; if available as per visit and assessment schedule, changes between 
baseline and 12 weeks will also be analyzed. 
Patients who withdraw from the study will be asked to complete a final examination which will be 
included in the data analysis. 
Parameters for explorative data analysis include 
WHO functional class (baseline to 12 weeks) 
 
Echocardiography 
• 
sPAP, RV-area and RA-area, TAPSE, LV-EI, RV-pump function and LV-EF.   
 
QoL assessed by the short form of the medical outcome questionnaire (SF-36 questionnaire)  
• 
(mental summation score as well as the 8 sub-scores) 
 
Lung function and lung diffusing capacity 
• 
FEV1 (forced expiratory volume in 1 second), TLC (total lung capacity), DLCO 
(diffusing capacity of the lung) 
 
Blood for blood gas analyses: 
• 
oxygen partial pressure, carbon dioxide partial pressure, SpO2, pH values, bicarbonates, 
base excess 
 
Analyses of blood samples: 
• 
NT-pro BNP  
 
Pulmonary hemodynamics by right heart catheterization: 
• CI, sPAP, mPAP, dPAP, PAWP, RAP, PVR, CO, SvO2  

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Sensitivity analyses  
Sensitivity analyses will be performed to investigate the effect on patients with higher vs. lower 
PVR and higher vs. lower mPAP. A multiple imputation strategy will be implied and analyzed for 
the primary endpoint. 
 
Safety analysis 
The safety analysis will be performed in the population valid for safety. All tabulations will be 
descriptive only. Tables will be produced for drug-related treatment-emergent adverse events and 
serious adverse events. Further tables will be produced for serious and/or drug-related treatment-
emergent adverse events. 
Mortality in the 24-week period of the study will be summarized descriptively. Any deaths in the 
study period will be listed, with day of death relative to start and stop of study drug and cause of 
death.  
The safety evaluation of laboratory data will include: 
listings of laboratory data out of normal range, evaluation of the significance if they are out of 
normal range, descriptive analysis of continuous laboratory parameters and their changes from 
baseline by visit and treatment group. Vital signs will be summarized by visit and treatment group. 
 
Clinical worsening (as exploratory safety endpoint) will comprise of the following parameters: 
• worsening of WHO functional class 
• deterioration of 6MWD >15% compared to baseline 
• need of initiation of targeted PAH treatment 
• hospitalization due to worsening of right heart function 
• all cause death or lung-transplantation 
• atrial septostomy 
Biometric analysis will be defined in the statistical analysis plan which has to be authorized before 
data base lock by the biometrician and the Coordinating Investigator. 
 

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11 Data Management 
11.1 Data Collection 
All entries made in the CRF must be verifiable against source documents. The source data 
parameters are to be verified and the identification of the source data must be documented. 
All findings including clinical and laboratory data will be documented in the subject's medical 
record and in the CRF. The investigator is responsible for ensuring that all sections of the CRF are 
completed correctly and that entries can be verified against source data. Any errors should have a 
single line drawn through them so that the original entry remains legible. The correct data should 
be entered at the site with the investigator's signature, date and reason for change to confirm the 
correctness of entries. Self-explanatory corrections need not to be justified. 
The correctness of entries in CRF will be confirmed by dated signature of the responsible 
investigator. 
 
11.2 Data Handling 
After completion of data entry, checks for plausibility, consistency, and completeness of the data 
will be performed. Based on these checks, queries will be produced combined with the queries 
generated by visual control.  
All missing data or inconsistencies will be reported back to the center and clarified by the 
responsible investigator. If no further corrections are to be made in the database it will be declared 
closed and used for statistical analysis. 
 
11.3 Storage and Archiving of Data 
All important trial documents (e.g. CRF) will be archived for at least 25 years after the trial 
termination.  
The investigator(s) will archive all trial data (source data and Investigator Site File (ISF) including 
subject identification list and relevant correspondence) according to the section 4.9 of the ICH 
Consolidated Guideline on GCP E6 (R2) and to local law or regulations. 
 
12 Ethical and Legal Aspects 
12.1 Good Clinical Practice 
The procedures set out in this trial protocol, pertaining to the conduct, evaluation, and 
documentation of this trial, are designed to ensure that all persons involved in the trial abide by 
Good Clinical Practice (GCP) and the ethical principles described in the applicable version of the 

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ICH-GCP E6 (R2) and the Declaration of Helsinki. The trial will be carried out in keeping with 
applicable European, national, local or other relevant legal and regulatory requirements. 
 
12.2 Subject Information and Informed Consent 
Before being admitted to the clinical trial, the subject must consent to participate after the nature, 
scope, and possible consequences of the clinical trial have been explained in a form understandable 
to him or her. The subject must give consent in writing. The signed Informed Consent Form will 
be filed by the investigator. 
A copy of the signed informed consent document must be given to the subject. The documents 
must be in a language understandable to the subject and must specify who informed the subject. 
The subjects will be informed as soon as possible if new information may influence his/her 
decision to participate in the trial. The communication of this information should be documented. 
 
12.3 Confidentiality 
The data obtained in the course of the trial will be treated pursuant to the General Data Protection 
Regulation (GDPR) (EU) 2016/679 and relevant national law. 
During the clinical trial, subjects will be identified solely by means of their initials, year of birth, 
and an individual identification code (subject number, randomization number). Trial findings 
stored on a computer will be stored in accordance with local data protection law and will be 
handled in strictest confidence. For protection of these data, organizational procedures are 
implemented to prevent distribution of data to unauthorized persons. The appropriate regulations 
of EU and national data legislation will be fulfilled in its entirety. 
The subject consents in writing to release the investigator from his/her professional discretion in 
so far as to allow inspection of original data for monitoring purposes by health authorities and 
authorized persons (inspectors, monitors, auditors).  
According to relevant European and national provisions authorized persons (clinical monitors, 
auditors, inspectors) may inspect the subject-related data collected during the trial. 
The investigator will maintain a subject identification list (subject numbers with the corresponding 
subject names) to enable records to be identified. Subjects who did not consent to circulate their 
pseudonymized data will not be included into the trial. 
 

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12.4 Responsibilities of the Investigator 
The investigator should ensure that all persons assisting with the trial are adequately informed 
about the protocol, any amendments to the protocol, the trial treatments, and their trial-related 
duties and functions. 
The investigator should maintain a list of sub-investigators and other appropriately qualified 
persons to whom he or she has delegated significant trial-related duties. 
 
12.5 Approval of Trial Protocol and Amendments 
Before the start of the trial, the trial protocol, informed consent document, and any other 
appropriate documents will be submitted to the competent IRB / EC for all participating centers.  
A written favorable vote of the respective EC and an (implicit) approval by the competent IRB are 
a prerequisite for initiation of this clinical trial. The statement of EC should contain the title of the 
trial, the trial code, the trial site, and a list of reviewed documents. It must mention the date on 
which the decision was made and must be officially signed by a committee member. This 
documentation must also include a list of members of the EC present on the applicable EC meeting 
and a GCP compliance statement. 
Before the first subject is enrolled in the trial, all ethical and legal requirements must be met. All 
planned substantial changes  will be submitted to IRB / EC in writing as protocol amendments, if 
required by applicable law.  
The investigator will keep a record of all communication with IRB / EC. 
 
12.6 Continuous Information to Independent Ethics Committee 
If required by national law, IRB / EC will be informed of all suspected unexpected serious adverse 
reactions (SUSARs). Both institutions will be informed in case the risk/ benefit assessment did 
change or any others new and significant hazards for subjects’ safety or welfare did occur. 
Furthermore, a report on all observed serious adverse events (SAEs) will be submitted once a year 
– Development Safety Update Report (DSUR). 
IRB / EC must be informed of the end of the trial. They will be provided with a summary of trial 
results within one year after the end of clinical phase, i.e. after last subject out (LSO). 
 
12.7 Notification of Regulatory Authorities 
The local regulatory authorities responsible for each particular investigator will be informed before 
the beginning, during and at the end of the trial according to the applicable regulations.  
 

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12.8 Registration of the Trial 
Prior to the beginning of the clinical phase (FPI) the coordinating/ principal investigator will 
register the trial at the EU Clinical Trials Register (https://www.clinicaltrialsregister.eu/) . Thus, 
the trial will be given a unique EudraCT number, which is a prerequisite for a publication in a 
peer-review paper.  
 
12.9 Insurance 
Sponsor must subscribe to an insurance policy covering its legal liability for injuries caused to 
participating persons and arising out of this research performed strictly in accordance with the 
scientific protocol as well as with applicable law and professional standards.  
 
Any impairment of health which might occur in consequence of trial participation must be notified 
to the insurance company named in the patient’s informed consent form. The subject is responsible 
for notification. The insured person will agree with all appropriate measures serving for 
clarification of the cause and the extent of damage as well as the reduction of damage. 
During the conduct of the trial, the subject must not undergo other clinical treatment except for 
cases of emergency. The subject is bound to inform the investigator immediately about any adverse 
events and additionally drugs taken. The terms and conditions of the insurance should be delivered 
to the subject. 
The insurance company has to be informed about all amendments that could affect subjects’ safety. 
 
13 Quality Assurance 
13.1 Monitoring  
Monitoring will be done by personal visits from a clinical monitor in order to comply with GCP 
guidelines. The center will be visited at regular intervals by a monitor to ensure compliance with 
the study protocol, GCP and legal aspects.  
The monitor will review the entries into the CRFs on the basis of source documents. This will 
include on-site checking of the CRF for completeness and clarity, cross-checking with source 
documents, and clarification of administrative matters. The investigator must allow the monitor to 
verify all essential documents including source documents and must provide support at all times 
to the monitor. 
By frequent communications (letters, telephone, fax), the site monitor will ensure that the trial is 
conducted according to the protocol and regulatory requirements. 

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13.2 Quality checks  
Quality checks will be done by review of the entries into the CRFs. This will include checking of 
the CRF/data for completeness and clarity, cross-checking for plausibility.  
 
13.3 Inspections/ Audits  
Regulatory authorities may request access to all source documents, CRF, and other trial 
documentation. Direct access to these documents must be guaranteed by the investigator who must 
provide support at all times for these activities. 
 
14 Agreements 
14.1 Financing of the Trial 
The trial will be co-financed using funds of MSD SHARP&DOHME GmbH Germany.  
This funding source had no role in the design of this study and will not have any role during 
analyses, interpretation of the data, or decision to submit results. 
 
14.2 Financial Disclosure 
Before the start of the trial, the investigator will disclose any proprietary or financial interests he 
or she might hold in the sponsors/ a funding company, in the investigational product(s) or any 
commercial organization being involved in the clinical trial. The investigator has also to confirm 
that he/she has not entered into any financial arrangement, whereby the value of compensation 
paid could affect the outcome of the clinical trial. 
The investigator agrees to update this information in case of significant changes.  
 
14.3 Reports 
The Biometrician will prepare the biometrical report. The final trial report will be prepared by the 
biometrician and the independent Steering Committee members.  
 
14.4 Publication 
All information concerning the trial is confidential before publication, which will be coordinated 
by the independent steering committee members of the trial.  
 

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15 Sponsor Signatures 
The present trial protocol was subject to critical review and has been approved in the present 
version by the persons undersigned. The information contained is consistent with: 
- 
the current risk-benefit assessment of the investigational medicinal product 
- 
The moral, ethical, and scientific principles governing clinical research as set out in the 
applicable version of Declaration of Helsinki and the principles of GCP. 
The investigator will be supplied with details of any significant or new finding including AEs 
relating to treatment with the investigational medicinal product. 
 
 
 
 
 
 
Date: 
Signature:
 
Name (block letters):  
Sebastian Frank 
Function: 
 
 
Sponsor; manager Thoraxklinik Heidelberg gGmbH 
 
 
Date: 
Signature:
 
Name (block letters):  
Prof. Dr. med. Ekkehard Grünig 
Function: 
 
 
Coordinating Investigator/ Investigator  
 
 
Date: 
Signature:
 
Name (block letters):  
Function: 
 
 
Biometrician  
 

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16 Declaration of Investigator 
I have read the above trial protocol and confirm that it contains all information to conduct the 
clinical trial. I pledge to conduct the clinical trial according to the protocol. 
I will enroll the first subject only after all ethical and regulatory requirements are fulfilled. I pledge 
to obtain written consent for trial participation from all subjects. 
I know the requirements for accurate notification of serious adverse events and I pledge to 
document and notify such events as described in the protocol. 
I pledge to retain all trial-related documents and source data as described. I will provide a 
Curriculum Vitae (CV) before trial start. I agree that the CV may be submitted to the responsible 
regulatory authorities 
 
 
Date:______________ 
Signature:_____________________________ 
 
Name (block letters):  
______________________________________ 
Function: 
 
 
Investigator 
 
Trial Center (address): 
______________________________________ 
 
 
 
 
______________________________________ 
______________________________________ 
 
 
 
 
 

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Jacobsen S, Khanna D, Lerstrøm K, Massarotti E, McCune J, Ruiz-Irastorza G, Sanchez-Guerrero J, 
Schneider M, Urowitz M, Bertsias G, Hoyer BF, Leuchten N, Tani C, Tedeschi SK, Touma Z, Schmajuk G, 
Anic B, Assan F, Chan TM, Clarke AE, Crow MK, Czirják L, Doria A, Graninger W, Halda-Kiss B, Hasni 
S, Izmirly PM, Jung M, Kumánovics G, Mariette X, Padjen I, Pego-Reigosa JM, Romero-Diaz J, Rúa-
Figueroa Fernández Í, Seror R, Stummvoll GH, Tanaka Y, Tektonidou MG, Vasconcelos C, Vital EM, 
Wallace DJ, Yavuz S, Meroni PL, Fritzler MJ, Naden R, Dörner T, Johnson SR. 2019 European League 
Against Rheumatism/American College of Rheumatology Classification Criteria for Systemic Lupus 
Erythematosus. Arthritis Rheumatol. 2019;71(9):1400-1412. 
Coghlan JG, Wolf M, Distler O, Denton CP, Doelberg M, Harutyunova S, Marra AM, Benjamin N, Fischer C, Grünig 
E. Incidence of pulmonary hypertension and determining factors in patients with systemic sclerosis. Eur 
Respir J. 2018;51(4). 
Galiè N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, Simonneau G, Peacock A, Vonk Noordegraaf A, 
Beghetti M, Ghofrani A, Gomez Sanchez MA, Hansmann G, Klepetko W, Lancellotti P, Matucci M, 
McDonagh T, Pierard LA, Trindade PT, Zompatori M, Hoeper M. 2015 ESC/ERS Guidelines for the 
Diagnosis and Treatment of Pulmonary Hypertension. Rev Esp Cardiol (Engl Ed). 2016;69(2):177. 
Galiè N, Müller K, Scalise AV, Grünig E. PATENT PLUS: a blinded, randomised and extension study of riociguat 
plus sildenafil in pulmonary arterial hypertension. Eur Respir J. 2015;45(5):1314-22 
Ghofrani HA, Galiè N, Grimminger F, Grünig E, Humbert M, Jing ZC, Keogh AM, Langleben D, Kilama MO, Fritsch 
A, Neuser D, Rubin LJ; PATENT-1 Study Group. Riociguat for the treatment of pulmonary arterial 
hypertension. N Engl J Med. 2013;369(4):330-40. 
Ghofrani HA, D'Armini AM, Grimminger F, Hoeper MM, Jansa P, Kim NH, Mayer E, Simonneau G, Wilkins MR, 
Fritsch A, Neuser D, Weimann G, Wang C; CHEST-1 Study Group. Riociguat for the treatment of chronic 
thromboembolic pulmonary hypertension. N Engl J Med. 2013;369(4):319-29 
Grünig E, Barner A, Bell M, Claussen M, Dandel M, Dumitrescu D, Gorenflo M, Holt S, Kovacs G, Ley S, Meyer 
JF, Pabst S, Riemekasten G, Saur J, Schwaiblmair M, Seck C, Sinn L, Sorichter S, Winkler J, Leuchte HH. 
Non-invasive diagnosis of pulmonary hypertension: ESC/ERS Guidelines with commentary of the Cologne 
Consensus Conference 2010. Dtsch Med Wochenschr. 2010;135 Suppl 3:S67-77.  
Humbert M, Yaici A, de Groote P, Montani D, Sitbon O, Launay D, Gressin V, Guillevin L, Clerson P, Simonneau 
G, Hachulla E. Screening for pulmonary arterial hypertension in patients with systemic sclerosis: clinical 
characteristics at diagnosis and long-term survival. Arthritis Rheum. 2011;63(11):3522-30. 
Humbert, M., G. Kovacs, M. M. Hoeper, R. Badagliacca, R. M. F. Berger, M. Brida, J. Carlsen, A. J. S. Coats, P. 
Escribano-Subias, P. Ferrari, D. S. Ferreira, H. A. Ghofrani, G. Giannakoulas, D. G. Kiely, E. Mayer, G. 
Meszaros, B. Nagavci, K. M. Olsson, J. Pepke-Zaba, J. K. Quint, G. Radegran, G. Simonneau, O. Sitbon, T. 
Tonia, M. Toshner, J. L. Vachiery, A. Vonk Noordegraaf, M. Delcroix, S. Rosenkranz, and Esc Ers Scientific 
Document Group. 2022. '2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary 
hypertension', Eur Heart J, 43: 3618-731.  
Jaafar S, Visovatti S, Young A, Huang S, Cronin P, Vummidi D, McLaughlin V, Khanna D. Impact of the revised 
haemodynamic definition on the diagnosis of pulmonary hypertension in patients with systemic sclerosis. 
Eur Respir J. 2019;54(2). 
Kovacs G, Berghold A, Scheidl S, Olschewski H. Pulmonary arterial pressure during rest and exercise in healthy 
subjects: a systematic review. Eur Respir J. 2009;34(4):888-94. 
Kovacs G, Maier R, Aberer E, Brodmann M, Graninger W, Kqiku X, Scheidl S, Tröster N, Hesse C, Rubin L, 
Olschewski H. Pulmonary arterial hypertension therapy may be safe and effective in patients with systemic 
sclerosis and borderline pulmonary artery pressure. Arthritis Rheum. 2012;64(4):1257-62 

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Marra AM, Egenlauf B, Ehlken N, Fischer C, Eichstaedt C, Nagel C, Bossone E, Cittadini A, Halank M, Gall H, 
Olsson KM, Lange TJ, Grünig E. Change of right heart size and function by long-term therapy with riociguat 
in patients with pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. Int J 
Cardiol. 2015;195:19-26. 
Marra AM, Halank M, Benjamin N, Bossone E, Cittadini A, Eichstaedt CA, Egenlauf B, Harutyunova S, Fischer C, 
Gall H, Ghofrani HA, Hoeper MM, Lange TJ, Olsson KM, Klose H, Grünig E. Right ventricular size and 
function under riociguat in pulmonary arterial hypertension and chronic thromboembolic pulmonary 
hypertension (the RIVER study). Respir Res. 2018;19(1):258. 
McLaughlin VV, Jansa P, Nielsen-Kudsk JE, Halank M, Simonneau G, Grünig E, Ulrich S, Rosenkranz S, Gómez 
Sánchez MA, Pulido T, Pepke-Zaba J, Barberá JA, Hoeper MM, Vachiéry JL, Lang I, Carvalho F, Meier C, 
Mueller K, Nikkho S, D'Armini AM. Riociguat in patients with chronic thromboembolic pulmonary 
hypertension: results from an early access study. BMC Pulm Med. 2017;17(1):216. 
Nagel C, Marra AM, Benjamin N, Blank N, Cittadini A, Coghlan G, Distler O, Denton CP, Egenlauf B, Fiehn C, 
Fischer C, Harutyunova S, Hoeper MM, Lorenz HM, Xanthouli P, Bossone E, Grünig E. Reduced Right 
Ventricular Output Reserve in Patients With Systemic Sclerosis and Mildly Elevated Pulmonary Artery 
Pressure. Arthritis Rheumatol. 2019;71(5):805-816. 
Opitz CF, Blindt R, Blumberg F, Borst MM, Bruch L, Leuchte HH, Lichtblau M, Nagel C, Peters K, Rosenkranz S, 
Schranz D, Skowasch D, Tiede H, Weil J, Ewert R. Pulmonary hypertension: Hemodynamic evaluation. 
Updated Recommendations of the Cologne Consensus Conference 2011. Int J Cardiol. 2011;154 Suppl 
1:S13-9. 
Pan Z, Marra AM, Benjamin N, Eichstaedt CA, Blank N, Bossone E, Cittadini A, Coghlan G, Denton CP, Distler O, 
Egenlauf B, Fischer C, Harutyunova S, Xanthouli P, Lorenz HM, Grünig E. Early treatment with ambrisentan 
of mildly elevated mean pulmonary arterial pressure associated with systemic sclerosis: a randomized, 
controlled, double-blind, parallel group study (EDITA study). Arthritis Res Ther. 2019;21(1):217. 
Rubin LJ, Galiè N, Grimminger F, Grünig E, Humbert M, Jing ZC, Keogh A, Langleben D, Fritsch A, Menezes F, 
Davie N, Ghofrani HA. Riociguat for the treatment of pulmonary arterial hypertension: a long-term extension 
study (PATENT-2). Eur Respir J. 2015;45(5):1303-13. 
Rudski LG, Lai WW, Afilalo J, Hua L, Handschumacher MD, Chandrasekaran K, Solomon SD, Louie EK, Schiller 
NB. Guidelines for the echocardiographic assessment of the right heart in adults: a report from the American 
Society of Echocardiography endorsed by the European Association of Echocardiography, a registered 
branch of the European Society of Cardiology, and the Canadian Society of Echocardiography. J Am Soc 
Echocardiogr. 2010;23(7):685-713. 
Shiboski CH, Shiboski SC, Seror R, Criswell LA, Labetoulle M, Lietman TM, Rasmussen A, Scofield H, Vitali C, 
Bowman SJ, Mariette X; International Sjögren's Syndrome Criteria Working Group. 2016 American College 
of Rheumatology/European League Against Rheumatism classification criteria for primary Sjögren's 
syndrome: A consensus and data-driven methodology involving three international patient cohorts. Ann 
Rheum Dis. 2017;76(1):9-16. 
Simonneau G, Montani D, Celermajer DS, Denton CP, Gatzoulis MA, Krowka M, Williams PG, Souza R. 
Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J. 
2019;53(1). 
Valerio CJ, Schreiber BE, Handler CE, Denton CP, Coghlan JG. Borderline mean pulmonary artery pressure in 
patients with systemic sclerosis: transpulmonary gradient predicts risk of developing pulmonary 
hypertension. Arthritis Rheum. 2013;65(4):1074-84. 
van den Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall A, Matucci-Cerinic M, Naden RP, Medsger 
TA Jr, Carreira PE, Riemekasten G, Clements PJ, Denton CP, Distler O, Allanore Y, Furst DE, Gabrielli A, 
Mayes MD, van Laar JM, Seibold JR, Czirjak L, Steen VD, Inanc M, Kowal-Bielecka O, Müller-Ladner U, 
Valentini G, Veale DJ, Vonk MC, Walker UA, Chung L, Collier DH, Csuka ME, Fessler BJ, Guiducci S, 
Herrick A, Hsu VM, Jimenez S, Kahaleh B, Merkel PA, Sierakowski S, Silver RM, Simms RW, Varga J, 
Pope JE. 2013 classification criteria for systemic sclerosis: an American College of Rheumatology/European 
League against Rheumatism collaborative initiative. Arthritis Rheum. 2013;65(11):2737-47. 
Xanthouli P, Jordan S, Milde N, Marra A, Blank N, Egenlauf B, Gorenflo M, Harutyunova S, Lorenz HM, Nagel C, 
Theobald V, Lichtblau M, Berlier C, Ulrich S, Grünig E, Benjamin N, Distler O. Haemodynamic phenotypes 

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and survival in patients with systemic sclerosis: the impact of the new definition of pulmonary arterial 
hypertension. Ann Rheum Dis. 2020;79(3):370-378. 
Zhao R, Jiang Y. Influence of riociguat treatment on pulmonary arterial hypertension: A meta-analysis of randomized 
controlled trials. Herz. 2019 Nov;44(7):637-643 
 
 
 

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18 Appendices 
SF-36 (English version „Health status questionnaire“), 
Patient diary (English version) 
Patient trial ID-card (English version) 
 
 

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HEALTH STATUS QUESTIONNAIRE  
 
This questionnaire is about your assessment of your health status over the past 4 weeks. The sheet allows 
you to track over time how you are feeling and how you are doing in your daily life. 
 
Please answer each of the following questions by ticking the number that best applies to you in the answer 
options. 
 
2) In general, how would you describe your health over the past 4 weeks? 
 (Please tick only one number). 
 
Excellent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 
 
Very good . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  2 
 
Good . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 
 
Not too good . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 
 
Bad . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 
 
 
2. Compared to a year ago, how would you describe your health a year ago. 
(Please tick only one number) 
 
Currently much better than a year ago. . . . . . . . . . . 1 
 
Currently somewhat better than a year ago. . . . . . . 2 
 
About the same as a year ago. . . . . . . . . . . . . . . . . 3 
 
Currently a little worse than a year ago. . . . . . . . . .  4 
 
Currently much worse than a year ago. . . . . . . . . . . 5 
 

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3. The following are some activities you might do on a normal day. Are you limited by your current health 
condition in these activities? If so, to what extent? 
(Please tick only one number in each line.) 
 
 
 
ACTIVITIES 
 
Yes, 
very 
limited 
 
Yes, 
somewhat 
limited 
 
No, not 
limited at all 
 
a. exhausting activities, e.g. running fast, 
    lifting heavy objects, strenuous sports 
 
 
1 
 
 
2 
 
 
3 
 
b.  moderately difficult activities, e.g. moving a 
table, vacuuming, bowling, playing golf, etc. 
 
 
1 
 
 
2 
 
 
3 
 
c.  Lifting or carrying shopping bags 
 
1 
 
2 
 
3 
 
d.  climbing several staircases 
 
1 
 
2 
 
3 
 
e.  climbing a staircase 
 
1 
 
2 
 
3 
 
f.  bending, kneeling, crouching 
 
1 
 
2 
 
3 
 
g.  walking more than 1 kilometer 
 
1 
 
2 
 
3 
 
h.  walking across several intersections 
 
1 
 
2 
 
3 
 
i.  walking across an intersection 
 
1 
 
2 
 
3 
 
j.  bathing or getting dressed 
 
1 
 
2 
 
3 
 

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4. In the past 4 weeks, have you had any difficulties at work or other daily activities at work or at home 
because of your physical health? 
(Please tick only one number in each line) 
 
 
DIFFICULTIES 
 
 
YES 
 
NO 
 
a. 
I could not work as long as usual 
 
1 
 
2 
 
b. 
I have managed less than I wanted 
 
1 
 
2 
 
c. 
I could do only certain things 
 
1 
 
2 
 
d. 
I had difficulties performing  (e.g. I had to make an extra effort) 
 
1 
 
2 
 
5. In the past 4 weeks, did you have any difficulties at work or other daily activities at work or at home 
due to mental health problems (e.g., because you felt down or anxious)? 
 (Please mark only one number in each line) 
 
 
DIFFICULTIES 
 
 
YES 
 
NO 
 
a. 
I could not work as long as usual 
 
1 
 
2 
 
b. 
I have managed less than I wanted 
 
1 
 
2 
 
c. 
I could not work as carefully as usual 
 
1 
 
2 
 
 
 

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6. During the past 4 weeks, how much have your physical health or mental health problems affected your 
normal contacts with family members, friends, neighbors, or acquaintances 
 (Please tick only one number) 
 
Not at all . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 
 
A little . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  2 
 
Moderately . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 
 
Pretty much . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  4 
 
Very much . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  5 
 
7. How severe has your pain been in the past 4 weeks? 
 (Please tick only one number) 
 
I have not had any pain. . . . . . . . . . . . . . . . . . . . . . . 1 
 
Very slight. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 
 
Slight . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 
 
Moderate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  4 
 
Severe . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 
 
Very severe . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 
 
8. In the past 4 weeks, to what extent has the pain interfered with you performing your daily activities at 
home and at work? 
 (Please tick only one number) 
 
Not at all . . . . . . . . . . . . . . . . . . . . . . . . . . . .  . . . . . 1 
 
A little . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 
 
Moderately . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 
 
Pretty much . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 
 
Very much. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 
 
 
9. These questions are about how you are feeling and how you have been feeling over the past 4 weeks. 
(Please tick the number in each line that most accurately reflects how you are feeling). In the past 4 weeks, 
how often have you been.... 
(Please tick only one number in each line). 

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PERSONAL FEELING 
 
always 
 
 
mostly 
 
quite often 
 
sometimes 
 
rarely 
 
never 
 
a.    ... full of vim and vigor? 
 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
b.    ...very nervous? 
 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
c.    ... so depressed, that nothing 
could have cheered you up? 
 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
d.    ... calm and relaxed? 
 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
e.    ...full of energy? 
 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
f.    ... discouraged and sad? 
 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
g.    ...exhausted? 
 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
h.    ...happy? 
 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
i.    ...tired? 
 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
 
 

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10. In the past 4 weeks, how often have your physical health or mental health problems affected your 
contacts with other people (visits to friends, relatives, etc.)? 
 (Please tick only one number) 
 
Always . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 
 
Mostly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 
 
Sometimes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 
 
Rarely . . . . .  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 
 
Never . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 
 
 
11. To what extent does each of the following statements apply to you? 
 (Please tick only one number in each line) 
 
STATEMENT 
absolutely 
true 
Largely 
true 
I do not 
know 
Largely 
not true 
Not 
true 
at all 
 
a.  I seem to get sick a little easier than  
others 
 
1 
 
2 
 
3 
 
4 
 
5 
 
b.  I am as healthy as everyone else I know 
 
1 
 
2 
 
3 
 
4 
 
5 
 
c.  I expect my health to decline 
 
1 
 
2 
 
3 
 
4 
 
5 
 
d. I am in excellent health 
 
1 
 
2 
 
3 
 
4 
 
5 
 
 
 

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Patient diary (English version) 
 
Title page 
Patient Diary 
Study name: ESRA 
Center no.: ………………………………………. 
Patient no.: ………………………………………. 
Randomization-no.: ………………………………………. 
Next study visit: ………………………………………. 
Please bring this diary with you to every study visit. 
 
 

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User instructions for taking the study medication: ESRA. 
The study medication must be kept only in the original bottle (inaccessible to children). 
The study medication must be taken three times a day, always at the same time of day, 
independently of meals: 
• Please record the date and time of taking the tablets in the patient diary until visit 3. One diary page is 
provided for each month (Table 1 of diary). 
• Tablets should be taken in the morning, at noon and in the evening at intervals of at least 6 hours apart. 
• Please bring any tablets you do not need back to the clinic using the original bottle. 
 
• Blood pressure measurements at home: Since the drug may lower blood pressure, we would like to ask 
you to measure your blood pressure with your device three times a day (morning, noon and evening) 
during the study for the first 8 weeks (titration phase) until you reach the dosage you tolerate best (target 
dose). After measuring your blood pressure, please record the upper and lower readings (syst. / diast.) 
as well as the pulse with date and time of the measurement in the patient diary (Table 1 of the diary). 
Please bring the diary with the measured values to all visits at the clinic. In addition, we will ask for the 
values during the telephone visits every two weeks (weeks 2, 4, 6 and 8) and enter them into our database. 
If the blood pressure values are lowered too far by the medication, it is not possible to increase the 
medication dose any further. Therefore, the measurements are important for therapy adjustment. After 
reaching the target dose, it is sufficient to measure the blood pressure only when necessary, e.g. when 
one feels unwell or other complaints occur. In preparation for the telephone visits, please complete Table 
2 of the patient diary. 
• Home pregnancy test: women will perform a home pregnancy test in the morning before the telephone 
visits at weeks 4, 8, 16, 20 and for telephone follow-up 30 days after the end of the study. Please record 
the result (negative or positive) as well as date and time of the test in the patient diary (Table 2 of the 
diary). A single table is provided for all telephone visits. Pregnancy tests will be provided to you in advance 
by your study team. 
 
Please note: 
If possible, always take the study medication at the same time of day. If you forget to take it at one point in 
time, do not take a double dose at the next point in time. The bottles of tablets you will receive will last until 
your next visit to the hospital. 
Please take the medicine three times a day. 
 
 

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Center No.:  
Patient No.: 
Month/Year: 
Diary - Table 1: Tablet intake and vital parameters 
Day 
Dose and time of tablet intake  
Vital parameters (VP)=blood pressure and pulse (VP) from week 0-8 only. 
 
morning 
hh:mm 
blood pressure/pulse 
noon 
hh:mm 
blood pressure/pulse 
evening 
hh:mm 
blood pressure/pulse 
comments 
1 
_____mg 
___:___ 
_____mg 
___:___ 
_____mg 
___:___ 
 
VP 
___/___mmHg 
___/min 
___/___mmHg 
___/min 
___/___mmHg 
___/min 
 
2 
_____mg 
___:___ 
_____mg 
___:___ 
_____mg 
___:___ 
 
VP 
___/___mmHg 
___/min 
___/___mmHg 
___/min 
___/___mmHg 
___/min 
 
3 
_____mg 
___:___ 
_____mg 
___:___ 
_____mg 
___:___ 
 
VP 
___/___mmHg 
___/min 
___/___mmHg 
___/min 
___/___mmHg 
___/min 
 
4 
_____mg 
___:___ 
_____mg 
___:___ 
_____mg 
___:___ 
 
VP 
___/___mmHg 
___/min 
___/___mmHg 
___/min 
___/___mmHg 
___/min 
 
5 
_____mg 
___:___ 
_____mg 
___:___ 
_____mg 
___:___ 
 
VP 
___/___mmHg 
___/min 
___/___mmHg 
___/min 
___/___mmHg 
___/min 
 
6 
_____mg 
___:___ 
_____mg 
___:___ 
_____mg 
___:___ 
 
VP 
___/___mmHg 
___/min 
___/___mmHg 
___/min 
___/___mmHg 
___/min 
 
7 
_____mg 
___:___ 
_____mg 
___:___ 
_____mg 
___:___ 
 
VP 
___/___mmHg 
___/min 
___/___mmHg 
___/min 
___/___mmHg 
___/min 
 
8 
_____mg 
___:___ 
_____mg 
___:___ 
_____mg 
___:___ 
 
VP 
___/___mmHg 
___/min 
___/___mmHg 
___/min 
___/___mmHg 
___/min 
 
9 
_____mg 
___:___ 
_____mg 
___:___ 
_____mg 
___:___ 
 
VP 
___/___mmHg 
___/min 
___/___mmHg 
___/min 
___/___mmHg 
___/min 
 
10 
_____mg 
___:___ 
_____mg 
___:___ 
_____mg 
___:___ 
 
VP 
___/___mmHg 
___/min 
___/___mmHg 
___/min 
___/___mmHg 
___/min 
 
11 
_____mg 
___:___ 
_____mg 
___:___ 
_____mg 
___:___ 
 
VP 
___/___mmHg 
___/min 
___/___mmHg 
___/min 
___/___mmHg 
___/min 
 
12 
_____mg 
___:___ 
_____mg 
___:___ 
_____mg 
___:___ 
 
VP 
___/___mmHg 
___/min 
___/___mmHg 
___/min 
___/___mmHg 
___/min 
 
13 
_____mg 
___:___ 
_____mg 
___:___ 
_____mg 
___:___ 
 
VP 
___/___mmHg 
___/min 
___/___mmHg 
___/min 
___/___mmHg 
___/min 
 
14 
_____mg 
___:___ 
_____mg 
___:___ 
_____mg 
___:___ 
 
VP 
___/___mmHg 
___/min 
___/___mmHg 
___/min 
___/___mmHg 
___/min 
 
15 
_____mg 
___:___ 
_____mg 
___:___ 
_____mg 
___:___ 
 
VP 
___/___mmHg 
___/min 
___/___mmHg 
___/min 
___/___mmHg 
___/min 
 
16 
_____mg 
___:___ 
_____mg 
___:___ 
_____mg 
___:___ 
 
VP 
___/___mmHg 
___/min 
___/___mmHg 
___/min 
___/___mmHg 
___/min 
 
17 
_____mg 
___:___ 
_____mg 
___:___ 
_____mg 
___:___ 
 
VP 
___/___mmHg 
___/min 
___/___mmHg 
___/min 
___/___mmHg 
___/min 
 
18 
_____mg 
___:___ 
_____mg 
___:___ 
_____mg 
___:___ 
 
VP 
___/___mmHg 
___/min 
___/___mmHg 
___/min 
___/___mmHg 
___/min 
 

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19 
_____mg 
___:___ 
_____mg 
___:___ 
_____mg 
___:___ 
 
VP 
___/___mmHg 
___/min 
___/___mmHg 
___/min 
___/___mmHg 
___/min 
 
20 
_____mg 
___:___ 
_____mg 
___:___ 
_____mg 
___:___ 
 
VP 
___/___mmHg 
___/min 
___/___mmHg 
___/min 
___/___mmHg 
___/min 
 
21 
_____mg 
___:___ 
_____mg 
___:___ 
_____mg 
___:___ 
 
VP 
___/___mmHg 
___/min 
___/___mmHg 
___/min 
___/___mmHg 
___/min 
 
22 
_____mg 
___:___ 
_____mg 
___:___ 
_____mg 
___:___ 
 
VP 
___/___mmHg 
___/min 
___/___mmHg 
___/min 
___/___mmHg 
___/min 
 
23 
_____mg 
___:___ 
_____mg 
___:___ 
_____mg 
___:___ 
 
VP 
___/___mmHg 
___/min 
___/___mmHg 
___/min 
___/___mmHg 
___/min 
 
24 
_____mg 
___:___ 
_____mg 
___:___ 
_____mg 
___:___ 
 
VP 
___/___mmHg 
___/min 
___/___mmHg 
___/min 
___/___mmHg 
___/min 
 
25 
_____mg 
___:___ 
_____mg 
___:___ 
_____mg 
___:___ 
 
VP 
___/___mmHg 
___/min 
___/___mmHg 
___/min 
___/___mmHg 
___/min 
 
26 
_____mg 
___:___ 
_____mg 
___:___ 
_____mg 
___:___ 
 
VP 
___/___mmHg 
___/min 
___/___mmHg 
___/min 
___/___mmHg 
___/min 
 
27 
_____mg 
___:___ 
_____mg 
___:___ 
_____mg 
___:___ 
 
VP 
___/___mmHg 
___/min 
___/___mmHg 
___/min 
___/___mmHg 
___/min 
 
28 
_____mg 
___:___ 
_____mg 
___:___ 
_____mg 
___:___ 
 
VP 
___/___mmHg 
___/min 
___/___mmHg 
___/min 
___/___mmHg 
___/min 
 
29 
_____mg 
___:___ 
_____mg 
___:___ 
_____mg 
___:___ 
 
VP 
___/___mmHg 
___/min 
___/___mmHg 
___/min 
___/___mmHg 
___/min 
 
30 
_____mg 
___:___ 
_____mg 
___:___ 
_____mg 
___:___ 
 
VP 
___/___mmHg 
___/min 
___/___mmHg 
___/min 
___/___mmHg 
___/min 
 
31 
_____mg 
___:___ 
_____mg 
___:___ 
_____mg 
___:___ 
 
VP 
___/___mmHg 
___/min 
___/___mmHg 
___/min 
___/___mmHg 
___/min 
 
 
 

EudraCT: 2021-001633-40 
 
Version 1.7  
15.01.2025  
ESRA 
 
85 
Diary - Table 2: Telephone visits 
Week 
 
Tolerability 
Women: Pregnancy test 
result and time 
 
systolic blood pressure /         side effects 
(upper value) ≥95 mmHg 
neg. /                     morning 
pos.                         hh:mm 
comments 
2 
 yes   no 
 yes   no 
 
 
 
4 
 yes   no 
 yes   no 
 
___:___ 
 
6 
 yes   no 
 yes   no 
 
 
 
8 
 yes   no 
 yes   no 
 
___:___ 
 
16 
 
 
 
___:___ 
 
20 
 
 
 
___:___ 
 
Follow-up  
 
 
 
___:___ 
 
 
 

EudraCT: 2021-001633-40 
 
Version 1.7  
15.01.2025  
ESRA 
 
86 
 
 
 
 
 
This patient participates in the study 
“Efficacy and safety of riociguat (MK-4836) in incipient pulmonary vascular disease 
as an indicator for early pulmonary arterial hypertension 
Double-blind, randomized, multicenter, multinational, placebo-controlled phase IIa 
study (ESRA)” 
Investigational drug: riociguat (MK-4836) vs. placebo 
Eudra-CT: 2021-001633-40 
For questions please contact  
Name________________________ Phone ____________________________ 
 
Name 
 
 
______________________ 
 
Surname 
 
 
______________________ 
 
Patient trial ID-card 
ESRA trial 
Study Center (Stamp):